NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Small Cell Lung

Cancer
Version 2.2017 — September 15, 2016
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 NCCN Guidelines Version 2.2017 Panel Members NCCN Guidelines Index
Table of Contents
Small Cell Lung Cancer Discussion

* Gregory P. Kalemkerian, MD/Chair † John C. Grecula, MD § Nisha Mohindra, MD †

University of Michigan The Ohio State University Comprehensive Robert H. Lurie Comprehensive Cancer
Comprehensive Cancer Center Cancer Center - James Cancer Hospital Center of Northwestern University
and Solove Research Institute
* Billy W. Loo, Jr., MD, PhD/Vice Chair § Julian Molina, MD, PhD ‡ Þ
Stanford Cancer Institute Matthew A. Gubens, MD, MS † Mayo Clinic Cancer Center
UCSF Helen Diller Family
Wallace Akerley, MD † Comprehensive Cancer Center Cesar A. Moran, MD ≠
Huntsman Cancer Institute The University of Texas
at the University of Utah Christine L. Hann, MD, PhD † MD Anderson Cancer Center
The Sidney Kimmel Comprehensive
Albert Attia, MD § Cancer Center at Johns Hopkins Daniel Morgensztern, MD †
Vanderbilt-Ingram Cancer Center Siteman Cancer Center at Barnes-
James A. Hayman, MD, MBA § Jewish Hospital and Washington
Laura QM Chow, MD † University of Michigan University School of Medicine
Fred Hutchinson Cancer Research Comprehensive Cancer Center
Center/Seattle Cancer Care Alliance Saraswati Pokharel, MD ≠
Rebecca Suk Heist, MD, MPH † Roswell Park Cancer Institute
Roy Decker, MD, PhD § Massachusetts General Hospital
Yale Cancer Center/Smilow Cancer Hospital Cancer Center David C. Portnoy, MD ‡ †
The University of Tennessee
M. Chris Dobelbower, MD, PhD § Marianna Koczywas, MD † ‡ Þ Health Science Center
University of Alabama at Birmingham City of Hope Comprehensive
Comprehensive Cancer Center Cancer Center Neal Ready, MD, PhD †
Duke Cancer Institute
Afshin Dowlati, MD † Ranee Mehra, MD †
Case Comprehensive Cancer Center/ Fox Chase Cancer Center Chad Rusthoven, MD §
University Hospitals Seidman Cancer University of Colorado Cancer Center
Center and Cleveland Clinic Taussig Robert E. Merritt, MD ¶
Cancer Institute The Ohio State University Comprehensive Charles C. Williams, Jr., MD †
Cancer Center - James Cancer Hospital Moffitt Cancer Center
Robert J. Downey, MD ¶ and Solove Research Institute
Memorial Sloan Kettering Cancer Center NCCN
Karin G. Hoffmann, RN, CCM
Charles Florsheim Miranda Hughes, PhD
Patient Advocate
† Medical oncology
Apar Kishor P. Ganti, MD †
Fred & Pamela Buffett Cancer Center ¶ Surgery/Surgical oncology
§ Radiation oncology
‡ Hematology/Hematology oncology
Þ Internal medicine
≠ Pathology
NCCN Guidelines Panel Disclosures *Discussion Section Writing Committee
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Table of Contents
Small Cell Lung Cancer Discussion

NCCN Small Cell Lung Cancer Panel Members

Summary of the Guidelines Updates
Clinical Trials: NCCN believes that
Small Cell Lung Cancer: the best management for any patient
• Initial Evaluation and Staging (SCL-1) with cancer is in a clinical trial.
• Limited Stage, Workup and Treatment (SCL-2) Participation in clinical trials is
• Extensive Stage, Initial Treatment (SCL-4) especially encouraged.
• Response Assessment Following Initial Therapy (SCL-5) To find clinical trials online at NCCN
• Surveillance (SCL-5) Member Institutions, click here:
• Progressive Disease: Subsequent Therapy and Palliative Therapy (SCL-6) [Link]/clinical_trials/[Link].
• Principles of Surgical Resection (SCL-A) NCCN Categories of Evidence and
• Principles of Supportive Care (SCL-B) Consensus: All recommendations
are category 2A unless otherwise
• Principles of Systemic Therapy (SCL-C) specified.
• Principles of Radiation Therapy (SCL-D)
See NCCN Categories of Evidence
Lung Neuroendocrine Tumors: and Consensus.
• Workup and Primary Treatment (LNT-1)
4Low-grade neuroendocrine carcinoma (typical carcinoid)
4Intermediate-grade neuroendocrine carcinoma (atypical carcinoid)
4High-grade neuroendocrine carcinoma (large-cell neuroendocrine carcinoma)
4High-grade neuroendocrine carcinoma (small cell carcinoma)
4Combined SCLC and NSCLC
• Primary and Adjuvant Treatment (LNT-2)
• Principles of Systemic Therapy (LNT-A)
Staging (ST-1)

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.
Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical
circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or
warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not
be reproduced in any form without the express written permission of NCCN. ©2016.
Version 2.2017, 09/15/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®
 NCCN Guidelines Version 2.2017 Updates NCCN Guidelines Index
Table of Contents
Small Cell Lung Cancer Discussion

Updates in Version 2.2017 of the NCCN Guidelines for Small Cell Lung Cancer from Version 1.2017 include:
MS-1
The Discussion section has been updated to reflect the changes in the algorithm.
Updates in Version 1.2017 of the NCCN Guidelines for Small Cell Lung Cancer from Version 1.2016 include:
SCL-1
• Initial evaluation
Bullet 3 modified: “CBC with differential, platelets”
Bullet 6 modified: “Chest/liver/adrenal CT with contrast whenever possible”
Bullet 7 modified: “Brain MRI (preferred) or CT with contrast whenever possible” (Also for SCL-5)
SCL-2
• Clinical stage T1-2, N0
Pathway statement removed: PET-CT scan “(if not previously obtained)”
Footnote removed: “PET-CT scan to identify distant disease and to guide mediastinal evaluation, if not previously done.”
SCL-3
• Initial Treatment
Clinical stage T1-2, N0; Pathologic mediastinal staging positive or medically inoperable or decision made not to pursue surgical resection:
Recommendations combined with Limited stage in excess of T1-2, N0.
Limited stage in excess of T1-2, N0, initial treatment option modified: “Systemic therapy ± RT (concurrent or sequential)”
Footnote “m” added: “For patients receiving adjuvant therapy, response assessment should occur only after completion of initial therapy
(SCL-5); do not repeat scans to assess response during adjuvant treatment.”
Footnote “n” added: “For patients receiving systemic therapy + concurrent RT, response assessment should occur only after completion
of initial therapy (SCL-5); do not repeat scans to assess response during initial treatment. For patients receiving systemic therapy alone or
sequential systemic therapy followed by RT, response assessment by CT chest/liver/adrenal with contrast should occur after every 2 cycles
of systemic therapy and at completion of therapy (SCL-5).”
SCL-4
• Footnote “o” added: “For patients with asymptomatic brain metastases receiving systemic therapy before whole-brain RT, brain MRI
(preferred) or CT with contrast should be repeated after every 2 cycles of systemic therapy and at completion of therapy (SCL-5).”
• Footnote “p” added: “During systemic therapy, response assessment by CT chest/liver/adrenal with contrast should occur after every 2–3
cycles of systemic therapy and at completion of therapy (SCL-5).”
SCL-5
• Response Assessment Following Initial Therapy
Bullet 2 modified: “Chest/liver/adrenal CT with contrast whenever possible”
Bullet 3 modified: “Brain MRI (preferred) or CT with contrast whenever possible, if prophylactic cranial irradiation (PCI) to be given”
Bullet removed: “Other imaging studies, to assess prior sites of involvement, as clinically indicated”
Bullet 5 modified: “CBC, platelets”
• Adjuvant Treatment; Extensive disease: “PCI + thoracic RT” changed to “PCI ± thoracic RT.”
• Surveillance; Bullet 1, sub-bullet 1 modified: “At every visit: H&P, CT chest imaging/liver/adrenal, bloodwork as clinically indicated”
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UPDATES
 NCCN Guidelines Version 2.2017 Updates NCCN Guidelines Index
Table of Contents
Small Cell Lung Cancer Discussion

Updates in Version 1.2017 of the NCCN Guidelines for Small Cell Lung Cancer from Version 1.2016 include:
SCL-6
• Footnote “s” added: “A response assessment by CT chest/liver/adrenal with contrast should occur after every 2–3 cycles of systemic
therapy.”
SCL-A
• Reference “5” added: “Yang CE, Chan DY, Speicher PJ, et al. Role of adjuvant therapy in a population based cohort of patients with early-
stage small-cell lung cancer. J Clin Oncol 2016;34:1057-1064.”
SCL-C 1 OF 3
• Title modified: “Principles of Chemotherapy Systemic Therapy” (also applies to SCL-C 2 of 3 and SCL-C 3 of 3)
• Systemic therapy as primary therapy or adjuvant therapy; Extensive stage: Carboplatin and etoposide regimen moved from bullet 4 to bullet
1.
• Subsequent systemic therapy
The decision point of “relapse <2–3 mo, PS 0-2” versus “relapse >2–3 mo up to 6 mo” removed.
Category 1 removed from topotecan.
Ifosfamide removed as an option.
Nivolumab ± ipilimumab added as a treatment option as a category 2A.
Statement modified: “Consider dose reduction versus growth factors in the poor performance status patient or growth factor support for
patients with PS 2”
SCL-C 2 OF 3
• Response Assessment section is new to the guideline (SCL-C 2 of 3).
SCL-D 2 of 3
• Brain Metastases
Bullet 1 modified: “Brain metastases should be treated with whole brain radiation therapy (WBRT) rather than stereotactic radiotherapy/
radiosurgery (SRT/SRS) alone, because these patients tend to develop multiple CNS metastases. In patients who develop brain metastases
after PCI, repeat WBRT may be considered in carefully selected patients. SRS may also be considered, especially if there has been a long-
time interval from initial diagnosis to occurrence of brain metastases and there is no uncontrolled extracranial disease.”

UPDATES
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 NCCN Guidelines Version 2.2017 NCCN Guidelines Index
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Small Cell Lung Cancer Discussion

DIAGNOSIS INITIAL EVALUATIONa STAGE

• H&P
• Pathology review
• CBC Limited stage
• Electrolytes, liver function tests See Additional
(See ST-1 for TNM
Small cell or (LFTs), Ca, LDH Workup (SCL-2)
Classification)
combined small • BUN, creatinine
cell/non-small cell • Chest/liver/adrenal CT with
lung cancer on contrast
biopsy or cytology • Brain MRIa,b (preferred) or CT with
of primary or contrast Extensive stage
metastatic site See Initial
• PET/CT scan (if limited stage is (See ST-1 for TNM
Treatment (SCL-4)
suspected)a,c Classification)
• Smoking cessation counseling
and intervention. See the NCCN
Guidelines for Smoking Cessation

aIf extensive stage is established, further staging evaluation is optional. However, brain imaging, MRI (preferred), or CT with contrast should be obtained in all patients.
bBrain MRI is more sensitive than CT for identifying brain metastases and is preferred over CT.
cIf PET/CT is not available, bone scan may be used to identify metastases. Pathologic confirmation is recommended for lesions detected by PET/CT that alter stage.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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SCL-1
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Small Cell Lung Cancer Discussion

STAGE ADDITIONAL WORKUP

• If pleural effusion is present, Clinical stage Pathologic mediastinal See Initial

thoracentesis is T1-2, N0 stagingf,g,h Treatment (SCL-3)
recommended; if
thoracentesis inconclusive,
consider thoracoscopyd
Limited stage • Pulmonary function tests
(See ST-1 for TNM Limited stage in See Initial
(PFTs) (if clinically indicated)
Classification) excess of T1-T2, N0 Treatment (SCL-3)
• Bone imaging (radiographs
or MRI) as appropriate if
PET/CT equivocal
• Unilateral marrow
aspiration/biopsy in select Bone marrow biopsy, See
patientse thoracentesis, or bone studies Extensive-Stage
consistent with malignancy Disease (SCL-4)

dWhile most pleural effusions in patients with lung cancer are due to tumor, there are a few patients in whom multiple cytopathologic examinations of pleural fluid are
negative for tumor and fluid is non-bloody and not an exudate. When these elements and clinical judgment dictate that the effusion is not related to the tumor, the
effusion should be excluded as a staging element. Pericardial effusion is classified using the same criteria.
eSelection criteria include: nucleated red blood cells (RBCs) on peripheral blood smear, neutropenia, or thrombocytopenia suggestive of bone marrow infiltration.
fSee Principles of Surgical Resection (SCL-A).
gMediastinal staging procedures include mediastinoscopy, mediastinotomy, endobronchial or esophageal ultrasound-guided biopsy, and video-assisted thoracoscopy.
If endoscopic lymph node biopsy is positive, additional mediastinal staging is not required.
hPathologic mediastinal staging is not required if the patient is not a candidate for surgical resection or if non-surgical treatment is pursued.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Version 2.2017, 09/15/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®
SCL-2
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Small Cell Lung Cancer Discussion

TESTING RESULTS INITIAL TREATMENTi ADJUVANT TREATMENT

Lobectomyf,j N0 Systemic therapyk See Response

(preferred) and Assessment +
Pathologic mediastinal
mediastinal lymph
stagingf,g negative Concurrent Adjuvant Treatment
node dissection (SCL-5)m
N+ systemic therapyk
or sampling
+ mediastinal RTl
Clinical stage
T1-2, N0
Pathologic
mediastinal stagingf,g
positive or medically
inoperable or decision
made not to pursue
surgical resection

Systemic therapyk + See Response

Good PS (0-2)
concurrent RTl (category 1) Assessment +
Adjuvant Treatment
Limited stage in Poor PS (3-4) Systemic therapyk ± RTl (SCL-5)n
excess of T1-2, N0 due to SCLC (concurrent or sequential)
Poor PS (3-4) not Individualized treatment
due to SCLC including supportive carei

fSee Principles of Surgical Resection (SCL-A).

gMediastinal staging procedures include mediastinoscopy, mediastinotomy, endobronchial or esophageal ultrasound-guided biopsy, and video-assisted thoracoscopy. If endoscopic lymph
node biopsy is positive, additional mediastinal staging is not required.
iSee Principles of Supportive Care (SCL-B).
jSelect patients may be treated with systemic therapy/RT as an alternative to surgical resection.
kSee Principles of Systemic Therapy (SCL-C).
lSee Principles of Radiation Therapy (SCL-D).
mFor patients receiving adjuvant therapy, response assessment should occur only after completion of initial therapy (SCL-5); do not repeat scans to assess response during adjuvant
treatment.
nFor patients receiving systemic therapy + concurrent RT, response assessment should occur only after completion of initial therapy (SCL-5); do not repeat scans to assess response
during initial treatment. For patients receiving systemic therapy alone or sequential systemic therapy followed by RT, response assessment by CT chest/liver/adrenal with contrast should
occur after every 2 cycles of systemic therapy and at completion of therapy (SCL-5).

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Version 2.2017, 09/15/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®
SCL-3
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Small Cell Lung Cancer Discussion

STAGE INITIAL TREATMENTi

• Good PS (0-2)
Combination systemic therapyk including
• Poor PS (3-4)
Extensive stage supportive carei
due to SCLC
without localized See NCCN Guidelines for Palliative Care
symptomatic sites
or brain metastases • Poor PS (3-4) Individualized therapy including
not due to supportive carei
SCLC See NCCN Guidelines for Palliative Care
Systemic therapyk ± RTl to
symptomatic sites
• SVC syndrome
If high risk of fracture due to osseous
• Lobar obstruction
structural impairment, consider See Response
• Bone metastases
Extensive stage Extensive stage + orthopedic stabilization and Assessment +
(See ST-1 for TNM localized palliative external-beam RTl Adjuvant Treatment
Classification) symptomatic sites RTl to symptomatic sites before (SCL-5)p
systemic therapy unless immediate
Spinal cord
systemic therapy is required.
compression
See NCCN Guidelines for Central
Nervous System Cancers

May administer systemic therapy first, with

Asymptomatic whole-brain RTl after systemic therapyk,o
Extensive stage with
brain metastases
Whole-brain RTl before systemic therapy,k
Symptomatic unless immediate systemic therapy is
indicated
iSee Principles of Supportive Care (SCL-B).
kSee Principles of Systemic Therapy (SCL-C).
lSee Principles of Radiation Therapy (SCL-D).
oFor patients with asymptomatic brain metastases receiving systemic therapy before whole-brain RT, brain MRI (preferred) or CT with contrast should be repeated after
every 2 cycles of systemic therapy and at completion of therapy (SCL-5).
pDuring systemic therapy, response assessment by CT chest/liver/adrenal with contrast should occur after every 2–3 cycles of systemic therapy and at completion of
therapy (SCL-5).

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Version 2.2017, 09/15/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®
SCL-4
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Small Cell Lung Cancer Discussion

RESPONSE ASSESSMENT FOLLOWING ADJUVANT SURVEILLANCE

INITIAL THERAPY TREATMENT
After recovery from primary
therapy:
• Oncology follow-up visits
Limited
PCIl,q (category 1) every 3–4 mo during y 1–2,
Complete stage every 6 mo during y 3–5,
response then annually
or partial At every visit: H&P,
response Extensive PCIl,q CT chest/liver/adrenal,
± thoracic RTl,r For Relapse,
stage bloodwork as clinically
• Chest x-ray (optional) see Subsequent
indicated
• Chest/liver/adrenal CT with Therapy (SCL-6)
• New pulmonary nodule
contrast should initiate workup for
• Brain MRIb (preferred) or CT potential new primary
with contrast, if prophylactic Stable • Smoking cessation
cranial irradiation (PCI) to be disease intervention, see the NCCN
given Guidelines for Smoking
• CBC Cessation
• Electrolytes, LFTs, Ca, BUN, • PET/CT is not recommended
creatinine for routine follow-up

Primary
See Subsequent Therapy/
progressive
Palliative Therapy (SCL-6)
disease

bBrain MRI is more sensitive than CT for identifying brain metastases and is preferred over CT.
lSee Principles of Radiation Therapy (SCL-D).
qNot recommended in patients with poor performance status or impaired neurocognitive function.
rSequential radiotherapy to thorax in selected patients with low-bulk metastatic disease and complete response (CR) or near CR after systemic therapy.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
SCL-5
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Small Cell Lung Cancer Discussion

PROGRESSIVE DISEASE SUBSEQUENT THERAPY/PALLIATIVE THERAPY

Consider
subsequent
Continue until two systemic
cycles beyond Progression therapyk,s or
best response PS 0-2 Palliative symptom
or management,
Response including localized
Progression or
development of RTl to symptomatic
Subsequent
sites
systemic therapyk,s unacceptable
(see SCL-C) toxicity Palliative
or symptom
PS 0-2 Palliative symptom No management,
PS 3-4
management, response or including
including localized unacceptable localized RTl to
RTl to symptomatic toxicity symptomatic sites
Relapse sites
or primary
progressive
disease

Palliative symptom
management, including
PS 3-4
localized RTl to
symptomatic sites

kSee Principles of Systemic Therapy (SCL-C).

lSee Principles of Radiation Therapy (SCL-D).
sResponse assessment by CT chest/liver/adrenal with contrast should occur after every 2–3 cycles of systemic therapy.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
SCL-6
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Small Cell Lung Cancer Discussion

PRINCIPLES OF SURGICAL RESECTION

• Stage I SCLC is diagnosed in less than 5% of patients with SCLC.
• Patients with disease in excess of T1-2, N0 do not benefit from surgery.1
• Patients with SCLC that is clinical stage I (T1-2, N0) after standard staging evaluation (including CT of the chest and upper abdomen, brain
imaging, and PET/CT imaging) may be considered for surgical resection.
Prior to resection, all patients should undergo mediastinoscopy or other surgical mediastinal staging to rule out occult nodal disease. This
may also include an endoscopic staging procedure.
Patients who undergo complete resection (preferably by a lobectomy with either mediastinal nodal dissection or sampling) should be
treated with postoperative systemic therapy. Patients without nodal metastases should be treated with systemic therapy alone. Patients
with nodal metastases should be treated with postoperative concurrent systemic therapy and mediastinal radiation therapy (RT).
• Because PCI can improve both disease-free and overall survival in patients with SCLC who have complete or partial response, PCI is
recommended after adjuvant systemic therapy in patients who have undergone a complete resection.2 PCI is not recommended in patients
with poor performance status or impaired neurocognitive functioning.3,4,5

1Lad T, Piantadosi S, Thomas P, et al. A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell
lung cancer to combination chemotherapy. Chest 1994;106:320S-3S.
2Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell cancer in complete remission. Prophylactic Cranial Irradiation
Overview Collaborative Group. N Engl J Med 1999;341:476-84.
3Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007;357:664-672.
4Le Péchoux C, Dunant A, Senan S, et al. Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in
complete remission after chemotherapy and thoracic radiotherapy. Lancet Oncol 2009;10(5):467-474.
5Yang CE, Chan DY, Speicher PJ, et al. Role of adjuvant therapy in a population based cohort of patients with early-stage small-cell lung cancer. J Clin Oncol
2016;34:1057-1064.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
SCL-A
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Small Cell Lung Cancer Discussion

PRINCIPLES OF SUPPORTIVE CARE

• Smoking cessation advice, counseling, and pharmacotherapy
Use the 5 A’s Framework: Ask, Advise, Assess, Assist, Arrange ([Link]
See NCCN Guidelines for Smoking Cessation

• Granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) is not recommended during
concurrent systemic therapy plus radiotherapy (category 1 for not using GM-CSF).1

• Syndrome of inappropriate antidiuretic hormone

Fluid restriction
Saline infusion for symptomatic patients
Antineoplastic therapy
Demeclocycline
Vasopressin receptor inhibitors (conivaptan, tolvaptan)

• Cushing’s syndrome
Consider ketoconazole. If not effective, consider metyrapone.
Try to control before initiation of antineoplastic therapy

• Leptomeningeal disease: See NCCN Guidelines for Carcinomatous/Lymphomatous Meningitis

• Pain management: See NCCN Guidelines for Adult Cancer Pain

• Nausea/vomiting: See NCCN Guidelines for Antiemesis

• Psychosocial distress: See NCCN Guidelines for Distress Management

• See NCCN Guidelines for Palliative Care as indicated

1Bunn PA, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell
lung cancer: a prospective phase III randomized study of the Southwest Oncology Group. J Clin Oncol 1995;13:1632-1641.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
SCL-B
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Small Cell Lung Cancer Discussion

PRINCIPLES OF SYSTEMIC THERAPY* (1 of 3)

Systemic therapy as primary or adjuvant therapy: Subsequent systemic therapy:
• Limited stage (maximum of 4–6 cycles): • Clinical trial preferred.
Cisplatin 60 mg/m2 day 1 and etoposide 120 mg/m2 days 1, 2, 31
Cisplatin 80 mg/m2 day 1 and etoposide 100 mg/m2 days 1, 2, 32 • Relapse ≤6 mo, PS 0-2:
Carboplatin AUC 5–6 day 1 and etoposide 100 mg/m2 days 1, 2, 33 topotecan PO or IV11-13
During systemic therapy + RT, cisplatin/etoposide is recommended irinotecan14
(category 1). paclitaxel15,16
The use of myeloid growth factors is not recommended during docetaxel17
concurrent systemic therapy plus radiotherapy (category 1 for not temozolomide18,19
using GM-CSF).** nivolumab ± ipilimumab20
vinorelbine21,22
• Extensive stage (maximum of 4–6 cycles): oral etoposide23,24
Carboplatin AUC 5–6 day 1 and etoposide 100 mg/m2 days 1, 2, 34 gemcitabine25,26
Cisplatin 75 mg/m2 day 1 and etoposide 100 mg/m2 days 1, 2, 35 cyclophosphamide/doxorubicin/vincristine (CAV)11
Cisplatin 80 mg/m2 day 1 and etoposide 80 mg/m2 days 1, 2, 36 bendamustine (category 2B)27
Cisplatin 25 mg/m2 days 1, 2, 3 and etoposide 100 mg/m2 days 1, 2, 37
Carboplatin AUC 5 day 1 and irinotecan 50 mg/m2 days 1, 8, 158 • Relapse >6 mo: original regimen28,29
Cisplatin 60 mg/m2 day 1 and irinotecan 60 mg/m2 days 1, 8, 159
Cisplatin 30 mg/m2 and irinotecan 65 mg/m2 days 1, 810 Consider dose reduction or growth factor support for patients
with PS 2

Response Assessment SCL-C 2 of 3

References on SCL-C 3 of 3

*The regimens included are representative of the more commonly used regimens for small cell lung cancer. Other regimens may be acceptable.
**Bunn PA, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell
lung cancer: a prospective phase III randomized study of the Southwest Oncology Group. J Clin Oncol 1995;13:1632-1641.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. SCL-C
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1 OF 3
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Small Cell Lung Cancer Discussion

PRINCIPLES OF SYSTEMIC THERAPY (2 of 3)

Response assessment
• Limited-stage
For patients receiving adjuvant therapy, response assessment should occur only after completion of initial therapy; do not repeat scans to
assess response during adjuvant treatment.
For patients receiving systemic therapy + concurrent RT, response assessment should occur only after completion of initial therapy; do not
repeat scans to assess response during initial treatment.
For patients receiving systemic therapy alone or sequential systemic therapy followed by RT, response assessment by CT chest/liver/
adrenal with contrast should occur after every 2 cycles of systemic therapy and at completion of therapy.

• Extensive-stage
During systemic therapy, response assessment by CT chest/liver/adrenal with contrast should occur after every 2–3 cycles of systemic
therapy and at completion of therapy.
For patients with asymptomatic brain metastases receiving systemic therapy before whole-brain RT, brain MRI (preferred) or CT with
contrast should be repeated after every 2 cycles of systemic therapy and at completion of therapy.

• Subsequent systemic therapy

Response assessment by CT chest/liver/adrenal with contrast should occur after every 2–3 cycles of systemic therapy.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. SCL-C
Version 2.2017, 09/15/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®
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Small Cell Lung Cancer Discussion

PRINCIPLES OF SYSTEMIC THERAPY (3 of 3)

References
1Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic 15Smit EF, Fokkema E, Biesma B, et al. A phase II study of paclitaxel in heavily
radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and pretreated patients with small-cell lung cancer. Br J Cancer 1998; 77:347-351.
etoposide. N Engl J Med 1999;340(4):265-271. 16Yamamoto N, Tsurutani J, Yoshimura N, et al. Phase II study of weekly paclitaxel for
2Saito H, Takada Y, Ichinose Y, et al. Phase II study of etoposide and cisplatin with relapsed and refractory small cell lung cancer. Anticancer Res 2006; 26:777-781.
concurrent twice-daily thoracic radiotherapy followed by irinotecan and cisplatin in 17Smyth JF, Smith IE, Sessa C, et al. Activity of docetaxel (Taxotere) in small cell lung
patients with limited-disease small-cell lung cancer: West Japan Thoracic Oncology cancer. Eur J Cancer 1994; 30A:1058-1060.
Group 9902. J Clin Oncol 2006;24(33): 5247-5252. 18Pietanza MC, Kadota K, Huberman K, et al. Phase II trial of temozolomide with
3Skarlos DV, Samantas E, Briassoulis E, et al. Randomized comparison of early versus relapsed sensitive or refractory small cell lung cancer, with assessment of
late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited methylguanine-DNA methyltransferase as a potential biomarker. Clin Cancer Res
disease small-cell lung cancer: a randomized phase II study of the Hellenic Cooperative 2012;18:1138-1145.
19
Oncology Group (HeCOG). Ann Oncol 2001;12(9):1231-1238. Zauderer MG, Drilon A, Kadota K, et al. Trial of a 5-day dosing regimen of temozolomide
4Okamoto H, Watanabe K, Nishiwaki Y, et al. Phase II study of area under the plasma- in patients with relapsed small cell lung cancers with assessment of methylguanine-DNA
concentration-versus-time curve-based carboplatin plus standard-dose intravenous methyltransferase. Lung Cancer 2014;86:237-240.
20
etoposide in elderly patients with small cell lung cancer. J Clin Oncol 1999;17(11):3540- Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus
3545. ipilimumab in recurrent small-cell lung cancer (Checkmate 032): a multicentre, open-label
5Spigel DR, Townley PM, Waterhouse DM, et al. Randomized phase II study of phase 1/2 trial. Lancet Oncol 2016;17:883-895.
bevacizumab in combination with chemotherapy in previously untreated extensive-stage 21Jassem J, Karnicka-Mlodkowska H, van Pottelsberghe C, et al. Phase II study of
small-cell lung cancer: results from the SALUTE trial. J Clin Oncol 2011;29:2215-2222. vinorelbine (Navelbine) in previously treated small cell lung cancer patients.
6Niell HB, Herndon JE, Miller AA, et al. Randomized phase III Intergroup trial of etoposide Eur J Cancer 1993; 29A:1720-1722.
and cisplatin with or without paclitaxel and granulocyte-colony stimulating factor in patients 22Furuse K, Kuboa K, Kawahara M, et al. Phase II study of vinorelbine in heavily
with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B trial 9732. J previously treated small cell lung cancer. Oncology 1996; 53:169-172.
Clin Oncol 2005;23:3752-3759. 23Einhorn LH, Pennington K, McClean J. Phase II trial of daily oral VP-16 in refractory small
7Evans WK, Shepherd FA, Feld R, et al. VP-16 and cisplatin as first-line therapy for cell lung cancer. Semin Oncol 1990; 17:32-35.
small-cell lung cancer. J Clin Oncol 1985;3(11):1471-1477. 24Johnson DH, Greco FA, Strupp J, et al. Prolonged administration of oral etoposide in
8Schmittel A, Fischer von Weikersthal L, Sebastian M, et al. A randomized phase II trial patients with relapsed or refractory small-cell lung cancer: a phase II trial. J Clin Oncol
of irinotecan plus carboplatin versus etoposide plus carboplatin treatment in patients 1990; 8:1613-1617.
with extended disease small-cell lung cancer. Ann Oncol 2006;17:663-667. 25Van der Lee I, Smit EF, van Putten JW, et al. Single-agent gemcitabine in patients with
9Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with resistant small-cell lung cancer. An Oncol 2001;12:557-561.
etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 2002;346(2): 26Masters GA, Declerck L, Blanke C, et al. Phase II trial of gemcitabine in refractory or
85-91. relapsed small-cell lung cancer. J Clin Oncol 2003;21:1550-1555.
10Hanna N, Bunn Jr. PA, Langer C, et al. Randomized phase III trial comparing 27
Lammers PE, Shyr Y, Li CI, et al. Phase II study of bendamustine in relapsed
irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated chemotherapy sensitive or resistant small-cell lung cancer. J Thorac Oncol 2014;9:559-
extensive-stage disease small-cell lung cancer. J Clin Oncol 2006;24(13):2038-2043. 562.
11von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, 28Postmus PE, Berendsen HH, van Zandwijk N, et al. Retreatment with the induction
doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. regimen in small cell lung cancer relapsing after an initial response to short term
J Clin Oncol 1999;17(2):658-667. chemotherapy. Eur J Cancer Clin Oncol 1987;23:1409-1411.
12O’Brien ME, Ciuleanu TE, Tsekov H, et al. Phase III trial comparing supportive care 29Giaccone G, Ferrati P, Donadio M, et al. Reinduction chemotherapy in small cell lung
alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. Eur J Cancer Clin Oncol 1987;23:1697-1699.
cancer. J Clin Oncol 2006;24(34):5441-5447.
13Eckardt JR, von Pawel J, Pujol JL, et al. Phase III study of oral compared with
intravenous topotecan as second-line therapy in small-cell lung cancer.
J Clin Oncol 2007;25(15):2086-2092.
14Masuda N, Fukuoka M, Kusunoki Y, et al. CPT-11: a new derivative of camptothecin for
the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 1992;
10:1225-1229.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. SCL-C
Version 2.2017, 09/15/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®
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Small Cell Lung Cancer Discussion

PRINCIPLES OF RADIATION THERAPY

General Principles:
• General principles of RT for lung cancer—including commonly used abbreviations; standards for clinical and technologic expertise and
quality assurance; and principles of RT simulation, planning, and delivery—are provided in the NCCN Guidelines for Non-Small Cell Lung
Cancer (see NSCL‑B) and are applicable to RT for SCLC.
• RT has a potential role in all stages of SCLC, as part of either definitive or palliative therapy. Radiation oncology input, as part of a
multidisciplinary evaluation or discussion, should be provided for all patients early in the determination of the treatment strategy.
• To maximize tumor control and to minimize treatment toxicity, critical components of modern RT include appropriate simulation, accurate
target definition, conformal RT planning, and ensuring accurate delivery of the planned treatment. A minimum standard is CT‑planned 3D
conformal RT. Multiple fields should be used, with all fields treated each day.
• Use of more advanced technologies is appropriate when needed to deliver adequate tumor doses while respecting normal tissue dose
constraints. Such technologies include (but are not limited to) 4D-CT and/or PET/CT simulation, IMRT/VMAT, IGRT, and motion management
strategies. Quality assurance measures are essential and are covered in the NSCLC guidelines (see NSCL‑B).
• Useful references include the ACR Appropriateness Criteria at: [Link]

Limited Stage:
• Timing: RT concurrent with systemic therapy is standard and preferred to sequential chemo/RT.1 RT should start early, with cycle 1 or 2 of
systemic therapy (category 1).2 A shorter time from the start of any therapy to the end of RT (SER) is significantly associated with improved
survival.3 
• Target definition: RT target volumes should be defined based on the pretreatment PET scan and CT scan obtained at the time of radiotherapy
planning. PET/CT should be obtained, preferably within 4 weeks and no more than 8 weeks, before treatment. Ideally, PET/CT should be
obtained in the treatment position.
• Historically, clinically uninvolved mediastinal nodes have been included in the RT target volume, whereas uninvolved supraclavicular nodes
generally have not been included. Consensus on elective nodal irradiation (ENI) is evolving.4 Several more modern series, both retrospective
and prospective, suggest that omission of ENI results in low rates of isolated nodal recurrences (0%–11%, most <5%), particularly when
incorporating PET staging/target definition (1.7%–3%).5-10 ENI has been omitted in current prospective clinical trials (including CALGB
30610/RTOG 0538 and the EORTC 08072 [CONVERT] trial).
• In patients who start systemic therapy before RT, the gross tumor volume (GTV) can be limited to the post‑induction systemic therapy
volume to avoid excessive toxicity. Initially involved nodal regions (but not their entire pre‑systemic therapy volume) should be covered.7,11 
• Dose and schedule: For limited‑stage SCLC, the optimal dose and schedule of RT have not been established; 45 Gy in 3 weeks (1.5 Gy twice
daily [BID]) is superior (category 1) to 45 Gy in 5 weeks (1.8 Gy daily).12,13 When BID fractionation is used, there should be at least a 6‑hour
inter‑fraction interval to allow for repair of normal tissue. If using once-daily RT, higher doses of 60–70 Gy should be used.14-17 The current
randomized trial CALGB 30610/RTOG 0538 is comparing the standard arm of 45 Gy (BID) in 3 weeks to 70 Gy in 7 weeks; accrual to an
experimental concomitant boost arm18 has closed.

See Extensive Stage, Normal Tissue Dose Constraints, Prophylactic Cranial Irradiation, Brain Metastases on SCL-D 2 of 3

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. SCL-D
Version 2.2017, 09/15/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®
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Small Cell Lung Cancer Discussion

PRINCIPLES OF RADIATION THERAPY

Extensive Stage:
• Consolidative thoracic RT is beneficial for selected patients with extensive‑stage SCLC that responds to systemic therapy. Studies have
demonstrated that consolidative thoracic RT is well tolerated, results in fewer symptomatic chest recurrences, and improves long‑term
survival in some patients.19,20 The Dutch CREST randomized trial of modest-dose thoracic RT in patients with extensive stage SCLC that
responded to systemic therapy demonstrated significantly improved two-year overall survival and six-month progression-free survival,
although the protocol-defined primary endpoint of one-year overall survival was not significantly improved.21
Normal Tissue Dose Constraints:
• Normal tissue dose constraints depend on tumor size and location. For similar RT prescription doses, the normal tissue constraints used for
NSCLC are appropriate (see NSCL‑B).
• When administering accelerated RT schedules (eg, BID) or lower total RT doses (eg, 45 Gy), more conservative constraints should be used.
When using accelerated schedules (eg, 3–5 weeks), the spinal cord constraints from the CALGB 30610/RTOG 0538 protocol should be used
as a guide: ie, the maximum spinal cord dose should be limited to ≤41 Gy (including scatter irradiation) for a prescription of 45 Gy BID in 3
weeks and limited to ≤50 Gy for more protracted schedules.
Prophylactic Cranial Irradiation (PCI):
• In patients with limited-stage SCLC who have a good response to initial therapy, PCI decreases brain metastases and increases overall
survival (category 1).22,23 In patients with extensive-stage SCLC that has responded to systemic therapy, PCI decreases brain metastases.
However, while a randomized trial conducted by the EORTC found improved overall survival with PCI,24 preliminary results from a Japanese
randomized trial found no improved overall survival in patients who had MRI to confirm absence of brain metastases.25 In patients not
receiving PCI, surveillance for metastases by brain imaging should be considered.
• The preferred dose for PCI to the whole brain is 25 Gy in 10 daily fractions. A shorter course (eg, 20 Gy in 5 fractions) may be appropriate
in selected patients with extensive-stage disease. In a large randomized trial (PCI 99-01), patients receiving a dose of 36 Gy had higher
mortality and higher chronic neurotoxicity compared to patients treated with 25 Gy.26,27
• Neurocognitive Function: Increasing age and higher doses are the most predictive factors for development of chronic neurotoxicity. In trial
RTOG 0212, 83% of patients older than 60 years of age experienced chronic neurotoxicity 12 months after PCI versus 56% of patients
younger than 60 years of age (P = .009).27 Concurrent systemic therapy and high total RT dose (>30 Gy) should be avoided in patients
receiving PCI.
• Administer PCI after resolution of acute toxicities of initial therapy. PCI is not recommended in patients with poor performance status or
impaired neurocognitive functioning.
Brain Metastases:
• Brain metastases should be treated with whole brain radiation therapy (WBRT) rather than stereotactic radiotherapy/radiosurgery (SRT/SRS)
alone, because these patients tend to develop multiple CNS metastases. In patients who develop brain metastases after PCI, repeat WBRT
may be considered in carefully selected patients.28,29 SRS may also be considered, especially if there has been a long-time interval from
initial diagnosis to occurrence of brain metastases and there is no uncontrolled extracranial disease.30,31
• Recommended dose for WBRT is 30 Gy in 10 daily fractions.

General Principles, Limited Stage on SCL-D 1 of 3

References on SCL-D 3 of 3
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. SCL-D
Version 2.2017, 09/15/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®
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Small Cell Lung Cancer Discussion

PRINCIPLES OF RADIATION THERAPY

References
1Takada 17Bogart
M, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic JA, Herndon JE, Lyss AP, et al. 70 Gy thoracic radiotherapy is feasible concurrent with
radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: chemotherapy for limited-stage small-cell lung cancer: analysis of Cancer and Leukemia Group B
results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 2002;20:3054-3060. study 39808. Int J Radiat Oncol Biol Phys 2004;59:460-468.
2Fried DB, Morris DE, Poole C, et al. Systematic review evaluating the timing of thoracic radiation 18Komaki R, Paulus R, Ettinger DS, et al. Phase II study of accelerated high-dose radiotherapy with

therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol concurrent chemotherapy for patients with limited small-cell lung cancer: Radiation Therapy Oncology
2004;22:4837-4845. Group protocol 0239. Int J Radiat Oncol Biol Phys 2012;83:e531-6.
3De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al. Time between the first day of 19Jeremic B, Shibamoto Y, Nikolic N, et al. Role of radiation therapy in the combined-modality treatment

chemotherapy and the last day of chest radiation is the most important predictor of survival in of patients with extensive disease small-cell lung cancer: A randomized study. J Clin Oncol 1999;17:
limited-disease small-cell lung cancer. J Clin Oncol 2006;24:1057-1063. 2092-2099.
4Videtic GMM, Belderbos JSA, Kong F-MS, et al. Report from the International Atomic Energy 20Yee D, Butts C, Reiman A, et al. Clinical trial of post-chemotherapy consolidation thoracic radiotherapy

Agency (IAEA) consultants’ meeting on elective nodal irradiation in lung cancer: small-cell for extensive-stage small cell lung cancer. Radiother Oncol 2012;102:234-238.
21Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-
lung cancer (SCLC). Int J Radiat Oncol Biol Phys 2008;72:327-334.
5De Ruysscher D, Bremer R-H, Koppe F, et al. Omission of elective node irradiation on basis of cell lung cancer: a phase 3 randomised controlled trial. Lancet. 2015 Jan 3;385:36-42.
22Arriagada R, Le Chevalier T, Rivière A, et al. Patterns of failure after prophylactic cranial irradiation in
CT-scans in patients with limited disease small cell lung cancer: a phase II trial. Radiother Oncol
2006;80:307-312. small-cell lung cancer: analysis of 505 randomized patients. Annals of oncology 2002;13:748-754.
6van Loon J, De Ruysscher D, Wanders R, et al. Selective nodal irradiation on basis of (18)FDG-PET 23Aupérin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell

scans in limited-disease small-cell lung cancer: a prospective study. Int J Radiat Oncol Biol Phys lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group.
2010;77:329-336. N Engl J Med 1999;341:476-484.
7Hu X, Bao Y, Zhang L, et al. Omitting elective nodal irradiation and irradiating postinduction versus 24Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung

preinduction chemotherapy tumor extent for limited-stage small cell lung cancer: interim analysis of cancer. N Engl J Med 2007;357:664-672.
25Seto T, Takahashi T, Yamanaka T, et al. Prophylactic cranial irradiation (PCI) has a detrimental effect
a prospective randomized noninferiority trial. Cancer 2012;118:278-287.
8Shirvani SM, Komaki R, Heymach JV, et al. Positron emission tomography/computed tomography- on the overall survival (OS) of patients (pts) with extensive disease small cell lung cancer (ED-SCLC):
guided intensity-modulated radiotherapy for limited-stage small-cell lung cancer. Int J Radiat Oncol Results of a Japanese randomized phase III trial. J Clin Oncol 2014;32:(Suppl 5): Abstract 7503
26Le Péchoux C, Dunant A, Senan S, et al. Standard-dose versus higher-dose prophylactic cranial
Biol Phys 2012;82:e91-97.
9Xia B, Chen G-Y, Cai X-W, et al. Is involved-field radiotherapy based on CT safe for patients with irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after
limited-stage small-cell lung cancer? Radiother Oncol 2012;102:258-262. chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT
10Colaco R, Sheikh H, Lorigan P, et al. Omitting elective nodal irradiation during thoracic irradiation in 99-01): a randomised clinical trial. The Lancet Oncology 2009;10:467-474.
27Wolfson AH, Bae K, Komaki R, et al. Primary analysis of a phase II randomized trial Radiation
limited-stage small cell lung cancer - Evidence from a phase II trial. Lung Cancer 2012;76:72-77.
11Liengswangwong V, Bonner JA, Shaw EG, et al. Limited-stage small-cell lung cancer: patterns of Therapy Oncology Group (RTOG) 0212: Impact of different total doses and schedules of prophylactic
intrathoracic recurrence and the implications for thoracic radiotherapy. J Clin Oncol 1994;12:496-502. cranial irradiation on chronic neurotoxicity and quality of life for patients with limited-disease small-cell
12Turrisi AT, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in lung cancer. Int J Radiat Oncol Biol Phys 2011;81:77-84.
28Sadikov E, Bezjak A, Yi Q-L, et al. Value of whole brain re-irradiation for brain metastases--single centre
limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med
1999;340:265-271. experience. Clinical oncology (Royal College of Radiologists (Great Britain)) 2007;19:532-538.
13Schild SE, Bonner JA, Shanahan TG, et al. Long-term results of a phase III trial comparing once-daily 29Son CH, Jimenez R, Niemierko A, et al. Outcomes after whole brain reirradiation in patients with brain

radiotherapy with twice-daily radiotherapy in limited-stage small-cell lung cancer. Int J Radiat Oncol metastases. Int J Radiat Oncol Biol Phys 2012;82:e167-172.
30Harris S, Chan MD, Lovato JF, et al. Gamma knife stereotactic radiosurgery as salvage therapy after
Biol Phys 2004;59:943-951.
14Choi NC, Herndon JE, Rosenman J, et al. Phase I study to determine the maximum-tolerated dose failure of whole-brain radiotherapy in patients with small-cell lung cancer. Int J Radiat Oncol Biol Phys
of radiation in standard daily and hyperfractionated-accelerated twice-daily radiation schedules with 2012;83:e53-59.
31Wegner RE, Olson AC, Kondziolka D, et al. Stereotactic radiosurgery for patients with brain metastases
concurrent chemotherapy for limited-stage small-cell lung cancer. J Clin Oncol 1998;16:3528-3536.
15Miller KL, Marks LB, Sibley GS, et al. Routine use of approximately 60 Gy once-daily thoracic from small cell lung cancer. Int J Radiat Oncol Biol Phys 2011;81:e21-27.
irradiation for patients with limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys
2003;56:355-359.
16Roof KS, Fidias P, Lynch TJ, et al. Radiation dose escalation in limited-stage small-cell lung cancer.

Int J Radiat Oncol Biol Phys 2003;57:701-708.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. SCL-D
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Lung Neuroendocrine Tumors Discussion

PATHOLOGY WORKUP
• Pathology review
• Chest/abdominal CT with IV contrast whenever
Low-grade neuroendocrine possible
carcinoma (typical carcinoid)a • Bronchoscopy, as clinically indicated
• If enlarged surgically unresectable lymph nodes See Treatment
Low grade (LNT-2)
on CT, then pursue pathologic mediastinal
stagingb
Intermediate-grade • Consider octreotide scan
neuroendocrine carcinoma • PET scan (optional)c
(atypical carcinoid) • Biochemical workup for Cushing’s syndrome,
if clinically indicated (See NE-B in the NCCN
Intermediate See Treatment
Guidelines for Neuroendocrine Tumors)
grade (LNT-3)
• Other biochemical evaluation as clinically
indicated (See NE-B in the NCCN Guidelines for
Biopsy Neuroendocrine Tumors)
High-grade neuroendocrine carcinoma
Treat per NCCN Guidelines for
(large-cell neuroendocrine carcinoma
Non-Small Cell Lung Cancerd
[LCNEC])

High-grade neuroendocrine Treat per NCCN Guidelines for

carcinoma (small cell carcinoma) Small Cell Lung Cancer
Treat per NCCN Guidelines for
Combined SCLC and NSCLC
Small Cell Lung Cancer

aManagement of endocrine symptoms as indicated (See the Carcinoid Tumors section in the NCCN Guidelines for Neuroendocrine Tumors).
bMediastinal staging procedures include mediastinoscopy, mediastinotomy, endobronchial or esophageal ultrasound-guided biopsy, and video-assisted thoracoscopy. If
endoscopic lymph node biopsy is positive, additional mediastinal staging is not required.
cPET scan is undergoing evaluation in clinical trials and should only be considered as a supplement and not a replacement to other studies.
dStage-specific management of LCNEC follows the NSCLC algorithm. However, available data suggest that chemotherapy regimens commonly used for SCLC (see
SCL-C) may represent the most reasonable option when systemic therapy is indicated. Niho S, Kenmotsu H, Sekine I, et al. Combination chemotherapy with irinotecan
and cisplatin for large-cell neuroendocrine carcinoma of the lung: a multicenter phase II study. J Thorac Oncol 2013;8:980-984; Rossi G, Cavazza A, Marchioni A,
et al. Role of chemotherapy and the receptor tyrosine kinases KIT, PDGFRα, PDGFRβ, and Met in large-cell neuroendocrine carcinoma of the lung. J Clin Oncol
2005;23:8774-8785; Le Treut J, Sault MC, Lena H, et al. Multicentre phase II study of cisplatin-etoposide chemotherapy for advanced large-cell neuroendocrine lung
carcinoma: the GFPC 0302 study. Ann Oncol 2013;24:1548-1552.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Lung Neuroendocrine Tumors Discussion

Low-Grade Lung Neuroendocrine Carcinoma (Typical Carcinoid)

CLINICAL STAGEe PRIMARY TREATMENT SURVEILLANCE

Stage I-II Surgery:

Lobectomy or other anatomic
Surgical resectionf + mediastinal lymph
Follow-up every 6–12 mo post-
candidate node dissection or sampling
treatment up to 10 y
Stage IIIA • H&P
Not surgical • Chest CT annually
Cisplatin/etoposideg + RTh
candidate • Biochemical evaluation, as
clinically indicated
Stage IIIB (except T4 due
to multiple lung nodules) Cisplatin/etoposideg + RTh

Consider observation for

Stage IIIB (T4 due to multiple asymptomatic, low-bulk disease
lung nodules) or stage IV or
Systemic therapyg

eSee Staging on page ST-1.

fWedge resection for peripheral low-grade neuroendocrine carcinoma (category 2B).
gSee Principles of Chemotherapy (LNT-A).
hSee Principles of Radiation Therapy (SCL-D).

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Lung Neuroendocrine Tumors Discussion

Intermediate-Grade Lung Neuroendocrine Carcinoma (Atypical Carcinoid)

CLINICAL STAGEe PRIMARY TREATMENT ADJUVANT TREATMENT SURVEILLANCE

Surgery: Stage I Observe

Stage I-II Lobectomy or other
anatomic resection +
Surgical mediastinal lymph node Cisplatin/etoposideg Follow-up every 6–12 mo
candidate dissection or sampling Stage II,III ± RTh post-treatment up to 10 y
(category 2B for RT) • H&P
Stage IIIA
• Chest CT annually
Not surgical • Biochemical evaluation,
Cisplatin/etoposideg + RTh as clinically indicated
candidate

Stage IIIB (except T4 due

to multiple lung nodules) Cisplatin/etoposideg + RTh

Stage IIIB (T4 due to multiple

Systemic therapyg
lung nodules) or stage IV

eSee Staging on page ST-1.

gSee Principles of Chemotherapy (LNT-A).
hSee Principles of Radiation Therapy (SCL-D).
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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LNT-3
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Lung Neuroendocrine Tumors Discussion

PRINCIPLES OF SYSTEMIC THERAPY

Low-Grade NET (Typical Carcinoid)* Intermediate-Grade NET (Atypical Carcinoid)

• Capecitabine + temozolomide1 • Cisplatin/etoposide3,4 (preferred)
• Everolimus2 • Capecitabine + temozolomide1
• Cisplatin/etoposide3,4 • Temozolomide5
• Temozolomide5 • Sunitinib6
• Sunitinib6 • Everolimus2
• Consider octreotide or lanreotide, if octreotide scan positive • Consider octreotide or lanreotide, if octreotide scan positive
or symptoms of carcinoid syndrome7,8 or symptoms of carcinoid syndrome7,8

*There is no substantial evidence for a preferred regimen.

1Fine RL, Gulati AP, Krantz BA, et al. Capecitabine and temozolomide (CAPTEM) for metastatic well differentiated neuroendocrine cancers: The Pancreas Center at
Columbia University experience. Cancer Chemother Pharmacol 2013;71:663-670.
2Fazio N, Granberg D, Grossman A, et al. Everolimus plus octreotide long-acting repeatable in patients with advanced lung neuroendocrine tumors: analysis of the
phase 3, randomized, placebo-controlled RADIANT-2 study. Chest 2013;143:955-962.
3Moertel CG, Kvols LK, O’Connell MJ, Rubin J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity
in the anaplastic variants of these neoplasms. Cancer 1991;68:227-232.
4Chong CR, Wirth LJ, Nishino M, et al. Chemotherapy for locally advanced and metastatic pulmonary carcinoid tumors. Lung Cancer 2014;86:241-246.
5Ekebald S, Sundin A, Janson ET, et al. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res
2007;13:2986-2991.
6Kulke MH, Lenz HJ, Meropol NJ, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 2008;26:3403-3410;
7Rinke A, Muller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor
growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009;27:4656-63.
8Caplin ME, Pavel M, Cwikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 2014;371:224-33.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Table 1 - Definition of small cell lung cancer consists of two stages:

(1) Limited-stage: AJCC (7th edition) Stage I-III (T any, N any, M0) that can be safely treated with definitive radiation doses. Excludes T3-4 due to multiple lung nodules
that are too extensive or have tumor/nodal volume that is too large to be encompassed in a tolerable radiation plan.
(2) Extensive-stage: AJCC (7th edition) Stage IV (T any, N any, M 1a/b), or T3-4 due to multiple lung nodules that are too extensive or have tumor/nodal volume that is
too large to be encompassed in a tolerable radiation plan.

Table 2 - Definitions of TNM1 N Regional Lymph Nodes

T Primary Tumor NX Regional lymph nodes cannot be assessed
TX Primary tumor cannot be assessed, or tumor proven by the presence of N0 No regional lymph node metastasis
malignant cells in sputum or bronchial washings but not visualized by N1 Metastasis to ipsilateral peribronchial and/or ipsilateral hilar
imaging or bronchoscopy lymph nodes, and intrapulmonary nodes including involvement by
T0 No evidence of primary tumor direct extension
Tis Carcinoma in situ N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
T1 Tumor 3 cm or less in greatest dimension, surrounded by lung or visceral N3 Metastasis in contralateral mediastinal, contralateral hilar,
pleura, without bronchoscopic evidence of invasion more proximal than the ipsilateral or contralateral scalene, or supraclavicular lymph
lobar bronchus (i.e., not in the main bronchus)* node(s)
T1a Tumor 2 cm or less in greatest dimension M Distant Metastasis
T1b Tumor more than 2 cm but 3 cm or less in greatest dimension M0 No distant metastasis
T2 Tumor with any of the following features of size or extent: M1 Distant metastasis
• More than 3 cm but 7 cm or less M1a Separate tumor nodule(s) in a contralateral lobe tumor
• Involves main bronchus, 2 cm or more distal to the carina with pleural nodules or malignant pleural (or pericardial)
• Invades the visceral pleura (PL1 or PL2) effusion**
• Associated with atelectasis or obstructive pneumonitis that extends to the M1b Distant metastasis
hilar region but does not involve the entire lung
T2a Tumor more than 3 cm but 5 cm or less in greatest dimension *The uncommon superficial spreading tumor of any size with its invasive
T2b Tumor more than 5 cm but 7 cm or less in greatest dimension component limited to the bronchial wall, which may extend proximally to the
T3 Tumor more than 7 cm or one that directly invades any of the following: main bronchus, is also classified as T1a.
parietal pleural (PL3) chest wall (including superior sulcus tumors), **Most pleural (and pericardial) effusions with lung cancer are due to tumor. In
diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumor a few patients, however, multiple cytopathologic examinations of pleura
in the main bronchus (less than 2 cm distal to the carina* but without (pericardial) fluid are negative for tumor, and the fluid is nonbloody and is not
involvement of the carina); or associated atelectasis or obstructive an exudate. Where these elements and clinical judgment dictate that the
pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe effusion is not related to the tumor, the effusion should be excluded as a
T4 Tumor of any size that invades any of the following: mediastinum, heart, staging element and the patient should be classified as M0.
great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body,
carina, separate tumor nodule(s) in a different ipsilateral lobe

1Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original and primary source for this information is the AJCC
Cancer Staging Manual, Seventh Edition (2010) published by Springer Science+Business Media, LLC (SBM). (For complete information and data supporting the
staging tables, visit [Link].) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this
information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC.

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Table 3 - Anatomic Stage/Prognostic Groups

Occult carcinoma TX N0 M0
Stage 0 Tis N0 M0
Stage IA T1 N0 M0
Stage IB T2a N0 M0
Stage IIA T2b N0 M0
T1 N1 M0
T2a N1 M0
Stage IIB T2b N1 M0
T3 N0 M0
Stage IIIA T1-2 N2 M0
T3 N1-2 M0
T4 N0-1 M0
Stage IIIB T1-2 N3 M0
T3 N3 M0
T4 N2-3 M0

Stage IV Any T Any N M1a

Any T Any N M1b

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original and primary source for this information is the AJCC
Cancer Staging Manual, Seventh Edition (2010) published by Springer Science+Business Media, LLC (SBM). (For complete information and data supporting the
staging tables, visit [Link].) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this
information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC.

Version 2.2017, 09/15/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®
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Discussion Prognostic Factors .................................................................... MS-6 

Treatment .................................................................................. MS-6 

NCCN Categories of Evidence and Consensus
Systemic Therapy ....................................................................................... MS-6 
Category 1: Based upon high-level evidence, there is uniform NCCN Elderly Patients ...................................................................................... MS-9 
consensus that the intervention is appropriate.
Second-Line and Beyond (Subsequent) Systemic Therapy ................... MS-10 
Category 2A: Based upon lower-level evidence, there is uniform
Radiotherapy ............................................................................................ MS-11 
NCCN consensus that the intervention is appropriate.
Thoracic Radiotherapy.......................................................................... MS-11 
Category 2B: Based upon lower-level evidence, there is NCCN
consensus that the intervention is appropriate. Prophylactic Cranial Irradiation ............................................................. MS-13 

Category 3: Based upon any level of evidence, there is major NCCN Palliative Radiotherapy ......................................................................... MS-14 
disagreement that the intervention is appropriate. Surgical Resection of Stage I SCLC ......................................................... MS-14 

All recommendations are category 2A unless otherwise noted. NCCN Guidelines ................................................................................. MS-15 

Surveillance ............................................................................ MS-15 

Table of Contents Lung Neuroendocrine Tumors .................................................... MS-16 

Overview....................................................................................... MS-2  Diagnosis and Staging ............................................................ MS-16 

Literature Search Criteria and Guidelines Update Methodology .... MS-2  Treatment ................................................................................ MS-16 

Small Cell Lung Cancer ................................................................ MS-3  References ................................................................................. MS-18 

Diagnosis .................................................................................. MS-3 

Screening .................................................................................................... MS-3 

Manifestations ............................................................................................. MS-3 

Pathology .................................................................................................... MS-4 

Staging ...................................................................................... MS-4 

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Overview chemotherapy alone can palliate symptoms and prolong survival in

Neuroendocrine tumors account for approximately 20% of lung cancers; most patients; however, long-term survival is rare.10 Note that the
most (approximately 14%) are small cell lung cancer (SCLC).1,2 In 2016, definitions for limited-stage and extensive-stage SCLC incorporate TNM
an estimated 31,000 new cases of SCLC will occur in the United staging (see the NCCN Guidelines for SCLC and Staging in this
States.3 Nearly all cases of SCLC are attributable to cigarette smoking.4 Discussion). Surgery is only appropriate for a few patients (2%–5%)
Although the incidence of SCLC has been decreasing, the incidence in with surgically resectable stage I SCLC.11 Clinical trials generally
women is increasing and the male-to-female incidence ratio is now 1:1.2 represent state-of-the-art treatment for patients with SCLC. Despite
Management of SCLC and other lung neuroendocrine tumors (LNTs) is recent advances, the standard therapy for SCLC as outlined by these
described in the NCCN Clinical Practice Guidelines in Oncology (NCCN NCCN Guidelines still needs to be improved. Thus, participation in
Guidelines®) for SCLC and for LNTs, which include the algorithms and clinical trials should be strongly encouraged.
this supporting Discussion text (see also Lung Neuroendocrine Tumors
Smoking cessation should be strongly promoted in patients with SCLC
in this Discussion). The Summary of the Guidelines Updates section in
and other high-grade neuroendocrine carcinomas (see the NCCN
the algorithm describes the most recent revisions, which have been
Guidelines for Smoking Cessation, available at [Link]).12 Former
incorporated into this revised Discussion (see the NCCN Guidelines®
smokers should be strongly encouraged to remain abstinent. Patients
for SCLC). For the 2017 update for SCLC, nivolumab and nivolumab
with SCLC who continue to smoke have increased toxicity during
with ipilimumab were added as new options for second-line and beyond
treatment and shorter survival.13 Programs using behavioral counseling
(ie, subsequent) systemic therapy;5 new imaging guidelines for
combined with FDA–approved medications that promote smoking
response assessment after systemic therapy were also added in
cessation can be very useful.
addition to other changes as outlined in the summary updates. The
NCCN Guidelines for SCLC were originally published 20 years ago and Literature Search Criteria and Guidelines Update
have been subsequently updated at least once every year (see Methodology
[Link]).6
Before the update of this version of the NCCN Guidelines for SCLC, an
SCLC is characterized by a rapid doubling time, high growth fraction, electronic search of the PubMed database was performed to obtain key
and early development of widespread metastases. Most patients with literature in SCLC—published between April 1, 2015 and May 1, 2016—
SCLC present with hematogenous metastases; approximately one third using the following search term: small cell lung cancer. The PubMed
present with limited disease confined to the chest. SCLC is highly database was chosen, because it is the most widely used resource for
sensitive to initial chemotherapy and radiotherapy; however, most medical literature and indexes only peer-reviewed biomedical literature.
patients eventually die of recurrent disease.7 In patients with The search results were narrowed by selecting studies in humans
limited-stage SCLC, the goal of treatment is cure using chemotherapy published in English. Results were confined to the following article
plus thoracic radiotherapy.8,9 In patients with extensive-stage disease, types: Clinical Trial, Phase 1; Clinical Trial, Phase 2; Clinical Trial,

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Phase 3; Clinical Trial, Phase 4; Guideline; Randomized Controlled Manifestations

Trial; Meta-Analysis; Systematic Reviews; and Validation Studies. SCLC typically presents as a large hilar mass and bulky mediastinal
lymphadenopathy that cause cough and dyspnea.17 Frequently, patients
The PubMed search resulted in 253 citations and their potential present with symptoms of widespread metastatic disease, such as
relevance was examined. The data from key PubMed articles as well as weight loss, debility, bone pain, and neurologic compromise. It is
articles from additional sources deemed as relevant to these NCCN uncommon for patients to present with a solitary peripheral nodule
Guidelines and discussed by the panel have been included in this without central adenopathy. In this situation, fine-needle aspiration
version of the Discussion section (eg, e-publications ahead of print, (FNA) may not adequately differentiate small cell carcinoma (which is a
meeting abstracts). Recommendations for which high-level evidence is high-grade neuroendocrine carcinoma) from low-grade (typical
lacking are based on the panel’s review of lower-level evidence and carcinoid), intermediate-grade (atypical carcinoid), or large-cell
expert opinion. The complete details of the development and update of neuroendocrine carcinoma (LCNEC) (which is also a high-grade
the NCCN Guidelines are available on the NCCN webpage. neuroendocrine carcinoma) (see the NCCN Guidelines for Lung
Neuroendocrine Tumors and Lung Neuroendocrine Tumors in this
Small Cell Lung Cancer
Discussion).18,19
Diagnosis
Screening Many neurologic and endocrine paraneoplastic syndromes are
Ideally, a screening test should detect disease at an early stage when it associated with SCLC.20-22 Neurologic syndromes include
is still curable. Currently, no effective screening test is available to Lambert-Eaton myasthenic syndrome, encephalomyelitis, and sensory
detect early-stage SCLC; the disease is typically diagnosed when neuropathy. Patients with the Lambert-Eaton syndrome present with
patients present with symptoms indicative of advanced-stage disease.14 proximal leg weakness that is caused by antibodies directed against the
The National Lung Screening Trial (NLST) reported that screening with voltage-gated calcium channels.23,24 Paraneoplastic encephalomyelitis
annual, low-dose, spiral CT scans decreased lung cancer–specific and sensory neuropathy are caused by the production of an antibody
mortality in asymptomatic high-risk individuals (see the NCCN (anti-Hu) that cross-reacts with both small cell carcinoma antigens and
Guidelines for Lung Cancer Screening, available at [Link]).15 human neuronal RNA-binding proteins resulting in multiple neurologic
Although low-dose CT screening can detect early-stage non-small cell deficits.25
lung cancer (NSCLC), it does not seem to be useful for detecting
SCLC cells sometimes produce polypeptide hormones, including
early-stage SCLC.14-16 Low-dose CT screening is probably not useful
vasopressin (antidiuretic hormone [ADH]) and adrenocorticotropic
because of the aggressiveness of SCLC, which results in the
hormone (ACTH), which cause hyponatremia of malignancy (ie,
development of symptomatic disease between annual scans, thereby
syndrome of inappropriate ADH secretion [SIADH]) and Cushing
limiting the potential effect on mortality.14
syndrome, respectively.26,27 In patients with SCLC, SIADH occurs more
frequently than Cushing syndrome. Cancer treatment and/or supportive

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care may also cause hyponatremia (eg, cisplatin, opiates).28 Treatment (NCAM; CD56), and synaptophysin.18 However, these markers alone
for SIADH includes fluid restriction (which is difficult for patients cannot be used to distinguish SCLC from NSCLC, because
because of increased thirst), demeclocycline, or vasopressin receptor approximately 10% of NSCLCs will be immunoreactive for at least one
inhibitors (ie, conivaptan, tolvaptan) (see Principles of Supportive Care of these neuroendocrine markers.34
in the NCCN Guidelines for SCLC).28-30 ADH levels and hyponatremia
usually improve after successful treatment for SCLC. Staging
The NCCN Panel adopted a combined approach for staging SCLC
Pathology using both the AJCC TNM staging system and the older Veterans
SCLC is a malignant epithelial tumor consisting of small cells with scant Administration (VA) scheme for SCLC (see the following 2
cytoplasm, ill-defined cell borders, finely granular nuclear chromatin, paragraphs).7,35 Historically, contralateral mediastinal and ipsilateral
and absent or inconspicuous nucleoli.18,31 The cells are round, oval, or supraclavicular lymphadenopathy were generally classified as
spindle-shaped; nuclear molding is prominent. The mitotic count is high. limited-stage disease, whereas the classification of contralateral hilar
The classic and distinctive histology on hematoxylin and eosin (H&E) and supraclavicular lymphadenopathy is more controversial and
may be sufficient for identifying SCLC; it is a poorly differentiated tumor treatment is individualized for the patients.7,35,36 Approximately 66% of
that is categorized as a high-grade neuroendocrine carcinoma.18 Up to patients present with overt hematogenous metastases, which commonly
30% of autopsies in patients with SCLC reveal areas of NSCLC involve the contralateral lung, liver, adrenal glands, brain, bones, and/or
differentiation; this finding is more commonly detected in specimens bone marrow. The AJCC is currently revising the TNM staging system
from previously treated patients and suggests that pulmonary for SCLC; new staging guidelines will be published in late 2016.37 The
carcinogenesis occurs in a pluripotent stem cell capable of SCLC panel will continue to use the combined VA/TNM system for
differentiation along divergent pathways. staging SCLC after publication of the 8th edition of the AJCC Cancer
Staging Manual.
Although 95% of small cell carcinomas originate in the lung, they can
also arise from extrapulmonary sites, including the nasopharynx, In 2010, the lung cancer TNM staging system was revised by the
gastrointestinal tract, and genitourinary tract.32,33 Both pulmonary and International Association for the Study of Lung Cancer (IASLC) and
extrapulmonary small cell carcinomas have a similar clinical and adopted by the AJCC (7th edition, 2010) (see Tables 2 and 3 in the
biologic behavior, leading to a high potential for widespread NCCN Guidelines for SCLC).38-41 This TNM staging system is applicable
metastases. to both NSCLC and SCLC based on studies that showed the prognostic
significance of the various stage designations in both diseases.38,40 In
Nearly all SCLCs are immunoreactive for keratin, epithelial membrane
the combined approach for staging SCLC, limited-stage SCLC is
antigen, and thyroid transcription factor–1 (TTF-1).18 Most SCLCs also
defined as stage I to III (T any, N any, M0) that can be safely treated
stain positively for markers of neuroendocrine differentiation, including
with definitive radiation therapy, excluding T3–4 due to multiple lung
chromogranin A, neuron-specific enolase, neural cell adhesion molecule

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nodules that are too extensive or have tumor/nodal volume that is too biopsies may be indicated in select patients with nucleated red blood
large to be encompassed in a tolerable radiation plan (see Table 1 in cells on peripheral blood smear, neutropenia, or thrombocytopenia
the NCCN Guidelines for SCLC). Extensive-stage SCLC is defined as suggestive of bone marrow infiltration and with no other evidence of
stage IV (T any, N any, M1a/b) or T3–4 due to multiple lung nodules metastatic disease. Bone marrow involvement as the only site of
that are too extensive or have tumor/nodal volume that is too large to be extensive-stage disease occurs in fewer than 5% of patients. If
encompassed in a tolerable radiation plan. limited-stage disease is suspected, a PET/CT scan can be performed to
assess for distant metastases.7,35 A bone scan can be performed if
The VA Lung Study Group’s 2-stage classification scheme is also used PET/CT is equivocal or not available.
to define the extent of disease in patients with SCLC: 1) limited-stage
disease is disease confined to the ipsilateral hemithorax, which can be PET scans can increase staging accuracy in patients with SCLC,
safely encompassed within a radiation field; and 2) extensive-stage because SCLC is a highly metabolic disease.43-45 PET/CT is superior to
disease is disease beyond the ipsilateral hemithorax, including PET alone.45 Approximately 19% of patients who undergo PET are
malignant pleural or pericardial effusion or hematogenous metastases.42 upstaged from limited- to extensive-stage disease, whereas only 8% are
Because most of the literature on SCLC classifies patients based on the downstaged from extensive- to limited-stage disease.36 For most
VA’s definitions of limited-stage or extensive-stage disease, these metastatic sites, PET/CT is superior to standard imaging; however,
definitions are often used for clinical decision making. However, the PET/CT is inferior to MRI or CT for the detection of brain metastases
TNM system is useful for selecting patients with T1-2, N0 disease who (see the NCCN Guidelines for Central Nervous System Cancers,
are eligible for surgery and for radiation treatment planning.35 Clinical available at [Link]).46 Changes in management based on PET
research studies should begin to use the TNM system, because it will staging were reported in approximately 27% of patients, mainly because
allow for more precise assessments of prognosis and specific therapy in of alterations in the planned radiation field as a result of improved
the future. detection of intrathoracic sites of disease.36,44,47 Although PET/CT seems
to improve staging accuracy in SCLC, pathologic confirmation is still
All patients with SCLC, even those with radiographically limited-stage required for PET/CT–detected lesions that result in upstaging.
disease (per the VA’s definition), require systemic therapy either as
primary or adjuvant therapy. Therefore, staging provides a therapeutic Before surgical resection, pathologic mediastinal staging is required to
guideline for thoracic radiotherapy, which is indicated primarily for confirm PET/CT scan results in patients who seem to have clinical
patients with limited-stage disease. Full staging includes a history and stage T1–2, N0 disease.7 However, mediastinal staging is not required if
physical examination; CT scan (with intravenous contrast) of the chest, the patient is not a candidate for surgical resection or if non-surgical
liver, and adrenal glands; and brain imaging using MRI (preferred) or treatment is planned. Invasive mediastinal staging can be performed
CT scan (with intravenous contrast).36 However, once a patient has either by conventional mediastinoscopy or by minimally invasive
been found to have extensive-stage disease, further staging is optional, techniques such as transesophageal endoscopic ultrasound–guided
except for brain imaging.7 Unilateral bone marrow aspirates and FNA (EUS-FNA), endobronchial ultrasound–guided transbronchial

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needle aspiration (EBUS-TBNA), or video-assisted thoracoscopy factors. Female gender, age younger than 70 years, normal LDH, and
(VATS).48,49 stage I disease are associated with a more favorable prognosis in
patients with limited-stage disease. Younger age, good PS, normal
Thoracentesis with cytologic analysis is recommended if a pleural creatinine level, normal LDH, and a single metastatic site are favorable
effusion is large enough to be safely accessed via ultrasound guidance. prognostic factors in patients with extensive-stage disease.50,51
If thoracentesis does not show malignant cells, then thoracoscopy can
be considered to document pleural involvement, which would indicate Treatment
extensive-stage disease. The effusion should be excluded as a staging Systemic Therapy
element if: 1) multiple cytopathologic examinations of the pleural fluid For all patients with SCLC, chemotherapy is an essential component of
are negative for cancer; 2) the fluid is not bloody and not an exudate; appropriate treatment. Adjuvant chemotherapy is recommended for
and 3) clinical judgment suggests that the effusion is not directly related those who have undergone surgical resection. For patients with
to the cancer. Pericardial effusions are classified using the same limited-stage SCLC in excess of T1-2, N0 and good PS (0–2),
criteria. recommended treatment consists of chemotherapy with concurrent
thoracic radiotherapy (category 1).9,52,53 For patients with
Staging should not focus only on sites of symptomatic disease or on
extensive-stage disease, chemotherapy alone is the recommended
sites suggested by laboratory tests. Bone scans are positive in up to
treatment, although radiotherapy may be used in select patients for
30% of patients without bone pain or an abnormal alkaline phosphatase
palliation of symptoms (see Initial Treatment and Principles of Systemic
level. Bone imaging with radiographs or MRI may be appropriate if
Therapy in the NCCN Guidelines for SCLC). In patients with extensive-
PET/CT is equivocal. Brain imaging (MRI preferred or CT scan) can
stage and brain metastases, chemotherapy can be given either before
identify central nervous system (CNS) metastases in 10% to 15% of
or after whole-brain radiotherapy depending on whether the patient has
patients at diagnosis, of which approximately 30% are asymptomatic.
neurologic symptoms (see Initial Treatment in the NCCN Guidelines for
Early treatment of brain metastases results in less chronic neurologic
SCLC).10,54
morbidity, arguing for the usefulness of early diagnosis in asymptomatic
patients. Because of the aggressive nature of SCLC, staging should not For the 2017 update, the NCCN Panel added new recommendations for
delay the onset of treatment for more than 1 week; otherwise, many response assessment during and after therapy in patients with limited-
patients may become more seriously ill in the interval, with a significant stage or extensive-stage SCLC. After adjuvant chemotherapy alone or
decline in their performance status (PS). chemotherapy with concurrent RT for patients with limited-stage
disease, response assessment using CT with contrast of the chest,
Prognostic Factors
liver, and adrenal gland should occur only after completion of initial
Poor PS (3–4), extensive-stage disease, weight loss, and markers therapy; repeating scans during therapy is not recommended. For
associated with excessive bulk of disease (such as lactate systemic therapy alone or sequential systemic therapy followed by RT
dehydrogenase [LDH]) are the most important adverse prognostic in patients with limited-stage disease, response assessment using CT
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with contrast of the chest, liver, and adrenal gland should occur after individual patient data from 4 randomized studies compared
every 2 cycles of systemic therapy and again at completion of therapy. cisplatin-based versus carboplatin-based regimens in patients with
During systemic therapy for patients with extensive-stage disease, SCLC.65 Of 663 patients included in this meta-analysis, 32% had
response assessment using CT with contrast of the chest, liver, and limited-stage disease and 68% had extensive-stage disease. No
adrenal gland should occur after every 2 to 3 cycles of chemotherapy significant difference was observed in response rate (67% vs. 66%),
and again at completion of therapy. Scanning for brain metastases is progression-free survival (5.5 vs. 5.3 months), or overall survival (9.6
also recommended in patients with extensive-stage disease who have vs. 9.4 months) in patients receiving cisplatin- versus
asymptomatic brain metastases and are receiving systemic therapy carboplatin-containing regimens, suggesting equivalent efficacy in
before whole-brain RT; brain MRI (preferred) or brain CT with contrast patients with SCLC.
should occur after every 2 cycles of chemotherapy and again at
completion of therapy. Many other combinations have been evaluated in patients with
extensive-stage disease, with little consistent evidence of benefit when
Single-agent and combination chemotherapy regimens have been compared with EP. The combination of irinotecan and a platinum agent
shown to be active in SCLC. Etoposide and cisplatin (EP) is the most initially appeared to be better than EP. A small phase 3 trial performed
commonly used initial combination chemotherapy regimen (see in Japan reported that patients with extensive-stage SCLC who were
Principles of Systemic Therapy in the NCCN Guidelines for SCLC).55 treated with irinotecan plus cisplatin experienced a median survival of
This combination replaced alkylator/anthracycline-based regimens 12.8 months compared with 9.4 months for patients treated with EP
based on its superiority in both efficacy and toxicity in the limited-stage (P=.002).66 In addition, the 2-year survival was 19.5% in the irinotecan
setting.56 EP plus concurrent thoracic radiotherapy is the recommended plus cisplatin group versus 5.2% in the EP group.66 However, 2
therapy for patients with limited-stage disease in excess of T1-2, N0 subsequent large phase 3 trials performed in the United States
(category 1).52,53,57,58 comparing irinotecan plus cisplatin with EP failed to show a significant
difference in response rate or overall survival between the regimens.67,68
In combination with thoracic radiotherapy, EP causes an increased risk
of esophagitis, pulmonary toxicity, and hematologic toxicity.59 The use of A phase 3 randomized trial (n = 220) found that median overall survival
myeloid growth factors is not recommended (category 1 for not using was slightly improved with irinotecan and carboplatin compared with
GM-CSF) in patients undergoing concurrent chemoradiation.60 In clinical carboplatin and oral etoposide (8.5 vs. 7.1 months, P = .04).69 Based on
practice, carboplatin is frequently substituted for cisplatin to reduce the these findings, the carboplatin and irinotecan regimen is an option in the
risk of emesis, neuropathy, and nephropathy.61 However, the use of NCCN Guidelines for patients with extensive-stage disease. A
carboplatin carries a greater risk of myelosuppression.62 Small meta-analysis suggests an improvement in PFS and overall survival
randomized trials have suggested similar efficacy of cisplatin and with irinotecan plus platinum regimens compared with etoposide plus
carboplatin in patients with SCLC as did a retrospective analysis in platinum regimens.70 However, this meta-analysis was not performed
patients with extensive-stage disease.61,63,64 A meta-analysis of using data from individual patients. In addition, the relatively small

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absolute survival benefit needs to be balanced against the toxicity consolidation chemotherapy beyond 4 to 6 cycles of standard treatment
profile of irinotecan-based regimens. Therefore, the NCCN Panel produces a minor prolongation of duration of response without
continues to consider etoposide plus platinum as the standard regimen improving survival and carries a greater risk of cumulative toxicity.78 A
for patients with either limited-stage or extensive-stage SCLC. meta-analysis reported that maintenance chemotherapy did not prolong
overall survival.79
In patients with limited-stage disease, response rates of 70% to 90%
are expected after treatment with EP plus thoracic radiotherapy, The inability to destroy residual cells, despite the initial chemosensitivity
whereas in extensive-stage disease, response rates of 60% to 70% can of SCLC, suggests the existence of cancer stem cells that are relatively
be achieved with combination chemotherapy alone. Unfortunately, resistant to cytotoxic therapy. To overcome drug resistance, alternating
median survival rates are only 14 to 20 months and 9 to 11 months for or sequential combination therapies have been designed to expose the
patients with limited- and extensive-stage disease, respectively. After tumor to as many active cytotoxic agents as possible during initial
appropriate treatment, the 2-year survival rate is approximately 40% in treatment.80 However, randomized trials have failed to show improved
patients with limited-stage disease, but less than 5% in those with PFS or overall survival with this approach.81,82
extensive-stage disease.71 Thoracic radiotherapy improves local control
rates by 25% in patients with limited-stage disease and is associated Multidrug cyclic weekly therapy was designed to increase dose
with improved survival.52,53 Data suggest that chemoradiotherapy may intensity. Early phase 2 results of this approach were promising,
be indicated for patients with limited-stage disease who have although favorable patient selection was of some concern.83,84
cytologically negative or indeterminate pleural effusions, but not for Nevertheless, no survival benefits were documented in randomized
those with pericardial effusions.72,73 trials, and excessive treatment-related mortality was noted with
multidrug cyclic weekly regimens.85-88 The role of higher-dose therapy
Many strategies have been evaluated in an effort to improve on the for patients with SCLC remains controversial. Higher complete and
standard treatment for extensive-stage SCLC, including the addition of partial response rates, and modestly longer median survival times, have
a third agent to standard 2-drug regimens. In 2 trials, the addition of been observed in patients receiving high doses when compared with
ifosfamide (or cyclophosphamide plus an anthracycline) to EP showed a those given conventional doses of the same agents.89 In general,
modest survival advantage for patients with extensive-stage disease.74,75 however, randomized trials comparing conventional doses to an
However, these findings have not been uniformly observed, and the incrementally increased dose intensity up to 2 times the conventional
addition of an alkylating agent, with or without an anthracycline, dose have not consistently shown an increase in response rate or
significantly increases hematologic toxicity when compared to EP survival.90-93 In addition, a meta-analysis of trials that compared
alone.76 Similarly, the addition of paclitaxel to either cisplatin or standard versus dose-intense variations of the cyclophosphamide,
carboplatin plus etoposide yielded promising results in phase 2 trials but doxorubicin, and vincristine (CAV) and EP regimens found that
did not improve survival and was associated with unacceptable toxicity increased relative dose intensity resulted in only a small, clinically
in a subsequent phase 3 study.77 The use of maintenance or

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insignificant enhancement of median survival in patients with survival rates in patients with SCLC through the addition of more agents
extensive-stage disease.94 or the use of dose-intense chemotherapy regimens, maintenance
therapy, or alternating non–cross-resistant chemotherapy regimens
Currently available cytokines (eg, granulocyte-macrophage have failed to yield significant advantages when compared to standard
colony-stimulating factor [GM-CSF], granulocyte colony-stimulating approaches.
factor) can ameliorate chemotherapy-induced myelosuppression and
reduce the incidence of febrile neutropenia, but cumulative Elderly Patients
thrombocytopenia remains dose limiting. Although trials involving The incidence of lung cancer increases with age. Although the median
patients with SCLC were instrumental in obtaining FDA approval for the age at diagnosis is 70 years, elderly patients are under-represented in
clinical use of cytokines,95 maintenance of dose intensity with growth clinical trials.105 Although advanced chronologic age adversely affects
factors does not prolong disease-free or overall survival.96,97 Thus, the tolerance to treatment, the functional status of an individual patient is
routine use of growth factors at the initiation of systemic therapy is not much more useful than age in guiding clinical decision making (see the
recommended. NCCN Guidelines for Senior Adult Oncology, available at [Link]).
Older patients who are functional in terms of the ability to perform
The benefits of antiangiogenic therapy are being evaluated in SCLC. In
activities of daily living should be treated with standard combination
patients with limited-stage SCLC, a phase 2 study of irinotecan,
chemotherapy (and radiotherapy, if indicated).106,107 However,
carboplatin, and bevacizumab with concurrent radiotherapy followed by
myelosuppression, fatigue, and lower organ reserves are encountered
maintenance bevacizumab was terminated early because of an
more frequently in elderly patients; therefore, they must be watched
unacceptable incidence of tracheoesophageal fistulae. In
carefully during treatment to avoid excessive risk. Greater attention to
extensive-stage SCLC, phase 2 trials of platinum-based chemotherapy
the needs and support systems of elderly patients is recommended to
plus bevacizumab have yielded promising response and survival data.98-
provide optimal care. Overall, elderly patients have a similar prognosis
101
However, at least one randomized trial has demonstrated no survival
as stage-matched younger patients.
benefit for the addition of bevacizumab to standard chemotherapy.102
Other randomized phase 3 trials are ongoing in patients with Randomized trials have indicated that less-intensive treatment (eg,
extensive-stage SCLC.103 Currently, the NCCN Panel does not single-agent etoposide) is inferior to combination chemotherapy (eg,
recommend use of bevacizumab in patients with SCLC. platinum plus etoposide) in elderly patients with good PS (0–2).108,109 A
recent retrospective analysis in 8637 elderly patients with limited-stage
Although immune checkpoint inhibitors have demonstrated activity in a disease reported that chemoradiation increased survival when
variety of cancers, including SCLC, a recent phase 3 randomized trial compared with chemotherapy alone.106 Several other strategies have
reported that the addition of ipilimumab to etoposide with either cisplatin
been evaluated in elderly patients with SCLC.64,110-112 The use of 4
or carboplatin did not improve either overall survival or PFS in patients
cycles of carboplatin plus etoposide seems to yield favorable results,
with extensive-stage SCLC.104 Overall, attempts to improve long-term
because the area-under-the-curve (AUC) dosing of carboplatin takes
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into account the declining renal function of the aging patient.112 Guidelines for SCLC).119-122 These agents are listed in order of
However, targeting carboplatin to an AUC of 5, rather than 6, is more preference in the NCCN Guidelines. Ifosfamide was deleted for the
reasonable in this population.113 The usefulness of short-course, 2017 update, because panel members no longer use this agent.
full-intensity chemotherapy has also been explored in elderly or infirm
patients, and the results with only 2 cycles of chemotherapy seem to be For the 2017 update, the NCCN Panel added recommendations for
acceptable, although this approach has not been directly compared with nivolumab and nivolumab plus ipilimumab (both are category 2A) as
standard therapy.114 options for subsequent therapy for patients who have relapsed 6
months or less after primary therapy. Nivolumab and ipilimumab are
Second-Line and Beyond (Subsequent) Systemic Therapy novel immunotherapeutic agents that stimulate the immune system and
Although SCLC is very responsive to initial treatment, most patients thus have different mechanisms of action when compared with standard
relapse with relatively resistant disease.115,116 These patients have a cytotoxic chemotherapy.123 These recommendations are based on a
median survival of only 4 to 5 months when treated with further recent phase 1/2 trial in which patients received either nivolumab alone
systemic therapy. Subsequent systemic therapy provides significant or various doses of nivolumab with ipilimumab for relapsed SCLC.5
palliation in many patients, although the likelihood of response is highly Response rates were 10% (10/98) for nivolumab 3 mg/kg, 23% (14/61)
dependent on the time from initial therapy to relapse.117 If this interval is for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 19% (10/54) for
less than 3 months (refractory or resistant disease), response to most nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The responses did not
agents or regimens is poor (≤10%). If more than 3 months have elapsed correlate with PD-L1 expression; studies indicate the SCLC has a lower
(sensitive disease), expected response rates are approximately 25%. If rate of PD-L1 expression than NSCLC.5 Diarrhea was the most
patients relapse more than 6 months after first-line treatment, then common grade 3 or 4 treatment-related adverse event. The overall
treatment with their original regimen is recommended.7,117,118 Response frequency of grade 3 or 4 adverse events was about 20%, and fewer
assessment should occur after every 2 to 3 cycles of subsequent than 10% of patients discontinued treatment because of treatment-
systemic therapy using CT with contrast of the chest/liver/adrenal gland. related adverse events.
Dose reduction or growth factor support should be considered for
Preliminary data suggest that temozolomide may be useful for patients
patients with PS 2 who are receiving subsequent systemic therapy.
with SCLC, especially those with brain metastases and methylated O6-
Based on phase 2 trials, recommended subsequent systemic therapy methylguanine-DNA methyltransferase (MGMT).120,124 A recent phase 3
agents for patients who have relapsed 6 months or less after primary trial (JCOG0605) from Japan in patients with sensitive relapsed SCLC
therapy include topotecan, irinotecan, paclitaxel, docetaxel, reported that the combination of cisplatin, etoposide, and irinotecan
temozolomide, nivolumab with or without ipilimumab, vinorelbine, oral improved survival (median, 18.2 months; 95% CI, 15.7–20.6) when
etoposide, gemcitabine, CAV, and bendamustine (category 2A for all compared with topotecan (12.5 months, 10.8–14.9; hazard ratio [HR],
agents except for bendamustine, which is a category 2B 0.67; 90% CI, 0.51–0.88; P = .0079). However, the toxicity of this
recommendation) (see Principles of Systemic Therapy in the NCCN
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approach was significant, and it is not recommended as standard Radiotherapy

second-line therapy.125 The Principles of Radiation Therapy in the algorithm describe the
radiation doses, target volumes, and normal tissue dose volume
A randomized phase 3 trial compared single-agent intravenous constraints for mainly limited-stage SCLC, and include references to
topotecan with the combination regimen CAV.126 Both arms had similar support the recommendations; prophylactic cranial irradiation (PCI) and
response rates and survival, but intravenous topotecan caused less treatment of brain metastases are also discussed (see the NCCN
toxicity. In another phase 3 trial, oral topotecan improved overall Guidelines for SCLC). The American College of Radiology (ACR)
survival when compared with best supportive care (26 vs. 14 weeks).127 Appropriateness Criteria are a useful resource.139 The Principles of
Single-agent topotecan is approved by the FDA as subsequent therapy Radiation Therapy in the NSCLC algorithm may also be useful (eg,
for patients with SCLC who relapse after initial response to general principles of radiotherapy, palliative radiotherapy) (see the
chemotherapy. Either oral or intravenous topotecan may be used, NCCN Guidelines for NSCLC, available at [Link]). This section
because efficacy and toxicity seem to be similar with either route.127,128 describes the studies supporting the NCCN recommendations for
SCLC. A few reports have suggested that stereotactic ablative
Many practicing oncologists have noted excessive toxicity with the
radiotherapy (SBRT) might be useful for select patients with limited-
standard regimen of 1.5 mg/m2 of intravenous topotecan for 5 days, and
stage SCLC; however, there are insufficient data to make a
studies suggest that an attenuated dose may be equally efficacious with
recommendation.140,141
lower toxicity.129 Published studies have yielded conflicting data
regarding the usefulness of weekly topotecan in patients with relapsed Thoracic Radiotherapy
SCLC, and this approach remains under investigation.130,131 Amrubicin is
The addition of thoracic radiotherapy has improved survival for patients
an active drug in patients with relapsed or refractory SCLC.132-135
with limited-stage disease. Meta-analyses that included more than 2000
However, grade 3–4 toxicity, primarily neutropenia, is common.136,137 A
patients show that thoracic radiation for limited-stage disease yields a
phase 3 trial reported that amrubicin did not improve overall survival as
25% to 30% reduction in local failure, and a corresponding 5% to 7%
second-line treatment for SCLC when compared to topotecan, except in
improvement in 2-year survival when compared with chemotherapy
a subset of patients with refractory disease.138
alone.52,53 However, achieving long-term local control using conventional
The optimal duration of subsequent systemic therapy has not been fully chemoradiotherapy for patients with limited-stage SCLC remains a
explored, although its duration is usually short and the cumulative challenge.
toxicity is frequently limiting even in patients who experience response.
Timing of Radiation with Chemotherapy
For these reasons, subsequent systemic therapy should be continued
The administration of thoracic radiotherapy requires the assessment of
until 2 cycles beyond best response, progression of disease, or
several factors, including the timing of chemotherapy and radiotherapy
development of unacceptable toxicity. Additional subsequent systemic
(concurrent vs. sequential), timing of radiotherapy (early vs. late),
therapy (eg, third line) can be considered if patients are still PS 0-2.
volume of the radiation port (original tumor volume vs. shrinking field as
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the tumor responds), dose of radiation, and fractionation of advantage, but a higher incidence of grade 3 to 4 esophagitis was seen
radiotherapy. Early concurrent chemoradiotherapy is recommended for when compared with the once-daily regimen. Median survivals were 23
patients with limited-stage SCLC based on randomized trials. A versus 19 months (P = .04), and 5-year survival rates were 26% versus
randomized phase 3 trial by the Japanese Cooperative Oncology Group 16% in the twice-daily and once-daily radiotherapy arms, respectively.147
assessed sequential versus concurrent thoracic radiotherapy combined A significant criticism of this trial is that the doses of radiation in the 2
with EP for patients with limited-stage disease. They reported that arms were not biologically equivalent. In light of this, ongoing trials are
patients treated with concurrent radiotherapy lived longer than those evaluating biologically equivalent doses of 45 Gy delivered twice daily
treated with sequential radiotherapy.59 versus 60 to 70 Gy delivered once daily.148 Another concern regarding
hyperfractionation is that twice-daily thoracic radiation is technically
Another randomized phase 3 trial (by the National Cancer Institute of challenging for patients with bilateral mediastinal adenopathy.
Canada)—comparing radiotherapy beginning with either cycle 2 or cycle
6 of chemotherapy—showed that early radiotherapy was associated Another randomized phase 3 trial showed no survival difference
with improved local and systemic control and with longer survival.142 between once-daily thoracic radiotherapy to 50.4 Gy with concurrent EP
Several systematic reviews and meta-analyses on the timing of thoracic and a split course of twice-daily thoracic radiotherapy to 48 Gy with
radiotherapy in limited-stage SCLC have reported that early concurrent concurrent EP.149 However, split-course radiotherapy may be less
radiotherapy results in a small, but significant improvement in overall efficacious because of interval tumor regrowth between courses.
survival when compared with late concurrent or sequential Overall, patients selected for combined modality treatment that
radiotherapy.143,144 Another meta-analysis in patients with limited-stage incorporates twice-daily radiotherapy must have an excellent PS and
SCLC showed that survival was improved with more rapid completion of good baseline pulmonary function.
the chemo/RT regimen (start of any chemotherapy until the end of
radiotherapy [SER]).145 A recent meta-analysis of individual patient data NCCN Guideline for Radiation in Limited-Stage SCLC
from 12 trials (2,668 patients) reported that early concurrent chemo/RT For limited-stage disease in excess of T1-2, N0, the NCCN Guidelines
increased 5-year overall survival (HR, 0.79; 95% CI, 0.69–0.91), recommend that radiotherapy should be used concurrently with
although severe acute esophagitis was also increased, when compared chemotherapy and that radiotherapy should start with the first or second
with late concurrent therapy.146 cycle (category 1). The optimal dose and schedule of radiotherapy have
not been established. However, 45 Gy in 3 weeks (twice-daily regimen)
Radiation Fractionation is superior to 45 Gy once daily in 5 weeks.147 For twice-daily
The ECOG/Radiation Therapy Oncology Group compared once-daily to radiotherapy, the recommended schedule is 1.5 Gy twice daily to a total
twice-daily radiotherapy with EP.147 In this trial, 412 patients with dose of 45 Gy in 3 weeks (category 1). For once-daily radiotherapy, the
limited-stage SCLC were treated with concurrent chemoradiotherapy recommended schedule is 2.0 Gy once daily to a total dose of 60 to 70
using a total dose of 45 Gy delivered either twice a day over 3 weeks or Gy (see Principles of Radiation Therapy in the NCCN Guidelines for
once a day over 5 weeks. The twice-daily schedule produced a survival SCLC).150-152 The minimum standard for thoracic irradiation is
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CT-planned 3-D conformal radiotherapy. More advanced technologies phase 3 trial by Slotman et al (Dutch CREST trial) reported that the
may also be used when needed (eg, 4D-CT) (see Principles of addition of sequential thoracic radiotherapy did not improve the primary
Radiation Therapy in the NCCN Guidelines for SCLC). The radiation endpoint of 1-year overall survival (33% vs. 28%, P = .066), but a
target volumes can be defined on the PET/CT scan obtained at the time secondary analysis did find improvement in 2-year overall survival (13%
of radiotherapy planning using definitions in reports 50 and 62 from the vs. 3%, P = .004) when compared with patients who did not receive
International Commission on Radiation Units & Measurement sequential thoracic radiotherapy.165
(ICRU).153,154 However, the pre-chemotherapy PET/CT scan should be
reviewed to include the originally involved lymph node regions in the Prophylactic Cranial Irradiation
treatment fields.152,155 Intracranial metastases occur in more than 50% of patients with SCLC.
Randomized studies have shown that PCI is effective in decreasing the
The normal tissue constraints used for NSCLC are appropriate for incidence of cerebral metastases, but most individual studies did not
SCLC when using similar radiotherapy doses (see the NCCN have sufficient power to show a meaningful survival advantage.166 A
Guidelines for NSCLC, available at [Link]). When using meta-analysis of all randomized PCI trials (using data from individual
accelerated schedules (eg, 3–5 weeks), the spinal cord constraints from patients) reported a 25% decrease in the 3-year incidence of brain
the CALCB 30610/RTOG 0538 protocol can be used as a guide (see metastases, from 58.6% in the control group to 33.3% in the PCI-
Principles of Radiation Therapy in the NCCN Guidelines for SCLC).156- treated group.167 Thus, PCI seems to prevent (and not simply delay) the
158
Intensity-modulated radiation therapy (IMRT) may be considered in emergence of brain metastases. This meta-analysis also reported a
select patients (see Principles of Radiation Therapy in the NCCN 5.4% increase in 3-year survival in patients treated with PCI, from
Guidelines for SCLC and the NCCN Guidelines for NSCLC).159-163 15.3% in the control group to 20.7% in the PCI group.167 Although the
number of patients with extensive-stage disease was small in this
Thoracic Radiation in Extensive-Stage SCLC meta-analysis, the observed benefit was similar in patients with both
Based on the results of a randomized trial by Jeremic et al,164 the limited- and extensive-stage disease.
addition of sequential thoracic radiotherapy may be considered in select
patients with low-bulk metastatic extensive-stage disease who have a A retrospective study of patients with limited-stage disease also found
complete or near complete response after initial chemotherapy. In this that PCI increased survival at 2, 5, and 10 years compared with those
trial, patients experiencing a complete response at distant metastatic who did not receive PCI.168 A randomized trial from the EORTC
sites after 3 cycles of EP were randomized to receive either 1) further assessed PCI versus no PCI in 286 patients with extensive-stage SCLC
EP; or 2) accelerated hyperfractionated radiotherapy (ie, 54 Gy in 36 whose disease had responded to initial chemotherapy; PCI decreased
fractions over 18 treatment days) in combination with carboplatin plus symptomatic brain metastases (14.6% vs. 40.4%) and increased the
etoposide.164 The investigators found that the addition of radiotherapy 1-year survival rate (27.1% vs. 13.3%) compared with controls.169
resulted in improved median overall survival (17 vs. 11 months). In Preliminary data from a Japanese phase 3 trial suggest that PCI did not
patients with extensive-stage SCLC who responded to chemotherapy, a
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improve survival in patients with extensive-stage disease who had MRI Palliative Radiotherapy
to confirm that they did not have brain metastases.170 For patients with localized symptomatic sites of disease (ie, painful bony
lesions, spinal cord compression, obstructive atelectasis) or with brain
Late neurologic sequelae have been attributed to PCI, particularly in metastases, radiotherapy can provide excellent palliation (see Initial
studies using fractions greater than 3 Gy and/or administering PCI Treatment in the NCCN Guidelines for SCLC and the NCCN Guidelines
concurrently with chemotherapy.171,172 Thus, PCI is not recommended for NSCLC, available at [Link]).178-180 Orthopedic stabilization may
for patients with poor PS (3–4) or impaired neurocognitive function.173,174 be useful in patients at high risk for fracture because of osseous
Older age (>60 years) has also been associated with chronic structural impairment. Because patients with SCLC often have a short
neurotoxicity.175 When given after the completion of chemotherapy and life span, surgery is not usually recommended for spinal cord
at a low dose per fraction, PCI may cause less neurologic toxicity. compression. Whole-brain radiotherapy is recommended for brain
metastases in patients with SCLC due to the frequent occurrence of
Before the decision is made to administer PCI, a balanced discussion
multiple metastases (see Principles of Radiation Therapy in the NCCN
between the patient and physician is necessary.176 PCI is a category 1
Guidelines for SCLC and the NCCN Guidelines for Central Nervous
recommendation for patients with limited-stage disease who attain a
System Cancers, available at [Link]).181 Although late
complete or partial response; PCI is a category 2A recommendation for
complications, such as neurocognitive impairment, may occur with
patients with extensive-stage disease.169,173 PCI is also recommended
whole-brain radiotherapy this is less of an issue in patients with SCLC
for all patients who have had a complete resection (see Principles of
because long-term survival is rare.171 The recommended dose for
Surgical Resection in the NCCN Guidelines for SCLC). The preferred
whole-brain radiotherapy is 30 Gy in 10 daily fractions.181 In patients
dose for PCI to the whole brain is 25 Gy in 10 daily fractions (2.5
who develop brain metastases after PCI, stereotactic radiosurgery may
Gy/fraction), (see Principles of Radiation Therapy in the NCCN
be considered.182
Guidelines for SCLC).167,169,177 The NCCN Panel feels that a shorter
course of PCI may be appropriate (eg, 20 Gy in 5 fractions) for selected Surgical Resection of Stage I SCLC
patients with extensive-stage disease.169 Higher doses (eg, 36 Gy) The Principles of Surgical Resection for SCLC are described in the
increased mortality and toxicity when compared with standard doses NCCN algorithm; studies supporting these recommendations are
(25 Gy).175,177 PCI should not be given concurrently with systemic described in this section. Briefly, the NCCN Guidelines state that
therapy, and high total radiotherapy dose (>30 Gy) should be avoided surgery should only be considered for patients with stage I (T1–2, N0)
because of the increased risk of neurotoxicity.175 Fatigue, headache, SCLC in whom mediastinal staging has confirmed that mediastinal
and nausea/vomiting are the most common acute toxic effects after lymph nodes are not involved.183 Data show that patients with clinically
PCI.174,177 After the acute toxicities of initial therapy have resolved, PCI staged disease in excess of T1–2,N0 do not benefit from surgery.184
can be administered. For patients not receiving PCI, surveillance for Note that only 5% of patients with SCLC have true stage I SCLC.39
metastases with brain imaging should be considered.

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The Lung Cancer Study Group conducted the only prospective out through mediastinal staging before resection.191 If resection is
randomized trial evaluating the role of surgery in SCLC.184 Patients with performed, the NCCN Panel favors lobectomy and does not feel that
limited-stage disease, excluding those with solitary peripheral nodules, segmental or wedge resections are appropriate for patients with SCLC.
received 5 cycles of chemotherapy with CAV; those showing a After complete resection, adjuvant chemotherapy or chemoradiation is
response to chemotherapy were randomly assigned to undergo recommended.173,187,192,193 Adjuvant chemotherapy alone is
resection plus thoracic radiotherapy or thoracic radiotherapy alone. The recommended for patients without nodal metastases, whereas
overall survival rates of patients on the 2 arms were equivalent, concurrent chemotherapy and postoperative mediastinal radiotherapy
suggesting no benefit to surgery in this setting. However, only 19% of are recommended for patients with nodal metastases (see Adjuvant
enrolled patients had clinical stage I (T1–2, N0, M0) disease. Treatment in the NCCN Guidelines for SCLC). Although panel members
agree that postoperative mediastinal radiotherapy is recommended in
Most data regarding the benefit of surgery are from retrospective this setting, it should be based on the extent of nodal
reviews.183,185-189 These studies report favorable 5-year survival rates of sampling/dissection and extent of nodal positivity; however, there are no
40% to 60% in patients with stage I disease. In most series, survival data to support this recommendation. PCI should be considered after
rates decline significantly in patients with more advanced disease, adjuvant therapy in select patients, because it can improve survival (see
leading to the general recommendation that surgery should only be Prophylactic Cranial Irradiation in this Discussion and Adjuvant
considered in those with stage I disease. Interpretation of these results Treatment in the NCCN Guidelines for SCLC).167 For the 2017 update,
is limited by the selection bias inherent in retrospective reviews and by the NCCN Panel added new recommendations for response
the variable use of chemotherapy and radiotherapy. assessment after adjuvant therapy. Response assessment using CT
with contrast of the chest, liver, and adrenal gland should occur only
Analyses of the SEER database also suggest that surgery may be
after completion of initial therapy for patients with limited-stage disease;
appropriate for some patients with localized disease.11,190 However,
repeating scans during therapy is not recommended.
these studies are limited by the lack of information on chemotherapy
use in the database. In addition, comparison of the survival of surgical Surveillance
patients to all those who did not undergo surgery is inherently flawed by
The schedule for follow-up examinations is shown in the algorithm (see
selection bias. Ultimately, the role of surgery in SCLC will not be fully
Surveillance in the NCCN Guidelines for SCLC); the frequency of
defined until results are available from trials comparing surgery plus
surveillance decreases during subsequent years because of the
adjuvant chemotherapy to concurrent chemoradiotherapy in patients
declining risk of recurrence.194 PET/CT or brain MRI (or CT) is not
who are rigorously staged.
recommended for routine follow-up. If a new pulmonary nodule
NCCN Guidelines develops, it should prompt evaluation for a new primary lung cancer,
In all patients with clinical stage I (T1–2, N0) SCLC who are being because second primary tumors are a frequent occurrence in patients
considered for surgical resection, occult nodal disease should be ruled who are cured of SCLC.195,196 Smoking cessation should be encouraged

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for all patients with SCLC, because second primary tumors occur less distinguishing LNTs from SCLC and LCNEC, although diagnosis can be
commonly in patients who quit smoking (see the NCCN Guidelines for difficult (see the NCCN Guidelines for Neuroendocrine Tumors and the
Smoking Cessation, available at [Link]).197-199 Former smokers NCCN Guidelines for NSCLC, available at [Link]).18,213 CD56,
should be encouraged to remain abstinent. chromogranin, and synaptophysin are useful immunohistochemical
markers for identifying neuroendocrine tumors.18 The proliferative
Lung Neuroendocrine Tumors marker Ki-67 may also be useful.19 Larger surgical specimens are often
LNTs encompass a wide spectrum of disease. Using the 2015 WHO needed to diagnose atypical carcinoids or LCNEC, which may be
criteria, LNTs are characterized as: 1) high-grade neuroendocrine difficult to diagnose using small biopsies or cytology.18
carcinomas (SCLC and LCNEC); 2) intermediate-grade neuroendocrine
carcinomas (atypical carcinoids); or 3) low-grade neuroendocrine LNTs are staged using the 7th edition of the AJCC staging system for
carcinomas (typical carcinoids).18,200-202 SCLC and LCNEC are poorly lung tumors (see Tables 2 and 3 in the NCCN Guidelines for
differentiated tumors that often have a poor prognosis, whereas typical SCLC).41,214 Both low-grade and intermediate-grade LNTs are usually
carcinoid is a well-differentiated neuroendocrine tumor that usually has stage I at diagnosis, although lymph node metastases (stages II–III) are
a good prognosis. Atypical carcinoid is a moderately differentiated more commonly seen in intermediate-grade tumors. Compared with
neuroendocrine cancer and, as such, carries an intermediate prognosis. other lung carcinomas, the prognosis is excellent for many patients with
Although many carcinoids occur in the GI tract (68%), they also occur in low-grade and intermediate-grade LNTs.18,215
the bronchopulmonary system (25%). Carcinoids are rare tumors, but a
Treatment
SEER analysis suggests that their incidence is increasing.203,204
Surgery is recommended for patients with stage I, II, or IIIA low-grade or
Diagnosis and Staging intermediate-grade LNTs (ie, typical or atypical carcinoids) (see Primary
Most LNTs are SCLCs, which are managed using the NCCN Guidelines Treatment in the NCCN Guidelines for Lung Neuroendocrine
for SCLC. LCNEC is associated with smoking and is managed using the Tumors).216-218 After surgical resection, 5- and 10-year survival rates are
NCCN Guidelines for NSCLC, because the conceptual algorithm used more than 90% for patients with typical carcinoids, whereas 5- and
to manage these patients is the same as that for patients with 10-year survival rates are 70% and 50% to 60% for patients with
NSCLC.205-207 However, data suggest that chemotherapy regimens used atypical carcinoids.218-220 Lymph node involvement decreases long-term
for SCLC may be a better option for LCNEC if systemic therapy is survival in both typical and atypical carcinoid.218-220 Recently, the NCCN
indicated.208-212 Low-grade lung neuroendocrine carcinomas (typical Panel slightly revised the primary treatment guidelines for patients with
carcinoids) and intermediate-grade lung neuroendocrine carcinomas stage IIIA LNTs. If surgery is not feasible, cisplatin/etoposide plus
(atypical carcinoids) account for 1% to 2% of lung cancers and are radiotherapy is recommended for stage IIIA typical or atypical
managed using the NCCN Guidelines for Lung Neuroendocrine carcinoids.221,222 Cisplatin/etoposide plus RT is also recommended for
Tumors. Both histologic and cytologic features can be useful for stage IIIB LNTs except for T4 due to multiple lung nodules. Systemic

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Small Cell Lung Cancer Discussion

therapy (eg, cisplatin/etoposide [preferred for atypical carcinoids],

temozolomide ± capecitabine, sunitinib, everolimus) is recommended
for patients with unresectable or advanced disease, although response
rates are modest and there is no evidence for a preferred regimen for
low-grade typical carcinoids.215,221,223-232 Octreotide (including long-acting
release [LAR]) or lanreotide may be considered for select patients with
positive octreotide scans or symptoms of carcinoid syndrome.221,233-235
Surveillance recommendations are also provided in the NCCN
Guidelines.

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