RADIATION

ONCOLOGY NOTES
FOR QUICK PART 1

REVISION

Dr Dulasiraman PGT, RIMS,

RADIOTHERAPY DEPT.
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CONTENTS

1. Basic Physics

2. Radioisotopes

3. Electron Beam Therapy

4. Techniques : TBI, CSI

5. Modern Radiotherapy

6. Radiobiology

7. Molecular Biology and Neoplasia

8. Tobacco and Cancer

9. Screening

10. Palliative Oncology

11. Chemotherapy, Targeted Therapy and MABs

12. Anatomy and Classifications

13. General Topics

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RADIATION PHYSICS , RADIOBIOLOGY AND GENERAL RADIOTHERAPY

1. Define Radioactivity, Half life, Effective Half life, Biological Half life, Decay constant.

Radioactivity :

 Radioactivity is a phenomenon in which radiation is given off by the nuclei of the elements.

 This radiation can be in the form of particles, electromagnetic radiation, or both.

 The unit of activity is the curie (Ci), defined as: 1 Ci = 3.7 × 1010 disintegrations/sec (dps).

 The SI unit for activity is the becquerel (Bq).

Half life :

 Physical Half Life : The term half-life (T1/2) of a radioactive substance is defined as the time
required for either the activity or the number of radioactive atoms to decay to half the initial value.

 Biological Half life : Time taken by the body to eliminate half of the radioactive element

 Effective Half Life : The net effect of both physical and biological half life in removing the
radioactive element from the body

Decay Constant :

 The proportion of atoms that will disintegrate in a given time.

 The number of atoms disintegrating per unit time (ΔN/Δt) is proportional to the number of radioactive
atoms (N) present.

2. What are Isotopes?

Isotopes, atoms having nuclei with the same number of protons but different number of neutrons

3. Write a short note on Electromagnetic Radiation:

• Electromagnetic radiations are characterized by oscillating electric and magnetic fields, always
perpendicular to each other and to the direction of their energy propagation.
• Wavelength (λ), frequency (ν), and velocity (c) of EM waves are related by c = νλ.
• Quantum model relates energy of a photon with its frequency of oscillation by E = hν, where h is
Planck’s constant.
• If λ is given in meters, the photon energy in electron volts (eV) is given by E = (1.24 × 10−6)/
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4. Explain with a neat diagram the parts of Linear Accelerator : Wave guide, Modulator, Electron
gun, Magnetron, Flattening filters

Parts of a Linear Accelerator:

1. Modulator
2. Magnetron / Klystron
3. Wave guide
4. Electron gun
5. Treatment Head – Flattening filter

Modulator:

Converts direct DC current into high voltage DC pulses.

Magnetron

 The magnetron is a device that produces microwaves.

 The magnetron has a cylindrical construction, having a central cathode and an outer anode with
resonant cavities machined out of a solid piece of copper.
 The space between the cathode and the anode is evacuated.
 The cathode is heated by an inner filament and the electrons are generated by thermionic emission.
 static magnetic field is applied perpendicular to the plane of the cross section of the cavities and a
pulsed DC electric field is applied between the cathode and the anode.
 The electrons emitted from the cathode are accelerated toward the anode by the action of the pulsed
DC electric field.
 Under the simultaneous influence of the magnetic field, the electrons move in complex spirals
toward the resonant cavities, radiating energy in the form of microwaves.
 The generated microwave pulses are led to the accelerator structure via the waveguide.
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Wave guide
 Rectangular copper tube
 To travel the microwaves
 It is pressurized with Freon gas

The klystron is not a generator of microwaves but rather a microwave amplifier. It needs to be driven by a low-
power microwave oscillator.

Treatment Head
1. Target
2. Flattening filter
3. Scattering foil
4. Beam Collimation and Monitoring

Flatening filters:

1. To make the intensity of the beam uniform

2. Made up of lead
3. Thick at the centre and thin at the periphery
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5. Write down the decay scheme of Cobalt 60:

 The 60Co source decays to 60Ni with the emission of β particles (Emax = 0.32 MeV) and two photons
per disintegration of energies 1.17 and 1.33 MeV
 These g rays constitute the useful treatment beam.
 The β particles are absorbed in the cobalt metal and the stainless-steel capsules resulting in the emission
of bremsstrahlung x-rays and a small amount of characteristic x-rays.
 However, these x-rays of average energy around 0.1 MeV do not contribute appreciably to the dose in
the patient because they are strongly attenuated in the material of the source and the capsule.
 The other “contaminants” to the treatment beam are the lower-energy g rays produced by the interaction
of the primary g radiation with the source itself, the surrounding capsule, the source housing, and the
collimator system.
 The scattered components of the beam contribute significantly (~10%) to the total intensity of the beam.
All these secondary interactions thus, to some extent, result in heterogeneity of the beam.
 In addition, electrons are also produced by these interactions and constitute what is usually referred to as
the electron contamination of the photon beam.

6. Discuss the parts of Telecobalt 60 :

 Source housing and radioactive source

 Collimator
 Gantry
 Patient support assembly
 Machine console
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Source Housing :

 A typical teletherapy Co 60 source is a cylinder of diameter ranging from 1.0 cm to 2.0 cm and is
positioned in the cobalt unit with its circular end facing the patient.
 The housing for the source is called the ―source head.
 It consists of a steel shell filled with lead for shielding purposes and device for bringing the source in
front of an opening in the head from which the useful beam emerges.
 Also a heavy metal alloy sleeve is provided to form an additional primary shield when the source is in
the OFF position.
 Source : Natural cobalt is a hard, stable, bluish-gray, easily breakable metal. Its atoms contain 27
protons, 32 neutrons, and 27 electrons.
 Non-radioactive cobalt can be found mixed with various minerals in nature, and has been used to impart
a blue color to glass and ceramics for thousands of years.
 The well-known isotope of cobalt is unstable radioactive Co-60.
 The 60Co source, usually in the form of solid cylinder, discs, or pellets, is contained inside a standard
stainless steel capsule and sealed by welding.
 The capsule is placed into another steel capsule, which is again sealed by welding. The double welded
seal is necessary to prevent any leakage of the radioactive material.
 two γ ray photons of energy 1.17 MeV and 1.33 MeV in cascade.
 The decay half-life is 5.26 years and the average photon energy is 1.25 MeV.
 Typical source activities are of the order of 5000–10 000 Ci (185–370 TBq) and provide a typical dose
rate at 80 cm from the teletherapy source of the order of 100–200 cGy/min.
 Often the output of a teletherapy machine is stated in Rmm (roentgens per minute at 1 m) as a rough
guide for the source strength.
 Treatment Head has the capacity to take a source with an activity of 10 000 Roentgens per hour at a
meter(RHm) (165 Roentgens per minute at a meter (Rmm)).
 The head leakage typically amounts to less than 1 mR/h (0.01 mSv/h) at 1 m from the source.
 International regulations require that the average leakage of a teletherapy machine head be less than 2
mR/h (0.02 mSv/h) at 1m from the source.

A number of methods have been developed for moving the source from OFF position to ON position-

1. Source mounted on a rotating wheel inside the source head to carry the source from OFF to On position
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2. Source mounted on a heavy metal drawer is moved horizontally by pneumatic system through a hole running
through the source head. In the ON position the source faces the aperture for the treatment beam and in the OFF
position the source moves to its shielded location and the light source mounted on the same drawer occupies the
ON position of the source.

3. Mercury is allowed to flow into a container immediately below the source to shut OFF the beam.

4. Source is fixed in front of the aperture and the beam can be turned ON and OFF by a shutter consisting of
heavy metal jaws.

Collimators :

 Collimators provide beams of desired shape and size.

 Collimators of teletherapy machines provide square and rectangular radiation fields typically ranging
from 5 × 5 to 35 × 35 cm2 at 80 cm from the source.
 The rotational movement of the collimator is continuous, and it can rotate 360° about its own axis.
 The collimator system can move to any position when the gantry is rotated.
Gantry :

 The gantry can rotate by 360°.

 The rotational movement of the gantry is motorized and controlled in two directions continuously; its
rotation speed can be adjusted.
 Teletherapy machines are most often mounted isocentrically, allowing the beam to rotate about the
patient at a fixed SAD.
 They can be used either as fixed field machines or rotation units.
 Modern teletherapy machines have SADs of 80 or 100 cm.
 The axis of rotation of the three structures:
o Gantry
o Collimator
o Couch
coincide at a point known as the Isocenter.
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Control Console : Control Console is situated outside the bunker

Interlocks present on the console for
1. Air Pressure
2. Door
3. Head Lock -Treatment Head has a swivel movement of +/- 180o
4. OFF Shield
5. Treatment Mode
6. Wedge Filter
7. Tray Interlock
8. Timer
Timer : The prescribed target dose is delivered with the help of two treatment timers:
Primary Timer - the primary timer actually controls the treatment time.
Secondary Timer - accounts for the source movement from OFF to ON position and again to OFF position
(shutter error).
Source ON/OFF Indicator – Red- ON Green- OFF Amber- TRANSIT

Beam characteristics for photon beam energy 60Co, SSD = 80 cm

1. Depth of maximum dose = 0.5 cm
2. Increased penetration (10-cm PDD = 55%)
3. Beam edge not as well defined—penumbra due to source size
4. Dose outside beam low because most scattering is in forward direction
5. Isodose curvature increases as the field size increases
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7. Discuss briefly about Penumbra :

Penumbra refers to the region at the edge of the beam where the dose-rate changes rapidly as a function of
distance from the beam axis.

Penumbra width depends upon:

1. Source diameter.
2. SSD.
3. Depth below skin.
4. Source to diaphragm distance (inversely)

Types:
1. Geometrical penumbra : Finite size of the source.

2. Transmission penumbra: Transmission through the edge of the collimator block.

3. Physical penumbra: Lateral distance between to specified isodose curves at a specific depth (90%
& 20% at Dmax). Takes scattered radiation into account.
Geometric Penumbra :

 Penumbra Trimmers consist of extensible, heavy metal bars to attenuate the beam in the penumbra region.

 Increase the source to diaphragm distance, reducing the geometric penumbra.

 Another method is to use secondary blocks placed close to the patient ( 15 – 20 cms).
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8. Difference between linear accelerator and cobalt 60

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9. Discuss the various collimators in radiotherapy :

Collimators provide beams of different size and shape

Classified into :

1. Fixed collimator
2. Movable collimator

Fixed Collimators
• Protects the patient from bulk of the radiation.
• Dictates the maximum field size for the machine.
• Maximum beam size is when exposure at periphery is 50% of that of the center.
• In megavoltage radiotherapy beam angle used is 20°.

Movable Collimators:
Define the required field size and shape.
• Placed below the master collimators results in trimming of the penumbra.
• Types: –Applicators
– Jaws / Movable diaphragms

A multileaf collimator (MLC) for photon beams consists of a large number of collimating blocks or leaves
that can be driven automatically, independent of each other, to generate a field of any shape.

 Typical MLC systems consist of 60 to 80 pairs, independently driven.

 The individual leaf has a width of 1 cm or less as projected at the isocenter.

 The leaves are made of tungsten alloy (r = 17.0 to 18.5 g/cm3) and have thickness along the
beam direction ranging from 6 cm to 7.5 cm, depending on the type of accelerator.

 The leaf thickness is sufficient to provide primary x-ray transmission through the leaves of less
than 2% (compared with about 1% for jaws and 3.5% for Cerrobend blocks).

 The interleaf (between sides) transmission is usually less than 3%. The primary beam
transmission may be further minimized by combining jaws with the MLC in shielding areas
outside the MLC field opening.

 Some MLC systems have double-focused leaves; that is, the leaves form a cone of irregular cross
section diverging from the source position and move on a spherical shell centered at the source.

 The rationale behind a double-focused MLC is to provide a sharp beam cutoff at the edge.
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 However, for high-energy beams this objective is achieved only to a limited extent, because the
dose falloff at the edge is largely determined by laterally scattered photons and electrons.

 Because double-focused MLCs are difficult to manufacture, some systems have been designed
with rounded leaf edges and directions of travel perpendicular to the central ray.

 The purpose of rounded edges is to provide constant beam transmission through a leaf edge,
regardless of its position in the field.

 An important consideration in the use of MLCs for stationary fields is the conformity between
the planned field boundary, which is continuous, and the jagged stepwise boundary created by
 the MLC.

 The degree of conformity between the two depends not only on the projected leaf width, but also
on the shape of the target volume and the angle of rotation of the collimator.

 The physical penumbra with MLC is larger than that produced by the collimator jaws or the
Cerrobend blocks .

 This is usually not a serious drawback except for the treatment of small fields or when blocking
is required close to critical structures.

 Also, jaggedness of the field edges makes it difficult to match adjacent fields.

 The use of MLC in blocking and field shaping is ideally suited for treatments requiring large
numbers of multiple fields because of automation of the procedure, thus resulting in a significant
reduction of setup time.

 MLC can practically eliminate the use of Cerrobend blocking except for shaping small fields or
“island” blocking in which an area within the open portion of the fields needs to be blocked.

 The importance of MLC is not just the replacement of Cerrobend blocking.

 The greater impact of this technology is in the automation of field shaping and modulation of
beam intensity.

 Modern radiotherapy techniques such as 3-D conformal radiation therapy and intensity-
modulated radiation therapy are dependent on dynamically controlled MLCs.

 Other applications include dynamic wedges and electronic compensatio

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10. Write a short Note on Cyclotron.

 The cyclotron is a charged particle accelerator, mainly used for nuclear physics research.
 In radiation therapy, these machines have been used as a source of high-energy protons for
proton beam therapy.
 More recently, the cyclotrons have been adopted for generating neutron beams.
 In the latter case, the deuterons (12 H _ )are accelerated to high energies and then made to strike
a suitable target to produce neutrons by nuclear reactions.
 One such reaction occurs when a beam of deuterons, accelerated to a high energy (~15 to 50
MeV), strikes a target of low atomic number, such as beryllium.
 Neutrons are produced by a process called stripping
 Another important use of the cyclotron in medicine is as a particle accelerator for the production
of certain radionuclides.
 The machine consists essentially of a short metallic cylinder divided into two sections, usually
referred to as Ds.
 These Ds are highly evacuated and placed between the poles of a DC magnet (not shown),
producing a constant magnetic field.
 An alternating potential is applied between the two Ds. Positively charged particles such as
protons or deuterons are injected into the chamber at the center of the two Ds.
 Under the action of the magnetic field, the particles travel in a circular orbit. The frequency of
the alternating potential is adjusted such that as the particle passes from one D to the other, it is
accelerated by the electric field of the right polarity.
 With each pass between the Ds, the particle receives an increment of energy and the radius of its
orbit increases.
 Thus, by making many revolutions, the particle such as a deuteron achieves kinetic energy as
high as 30 MeV.
 There is a limit to the energy that a particle can attain by the above process. According to the
theory of relativity, as the particle reaches high velocity (in the relativistic range), further
acceleration causes the particle to gain in mass. This causes the particle to get out of step with
the frequency of the alternating potential applied to the Ds.
 This problem has been solved in the synchrotrons where the frequency of the potential is
adjusted to compensate for the increase in particle mass.
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11. Write a short note on Betatron.

 The operation of the betatron is based on the principle that an electron in a changing magnetic
field experiences acceleration in a circular orbit.
 The accelerating tube is shaped like a hollow doughnut and is placed between the poles of an
alternating current magnet.
 A pulse of electrons is introduced into this evacuated doughnut by an injector at the instant that
the alternating current cycle begins.
 As the magnetic field rises, the electrons experience acceleration continuously and spin with
increasing velocity
 The operation of the betatron is based on the principle that an electron in a changing magnetic
field experiences acceleration in a circular orbit.
 The accelerating tube is shaped like a hollow doughnut and is placed between the poles of an
alternating current magnet.
 A pulse of electrons is introduced into this evacuated doughnut by an injector at the instant that
the alternating current cycle begins.
 As the magnetic field rises, the electrons experience acceleration continuously and spin with
increasing velocity.
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12. Write a short note on DT Generator.

 High-energy neutron beams for radiotherapy are produced by deuterium–tritium (D–T) generators,
cyclotrons, or linear accelerators.

 The bombarding particles are either deuterons or protons and the target material is usually beryllium,
except in the D–T generator in which tritium is used as the target,

 A low-energy deuteron beam (100 to 300 keV) incident on a tritium target yields neutrons by the
following reaction:

 The disintegration energy of 17.6 MeV is shared between the helium nucleus (a particle) and the
neutron, with about 14 MeV given to the neutron.

 The neutrons thus produced are essentially monoenergetic and isotropic (same yield in all directions).

 The major problem is the lack of sufficient dose rate at the treatment distance.

 The highest dose rate that has been achieved so far is about 15 cGy/min at 1 m.

 The advantage of D–T generators over other sources is that its size is small enough to allow isocentric
mounting on a gantry.

13. Write short note pi mesons.

 The existence of pi mesons was theoretically predicted by Yukawa in 1935 when he postulate that
protons and neutrons in the nucleus are held together by a mutual exchange of pi mesons.
 A pi meson (or pion) has a mass 273 times that of electron and may have a positive charge, negative
charge, or may be neutral. The charged pions decay into mu mesons and neutrinos with a mean life of
2.54 × 10−8 seconds and the neutral pions decay into pairs of photons with a mean life of about 10−16
seconds.
 Only negative pions have been used for radiation therapy.
 Beams of negative pions can be produced in a nuclear reaction. Protons of energy in the range of 400 to
800 MeV, produced in a cyclotron or a linear accelerator, are usually used for pion beam production for
radiotherapy. Beryllium is a suitable target material.
 Pions of positive, negative, and zero charge with a spectrum of energies are produced and negative pions
of suitable energy are extracted from the target using bending and focusing magnets.
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 Pions of energy close to 100 MeV are of interest in radiation therapy, providing a range in water of
about 24 cm.
 The Bragg peak exhibited by pions is more pronounced than other heavy particles because of the
additional effect of nuclear disintegration by π− capture.
 This phenomenon, commonly known as star formation, occurs when a pion is captured by a nucleus in
the medium near the end of its range.
 A pion capture results in the release of several other particles such as protons, neutrons, and a particles.
 Although pion beams have attractive radiobiologic properties, they suffer from the problems of low dose
rates, beam contamination, and high cost.

14. Write a short note on Linear Attenuation Co-efficient.

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15. Write a short note on Half Value Layer.

 The term half-value layer (HVL) is the thickness of an absorber of specified composition required to
attenuate the intensity of the beam to half its original value.
 Combination filters containing plates of tin, copper, and aluminum have been designed to increase the
resulting HVL of the orthovoltage beams without reducing the beam intensity to unacceptably low
values.
 Such filters are called Thoraeus filters
 It is important that the combination filters be arranged in the proper order, with the highest-atomic-
number material nearest the x-ray target.
 Thus, a Thoraeus filter is inserted with tin facing the x-ray tube and the aluminum facing the patient,
with the copper sandwiched between the tin and the aluminum plates.
 In the diagnostic and superficial x-ray energy range , primarily aluminum filters are used to harden the
beam. The HVLs of these beams are also expressed in terms of millimeters of aluminum.
 In the orthovoltage range, however, combination filters are often used to obtain HVLs in the range of
about 1 to 4 mm Cu.
 For cesium and cobalt teletherapy machines, on the other hand, filters are not needed because the beams
are almost monoenergetic.
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16. Interaction of Photon with matter.

Photon beams interact with matter through five major processes:
 Coherent scattering,
 Photoelectric effect
 Compton effect,
 Pair production,
 Photodisintegration.
• Coherent scattering involves no net loss of energy. This type of interaction is probable with low-energy
photons and high-Z materials—not important for radiation therapy beams interacting with body tissues, which
have low Z.

• Photoelectric effect involves complete absorption of photon energy by the atom and transferring that energy
to an orbital electron, which is ejected. The process results in the emission of photoelectron, characteristic x-
rays (fluorescent radiation), and Auger electrons.
• Photoelectric probability varies as 1/E3 and Z3.
• Photoelectric effect in water (or soft tissue) is predominant for photon energies of up
to 25 keV (average energies of x-ray beams generated at potentials up to 75 kVp).

• Compton effect involves photon interaction with a “free electron” (loosely bound electron— binding energy
much less than the incident photon energy).
• Compton interaction probability in water increases with photon energy from 10 to 150 keV. It then decreases
with further increase in energy. However, it is the predominant mode of interaction in water for 30 keV to 24
MeV. That includes all x-ray beams used in radiation therapy.
• Compton probability is almost independent of Z. It depends on electron density (number of electrons per cm3).
• Maximum energy of a photon scattered at 90 degrees is 0.511 MeV, and at 180 degrees it is 0.255 MeV.

• Pair production involves a high-energy photon interaction with the electromagnetic field of a nucleus.
Photon energy is all used up in creating a pair of electron (e−) and positron (e+) and providing it with kinetic
energy.
• The threshold energy for pair production is 1.02 MeV—just enough to create the electron–
positron pair.
• Pair production probability increases slowly with energy beyond 1.02 MeV. It increases from about 6% at 4
MeV to 20% at 7 MeV (average energies of 12 to 21 MV x-ray beams).
• Pair production coefficient varies approximately as Z2 per atom, Z per electron, and Z per gram.
• The reverse of pair production process is the electron–positron annihilation, giving rise to two photons each of
0.511 MeV ejected in the opposite direction.

Photodisintegration involves a photon creating a nuclear reaction

In most cases, it results in the emission of a neutron. The process is only important at high photon energies and
is responsible for neutron contamination of therapy beams of energy greater than 10 MV.
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17. Explain Charged particle interaction with matter.

Electron Interaction:

Neutron Interaction :

Neutrons interact basically by two processes:

(a) recoiling protons from hydrogen and recoiling heavy nuclei from other elements, and
(b) nuclear disintegrations.
The first process may be likened to a billiard-ball collision in which the energy is redistributed after the
collision between the colliding particles.

18. Define Roentgen.

1 Roentgen was originally defined as 1 R = 1 electrostatic unit (esu)/cm3 air at standard temperature and
pressure (STP) (0°C, 760 mmHg).
The current definition of 1 R = 2.58 × 10−4 C/kg air is equivalent to the original if the charge is expressed in
coulombs (1 esu = 3.333 × 10−10 C) and the volume of air is changed to mass (1 cm3 of air at STP weighs
1.293 × 10−6 kg).

The roentgen is a unit of exposure.

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19. Write a short note on Ion Chambers

 Used for the determination of radiation dose

 Basically a gas filled cavity surrounded by a conductive outer wall and has a central collecting electrode
 The wall and the collecting electrode are separated with a high quality insulator to reduce the leakage
current when a polarizing voltage is applied to the chamber.
 A guard electrode is usually provided in the chamber to further reduce chamber leakage.
 to prevent the leakage current from the high-voltage electrode (the collector)
 to define the ion-collecting volume.

FARMER CHAMBERS
 Chamber wall: graphite or plastic such as PMMA (acrylic), nylon, A.E. (air-equivalent) plastic, and T.E.
(tissue-equivalent) plastic.
 Outer Electrode: thimble wall (if made of a conducting material) or the inner surface of the thimble wall
coated with a conducting material
 Central Electrode: thin aluminum rod of 1 mm diameter
 Guard Electrode: A cylindrical conductor that wraps around the insulator surrounding the central
electrode in the stem of the chamber.
 Chamber (or cavity) volume: a cylindrical cavity with a nominal volume of 0.6 mL.
 Energy dependence: change in response/unit exposure with beam energy depends on the composition
and thickness of the wall material.

THIMBLE CHAMBER

 Inner surface of the thimble wall is coated to make it electrically conducting- one electrode

 Other electrode is a rod of low-atomic-number material (graphite / aluminium) held in the center but
electrically insulated
Most popular design
Independent of radial beam direction
Typical volume between 0.05 - 1.00 cm3
Typical radius -27 mm
Length -4 - 25 mm
Thin walls: 0.1 g/cm2
Used for:
electron, photon, proton, or ion beams
Calibration of megavoltage photon beams
ELECTROMETERS
 Electrometers are devices for measuring small currents, of the order of 10–9 A or less.
 A high gain, negative feedback, operational amplifier with a standard resistor or a standard capacitor in
the feedback path to measure the chamber current and charge, respectively, collected over a fixed time
interval.
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PARALLEL-PLATE (PLANE-PARALLEL) IONIZATION CHAMBER

• 1 Polarizing electrode
• 2 Measuring electrode
• 3 Guard ring
• a is height (electrode separation) of the air cavity.
• d is diameter of the polarizing electrode.
• m is diameter of the collecting electrode
• g is width of the guard ring.
• The parallel-plate chamber is recommended for dosimetry of electron beams with energies below 10
MeV.
• Useful for depth dose measurements.
• Also used for surface dose and depth dose measurements in the build-up region of megavoltage photon
beams

• EXTRAPOLATION CHAMBER

• Parallel-plate chambers with a variable electrode separation.

• Used in absolute radiation dosimetry (when embedded into a tissue equivalent phantom).
• The cavity perturbation for electrons can be eliminated by:
• making measurements as a function of the cavity thickness
• extrapolating to zero thickness.
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20. Define Absorbed Dose and Kerma. How is it measured?

Absorbed Dose Kerma

Absorbed dose – measure of energy absorbed from a Kerma is the kinetic energy released in the medium
radiation beam per unit mass of material. per unit mass.

Unit – Gray Unit – J/Kg

 A radiation dosimeter is a device that measures directly or indirectly

 Absorbed dose
 Kerma
 Exposure
 Equivalent dose

Absolute / Primary Dosimeters Secondary Dosimeters

1. Calorimeter Film dosimetry
2. Fricke dosimeter  Radiographic films
 Radio chromic films
Luminescence dosimetry
 TLD (Thermo Luminescent Dosimeters),
 OSL (Optically Stimulated Light-emitting
Dosimeters)
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21. Write Briefly on Film Dosimetry :

 Radiographic film –
o Qualitative and quantitative dose measurements (including electron beam dosimetry)
o Quality control of radiotherapy machines
 Congruence of light and radiation fields
 Determination of the position of a collimator axis
 Dose profile at depth in phantom
 Star-test
Verification of treatment techniques in various phantoms

o Portal imaging
o Archival property

Mechanism of Action:

Film - transparent polyester material (the base) on which is deposited a layer of AgBr trapped in a gel (the
emulsion)

o When irradiated, lattice bonds are broken and electrons are transferred from the bromine to the
silver ions
o In the subsequent development process, the silver ions of developable crystals are converted to
atoms of silver fixed in position on the film while the rest of the emulsion, including any non-
developable crystals, is removed.
o The deposited silver absorbs light so these regions of the film appear black while the rest appears
transparent.
o The degree of blackness depends on the relative concentration of deposited crystals which, in
turn, depends upon the intensity of radiation
Typically, film is used for qualitative dosimetry, but with proper calibration, careful use and analysis film can
also be used for dose evaluation

Various types of film are available for radiotherapy work for field size verification: direct exposure non-screen
films with simulators: phosphor screen films, in portal imaging: metallic screen films

The useful dose range of film is limited and energy dependence is pronounced for lower energy photons

Consistent processing of the film is a particular challenge

 24

Advantages : Disadvanatges:

2-D spatial resolution.  Darkroom and processing facilities required.

Very thin: does not perturb the beam.  Processing difficult to control
 Variation between films & batches.
 Needs proper calibration against ionization
chamber measurements
 Energy dependence problems.
 Cannot be used for beam calibration.

Radiochromic film :

1. Principle: contains a special dye that is polymerized and develops a blue color upon exposure to
radiation
2. This film type is self-developing, requiring neither developer nor fixer
3. Most commonly used radiochromic film type is the GafChromic film.
4. A colourless film with a nearly tissue equivalent composition (9.0 % hydrogen, 60.6 % carbon, 11.2
% nitrogen and 19.2 % oxygen)
Advantages Disadvantages
 No quality control on film processing needed  GafChromic films are generally less sensitive
 Grainless -very high resolution than radiographic films
 Useful in high dose gradient regions for
dosimetry, such as
 Stereotactic fields
 The vicinity of brachytherapy sources
 Dose rate independence.
 Better energy characteristics except for low
energy x rays (25 kV)

22. Write Briefly on TLD:

 Upon absorption of radiation, some materials retain part of the absorbed energy in metastable states.
When this energy subsequently released in the form of UV, visible or IR light, this phenomenon is
called luminescence

 There are two types of luminescence:

o Fluorescence

o Phosphorescence

 If the exciting agent is heat, the phenomenon is known as thermoluminescence

 25

 When used for purposes of dosimetry, the material is called thermoluminescent (TL) material or a
thermoluminescent dosimeter (TLD).

 If the exciting agent is light, the phenomenon is referred to as optically stimulated luminescence
(OSL)

 When a thermoluminescent material is irradiated, electrons are transported into the conduction band.

 A small number of these electrons (1%) fall into the thermoluminescent traps

 When the material is later heated to a temperature that allows the traps to empty, light is given off

 The amount of light is proportional to the number of electrons trapped and hence to the radiation dose
delivered to the crystal material

TYPES OF TLDs

 TL dosimeters (based on their tissue equivalence):

o LiF: Mg, Mn, Cu,

o Li2B4O7:Mn

 based on high sensitivity:

o CaSO4:Dy

o Al2O3:C

o CaF2:Mn

 TLDs are available in various forms (e.g., powder, chip, rod, ribbon)

 Before use, TLDs have to be annealed to erase any residual signal.

Thermoluminescent dosimetry uses equipment (the TLD reader) that both heats the detector and
simultaneously measures the amount of light emitted

 A basic TLD reader system consists of:

 Planchet for positioning and heating the TLD dosimeter;

 Photomultiplier tube (PMT) to detect the TL light emission, convert it into electrical signal, and
amplify it.

 Electrometer for recording the PMT signal as charge or current.

 26

Advantages Disadvantages
• Small in size: point dose measurements • Signal erased during readout
possible • Easy to lose reading
• Available in various forms • No instant readout
• Some are reasonably tissue equivalent • Accurate results require care
• Not expensive • Readout and calibration time consuming
• Not recommended for beam calibration

 Optically stimulated luminescence (OSL) :

 Principle similar to that of the TLD. Instead of heat, light (from a laser) is used to release the trapped
energy in the form of luminescence
 Most promising material is Al2O3:C.
 To produce OSL, the chip is excited with a laser light through an optical fiber and the resulting
luminescence (blue light) is carried back in the same fiber, reflected through a 90° by a beam-splitter
and measured in a PMT.
 27

CLASSICAL RADIATION PHYSICS

1. Write a short note on Phantoms.

Since it is not always possible to put radiation detectors in water, solid phantoms have been
developed as substitutes for water.
Ideally, for a given material to be tissue or water equivalent, it must have the same effective atomic number,
number of electrons per gram, and mass density.

However, since the Compton effect is the most predominant mode of interaction for megavoltage
photon beams in the clinical range, the necessary condition for water equivalence for such beams
is to have the same electron density (number of electrons per cubic centimeter) as that of water.

Examples:

 Water
 Polystyrene
 Perspex, Lucite
 Polyethylene
 Paraffin
 Mix D

2. Describe the Percentage Depth Dose cure and Factors Affecting it :

• A percentage of the absorbed dose at any depth d to the absorbed dose at a reference depth d0, along the
central axis of the beam.

• For orthovoltage (up to about 400 kVp) and lower-energy x-rays, the reference depth is usually the
surface (d0 = 0).
 28

• For higher energies, the reference depth is usually taken at the position of the peak absorbed dose (d0 =
dm) or Dmax which occurs at greater depths, depending on energy.
PARTS OF PDD CURVE:

Surface dose: • High energy electrons produced by photon interactions in air and
any shielding structures
• Photons scattered from the collimators, flattening filter and air
• Photons backscattered from the patient
 Typical values of surface doses-
• 100%- superficial and orthovoltage
• 30%- Cobalt 60 gamma rays
• 15%- 6 MV x-ray beams
• 10%- 18 MV x-ray beams

Build up region • Dose region between the surface (depth z = 0) and depth z = zmax in
megavoltage photon beams
• Results from secondary charged particles (electrons and positrons)
that are first released in the patient by photon interactions
(photoelectric effect, Compton effect, pair production) and then
deposit their kinetic energy in the patient

Dmax  zmax depends upon

• Photon beam energy (main effect)
• Field size (secondary effect)
 For a given field size:
• zmax increases with photon beam energy.
• For 5x5 cm2 fields, the nominal values of zmax are

Exit dose • Dose delivered to the patient at the beam exit point
• close to the beam exit point the dose distribution curves slightly
downwards from the extrapolated dose distribution curve.
• This relatively small effect is attributed to the missing scatter
contribution at the exit point from points beyond the exit dose
point.
 29

Factors affecting PDD:

 Percentage depth dose depends on four parameters:

DEPTH For a constant A, f, and hv , PDD first increases from the surface to z = zmax
(buildup region), and then decreases with z

FIELD SIZE For a constant z, f, and hv , PDD increases with increasing field size A because of
increased scatter contribution to points on the central axis

SSD For a constant z, A, and hv , PDD increases with increasing f because of a

decreasing effect of depth z on the inverse square factor, which governs the
primary component of the photon beam

ENERGY increases with beam energy. Higher-energy beams have greater penetrating power
and thus deliver a higher-percentage depth dose at a given depth

3. Write briefly about Tissue Air Ratio:

TAR - the ratio of the dose (Dd) at a given point in the phantom to the dose in free space (Dfs) at the same
point.

TAR depends on 3 beam parameters:

Depth of isocentre z
Field size at isocentre AQ
Beam energy hv
It is independent of SSD

Uses :

1. Dose calculation of Low energy beams and Co 60

2. Dose calculation Isocentre Technique / Rotation techniques
 30

3. Tissue inhomogenity correction

Allows calculation of dose at isocenter WITHOUT correcting for varying SSDs.

TAR removes the influence of SSD as it is a ratio of two doses at the SAME point.

Back-scatter factor :

It is the TAR at the reference depth of maximum dose on the central axis of beam
 31

ISODOSE CURVES

• Isodose chart for a given single beam consists of a family of isodose curves usually drawn at regular
increments of PDD
• For SSD set-ups, all isodose values are normalized to 100 % at point P on the central beam axis (point of
dose maximum).
• For SAD set-ups, the isodose values are normalized to 100 % at the isocentre.
32
 33

WEDGE FILTERS

Definition : Beam Modifying Device which causes a progressive decrease in intensity across the beam,
resulting in tilting the isodose curves. Degree of the tilt depends upon the slope of the wedge filter.

• Material: tungsten, brass, lead or steel.

• Usually wedges are mounted at a distance of 15 centimeters from the skin surface.
• The sloping surface is made either straight or sigmoid in shade.
• A sigmoid shape produces a straighter isodose curve.
• Mounted on trays which are mounted on to the head of the gantry.
• In some isodose charts used in cobalt machines the wedge transmission factor is already incorporated,
and no further correction is necessary.
• The two dimensions of wedges are important – “X” or width and “Y” or length.
• All wedges are aligned so that the central axis of the beam is at the central axis of the wedge.
• If the X dimension of field is longer then we can’t use the wedge without risking a hot spot!!

•
Classification :

1. Physical
2. Non physical

Other Classification :

1. Individualized wedge.

2. Universal wedge.

3. Dynamic wedges

4. Virtual wedges

5. Pseudo wedges

Individualised wedges :

• Individual wedges are useful in Cobalt beams

• Using bigger wedges than necessary will reduce output of the machine → increased treatment time.
 34

• The width (W) of the wedge is fixed and important.

• The wedge systems available are:

• 6W ( x 15)

• 8W ( x 15)

• 10W ( x 15)

• All systems have the following four angles 15°, 30°, 45°, 60°.

• The same wedge can however be used for fields with lesser lengths or breadths.

Universal Wedges :

• Universal wedges are designed so that the same wedge can be used with all field sizes.

• This is useful as it saves time.

• However not suitable for cobalt beams because of excessive reduction of beam output with smaller
fields.

• Come in one size of 20 x 30 cms (except 60°).

• Wedge angles used are: 60°, 45°, 30° & 15°.

Dynamic / Motorized Wedge filters :

• 60° wedge mounted in the treatment head itself.

• This wedge was moved into the field for part of the time to create the wedge beam profile desired.

• Virtual wedges or dynamic enhanced wedges are moving jaws that are moved by computer control to
create wedge beam profiles.

• However use has not resulted in significant improvement over conventional wedges.

• Fixed jaws can be used to produce pseudo wedges where part of the treatment field requiring greater
dose would be irradiated using smaller field sizes.

PLACEMENT OF WEDGE :

• Beams are usually directed from the same side of the patient.

• The broad edges of the wedges should be aligned together.

• The wedge angle choosen depends on the angle between the central rays of the two beams also called
the “hinge angle”(φ).

Wedge Angle :
 35

• The wedge isodose angle (θ) is the complement of the angle through which the isodose curve is tilted
with respect to the central ray of the beam at any specified depth.

• This depth is important because the angle will decrease with increasing depth.

• The choice of the reference depth varies:

• 10 centimeters.

• 1/2 - 2/3rd of the beam width.

• At the 50% isodose curve (kV).

The overlap region is also called the “plateau region”.

Thus the 2 factors on which the wedge angle is choosen are: The hinge angle. The wedge separation.

The wedge angle that will make the isodose curves parallel to each other and the hinge angle bisector is
obtained using the equation.

Wedge Transmission Factor :

• The presence of the wedge decreases output of the machine.

• WTF = Dose with the wedge/ Dose without the wedge (at a point in the phantom, along the central axis
of the beam).

• Usually measured at a suitable depth below the Dmax usually 5 -10 cms! This minimises the error in
calculation of PDD.

• The resultant reduction in output results in an increase in the treatment time.

Application of Wedges in Radiotherapy :

• They decrease the Hot spot

• To have more uniform dose distribution
• As a compensator

1. Carcinoma Maxilla
2. Carcinoma Larynx
3. Carcinoma Breast
4. Brain Tumours
5. Carcinoma Palate
6. Carcinoma Ear
 36

4. Describe the advantages and disadvantages of parallel opposed beam.

Advantage:

• Parallel opposed fields are the simplest technique when using multiple fields.
• By aiming the two beams along the same axis, the dose fall off in one will be compensated for by
the increased dose in the other.
• The resulting distribution has relatively uniform distribution along the central axis.
• For small separations ( 10cm low energy beams are well suited, since they have a sharp rise to a
maximum dose and a relatively flat dose plateau in the region between both maximums.
Disadvantage:

• Parallel fields are limited by the high dose to all structures within the two fields.
• Patients with a large thickness require use of higher energy beams and may have higher ‘hot spots’ in
the superficial regions.
• This is due to a shallow z max where the highest dose is deposited.
• It is also important to treat both fields on the same day rather than alternating on a daily basis, due to
normal tissue damage when the latter method is used.
• For large separations (>15 cm), higher energy beams provide a more homogeneous distribution whereas
low energy beams can produce significant hot-spots at the zmax locations of the two beams (>30%).

5. Integral Dose

 One way of comparing dose distributions for different-quality beams is to calculate the integral dose
for a given tumor dose.
 Integral dose is a measure of the total energy absorbed in the treated volume.

 If a mass of tissue receives a uniform dose, then the integral dose is simply the product of mass and
dose.

 However, in practice, the absorbed dose in the tissue is nonuniform so rather complex mathematical
formulas are required to calculate it.

 Because integral dose is basically the product of mass and dose, its unit is the kilogram-gray
or simply joule (since 1 Gy = 1 J/kg).
 37

6. Describe SSD and SSD Technique :

SSD Technique SAD Technique

Relatively less homogenous dose Distribution Less number of MUs required

◦ Setup possible without requiring expensive aids ◦ Time taken is less

e.g. Laser
◦ Impact of setup inaccuracies is minimized in 2 field
◦ PDD charts can be used for simple dose techniques
Calculations
◦ Ease of setup reproducibility in multi field
◦ More skin reactions treatments.

7. Describe the SSD indicator and explain Pin and Arc Method :

1. Detachable device to measure the SSD and align the beam axis.
2. Designed so that it may be swung out of the beam path during treatment.
3. The back pointer can be moved in the sleeve.
4. A nipple is used to allow compression.
5. The arrow lies along the central ray.
6. Front pointer and back pointer used in the following situations: ◦ Head and Neck ◦ Breast ◦ Brain tumors
7. Limitations :
 Requires skin marks – inherently unreliable.
 Back pointer is unreliable when compression is desired.
 Both front and back points must be accessible.
 Accurate localization of tumor center is mandatory.
Pin & Arc Method
Based on the principle of parallelogram.
arrangement of pin & arc is such that when pin is at it’s lowest position, it’s lower end is on the central axis of
beam & on centre of curvature of arc.
 Depth of the tumor is already known.
 Pin is withdrawn the reqd. distance & it’s lower end is brought in contact with the surface mark.
 Mostly in midline tumors situated at a depth ◦ Esophagus ◦ Cervix ◦ Bladder ◦ Rectum ◦ Vagina ◦ Lung
sometimes
Advantages of Pin & Arc :
 Allows Isocentric treatment of ◦ Deep tumors. ◦ Eccentric tumors.
 Can be used with compression e.g. in treating deep seated tumors.
 Can be used for manual verification of Isocentric placement of machines.
 38

8. Write about CT Simulators.

 Dedicated CT scanner for use in RT treatment simulation & planning with multislice capability
 Large bore
 Flat table top
 High quality laser patient positioning & marking systems
 Special software for virtual simulation.
 A dedicated radiation therapy CT scanner with simulation accessories such as flat table, lasers,
immobilization and image registration device, and software for virtual simulation

 Uses CT scanner to localize the treatment fields

 Positioning, lebelling and imobilization is done in treatment position

 Image are sent electronically to preserve electron density data

 A software(exclusively written for simulation) provides outlining of contours, target volumes and
critical structures, interactive portal displays and placement, review of multiple plans, and a display of
isodose distribution/a virtual simulation.
 It is so called as patient is represented by CT images and radiation machine by beam geometry and
expected dose distirbution

DRR :

 Synthetic radiograph of the pt. obtained from CT data

 Produced by tracing ray lines from a virtual source position through CT data of the pt to a virtual plane.
 The sum of the attenuation coefficient along any one line gives a quantity analogous to optical density
on a radiograph

BEV :

 Projections of treatment beam axes, field limits & outlined structures through the patient on to the
corresponding virtual film plane
 Frequently superimposed on to the corresponding DRR resulting in a synthetic representation of a
simulation radiograph
 39

4 D CT SIMULATOR
 Breathing/organ motion -problems with accurate target definition (moving targets may appear with
distorted shapes and in wrong locations on CT) -increased irradiation of normal tissues (larger fields are
often used to ensure that the tumor is not missed). 4D CT
 Takes respiratory motion into account that can be used for planning, delivery and verification
 Takes phase images of deep inspiration-> mid inspiration-> mid expiration->deep expiration
 Other images such as MIP, minMIP can be generated
 40

9. Describe the ALARA Principle and Maximum ermissible Dose :

ALARA - As Low As Reasonably Achievable

n Refers to the continual application of the optimization principle in the day-to-day practice
n Optimization means that minimum risk and maximum benefits should be achieved
n Time
n Distance (inverse square law)
n Shielding

n Time – minimize exposure time

n Distance – increasing distance
n Shielding– use shielding effectively; portable and pull-down shields; protective aprons; stand behind
someone else

10. Write short note on Equivalent Dose and Effective Dose:

Equivalent Dose , H (Radiation weighted dose)

H = D.Q
D = absorbed dose averaged over the tissue or organ
Q = selected for the type and energy of radiation involved

The unit is sievert

 41

Effective Dose:

n Whole body exposures are rarely uniform. “the sum of the weighted dose equivalents for irradiated
tissues or organs”
n HE = H + TWF
 42

11. Teletherapy facility – Basic requirements. Diagram of conduit , viewing window, primary barrier,
secondary barrier, maize wall and iso-centre.

 Minimum Requirement for a small RT centre

 Radiation oncologist: 1
 Medical physicist-1
 Radiation technologist-2
 Medical physicist may be designated as rso

Requirements:

 Setup up a Department with adequate Staff

 Register Institute and personnel with AERB

 Declaration of Instrument

 Nomination and Approval of Radiological Safety Officer

 Clearance of the unit by AERB

 Approval of Room Layout Plan of Radiation Therapy Installation

 Procurement of Personnel Monitors

 Measuring, Monitoring , QA, Safety Instruments

 Authorisation to procure Radiation Sources

 43

Primary barrier :

A barrier sufficient to attenuate the useful beam to the required degree

n The choice of barrier material - concrete, lead, or steel, depends on structural and spatial considerations.

n Because concrete is relatively cheap, the walls and roof barriers are usually constructed out of concrete.

n For megavoltage x- and γ radiation, equivalent thickness of various materials can be calculated by
comparing tenth value layers (TVLs) for the given beam energy.

Maximum expected exposure = WUT/d2

Suppose the maximum permissible dose equivalent for the area to be protected is P (e.g., 0.1 rad/week for
controlled and 0.01 rad/week for noncontrolled area).

If B is the transmission factor for the barrier to reduce the primary beam dose to P in the area of interest,
then:

Secondary Barrier :

The required barrier against stray radiation (leakage and scatter)

n Leakage dose rate from this source housing with the beam in the “off” position shall not exceed 2
mrad/h on the average and 10 mrad/h maximum in any direction, at a distance of 1 m from the source.

n With the beam in the “on” position, the leakage dose rate from the source housing shall not exceed
0.1% of the useful beam dose rate, both measured at a distance of 1 m from the source.

Maze wall

n Reduce the radiation dose near the entrance

n A maze ensures that photon radiation can only exit the room after scattering has attenuated it.

n Reduces the need for a heavy shielding door.

n Last Man Out Switch (LMOS) : AERB Recommendation – 2015 , Should be installed in ALL
Radiotherapy units , can be coupled with door interlock. Wired / unwired
 44

RADIATION MONITORING DEVICES

 Ionization Chambers,
 Geiger Counters,
 Thermoluminescent Dosimeters (Tlds),
 Photographic Film.

Ionisation Chamber :

 An ionization chamber used for low-level x-ray measurements (of the order of milliroentgens per hour)
has a large volume (~600 mL) to obtain high sensitivity.
 A direct-current voltage is applied between the outer shell and the central electrode to collect ionization
charge produced by radiation in the internal air volume when the chamber is exposed to [Link] ion
chamber survey meter is usually calibrated for exposure in a g-ray beam from a cesium or a radium
brachytherapy source using an open-air measurement geometry.
 For accurate usage at middle and high energies, the energy response curve for the chamber should be
used to correct the exposure.
 Additional corrections for scale linearity, air temperature, and pressure and angular dependence may
also be necessary.
GM counter
 The Geiger-Müller counter (G-M tube) consists essentially of a cylindrical cathode with a fine wire
stretched along the axis of the cylinder.
 The tube is filled with a special mixture of gases at a pressure of about 100 mmHg.
 The voltage applied to the electrodes is much higher than the saturation voltage applied to an ionization
chamber.
 Potential is so high that the particles from the original ionization become energetic enough to produce
further secondary ionization giving rise to “gas amplification.”
 If the voltage is high enough that an “avalanche” of charge is generated by the original ionizing event,
independent of its size, the detector is called a Geiger-Müller counter.
 The G-M tube is much more sensitive than the ionization chamber. For example, the Geiger counter can
detect individual photons or individual particles that could never be observed in an ionization chamber.
 However, this detector is not a dose-measuring device. Although a Geiger counter is useful for
preliminary surveys to detect the presence of radiation, ionization chambers are recommended for
quantitative measurement.
 Because of their inherently slow recovery time (~50 to 300 μs), they can never record more than 1
count/machine pulse.
 Thus, a G-M counter could significantly underestimate radiation levels when used to count radiation
around pulsed machines such as accelerators.
 45

GM Counter :

n Principle : Gas Amplification

 Not a dosimeter - just a counter of radiation events
 Very sensitive
 Light weight and convenient to use
 Suitable for miniaturization
n Useful for , area monitoring , room monitoring , personnel monitoring, Care required in regions of high
dose rate or pulsed beams as reading may be inaccurate

PERSONAL MONITORING DEVICES:

46
47
48
49
50
51
52
53
 54

QUALITY ASSURANCE IN RADIOTHERAPY

For Co 60.
 55

FOR Linear Accelerator:

 56

BEAM MODIFING DEVICES:

1. Shielding Devices/Field Blocking devices

- Shielding blocks.

- Custom blocks.

- Independent Jaws.

- Multileaf collimators

2. Compensators.

3. Beam spoilers

4. Wedge filters.

5. Beam flattening filters.

6. Bolus

7. Breast cone.

8. Penumbra trimmers.

Shielding: To eliminate radiation dose to some special parts of the zone at which the beam is directed.

Compensation: To allow normal dose distribution data to be applied to the treated zone, when the beam enters
irregular surface or obliquely through the body or where different types of tissues are present.

Wedge filtration: Where a special tilt in isodose curves is obtained.

Flattening: Where the spatial distribution of the natural beam is altered by reducing the central exposure rate
relative to the peripheral.

Shielding Blocks

• Most commonly used

• Most commonly used shielding material is lead

• Thickness depends upon the energy of the radiation

• Half value-layer - Thickness of material which will reduce the intensity of the primary beam by 50%.

• A primary beam transmission of 5% through the block is considered acceptable.

-A thickness between 4.5 and 5.0 half- value layers

• For CO 60 – 5 cm lead thickness.

• Megavoltage – Thicker Blocks needed

 57

- Placed 15 – 20 cms from skin

- Skin Sparring effect preserved

• Block Divergence – Transmission penumbra

Custom Blocks

• Most common material used

– Alloy of 50.0% bismuth, 26.7% lead, 13.3% tin, and 10.0% cadmium - Lipowitz metal/
Cerrobend

- Advantage:

- Melts at about 70°C (327°C for lead) - Easily cast into any shape.

- Thickness - 7.5 cm equivalent to 6 cm of lead.

• Types:

- Positive Blocks – Solid blocks, rays pass around it

- Negative blocks - central area open and peripheral areas blocked

Half Beam Block’

• A beam modifying and directing device used for a tangential fields therapy

• Directs beam to the central axis of the area of interest

• Most commonly used in breast

BEAM SPOILERS ;

• Shadow trays made from Lucite are kept at a certain distance from the skin

• Based on the principle that relative surface dose increases when the surface to tray distance is reduced

• First used by Doppke to increase dose to superficial neck nodes in head and neck cancers using 10 MV
photon beams.

BOLUS:

• A tissue equivalent material used to reduce the depth of the maximum dose (Dmax) and/or compensate
for missing tissue..

• Buildup bolus - thick enough to provide adequate dose buildup over the skin surface

• Placed in contact with the skin

 58

• Secondary electrons produced by the bolus also increase the skin dose, since the bolus

is in contact with skin

• Several flab-like materials have been developed commercially

• Cellophane wrapped wet towels or gauze offer low cost substitutes.

• Thickness of the bolus used varies according to the energy of the radiation

• In megavoltage radiation:

• Co60 : 5 mm

• 6 MV : 7- 8 mm

• 10 MV : 12 - 14 mm

• 25 MV: 18 - 20 mm

FLATTENING FILTERS:

 A beam flattening filter reduces the central exposure rate relative to that near the edge of the beam.

 Used for Linear accelerators.

 Due to the lower scatter the isodose curves are exhibit “forward peaking”.

 The filter is designed so that the thickest part is in centre.

 Material: copper or brass.

 Greatest influence in determining the shape of the isodose curves.

 Without this filter, the isodose curves will be conical in shape, showing markedly increased x-ray

intensity along the central axis and a rapid reduction transversely.

 The function of the flattening filter is to make the beam intensity distribution relatively uniform

across the field (i.e., “flat”).

 Therefore, the filter is thickest in the middle and tapers off toward the edges.

 Penetrating power should not increase as this will alter the PDD as well as reduce the flattening.

 Not required in cobalt beams, as :

 The beam is almost monoenergetic.

 59

 Source emits uniform radiation all around

 Creates beam of sufficient area & uniformity for clinical use

 Compensates for rapid variation of central beam & the periphery

 Found that Al is material of choice

 The beam flatness is specified at 10 centimeters.

 The extent of flatness should be ± 3% along the central axis of the beam at 10 centimeters.

 Should cover 80% or more of the field, or reach closer than one centimeter from the edge.

 No point parallel to the surface should receive a dose > 107% of the central axis dose.

 There is usually over flattening of isodoses, near the surface. This results in production of “horns” or hot

spots.

 Because of the thinner outer rim, the average beam energy is lower at the periphery as compared to the

centre

 The beam flatness is specified at 10 centimeters.

 The extent of flatness should be ± 3% along the central axis of the beam at 10 centimeters.

 Should cover 80% or more of the field, or reach closer than one centimeter from the edge.

 No point parallel to the surface should receive a dose > 107% of the central axis dose.

 There is usually over flattening of isodoses, near the surface. This results in production of “horns” or hot

spots.

 Because of the thinner outer rim, the average beam energy is lower at the periphery as compared to the

centre
 60

COMPENSATORS:

• A beam modifying device which evens out the skin surface contours, while retaining the skin-sparing
advantage.

• It allows normal depth dose data to be used for such irregular surfaces.

• Compensators can also be used for

• To compensate for tissue heterogeneity. This was first used by Ellis, and is primarily used in total body
irradiation.

• To compensate for dose irregularities arising due to reduced scatter near the field edges (example
mantle fields), and horns in the beam profile

• The dimension and shape of a compensator must be adjusted to account for :

• Beam divergence.

• Linear attenuation coefficients of the filter material and soft tissue.

• Reduction in scatter at various depths due to the compensating filters, when it is placed at the distance
away from the skin.

• To compensate for these factors a tissue compensator is always has an attenuation less than that required
for primary radiation.

• As the distance between the skin and compensator increases the thickness ratio (h’/h) decreases.

• 2D Compensators

• Used when proper mould room facilities are not available.

• Thickness varies, along a single dimension only.

• Can be constructed using thin sheets of lead, Lucite or aluminum. This results in production of a
laminated filter.

• Constructed by gluing together sheets of lead or other material in a stepwise fashion to form a laminated
filter.

• The total thickness of the filter at any point is calculated to compensate for the air gap at the point below
it.

• 3-D compensators

• are designed to measure tissue deficits in both transverse and longitudinal cross sections.

• Various devices are used to drive a pantographic cutting unit.

• Cavity produced in the Styrofoam block is used to cast compensator filters.

 61

• Medium density materials are preferred to reduce errors.

• Various systems in use for design of these compensators are:

• Moiré Camera.

• Magnetic Digitizers.

• CT based compensator designing systems.

Compensating wedges:

• Compensating wedges are useful where the contour can be approximated with a straight line for an
oblique beam.

• Three important differences between compensating wedges and wedge filters are:

• Standard isodose curves, can be used

• No wedge transmission factors are required.

• Partial field compensation can be done.

Set up

• At the filter-surface distance calculated ≥ 20 cm.

• Nominal SSD measured from a plane perpendicular to beam axis touching the highest point in
the contour.

• In SAD technique the depth of the isocentre is measured from the same elevated point only.

Scattering foil

• A device to widen the thin pencil beam (3 mm) of electrons.

• Metallic plates of tin, lead or aluminum.

• Disadvantages:

- Beam attenuation.

• Advantages:

- Less prone to mechanical errors.

- Less expensive.

- Requires less instrumentation. Nowadays dual foil systems are used.

 62

RADIO-ISOTOPES PROPERTIES & CLINICAL USES

 63

 Isotopes : Substances with the same atomic no but diff mass nos.

 Identical chemical properties but different physical properties.

 e.g 12
6C & 146C

Radioactive isotopes Non radioactive isotopes

Stable
 consists of unstable atoms with an e.g carbon
unusual no of neutron oxygen
 the nucleus become stable nitrogen
 accompanied by emission of energy hydrogen
(radioactive decay) sulphur etc

RADIOACTIVE ISOTOPES
Natural occuring:

grouped into↗ Uranium series

→Thorium series Lead(stable)
↘Actinium series

Artificial Produced radioisotopes:

 By neutron bombardment- m.c

e.g 27 59Co + 0 1n →60 27Co + gamma rays

 By proton bombardment

e.g 1634S + 01p → 1734Cl + 01n

 Fission products

e.g 92235U + 01n → 55137Cs + 3797Rb + 01n + 01n +enrgy

Permanently sealed into suitable containers.

 contents radio isotops of long T ½.
 e.g 226Ra, 222Rn, 137Cs , 192 Ir, 60Co,125 I, 103Pb, 198
Au, 90Sr.
 Developmmental S.S
 241Am, 169 Yb, 252, Cf

Unsealed source
 Short T1/2,many r pure beta rays emitters.
 Source strengths much less than those of S.S.
 e.g Iodine-131, phosphorus-32, Samarium-159, Strontium 89
 64

Physical property:

 Half life (T ) : The time reqd for the no of atom in a particular sample to decrease by one half.

It does not depend upon the amount of radioactivity.

 Specific activity: Nos of disintegration per second

(curie)

 Specific gamma ray constant: exposure rate in roentgen per hr at 1cm from a 1 millicurie point source
of the material.

 Photon energy: packages / bundles of energy delivered by EMR. (MeV)

TELETHERAPY BRACHYTHERAPY

 High specific activity  Energy shud b Optimum:0.2-0.4 MeV

 Longer half life  HALF LIFE should be such that correction for
 Penetrable energies initial decay during treatment is minimum
 Economical viability  Absence of charged particle emission or it
 No contamination problem should be easily screened
 No gaseous disintegration product to cause
physical damage of the source or
contamination of the source
 High average photon yield and high specific
energy of the source
 Material- insoluble and non toxic
 Material – not in powder form
 Material should withstand sterilisation process
 60Co  226
Ra
 226 Ra  222
Rn
 137 Cs  60
Co
 192
Ir
 198
Au
 103
Pd
 125
I
 65

Cobalt 60
60
• Co machines – Theraton 780 & Theraton 1000

• It decays by beta emission to form stable nickel-60 t 1/2 is 5.26 yrs with avg photon energy of 1.25
MeV.

• high specific activity n gamma rays constant

• source actiivity(5000 ci to 13000 ci) n exposure rate

• field size 4x4cm to 35x35cm at SSD of 80/100cm

• Available in metal form n very small sources of high output can b fabricated.
 66

BRACHYTHERAPY

PROPERTIES OF AN IDEAL BRACHYTHERAPY SOURCE (GODDEN,1988)

• Gamma ray energy high enough to avoid energy deposition in bone by photo-electric effect.

• Low enough to minimize need for radiation protection.

(ideal 0.2-0.4MeV)

• T1/2 such that correction for decay during Rx is minimal

• Absent / easily screened charge particle emission

• High specific activity eg. 192 Ir

• No gaseous disintegration product eg. radon

• Insoluble & non-toxic

• Not in powder form eg. Radium sulphate

• Can be made in different shapes eg. 192 Ir

• Perm. Implants- t1/2 should be short

 67

γ emitters : 226Ra,222Rn,60Co,137Cs,192Ir,198Au, 125I, 103Pd,169Yb,145Sm,241Am.

β emitters : 32P,90Sr, 90Y,106Ru,49Va,166Ho,144Pr

neutron emitter: 252Cf

 68

RADIUM-226

• Earliest & once the most commonly used isotope

• Naturally occuring

• T ½ =1626 yrs

• Disintegrates very slowly to hazardous radioactive gas Radon

• At least 78 γ rays from Ra & its decay products of energy- ranging from

0.184 MeV - 2.45 MeV (avg.0.83Mev)

• Some high energy β rays (max.3.26 Mev)

• β filtration : 0.5 mm of Lead/ platinum

• Has been widely used for intracavitary,interstitial & mould applications

• Radium sulfate/Ra chloride mixed with inert filler & loaded in cell (1cm long &1mm in [Link] of 0.1-0.2
mm thick Gold foil. )

NOW OBSOLETE because

• Leak of radioactive salt/gas

• High cost

• Difficulty in Disposal

• Better Radium substitute

• Produces hazardous radioactive gas Radon

• Specific activity low

• Mixture of several intermediate radioactive products-dose calculation error can occur.

 69

CESIUM 137: ( Cs137)

• Recovered from fission products made in Nuclear Reactor

• T1/2 : 30 yrs

• Relatively cheaper, extraction simple,

• Decay system :

• 55

137 Cs 137

56Ba + 0

-1e + γ

• No gaseous decay product, safer than Ra

• γ ray energy = 0.662 MeV

• Beta filtration – 0.5 mm Pt or stainless steel

• Available in tubes, needles, pellets.

• Replaced Ra in t/t of gynaecologic cancers.

Manual afterloading system of Cs Remote afterloading system of Cs

Source train consist of flexible stainless steel holder Cs 137 is incorporated in glass bead & encapsulated in
containing, miniature source separated by spherical stainless steel ball bearing. which with inactive spacer
steel spacers 1.8 mm in diameter. beads, can be pneumatically loaded from intermediate
safe to pt. applicator
Sources and spacers retained by a steel spring.
 70

COBALT 60 (60Co)

• Produced by neutron activation of stable isotope 59Co

• Decay scheme: 60

27Co 60

28Ni+ -1

0e + y

• T1/2 = 5.26 yrs

• Each disintegration produces 2 y rays of energy 1.33 & 1.17 MeV

(avg energy 1.25 MeV)

• β energy= 0.318 MeV

• HVL in Lead = 10 mm

• Relatively high penetrating power makes an excellent isotope in teletherapy.

• Recently used in opthalmic plaques for t/t of ocular melanomas & retinoblastomas.

• Activity higher , can be used in brachytherapy.

Reasons for re-emergence of 60Co as brachytherapy source

• No need for frequent replacements

• Cost effective, Miniaturised,(same size of conventional Ir192 source), High activity

• Low operating cost

Cobalt 60 IRIDIUM 192

• rarely used nowadays

 Available in the form of thin flexible wires or
 T1/2 -5.26 yrs nylon ribbons.
 T1/2 -73.8 days.
 Advantage: higher sp activity allowing  γ ray emitter-Avg energy 0.38 Mev.
fabrication of small sources.
Advantages:
 Compatibility with after loading technique,
 Disadvantage: expensive than 137Cs & shorter  technical flexibility
half –life  Require less shielding

Disadvantage : short half life

costly
 71

IRIDIUM 192 (192Ir)

• Produced in Nuclear reactors.

• T1/2 =73.8 days

• Decays through β emission and electron capture to 192Pt and 192Osmium

• Decay scheme: 192I 192 Pt+ 0

-1e+ γ

• Emits 11 γ rays of energies ranging from 0.136 to 0.613 MeV

• Effective γ rays energy is appr. 0.380 MeV

• Emits β particles max energy 0.670 MeV

• β filtration =0.1mm of platinum

• (Eliminated by stainless steel capsule)

• HVT- 4.5mm of Lead (Pb)

• Available in nylon strands or as platinum cladded wire.

PHYSICAL PROPERTIES OF 192Ir seed

Seeds are 3mm long & 0.5 mm in dia.

Internal diameter core of 30%Ir +70%Pt surrounded by 0.2 mm thick stainless wall
 72

IODINE( 125I)

• Produced in Nuclear reactors

• Used in permanent implants & can also be used in removable implants.

• T1/2 = 59.6 days

• Y ray photon Energy = 0.274 MeV & 0.355 MeV

• Decay scheme = electron capture

124Xenon 125I 125Telleurium

• Adv over Rn & Au –longer t1/2

-convenient for storage

- low photon energy, less shielding .

But- dosimetry is much complex & most T/t planning systems doesn’t take anisotropy in account

Types of Iodine 125 implants

• Type 6702: used in temporary interstitial implants • Sources available with air kerma rate of 1m of
0.13-7.58 μGy h-1
• Consists of welded Titanium capsule containing 3
resin spheres onto which

125I is adsorbed by ion exchange. Model 2300 of 125I

• Sources available in air kerma rate at 1 m of 6.4- • Radioactive Iodine adsorbed on a tungston wire
51.9 μGy h-1 that is encapsulated by 2

• Effective energy 28.5 kev walls of titanium

• Suitable for both temporary & permanent

implantations as available in wide
Type 6711
range of source strengths.
• Used in permanent implant
• Tungston wire –radiographic marker
• Consists of welded titanium capsule containing I
125adsorbed onto a silver • Double walled encapsulation –reduces risk of
radioact
rod (which also act as x ray marker)

• Active length=3mm & dia. 0.5 mm

• Overall length = 4.5mm & dia.0.8mm

 73

GOLD (198Au)

• Produced in Nuclear reactor when 197Au absorbs one neutron

• Emits primarily Y rays

• Energy 0.412 MeV (monoenergetic)

• T1/2 = 64.7 hrs ( 2.7 days)

• Available in seeds and grain forms encased in Pt (0.1mm) filters β radiation.

• Suitable for permanent implants ( Short half life)

• Replaced Radon seeds in permanent implants

• Protection problem easily solved ( Emit only 3Y rays in contrast to complex

spectrum of Ra & also lower y energy)

• Also prepared in colloidal form for t/t of ascitis due to intraperitoneal tumors.

PALLADIUM 103 (103 Pd)

• Produced in nuclear reactors when stable 102Pd absorbs a neutron.

• Decay scheme = via electron capture ( 1st & 2nd excited states of Ruthenium103)

• T1/2 = 17 days

• Photon energy = 21 kev

• Useful in permanent implants

• HVL for Lead= 0.008 mm

• Substitute for 125I (shorter half life)

• Available in form of seeds

• Used in prostate implants

 74

STRONTIUM 90 (90 Sr) & Yttrium90 (90Y)

90Sr decays through β ray emission to 90Y

90Sr always coexist in equilibrium with radioactive daughter 90Yttrium

• T1/2=28 yrs

• Max β ray energy =0.54 MeV

• Dose falls very rapidly away from the applicator & is appr.20% at 2mm depth in tissue.

• Dose rate on surface in range of 100 cGy /S thus t/t delivered in seconds

• Used in corneal ulcers, pterygium, corneal vascularization & neoplasms.

• Yttrium in colloidal preparations used in malignant effusions.

• Yttrium pellets in pituitary gland to abolish its secretary activity in hormonal control of breast cancers.

• Yttrium used in SIR (selective internal radiation) in liver malignancies.

89Sr (non-sealed) used in t/t of bone mets.

PHOPHORUS 32 (32 P)

• Unsealed radioisotope

• Produced in nuclear reactor by neutron bombardment of sulfur,

• Pure β-emitter

• Max β energy =1.71 MeV

• T1/2 =14.7 days

• Formerly used in t/t of polycythemia vera & other hemat. malignancies

• Also in t/t of superficial warts, basal cell ca, angiomas.

• Now used in intrapleural, intraperitonial instillations.

•32P coated stents - used in t/t of arterial restenosi

 75

CALIFORNIUM 252 (252Cf)

• Neutron emitter (Radiobiological superiority)

• Production from multiple neutron capture by 238U

• Decay scheme – alfa emission

• Produces charged particles, gamma rays & neutrons

• T1/2=2.63 yrs

• Neutron energy= 2.3 MeV

• Typical source -0.25ug – 0.45ug (each ug emits 2.34 x106 neutrons)

• Available in seeds or tubes form

• Used in ca cervix LDR ICA

NEWER RADIOISOTOPES

RUTHENIUM 106 VANADIUM 49 HOLMIUM166 PRASEODYMUM 144

(106 Ru) ( 49 Va) (166HO) (144 Pr)

• Fission by-product • Produced through (p,n) • Produced through (n,y) • Fission byproduct of
reaction with 48Ti reaction with 165 Ho Cerium144
• Decay scheme- β
emission • Emits positrons & • Decay scheme-β • Decay scheme –β
gamma rays emission emission
• Max energy -0.039
MeV, [Link]-0.009 • Positrons avg energy - • 166Ho 165 Ho+ β • T1/2 =285 days 144Pr
MeV 0.696MeV , y ray avg 166Er(stable) 144Ni+ β
energy- 0.511 MeV
•106Ru 106Rh + β • Max β energy= 1.9 • Max β energy 3 MeV
• T1/2= 16 days MeV (avg 0.63) (avg 1MeV)
• T1/2=368 days
• Stent being utilized for • T1/2=27 hrs • Considered for
•106Ru in radioactive intracoronary intravascular
equilibrium with applications • Considered for brachytherapy.
daughter 106Rh intravascular
• Used in shallow brachytherapy
opthalmic lesions
 76

Tc‐99m

Technetium‐99m is the most utilized element in nuclear medicine and is employed in a wide variety of
nuclear medicine imaging studies.

Tc99m nuclear isotope is used for medical imaging in 90% of cases all over the world due to its near ideal
nuclear characteristics of a 6 h halflife and γ‐ray emission energy of 142 keV

The radionuclide 99Mo decays continuously to 99mTc which can be periodically and preferentially eluted
with physiological saline solution (0.15 m NaCl) over a period of 7–10 days.

Therefore the supply of Tc‐99m generators strongly depends on the ability to produce Mo‐99.

Somebody says it is a by‐product of nuclear industry.

No, it is the special target product 235U (n,f) [99Mo + 136Sn + n]

! • We never produce Tc‐99m !

• We have no Tc‐99m in the patient’s body in 2‐3 days after injection

Types of technetium imaging agents

‘Tc essential’ or 1st generation agents (A) have been deployed with great success to image organs such as
the heart, the brain, the kidney and the liver.

• 2nd generation agents (B) ‐ the targeting capability resides in a biologically active molecule (BAM)
covalently linked to an appropriate Tc complex (typically – peptide).

• 3rd generation agents (C) are under way

1st generation Tc imaging agents

Brain imaging : • The principle demand to the agent that is to be accumulated in the brain is that it should
be capable for traversing the blood–brain barrier (BBB).
 77

Liver : Three 99mTc‐HIDA analogues have been approved: • 99mTc‐Lidofenin (TechneScan HIDA) •
99mTc‐Mebrofenin (Choletec) and • 99mTc‐Disofenin (Hepatolite).

99mTc‐DTPA, DTPA = diethylenetriaminepentaacetic acid, has approval for use as a kidney imaging
agent.

Bone imaging : Tc ‐99 ‐Diphosphonates such as methylenediphosphonate [MDP, show high performance
as bone ‐imaging agents.

Second generation

99mTc‐ SULPHUR COLLOID : Ascending chromatography

 78

Electron Beam Physics

 79

Electron Interactions:
Atomic Electron Atomic nucleus
Inelastic Ionization and Excitation Bremsstrahlung X rays
❖ In low-atomic-number media, electrons lose ❖ In higher atomic-number materials,
energy predominantly through ionization/excitation bremsstrahlung production is more
events with atomic electrons important
Low atomic number materials have more High atomic number materials have
electrons less electrons
Low atomic number materials electrons are High atomic number materials have
loosely bound electrons are tighly bound
If the kinetic energy acquired by the stripped More common in high energy electrons
electron is large enough for it to cause further
ionization, the electron is known as a secondary
electron or a δ-ray.
Elastic Electron-electron scattering Nuclear scattering

Stopping Power : The rate of energy loss per gram per centimeter squared.
1. Collision stopping power 2. Radiant stopping power

Due Electron-electron interation Bremstralung production

Decreases with Z Increases with Z

Restricted stopping power is calculated which ignores the knock out electrons.
Scattering Power, T: It describes the angular path of the electron

It increases with atomic number Z and decreases with energy.

Absorbed Dose = Electron Energy + Restricted Stopping Power

 80

Physical Properties of Electron Beam

1. Percentage Depth Dose :
 3 regions : Build up region , fall off region and tail
a. High surface dose
b. Modest skin sparing effect
 Almost constant dose to depth just beyond Dmax
a. Sharp fall-off with increasing depth
b. Sparing of underlying tissues
 Major attractions: Shape of depth dose curve. (mostly 6 -15 MeV). Rapid drop-off.
 The dose at any arbitrary point in the reference plane should not exceed 103% of the central axis
value.
 Percentage depth dose increases as the energy increases
 Percentage depth dose increases as the field size increases but comes to equilibrium after a
point.
 Dmax doesnot follow a linear relationship with increase energy
 Tail represent the bremstralung production
a. Contamination increases with energy.
b. In a modern linear accelerator, ~0.5%-1% for 6-12 MeV. ~1%-2% for 12-15 MeV. ~2%-
5% for 15-20MeV.
c. Contamination is least in the scanning beam type of accelerator.

2. Isodose Curves
 low-energy beams (<50%)all the isodose curves show some expansion and bulges out.
 In higher energies(50-80%) only the low-value isodose levels bulge out.
 The higher isodose levels(>80%) tend to show lateral constriction, which becomes worse
with decreasing field size.

3. Beam symmetry
 Compares one side of central axis to other
 Shouldnot vary more than 2 %

4. Beam flatness :
 Should be specified by a perpendicular to the central axis at 95% dose

5. Virtual Source :
 Is measured at patient surface
 Intersecting point of the back projections along the most probable directions of electrons.

6. Beam is a pencil beam and suffers scatterin

 81

FACTORS TO BE CONSIDERED IN ELECTRON BEAM

Choice of Energy  “The electron energy should be selected so that the maximum of the depth
curve is located at the center of PTV.” - ICRU 71.

 Ep =3.3xR90 eg. ( Tumour)

 Ep = 2 x Rp eg.( spinal cord)

Field size  The choice of field size should be based on adequacy of isodose coverage
of PTV.
 Ensure that minimum dose to PTV should be adequate to sterilize the
tumor and maximum dose doesn't exceed the tolerance of normal tissue.

Oblique surface  The curved contour alters the depth dose distribution.
 Ideal situation would be a flat surface.
 The more oblique, the more is the surface dose. More xray contamination.

Tissue  Electron beam dose distribution can be significantly altered in the presence
Inhomogeneties of tissue inhomogeneities such as bone, lung, and air cavities
 It is difficult to determine dose distribution within or around small
inhomogeneities because of enhanced scattering effects
 However, for large and uniform slabs, dose distribution beyond the
inhomogeneity can be corrected by using the coefficient of equivalent
thickness (CET) method
 Sharp surface irregularities produce localized hot and cold spots in the
underlying medium due to scattering.
 Electrons are predominantly scattered outward by steep projections and
inward by steep depressions.
 In practice, such sharp edges may be smoothed with an appropriately
shaped bolus

Use Of Bolus And  1. Flatten out an irregular surface

Absorbers  2. Reduce the penetration of the electrons in parts of the field
 3. Increase the surface dose
➢ Constant thickness (slab) bolus is used to increase surface dose and to fine
tune electron-beam penetration
➢ Its location is important for irradiation by a small field (3 by 3 cm2) and
low energy (7-MeV) electron beam.

Adjacent Fields  Separating the fields may seriously underdose parts of the tumor.
 Because the tumors treated with electrons are mostly superficial, the
electron fields are usually abutted on the surface

Field shaping  Lead or Lipowitz metal (Cerrobend, Ostalloy, and Lometoy) cutouts are
used.
 82

 Lead is placed on the treatment surface, cerrobend on the distal end of

applicator.
 For lower-energy electrons (<10 MeV), less than 5 mm thickness of lead is
required for adequate shielding (e.g., ≤5% transmission)
 Thickness required : ~ 1mm / 2MeV
 The treatment of lip, buccal mucosa, and eyelid lesions, internal shielding
is useful to protect the normal structures beyond the target volume
 Eye shields are made of tungsten and plastic and inserted inside the
eyelids.

CALULATION OF ABSORBED DOSE

1. Calculate the Monitor units , MU

2. Calculate the output

3. Use the algorithms

▶ PBA (pencil beam algorithm): For the past 20 years, the standard methodology for dose

calculation in the patient has been the PBA.

▶ Pencil-beam redefinition algorithm (PBRA): New dose algorithms that are accurate to 4% or

better.

▶ Monte Carlo methods: newer algorithms, with superior results.

HOW DO YOU MEASURE PDD AND ISODOSE CURVES / ABSORBED DOSE?

Ionisation chamber Silicon Diodes Film Dosimetry

 Cylindrical ionization  Small size  Rapid
chambers are used  High sensitivity  Convenient
 Inoization curves are  But should be checked  Not a absolute dosimeter
measured by corrections with ion chamber
a. Correction for restricted
stopping power
b. Chamber replacement
correction
Calorimetry is the most basic method of determining the absorbed dose
 83

TECHNIQUES OF TBI AND CSI

 84

TOTAL BODY IRRADIATION

Definition: “Total body irradiation (TBI) is a special radio therapeutic technique that delivers to a patient’s
whole body a dose uniform to within 10% of the prescribed dose.”

TASKS OF TBI

• Eradicating diseased marrow

• Reducing tumor burden

• Immunosuppression- lymphocyte elimination to allow grafting of donor bone marrow

• Deplete the BM to allow physical space for engraftment of healthy donor marrow

• Eradication of cells with genetic disorders Fanconi’s anemia, thalassemia major, Wiskott- Aldrich
syndrome

TBI IN CONDITIONING REGIMENS

MALIGNANT NON MALIGNANT CONDITIONS

1. Lukemias, Immune disorders

Acute myeloid lukemia (aml) Aplastic anemia
Acute lymphoblastic lukemia (all) Genetic disorders
Chronic myeloid lukemia (cml) Wiskott aidrich syndrome
Hairy cell lukemia Osteopeterosis
Tar syd
Fanconi anemia
2. Lymphomas/ myeloproliferative disorders
Non hodgkins lymphomas CURRENT INDICATIONS
Refractory hodgkins diseases
Myelodysplasia • High risk aml/cml in first remission
• second remission aml
[Link] myeloma • second remission all if there is hla compatible
sibling donor
4. pediatric solid tumors • first remission all with cns involvement / ph
Neuroblastoma Chromosome postivity
Ewings sarcoma • low grade lymphoma after chemo failure
• childhood aml/ all in second / subsequent
5. adult solid tumors remissions
Small cell of lung
Testicular carcinoma
 85

ADVANTAGES DISADVANTAGES

• Potential late side effects

• No sparing of sanctuary sites (testis, brain) Sterility
• Dose homogeneity regardless of blood supply Cataract
• Independent of hepatic & renal functions Growth retardation
• No problems with excretion or detoxification Neurological toxicity
• Ability to tailor the dose distribution by shielding • Patient body contour irregularities causes
specific organs or by boosting sites adding of compensators

PRE- REQUISITES FOR TBI

• Medical history and evaluation

• Interdisciplinary approach from doctors and health professionals

• RT & BM transplantation facility must be in same center

• Conditions with a low risk of infections is recommended

PHYSICAL EXAMINATION

• Evaluation of oral cavity and dentition

• Neurological evaluation

• PS

• Organ function analysis

CCT> 60 ml/min

AST / ALT < twice the upper level of normal

PFT

EF> 40%

• Infectious disease evaluation

• Sperm banking
 86

TECHNIQUES OF TBI

• Patient comfort and Reproducibility

• Position of patient and stability

• The common factor in the different techniques of TBI is to deliver the prescribed dose of radiation to the
entire body in uniformity of +/-10% of the prescription dose. +/-5% considered as the best.

Bilateral TBI AP-PA TBI MODIFIED

CONVENTIONAL
MACHINES
• Large stationary Beam ,
PATIENT SITTING OR LYING STANDING stationary patient
DOWN ON A COUCH
• Irradiated anteroposteriorly by Extended SSD technique
Good Patient comfort parallel opposed fields while Collimator removal method
positioned upright several meters
Less homogeneous dose distribution from the source • Moving techniques
due to variable body thickness,
needs compensating blocks. • More homogeneous dose Translational beam method
distribution Sweeping beam method

• The principle of the technique is

that the standing TBI allows
shielding of certain critical organs
from photons and boosting of
superficial tissues in the shadow of
the blocks with electrons
 87

DOSE PRESCRIPTION POINT

The TBI dose is prescribed to a point inside the body

Midpoint at the level of the umbilicus

Prescribed dose must be within ±10% of the prescribed point dose

Uniformity of dose is achieved with the use of bolus or compensators

High dose TBI single session or 6 fractions of 200 cGy)

DOSE FOR TBI

 Low dose TBI 10–15 fractions of 10–15 cGy each;

 Half-body irradiation 8 Gy delivered to the upper or lower half body in a single session

Total nodal irradiation, with a typical nodal dose of 40 Gy delivered in 20 fractions.

DOSE PRESCRIPTION

• High Dose TBI – 13.2 Gy in 6 fractions over 3 days

• Standard dose TBI – 12 Gy in 6 fractions over 3 days

• Low dose TBI – 2 Gy in single fraction

• Lung is the dose-limiting organ (maximum 10 Gy).

BEAM SPOILER

Skin/ surface doses in Megavoltage beams is less than D max

 88

Beam spoiler has to be positioned close to the patient, For build-up the surface dose up to at least 90% of
the prescribed dose

1-2 cm thick acrylic is sufficient to meet these requirements

The thickness of compensator required along a ray-line depends on:

• the tissue deficit compared to the reference depth at the prescription point, •

material of the compensator (e.g., its density),

• distance of the compensator from the patient,

• depth of the point of dose compensation,

• field size,

• and beam energy A good approximation for the compensator thickness is given by:

Where t c = compensator thickness,

TD = tissue deficit, τ= thickness ratio ~0.7 ρc = compensator physical density

 89

50% transmission block to protect the lungs, chestwall boost by electron beams.

IN-VIVO PATIENT DOSIMETRY

In vivo patient dose can be measured with TLD, diodes with suitable buildup bolus.

Expected doses are calculated taking into account thickness, and off-axis ratio.

Measured and expected doses should agree to within ±5%.

Dose uniformity on the patient should be within ±10%.

TBI Program Implementation

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PROBLEMS OF DOSIMETRY FOR TBI

Phantom size

Irradiation of ionization chamber cable

Non-application of inverse square lay.

Unreliability of monitor chambers for long time irradiation.

TAR, TMR and TPR becomes distance dependent?????

Lacking of output factors if shielding is there?????

The use of TBI in conjunction with bone marrow transplantation involves numerous protocols,
specifying many different regimens:

 single fraction with low dose rate,

 single fraction with high dose rate,
 fractionated TBI,
 hyperfractionated TBI,
 AP/PA technique,
 bilateral technique,
 use of compensators or no compensators,
 blocking of critical organs or no blocking
IMPLEMENTATION OF A TBI PROGRAM:

 patient measurements (AP or lateral separation),

 patient set-up,
 dosimetry,
 quality assurance procedures,
 worksheets specifically designed for TBI.

ACUTE COMPLICATIONS
• Nausea& Vomiting
• Headache
• Fatigue
• Ocular dryness
• Esophagitis
• Loss of apetite
• Erythema/hyperpigmentation
• Mucositis
• Diarrhea
• Fever
 91

CHRONIC COMPLICATIONS
• Ocular – Cataract, dryness, keratitis
• Salivary glands – Xerostomia, dental caries, tooth abnormalities
• Pneumonitis or pulmonary fibrosis
• Hepatotoxicity
• Radiation nephropathy
• Growth abnomalities in children
• Sterility and endocrine abnormalities
• Secondary mets

Bilateral TBI APPA TBI

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 94

CRANIOSPINAL RADIATION

Indications:

Medulloblastoma

Germinoma

Pineoblastoma

Supratentorial PNET

Anaplastic ependymoma

INTRODUCTION

CSI is a very complex technique

Goal is to achieve uniform dosage throughout the subarachnoid space, encompassing the entire
intracranial vault and spinal canal.

Fundamental is

the use of opposed lateral fields including the cranium and upper cervical spinal canal,

matching a posterior spinal field including the full spinal subarachnoid space with cranial field

in larger children, the upper posterior spinal field matching with a separate lower posterior spinal field.

RATIONALE:

Medulloblastoma forms the most common indication for CSI

In medulloblastoma , CSF Dissemination is known in 20 - 30 % of cases, producing a risk of metastases

along the neuraxis.
 95

Posterior fossa, spinal cord, ventricular walls & supratentorial region including the cribriform plate form
the main sites of relapse

Being a radiosensitive tumour, RT is curative in upto 70 % of average risk patients.

DIFFICULTIES

Patient positioning and immobilization difficult, especially in paediatric cases (may require anaesthesia)

Large, irregular target volume

Critical structures, with special importance to paediatric cases, who are potential long term survivors

Problems of matching junctions between the divergent brain and spinal cord fields

OAR

Pituitary

Eyes / Lens

Cochlea / Inner ear

Parotid

Oral cavity

Mandible

Thyroid

Larynx

Heart

Lungs

Oesophagus

Liver

Kidneys

Gonads (Testes / Ovaries)

Target Volume:

Phase I : Craniospinal radiotherapy (two parallel opposed lateral cranial fields

orthogonally matched with the posterior spinal field to cover the entire length of the spinal cord)

Phase II : Posterior fossa boost (whole posterior fossa irradiation or conformal

 96

boost to tumour bed)

EVALUATION:

Detailed history & operative notes.

General physical & complete neurologic examination (ophthalmoscopy included)

Gadolinium enhanced pre-op MRI of the brain & spine.

Immediate post-op MRI brain for residual disease status.

Delayed post-op MRI of the spine (if pre-op scans not done).

CSF cytology

Target Volume:

Entire brain and its meningeal coverings with the CSF

Spinal cord and the leptomeninges with CSF

Posterior fossa – boost

Energy

4-6 MV linac or Co60

Portals

Whole Brain: Two parallel opposed lateral field.

Spine: Direct Posterior field

Scheduling of radiotherapy:

Starting time : within 28 days following surgery

Duration of treatment : 45 to 47 days

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POSITIONING

Immobilization

Simulation

Field arrangement

Matching of CSI

Aligning of spinal field

Implementation of plan

Prone: Supine: Head position

Direct visualization of light More comfortable for the

fields for spine field setup patient. Slightly extended and the
In-anaesthetic patient shoulders pulled down
to avoid beam divergence into the
mandible & dentition.
Facilitates the use of a moving
junction between the cephalad
border of post. Spine field and the
lower borders of cranial fields.

[Link](Thermoplastic devices)for immobilization of the head, cervical

spine & shoulder

[Link] children –inverted full body plaster cast with facial area open

for access for anesthesia

[Link] cradle

[Link] lok

[Link] board: Lucite base plate fitted on which is a sliding semicircular lucite structure for head-rest & chin-
rest.

Slots from A to E to allow various degrees of extension of neck, so as to avoid exit of superior border of the
spinal field through the oral cavity.

Thermocol wedge for supporting the chest wall.

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SIMULATION

Spinal field simulated first, as easier to match divergence of spinal field with the cranial field by means
of collimator rotation

SSD technique

Field width ~ 4 cm in small children to 6 - 7 cm in adults to cover the lateral spinal roots

Gap of 5 mm between spinal and cranial fields

Issues :

Level of craniospinal junction higher (C1 - C2) or lower (C5 - C7)

Determination of the lower border of termination of thecal sac

Total length of the patient’s thecal sac, to decide whether 1 or 2 spinal fields required

JUNCTION

Higher level - C1 / C2 interspace is routinely practised, since overdose at cord is low as compared to low
junction

Lower level - lowest level in the neck with exclusion of the shoulders in the lateral fields (from C5 to
C7), lowers the exit dose to thyroid, mandible, larynx & pharynx

Cause of overdose at the neck region (Halperin IJROBP 1996) :

Narrow neck separation than cranium & dose prescription at midplane

of brain

Couch rotation towards gantry leads to decreased treatment distance.

LOWER BORDER

Traditional recommendation for lower border of spinal field is at inferior edge of S2 (myelogram &
autopsy studies)

It adequately treats majority of patients.

8.7% patients have termination below S2-S3 interspace.

MRI has been advocated to set the lower border of the spinal field as it accurately determines the level of
termination of the thecal sac & the extent of neuraxial disease if present

Helps to minimize gonadal toxicity as radiation scatter to ovaries or testes is dependent on how close the
lower border is to the gonads.

In children, one field is often sufficient to cover the entire length of cord,
 99

single craniospinal junction

ONE OR TWO FIELDS

In adults - two fields required; cranio-spinal & spinal-spinal junction

Usually, 2 spinal fields required if length > 36 cm

Junction between two spinal fields generally placed at L2 - L3

Field matching at both the junctions critical

1. Cranio-spinal junction : various techniques; described subsequently

2. Spinal-spinal junction : no gap / fixed gap / calculated gap can be employed for matching as central axes
of both the beams are parallel

GAP

Proponents of no gap argue that as medulloblastoma is a radiosensitive tumor, small reduction in dose per
fraction or total dose to part of TV, owing to a gap, may produce significant difference in cell kill over a
fractionated course of CSI, seen as local recurrences (Tinkler, IJROBP 1995)

Proponents of gap argue that no gap risks overdose at the junction & cervical spine & may result in
disabling late toxicity

Many institutes use a fixed gap ranging from 5 mm - 10 mm

A customized gap calculated for each patient depending on field

length & depth of prescription, is more appropriate

S = ½ L1. d/SSD1 + ½ L2 . d/SSD2

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After gap calculation, the spinal fields are simulated

SSD = 100 cm

Width - vertebral body + 1 cm to include the intervertebral foramina; width 5 - 7 cm

Ensure that the spine field is not exiting through oral cavity

Mark the divergent boundary of the superior margin of spinal field (red line) on the lateral aspect of neck
to provide a match line for the lateral cranial field (blue line)

Open length of field to a maximum length and mark inferior border

If adequate coverage inferiorly (upto 4th sacral foramen),

Nothing else required. If not, additional spinal field required

AP width includes entire skull with 2 cm clearance

Superiorly, clearance of ~ 4 cm to allow for symmetric field reduction while doing junction shift

Inferiorly, the border is matched with superior border of spinal field (typically placed at C3 - C4
junction)

to provide adequate margin to posterior fossa tumour

to facilitate matching with the spinal field.

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SHIELDING

Critical to appropriately shape the shielding particularly in frontal (cribriform plate) & temporal regions as

recurrences due to inadequate coverage are known.

SFOP defines the inferior border of lateral brain field to be 5mm below the orbital roof.

Lens can be adequately shielded using MLC’s of smaller leaf width (lower penumbra).

MATCHING

Collimator rotation (7 - 10°) to match divergence of spinal field with the cranial field

Couch rotation (~ 6°) to match divergence of cranial field with the spinal field

With use of these, no collimator or couch rotation required

Half beam block

Asymmetric jaws

Penumbra trimmers
 102

COLLIMATOR ROTATION (7 - 10°)

Cranial field is set up so that caudal field margin is parallel with the diverging superior margin of the
spinal field

Collimator angle = tan-1 {½ L1/SSD}

L1 is spinal field length.

COUCH ROTATION (~ 6°)

To match the diverging cranial fields with the diverging spinal field the couch must also be rotated in
addition to the collimator rotation.

Couch angle = tan-1 { ½ L2/SAD}

L2 is cranial field length

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FIXED JUNCTION OR MOVING JUNCTION?

Owing to lateral scatter of photons & electrons, a gap on skin as defined by the light beam will be reduced
by 1-2mm at depth

(Tatcher, 1989, IJROBP).

At doses relevant for medulloblastoma, a 5mm overlap at 4 MV photons can result in 30 to 40%
overdose i.e. 14Gy for 36Gy prescribed dose, which may exceed cord tolerance

(Hopulka, 1993, IJROBP)

Systematic error during radiotherapy delivery could further lead to an overlap or gap. Acceptable
systematic set up error for CSI is 2 mm

Concurrent CT recently being used for high risk patients can also result in long term neurotoxicity.

Moving the junction / Feathering after every 5 to 7 fractions smoothes out any overdose or underdose
over a longer segment of cord

Done every few fractions (every 7 #)

Can be done either cranially or caudally.

Cranial inferior collimator is closed & spinal superior collimator is

advanced by the same distance superiorly (if junction to be shifted

cranially).

Similarly, lower border of superior spinal field & superior border of

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inferior spinal field are also shifted superiorly, maintaining the

calculated gap between them.

Usually shifted by 1 to 2 cm each time.

POSTERIOR FOSSA BOOST

Anterior: posterior clinoid process (avoid pituitary)

Posterior: internal occipital protuberance

Inferior: C1-C2 interspace

Superior: Midpoint of foramen magnum & vertex or 1 cm above the tentorium (as seen on MRI)

Field arrangement - two lateral opposing fields

3DCRT boost to the pre-op tumor bed with margins

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 106

3 –DIMENSIONAL CONFORMAL RADIOTHERAPY

What is 3D-CRT?

• Based on 3D anatomic information and dose distribution conforms to the target, and avoids critical
organs and normal tissues.

• May also include clinical objectives such as TCP and NTCP

Difficulties of 3D-CRT:

• Tumor (CTV) delineation

• Treatment uncertainties (setup uncertainty, organ motion, etc.)

• Lack of clinical data to verify TCP and NTCP models

STEPS OF 3DCRT

1. Positioning and Immobilisation

2. Imaging and Data Acquisition
3. Image Registration
4. Image Segmentation
5. Field Multiplicity and Collimation
6. Plan Optimization
7. Plan Evaluation
8. Dose Calculation

1. Positioning an Immbolisation :
Important component of conformal RT
• Position
– Should be comfortable & Reproducible
– Should be suitable for beam entry, with minimum accessories in beam path
• For this purpose positioning devices may be used
• Positioning devices are ancillary devices used to help maintain
the patient in a non-standard treatment position.
Patient is immobilized using individualized casts or moulds.
• An immobilization device is any device that helps to establish and maintain the patient in a fixed,
well-defined position from treatment to treatment over a course of radiotherapy-reproduce the
treatment everyday.
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2. Imaging and Data Acquisition :

• It provides foundation for treatment planning
• Usually more than one imaging modalities are required for better
delineation of target volume
• Images are acquired for :
– Treatment planning
– Image guidance and/or treatment verification
– Follow-up studies (during & after treatment)
• No single imaging modality produces all the information, needed for the accurate identification
and delineation of the target volume and critical organs.
• Various imaging modalities used are : – CT – MRI – PET-CT
• Advantages of CT
– Gives quantitative data in form of CT no. (electron density) to account for tissue heterogeneities
while
computing dose distribution.
– Gives detailed information of bony structures
– Potential for rapid scanning
– 4 -D imaging can be done.
– Widely available; (relatively) inexpensive
Advantages of MRI
– No radiation dose to patient
– Unparalleled soft tissue delineation
– scans directly in axial, sagittal, coronal or oblique planes
– Vascular imaging with contrast agents
ADV. of PET/CT
– Earlier diagnosis of tumor
– Precise localization
– Accurate staging
– Precise treatment
– Monitoring of response to treatment
Steps :
CT is done with pt in the treatment position with immobilization device if used.
• Radio opaque fiducial are placed .
• These fiducial assist in any coordinate transformation needed as a result of 3D planning and
eventual plan implementation.
• A topogram is generated to insure that patient alignment is correct & then using localizer, area to
be scanned is selected.
• The FOV is selected to permit visualization of the external contour, which is required for accurate
dose calculations.
• Using site dependent protocols, images are acquired.
• The planning CT data set is transferred to a 3D-TPS or workstation via a computer network.
 108

TREATMENT PLANNING SYSTEM :

TPS provides tools for
– Image registration
– Image segmentation or contouring
– Virtual Simulation
– Dose calculations
– Plan Evaluation
– Data Storage and transmission to console
– Treatment verification

3. Image registration :
• registration allows use of complementary features of different scan types.
• Employs a unique algorithm that allows full voxel to voxel intensity match, Image Fusion
automatically correlates thousands of points from two image sets, providing true volumetric fusion
of anatomical data sets.
• This requires calculation of 3D transformation that relates coordinates of a particular imaging
study to planning CT coordinates.
• Various registration techniques include
– Point-to-point fitting,
– Line or curve matching
– Surface or topography matching
– Volume matching
• Identifying the volume of a tumour on a preoperative scan and transferring it to the postoperative
treatment planning scan to define the target volume.
• Visualizing CNS structures more clearly seen on MRI and mapping them to CT image for
planning-fusion
• Combining functional or biochemical signals from emission tomography onto CT scans for
planning purposes.
• For organ motion studies
• Image guidance
• For follow-up studies
• 4D CT
• Image registration allows computation of cumulative doses from multiple plans done on different
image sets for same patient.
• Point-based registration - minimizes discrepancy between corresponding point pairs
• Surface-based registration – minimizes discrepancy between two surfaces
• Image (intensity)-based registration – minimizes a similarity metric (mutual information, cross
correlation, etc.) between two images.
• Deformable registration – usually image-based, point-to-point transformation to minimize a
similarity metric between two images.
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4. IMAGE SEGMENTATION OR CONTOURING :

Most labour-intensive component of 3-D CRT
• Necessary for the qualitative and quantitative evaluation of treatment plan.
• Reconstructed sagittal & coronal images provide additional orientation cues & are useful in
defining spatially consistent volumes of interest.
• Segmentation is done manually or automatically delineating anatomic regions of interest on a
slice-by-slice basis
• The segmented regions can be rendered in different colors.
• High contrast structures e.g. lungs, bones & air cavities can be contoured with edge detection &
edge tracking techniques.
• The computer automatically tracks path of a specified pixel value &connects the pixels into a
contour outline
• Basic features of contouring software are manipulating image contrast and brightness, zoom, pan,
sampling pixel values, distance measurement.
• Contours drawn on a limited number of widely separated image sections can be interpolated.
Volume definitions:
ICRU 50 ICRU 62 ICRU 83
• Two volumes should be Set up Margin (SM): • Gross tumor volume
defined prior to treatment • Clinical target volume
planning, these volumes are: • It accounts for the • Planning target volume
– Gross tumor volume uncertainties in patient • Organ at risk or OAR
(GTV). positioning and aligning of • Planning organ-at-risk volume
– Clinical target volume therapeutic beams. or PRV
(CTV). • Internal target volume or ITV
• It includes the treatment • Treated volume or TV
• During the treatment planning planning session as well as all • Remaining volume at risk or
process, other volumes have to the treatment sessions. RVR
be defined.
– Planning target volume Planning organ at risk
(PTV). volume
– Organs at risk. (PRV): • An integrated margin
must be added to the OR to
• As a result of treatment compensate for variations
planning, further volumes can including the movement of
be described. These are: organ as well as setup
– Treated volume (TV). uncertainties.
– Irradiated volume (IRV)
• In particular the internal
margin & the setup margin for
the OR must be identified. This
leads to the concept of PRV.
 110

Biological Target Volume :  A target volume that incorporated data from molecular imaging
techniques  Target volume drawn incorporates information regarding:  Cellular burden  Cellular
metabolism  Tumor hypoxia  Tumor proliferation  Intrinsic Radioresistance or sensitivity

Digitally Reconstructed Radiograph-DRR

A synthetic radiograph produced by tracing ray-lines from a virtual source position through the CT
data to a virtual film plane .
The digitally composite radiograph is a type of DRR that allows different ranges of CT numbers
related to a certain tissue type to be selectively suppressed or enhanced in the image.
• It is analogous to conventional simulation radiographs.
• DRR is used
– for treatment portal design
– for verification of treatment portal by comparison with port films or electronic portal images
– provides planar reference image for transferring 3D treatment plan to clinical setting

Beam Eye View-BEV

• In BEV observer’s viewing point is at the source of radiation looking out along axis of radiation
beam.
– Demonstrates geometric coverage of target volume by the beam
– Shielding & MLCs are designed on BEV
– Useful in identifying best gantry, collimator, and couch angles to irradiate target & avoid adjacent
normal structures by interactively moving patient and treatment beam.

Room Eye View-REV

• The REV display provides a viewing point simulating any arbitrary location within the treatment
room. • The REV helps
– To better appreciate overall treatment technique geometry and placement of the isocenter

5. Field Mutliplicity and collimation: MLCS

– Gantry angle,
– Collimator length, width & angle,
– MLC leaf settings,
– Couch latitude, longitude, height & angle.

6. Plan Optimization :
 Refers to the technique of finding the best physical and technically possible treatment plan to
fulfill the specified physical and clinical criteria.
 A mathematical technique that aims to maximize (or minimize) a score under certain constraints.
 It is one of the most commonly used techniques for inverse planning.
The objective of the Optimization process is to vary the beam intensities so that the dose
requirement is best approximated. This could be based on a ‘Cost Function’ - a figure of merit
 111

based on the specification for target and sensitive organ dose requirement. Or simply trying to
match the dose requirement pattern.
• During the optimization process, each beam is divided into small “beamlets”
• Intensity of each is varied until the optimal dose distribution is derived
• We can Optimize following parameters
– Intensity maps
– Number of intensity levels
– Beam angles
– Number of beams
– Beam Energy
 Types:
 Physical Optimization Criteria: Based on physical dose coverage

 Biological Optimization Criteria: Based on TCP and NTCP calculation

 A total objective function (score) is then derived from these criteria.
 Priorities are defined to tell the algorithm the relative importance of the different planning
objectives (penalties)
 The algorithm attempts to maximize the score based on the criteria and penalties.

7. PLAN EVALUATION :
• The following tools are used in the evaluation of the planned dose distribution:
– 2-D display : • Isodose lines • Color wash
• DVHs (Dose volume histograms ) - Dose distribution statistics.
–
2D EVALUATION
• Isodose lines superimposed on CT images
• Color wash
- Spectrum of colors superimposed on the anatomic information represented by modulation of
intensity – Gives quick over view of dose distribution
– Easy to assess overdosage in normal tissue that are not contoured.
– To assess dose heterogeneity inside PTV
• Slice by slice evaluation of dose distribution can be done.
 112

DOSE VOLUME HISTOGRAM – DVH

• DVHs summarize the information contained in the 3-D dose distribution & quantitatively
evaluates treatment plans.
• DVHs are usually displayed in the form of ‘per cent volume of total volume’ against dose.
• The DVH may be represented in two forms:
– Cumulative integral DVH
– Differential DVH.
Cumulative DVH Differential DVH
• It is plot of volume of a given structure • The direct or differential DVH is a plot of
receiving a certain dose. volume receiving a dose within a specified dose
• Any point on the cumulative DVH curve interval (or dose bin) as a function of dose.
shows the volume of a given structure that • It shows extent of dose variation within a
receives the indicated dose or higher. given structure.
• It start at 100% of the volume for zero dose, • The ideal DVH for a target volume would be a
since all of the volume receives at least more single column indicating that 100% of volume
than zero Gy. receives prescribed dose.
• For a critical structure, the DVH may contain
several peaks indicating that different parts of
the organ receive different doses.

3-D DOSE CLOUD:

Map isodoses in three dimensions and overlay the resulting isosurface on a 3-D display with surface
renderings of target & other contoured organs.

DOSE STATISTICS
• It provide quantitative information on the volume of the target or critical
structure and on the dose received by that volume.
• These include:
– The minimum dose to the volume
– The maximum dose to the volume
– The mean dose to the volume
– Modal dose
• Useful in dose reporting.

• The planned dose distribution approved by the radiation oncologist is one in which
– a uniform dose is delivered to the target volume (e.g., +7% and –5% of prescribed dose)
– with doses to critical structures held below some tolerance level specified by the radiation
oncologist
• Acceptable dose distribution is one that differs from desired dose distribution
– within preset limits of dose and – only in regions where desired dose distribution can’t be
physically achieved.
 113

DOSE CALCULATION :

• Correction-based: semi-empirical, based on measured data such as TMR, OCR, etc.

• Model-based: based on phase-space data (energy spectra, angular distribution), Monte-Carlo

generated dose kernels, ray-tracing 3D inhomogeneity correction.

• Monte Carlo: simulation of physical events by random sampling; commonly used codes EGS4,
MCNP, FLUKA’ GEANT, etc; still too slow for routine clinical use.

8. PLAN IMPLEMENTATION :
• Once the treatment plan has been evaluated & approved, documentation for plan implementation
must be generated.
• It includes – beam parameter settings transferred to the treatment machine’s record and verify
system, – MLC parameters communicated to computer system that controls MLC system of the
treatment machine,
– DRR generation & printing or transfer to an image database.

9. PLAN VERIFICATION :
• Involves mapping the plan fields onto a phantom, to create a verification plan & comparing the
results with measurements made on that phantom.
• Assuming that validity of results for the phantom can be extrapolated to the patient.
• CT images of the IMRT phantom with ionization chamber in the slot, are taken with 2.5mm slice
thickness.
• Phantom images are transferred to TPS & body of phantom is contoured.
• A phantom plan is created by superimposing the patient plan on to the IMRT phantom.
• All gantry angles are made to zero-degree orientation for the measurement without changing
anything further so that isodose and profile remained the same, & it is called verification plan.

************
 114

Intensity Modulated Radiation Therapy

IMRT refers to a radiation therapy technique in which nonuniform fluence is delivered to the patient from
any given position of the treatment beam using computer-aided optimization to attain certain specified
dosimetric and clinical objectives.

IMRT is an advanced form of 3D CRT.

IMRT RATIONALE :

1. More conformal than 3D CRT

2. Dose distribution more homogeneous within PTV
3. A sharp fall off PTV boundary
4. Reduction of normal tissue dose
5. To create concave isodose surfaces or low-dose areas surrounded by high dose.
6. Lower rate of complication-lower cost of patient care following treatment
7. Large fields and boosts can be integrated in single treatment plan
8. Radiobiologic advantage.
FEATURES :

 Divides each treatment field into multiple segments upto (500/angle)

 Allows dose escalation to most aggressive tumor cells; best protection of healthy tissue
 Modulates radiation intensity; gives distinct dose to each segment
 Uses 9+ beam angles, thousands of segments
 Improves precision/accuracy
 Requires inverse treatment planning software to calculate dose distribution.
IMRT Planning

IMRT planning is an inverse planning.

• It is so called because this approach starts with desired result (a uniform target dose) & works backward
toward incident beam intensities.

• After contouring, treatment fields & their orientation ( beam angle) around patient is selected.

• Next step is to select the parameters used to drive the optimization algorithm to a particular solution.

•Dose-volume constraints for the target and normal tissues are entered into the optimization program of
TPS

– Maximum and minimum target doses

– Maximum normal tissues doses

– Priority scores for target and normal tissues

 115

• The dose prescription for IMRT is more structured and complex than single-valued prescription used in 3-
D CRT & conventional RT

• Ideally some dose value is prescribed to every voxel.

IMRT DELIVERY

• Having calculated the fluence distributions or fluence maps for each field angle, one now needs to have a
means of delivering those fluence maps.

• Methods to deliver an IMRT treatment are:

MLC BASED IMRT

STEP & SHOOT IMRT

• In static or step & shoot mode the intensity modulated fields are delivered with a sequence of small
segments or subfields, each subfield with a uniform intensity.

• The beam is only turned on when the MLC leaves are stationary in each of the prescribed subfield
positions.

• Adv. of SMLC

– Simple concept resembles conventional treatment

– Easy to plan, deliver & to verify

– an interrupted treatment is easy to resume

– fewer MUs in comparison to DMLC

– less demanding in terms of QA

 116

• Disadv. of SMLC

– Slow dose delivery (5 min/field)

– Hard on MLC hardware

DYNAMIC MODE

• In the DMLC or sliding window mode, the leaves of MLC are moving during irradiation i.e. each
pair of opposing leaf sweeps across target volume under computer control.

• Adv. Of DMLC

– Better dose homogeneity for target volumes

– Shorter treatment time for complex IM beams

• Disadv of DMLC

– More demanding in terms of QA

• leaf position (gap), leaf speed need to be checked

– Beam remains on throughout – leakage radiation increased

– Total MU required is more than that for SMLC

• increased leakage dose

 117

IMAT

Uses rotational cone beams of varying shapes and varying dose weighings to achieve intensity
modulation.

It is alternative to tomotherapy.

Advantages over tomotherapy

1. Does not need to move the patient.

2. Uses non coplanar beams and arcs
3. great value for brain and head and neck tumors.
4. Uses conventional linac hence complex rotational
5. simple palliative treatment can be delivered with the same unit.
VMAT

•VOLUMETRIC MODULATED ARC THERAPY/ RAPID ARC

•Delivers a precisely sculpted 3D dose distribution with a single 360 degree rotation of LIN-AC Gantry.

•Treatment Algorithm depends upon three parameters-

1/ Rotation speed of the Gantry.

2/ Shape of the treatment aperture using multileaf collimator leaves.

3/ Delivery dose rates.

•Delivers dose to the whole volume, rather than slice by slice.

•Treatment planning algorithm ensures the treatment precision and helps to spare the normal tissue.
 118

Difference between 3DCRT and IMRT

[Link] 3 DCRT IMRT

1. Forward Planning Inverse Planning
2. Less Conformal More Conformal
3. No need of volume and OAR OAR Target and OAR must be specifiedd
4. Uniform dose High Gradient dose
5. Dose defined to volume but specified at Isocenter dose undefined
isocenter
6. Analogue dose distribution Digital dose distribution
7. No dose escalation More dose escalation
8. Target dose less homogenous Target dose more homogenous
9. No dose intensity modulation Dose intensity can be
modulated within target
10. No sharp fall off sharp fall off PTV boundary
11. cannot avoid selectively selectively avoid critical structures and tissues
12. Exact solution Approximate solution
13. Less reduction of normal  More reduction of normal tissue dose
 creation of concave isodose surface
 Simultaneous integrated boost
 More chances of geographical
 miss of target
14. Less time consuming More time consuming
15. Less Expensive More Expensive

LIMITATIONS OF IMRT

 Many dose distributions physically not achievable

 Interfraction variation
 Positioning
 Displacement and distortion of internal anatomy
 Intrafraction motion
 Changes of physical and radiobiologic characteristic of tumor and normal tissue
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TOMOTHERAPY

What is Tomotherapy?

A type of IMRT technique in which the radiation is delivered slice-by-slice. Hence the use of
the Greek prefix tomo-, which means "slice“.

Two types: Serial : The delivery of multiple fan beams with the couch indexed one to two slices at a time

Helical :Continuous synchronized gantry and table motion.

SERIAL TOMOTHERAPY : THE PEACOCK SYSTEM

 The NOMOS collimator device is called the MIMiC (multileaf intensity-modulating collimator)

 Is used in conjunction with a TPS, PEACOCK PLAN

 The MIMiC and the PEACOCK PLAN together are known as the PEACOCK system

 A special indexing table called the CRANE, CRANE: capable of moving the couch longitudinally
with a 300-lb weight to distances of 0.1 to 0.2 mm

 A patient fixation device called the TALON, TALON: An invasive head fixation system with two
bone screws into the inner table of the skull.

 And an ultrasound-based target localization system called the BAT

 The MIMiC collimator consists of a long transverse slit aperture provided with two banks of 20
leaves each

 Each leaf can be moved independently and can provide an opening (at isocenter) of either (1 cm × 1
cm) or (1 cm × 2 cm)

 Each bank can therefore treat 1- or 2-cm-thick slices of tissue 20 cm in diameter

 Because there are two such banks, a 2- or 4-cm slice of tissue can be treated at one time

 The fan beam thickness can be either 0.8 or 1.6 cm

 The MIMiC leaves are made of tungsten and are approximately 8 cm thick. Each leaf can be
switched in 100 to 150 milliseconds

 Radiation delivery consists of a machine that rotates around the patient while the beam is on and the
leaves rapidly move in and out depending on the target

 After two simultaneous slices have been delivered, the patient is translated by two slice thicknesses
and the next two slices are delivered until the total treatment volume is covered. The determination
of leaf sequencing is done by a computerized treatment planning system
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Limitation of Serial Tomotherapy:

1. Limited rotation ~370°

2. Inability to move the couch smoothly and automatically during radiation delivery
3. Unable to image the patient in treatment position
4. Therefore, unable to assure the accurate placement of the high dose volume with respect to
the malignant region
HELICAL TOMOTHERAPY

 The linear accelerator is mounted on a CT-like gantry and rotates through a full circle

 A method of IMRT delivery in which the linac head and gantry rotate while the patient is
translated

 The problem of interslice matchlines is minimized because of the continuous helical motion of the
beam around the longitudinal axis of the patient.

1. DESIGN  Nominal SAD = 85 cm

PRINCIPLES:  1 – 6 rotations per minutes
 2 operating energies
 6 MV photon beam output for treatment
 3.5 MV photon for imaging
 No flattening filter
 However a beam hardener and electron stopper is provided
 Output increased to 8 Gy/min at center of bore – 2 times that of
periphery

2. JAW  23 cm of 95% tungsten shielding is used in the linac support fixture

CHARACTERISTICS and combination of primary collimator and jaws
 The average leakage from head is 0.01%.
 Independent Y jaws have been provided – slice thickness .5 – 5 cm at
the isocenter
 Main scatter is from the beam itself and minimal scatter from the
head.

3. BEAM  For treatment delivery the full rotation is divided into 51 projections.
CHARACTERISTICS:  Each projection covers an arc segment of 7º
 Each projection is characterized by it's own leaf opening and closing
pattern
 Between each projections all leaves are closed for a short period of
time – highly segmented step and shoot approach
 The rotational fan beams overlap with each point seeing from 2 to 5
rotations or about 100 to 250 possible beamlets
 Three fan beam widths used – 1, 2.5 and 5 cm

4. BINARY MLC  Binary MLCs are provided –

CHARACTERISTICS: 2 positions – open or closed
 Consist of 64 leaves
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 Open-close time of 20 ms
 Width 6.25 mm at isocenter
 10 cm thick
 Interleaf transmission –
0.5% in field and 0.25% out field

5. COUCH  Flat Couch provided allows automatic translations during treatment

CHARACTERISTICS  Target Length long as 160 cm can be treated
 Automatic longitudinal and vertical motions possible
 Manual lateral couch translations possible
 Possible to treat anywhere within a cylindrical volume 40 cm in
diameter by 160 cm long

6. WORKSTATION:  Includes:
 An operator station
 Planning station
 32 CPU computer , cluster attached to database server
 Treatment machine

Advantages Disadvantages
 Owing to daily adaptation of treatment  The integral dose, is much higher in patients
techniques, higher dose can be delivered and receiving tomotherapy
so higher cure rates  With low dose radiation, increased risk of
 Normal tissue sparing, so lower radiation-induced second malignancies
complication rate  The risk is significantly higher in paediatric
 Can sculpt powerful and precise radiation and young adult patients
beam to hard to reach areas  Overconfidence in the accuracy of imaging
 Multiple tumor sites, various sizes, one increases the chance of missing lesions
region or several can be treated to the same  Expensive and resource-consuming treatment
dose or multiple different doses
 Patients who have reached their maximum
radiation tolerance dose of traditional
radiation may be a candidate for
tomotherapy radiation
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IMAGING

This imaging is generally performed with standard diagnostic imaging equipment or CT-simulators

MVCT may be used under special circumstances

The CT detection system can be used for:

1. Patient set-up verification and repositioning, if necessary

2. Verification of leaf positions during treatment

3. Reconstruction of the actual dose delivered to the patient with the possibility of making corrections
in subsequent fractions

 Although megavoltage CT images generally have inferior tissue contrast compared with kilovoltage
CT

Definition of Target Volume and Organs at Risk

The target volume as well as the organs at risk are contoured at the CT-simulator or on a conventional
3-D treatment planning computer

After the set target volume is ready to be transferred to the treatment planning system
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Data Transfer to Tomotherapy Planning Computer:

 Datas of 3-D imaging & TV of OAR are transferred to the tomotherapy treatment planning
computer

 Delivery optimization calculations is performed

Optimized Planning:

 The planning constraints or objectives are defined

 Uses "inverse planning"

 The computation is carried out until all the constraints are satisfied or have been optimized

 Involves the delivery of tens of thousands or even hundreds of thousands of pencil beams of
radiation

 The optimization takes approximately one hour of computation time

Creation of Verification Data:

 Consists of the expected beam intensity at the detector array for each gantry angle and couch
position

 This intensity pattern is referred to as a "sinogram“

 because each point irradiated in the patient maps a sine wave pattern at the CT detector as the
gantry revolves

 This sinogram is used to register the position of the patient

Transfer of Planning Data to the Treatment Unit:

 Once the multileaf delivery configuration has been established by the treatment planning
optimization calculation

 the leaf positions for each gantry angle and couch position are transferred to the tomotherapy unit
for delivery implementation

Phantom Verification:

 Involves treating a phantom with the clinical multileaf collimator configuration and performing the
actual measurements to verify its accuracy

Pre-Treatment Megavoltage CT:

 A pre-treatment CT scan is performed for the verification of the patient position and the location of
the internal anatomy
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 This allows for the relocation of the patient or for the replanning of the MLC configuration

 This ensures dose delivery to the right tissues within the patient

Delivery Modification:

 dependent on the information obtained from the pre-treatment megavoltage CT

Tomotherapy Delivery:

 The dose is delivered according to the planned multileaf configuration

 The leaves moving in and out while the beam is on

 The gantry is rotating and the couch is moving simultaneously

Delivery Verification:

 While the patient is being treated, the detector array is actively measuring the radiation transmitted
through the patient

 This is used to determine actual radiation incident on the patient

 Can be used to verify dose delivery during or after treatment

Is a new, advanced, state of the art, helical IMRT delivery system with CT image guidance (highly
integrated adaptive radiotherapy)

The system was developed at the University of Wisconsin-Madison

The first patient was treated in 2003

Tomotherapy Hi-Art can Deliver: , IMRT, IGRT , SBRT, SRS

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STEREOTACTIC RADIOTHERAPY

Stereotaxy (stereo + taxis – Greek, orientation in space) is a method which defines a point in the patient’s
body by using an external three-dimensional coordinate system which is rigidly attached to the patient.

 This results in a highly precise delivery of the radiation dose to an exactly defined target (tumor) volume.

Stereotactic Radiosurgery Stereotactic Radiotherapy

The delivery of a single, high dose of irradiation to a The delivery of multiple fractionated doses of
small and critically located intracranial volume, radiation to a
sparing normal definitive target volume sparing normal structure
structure (both intra as well as extracranial)
The aim is to encompass the target volume in the
high dose area and, by means of a steep dose
gradient, to spare the surrounding normal tissue

RADIOBIOLOGY

The intention of SRS is to produce enough cell kill within the target volume in a single fraction in order to
eradicate the tumor.

 This single high irradiation dose can produce considerable side effects in normal tissue located close to
the tumor or within the target volume.

 The SRT combines the precision of target localization and dose application of SRS with the
radiobiological advantage of fractionated radiotherapy, i.e., breaking the total dose into smaller parts and
thus allowing repair of DNA damage in normal tissue during the time between fractions.

 Time intervals of more than 6 h between fractions can significantly reduce the risk of side effects in
normal tissue.
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STEROTACTIC CO-ORDINATES

The stereotactic coordinates are a cartesian three dimensional coordinates system attached to the
stereotactic frame in a rigid relationship.

The origin of the stereotactic coordinates system is generally in the center of the volume defined by the
stereotactic frame:

The x and y axes correspond to the lateral and frontal side of the frame and the z axis to the cranio-
caudal direction.

The main steps in the planning and delivering of stereotactic irradiation treatment are:

1. Rigid application of the stereotactic frame to the patient

2. Imaging (CT, MRI, angiography) of the patient with the frame and localizer attached to the frame

3. Treatment planning

4. Positioning of the patient for the stereotactic radiation therapy

5. Delivery of the irradiation

6. Quality assurance.

STEREOTACTIC FRAME :

Stereotactic radiotherapy is based on the rigid connection of the stereotactic frame to the patient during
CT, MRI, and angiography imaging

The stereotactic frame is the base for the fixation of the other stereotactic elements (localizer and
positioner) and for the definition of the origin (point 0) of the stereotactic coordinates.

During the whole treatment procedure, from the performance of the stereotactic imaging to the delivery
of the irradiation treatment, the stereotactic frame must not be removed from the patient.

In case of relocatable frames it must be assured that the position of the patient is exactly the same
relative to the

frame after reapplication of the relocatable frame

There are different stereotactic frame systems described in detail in the literature:

the BRW system

the CRW system

the Leksell system

the BrainLAB system

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Each system is different with regard to material of the stereotactic frame, design, and connection with the
localizer and positioner and accuracy of repositioning.

Imaging is used in stereotactic radiotherapy for:

(a) Localization and positioning;

(b) Definition of target volume and organs at risk; and

(c) Calculation and 3D representation of the isodose distribution

MRI describes the anatomical structures of soft tissue with a high accuracy

CT is important for the delineation of bone and soft tissue

Positron emission tomography (PET) and single photon computed emission tomography (SPECT) offer
additional information about tumor extension and biology

Angiography is essential for the visualization of the arteriovenous malformations

Most stereotactic systems use CT for localization

During the CT investigation the localizer is attached to the frame

The localizer is a box with CT-compatible fiducial markers on each plane, which are visualized
on CT on each scan; thus, the localizer defines the link between the stereotactic coordinates and the
imaging coordinates, so that for any point in the imaging the 3D stereotactic coordinates can be
determined.

The stereotactic frame, the patient fixation system, and the localizer form a fix unit.
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PLANNING

1. DEFINING THE TARGET VOLUME :

 The tumor-specific morphology, the growth pattern of the tumor, and the anatomical relationship
to the normal tissue are essential parameters in defining the target volume.
 Of major importance for the stereotactic radiation therapy is the delineation of the organs at risk.
 All the organs at risk which may get significant dose have to be delineated.
2. Defining the Stereotactic point.
The target point is the point in the target volume that must be positioned with exact precision in
the isocenter of the LINAC.
The position of the target point can be defined interactively.
One or more target points can be defined.
In stereotactic planning programs the coordinates of the target points are related in such way that
the resulting dose distribution meets the clinical requirements.
The planning system outputs the position of these points in stereotactic coordinate.
Prior to therapy, these coordinates will be used to correctly position the patient.
This is performed with a positioner, a device attached to the stereotactic frame, which allows the
connection of the stereotactic coordinate system to the room coordinate system, where the isocenter
of the treatment device is defined

3. Planning of the Radiation Technique the number and position of the target points;
the number of the radiation arcs and static fields and their shape;
the position of the gantry and radiation table; and
the radiation dose in the target point for each field or arc.
The stereotactic radiation is characterized by a very steep dose fall-off on the margin of the target
volume.
 The steep dose gradient is achieved by the use of appropriate collimators and a multitude of
radiation directions.

 Stereotactic Collimators. Tertiary stereotactic collimators for circular or oval target volumes are
attached to the tray holder of the LINAC. The diameter of the irradiated area is defined by the size
of the circular collimators and varies usually between 1 and 35 mm.
Micro-multileaf collimators have recently become available .
The beam shape can be selected by computer or by hand. In this way the contours of the irradiation
field can be adjusted individually to the tumor shape.
Micro-multileaf collimators, in comparison with the traditional multi-leaf collimators, have the
advantage of a decreased leaf width and therefore optimized the resolution (between 1 and 3 mm).

Convergent Radiation Techniques. The radiation techniques are in general isocentric and
implemented by using a rotational technique (using circular collimators or dynamic fields) or a
static-field technique; both can be combined with an isocentric table rotation.
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 In the rotational technique usually five to ten radiation arcs are used.  The size and the angle
between the arcs are variable and are responsible for the conformal isodose distribution.  The
stereotactic irradiation with the micro-multileaf collimator is done with multiple static irradiation
fields (usually 6–12 fields)

4. 3D Dose Calculation
Most of the planning systems use CT images for the calculation of the correct dose.
 The planning software converts the Hounsfield number of the CT data into an electron density.
 Some planning software programs use MRI information only, by considering homogenous soft
tissue density for the calculation of the dose.
 Stereotactic radiation therapy can use simple dose-calculation algorithms because no large-
density inhomogeneities are in the brain.

5. Dose Specification
 The prescribed dose, Do, is the isodose surface which is intended to completely encompass the
PTV.
 The minimal dose, Dmin, and the maximal dose, Dmax, in the PTV have to be specified as well.
 In the radiation plan, based on ICRU 50, different volumes have to be considered as well: PTV,
treated volume, as well as the percentage of the target volume which will be irradiated with a dose
higher than Do.  The maximal dose in the area of risk structures has to be defined as well.

6. Visualization of the Dose Distribution

 The decision for the best radiation plan is made after evaluation of the dose distribution based on
the isodose curves dose volume histograms, conformity index, or mathematical models for the
normal tissue complication probability and tumor control probability, similar to the conventional 3D
radiation.
 The definitive decision for the best treatment plan must be made by the physician, using clinical
judgment, after the rigorous evaluation of the dose distribution in the complete 3D data base.

DELIVERY OF RT
 The positioning of the patient on the LINAC is done by using a stereotactic positioner .
 This instrument allows to project the coordinates of the target point onto orthogonal planes
attached to the stereotactic frame.
 By the use of this projected target point, the patient can be positioned in a way that the target
point and the isocenter of the LINAC overlap exactly.
 The position of the isocenter is indicated by a room-based laser positioning system.
After positioning the patient, the target instrument (positioner) is removed and the radiation can
start.
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 The most important requirement for the use of the isocentric LINAC for RS and stereotactic
radiation therapy is the accuracy of the isocenter: under ideal conditions the axis of the gantry
rotation, the central axis of the beams and the rotation axis of the rotation table convert in one point,
the isocenter
 In general, it is acceptable that the three axes – gantry rotation axis, central axis, and table rotation
axis – meet in a sphere which coincides with the isocenter and has a diameter of approximately 1
mm.  They must be constantly controlled during regular quality-control procedures.

Choice Between SRS and SRT

Tumor volume — As the size of the target lesion for SRS increases, incidental irradiation to the
surrounding normal tissue also increases. This may be important since a much higher dose of
irradiation is administered with SRS compared to fractionated RT.

SRS was not recommended for lesions >4 cm because adequate control could not be achieved
without an unacceptable level of radiation toxicity to surrounding normal tissue.

Proximity to cranial nerves — The proximity of a target to cranial nerves can cause radiation
neurotoxicity, despite the steep decrease in dose outside the intended target Fractionated RT should
be considered when SRS may jeopardize cranial nerve function. Cranial nerves II and VIII are
more sensitive to radiation injury than the other cranial nerves. SRS is generally avoided if the
maximal dose delivered to the optic nerve exceeds 10 Gy.

Location of the lesion — The risk of developing permanent damage following SRS varies
dramatically with the location of the lesion in the brain. Fractionated RT is often preferred to SRS
for the treatment of lesions in the deep gray matter or the brainstem.

ADVANTAGES
 Clinical Outcome-Documented scientific data shows better or equal results compared with
microsurgery, Fewer complications, Reproducible results ,Treatment solution for inoperable
patients, Combined treatment with microsurgery and endovascular techniques extend the
capabilities
 Quality Of Life- Minimally invasive, Less trauma, Faster recovery, Minimal hospitalization,
Fewer complications , Documented efficacy
 Time Factor
DISADVANTAGES :
High cost of purchase and use
Risk of neurological injury
Risk of mechanical inaccuracy
Potential necessity of multiple visits
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Indications
BENIGN MALIGANT
Vascular Meningioma
AVM Pituitary tumors
Functional Acoustic neuromas
Trigeminal Neuralgia Metastatic brain lesions
Research Areas Glioma
. Movement Disorders
. Intractable Pain
. Epilepsy
. Macular Degeneration
. Uveal Melanoma

VARIOUS METHODS OF DELIVERING SRS

1. X knife
2. Gamma Knife and RGS
3. Proton Radiosurgery
4. Tomotherapy
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IMAGE GUIDED RADIATION THERAPY

Definition : A procedure that uses image guidance at various stages of its process: patient data acquisition,
treatment planning, treatment simulation, patient set up and target localization before and during treatment.

Rationale of IGRT- To provide the tools needed to manage both inter and intrafraction motion to improve
the accuracy of treatment delivery.

Inter-fraction motion : Intra-fraction motion :

 changes in tumour position from day-to-  changes in tumour position during a treatment
day. session.
 Factors include therapist’s skill in setting up  The main contributors are normal respiratory,
the patient, variable filling of digestive or cardiac, peristaltic organ motion or along
urinary organs, tumour shrinkage, weight with voluntary movement.
gain or loss or even the patient’s cognitive
state.

Important uncertainties or factors which led advent of IGRT

1. Some concerns of IMRT – prolonged treatment time and steep dose gradient.

2. IGRT when combined with IMRT can reduce the toxicities of Concurrent RT.

3. Use of hypo fractionation in sites, where it distinct radiobiological advantages.

4. Systemic therapies prolonging survival, importance of radiation therapy related toxicities should be
carefully dealt.

5. Advent of functionally based imaging techniques.

Portal 1. KV
and 1) Gantry mounted kV imaging systems on Linac that is orthogonal to the therapy
Radiogra MV x ray beam
phic 2) Ceiling mounted kV imaging system
Imagers  Advantages
(2 D) - good quality images.
- Fluoroscopic mode for observing motion of internal anatomy or implanted
fiducial marker.
 Disadvantages- more susceptibility for artefacts caused by metallic stents.
[Link]
 Most commonly used radiographic imaging tool.
 Uses x ray therapy beams and aSi flat panel image detector.
 Advantages-verification of target
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- In vivo dosimetry
- verifies treatment beam apertures
 Disadvantages- higher dose to the patient
- poor image quality
2. kV 1) Single slice Phillips CT scanner & Varian Clinac 2100EX
Helical CT 2) Seimens medical Linac & moveable Seimens CT scanner

CT on rails : a rail system to transport the patient b/w treatment and CT couches.
Mechanical accuracy of the system is
found to be within 0.5mm.

3. Cone [Link] Cone Beam CT

beam CT  Acquisition of projection images of the patient as the gantry rotates through an arc
at least 180 degree plus cone beam angle ( total ≈200 degree) and filtered back
algorithm is used to reconstruct the volumetric images.
 Geometric calibration is periodically needed.
Limitations
- elevated x ray scatter
- reduces image contrast & introduces cuppy artefacts.
- Image quality is affected by resp motion.

[Link] Cone Beam CT

 Uses EPID mounted on Linac gantry & therapy MV x ray as basic configuration
for CT imaging.
 Advantages and disadvantages are same as tomotherapy.
 MVCBCT has good image quality for bony
structures & acceptable quality for soft tissue.
 Used in H&N, lung and pelvic tumours.

4. MV Combination of MV Helical CT and Linac specifically design to deliver IMRT.

Helical CT
(Tomother Typically low dose(1-2cGy) pre treatment MVCT images are obtained from same
apy) treatment beam with 4MV energy. A CT detector uses a array of 738 channel xenon ion
chamber & FOV of 40cm.

Used for lung, prostate, spinal tumours.

Advantages- MVCT no. are linear to electron density of target helps dose calculation. -
less susceptibility for artefacts d/t metallic implants.

Disadvantages - image quality not as good as diagnostic CT

- higher noise level
- low contrast resolution is less

[Link] Uses BAT system eg. Prostate

nd
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MANAGEMENT OF RESPIRATORY MOTIONS

AAPM TG-76 report recommendations for RMM –

1) RMM should be considered , if range of motion >5mm in any direction or if significant normal
tissue sparing can be gained with use of RMM techniques.
2) Assessment of tumour mobility in 3D. If magnitude of motion <5mm, the use of RMM tech is
unwarranted.
3) If patient specific tumour motion measurement is made, the information should be used in designing
PTV.
4) The Radiation Oncologist & team should be well trained in the procedure and should be available
for participation/assistance.
5) Before deciding RMM, assessment should be made if the pt. can tolerate TMM techniques.
6) Quality Assurance has a crucial role.
4D CT PLANNING REAL TIME TUMOUR TRACKING RTTT

1. Prospective Gating 1. Fluroscopic Bases Tracking systems

2. Retrospective Gating [Link] Mounted

[Link] Mounted

[Link]

2. Electromagnetic Field Tracking

Respiratory Gating by 4 DCT

 Respiratory gating involves the administration of radiation (during both imaging and treatment
delivery) within a particular portion of the patient’s breathing cycle, commonly referred to as the
“gate.”

 Most accurate RMM and may be widely adopted in clinical practice.

2 approaches – internal (implanted fiducial marker)

external gating (RPM system)

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PARTICLE BEAM THERAPY

PROTON BEAM THERAPY

RATIONALE :

 To Reduce dose to non target regions

 Dose escalation
 To Reduce probable second malignancies
 Better constraints to Organ at Risk
PHYSICAL PROPERTIES :

1. Protons are produced from hydrogen gas

 [Link] obtained from electrolysis of deionized water or
 commercially available high-purity hydrogen gas.
 Application of a high-voltage electric current to the hydrogen gas strips the electrons off the
hydrogen atoms, leaving positively charged protons.
2. Proton is the nucleus of hydrogen atom
3. It has a positive charge of 1.6 x 10 19 C
4. Its mass is 1.6x10-27 kg (1840 times of electron)
5. It consists of 3 Quarks(two up and one down)
6. It is the most stable particle in universe with half life of >10 32 years
7. It interacts with electrons and atomic nuclei in the medium through coulomb force a. Inelastic
collisions b. Elastic scattering.
8. Protons scatter through smaller angles so they have sharper lateral distribution than photons.
9. Mass Stopping Power  It is more with low atomic number materials and low with high atomic
number materials.
 146

a. High Z materials= Scattering

b. Low Z materials= Absorption of energy and slowing down Protons

10. Percentage Depth Dose Curve :

 Low entrance dose (plateau)
 Maximum dose at depth (Bragg peak)
 Rapid distal dose fall-off
 Protons have the ability of loosing little energy when entering tissue . But depositing more
and more as they slow down. Finally, depositing a heavy dose of radiation just before they
stop , giving rise to the so-called Bragg peak
 a proton’s linear rate of energy loss “linear energy transfer” (LET) • is given by the Bethe
Block formula
 The range is( the depth of penetration from the front surface to the distal point on the Bragg
peak)
 Bragg peak depends on the initial energy of the protons so the greater the energy, the greater
the range.
MeV Depth
70 4 cm
100 7 cm
150 15 cm
200 25cm
250 37 cm

 The Bragg peak is too narrow to fit the shape & depth of the tumor.
 The spread-out Bragg peak (SOBP): • Extending the dose in depth means An extension in
depth can be achieved by proton beams of successively delivering not just one, but many
Bragg peaks each with different range (energy).
 1) passive scattering. : The modulator spins around in front of the proton beam pulling the
beam back and forward causing a flat topped dose distribution providing the tumor with a
uniform dose.
 2) Scanned beam. : Expand the lateral dimensions of a proton beam by using the
electromagnetic technique to scan the beam laterally & in shape .
11. RBE is 1.1
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PROTON ACCLERATORS

Cyclotron Synchrotron
 It is a fixed energy machine which produces They produce the proton beam .
continuous beam of monoenergitic (250Mev Range) It is a modified Cyclotrons. synchrotron provides
protons. energy variation by extracting the protons when they
 Cyclotrons can produce a large proton beam current have reached the desired energy.
of up to 300 nA and thus deliver proton therapy at a  Produce proton beams of selectable energy, thereby
high dose rate. eliminating the need for the energy degrader and
 Energy Degradators :Modify Range and intensity energy selection devices.
of beam  Beam currents are typically much lower than with
] Energy selection system (ESS) consist of energy cyclotrons, thus limiting the maximum dose rates that
slits, bending magnets, and focusing magnets, is then can be used for patient treatment, especially for larger
used to eliminate protons with excessive energy or field sizes.
deviations in angular direction. - Shielding requirements are less
 The pulsed nature of the beam introduces additional
complexity in certain treatment delivery scenarios,
such as gated treatment of mobile targets and intensity-
modulated proton therapy (IMPT).

Beam Transport System :

The proton beam, whether exiting the ESS or a synchrotron-based system is transported to the treatment
room(s) via the beam transport system.

 Maintenance of beam focusing, centering, spot size, and divergence throughout the beam transport
system is critical to maintaining a high-quality proton beam for treatment delivery.

Beam delivery system :

The proton beam exiting the transport system is a pencil-shaped beam with minimal energy and direction
spread.

 The beam has a small spot size in its lateral direction and a narrow Bragg peak dose in its depth
direction.

 This dose distribution is not suitable for practical size of tumors.

Pencil beam is modified either by [Link] Beam Technique [Link] Beam Technique

Scattering beam technique :

 It aims to produce a dose distribution with a flat lateral profile.

 The depth-dose curve with a plateau of adequate width is produced by summing a number of
Bragg peaks
 148

 Range modulation wheels consisting of variable thicknesses of acrylic glass or graphite steps are
traditionally used for this purpose.

Scanning beam technique :

 As the pencil beam exits the transport system, it is magnetically steered in the lateral directions to
deliver dose to a large treatment field.

 The proton beam intensity may be modulated as the beam is moved across the field, resulting in
the modulated scanning beam technique or IMPT

CLINICAL APPLICATIONS OF PROTON BEAM

Skull base sarcomas :

- Skull-base sarcomas frequently are not amenable to complete resection

- Require very high radiation doses for disease control.
- Proton therapy can achieve dose distributions that often permit the delivery of potentially curative
doses of radiation to the tumor.
- The major advantage is the sharp gradient between the target and brainstem achievable with the
proton plan. The maximum and mean relative doses to the brainstem are 71% and 42% with IMRT
compared to 59% and 11% with protons, respectively.
- In addition, there is a substantial reduction in low-dose exposure to non targeted tissue, which
might result in more acute tolerance of treatment or fewer late neurocognitive sequelae.

Paranasal Sinus Tumors :

They frequently extend into the orbit or anterior cranial fossa adjacent to critical optic structures

 With photon-based therapy, it is often difficult to deliver adequate doses to the entire tumor target
without injury to at least one of the critical optic structures.

 The physician must choose between prioritizing tumor control and preserving vision

 In this particular case, the major advantages to the proton plan compared to the IMRT plan are
[Link] in mean dose to chaism and brain stem 2. Better Dose Homogenity

Craniopharyngioma :

It is usually diagnosed in children and adolescents.

Its suprasellar location places the temporal lobes, hippocampus, hypothalamus, optic chiasm, and nerves
at risk for radiation injury.
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 Reductions in dose to nontargeted brain tissues with proton therapy are likely to result in reduced loss in
neurocognitive and auditory function.

Cranio spinal Irradiation :

Craniospinal axis irradiation is required in  Medulloblastomas  Germ cell tumors  Primitive

neuroectodermal tumors (PNETs)  Ependymomas.

Most patients with these tumors are young and at risk for late effects of radiation.

 The Exit dose from photon therapy exposes the thyroid, heart, lung, gut, and gonads to functional and
neoplastic risks that can be avoided with proton therapy.

Lymphomas :

 Lymphomas frequently involve the Mediastinum

 Typically require only a moderate dose of radiation therapy in conjunction with chemotherapy for
disease control.

 Unfortunately, even low to moderate radiation doses place the patient at risk for late cardiac injury and
second cancers, particularly breast cancers.

Lung Cancers :

 Lung cancers typically are diagnosed at an advanced stage and occur in patients with underlying lung
damage.

 Consequently, concern for protection of unaffected lung tissue often mandates compromise in the tumor
dose.

 A smaller volume of non targeted lung tissue, spinal cord, esophagus, and heart is exposed to radiation
with proton therapy.

The proton plan lowers the risk of  Acute (potentially fatal) pneumonitis  Acute esophagitis, Has impact
on the delivery of chemotherapy, as well as the cardiac exposure, likely correlating with greater chance of
survival.

Prostate Cancer :

Prostate cancer results with IMRT are generally excellent, but dose-escalation trials are significantly
associated with the incidence of gastrointestinal toxicity.  Dosimetry studies show that the low to
moderate doses delivered to the rectum with proton therapy are less than with IMRT
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TOXICITY : EFFICACY :

 Lack of controlled  In most clinical situations, level 1 evidence of comparative

studies effectiveness is desirable  It has been difficult to conduct
 Small patient numbers randomized controlled trials in proton therapy.  Only small
 Lack of appropriate differences in RBE of proton therapy compared to photon therapy. 
comparitive groups Therefore, the basic difference between protons and photons is simply
 Variable criteria for toxicity the difference in entrance dose and exit dose to non target structures.
assessment
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NEUTRON BEAM THERAPY

1. Fast Neutron Therapy Beams
2. Boron Neutron Capture Therapy

FAST NEUTRONS
Production : Neutrons can be produced in a cyclotron by accelerating deuterons or protons and impinging
them on a beryllium target. Protons or deuterons must be accelerated to ≥50 MeV to produce neutron
beams with penetration comparable to megavoltage x-rays.

Accelerating deuterons to ≥50MeV • Requires very large cyclotron, too large for hospital.

• Stripping Process
• Proton is stripped from the deuteron.
• Recoil neutron retains some of the incident kinetic energy of the accelerated deuteron.
• For each neutron produced, one atom of Be is converted to B
Accelerating protons to ≥50MeV • Much smaller cyclotron b/c proton has ½ the mass of deuteron.

• Knock-out Process
• Protons impinge target of beryllium, where they knock-out neutrons.
• For each neutron “knocked-out”, one atom of Be is converted to B.

LARGE RADIORESISTANT TUMORS ARE NOT WELL CONTROLLED BY PHOTON (OR

PROTON) THERAPY
• Resting cells are radioresistant
• Hypoxic (low oxygen) cells are radioresistant
Neutron therapy is less affected by cell cycle or oxygen content

RADIOBIOLOGY :
• Neutrons are more effective per unit dose than x-rays
• Cell survival curves for neutrons are more nearly exponential than those of x-rays
• The modifying effect of hypoxia is smaller for neutrons than for photons
• Cell sensitivity to neutrons is much less dependent on cell growth stage than cell sensitivity to photons.
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CLINICAL APPLICATIONS :
Neutrons have effective for patients with slower growing tumors such as
• adenoidcystic carcinoma (cancer of parotid glands)
• locally advanced prostate cancer
• locally advanced head and neck tumors
• inoperable sarcomas
• cancer of the salivary glands

ADVANTAGES :
o LET comparisons of low LET electrons and high LET electrons electrons produced from X-
rays have high energy and low LET cause only few ionizations , when they interact with a
cell , and so single strand breaks of the DNA molecule are possible ,which can be readily
repaired.
 The high LET charged particles produced from neutron irradiation cause many ionizations as they
traverse a cell, and so double-strand breaks of the DNA molecule are possible.
 DNA repair of double-strand breaks are much more difficult for a cell to repair, and more likely to
lead to cell death.
 Oxygen effect : Neutron irradiation overcomes the effect of tumor hypoxia

BORON NEUTRON CAPTURE THERAPY (BNCT)

 Neutron capture therapy might be considered a type of particle therapy, as the damage it does to
tumors is mostly from energetic ions produced by the secondary nuclear reaction after the neutrons
in the external beam are absorbed into boron-10 (or occasionally some other nuclide), and not due
primarily to the neutrons themselves.
 It is therefore a type of secondary particle therapy.
 BNCT is a form of cancer therapy which uses a boroncontaining compound that preferentially
concentrates in tumor sites.
 The neutrons irradiated interact with the boron in the tumor to cause the boron atom to split into an
alpha particle and lithium nucleus.
 Both of these particles have a very short range (about one cellular diameter) and cause significant
damage to the cell in which it is contained.
Boron is injected to the patient. The uptake of Boron to tumor 20 𝜇g of B/g of tumor cell
Irradiation of boron through neutron
Non-radioactive B-10 converted in to radioactive B-11
B-11 form Li and He (High LET particles)
He and Le, particle range within the tumor cells are 9µm and 4µm (diameter of tumor cells )
respectively.
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Low LET 𝜸 radiation • Thermal neutron absorbed by H atom of normal tissue

High LET proton • Thermal neutron absorbed by N atom • 14N + 1n →14C + 1H
High LET 𝛼 particle Thermal neutron capture and fission reaction with boron
• 10B + 1n → 7Li + 4He

BORON
1. it is non-radioactive and readily available, comprising approximately 20% of naturally occurring boron;
2. Emitted particles (a and 7Li) have high LET
3. Chemistry of boron is well understood and allows it to be readily incorporated into a multitude of
different chemical structures.

Requirements for a successful boron delivery agent:

 low systemic toxicity and normal tissue uptake with high tumor uptake and concomitantly high
tumor/brain and tumor/ blood concentration ratios
 B-10 concentration : 20𝜇g /g tumor
 Rapid clearance from blood and normal tissues
 Retain ability of boron in tumor than normal cells
Optimizing Delivery of Boron-Containing Agents Delivery of boron agents to brain tumors is
dependent on

 the plasma concentration profile of the drug, which depends on the amount and route of administration

 the ability of the agent to cross the Blood brain barrier (Lipophilicity)

 blood flow within the tumor

DOOR DESIGN FOR NEUTRON SHIELDING DETAILS

1. Boronated polyethylene:
 The polyethylene (high H content) slows (moderates) the fast and intermediate energy neutrons to
thermal energies.
 The 5% Boron absorbs the low energy neutrons (high cross section for thermal neutron
absorption).
2. Lead absorbs the 0.48 MeV photon that results from the (n,a) and capture gammas ( from maze
ceiling, and floor).
Neutron beam requirements :

 epithermal neutron flux  109 neutrons/cm2s (at the therapy position)

 neutron energy ~ 1 eV to ~ 10.0 keV
 gamma dose rate  2х10-13 Gy/cm2
 fast neutron dose rate  2х10-13 Gy/cm2
 current:flux (J/) ratio > 0.8
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APPLICATION

1. Brain tumors
2. head and neck cancers
3. Melanoma
4. Colon cancer
5. Liver : Hepatic tissue morphology preserved from radiotherapy • Require heavy operation(auto-
transplantation), difficulty of determine procedure length, fast system for infusion of blood, well
trained surgeon

Advantages and Disadvantages

 Clinical interest in BNCT has focused primarily on the treatment of high-grade gliomas and melanoma,
most recently, head and neck and liver cancer

 There are no boron compounds which have a sufficiently high tumor to healthy tissue ratio, to ensure that
healthy tissues will not be affected by BNCT treatment

 Undesirable dose components produced as an unavoidable side-effect (like gamma rays)  Well trained
surgeon

Critical Issues which require improvement

 Require more selective and effective boron delivery agents

 Radiation dosimetry depends on uptake of boron concentration.

Measurement of accurate, real time dosimetry to better estimate the radiation doses delivered to the tumor
and normal tissues

 Need for randomized clinical trial

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Radiobiology
 156

Question 1 : Explain Cell Cycle with a help of a neat diagram and its importance:

Definition : The entire sequence of events that produces two daughter cells more or less indistinguishable
from a parent cell is called cell division
cycle or cell cycle.

Go to G1 phase :

Growth factors are responsible for initation

from resting phase to progression of G1
phase

G1 phase :

Formation of cyclin D–CD 4 complexes ,

Phorshyrylation of RB gene, Activation of
E2F , Progression to S phase.

S phase : initiation of DNA replication

involve the formation of an active complex
between cyclin E and CDK2. Activated E2F
increases the transcription of cyclin E and
of polymerases needed for DNA replication,
thus stimulating DNA synthesis.

Steps : Prophase – chromatin condensation,

Metaphase – Chromosome alignment ,
Anaphase- Chromosome split, Telophase –
chromosome decondensation.

G2-M phase : Cyclin B-CDK1 activation

causes the breakdown of the nuclear
envelope and initiates mitosis. Newly
divided cells can then return to G1 and
initiate a new replicative cycle or go into
5 phases :
quiescence.

CHECKPOINTS : G0 – Quiescent phase ( Variable )

G1 phase – Pre synthetic phase ( variable )
G1/S Check point ‘: is the cell damaged ? – S phase – DNA synthesis phase ( 6-8 hours )
send for DNA repair or apoptosis G2- Post synthetic – pre mitotic phase (1-2 hours )
M – Mitotic phase (0.5 – 1 hour )
G2/M check point : Completion of DNA replication

CELL CYCLE INHIBITORS :

Cip/Kip family : p21. p27,p57 inhibit cyclin D / cdk4

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INK4/ARF family : 1. P16 inhibits cdk4 , 2. P14 inhibits P53

CELL CYCLE REGULATORS :

Cyclin : D, E, A, B and CDKS : cdk4 , cdk2, cdk1

Importance of Cell cycle in Radiotherapy:

1. G 2 M phase is most radiosensitive phase

2. Redistribution of cells during Fractionated RT
3. Understanding the Chronobiology of the tumour

Cells are the most sensitive in M and G2: survival curves are steep and have no shoulder

Cells in the latter part of S phase (LS) exhibit a survival curve that is less steep, but has a very broad
shoulder

The range of sensitivity between the most sensitive cells (mitotic) and the most resistant cells (late S) is of
the same order of magnitude as the oxygen effect

Chemotherapy

G1 Vinblastine
S Animetabolites
G2 Etoposide , tenipoposide
M Taxanes , vinca alcaloids
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Question 2 : Discuss briefly Radiation induced cell death and explain DNA Damages :

Ionising radiation affect the cell directly or indirectly

Direct – ionisation / excitation of biological molecules – DNA damage - Apoptosis

Indirect – formation of free radicals by interating with molecules – Apoptosis

Classification of Radiation induced cell death :

Reproductive Death (Mitotic Death) Interphase Death (apoptosis)

– Main mode of cell death after RT – Death of the cells before mitosis
– Loss of proliferative ability of cell
– Occurs in most of the cells – Early after irradiation
– Loss of potency of cell growth and doesnot
mean cell death
– Cardinal factor in estimating radiosensitivity – Occurs in lymphocytes,thymocytes, crypt
in cancer cells undergoing RT. cells of intestine

– 4 - 24 hours

Cell Death pathways :

1. Apoptosis: highly regulated (programmed) process occuring due to enzymatic activity

2. Autophagy: digestion of parts of cytoplasm to generate basic nutrients and to eliminate damaged proteins
and organelles

3. Mitotic catastrophe: death following aberrant mitosis

4. Senscence: Permanent loss of ability to divide

5. Necrosis: death due to extremely unfavorable conditions

TYPES OF CELL DAMAGE:

A. Lethal damage : irreversible, direct damage , due to DS breaks , assc. with high LET radiations,
B. Sub-lethal damage: indirect damage, due to ss breaks, assc. with low LET radiations

C. Potentially lethal damage : lethal for cells in mitosis, repair under suboptimal conditions
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Question 3: Write Briefly on Apoptosis

Definition : Tightly regulated intracellular program in which cells destined to die activate enzymes that
degrade the cells' own nuclear DNA and nuclear and cytoplasmic proteins.

Morphology - Nuclear fragmentation with formation of apoptotic bodies , Blebbing of cell membrane, but
no early loss of membrane integrity , Lack of an inflammatory response and phagocytosis by local cells

2 pathways - The extrinsic (Death Receptor-Initiated) Pathway. The Intrinsic (Mitochondrial) Pathway.

Regulation of Apoptosis :

Anti-apototic genes - Bcl-2 , bcl-XL , Mcl-1 , Increase IAP , Inhibit Apoptosis

Pro-apototic genes - Bad, bim, bid ,Puma, p53,Noxa , Increase Cytochrome C , Increases Apoptosis

Radiation kill cells by apoptosis:

1. DNA damage, p53-dependent gene transcription is increased and ubiquitin-dependent degradation of the
protein is blocked leading to induction of apoptosis and/or cell cycle arrest. ( Main Mode )

2. Disrupt mitochondrial membranes, releasing factors that activate the caspase cascade of proteolytic
enzymes and endonucleases that cleave DNA between nucleosomes to commit cellular “suicide.

3. Ionising radiation activates sphingomyelinase, which catalyses the hydrolysis of sphingomyelin to the
lipid second messenger, ceramide, thereby inducing interphase death by apoptosis.

4. Because radiation can induce expression of both TNF and TNFR family members, these pathways may
form an additional indirect pathway leading to death or survival of some cell types following irradiation.

Resistant Mechanisms leading to Cancer :

1. Expression of anti-apoptotic proteins (Bcl-2 over-expression in follicular B-cell lymphoma; over-

expression of IAPs in different types of cancers including neuroblastoma)
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2. Inactivation of pro-apoptotic genes (BAX mutation; APAF-1 in melanomas)

3. Alteration of p53 pathway (p53 mutation)
4. Altered survival signalling (alteration of PI3K/Akt pathway- for example PTEN deletion)
(SAHA) (vorinostat) has received approval for treatment of non-Hodgkin’s lymphoma

Question 4 : Explain the DNA repair Mechanism :

1. Base Excision Repair pathway: Base damage is repaired, defects in BER may lead to
increased . mutation rate but no effect in radio- sensitivity.
o Removal of single base mutation by glycosylase/DNA lyase
o Sugar residue removal by apurinic endonuclease 1

o Replacement of correct nucleotide by DNA pol ymerase 

o Ligation by DNA ligase III, XRCC1 mediated ligation.
2. Nucleotide Excision Repair Pathway: removes pyrimidine dimers, divided into: 1. Global
genome repair (GGR) 2. Transcription-coupled repair (TCR)
3. Nonhomologous End-Joining: Immediate response to DNA DSB

– DSB Detection
– End recognition by ATM & MRN complex, resulting in resection of the DNA ends and binding by
Ku70/80 heterodimer
– Recruitment of DNA-dependent protein kinase catalytic subunit (DNA-PKcs)
– End processing
– fill-in synthesis or end bridging by the Artemis endonuclease activity
– Ligation is promoted by ligase complex (XRC4/XLF-LIGIV/PNK)
4. Crosslink Repair: Several DNA-DNA & DNA-protein crosslink are produced by IR . A combination of
NER and recombinational repair pathways is needed to repair DNA crosslinks. Individuals afflicted with
the syndrome Fanconi anemia are hypersensitive to crosslinking agents

5. Mismatch Repair: Removes base-base & small insertion mismatches. Mutations in any of the
mismatch MSH, MLH, and PSM families leads to microsatellite instability and cancer, especially
hereditary nonpolyposis colon cancer (HNPCC)
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1 2 3 4

Question 5 : Difference between Radiosensitvity and curability. Factors affecting Radiation

Response:

Radiosensitivity is a measure of tumor–radiation response, thus describing the degree and speed of
regression during and immediately after radiotherapy.

Radiocurability refers to the eradication of tumor at the primary or regional site and reflects a direct effect
of the irradiation; this does not necessarily equate with the patient’s cure from cancer.

Question 6 : Define Therapeutic Ratio. How do you enhance Radiation Response ?

Tumor Control Probability and Normal How to improve Therapeutic Ratio?

Tissue Complication Probablitiy :
1. Physical modifiers of low-LET radiations.
The probability of tumor control increases as 2. High LET radiations
radiation dose increases, although not linearly. 3. Hyperbaric oxygen or tourniquet methods
Success or failure depends on killing the last 4. Hypoxic sensitizers
surviving clonogen. Permanent tumor control (not 5. Hyperbaric oxygen
palliation) is achieved abruptly as the last 6. Perflurocarbons
clonogen is sterilized. A plot of tumor control 7. Cytotoxic agents
probability (TCP) versus dose for a single tumor 8. EGFR - Cetuximab
therefore shows no response up to a certain dose 9. Radioprotectos
and then an immediate increase to 100% at death 10. Hyperthermia
of the last clonogen. Therapeutic Ratio (Gain) :
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The improved definitions of TCP and NTCP,

imply that there is an optimal radiation dose that
produces a maximum tumor control with a
minimum (reasonably acceptable) frequency of
complications, also called treatment sequelae.
The farther the TCP and NTCP curves diverge,
the more favorable is the therapeutic ratio . The
therapeutic ratio or therapeutic gain factor (TGF)
of a given regimen could be expressed as a ratio:
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APPLIED RADIOBIOLOGY
Question 7 : Define LET. Advantages of High LET radiations :

Linear energy transfer (LET) is the energy transferred per unit length of the track. The special unit usually
used for this quantity is kiloelectron volt per micrometer (keV/_m) of unit density material. The LET (L) of
charged particles in medium is the quotient of dE/dl, where dE is the average energy locally imparted to the
medium by a charged particle of specifi ed energy in traversing a distance of dl.
That is,
L = dE/dl

Question 8 : Explain oxygen enhancement ratio (OER) :

Definition : The ratio of doses administered under hypoxic to aerated conditions needed to achieve the same
biologic effect is called the oxygen enhancement ratio (OER).

Factors affecting OER:

1. LET 2. Cell Cycle

LET : For sparsely ionizing radiations, such as x- and -rays, the OER at high doses has a value of between 2.5
and 3.5.

Cell Cycle: Cells in G1 phase have a lower OER than those in S, and because G1 cells are more radiosensitive,
they dominate the low-dose region of the survival curve. For this reason, the OER of an asynchronous
population is slightly smaller at low doses than at high doses.

 The OER was measured at 2.3 to 2.4 for G2 phase cells, compared with 2.8 to 2.9 for S phase,
with G1 phase cells showing an intermediate value.
 The OER appears to be smaller at high levels of survival, at which the survival curve is
dominated by the killing of the most sensitive moieties of the population; the OER appears to be
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larger at higher doses and lower levels of survival, at which the response of the most resistant (S
phase) cells, which also happen to exhibit the largest OER, dominates.

Question 9 : Explain Radiobiological Effectiveness (RBE)

Definition : ratio D250/Dr, where D250 and Dr are, respectively, the doses of x-rays and the test radiation
required for equal biologic effect.

 To measure the RBE of some test radiation, one first chooses a biologic system in which the effect of
radiations may be scored quantitatively.

Example -

 Suppose we are measuring the RBE of fast neutrons compared with 250-kV x-rays, using the lethality of
plant seedlings as a test system. Groups of plants are exposed to graded doses of x-rays; parallel groups
are exposed to a range of neutron doses. At the end of the period of observation, it is possible to
calculate the doses of x-rays and then of neutrons that result in the death of half of the plants in a group.

 This quantity is known as the LD50, the mean lethal dose. Suppose that for x-rays, the LD50 turns out
to be 6 Gy and that for neutrons, the corresponding quantity is 4 Gy.

 The RBE of neutrons compared with x-rays is then simply the ratio 6:4 or 1.5.

Characteristics :

 The RBE generally increases as the dose is decreased, reaching a limiting value that is the ratio of the
initial slopes of the x-ray and neutron survival curves.
 RBE increases with LET to a maximum at about 100 keV/m, thereafter decreasing with higher LET.
 For radiation with the optimal LET of 100 keV/m, the average separation between ionizing events is
similar to the diameter of the DNA double helix (2 nm), so that DSBs can be most effi ciently produced
by a single track.
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 The RBE of high-LET radiations compared with that of low-LET radiations increases as the dose per
fraction decreases. This is a direct consequence of the fact that the dose-response curve for low-LET
radiations has a broader shoulder than for high-LET radiations.
 RBE varies according to the tissue or end point studied. In general, RBE values are high for cells or
tissues that accumulate and repair a great deal of sublethal damage, so that their dose-response curves
for x-rays have a broad initial shoulder.
 RBE depends on the following:
Radiation quality (LET)
Radiation dose
Number of dose fractions
Dose rate
Biologic system or end point
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Question 10 : What is the radiobiological explanation for Fractionation. Explain 4Rs in Radiobiology.

ADVANTGES OF FRACTIONATION

 Acute effects of single dose of radiation can be decreased

 Pt.’s tolerance improves with fractionated RT

 Exploits diff. in recovery rate b/w normal tissues & tumors.

 Radn induced redistribution & sensitization of rapidly proliferating cells.

 Reduction in hypoxic cells leads to –

o Reoxygenation

o Opening of compressed blood vessels

 Reduction in no. of tumor cells with each dose #

1) Repair: prompt repair of normal cells by SLDR, minimum gap of 6 hours

2) Reassortment: progression of cells through the cell cycle during the interval between the split doses

3) Repopulation: if the interval between the split doses exceeds the length of cell cycle

4) Reoxygenation: the proportion of hypoxic cells returns to its original pretreatment level after delivery
of a fractionated dosage schedule

REPAIR:

 Most important rationale for fractionation

 Mammalian cells can repair radiation damage in b/w dose fractions. This is a complex process involving
repair of SLD by a variety of repair enzymes & pathways.

 Since tumerocidal doses are very high as compared to NTT there are two ways to deliver such high
doses:
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 One option is to deliver much higher dose to tumor than to normal tissue – basis of conformal
radiotherapy

 Other option is to fractionate the dose. So that there is sufficient time b/w consecutive fractions
for complete repair of all cell that suffered SLD during 1st # before 2nd #& so on.

 So small dose /# spares late reactions preferentially & a reasonable schedule duration allows
regeneration of early reacting tissues.

SLD & ITS REPAIR

 Initial shoulder in cell survival curve reflects ability of cells to accumulate SLD

 Ability of cells to recover from SLD demonstrated by Elkind & Sutton by split dose experiments.

 A given total dose delivered as single # is found to be more effective compared to same dose delivered
in more #s.

REDISTRIBUTION ;

 Redistribution of proliferating cell populations throughout the cell cycle increases cell kill in
fractionated treatment relative to a single session treatment.

 Cells are most sensitive during M & G2 phase & are resistant during S phase of cell cycle .

 Redistribution can be a benefit in fractionated course of RT if cells are caught in sensitive phase after
each fraction .

REPOPULATION :

 In b/w dose fractions normal cells as well as tumor cells repopulate.

 So longer a radiotherapy course lasts, more difficult it becomes to control tumor & may be detrimental

 But acutely responding normal tissue need to repopulate during course of radiotherapy .

 Thus fractionation must be controlled so as not to allow too much time for excessive repopulation of
tumor cells at the same time not treating so fast that acute tolerance is exceeded

Accelerated Repopulation:

 Treatment with any cytotoxic agent , including radn , triggers surviving cells (clonogens) in a tumor to
divide faster than before

 Dose escalation is needed to overcome this proliferation. e.g. it starts in head & neck cancer 4wks after
initiation of fractionated RT

 Implication : Treatment should be completed as soon after it is started . It is better to delay a treatment
than to introduce delay during treatment .
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REOYGENATION:

 Cells at the center of tumor are hypoxic & are resistant to low LET radiation. Hypoxic cells get
reoxygenated occurs during a fractionated course of treatment, making them more radiosensitive to
subsequent doses of radiation.

Question 11 : What is Dose Rate Effect and inverse dose effect?

Dose Rate Effect Inverse Dose rate effect

In low dose rate brachytherapy there is no shoulder Reappreance of the shoulder by lowering the dose
rate
In High dose rate brachytherapy there is a shallow
shoulder. Due to accumulation of cells in the G2 phase.

Toxicity of LDR Vs HDR Response of LDR Vs HDR

LDR is less toxic than HDR because of time for LDR is radiologically better because most cells are
SLDR killed in the G2 , which is a radiosentive phase

1. Dose rate effect : Repair of sublethal damage occurs when radiation is delivered at a low dose rate, and
the treatment time is extended to a point where it is comparable to the repair half-time. As the dose rate
is reduced, more sublethal damage is repaired because the radiation injury is spread over a longer period.
The cell survival curves become progressively less steep, and at the same time the extrapolation number
approaches unity.
2. Redistribution and accumulation of cells throughout the cell cycle occur with a low dose rate in which
proliferation is decreased because cells are arrested and accumulate in G2. This phase of the cycle is
relatively radiosensitive. As a result, cell killing may be greater for a lower dose rate. This effect occurs
over a narrow dose-rate range and is known as the inverse dose-rate effect.
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Question 12 : Explain the various Fractionation shedules :

CONVENTIONAL FRACTIONATION:
 Most common fractionation for curative radiotherapy is 1.8 to 2.2Gy/#
 Division of dose into multiple # spares normal tissue through repair of SLD b/w dose #s & repopulation
of cells.
 Concurrently , fractionation increases tumor damage through reoxygenation & redistribution of tumor
cells.
 Hence a balance is achieved b/w the response of tumor & early & late reacting normal tissue.

HYPERFRACTIONATION : It is delivering radiation more than once in a day with 6 hours interval keeping
the overall treatment time and dose same.

“Pure” hyperfractionation “impure” hyperfractionation

might be defined as keeping the same total dose as involves an increase in the total dose and
in a conventional regimen in the same overall time sometimes a longer overall time as well as many
but delivering it in twice as many fractions by the more fractions delivered twice per day.
expedient of treating twice per day.

This would not be satisfactory because the total dose The intent is to further reduce late effects but
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would need to be increased if the dose per fraction is achieve the same or better tumor control and the
decreased. same or slightly increased early effects.

 Rationale –
 To take maximal adv. of diff. in repair capacity of late reacting normal tissue compared with
tumors.
 Radio sensitization through redistribution.

A hyper fractionated schedule of 80.5Gy/70#(1.15Gy twice/day)/7wks compared with 70Gy/35#/7wks in head

& neck cancer.
Implications –
Increased local tumor control at 5yr from 40 to59%
Reflected in improved survival
No increase in side effects

ACCELERATED TREATMENT : It is delivering radiation in with a reduced overall treatment time by either
of 2 ways:
1. 6 days in a week rather than 5 days
2. More than one fraction in a day

“Pure” accelerated treatment Impure accelerated treatment

might be defined as the same total dose delivered – dose is reduced or rest period is interposed in the
in half the overall time by the expedient of giving middle of treatment
two or more fractions each day.

In practice, it is never possible to achieve this

because the acute effects become limiting.

 Multiple std # / day

 Comparison of head & neck cases accelerated regimen 72Gy/45# (1.6Gy,3#/day)/5wks with
70Gy/35#/7wks
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 Implications –
 15% increase in loco regional control
 No survival adv.
 Increased acute effects
 Unexpected increase in late complications

Continuous Hyperfractionated Accelerated Radiation Therapy (CHART) :

 Regimen conceived at Mount Vernon Hospital, London

Characteristics of CHART included the following:

■ Low dose/fractionation: 36 fractions
■ Short overall time: 12 consecutive days
■ No gap in treatment: three fractions per day at 6-hour intervals
■ Three fractions per day: 1.4 to 1.5 Gy per fraction, 50 to 54 Gy total
 Implications-
 Better local tumor control
 Acute reactions are brisk but peak after treatment is completed
 Dose/# small hence late effects acceptable
 Promising clinical results achieved with considerable trauma to pt.

SPLIT-COURSE
 Total dose is delivered in two halves with a gap in b/w with interval of 4wks.
 Purpose of gap is
 to allow elderly pts. to recover from acute reactions of treatment
 to exclude pts. from further morbidity who have poorly tolerated 1st half or disease progressed
despite treatment.
 Applied to elderly pts. in radical treatment of ca bladder & prostate & lung cancer.
 Disadv : impaired tumor control due to prolong T/T time that results in tumor cell repopulation
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HYPOFRACTIONATION
 High dose is delivered in 2-3# / wk
 Rationale
 Treatment completed in a shorter period of time.
 Machine time well utilized for busy centers.
 Higher dose /# gives better control for larger tumors.
 Higher dose /# also useful for hypoxic fraction of large tumor.
 Disadv.
 Higher potential for late normal tissue complications.
 E.g. 50Gy/10#/5wks treating 2 days a wk in head & neck cancer.

Accelerated Hyperfractionated Radiation Therapy while Breathing Carbogen and with the Addition of
Nicotinamide (ARCON) :

The last experimental protocol that deserves mention is accelerated hyperfractionated radiation therapy while
breathing carbogen and with the addition of nicotinamide (ARCON). The strategy was to accelerate treatment to
avoid tumor proliferation, hyperfractionate (small doses per fraction) to minimize late effects, and add carbogen
breathing to overcome chronic hypoxia and nicotinamide to overcome acute hypoxia. Clinical trials to test this
complex but imaginative protocol are under way in Europe. Early results of a trial of ARCON in the
Netherlands, involving advanced laryngeal cancer, showed spectacular results compared with historical
controls. Results of a prospective randomized trial have yet to be published.

Characteristics of ARCON are summarized as follows:

 Accelerated treatment to overcome proliferation
 Hyperfractionated to spare normal tissues
 Carbogen breathing to overcome chronic hypoxia
 Nicotinamide to overcome acute hypoxia
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Question 1 : Explain the concept of Time, Dose and Fractionation :

1. NSD Method
2. CRE Method
3. TDF Method
4. LQ Model

THE STRANDQUIST PLOT AND THE ELLIS NOMINAL STANDARD DOSE SYSTEM :

It commonly was found in these plots that the slope of the isoeffect curve for skin was about 0.33; that is, the
total dose for an isoeffect was proportional to T0.33

The most important contribution in this area, made by Ellis and his colleagues with the introduction of the
nominal standard dose (NSD) system, was the recognition of the importance of separating overall time from
the number of fractions.
According to this hypothesis, total dose for the tolerance of connective tissue is related to the number of
fractions (N) and the overall time (T) by the relation

Total dose + NSD (T0.11 x N0.24)

*The NSD system has been discussed extensively. It does enable predictions to be made of equivalent dose
regimens, provided that the range of time and number of fractions are not too great and do not exceed the range
over which the data are available.

For example, in changing a treatment protocol from fi ve to four fractions per week, the formula can be used to
calculate the size of dose fractions needed to result in the same normal tissue tolerance with the two different
protocols.

Of course, because the system is based ultimately on skin reaction data, it does not, in any way, predict late
effects.
An obvious weakness of the NSD system is that time is allowed for in terms of a single power function, in
which the nominal single dose is proportional to T0.11.

In fact, biologic experiments with small animals have shown that this relationship is far from accurate.
Proliferation does not affect the total dose required to produce a given biologic reaction at all until some time
after the start of irradiation but, then, the dependence in time is much greater than allowed for by the Ellis
formula. For these and other reasons, the NSD system is seldom used nowadays.
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Question 14: Explain Cell Survival Curves :

Definition : A cell survival curve is a plot that determines the relationship between radiation dose and
proportion of cells that survive. Thus, cell survival curves measure reproductive cell death. Reproductive
death- refers to loss of reproductive integrity.

Survival curve in vitro : determination

Plating efficiency(PE)- indicates the percentage of

cell seeded that grow into colonies (under normal
conditions.)
PE= no. of colonies counted × 100
no. of cell seeded

Survival fraction(SF)- the colonies counted divided

by the number of colonies plated with a correction
for the plating efficiency(post irradiation)
SF = colonies counted
cells seeded× (PE/100)

If the dose is plotted on the y-axis and the SF is plotted on the x-axis, a sigmoid curve is obtained. If the
logarithm of the SF is plotted on the x-axis, a semi-logarithmic curve is obtained.

Survival Curve Features

1. Simple to describe qualitatively

2. Difficulty lies in explaining underlying biophysical events
3. Many models have been proposed
4. Steepness of curve represent the radio-sensitivenes
Question 15 : List the models which explains cell kill. Explain LQ model or Alfa/beta model :

1. Single Hit Single Target Model

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2. Multi Target Model or Two component Model

3. LQ model or Alfa/Beta Model
Single Hit Single Target Model : Describes a simple situation where an individual cell that receives a dose
more than Do will die, otherwise it survives. some cells receive more than one hit, some receive exactly one hit,
and some receive zero hits.

ln SF = −D/D0 where D/D0 is the average number of hits per cell.

The single-target/single-hit model can be used to describe data resulting from experiments involving viruses and
bacteria,but is generally a poor model for describing mammalian cell survival.

Multi Target Model or Two component Model : uses densely (high-LET) and sparsely ionizing (low-LET)
radiations

LQ model : Although similar to TC model but gives a better description for low dose region, Continuously
bending,

Assumes cell is killed by two ways : 1. Single lethal event 2 Accumulation of sublethal events.
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D1 initial slope due to single even killing is the dose to reduce survival to 37%

Do final slope due to multiple event killing is the dose to reduce survival by 67% from any point on the linear
portion of the curve

Extrapolation of Do to y axis yields n – measure of shoulder

When linear contribution equals quadratic contribution, αD = βD2 D= α/β

Do is never constant, changes with increasing dose due to the continuously bending curve Do = 1/(α+ 2βD)

Uses of LQ Model

1. To formulate equivalent fractionation schemes.

2. To calculate additional doses after breaks from radiotherapy.
3. To get information on acute and late responses.
Advantage of LQ model over Multitarget model - it has 2 adjustable parameters

Disadvantage of LQ Model -does not take treatment dutation into account

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Question 16 : What is a/b ratio ? Explain in detail.

The a/b ratio is the dose at which cell killing by the linear (a) and the quadratic (b) components are equal.

 In particular, there is a clear distinction between tissues that are early responding, such as the skin,
mucosa, and intestinal epithelium, and those that are late responding, such as the spinal cord.

 The dose– response relationship for late-responding tissues is more curved than that for early-
responding tissues.

 For early effects, / is large; as a consequence, dominates at low doses, so that the dose-response curve
has a marked initial slope and does not bend until higher doses.

 The linear and quadratic components of cell killing are not equal until about 10 Gy. For late effects, / is
small, so that the term has an infl uence at low doses.

 The dose-response curve bends at lower doses to appear more curved; the linear and quadratic
components of cell killing are equal by about 2 Gy.

 First, if a fractionation scheme is changed in clinical practice from many small doses to a few large
fractions and the total dose is titrated to produce equal early effects, the treatment protocol involving a
few large fractions results in more severe late effects. There is an abundance of clinical evidence for the
truth of this statement.

 early-responding tissues, / (i.e., the dose at which single- and multiple-event cell killing is about equal)
occurs at the dose of about 10 Gy. By contrast, / for late-responding tissues is about 2 Gy

A Possible Explanation For The Difference In Shape Of Dose–Response Relationships For Early- And Late-
Responding Tissues :
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1. A population proliferating so fast that S phase occupies a major portion of the cycle.
2. A population proliferating so slowly that many cells are in early G1 or not proliferating at all, so that many
resting cells are in G0.

It is thought that many late-responding normal tissues are resistant, owing to the presence of many resting cells.
This type of resistance applies particularly to small doses per fraction and disappears at larger doses per
fraction.
If resistance results from the presence of many cells in S phase in a rapidly proliferating population,
redistribution occurs through all the phases of the cell cycle, which can be considered as a “self-sensitizing”
activity. The fast proliferation itself is a form of resistance because the new cells produced by division offset
those killed by the dose fractions.

This applies to acutely responding tissues and also to tumors. Proliferation occurring during a protracted,
fractionated regimen helps to spare normal tissues but, of course, is a potential danger as far as the tumor is
concerned.

Question 17 : Explain BED in detail :

Definition : Quantity E/a is the biologically effective dose (BED) and is the quantity by which different

fractionation regimens are intercompared

( d = dose of fractionation eg. 2Gy for conventional fractionation )

Example :
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Tumor Doubling Time :

The decrease in the number of clonogens because of cell killing by the fractionated radiation regimen is
balanced to some extent by cell division of the surviving clonogens.

 The time t is the time in days available for proliferation.

 Rapid proliferation in tumors appears not to start up until about 21 to 28 days after treatment begins in
head and neck tumors.
 Therefore, t= T21 or t= T28 is a suitable value, where T is overall time. The start-up time is called TK
for “kick-off” time, and t = TTK.
 It is now necessary to assume a value for alfa, the initial slope of the cell survival curve, as well as for
Tpot, the potential doubling time of the tumor.
 A reasonable value for alfa is 0.3/Gy.
 Tpot may have a value of 2 to 25 days, with a median value of about 5 days
 180

Question 18 : Discuss the Factors affecting cell survival curve

1. LET

2. Fractionation

3. Dose rate effect

4. Intrinsic radiosensitivity

5. Cell age

6. Oxygen presence

1. LET : Increases the steepness of the survival curve. Results in a more linear curve . Shoulder disappears
due to increase of killing by single-events

 Low-LET radiations -
 Low dose region - shoulder region appears
 High dose region - survival curve becomes linear and surviving fraction to an exponential function of
dose
 Surviving fraction is a dual exponential S = e-(aD+bD2)
 High-LET radiations - Survival curve is linear
 Surviving fraction is a pure exponential function of dose S = e-(aD)

2. Fractionation : If the dose is delivered as equal fractions with sufficient time, repair of sub-lethal
damage occurs Elkind & Sutton showed that when two exposure were given few hours apart ,the
shoulder reappeared. Elkind’ s recovery takes place between radiation exposure - cell act as fresh
target. Dose delivered as equal fractions with sufficient time between for repair of the sub-lethal (non-
killing) damage, the shoulder of the survival curve is repeated many times. The effective survival curve
becomes a composite of all the shoulder repetitions. Dose required to produce the same reduction in
surviving fraction increases Do is 3 Gy.

3. Dose rate : Dose rate determines biological impact

Reduction in dose rate causes reduced cell killing, due to repair of SLD

Reduction in dose rate generally reduces survival-curve slope (Do increases)

Inverse dose-rate effect occurs in some cell lines at ‘optimal’ dose rate due to accumulation of cells in G2

4. Intrinsic radiosensitivity : Mammalian cells are significantly more radio-sensitive than

microorganisms Due to the differences in DNA content . Represents bigger target for radiation damage
.Sterilizing radiation dose for bacteria is 20,000 Gy.
 181

5. Cell Age : Cells are most sensitive to radiation at or close to M. Cells are most resistant to radiation in
late S. For prolonged G1 a resistant period is evident early G1 followed be a sensitive period in late
G1. Cells are usually sensitive to radiation in G2 (almost as sensitive as in M).

6. Oxygen effect : OER – ratio of hypoxic : aerated doses needed to achieve the same biological effect
X-Rays/γ-Rays at high doses is 2.5-3.5

at lower doses ~ 2.5

OER is absent for high LET radiations like alpha-particles and is intermediate for fast [Link] is lower for
types of radiation predisposed to killing cells by single-hit mechanisms
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Question 19 : What is a Radiosensitizer ? Classifcation of Radiosensitizer. Explain in detail.

Definition : Chemical or pharmacologic agents that increase the lethal effects of radiation if administered in
conjunction with RT. The aim is to move tumor-control curve to lower doses by sensitising tumor cells without
affecting the normal-tissue complication curve. To increase the tumor control probability for a given level of
normal-tissue complications.

Classification :

1. Hypoxia related radiosensitizers

Tumor oxygenation Hypoxic cell Hypoxic cytotoxins
radiosensitizers
Hyperbaric oxygen , Misonidazole Mitomycin C
Carbogen breathing , Etanidazole Tirapazamine
Oxygen delivery Nimorazole
methods
2. Cytotoxic Chemotherapy
5-FU, Taxanes, Fludarabine

3. Targeted therapy
Cetuximab , Bevacizumab

4. Hyperthermia

1. Hypoxia related radiosensitizers

Hyperbaric oxygen Therapy

Oxygen is relatively insoluble in plasma under normobaric conditions, but hyperbaric conditions, considerable
quantities can dissolve into plasma. Chambers filled with pure oxygen raised to pressure of 3 atmospheres.

Improved local control & survival- Ca Cx & HNN

Disadvantages : Claustrophobia, Risk of fire , Results not satisfactory due to unconventional fractionation
schemes

Carbogen breathing : 95% Oxygen and 5 % Carbon dioxide

With or without nicotinamide . Improve tumor oxygenation in some pts of Ca cx & HNN

Carbogen: overcome chronic hypoxia (oxygen unable to diffuse more than 100/150 µm or 10-12 cell diameters
thro respiring tissue)

Nicotinamide: Vit B3 analogue- prevents acute hypoxia (due to intermittent closing down of blood vessels)

Hypoxic cell radiosensitizers

 Selectively sensitize hypoxic cells at acceptable toxicity to normal tissues.

 They are not rapidly metabolised by the tumor cells through which they diffuse.
 183

 They can penetrate further than oxygen and reach all of the hypoxic cells in the tumor, including those
remote from blood supply
 Should be chemically stable and not rapidly metabolise.
 Highly water and lipid soluble and be able to reach the hypoxic cell.
 Effective at the relatively low daily doses of few grays used conventionally.
 Greatest benefit for H&N . Hypoxia marginal in [Link] important in squamous cell
carcinoma.

Misonidazole Etanidazole Nimorazole

Dose: 11gm% . less neurotoxicity 1.2 gm%

Ca larynx & pharynx-with split penetrate poorly into nerve Same class as metronidazole
course irradiation. tissues Less effective than miso & etanidazole
Peripheral neurotoxicity- 26% does not cross BBB but less toxic
Nausea & vomitting

2. Chemotherapeutic agent act as radiosensitizer

1. Shifting of cell to more radiosensitive cell cycle phase(5-FU, Taxanes, Fludarabine)

2. Inhibition of radiation induced DNA double strand break repair(Hydroxyurea, 5-FU, CDDP,
Vinorelbine)
3. Increasing no. of DNA double strand breaks(5-FU)
4. Reduction in base excision repair(Fludarabine)
5. Increases in complimentary DNA damage and modulation of growth factor signalling(Gemcitabine)
 184

Question 20 : Explain Hyperthermia in Radiation Therapy

Hyperthermia : Use of elevated temperature for the treatment of cancer to a supraphysiologic level, between
40° and 45° C for 1 hr.

Mechanism of Action:

HT can kill cells in its own, it can sensitize tumor cells to other forms of therapy, including RT and
chemotherapy (CT) by

1. inhibition of potentially lethal damage and sublethal damage repair,

2. cell cycle sensitivity,
3. effects of hypoxia and nutrient deprivation.
4. thermally induced reoxygenation.
5. Changes induced in microvessel pore size can lead to increased delivery of nanoparticle drugs
,macromolecular therapeutic agents, such as monoclonal antibodies drug-carrying polymers.
6. HT can augment the immunologic response toward tumors
7. increased immunogenicity , increased T-cell, NK-cell, and dendritic cell maturation and activity
,enhanced trafficking of immune effector cells into tumors and lymphatic organs
Cytotoxicity :

1. primary target for hyperthermic cell killing is protein

2. the heat the range for protein denaturation 130 to 170 kcal/mole
3. Heat exposure stops the synthesis of nearly all proteins but the heat shock proteins(HSP) synthesis is
upregulated
4. primary functions of HSP is to refold other proteins that have been denatured or damaged and protect
the cells from thermal damage
5. Cytoskeletal collapse disrupts cytoskeletal-dependent signal transduction pathways
6. damages centriole leads to chromosomal aberrations
7. DNA-repair proteins are heat sensitive
8. Bilipid membrane layer destabilization
HT kills cells in a log-linear fashion, depending on the time at a defined temperature

1. survival curves typically have an initial shoulder region, followed by an exponential portion.
2. The initial shoulder region indicates that damage has to accumulate to a certain level before cells begin
to die
3. At lower temperatures, a resistant tail may appear at the end heating due to the induction of
thermotolerance
4. >43°C -no thermotolerance observed
 185

Thermal isodose :

1. the temperature dependence of the rate of cell killing by heat is referred to as the Arrhenius relations
2. Arrhenius plots the point at which the slope changes is referred to as a breakpoint.
3. Above the breakpoint a change in temperature of 1°C will double the rate of cell killing.
4. HT results in temperatures within tumors that are almost always nonuniform, with variable time–
temperature history.
5. CEM 43°C = tR(43 – T)
6. the thermal dose from multiple treatments can be summed to obtain the cumulative equivalent minutes
(CEM) at 43° C for an entire treatment course
Thermotolerance :

1. a transient adaptation to thermal stress that makes heated cells to become more resistant to additional
heat stress
2. Damages depend on the net balance between how much protein is damaged and how much is protected
and repaired via thermotolerance.
3. can develop either during or after heat stress & can persist for several days
4. If cells are not exposed to thermal stress again, thermotolerance will decay.
5. heat shock protein can be rised in HT, hypoxia and hypoxia–reoxygenation injury
HT+ RT

1.
Cells in S phase are radioresistant but are sensitive to HT.
2.
Hypoxic cells are three times more resistant to radiation compared with aerobic cells,
3.
HT can lead to reoxygenation, which improve radiotherapy response.
4.
HT inhibits the repair of both sublethal and potentially lethal damage
5.
Induction of apoptosis could lead to reoxygenation leads to which increase RT sensitivity
“thermal enhancement ratio” (TER), defined as the ratio of doses of RT to achieve an isoeffect for
6.
RT/RT + HT.
HT+CT

1. HT enhances cellular uptake of drug

2. increased oxygen free radical production
 186

3. increased DNA damage and inhibition of repair.

4. Hypoxia and pH appear to be important in the thermochemotherapeutic response
5. important factor in the potential use of HT with many drugs is its ability to reverse the resistance
6. HT increases liposomal drug accumulation in tumors, especially low-temperature–sensitive liposomes
leading to enhanced antitumor efficacy
7. drugs with molecular weight <1,000, HT has relatively little effect
8. The timing of application heat and drug can be simultaneously or to give the drug immediately before
the onset of heating
Clinical hyperthermia :

The goal of hyperthermia therapy is to achieve tumor temperatures in the range of 40°C to 45°C / 1 hour.
thermal conductivity is complicated . irregularities of patient anatomy and tissue interfaces. blood perfusion,
which varies dramatically among tissue types, as a function of time and local temperature. so its difficult to
achieve uniform distribution

1. thermal conduction (e.g., circulating hot water in a needle, a catheter, or a surface pad)
2. nonionizing electromagnetic radiation (EM)
3. ultrasound (US)
4. Energy can be delivered deeper into tissue using EM or US fields that dependent on frequency and
applicator type
5. the absorbed power distribution is commonly normalized by the respective tissue density - the specific
absorption rate (SAR)
6. EM heating devices has two categories:
7. superficial HT applicators penetration into tissue in the range of 1 to 4 cm
8. deep HT devices-penetration >4 cm
Determination of Thermal dose :

Treatment outcome will be associated with minimum temperature attained by all tumor cells.

Current standard is invasive methods

1. placing thermometry probes into the tumor within implanted needles or catheters to read subsurface
temperatures sufficiently precise (typically, ±0.2° C) , discomfort to the patient, risk of haemorrhage and
infection, physician time required for catheter placement and image verification, less data availability
2. most common method - insert blind-ended catheters into a tumor, using either ultrasound or computed
tomography (CT) guidance
Non invasive thermometry approaches, which include backscatter ultrasound, electrical impedance tomography
active microwave imaging, passive microwave radiometry, magnetic resonance thermal imaging , complete 3D
characterization of tissue temperature distributions possible with multiple-slice MR thermal imaging

Uses :

1. local regional HT has also been combined with CT in a variety of clinical situations, including
2. intraperitoneal carcinomatosis from ovarian carcinoma, colorectal carcinoma, appendiceal
carcinoma, and primary peritoneal carcinomatosis,
3. limb perfusion primarily for malignant melanoma
 187

[Link] treatment of locally advanced soft tissue sarcomas,

[Link] treatment of chest wall recurrences, primarily from breast carcinoma,
[Link] treatment of recurrent bladder carcinoma with intravesical CT,
[Link] treatment of locally advanced esophageal carcinoma,
[Link] as a part of trimodality therapy (RT, CT and HT) for locally advanced rectal carcinoma,
cervical carcinoma
Adverse effects :

1. the most common toxicities are superficial tissue burns.

2. generally first or second degree -5% to 10%.
3. Third-degree burns—<1% of patients
4. deep regional heating, cause subcutaneous fat necrosis -about 10%.
5. presents as firm small subcutaneous nodules.
6. They are rarely painful and gradually resolve with time. They may be confused with local recurrence of
cancer.
7. infection at the catheter site.
8. If intratumoral temperature measurement catheters are removed and replaced with each treatment,
catheter complications then become infrequent
 188

Question : What are Radioprotectors ? Amifostine is a Radioprotector . Explain

Agents which selective normal tissue radioprotection and improves TI

Mechanism of Action : Mainly revolves around use of thiols to interrupt radiation induced ionisation events

Examples :

1. Cysteine
2. AMIFOSTINE(WR-2721)
3. Clinical Trials : Palifermin , IL -1 (Endogenous ) , GM CSF, KGF
Cysteine AMIFOSTINE(WR-2721)
Patt (in 1948) – Cysteine reduced Most effective thiol till date Dosage and administration:
lethality of single dose of Prodrug – converted to active 1. 910 mg/m2/day initially then
radiation(800 R) compound WR-1065 by ALP 740 mg/m2
Toxic – Nausea and vomiting inside cells 2. 200 mg/m2/day
Given post radiation – No Uses :
radioprotection 1. To reduce cumulative 15-30 minutes before treatment to
renal toxicity associated exploit the slower uptake in tumor
with repeated tissue
Palifermin - 60 μg/kg/day administration of CDDP
Reduces mucositis in CCRT in patients with advanced Decreased rates of acute and late
ovarian cancer or xerostomia, esophagitis,
NSCLC dysphagia, acute pneumonitis and
2. To decrease incidence of cystitis
moderate to severe
xerostomia in patients Amifostine – though reduces side-
undergoing post-op RT effects, not very popular due to
for head and neck cancer fear of tumor protection and
evolution of conformal RT
delivery
 189

MOLECULAR BIOLOGY OF CANCER AND ANGIOGENESIS

 190

1. Describe the Stages of Carcinogenesis.

Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are
transformed into cancer cells.

The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnormal cell
division.

FOUR PHASES:

(1) Malignant change in the target cell, referred to as transformation

(2) Growth of the transformed cells : Angiogenesis

(3) Local invasion

(4) Distant metastases

Transformation

• The first step is hyperplasia, meaning that there are too many cells resulting from uncontrolled cell
division. These cells appear normal, but changes have occurred that result in some loss of control of
growth.

• The second step is dysplasia – loss in uniformity and architecture , presence of typical mitotic figures

• The third step requires additional changes, which result in cells that are even more abnormal and can
now spread over a wider area of tissue.

• Anaplastic – Absence of diffferentiation and atypical mitotic figures.

Angiogenesis:
 191

Invasion:

• Nearly all benign tumors - site of origin and do not have the capacity to infiltrate, invade, or metastasize
to distant sites, as do malignant tumors.

• The growth of cancers is accompanied by progressive infiltration, invasion, and destruction of the
surrounding tissue.

• In situ epithelial cancers display the cytologic features of malignancy without invasion of the basement
membrane.

• They may be considered one step removed from invasive cancer; with time, most penetrate the basement
membrane and invade the subepithelial stroma.

Metastasis:

Mechanistic theory: determined by the pattern of blood flow.

“Seed and soil” theory: the provision of a fertile environment in which compatible tumor cells could grow
 192

ONCOGENES

• Oncogenes encode proteins that possess the ability to cause cellular transformation.

• These genes act in a dominant fashion, either through overexpression or activating mutations.

• Source - UV light, Xrays, natural or synthetic chemicals,Virus (ex. HPV and cervical cancer)
 193

Tumor suppressor genes

 Often DNA damage will cause the presence of free-floating genetic material as well as other signs,
and will trigger enzymes and pathways that lead to the activation of tumor suppressor genes.
 194

ANGIOGENESIS

The word “Angio” means blood vessels while “genesis” means creation, i.e. Angiogenesis is the formation of
new blood vessels from pre-existing vessels.

 Angiogenesis is a normal process in growth and development, as well as in wound healing.  Angiogenesis
mainly occurs by two ways:

1. Sprouting angiogensis

2. Intussusceptive angiogenesis

SPROUTING ANGIOGENESIS

It occurs in several well-characterized stages:

1. Activation of VEGF receptors of endothelial cells present in pre-existing veins.

2. The activated endothelial cells escape from the original vessel walls by help of protease.

3. Proliferation of endothelial cells into the surrounding matrix.

4. Migration of endothelial towards the source of the angiogenic stimulus

5. Re-organisation of endothelial cells to form tubules with a central lumen & interconnection of new tubules to
form a branched network.

INTUSSUSCEPTIVE ANGIOGENESIS

Intussusceptive, also known as Splitting angiogenesis i.e. a single vessel split in two.

There are four phases of intussusceptive angiogenesis.

1. Two opposing capillary walls establish a zone of contact.

2. Perforation of vessel bilayer to allow growth factors and cells to penetrate into the lumen.

3. Formation of a core at the zone of contact between two vessels & is filled with pericytes and myofibroblasts.
4. The core is fleshed out with no alterations to the basic structure

STIMULATORS OF ANGIOGENESIS

 Basic fibroblast growth factor (bFGF)

 Vascular endothelial growth factor (VEGF)

 Angiogenin
 195

 Epidermal growth factor

 Interleukin 8

 Granulocyte colony stimulating factor

 Placental growth factor

 Platelet-derived endothelial growth factor

 Tumor necrosis factor alpha (TNF-α)

INHIBITORS:
 196

FIELD CANCERISATION

The oral cavity was proven to be most susceptible area Exposed to a wide range of environmental carcinogens
which affect the entire mucosa Simultaneous occurrence of premalignant states

• This led to various molecular analyses to investigate the genetic mutations and clonality to validate
Carcinogenesis model.

Concept of field cancerization

• Field cancerization involves the formation of multiple patches of premalignant disease with a higher-than-
expected rate of multiple local second primary tumors.

• The environmental carcinogens reach simultaneously a large area and can damage a large proportion of cells
contributing to premalignant states within the entire surface exposed.

Theories of field cancerization

Varies theories have been postulated to explain the occurrence of carcinomas in specific sites:

One theory states that multiple squamous cell lesions occur independently of each other -- due to the exposure
of the oral cavity to carcinogens in at the same time leading to multiple genetic abnormalities in the entire area.

An alternative theory states that multiple lesions arise due to the migration of dysplastic and altered cells with
two different patterns as follows:

i) Migration of malignant cells through the saliva (micro metastasis);

ii) ii) Intra-epithelial migration of the progeny of initially transformed malignant cells.
clonality models

• Oral field cancerization occurs by either cell migration or development from independent cells. • An early
cytogenetic technique used to determine clonality is karyotype analysis. • The method used initially was the X
chromosome inactivation which occurred when large patches of cells were derived from a common ancestor
especially during embryonic development.

Microsatellite alterations have been widely utilized to determine clonality between lesions. • Currently p53
mutations are used as clonal markers for multiple primary tumors, as their expression has been observed in the
normal tissue far from the tumor sites.
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FLOW CYTOMETRY

Definition: Measuring properties of cell as they flow in a fluid suspension across an illuminated light
path.

This method allows the quantitative and qualitative analysis of several properties of cell

populations from virtually any type of fresh unfixed tissue or body fluid.

The properties measured include a particle’s related size, relative granularity or internal

complexity, and relative fluorescence intensity

Most commonly analyzed materials are:

blood,

bone marrow aspirate and

lymph node suspensions.

 ANALYSIS  Immunophenotyping  Dyes that bind to nucleic acids (DNA, RNA)  Functional assays
 198

TUMOUR MARKERS

Tumor markers are substances, usually proteins, that are produced by the body in response to cancer growth or
by the cancer tissue itself and that may be detected in blood, urine, or tissue samples.

• Some tumor markers are specific for a particular type of cancer, while others are seen in several cancer types.

Definition

• Most of the well-known markers may also be elevated in non-cancerous conditions. Consequently, tumor
markers alone are not diagnostic for cancer.

• There are well-established tumor markers that are routinely used

. Many other potential markers are still being researched.

Tumor markers can be classified in two groups:

1-Cancer-specific markers

2-tissue-specific markers.

Cancer-specific markers

- Related to the presence of certain cancerous tissue

- these markers might not be specific in making a diagnosis

- useful in the follow-up of treated patients -to describe progress of the disease -response to treatment.

Examples of these markers are CEA, CA19-9, CA125

Tissue-specific markers

• Related to specific tissues which have developed cancer

- these substances are not specifically related to the tumor, and may be present at elevated levels when no
cancer is present.

- But unlike the previous group, elevated levels point to a specific tissue being at fault.

- Examples include PSA, beta-HCG, ), AFPL3, and Thyroglobulin.

CEA • carcinoembryonic antigen, is a blood-borne protein, first noted to be

produced by tumors of the gastrointestinal system.

- it was produced by the lung and breast cancer case,an elevated level
does not necessarily mean a bowel cancer.

- a rising CEA level can be an early sign of recurring bowel cancer.

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AFP AFP is a major plasma protein( glycoprotein ) produced by the yolk sac
and the liver during fetal development that is thought to be the fetal form
of serum albumin.
- AFP is measured in pregnant women through the analysis of maternal
blood or amniotic fluid, as a screening test for a subset of developmental
abnormalities
-Increased in open neural tube defects and omphalocoele .
-Decreased in Down syndrome.
AFP • - It used as a biomarker to detect a subset of tumors in non-
pregnant women, men, and children. A level above 500
nanograms/milliliter of AFP in adults can be indicative of : -
Hepatocellular carcinoma -Germ cell tumors -Metastatic cancers of the
liver.

CA 19.9 Pancreatic, sometimes colorectal and bileducts

• Pancreatitis and inflammatory bowel disease
CA 15-3 Breast cancer and lung, ovarian
B2M (Beta-2 microglobulin) Multiple myeloma and lymphomas • Crohn's disease and hepatitis
 200

USES

1-Screen • PSA testing may be used to screen for prostate cancer.

• 2-Diagnose • CA-125 for ovarian cancer.

• 3-Stage

• 4-Determine Prognosis

• 5-Guide Treatment • Breast cancer patients who are Her2/neu positive are more likely to respond to Herceptin
treatment).

6-Monitor Treatment AFP in a child previously treated for teratoma suggests relapse with endodermal sinus
tumor.

• 7-Determine Recurrence.
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PARANEOPLASTIC SYNDROME

A paraneoplastic syndrome is a syndrome (a set of signs and symptoms) that is the consequence of cancer in
the body, but unlike mass effect, is not due to the local presence of cancer cells.
In contrast, these phenomena are mediated by humoral factors (such as hormones or cytokines) secreted by
tumor cells or by an immune response against the tumor.
ENDOCRINE

 small-cell lung cancer Ectopic ACTH and ACTH-like

Cushing syndrome  Pancreatic carcinoma substance
 Neural tumors
 Thymoma
Syndrome of inappropriate  Small-cell lung cancer Antidiuretic hormone
antidiuretic hormone  CNS malignancies
Hypercalcemia  Lung cancer (typically squamous PTHrP (Parathyroid hormone-
cell) related protein), TGF-α, TNF, IL-
 Breast carcinoma 1[10]
 Renal and bladder carcinoma
 Multiple myeloma (may occur
independent of osteolytic lesions)
 Adult T cell leukemia/lymphoma
 Ovarian carcinoma
 Squamous cell carcinoma (eg,
lung, head, neck, esophageus)
Hypoglycemia  Fibrosarcoma Insulin or insulin-like substance
 Other mesenchymal sarcomas or "big" IGF-II
 Insulinoma
 Hepatocellular carcinoma
Carcinoid syndrome  Bronchial Serotonin, bradykinin
adenoma (carcinoid type)
 Pancreatic carcinoma
 Gastric carcinoma
Hyperaldosteronism  Adrenal adenoma / Conn's Aldosterone[
syndrome
 Non-Hodgkin's lymphoma
 Ovarian carcinoma
 Pulmonary
 202

NEUROLOGICAL

 Small-cell lung cancer Immunologic

Lambert-Eaton
myasthenic syndrome

Paraneoplastic cerebellar  Lung cancer

degeneration  Ovarian cancer
 Breast carcinoma
 Hodgkin's lymphoma
Encephalomyelitis Inflammation of the brain and spinal cord
Limbic encephalitis  Small-cell lung
carcinoma
Brainstem encephalitis  Lung cancer Antineuronal antibodies (anti-Hu, anti-Ri, and
 Testicular cancer anti-Ma2). Some forms are amenable to
immunotherapy while others are not.
Opsoclonus myoclonus  Breast carcinoma Autoimmune reaction against the RNA-binding
ataxiasyndrome  Ovarian carcinoma protein Nova-1
 Small-cell lung
carcinoma
 Neuroblastoma (in
children)
Anti-NMDA receptor  Teratoma Autoimmune reaction against NMDA-
encephalitis receptor subunits
 203

MUCOCUTANEOUS

 Gastric carcinoma  Immunologic

Acanthosis nigricans  Lung carcinoma  Secretion of epidermal growth factor
 Uterine carcinoma
Dermatomyositis  Bronchogenic carcinoma Immunologic
 Breast carcinoma
 Ovarian cancer
 Pancreatic cancer
 Stomach cancer
 Colorectal cancer
 Non-Hodgkin lymphoma
Leser-Trélat sign
Necrolytic migratory erythema Glucagonoma
Sweet's syndrome
Florid cutaneous papillomatosis
Pyoderma gangrenosum
Acquired generalized hypertrichosis
Granulocytosis

HEMATOLOGICAL

Granulocytosis G-CSF

 Renal carcinoma Erythropoietin

Polycythemia  Cerebellar hemangioma
 Hepatocellular carcinoma
Trousseau sign  Pancreatic carcinoma Mucins that activate clotting, others
 Bronchogenic carcinoma
Nonbacterial thrombotic endocarditis  Advanced cancers Hypercoagulability
Anemia  Thymic neoplasms Unknown
 204

HYPERCALCAEMIA

 Hypercalcaemia, also spelled hypercalcemia, is a high calcium (Ca2+) level in the blood serum.
 The normal range is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L) with levels greater than
2.6 mmol/L defined as hypercalcemia.

Those with a mild increase that has developed slowly typically have no symptoms.
 In those with greater levels or rapid onset, symptoms may include abdominal pain, bone
pain, confusion, depression, weakness, kidney stones, or anabnormal heart rhythm including cardiac
arrest.
 Most cases are due to primary hyperparathyroidism or cancer.
 Other causes include sarcoidosis, tuberculosis, Paget disease, multiple endocrine
neoplasia(MEN), vitamin D toxicity, familial hypocalciuric hypercalcaemia, and
certain medications such as lithium and hydrochlorothiazide.
 Diagnosis should generally include either a corrected calcium or ionized calcium level and be confirmed
after a week.
 Specific changes, such as a shortened QT interval, may be seen on anelectrocardiogram (ECG)

TREATMENT

Fluids and diuretics

Initial therapy:

 hydration, increasing salt intake, and forced diuresis.

 hydration is needed because many patients are dehydrated due to vomiting or kidney defects in
concentrating urine.
 increased salt intake also can increase body fluid volume as well as increasing urine sodium excretion,
which further increases urinary potassium excretion.
 after rehydration, a loop diuretic such as furosemide can be given to permit continued large volume
intravenous salt and water replacement while minimizing the risk of blood volume overload
and pulmonary oedema. In addition, loop diuretics tend to depress calcium reabsorption by the kidney
thereby helping to lower blood calcium levels
 can usually decrease serum calcium by 1–3 mg/dL within 24 hours
 caution must be taken to prevent potassium or magnesium depletion

Bisphosphonates bisphosphonates are pyrophosphate analogues with high affinity for bone, especially areas of
high bone-turnover.

 they are taken up by osteoclasts and inhibit osteoclastic bone resorption

 current available drugs include (in order of potency): (1st gen) etidronate, (2nd gen) tiludronate,
IV pamidronate, alendronate (3rd gen) zoledronate and risedronate
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 all people with cancer-associated hypercalcaemia should receive treatment with bisphosphonates since
the 'first line' therapy (above) cannot be continued indefinitely nor is it without risk. Further, even if the
'first line' therapy has been effective, it is a virtual certainty that the hypercalcaemia will recur in the
person with hypercalcaemia of malignancy. Use of bisphosphonates in such circumstances, then,
becomes both therapeutic and preventative
 people in kidney failure and hypercalcaemia should have a risk-benefit analysis before being
given bisphosphonates, since they are relatively contraindicated in kidney failure.
 Calcitonin blocks bone resorption and also increases urinary calcium excretion by inhibiting calcium
reabsorption by the kidney
 Usually used in life-threatening hypercalcaemia along with rehydration, diuresis, and bisphosphonates
 Helps prevent recurrence of hypercalcaemia
 Dose is 4 international units per kilogram via subcutaneous or intramuscular route every 12 hours,
usually not continued indefinitely due to quick onset of decreased response to calcitonin

Other therapies

 rarely used, or used in special circumstances

 plicamycin inhibits bone resorption (rarely used)
 gallium nitrate inhibits bone resorption and changes structure of bone crystals (rarely used)
 glucocorticoids increase urinary calcium excretion and decrease intestinal calcium absorption
 no effect on calcium level in normal or primary hyperparathyroidism
 effective in hypercalcaemia due to osteolytic malignancies (multiple
myeloma, leukaemia, Hodgkin's lymphoma, carcinoma of the breast) due to antitumour properties
 also effective in hypervitaminosis D and sarcoidosis
 dialysis usually used in severe hypercalcaemia complicated by renal failure. Supplemental phosphate
should be monitored and added if necessary
 phosphate therapy can correct the hypophosphataemia in the face of hypercalcaemia and lower serum
calcium
 A hypercalcaemic crisis is an emergency situation with a severe hypercalcaemia, generally above
approximately 14 mg/dL (or 3.5 mmol/l).
 The main symptoms of a hypercalcaemic crisis are oliguria or anuria, as well as somnolence or coma.
 After recognition, primary hyperparathyroidism should be proved or excluded.
 In extreme cases of primary hyperparathyroidism, removal of the parathyroid gland after surgical neck
exploration is the only way to avoid death.
 The diagnostic program should be performed within hours, in parallel with measures to lower serum
calcium.
 Treatment of choice for acutely lowering calcium is extensive hydration and calcitonin, as well
as bisphosphonates (which have effect on calcium levels after one or two days)
*********
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TOBACCO AND CANCER

 207

SMOKING Chewing tobacco

• Loose leaf
• Cigars • Pellets
• Blunts • Plug
• Cigarillos • Guṭkha is a preparation of crushed areca nut,
• Little cigars tobacco, catechu, parafin wax, slaked lime and sweet
• Cigarettes flavourings
• Filter cigarettes • Zarda consists of tobacco, lime, spices and vegetable
• Pipe smoking dyes • Khaini is made from sun-dried or fermented
• Electronic cigarretes coarsely cut tobacco leaves.
• Bidis
• Kreteks

Tobacco Use Behaviors

• Primary driver of smoking behavior is nicotine—the major addictive substance and primary reinforcer of
continued smoking

• Rate of nicotine metabolism

• Nicotine is metabolized primarily to cotinine, which is further metabolized to trans-3′-hydroxycotinine (3HC),

catalyzed by the liver cytochrome P450 2A6 enzyme

CARCINOGENS IN TOBACCO PRODUCTS

• The International Agency for Research on Cancer (IARC)

• Identified 72 measurable carcinogens in cigarette smoke

• Group 1 (carcinogenic to humans),

• 2A (probably carcinogenic to humans), or

• 2B (possibly carcinogenic to humans).

The key provisions of COTPA -2003 are as follows:

• Prohibition of smoking in public places (including indoor workplaces). This has been implemented from 2nd
October 2008 in the whole of India.

• Prohibition of advertisement, direct and indirect (point-of-sale advertising is permitted), sponsorship and
promotion of tobacco products.

• Prohibition of sales to minors (tobacco products cannot be sold to children less than 18 years of age and
cannot be sold within a radius of 100 yards of any educational institutions).
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• Regulation of health warning in tobacco products packs. English and one more Indian language to be used for
health warnings on tobacco packs. Pictorial health warnings also to be included.

• Regulation and testing of tar and nicotine contents of tobacco products and declaring on tobacco products
packages.

Nicotine Palatinus of reverse smoker:

Characterized into:

1. Keratosis – diffuse whitening of the entire palatal mucosa

2. Excrescences – 1-3mm elevated nodules often with central red dots corresponding to the opening of palatal
mucous glands.

3. Patches – well-defined elevate white plaques which could qualify for the clinical term of leucoplakia.

4. Red areas – well-defined reddening of the palatal mucosa.

5. Ulcerated areas – crater-like areas covered by fibrin. 6. Non-pigmented areas – areas of palatal mucosa which
are devoid of pigmentation.

MECHANISM OF TOBACCO CARCINOGENESIS

 Tobacco consumption is correlated with

 accumulation of DNA damage

 exposure to tobacco-related chemical carcinogens  Can provide direct damaging effects on the cellular DNA
in the human oral cavity.

 There are >60 carcinogens in cigarette smoke & at least 16 in unburned tobacco have been evaluated by IARC.
 209

CARCINOGEN BIOMARKERS

 Provide objective measures of carcinogen uptake, metabolic activation and detoxification in people who use,
or are otherwise exposed to tobacco products

 Among carcinogen biomarkers:

 DNA adducts potentially provide the most direct link to cancer

 Protein adducts are useful alternatives to DNA adducts

 Urinary metabolites are probably the most practical biomarkers and provide important information about
carcinogen dose and metabolism.

 Important in establishing carcinogen dose in people who are exposed to tobacco products and in understanding
mechanisms of carcinogenesis, and might ultimately be useful in predicting cancer risk.
 210

\
 211

CANCER EPIDEMIOLOGY, SCREENING AND PREVENTION

 212

NATIONAL CANCER CONTROL PROGRAM

 1975-76 - National Cancer Control Programme was launched with priorities given for equipping the
premier cancer hospital/ institutions.

 Central assistance at the rate of Rs.2.50 lakhs was given to each institution for purchase of cobalt
machines.

 1984-85 - The strategy was revised and stress was laid on primary prevention and early detection of
cancer cases.

 1990-91 - District Cancer Control Programme was started in selected districts (near the medical college
hospitals).

 2000-01 - Modified District Cancer Control programme initiated.

 2004 - Evaluation of NCCP was done by National Institute of Health & Family Welfare, New Delhi.

 2005 - The programme was further revised after evaluation

 National program for prevention and control of Diabetes, Cardiovascular diseases and Stroke (NPDCS)
was formulated in second half of 2010.

 Since cancer and the other 3 NCDs are preventable by modifying the four common risk factors –

1. Tobacco use 2. Harmful use of alcohol

3. Unhealthy diet 4. Physical inactivity

 In 2011, NPDCS was integrated with NCCP to form the National program for prevention and control of
Cancer, Diabetes, Cardiovascular diseases and Stroke (NPCDCS)

GOALS & OBJECTIVES

1. Primary prevention of cancers by health education specially regarding hazards of tobacco

consumption and necessity of genital hygiene for prevention of cervical cancer.

2. Secondary prevention i.e. early detection and diagnosis of cancers, for eg, ca cervix, breast and oro-
pharyngeal cancer by screening methods and patients’ education on self examination methods.

3. Strengthening of existing cancer treatment facilities, which are woefully inadequate.

4. Palliative care in terminal stage of the cancer.

 213

EXISTING SCHEMES UNDER NATIONAL CANCER CONTROL PROGRAMME (NCCP)

[Link] OF NEW REGIONAL CANCER CENTRES (RCCS)

To enhance the cancer treatment facilities across the country and reduce the geographical gap in the country in
the availability of cancer care facilities, A one-time grant of Rs. 5.00 crores is being provided for New RCC’s.

[Link] OF EXISTING REGIONAL CANCER CENTRES

A one-time grant of Rs.3.00 crores is provided to the existing Regional Cancer Centres to further strengthen
the cancer care services.

 The RCCs should provide Comprehensive cancer treatment services.

 There should be a mechanism in place or proposed, to spread awareness in the community and among
health personnel regarding common cancers and their early detection/ prevention.

 The institution should undertake training of medical officers and health workers, in early detection and
prevention of cancers and supportive care.

 A referral linkage should be developed between the RCC and the hospitals under the DCCP so as to
ensure continuity in the treatment chain.

 Outreach and research activities in prevention and treatment of cancers should also be carried out.

 The RCC will have to undergo periodic monitoring and evaluation to ensure satisfactory functioning.

3. DEVELOPMENT OF ONCOLOGY WING

 Objective- reducing the geographical gaps in cancer treatment facilities in the country by

establishing cancer treatment centres in areas where these are deficient.

 Government Hospitals & Government Medical Colleges are provided with a grant of Rs.3.00 crores for
the development of Oncology Wing.

[Link] CANCER CONTROL PROGRAMME : Launched in 1990-91

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The district programme has five elements:

1. Health education.

2. Early detection.

3. Training of medical & paramedical personnel’s.

4. Palliative treatment and pain relief.

5. Coordination and monitoring.

 Linked with

1. ¢ Regional Cancer Centres

2. ¢ Government Hospitals

3. ¢ Medical Colleges

 For effective functioning -one District Cancer Society is chaired by local Collector/Chief Medical
Officer.

 Other members are Dean of medical college, Zila parishad representative, NGO representative etc.

5. DECENTRALIZED NGO SCHEME

This scheme has been devised to promote (IEC) prevention and early detection of cancers.

NGO will implement these activities under the coordination of the Nodal Agency, which will be an RCC or an
Oncology wing.

A grant of Rs.8000/- per camp will be provided to the NGOs for IEC activities.

ACHIEVEMENTS (AS OF 2008)

Regional Cancer Centres:

 27 RCCs, including 6 NGOs, providing comprehensive cancer care services.

 Outreach and research activities in prevention and treatment of cancers are carried out by these centres.

Oncology wing:

 Support has been given to 82 institutes in both Government Medical Colleges and Hospitals.
 215

 At present there are 246 institutions with radiotherapy facilities across the country, including the 27
RCCs.

District Cancer Control Programme:

The District Cancer Control Programme, which has been developed to initiate awareness and early detection
activities at the district level; are in place in 28 districts at present.

IEC Activities:

The programme supports activities of health magazine ‘Kalyani’ and telecast by Prasar Bharti targeting
especially those living in the most populous States.

NEW INITIATIVES

 India has become the member of international agency for research on cancer(IARC)

 The pap smear kits and can-scan software supplied to12 RCC.

 Onconet India: telemedicine project to connect 27 RCCs and 4 to 5 peripheral centers is being
operationalized.

 Training of cytopathologists and cytotechicians in the quality assurance in pap smear.

 Participation in health mela and distribution of health education material.

 India has become the member of international agency for research on cancer(IARC)

 The pap smear kits and can-scan software supplied to12 RCC.

 Onconet India: telemedicine project to connect 27 RCCs and 4 to 5 peripheral centers is being
operationalized.

 Training of cytopathologists and cytotechicians in the quality assurance in pap smear.

 Participation in health mela and distribution of health education material.

 216

NATIONAL CANCER REGISTRY PROGORAMME/CANCER REGISTERS

launched in 1982 by Indian Council of Medical Research (ICMR) to provide true information on cancer
prevalence and incidence.

• Commenced by ICMR with a network of cancer registries across the country in December 1981

• Started with three PBCR -Bangalore, Chennai and Mumbai and three HBCR -Chandigarh, Dibrugarh
and Thiruvananthapuram

• Now there are 28 PBCR and 7 HBCR sites in India

• The NCRP is a long-term activity of the Indian Council of Medical Research. The programme is one of
the many major activities of the Division of Non-Communicable Diseases. The Chief of the Division is
the Director of the Programme with a Project officer who coordinates the activities through the
Coordinating Unit.

Objectives :

• Objectives of this programme

 To generate reliable data on the magnitude and patterns of cancer

 Undertake epidemiological studies based on results of registry data

 Help in designing, planning, monitoring and evaluation of cancer control activities under the

 National Cancer Control Programme (NCCP)

 Develop training programmes in cancer registration and epidemiology

Steering Committee and a Monitoring Committee meets periodically to oversee and guide –functioning

A review meeting is held annually –Principal Investigators and staff of the registries present results and
participate in the discussions-preceded by a workshop

Death certificates are also scrutinized from the municipal corporation units

CANCER ATLAS

 To bridge the gap, a project of atlas of the cancer in India was started under WHO-ICMR since 2003
mainly to have an idea of patterns of cancer in several parts of the country.

 Under this programme ICMR has developed an Atlas of cancer in India based on the information
collected for the year 2001-02 from 105 collaborating centres to have an idea of the pattern of cancer
across the country.

• A CANCER REGISTRY is a unit that

• Continually and systematically records all new cancer cases within a defined population
 217

• Periodically analyses and reports such data

• Provides epidemiological data on cancer useful for research, cancer prevention, and planning and
evaluation of health services (Shanmugaratnam, 1991)

Types of cancer registry

USES:

1. Epidemiological research

a. Descriptive studies

b. Analytical studies

2. Health care planning and monitoring

a. Patient care

b. Survival studies

c. Cancer screening

PROCEDURE

• All registries are required to register all malignant neoplasms coded as per the International
Classification of Diseases for Oncology (ICD-O) with a behaviour code /3 (WHO, 1975,76).
 218

• Besides identifying information and duration of stay at the permanent place of residence they also
collect information on educational status, religion, language spoken, method of arriving at a final
diagnosis of cancer, extent of disease at the time of diagnosis and mode of treatment(s) given up to six
months of diagnosis

• A workshop is held annually, with the objectives of discussing the various aspects of working of the
registry, problematic cases, use of coding and discussion on medical terminology, statistical and
epidemiological methods. About 2-3 senior and junior staff of all the registries under the NCRP,
participate in the workshop.

POPULATION BASED CANCER REGISTRIES:

• Basic thrust of a PBCR is cancer in community

• PBCR provides - data on incidence and mortality (also variation in incidence and mortality)

• Three new centers Patiala, Naharalagun,Pasighat has started

• Good PBCR requires

 Meticulous planning

 Cooperation from medical institutes

 Dedicated personal and adequate funding

Data collection-

Facilities

Clinician and pathologist

Death certificate

Recommended variables

Date of last contact

Status at last contact (at least dead or alive)

Stage or extent of disease at diagnosis

Initial treatment
 219

HOSPITAL BASED CANCER REGISTRIES

• 1984- Blore, Chennai, Mumbai

• The primary purpose -to contribute to patient care by providing readily accessible information on the
patients

• Data - used for clinical research and for epidemiological purposes

• Within the hospital, a registry - integral part of the hospital’s cancer programme or health care delivery
system

• Objectives-

 Assess Patient Care

 Participate in Clinical Research to Evaluate Therapy

 Provide an idea of the patterns of cancer in the area

 Help plan hospital facilities

4. TOBACCO CONTROL LEGISLATION

 “The Cigarettes and other tobacco products (Prohibition of advertisement and regulation of trade and
commerce production, supply and distribution) Act 2003” – passed in April 2003 and notified in 25th
Feb 2004.

a. Prohibition of smoking in public place

b. Prohibition of direct & indirect advertisement of cigarette & other products

c. Prohibition of cigarette & other tobacco products to a person below the age of 18 yrs

d. Prohibition of sale of tobacco products near educational institutions

e. Mandatory depiction of statutory warnings on tobacco packs

f. Mandatory depiction of tar & nicotine contents along with maximum permissible limits on tobacco pack
 220

SCREENING

• Definition :
Secondary prevention method in which earlier therapeutic intervention is possible through screening
an asymptomatic population to identify cancer at an earlier stage than it would have been diagnosed in
absence of screening.

• Goal :
To reduce mortality and/or severity of the disease through early detection and treatment.

Ideal screening test

Cheap, Sensitive, Specific, Accessible, Safe, Acceptable

Pitfalls of screening
• False-positive test result
• Over diagnosis
• False-negative test result
Common Cancers where screening is done

1. Breast cancer

2. Cervical cancer

3. Ovarian cancer

4. Colorectal cancer

5. Lung cancer

6. Prostate cancer

7. Endometrial cancer

8. Oral cancer
 221

BREAST CANCER SCREENING

RISK FACTORS OF BREAST CANCER

From the History

 AGE: risk increases exponentially till menopause

 PRIOR HISTORY: 10-15% risk of second contralateral breast cancer

 RADIATION EXPOSURE:

 ALCOHOL CONSUMPTION: 50% higher risk-average consumption reported 6g per day

 FAMILY HISTORY :first degree relative-1.5 and second degree relative-1.7-2.5

 GENETIC FACTOR:
o mutations in brca1 & brca2, p53 gene (li-fraumeni synd.)
o -similar risk pts treated for invasive breast ca or dcis
Obs and Gynae His

1. EARLY MENARCHE
2. LATE MENOPAUSE
3. NULLIPAROUS WOMEN
4. CHILD BEARING: younger age-protective, childbirth over 35 years-risk greater than
5. BREAST-FEEDING
6. EXOGENOUS HORMONE: prolonged use of combination pills

Examination finding

 BODY MASS INDEX- high estradiol level- high adipose tissue- high aromatase-↑ed estradiol
 physical activity: sedentary
 diet-obesity, high fat, meat
 mammographic density

What is GAIL Model ?

It is important to consider the combination of risk factors when a generalized risk profile is determined.
Gail et al. have used these epidemiologic risk factors to derive a model for predicting an individual’s
annual and lifetime risks of breast cancer.
In the Gail model, an individual`s annual risk of breast cancer is based on her
 Present age
 Number of first-degree relatives with breast cancer
 Age at first birth,
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 Age at menarche,
 Number of breast biopsies and history of atypical ductal hyperplasia
1. Familial Breast Cancer

 Approximately 10% of breast cancer patients have familial breast cancer, typically defined as
breast cancer showing an AUTOSOMAL DOMINANT inheritance pattern.
 During the 1990s, germline mutations in three important tumor suppressor genes—p53,
BRCA1, and BRCA2—were discovered in family members of individuals with familial breast
cancer.
 All three genes have been shown unequivocally to predispose to breast cancer.
 Germline mutations in the p53 gene are very rare and result in Li-Fraumeni syndrome
 Breast cancer is the most common malignancy in patients with Li-Fraumeni syndrome; the
lifetime risk is estimated to be 90%

BRCA1 BRCA2
1995 1996

Individuals with a germline mutation in BRCA2 mutation carriers are

BRCA1 have a lifetime risk of breast cancer of also at increased risk for ovarian cancer
65% to 85%. compared with the general population, but their
risk is much less than the risk in women with
In addition, these individuals have an elevated BRCA1 mutations.
lifetime risk of ovarian
cancer, which may approach 50%. BRCA2 is also associated with male breast
cancer and pancreatic cancer.
Other types of cancer that develop more
frequently in BRCA1 carriers include colon
and prostate cancers.

In the context of pre- and post test counseling, the NCCN recommends that genetic testing be offered
when:

1. The individual has a family history of a known BRCA1/ BRCA2 mutation,

2. Personal history of breast cancer plus one of the following:
a. Diagnosed age 45 years or younger
b. Diagnosed age ≤50 years with one or more close blood relatives with breast cancer ≤50 years
c. Two breast primaries when first breast primary occurred before age 50
d. Diagnosed at any age, with two or more close blood relatives with breast and/or epithelial
ovarian/fallopian tube/ primary peritoneal cancer at any age
e. Close male relative with breast cancer
f. An individual of ethnicity associated with higher mutation frequency (e.g., Ashkenazi Jewish).

Personal history of epithelial ovarian/fallopian tube/primary peritoneal cancer, or Personal history of

male breast cancer.
 223

Two groups acc. to NCCN guidelines :

1. Average risk

2. Increased risk :

- prior history of breast cancer

- women ≥35 yrs with a 5 yr risk of invasive breast cancer ≥1.7 % by per Gail model

- women with lifetime risk of breast cancer > 20% based on family history

- with previous history of thoracic radiations- 10-30 yrs

- With LCIS

- Pedigree suggestive or with known genetic predisposition.

• Women aged 40 to 44 should have the choice to start annual breast cancer screening with mammograms
(x-rays of the breast) if they wish to do so.

• Women aged 45 to 54 should get mammograms every year.

• Women 55 and older should switch to mammograms every 2 years, or can continue yearly screening.

• Screening should continue as long as a woman is in good health and is expected to live 10 more years or
longer.

• All women should be familiar with the known benefits, limitations, and potential harms linked to breast
cancer screening.

SCREENING IN BREAST CANCER

The NCCN has published a guideline recommending that individuals with a genetic predisposition undergo
annual clinical and self-breast examination prior to age 25 and annual mammography or magnetic resonance
imaging (MRI) and semiannual clinical and self breast examination after age 25.
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SCREENING BY PHYSICAL EXAMINATION

Two studies have evaluated the effectiveness of screening by breast self-examination alone, the United
Kingdom and the Canadian trials.

In the Breast Cancer Detection Demonstration Project, the estimated overall sensitivity of breast self-
examination in detecting breast cancer was 26%, compared with 75% for the combination of clinical breast
examination and mammography.

Clinical breast examination and self-examination may be complementary to mammography, perhaps

detecting interval cancers in the 10% to 12% of cancers not visualized by mammography.

MAMMOGRAHY

 In the United States, screening mammography beginning at age 40 years is recommended for the
general population.
 For some women at high risk for development of breast cancer, annual screening may be started at
an earlier age. These women include those with a personal history of breast cancer, those who have
had therapeutic radiation to the breast area especially for Hodgkin lymphoma, BRCA-positive
women, women with a family history of a first-degree relative with breast cancer at a young age, and
women with a biopsy diagnosis of LCIS or atypical ductal hyperplasia.
 It recommended against routine screening mammography in women aged 40 to 49 years and
recommended biennial screening mammography for women between the ages of 50 and 74 years.
 The group felt there was insufficient evidence to assess the additional benefits and harms of
screening mammography in women 75 years or older.

Digital Versus Screen Film Mammography

There has been increased utilization of digital mammography for screening. This technology utilizes a
special detector capable of transforming x-ray images into electronic digital image.

Advantages include no film processing, faster image acquisition, and less call-backs due to the ability to
manipulate the image digitally.

Screening mammography refers to routine mammographic images in asymptomatic women and consists
of two views: craniocaudal and mediolateral oblique of each breast.

Diagnostic mammography is used to characterize abnormalities detected at screening or in women with

palpable masses, employs additional magnification views, and is generally done with the radiologist present
to determine the need for additional views or follow-up studies.

FINDINGS

Calcifications can be associated with either benign or malignant conditions of the breast. However,
calcifications associated with malignant tumors are typically 100 to 300 μm in size and are rod like, tubular,
branching, or punctate.
 225

Clusters of microcalcifications (more than five) are suggestive of intraductal disease, and in nonpalpable
lesions needle localization aids in the diagnosis.

For patients undergoing biopsy of a suspicious mass or calcifications, about 30% will yield a diagnosis of
malignancy.

The average sensitivity of mammography is approximately 90% (60% to 95%) and the specificity is 94%
(50% to 98%).

The positive predictive value is approximately 8% to 14% for screened patients, but is significantly higher
for patients with symptoms or palpable masses. If microcalcifications were initially present, radiographs of
the surgical specimen and postlumpectomy mammography are important to rule out residual disease for
patients considering breast-conservation therapy

MAGNETIC RESONANCE IMAGING SCREENING

 For women at high risk for breast cancer due to strong family history or positive BRCA1/BRCA2
status, the standard screening techniques of breast self-examination, clinical breast examination, and
mammography may be suboptimal.
 Nearly half of the cancers in this population are detected by physical examination between routine
radiographic surveillance.
 In this population, increased breast density and rapid proliferative rates likely contribute to the
relative insensitivity of mammography.

ULTRASOUND SCREENING

 Ultrasound is a complementary tool to mammography for the diagnosis of breast cancer.

 As with MRI, it is unlikely to replace mammography for screening the general population.
 The NCCN recommends ultrasound for those women presenting with a dominant mass or
asymmetric thickening or nodularity
 Ultrasonography has a reported sensitivity of 73% and specificity of 95%.
 It is very helpful in differentiating cysts from solid tumors, and its primary use is the identification
and characterization of palpable and nonpalpable abnormalities of the breast detected by physical
examination or mammograph
 226

CARCINOMA CERVIX : RISK FACTORS AND SCREENING

1. HPV - 90% of cervical cancers are related to the presence of HPV

 HPV is a small, double-stranded DNA virus
 HPV 16 and 18 mainly, mediated by E6 and E7 oncogene
 Others – 31, 33, 35, 39, 45, 51, 52, 56, 58
Mechanism of action : The HPV genome integrates into the host cell chromosomes in cervical
epithelial cells and codes for six early and two late open reading frame proteins, of which three (E5,
E6, and E7) alter cellular proliferation.

 Two viral genes, E6 and E7, are typically expressed in HPV-positive cervical-cancer cells.
 The E6 protein inactivates the major tumor suppressor p53; this causes chromosomal instability,
inhibits apoptosis, and activates telomerase.
 The E7 protein affects the retinoblastoma protein (Rb), resulting in a loss of regulation of the
cell’s proliferation and immortalization
 Although a high prevalence of HPV exists worldwide, peaking at ages 25 to 35 years, <15% of
exposed women develop persistent infection that results in dysplasia, whereas the majority of
women clear the infection within 2 years.
 Cervical cancer may develop 10 to 20 years after initial exposure to HPV.
 Circumcision in male – does it prevent ca cervix in female is controversial
 HPV VACCINATION : The quadrivalent human papillomavirus recombinant vaccine for HPV
types 6, 11, 16, and 18, first approved in the United States in 2006 for girls and women ages 9 to
26 years, is now available for boys ages 9 to 26 years, with the goal of eradicating HPV related
gynecologic, penile, anal, and oropharyngeal cancers.
 A second vaccine with strong immunogenicity to HPV types 16 and 18, approved for girls 9 to
25 years old, is more frequently administered in Europe.
2. Smoking
3. A weak immune system
4. Birth control pills
5. Starting sex at a young age
6. Having many sexual partners
7. Male partner with a history of multiple sexual partners
8. Large number of pregnancies
9. History of sexually transmitted disease including gonorrhoea, chlamydia, HSV II, HIV
Protective factor ? IUDs
 227

Vaccinated : Same

PAP Smear test- 2 types

1. Conventional

2. Liquid Based

COLPOSCOPY:

It is the initial step of abnormal pap smear, a procedure in which a colposcope (dissecting microscope with

various magnification lenses) is used to provide a magnified view of the cervix, vagina and vulva
 228

HPV VACCINATION
 229

OVARIAN CANCER – RISK FACTORS AND SCREENING

Risk Factors Protective factors

 oral contraceptives, oophorectomy ,

• Increasing age Multiparity
• Personal history of breast cancer

• Nulliparity The lifetime risk of ovarian cancer

• Early menarche • BRCA 1 mutations - 20% to 40%
• Late menopause • BRCA 2 mutations - 1 0 % to 20
• Infertility The majority of BRCA 1-associated cancers
• Polycystic ovarian syndrome Serous adenocarcinomas,
• Endometriosis with an average age at diagnosis of 48 years
• ovulation inducing drugs
• Hormone replacement therapy The mean age for BRCA 2-associated ovarian
cancers is 60 years.
• Family history of ovarian cancer
• BRCA 1 / 2 mutations Prophylactic Oopherectomy :
• Hereditary nonpolyposis colorectal cancer
Strongest risk factor is a family history of ovarian
• Obesity and high fat diet cancer
• Talc exposure • only 5–10% of tumors result from a known
• Cigarette smoking (for mucinous ovarian cancer) genetic disposition.
• Lifetime risk:
- general population 1.8%,
- one first-degree relative: 5%,
- two first-degree relatives: 25–50%.

SCREENING:

 Routine pelvic examination NOT effective. Serum CA125 in IU/ml and can vary between 0 and
hundreds or even thousands of units. ACS, ACOG, SGO, NCCN do NOT recommend ovarian cancer
screening for general population
 Screening with ultrasound and CA125 is recommended for women BRCA (+) mutations
 a pelvic examination, TVU, and a CA-125 blood test
 every 6 months beginning between the ages of 30 to 35 years, or 5 to 10 years earlier than the earliest
age of first Epithelial ovarian cancer (EOC) diagnosis in the family.
 Risk of Malignancy Index (RMI)
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RMI = U x M x CA125. ultrasound result is scored 1 point for each of the following characteristics:
multilocular cysts, solid areas, metastases, ascites and bilateral lesions. menopausal status is scored as
1 = pre-menopausal and 3 = post-menopausal.

LUNG CANCER : RISK FACTORS AND SCREENING

Individual factors Environment Genetic

Smoking • Environmental tobacco smoke • Genetic Alterations

- 80% NSCLC in exposure
men • Asbesos Exposure - p53 Mutation
• Environmental & Occupational
- 50% in women
exposure - deletion of chromosome 3p,5q,9p,11p &
17p - asbestos, silica fibers
nickel, chromium, cobalt & cadmium
- ingestion of Arsenic - diesel fumes & air pollution
• Ionizing Radiation
- Radon

- 20–50% of lung ca in never smokers in US

PREVENTION: The most cost effective method of lung cancer prevention is to stop smoking.

– Chemoprevention strategies in primary and secondary lung cancers have not been fruitful.

– Addition of β carotene actually increased incidence & mortality in patients with high risk factors
e.g. smoking.

CARET trial and ATBC lung cancer prevention trials.

• Screening of lung cancer was initiated with CXR and sputum cytology

• Disadvantages:

– Early detection failed to improve prognosis even in high risk groups.

– False positive results may be as high as 5% in CXR

– Both are relatively insensitive to early stages.

– The prevalence in the population is not high enough to justify routine mass screening.

• 3 major randomized trials have failed to provide evidence of any benefit from screening.

• In USA non-contrast spiral CT is being evaluated as a screening tool in the high risk group.
 231

• NCCN Screening Panel recommends lung cancer screening using helical Low dose CT for individuals
with following high risk factors.

1. Age 55-74 yrs : 30 or more pack year history and if former smoker, have quit within 15 yrs. Annual
screening recommended every 2 yrs.

2. Age<50 yrs : 20 or more pack year history and additional risk [Link] Panel does not currently
believe that exposure to second hand smoke is an independent risk factor because the data is weak.

COLON CANCER: RISK FACTORS AND SCREENING

Patient Factors Environmental

 Male sex  Hereditary Conditions (FAP,
 Family history of colorectal  Environmental & dietary factors HNPCC)
cancer  Chemical carcinogenesis.
 Personal history of colorectal
cancer, ovary, endometrial, breast
 Excessive BMI
 Processed meat intake
 Excessive alcohol intake
 Low folate consumption
 Neoplastic polyps.

Three pathways:

1) Chromosomal instability ( CIN): found in 50-70% cases

-Mutations in KRAS, APC, TP53

-Underlying mechanism in FAP

2) Microsatellite instability (MSI): responsible for majority of HNPCC’s, some sporadic cases

-Mutations in the microsatellite sequences involving TGFβ II,BAX, hMSH3, hMSH6

3) CpG island methylator phenotype( CGI): 10-30% of cases

-KRAS, BRAF mutations

-lacks chromosomal instability

-poorest prognosis

SYNDROMES ASSOCIATED WITH CRC’s

 Familial adenomatous polyposis (FAP): Multiple adenomatous polyps (>100) and ca. colon and
rectum; duodenal polyps and carcinomas; fundic gland polyps in the stomach; congenital hypertrophy of
retinal pigment epithelium ; APC (>90%)
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 Gardner syndrome: Same as FAP; also desmoid tumors and mandibular osteomas ;APC

 Attenuated adenomatous polyposis coli (AAPC): Less than 100 polyps, although marked variation in
polyp number (from ~5 to >1,000 polyps) ; APC predominantly 5’ mutations

 Hereditary nonpolyposis colorectal cancer (HNPCC): Colorectal cancer without extensive polyposis;
endometrial ,ovarian and stomach cancer; occasionally urothelial, hepatobiliary, and brain tumors
MSH2, MLH1, PMS1, PMS2, GTBP/MSH6

 Turcot's syndrome :Polyposis and colorectal cancer with brain tumors (medulloblastoma), CRC and
brain tumors (glioblastoma); APC, MLH1, PMS2

 MYH-associated polyposis (MAP): Multiple adenomatous gastrointestinal polyps, autosomal

recessive. Often associated with somatic K-ras mutations; MYH

 Peutz-Jeghers syndrome: Hamartomatous polyps throughout the gastrointestinal tract; mucocutaneous

pigmentation; estimated 9- to 13-fold increased risk of GI and non-GI cancers; LKB1/STK11
(30%–70%)

 Cowden syndrome: Multiple hamartomas involving breast, thyroid, skin, CNS, and GI tract; increased
risk of breast, uterus, and thyroid cancer; risk of GI cancer unclear. PTEN

 Juvenile polyposis syndrome: Multiple hamartomatous/ juvenile polyps with predominance in colon
and stomach; variable increase in colorectal and stomach cancer risk; facial changes DPC4(15%),
BMPR1a (25%), PTEN (5%)

FOR THE AVERAGE-RISK

POPULATION: INCREASED RISK FOR CRC

 should begin at age 50 yrs  affected 1st degree relative with CRC;
 Flexible sigmoidoscopy: every
5yr personal h/o SSP, CRC, IBD;
 Double contrast barium enema:
every 5 yr  family h/o high risk syndromes
 Computed tomography (CT)
colonography every 5 years  First degree relative with CRC/ polyp before
 Colonoscopy: every 10 yrs
 FOBT: every year, guaic based 60 yrs or 2 relatives with CRC at any age:
or immunochemical test
 If polyp: colonoscopy every yr colonoscopy at 40 yrs or 10 yrs before earliest
until polyp free
diagnosis, every 5 yrs

 FAP : flexible sigmoidoscopy 10-12 yrs

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 HNPCC: colonoscopy starting at 20-25 yrs or

10 yrs earlier than youngest case, every 1-2

yrs

 Personal h/o adenomatous polp: single polyp ,

large, malignant, sessile or incomplete

colonoscopy- short term colonoscopy

 ≥3 polyps, F.U colonoscopy 3 yrs

 1-2 polyps (<1cm) colonoscopy 5 yearly

 Personal h/o CRC : repeat colonoscopy after 6

months if not done at diagnosis, if

colonoscopy complete repeat 3 yearly; if

normal 5 yearly

 IBD: surveillance colonoscopy recommended

8-10yrs

Screening Modalities that detect Adenomatous polyps &Cancer

 - Colonoscopy every 10 yrs

 - Flexible Sigmoidoscopy every 5 yrs

 - CT colonography (CTC) every 5 yrs

 - Double contrast barium enema every 5 yrs

Screening modalities that primarily detect cancer (Stool based)

- Guaiac-based screening annually

- Immunochemical based testing annually

- Stool DNA test with high sensitivity (interval for screening is uncertain)

1 . Guaiac test :
 234

• Based on the pseudoperoxidase activity of heme in human blood.

• 3 stool samples required and prescribed diet followed before the test.

• High chance of false positive ( to avoid red meat, raw fruits and veg. esp. radish, melon, turnip etc and
medicines like NSAIDS and iron)

• Vit. C causes false negative – due to antioxidant property.

2 . Immunochemical test :

• Detects human globin in human Hb. A single test sample required and no prescribed diet needed.
Positive test in both test require further evaluation
 235

PROSTATE CANCER

• DRE and PSA are the two components used in Prostate Screening.

• TRUS has been associated with a high false positive rate, making it unsuitable as a screening tool.

• In 2010, ACS recommended that men can make an informed decision about whether to be screened for
prostate cancer.

• If screening is done, it should begin at age 50 in men at average risk who have a life expectancy of at
least 10 yrs.

• PSA<2.5 ng/ml – retesting every 2 yrs

>2.5 ng/ml – retesting annually

DRE

• Specificity- 50% and Sensitivity- 70%

• Only 25-50% of men with an abnormal DRE have cancer

• DRE+PSA specificity 87%

PSA:

Identified from prostatic tissue by wang et al. in 1979. Found also in serum, semen of ca prostate patients.

The half-life of PSA is around 2.2–3.2 days, and reaches its lowest level 2–3 weeks after radical
prostatectomy (RP). PSA>4 ng/ml is suspicious for cancer( positive predictive value is 31%-54%)

Also detected by immunohistochemical techniques in pancreas , salivary gland and in woman, in conditions
like prostatitis, BPH/increased prostate volumes, DRE, prostatic calculi, post-TRUS,TURP. A greater yield
is found if coupled with USG &DRE.

PSA density (PSAD):

• The threshold level of 0.15 or above indicates prostate cancer, while 0.15 or below indicates benign
disease.

PSA velocity(PSAV):

• The change in PSA level over time. At least three values are taken in an interval of 6 months.

• The upper limit for the PSAV is taken to be 0.75 ng/mL/year

• Free PSA

• a ratio of free to total PSA ≤0.2 was most likely associated with prostate cancer and a ratio of ≤0.15 was
associated with higher gleason score and poorer prognosis
 236

• PSA doubling time (PSADT):Which measures the exponential increase In serum PSA over time,
Reflecting a relative change

ORAL CAVITY CANCER : RISK FACTORS AND SCREENING

Chemical irritants (tobacco,alcohol,mouthwashes with high alcohol content)

• Physical irritants(Denture use, prolonged denture irritaion, irregular teeth or restoraion, chronic cheek
biting habits)

• Nutritional factors(defficiency of vitamin A and caretenoid supplementation)

• Prolonged sun exposure

• Hormonal effects

• Increased cellular aging

• Decreeased immunologic surveillance with aging

• Viruses(HSV-1,[Link])

Increased risk:

 Patient age 40 and older(95% of cases) 18-39 years of age combined with the following:

• Tobacco use

• Chronic alcohol consumption

• Oral HPV infection

Highest risk:

Patient age 65 and older with lifestyle risk factors

Patients with history of other cancer.

Oral cancer screening:

 It is an examination performed by the dentist of the doctor to look for the signs of cancer or
precancerous conditions in your mouth.
 The goal of oral cancer screening is to identify mouth cancer early, when there is a greater chance
for a cure.
 It can be done by examination of mouth during a routine dental check up or by use of additional tests
to aid in identifying areas of abnormal cells in the mouth.
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PALLIATIVE ONCOLOGY

Pain Control in Cancer Patients

Pain Definition – IASP:

Unpleasant , sensory and emotional experience associated with actual or potential tissue damage, or
described in relation to such damage

Cancer Pain Incidence :

• 70 to 80 % patients with advanced cancer experience pain

• 30 to 50 % patients experience pain during treatment

• 40 % patients receive inadequate pain relief

• Less than 40 % patients receive palliative care

BARRIERS TO EFFECTIVE TREATMENT OF PAIN

Patient factors leading to reluctance to report pain

 Fear of disease progression

 Cultural and religious preferences: suffering is good

 If drugs are taken too soon, they might not work later when needed more

 Pain medications are for the dying

 Fear of addiction to pain medications

Physician factors leading to inadequate pain management

 Inadequate pain assessment

 Reluctance to prescribe narcotics

 Inadequate knowledge regarding pain management

 238

Etiology of cancer pain:

Tumor Directly

1. Tumor infiltrating the tissues, organs

2. Compression of nerves, vessels or organs

Tumor Indirectly

1. Infection

2. Inflammation

3. DVT or Lymphedema

Others :

1. Diagnostic / Therapeutic

2. Medical illness

Principles of Pain Management:

1. Comprehensive Assessment of Pain

2. Choosing the right treatment plan for the right patient

3. Ongoing assessment of treatment outcomes and regular review of the plan of care

4. Either eliminate pain or reduce it by at least 50% by subjective ratings

5. Keep side effects minimal

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COMPREHENSIVE PAIN ASSESSMENT

• PATIENT`S SELF REPORTING is the standard of care (alternative methods for non-verbal
patients )

1. Etiology of pain

2. Pathophysiology of pain

3. Pain experience

4. Location

5. Intensity

6. Interference with Activity

7. Timing

8. Description or quality of pain

9. Aggraveting and relieving factors

10. Medication History

11. Response to current medications / breakthrough pain

• PHYSICAL EXAMINATION AND NECESSARY INVESTIGATION

PAIN INTENSITY RATING

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Pain assessment in nonverbal patients – Observation of Behavior

Patients who are intubated or unconscious

- Behavioral Pain scale

- Critical care pain observation tool (CPOT)

Patients with dementia

- Assessment of discomfort in dementia protocol

- Checklist of nonverbal pain indicators

- PAINAD Scale

Guidelines for Cancer Pain Management

• By the mouth

• By the clock

• By the ladder

• For the individual

• Attention to the detail

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OPIOIDS:

i. Natural alkaloids ii. Semi-synthetic opioids: iii. Synthetic opioids:

Morphine (10%) Diacetylmorphine Methadone

Codeine (0.5%) Hydromorphone Fentanyl
Thebaine (0.3%) Oxymorphone Pentazocine
Oxycodone Tramadol
Meperidine (pethidine)

Mechanism of Action of Opioids:

Mu (μ1 and μ2 )

• μ1-Supra spinal analgesia

• μ2 spinal analgesia, respiratory depression, constipation, physical dependence , euphoria

Kappa (k1 & k3)

• Only modest analgesia (spinal κ1 and supraspinal κ3)

• Little or no respiratory depression, little or no dependence, Dysphoric effects ,miosis , reduced GI

motility

Delta (δ) – supra spinal analgesia

How to start a Opioid ?

• Before starting : How is the pain ? History of previous opioid exposure ,, age of the patient, presence of
hepatic and renal failure.
 242

• Morphine is the narcotic of first choice

• Dose : 5mg-1000mg Q4hourly ( IR – Q4H ; SR – Q12H) + Bowel Regimen

• Pain relief : 10-30mg

• Dose titration :

Increases by approximately 30%

Regular dose + Breakthrough pain

------------------------------------------------ = New 4 hourly dose

BREAKTHROUGH PAIN

• Defined as transitory exacerbation of pain in a patient who has relatively stable and adequately
controlled baseline pain (rapid onset, brief flare of severe pain despite regular analgesia).

3 categories of Breakthrough pain :

1. Incident pain – on physical activity

2. End of Dose pain

3. Uncontrolled Persistent pain

 243

Convert or rotate opioids ?

1. 24 hour dose

2. Equivalent table

3. Reduction of total dose by 25-50% to avoid cross tolerance

4. Divided the number of frequency

5. 5 to 15% for breakthrough pain

6. Do not use for Methadone or fentanyl

• Example : How much dose of oral morphine SR required to if the patient is currently on IV
Hydromorphone 12 mg in 24 hours?

• X dose of Morphine = 30mg of Morphine

-------------------------- --------------------------

12 mg of IV Hydromorphone 1.7 mg of IV Hydromorphone

• 240 mg Total Dose

• 120mg Total Dose (Reduction of total dose by 25-50% to avoid cross tolerance)

• Dose = 60 mg BD

• Dose for Break Through pain ( 5 to 15 %) = 10mg when BTP occurs

Opioid Side Effects:

Common

• Constipation

• Dry mouth

• Nausea/vomiting

• Sedation
 244

• Sweats

Less Common

• Bad dreams or hallucinations

• Delirium

• Myoclonus

• Seizures

• Pruritus, urticaria

• Respiratory depression

• Urinary retention

ROLE of adjuvants:

• nociceptive responses i.e., neuropathic pain and reduction of opiate side effects.
 245

Step 4 - Interventional Methods:

• 1. Nerve Block

• 2. Splanchnicectomy

• 3. Thoracoscopic sympathectomy

• 3. Percutaneous cementoplasty

• 4. Vertebroplasty and kyphoplasty

Intra spinal opioid administration:

• Intrathecal or epidural

• Implanted programmable pump with several programming options

Patient selection :

• Intractable pain score crossing 5/10

• Daily PO morphine >200mg

• Intolerable side effects to low dose

• Life expectancy >4-6months

Celiac plexus Block:

Radiofrequency Ablation:

• High frequency AC current which is passed through the electrode within the tumor with a probe

• Tissue is heated at 113` for 10-15min

• Leads to cellular death through heat

ROLE OF RT IN PALLIATION OF BONE PAIN:

• Breast, prostate, or lung cancer. thyroid, melanoma, and kidney.

• partial pain relief seen in 80% to 90% of patients and complete pain relief in 50% of patients

• Local-field EBRT - Oligometastasis : 20Gy/5# Vs 40.5 Gy in 15 fractions

Multiple painful metastases : 30 Gy in 10 fractions

15 Gy in 5#
 246

20 Gy in 5#

25 Gy in 5#

• Landmark trial : Dutch trial 8 Gy/1# Vs 24 Gy/6#

• SRT - 8 Gy Vs 16 Gy

• 500 cases - 12.5 to 25 Gy long-term pain level improvement in 86% of cases.

• Hemibody RT – Upper , Mid and lower

• 6Gy if the lung dose was uncorrected and 7 Gy if lung corrections were used.

• Overall, the response rate in terms of pain relief was 73%, with complete relief of symptoms seen in
19%.

• Pain relief was seen relatively rapidly, with 50% of responses occurring within 2 days and 95% of
responses within 2 weeks.

BISPHOSPHANATES

• Ibadronate + EBRT

• Pamidronate + EBRT

RADIOPHARMACEUTICALS:

• Phosphorous-32 – Unacceptable Bone Marrow suppression

Strontium 89

• chemically similar to calcium and is deposited in the bone matrix, preferentially in sites of active
osteogenesis.

• Sr-89 is a pure β-emitter with an energy of 1.4 MeV and a half-life of 50.6 days

Trials : 1. Sr-89 versus placebo

2. Sr-89 versus external-beam radiation therapy.

3. Sr + CT

Samarium-153

• The physical half-life of Sr-153 is 46.3 hours

Trials : 1. Sm-153 Vs Placebo

3. Dosing of Sm-153
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PALLIATIVE RADIOTHERAPY

Introduction:

 Palliative radiotherapy is a safe, effective treatment for various symptoms of advanced cancer

 Short course, Hypofractionated

 With minimal cost

 Convenience of treatment

Goals:

 Improves quality of life

 Reduces symptom burden, thereby reduces depression

 Increases patient and family satisfaction with care, May decrease burnout among other providers

 May improve length of survival

 Rapid and durable symptom relief

 Minimize side effects

 Minimize treatment time

Questions fundamental to palliative RT:

 To treat or not to treat? (based on goals, priorities, prognosis)

› What dose/fractionation scheme should be utilized?

› What technique should be utilized?

 Is local tumor control important for palliation for any given patient?

 About 30-45 % of patients receiving radiotherapy are palliative.

Signs versus Symptom-based palliative RT:

 Principle is to tailor palliative radiotherapy to patient based on signs and symptoms of progressive
cancer
 248

Palliation of “symptoms” of progression Palliation of “signs” of progression

Aims may be: Aims may be:

•No overall effect on disease •Local control

•Alleviation of symptoms/distress •Prevention of symptoms

•Neither hastening nor postponing death •Prolongation of life

•Side effects unacceptable •Some side effects tolerated

Consider single (or few fractions) Consider higher BED

Consider 2D/3D treatment Consider more conformal treatment

Indications for Palliative Radiation

 Pain relief from bone mets.

 Prevention of pathological #

 Spinal cord compression.

 Impending or actual obstruction hollow viscera.

 Brain mets.

 Control of Haemorrhage.

 Control of ulceration/ fungation.

Emergency Indications:

 Spinal cord compression

 Haemorrhage/bleeding

 Superior Vena caval obstruction

 Seizures/ Fittin
 249

Brain metastases

 Whole brain radiation (WBRT) continues to be the standard of care in patients with brain metastasis.

› „20Gy in 5#

› „30Gy in 10#„ „

 „Median survival though was only 3-6 months

SRS in Brain Metastasis:

 Cochrane Database Syst Rev. 2010 Jun 16

WBRT alone Vs WBRT + SRS

 “Analysis of SRS + WBRT, did not show a survival benefit over WBRT alone. However, performance
status and local control were significantly better in the SRS + WBRT group. Furthermore, significantly
longer OS was reported in the combined treatment group for RPA Class I patients as well as patients
with single metastasis.”

Bleeding

 Hemoptysis

› „Nodes or tumour eroding into airway

 „Bladder Ca

 „Prostate „ „

 Cervix „

 Rectal „

 All commonly cause bleeding; can use radiation

 Fractionation schedule:

› 8 Gy / 1#

› 20 - 25 Gy / 4-5#
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› 30 Gy / 10#

Vaginal Bleeding Or Discharge:

 EBRT:

› 10 Gy single #, q 3-4 wkly, 2-3 times

› 4 Gy/# for 5-6 times

› 3 Gy/# for 10 times

› For newly diagnosed: 3-4 Gy /#, 2-3 times followed by std. regimen

 Brachytherapy:

LDR single insertion with tandem & colpostats for 55 Gy to point A

Malignant lower airway obstruction

 Intrinsic compression:

› Brachytherapy is typically the best option with prior EBRT at dose 7.5 Gy /3# or 10 Gy/2#

 Extrinsic compression: (EBRT)

› 30 Gy/10 #or greater

› 20 Gy/5#

› 17 Gy/2 #or 10 Gy in/1#

Liver Metastases:

 Whole-liver radiation therapy:

› 30 Gy/15#

› 25.6 Gy/16#

› 20 Gy/10#

› 21 Gy/7#

 Selective internal radiation therapy (SIRT):

› yttrium-90 (90Y) glass or resin microspheres - intra-arterial infusions into the liver

› intra-arterial floxuridine alone or plus SIRT with 90Y resin microspheres

 251

PLANNING OF BONE METASTASIS

• Common occurrence in the event of malignancy

• Third most common site of distant metastases after liver and lung

• Cause significant and debilitating pain

• Pathological fracture and spinal cord compression

• Significant morbidity

• Multimodality approach

• Aims at alleviation of pain and prevention of future complications

• Palliative irradiation should be delivered such that side effects should not be more distressing than the
symptoms to be treated

Sites of preference of bone mets:

• Spine (69%)

• Ribs

• Pelvis (41%)

• Skull (14%)

• Long bones ends (25%)

• Spinal Location

Thoracic 60 to 70%
 252

Lumbar 15 to 30%

Cervical 10 to 15%

Multiple 20 to 35%

Types of bone metastasis:

Osteolytic lesions : Osteoblastic lesions : Mixed lesions :

• Multiple myeloma • Prostate • Breast

• Mets from – Breast • Breast

- Kidney • Hodgkins disease

- Thyroid gland

Presentation:

• Pain MC

– initially well-localized/ diffuse ache/ radiculopathy/ difficult movement

– Biologic pain

– Tumor's presence in the bone.

– The release of inflammatory mediators.

– Irritation of nerve endings.

• Functional pain

– Caused by the mechanical weakness of the bone.

– loss of structural integrity in blastic lesions

• The development of functional pain is a marker for a bone at risk for fracture.

Imaging  Plain radiographs:

• Most specific but least sensitive.

• Inexpensive and easily obtained

• Basis for the initial evaluation, planning, and follow-up

• Evaluate the structural integrity of bone and the risk of impending pathologic fracture
 253

• Important in decision making, plain radiography should be the first test ordered to evaluate bone pain.

• Loss of trabeculations and cortical erosion is characteristic

Bone scan:

• Highlights regions of bone turnover with areas of new bone deposition.

• 72% to 84% sensitive in detecting occult bone lesions

• Integral in the evaluation of a patient with bone pain.

• Detects functional changes

• Not specific/ no structural detail

• Radiographs required

• Lytic lesions appear cold

CT Scan:

• Not a primary tool/ a useful adjunctive study

• 3 D evaluation of bone integrity for planning in shoulder and pelvic lesions

• Extent of cortical destruction

• Soft tissue component

• Identify a target for needle biopsy

• Bony anatomy well in the spine

• No epidural extension and neural compression

• No extent of medullary involvement

MRI Scan:

• Marrow involvement

• Early detection of [Link] [Link] tumor

• Neural compression, ST Mass

• Differentiates pathologic compression # from osteoporotic compression #s of the spine.

• Difficulty differentiating infection, inflammation, and metastatic disease of bone.

• MRI is not a stand-alone study and images require correlation with plain radiographs.

• Inv. of choice
 254

• Images whole spine and and areas around spine

• Overall accuracy is 95%( sensitivity-93% & specificty-97%)

• Non invasive

• MRI standard of care in centers that have access

PET Scan:

• Unknown primary

• Multiple sites of metastatic disease.

• Although the PET imaging modality shows promise, it is currently only an investigational tool for most
cancers.

• Correlation with structural imaging is required for treatment planning.

Therapeutic Goals:

• Improvement in the QOL

• Pain relief

• Maintenance and restoration of function

• Close surveillance for the development complications

• Treatment should be tailored to the patient's prognosis and life expectancy

LOCAL FIELD RADIOTHERAPY

Immobilization:

• No formal immobilization used

• Cervical spine – head fixation

• Adequate analgesia before & after RT

• Position :

• Most Comfortable to Pt

• Cervical vertebral mets : Supine

• Thoracic vertebral mets : Prone

• Lumbar vertebral mets : Prone

• If pt is not able to lie prone, can be simulated in supine position & treated from under couc
 255

RADIATION PORTALS

• Cervical spine :

• Lateral portals – reduce morbidity by sparing upper aerodigestive structures

• Thoracic spine :

• Direct Posterior portal

• Lumbar spine :

• Direct Posterior portal

• AP / PA portal if pt thin

• Ribs :

• Electron beams

• Tangential photon beams

• Superior margin : one vertebra above the highest involved vertebra (2-3cm)

• Inferior margin : one vertebra below the lowest involved vertebra (2-3cm)

• Width : to include transverse process on both sides ( appr. 7-8 cm)

• For long bones : Margins 2 - 3cm above and below

Depth of prescription:

• To be decided with available images

• Direct posterior portal – distance from skin to Ant. Vertebral body of the involved vertebra

• AP/PA Portal – mid separation

• Bilateral portal - mid separation

• Cervical spine – 3cm

• Thoracic spine – 4cm

• Lumbar spine – 5-6 cm

 256

HEMIBODY IRRADIATION

• HBI – a form of Subtotal Body Irradiation

• One half of body irradiated

• Intent of Treatment – Palliative

• Indication : disseminated bony metastasis involving either half of body

• Most common primaries associated : Breast, Lung, Prostate

Types of HBI:

UHBI (above umbilicus) – Skull, Cervical, Dorsal, Lumbar spine upto L3, Ribs, Sternum, Clavicle, Scapula,
Upper limbs

LHBI (below umbilicus) – Lumbar spine below L3, Sacrum, Pelvis, Lower limbs

MBI (diaphragm to obturator foramen) – Lumbosacral spine, Pelvis, Femoral heads

CLINICAL EVALUATION:

• History –

* Pain - most painful site; helps decide

Focal RT / HBI; if HBI, the type of HBI

• Physical Examination –

* Tenderness – site of max. tenderness

(intense pain at one site may mask pain perception at other sites)

* Neurological exam for spinal cord mets

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• Complete Blood Count

• Biochemistry (S. Alk PO4, LFT, RFT)

• Chest X-Ray / CT Thorax

• USG Abdomen / Pelvis

• Search for primary if unknown

* Imaging

* Markers : CEA, CA19.9, CA-125,

AFP, PSA

Decision Making

• Review CBC

Abnormal (de novo / chemo induced)

Hb < 12, WBC < 4000, Plt < 1 lakhs

Salazar, IJROBP, 1997

* HBI to be deferred till counts recover

• Bone Scan report

* Focal RT / HBI or both

* If HBI, type of HBI

TREATMENT PARAMETERS

• Borders

* UHBI :

Upper – Air (3 cm above head)

Lower – L3 / L4(Upper border of umbilicus)

* LHBI :

Upper – L3 / L4

Lower – 3-4 cm below patella

* MBI :

Upper - D6 (domes of diaphragm) /

 258

D10 (insertion of diaphragm)

Lower – Cover Obturator foramen

Go lower down if overt

disease present

Laterally, cover whole extent of body

TREATMENT PARAMETERS:

• Separation

* UHBI

- Forehead

- Mid sternum

- Umbilicus

• Separation

* LHBI

- Umbilicus

- Pubic symphysis

- Mid thigh

• Depth – (Average of 3 separations) / 3

e.g. For separations of 18,16,and 11

Average separation = 18 + 16 +11

= 15 cm

Depth = 15 / 2 = 7.5 cm

TREATMENT PARAMETERS

• Head Rest - Pillow

• Patient position – Alternate supine / prone

• Arm position –
 259

* UHBI – over head

* LHBI – over chest

* MBI – over chest

• Portals – Parallel opposed AP/PA

• Energy – 6 MV photons

• Field Size – 40 cm x 40 cm

• Dose –

* UHBI – 6 Gy / 1 # Prescribed at average

* LHBI – 8 Gy / 1 # mid thickness depth on

* MBI – 8 Gy / 1 # central axis

• Extended SSD / STD –180 cm

• Machine – 6EX or 2100CD

40 x 40 Field Size

Max openable field size in most LINACs

Conveniently encompasses the desired half of body at extended SSD

No / minimal chances of mets in distal extrimities.

PATIENT PREPARATION:

• Check for overnight fasting

• Premedications

* Inj. Emeset 8 mg i.v.

* Inj. Dexa. 8 mg i.v.

* Inj. Rantac 50 mg i.v.

EXPECTED SIDE EFFECTS

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POST R.T. MEDICATION

• Continue pain medications

• Tab. Emeset 4 mg T.D.S.

• Tab. Rantac 150 mg B.D.

• Tab Lomotil T.D.S.

• Patient asked to review after 2 weeks / SOS

SEQUENTIAL HBI

• Gap of at least 4-6 weeks to allow recovery of blood cells and irradiated marrow

• Allows more radiation to whole body with less acute toxicity

• 1 cm gap between borders

************
 261

CARE FOR TERMINALLY ILL CANCER PATIENTS

 Terminal illness is a disease that cannot be cured or adequately treated and that is reasonably expected to
result in the death of the patient within a short period of time

 No precise definition

 Very difficult to accurately predict an individual’s time of death.

BAD DEATH : death with inadequate palliative support, inadequate compassion, and inadequate human
presence and witness.

GOOD DEATH

• Adequate pain and symptom management.

Avoiding a prolonged dying process.
Clear communication about decisions by patient, family and physician.
Adequate preparation for death, for both patient and loved ones.
Feeling a sense of control.
Finding a spiritual or emotional sense of completion.
Affirming the patient as a unique and worthy person.
Strengthening relationships with loved ones.
Not being alone

Prognosticatation:

• When the disease advanced but the patient is still receiving antineoplastic therapy, the oncologist faces
a difficult choice

• 48% of oncologists explain prognoses to patients only when they ask for it

• More experienced clinicians favored no disclosure

• physicians who refer patients to a hospice program usually do not tell them the most likely prognostic
estimate

• patients with advanced refractory disease themselves they dont ask

Discussions in end-of-life with physician

 less aggressive medical care near death,

 earlier hospice referrals,
 cost-savings at end of life
 improved bereavement adjustment for caregivers
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Hospice program:

• In 2006, hospice and palliative medicine was accepted as a specialty by the American Board of Medical
Specialties.

• palliative care team provides

 physical symptom management, emotional support, and spiritual comfort.

• Hospice team manages

 physical problems

 family education, practical support, and psychological and spiritual counseling

 Hospice teams (including nurses, medical directors, social workers, chaplains, and volunteers

 routine home care, continuous home care, respite care in nursing homes, and inpatient care.

Symptoms:

• Fatigue is common in the last weeks of life

• caffeine, dextroamphetamine, or methylphenidate, Modafinil

• Insomnia

• undertreated pain, depression, anxiety, delirium, dyspnea, nocturnal hypoxia, nausea and vomiting, or
rarely, pruritus, drugs benzodiazepines (oxazepam or temazepam) patients with night time delirium, oral
quetiapine 25 to 50 mg orally at bedtime (for elderly patients),

• olanzapine 2.5 to 5.0 mg orally at bedtime

• haloperidol (beginning at 0.5 to 2.0 mg orally and increasing as needed to 5 mg) will be needed

Nutrition:

• starting and stopping nutrition support in terminally ill patients is often less clear

• Benefits of Nutrition

• reducing physical deterioration

• improving quality of life

• preventing the emotional effect of “starving the patient to death

• Burdens of Nutrition

• suffering in terminally ill patients due to increased nausea, vomiting, bleeding, edema, pulmonary
edema, incontinence (bladder and bowel), or infections, as well as a potential requirement for patient
restraint
 263

Psychological:

• depression, anxiety, and delirium

• Depression in terminally ill patients

• due to poorly controlled pain

• drugs (e.g., opioids, corticosteroids)

• central nervous system tumor

• metabolic abnormalities (e.g., hypercalcemia, hyponatremia)

• vitamin deficiency, or anemia.

• The psycho stimulants dextroamphetamine and methylphenidate (2.5 to 5 mg 8 a.m. and noon,
maximum dose 60 to 90 mg) often act within a few days.

• If the patient is expected to live longer than weeks to a few months, a trial of a stimulant and (SSRI)
should be initiated.

**********
 264

NUTRITIONAL MANAGEMENT IN ONCOLOGY

• Cancer patient’s nutritional status is gravely affected by his disease; in addition, the patient’s nutrition
during his treatment may aid or hamper his or her recovery.

• Cancer treatment and its multiple adverse effects can affect not only food’s nutrients but also the
patient’s own ability or desire to ingest food.

• Lean body mass is an important factor

• LBM= TBW – BF

Nutrition Assessment:

• Pt. history and examination

• Anthropometric measurement

• 24 hrs urine collection for the measurement of - Nitrogen

• S. Albumin, CR proteins, Transferrin

• Skin fold thickness –triceps

• Mid arm circumference, lean body mass

• Immunocompetence: -peripheral blood: Lymphocyte count - skin test – delayed hypersensitivity

• Others- Hb, BUN, LFT

Scored Patient-Generated Subjective Global Assessment:

• The scored Patient-Generated Subjective Global Assessment (PG-SGA) is an adaptation of SGA

specifically developed for use in the cancer population.

• Typical scores range from 0-47 with a higher score reflecting a greater risk of malnutrition.

• Subjective global assessment (SGA) determines nutritional status on the basis of

• medical history

• physical assessment

• The features are combined subjectively into an overall or global assessment where patients are rated as
being well nourished (SGA A), moderately or suspected of being malnourished (SGA B) or severely
malnourished (SGA C).
 265

CLASSIFICATION OF WEIGHT STATUS AND RISK OF DISEASE:

BMI (kg/m2) , Obesity Class, Risk of Disease

• Severe underweight-<16

• Mod. Underweight-16.0-16.9

• Mild underweight- 17-18.49

• Healthy weight -18.5–24.9,

• Overweight/pre obese- 25.0–29.9, Increased risk

• Obesity Class I 30.0–34.9- I, High risk

• Obesity Class II 35.0–39.9- II, Very high

• Extreme Obesity/ Class III 40 –III, Extremely high risk

Protein metabolism – skeletal muscle protein synthesis ↓ & catabolism ↑

Hepatic protein synthesis ↑- acute phase protein → amyloid A, hepatoglobulin, CRP ↑

• total shift of protein synthesis from muscle to liver

• Lipid metabolism –

– lipolysis ↑,

– lipogenesis ↓

– serum TG ↑,

– hepatic lipolysis ↑,

– lipid store ↓.

• Carbohydrate metabolism–

– Glucose turnover↑

– hepatic gluconeogenesis ↑

– glyocogen store ↑

• A relative gluc. intolerance and insulin resist. may develop.

 266

PHARMACOLOGICAL APPROACH

• Corticosteroids –

in anorexia - improves app., food intake

– ↓nausea

– feeling of well being

– ↑performance status

– ↓ cytokine release

PROGESTETIONAL DRUGS

• MEGESTROL ACETATE

– wide range of dose

– expensive

– ↑calorie intake

– wt. gain. – fat

– well being

– improvement in 10 Days

CYPROHEPTADINE

stimulates appetite and food intake

8mg TDS

HYDRAZINE SULPHATE

↓ TNF activity

CANABINOID

↑appetite

wt. gain

LEUCINE

protein synthesis, muscle formation, lean body mass.

 267

PARENTERAL NUTRITION: INDICATIONS

• Unable to tolerate feeding via gastrointestinal tract

• Intestinal obstruction

• Intractable vomiting

• Paralytic ileus

• High-output enterocutaneous fistula

• Intestinal ischemia

• High-volume diarrhea/malabsorption

• Gastrointestinal graft vs host disease

• Peritonitis

• Short bowel syndrome

• Radiation enteritis

• Dedicated central venous access available

GASTROSTOMY

• Indicated in prolonged enteral feed requirement

• Unresectable head & neck, oesophageal malignancy patients, unable to meet required calories

• By laprotomy, PEG (can avoid surgery)

JEJUNOSTOMY

• Proximal GIT problems

• Needle catheter method during surgery, witzel tunnel, laproscopic methods

***********
 268

ANATOMY AND CLASSIFICATIONS

 269

1. Anatomy of Nasopharynx, Lymphatic drainage, etiology and mode of spread?

 4cm high, 4cm wide and 3cm in length

 Anterior - choanal orifice and posterior margin of nasal septum

 Roof : Body of the sphenoid, Basiocciput, First two cervical vertebrae

 Floor - upper surface of the soft palate

 Lateral wall- Eustachian Tube orifice and Fossa of ROSSENMULLER

 Posterior wall – Superior constrictor muscle, Pharyngobasilar fascia and buccopharyngeal fascia

Relations

• Anteriorly : eustachian tube and levator palatini

• Posteriorly : pharyngeal wall mucosa overlying pharyngobasilar fascia & retropharyngeal space

• Medially : nasopharyngeal cavity

• Superiorly : foramen lacerum & floor of carotid canal

• Posterolateral : carotid canal & petrous apex, foramen ovale and spinosum

Histology:
 Pseudostratified columnar ciliated epithelium- near the choanae and the adjacent part of the roof of
the nasopharynx
 transitional epithelium -roof and the lateral walls
 stratified squamous epithelium- along the posterior and inferior portions of the nasopharynx
 270

LYMPHATIC DRAINAGE :

 Richest lymphatic plexus in the head and neck region.

 Submucosal lymphatics congregate at the pretubal region – “pretubal plexus”.
 These then pass on to the retropharyngeal nodes as 8 -12 trunks which decussate in the midline.
 Lymphatic trunks pierce the level of the base of the skull and run between the pharyngobasilar fascia
and the longus capitis.

The lymphatic trunks drain in three directions:

 To the retropharyngeal nodes.
 To do the posterior cervical nodal and the confluence of the 11th, cranial nerve and the jugular lymph
node chains, situated at the tip of the mastoid.
 To the Jugulo-digastric nodes (Lederman )

RPLN :
• The retropharyngeal nodes are present in two groups.
– Median group.
– Lateral group.
• The median group consists of 1 - 2 nodes interconnected in the midline.
• The lateral group consists of 1- 3 nodes located between the lateral aspect of the posterior pharyngeal
wall and the carotid artery.
• These nodes are present from the vertebral levels C1- C3.
• The superior-most lymph node of the latter group is also known as the node of Rouviere.
• This node lies in front of the arch of the Atlas being separated from it by the longus colli muscle.

Parapharyngeal Space :
• The parapharyngeal space is located deep within the neck lateral to the pharynx and medial to the ramus
of the mandible.
• Shape of an inverted pyramid with the floor at the skull base and it’s tip at the greater cornu of the hyoid
bone
• Two compartments : Prestyloid and retrostyloid
 271

ETIOLOGY :

Viral Environmental Genetic

 Non keratinizing type Ingestions  HLA A2
 More than 90% of  salted fish - Nitrosamine  HLA B12
patients having elevated  smoked food  HLA B 46
antibody titres to Epstein- Occupation
Barr virus are those  inhalation of chemical
who have NPC of fumes
the undifferentiated / poorly Cooking habits
differentiated forms  household smoke and fumes
 moderate to well Smoking
differentiated NPC are Alcohol
devoid of Epstein-Barr
virus antigen

Molecular Biology of EBV in causing NPC :

 Tumorogenic potential of the virus due to
 Latent genes : LMP 1 , 2A, 2B
 Nuclear antigens ; EBNA 1 , EBNA 2
 272

SPREAD OF NASOPHARYNGEAL CARCINOMA :

1. Local Extension
2. Lymphatic
3. Haematogenous Spread
Local Extension :

Lymphatic Spread :
 Avalvular Lymphatic capillary network

Haematogenous Spread ( Distant Metastasis) :

• Incidence rate is about 30%
• Sites commonly involved:
 skeletal - thoracolumbar spine > 50%, lung metastasis and liver metastasis
• 90% of patients die within the 1st year of diagnosis of the first metastasis
 273

2. Discuss the Anatomy and Lymphatic Drainage of Tongue:

 Anterior 2/3rd – The lingual swellings, one on each side, derived from the first branchial arch fuse in
the midline ( supplied by V CN and reinforced by chorda tympani.)

 Posterior 1/3rd - A central swelling in the pharyngeal floor which represents the 2nd, 3rd and 4th
arches (nerve supply IX and X).

 The tongue muscles - derive from the occipital myotomes which migrate forward dragging with them
their nerve supply (XII, the hypoglossal nv).

PARTS

 Dorsum, apex, inferior surface and root

 The sulcus terminalis, V-shaped groove on its dorsal surface and the circumvallate papillae, divides the
tongue into the oral (ant. 2/3) and pharyngeal (post. 1/3) parts

 The valleculae , are 1-cm strips of smooth mucosa that form the transition between the tongue base and
the epiglottis.

 The lingual septum divides the tongue into two symmetrical muscular halves.

MUSCLES:

 The intrinsic muscles are disposed in vertical, longitudinal and transverse bundles; they alter the shape
of the tongue.

 The extrinsic muscles , the genioglossus, hyoglossus, styloglossus and palatoglossus : move the tongue
as a whole

BLOOD SUPPLY : lingual branch of the external carotid artery

NERVE SUPPLY:

 The anterior two-thirds

- sensory - lingual branch of V nerve

- gustatory fibres of the chorda tympani (VII nerve).
 Posterior one-third

- sensory – IX and superior laryngeal nerve (X)

 Muscles of the tongue except palatoglossus are supplied by XII (hypoglosal nv) cranial nerve
 274

- Palatoglossus - pharyngeal branch of X

3. LYMPHATIC DRAINAGE OF TONGUE :

 Tip of tongue - Submental nodes

 Ant. two-thirds - Submental and submandibular nodes ⇾ lower nodes of the deep cervical chain

 Post. one-third - Upper nodes of the deep cervical chain.

 Post. one-third -Rich lymphatic anastomosis across the midline - tumour on one side readily
metastasizes to contralateral nodes

 Ant 2/3 - lymphatics of the inner two-thirds drain to B/L neck nodes,
- tumour extending more than 5 mm from lateral

*tongue margin - increased B/L nodal metastasis.

 275

4. Anatomy of maxillary antrum

 It is the largest air sinus in the body.

 Found in the body of the maxilla, this sinus has three recesses: an alveolar recess pointed inferiorly,
bounded by the alveolar process of the maxilla;
 a zygomatic recess pointed laterally, bounded by the zygomatic bone; and an infraorbital recess
pointed superiorly, bounded by the inferior orbital surface of the maxilla.
 The medial wall is composed primarily of cartilage. The ostia for drainage are located high on the
medial wall and open into the semilunar hiatus of the lateral nasal cavity; because of the position of
the ostia, gravity cannot drain the maxillary sinus contents when the head is erect (see pathology).
 The ostium of the maxillary sinus is high up on the medial wall and on average is 2.4 mm in
diameter; with a mean volume of about 10 ml.
 Stand near the person during an extraoral examination to visually inspect and bilaterally palpate the
maxillary sinuses.
 The infraorbital canal usually projects into the cavity as a well-marked ridge extending from the roof
to the anterior wall; additional ridges are sometimes seen in the posterior wall of the cavity and are
caused by the alveolar canals.
 The mucous membranes receive their postganglionic parasympathetic nerve innervation for mucous
secretion originating from the greater petrosal nerve (a branch of the facial nerve). The superior
alveolar (anterior, middle, and posterior) nerves, branches of the maxillary nerve provide sensory
innervation.
Nasal wall/base

Its nasal wall, or base, presents, in the disarticulated bone, a large, irregular aperture, communicating with
the nasal cavity.

Posterior wall

On the posterior wall are the alveolar canals, transmitting the posterior superior alveolar vessels and nerves
to the molar teeth.[citation needed]

Floor

The maxillary sinus can normally be seen above the level of the premolar and molar teeth in the upper jaw.
This dental x-ray film shows how, in the absence of the second premolar and first molar, the sinus became
pneumatized and expanded towards the crest of the alveolar process (location at which the bone meets the
gum tissue).

The floor is formed by the alveolar process of the maxilla, and, if the sinus is of an average size, is on a
level with the floor of the nose; if the sinus is large it reaches below this level.

Projecting into the floor of the antrum are several conical processes, corresponding to the roots of the first
and second maxillary molar teeth; in some cases the floor can be perforated by the apices of the teeth.

Roof
 276

The roof is formed by floor of the orbit. It is traversed by infraorbital nerves and vessels.[citation needed]

Ohngren's line

In head and neck cancer, is a line that connects the medial canthus of the eye to the angle of the mandible.

The line defines a plane orthogonal to a sagittal plane that divides the maxillary sinus into (1) an anterior-
inferior part, and (2) a superior-posterior part. Tumours that arise in the anterior-inferior part, i.e. below
Ohngren's line, generally have a better prognosis than those in the other group.

Addition to above a vertical line through pupil is also considered, which divides the above-mentioned
structures into 4 different regions.

The structures at posterosuperior medial have worst prognosis and that at anteroinferior medial are least
dangerous.
 277

5. Lymphatic drainage of Neck and Various Neck Dissection

• Level 1:

– Submentel: lower lip, chin, tip of tongue.

– Submandibular: Upper & lower lips, oral tongue, floor of mouth, facial skin.

• Level 2(upper jugular): Nasopharynx, oropharynx, parotid, supra glottic larynx.

• Level 3(middle jugular): Oropharynx, hypopharynx, supraglottic larynx.

• Level 4(lower jugular):Subglottic larynx, hypopharynx, esophagus, thyroid

• Level 5(posterior cervical): Naso pharynx, oropharynx.

• Level 6 (upper visceral) & 7(superior mediastinal): Thyroid, larynx, lung.

 278

ORAL CAVITY: superior deep jugular nodes.

Oral tongue: upper jugular> submandibular

FOM: submandibular>upper jugular

RMT: upper jugular>submandibular

Lip: submental and submandibular

Buccal mucosa: periparotid and level I

NASOPHARYNX: (85-90% i/l, 50% b/l) Level II>=RP: lateral>medial, followed by level III> V>IV

OROPHARYNX: tonsil, bot,soft palate.

Ipsilateral level II & III >IV

HYPOPHARYNX (50% at diagnosis): level II to IV and retropharyngeal.

Pyriform sinus (75%): jugulodigastric
Postcricoid (40%): level VI also

LARYNX:
Supraglottis(55%): level II>level III
Sub glottis: level VI

NECK DISSECTION

1. Radical Neck Dissection (RND) - removal of all ipsilateral cervical lymph node groups from levels I
through V, together with SAN, SCM and IJV.
2. Modified Radical Neck Dissection (MRND) - removal of all lymph node groups routinely removed in
a RND, but with preservation of one or more nonlymphatic structures (SAN, SCM and IJV).
3. Selective Neck Dissection (SND) (together with the use of parentheses to denote the levels or sublevels
removed) - cervical lymphadenectomy with preservation of one or more lymph node groups that are
routinely removed in a RND. Thus for oral cavity cancers, SND (I-III) is commonly performed. For
oropharyngeal, hypopharyngeal and laryngeal cancers, SND (II-IV) is the procedure of choice.
4. Extended Neck Dissection - This refers to removal of one or more additional lymph node groups or
nonlymphatic structures, or both, not encompassed by the RND.
 279

5. Anatomy of breast .

 The female breast lies on the anterior chest wall superficial to the pectoralis major muscle.

 The breast can extend from the midline to near the mid axillary line and cranial caudally from
the second anterior rib to the sixth anterior rib.

 The upper outer quadrant of the breast extends into the region of the low axilla and is frequently
referred to as the axillary tail of Spence.

 This anatomical feature results in the upper outer quadrant of the breast containing a greater
percentage of total breast tissue compared with the other quadrants, and, therefore, a greater
percentage of breast cancers occur in this anatomical location.

 The breast is made up of the mammary gland, fat, blood vessels, nerves, and lymphatics

 The surface of the breast has deep attachments of fibrous septa, called COOPER’S
LIGAMENT, which run between the superficial fascia (attached to the skin) and the deep fascia
(covering the pectoralis major and other muscles of the chest wall). Skin dimpling may be caused
by tumors affecting these supporting structures.

 It is important to realize, from a staging perspective, that the chest wall includes the ribs,
intercostal muscles, and the serratus anterior muscle, but not the pectoral muscles.

 The breast parenchyma is composed of lobules and ducts.

 The function of the lobules is to produce milk and the function of the ducts is to transport
lactation products to the nipple.

 The peripheral ducts converge into major lactiferous ducts, which then communicate with the
nipple–areola complex.

 Most breast cancers develop at the interface between the ductal system and the lobules, a region
called the terminal ductal lobular unit.

Lymphatic Drainage of Breast

 AXILLARY

 INT. MAMMARY

 SC
 280

Axillary
 The predominant lymphatic drainage of the breast is to axillary lymph nodes, which is commonly
described in three levels, based on the relation of the lymph node regions to the pectoralis minor muscle.

 The level I axilla is caudal and lateral to the muscle,

 level II is beneath the muscle, and level III (also known as the infraclavicular region) is cranial and
medial to the muscle.

 A standard axillary lymph node dissection resects the tissue and lymph nodes within levels I and II.

 It is very unusual to have involvement of level III of the axilla without disease in level I or II.

 The axillary lymph nodes continue underneath the clavicle to become the supraclavicular lymph nodes,
which can be involved in locally advanced breast cancers.

Internal mammary lymph node chain

 Lymphatics can also drain directly into the internal mammary lymph node chain (IMC), which are
intrathoracic structures located in the parasternal space.

 Although these nodes are not usually visualized on computed tomography (CT), the anatomical region
of the IMC can be determined by the internal mammary artery and vein, which are easily visualized by
CT and usually lie 3 to 4 cm lateral to midline.

 When breast cancer involves the IMC, the majority of patients will have disease that is limited to lymph
nodes in the first three interspaces.

 Regardless of location in the breast, the axilla is the most common site of lymphatic involvement.
However, breast cancers that develop in the medial, central, or lower breast more commonly drain to the
IMC (in addition to the axilla) than those occurring in the lateral and upper quadrants.

 The use of lymphoscintigraphy, by injecting technicium-99 radiocolloid into the peritumoral region
followed by scintillation scanning, is used now for sentinel lymph node imaging.

 However, internal mammary drainage was present in over 50% of lower inner quadrant lesions.
 281

6. Anatomy of oesophagus :

 The Esophagus is a hollow muscular tube (25cm)

 Origin - cricopharangeus ms. at the level of the Cricoid cartilage(C6) to GE junction (T12)

 Three minor deviations

 Three constrictions along the entire course of length.

Anatomical: (Endoscopy, distance from incisor teeth)

 Cervical: Cricopharynx to thoracic inlet (D1, 18 cm)

 Thoracic: Upper third- thoracic inlet to carina (D4, 24 cm)
 Middle third- carina to inferior pulmonary vein (D7/8, 32 cm)
 Lower third- inferior pulmonary vein to GEJ (D10, 38 cm)
 Abdominal: Distal 2 cm after piercing the diaphragm (D12, 40 cm)
Histology :

 Esophageal wall is composed of - mucosa - submucosa & - muscularis propria.

 It is lined with stratified keratinized squamous epithelium

Blood Supply:

Inf. Thyroid A in its upper part .

Bronchial & Direct Aortic A in its middle part.

Left Gastric A & Inf. Phrenic A in its lower part.

Lymphatics : First-echelon lymph node drainage is to the paraesophageal nodes

Upper Esophagus – cervical nodes, periesophageal & supraclavicular.

Mid Esophagus – mediastinal & Tracheobronchial LN

Lower Esophagus – cardiac, perigastric & coeliac nodes.

 Extensive lymphatic network & rich mucosal & submucosal lymphatics within the wall of esophagus +
lack of serosa result in skip metastasis.
 Lymph node involvement correlates with T stage.
 Majority of the patients have extensive LN involvement at presentation (70%) irrespective of histologic
type.
 Depth of tumor invasion & LN involvement correlates with the incidence of distant metastasis.
 282

7. Anatomy of kidney :
 The kidneys are retroperitoneal structure, located at the level between the 11th rib and the transverse
process of the L3 vertebral body

 The right kidney is inferior to the right hepatic lobe and slightly more inferior than the left kidney

 ~11-12 cm in length, 6 cm width & 4 cm thick

 Weighs around 150 gm in male & 135 gm in female

 Moves vertically within retroperitoneum 0.9-1.3 cm, as much as 4 cm during normal respiration

 The kidney is encased by a fibrous capsule & surrounded by perinephric fat, which is itself enveloped by
Gerota’s fascia

 The kidney consists of the cortex and the medulla

Relations of right kidney:

 Liver superiorly, the duodenum and the vertebral bodies medially,and the transverse colon and small
bowel anteriorly

Relations of left kidney:

 The kidney abuts the spleen laterally; the stomach, pancreas, and vertebral bodies medially; and the
small bowel and colon anteriorly

Blood Supply:

 Renal artery on each side, arising from abdominal aorta

 Renal vein emerges from hilum and drains into IVC

Lymphatic Drainage:

 Drains into the lateral aortic nodes around the origin of the renal artery

 The right kidney drains predominantly into the paracaval and interaortocaval LN

 The left kidney drains exclusively to the paraaortic LN

Nerve Supply:

 Through renal sympathetic plexus (T10-L1) fibers which are chiefly vasomotor

 Afferent nerves belongs to T10-T12 thoracic nervE

 283

8. Describe the Anatomy of Rectum and its significance:

• 12-15 cm from anal verge.

• Diameter ▫ 4 cm (upper part)

▫ Dilated (lower part)

• Posterior part of the lesser pelvis and in front of lower three pieces of sacrum and the coccyx

• Begins at the rectosigmoid junction, at level of third sacral vertebra

• Ends at the anorectal junction, 2-3 cm in front of and a little below the coccyx.

Divided into 3 parts • Upper third • Middle third • Lower third • 3 distinct intraluminal curves ( Valves of
Houston)

Upper Third Middle Third Lower Third

Arterial Supply • Middle rectal A- fr. Internal
Superior rectal A – fr. IMA iliac A. (supplies lower rectum)

Venous Drainage Superior rectal V- upper & middle third rectum Middle rectal V

Lymphatic Drainage ▫ Pararectal lymph nodes, located directly on the ▫ Sacral group of lymph nodes
muscle layer of the rectum or
Internal iliac lymph nodes
▫ Inferior mesenteric lymph nodes, via the nodes
along the superior rectal vessels
Peritoneal covering Covered by peritoneum Covered by Devoid of peritoneum
on the anterior and lateral peritoneum on the ▫ Close proximity to adjacent
surfaces anterior surface structure including boney
pelvis.

Note: - Distal rectal tumors have no serosal barrier to invasion of adjacent structures and are more difficult to
resect given the close confines of the deep pelvis.
 284

9. ANATOMY OF CERVIX :
Cervix measures approximately 3 by 3 cm and is predominantly a fibrous organ.
Parts of cervix : The cervix is divided into an upper or supravaginal portion, above the ring containing the
endocervical canal, and the vaginal portion, projecting in the vaginal vault.

1. Ectocervix - Anterior and Posterior lip, external os

2. Endocervix
3. Endocervical canal
4. External Os : opens into the vagina
5. Internal OS : opens into the uterine cavity
Central in the rounded vaginal region is the external os, bounded by the anterior and posterior lips of the cervix,
extending inward to the internal os, the endocervical canal, and endometrial canal.

LYMPHATIC DRAINAGE OF CERVIX :

1. Lateral channel - Paracervical lymph nodes; from

there it goes to the external iliac (of which the
obturator nodes are the innermost component)
2. Postero-lateral channel - hypogastric lymph nodes
(internal iliac) and to common iliac
3. Posteriorly – sacral lymph nodes.

Relations : Anteriorly – trigone of bladder , Posteriorly – Recto uterine pouch

What is parametrium ? There are 2 layers of peritoneum forming the broad ligament between the uterus and
lateral pelvic wall. It contains nerves, vessels, ureters and lymphatics. Ureters lies 1.5 cm lateral to the cervix.

Arterial supply:- uterine artery, which is the ant division of the hypogastric artery

Histology : Ectocervix : Squammous , Endocervix - Columnar . Transformation – the columnar cells are
transformed into the squamous epithelium – most common site of Ca cervix.
 285

10. Anatomy of Testis and spread of testicular malignancies:

 Paired oval glands in the scrotum

 Develops near kidney and descends through inguinal canals near 7th month of fetal development
 Tunica vaginalis partially covers testes
 Tunica albuginea – internal to tunica vaginalis
Extends inward forming septa that divide testis into lobules
 Each of 200-300 lobules contains 1-3 seminiferous tubules
 Sperm produced here through spermatogenesis
Lymph node drainage :

Right Testis Left Testis

R testicle: testicular vein → IVC below L testicle: testicular vein → L renal vein : Lt
level of renal vein : Rt Paracaval & Paraaortic LN . preaortic  common iliac
Interaortocaval at L2  precaval 
preaortic  Right common iliac

cross-over within the retroperitoneum mostly without cross-over

Spread of testicular malignancies:

 Lymphatic route is the predominant way of spread of seminoma, while nonseminoma favors
hematogenous spread.

 Local extension involves the rete testis, epididymis, or spermatic cord but rarely areas outside the tunica
albuginea,

 Blood (Distant metastases in decreasing order) : Lung Liver Brain Bone

 286

11. Explain the CSF Pathway :

 Cerebrospinal fluid (CSF) is a clear, colorless body fluid found in the brain and spinal cord.
 It is produced in the choroid plexuses of the ventricles of the brain, and absorbed in the arachnoid
granulations.
 There is about 125mL of CSF at any one time, and about 500mL is generated every day.
 CSF acts as a cushion or buffer for the brain, providing basic mechanical and immunological protection
to the brain inside the skull. CSF also serves a vital function in cerebral autoregulation of cerebral blood
flow.
 CSF occupies the subarachnoid space (between the arachnoid mater and the pia mater) and the
ventricular system around and inside the brain and spinal cord.
 It fills the ventricles of the brain, cisterns, and sulci, as well as the central canal of the spinal cord.
 There is also a connection from the subarachnoid space to the bony labyrinth of the inner ear via the
perilymphatic duct where the perilymph is continuous with the cerebrospinal fluid.
 A sample of CSF can be taken via lumbar puncture. This can reveal the intracranial pressure, as well as
indicate diseases including infections of the brain or its surrounding meninges.
 287

CLASSIFICATIONS

1. Classification of Lung cancer.

 288

2. Oesophagus

3. Pathological classification of breast cancer.

The World Health Organization has classified proliferative conditions and tumors of the breast into the
following categories: benign mammary dysplasias, benign or apparently benign tumors, carcinoma,
sarcoma, carcinosarcoma, and unclassified tumors.

The AJCC Classf.

Non invasive Invasive

DCIS  Ductal
LCIS  Inflammatory
Paget’s disease  Medullary, NOS
 Medullary with lymphoid stroma
 Mucinous
 Papillary (predominantly micropapillary
pattern)
 Tubular
 Lobular
 Paget’s disease
 Undifferentiated
 Squamous cell
 Adenoid cystic
 Secretory
 Cribriform
 289

4. Stomach
 290

5. Colon cancer
 EPITHELIAL TUMOURS : Mixed carcinoid-adenocarcinomas
 Adenoma Others
Tubular
Villous
Tubulovillous
Serrated
 Intraepithelial neoplasia 2
(dysplasia)associated with chronic
inflammatory diseases NON EPITHELIAL TUMOURS

Low-grade glandular intraepithelial Lipoma

neoplasia
Leiomyoma
High-grade glandular intraepithelial
Gastrointestinal stromal tumour
neoplasia
Leiomyosarcoma
 Carcinoma
Angiosarcoma
Adenocarcinoma
Kaposi sarcoma
Mucinous adenocarcinoma
Malignant melanoma
Signet-ring cell carcinoma
Others
Small cell carcinoma
Malignant lymphomas
Squamous cell carcinoma
Adenosquamous carcinoma
SECONDARY TUMOURS
Medullary carcinoma
Undifferentiated carcinoma
POLYPS
Carcinoid (well differentiated endocrine
neoplasm)
EC-cell, serotonin-producing
neoplasm
L-cell, glucagon-like peptide and
PP/PYY producing tumour
Others
 291

6. Ovary

EPITHELIAL TUMORS GERM CELL TUMORS SEX CORD TUMORS

Serous Embryonal carcinoma Granulosa-stromal cell tumors

 Adenocarcinoma Granulosa cell tumor
Polyembryoma
 Surface papillary carcinoma Adult type
 Adenocarcinofibroma Choriocarcinoma Juvenile type
(malignant adenofibroma) Dysgerminoma
Mucinous Endodermal sinus tumor Thecoma-fibroma group
 Adenocarcinoma Thecoma
 Adenocarcinofibroma Fibroma-fibrosarcoma
Teratoma
(malignant adenofibroma) Sclerosing stromal tumor
Immature
 Mucinous cystic tumor with M ature
mural nodules Solid
 Mucinous cystic tumor with Sertoli-stromal cell tumors
Cystic
Sertoli cell tumor
pseudomyxoma peritonei Dermoid cyst with malignant
Leydig cell tumor
transformation
Sertoli-Leydig cell tumor
Clear cell carcinoma Monodermal
Sex cord tumor with annular
 Adenocarcinoma Mixed
tubules
 Adenocarcinofibroma
(malignant adenofibroma)
Tumors composed of germ cells
Steroid cell tumors
Endometrioid and sex cord–stromal derivative
Stromal luteoma
 Adenocarcinoma NOS Leydig cell tumor
 Adenocarcinofibroma Gonadoblastoma
Steroid cell tumor NOS
(malignant adenofibroma)
 Malignant müllerian mixed Mixed germ cell-sex cord-stromal
Unclassified
tumor (carcinosarcoma) tumor
 Adenosarcoma Gynandroblastoma
 Endometrioid stromal
sarcoma
 Undifferentiated ovarian
carcinoma

Transitional cell carcinoma

Squamous cell tumors

Mixed epithelial tumors

Undifferentiated and unclassified

tumors
 292

7. TESTIS

Germ cell tumors ( 95%) Sex Cord–Stromal Tumors

(3-4%)

Seminoma Non seminoma  Leydig cell tumor

 Sertoli cell tumor
Classical or typical type Embryonal carcinoma (most  Granulosa cell tumor
 >90% of cases, common NSGCT),  Fibroma-thecoma
 stains + for stromal tumor
PLAP Yolk sac tumor  Sex cord–stromal
Spermatocytic  elevated AFP, tumor with annular
 older age,  Schiller Duval tubules
 cured by bodies.  Gonadoblastoma
orchiectomy,  Sex cord–stromal
 rarely Choriocarcinoma tumor unclassified
metastasizes,  Widespread mets type
 Stains(-)  elevated b-hCG,
forPLAP.  rarest pure GCT.

Teratoma

Mixed GCTs.

8. Lymphoma

WORKING FORMULATION :

Low grade Intermediate High grade

1. Small lymphocytic cell 1. Follicular (predomiently 1. Immunoblastic

2. Follicular predominantly large cell) 2. Lymphoblastic
small cleaved cell 2. Diffuse small cleaved cell 3. Burkitt
3. Follicular mixed ( small 3. Diffuse mixed small and
cleaved + large cell ) large cell
4. Diffuse large cell
REAL CLASSIFICATION :

Indolent Aggressive Highly Aggressive

 CLL/SLL 1. Follicle centre 1. Immunoblastic

 Follicle lymphoma, lymphoma, follicular, 2. Lymphoblastic
 293

 grade I-II grade III 3. Burkitt

 MZL (Extranodal (MALT) 2. DLCL 4. Adult T cell lymphoma
and Nodal , Splenic 3. Mantle cell lymphoma
marginal zone lymphoma 4. Primary mediastinal
 Hairy cell leukemia large B-cell lymphoma
5. Multiple Myeloma

WHO : on the basis of morphologic, immunologic, and genetic characteristics.

B-Cell Neoplasms T-Cell and NK-Cell Neoplasms

1. Small lymphcytic lymphoma  T-cell prolymphocytic leukemia

2. Follicular  T-cell large granular lymphocytic leukemia
Grade 1, 0-5 centroblasts/hpf  Chronic lymphoproliferative disorder of NK
– Grade 2, 6-15 centroblasts/hpf cells
– Grade 3, >15 centroblasts/hpf  Aggressive NK cell leukemia
3a, >15 centroblasts, but centrocytes  Primary cutaneous CD30 positive T-cell
still present lymphoproliferative disorders
3b, centroblasts from solid sheets with  Mycosis fungoides
no residual centrocytes
 Sézary syndrome
3. Diffuse large B-cell lymphoma (DLBCL)
 T-cell/histiocyte-rich large B-cell
lymphoma
 Primary DLBCL of the CNS
 Primary cutaneous DLBCL, leg
type
 E BV positive DLBCL of the
elderly
 DLBCL associated with chronic
inflammation
4. Marginal Zone or MALTOMA
5. Splenic marginal zone lymphoma
6. Nodal marginal zone lymphoma
7. Mantle cell lymphoma
8. Plasma cell neoplasms
9. Plasmablastic lymphoma
10. Heavy chain diseases
11. Hairy cell leukemia
12. Primary mediastinal large B-cell
lymphoma
13. Intravascular large B-cell lymphoma
14. ALK positive large B-cell lymphoma
15. Primary effusion lymphoma
16. Burkitt lymphoma
 294

17. B-cell lymphoma, unclassifiable, with

features intermediate between DLBCL and
18. Burkitt lymphoma

8. BRAIN
 295

9. BONE
 296

10. GTD
 297

GENERAL TOPICS
 298

Radiotherapy Toxicities

HEAD AND NECK :

Tissue Grade 1 2 3 4
Skin Follicular, faint or Tender or bright erythema, Confluent, moist Ulceration,
dull erythema / patchy moist desquamation other hemorrhage,
epilation / dry desquamation / moderate than skin folds, necrosis
desquamation / edema pitting edema
decreased sweating
Mucous Irritation / may Patchy mucositis that may Confluent fibrinous Ulceration,
membrane experience mild pain produce an inflammatory mucositis / may hemorrhage or
not requiring serosanguinous discharge / include severe pain necrosis
analgesic may experience moderate requiring narcotic
pain requiring analgesia
Eye Mild conjunctivitis Moderate conjunctivitis w/ Severe keratitis with Loss of vision (uni
w/ or w/o scleral or w/o keratitis requiring corneal ulceration / or bilateral)
injection / increased steroids and/or antibiotics objective decrease
tearing / dry eye requiring in visual acuity or in
artificial tears / iritis with visual fields / acute
photophobia glaucoma /
panophthalmitis
Ear Mild external otitis Moderate external otitis Severe external Deafness
with erythema, requiring topical otitis with discharge
pruritus, secondary medication / serous otitis or moist
to dry desquamation media / hypoacusis on desquamation /
not requiring testing only symptomatic
medication. hypoacusis /
tinnitus, not drug
related
Salivary Mild mouth dryness Moderate to complete (none) Acute salivary gland
gland / slightly thickened dryness / thick, sticky necrosis
saliva / may have saliva / markedly altered
slightly altered taste taste in alteration in
such as metallic taste baseline feeding behavior,
/ these changes not such as increased use of
reflected liquids with meals
Pharynx & Mild dysphagia or Moderate dysphagia or Severe dysphagia or Complete
esophagus odynophagia / may odynophagia / may require odynophagia with obstruction,
require topical narcotic analgesics / may dehydration or ulceration,
anesthetic or non- require puree or liquid diet weight loss > 15% perforation, fistula
narcotic analgesics / from pretreatment
may require soft diet baseline requiring
NG feeding tube, IV
fluids, or
hyperalimentation
 299

LATE TOXICITY

Skin Slight atrophy; Patch atrophy; Marked atrophy; Ulceration

pigmentation moderate gross telangiectasia
change; some hair telangiectasia; total
loss hair loss
Subcutaneous tissue Slight induration Moderate fibrosis Severe induration Necrosis
(fibrosis) and loss of but asymptomatic; and loss of
subcutaneous fat slight field subcutaneous tissue;
contracture; <10% field contracture >
linear reduction 10% linear
measurement
Mucous membrane Slight atrophy and Moderate atrophy Marked atrophy Ulceration
dryness and telangiectasia; with complete
little mucous dryness
Salivary glands Slight dryness of Moderate dryness of Complete dryness of Fibrosis
mouth; good mouth; poor mouth; no response
response on response on on stimulation
stimulation stimulation
Skin Slight atrophy; Patch atrophy; Marked atrophy; Ulceration
pigmentation moderate gross telangiectasia
change; some hair telangiectasia; total
loss hair loss
Subcutaneous tissue Slight induration Moderate fibrosis Severe induration Necrosis
(fibrosis) and loss of but asymptomatic; and loss of
subcutaneous fat slight field subcutaneous tissue;
contracture; <10% field contracture >
linear reduction 10% linear
measurement
Eye Asymptomatic Symptomatic Severe keratitis; Panophthalmitis /
cataract; minor cataract; moderate severe retinopathy blindness
corneal ulceration or corneal ulceration; or detachment
keratitis minor retinopathy or
glaucoma
Larynx Hoarseness; slight Moderate arytenoid Severe edema; Necrosis
arytenoid edema edema; chondritis severe chondritis
Spinal cord Mild L'Hermitte's Severe L'Hermitte's Objective Mono, para
syndrome syndrome neurological quadraplegia
findings at or below
cord level treated
 300

LUNG AND HEART

Lung Mild symptoms of Persistent cough Severe cough Severe respiratory

Acute dry cough or requiring narcotic, unresponsive to insufficiency /
dyspnea on exertion antitussive agents / narcotic antitussive continuous oxygen
dyspnea with agent or dyspnea at or assisted
minimal effort but rest / clinical or ventilation
not at rest radiological
evidence of acute
pneumonitis /
intermittent oxygen
or steroids may be
required

LungLate Asymptomatic or Moderate Severe symptomatic Severe respiratory

mild symptoms (dry symptomatic fibrosis or insufficiency /
cough); slight fibrosis or pneumonitis; dense Continuous oxygen
radiographic pneumonitis (severe radiographic / assisted ventilation
appearances cough); low grade changes
fever; patchy
radiographic
appearances
Heart Asymptomatic but Symptomatic with Congestive heart Congestive heart
Acute objective evidence EKG changes and failure, angina failure, angina
of EKG changes or radiological pectoris, pericardial pectoris, pericardial
pericardial findings of disease responding disease, arrhythmias
abnormalities congestive heart to therapy not responsive to
without evidence of failure or pericardial nonsurgical
other heart disease disease / no specific measures
treatment required
Heart Asymptomatic or Moderate angina on Severe angina; Tamponade / severe
Late mild symptoms; effort; mild pericardial effusion; heart failure; severe
transient T wave pericarditis; normal constrictive constrictive
inversion & ST heart size; persistent pericarditis; pericarditis
changes; sinus tachy abnormal T wave moderate heart
> 110 (at rest) and ST changes; failure; cardiac
low ORS enlargement; EKG
abnormalities
 301

GIT

Upper GI Anorexia with ≤ 5% weight Anorexia with ≤ Anorexia with > Ileus, subacute or
loss from pretreatment 15% weight loss 15% weight loss acute obstruction,
baseline / nausea not from pretreatment from pretreatment perforation, GI
requiring antiemetics / baseline / nausea baseline or bleeding requiring
abdominal discomfort not and/or vomiting requiring NG tube transfusion /
requiring parasympatholytic requiring or parenteral abdominal pain
drugs or analgesics antiemetics / support. Nausea requiring tube
abdominal pain and/or vomiting decompression or
requiring analgesics requiring tube or bowel diversion
parenteral support /
abdominal pain,
severe despite
medication /
hematemesis or
melena / abdominal
distention (flat plate
radiograph
demonstrates
distended bowel
loops)
Lower GI / Increased frequency or Diarrhea requiring Diarrhea requiring Acute or subacute
Pelvis change in quality of bowel parasympatholytic parenteral support / obstruction, fistula
habits not requiring drugs (e.g. Lomotil) severe mucous or or perforation; GI
medication / rectal / mucous discharge blood discharge bleeding requiring
discomfort not requiring not necessitating necessitating transfusion;
analgesics sanitary pads / sanitary pads / abdominal pain or
rectal or abdominal abdominal tenesmus requiring
pain requiring distention (flat plate tube decompression
analgesics radiograph or bowel diversion
demonstrates
distended bowel
loops)
Small/Large Mild diarrhea; mild Moderate diarrhea Obstruction or Necrosis /
intestine cramping; bowel movement and colic; bowel bleeding, requiring perforation fistula
5 times daily; slight rectal movement > 5 times surgery
discharge or bleeding daily; excessive
rectal mucus or
intermittent
bleeding
 302

Bladder

Genitourinary Frequency of Frequency of Frequency with Hematuria requiring

Acute urination or nocturia urination or nocturia urgency and transfusion / acute
twice pretreatment that is less frequent nocturia hourly or bladder obstruction
habit / dysuria, than every hour. more frequenty / not secondary to
urgency not Dysuria, urgency, dysuria, pelvis pain clot passage,
requiring bladder spasm or bladder spasm ulceration, or
medication requiring local requiring regular, necrosis
anesthetic (e.g. frequent narcotic /
Pyridium) gross hematuria
with/without clot
passage
Bladder Slight epithelial Moderate Severe frequency & Necrosis/contracted
Late atrophy; minor frequency; dysuria; severe bladder (capacity <
telangiectasia generalized telangiectasia (often 100 cc); severe
(microscopic telangiectasia; with petechiae); hemorrhagic cystitis
hematuria) intermittent frequent hematuria;
macroscopic reduction in bladder
hematuria capacity (<150 cc)

BLOOD

Hgb / Hct 11 - 9.5 (28% - < < 9.5 - 7.5 ( < 28%) < 7.5 - 5.0 (Packed (none)
32%) cell transfusion
required)
WBC 3.0 - < 4.0 2.0 - < 3.0 1.0 - < 2.0 < 1.0
Neutrophils 1.5 - < 1.9 1.0 - < 1.5 0.5 - < 1.0 < 0.5 or sepsis
Platelets 75 - < 100 50 - < 75 25 - < 50 <25 or spontaneous
bleeding

SOMA
 303

PERFORMANCE STATUS

Karnofsky scoring
The Karnofsky Performance Score (KPS) ranking runs from 100 to 0, where 100 is "perfect" health and 0 is
death. Practitioners occasionally assign performance scores in between standard intervals of 10. This scoring
system is named after Dr. David A. Karnofsky, who described the scale with Dr. Walter H. Abelmann, Dr.
Lloyd F. Craver, and Dr. Joseph H. Burchenal in 1948.[1] The primary purpose of its development was to allow
physicians to evaluate a patient's ability to survive chemotherapy for cancer.

 100 – Normal; no complaints; no evidence of disease.

 90 – Able to carry on normal activity; minor signs or symptoms of disease.
 80 – Normal activity with effort; some signs or symptoms of disease.
 70 – Cares for self; unable to carry on normal activity or to do active work.
 60 – Requires occasional assistance, but is able to care for most of their personal needs.
 50 – Requires considerable assistance and frequent medical care.
 40 – Disabled; requires special care and assistance.
 30 – Severely disabled; hospital admission is indicated although death not imminent.
 20 – Very sick; hospital admission necessary; active supportive treatment necessary.
 10 – Moribund; fatal processes progressing rapidly.
 0 – Dead

ECOG/WHO/Zubrod score
The Eastern Cooperative Oncology Group (ECOG) score (published by Oken et al. in 1982), also called
the WHO or Zubrod score (after C. Gordon Zubrod), runs from 0 to 5, with 0 denoting perfect health and 5
death:[2] Its advantage over the Karnofsky scale lies in its simplicity.

 0 – Asymptomatic (Fully active, able to carry on all predisease activities without restriction)
 1 – Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory and
able to carry out work of a light or sedentary nature. For example, light housework, office work)
 2 – Symptomatic, <50% in bed during the day (Ambulatory and capable of all self care but unable to carry
out any work activities. Up and about more than 50% of waking hours)
 3 – Symptomatic, >50% in bed, but not bedbound (Capable of only limited self-care, confined to bed or
chair 50% or more of waking hours)
 4 – Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair)
 5 – Death
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Lansky score
Children, who might have more trouble expressing their experienced quality of life, require a somewhat more
observational scoring system suggested and validated by Lansky et al. in 1987:[3]

 100 – fully active, normal

 90 – minor restrictions in strenuous physical activity
 80 – active, but gets tired more quickly
 70 – greater restriction of play and less time spent in play activity
 60 – up and around, but active play minimal; keeps busy by being involved in quieter activities
 50 – lying around much of the day, but gets dressed; no active playing participates in all quiet play and
activities
 40 – mainly in bed; participates in quiet activities
 30 – bedbound; needing assistance even for quiet play
 20 – sleeping often; play entirely limited to very passive activities
 10 – doesn't play; does not get out of bed
 0 – unresponsive

Comparison
A translation between the Zubrod and Karnofsky scales that works especially well for healthy patients has been
validated in a large sample of lung cancer patients:[4]

 Zubrod 0–1 equals Karnofsky 80–100

 Zubrod 2 equals Karnofsky 60–70
 Zubrod 3–4 equals Karnofsky 10–50
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RECIST AND PERCIST

 306

IMMOBILISATION DEVICES IN RADIOTHERAPY

Definition

 Any device that helps to establish and maintain the patient in a fixed, well defined position from treatment to
treatment over a course of radiotherapy or prevent the patient from moving during a single treatment session.

Objectives Main:

 to limit the patient movement

 to reduce the probability of positioning errors

Incidental benefits:

 Redn in daily set up time

 Redn in pt s fear and worry ‘

 No need for pt to be awake, alert & co-op

 Conversion into a rigid body

Desirable characteristics

Ease of use

Ease of constructing the device

Patient Comfort: Fully supported in a comfortable and relaxed position

Tactile reminder to the pt of how it feels

All movements be constrained

Device conforms to the pt’s external surface contours(H&N)

The device be appropriate to the particular patient(e.g. obese) and anatomy(e.g. abdomen) under trtmt.

The device should optimally position the patient so as to minimize the normal tissue complications

It should not obstruct the path for beam

Device be usable on simulator, CT/MRI and other trtmt planning imaging systems

Surface dose should not be altered.

Adequate space for reference marks.

Rigid & holds its shape over time

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Cost considerations:

Of materials and device itself

Staff time 4 construction of device

Staff time 4 each patient set up

Necessary supplies

Re-usability

Storage space

THERMOPLASTICS

Low-temperature orthopedic plastics.

Polycaprolactone

Softens at 60 C (working temp)

Melts at 150 C (melting pt)

solid sheets or a flat plastic mesh of diff thicknesses

precut thermoplastic mesh

softened by soaking in warm water for a few minutes.

Then mask stretched around the topside of a patient who is already in the treatment position

soft thermoplastic moulded to the patient's facial contours, and in a few minutes the mask hardens.

no strength or cushioning properties

wont support the patient's weight.

easy to use.

allow treatments with few skin marks.

Reference lines drawn on the plastic sheet.

some loss of skin sparing through the material.

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VACUUM BAGS

Radiolucent plastic cushions filled with tiny polystyrene ball.

Semi-deflated cushion moulded around the patient's gross body contours.

Using vacuum pump air is pumped out and the balls come together to form a firm solid support.

The cushion becomes an entirely rigid and comfortable mold of the patient's body.
 309

ALPHA CRADLE

2 component chemical systems

Patient placed in the treatment position on top of a plastic bag.

The bag rests within a specialized form constructed of solid Styrofoam blocks.

When two chemicals are combined in the bag, they begin to expand into a polyurethane foam.

As the foam rises, technician maneuvers it around the patient .

Support given to anatomic structures that do not lie flat on the treatment couch.

Once the foam hardens, the customized device is ready for use.

used in combination with other patient support systems for  ca breast  ca prostate  lower extremities  lung
 pituitary gland  head and neck region  Hodgkin's disease.

Base Plate

The plate onto which the head immobilization systems are secured is usually referred to as a base plate.

• Its material should be strong ,yet it should minimally attenuate the radiation beam.

• Most base plates are acrylic and recently carbon fiber base plates are hugely devolped

Indexer

• The indexing bar can be placed at the desired indexing indents of the couch and it can be locked

down by rotating the levers.

• The base plates then can be positioned over the pins of the two pin indexing bar.
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OLD METHODS : Body CAST TECHNIQUES

Acrylic Mould / Cobex cast

Made from perspex sheets

It forms hard nonmalleable material when mixed and allowed to set.

Materials required :

POP bandage & powder

Perspex sheet

Vaseline

base plate

head rest
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POSITIONING DEVICES

 All immobilization devices in some sense are positioning devices.

 positioning devices are ancillary devices which maintain the patient in a nonstandard treatment position.

Need for positioning devices

 set up the patient in a special position designed to improve the therapeutic ratio and patient's comfort.

 optimal beam access is limited by external anatomic features such as the extremities, a large belly, or a
pendulous breast.

 proximity of the target (PTV) to the surrounding radiosensitive structures.

NECK ROLL, FOAM WEDGE, HEAD HOLDER AND TIMO

 used to maneuver body parts out of the way of the beam or into a better position

Arm board, knee saddle, and thigh stirrups

 Designed to position the extremities in a comfortable and reproducible manner.

 Used for soft tissue sarcomas in the arms or legs.

 Necessary to remove the uninvolved arm or leg from the path of the radiation beam.

OVERHEAD ARM POSITIONER

 Used to position the extremities if interfering with treatment of some other region.

 Positioned above the head or at the sides with either:

 1)couch rail mounted or tilt board mounted hand grips and arm supports .

 2) or an overhead arm positioner hand grip device. (e.g., the butterfly or the Tbar)

Shoulder retractors

 Patient nudged into a position with arms and shoulders down.

 Footboard attached to hand grips through nylon ropes with adjustable tension.

 Reproducible.

 very useful for treating head and neck cancers with lateral fields.
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BREAST BOARD

 Used in the treatment of breast cancer with parallel opposed tangential fields.

 Advntg:

 Provides arm support to bring the arm above the shoulders and out of the way of the lateral field.

 Allows the patient to be positioned with the chest wall horizontal avoiding angulation of the collimator.

 Takes advantage of gravity to pull the large breast down into a better treatment position.

WING BOARD

 It comfortably supports the patients arms during trtmt of breast, lung and thorax.

BELLY BOARD

 Thick mattress for supporting the patient prone with a window cutout for the patient's belly.

 provide more comfort and stability in the prone position (obese patient) .

 Reduces the amount of intestine in the lateral radiation fields.

Head Fixation Devices

 Stereotactic radio surgery(SRS) immobilization requires greater precision and accuracy.

 Stereotactic frame bolted to the patient's skull before the target localization procedure and attached until
treatment is complete.

 Single-fraction technique.

 Impractical for fractionated radiotherapy

 1. Gill-Thomas-Cosman system

 frame fixed to the head with a dental mold. occipital tray with a cast of the occiput. strap that holds the device
tightly to the head.

2nd device consist of a rod in each external auditory canal and a clip molded to the bridge of the nose.

 For IMRT of head& neck

 bone screws set into the inner table of the skull.

 screws have internal threads and can receive the standoffs which remain in place during the course of therapy.
 313

CHEMOTHERAPY
 314

CLASSIFICATION OF ANTI-NEOPLASTIC DRUGS

Class and Type Agents

[Link] agents
Nitrogen mustard Chlorambucil, cyclophosphamide, estramustine,
ifosfamide, mechlorethamine, melphalan
Nitrosourea Carmustine, lomustine, streptozocin
Alkyl sulfonate Busulfan
Ethylenimine derivative Thiotepa (triethylenethiophosphoramide)
Triazene Dacarbazine, temozolamide
[Link] complexes (Metal salt) Carboplatin, cisplatin, oxaliplatin
3. Antimetabolites
Antifolates Methotrexate, pemetrexed, raltitrexed, trimetrexate
Purine analogs Cladribine, clofarabine, fludarabine, mercaptopurine,
nelarabine, pentostatin, thioguanine
Pyrimidine analogs Azacitidine, capecitabine, cytarabine, decitabine,
floxuridine, fluorouracil, gemcitabine
[Link] products
Mitotic inhibitor Vinblastine, vincristine, vindesine, vinorelbine
Microtubule polymer stabilizer Docetaxel, paclitaxel
Topoisomerase I inhibitors Irinotecan, topotecan
Topoisomerase II inhibitors Etoposide, teniposide
Antibiotics Bleomycin, dactinomycin, daunorubicin, doxorubicin,
epirubicin, idarubicin, mitomycin, mitoxantrone,
valrubicin
Enzyme Asparaginase
[Link] and hormone antagonists
Androgen Fluoxymesterone and others
Androgen antagonist Bicalutamide, flutamide, nilutamide
Aromatase inhibitor Aminoglutethimide, anastrozole, letrozole, exemestane
Corticosteroid Dexamethasone, prednisone
Estrogen Diethylstilbestrol
Estrogen antagonist (selective estrogen receptor Fulvestrant, raloxifene, tamoxifen, toremifene
modulator)
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Luteinizing hormone–releasing hormone agonist Goserelin, leuprolide, triptorelin

Polypeptide hormone release suppression Octreotide
Progestin Megestrol acetate, medroxyprogesterone acetate
Thyroid hormones Levothyroxine, liothyronine
[Link] targeted agents
Gene expression modulators Retinoids, rexinoids
Interleukin 2 receptor toxin Denileukin diftitox
Monoclonal antibody Alemtuzumab, cetuximab, gemtuzumab, ibritumomab
tiuxetan, panitumumab, trastuzumab, rituximab, 131I-
tositumomab
mTOR kinase inhibitor Temsirolimus
Proteosome inhibitor Bortezomib
Receptor tyrosine kinase inhibitors Dasatinib, erlotinib, gefitinib, imatinib mesylate,
lapatinib, semaxanib, sorafenib, sunitinib
Retinoic acid receptor expression modification Tretinoin (ATRA)
7. Biologic response modifiers
Interferons Interferon α-2a, interferon α-2b
Interleukins Aldesleukin (interleukin 2), oprelvekin, denileukin
diftitox
Myeloid- and erythroid-stimulating factors Epoetin, filgrastim, sargramostim
Nonspecific immunomodulation Thalidomide, lenalidomide
8. Miscellaneous agents
Adrenocortical suppressant Mitotane
Bisphosphonates Pamidronate, zoledronic acid
Cytoprotector (reactive species antagonists) Amifostine, dexrazoxane, mesna
Methylhydrazine derivative Procarbazine
Photosensitizing agents Porfimer
Platelet-reducing agent Anagrelide
Salt Arsenic trioxide
Somatostatin analog Octreotide
Substituted melamine Altretamine (hexamethylmelamine)
Substituted urea Hydroxyurea
 316

ALKYLATING AGENTS

 These compounds produce highly reactive carbonium ion intermediates which transfer alkyl groups to
cellular macromolecules by forming covalent bonds.
 The position 7 of guanine residues in DNA is especially susceptible, but other molecular sites are also
involved. They may react with carboxyl, hydroxyl, amino, sulfhydryl and phosphate groups of
biomacromolecules.
 Alkylation results in cross linking/abnormal base pairing/scission of DNA strand. Cross linking of
 nucleic acids with proteins can also take place. Alkylating agents have cytotoxic and radiomimetic (like
ionizing radiation) actions.
 Most are cell cycle non-specific, i.e. act on dividing as well as resting cells.
 Some have CNS stimulant and cholinergic properties.
Nitrogen mustard Chlorambucil, cyclophosphamide, estramustine,
ifosfamide, mechlorethamine, melphalan
Nitrosourea Carmustine, lomustine, streptozocin
Alkyl sulfonate Busulfan
Ethylenimine derivative Thiotepa (triethylenethiophosphoramide)
Triazene Dacarbazine, temozolamide

NITROGEN MUSTARD

Cyclophosphamide

 It is inactive as such: produces few acute effects and is not locally damaging.
 Transformation into active metabolites (aldophosphamide, phosphoramide mustard) occurs in the liver,
and a wide range of antitumouractions is exerted.
 It has prominent immunosuppressant property.
 Thus, it is one of the most popular alkylating agents useful in many solid tumours.
 It is less damaging to platelets, but alopecia and cystitis (due to another metabolite acrolein) are
prominent. Chloramphenicol retards the metabolism of cyclophosphamide.
 Dose: 2–3 mg/kg/day oral; 10–15 mg/kg i.v. every 7–10 days, i.m. use also possible.
 ENDOXAN, CYCLOXAN 50 mg tab; 200, 500, 1000 mg inj.
Ifosfamide

 This congener of cyclophosphamide has a longer and dose-dependent t½. It has found utility in
bronchogenic, breast, testicular, bladder, head and neck carcinomas, osteogenic sarcoma and some
lymphomas.
 The dose limiting toxicity of ifosphamide is haemorrhagic cystitis.
 To prevent the same, mesna is routinely given with it. Mesna is a –SH compound that is excreted in
urine—binds and inactivates the vasicotoxic metabolites of ifosfamide and cyclophosphamide.
 Ifosfamide causes less alopecia and is less emetogenic than cyclophosphamide.
Chlorambucil
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 It is a very slow acting alkylating agent, especially active on lymphoid tissue: Myeloid tissue is largely
spared. It is the drug of choice for long-term maintenance therapy for chronic lymphatic leukaemia; non-
Hodgkin lymphoma and few solid tumours also resolve.
 It has some immunosuppressant property.
 Dose: 4–10 mg (0.1–0.2 mg/kg) daily for 3–6 weeks, then 2 mg daily for maintenance; LEUKERAN 2,
5 mg tab.
Melphalan

 It is very effective in multiple myeloma and has been used in advanced ovarian cancer. Bone marrow
depression is the most important toxicity. Infections, diarrhoea and pancreatitis are the complications.
 Dose: 10 mg daily for 7 days or 6 mg/day for 2–3 weeks—4 weeks gap—2 to 4 mg daily for
maintenance orally.
 Also used for regional perfusion in malignant melanoma
 318

PACLITAXEL

Taxane, anti microtubule agent

Mechanism of Action

• Isolated from the bark of the Pacific yew tree, Taxus brevifolia .

• Cell cycle–specific, active in the mitosis (M) phase of the cell cycle.

• High-affinity binding to microtubules enhances tubulin polymerization.

Normal dynamic process of microtubule network is inhibited, leading to inhibition of mitosis and cell division.

Indications

1. Ovarian cancer.

2. Breast cancer.

3. Non–small cell and small cell lung cancer.

4. Head and neck cancer.

5. Esophageal cancer.

6. Prostate cancer.

7. Bladder cancer.

8. AIDS-related Kaposi’s sarcoma.

Dosage Range

1. Ovarian cancer: 135–175 mg/m 2 IV as a 3-hour infusion every 3 weeks.

2. Breast cancer: 175 mg/m 2 IV as a 3-hour infusion every 3 weeks.

3. Bladder cancer, head and neck cancer: 250 mg/m 2 IV as a 24-hour infusion every 3 weeks.

4. Weekly schedule: 80–100 mg/m 2 IV each week for 3 weeks with 1-week rest.

5. Infusional schedule: 140 mg/m 2 as a 96-hour infusion.

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Toxicity

1. Myelosuppression. Dose-limiting neutropenia with nadir at day 8–10 and recovery by day 15–21.
Decreased incidence of neutropenia with 3-hour schedule when compared to 24-hour schedule.
2. HSR. Occurs in up to 20%–40% of patients. Characterized by generalized skin rash, flushing, erythema,
hypotension, dyspnea, and/or bronchospasm.
3. Usually occurs within the first 2–3 minutes of an infusion and almost always within the first 10 minutes.
Incidence of HSR is the same with 3- and 24-hour schedules. Premedication regimen, as outlined in
Special Considerations, has significantly decreased incidence.
4. Neurotoxicity mainly in the form of sensory neuropathy with numbness and paresthesias. Dose-
dependent effect. Other risk factors include prior exposure to known neurotoxic agents (e.g., cisplatin)
and pre-existing medical disorders such as diabetes mellitus and chronic alcoholism. Also more frequent
with longer infusions and at doses . 175 mg/m 2 . Motor and autonomic neuropathy observed at high
doses. Optic nerve disturbances with scintillating scotomata observed rarely.
5. Transient asymptomatic sinus bradycardia is most commonly observed cardiotoxicity. Occurs in 30% of
patients. Other rhythm disturbances are seen, including Mobitz type I, Mobitz type II, and third-degree
heart block, as well as ventricular arrhythmias.

ALBUMIN-BOUND PACLITAXEL

Mechanism of Action

• Albumin-bound form of paclitaxel with a mean particle size of about 130 nm. Selective binding of albumin-
bound paclitaxel to specific albumin receptors present on tumor cells versus normal cells.

• Active moiety is paclitaxel, which is isolated from the bark of the Pacific yew tree, Taxus brevifolia.

• Cell cycle–specific, active in the mitosis (M) phase of the cell cycle.

• High-affinity binding to microtubules enhances tubulin polymerization. Normal dynamic process of

microtubule network is inhibited, leading to inhibition of mitosis and cell division.

Absorption : Administered by the IV route, as it is not orally bioavailable

Indications

1. FDA-approved for the treatment of breast cancer after failure of combination chemotherapy for metastatic
disease or relapse within 6 months of adjuvant chemotherapy.

2. FDA-approved for treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in
combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

Dosage Range

1. Recommended dose for metastatic breast cancer is 260 mg/m 2 IV on day 1 every 21 days.
 320

2. An alternative regimen is a weekly schedule of 125 mg/m 2 IV on days 1, 8, and 15 every 28 days.

3. Recommended dose for NSCLC is 1000 mg/m 2 IV on days 1, 8, and 15 every 21 days.

DOCETAXEL
Taxane, antimicrotubule agent

Mechanism of Action
• Semisynthetic taxane. Derived from the needles of the European yew tree.
• High-affinity binding to microtubules enhances tubulin polymerization.
Normal dynamic process of microtubule network is inhibited, leading to inhibition of mitosis and cell division.
• Cell cycle–specific agent with activity in the mitotic (M) phase.

Indications
1. Breast cancer—FDA-approved for the treatment of locally advanced or metastatic breast cancer after failure
of prior chemotherapy.
2. Breast cancer—FDA-approved in combination with doxorubicin and cyclophosphamide for adjuvant
treatment of patients with node-positive breast cancer.
3. Non–small cell lung cancer—FDA-approved for locally advanced or metastatic disease after failure of prior
platinum-based chemotherapy.
4. Non–small cell lung cancer—FDA-approved in combination with cisplatin for treatment of patients with
locally advanced or metastatic disease who have not previously received chemotherapy.
5. Prostate cancer—FDA-approved in combination with prednisone for androgen-independen (hormone-
refractory) metastatic prostate cancer.
6. Gastric cancer—FDA-approved in combination with cisplatin and 5-fluorouracil for advanced gastric cancer,
including adenocarcinoma of the gastroesophageal junction, in patients who have not received
prior chemotherapy.
7. Head and neck cancer—FDA-approved for use in combination with cisplatin and 5-fluorouracil for induction
treatment of patients with inoperable, locally advanced disease.
8. Small cell lung cancer.
9. Refractory ovarian cancer.
10. Bladder cancer.
 321

Dosage Range
1. Metastatic breast cancer—60, 75, and 100 mg/m 2 IV every 3 weeks or 35–40 mg/m 2 IV weekly for 3 weeks
with 1 week of rest.
2. Breast cancer—75 mg/m 2 IV every 3 weeks in combination withcyclophosphamide and doxorubicin for
adjuvant therapy.
3. Non–small cell lung cancer—75 mg/m 2 IV every 3 weeks or 35–40 mg/m 2 IV weekly for 3 weeks with 1
week rest after platinumbased chemotherapy.
4. Non–small cell lung cancer—75 mg/m 2 IV every 3 weeks in combination with cisplatin in patients who
have not received prior chemotherapy.
5. Metastatic prostate cancer—75 mg/m 2 IV every 3 weeks in combination with prednisone.
6. Advanced gastric cancer—75 mg/m 2 IV every 3 weeks in combination with cisplatin and 5-FU.
7. Head and neck cancer—75 mg/m 2 IV every 3 weeks in combination with cisplatin and 5-FU for induction
therapy of locally advanced disease.
Toxicity
 Myelosuppression. Neutropenia is dose-limiting with nadir at days 7–10 and recovery by day 14.
Thrombocytopenia and anemia are also observed.
 Hypersensitivity reactions with generalized skin rash, erythema, hypotension, dyspnea, and/or
bronchospasm. Usually occur within the first 2–3 minutes of an infusion and almost always within the
first 10 minutes.
 Most frequently observed with first or second treatments. Usually prevented by premedication with
steroid; overall incidence decreased to less than 3%.
 When it occurs during drug infusion, treat with hydrocortisone IV, diphenhydramine 50 mg IV, and/or
cimetidine 300 mg IV.
 Fluid retention syndrome. Presents as weight gain, peripheral and/or generalized edema, pleural
effusion, and ascites. Incidence increases with total doses . 400 mg/m 2 . Occurs in about 50% of
patients.
 Maculopapular skin rash and dry, itchy skin. Most commonly affect forearms and hands. Brown
discoloration of fingernails may occur. Observed in up to 50% of patients usually within 1 week after
therapy.
 Alopecia occurs in up to 80% of patients.
 Mucositis and/or diarrhea seen in 40% of patients. Mild-to-moderate nausea and vomiting, usually of
brief duration.
 Peripheral neuropathy is less commonly observed with docetaxel than with paclitaxel.
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CABAZITAXEL

Taxane, antimicrotubule agent

Mechanism of Action

• Semisynthetic taxane prepared with a precursor extracted from yew needles.

• Binds to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly.
This effect leads to stabilization of microtubules, which results in the inhibition of mitotic and interphase
cellular functions.

• Cell cycle–specific agent with activity in the mitotic (M) phase.

Indications

FDA-approved for the treatment of patients with hormone-refractory metastatic prostate cancer previously
treated with a docetaxel-containing treatment regimen.

Dosage Range

Recommended dose is 25 mg/m 2 as a 1-hour infusion every 3 weeks in combination with oral prednisone 10
mg administered daily throughout cabazitaxel treatment.

Toxicity

1. Myelosuppression with dose-limiting neutropenia. Thrombocytopenia and anemia are also observed.
2. Hypersensitivity reaction (HSR) characterized by generalized skin rash, flushing, erythema,
hypotension, dyspnea, and/or bronchospasm. Usually occurs within the first few minutes of infusion and
more frequently with the first and second infusions.
3. Diarrhea, nausea/vomiting, constipation, abdominal pain, dysgeusia, and loss of appetite are the main GI
side effects.
4. Fatigue and asthenia.
5. Neurotoxicity, mainly in the form of peripheral neuropathy, dizziness, and headache.
6. Myalgias and arthralgias.
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Arsenic trioxide (As 2 O 3 )

Natural product

Category

Chemotherapy and differentiating agent

Mechanism of Action

• Precise mechanism of action has not been fully elucidated.

• Induces differentiation of acute promyelocytic leukemic cells by degrading the chimeric PML/RAR- a protein,
resulting in release of the maturation block at the promyelocyte stage of myelocyte differentiation.

• Induces apoptosis through a mitochondrial-dependent pathway, resulting in release of cytochrome C and

subsequent caspase activation.

• Direct antiproliferative activity by arresting cells at either the G1-S or G2-M checkpoints.

• Inhibits the process of angiogenesis through apoptosis of endothelial cells and/or inhibition of production of
critical angiogenic factors, including vascular endothelial growth factor.

Indications

Acute promyelocytic leukemia (APL)—FDA-approved for induction of remission and consolidation in patients
with APL who are refractory to or have relapsed following first-line therapy with all-trans retinoic acid (ATRA)
and anthracycline-based chemotherapy and whose APL is characterized by the presence of the t(15;17)
translocation or PML/RAR- a gene expression.

Dosage Range

1. Induction therapy—0.15 mg/kg/day IV for a maximum of 60 days.

2. Consolidation therapy—Should be initiated 3 weeks after completion of induction treatment and only in those
patients who achieve a complete bone marrow remission. The recommended dosage is 0.15 mg/ kg/day IV for 5
days/week for a total of 5 weeks.

Toxicity : Fatigue.

Prolonged QT interval ( . 500 msec) on EKG seen in 40%–50% of patients. Torsade de Pointes ventricular
arrhythmia and/or complete AV block can be observed in this setting.

APL differentiation syndrome. Occurs in about 30% of patients and is characterized by fever, dyspnea, skin
rash, fluid retention and weight gain, pleural and/or pericardial effusions. This syndrome is identical to the
retinoic acid syndrome observed with retinoid therapy.

Leukocytosis is observed in 50%–60% of patients with a gradual increase in white blood cells (WBCs) that
peaks between 2 and 3 weeks after starting therapy.
 324

BLEOMYCIN

Antitumor antibiotic

Mechanism of Action

• Small peptide with a molecular weight of 1500.

• Contains a DNA-binding region and an iron-binding region at opposite ends of the molecule.

• Iron is absolutely necessary as a cofactor for free radical generation and bleomycin’s cytotoxic activity.

• Cytotoxic effects result from the generation of activated oxygen-free radical species, which causes single- and
double-strand DNA breaks and eventual cell death.

1. Hodgkin’s and non-Hodgkin’s lymphoma.

2. Germ cell tumors.

3. Head and neck cancer.

4. Squamous cell carcinomas of the skin, cervix, and vulva.

5. Sclerosing agent for malignant pleural effusion and ascites.

Dosage Range

1. Hodgkin’s lymphoma–10 units/m 2 IV on days 1 and 15 every 28 days, as part of the ABVD regimen.

2. Testicular cancer–30 units IV on days 2, 9, and 16 every 21 days, as part of the PEB regimen.

3. Intracavitary instillation into pleural space–60 units/m 2 .

Toxicity:

1. Skin reactions are the most common side effects and include erythema, hyperpigmentation of the skin,
striae, and vesiculation. Skin peeling, thickening of the skin and nail beds, hyperkeratosis, and ulceration
can also occur. These manifestations usually occur in the second and third week aftertreatment, when
the cumulative dose has reached 150–200 units. Alopecia is common.
2. Pulmonary toxicity is dose-limiting. Occurs in 10% of patients. Usually presents as pneumonitis with
cough, dyspnea, dry inspiratory crackles, and infiltrates on chest X-ray. Increased incidence in patients .
70 years of age and with cumulative doses . 400 units. Rarely progresses to pulmonary fibrosis but can
be fatal in about 1% of patients. PFTs are the most sensitive approach to follow, with specific focus on
DLCO and vital capacity. A decrease of 15% or more in the PFTs should mandate immediate stoppage
of the drug.
3. Hypersensitivity reaction in the form of fever and chills observed in up to 25% of patients. True
anaphylactoid reactions are rare but more common inpatients with lymphoma.
4. Vascular events, including myocardial infarction, stroke, and Raynaud’s phenomenon, are rarely
reported.
5. Myelosuppression is relatively mild.
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DOXORUBICIN

Antitumor antibiotic

Mechanism of Action

• Anthracycline antibiotic isolated from Streptomyces species.

• Intercalates into DNA resulting in inhibition of DNA synthesis and function.

• Inhibits transcription through inhibition of DNA-dependent RNA polymerase.

• Inhibits topoisomerase II by forming a cleavable complex with DNA and topoisomerase II to create
uncompensated DNA helix torsional tension, leading to eventual DNA breaks.

• Formation of cytotoxic oxygen-free radicals results in single- and double-stranded DNA breaks with
subsequent inhibition of DNA synthesis and function.

Indications

1. Breast cancer.

2. Hodgkin’s and non-Hodgkin’s lymphoma.

3. Soft tissue sarcoma.

4. Ovarian cancer.

5. Non–small cell and small cell lung cancer.

6. Bladder cancer.

7. Thyroid cancer.

8. Hepatoma.

9. Gastric cancer.

10. Wilms’ tumor.

11. Neuroblastoma.

12. Acute lymphoblastic leukemia.

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Dosage Range

1. Single agent—60–75 mg/m 2 IV every 3 weeks.

2. Single agent—15–20 mg/m 2 IV weekly.

3. Combination therapy—45–60 mg/m 2 every 3 weeks.

4. Continuous infusion—60–90 mg/m 2 IV over 96 hours.

Special Considerations

1. Use with caution in patients with abnormal liver function. Dose reduction is required in the setting of liver
dysfunction.

2. Because doxorubicin is a strong vesicant, administer slowly with a rapidly flowing IV. Avoid using veins
over joints or in extremities with compromised venous and/or lymphatic drainage. Use of a central venous
catheter is recommended for patients with difficult venous access and mandatory for prolonged infusions.
Careful monitoring is necessary to avoid extravasation. If extravasation is suspected, immediately stop infusion,
withdraw fluid, elevate extremity, and apply ice to involved site. May administer local steroids. In severe cases,
consult a plastic surgeon.

3. Monitor cardiac function before (baseline) and periodically during therapy with either MUGA radionuclide
scan or echocardiogram to assess LVEF. Risk of cardiotoxicity is higher in patients . 70 years of age, in patients
with prior history of hypertension or pre-existing heart disease, in patients previously treated with
anthracyclines, or in patients with prior radiation therapy to the chest. Cumulative doses of . 450 mg/m 2 are
associated with increased risk for cardiotoxicity.

4. Risk of cardiotoxicity is decreased with weekly or continuous infusion schedules. Use of the iron-chelating
agent dexrazoxane (ICRF-187) also is effective at reducing the development of cardiotoxicity.

5. Use with caution in patients previously treated with radiation therapy as doxorubicin can cause radiation
recall skin reaction. Increased risk of skin toxicity when doxorubicin is given concurrently with radiation
therapy.

6. Patients should be cautioned to avoid sun exposure and to wear sun protection when outside.

7. Patients should be warned about the potential for red-orange discoloration of urine for 1–2 days after drug
administration.
 327

8. Pregnancy category D. Breastfeeding should be avoided.

Toxicity

1. Myelosuppression. Dose-limiting toxicity with leukopenia more common than thrombocytopenia or

anemia. Nadir usually occurs at days 10–14 with full recovery by day 21.
2. Nausea and vomiting. Usually mild, occurring in 50% of patients within the first 1–2 hours of treatment.
3. Mucositis and diarrhea. Common but not dose-limiting.
4. Cardiotoxicity. Acute form presents within the first 2–3 days as arrhythmias and/or conduction
abnormalities, EKG changes, pericarditis, and/or myocarditis. Usually transient and mostly
asymptomatic and not dose-related.
5. Chronic form results in a dose-dependent, dilated cardiomyopathy associated with congestive heart
failure. Risk increases when cumulative doses are greater than 450 mg/m 2 .
6. Strong vesicant. Extravasation can lead to tissue necrosis and chemical thrombophlebitis at the site of
injection.
7. Hyperpigmentation of nails, rarely skin rash, and urticaria. Radiation recall skin reaction can occur at
prior sites of irradiation. Increased hypersensitivity to sunlight.
8. Alopecia. Universal but usually reversible within 3 months after termination of treatment.
 328

DOXORUBICIN LIPOSOME

Antitumor antibiotic

Mechanism of Action

• Liposomal encapsulation of doxorubicin.

• Protected from chemical and enzymatic degradation, reduced plasma protein binding, and decreased uptake in
normal tissues.

• Penetrates tumor tissue into which doxorubicin is released.

• Intercalates into DNA resulting in inhibition of DNA synthesis and function.

• Inhibits transcription through inhibition of DNA-dependent RNA polymerase.

• Inhibits topoisomerase II by forming a cleavable complex with DNA and topoisomerase II. This creates
uncompensated DNA helix torsional tension, leading to eventual DNA breaks.

• Formation of cytotoxic oxygen-free radicals results in single- and double-stranded DNA breaks and
subsequent inhibition of DNA synthesis and function.

Indications

1. AIDS-related Kaposi’s sarcoma—Used in patients with disease that has progressed on prior combination
chemotherapy and/or in patients who are intolerant to such therapy.

2. Ovarian cancer—Metastatic disease refractory to both paclitaxel and platinum-based chemotherapy regimens.

3. Multiple myeloma—FDA-approved in combination with bortezomib in patients who have not previously
received bortezomib and who have received at least one prior therapy.

Dosage Range

1. Kaposi’s sarcoma—20 mg/m 2 IV every 21 days.

2. Ovarian cancer—50 mg/m 2 IV every 28 days.

3. Multiple myeloma—30 mg/m 2 IV on day 4 after bortezomib, which is administered at 1.3 mg/m 2 IV on
days 1, 4, 8, and 11 every 21 days.
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Toxicity 1

1. Myelosuppression. Dose-limiting toxicity with leukopenia more commonthan thrombocytopenia or

anemia. Nadir usually occurs at days 10–14, with full recovery by day 21.
2. Nausea and vomiting. Usually mild, occurring in 20% of patients.
3. Mucositis and diarrhea. Common but not dose-limiting.
4. Cardiotoxicity. Acute form presents within the first 2–3 days as arrhythmias and/or conduction
abnormalities, EKG changes, pericarditis, and/or myocarditis.
5. Usually transient and mostly asymptomatic, and not dose-related.
6. Chronic form results in a dose-dependent dilated cardiomyopathy associated with congestive heart
failure.
7. Skin toxicity manifested as the hand-foot syndrome with skin rash, swelling, erythema, pain, and/or
desquamation. Usually mild with onset at 5–6 weeks after the start of treatment. May require subsequent
dose reduction.
8. More commonly observed in ovarian cancer patients (37%) than in those with Kaposi’s sarcoma (5%).
9. Hyperpigmentation of nails, skin rash, and urticaria. Radiation recall skin reaction can occur at prior
sites of irradiation
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EPIRUBICIN

Antitumor antibiotic

Mechanism of Action

• Anthracycline derivative of doxorubicin. • Intercalates into DNA, which results in inhibition of DNA synthesis
and function. • Inhibits topoisomerase II by forming a cleavable complex with topoisomerase II and DNA.

• Formation of cytotoxic oxygen-free radicals, which can cause singleand double-stranded DNA breaks.

Indications

1. Breast cancer—FDA-approved as part of adjuvant therapy in women with axillary node involvement
following resection of primary breast cancer.

2. Metastatic breast cancer.

3. Gastric cancer—Active in the treatment of metastatic disease as well as early-stage disease.

Dosage Range

1. Usual dose is 100–120 mg/m 2 IV every 3 weeks. 2. In heavily pretreated patients, consider starting at lower
dose of 75–90 mg/m 2 IV every 3 weeks. 3. Alternative schedule is 12–25 mg/m 2 IV on a weekly basis.

Monitor cardiac function before (baseline) and periodically during therapy with either MUGA radionuclide scan
or echocardiogram to assess LVEF. Risk of cardiotoxicity is higher in elderly patients . 70 years of age, in
patients with prior history of hypertension or pre-existing heart disease, in patients previously treated with
anthracyclines, or in patients with prior radiation therapy to the chest. In patients with no prior history of
anthracycline therapy, cumulative doses of 900 mg/m 2 are associated with increased risk for cardiotoxicity.

Toxicity

1. Myelosuppression. Dose-limiting toxicity with leukopenia more common than thrombocytopenia. Nadir
typically occurs 8–14 days after treatment, with recovery of counts by day 21. Risk of myelosuppression
greater in elderly patients and in those previously treated with chemotherapy and/or radiation therapy.
2. Cardiotoxicity. Cardiac effects are similar to but less severe than those of doxorubicin. Acute toxicity
presents as rhythm or conduction disturbances, chest pain, and myopericarditis syndrome that typically
occurs within the first 24–48 hours of drug administration. Transient and mostly asymptomatic, not
dose-related.
 331

METHOTREXATE

Antimetabolite

Mechanism of Action

• Cell cycle–specific antifolate analog, active in S-phase of the cell cycle.

• Enters cells through specific transport systems mediated by the reduced folate carrier and the folate receptor
protein.

• Requires polyglutamation by the enzyme folylpolyglutamate synthase (FPGS) for its cytotoxic activity.

• Inhibition of dihydrofolate reductase (DHFR) resulting in depletion of critical reduced folates.

• Inhibition of de novo thymidylate synthesis.

• Inhibition of de novo purine synthesis.

• Incorporation of dUTP into DNA resulting in inhibition of DNA synthesis and function.

Indications

1. Breast cancer.

2. Head and neck cancer.

3. Osteogenic sarcoma.

4. Acute lymphoblastic leukemia.

5. Non-Hodgkin’s lymphoma.

6. Primary CNS lymphoma.

7. Meningeal leukemia and carcinomatous meningitis.

8. Bladder cancer.

9. Gestational trophoblastic cancer.

Dosage Range
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1. Low dose: 10–50 mg/m 2 IV every 3–4 weeks.

2. Low dose weekly: 25 mg/m 2 IV weekly.

3. Moderate dose: 100–500 m/m 2 IV every 2–3 weeks.

4. High dose: 1–12 gm/m 2 IV over a 3- to 24-hour period every 1–3 weeks.

5. Intrathecal: 10–15 mg IT two times weekly until CSF is clear, then weekly dose for 2–6 weeks, followed by
monthly dose.

6. Intramuscular: 25 mg/m 2 IM every 3 weeks.

Toxicity

 Myelosuppression is dose-limiting toxicity with leukocyte nadir at days 4–7 and recovery usually by day
14.
 Mucositis can be dose-limiting. Typical onset is 3–7 days after methotrexate therapy and precedes the
decrease in leukocyte and platelet count.
 Nausea and vomiting are dose-dependent.
 Acute renal failure, azotemia, urinary retention, and uric acid nephropathy.
 Renal toxicity results from the intratubular precipitation of methotrexate and its metabolites.
Methotrexate itself may exert a direct toxic effect on the renal tubules.
 Transient elevation in serum transaminases and bilirubin are often observed with high-dose therapy.
May occur within the first 12–24 hours after start of infusion and returns to normal within 10 days.
 Poorly defined pneumonitis characterized by fever, cough, and interstitial pulmonary infiltrates.
 Acute chemical arachnoiditis with headaches, nuchal rigidity, seizures, vomiting, fever, and an
inflammatory cell infiltrate in the CSF observed immediately after intrathecal administration. Chronic,
demyelinating encephalopathy observed in children months to years after intrathecal methotrexate and
presents as dementia, limb spasticity, and in advanced cases, coma.
 333

CAPECITABINE

Classification : Antimetabolite

Mechanism of Action

• Fluoropyrimidine carbamate prodrug form of 5-fluorouracil (5-FU). Capecitabine itself is inactive.

• Activation to cytotoxic forms is a complex process that involves three successive enzymatic steps.
Metabolized in liver to 5 9 -deoxy-5- fluorocytidine (5 9 -DFCR) by the carboxylesterase enzyme and then to 5
9 -deoxy-5-fluorouridine (5 9 -DFUR) by cytidine deaminase (found in liver and in tumor tissues).
Subsequently converted to 5-FU by the enzyme thymidine phosphorylase, which is expressed in higher levels in
tumor versus normal tissue.

• Inhibition of the target enzyme thymidylate synthase (TS) by the 5-FU metabolite FdUMP.

• Incorporation of 5-FU metabolite FUTP into RNA resulting in alterations in RNA processing and/or mRNA
translation.

• Incorporation of 5-FU metabolite FdUTP into DNA resulting in inhibition of DNA synthesis and function.

• Inhibition of TS leads to accumulation of dUMP and subsequent misincorporation of dUTP into DNA,
resulting in inhibition of DNA synthesis and function.

Indications

1. Metastatic breast cancer—FDA-approved when used in combination with docetaxel for the treatment of
patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.

2. Metastatic breast cancer—FDA-approved as monotherapy in patients refractory to both paclitaxel- and

anthracycline-based chemotherapy or when anthracycline therapy is contraindicated.

3. Metastatic colorectal cancer—FDA-approved as first-line therapy when fluoropyrimidine therapy alone is

preferred.

4. Stage III colon cancer—FDA-approved as adjuvant therapy when fluoropyrimidine therapy alone is
preferred.
 334

Dosage Range

1. Recommended dose is 1250 mg/m 2 PO bid (morning and evening) for 2 weeks with 1 week rest. For
combination therapy (capecitabine in combination with docetaxel) with docetaxel being dosed at 75 mg/m 2 day
1 of a 21-day cycle.

2. May decrease dose of capecitabine to 850–1000 mg/m 2 bid on days 1–14 to reduce risk of toxicity without
compromising efficacy

3. An alternative dosing schedule for capecitabine monotherapy is 1250–1500 mg/m 2 PO bid for 1 week on
and 1 week off. This schedule appears to be well tolerated, with no compromise in

clinical efficacy.

4. Capecitabine should be used at lower doses (850–1000 mg/m 2 bid on days 1–14) when used in combination
with other cytotoxic agents, such as oxaliplatin.

Toxicity:

 Diarrhea is dose-limiting, observed in up to 55% of patients. Similar to GI toxicity observed with

continuous infusion 5-FU. Mucositis, loss of appetite, dehydration also noted.
 Hand-foot syndrome (palmar-plantar erythrodysesthesia). Severe handfoot syndrome is seen in 15%–
20% of patients. Characterized by tingling, numbness, pain, erythema, dryness, rash, swelling, increased
pigmentation, and/or pruritus of the hands and feet. Similar to dermatologic toxicity observed with
continuous infusion 5-FU.
 Nausea and vomiting occur in 15%–53% of patients.
 Elevations in serum bilirubin (20%–40%), alkaline phosphatase, and hepatic transaminases (SGOT,
SGPT). Usually transient and clinically asymptomatic.
 Myelosuppression is observed less frequently than with IV 5-FU.
 Leukopenia more common than thrombocytopenia.
 Neurologic toxicity manifested by confusion, cerebellar ataxia, and rarely encephalopathy.
 Cardiac symptoms of chest pain, EKG changes, and serum enzyme elevation.
 Rare event but increased risk in patients with prior history of ischemic heart disease.
 335

BIOLOGIC RESPONSE MODIFIERS

Interferons Interferon α-2a, interferon α-2b
Interleukins Aldesleukin (interleukin 2), oprelvekin, denileukin
diftitox
Myeloid- and erythroid-stimulating factors Filgrastim , sargramostim , Epoetin,
Nonspecific immunomodulation Thalidomide, lenalidomide

INTERFERON- A:

Mechanism of Action

• Precise mechanism of antitumor action remains unknown.

• Direct antiproliferative effects on tumor cell mediated by: induction of 2 9 5 9 -oligoadenylate synthetase and
protein kinase leading to decreased translation and inhibition of tumor cell protein synthesis; induction of
differentiation; prolongation of the cell cycle; modulation of oncogene expression.

• Indirect induction of host antitumor mechanisms mediated by: induced activity of at least four immune
effector cells, including cytotoxic T cells, helper T cells, NK cells, and macrophages; enhancement of tumor
surface expression of critical antigens that are recognized by the immune system; inhibition of angiogenesis
through decreased expression of various angiogenic factors.

Indications

1. Malignant melanoma—Adjuvant therapy.

2. Chronic myelogenous leukemia—Chronic phase.

3. Hairy cell leukemia.

4. AIDS-related Kaposi’s sarcoma.

5. Cutaneous T-cell lymphoma.

6. Multiple myeloma.

7. Low-grade, non-Hodgkin’s lymphoma.

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8. Renal cell cancer.

9. Hemangioma.

Dosage Range

1. Chronic myelogenous leukemia: 9 million IU SC or IM daily.

2. Hairy cell leukemia: 3 million IU SC or IM daily for 16–24 weeks.

3. Malignant melanoma: 20 million IU/m 2 IV, 5 times weekly for 4 weeks, then 10 million IU/m 2 SC, three
times weekly for 48 weeks.

4. Malignant melanoma (Peginterferon- a 2b): 6 m g/kg/week SC for 8 doses followed by 3 m g/kg/week SC for
up to 5 years.

5. Kaposi’s sarcoma: 36 million IU SC or IM daily for 12 weeks.

Toxicity

1. Flu-like symptoms with fever, chills, headache, myalgias, and arthralgias. Occur in 80%–90% of
patients, usually beginning a few hours after the first injection and lasting for up to 8–9 hours. Incidence
decreases with subsequent injections. Can be controlled with acetaminophen and/or indomethacin.
2. Fatigue and anorexia are dose-limiting with chronic administration.
3. Somnolence, confusion, or depression. Patients . 65 years of age are more susceptible to the neurologic
sequelae of interferon- a .
4. Myelosuppression with mild leukopenia and thrombocytopenia. Reversible upon discontinuation of
therapy.
5. Mild, transient elevations in serum transaminases. Dose-dependent toxicity
6. observed more frequently in the presence of pre-existing liver abnormalities.
 337

ALDESLEUKIN

Mechanism of Action

• Glycoprotein cytokine that functions as a T-cell growth factor.

• Biologic effect of interleukin-2 (IL-2) is mediated by specific binding to the interleukin-2 receptor (IL-2R).

• Precise mechanism by which IL-2 mediates its anticancer activity remains unknown but appears to require an
intact immune system.

• Enhances lymphocyte mitogenesis and lymphocyte cytotoxicity.

• Induces lymphokine-activated (LAK) and natural killer (NK) cell activity.

• Induces interferon- g production.

Indications

1. Metastatic renal cell cancer.

2. Metastatic malignant melanoma.

Dosage Range

Renal cell cancer—600,000 IU/kg IV every 8 hours for a maximum of 14 doses. Following 9 days of rest, the
schedule is repeated for another 14 doses, for a maximum of 28 doses per course.

Toxicity

 Flu-like symptoms, including fever, chills, malaise, myalgias, and arthralgias. Observed in all patients.
 Vascular leak syndrome. Usual dose-limiting toxicity, characterized by weight gain, arrhythmias,
tachycardia, hypotension, edema, oliguria and renal insufficiency, pleural effusions, and pulmonary
congestion.
 Myelosuppression with anemia, thrombocytopenia, and neutropenia.
DENILEUKIN DIFTITOX:

Persistent or recurrent cutaneous T-cell lymphoma whose malignant cells express the CD25 component of the
IL-2 receptor.

Dosage Range : Recommended dose is 9 or 18 m g/kg/day IV on days 1–5 every 21 days.

 338

THALIDOMIDE

Immunomodulatory agent, anti-angiogenic agent

Mechanism of Action

• Mechanism of action is not fully characterized.

• Inhibition of TNF- a synthesis and down-modulation of selected cell surface adhesion molecules.

• May exert an anti-angiogenic effect through inhibition of basic FGF and VEGF as well as through as yet
undefined mechanisms.

Indications

1. FDA-approved in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma.

2. FDA-approved for the treatment of the cutaneous manifestations of erythema nodosum leprosum (ENL).

3. Thalidomide has activity in MDS and in a broad range of solid tumors.

Dosage Range

No standard dose recommendations for use in cancer patients have been established. When used in combination
with chemotherapy, doses are typically titrated up to 400 mg PO daily given as a single bedtime dose. As a
single agent, doses have been in the range of 100 mg to 1200 mg daily.

Toxicity

 Teratogenic effect is most serious toxicity. Severe birth defects or death to an unborn fetus. Manifested
as absent or defective limbs, hypoplasia or absence of bones, facial palsy, absent or small ears, absent or
shrunken eyes, congenital heart defects, and GI and renal abnormalities.
 General neurologic-related events that occur frequently include fatigue, orthostatic hypotension, and
dizziness. Specific peripheral neuropathy in the form of numbness, tingling, and pain in the feet or hands
does not appear to be dose- or duration-related. Prior exposure to neurotoxic agents increases the risk of
occurrence.
 Constipation is most common GI toxicity.
 No known direct myelosuppressive effects. Effects on blood cell counts may occur indirectly through its
effect on TNF- a or other cytokines that influence blood cell regulation, recruitment, and activation.
 339

Certain patient populations (ENL and HIV) have reported a higher incidence of abnormalities in blood
counts. Maculopapular skin rash, urticaria, and dry skin.
LENALIDOMIDE

Immunomodulatory analog of thalidomide, anti-angiogenic agent

Mechanism of Action

• Mechanism of action is not fully characterized.

• Immunomodulatory drug (IMid) that stimulates T-cell proliferation as well as IL-2 and IFN- g production.

• Inhibition of TNF- a and IL-6 synthesis and down modulation of cell surface adhesion molecules similar to
thalidomide.

• May exert anti-angiogenic effect by inhibition of basic fibroblast growth (bFBG) and vascular endothelial
growth factor (VEGF) and through as yet undefined mechanisms.

• Overcomes cellular drug resistance to thalidomide.

Indications

1. FDA-approved for the treatment of low- or intermediate-1-risk myelodysplastic

syndromes (MDS) associated with the deletion 5q (del 5q) cytogenetic

abnormality with or without additional cytogenetic abnormalities.

2. FDA-approved for the treatment of multiple myeloma in combination with dexamethasone for patients who
have received at least oneprior therapy.

3. FDA-approved for the treatment of mantle cell lymphoma whose disease has relapsed or progressed after two
prior therapies, one of which included bortezomib.

Dosage Range

1. Myelodysplastic syndrome: 10 mg PO daily.

2. Multiple myeloma: 25 mg PO daily on days 1–21 and 40 mg Decadron PO on days 1–4, 9–12, and 17–20 of
a 28-day cycle. An alternative regimen is to use 40 mg Decadron PO on days 1, 8, 15, and 22 of a 28-day cycle.

3. Mantle cell lymphoma: 25 mg PO daily on days 1–21 of a 28-day cycle.

 340

PRINCIPLES OF COMBINATION CHEMOTHERAPY

With rare exceptions (e.g., choriocarcinoma and Burkitt’s lymphoma), single drugs at clinically tolerable doses
have been unable to cure cancer.

In the 1960’s and early 1970’s, drug combination regimens were developed based on known biochemical
actions of available anticancer drugs rather than on their clinical efficacy. Such regimens were, however, largely
ineffective.

The era of combination chemotherapy really began when several active drugs from different classes became
available for use in combination in the treatment of the acute leukemias and lymphomas.

Following this initial success with hematologic malignancies, combination chemotherapy was extended to the
treatment of solid tumors.

Combination chemotherapy with conventional cytotoxic agents accomplishes several key objectives not
possible with single-agent therapy.

First, it provides maximal cell kill within the range of toxicity tolerated by the host for each drug as long as
dosing is not compromised.

Second, it provides a broader range of interaction between drugs and tumor cells with different genetic
abnormalities in a heterogeneous tumor population.

Finally, it may prevent and/or slow the subsequent development of cellular drug resistance.

First, only drugs known to be partially effective against the same tumor when used alone should be selected for
use in combination. If available, drugs that produce some fraction of complete remission are preferred to those
that produce only partial responses.

Second, when several drugs of a class are available and are equally effective, a drug should be selected on the
basis of toxicity that does not overlap with the toxicity of other drugs to be used in the combination. Although
such selection leads to a wider range of side effects, it minimizes the risk of a potentially lethal effect caused by
multiple insults to the same organ system by different drugs. Moreover, this approach allows dose intensity to
be maximized.

In addition, drugs should be used in their optimal dose and schedule, and drug combinations should be given at
consistent intervals. The treatment-free interval between cycles should be the shortest possible time necessary
for recovery of the most sensitive normal target tissue, which is usually the bone marrow.
 341

The biochemical, molecular, and pharmacokinetic mechanisms of interaction between the individual drugs in a
given combination should be understood to allow for maximal effect.

Finally, arbitrary reduction in the dose of an effective drug to allow for the addition of other less-effective drugs
may dramatically reduce the dose of the most effective agent below the threshold of effectiveness and destroy
the capacity of the combination to cure disease in a given patient.

One final issue relates to the optimal duration of chemotherapy drug administration. Several randomized trials
in the adjuvant treatment of breast and colorectal cancer have shown that short-course treatment on the order of
6 months is as effective as long-course therapy (12 months). Studies are currently ongoing to determine whether
3 months of adjuvant chemotherapy will yield the same level of clinical benefit as 6 months of treatment of
early-stage colon cancer.

However, optimal duration may be dependent upon the particular tumor type as it is now appreciated that
prolonged duration of adjuvant therapy in patients with surgically resected GIST results in improved clinical
benefit.
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TARGETED MOLECULAR THERAPY

Classification:

Signal transduction inhibitors: Angiogenesis inhibitors Receptor targeted therapy

 Tyrosin kinase inhibitors Anti-VEGF (Bevacizumab) Anti-HER2 : Trastuzumab

 Farnesyl transferase inhibitors  Thalidomide Anti-EGFR
 Cycline-dependent kinase  Interferon-α/β  Gefitinib
inhibitors  Marimastat  Erlotinib
 Retinoids  ZD5416, ZD6474  Cetuximab
 LY317615 (endothelin
inhibitor)
 Endostatin/angiostatin

Signaling pathways activated by the stimulation of the growth factor receptor

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Epidermal Growth Factor Receptor

 EGFR - ErbB family of transmembrane receptor tyrosine kinases

 EGFR Inhibitors – Gefitinib (Iressa) – Erlotinib (Tarceva)

 EGFR Monoclonal antibodies – Cetuximab (Erbitux)

 VEGF Monoclonal antibodies – Bevacizumab (Avastin)

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GEFITINIB

Mechanism of Action
• Potent and selective small molecule inhibitor of the EGFR tyrosine kinase, resulting in inhibition of
EGFR autophosphorylation and inhibition of EGFR signaling.

• Inhibition of the EGFR tyrosine kinase results in inhibition of critical mitogenic and anti-apoptotic
signals involved in proliferation, growth, metastasis, angiogenesis, and response to chemotherapy and/or
radiation therapy.

Indications
Treatment of NSCLC that is refractory to platinum-based chemotherapy
and/or second-line docetaxel therapy.
FDA-approved for patients who are currently receiving and benefiting or who have previously received
and benefited from gefitinib treatment.

Dosage Range
Recommended dose is 250 mg/day PO.

Toxicity
 Elevations in blood pressure, especially in those with underlying hypertension.
 Pruritus, dry skin with mainly a pustular, acneiform skin rash.
 Mild-to-moderate elevations in serum transaminases. Usually transient and clinically asymptomatic.
 Asthenia and anorexia.
 Mild nausea/vomiting and mucositis.
 Conjunctivitis, blepharitis, and corneal erosions. Abnormal eyelash growth may occur in some patients.
 Rare episodes of hemoptysis and GI hemorrhage.
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ERLOTINIB

Mechanism of Action

• Potent and selective small molecule inhibitor of the EGFR tyrosine kinase, resulting in inhibition of EGFR
autophosphorylation and inhibition of EGFR signaling.

• Inhibition of the EGFR tyrosine kinase results in inhibition of critical mitogenic and anti-apoptotic signals
involved in proliferation, growth, metastasis, angiogenesis, and response to chemotherapy and/or radiation
therapy.

• Active in the absence or presence of EGFR–activating mutations, although activity appears to be higher in
tumors that express EGFR– activating mutations.

Indications

1. FDA-approved as first -line treatment of metastatic non–small cell lung

cancer with EGFR exon 19 deletions or exon 21 (L858R) substitution

mutations.

2. FDA-approved as monotherapy for the treatment of locally advanced or metastatic non–small cell lung
cancer after failure of at least one prior chemotherapy regimen.

3. FDA-approved as maintenance treatment of patients with locally advanced or metastatic non–small cell lung
cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

4. FDA-approved in combination with gemcitabine for the first-line treatment of patients with locally advanced
unresectable or metastatic pancreatic cancer.

Dosage Range

1. Non–small cell lung cancer—Recommended dose is 150 mg/day PO.

2. Pancreatic cancer—Recommended dose is 100 mg/day PO in combination with gemcitabine.

Toxicity

1. Pruritus, dry skin with mainly a pustular, acneiform skin rash occurring most often on face and upper
trunk. Nail changes, paronychia, painful fissures or cracking of the skin on hands and feet, and hair
growth abnormalities, including alopecia, thinning hair with increased fragility (trichorrhexis),
darkening and increased thickness of eyelashes and eyebrows (trichomegaly), and hirsutism.
2. Diarrhea is most common GI toxicity. Mild nausea/vomiting and mucositis.
3. Pulmonary toxicity in the form of ILD manifested by increased cough, dyspnea, fever, and pulmonary
infiltrates. Observed in less than 1.1% of patients and more frequent in patients with underlying
pulmonary disease.
4. Mild-to-moderate elevations in serum transaminases. Usually transient and clinically asymptomatic.
 346

IMATINIB

Mechanism of Action

• Phenylaminopyrimidine methanesulfonate compound that occupies the ATP binding site of the BCR-ABL
protein and a very limited number of other tyrosine kinases. Binding in this ATP pocket results in subsequent
inhibition of substrate phosphorylation.

• Potent and selective inhibitor of the P210 BCR-ABL tyrosine kinase resulting in inhibition of clonogenicity
and tumorigenicity of BCR-ABL and Ph 1 cells.

• Induces apoptosis in BCR-ABL positive cells without causing cell differentiation.

• Inhibits other activated ABL tyrosine kinases, including P185 BCRABL, and inhibits other receptor tyrosine
kinases for platelet-derived growth factor receptor (PDGFR), stem cell factor (SCF), and c-Kit.

Indications

1. Chronic phase of CML—FDA-approved first-line therapy in adult patients.

2. Chronic phase of CML after failure on interferon- a therapy—FDAapproved.

3. CML in accelerated phase and/or in blast crisis—FDA-approved.

4. Newly diagnosed pediatric patients with Ph 1 acute lymphocytic leukemia (Ph 1 ALL)—FDA-approved.

5. Chronic phase Ph 1 CML in pediatric patients whose disease has recurred after stem cell transplant or is
resistant to interferon- a .

6. Myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with PDGFR gene rearrangements.

7. Hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL).

8. Relapsed/refractory adult Ph 1 ALL.

9. Gastrointestinal stromal tumors (GIST) expressing c-Kit (CD117)—Unresectable and/or metastatic disease.

Dosage Range

1. Recommended starting dose is 400 mg/day for patients in chronic phase CML and 600 mg/day for patients in
accelerated phase or blast crisis.

2. Recommended starting dose is 400 mg/day for patients with unresectable and/or metastatic GIST. Limited
data exist on the effect of dose increases from 400 mg to 600 mg or 800 mg in patients progressing at the lower
dose.

3. Recommended dose is 400 mg/day for 3 years of adjuvant therapy of patients with early-stage GIST.
 347

4. Recommended starting dose is 400 mg/day for patients with MDS/MPD.

5. Recommended starting dose is 400 mg/day for patients with HES/CEL.

6. Recommended starting dose is 600 mg/day for patients with Ph 1 ALL.

LAPATINIB

Mechanism of Action

• Potent small molecule inhibitor of the tyrosine kinases associated with epidermal growth factor receptor
(ErbB1; EGFR) and HER2 (ErbB2), resulting in inhibition of phosphorylation and downstream signaling.

• Inhibition of the EGFR and HER2 tyrosine kinases results in inhibition of critical mitogenic and anti-apoptotic
signals involved in proliferation, growth, invasion/metastasis, angiogenesis, and response to chemotherapy
and/or radiation therapy.

Indications

FDA-approved in combination with capecitabine for the treatment of patients with advanced or metastatic
breast cancer whose tumors overexpress HER2 and who have received prior therapy, including an
anthracycline, a taxane, and trastuzumab.

Dosage Range

Recommended dose is 1250 mg PO daily on days 1–21 continuously in combination with capecitabine 1000
mg/m 2 PO bid on days 1–14, with each cycle repeated every 21 days.

Toxicity

 Diarrhea is the most common dose-limiting toxicity and occurs in 65% of patients. Mild
nausea/vomiting may also occur.
 Cardiac toxicity with reduction in LVEF. QT prolongation observed rarely.
 Myelosuppression with anemia more common than thrombocytopenia or neutropenia.
 Fatigue and anorexia.
 Mild-to-moderate elevation of serum transaminases and serum bilirubin.
 Hand-foot syndrome (palmar-plantar erythrodysesthesia) and skin rash.
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SORAFENIB

Mechanism of Action

• Inhibits multiple receptor tyrosine kinases (RTKs), some of which are involved in tumor growth, tumor
angiogenesis, and metastasis.

• Potent inhibitor of intracellular kinases, including c-Raf and wildtype and mutant B-Raf.

• Targets vascular endothelial growth factor receptors, VEGF-R2 and VEGF-R3, and platelet-derived growth
factor receptor- b (PDGFR- b ), and in so doing, inhibits angiogenesis.

Indications

1. FDA-approved for the treatment of advanced renal cell cancer.

2. FDA-approved for the treatment of unresectable hepatocellular cancer (HCC).

Dosage Range

Recommended dose is 400 mg PO bid. Dose may need to be reduced in Asian patients, as they experience
increased toxicity to sorafenib.

1. Hypertension usually occurs within 6 weeks of starting therapy and well-controlled with oral
antihypertensive medication.
2. Skin rash. Hand-foot skin reaction occurs in up to 30%. Rare cases of actinic keratoses and cutaneous
squamous cell cancer have been reported.
3. Bleeding complications with epistaxis most commonly observed.
4. Wound healing complications.
5. Constitutional side effects with fatigue and asthenia.
6. Diarrhea and nausea are the most common GI side effects.
7. Hypophosphatemia occurs in up to 45% of patients, but usually clinically asymptomatic.
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SUNITINIB

Mechanism of Action

• Inhibits multiple RTKs, some of which are involved in tumor growth, tumor angiogenesis, and metastasis.

• Potent inhibitor of platelet-derived growth factor receptors (PDGFR- a and PDGFR- b ), vascular endothelial
growth factor receptors (VEGF-R1, VEGF-R2, and VEGF-R3), stem cell factor receptor (KIT), Fms-like
tyrosine kinase-3 (FLT3), colony-stimulating factor receptor type 1 (CSF-1R), and the glial cell-line derived
neurotrophic factor receptor (RET).

Indications

1. FDA-approved for GIST after disease progression on or intolerance to imatinib.

2. FDA-approved for advanced renal cell cancer.

3. FDA-approved for progressive, well-differentiated pancreatic neuroendocrine tumors (PNET) in patients with
unresectable locally advanced or metastatic disease.

Dosage Range

GIST and RCC: Recommended dose is 50 mg/day PO for 4 weeks followed by 2 weeks off.

PNET: Recommended dose is 37.5 mg/day PO continuously.

Toxicity

1. Hypertension occurs in up to nearly 30% of patients. Usually occurs within 3–4 weeks of starting
therapy and well-controlled with oral antihypertensive medication.
2. Yellowish discoloration of the skin occurs in approximately 30% of patients.
3. Skin rash, dryness, thickness, and/or cracking of skin. Depigmentation of hair and/or skin may also
occur.
4. Bleeding complications with epistaxis most commonly observed.
5. Constitutional side effects with fatigue and asthenia, which may be significant in some patients.
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PAZOPANIB

Mechanism of Action

• Oral multikinase inhibitor of angiogenesis.

• Inhibits vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived
growth factor receptor (PDGFR)- a and PDGFR– b , fibroblast growth factor receptor (FGFR)-1 and FGFR-3,
c-Kit, interleukin-2 receptor inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and
transmembrane glycoprotein receptor tyrosine kinase (c-Fms).

Indications

1. FDA-approved for the treatment of advanced renal cell carcinoma.

2. FDA-approved for the treatment of advanced soft tissue sarcoma (STS) following treatment with prior
chemotherapy. The efficacy of pazaponib has not been docmented in adipocytic STS or GIST.

Dosage Range

Recommended dose is 800 mg PO once daily without food at least 1 hour before or 2 hours after a meal.

Toxicity

1. Hypertension occurs in nearly 50% of patients. Usually occurs within the first 18 weeks of therapy and
is well controlled with oral antihypertensive medications.
2. Diarrhea, nausea/vomiting, and abdominal pain are the most common
3. GI side effects. Elevations in serum lipase have been observed in up to 30% of patients. Increased risk of
GI fistulas and/or perforations.
4. Fatigue, asthenia, and anorexia may be significant in some patients.
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MONOCLONAL ANTIBODIES

RITUXIMAB

Monoclonal antibody, Biologic response modifier agent

Mechanism of Action

• Chimeric anti-CD20 antibody consisting of human IgG1-k constant regions and variable regions from the murine
monoclonal anti-CD20 antibody.

• Targets the CD20 antigen, a 35 kD cell surface nonglycosylated phosphoprotein expressed during early pre–B cell
development until the plasma cell stage. Binding of antibodies to CD20 results in inhibition CD20-mediated signaling that
leads to inhibition of cell activation and cell cycle progression.

• CD20 is expressed on more than 90% of all B-cell non-Hodgkin’s lymphomas and leukemias.

• CD20 is not expressed on early pre–B cells, plasma cells, normal bone marrow stem cells, antigen-presenting dendritic
reticulum cells, or other normal tissues.

• Chimeric antibody mediates complement-dependent cell lysis (CDC) in the presence of human complement and
antibody-dependent cellular cytotoxicity (ADCC) with human effector cells.

Indications

1. Relapsed and/or refractory low-grade or follicular, CD20 1 , B-cell non-Hodgkin’s lymphoma.

2. Intermediate- and/or high-grade, CD20 1 , B-cell non-Hodgkin’s lymphoma—Used as a single agent or in combination
with anthracycline-based chemotherapy regimens such as EPOCH or CHOP.

3. FDA-approved for first-line treatment of patients with low-grade or follicular CD20-positive, B-cell non-Hodgkin’s
lymphoma in combination with CVP chemotherapy or after CVP chemotherapy.

4. FDA-approved in combination with fludarabine and cyclophosphamide for the treatment of previously untreated and
previously treated patients with CLL.

Dosage Range

 Recommended dose is 375 mg/m 2 IV on a weekly schedule for 4 or 8 weeks.

Toxicity:

 Infusion-related symptoms, including fever, chills, urticaria, flushing, fatigue, headache, bronchospasm, rhinitis,
dyspnea, angioedema, nausea, and/or hypotension. Usually occur within 30 minutes to 2 hours after the start of
the first infusion. Usually resolves upon slowing or interrupting the infusion and with supportive care. Incidence
decreases with subsequent infusion.
 Tumor lysis syndrome. Characterized by hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and
renal insufficiency. Usually occurs within the first 12–24 hours of treatment. Risk is increased in patients with
high numbers of circulating malignant cells ( . 25,000/mm 3 ) and/or high tumor burden.
 Skin reactions, including pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, and toxic epidermal
neurolysis. Usual onset ranges from 1 to 13 weeks following drug treatment.
 Arrhythmias and chest pain, usually occurring during drug infusion. Increased risk in patients with pre-existing
cardiac disease.
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TRASTUZUMAB

Monoclonal antibody , Biologic response modifier agent

Mechanism of Action

• Recombinant humanized monoclonal antibody directed against the extracellular domain of the HER2/neu growth factor
receptor. This receptor is overexpressed in several human cancers, including 25%–30% of breast cancers and up to 20%
of gastric cancers.

• Precise mechanism(s) of action remains unknown.

• Downregulates expression of HER2/neu receptor.

• Inhibits HER2/neu intracellular signaling pathways.

• Induction of apoptosis through as yet undetermined mechanisms.

• Immunologic mechanisms may also be involved in antitumor activity, and they include recruitment of antibody-
dependent cellular cytotoxicity (ADCC) and/or complement-mediated cell lysis.

Indications

1. Metastatic breast cancer—First-line therapy in combination with paclitaxel. Patient’s tumor must express HER2/neu
protein to be treated with this monoclonal antibody.

2. Metastatic breast cancer—Second- and third-line therapy as a single agent in patients whose tumors overexpress the
HER2/neu protein.

3. Early-stage breast cancer—FDA-approved for the adjuvant therapy of node-positive, HER2-overexpressing breast
cancer as part of a treatment regimen containing doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel.

4. Metastatic gastric and gastroesophageal junction adenocarcinoma— FDA-approved in combination with cisplatin and
capecitabine or 5-fluorouracil for the treatment of patients with HER2 overexpressing metastatic gastric or
gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease.

Dosage Range

1. Recommended loading dose of 4 mg/kg IV administered over 90 minutes, followed by maintenance dose of 2 mg/kg IV
on a weekly basis. One week following the last weekly dose of Herceptin, administer Herceptin at 6 mg/kg as an
intravenous infusion over 30–90 minutes every three weeks.

2. Alternative schedule is to give a loading dose of 8 mg/kg IV administered over 30–90 minutes, followed by
maintenance dose of 6 mg/kg IV every 3 weeks.

3. Administer Herceptin, alone or in combination with paclitaxel, at an initial dose of 4 mg/kg as a 90 minute intravenous
infusion followed by subsequent once weekly doses of 2 mg/kg as 30 minute intravenous infusions until disease
progression.

4. Administer Herceptin at an initial dose of 8 mg/kg as a 90 minute intravenous infusion followed by subsequent doses of
6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks until disease progression.
 353

Toxicity

1. Infusion-related symptoms with fever, chills, urticaria, flushing, fatigue, headache, bronchospasm, dyspnea,
angioedema, and hypotension. Occur in 40%–50% of patients. Usually mild to moderate in severity and observed
most commonly with administration of the first infusion.
2. Nausea and vomiting, diarrhea. Generally mild.
3. Cardiotoxicity in the form of dyspnea, peripheral edema, and reduced left ventricular function. Significantly
increased risk when used in combination with an anthracycline-based regimen. In most instances, cardiac
dysfunction is readily reversible.
4. Myelosuppression. Increased risk and severity when trastuzumab is administered with chemotherapy.
5. Generalized pain, asthenia, and headache.
6. Pulmonary toxicity in the form of increased cough, dyspnea, rhinitis, sinusitis, pulmonary infiltrates, and/or
pleural effusions
ADO-TRASTUZUMAB EMTANSINE:

Antibody-drug conjugate, Biologic response modifier agent/chemotherapy drug

Mechanism of Action

• HER2-targeted antibody-drug conjugate that is made up of trastuzumab and the small molecule microtubule
inhibitor DM1.

• Upon binding to the HER2 receptor, ado-trastuzumab emtansine undergoes receptor-mediated internalization
and lysosomal degradation, leading to intracellular release of the DM1 molecule.

• Binding of DM1 to tubulin leads to disruption of the microtubule network, resulting in cell cycle arrest and
apoptosis.

• Inhibits HER2 downstream signaling pathways.

• Immunologic-mediated mechanisms, such as antibody-dependent cell-mediated cytotoxicity (ADCC), may

also be involved in antitumor activity.

Administered only via the intravenous (IV) route.

Dosage Rang : Recommended dose is 3.6 mg/kg IV every 3 weeks.

Indications Toxicity
1. FDA-approved for patients with HER2-positive Cardiac toxicity in the form of cardiomyopathy.
metastatic breast cancer who have received prior Infusion-related reactions.
treatment with trastuzumab and a taxane chemotherapy. Hepatotoxicity with transient elevations in LFTs.
2. Patients should already have been treated for their Severe drug-induced liver injury and hepatic
metastatic breast cancer or have had their early-stage encephalopathy have been reported rarely. Rare cases
disease recur during or within 6 months after completion of nodular regenerative hyperplasia of the liver have also
of adjuvant therapy. been reported.

BEVACIZUMAB
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Classification

Monoclonal antibody, anti–VEGF antibody

Category

Biologic response modifier agent

Mechanism of Action

• Recombinant humanized monoclonal antibody directed against the vascular endothelial growth factor
(VEGF).

Binds to all isoforms of VEGF-A. VEGF is a pro-angiogenic growth factor that is overexpressed in a wide
range of solid human cancers, including colorectal cancer.

• Precise mechanism(s) of action remains unknown.

• Binding of VEGF prevents its subsequent interaction with VEGFRreceptors on the surface of endothelial cells
and tumors, and in so doing, results in inhibition of VEGFR-signaling.

• Inhibits formation of new blood vessels in primary tumor and metastatic tumors.

• Inhibits tumor blood vessel permeability and reduces interstitial tumoral pressures, and in so doing, may
enhance blood flow delivery within tumor.

• Restores antitumor response by enhancing dendritic cell function.

• Immunologic mechanisms may also be involved in antitumor activity, and they include recruitment of ADCC
and/or complementmediated cell lysis.

Uses :

1. Metastatic colorectal cancer—FDA-approved for use in combination with any intravenous 5-fluorouracil (5-
FU)–based chemotherapy in first-line therapy.

2. Metastatic colorectal cancer—FDA-approved for use in the second –line setting in combination with
fluoropyrimidine-based chemotherapy after progression on first-line treatment that includes bevacizumab.

3. Non–small cell lung cancer—FDA-approved for nonsquamous, NSCLC in combination with

carboplatin/paclitaxel.

4. Glioblastoma—FDA-approved as a single agent for glioblastoma with progressive disease following prior
therapy.

5. Renal cell cancer—FDA-approved in combination with interferon- a for metastatic renal cell cancer.
 355

Dosage Range

1. Recommended dose for the first-line treatment of advanced colorectal cancer is 5 mg/kg IV in combination
with intravenous 5-FU– based chemotherapy on an every 2-week schedule.

2. Recommended dose for the second-line treatment of advanced colorectal cancer in combination with
FOLFOX-4 is 10 mg/kg IV on an every 2-week schedule.

3. Can also be administered at 7.5 mg/kg IV every 3 weeks when used in combination with capecitabine-based
regimens for advanced colorectal cancer.

4. Recommended dose for advanced NSCLC is 15 mg/kg IV every 3 weeks with carboplatin/paclitaxel.

5. Recommended dose for glioblastoma is 10 mg/kg IV every 2 weeks.

6. Recommended dose for renal cell cancer is 10 mg/kg IV every 2 weeks with interferon alfa.

Toxicity

1. Gastrointestinal perforations and wound healing complications.

2. Bleeding complications with epistaxis being most commonly observed.
3. Serious life-threatening pulmonary hemorrhage occurs in rare cases in patients with NSCLC as outlined
previously in Special Considerations.
4. Increased risk of arterial thromboembolic events, including myocardial infarction, angina, and stroke.
There is also an increased incidence of venous thromboembolic events.
5. Hypertension occurs in 5–18%. Usually well controlled with oral antihypertensive medication.
6. Proteinuria with nephrotic syndrome ,1%.
7. Infusion-related symptoms with fever, chills, urticaria, flushing, fatigue, headache, bronchospasm,
dyspnea, angioedema, and hypotension. Infusion reactions occur in ,3% of patients and severe reactions
occur in 0.2% of patients.
 356

BRENTUXIMAB:

Monoclonal antibody, Biologic response modifier agent

Mechanism of Action

• Brentuximab is a CD30-directed antibody-drug conjugate (ADC) that is made up of three components: (1)
chimeric IgG1 antibody cAC10, specific for CD30; (2) microtubule-disrupting agent monomethyl auristatin E
(MMAE); and (3) protease-cleavable linker that covalently attaches MMAE to cAC10. Approximately four
molecules of MMAE are conjugated to each antibody molecule.

• Targets the CD30 antigen, a cell surface protein expressed on the surface of Hodgkin’s Reed-Sternberg cells
and on anaplastic largecell lymphomas (ALCLs), embryonal carcinomas, and select subtypes of B-cell–derived,
non-Hodgkin’s lymphomas and mature T-cell lymphomas. Normal expression of CD30 is highly restricted to a
relatively small population of activated B cells and T cells and a small portion of eosinophils.

• Binding of the ADC to CD30-expressing cells is followed by internalization of the ADC-CD30 complex with
subsequent release of MMAE via proteolytic cleavage.

• MMAE inhibits the microtubule network within the tumor cell, resulting in cell cycle arrest at the G2/M
interphase and apoptotic death.

• Chimeric antibody mediates complement-dependent cell lysis (CDCC) in the presence of human complement
and antibody-dependent cellular cytotoxicity (ADCC) with human effector cells.

Indications

1. FDA-approved for patients with Hodgkin’s lymphoma after failure of autologous stem cell transplant
(ASCT) or after failure of at least two prior multiagent chemotherapy regimens in patients who are not ASCT
candidates.

2. FDA-approved for patients with anaplastic large cell lymphoma after failure of at least one prior multiagent
chemotherapy regimen.

Dosage Range :Recommended dose is 1.8 mg/kg IV every 3 weeks.

Toxicity

1. Infusion-related symptoms, including fever, chills, urticaria, flushing, fatigue, headache, bronchospasm,
rhinitis, dyspnea, angioedema, nausea, and/or hypotension.
2. Tumor lysis syndrome. Characterized by hyperkalemia, hyperuricemia,
3. hyperphosphatemia, hypocalcemia, and renal insufficiency. Usually occurs within the first 12–24 hours
of treatment. Risk is increased in patients with high numbers of circulating malignant cells ( .
25,000/mm 3 ) and/or high tumor burden.
4. Myelosuppression with neutropenia and anemia being most commonly observed.
5. Peripheral sensory neuropathy is the most common neurologic side effect.
6. Progressive multifocal leukoencephalopathy (PML).
7. Skin reactions, including rash, pruritus, and Stevens-Johnson syndrome.
 357

8. Mild nausea/vomiting and diarrhea are the most common GI side effects.
CETUXIMAB

Monoclonal antibody, anti–EGFR antibody, Biologic response modifier agent

Mechanism of Action

• Recombinant chimeric IgG1 monoclonal antibody directed against the epidermal growth factor receptor
(EGFR). EGFR is overexpressed in a broad range of human solid tumors, including colorectal cancer, head and
neck cancer, non–small cell lung cancer, pancreatic cancer, and breast cancer.

• Precise mechanism(s) of action remains unknown.

• Binds with nearly 10-fold higher affinity to EGFR than normal ligands EGF and TGF- a , which then results in
inhibition of EGFR.

Prevents both homodimerization and heterodimerization of the EGFR, which leads to inhibition of
autophosphorylation and inhibition of EGFR signaling.

• Inhibition of the EGFR signaling pathway results in inhibition of critical mitogenic and anti-apoptotic signals
involved in proliferation, growth, invasion/metastasis, and angiogenesis.

• Inhibition of the EGFR pathway enhances the response to chemotherapy and/or radiation therapy.

• Immunologic mechanisms may also be involved in antitumor activity, and they include recruitment of ADCC
and/or complement-mediated cell lysis.

Indications

1. FDA-approved for the treatment of EGFR-expressing mCRC in combination with irinotecan in irinotecan-
refractory disease or as monotherapy in patients who are deemed to be irinotecan-intolerant. The use of
cetuximab is not recommended for the treatment of mCRC with KRAS mutations.

2. Approved in Europe in combination with cytotoxic chemotherapy in the front-line treatment of wild-type
KRAS mCRC. FDA-approved in combination with FOLFIRI in the front-line treatment of wild-type KRAS
mCRC.

3. Head and neck cancer—FDA-approved for use in combination with radiation therapy for the treatment of
locally or regionally advanced squamous cell cancer of the head and neck.

4. Head and neck cancer—FDA-approved for use in combination with platinum-based therapy with 5-FU for
the treatment of recurrent locoregional disease or metastatic squamous cell cancer of the head and neck.

5. Head and neck cancer—FDA-approved as monotherapy for the treatment of recurrent or metastatic squamous
cell cancer of the head and neck progressing after platinum-based therapy.

Dosage Range

1. Loading dose of 400 mg/m 2 IV administered over 120 minutes, followed by maintenance dose of 250 mg/m
2 IV given on a weekly basis.
 358

2. An alternative dosing schedule is 500 mg/m 2 IV every 2 weeks with no need for a loading dose.

Toxicity

1. Infusion-related symptoms with fever, chills, urticaria, flushing, fatigue, headache, bronchospasm,
dyspnea, angioedema, and hypotension. Occurs in 40%–50% of patients, although severe reactions
occur in less than 1%.
2. Usually mild-to-moderate in severity and observed most commonly withadministration of the first
infusion.
3. Pruritus, dry skin with mainly a pustular, acneiform skin rash. Presents mainly on the face and upper
trunk. Improves with continued treatment and resolves upon cessation of therapy.
4. Pulmonary toxicity in the form of interstitial lung disease (ILD) manifested by increased cough,
dyspnea, and pulmonary infiltrates. Observed in less than 1% of patients and more frequent in patients
with underlying pulmonary disease.
5. Hypomagnesemia.
6. Asthenia and generalized malaise observed in nearly 50% of patients.
7. Paronychial inflammation with swelling of the lateral nail folds of the toes and fingers. Occurs with
prolonged use.
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RADIOIMMUNOTHERAPY

Tositumomab

Monoclonal antibody, Biologic response modifier agent

Mechanism of Action

• Radioimmunotherapeutic monoclonal antibody-based regimen composed of the tositumomab monoclonal

antibody and the radiolabeled monoclonal antibody I-131 tositumomab, a radioiodinated derivative of
tositumomab that has been covalently linked to I-131.

• The antibody moiety is tositumomab, which targets the CD20 antigen, a 35 kDa cell surface
nonglycosylated phosphoprotein expressed during early pre–B cell development until the plasma cell stage.
Binding of the antibody to CD20 induces a transmembrane signal that blocks cell activation and cell cycle
progression.

• CD20 is expressed on more than 90% of all B-cell non-Hodgkin’s lymphomas and leukemias. CD20 is not
expressed on early pre–B cells, plasma cells, normal bone marrow stem cells, antigen-presenting

dendritic reticulum cells, or other normal tissues.

• Ionizing radiation from the I-131 radioisotope results in cell death.

Absorption

Tositumomab is given only by the IV route.

Indications

Relapsed and/or refractory CD20-positive, follicular non-Hodgkin’s lymphoma with and without
transformation—disease is refractory to rituximab therapy and has relapsed following chemotherapy.

Dosage Range

Treatment schema is as follows: Day 0, Begin Lugol’s solution or oral potassium iodide solution; Day 1,
Dosimetric dose: 450 mg unlabeled tositumomab, followed by 5 mCi of I-131 tositumomab (35 mg).
Measurement of whole body counts and calculation of therapeutic dose; Day 7 up to Day 14,

Therapeutic dose: 450 mg unlabeled tositumomab, followed by calculated therapeutic dose of I-131
tositumomab to deliver 75 cGy; Days 8–21, Continue Lugol’s solution or oral potassium iodide solution.

Toxicity

1. Infusion-related symptoms, including fever, chills, urticaria, flushing, fatigue, headache,

bronchospasm, rhinitis, dyspnea, angioedema, nausea, and/or hypotension. Usually resolve upon
slowing and/or interrupting the infusion and with supportive care.
2. Myelosuppression is most common side effect with neutropenia, thrombocytopenia
 360

IBRITUMOMAB

Mechanism of Action

• Immunoconjugate consisting of a stable thiourea covalent bond between the monoclonal antibody
ibritumomab and the linker-chelator tiuxetan. This linker-chelator provides a high-affinity,
conformationally-restricted site for indium-111 and/or yttrium-90.

• The antibody moiety is ibritumomab, which targets the CD20 antigen, a 35 kDa cell surface
nonglycosylated phosphoprotein expressed during early pre–B-cell development until the plasma cell stage.
Binding of antibodies to CD20 induces a transmembrane signal that blocks cell activation and cell cycle
progression.

• CD20 is expressed on more than 90% of all B-cell non-Hodgkin’s lymphomas and leukemias. CD20 is not
expressed on early pre–B cells, plasma cells, normal bone marrow stem cells, antigen-presenting dendritic
reticulum cells, or other normal tissues.

• The beta emission from yttrium-90 induces cellular damage by the formation of free radicals in the target
and neighboring cells.

Indications

1. FDA-approved for relapsed and/or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s
lymphoma, including patients refractory to rituximab therapy.

2. FDA-approved for patients with previously untreated follicular NHL who achieve either a PR or CR to
first-line chemotherapy.

Dosage Range

The regimen consists of two low doses of rituximab, an imaging dose, two or three whole body scans, and a
therapeutic dose, all of which are delivered on an outpatient basis over a period of 8 days. The
recommended dose is 0.4 mCi/kg for patients with platelet counts greater than 150,000 and 0.3 mCi/kg for
patients with platelet counts between 100,000 and 149,000. In either case, the maximum dose is 32 mCi.

Toxicity:

1. Infusion-related symptoms, including fever, chills, urticaria, flushing, fatigue, headache,

bronchospasm, rhinitis, dyspnea, angioedema, nausea, and/or hypotension. Severe symptoms include
pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular
fibrillation, and/or cardiogenic shock. Usually occur within 30 minutes to 2 hours after the start of
the first infusion. Usually resolve upon slowing or interrupting the infusion and with supportive care.
2. Myelosuppression is the most common side effect. Thrombocytopenia is observed more frequently
than neutropenia. The median duration of cytopenias ranges from 22 to 35 days, and the median time
to nadir is 7–9 weeks. In , 5% of patients, severe cytopenias remained beyond 12 weeks after
therapy.
 361

Ipilimumab FDA-approved for the treatment of unresectable or Recommended dose is 3 mg/kg IV

metastatic malignant over 90 minutes every 3 weeks for a
melanoma. total of four doses.

Ofatumumab 1. Refractory CLL—FDA-approved for CLL that is refractory Recommended dose and schedule is
to fludarabine 12 doses administered as follows:
and alemtuzumab. • 300 mg initial dose (dose 1),
2. Relapsed and/or refractory follicular, CD20 1 , B-cell non- followed 1 week later by
Hodgkin’s • 2000 mg weekly for seven doses
lymphoma. (doses 2 through 8), followed
3. Intermediate- and/or high-grade, CD20 1 , B-cell non- 4 weeks later by
Hodgkin’s • 2000 mg every 4 weeks for 4 doses
lymphoma. (doses 9 through 12)

Panitumumab Indications 1. Recommended dose for the

1. FDA-approved as monotherapy for the treatment of treatment of mCRC is 6 mg/kg IV on
advanced colorectal cancer following fluoropyrimidine-, an
oxaliplatin-, and irinotecan-containing regimens. Use of every 2-week schedule.
panitumumab is not recommended in mutant KRAS mCRC. 2. An alternative schedule is 2.5
2. Approved in Europe as monotherapy for advanced, mg/kg IV every week.
refractory disease in wild-type KRAS CRC.
3. Used in combination with cytotoxic chemotherapy in the
front- and second-line treatment of wild-type KRAS mCRC.
Pertuzumab Indications Recommended initial dose is 840 mg
1. FDA-approved in combination with trastuzumab and IV administered over 60 minutes,
docetaxel for followed by a maintenance dose of
patients with HER2-positive metastatic breast cancer who 420 mg over 30–60 minutes every
have 3 weeks.
not received prior anti-HER2 thereapy or chemotherapy for
metastatic disease.
2. Patients must express HER2/neu protein to be treated
with this
monoclonal antibody.
Alemtuzumab Indications Dosage Range
1. Relapsed and/or refractory B-cell chronic lymphocytic Recommended dose is 30 mg/day IV
leukemia three times per week for a maximum
(B-CLL)—Indicated in patients who have been treated with of 12 weeks.
alkylating
agents and who have failed fludarabine therapy.
2. T-cell prolymphocytic leukemia—Clinical activity in
patients who
failed first-line therapy.
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MONOCLONAL ANTIBODIES (MAB)

• are antibodies that are identical because they were produced by one type of immune cell, all clones of a
single parent cell.

Nomeclature of Monoclonal Antibodies

• Variable

• Target Stem : Where it acts?

tumour – tu

Bacteria – ba

Virus - vi

• Source Stem : From where it is prepared?

Mouse – o

Human - u

Humanised – zu

Chimeric - xi

• Stem – Additional words

Pegelated - pega
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Naked Monoclonal Antibodies:

 Examples : Rituximab , Trastuzumab, Bevacizumab

Mechanism of Action :

 Antibody dependent cellular cytotoxicity (ADCC)

 ADEPT (Antibody mediated Enzyme prodrug therapy)

Radio-immunotherapy:

 By conjugating a radioactive isotope to a murine antibody, targeted immunotherapy is possible.

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Why Monoclonal Antibodies?

1)Homogeneity

2) Specificity

3) Immunizing Antigen

4) Selection

5) Antibody Production

Problems with monoclonal therapy:

 HAMA(human anti-mouse antibodies).

 Cross Reaction

 These not only causes rapid elimination from the host,but also form immune complexes that causes
damage to kidneys.

 Two approaches are used to reduce the problem:

Chimeric antibodies

Humanised antibodies

**********
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ANAPHYLACTIC SHOCK

• Anaphylaxis is a severe, life-threatening, generalised or systemic hypersensitivity reaction.

• Nearly all of the available chemotherapeutic agents can produce hypersensitivity reactions (HSRs) in at
least an occasional patient, and some cause reactions in 5% or more of patients receiving the drug.

• There are multiple agents [l-asparaginase, taxanes, procarbazine, epipodophyllotoxins, and monoclonal
antibodies (MAbs)] for which HSRs are frequent enough to be a major form of treatment-limiting
toxicity.
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Classification of Teratogenic Potential and Use in Pregnancy for Chemotherapy Agents

Pregnancy Category A. Controlled studies show no risk in pregnancy.

Controlled studies in pregnant women have not shown an increased risk of fetal abnormalities when the drug is
administered during pregnancy. The possibility of fetal harm appears remote when the drug is used during
pregnancy.

Pregnancy Category B. No evidence of risk in pregnancy.

(a) Controlled studies in animals have shown that the drug poses a risk to the fetus. However, studies in
pregnant women have failed to show such a risk.

(b) Controlled studies in animals do not show evidence of impaired fertility or harm to the fetus. However,
similar studies have not been performed in humans. Because animal studies are not entirely predictive of human
response, the drug should be used during pregnancy only if clearly needed.

Pregnancy Category C. Risk in pregnancy cannot be ruled out.

Controlled studies either have not been conducted in animals or show that the drug is teratogenic or has an
embryocidal effect and/or other adverse effect in animals. However, there are no adequate and well-controlled
studies in pregnant women. The drug should be used during pregnancy only if the potential benefi t justifi es the
potential risk to the fetus. The drug can cause fetal harm when administered to a pregnant woman. If the drug is
used during pregnancy, or if a patient becomes pregnant while taking this drug, the patient should be informed
of the potential hazard to the fetus. However, the potential benefi ts of treatment may outweigh any potential
risk.

Pregnancy Category D. Clear evidence of risk in pregnancy.

The drug can cause fetal harm when administered to a pregnant woman. If the drug is used during pregnancy, or
if a patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to
the fetus. However, the potential benefi ts of treatment may outweigh any potential risk.

Pregnancy Category X. Absolutely contraindicated in pregnancy.

The drug has been shown to cause fetal harm when administered to a pregnant woman. The drug is absolutely
contraindicated in women who are or who may become pregnant. If this drug is used during pregnancy or if a
patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to the
fetus. In this setting, the potential risk outweighs any potential benefit from treatment.
 371

COMMON ANTIEMETIC REGIMENS FOR CHEMOTHERAPYINDUCED

NAUSEA AND VOMITING:
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EXTRAVASATION

 Extravasation is an infiltration or leakage of a CT agent into the local tissues outside the vessel wall
 Symptoms of an extravasation can be immediate or progressive or subtle.
 Often the problem begins with pain or burning at the IV site, progressing to edema, superficial skin loss,
and tissue necrosis.
 Necrosis may not develop for 1-4 weeks after extravasation.

Degree of injury from an extravasation depends on:

 whether drug is a vesicant or irritant
 drug concentration
 amount of drug extravasated
 duration of tissue exposure
 site of venipuncture
 devise and technique used for access
 individual responses

Dealing with extravasation:

 Immediately stop injection & withdraw drug

 Remove canula
 Some give antidote through the canula
 Dilution: hyaluronidase / saline
 Neutralize & reduce inflammation: steroid
 Apply hot or cold packs
 Elevate limb
 Analgesic / anti-inflammatory
 Blistering / breakdown: Plastic surgery
 374

BCG IMMUNOTHERAPY

Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, is currently the only agent
approved by the US Food and Drug Administration for primary therapy of carcinoma in situ (CIS; see image
below) of the bladder.

BCG supplanted cystectomy as the treatment of choice for CIS in the mid-1980s.

BCG therapy also reduces the risk of recurrence, and ongoing maintenance therapy with BCG reduces the risk
of progression in patients with high-grade non–muscle invasive bladder cancer.

For BCG to be effective, all the following criteria should be met:

The patient is immunocompetent

The tumor burden is small
BCG makes direct contact with the tumor
The dose is adequate to incite a reaction

Dosage Forms & Strengths

intravesical solution 1-8 x 10&sup8; CFU/vial

Carcinoma in Situ (CIS) of the Urinary Bladder

Tice BCG: 1 vial of Tice BCG suspended in preservative-free saline 50 mL instilled into bladder by gravity
flow via catheter; agent should be retained in bladder 2 hr and then voided
Papillary Tumors

Indicated for prophylaxis of primary or recurrent stage Ta and/or T1 papillary tumors following transurethral
resection (TUR)

Limitations: BCG live is not recommended for stage TaG1 papillary tumors, unless they are judged to be at
high risk of tumor recurrence

Tice BCG: 1 vial of Tice BCG suspended in preservative-free saline 50 mL instilled into bladder by gravity
flow via catheter; agent should be retained in bladder 2 hr and then voided
 375

METRONOMIC CHEMOTHERAPY

Metronomic chemotherapy exerts both direct and indirect effects on tumor cells and their microenvironment. It
can inhibit tumor angiogenesis, stimulate anticancer immune response and also induces tumor dormancy.

1. Anti-angiogenic properties

Metronomic chemotherapy exerts its anti-cancer activity mainly by inhibiting tumor angiogenesis. Metronomic
protocol of drug administration has been proved to increase the anti-angiogenic properties of some
chemotherapeutic drugs in-vitro significantly, such as CPA and taxanes.

2. Activation of immunity

3. Induction of tumor dormancy

4. Induction of senescence

5. Four-dimensional effect
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WHAT IS INTRAPERITONEAL (IP) CHEMOTHERAPY?

Intraperitoneal is described as the space within the peritoneum. The peritoneum is the membrane (thin tissue)
that lines the abdominal cavity and surrounds your abdominal organs. Chemotherapy can be administered
directly into this space to treat cancers of the abdominal region such as gastric (stomach), appendiceal
(appendix) and ovarian.

There are two types of IP chemotherapy.

The first type is infused through a port in the abdomen and is administered in either the hospital or an outpatient
(clinic) setting.

The second type, referred to as Hyperthermic Intraperitoneal Chemotherapy (HIPEC), is administered in the
operating room after a surgery to debulk tumor tissue. The chemotherapy is warmed and infused directly into
the intraperitoneal cavity.

Benefits of Intraperitoneal Chemotherapy

 Chemotherapy is administered in a way that allows it to directly affect the cancer cells, which studies
have shown can improve survival in certain types and stages of cancer.
 Potentially fewer side effects in other areas of the body.
 A higher dose of chemotherapy can be safely administered than can be prescribed for intravenous use.
 Treatment using HIPEC may require only one round of chemotherapy, which is completed in the
operating room.
Risks of IP Chemotherapy
 Side effects can include: nausea, vomiting, electrolyte imbalance, abdominal pain and kidney injury.
Some patients will experience low blood counts (called myelosuppression), which may be caused by the
IP chemotherapy or IV chemotherapy given in conjunction with IP.
 Other side effects are possible based on the type of chemotherapy you are receiving. Your doctor or
nurse will discuss the potential side effects related to the medications you will be receiving.
 The need to lie flat for a prolonged period of time may be difficult for some.
 Issues with your port including infection, pain and inability to infuse the chemotherapy due to kinking of
the catheter.
 Penetration of chemotherapy directly into tumor is limited, so tumor must be debulked to less than 1cm
in size.
 Metastasis beyond the peritoneal cavity may not be affected by IP chemotherapy due to minimal
absorption into the blood stream.

Hyperthermic Intraperitoneal Chemotherapy

During surgery to debulk a tumor, cancer cells may be left behind in the abdomen. HIPEC is administered to
directly kill these cells after surgery.
The chemotherapy is warmed because it is thought that heat helps break down and eliminate cancer cells more
effectively.
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After your surgeon has removed as much of the tumor as they can, warmed chemotherapy will be infused into
the peritoneal cavity.
The chemotherapy runs through a machine to warm it and fills the peritoneal cavity. The chemotherapy is then
manually dispersed (moved around) by a physician using his or her hands, or by manipulating the patient's
position.
The goal is for the entire abdominal cavity to be uniformly exposed to the heated chemotherapy. If there are any
complications, such as bleeding or the patient becomes unstable, the chemotherapy is suctioned out of the
peritoneal cavity and the patient is treated for the complication. The chemotherapy is manipulated for about 90
minutes.
Then the chemotherapy remains in the peritoneal cavity and the surgical wound is closed. The chemotherapy is
slowly absorbed into the peritoneal cavity (abdominal cavity), with about 90% being absorbed within 4 hours.
 378

CHEMOTHERAPY-INDUCED ACRAL ERYTHEMA

Chemotherapy-induced acral erythema (also known as palmar-plantar erythrodysesthesia, palmoplantar

erythrodysesthesia, or hand-foot syndrome) is reddening, swelling, numbness and desquamation (skin
sloughing or peeling) on palms of the hands and soles of the feet (and, occasionally, on the knees, elbows, and
elsewhere) that can occur after chemotherapy in patients with cancer.

Hand-foot syndrome is also rarely seen in sickle-cell disease.

These skin changes usually are well demarcated. Acral erythema typically disappears within a few weeks after
discontinuation of the offending drug.

Signs and symptoms:

1. The symptoms can occur anywhere between days to months after administration of the offending
medication, depending on the dose and speed of administration.

2. The patient first experiences tingling and/or numbness of the palms and soles that evolves into painful,
symmetric, and well-demarcated swelling and red plaques.

3. This is followed by peeling of the skin and resolution of the symptoms.

Causes:

Acral erythema is a common adverse reaction to cytotoxic chemotherapy drugs,
particularly cabozantinib, cytarabine, doxorubicin, and fluorouracil and its prodrug capecitabine.

 Targeted cancer therapies, especially the tyrosine kinase inhibitors sorafenib and sunitinib, have also
been associated with a high incidence of acral erythema.

 However, acral erythema due to tyrosine kinase inhibitors seems to differ somewhat from acral
erythema due to classic chemotherapy drugs

PATHOGENESIS:

The cause of PPE is unknown. Existing hypotheses are based on the fact that only the hands and feet are
involved and posit the role of temperature differences, vascular anatomy, differences in the types of cells
(rapidly dividing epidermal cells and eccrine glands).

In the case of PPE caused by PLD, the following mechanism has been demonstrated: sweat deposits and spreads
the drug on the skin surface; then the drug penetrates into the stratum corneum like an external agent; palms and
soles have high density of sweat glands, and their stratum corneum is approximately 10 times thicker than the
rest of the body, and becomes an efficient long-term reservoir for the penetrating PLD, which was deposited on
the skin before
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TREATMENT:

The main treatment for acral erythema is discontinuation of the offending drug, and symptomatic treatment to
provide analgesia, lessen edema, and prevent superinfection.

However, the treatment for the underlying cancer of the patient must not be neglected. Often, the discontinued
drug can be substituted with another cancer drug or cancer treatment.

Symptomatic treatment can include wound care, elevation, and pain medication.
Corticosteroids and pyridoxine have also been used to relieve symptoms.

Other studies do not support the conclusion. A number of additional remedies are listed in recent medical
literature
 380

TUMOR LYSIS SYNDROME

 Tumor lysis syndrome (TLS) is a group of metabolic abnormalities that can occur as
a complication during the treatment of cancer, where large amounts of tumorcells are killed off (lysed)
at the same time by the treatment, releasing their contents into the bloodstream.

 This occurs most commonly after the treatment of lymphomasand leukemias.

 In oncology and hematology, this is a potentially fatal complication, and patients at increased risk for
TLS should be closely monitored before, during, and after their course of chemotherapy.

 Tumor lysis syndrome is characterized by high blood potassium (hyperkalemia), high blood phosphate
(hyperphosphatemia), low blood calcium (hypocalcemia), high blood uric acid (hyperuricemia), and
higher than normal levels of blood urea nitrogen (BUN) and other nitrogen-containing compounds
(azotemia).

 These changes in blood electrolytes and metabolites are a result of the release of cellular contents of
dying cells into the bloodstream from breakdown of cells.

 In this respect, TLS is analogous to rhabdomyolysis, with comparable mechanism and blood chemistry
effects but with different cause.

 In TLS, the breakdown occurs aftercytotoxic therapy or from cancers with high cell turnover and tumor
proliferation rates.

 The metabolic abnormalities seen in tumor lysis syndrome can ultimately result in nausea and vomiting,
but more seriously acute uric acid nephropathy, acute kidney failure, seizures, cardiac arrhythmias, and
death.

SIGNS AND SYMPTOMS

 Hyperkalemia. Potassium is mainly an intracellular ion. High turnover of tumor cells leads to spill of
potassium into the blood. Symptoms usually do not manifest until levels are high (> 7 mmol/L) [normal 3.5-
5.0 mmol/L] and they include
 cardiac conduction abnormalities (can be fatal)
 severe muscle weakness or paralysis
 Hyperphosphatemia. Like potassium, phosphates are also predominantly intracellular. Hyperphosphatemia
causes acute kidney failure in tumor lysis syndrome, because of deposition of calcium phosphatecrystals in
the kidney parenchyma.
 Hypocalcemia. Because of the hyperphosphatemia, calcium is precipitated to form calcium phosphate,
leading to hypocalcemia. Symptoms of hypocalcemia include (but are not limited to):
 tetany
 sudden mental incapacity, including emotional lability
 Parkinsonian (extrapyramidal) movement disorders
 papilledema
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 myopathy
 Hyperuricemia and hyperuricosuria. Massive cell death and nuclear breakdown generates large quantities
of nucleic acids. Of these, the purines (adenine and guanine) are converted to uric acid via the purine
degradation pathway and excreted in the urine. However, at the high concentrations of uric acid generated
by tumor lysis, uric acid is apt to precipitate as monosodium urate crystals.
Acute uric acid nephropathy (AUAN) due to hyperuricosuria has been a dominant cause of acute kidney failure
but with the advent of effective treatments for hyperuricosuria, AUAN has become a less common cause than
hyperphosphatemia. Two common conditions related to excess uric acid, gout and uric acid nephrolithiasis, are
not features of tumor lysis syndrome.

 Lactic acidosis.
 Pretreatment spontaneous tumor lysis syndrome. This entity is associated with acute kidney failure due
to uric acid nephropathy prior to the institution of chemotherapy and is largely associated with lymphoma
and leukemia. The important distinction between this syndrome and the post-chemotherapy syndrome is
that spontaneous TLS is not associated with hyperphosphatemia. One suggestion for the reason of this is
that the high cell turnover rate leads to high uric acid levels through nucleobase turnover but the tumor
reuses the released phosphate for growth of new tumor cells. In post-chemotherapy TLS, tumor cells are
destroyed and no new tumor cells are being synthesized

Risk factors for tumor lysis syndrome

 Tumor Characteristics: Tumors with a high cell turnover rate, rapid growth rate, and high tumor bulk
tend to be more associated with the development of tumor lysis syndrome. The most common tumors
associated with this syndrome are poorly differentiated lymphomas (such as Burkitt's lymphoma),
other Non-Hodgkin Lymphomas (NHL), acute lymphoblastic leukemia (ALL), acute myeloid
leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous
leukemia (CML). Other cancers (such as melanoma) have also been associated with TLS but are less
common.
 Patient Characteristics: Certain patient-related factors can affect the development of clinical tumor
lysis syndrome. These factors include elevated baseline serum creatinine, renal insufficiency,
dehydration, and other issues affecting urinary flow or the acidity of urine.
 Chemotherapy Characteristics: Chemo-sensitive tumors, such as lymphomas, carry a higher risk for
the development of tumor lysis syndrome. Those tumors that are more responsive to a chemotherapy
agent carry a higher TLS risk. Usually, the precipitating medication regimen includes
combination chemotherapy, but TLS can be triggered in cancer patients by steroid treatment alone, and
sometimes without any treatment—in this case the condition is referred to as "spontaneous tumor lysis
syndrome"
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Cairo-Bishop definition
In 2004, Cairo and Bishop defined a classification system for tumor lysis syndrome.

 Laboratory tumor lysis syndrome: abnormality in two or more of the following, occurring within three
days before or seven days after chemotherapy.
 uric acid > 8 mg/dL or 25% increase
 potassium > 6 meq/L or 25% increase
 phosphate > 4.5 mg/dL or 25% increase
 calcium < 7 mg/dL or 25% decrease
 Clinical tumor lysis syndrome: laboratory tumor lysis syndrome plus one or more of the following:
 increased serum creatinine (1.5 times upper limit of normal)
 cardiac arrhythmia or sudden death
 seizure

A grading scale (0-5) is used depending on the presence of lab TLS, serum creatinine, arrhythmias, or seizures.
Howard Definition
In 2011, Howard proposed a refinement of the standard Cairo-Bishop definition of TLS accounting for 2
limitations:

 Two or more electrolyte laboratory abnormalities must be present simultaneously to be considered related to
TLS. In fact, some patients may present with one abnormality, but later another one may develop that is
unrelated to the TLS (e.g., hypocalcemia associated with sepsis).
 A 25% change from baseline should not be considered a criterion since such increases are rarely clinically
important unless the value is already outside the normal range.
Moreover, any symptomatic hypocalcemia should constitute clinical TLS
Treatment is first targeted at the specific metabolic disorder.
Acute kidney failure prior to chemotherapy. Since the major cause of acute kidney failure in this setting is
uric acid build-up, therapy consists of rasburicase to wash out excessive uric acid crystals as well as aloop
diuretic and fluids. Sodium bicarbonate should not be given at this time. If the patient does not
respond, hemodialysis may be instituted, which is very efficient in removing uric acid, with plasma uric acid
levels falling about 50% with each six-hour treatment.
Acute kidney failure after chemotherapy. The major cause of acute kidney failure in this setting is
hyperphosphatemia, and the main therapeutic means is hemodialysis. Forms of hemodialysis used include
continuous arteriovenous hemodialysis (CAVHD), continuous venovenous hemofiltration (CVVH), or
continuous venovenous hemodialysis (CVVHD).
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PREVENTION
People about to receive chemotherapy for a cancer with a high cell turnover rate, especially lymphomas and
leukemias, should receive prophylactic oral or IV allopurinol (a xanthine oxidase inhibitor, which inhibits uric
acid production) as well as adequate IV hydration to maintain high urine output (> 2.5 L/day). Allopurinol
mechanically blocks rasburicase's operation to solubilize.
Rasburicase is an alternative to allopurinol and is reserved for people who are high-risk in developing TLS. It is
a synthetic urate oxidase enzyme and acts by degrading uric acid. However, it's not clear if it results in any
important benefits as of 2014.
Alkalization of the urine with acetazolamide or sodium bicarbonate is controversial. Routine alkalization of
urine above pH of 7.0 is not recommended. Alkalization is also not required if uricase is used.[
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FEBRILE NEUTROPENIA

NCCN Definition:

Fever: Fever is defined as a single oral temperature of 38.3ºc or higher, or 38.0ºc or higher over 1 hr in the
absence of an obvious cause.

Neutropenia: An absolute neutrophil count(ANC) < 500 cells/µl, or an ANC < 1000 cells/µl and a predicted
decline to 500 /µl or less over the next 48 hrs.

Duration of Neutropenia:
Low risk = <7 days
Intermediate risk= 7 – 14 days
High risk= >14 days

Initial evaluation of fever & neutropenia:

 Complete site specific history & physical examination: intervenous access devices, skin, lungs &
sinus, alimentary canal, perirectal/ perivaginal, urological & neurological

 Suplimentary historical information: co-morbid illness, time since last chemo, h/o prior documented
inf, recent antibiotic administration, medications & exposures

 Laboratory/radiological assessments:
 Complete Blood Count (including differential)
 Serum Biochemistry
 Microbiology
 Blood cultures (peripheral and all central line)
 Oral ulcers or sores – send swabs ( Viral Cx and fungal Cx )
 Exit site swabs
 Wound swabs
 Urine Cultures (Foley Catheter)
 Stool Cultures for [Link] assay & enteric patho.
 Viral diagnostics (PCR & DFA based tests)
 Radiology
 Chest Xray(baseline)
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CANCER VACCINES

INTRODUCTION:

 A cancer vaccine is a vaccine that treats existing cancer or prevents the development of cancer in certain
high-risk individuals.

 The aim of cancer vaccines is to stimulate the immune system to be able to recognise cancer cells as
abnormal and destroy them.

 In 1891, Dr. William Coley made the first attempt to stimulate the immune system for improving a
cancer patient's condition by intratumoral injections of inactivated Streptococcus pyogenes and Serratia
marcescens (Coley's Toxin).

IMMUNOTHERAPY:

 Immunotherapy is treatment that uses your body's own immune system to help fight cancer.

 Considered by many to be the “fourth modality of cancer treatment” after chemotherapy, radiation, and
surgery.

 Based on utilizing the patient’s immune system to fight the cancer.

 Cancer vaccines fall under this category of treatment.

CANCER VACCINES:

 Cancer vaccines are medicines that belong to a class of substances known as Biological response
modifiers. Biological response modifiers work by stimulating or restoring the immune system’s ability
to fight infections and disease.

 Two broad types of cancer vaccines:

•Preventive (or prophylactic) vaccines

•Treatment (or therapeutic) vaccines

TYPES OF CANCER VACCINES:

1. TUMOR CELL VACCINE

2. ANTIGEN VACCINE
 390

3. ANTI-IDIOTYPE VACCINE

4. DENDRITIC CELL VACCINE

5. DNA VACCINE

TUMOR CELL VACCINE:

2 types : Autologous and Allogenic

 Autologous tumor vaccines are prepared using patient-derived tumor cells whereas allogenic uses the
tumor cells of another patient.

 The cells are altered (and killed) in the lab to make them more likely to be attacked by the immune
system and then injected back into the patient.

 One major advantage of whole tumor cell vaccines is its potential to present the entire spectrum of
tumor-associated antigens to the patient's immune system.

 However, preparation of autologous tumor cell vaccines requires sufficient tumor specimen, which
limits this technology to only certain tumor types or stages.

ANTIGEN VACCINE:

 These use tumor-specific antigens - proteins displayed on a tumor cell - to stimulate the immune system.

 By injecting these antigens into the cancerous area of the patient, the immune system will produce an
increased amount of antibodies or cytotoxic T lymphocytes, also known as killer T cells, to attack cancer
cells that carry that specific antigen.

 Multiple antigens can be used in this type of vaccine to vary the immune system response.

ANTI-IDIOTYPE VACCINE:

 Based on the idea that antibodies can also act as antigens triggering an immune response.

 This idea would be used to create a vaccine in which the antibodies (which resemble the cancer cells)
would be injected into the cancer patient eliciting an immune response.

 Primary target is LYMPHOMA

Dendritic Cell Vaccines:

 These cells are one of the most potent antigen presenting cells and it breaks the antigens on the cancer
cell surfaces into smaller pieces.
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 The dendritic cells then act as most-wanted posters for the immune system, displaying those antigen
pieces to the killer T cells.

 In order to make dendritic cell vaccines some of the patient's dendritic cells are extracted and immune
cell stimulants are used to reproduce large amounts of dendritic cells in the lab.

 These dendritic cells are then exposed to antigens from the patient's cancer cells.

 This combination of dendritic cells and antigens is then injected into the patient and the dendritic cells
work to program the T cells.

DNA Vaccines:

 Bits of DNA from the patient's cells are injected into the patient, which instructs the other cells to
continuously produce certain antigens.

 The idea of these vaccines is that the body would be provided with a constant supply of antigens to
allow the immune response to continue against the cancer

CANCERS IN WHICH VACCINES ARE STUDIED:

 Brain tumors (especially glioblastoma)

 Breast cancer

 Cervical cancer

 Colorectal cancer

 Kidney cancer

 Lung cancer

 Lymphoma

 Melanoma

 Pancreas cancer

 Prostate cancer
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PREVENTIVE VACCINES

Only two are FDA approved

1. HPV VACCINE

2. HEPATITIS B VACCINE

HPV VACCINE

 Available vaccines protect against HPV are either Bivalent, Quadrivalent or Ninevalent respectively.

1. GARDASIL : 6, 11, 16, 18 ( FDA approved – June,2006)

2. CERVARIX : 16,18 (FDA approved – Oct 2009)

3. GARDASIL 9 : 6, 11, 16, 18, 31, 33, 45, 52, 58

(FDA approved – Dec 2014)

 According to Centers for Disease Control and Prevention (CDC) Guidelines and Advisory Committee
on Immunization Practices (ACIP) November 4,2016.

 HPV vaccination is not currently recommended for women over age 26 years.
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 For women over age 26 years, the best way to prevent cervical cancer is to get routine cervical cancer
screening, as recommended.

 In October 2016, the FDA approved a 2-dose schedule for boys and girls initiating vaccination with
Gardasil 9 at ages 9 to 14 years (the second dose is to be administered 6–12 months after the first)

Hepatitis b vaccine:

 Chronic HBV infection can lead to liver cancer.

 The FDA has approved multiple vaccines that protect against HBV infection.

 Two vaccines, Engerix-B and Recombivax HB are approved for use in individuals of all ages.

 Twinrix protects against Hep B and Hep A virus.

 The original HBV vaccine was approved by the FDA in 1981, making it the first cancer preventive
vaccine to be successfully developed and marketed.
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THERAPEUTIC VACCINES:

Sipuleucel-T (PROVENGE)

 First FDA approved cancer treatment vaccine in April, 2010

 Dendritic cell vaccine approved for treatment of asymptomatic or minimally symptomatic metastatic
castrate-resistant (hormone refractory) prostate cancer which increased the survival by only 4 months.

 Target -prostatic acid phosphatase (PAP), which is found in 95% of prostate cancers.

 Note: The three-course treatment will cost $93,000.

DOSAGE AND ADMINISTRATION

 For intravenous use only.

 Administer 3 doses at approximately 2-week intervals.

 Premedicate patients with oral acetaminophen and an antihistamine 30 mins prior to avoid infusion
reaction.

 Infuse intravenously over 60 minutes.

 The most common adverse reactions (incidence ≥ 15%) are chills, fatigue, fever, back pain, nausea, joint
ache and headache.

Cancer Vaccines Which Are Currently under Clinical Trials::

 Onyvax: (a monoclonal antibody 105AD7 anti-idiotype vaccine)

- Advanced colorectal adenocarcinoma.

 OncoVAX

- Autologous vaccine for Stage II colon cancer.

 NY-ESO-1 Peptide Vaccine

- Soft tissue Sarcoma

 A Monoclonal Antibody 11D10Anti-idiotype Vaccine and Monoclonal Antibody 3h1

AntiidiotypeVaccine

- stage II or IIIA non-small cell lung cancer (T1-3, N1-2, M0).

 Cancer VAX

- used together with the surgical treatment in the treatment of melanoma III stage.
 395

Side Effects of Cancer Vaccine:

 Inflammation at the site of injection, including redness, pain, swelling, warming of the skin, itchiness
and occasionally a rash.

 People sometimes experience flu-like symptoms after receiving a cancer vaccine, including fever, chills,
weakness, dizziness, nausea or vomiting, muscle ache, fatigue, headache and occasional breathing
difficulties.

 These side effects, which usually last for only a short time, indicate that the body is responding to the
vaccine and making an immune response, as it does when exposed to a virus.

CONCLUSION:

 Effective, safe and enduring cancer treatments constitute major challenges of medical sciences, with
therapeutic cancer vaccines emerging as attractive approaches for provoking long-lasting protective
antitumor immunity.

 Improving our understanding of the basic biology underlying how immune system cells and cancer cells
interact will be very important for developing cancer vaccines.

 Clinically not yet at our fingertips and more research still needs to be done including larger studies.

 Researchers are actively trying to overcome hurdles in the making of these vaccines.

 Most importantly these vaccines could mean better quality of life and longer survival for our patients!!
 396

GENE THERAPY

• an experimental technique for correcting defective genes that are responsible for disease development.

• The material to be transferred into patient cells may be

• genes,

• gene segments,

• oligonucleotides.

Basic process:

• Identification of the gene, duplication of the gene, insertion of the gene into human genome.

• Gene in question  isolated by attatching molecular marker to the gene  removed by restriction
enzyme PCR amplification  insertion into the cell

Target Cells:

• Target cells may be normal cells, cancerous cells, immune mediated cells, or pleuripotent stem cells.

• Once the transgene enters a cancer cell, it can then assist in its death or restore normal cellular functions.

• For normal cells, the transgene can protect them from drug-induced toxicities, or activate an immune
cell to get rid of the cancer cell.

Functional Classification:

• Base on the purpose of gene therapy it can be-

 Gene replacement therapy

 Gene deactivation therapy

 Transgenesis

 Gene Enhancement therapy

 Gene activation therapy

Methods of gene transfer

• Physical methods

• Chemical methods

• Bacterial mediated

• Viral mediated
 397

How to introduce the genes:

• Ex vivo

• In vivo

• In vitro

What are Vectors and why are they needed ?

• Vectors are needed since the genetic material has to be transferred across the cell membrane and
preferably in to the cell nucleus.

• Different carrier systems are used for gene delivery-

1) Viral systems
 398

2) Non viral systems

Viral Vectors:

• Virus bind to their hosts and introduce their genetic material into the host cell.

• Plausible strategy for gene therapy, by removing the viral DNA and using the virus as a vehicle to
deliver the therapeutic DNA.

• The viruses used are altered to make them safe, although some risks still exist with gene therapy.

• Retroviruses

• Adeno viruses

• Adeno associated viruses

• Herpes simplex viruses

What are non viral systems?

• 1) Uncovered plasmids (naked DNA plasmids, im) OR pure DNA constructs

• 2) Plasmid liposome complex

• 4) Gene gun methods

• 5) Electroporation(malignant melanoma, prostate cancer, colorectal cancer, and leukemia)

• 6) Microinjections.

Gene Gun:

• Employs a high-pressure delivery system to shoot tissue with gold or tungsten particles that are coated
with DNA

Microinjection:

• Process of using a glass micropipette to insert microscopic substances into a single living cell.

• Normally performed under a specialized optical microscope setup called a micromanipulator

EFFECT:

 EFFECT:

 SILENCING,

 DOWN-REGULATION,

 MODIFICATION, OR
 399

 REPAIR OF THE TARGET CELL GENES.

 OUTCOME:

 SUICIDE GENE

 GENE SILENCING

 GENE MODIFICATION

 GENE REPAIR

FDA APPROVED GENE THERAPY:

• Chimeric antigen receptor T- cell therapy (tisagenlecluecel): FDA : August 2017

• T cell based immunotherapy

• Extraction of own T- cell  Mixed with disarmed virus with specific receptors (Chimeric antigen
receptor) identified by CD 19 and others  multiplication of the cells

• Leukemia

• YESCARTA (axicabtagene ciloleucel) OCTOBER 19,2017, LYMPHOMA

***********
 400

STEM CELL THERAPY

 Stem cell biology is a relatively new field that explores the characteristics & possible clinical application
of the different types of pluripotential cells that serve as the progenitors of more differentiated cell types,
and attempts to change the course of various chronic diseases thro’ the help of regeneration of
tissues/organ

 Stem cell defined as a cell with a unique capacity to produce unaltered daughter cells (self-renewal) &
to generate specialized cell types (potency)

Types of Stem cell :

Embryonic stem cells

Adult stem cells

Indications for SCT

Neoplastic disorders

 Hematological malignancies

 Lymphomas (Hodgkin and non-Hodgkin)

 Leukemias (acute and chronic)

 Multiple myeloma

 MDS

 Solid tumors

Non-neoplastic disorders

 Aplastic anemia

 Autoimmune diseases

 Immunodeficiency

 Inborn errors of metabolism

 Thalassemia
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Sources of HSC

a) Bone marrow

b) Peripheral Blood

c) Cord Blood

- in utero

- ex utero

d) foetal liver

Types of stem cell sources :

Autologous : from the patients themselves

Syngeneic : from an identical twin

Allogeneic : from another person

- HLA-matched related donor

- HLA-matched unrelated donor – from donor registry

 Choice of graft is based on disease type, patient condition, donor compatibility and health

Conditioning regimens :

 Prior to transfusion of hematopoietic progenitor cells, pts treated with chemotherapy and/or radiation
therapy

 This is called as conditioning therapy or preparative therapy

 Purposes : 1) to overcome the drug resistance of the tumour cells → eradication of malignant disease

2) to suppress recipient’s immune system → ↓ chance of GVHD

Types of conditioning regimens :

 Myeloablative

 Non- myeloablative

Pre-transplant investigations :

 HLA-matching:

class I HLA-A,HLA-B,HLA-C, HLA-DR, HLA-DQB1

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class II HA-I, HA-2, HA-8, H-Y

 ABO/ Rh grouping

 Transmissible diseases

 Nucleated cell count

 CD34 count

After care :

Pt should be cared in single room with laminar air flow, or high efficiency particulate air infiltration

Prophylactic antibacterial , antifungal, antiviral administration

Revaccinations, particularly allogeneic SCT (12 months)

All cellular blood products should be irradiated (using 25Gy) prior to administration (prevent transfusion related
GVHD)– 6 weeks prior to transplant and 6 months after transplant (autograft), or indefinite (allograft)

Establish central venous line

Prevention of acute GVHD :

Mtx + cyclosporine

T cell depletion

Treatment :

Corticosteroids (methylpred or pred)

Antithymocyte globulin (ATG)

 403

CLINICAL TRIALS IN CANCER RESEARCH

Introduction:

• Clinical research is necessary to establish the safety and effectiveness of specific health & medical
products and practices

• Randomized controlled trials form the foundation for evidence-based medicine

• Must follow the Good Clinical Research Practice guidelines- incorporate established ethical and
scientific quality standards for the design, conduct, recording and reporting of clinical research

TYPES OF CLINICAL TRAILS:

Descriptive trials: Hypotheses generation

• Describe and document characteristics of human diseases

• Simple and inexpensive

• Do not have the power or design to establish cause-effect relationships

• Eg : case reports, case series, population studies

Analytic/observational trials: Relate associations between causes and diseases

• Seek causes, etiologies, predictors, assesses therapy.

• The investigator is observing nature rather than controlling treatment allocation

• Compare groups of subjects to determine relationships of potential cause/effect using statistical

methodologies

• Eg: Case-control studies ,Cross-sectional studies, Cohort studies

Experimental trials: Demonstrate efficacy and safety

• Compare outcomes (etiology, cause, efficacy) of trial group and control group following an intervention

• Most powerful tool to assess efficacy

• Controlled, randomized, double-blind trials are the “Gold Standard” in clinical research
 404

STEPS OF CLINICAL TRIALS

• Phase 0

• Phase 1

• Phase 2

• Phase 3

• Phase 4

PHASE 0 TRIALS:

• Pre-phase 1 trial/ Pilot study/ Exploratory Investigational New Drug (IND) study

• Most drugs in clinical development do not make it to registration; most drugs that fail, fail in late stages
of clinical development

• Failure rate is higher for oncology drugs

• Late failure means wasted resources, including patients

• Find out whether the drugs do what they are expected to do

• Limited number of subjects (≈10-12)

• Low, supposedly non-toxic doses

• Limited duration of dosing (≈ ≤7 days)

• One course

• No therapeutic (or diagnostic) intent

• Can be initiated with a less extensive pre-clinical data than traditional Phase 1 trials

 Pre-clinical stage:

• Validate pharmacodynamics biomarker assay

• Simulate human tissue acquisition, handling and processing

• Demonstrate drug effect on target or biomarker

• Determine pharmacodynamics- pharmacokinetics relationships

• Evaluate drug bio-distribution and binding using imaging technologies

 Clinical stage :

• Interrogating and validating target or biomarker assay in human tumour biopsies and/or surrogate tissue
 405

• Developing an SOP for human tissue acquisition, handling and processing

• Demonstrating drug target or biomarker effect

• Determining pharmacodynamics- pharmacokinetics relationships

• Drug bio-distribution and binding using novel imaging technologies

Problems :

-No therapeutic intent or chance of benefit

-Pre- and post-treatment tissue biopsies

-Delay or exclusion from other trials or therapies

-External concerns about ethics and availability of patients for study

Advantages :

-Promising candidate drugs are identified, prioritized early

-Efficiency and success rate of Phase 1-2 trials are improved, higher

proportion of drugs make it to registration

-Appropriate utilization of resources including highly valued patient participation

PHASE I TRIALS

• To determine the maximum tolerable dose(MTD), pharmacokinetics of drug distribution

• Sequential dose escalation till adverse effects reach a predetermined level or unexpected toxicity

• Escalation only after sufficient time has passed to observe side effects

• Dose for phase 2 is highest dose for which the DLT is <33%

• Dose escalation in modified Fibonacci sequence

• Accelerated titration : uses a single patient per dose level with a maximum level 2 toxicity

• Data is fitted into a statistical model

• Allows lesser number of patients to be used for finding maximal tolerable dose, reduce undertreated
cases, provide more information

• Dose toxicity model/ continual reasessment method : a Bayesian prior distribution is established for the
steepness of dose toxicity curve, updated after each patient is treated
 406

• Oncology trials involving molecular targeted drugs determine determined serum conc. to maximally
inhibit the target or in case of vaccines the biologic effect

PHASE 2 TRIALS

• Primary objective to determine the response rate

• Others – response duration, PFS, LRC

• Specific targets selection and development of their biomarker assays before trials

• Single arm trials: to determine the activity of the drug against the specific tumour

• Two or three stage designs with progression to the next stage only if the drug shows a minimum level of
activity(p0)

• Tables show the minimax designs; optimise protection of patients from exposure to inactive drugs

• Molecular targetted therapy may be cytostatic, PFS better indicator than tumour response

• Combination regimens may be tested using activity of standard regimens as the minimum activity
acceptable

• Sample size using appropriate formulas for RCT’s

• Continual monitoring of tumour response or time to event end points or monitoring of efficacy and
toxicity

• Randomised phase 2 trials: uses a sensitive indicator of antitumour effect which need not be validated

• Determines if a phase 3 trial can be conducted with an acceptable end point

• Optimisation of regimens being carried forward to phase 3, information regarding best target population

• Type I error can be increased from two sided 5% used in phase 3 to one sided 10%; optimal use of
patient resources

• Early stoppage of accural if results for regimens not promising

PHASE 3 TRIALS

• Confirm the effectiveness of a drug/regimen, monitor side effects, compare to standard treatments

• Usually randomised, compare 2 or more drugs/ regimens

• Large number of patients from different age, ethnicity and gender

• Last stage before seeking drug approval form regulatory authority

• Assignment of the patients into treatment and control groups by random treatment assignment

• Distribution of known and unknown prognostic factors between 2 arms excludes any systemic bias
 407

• Randomisation distributes the unknown prognostic factors according to a known random distribution,
effects can be allowed for in significance tests and confidence intervals

• Stratification on the basis of known prognostic factors, a separate randomisation list for each for each
strata

• Helps to ensure balance for interim analysis when sample sizes may be limited; greater confidence
because of the absence of complex adjustments

• RANDOMISATION: allocation of patients using a chance mechanism so that neither the patient nor the
physician knows in advance which treatment will be assigned.

• Simple randomisation: randomisation without restriction; equal probability of being alloted to both
arms.

• Block randomisation: recruiting participants in short blocks, half of the participants within each block
are allocated to one treatment and the other half to another. Within each block, the order of patients is
random.

• Stratified randomisation: divides the patient population according to its levels e.g. sex, age, recruitment
centres Treatments are allocated within each stratum using any of the previous methods.

INTENTION TO TREAT ANALYSIS:

• All randomised patients must be included in the primary analysis of the trial

• Exclusion due to death, treatment deviations or withdrawal can severely distort results

• Compliance in the 2 arms may differ due to different reasons

INTERIM ANALYSIS:

• Usually done by the data monitoring commitee

• Haybittle’s design: interim differences are discounted unless it is statistically significant at the 2 sided
p<0.005 level

• If the differences are not significant, the study continues till its intended size

• Final analysis performed regardless of the interim analysis

• Futility analyses to avoid exposing patients yo more toxic/ debilitating regimen

 408

PHASE 4 TRIALS

• Post marketing surveillance

• Involve pharmacovigilance and technical support for the drug after regulatory approval

• To identify the rare or long term effects of the drugs and treatments

• Safest as the therapy has been studied in previous groups of patients

• Study over a much larger population over an extended period of time

• Scope to study interaction with other drugs; effects on population groups not likely to subject to trials

• May require the usage of the drug to be restricted or complete withdrawal

WHO Principles of GCP:

• Principle 1: should be scientifically sound and conducted in accordance with basic ethical principles

• Principle 2: Research involving humans should be scientifically justified and described in a clear, detailed
protocol.

• Principle 3: foreseeable risks and discomforts and any anticipated benefi t(s) for the individual research subject
and society should be identified

• Principle 4: initiated only if the anticipated benefit(s) for the individual research subject and society clearly
outweigh the risks.

• Principle 5: Research involving humans should receive IEC/IRB approval/ favourable opinion prior to initiation.

• Principle 6: conducted in compliance with the approved protocol.

• Principle 7: Freely given informed consent should be obtained from every subject prior to research participation

• Principle 8: continued only if the benefit-risk profile remains favourable.

• Principle 9: qualified and duly licensed medical personnel should be responsible for the medical care of research
subjects, and for any medical decision/s

• Principle 10: each individual involved in conducting a trial should be qualified by education, training, and
experience to perform his or her respective tasks

• Principle 11: information should be recorded, handled, and stored in a way that allows its accurate reporting,
interpretation, and verification.

• Principle 12: confidentiality of records that could identify subjects should be protected

• Principle 13: investigational products should be manufactured, handled and stored in accordance with applicable
GMP; used in accordance with the approved protocol.

• Principle 14: Systems with procedures that assure the quality of every detail of the trial should be implemented
409
 410

ONCOLOGICAL EMERGENCIES
 411

A clinical condition resulting from a metabolic, neurologic, cardiovascular, hematologic, and/or infectious
change caused by cancer or its treatment that requires immediate intervention to prevent loss of life or quality
of life.

Conditions are:
• SVCO
• Spinal cord compression
• Raised ICT
• Bleeding solid tumours
• Acute Respiratory obstruction
• Hypercalcemia
• Tumor Lysis Syndrome
• SIADH
• Neutropenic fever

SUPERIOR VENA CAVA OBSTRUCTION

• Ac pathophysiological condition
• Sec to obstruction of great vessels in the superior mediastinum.

PATHOPHYSIOLOGY :
• - SVCO is caused by direct compression,invasion and or iv thrombosis.
- The LN & progressively increasing tumour can
-
• compress /invade walls of SVC.
- Occurs when blood flow through the superior vena

• cava is compressed: ↓ venous return to heart, ↓ CO , ↑ venous congestion & edema

- Venous collaterals development due to compression – engorged veins.

 412

• Types of SVCO :
• - Ac (within days) -Ca lung, Lymphomas.
- Subacute ( < 6 wks)
- Ch (> 6wks ).
Cl presentation :
• Dyspnea
• sensation of fullness in head & facial swelling
• venous distention of the neck ( 66 % ) and chest wall( 54 % )
• facial edema (46 % ) ,
• plethora ( 1 9 % ) , &
• cyanosis( 1 9 % ) .
o Aggravated by bending forward, stooping, or lying down.

Causes :
o lung cancer,
o lymphoma,
o GCT
o metastatic mediastinal tumors,,
o breast cancer,
o indwelling venous catheters.

Diagnostic procedures :
CXR - mass, sup mediastinal widening & pl effusion.
CTScan –parenchymal ds, mediastinal adenopathy
MRI
CT phlebography
FDG-PET Scan
Venogram – localization of intraluminal lesions
 413

TREATMENT :
Steriods
Oxygen,Sedation
Diuretics
RT
Endovascular Stenting & angiopasty
Surgery (sternotomy or thoracotomy with extensive resection of the
tumor and reconstruction of the SVC)
Thrombolytic agents.

Radiation therapy:
Indication for RT :
- if a histologic diagnosis cannot be established & the cl status is deteriorating.
- SVCS an absolute emergency that requires radiotherapy without a specific diagnosis
- prompt treatment with irradiation may be required without any delay.
Dose : 3Gy X 10 , 4 Gy X 5, 2.5 Gy X 15, followed by conventional fractionation to a total dose of 30 - 50 Gy.
The symptomatic improvement achieved by RT is due to :
- improvement of flow through the SVC,
- development of collaterals.

Endovascular Stenting and Angioplasty

Percutaneous transluminal angioplasty using the balloon technique, insertion of expandable wire stents.
Balloon dilatation ( angioplasty) can also be used before stenting.
Combination endovascular therapy: thrombolysis, angioplasty, and stem therapy.

Complication rates for endovascular therapy (0-50%) :

 bleeding,
 stem migration,
 stem occlusion, &
 pulmonary embolus.
 414

SPINAL CORD COMPRESSION

5 – 10 % cancer pts.

• Compression occurs in 3 ways :

1. extradural,
2. intradural
3. intramedullary.
Causes :
1. breast ( >50%),
2. lung cancer( > 20%),
3. prostate,
4. lymphoma,
5. RCC,
6. M myeoma,
7. thyroid ca .

• The axial skeleton, most common organ systems involved by metastatic spread.
 -Invasion of epidural space
- Haematogenous spread

Site :
• Dorsal > Lumbar > Cervical spine

• Prolong compression
• Vascular compromise and permanent neurological compromise.
CL PRESENTATION :

• Pain
• Pain precedes neurological dysfunction complete paralysis autonomic involvement.
• Motor dysfunction (weakness, spasticity) occurs earlier than sensory.
- Cx spine –Brown sequard syndrome.
- Thoracic spine : Paraparesis –paraplegia.
• Spinal tenderness.
 415

INVESTIGATIONS :

• X –ray Spine (AP & Lat)- loss of pedicle, vertebral ht , # affected spine.
• Image guided aspiration/biopsy
• MRI of the entire spine : demonstrate lesion in cord .
• Myelography : breaking bamboo sign (intramedullary)
• CECT : course of compression , tumour vol for RT planning.
Management

• Steroids
• : iv 4-8mg 8 hrly.
 : initial bolus of 100 mg followed by 4-8 mg tid X 48 hrs and taper over 7-10 d.
• Debulking Sx + stabilization RT, Laminectomy, RT alone.

RT TECHNIQUES :

• Rx volm-2 vertebrae above & below the ds spine.

• AP/PA or PA field
• Dose: 3 Gy X 10 # ;4 Gy X 5# ; 8 Gy X 1# ; 2.5 Gy X 15 # .
• Prognosis :
• depends on histoogy, responsiveness of tumour.
• Poor prognosis –melanoma,soft tissue Sa.

*********
 416

SOME GENERAL TOPICS

 417

GENERAL GUIDELINES FOR THE TREATMENT OF HIV-ASSOCIATED CANCERS

Optimal treatment of patients with HIV-associated malignancies includes input from a multidisciplinary
team consisting of a pharmacist, an infectious disease specialist, and a hematologist/oncologist.

HIV medications can inhibit the Cyt p450 system, potentially augmenting toxicities by preventing
chemotherapy metabolism (see Table 4 as a guide).

Multiple overlapping toxicities are seen with HIV medications and chemotherapy agents (see Table 5 as
a guide).

Supportive care medications can also augment chemotherapy toxicities (i.e., azole antifungals and
vincristine).

Avoid the use of ritonavir when combined with vinblastine in the setting of Hodgkin's lymphoma.

Rituximab offers substantial benefit when used with combination chemotherapy for treatment of CD20+
aggressive B cell lymphomas. Rituximab should not be withheld for patients with CD4+ T cell counts less than
50 cells/mm3. But care should be taken, as patients with low CD4+ T cell counts are more prone to infectious
complications..

CD4+ T cell counts can decrease during chemotherapy and or in the setting of pelvic radiation. Thus
prophylaxis during therapy for opportunistic infections is often warranted despite a normal CD4+ T cell count at
therapy onset.

Granulocyte colony-stimulating agents and antibiotic prophylaxis are strongly encouraged to minimize
the effects of chemotherapy-induced neutropenia during the treatment of AIDS-related lymphomas.
 418

The incidence of AIDS-defining cancers (ADCs) -- Kaposi sarcoma, primary central nervous system
lymphoma, non-Hodgkin lymphoma, and cervical cancer -- although on the decline since shortly after the
introduction of highly active antiretroviral therapy (HAART), has continued to be greater even in treated HIV-
infected persons than in the general population.

While the survival of newly infected people living with HIV/AIDS now rivals that of the general
population, morbidity and mortality associated with non-AIDS-defining cancers (NADCs) such as lung, liver,
anal and melanoma are significant and also continue to rise.

Increasing age (i.e., longevity) is the greatest risk factor for NADCs, but longevity alone is not sufficient
to fully explain these trends in cancer epidemiology.

In this review, we briefly review the epidemiology and etiology of cancers seen in HIV/AIDS, and in
this context, discuss preclinical research and broad treatment considerations. Investigation of these
considerations provides insight into why malignancies continue to be a major problem in the current era of
HIV/AIDS care.
 419

SENTINEL LYMPH NODE

SENTINEL LYMPH NODE is the hypothetical first lymph node or group of nodes draining a cancer.
In case of established cancerous dissemination it is postulated that the sentinel lymph node/s is/are the target
organs primarily reached by metastasizing cancer cells from the tumor. Thus, sentinel lymph nodes can be
totally void of cancer because they were detected prior to dissemination.

The sentinel node procedure is the identification, removal and analysis of the sentinel lymph nodes of
a particular tumour.

Uses:

 To perform a sentinel lymph node biopsy, the physician performs a lymphoscintigraphy, wherein a low-
activity radioactive substance is injected near the tumor. The injected substance, filtered sulfur colloid,
is tagged with the radionuclide technetium-99m.

The injection protocols differ by doctor but the most common is a 500 μCi dose divided among 5
tuberculin syringes with 1/2 inch, 24 gauge needles.[citation needed]
 In the UK 20 megabecquerels of nanocolloid is recommended.[5] The sulphur colloid is slightly acidic
and causes minor stinging.
 A gentle massage of the injection sites spreads the sulphur colloid, relieving the pain and speeding up
the lymph uptake.
 Scintigraphic imaging is usually started within 5 minutes of injection and the node appears from 5 min
to 1 hour.
 This is usually done several hours before the actual biopsy. About 15 minutes before the biopsy the
physician injects a blue dye in the same manner.
 Then, during the biopsy, the physician visually inspects the lymph nodes for staining and uses a gamma
probeor a Geiger counter to assess which lymph nodes have taken up the radionuclide. One or several
nodes may take up the dye and radioactive tracer, and these nodes are designated the sentinel lymph
nodes.
 The surgeon then removes these lymph nodes and sends them to a pathologist for rapid examination
under a microscope to look for the presence of cancer.
 A frozen section procedure is commonly employed (which takes less than 20 minutes), so if neoplasia is
detected in the lymph node a further lymph node dissection may be performed. With malignant
melanoma, many pathologists eschew frozen sections for more accurate "permanent" specimen
preparation due to the increased instances of false-negative with melanocytic staining.
 420

Clinical advantages:

1. There are various advantages to the sentinel node procedure. First and foremost, it decreases lymph node
dissections where unnecessary, thereby reducing the risk oflymphedema, a common complication of this
procedure.
2. Increased attention on the node(s) identified to most likely contain metastasis is also more likely to
detect micro-metastasis and result in staging and treatment changes.
3.
It The main uses are in breast cancer and malignant melanoma surgery, although it has been used in
other tumor types (colon cancer) with a degree of success.
4. If undertaken prior to breast reconstruction, sentinel lymph node biopsy before helps to predict breast
radiotherapy and avoids its complications on breast reconstruction.
5. Other cancers which have been investigated with this technique are penile cancer, urinary bladder
cancer, prostate cancer, testicular cancer and renal cell cancer.
Disadvantages
1.
However, the technique is not without drawbacks, particularly when used for melanoma patients. This
technique only has therapeutic value in patients with positive nodes.
2. Failure to detect cancer cells in the sentinel node can lead to a false negative result—there may still be
cancerous cells in the lymph node basin.
3. In addition, there is no compelling evidence that patients who have a full lymph node dissection as a
result of a positive sentinel lymph node result have improved survival compared to those who do not
have a full dissection until later in their disease, when the lymph nodes can be felt by a physician. Such
patients may be having an unnecessary full dissection, with the attendant risk of lymphedema
 421

PRINCIPLES OF COMBINING RADIOTHERAPY WITH CHEMOTHERAPY

Therapeutic index:

The therapeutic index (or therapeutic ratio), is the ratio of the probability of tumor control to the probability of
normal tissue toxicity

 The greater the separation of these two curves, the greater is the therapeutic index.

Strategies to Improve the Therapeutic Index:

Steel & Peckham outlined specific strategies of using combined radiotherapy-chemotherapy:

1. Independent Toxicity:

 Normal tissue toxicity is the main dose-limiting factor

 Agents chosen where there is nil to less overlap of toxicities.

 Eg- methotrexate is not used with cranial irradiation, Adriamycin is not used with breast
irradiation, and bleomycin is not used with lung irradiation.

2. Normal Tissue Protection: Only a few clinically relevant, therapeutic agents have been identified.
Promoting normal tissue protection without protecting tumors. Eg- Amifostine in head n neck to xerostomia
rate.

 Spatial Cooperation: chemotherapy acting systemically(i.e., targeting micrometastatic disease)

And radiation therapy acting locoregionally. Eg- Sequential therapy.

4. Enhanced Tumor Response:

 Cytotoxic enhancement.

 An improved antitumor effect.

5. Biologic Cooperation:

 Targeting radiation resistant portion by drug given concomitantly.

 Eg- hypoxic cell cytotoxin- tirapazamine.

6. Temporal Modulation:

 Therapeutics that optimizes the four Rs between fractionated radiation treatments.

 422

Potential biologic mechanisms of drug-radiation interactions::

 Increasing Initial Radiation Damage:

 By incorporating itself into the cell’s DNA, thereby increasing the susceptibility of the DNA to
radiation damage.

 Eg- 5-FU and cisplatin.

 Inhibition of DNA Repair:

 compounds that interfere with the DNA damage repair signal transduction pathway can
potentially enhance radiation damage.

 Eg- 5-FU, bromodeoxyuridine, gemcitabine, fludarabine, methotrexate, etoposide, and

hydroxyurea as well as cisplatin.

 Cell Cycle Effects:

 Cell cycle specific chemotherapeutic agents.

 Taxanes can block transition of cells through mitosis,

 Nucleoside analogs- gemcitabin or fludarabin eliminates radioresistant S-phase cells, and

induces surviving cells to accumulate in G₂/M phase.

 Targeting repopulation:

 Chemotherapeutic with cytotoxic or cytostatic effects given concurrently with RT can counteract
repopulation and enhance efficacy.

 The main limitation of therapy is the enhanced toxicity of rapidly dividing normal tissues.

 Eg- antimetabolites.

 Hypoxia targeting:

 Selectively targeting hypoxic cells.

 Eg- Mitomycin C and tirapazamine.

 Other potential interactions:

1. Targeting molecular Signaling Pathways:

 Involved in resistance to cytotoxic therapy including radiation treatment

 Eg- EGFR inhibitor cetuximab with radiation therapy.

2. Tumor microenvironment targeting:

 423

 Antibody that targets VEGF can potentially normalize vascular flow by eliminating the aberrant
neovasculature of the tumor.

 Eg- Bevacizumab.

 Cancer Stem Cells:

1. Cancer stem cells is a source of radiation resistance for solid tumors.

2. Under active investigation.

Timing of drug administration in relation to radiation therapy:

 Induction/neoadjuvant Chemotherapy:

 may reduce the number of clonogenic cells and cause the reoxygenation of the surviving hypoxic
cell.

 which render tumors more controllable by radiation.

 chemotherapy-induced tumor shrinkage may allow the use of smaller radiation fields.

 Concurrent chemotherapy:

 Intended to cope with both disseminated lesions and the primary tumor.

 To maximize tumor radioresponse.

 Adjuvant chemotherapy:

 The primary objective is to eradicate disseminated disease

 424

PRINCIPLES OF COMBINING RADIATION THERAPY WITH SURGERY

• 1. Pre operative

• 2. Intraoperative

• 3. Post operative

PRE OPERATIVE IRRADIATION

Radiation prior to surgery

Principles –

• 1. The small nests of isolated cells which surround most malignant tumors maybe controlled by smaller
doses than are for a larger primary.

• 2. Irradiation can change the natural history of some malignant tumors in the irradaiated volume.

3. The periphery of tumor is more sensitive than its core.

4. Importance of the waiting period.

5. We should be prepared to accept the complications.

6. With the advent of supervoltage it is now possible to have surgery after a radical dose of irradiation with less
complications.

ADVANTAGES

• 1. Render inoperable tumors operable.

• 2. Control of lymph node metastasis inaccessible to surgery.

• 3. Reduction of local and systemic seeding during surgical manipulation.

• 4. Added irradiation of lymphatics and vascular channels arrests the tumor cells- downstaging.

• 5. Irradiation of surgically undisturbed tumor allows radiation of lower dose than recommended post
operative dose

DISADVANTAGES:

1. The main objection is the delay in wound healing.

2. If the time to surgery is prolonged after irradiation, the histopathology report may become less reliable-
altered tumor biology.

3. Inaccurate surgical staging.

4. Mandatory waiting time maybe quite stressful and expensive for the patient.
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DOSE SCHEDULE:

• Usually moderate- 40 to 50 Gy – given in 200cGy per # 5 days a week

• Smaller total doses in larger fractions – 30 Gy in 10 # (300cGy per #) in 2 weeks

• If dose exceeds 40 Gy, it is valuable to delay surgery by 4 to 6 weeks.

POST OPERATIVE RADIATION:

• Radiation after surgery

INDICATIONS:

• Large infiltrating tumor

• Microscopically +ve resection margins

• Perineural spread

• Extension-deep soft tissue/bone destruction

• Multiple/large lymph nodes & extra [Link] spread

Role of surgeon:

• The findings during surgery should be documented properly.

1. Mark lines of excision, tumor margins and residual cancer with metallic chips;

2. Estimate the volume of residual cancer;

3. Place ostomies out of any anticipated radiation fields;

4. Call the radiation oncologist to the operating room so he too may fully appreciate the problems;

5. Finally, describe operative findings in terms which will guide the planning of irradiation.

Role of Pathologist:

• Plays a critical role in recommending either for or against postoperative irradiation.

• The findings weigh heavily in optimizing techniques. Important in this regard are

1. Histologic type and grade,

2. Tumor size and precise location,

3. Infiltration of adjacent soft tissue and viscera,

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Presence or absence of cancer in regional lymph nodes or in the margins of the resected specimen

ADVANTAGES:

1. No delay in surgery

2. Sterilise the surgical bed

3. Tumor pathology is less distorted- more accurate histopathology reports

4. Less delay in wound healing

5. Proper surgical staging- accurate extent of disease.

6. Surgical complications reduced.

DISADVANTAGES:

1. Radiation is delayed

2. Tumor bed requires high dose

3. Volume of tumor bed requiring irradiation-larger

4. Surgical procedure may fix certain organs in/adjacent surgical bed

5. Radiobiological effect- compromised

6. Fibrosis

TIME INTERVAL:

• Tumor cell repopulation

Preoperative

• Low dose -1-2 wks of RT

• Intermediate radiation- 2-4 wks

• High dose - 4-6 wks

Postoperative

• 3 – 6 wks
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INTRAOPERATIVE RADIATION

• A technique where – a high, single-fraction radiation dose is delivered during a surgical procedure to
macroscopic tumors or tumor beds with minimal exposure of surroundings tissues which are displaced
and shielded during the procedure.

• 2 types-

• 1. IOERT (Intraoperative electron beam RT)

• 2. HDR-IORT (High dose rate-IORT)

ADVANTAGES:

• [Link] the chance of residual disease at the site of surgery by eliminating microscopic tumor foci

• 2. Maximizing the radiobiological effect of a single high dose of radiation with attainment of total
dosage that exceed those of EBRT

• 3. Optimizing the timing of the combined surgery and radiotherapy earlier irradiation & avoidance of
accelerated repopulation

• Reduce volume of irradiation field by direct visualisation of tumor/tumor bed

5. Exclude part/all dose limiting structures by operative mobilization, direct shielding or varying electron beam
energy

6. Allows delivery of high dose irradiation

7. Dose homogenesity

SHORTCOMINGS:

1. Dedicated equipment (mobile linac/HDR machine).

2. Well equiped & shielded OT with appropriate radiation safety.

3. Multidisciplinary team work.

4. Higher risk of late effects, such as fibrosis, in late responding.

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INDICATIONS WITH EVIDENCE:

• Breast

• Pancreas

• Stomach

• Lung

• Esophagus

• Colorectum

• Soft tissue Sarcomas

• Paediatric tumors

• Bladder & kidney

• Gynaecologic sites

DOSE SCHEDULE:

• DEPENDS ON-

- Extent of residual disease at resection

- Previous EBRT delivered

- Type & volume of normal tissue irradiated

• Preoperative dose – 10-20 GY

• Microscopic margin – 10-12.5 GY

• Gross residual disease – 15-20 GY

• Previously irradiated – 15-20 GY

• NO – limited EBRT – 25-30 GY

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RADIOTHERAPY IN BENIGN DISEASES

Radiobiological Principles:

• Low dose radiation – anti inflammatory

• Rapid response seen by vascular endothelial cells

Modulation of cytokine and

adhesion molecule expression

Pro-inflammatory cytokines

Complimentary cascade and

PGs

Change in iNOS

• Specific effects in specific diseases(E.g. Fibroblast proliferation in keloids)

• Cell killing also

Suppression of T-cell
populations

Antigen – antibody
reactions

Chronic inflammation
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General dose concepts:

CNS Tumors:

• Benign tumors of CNS

- Pressure and mass effect

- can lead to severe, life-threatening symptoms

• Inaccessible areas and STR – indication of RT

MENINGIOMA:

MC Benign tumor of CNS

Symptomatic – GTR

Radiation – Primary/Adjuvant

Primary RT

• Refusal

• Not feasible

Adjuvant RT
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• STR(Simpson IV and V)

• Histological grade II and III

• Recurrence

Technique

• 3DCRT, IMRT, FSRT, Proton – 54 to 60 Gy

• SRS - 12 to 18 Gy

PITUITARY ADENOMAS:

Primary RT – medical inoperability

Adjuvant RT

• Recurrence

• Persistent hormone elevation

• STR

 Discontinue pharmacologic therapy 1 – 2 months before RT

 Non secretory – 45 to 50.4 Gy(SRS 16 to 20 Gy)

 Secertory – 50.4 to 54 Gy(SRS 20 to 25 Gy)

 Hormone normalizes after many years(GH<TSH)

CRANIOPHARYNGIOMA:

• Maximal safe resection + adjuvant RT – TOC

• <3 yr old - Observation foll STR

• 3DCRT, IMRT(54Gy/1.8Gy#)

• Proton(50.4 to 59.4 GyE)

• FSRT, SRS

• Intralesional Y90(cystic type) – 200 to 250 Gy

 Cyst regrowth can occur during RT

ACOUSTIC NEUROMA

• Primary treatment option

• Surgery
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– More complications

– Indicated in large, symptomatic lesions

SKULL BASE CHORDOMA

• Surgery alone – poor local control

• Salvage after Sx – 50% 5 yr Survival

• Adjuvant RT – 80% 5 yr Survival

– 60 Gy/1.8 – 2 Gy# with 3DCRT/IMRT

– Dose escalation with proton/carbon

• SRS/FSRT – primary/adjuvant/salvage

JNA

Sx + embolisation - TOC

RT as primary modality

• Chandler Stage IV (intra-cranial extension)

• Medically inoperable

• Salvage

• Fractionated IMRT

– 30 to 50 Gy/2.0 – 3.0 Gy#

– Remission is slow

Langerhans Cell Histiocytosis

Treatment – site and extent

RT to bony sites

• Relapse

• Exhaustion of other modalities

• Emergency

• 5 to 10 Gy/1.5 – 2 Gy#

• 87% LC rate
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AV Malformations

• Nidus – bleeding risk 3%/year

• Surgery – immediate cure with increased risks

• SRS – TOC

• Time to obliteration 1- 4 years

• Bleeding risk reduced by 88%

• 16 – 24 Gy/1-2#

TRIGEMINAL NEURALGIA

• Medically refractory – Sx/RFA/balloon compression/glycerol injection

SRS

• >70 Gy >90% control

• Root entry of nerve as it enters Pons to the semilunar ganglion

• Complications - Facial numbness(15%)

Epilepsy

• Mesial temporal lobe epilepsy

• Alternative to surgery in medically refractory

• SRS 24 Gy/single # to amygdala, hippocampus, parahippocampal gyrus

• 67 % 3 yr seizure free rate

Parkinson Disease

• Medically refractory cases – alternative

SRS pallidotomy

• 120 to 180 Gy to globus pallidus internus

• 80 % 2 yr success rate(rigidity relief)

Psychiatric disorders

OCD

• SRS 180 Gy to anterior limb of internal capsule

• Pending Phase II
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Eye disorders

Pterygium – post op RT

• Sr 90 beta irradiation 20 to 60 Gy(1 to 10#)

Choroidal Hemangioma –

• Lesions near macula/papilla

• Non responders to other modality

• Diffuse disease

3DCRT, proton, Plaque brachytherapy

Graves opthalmoplegia

Orbital pseudotumor

• Recurrence after surgery

• Steroid refractory

• 3DCRT – 20 Gy/10#

Skin and connective tissue:

Desmoid tumors

• Symptomatic, growing lesions – function preserving surgery

• Abdominal desmoids – surgery is counter productive

Medical therapy – Sulindac ± Tamoxifen

• Others – CT, Imatinib, RFA, IL injections

RT

• Inoperable patients

• Recurrence

• 56 Gy – 75% local control

• Incomplete resection - 50 Gy

Peyronie Disease

• Primarily for pain relief

• Early stage of disease process

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• Electrons/orthovoltage (12 to 20 Gy)

Dupuytren’s Contracture:

Prophylactic (8% failure in 1 year)

• In early stage

• <10 degree extension deficit

Electrons/orthovoltage : 20 to 30 Gy

Keloid and Hypertrophic Scar:

Adjuvant

• Repeated recurrences

• Post op with high risk

Primary treatment

• Resection causing functional impairment

• Actively proliferating keloid within 6 months of inciting trauma

Technique

• Deeper electrons/brachytherapy

• 24 hrs after surgery

• Scar + 1cm margin

• 12 to 20 Gy(3 to 4#), 7.5 to 10Gy/1#

Bone

Gorham Stout syndrome

• EBRT 36 to 45 Gy - >75% control

Pigmented villonodular synovitis - Sx

• Diffuse disease

• Recurrence

• Bulky disease

• 35 to 50 Gy
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Vertebral Hemangioma

• Pain relief – 36 to 40 Gy/2Gy#

Heterotopic ossification

• Prophylactic RT after total hip arthroplasty

• Perioperative 7 or 8 Gy/1#

Endovascular Brachytherapy

• Beta – cath system Sr/Y90

DES superior to VBT in coronary in-stent restenosis

Safe and effective in DES failures, diffuse long lesions, small vessels, bifurcation lesions, diabetic lesions

Increased role in vein graft in-stent restenosis and for PVD

Cost effective in the long run

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POSITRON EMISSION TOMOGRAPHY

A positron emission tomography is a nuclear medical imaging technique which produces a three dimensional
image of functional processes in the body.

A short lived radioactive tracer isotope, is injected in to the living subject (usually in to blood circulation) . The
tracer is chemically incorporated in to a biologically active molecule.

There is a waiting period while the active molecule becomes concentrated in tissues of interest.

As the radioisotope undergoes positron emission decay (also known as positive beta decay), it emits a positron,
an antiparticle of the electron with opposite charge.

After traveling up to a few millimeters the positron encounter an electron.

The encounter annihilates them both, producing a pair of (gamma) photon moving in opposite directions.

These are detected when they reach scintillator in the scanning device creating a burst of light which is detected
by photomultiplier tubes.

The technicians can then create an image of the parts of your brain, for example which are overactive.

Tracer:

 nitrogen,oxygen,gallium and 18F used as a substitute of hydrogen.

 Only radioactive forms of natural elements that will pass safely through your body and be detected by
the scanner.

 The type of scanner used depends on what your doctor wants to measure. For example, if your doctor is
looking at the tumor, he might use radio labeled glucose (FDG) and watch how it is metabolized by the
tumor.

Uses:

 Detect cancer.

 Determine whether a cancer has spread in the body.

 Assess the effectiveness of a treatment plan, such as cancer therapy.

 Determine if a cancer has returned after treatment.

 Determine blood flow to the heart muscle.

 Determine the effects of a heart attack, or myocardial infarction, on areas of the heart.

 Identify areas of the heart muscle that would benefit from a procedure such as angioplasty or coronary
artery bypass surgery (in combination with a myocardial perfusion scan).
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 Evaluate brain abnormalities, such as tumors, memory disorders and seizures and other central nervous
system disorders.

 To map normal human brain and heart function.

Limitations of PET scan:

 Time-consuming.

 The resolution of structures of the body with nuclear medicine may not be as clear as with other imaging
techniques, such as CT or MRI.

 PET scanning can give false results if chemical balances within the body are not normal.

 Because the radioactive substance decays quickly and is effective for only a short period of time, it is
important for the patient to be on time for the appointment and to receive the radioactive material at the
scheduled time.

 A person who is very obese may not fit into the opening of a conventional PET/CT unit.
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TNM STAGING SYSTEM

The TNM Classification of Malignant Tumours (TNM) is a notation system that describes the stage of
a cancer which originates from a solid tumour with alphanumeric codes.

 T describes the size of the original (primary) tumour and whether it has invaded nearby tissue,
 N describes nearby (regional) lymph nodes that are involved,
 M describes distant metastasis (spread of cancer from one part of the body to another).
The TNM staging system for all solid tumours was devised by Pierre Denoix between 1943 and 1952, using the
size and extension of the primary tumor, its lymphatic involvement, and the presence of metastases to classify
the progression of cancer.
it is a classification of the anatomical extent of disease. It has gained wide international acceptance for many
solid tumour cancers, but is not applicable to leukaemia and tumours of the central nervous system (CNS).
TNM is developed and maintained by the Union for International Cancer Control (UICC) to achieve consensus
on one globally recognised standard for classifying the extent of spread of cancer.
The TNM classification is also used by the American Joint Committee on Cancer (AJCC) and the International
Federation of Gynecology and Obstetrics (FIGO). In 1987, the UICC and AJCC staging systems were unified
into a single staging system.

Mandatory parameters

Diagram showing the T stages ofbladder cancer

 T: size or direct extent of the primary tumour

 Tx: tumour cannot be assessed
 Tis: carcinoma in situ
 T0: no evidence of tumour
 T1, T2, T3, T4: size and/or extension of the primary tumor
 N: degree of spread to regional lymph nodes
 Nx: lymph nodes cannot be assessed
 N0: no regional lymph nodes metastasis
 N1: regional lymph node metastasis present; at some sites, tumour spread to closest or small number of
regional lymph nodes
 N2: tumour spread to an extent between N1 and N3 (N2 is not used at all sites)
 N3: tumour spread to more distant or numerous regional lymph nodes (N3 is not used at all sites)
 M: presence of distant metastasis
 M0: no distant metastasis
[2]
 M1: metastasis to distant organs (beyond regional lymph nodes)
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The Mx designation was removed from the 7th edition of the AJCC/UICC system, but referred to cancers that
could not be evaluated for distant metastasis.
Other parameters

 G (1–4): the grade of the cancer cells (i.e. they are "low grade" if they appear similar to normal cells, and
"high grade" if they appear poorly differentiated)
 S (0–3): elevation of serum tumor markers
 R (0–2): the completeness of the operation (resection-boundaries free of cancer cells or not)
 L (0–1): invasion into lymphatic vessels
 V (0–2): invasion into vein (no, microscopic, macroscopic)
 C (1–5): a modifier of the certainty (quality) of the last mentioned parameter (has been removed in the
TNM 8th edition)

Prefix modifiers

 c: stage is determined from evidence acquired before treatment (including clinical examination, imaging,
endoscopy, biopsy, surgical exploration). The c-prefix is implicit in absence of the p-prefix.
 p: stage given by histopathologic examination of a surgical specimen
 y: stage assessed after chemotherapy and/or radiation therapy; in other words, the individual
had neoadjuvant therapy.
 r: stage for a recurrent tumor in an individual that had some period of time free from the disease.
 a: stage determined at autopsy.
 u: stage determined by ultrasonography or endosonography. Clinicians often use this modifier although it is
not an officially defined one

Dr Dulasiraman PGT, RADIOTHERAPY