Particle Therapy

Mod : Prof S.C. Sharma

 Interaction of Charged Particles
Elastic – Scatter, no energy loss

Inelastic interactions – Collision - mediated by Coulomb

Force

• Collisions with electrons - Ionization & Excitation

• Collisions with nucleus - Radiative loss of energy
(bremsstrahlung).
• Stopping Power (S) - The rate of kinetic energy loss per
unit path length of the particle (dE/dx).
• Mass Stopping Power (S/ρ ) – stopping power per
unit density of the medium (MeV cm2/g).
 Heavy Charged Particles
• Stopping power is proportional to
– Square of particle charge
– Inversely to square of its velocity.
• Thus, as particle slows down, its rate of
energy loss increases and so does the
ionization or absorbed dose to the medium.
• Bragg peak.
• Minimal scattering,
• Concentrate dose inside the target volume
• Minimize dose to surrounding normal tissues
• Finite range.
– Better depth-dose distribution
– Reduced penumbra
– This allows for the ultimate expression of
intensity modulated, conformal radiotherapy.
• Although the electron is certainly a particle,
– Routinely Used,
– No Bragg Peak due to small mass and easily scattered.
– No extraordinary Radiobiologic properties.

Particles currently used

– Neutrons
– Protons heavy particles
– Carbon and neon ions,
– Mesons
– Neon ions.
 INTERACTIONS OF NEUTRONS
• No coulomb interaction
• In directly ionizing
• recoiling protons from hydrogen and recoiling
heavy nuclei from other elements,
– billiard-ball collision-energy
– energy transfer is very efficient if colliding
particles have same mass, e.g., hydrogen
nucleus.
– fat exposed to a neutron beam is about 20%
higher than in muscle.
• Nuclear disintegrations.
– emission of heavy charged particles, neutrons,
and γ rays
– 30% of the tissue dose.
• Interaction exponential like photon
• No finite range
• Mean path length equal to inverse of
neutron attenuation coeiff.
 Basic Radiobiology
• LET
• Co60/ electron 0.2 to 2 keV/µm,
• 250 Kvp photon – 2 keV/µm,
• Fast neutron - 5 to 150 keV/µm.
• Alpha particle – 100-150
keV/µm,
• Heavy, ions - 100 to 1,000
keV/µm.

So, a dose of 1 Gy of Xray to 1gm tissue is not equivallent

to 1Gy of neutron or alpha particle.
It is the microdosimetric pattern of energy deposition which
determines the biological effectiveness.
 RBE
• More densely ionizing
– No or very little sublethal
damage
– Loss of shoulder in survival
curve in acute reaction
– Little or no sparing of late
normal tissue by
fractionation, dose rate
– Decrease in normal tissue
tolerance
– OER decreases
– Variation for cell cycle
eliminated.
 RATIONALE FOR ION THERAPY
• Physical selectivity comparable to, or better than, best low LET
therapy techniques.
– Penumbra – narrow & dose ratio between SOBP and entrance plateau is better
– Sharp dose fall beyond SOBP.
• The LET & consequently RBE, increases with depth,
– Increases ratio of biologically weighted doses between SOBP and entrance
plateau.
– The RBE is comparable to neutrons, but the physical dose selectivity improved.
• At the level of the SOBP, where the PTV is located, high LET
makes heavy ion beams specifically effective for treatment of
some tumour types that are resistant to low LET radiation.
• After fractionated irradiation,
– Reduced possibility for repair in PTV located in SOBP,
– Normal tissues located outside SOBP, exposed to lower LET rad, thus may repair.
Particles currently used

– Neutrons
– Protons heavy particles
– Carbon and neon ions,
– Mesons
– Neon ions.
Fast Neutron Radiotherapy
 Salivary Gland Tumors
• Major therapeutic advantage
• RBE
• Normal late tissue- 3-3.5
• CNS -4-4.5
• Salivary gland – 8 (Battermann, et al)
• Doses of 20 Gyn
• = photon dose of 60 - 70 Gy-equivalent,
normal tissues
• 160 Gy-equivalent as far as the tumor is
concerned.
• The therapeutic gain factor 2.3 to 2.6.

•RTOG & MRC Great Britain) RCT

•local regional control at 10 years (56% vs. 17%; p = 0.009)
•Increased median survival of 8 month(not significant)
•Cause of death –
•Neutron – Distant faiure
•Photon – Local failure
 Salivary Gland Tumors
Salivary Gland Tumors
• University of Washington Douglas et
al.
• 279 pts, 263 – gross disease, 141- major
sal, 138 minor sal
• 6 yr cause specific survival – 67%
• Tumor size
• <4 cm, local control rate at 9 years was
78%.
• >4 cm LC- 40%
• Multivariate analysis - improved
survival
• stage I/II,
• minor salivary gland tumour,
• lack of base of skull invol,
• primary farther from secondary
• Another analysis of Douglas et al.
 Salivary Gland Tumors

• Gamma knife boost

• To boost areas of skull base disease
• Follow-up too short.
• Risk of developing distant metastases
• 50% at 2 yrs for node positive pats
• 50% at 10 yrs, for node negative pats.
• Clearly better systemic therapy is needed for
this tumor.
 Salivary Gland Tumors
• Combination of neutrons and photons (mixed beam
regimen)
• Adenoid cystic carcinomas . Huber et al.
• 5-year local control rate
• 75% for neutrons alone
• 32% for mixed beam regimen /photons alone.
• Greater the neutron proportion better tumour control
• high rate of distant metastases prevented improved local/regional
control translated into improved survival.
• High-risk, multiple recurrent pleomorphic adenomas of
major salivary glands
• The 15-year local/regional control –
• 76% for gross disease
• 100% for microscopic disease.
 Prostate Cancer
• RTOG
• mixed (neutron/photon) beam /Photon alone – 70 Gy
• T3 N0/1
• 10-year improved local/regional control (70% vs. 58%; p =
0.03)
• Survival (46% vs. 29%; p = 0.04)
• No difference in complications
• Criticisms
• small size (91 evaluable patients),
• unbalanced randomization (3:2 in favor of the
experimental arm),
• Photon control group did worse than historical results.
 Prostate Cancer
Prostate Cancer
• NTCWG RCT
• Neutron alone – 20.4 Gyn Vs. Photon – 70 Gy.
• High grade T2 or any grade T3 to T4, N0 to N1, or M0
tumors.172 pts
• LFR - Neutron arm -11%, photon – 32%(p <0.01).
• No difference in OS or cause-specific survival
• Post-treatment PSA levels in at risk at 5-plus years
• elevated in 17% neutron arm,
• 45% photon arm (p <0.001).
• Increased treatment morbidity on neutron arm,not having
a multileaf collimator to shape precisely the radiation
fields
• Wayne State group
• (a) giving the neutron portion of the treatment before the
photon portion and
• (b) giving the photon portion prior to the neutron portion.
• DFS= 93% - neutron given prior to photon
• DFS=73% photon given initially.
• Overall c/cn rate was same as photon 3-dim conformal
• The Wayne State group now uses 10 Gyn followed by
40 Gy photon as its standard mixed beam treatment
for prostate cancer.

Neutron studies were generally done with no antiandrogen therapy,

which has been shown to be advantageous in improving survival in
photon-treated patients.
 Sarcomas
• Radio resistant
• Characteristics favourable for high RBEs for neutron
radiotherapy.
• Historical data - inoperable gross disease
• Control rates Neutron Vs. photon
• 53% versus 38% for soft-tissue sarcomas,
• 55% versus 21% for osteogenic sarcomas,
• 49% versus 33% for chondrosarcomas
• Schwarz et al. - 1,171 pts
• R0 to R1 – LCR- 90%= conventional postoperative photon
irradiation.
• R2- 47% - Proton therapy.
• C/n rates- 7% and 29% depending on field size & technical
sophistication.
 SCC of Head & Neck
• Results have not paralleled salivary gland tumors
• RTOG RCT
• photon irradiation / mixed beam fractionation schedule
• Inoperable SCC.
• No improvement in LCR of primary tumor
• NO change of survival,
• ? apparent benefit in regional control in neck positive
adenopathy.
• Criticism
• neutron arm did not correspond to std. at Hammersmith.
• it was diluted with photon irradiation
• Had longer overall treatment time of 7 weeks compared to the
4-week fractionation schema used at Hammersmith.
• The Neutron Therapy Cooperative Working
Group (NTCWG)
• no benefit in LRC OS.
• ? improved regional control of clinically positive
nodes
• Late complications
• severe or greater - 40% - neutron arm .
• 17% photon arm (p = 0.008).
• Hence, it currently is felt that neutron
radiotherapy is of limited utility in the treatment
of head and neck squamous-cell tumors with the
possible exception of patients with massive
cervical adenopathy.
 Non-Small-Cell Lung Cancer
• Eichhorn - very low energy neutron beam.
• Autopsy
• higher rates of tumor sterilization as the percentage of the dose given
with neutrons increased:
• Photons alone - 33% sterilization rate in 149 patients,
• mixed beam (20% neutrons and 80% photons) 48% in 75 patients,
• mixed beam (37% neutrons and 63% photons) 57% in 49 patients.
• Series Pancoast's or superior sulcus tumors:
• Komaki et al.-
• 91% local control rate,
• Translated improved survival
• Sawada et al.
• mean survival of 11.5 months for 18 patients treated with neutrons
• four months for five patients on photon
 Inoperable NSCLC – RCT
• Three-armed study comparing
• Photon vs mixed vs neutron alone
• C/n rate higher in neutron-only arm.
• no difference in overall survival.

• Neutron-only regimen Vs. photon

• No diff in OS.
• But significant
•Aggressive survival
RT deliver advantage
higher dosesfor- improved local control
squamous-cell histology.
• Affect survival in favorable subgroup, not prone to early distant
•mets
Also a trend toward increased survival (p =
0.15) for patients of all histologies with
•No reported
favorablestudies for factors
prognostic chemotherapy used along neutrons.
• no pleural effusion,
• not T4 or N3 in stage,
• weight loss <5% of normal body weight
• Except for skin and subcutaneous changes,
acute and late toxicity were comparable.
Charged Particle Therapy
Proton Therapy
 Uveal Melanoma
• Std Rx - enucleation
• MC cause of failure- distant mets.
• XRT
• proximity of critical structures , wont
preserve useful vision
• Radioactive plaque brachytherapy
• <8 mm in thick lessions.
• MCH - 70CGE in 5 # Protons,
• 95% of tumors were locally controlled
• eye retention probability at 5 years 90%
• risk factors for enucleation
• involvement of the ciliary body, tumor height >8 mm,
and tumor proximal to the fovea.
• 50 CGE, for small and intermediate-sized
lesions located near optic disc or macula
• no improvement in visual acuity was seen.
• visual field analysis showed a smaller mean defect
 Optic Pathway Gliomas

• Loma Linda University -7 children

• Median follow-up - 37 months
• All locally controlled.(reduction in TV-3, stable -4)
• Visual acuity was stable in those, who presented
with useful vision.
• 47% reduction in the dose to the contralateral
optic nerve.
• 11% reduction to chiasm
• 13% reduction to pituitary gland.
 Benign and malignant
meningiomas of the skull base
• Benign meningiomas 20% of all intracranial neoplasms.
• Postoperative radiotherapy improve LCR at 5 and 10
years with 55.8 Gy,
• 10-year local control rate is still only about 50%.
• MGH - 46 patients with recurrent and/or partially
resected/biopsied tumors
• Combination of protons and photons to a median dose of
59.8 CGE
• Recurrence-free survival at 10 years of 88%
• 8 pts developed a sig. long-term morbidity
• one died of a brainstem necrosis.
 Benign and malignant
meningiomas of the skull base
• PSI - 16 recurrent, residual, or untreated intracranial
meningiomas
• Dose 56 CGE (52 to 64) at 1.8- 2 CGE/#.
• Cumulative 3-year local control – 91%, progression-free survival91%, and
overall survival 92%.
• No patient died of recurrent meningioma.
• Radiographic objective response in three patients and stable disease in 12
patients.
• Cumulative 3-year toxicity-free survival was 76%.
• No radiation-induced hypothalamic/pituitary dysfunction was observed.
• National Accelerator Centre (South Africa) protons using SRS approach
(20 CGE/3#) Vs. conventional fractionation approach (61.6 CGE/16 #).
• Radiologic control rate was 88% in conventional
• 100% in SRS
• 3 pts - neurologic deficits.
 Pituitary Tumors
• Nonsecreting pituitary tumors
• Standard Rx consists of transsphenoidal resection
followed by PORT ,
• Secretory tumors
• results are less optimal.
• MGH – 510 pts with GH-secreting tumors
• proton radiosurgery primary Rx in 67%.
• follow-up rate - 85%,
• Mean (HGH) levels decreased by 80% at 2 years, 98% by
20 years.
• Cushing's disease,145 pts Stereotactic proton
radiosurgery 120 to 140 CGE in a single#
• remission rates of 55% at 2 years and 80% at 5 years.
 Pituitary
Pituitary Tumors
Tumors
• Fractionated proton beam radiotherapy
• Loma Linda - 47 pts pituitary adenomas, 42 pre op & 5 primary RT
• Dose - 54 CGE.
• Tumor stabilization occurred in all 41 patients (follow-up imaging)
• 10 pts -no residual tumor,
• 3 had >50% reduction in tumor size.
• 17 had normalized or decreased hormone levels;
• 3 pts had progression
• Six patients died;
• 2 functional progression.
• 1 temporal lobe necrosis
• 3 new significant visual deficits
• 11 incident hypopituitarism
• Another challenge is re-radiation of pituitary tumor
 Acoustic Neuromas
• Large and have an irregular shape,
• Loma Linda - # proton RT – vestibular schwanoma – 30 pts
• useful hearing pts - 54 CGE,
• without functional hearing- 60 CGE.
• At 34 months,
• none had tumor progression
• 11 had decreased in size
• Of 13 patients with functional hearing, 31% maintained functional hearing.
• No transient or permanent facial or trigeminal nerve dysfunction
• MGH – proton SRS - 88 pts - vestibular schwannomas
• Dose -12 CGE to 70% isodose line.
• At 38.7 months
• 94.3% locally controlled.
• 5 required salvage therapy
• 33.3% retained functional hearing
 Astrocytomas
• MGH- phase II study – 23 pts
• 90 CGE with conformal protons and photons in
accelerated fractionation (twice a day)
• Actuarial survival rates at 2 and 3 years were 34% and
18%,
• The median survival time was 20 months,
• All patients developed new areas of gadolinium
enhancement during the follow-up period.
• Histological examination in 15 patients.
• 7- Radiation necrosis without recurrent tumor.
 Paranasal Sinus
• Rationale
• sparse lymphatic drainage pattern
• increased local control translates into increased survival.
• combined conformal proton and photon radiotherapy at MGH
• 91 patients - stage III to IV non mets , 67% post op, various histologies
• Median prescribed dose (primary TV) - 73.6 CGE (range 59.40 to
77.80).
• median proportion of proton dose was 49% (range 23 to 84).
• 87% - continuous accelerated hyperfractionated RT
• 32 received chemotherapy.
• At follow-up of 45 months, Failures
• 11- LR
• 6 – Neck
• 19 – Distant
 Nasopharyngeal Tumours
• Loma Linda - 16 pts with recurrent nasopharyngeal tumors
• re-treated with protons to doses of 59.4 to 70.2 CGE
• At 2 years
• OS - 50%
• No CNS side effects were reported.
• Chan et al - 17 pts with newly diagnosed T4 N0 to N3 -combined
conformal proton and photon radiotherapy.
• Median dose to GTV- 73.6 CGE (range 69 to 76.8).
• 11 received twice-daily radiation
• 10 received induction or concurrent chemotherapy.
• All except one completed the planned CCRT
• At 43 months - 1 LF, 2-systemic failures.
• 3-year RFS 91% Vs. 50% CRT
• 3-year OS 91% Vs. 40%
• Late toxicities 5 - radiographic changes of the temporal lobes, 1
osteoradionecrosis of the mandible.
 Juxtaspinal Cord
Tumors
• complete surgical resection is generally
impossible
• tumor invasion or adherence to vertebrae, spinal
cord,peripheral nerve roots.
• Photon radiotherapy
• spinal cord main dose-limiting organ
• Charged particle radiotherapy,
• wrap the isodose distribution around the spinal cord
• reproducible patient immobilization easier in cervical
region
 Prostate Cancer
• Loma Linda – 319 early-stage (T1 to T2b, PSA <15 ng/mL)
• Conformal photon or proton fields to doses of 74 to 75 CGE
• At 5 years
• OS - 97%
• Biochemical DFS- 88%,
• No severe toxicity
• PROG RCT - 393 stage T1b, T2b and PSA levels <15 ng/mL
• Total dose - 70.2 or 79.2 CGE at 1.8 CGE /day, with 50.4 Gy by conformal
photons & boost of either 19.8 CGE or 28.8 CGE with protons
• free from biochemical failure at 5 years
• 61.4% for conventional-dose
• 80.4% for high-dose therapy (p <0.001).
• The advantage in both low-risk and high-risk subgroups.
• Only 1% of conventional dose and 2% high-dose radiation experienced acute
urinary or rectal morbidity of grade 3 or greater
• only 2% and 1%, late morbidity>grade 3
 Gastrointestinal Cancer

• Tsukuba University Japan- 122 pts primary

HCC -72 CGE /4 CGE per#
• 7-year LC - 94% survival - 27%, respectively.
• No clinical symptomatic liver toxicity
• only transient increase in liver transaminases
being observed.
• LLU also did similar study with similar
conclusion.
 Heavy Ion Radiotherapy
• First published clinical results - Bevalac facility
at LBL
• Stripped carbon and neon nuclei
• beam time constraints - most of patients had a
component of low LET rad & particle or photon
radiation as well.
• Hence, it is difficult to assign any benefit or
adverse effect to the heavy ions themselves in the
LBL work.
The Heavy Ion Medical Accelerator in
Chiba (HIMAC), Japan.
• Nuclei of Carbon, Neon, Silicon, & Argon.
• Currently, fully ionized 12C is the ion of choice for clinical
work.
• 12C beam of 80 keV/µm in the spread Bragg peak has
approximately equivalent RBE as 30 MeV Be neutron beam
• No randomized clinical trials
• 2,300 patients had been treated, 52.8-73.6 GyE /16#/4w
• There is a preliminary indication that nonsquamous tumors
responded better than squamous-cell carcinomas.
• Sarcoma
• Head and neck melanomas and salivary gland tumors
• Small-cell lung cancer
• Base of skull chordomas & chondrosarcomas.
 Carbon Ion Therapy

• Gesellschaft Institute – 87 chordoma pts &

low grade chondrosarcoma of skull base
– 3 yr LC – 81% chordoma, 100% chondrosarcoma
– Grade 4 , 5 toxicity was not seen.
– So it was found to be safe and valid option.
 Neon ion therapy

• High LET particle

• Tried in GBM – Overcome Radioresistance
• UCSF and LBL- 2 dose schedules 0f 20 / 25 Gy
in 4 wks compared
– No sig diff observed in OS – 13-14 months
– Optimal dose not identified.
 Meson Radiotherapy
• Sub atomic particle holding nucleons
• Produced when protons 600+MeV hit target.
• 3 types – neutral, +ve, neg
• Neg meson (pions) used
• When they decelerate, captured by nucleus causing it to explode
in a star like event producing neutron and charged nuclear
fragments
• TRIUMF Columbia – 81 High-grade gliomas
• 33-24.5 pion Vs. 60 Gy photon
• OS – 10 m both arms
• No diff in time to progression, rad toxicity, performance status QOL.
• TRIUMF – Locally advanced prostate cancer
• Photon Vs. pion
• No diff in LC/ survival, more acute toxicity grade 3,4 in bladder for
pion, no diff in late toxicity.
 Conclusion
• Neutrons were the first particles to enter widespread
clinical trials.
• Despite initial promise, neutrons have not been shown
to have widespread applicability.
• There are no ongoing multi-institutional clinical trials
taking place using neutrons.
• However, they have an established role in treatment of
some so-called radioresistant tumors such as
• salivary gland malignancies;
• sarcomas of bone and soft tissue;
• nonhormonally responsive, locally advanced prostate
cancer
 Conclusion
• In Charged-particles, majority of work has been done
with proton beams
• These beams are ideal for the treatment of well-
defined lesions in critical locations.
• Such tumors do not lend themselves well to
randomized phase III trials.
• There are a small number of centers using heavy ion
beams to treat cancers.
• In principle, such beams offer the best of both worlds
the radiobiologic advantage of high LET radiotherapy
and the precise dose delivery of proton beams.
• Need of time will be to prove whether the cost of
additional facilities is clinically justified.
• Thank you
 Technical Aspects
• Beam Production
– Cyclotrons - 80-250Mev
• continuous beams with fixed energy
• design quite simple, operation easy
• accelerator operates at a fixed radio frequency and all beam
lines are predetermined.
– Synchrotron - treat deep-seated tumors > 250MeV
• pulsed beams, energy varied from 1 cycle to next in steps
• modulation of Bragg Peak to scan a target in depth can be
achieved without absorbers,
• avoiding scattering and degradation of sharpness in energy.
• much more complicated hence more costly
 • Active-beam shaping
– tightly focused pencil beam
– deflected laterally by 2 magnetic dipoles
– Synchrotron, pulse to adapt the range of particles in tissue.
– target vol scanned in 3 dim & dose tailored to any irregular shape without any
passive absorbers or patient specific devices, like compensators or collimators.
– Therefore, the high dose region can also be conformed to proximal end of
target
– integral dose as well as the nontarget vol receive high LET radiation
• Beam-Delivery Systems (Gantries)
– Experience mainly in laboratories using horizontal beam lines.
– weight of proton gantry - 100 tons, dia- 10 meters,
– isocentric gantry for carbon ions- 600 tons,dia 13 meters
– Instead of flexible beam-delivery systems,
• fixed inclined-beam lines with vertical beams and beams with 45° inclination with horizontal
beams.
• move the patient rather than the [Link] chairs and molds that can be rotated around
the patient’s longitudinal axis by 15°.

Beam-Application Systems
Passive-beam shaping
3 major disadvantages:
• depth dose can only be tailored to
distal end of target, not to proximal end
• amount of material in the beam line is
considerable, leading to increase in
nuclear fragments
• higher LET and thus an increased
biological effective dose of the beam
already in the entrance region.
 10 3

8
R 6
O
B
E
E 2
R
4

2
1
1000
L ET 1 10 100
Argon
X ray Neon
Carbon
Neutron
 Basic Radiobiology
• The RBE versus LET curve for most systems peaks at
about 160 keV/µ.
• RBE dependent upon
• tissue type,
• chosen end point,
• dose fractionation schema,
• standard forms of radiotherapy taken to have an
RBE of 1
• protons and α-particles- 1.1 to 1.2.
• Fast neutrons- 3 to 3.5(normal tissue late effects), 4
to 4.5 (CNS), 8 (salivary gland malignancies
• Heavy charged particles -2 to 4 (most normal
tissues)
• Therefore, radiobiology of protons and α-particles
is considered to be essentially the same as that of
standard radiotherapy except at the very end of
the Bragg peak, where the LET increases. The high
LET forms of radiation offer potential therapeutic
advantages in several clinical situations.
• Mammalian cells are more radiosensitive in M and late
G1/early S phases than in early G1 and G2.
• If radiation is given to an asynchronously dividing cell
population,
• cells in sensitive portions of cycle are killed preferentially.
• Over a course of fractionated RT, cells continue through the
cycle,
• other fractions are delivered, many of formerly resistant
cells are in more sensitive phases of the cycle.
• The variation in radiosensitivity across the cell cycle is
about a factor of 4 less with high LET radiation
• Hence, tumors with long cell-cycle times theoretically
would be better treated with high LET radiation.
 Low LET radiation
• primarily kills cells via an indirect, free radical mediated
mechanism.
• free radicals are produced predominately in cell cytoplasm and
have to diffuse to the nuclear DNA (or other critical target) to
damage it.
• For this to be effective, a long free radical lifetime is desirable.
• Oxygen acts as an electron scavenger; hence, free radical
lifetimes are longer in cells that are well oxygenated.
• Oxygen also acts to stabilize the free radical damage.
• In hypoxic cells, the free radical lifetimes are shorter; hence,
these cells are protected from much of the damage.
• Thus it takes a higher radiation dose in hypoxic cells to achieve
the same biologic end point compared to the required dose in
well-oxygenated cells.
• High LET radiation
• higher proportion of direct damage to the critical
cellular targets
• therefore is not as dependent on free radical
intermediary.
• OER
• For most mammalian cells, for conventional low LET
radiation 2.5 to 3,
• high LET radiation, 1.4 to 1.7
• Although the lower OER was one of the primary motivating
factors in using high LET radiation, its actual importance in
most clinical settings may not be that great because of
reoxygenation during a course of fractionated radiotherapy.
• Another potential advantage to high LET radiation - reduced ability of cells
to repair radiation damage it produces.
• dense chain of ionization events produced by high LET radiation
• causes simultaneous damage to both strands of the cellular DNA.
• Cell survival curves for low LET radiation exhibit a shoulder at low radiation
doses, indicating the ability of the cells to repair this sublethal damage.
• High LET radiation,exhibits a very reduced shoulder,
• cell survival curve that is almost log-linear in shape over the range of radiation doses of
clinical relevance
• therefore tumors having a large capacity for radiation damage repair to be best treated
with high LET radiation.
• Although the cell survival curves for experimental tumor types vary considerably
• it does appear that tumors where there is a clinically proven advantage for high LET
radiation fall into this category.
• Another type of radiation damage is potentially lethal damage, which occurs in cells
that are in a noncycling, plateau phase .
• In laboratory important in tumors having a large fraction of cells in G0 phase of cell
cycle.
• This repair is less pronounced for high LET radiation than for low LET radiation.
• 1938-1943 Robert Stone Rx 240 patients with fast neutron radiotherapy.
• Beams had depth-dose properties similar to those of orthovoltage x-rays,
• many of his patients had received prior radiotherapy.
• There were few long-term survivors
• the patients who did survive experienced severe radiation sequelae.
• review of Stone's work by Brennan and Phillips showed
• inappropriate value for RBE had been used and therefore Stone's patients
inadvertently had been overdosed.
• 1960s Catterall et al concluded
• with appropriate fractionation schemas, neutron radiation was well
tolerated and many advanced tumors responded extremely well.
• There are currently five operating neutron radiotherapy facilities, which
are listed in Table 18.1 along with some of their more important
characteristics.
 COMPARATIVE BEAM
CHARACTERISTICS
• No one kind of radiation beam is ideal for radiation therapy.
• Physical advantages of a radiation therapy beam are derived from
the depth-dose distributions and scatter characteristics. Figures
5.13, 5.14, and 5.15 compare the depth-dose characteristics of
various beams. It is seen that the depth dose distribution of
neutron beams is qualitatively similar to the 60Co γ rays. The heavy
charged particle beams, the Bragg peaks of which were modulated
using filters (as is typically done in clinical situations), show a flat
dose distribution at the peak region and a sharp dose dropoff
beyond the range. Electron beams also show a constant dose
region up to about half the particle range and a sharp dose dropoff
beyond that point. However, for higher electron energies, the
characteristic falloff in dose becomes more gradual. Protons, on the
other hand, maintain a sharp cutoff in dose beyond the range,
irrespective of energy.
• Charged Particle Radiotherapy
• When charged particles pass through tissue, they deposit most of their energy at the end of their path, producing a
so-called Bragg peak. The particular depth at which this occurs depends on the energy, mass, and charge of the
particle. The main advantage of charged particle radiotherapy lies in the sharp falloff of dose beyond this Bragg
peak and the smaller amount of energy deposited in intervening tissue. The lateral edges of the fields can also be
sharper up to certain depths in tissue because of less large-angle scattering. The size of the Bragg peak along the
axis of the beam is only a few millimeters, as is the cross section of the beam as it exits the accelerator. Applying
such beams to cancer therapy requires specialized technology in order to match the dose distribution to the size,
location, and shape of the tumor.
• Historically, the particle beam was shaped to the tumor size by passive scattering and collimation methods, and
this is the method currently used in the majority of charged particle facilities. Improvements in magnets,
computers and control systems have recently made it practical to actively scan the small Bragg peak throughout
the tumor volume. The Paul Scherrer Institute (PSI) in Villigen, Switzerland, and the Gesellschaft for
Schwerionenforschung (GSI) in Darmstadt, Germany, have implemented some aspects of these advanced
methods. Active scanning allows the high-dose Bragg peak region to be more tightly confined to the tumor volume
and scatter to be reduced. There is also the potential for intensity modulated proton therapy (IMPT). The
disadvantages are the increased technology and the fact that the dose is delivered at different times to different
parts of the tumor, which can be problematic if there is tissue movement. These are the same problems faced in
using intensity modulated photon therapy (IMRT).
• IMRT offers some of the dose localization advantages of charged particles, particularly when passive scattering and
collimation methods are utilized. However, charged particles still appear superior in terms of reducing the integral
dose, reducing the time needed to treat (since fewer beams are needed), and using the Bragg peak to provide near
total sparing of selected normal tissues. These advantages suggest applications to the treatment and retreatment
of tumors adjacent to critical structures already at tolerance doses, of pediatric tumors, and of lung tumors where
normal tissue integral dose constraints are important. IMPT theoretically will increase these advantages.
• In the 1950s clinical trials using charged particles began at LBL first with protons and then with α-particles. Both
high-energy protons and α-particles are considered to be low LET particles with clinical RBEs in the range of 1.1 to
1.2; therefore, their advantage over conventional photon radiotherapy lies entirely in their better dose-localization
properties. Although there are no facilities currently using α-particles for therapy, there is burgeoning interest in
the use of proton beams. As of July 2005 there were 19 treatment centers using proton radiotherapy throughout
the world (Table 18.3). In addition, approximately 20 facilities are in various stages of the planning or construction
process. Many of the older centers use fixed, horizontal beams, with eye tumors and arteriovenous malformations
(AVMs) of the CNS being the most common entities treated. The newer, more modern centers have higher energy
beams coupled with isocentric gantries, making it possible to treat tumors located anywhere in the body.
• “Heavy” ions such as carbon, nitrogen, argon, neon, and silicon nuclei stripped of their
electrons are high LET particles and combine the depth-dose localization properties of protons and
α-particles with the RBE advantage of fast neutrons. Clinical trials using heavy, charged particles
began at LBL in 1975 with a total of 433 patients being treated before the project was
discontinued. Currently there are three active centers treating with heavy particles: HIMAC in
Chiba, Japan; HARIMAC in Hyogo, Japan; and GSI in Darmstadt, Germany. Most of the ongoing
clinical work utilizes carbon nuclei. A new combined proton-heavy ion radiotherapy center is being
planned in Heidelberg, Germany.
• Ï€-mesons are a third category of particle radiation that has been used clinically. Ï€-mesons
mediate the binding force between nuclear particles and can be produced in significant quantities
when a high-energy proton beam impacts a suitable target. Although there are three charge states
for the π-meson, only the π--meson has been used clinically. It is attractive for radiotherapeutic
purposes because when it “slows down” it is captured by a nucleus, causing it to
“explode” in a shower of charged particles and neutrons. It provides a mixture of high and
low LET components as a result of its high energy and low mass compared to the proton. It
deposits low LET events along its entry path, with the high LET events being confined to the
“peak” region at the end of its path. Clinical trials using π-mesons began at Los Alamos, New
Mexico, in 1974, with 272 patients being treated before 1982 when the project was closed because
of lack of accrual. Other π-meson projects were carried out at the TRIUMF facility in Vancouver,
British Columbia, and at the Swiss Institute for Nuclear Physics Research (SIN) facility in Villigen,
Switzerland. There are no clinical centers currently treating with π-mesons.
• P.413
•
According to unpublished data compiled by the Proton Therapy Co-Operative Group (PTCOG), as of
July 2005 a total of 48,386 patients had received some form of particle radiotherapy: 1,100 with π-
mesons, 4,520 with heavy ions or α-particles, and 42,766 with protons. In the following sections
we will review the clinical results for each of these modalities. Because of their similar properties,
we will discuss protons and α-particles together.
• Proton and α-Particle Radiotherapy
• Although there is a slight difference in the clinically employed RBEs of protons and
α-particles, 1.1 and 1.3 respectively, both are considered “low LET” forms of
radiation. Doses are typically specified in terms of “cobalt gray equivalent”
(CGE) where CGE equals the physical dose multiplied by RBE. The first clinical trials
in the United States using these particles began in the 1970s with α-particles at
LBL and with protons at the Massachusetts General Hospital–Harvard Cyclotron
Laboratory (MGH–HCL). The majority of treated patients had tumors adjacent to
critical structures and so in most cases it was not felt possible to conduct
randomized trials with photon radiotherapy. With the advent of photon IMRT, it
now may be possible to conduct certain trials and directly compare the two
modalities. However, it is important to recognize that the better target volume
dose of photon IMRT comes at the price of increased doses to normal tissue at low
to moderate levels. This increased “integral dose” associated with IMRT may
put patients at increased risk for secondary radiation-induced malignancies (54).
This is particularly important in the treatment of pediatric patients, where other
consequences of radiation dose to normal tissue such as growth retardation or
arrest, gonadal injury, pneumonitis, or late cardiac injury might be eliminated or
reduced with protons.
• Between 1976 and 1987, 52 patients with juxtaspinal cord tumors were treated with α particles at
LBL (99). A mix of tumors was involved consisting of chordomas, chondrosarcomas, and other types
of sarcomas, and there were patients with metastatic lesions. The tumors were distributed along
the cord, with 16 occurring in the cervical spine, 23 in the thoracic spine, 11 in the lumbar spine,
and two in both the thoracic and lumbar spine. The median tumor dose was 70 CGE. An overall
local control rate of 52% was achieved. Only one patient developed a radiation myelitis. Fifty-one
patients with chordomas of the cervical spine were treated at MGH–HCL between 1975 and
1993. A local control rate of 65% was achieved (32). Hug et al. (62) presented results on combined
photon/proton treatment of 47 patients with osteo- and chondrogenic tumors of the axial
skeleton. Actuarial local control (5-year) and survival for patients with chondrosarcoma were 100%
and 100%, and with chordoma were 53% and 50%. Actuarial 5-year local control for patients with
osteosarcoma was 59%.
• Weber et al. (125) carried out a treatment planning comparison of IMRT and IMPT for paraspinal
sarcomas. Plans for five patients were computed for IM photons (seven coplanar fields) and
protons (three coplanar beams). Prescribed dose was 77.4 CGE for protons to the gross tumor
volume. Surface and center spinal cord dose constraint for all techniques was 64 and 53 CGE,
respectively. Gross tumor volume coverage was optimal and equally homogeneous with both IM
photon and IM proton plans. Median heart, lung, kidney, stomach, and liver mean dose and dose
at the 50% volume level were consistently reduced by a factor of 1.3 to 25. Tumor dose
homogeneity in IMPT plans was always better than IMRT plans. IMPT dose escalation (to 92.9 CGE
to the GTV) was possible in all patients without exceeding the normal-tissue dose limits.
• Arteriovenous Malformations of the Brain
• Surgery has been the most widely used method for treating AVMs, with its primary advantage being its ability to reduce the risk of immediate
hemorrhage. Surgery, however, is associated with varying degrees of morbidity, dependent largely on location and size of the AVM. Radiation
therapy in the form of stereotactic radiotherapy also has been used in the treatment of AVMs, especially in deeply seated lesions ill suited for surgical
resection. Both charged particles and photons from either a gamma knife or a specially modified linear accelerator have been used in this manner.
• Success rates with radiosurgery are highly dependent on the volume of the AVM treated. Using gamma knife technology, researchers at the
University of Pittsburgh have demonstrated 2-year obliteration rates of 100% for lesions smaller than 1 cm in diameter, 85% for those 1 to 4 cm, and
58% for those larger than 4 cm (89). Stereotactic radiosurgery using modified linear accelerators yields similar 2-year complete obliteration rates in
the range of 29.4% to 84%. In particular, Colombo et al. (22) report complete obliteration rates of 96% for lesions <1.5 cm diameter, 74% for those
1.5 to 2.5 cm, and 33% for those larger than 2.5 cm. Protons and other charged particles have been used in the treatment of AVMs since 1965.
Kjellberg et al. (70,71) have treated more than 1,000 patients with AVMs using protons generated from the 160 MeV Harvard Cyclotron, reporting a
20% complete angiographic obliteration rate, with 56% of AVMs showing a reduction in volume of more than 50%. Charged-particle therapy at LBL
has been used to treat more than 400 patients. Published results demonstrate complete, angiographically determined obliteration rates at 3 years of
100% for lesions smaller than 4 cc volume, 95% for those 4 to 25 cm3, and 70% for lesions larger than 25 cm3 (31). Smaller lesion size and higher
radiation doses correlated with a more rapid response. The complication rate correlated directly with AVM size and dose received. Large AVMs
(diameters >3 cm) may be better treated with charged particles due to their dose-localization properties.
• Lung Cancer
• Bush et al. (11) performed a prospective study to assess the efficacy and toxicity of proton beam therapy for patients with inoperable stage I to IIIA
non–small-cell lung cancer (27 stage P.418
•
I, 2 stage II, 8 stage IIIA). Thirty-seven patients were treated with either 45 Gy photon therapy to the primary tumor and mediastinum followed by
28.8 CGE boost to the primary with protons, or in cases of limited cardiopulmonary reserve, 51 CGE proton therapy in 10 fractions only to the
primary site. At a median follow up of 14 months, actuarial disease-free survival was 63% for the entire group and 86% for patients with stage I
disease. Two cases of radiation pneumonitis were diagnosed with both responding to a short course of steroids. The authors concluded that high
dose proton radiation could be delivered safely to patients with poor pulmonary function.