Small Cell Lung Cancer: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
Small Cell Lung Cancer

Version 3.2020 — February 5, 2020
NCCN.org
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Version 3.2020, 02/05/20 © 2020 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
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NCCN Guidelines Version 3.2020 NCCN Guidelines Index

Table of Contents
Small Cell Lung Cancer Discussion
Apar Kishor P. Ganti, MD, Chair † Charles Florsheim Daniel Morgensztern, MD †

Fred & Pamela Buffett Cancer Center Patient Advocate Siteman Cancer Center at Barnes-
*Billy W. Loo, Jr., MD, PhD/Vice Chair § Kathryn A. Gold, MD † Jewish Hospital and Washington
Stanford Cancer Institute UC San Diego Moores Cancer Center University School of Medicine
Wallace Akerley, MD † John C. Grecula, MD § Saraswati Pokharel, MD ≠

Huntsman Cancer Institute The Ohio State University Comprehensive Roswell Park Comprehensive Cancer Center
at the University of Utah Cancer Center - James Cancer Hospital David C. Portnoy, MD ‡ †
Michael Bassetti, MD § and Solove Research Institute The University of Tennessee
University of Wisconsin Carbone Cancer Center Christine L. Hann, MD, PhD † Health Science Center
Jessica Bauman † The Sidney Kimmel Comprehensive Sonam Puri, MD † ‡ Þ

Cancer Center at Johns Hopkins Huntsman Cancer Institute
Fox Chase Cancer Center at the University of Utah
Abigail Berman, MD, MSCE § James A. Hayman, MD, MBA §
University of Michigan Deborah Rhodes, MD Þ
Abramson Cancer Center Mayo Clinic Cancer Center
at the University of Pennsylvania Rogel Cancer Center
Wade Iams, MD † Chad Rusthoven, MD §
Collin Blakely, MD, PhD † University of Colorado Cancer Center
UCSF Hellen Diller Family Vanderbilt-Ingram Cancer Center
Comprehensive Cancer Center Marianna Koczywas, MD † ‡ Þ Jacob Sands, MD †
City of Hope Dana Farber/Brigham and Women's
Anne Chiang, MD, PhD † National Medical Center Cancer Center
Yale Cancer Center/Smilow Cancer Hospital
Robert E. Merritt, MD ¶ Rafael Santana-Davila, MD †
Thomas A. D'Amico, MD ¶ The Ohio State University Comprehensive Fred Hutchinson Cancer Research Center/
Duke Cancer Institute Cancer Center - James Cancer Hospital Seattle Cancer Care Alliance
M. Chris Dobelbower, MD, PhD § and Solove Research Institute
Michael Shafique, MD †
O'Neal Comprehensive Nisha Mohindra, MD † Moffitt Cancer Center
Cancer Center at UAB Robert H. Lurie Comprehensive Cancer Center
Afshin Dowlati, MD † of Northwestern University NCCN
Case Comprehensive Cancer Center/University Julian Molina, MD, PhD ‡ Þ Miranda Hughes, PhD
Hospitals Seidman Cancer Center and Cleveland Mayo Clinic Cancer Center Jennifer Keller, MSS
Clinic Taussig Cancer Institute
Cesar A. Moran, MD ≠
Robert J. Downey, MD ¶ The University of Texas ‡ Hematology/Hematology oncology
Memorial Sloan Kettering Cancer Center MD Anderson Cancer Center Þ Internal medicine
Anna Farago, MD, PhD † † Medical oncology
≠ Pathology
Massachusetts General Hospital Cancer Center Continue § Radiotherapy/Radiation oncology
¶ Surgery/Surgical oncology
NCCN Guidelines Panel Disclosures *Discussion writing committee member

Table of Contents
NCCN Small Cell Lung Cancer Panel Members

Summary of the Guidelines Updates Clinical Trials: NCCN believes that
the best management for any patient
with cancer is in a clinical trial.
Initial Evaluation and Staging (SCL-1) Participation in clinical trials is
Limited Stage, Workup and Treatment (SCL-2) especially encouraged.
Extensive Stage, Initial Treatment (SCL-5)
To find clinical trials online at NCCN
Response Assessment Following Initial Therapy and Surveillance (SCL-6)
Member Institutions, click here:
Progressive Disease: Subsequent Therapy and Palliative Therapy (SCL-7) nccn.org/clinical_trials/member_
institutions.aspx.
Signs and Symptoms of Small Cell Lung Cancer (SCL-A)
Principles of Pathologic Review (SCL-B) NCCN Categories of Evidence and
Consensus: All recommendations
Principles of Surgical Resection (SCL-C) are category 2A unless otherwise
Principles of Supportive Care (SCL-D) indicated.
Principles of Systemic Therapy (SCL-E)
Principles of Radiation Therapy (SCL-F) See NCCN Categories of Evidence
and Consensus.
Staging (ST-1) NCCN Categories of Preference:
All recommendations are considered
Lung Neuroendocrine Tumors – See the NCCN Guidelines for Neuroendocrine and Adrenal appropriate.
Tumors See NCCN Categories of Preference.
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. ©2020.

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Updates in Version 3.2020 of the NCCN Guidelines for Small Cell Lung Cancer from Version 2.2020 include:
SCL-F 3 of 4
• Brain Metastases
Bullet 4 added: For patients with a better prognosis (eg, ≥ 4 months), consider hippocampal-sparing WBRT using IMRT
• Palliative Radiation for Extracranial Metastases section added
Bullet 1 added: Common radiation dose-fractionation regimens (eg, 30 Gy in 10 fractions, 20 Gy in 5 fractions, 8 Gy in 1 fraction) used for
palliation of other solid tumors are appropriate for palliation of SCLC metastases in most patients.
Bullet 2 added: Conformal techniques, such as IMRT, and/or higher dose intensity approaches, including SABR or SRS, may be appropriate
in selected patients (eg, tumors with close proximity to organs at risk, re-irradiation, or better prognosis).
SCL-E 1 of 4 Durvalumab in combination with chemotherapy (etoposide with either carboplatin or cisplatin) has been added as a preferred
first-line treatment option (category 1) followed by maintenance durvalumab for patients with extensive stage SCLC.
SCL-1 (SCL-6). If brain metastases progress while on systemic therapy,
• Initial Evaluation then initiate WBRT.
Bullet 5 modified here and as appropriate throughout the
guidelines: Chest/abdomen/pelvis CT with contrast SCL-6
Bullet six modified: Consider PET/CT scan (skull base to mid- • Footnote u modified: Not recommended in patients with poor
thigh), if limited stage is suspected or if needed to clarify stage performance status or impaired neurocognitive function. Increased
Bullet 9 added: Molecular profiling (only for never smokers with cognitive decline after PCI has been observed in older adults (≥60
extensive stage) years) in prospective trials; the risks and benefits of PCI versus
• Footnotes close surveillance should be carefully discussed with these patients.
Footnote f added: Molecular profiling may be considered in never • Footnote v added: The benefit of PCI is unknown in patients who
smokers with extensive stage SCLC to help clarify diagnosis and have undergone complete resection for pathologic stage I-IIA (T1-
evaluate for potential targeted treatment options. 2,N0,M0) SCLC. See Principles of Surgical Resection (SCL-C).
SCL-B 1 of 2
SCL-5 • Pathologic Evaluation
• Initial Treatment Bullet 6 added: Combined SCLC consists of both SCLC histology
Extensive stage with brain metastases, Asymptomatic, modified: and NSCLC histology (squamous cell, adenocarcinoma, spindle/
May administer systemic therapy first, with whole-brain RT (WBRT) pleomorphic, and/or large cell). There is no minimal percentage of
after completion of induction systemic therapy NSCLC histologic elements required; when any are present along
• Footnotes: with SCLC, this can be called combined SCLC.
Footnote r modified: For patients with asymptomatic brain
metastases receiving systemic therapy before whole brain WBRT, SCL-C
brain MRI (preferred) or CT with contrast should be repeated after • Principles of Surgical Resection
every 2 cycles of systemic therapy and at completion of therapy Bullet 4 modified: Patients who undergo complete resection should
Continued
Version 3.2020, 02/05/20 © 2020 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
UPDATES

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be treated with postoperative systemic therapy. Patients without Reference 35 added: Ott PA, Elez E, Hiret S, et al. Pembrolizumab in
nodal metastases should be treated with systemic therapy patients with extensive-stage small-cell lung cancer: results from the
alone. Patients with N2 or N3 nodal metastases should be phase Ib KEYNOTE-028 study. J Clin Oncol 2017;35:3823-3829.
treated with postoperative concurrent or sequential systemic SCL-F 1 of 4
therapy ± concurrent or sequential and mediastinal RT. Patients • General Treatment Information
with N1 nodal metastases may be considered for postoperative
Limited stage, sub-bullet 1 added: In patients with clinical stage I-IIA
mediastinal radiation.
(T1-2,N0,M0) who have undergone lobectomy and are found to have
regional nodal involvement on final pathology, postoperative RT is
SCL-E 1 of 4
recommended in pathologic N2 and may be considered in pathologic
• Primary or Adjuvant Therapy for Limited Stage SCLC
N1 stage, either sequentially or concurrently with chemotherapy.
All of the systemic therapy regimens have been categorized
Principles of postoperative RT for NSCLC, including target volumes
using a new preference stratification system; certain regimens
and doses, are recommended.
are now recommended as preferred interventions, whereas
Limited stage, sub-bullet 5 modified: Historically, clinically uninvolved
other regimens are categorized as either other recommended
mediastinal nodes have been included in the RT target volume,
interventions or useful under certain circumstances.
whereas uninvolved supraclavicular nodes generally have not been
Treatment cycle length added: Planned cycle length should be
included. Consensus on elective nodal irradiation (ENI) is evolving.
every 21–28 days during concurrent RT.
Several more modern series, both retrospective and prospective,
• Footnotes
suggest that omission of ENI results in low rates of isolated nodal
Footnote a added: Cisplatin contraindicated or not tolerated.
recurrences (0%–11%, most <5%), particularly when incorporating
Footnote c added: Contraindications for treatment with
PET staging/target definition (1.7%–3%). ENI has been omitted in
PD-1/PD-L1 inhibitors may include active or previously
current prospective clinical trials (including CALGB 30610/RTOG 0538
documented autoimmune disease and/or concurrent use of
and the EORTC 08072 [CONVERT] trial). Inclusion of the ipsilateral
immunosuppressive agents.
hilum in the target volume, even if not grossly involved, differs
Footonote removed: The regimens included are representative
between these trials but may be reasonable.
of the more commonly used regimens for SCLC. Other regimens
may be acceptable. SCL-F 2 of 4
Footnote removed: If not used as original regimen, may be used • General Treatment Information
as therapy for primary progressive disease. Extensive stage, first sentence of sub-bullet 1 modified: Consolidative
thoracic RT is beneficial for selected patients with extensive‑stage
SCL-E 4 of 4
SCLC with complete response or good response to systemic therapy,
• References
especially with residual thoracic disease and low-bulk extrathoracic
Reference 34 added: Chung HC, Piha-Paul SA, Lopez-Martin J,
metastatic disease.
et al. Pembrolizumab after two or more lines of prior therapy in
• Prophylactic Cranial Irradiation
patients with advanced small-cell lung cancer (SCLC): Results
Bullet 1 modified: In patients with limited-stage SCLC who have a
from the KEYNOTE-028 and KEYNOTE-158 studies. 2019 AACR
good response to initial therapy, PCI decreases brain metastases
Annual Meeting. Abstract CT073. Presented April 1, 2019.
Continued
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and increases overall survival (category 1).In patients with
extensive--stage SCLC that has responded to systemic therapy,
PCI decreases brain metastases. A randomized trial conducted
by the EORTC found improved overall survival with PCI.However,
a Japanese randomized trial found that in patients who had no
brain metastases on baseline MRI, PCI did not improve overall
survival compared with routine surveillance MRI and treatment
of asymptomatic brain metastases upon detection. In patients
not receiving PCI, surveillance for metastases by brain imaging
should be performed. Surveillance imaging for brain metastases is
recommended for all patients regardless of PCI status.
SCL-F 3 of 4
• Brain Metastases
Bullet 1 modified: Brain metastases should typically be treated
with WBRT; however, selected patients with a small number
of metastases may be appropriately treated with stereotactic
radiotherapy (SRT)/radiosurgery (SRS) rather than stereotactic
radiotherapy/radiosurgery (SRT/SRS) alone, because these
patients tend to develop multiple central nervous system (CNS)
metastases.
Bullet 3 modified: Recommended dose for WBRT is 30 Gy in 10
daily fractions. Consider adding memantine during and after RT
(see Prophylactic Cranial Irradiation for memantine dosing).
UPDATES

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DIAGNOSIS INITIAL EVALUATIONa STAGE
• H&Pb
• Pathology reviewc
• CBC
• Electrolytes, liver function tests Limited stage
(See ST-1 for TNM See Additional
(LFTs), BUN, creatinine Workup (SCL-2)
Small cell lung • Chest/abdomen/pelvis CT with Classification)
cancer (SLCL) or contrast
combined SCLC/ • Brain MRIa,d (preferred) or CT with
non-small cell lung contrast
cancer (NSCLC) on • Consider PET/CT scan (skull base
biopsy or cytology to mid-thigh), if limited stage is Extensive stage
of primary or suspected or if needed to clarify See Initial
(See ST-1 for TNM
metastatic site stagea,e,f Treatment (SCL-5)
Classification)
• Smoking cessation counseling
and intervention. See the NCCN
Guidelines for Smoking Cessation.
• Molecular profiling (only for never
smokers with extensive stage)f
a If extensive stage is established, further staging evaluation is optional. However, brain imaging, MRI (preferred), or CT with contrast should be obtained in all patients.
b See Signs and Symptoms of Small Cell Lung Cancer (SCL-A).
c See Principles of Pathologic Review (SCL-B).
d Brain MRI is more sensitive than CT for identifying brain metastases and is preferred over CT.
e If 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.
f Molecular profiling may be considered in never smokers with extensive stage SCLC to help clarify diagnosis and evaluate for potential targeted treatment options.
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-1

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STAGE ADDITIONAL WORKUP
• If pleural effusion is present,

thoracentesis is Clinical stage Pathologic mediastinal See Initial
recommended; if I-IIA (T1-2,N0,M0) stagingi,j,k Treatment (SCL-3)
thoracentesis inconclusive,
consider thoracoscopyg
• Pulmonary function tests
(PFTs) during evaluation
Limited stage Limited stage
for surgery or definitive See Initial
(See ST-1 for TNM IIB-IIIC (T3-4,N0,M0;
radiation therapy (RT) Treatment (SCL-4)
Classification) T1-4,N1-3,M0)
• Bone imaging (radiographs
or MRI) as appropriate if
PET/CT equivocal (consider
biopsy if bone imaging is
equivocal) Bone marrow biopsy, See
• Unilateral marrow thoracentesis, or bone studies Extensive-Stage
aspiration/biopsy in select consistent with malignancy Disease (SCL-5)
patientsh
g While 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.
h Selection criteria include: nucleated red blood cells (RBCs) on peripheral blood smear, neutropenia, or thrombocytopenia suggestive of bone marrow infiltration.
i See Principles of Surgical Resection (SCL-C).
j Mediastinal 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.
k Pathologic mediastinal staging is not required if the patient is not a candidate for surgical resection or if non-surgical treatment is pursued.

SCL-2

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TESTING RESULTSk INITIAL TREATMENT ADJUVANT TREATMENT

N0 Systemic therapym
Lobectomyi,l Systemic therapym

Pathologic mediastinal (preferred) and ± mediastinal RTn
stagingi,j negative N1 (sequential or
mediastinal lymph
node dissection or concurrent) See Response
sampling Assessment +
Adjuvant Treatment
Systemic therapym (SCL-6)o
+ mediastinal RTn
N2
(sequential or
Clinical stage concurrent)
I-IIA (T1-2,N0,M0)
SABRn Systemic therapym
Medically inoperable or
decision made not to
See Response
pursue surgical resectionk Systemic therapym
Assessment +
+ concurrent RTn
Adjuvant Treatment
(See SCL-4)
(SCL-6)p
Pathologic
mediastinal stagingi,j See SCL-4
positive

j Mediastinal 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.
k Pathologic mediastinal staging is not required if the patient is not a candidate for surgical resection or if non-surgical treatment is pursued.
l Select patients may be treated with systemic therapy/RT as an alternative to surgical resection.
m See Principles of Systemic Therapy (SCL-E).
n See Principles of Radiation Therapy (SCL-F).
o For patients receiving adjuvant systemic therapy ± RT, response assessment should occur only after completion of adjuvant therapy (SCL-6); do not repeat scans to
assess response during adjuvant treatment.
p For patients receiving systemic therapy + concurrent RT, response assessment should occur only after completion of initial therapy (SCL-6); 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 chest/
abdomen/pelvis CT with contrast should occur after every 2 cycles of systemic therapy and at completion of therapy (SCL-6).

SCL-3

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INITIAL TREATMENT ADJUVANT TREATMENT
Systemic therapym +
Good PS (0-2) concurrent RTn (category 1)
See Response
Assessment +
Adjuvant Treatment
(SCL-6)p
Limited stage
IIB-IIlC (T3-4,N0,M0; Poor PS (3-4) Systemic therapym ± RTn
T1-4,N1-3,M0) due to SCLC (concurrent or sequential)
Poor PS (3-4) Individualized treatment

not due to SCLC including supportive careq
See NCCN Guidelines for
Palliative Care

p For patients receiving systemic therapy + concurrent RT, response assessment should occur only after completion of initial therapy (SCL-6); 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 chest/
abdomen/pelvis CT with contrast should occur after every 2 cycles of systemic therapy and at completion of therapy (SCL-6).
q See Principles of Supportive Care (SCL-D).

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STAGE INITIAL TREATMENTq

• Good PS (0-2)
Combination systemic therapym including
• Poor PS (3-4)
Extensive stage supportive careq
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 careq
SCLC See NCCN Guidelines for Palliative Care
Systemic therapym ± RTn to

• Superior vena symptomatic sites
cava (SVC) If high risk of fracture due to osseous
syndrome structural impairment, consider
orthopedic stabilization and See Response
Extensive stage Extensive stage + • Lobar obstruction
• Bone metastases palliative external beam RT (EBRT)n Assessment +
(See ST-1 for TNM localized Adjuvant Treatment
Classification) symptomatic sites (SCL-6)r
RTn to symptomatic sites before
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 RT (WBRT)n after completion
Extensive stage with of induction systemic therapym,r
brain metastases
WBRTn before systemic therapy,m unless
Symptomatic immediate systemic therapy is indicated

r For patients with asymptomatic brain metastases receiving systemic therapy before WBRT, brain MRI (preferred) or CT with contrast should be repeated after every 2
cycles of systemic therapy and at completion of therapy (SCL-6). If brain metastases progress while on systemic therapy, then initiate WBRT.
s During systemic therapy, response assessment by chest/abdomen/pelvis CT with contrast should occur after every 2–3 cycles of systemic therapy and at completion of
therapy (SCL-6).

SCL-5

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RESPONSE ASSESSMENT FOLLOWING ADJUVANT SURVEILLANCEt

INITIAL THERAPY TREATMENT
After completion of initial • Provide survivorship
therapy:
Limited Prophylactic • Oncology follow-up care plan after
stage cranial irradiation visits every 3 mo during completion of initial
(PCI)i,n,u,v y 1–2, every 6 mo during therapyt
Complete y 3, then annually • At every visit: H&P,b CT
response (category 1)
chest/abdomen/pelvis;
or partial blood work only as
response clinically indicated
• Consider PCIn,u After completion of initial • MRI (preferred) or CT
or subsequent therapy:
Extensive or MRI brain • Oncology follow-up brain with contrast every
stage surveillance visits every 2 mo during 3–4 months during y 1,
• Chest/ • Consider y 1, every 3–4 mo during then every 6 months For
abdomen/ thoracic RTn,w y 2–3, then every 6 mo during y 2 (regardless of Relapse,
pelvis CT during years 4–5, then PCI status)n see
with contrast annually • New pulmonary nodule Subsequent
• Brain MRId should initiate workup Therapy
(preferred) After completion of initial therapy:
Limited • Oncology follow-up visits every 3 mo during y for potential new (SCL-7)
or CT with stage primary
1–2, every 6 mo during y 3, then annually
contrast • Smoking cessation
• CBC Stable intervention, see the
• Electrolytes, disease NCCN Guidelines for
LFTs, BUN, After completion of initial or subsequent therapy: Smoking Cessation
creatinine Extensive • Oncology follow-up visits every 2 mo during y
1, every 3–4 mo during y 2–3, then every 6 mo • PET/CT is not
stage
during years 4–5, then annually recommended for
routine follow-up
Primary progressive disease See Subsequent Therapy/Palliative Therapy (SCL-7)
b See Signs and Symptoms of Small Cell Lung Cancer (SCL-A).

d Brain MRI is more sensitive than CT for identifying brain metastases and is preferred over CT.
t See NCCN Guidelines for Survivorship.
u Not recommended in patients with poor performance status or impaired neurocognitive function. Increased cognitive decline after PCI has been observed in older adults (≥60 years)
in prospective trials; the risks and benefits of PCI versus close surveillance should be carefully discussed with these patients.
v The benefit of PCI is unknown in patients who have undergone complete resection for pathologic stage I-IIA (T1-2,N0,M0) SCLC. See Principles of Surgical Resection (SCL-C).
w Sequential RT to thorax in selected patients, especially with residual thoracic disease and low-bulk extrathoracic metastatic disease that has responded to systemic therapy.

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PROGRESSIVE DISEASE SUBSEQUENT THERAPY/PALLIATIVE THERAPY
• Consider
subsequent
systemic
therapym,y
Continue until • Palliative
progression PS 0-2 symptom
management,q,x
or including
Subsequent Response localized RTn
systemic therapym,y to symptomatic
Development of
unacceptable sites
or
toxicity
PS 0-2 Palliative symptom
managementq,x
including localized No Palliative
RTn to symptomatic response or symptom
Relapse sites unacceptable management,q,x
or primary PS 3-4
toxicity including
progressive localized RTn to
disease symptomatic sites
Palliative symptom
PS 3-4 management,q,x including
localized RTn to symptomatic sites

x See NCCN Guidelines for Palliative Care.
y Response assessment by chest/abdomen/pelvis CT with contrast should occur after every 2–3 cycles of systemic therapy.

SCL-7

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SIGNS AND SYMPTOMS OF SMALL CELL LUNG CANCER
Signs and symptoms due to local primary tumor growth

• Cough – endobronchial irritation, bronchial compression
• Hemoptysis – usually central or cavitary lesion
• Wheezing – partially obstructing endobronchial lesion
• Fever – postoperative pneumonia
• Dyspnea – bronchial obstruction, pneumonia, pleural effusion
Signs and symptoms due to primary tumor invasion or regional lymphatic metastases
• Hoarseness – left vocal cord paralysis due to tumor invasion or lymphadenopathy in the aortopulmonary window
• Hemidiaphragm elevation – due to phrenic nerve compression
• Dysphagia – due to esophageal compression
• Chest pain – involvement of pleura or chest wall, often dull and non-localized
• SVC syndrome – due to local invasion into mediastinum or lymphadenopathy in right paratracheal region
• Pericardial effusion and tamponade
• Cervical or supraclavicular lymph node enlargement
Signs and symptoms due to extrathoracic (hematogenous) metastases

• Brain metastases:
Headache, focal weakness or numbness, confusion, slurred speech, gait instability, incoordination
• Leptomeningeal carcinomatosis:
Headache, confusion, cranial nerve palsy, diplopia, slurred speech, radicular back pain, spinal cord compression
• Adrenal metastases:
Mid-back or flank pain, costovertebral angle tenderness
Adrenal insufficiency due to tumor involvement is rare
• Liver metastases:
Right upper quadrant pain or tenderness, jaundice, fatigue, fever, hepatomegaly
• Bone metastases:
Bone pain
Spinal cord compression – back pain, muscle weakness, numbness, paresthesia, loss of bowel and bladder control
• Constitutional:
Anorexia/cachexia – weight loss
Fatigue
Continued
SCL-A
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SIGNS AND SYMPTOMS OF SMALL CELL LUNG CANCER
Signs and symptoms of paraneoplastic syndromes

• Presence does not imply metastases or incurability
• Endocrine:
Due to ectopic peptide hormone production
Usually reversible with successful anti-tumor therapy
Syndrome of inappropriate antidiuretic hormone secretion (SIADH):
◊◊Ectopic vasopressin (antidiuretic hormone, ADH) secretion
◊◊Clinically significant hyponatremia in 5%–10% of SCLC
◊◊Malaise, weakness, confusion, obtundation, volume depletion, nausea
◊◊Hyponatremia, euvolemia, low serum osmolality, inappropriately concentrated urine osmolality, normal thyroid and adrenal function
Cushing’s syndrome:
◊◊Ectopic adrenocorticotropic hormone (ACTH) secretion
◊◊Weight gain, moon facies, hypertension, hyperglycemia, generalized weakness
◊◊High serum cortisol and ACTH, hypernatremia, hypokalemia, alkalosis
• Neurologic: All specific syndromes are rare

If paraneoplastic neurologic syndrome is suspected, consider obtaining comprehensive paraneoplastic antibody panel
Subacute cerebellar degeneration (anti-Yo antibody) – ataxia, dysarthria
Encephalomyelitis (ANNA-1 [anti-Hu] antibody) – confusion, obtundation, dementia
Sensory neuropathy (anti-dorsal root ganglion antibody) – pain, sensory loss
Eaton-Lambert syndrome (anti-voltage-gated calcium channel antibody) – weakness, autonomic dysfunction
Cancer-associated retinopathy (anti-recoverin antibody) – visual loss, photosensitivity
• Hematologic:
Anemia of chronic disease
Leukemoid reaction – leukocytosis
Trousseau’s syndrome – migratory thrombophlebitis

SCL-A
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PRINCIPLES OF PATHOLOGIC REVIEW
Pathologic Evaluation
• Pathologic evaluation is performed to determine the histologic classification of lung tumors and relevant staging parameters.
• The World Health Organization (WHO) tumor classification system provides the foundation for the classification of lung tumors, including
histologic subtype, staging factors, clinical features, molecular characteristics, genetics, and epidemiology.1-3
• SCLC is a poorly differentiated neuroendocrine carcinoma. Distinguishing SCLC from other neuroendocrine tumors, particularly typical and
atypical carcinoids, is important due to significant differences in epidemiology, genetics, treatment, and prognosis.4-6
• SCLC can be diagnosed on good-quality histologic samples via high-quality hematoxylin and eosin (H&E)-stained sections or on well-
preserved cytologic samples.
SCLC is characterized by small blue cells with scant cytoplasm, high nuclear-to-cytoplasmic ratio, granular chromatin, and absent or
inconspicuous nucleoli.
SCLC cells are round, oval, or spindle-shaped with molding and high mitotic counts.7-9
The most useful characteristics for distinguishing SCLC from large-cell neuroendocrine carcinoma (LCNEC) are the high nuclear-to-
cytoplasmic ratio and paucity of nucleoli in SCLC.
• Careful counting of mitoses is essential, because it is the most important histologic criterion for distinguishing SCLC from typical and
atypical carcinoids.
SCLC (>10 mitoses/2 mm2 field); atypical carcinoid (2–10 mitoses/2 mm2 field); typical carcinoid (0–1 mitoses/2 mm2 field)
Mitoses should be counted in the areas of highest activity and per 2 mm2 field, rather than per 10 high-power fields.
In tumors that are near the defined cutoffs of 2 or 10 mitoses per 2 mm2, at least three 2-mm2 fields should be counted and the calculated
mean (rather than the single highest mitotic count) should be used to determine the overall mitotic rate.1,2
• Combined SCLC consists of both SCLC histology and NSCLC histology (squamous cell, adenocarcinoma, spindle/pleomorphic, and/or large
cell). There is no minimal percentage of NSCLC histologic elements required; when any are present along with SCLC, this can be called
combined SCLC.
Immunohistochemical Staining
• Immunohistochemistry can be very helpful in diagnosing SCLC in limited samples.5,7
Nearly all SCLCs are positive for cytokeratin antibody mixtures with broad reactivity, such as AE1/AE3 and CAM5.2.1,10
The majority of SCLCs are reactive to markers of neuroendocrine differentiation, including CD56/NCAM, synaptophysin, and
chromogranin A. Fewer than 10% of SCLCs are negative for all neuroendocrine markers.
Thyroid transcription factor-1 (TTF-1) is positive in 85% to 90% of SCLCs.11-14
• Ki-67 immunostaining can be very helpful in distinguishing SCLC from carcinoid tumors, especially in small biopsy samples with crushed or
necrotic tumor cells in which counting mitotic figures is difficult.4,5
The Ki-67 proliferative index in SCLC is typically 50% to 100%.1
References on
Note: All recommendations are category 2A unless otherwise indicated. SCL-B 2 of 2
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PRINCIPLES OF PATHOLOGIC REVIEW

References
1Travis WD, Burke AP, Marx A, Nicholson AG. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press. 2015.
2Travis WD, Brambilla E, Burke AP, et al. Introduction to The 2015 World Health Organization Classification of Tumors of the Lung, Pleura, Thymus, and Heart. J Thorac
Oncol 2015;10:1240-1242.
3Travis WD, Brambilla E, Nicholson AG, et al and WHO Panel. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and
Radiologic Advances Since the 2004 Classification. J Thorac Oncol 2015;10:1243-1260.
4Pelosi G, Rindi G, Travis WD, Papotti M. Ki-67 antigen in lung neuroendocrine tumors: unraveling a role in clinical practice. J Thorac Oncol 2014;9:273-284.
5Pelosi G, Rodriguez J, Viale G, Rosai J. Typical and atypical pulmonary carcinoid tumor overdiagnosed as small-cell carcinoma on biopsy specimens: a major pitfall in
the management of lung cancer patients. Am J Surg Pathol 2005;29:179-187.
6Rindi G, Klersy C, Inzani F, et al. Grading the neuroendocrine tumors of the lung: an evidence-based proposal. Endocr Relat Cancer 2014;21:1-16.
7Travis WD. Advances in neuroendocrine lung tumors. Ann Oncol 2010;21:vii65-71.
8Zakowski MF. Pathology of small cell carcinoma of the lung. Semin Oncol 2003;30:3-8.
9Nicholson SA, Beasley MB, Brambilla E, et al. Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens. Am J Surg Pathol
2002;26:1184-1197.
10Masai K, Tsuta K, Kawago M, et al. Expression of squamous cell carcinoma markers and adenocarcinoma markers in primary pulmonary neuroendocrine carcinomas.
Appl Immunohistochem Mol Morphol 2013;21:292-2977.
11Ordonez NG. Value of thyroid transcription factor-1 immunostaining in distinguishing small cell lung carcinomas from other small cell carcinomas. Am J Surg Pathol
2000;24:1217-1223.
12Kaufmann O, Dietel M. Expression of thyroid transcription factor-1 in pulmonary and extrapulmonary small cell carcinomas and other neuroendocrine carcinomas of
various primary sites. Histopathology 2000;36:415-420.
13Lantuejoul S, Moro D, Michalides RJ, et al. Neural cell adhesion molecules (NCAM) and NCAM-PSA expression in neuroendocrine lung tumors. Am J Surg Pathol
1998;22:1267-1276.
14Wick MR. Immunohistology of neuroendocrine and neuroectodermal tumors. Semin Diagn Pathol 2000;17:194-203.

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PRINCIPLES OF SURGICAL RESECTION
• Stage I-IIA SCLC is diagnosed in less than 5% of patients with SCLC.

• Patients most likely to benefit from surgery are those with SCLC that is clinical stage I-IIA (T1-2,N0,M0) after standard staging evaluation
(including CT of the chest and upper abdomen, brain imaging, and PET/CT imaging).1,2
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.
For patients undergoing definitive surgical resection, the preferred operation is lobectomy with mediastinal lymph node dissection.
• Patients who undergo complete resection should be treated with postoperative systemic therapy.3 Patients without nodal metastases
should be treated with systemic therapy alone. Patients with N2 or N3 nodal metastases should be treated with postoperative concurrent
or sequential systemic therapy and mediastinal RT. Patients with N1 nodal metastases may be considered for postoperative mediastinal
radiation.
• The benefit of PCI is unknown in patients who have undergone complete resection for pathologic stage I-IIA (T1-2,N0,M0) SCLC. These
patients have a lower risk of developing brain metastases than patients with more advanced, limited-stage SCLC, and may not benefit from
PCI.4 However, PCI may have a benefit in patients who are found to have pathologic stage IIB or III SCLC after complete resection; therefore,
PCI is recommended in these patients after adjuvant systemic therapy.4,5 PCI is not recommended in patients with poor performance status
or impaired neurocognitive function.6
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.
2Yang CJ, Chan DY, Shah SA, et al. Long-term survival after surgery compared with concurrent chemoradiation for node-negative small cell lung cancer. Ann Surg
2018;268:1105-1112.
3Yang 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.
4 Yang Y, Zhang D, Zhou X, et al. Prophylactic cranial irradiation in resected small cell lung cancer: a systematic review with meta-analysis. J Cancer 2018;9:433-439.
5 Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation
Overview Collaborative Group. N Engl J Med 1999;341:476-484.
6Le 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 (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 9901): a randomised clinical trial. Lancet
Oncol 2009;10(5):467-474.

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PRINCIPLES OF SUPPORTIVE CARE
• Smoking cessation advice, counseling, and pharmacotherapy

Use the 5 A’s Framework: Ask, Advise, Assess, Assist, Arrange (https://www.ahrq.gov/prevention/guidelines/tobacco/5steps.html)
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 RT (category 1 for not using GM-CSF).1
• SIADH
Fluid restriction
Saline infusion for symptomatic patients
Antineoplastic therapy
Demeclocycline
Vasopressin receptor inhibitors (ie, conivaptan, tolvaptan) for refractory hyponatremia
• Cushing’s syndrome
Consider ketoconazole. If not effective, consider metyrapone.
Try to control before initiation of antineoplastic therapy.
• Leptomeningeal disease: See NCCN Guidelines for Central Nervous System Cancers
• 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.

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PRINCIPLES OF SYSTEMIC THERAPY

PRIMARY OR ADJUVANT THERAPY FOR LIMITED STAGE SCLC:
Maximum of 4–6 cycles
Planned cycle length should be every 21–28 days during concurrent RT.
During systemic therapy + RT, cisplatin/etoposide is recommended (category 1).
The use of myeloid growth factors is not recommended during concurrent systemic therapy plus RT
(category 1 for not using GM-CSF).4
Preferred Regimens
• Cisplatin 75 mg/m2 day 1 and etoposide 100 mg/m2 days 1, 2, 31
Other Recommended Regimens
• Cisplatin 25 mg/m2 days 1, 2, 3 and etoposide 100 mg/m2 days 1, 2, 31
• Carboplatin AUC 5-6 day 1 and etoposide 100 mg/m2 days 1, 2, 3a,3
PRIMARY OR ADJUVANT THERAPY FOR EXTENSIVE STAGE SCLC:
Maximum of 4–6 cycles
Preferred Regimen
• Carboplatin AUC 5 day 1 and etoposide 100 mg/m2 days 1, 2, 3 and atezolizumab 1,200 mg day 1
every 21 days x 4 cycles followed by maintenance atezolizumab 1,200 mg day 1, every 21 days (category 1, for all)b,c,5
• Carboplatin AUC 5-6 day 1 and etoposide 80-100 mg/m2 days 1, 2, 3 and durvalumab 1,500 mg day 1 every 21 days x 4 cycles followed by
maintenance durvalumab 1,500 mg day 1 every 28 days (category 1 for all)b,c,36
• Cisplatin 75-80 mg/m2 day 1 and etoposide 80-100 mg/m2 days 1, 2, 3 and durvalumab 1,500 mg day 1 every 21 days x 4 cycles followed by
maintenance durvalumab 1,500 mg day 1 every 28 days (category 1 for all)b,c,36
• Carboplatin AUC 5–6 day 1 and etoposide 100 mg/m2 days 1, 2, 36
• Cisplatin 25 mg/m2 days 1, 2, 3 and etoposide 100 mg/m2 days 1, 2, 39
Useful In Certain Circumstances
• Carboplatin AUC 5 day 1 and irinotecan 50 mg/m2 days 1, 8, 1510
• Cisplatin 60 mg/m2 day 1 and irinotecan 60 mg/m2 days 1, 8, 1511
• Cisplatin 30 mg/m2 days 1, 8 and irinotecan 65 mg/m2 days 1, 812
a Cisplatin contraindicated or not tolerated.
b
Regimen not recommended for relapsed disease in patients on maintenance atezolizumab or durvalumab at time of relapse. For patients who relapse after >6 Subsequent Systemic Therapy (SCL-E 2 of 4)
months of atezolizumab or durvalumab maintenance therapy, recommend re-treatment with carboplatin + etoposide alone or cisplatin + etoposide alone. Response Assessment (SCL-E 3 of 4)
c Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or concurrent use of
References
immunosuppressive agents. (SCL-E 4 of 4)
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Consider dose reduction or growth factor support for patients with PS 2.
SCLC SUBSEQUENT SYSTEMIC THERAPY:d

Relapse ≤6 months
PS 0-2
Preferred Regimens
• Topotecan PO or IV13-15
• Clinical trial
• Nivolumab ± ipilimumabb,c,22,23
• Pembrolizumabb,c,24,34,35
• Paclitaxel17,18
• Docetaxel19
• Irinotecan16
• Temozolomide20,21
• Cyclophosphamide/doxorubicin/vincristine (CAV)12
• Oral etoposide27,28
• Vinorelbine25,26
• Gemcitabine29,30
• Bendamustine (category 2B)31
Relapse >6 months
• Original regimenb,32,33
b Regimen not recommended for relapsed disease in patients on maintenance atezolizumab or durvalumab at time of relapse. For patients who relapse after >6 months
of atezolizumab or durvalumab maintenance therapy, recommend re-treatment with carboplatin + etoposide alone or cisplatin + etoposide alone.
c Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or concurrent use of
immunosuppressive agents.
d Subsequent systemic therapy refers to second-line and beyond therapy.
Response Assessment (SCL-E 3 of 4)
References
(SCL-E 4 of 4)
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Response Assessment
• Limited stage
For patients receiving adjuvant therapy, response assessment should occur only after completion of adjuvant 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 chest/abdomen/
pelvis CT with contrast should occur after every 2 cycles of systemic therapy and at completion of therapy.
• Extensive stage
During systemic therapy, response assessment by chest/abdomen/pelvis CT 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 WBRT, 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 chest/abdomen/pelvis CT with contrast should occur after every 2–3 cycles of systemic therapy.
References
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References
1Faivre-Finn C, Snee M, Ashcroft L, et al. Concurrent once-daily versus twice-daily chemoradiotherapy 18Yamamoto N, Tsurutani J, Yoshimura N, et al. Phase II study of weekly paclitaxel for relapsed and
in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, refractory small cell lung cancer. Anticancer Res 2006;26:777-781.
superiority trial. Lancet Oncol 2017;18:1116-1125. 19Smyth JF, Smith IE, Sessa C, et al. Activity of docetaxel (Taxotere) in small cell lung cancer. The
2Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy Early Clinical Trials Group of the EORTC. Eur J Cancer 1994; 30A:1058-1060.
in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 20Pietanza MC, Kadota K, Huberman K, et al. Phase II trial of temozolomide with relapsed sensitive
1999;340(4):265-271. or refractory small cell lung cancer, with assessment of methylguanine-DNA methyltransferase as a
3Skarlos DV, Samantas E, Briassoulis E, et al. Randomized comparison of early versus late potential biomarker. Clin Cancer Res 2012;18:1138-1145.
hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-cell 21Zauderer MG, Drilon A, Kadota K, et al. Trial of a 5-day dosing regimen of temozolomide in patients
lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology Group (HeCOG). Ann with relapsed small cell lung cancers with assessment of methylguanine-DNA methyltransferase. Lung
Oncol 2001;12(9):1231-1238. Cancer 2014;86:237-240.
4Bunn PA, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage 22
Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in
colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase recurrent small-cell lung cancer (Checkmate 032): a multicentre, open-label phase 1/2 trial. Lancet
III randomized study of the Southwest Oncology Group. J Clin Oncol 1995;13:1632-1641. Oncol 2016;17:883-895.
5Horn L, Mansfield A, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage 23Hellmann MD, Ott PA, Zugazagoitia J, et al. Nivolumab (nivo) ± ipilimumab (ipi) in advanced
small-cell lung cancer. N Engl J Med 2018;379:2220-2229. small-cell lung cancer (SCLC): First report of a randomized expansion cohort from CheckMate 032
6Okamoto H, Watanabe K, Nishiwaki Y, et al. Phase II study of area under the plasma-concentration- [abstract]. J Clin Oncol 2017;35: Abstract 8503.
versus-time curve-based carboplatin plus standard-dose intravenous etoposide in elderly patients with 24Chung HC, Lopez-Martin JA, Kao S, et al. Phase 2 study of pembrolizumab in advanced small-cell
small cell lung cancer. J Clin Oncol 1999;17(11):3540-3545. lung cancer (SCLC): KEYNOTE-158 J Clin Oncol 2018; 36: Abstract 8506.
7Spigel DR, Townley PM, Waterhouse DM, et al. Randomized phase II study of bevacizumab in 25Jassem J, Karnicka-Mlodkowska H, van Pottelsberghe C, et al. Phase II study of vinorelbine
combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: results (Navelbine) in previously treated small cell lung cancer patients. EORTC Lung Cancer Cooperative
from the SALUTE trial. J Clin Oncol 2011;29:2215-2222. Group. Eur J Cancer 1993;29A:1720-1722.
8Niell HB, Herndon JE, Miller AA, et al. Randomized phase III Intergroup trial of etoposide and cisplatin 26Furuse K, Kuboa K, Kawahara M, et al. Phase II study of vinorelbine in heavily previously treated
with or without paclitaxel and granulocyte-colony stimulating factor in patients with extensive-stage small cell lung cancer. Japan Lung Cancer Vinorelbine Study Group. Oncology 1996;53:169-172.
small-cell lung cancer: Cancer and Leukemia Group B trial 9732. J Clin Oncol 2005;23:3752-3759. 27Einhorn LH, Pennington K, McClean J. Phase II trial of daily oral VP-16 in refractory small cell lung
9Evans WK, Shepherd FA, Feld R, et al. VP-16 and cisplatin as first-line therapy for small-cell lung cancer: a Hoosier Oncology Group study. Semin Oncol 1990;17:32-35.
cancer. J Clin Oncol 1985;3(11):1471-1477. 28Johnson DH, Greco FA, Strupp J, et al. Prolonged administration of oral etoposide in patients with
10Schmittel A, Fischer von Weikersthal L, Sebastian M, et al. A randomized phase II trial of irinotecan relapsed or refractory small-cell lung cancer: a phase II trial. J Clin Oncol 1990;8:1613-1617.
plus carboplatin versus etoposide plus carboplatin treatment in patients with extended disease small- 29Van der Lee I, Smit EF, van Putten JW, et al. Single-agent gemcitabine in patients with resistant
cell lung cancer. Ann Oncol 2006;17:663-667. small-cell lung cancer. Ann Oncol 2001;12:557-561.
11Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide plus 30Masters GA, Declerck L, Blanke C, et al. Phase II trial of gemcitabine in refractory or relapsed small-
cisplatin for extensive small-cell lung cancer. N Engl J Med 2002;346(2):85-91. cell lung cancer: Eastern Cooperative Oncology Group Trial 1597. J Clin Oncol 2003;21:1550-1555.
12Hanna N, Bunn Jr. PA, Langer C, et al. Randomized phase III trial comparing irinotecan/cisplatin 31Lammers PE, Shyr Y, Li CI, et al. Phase II study of bendamustine in relapsed chemotherapy sensitive
with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung or resistant small-cell lung cancer. J Thorac Oncol 2014;9:559-562.
32
cancer. J Clin Oncol 2006;24(13):2038-2043. Postmus PE, Berendsen HH, van Zandwijk N, et al. Retreatment with the induction regimen in small
13von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and cell lung cancer relapsing after an initial response to short term chemotherapy. Eur J Cancer Clin
vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999;17(2):658-667. Oncol 1987;23:1409-1411.
14O’Brien ME, Ciuleanu TE, Tsekov H, et al. Phase III trial comparing supportive care alone with 33Giaccone G, Ferrati P, Donadio M, et al. Reinduction chemotherapy in small cell lung cancer. Eur J
supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol Cancer Clin Oncol 1987;23:1697-1699.
2006;24(34):5441-5447. 34Chung HC, Piha-Paul SA, Lopez-Martin J, et al. Pembrolizumab after two or more lines of prior
15Eckardt JR, von Pawel J, Pujol JL, et al. Phase III study of oral compared with intravenous topotecan therapy in patients with advanced small-cell lung cancer (SCLC): Results from the KEYNOTE-028 and
as second-line therapy in small-cell lung cancer. J Clin Oncol 2007;25(15):2086-2092. KEYNOTE-158 studies. 2019 AACR Annual Meeting. Abstract CT073. Presented April 1, 2019.
16Masuda N, Fukuoka M, Kusunoki Y, et al. CPT-11: a new derivative of camptothecin for the treatment 35 Ott PA, Elez E, Hiret S, et al. Pembrolizumab in patients with extensive-stage small-cell lung cancer:
of refractory or relapsed small-cell lung cancer. J Clin Oncol 1992;10:1225-1229. results from the phase Ib KEYNOTE-028 study. J Clin Oncol 2017;35:3823-3829.
17Smit EF, Fokkema E, Biesma B, et al. A phase II study of paclitaxel in heavily pretreated patients with 36 Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-
small-cell lung cancer. Br J Cancer 1998;77:347-351. etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised,
controlled, open-label, phase 3 trial. Lancet. 2019 Oct 4. [Epub ahead of print]

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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‑C) 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 daily.
• 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, intensity-modulated RT (IMRT)/volumetric modulated arc therapy
(VMAT), image-guided RT (IGRT), and motion management strategies. IMRT is preferred over 3D conformal EBRT on the basis of reduced toxicity in
the setting of concurrent chemotherapy/RT.1 Quality assurance measures are essential and are covered in the NCCN Guidelines for Non-Small Cell
Lung Cancer (see NSCL‑C).
• Useful references include the ACR Appropriateness Criteria at: http://www.acr.org/quality-safety/appropriateness-criteria
General Treatment Information:

• Limited stage:
�In patients with clinical stage I-IIA (T1-2,N0,M0) who have undergone lobectomy and are found to have regional nodal involvement on final
pathology, postoperative RT is recommended in pathologic N2 and may be considered in pathologic N1 stage, either sequentially or concurrently
with chemotherapy. Principles of postoperative RT for NSCLC, including target volumes and doses, are recommended.
Selected patients with stage I-IIA (T1-2,N0,M0) SCLC who are medically inoperable or in whom a decision is made not to pursue surgery may be
candidates for stereotactic ablative RT (SABR) to the primary tumor followed by adjuvant systemic therapy. Principles of SABR for SCLC are similar
to those for NSCLC (see NCCN Guidelines for Non-Small Cell Lung Cancer: NSCL-C).2-4
Timing: RT concurrent with systemic therapy is standard and preferred to sequential chemo/RT.5 RT should start early, with cycle 1 or 2 of systemic
therapy (category 1).6 A shorter time from the start of any therapy to the end of RT (SER) is significantly associated with improved survival.7
Target definition: RT target volumes should be defined based on the pretreatment PET scan and CT scan obtained at the time of RT 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.8 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%).9-14 ENI has been omitted in current prospective clinical trials (including CALGB 30610/RTOG 0538 and the
EORTC 08072 [CONVERT] trial). Inclusion of the ipsilateral hilum in the target volume, even if not grossly involved, differs between these trials but
may be reasonable.
See Limited Stage (cont.), Extensive Stage, Normal Tissue Dose Constraints, Prophylactic Cranial Irradiation (SCL-F 2 of 4)
References
Note: All recommendations are category 2A unless otherwise indicated. (SCL-F 4 of 4)
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• Limited stage (cont.):
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.11,15
Dose and schedule: For limited‑stage SCLC, the optimal dose and schedule of RT have not been established.
◊◊Based on the randomized phase III trial, INT 0096, 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).16,17 When BID fractionation is used, there should be at least a 6‑hour interfraction interval to allow for repair of normal tissue.
◊◊If using once-daily RT, higher doses of 60–70 Gy should be used.18-21 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. The randomized, phase III European CONVERT trial did not demonstrate
superiority of 66 Gy (once daily) over 45 Gy (BID), but overall survival and toxicity were comparable.22
• Extensive stage:
Consolidative thoracic RT is beneficial for selected patients with extensive‑stage SCLC with complete response or good response to systemic
therapy, especially with residual thoracic disease and low-bulk extrathoracic metastatic disease. Studies have demonstrated that consolidative
thoracic RT up to definitive doses is well-tolerated, results in fewer symptomatic chest recurrences, and improves long‑term survival in some
patients.23,24 The Dutch CREST randomized trial of modest-dose thoracic RT (30 Gy in 10 fractions) in patients with extensive-stage SCLC that
responded to systemic therapy demonstrated significantly improved 2-year overall survival and 6-month progression-free survival, although the
protocol-defined primary endpoint of 1-year overall survival was not significantly improved.25 Subsequent exploratory analysis found the benefit
of consolidative thoracic RT is limited to the majority of patients who had residual thoracic disease after systemic therapy.26
Dosing and fractionation of consolidative thoracic RT should be individualized within the range of 30 Gy in 10 daily fractions to 60 Gy in 30 daily
fractions, or equivalent regimens in this range.
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‑C).
• 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:

• In patients with limited-stage SCLC who have a good response to initial therapy, PCI decreases brain metastases and increases overall survival
(category 1).27,28 In patients with extensive-stage SCLC that has responded to systemic therapy, PCI decreases brain metastases. A randomized
trial conducted by the EORTC found improved overall survival with PCI.29 However, a Japanese randomized trial found that in patients who had
no brain metastases on baseline MRI, PCI did not improve overall survival compared with routine surveillance MRI and treatment of asymptomatic
brain metastases upon detection.30 Surveillance imaging for brain metastases is recommended for all patients regardless of PCI status.
See Prophylactic Cranial Irradiation (cont.), Brain Metastases (SCL-F 3 of 4)

References
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Prophylactic Cranial Irradiation (cont.):
• 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.31,32
• 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).32 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.
• When administering PCI, consider adding memantine during and after RT, which has been shown to decrease neurocognitive impairment
following WBRT for brain metastases.33 The dose of memantine used on RTOG 0614 was as follows: week 1 (starting on day 1 of WBRT), 5
mg each morning; week 2, 5 mg each morning and evening; week 3, 10 mg each morning and 5 mg each evening; and weeks 4–24, 10 mg
each morning and evening.
Brain Metastases:
• Brain metastases should typically be treated with WBRT; however, selected patients with a small number of metastases may be appropriately
treated with stereotactic radiotherapy (SRT)/radiosurgery (SRS)
• Recommended dose for WBRT is 30 Gy in 10 daily fractions. Consider adding memantine during and after RT (see Prophylactic Cranial
Irradiation for memantine dosing).33
• In patients who develop brain metastases after PCI, repeat WBRT may be considered in carefully selected patients.34,35 SRS is preferred, if
feasible.36,37
• For patients with a better prognosis (eg, ≥4 months), consider hippocampal-sparing WBRT using IMRT38
Palliative Radiation for Extracranial Metastases:

• Common radiation dose-fractionation regimens (eg, 30 Gy in 10 fractions, 20 Gy in 5 fractions, 8 Gy in 1 fraction) used for palliation of other
solid tumors are appropriate for palliation of SCLC metastases in most patients.
• Conformal techniques, such as IMRT, and/or higher dose intensity approaches, including SABR or SRS, may be appropriate in selected
patients (eg, tumors with close proximity to organs at risk, re-irradiation, or better prognosis).
References
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References
1Chun SG, Hu C, Choy H, et al. Impact of intensity-modulated radiation therapy technique for locally advanced 20Roof KS, Fidias P, Lynch TJ, et al. Radiation dose escalation in limited-stage small-cell lung cancer. Int J Radiat
non-small-cell lung cancer: a secondary analysis of the NRG Oncology RTOG 0617 randomized clinical trial. J Oncol Biol Phys 2003;57:701-708.
Clin Oncol 2017;35:56-62. 21Bogart JA, Herndon JE, Lyss AP, et al. 70 Gy thoracic radiotherapy is feasible concurrent with chemotherapy for
2Shioyama Y, Onishi H, Takayama K, et al. Clinical outcomes of stereotactic body radiotherapy for patients with limited-stage small-cell lung cancer: analysis of Cancer and Leukemia Group B study 39808. Int J Radiat Oncol
stage I small-cell lung cancer: Analysis of a subset of the Japanese Radiological Society Multi-Institutional SBRT Biol Phys 2004;59:460-468.
Study Group Database. Technol Cancer Res Treat 2018;17:1533033818783904. 22Faivre-Finn C, Snee M, Ashcroft L, et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients
3Verma V, Simone CB 2nd, Allen PK, Lin SH. Outcomes of stereotactic body radiotherapy for T1-T2N0 small cell with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial.
carcinoma according to addition of chemotherapy and prophylactic cranial irradiation: a multicenter analysis. Clin Lancet Oncol 2017;18:1116-1125.
Lung Cancer 2017;18:675-681.e1. 23Jeremic B, Shibamoto Y, Nikolic N, et al. Role of radiation therapy in the combined-modality treatment of patients
4Verma V, Simone CB 2nd, Allen PK, et al. Multi-institutional experience of stereotactic ablative radiation therapy with extensive disease small-cell lung cancer: A randomized study. J Clin Oncol 1999;17:2092-2099.
for stage I small cell lung cancer. Int J Radiat Oncol Biol Phys 2017;97:362-371. 24Yee D, Butts C, Reiman A, et al. Clinical trial of post-chemotherapy consolidation thoracic radiotherapy for
5Takada M, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy extensive-stage small cell lung cancer. Radiother Oncol 2012;102:234-238.
in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical 25Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung
Oncology Group Study 9104. J Clin Oncol 2002;20:3054-3060. cancer: a phase 3 randomised controlled trial. Lancet 2015;385:36-42.
6Fried DB, Morris DE, Poole C, et al. Systematic review evaluating the timing of thoracic radiation therapy in 26Slotman BJ, van Tinteren H, Praag JO, et al. Radiotherapy for extensive stage small-cell lung cancer-Authors’
combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol 2004;22:4837-4845. reply. Lancet 2015;385:1292-1293.
7De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al. Time between the first day of chemotherapy and the 27Arriagada R, Le Chevalier T, Rivière A, et al. Patterns of failure after prophylactic cranial irradiation in small-cell
last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J lung cancer: analysis of 505 randomized patients. Ann Oncol 2002;13:748-754.
Clin Oncol 2006;24:1057-1063. 28Aupérin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in
8Videtic GMM, Belderbos JSA, Kong F-MS, et al. Report from the International Atomic Energy Agency (IAEA) complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 1999;341:476-
consultants’ meeting on elective nodal irradiation in lung cancer: small-cell lung cancer (SCLC). Int J Radiat 484.
Oncol Biol Phys 2008;72:327-334. 29Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N
9De Ruysscher D, Bremer RH, Koppe F, et al. Omission of elective node irradiation on basis of CT-scans in Engl J Med 2007;357:664-672.
patients with limited disease small cell lung cancer: a phase II trial. Radiother Oncol 2006;80:307-312. 30Takahashi T, Yamanaka T, Seto T, et al. Prophylactic cranial irradiation versus observation in patients with
10van Loon J, De Ruysscher D, Wanders R, et al. Selective nodal irradiation on basis of (18)FDG-PET scans in extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol
limited-disease small-cell lung cancer: a prospective study. Int J Radiat Oncol Biol Phys 2010;77:329-336. 2017;18:663-671.
11Hu X, Bao Y, Zhang L, et al. Omitting elective nodal irradiation and irradiating postinduction versus preinduction 31Le Péchoux C, Dunant A, Senan S, et al. Standard-dose versus higher-dose prophylactic cranial irradiation
chemotherapy tumor extent for limited-stage small cell lung cancer: interim analysis of a prospective randomized (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic
noninferiority trial. Cancer 2012;118:278-287. radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet
12Shirvani SM, Komaki R, Heymach JV, et al. Positron emission tomography/computed tomography-guided Oncol 2009;10:467-474.
intensity-modulated radiotherapy for limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys 32Wolfson AH, Bae K, Komaki R, et al. Primary analysis of a phase II randomized trial Radiation Therapy Oncology
2012;82:e91-97. Group (RTOG) 0212: Impact of different total doses and schedules of prophylactic cranial irradiation on chronic
13Xia B, Chen G-Y, Cai X-W, et al. Is involved-field radiotherapy based on CT safe for patients with limited-stage neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer. Int J Radiat Oncol Biol
small-cell lung cancer? Radiother Oncol 2012;102:258-262. Phys 2011;81:77-84.
14Colaco R, Sheikh H, Lorigan P, et al. Omitting elective nodal irradiation during thoracic irradiation in limited-stage 33Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction in patients receiving
small cell lung cancer - Evidence from a phase II trial. Lung Cancer 2012;76:72-77. whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol 2013;10:1429-1437.
15Liengswangwong V, Bonner JA, Shaw EG, et al. Limited-stage small-cell lung cancer: patterns of intrathoracic 34Sadikov E, Bezjak A, Yi Q-L, et al. Value of whole brain re-irradiation for brain metastases--single centre
recurrence and the implications for thoracic radiotherapy. J Clin Oncol 1994;12:496-502. experience. Clin Oncol (R Coll Radiol.) 2007;19:532-538.
16Turrisi AT, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell 35
Son CH, Jimenez R, Niemierko A, et al. Outcomes after whole brain reirradiation in patients with brain
lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999;340:265-271. metastases. Int J Radiat Oncol Biol Phys 2012;82:e167-172.
17Schild SE, Bonner JA, Shanahan TG, et al. Long-term results of a phase III trial comparing once-daily 36
Harris S, Chan MD, Lovato JF, et al. Gamma knife stereotactic radiosurgery as salvage therapy after failure of
radiotherapy with twice-daily radiotherapy in limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys whole-brain radiotherapy in patients with small-cell lung cancer. Int J Radiat Oncol Biol Phys 2012;83:e53-e59.
37
2004;59:943-951. Wegner RE, Olson AC, Kondziolka D, et al. Stereotactic radiosurgery for patients with brain metastases from
18Choi NC, Herndon JE, Rosenman J, et al. Phase I study to determine the maximum-tolerated dose of small cell lung cancer. Int J Radiat Oncol Biol Phys 2011;81:e21-e27.
38
radiation in standard daily and hyperfractionated-accelerated twice-daily radiation schedules with concurrent Gondi V, Pugh S, Brown PD, et al. Significant preservation of neurocognitive function (NCF) and patient-reported
chemotherapy for limited-stage small-cell lung cancer. J Clin Oncol 1998;16:3528-3536. symptoms with hippocampal avoidance (HA) during whole brain radiotherapy for brain metastaases: final results
19Miller KL, Marks LB, Sibley GS, et al. Routine use of approximately 60 Gy once-daily thoracic irradiation for of Ngr Oncology. CC001 [abstract] Int J Radiat Oncol Biol Phys 2019;105:S12-S13.
patients with limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys 2003;56:355-359.

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

(1) Limited-stage: 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: 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 - American Joint Committee on Cancer (AJCC) Eighth ed., 2017 Definitions of TNM
T Primary Tumor
TX Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not
visualized by imaging or bronchoscopy
T0 No evidence of primary tumor
Tis Carcinoma in situ
Squamous cell carcinoma in situ (SCIS)
Adenocarcinoma in situ (AIS): adenocarcinoma with pure lepidic pattern, ≤3 cm in greatest dimension
T1 Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more
proximal than the lobar bronchus (i.e., not in the main bronchus)
T1mi Minimally invasive adenocarcinoma: adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm
invasion in greatest dimension
T1a Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial
wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
T1b Tumor >1 cm but ≤2 cm in greatest dimension
T1c Tumor >2 cm but ≤3 cm in greatest dimension
T2 Tumor >3 cm but ≤5 cm or having any of the following features: (1) Involves the main bronchus, regardless of distance to the
carina, but without involvement of the carina; (2) Invades visceral pleura (PL1 or PL2); (3) Associated with atelectasis or obstructive
pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4
cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
T2a Tumor >3 cm but ≤4 cm in greatest dimension
T2b Tumor >4 cm but ≤5 cm in greatest dimension
T3 Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including
superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary
T4 Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea,
recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of
the primary
Continued
Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing.
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Table 2. Definitions for T, N, M (continued) Table 3. AJCC Prognostic Groups

N Regional Lymph Nodes Prognostic Stage Groups T N M
NX Regional lymph nodes cannot be assessed T N M Occult TX N0 M0
N0 No regional lymph node metastasis carcinoma
Stage IIIB T1a N3 M0
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral Stage 0 Tis N0 M0
T1b N3 M0
hilar lymph nodes and intrapulmonary nodes, including Stage IA1 T1mi N0 M0
involvement by direct extension T1c N3 M0
T1a N0 M0
N2 Metastasis in ipsilateral mediastinal and/or subcarinal T2a N3 M0
lymph node(s) Stage IA2 T1b N0 M0
T2b N3 M0
N3 Metastasis in contralateral mediastinal, contralateral hilar, Stage IA3 T1c N0 M0
T3 N2 M0
ipsilateral or contralateral scalene, or supraclavicular lymph Stage IB T2a N0 M0
node(s) T4 N2 M0
Stage IIA T2b N0 M0
Stage IIIC T3 N3 M0
Stage IIB T1a N1 M0
M Distant Metastasis T4 N3 M0
Stage IV Any T Any N M1 T1b N1 M0
MX Distant metastasis cannot be assessed
Stage IVA Any T Any N M1a T1c N1 M0
M0 No distant metastasis
Any T Any N M1b T2a N1 M0
M1 Distant metastasis
Stage IVB Any T Any N M1c T2b N1 M0
M1a Separate tumor nodule(s) in a contralateral lobe; tumor
with pleural or pericardial nodules or malignant pleural or T3 N0 M0
pericardial effusiona Stage IIIA T1a N2 M0
M1b Single extrathoracic metastasis in a single organ (including T1b N2 M0
involvement of a single nonregional node)
T1c N2 M0
M1c Multiple extrathoracic metastases in a single organ or in
multiple organs T2a N2 M0
T2b N2 M0
T3 N1 M0
T4 N0 M0
T4 N1 M0
aMost pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for
tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a
staging descriptor.
Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing.
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NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.
NCCN Categories of Preference

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,
Preferred intervention affordability.
Other recommended Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
intervention or significantly less affordable for similar outcomes.
Useful in certain
Other interventions that may be used for selected patient populations (defined with recommendation).
circumstances
All recommendations are considered appropriate.

CAT-1
NCCN Guidelines Version 3.2020

Discussion This discussion corresponds to the NCCN Guidelines for Prophylactic Cranial Irradiation............................................... MS-15
Small Cell Lung Cancer. Last updated on 08/05/2019.
Palliative Radiotherapy .......................................................... MS-17
Table of Contents
Surgical Resection of Stage I to IIA SCLC ................................. MS-17
Overview ......................................................................................... MS-2
Surveillance .................................................................................. MS-18
Literature Search Criteria and Guidelines Update Methodology........ MS-2
Summary ...................................................................................... MS-19
Diagnosis ........................................................................................ MS-3
References ................................................................................... MS-20
Screening .................................................................................... MS-3
Manifestations.............................................................................. MS-3
Pathology .................................................................................... MS-4
Staging............................................................................................ MS-4
Prognostic Factors .......................................................................... MS-6
Treatment........................................................................................ MS-6
Primary or Adjuvant Systemic Therapy ......................................... MS-6
Response Assessment ............................................................. MS-7
Limited-Stage SCLC ................................................................. MS-7
Cisplatin versus Carboplatin ..................................................... MS-7
Extensive-Stage SCLC ............................................................. MS-8
Elderly Patients .......................................................................... MS-10
Subsequent Systemic Therapy ................................................... MS-11
Radiotherapy ............................................................................. MS-13
Thoracic Radiotherapy ............................................................ MS-13
MS-1
Version 3.2020 © 2020 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

with limited disease confined to the chest. SCLC is highly sensitive to

Overview initial chemotherapy and radiotherapy; however, most patients eventually
Neuroendocrine tumors account for approximately 20% of lung cancers; die of recurrent disease.6 In patients with limited-stage SCLC, the goal of
most (approximately 14%) are small cell lung cancer (SCLC).1,2 In 2019, treatment is cure using chemotherapy plus thoracic radiotherapy; some
an estimated 29,660 new cases of SCLC will occur in the United States.1,3 patients are eligible for curative surgery followed by systemic therapy with
Nearly all cases of SCLC are attributable to cigarette smoking.4 Although or without mediastinal radiotherapy.7,8 In patients with extensive-stage
the incidence of SCLC has been decreasing, the incidence in women is disease, systemic therapy alone can palliate symptoms and prolong
increasing and the male-to-female incidence ratio is now 1:1.1,2 survival in most patients; however, long-term survival is rare.9 Note that
Management of SCLC is described in the NCCN Clinical Practice the definitions for limited-stage and extensive-stage SCLC incorporate
Guidelines in Oncology (NCCN Guidelines®) for Small Cell Lung Cancer, TNM staging (see the algorithm and Staging in this Discussion). Surgery is
which includes the algorithm and this supporting Discussion text. only recommended for certain patients with surgically resectable stage I to
Management of other lung neuroendocrine tumors (LNTs) is described in IIA SCLC; stereotactic ablative radiotherapy (SABR) is an option for
a different guideline (see Lung Neuroendocrine Tumors in the NCCN certain patients with medically inoperable stage I to IIA SCLC.10-13 Clinical
Guidelines® for Neuroendocrine and Adrenal Tumors, available at trials generally represent state-of-the-art treatment for patients with SCLC.
www.NCCN.org). Despite recent advances, the recommended therapy for SCLC as outlined
in these NCCN Guidelines still needs to be improved. Thus, participation
The NCCN Guidelines for Small Cell Lung Cancer were originally in clinical trials should be strongly encouraged.
published 20 years ago and have been subsequently updated at least
once every year (see www.NCCN.org).5 The Summary of the Guidelines Smoking cessation should be strongly promoted in patients with SCLC
Updates section in the SCLC algorithm describes the most recent and other high-grade neuroendocrine carcinomas (see the NCCN
revisions for 2019, which are described in greater detail in this revised Guidelines for Smoking Cessation, available at www.NCCN.org).14 Former
Discussion text; recent references have been added (see Summary in this smokers should be strongly encouraged to remain abstinent. Patients with
Discussion and the algorithm). For example, new immunotherapy options SCLC who continue to smoke have increased toxicity during treatment
have been added for patients with SCLC. Additional supplemental material and shorter survival.15 Programs using behavioral counseling combined
in the SCLC algorithm includes the Signs and Symptoms of Small Cell with FDA-approved medications that promote smoking cessation can be
Lung Cancer, Principles of Pathologic Review, Principles of Surgical very useful.
Resection, Principles of Supportive Care, Principles of Systemic Therapy,
Principles of Radiation Therapy, and staging tables. Literature Search Criteria and Guidelines Update
Methodology
SCLC is characterized by a rapid doubling time, high growth fraction, and An electronic search of the PubMed database was performed to obtain
early development of widespread metastases. Most patients with SCLC key literature in SCLC using the following search term: small cell lung
present with hematogenous metastases; approximately one third present cancer. The PubMed database was chosen because it is the most widely
MS-2

used resource for medical literature and indexes peer-reviewed biomedical symptomatic disease between annual scans, thereby limiting the potential
literature. The search results were narrowed by selecting studies in effect on mortality.16
humans published in English. Results were confined to the following article
types: Clinical Trial, Phase 1; Clinical Trial, Phase 2; Clinical Trial, Phase Manifestations
3; Clinical Trial, Phase 4; Guideline; Randomized Controlled Trial; SCLC typically presents as a large hilar mass and bulky mediastinal
Meta-Analysis; Systematic Reviews; and Validation Studies. lymphadenopathy that cause cough and dyspnea.20 Frequently, patients
present with symptoms of widespread metastatic disease, such as weight
The data from key PubMed articles as well as articles from additional loss, debility, bone pain, and neurologic compromise. The NCCN SCLC
sources deemed as relevant to these NCCN Guidelines and discussed by Panel recently added a new section describing signs and symptoms of
the NCCN SCLC Panel have been included in this version of the SCLC based on the tumor location and type of metastases (see Signs and
Discussion section (eg, e-publications ahead of print, meeting abstracts). Symptoms of Small Cell Lung Cancer in the algorithm). It is uncommon for
Recommendations for which high-level evidence is lacking are based on patients to present with a solitary peripheral nodule without central
the panel’s review of lower-level evidence and expert opinion. The adenopathy. In this situation, fine-needle aspiration (FNA) may not
complete details of the development and update of the NCCN Guidelines adequately differentiate small cell carcinoma (which is a high-grade
are available at www.NCCN.org. neuroendocrine carcinoma) from low-grade (typical carcinoid),
intermediate-grade (atypical carcinoid), or large-cell neuroendocrine
Diagnosis
carcinoma (LCNEC) (which is also a high-grade neuroendocrine
Screening carcinoma) (see Lung Neuroendocrine Tumors in the NCCN Guidelines
Ideally, a screening test should detect disease at an early stage when it is for Neuroendocrine and Adrenal Tumors, available at
still curable. Currently, no effective screening test is available to detect www.NCCN.org).21,22
early-stage SCLC; the disease is typically diagnosed when patients
present with symptoms indicative of advanced-stage disease (see Signs Many neurologic and endocrine paraneoplastic syndromes are associated
and Symptoms of Small Cell Lung Cancer in the algorithm).16 The National with SCLC.23-25 Neurologic syndromes include Lambert-Eaton myasthenic
Lung Screening Trial (NLST) reported that screening with annual, syndrome, encephalomyelitis, and sensory neuropathy. Patients with the
low-dose, spiral CT scans decreased lung cancer-specific mortality in Lambert-Eaton myasthenic syndrome present with proximal leg weakness
asymptomatic high-risk individuals (see the NCCN Guidelines for Lung that is caused by antibodies directed against the voltage-gated calcium
Cancer Screening, available at www.NCCN.org).17 Although low-dose CT channels.26,27 Paraneoplastic encephalomyelitis and sensory neuropathy
screening can detect early-stage non-small cell lung cancer (NSCLC), it are caused by the production of an antibody (anti-Hu) that cross-reacts
does not seem to be useful for detecting early-stage SCLC.16-19 Low-dose with both small cell carcinoma antigens and human neuronal RNA-binding
CT screening is probably not useful for SCLC because of the proteins resulting in multiple neurologic deficits; paraneoplastic
aggressiveness of the disease, which results in the development of encephalomyelitis may precede the diagnosis of a tumor.28 For the 2019
update, the NCCN SCLC Panel now recommends that if neurologic
MS-3

paraneoplastic syndrome is suspected, then obtaining a comprehensive for Neuroendocrine and Adrenal Tumors, available at
paraneoplastic antibody panel should be considered. www.NCCN.org).34,39 Up to 30% of specimens from patients with SCLC
reveal areas of NSCLC differentiation (mainly large cell carcinoma);38 this
SCLC cells sometimes produce polypeptide hormones, including finding is more commonly detected in specimens from previously treated
vasopressin (antidiuretic hormone [ADH]) and adrenocorticotropic patients and suggests that pulmonary carcinogenesis occurs in a
hormone (ACTH), which cause hyponatremia of malignancy (ie, syndrome pluripotent stem cell capable of differentiation along divergent pathways.
of inappropriate ADH secretion [SIADH]) and Cushing syndrome, Although 95% of small cell carcinomas originate in the lung, they can also
respectively.29,30 In patients with SCLC, SIADH occurs more frequently arise from extrapulmonary sites, including the nasopharynx,
than Cushing syndrome. Cancer treatment and/or supportive care may gastrointestinal tract, and genitourinary tract.40,41 Both pulmonary and
also cause hyponatremia (eg, cisplatin, opiates).31 Primary treatment for extrapulmonary small cell carcinomas have a similar clinical and biologic
SIADH includes fluid restriction (which is difficult for patients because of behavior, leading to a high potential for widespread metastases.
increased thirst) and demeclocycline; vasopressin receptor inhibitors (ie,
conivaptan, tolvaptan) can be used for refractory hyponatremia (see Immunohistochemistry is useful for diagnosing SCLC in limited
Principles of Supportive Care in the algorithm).31-33 Hyponatremia usually samples.21,39,42 Nearly all SCLCs are immunoreactive for cytokeratin
improves after successful treatment for SCLC. (AE1/Ae3, CAM5.2); 85% to 90% of SCLCs are positive for thyroid
transcription factor-1 (TTF-1).21,43-45 Most SCLCs also stain positively for
Pathology markers of neuroendocrine differentiation, including chromogranin A,
The NCCN Guidelines for SCLC include a section on pathology (see neuron-specific enolase, neural cell adhesion molecule (NCAM; CD56),
Principles of Pathologic Review in the algorithm). The WHO classification and synaptophysin.21 However, these markers alone cannot be used to
system is used to classify lung tumors.34-36 SCLC is a poorly differentiated distinguish SCLC from NSCLC, because approximately 10% of NSCLCs
malignant epithelial tumor that is categorized as a high-grade will be immunoreactive for at least one of these neuroendocrine markers.46
neuroendocrine carcinoma.21 The classic and distinctive histology on Ki-67 immunostaining is useful for distinguishing SCLC from carcinoid
hematoxylin and eosin (H&E) may be sufficient for identifying SCLC in tumors.34,39,47
good-quality histologic samples including small blue cells with scant
cytoplasm, ill-defined cell borders, finely granular nuclear chromatin, and Staging
absent or inconspicuous nucleoli.21,37 The cells are round, oval, or The NCCN SCLC Panel adopted a combined approach for staging SCLC
spindle-shaped; nuclear molding is prominent.38 The mitotic count is high using both the AJCC TNM staging system and the older Veterans
in SCLC when compared with the count in atypical and typical carcinoids. Administration (VA) scheme for SCLC.6,48 The VA Lung Study Group’s
2-stage classification scheme has historically been used to define the
It is important to distinguish SCLC from other neuroendocrine tumors, extent of disease in patients with SCLC: 1) limited-stage disease is
especially typical and atypical carcinoids, because treatment differs for disease confined to the ipsilateral hemithorax, which can be safely
these tumors (see Lung Neuroendocrine Tumors in the NCCN Guidelines encompassed within a radiation field; and 2) extensive-stage disease is
MS-4

disease beyond the ipsilateral hemithorax, including malignant pleural or radiotherapy, which is indicated primarily for patients with limited-stage
pericardial effusion or hematogenous metastases.49 Contralateral disease. Full staging includes a history and physical examination; CT scan
mediastinal and ipsilateral supraclavicular lymphadenopathy are generally (with intravenous contrast) of the chest/abdomen; and brain imaging using
classified as limited-stage disease, whereas the classification of MRI (preferred) or CT scan (with intravenous contrast).50,53 However, once
contralateral hilar and supraclavicular lymphadenopathy is more a patient has been found to have extensive-stage disease, further staging
controversial and treatment is individualized.6,48,50 Approximately 66% of is not required, except for brain imaging.6 Unilateral bone marrow
patients present with overt hematogenous metastases, which commonly aspirates and biopsies may be indicated in select patients with nucleated
involve the contralateral lung, liver, adrenal glands, brain, bones, and/or red blood cells on peripheral blood smear, neutropenia, or
bone marrow. The AJCC recently revised the TNM staging system for lung thrombocytopenia suggestive of bone marrow infiltration and with no other
cancer; new staging guidelines (8th edition) became effective on January evidence of metastatic disease. Bone marrow involvement as the only site
1, 2018 (see Staging in the algorithm).51,52 The NCCN SCLC Panel will of extensive-stage disease occurs in fewer than 5% of patients. If
continue to use both the VA and the TNM systems for staging SCLC. limited-stage disease is suspected, a PET/CT scan (skull base to
mid-thigh) can be performed to assess for distant metastases.6,48 A bone
In applying the TNM classifications to the VA system, limited-stage SCLC scan can be performed if PET/CT is equivocal or not available; bone
is defined as stage I to III (T any, N any, M0) that can be safely treated biopsy can be considered if bone imaging is equivocal.
with definitive radiation therapy (RT), excluding T3-4 due to multiple lung
nodules that are too extensive or have tumor/nodal volume that is too PET scans can increase staging accuracy in patients with SCLC, because
large to be encompassed in a tolerable radiation plan (see Table 1 in the SCLC is a highly metabolic disease.54-56 PET/CT is superior to PET
algorithm). Extensive-stage SCLC is defined as stage IV (T any, N any, alone.56 Approximately 19% of patients who undergo PET are upstaged
M1a/b/c) or T3–4 due to multiple lung nodules as previously described. from limited-stage to extensive-stage disease, whereas only 8% are
downstaged from extensive-stage to limited-stage disease.50 For most
Because most of the literature on SCLC classifies patients based on the metastatic sites, PET/CT is superior to CT imaging; however, PET/CT is
VA’s definitions of limited-stage or extensive-stage disease, these inferior to MRI or CT for the detection of brain metastases (see the NCCN
definitions are often used for clinical decision-making. However, the TNM Guidelines for Central Nervous System Cancers, available at
system is useful for selecting patients with T1-2,N0 disease who are www.NCCN.org).57 Changes in management based on PET staging were
eligible for surgery and for radiation treatment planning.48 Clinical research reported in approximately 27% of patients, mainly because of alterations in
studies should begin to include use of the TNM system, because it will the planned radiation field as a result of improved detection of intrathoracic
allow for more precise assessments of prognosis and specific therapy in sites of disease.50,55,58 Although PET/CT seems to improve staging
the future.51 accuracy in SCLC, pathologic confirmation is still required for
PET/CT-detected lesions that would result in upstaging.
All patients with SCLC, even those with radiographically limited-stage
disease, require systemic therapy either as primary or adjuvant therapy.
Therefore, staging provides a therapeutic guideline for thoracic
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Before surgical resection, pathologic mediastinal staging is required to patients may become more seriously ill in the interval, with a significant
confirm PET/CT scan results in patients with clinical stage I to IIA SCLC decline in their performance status (PS).
(T1–2,N0,M0) to rule out occult nodal disease.6 However, mediastinal
staging is not required if the patient is not a candidate for surgical Prognostic Factors
resection or if non-surgical treatment is planned. Invasive mediastinal Poor PS (3–4), extensive-stage disease, weight loss, and markers
staging can be performed either by conventional mediastinoscopy or by associated with excessive bulk of disease (such as lactate dehydrogenase
minimally invasive techniques such as transesophageal endoscopic [LDH]) are the most important adverse prognostic factors. Female gender,
ultrasound-guided FNA (EUS-FNA), endobronchial ultrasound-guided age younger than 70 years, normal LDH, and stage I disease are
transbronchial needle aspiration (EBUS-TBNA), or video-assisted thoracic associated with a more favorable prognosis in patients with limited-stage
surgery (VATS).59,60 disease. Younger age, good PS, normal creatinine level, normal LDH, and
a single metastatic site are favorable prognostic factors in patients with
Thoracentesis with cytologic analysis is recommended if a pleural effusion extensive-stage disease.61,62
is large enough to be safely accessed via ultrasound guidance. If
thoracentesis does not show malignant cells, then thoracoscopy can be Treatment
considered to document pleural involvement, which would indicate
Primary or Adjuvant Systemic Therapy
extensive-stage disease. The effusion should be excluded as a staging
For all patients with SCLC, systemic therapy is an essential component of
element if: 1) multiple cytopathologic examinations of the pleural fluid are
appropriate treatment. Many single-agent and combination chemotherapy
negative for cancer; 2) the fluid is not bloody and not an exudate; and 3)
regimens have been shown to be active in SCLC. Adjuvant chemotherapy
clinical judgment suggests that the effusion is not directly related to the
is recommended for patients who have undergone surgical resection or
cancer. Pericardial effusions are classified using the same criteria.
SABR for early-stage disease. For patients with limited-stage IIB to IIIC
Staging should not focus only on sites of symptomatic disease or on sites (T3–4,N0,M0; T1–4,N1–3,M0) and with good PS (0–2), recommended
suggested by laboratory tests. Bone scans are positive in up to 30% of treatment consists of chemotherapy with concurrent thoracic radiotherapy
patients without bone pain or without an abnormal alkaline phosphatase (category 1).8,63,64 For patients with extensive-stage disease, systemic
level. Bone imaging with radiographs or MRI may be appropriate if therapy alone is the recommended treatment; however, radiotherapy may
PET/CT is equivocal. Brain imaging (MRI preferred or CT with contrast) be used in select patients for palliation of symptoms (see Initial Treatment
can identify central nervous system (CNS) metastases in 10% to 15% of and Principles of Systemic Therapy in the algorithm; see NCCN
patients at diagnosis, of which approximately 30% are asymptomatic. Guidelines for Palliative Care, available at www.NCCN.org). For the 2019
Early treatment of brain metastases results in less chronic neurologic update (Version 1), the NCCN SCLC Panel added a
morbidity, arguing for the usefulness of early diagnosis in asymptomatic chemo-immunotherapy regimen as a preferred option for patients with
patients. Because of the aggressive nature of SCLC, staging should not extensive-stage SCLC, which is described in greater detail later in this
delay the onset of treatment for more than 1 week; otherwise, many section.65 In patients with extensive-stage disease and brain metastases,
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systemic therapy can be given either before or after whole-brain therapy for patients who have undergone resection of stage IA to IIA
radiotherapy depending on whether the patient has neurologic symptoms SCLC. If pathologic lymph node involvement is found at surgery, then
(see Initial Treatment in the algorithm).9,66 If systemic therapy is given first, thoracic radiotherapy can be added concurrently or sequentially to EP.
whole-brain radiotherapy is administered after completion of systemic For patients with limited-stage IIB to IIIC (T3–4,N0,M0; T1–4,N1–3,M0),
therapy. EP plus concurrent thoracic radiotherapy is the recommended therapy
(category 1).63,64,71,72 For the 2019 update, the NCCN SCLC Panel
Response Assessment slightly revised the recommended EP regimens for limited-stage SCLC
Response assessment is an important aspect of the management of based on the dosing used in the CONVERT trial (see Principles of
patients with SCLC. After adjuvant chemotherapy alone or chemotherapy Systemic Therapy in the algorithm).73 Thus far, there are no data to
with concurrent RT for patients with limited-stage disease, response support the use of immunotherapy in patients with limited-stage SCLC.
assessment using CT with contrast of the chest/abdomen should occur
only after completion of therapy; repeating CT scans during therapy is not Thoracic radiotherapy improves local control rates by 25% in patients with
recommended. For systemic therapy alone or sequential systemic therapy limited-stage disease and is associated with improved survival.63,64 Data
followed by RT in patients with limited-stage disease, response suggest that chemoradiotherapy may be indicated for patients with
assessment using CT with contrast of the chest/abdomen should occur limited-stage disease who have cytologically negative or indeterminate
after every 2 cycles of systemic therapy and again at completion of pleural effusions but not for those with pericardial effusions.74,75 In
therapy. During systemic therapy for patients with extensive-stage combination with thoracic radiotherapy, EP causes an increased risk of
disease, response assessment using CT with contrast of the esophagitis, pulmonary toxicity, and hematologic toxicity.76 The use of
chest/abdomen should occur after every 2 to 3 cycles of systemic therapy myeloid growth factors is not recommended (category 1 for not using
and again at completion of therapy. Serial brain imaging is also granulocyte-macrophage colony-stimulating factor [GM-CSF]) in patients
recommended in patients with extensive-stage disease who have undergoing concurrent chemoradiation.77 In patients with limited-stage
asymptomatic brain metastases and are receiving systemic therapy before disease, treatment with EP plus definitive thoracic radiotherapy results in
whole-brain RT; brain MRI (preferred) or brain CT with contrast is response rates of 70% to 90% with a median overall survival of only 24
recommended after every 2 cycles of systemic therapy and again at to 30 months and 5-year overall survival rates of 25% to 30%.73
completion of therapy.
Cisplatin versus Carboplatin
Limited-Stage SCLC In clinical practice, carboplatin is frequently substituted for cisplatin to
Etoposide plus cisplatin (EP) is the most commonly used initial reduce the risk of emesis, neuropathy, and nephropathy.78 However, the
combination chemotherapy regimen for patients with limited-stage SCLC use of carboplatin carries a greater risk of myelosuppression.79 Small
(see Principles of Systemic Therapy in the algorithm).67 This combination randomized trials in patients with SCLC have suggested similar efficacy of
replaced alkylator/anthracycline-based regimens based on its superiority cisplatin and carboplatin regimens, as did a retrospective analysis in
in both efficacy and toxicity.68-70 EP alone is recommended as adjuvant patients with extensive-stage disease.78,80,81 A meta-analysis of individual
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patient data from 4 randomized studies compared cisplatin-based versus Atezolizumab may cause unique immune-mediated adverse events that
carboplatin-based regimens in patients with SCLC.82 Of 663 patients are not seen with traditional cytotoxic chemotherapy; therefore, health
included in this meta-analysis, 32% had limited-stage disease and 68% care providers should be aware of the spectrum of potential
had extensive-stage disease. No significant difference was observed in immune-mediated adverse events, know how to manage these adverse
response rate (67% vs. 66%), progression-free survival (PFS) (5.5 vs. 5.3 events, and educate their patients about possible side effects. High-dose
months), or overall survival (9.6 vs. 9.4 months) in patients receiving corticosteroids are generally recommended for immune-mediated adverse
cisplatin-containing versus carboplatin-containing regimens, suggesting events based on the severity of the reaction. In addition, atezolizumab
equivalent efficacy in patients with SCLC. should be withheld or discontinued for severe or life-threatening
immune-mediated adverse events when indicated (see prescribing
Extensive-Stage SCLC
information).
For many years, platinum plus etoposide had been the standard treatment
for patients with extensive-stage SCLC, with a preference for carboplatin Other Primary Systemic Therapies
over cisplatin due to its equivalent efficacy and more tolerable toxicity Prior to the recent favorable data on immunotherapy, many other
profile. Recently, this standard has changed due to a randomized phase 3 chemotherapy combination regimens had been evaluated in patients with
trial (IMpower133) demonstrating improved survival with the addition of extensive-stage disease with little consistent evidence of benefit when
atezolizumab, a PD-L1–targeted immune checkpoint inhibitor, to platinum compared with EP. For example, the combination of irinotecan and
plus etoposide.65 In this study, standard cisplatin or carboplatin plus cisplatin initially appeared to be better than EP. A small phase 3 Japanese
etoposide was compared to the same chemotherapy plus atezolizumab trial reported that patients with extensive-stage SCLC who were treated
followed by maintenance atezolizumab in 403 patients with previously with irinotecan plus cisplatin had a median survival of 12.8 months
untreated extensive-stage SCLC. Response rates were similar in both compared with 9.4 months for patients treated with EP (P = .002).83 In
arms (60% with chemotherapy plus atezolizumab versus 64% with addition, the 2-year survival was 19.5% in the irinotecan plus cisplatin
chemotherapy alone), but the median overall survival was significantly group versus 5.2% in the EP group.83 However, two subsequent large
longer with the addition of atezolizumab (12.3 months [95% CI, 10.8–15.9] phase 3 trials performed in the United States comparing irinotecan plus
vs. 10.3 months [95% CI, 9.3–11.3]). Similarly, the 1-year overall survival cisplatin with EP failed to show a significant difference in response rate or
rate was 51.7% versus 38.2%, favoring the atezolizumab-containing overall survival between the regimens.84,85 A phase 3 randomized trial of
regimen (hazard ratio [HR] for death, 0.7 [95% CI, 0.54–0.91; P = .007]). 220 patients with extensive-stage SCLC found that median overall survival
The rate of grade 3 or 4 adverse events was similar in both groups (56%). was slightly improved with irinotecan and carboplatin compared with
For the 2019 update (Version 1), the NCCN SCLC Panel now carboplatin and oral etoposide (8.5 vs. 7.1 months, P = .04).86 Based on
recommends (category 1) carboplatin/etoposide/atezolizumab as the these studies, the cisplatin or carboplatin plus irinotecan regimens are
preferred first-line systemic therapy option followed by maintenance included as options in the NCCN Guidelines for patients with
atezolizumab for patients with extensive-stage SCLC.65 extensive-stage disease. In addition, a meta-analysis suggested an
improvement in PFS and overall survival with irinotecan plus platinum
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regimens compared with etoposide plus platinum regimens.87 However, many active cytotoxic agents as possible during initial treatment.96
the relatively small absolute survival benefit needs to be balanced against However, randomized trials have failed to show improved PFS or overall
the toxicity profile of irinotecan-based regimens. Therefore, the NCCN survival with this approach.97,98
SCLC Panel continues to recommend etoposide plus platinum regimens
for patients with either limited-stage or extensive-stage SCLC. Multidrug cyclic weekly chemotherapy was designed to increase dose
intensity. Early phase 2 results of this approach were promising, although
Many other strategies have been evaluated in an effort to improve on the favorable patient selection was of some concern.99,100 Nevertheless, no
recommended treatment for extensive-stage SCLC, including the addition survival benefits were documented in randomized trials, and excessive
of a third agent. In two trials, the addition of ifosfamide (or treatment-related mortality was noted with multidrug cyclic weekly
cyclophosphamide plus an anthracycline) to EP showed a modest survival chemotherapy regimens.101-104 The role of higher-dose chemotherapy for
advantage.88,89 However, these findings have not been uniformly patients with SCLC remains controversial. Higher complete and partial
observed, and the addition of an alkylating agent, with or without an response rates, and modestly longer median survival times, have been
anthracycline, significantly increases hematologic toxicity when compared observed in patients receiving high chemotherapy doses when compared
to EP alone.90 Two phase 3 randomized trials have confirmed the lack of with those given conventional doses of the same agents.105 In general,
improvement in survival with three-drug systemic therapy regimens however, randomized trials comparing conventional chemotherapy doses
compared to platinum plus etoposide in patients with extensive-stage to an incrementally increased dose intensity up to 2 times the conventional
SCLC. One of these studies assessed the combination of ifosfamide, dose have not consistently shown an increase in response rate or
etoposide, and epirubicin versus EP, while the other evaluated carboplatin survival.106-109 In addition, a meta-analysis of trials that compared
plus etoposide with or without palifosfamide.91,92 Similarly, the addition of recommended versus dose-intense variations of the cyclophosphamide,
paclitaxel to either cisplatin or carboplatin plus etoposide yielded doxorubicin, and vincristine (CAV) and EP regimens found that increased
promising results in phase 2 trials, but did not improve survival and was relative dose intensity resulted in only a small, clinically insignificant
associated with unacceptable toxicity in a phase 3 study.93 enhancement of median survival in patients with extensive-stage
disease.110
The use of maintenance or consolidation chemotherapy beyond 4 to 6
cycles of recommended treatment produces a minor prolongation of Currently available cytokines (eg, GM-CSF, G-CSF) can ameliorate
duration of response without improving survival and carries a greater risk chemotherapy-induced myelosuppression and reduce the incidence of
of cumulative toxicity.94 A meta-analysis reported that maintenance febrile neutropenia, but cumulative thrombocytopenia remains
chemotherapy did not prolong overall survival.95 The inability to destroy dose-limiting. Although trials involving patients with SCLC were
residual cells, despite the initial chemosensitivity of SCLC, suggests the instrumental in obtaining FDA approval for the clinical use of cytokines,111
existence of cancer stem cells that are relatively resistant to cytotoxic maintenance of dose intensity with growth factors does not prolong
therapy. To overcome drug resistance, alternating or sequential disease-free or overall survival.112,113 Thus, the routine use of growth
combination therapies have been designed to expose the tumor to as factors at the initiation of systemic therapy is not recommended. Despite
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the recent success with atezolizumab, other immunotherapy-based suggests that concurrent chemoradiation yields equivalent median survival
strategies have not been as favorable. A phase 3 randomized trial in older versus younger patients with limited-stage SCLC (29 vs. 30
reported that the addition of ipilimumab to etoposide with either cisplatin or months; P = .38).122 However, myelosuppression, fatigue, and lower organ
carboplatin as first-line therapy did not improve either overall survival or reserves are encountered more frequently in elderly patients; therefore,
PFS in patients with extensive-stage SCLC.114 they must be watched carefully during treatment to avoid excessive risk.122
Greater attention to the needs and support systems of elderly patients is
The benefits of antiangiogenic therapy have also been evaluated in SCLC. recommended to provide optimal care. Overall, elderly patients have a
In patients with limited-stage SCLC, a phase 2 study of irinotecan, similar prognosis as stage-matched younger patients.
carboplatin, and bevacizumab with concurrent radiotherapy followed by
maintenance bevacizumab was terminated early because of an Randomized trials have indicated that less-intensive treatment (eg,
unacceptable incidence of tracheoesophageal fistulae. In extensive-stage single-agent etoposide) is inferior to combination chemotherapy (eg,
SCLC, phase 2 trials of platinum-based chemotherapy plus bevacizumab platinum plus etoposide) in elderly patients with good PS (0–2).125,126 A
have yielded promising response and survival data.115-118 However, at least retrospective analysis in 8637 elderly patients with limited-stage disease
two randomized trials have demonstrated no survival benefit for the reported that chemoradiation increased survival when compared with
addition of bevacizumab to standard chemotherapy.119,120 Currently, the chemotherapy alone.123 Several other strategies have been evaluated in
NCCN SCLC Panel does not recommend use of bevacizumab in patients elderly patients with SCLC.81,127-129 The use of 4 cycles of carboplatin plus
with SCLC. Overall, attempts to improve long-term survival rates in etoposide seems to yield favorable results, because the
patients with SCLC through the addition of more agents or the use of area-under-the-curve (AUC) dosing of carboplatin takes into account the
dose-intense chemotherapy regimens, maintenance therapy, or alternating declining renal function of the aging patient.129 However, targeting
non–cross-resistant chemotherapy regimens have failed to yield significant carboplatin to an AUC of 5, rather than 6, is more reasonable in this
advantages when compared to recommended approaches. population.130 The usefulness of short-course, full-intensity chemotherapy
has also been explored in elderly or infirm patients, and the results with
Elderly Patients only 2 cycles of chemotherapy seem to be acceptable, although this
The incidence of SCLC increases with age. Although the median age at approach has not been directly compared with 4 to 6 cycles of therapy.131
diagnosis is older than 70 years, elderly patients are underrepresented in Prophylactic cranial irradiation (PCI) should be used with caution in elderly
clinical trials.121 While advanced chronologic age does adversely affect patients. Elderly patients (≥60 years) are at increased risk for cognitive
tolerance to treatment, the functional status of an individual patient is decline after PCI; therefore, the risks and benefits of PCI versus close
much more useful than age in guiding clinical decision-making (see the surveillance need to be discussed in detail with elderly patients.132-135 A
NCCN Guidelines for Older Adult Oncology, available at www.NCCN.org). Dutch analysis in more than 5000 patients suggests that median survival
Older patients who are able to perform activities of daily living should be is decreased in older patients treated with PCI when compared with
treated with combination systemic therapy (and radiotherapy, if younger patients regardless of stage.136
indicated).122-124 For example, a subgroup analysis of the CONVERT trial
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Subsequent Systemic Therapy improved symptoms of dyspnea, anorexia, hoarseness, and fatigue. In
Although SCLC is very responsive to initial treatment, most patients another phase 3 trial, oral topotecan improved overall survival when
relapse with relatively resistant disease.137,138 These patients have a compared with best supportive care (26 vs. 14 weeks).146 Single-agent
median survival of only 4 to 5 months when treated with further systemic topotecan is approved by the FDA as subsequent therapy for patients with
therapy. Subsequent systemic therapy provides significant palliation in SCLC who relapse after initial response to systemic therapy. Either oral or
many patients, although the likelihood of response is highly dependent on intravenous topotecan may be used, because efficacy and toxicity seem to
the time from initial therapy to relapse.139 If this interval is less than 3 be similar with either route.146,147 Many practicing oncologists have noted
months (refractory or resistant disease), response to most agents or excessive toxicity when using 1.5 mg/m2 of intravenous topotecan for 5
regimens is poor (≤10%). If more than 3 months have elapsed (sensitive days, and studies suggest that an attenuated dose may be equally
disease), expected response rates are approximately 25%. If patients efficacious with lower toxicity.148 Published studies have yielded conflicting
relapse more than 6 months after first-line treatment, then treatment with data regarding the usefulness of weekly topotecan in patients with
their original regimen is recommended, However, the NCCN SCLC Panel relapsed SCLC.149,150
added a caveat that patients who relapse after 6 months while on
Irinotecan was assessed in a phase 2 study in patients with refractory or
maintenance atezolizumab should receive carboplatin plus etoposide
relapsed SCLC; 47% of patients responded (7/15; [95% CI, 21.4%–
(without atezolizumab).6,139,140 For patients on subsequent systemic
71.9%]); myelosuppression, diarrhea, and pulmonary toxicity were
therapy, response assessment should occur after every 2 to 3 cycles
reported.151 Paclitaxel was assessed in a phase 2 study in patients with
using CT with contrast of the chest/abdomen. Dose reduction or growth
refractory or relapsed SCLC; 24% of patients responded (5/21).152 Grade 3
factor support should be considered for patients with a PS of 2 who are
to 4 toxicity included neutropenia, infection, rash, neuropathy, and
receiving subsequent systemic therapy.
pulmonary toxicity. Another phase 2 study of paclitaxel in patients with
Based on phase 2 trials, recommended subsequent systemic therapy refractory SCLC yielded a response rate of 29% (7/24; 95% CI, 12%–
agents for patients who have relapsed 6 months or less after primary 51%).153 Docetaxel was assessed in a phase 2 trial in patients with
therapy include topotecan, irinotecan, paclitaxel, docetaxel, temozolomide, previously treated SCLC; 25% of patients responded (7/28). Reported
nivolumab with or without ipilimumab, pembrolizumab, vinorelbine, oral toxicities included neutropenia and asthenia.154
etoposide, gemcitabine, CAV, and bendamustine (category 2A for all
Data suggest that temozolomide may be useful for patients with SCLC,
agents except for bendamustine, which is a category 2B recommendation)
especially those with brain metastases and methylated
(see Principles of Systemic Therapy in the algorithm).141-144 A randomized
O6-methylguanine-DNA methyltransferase (MGMT).142,155,156 A phase 2
phase 3 trial compared single-agent intravenous topotecan with the
study assessed temozolomide in patients with relapsed or refractory
combination regimen CAV.145 Both arms had similar response rates
SCLC. In patients with sensitive SCLC, the overall response rate was 23%
(topotecan: 24.3% [26/107]; CAV: 18.3% [19/104]) and survival (25
(95% CI, 12%–37%). The response rate was improved for patients with
weeks), but intravenous topotecan caused less grade 4 neutropenia
methylated MGMT compared to those with unmethylated MGMT (38% vs.
(37.8% vs. 51.4%; P < .001). When compared with CAV, topotecan also
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7%; P = .08). A phase 3 trial (JCOG0605) from Japan in patients with Preliminary data show that overall survival was similar between the groups
sensitive relapsed SCLC reported that the combination of cisplatin, (nivolumab: 7.5 months vs. chemotherapy: 8.4 months; HR, 0.86 [95% CI,
etoposide, and irinotecan improved survival when compared with 0.72–1.04]; P = .11). Treatment-related deaths occurred in two patients
topotecan (median survival, 18.2 vs. 12.5 months; HR, 0.67 [90% CI, receiving nivolumab and in three patients receiving chemotherapy. Fewer
0.51–0.88]; P = .0079). However, the toxicity of this approach was grade 3 to 4 adverse events occurred in patients receiving nivolumab
significant and it is not recommended for subsequent therapy.157 compared with chemotherapy (14% vs. 73%, respectively). The NCCN
Amrubicin is an active drug in patients with relapsed or refractory SCLC Panel recommends nivolumab or nivolumab plus ipilimumab (both
SCLC.158-161 However, grade 3 to 4 toxicity, primarily neutropenia, is are category 2A) as subsequent therapy options for patients who have
common.162,163 A phase 3 trial reported that amrubicin did not improve relapsed 6 months or less after primary therapy.166,167,169 However,
overall survival as second-line treatment for SCLC when compared to patients whose disease progresses while on atezolizumab as part of
topotecan, except in a subset of patients with refractory disease.164 first-line therapy should not be treated with other immune checkpoint
inhibitors.
Immune checkpoint inhibitors have also been evaluated in patients with
relapsed SCLC.165 A phase 1/2 trial (CheckMate 032) assessed nivolumab A recent combined analysis of two studies, one phase 1b (KEYNOTE-028)
alone or various doses of nivolumab plus ipilimumab for relapsed SCLC.166 and one phase 2 (KEYNOTE-158), evaluated the activity of
Response rates were 10% (10/98) for nivolumab 3 mg/kg, 23% (14/61) for pembrolizumab in 83 evaluable patients with relapsed SCLC.170 This
nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 19% (10/54) for analysis reported a response rate of 19.3% and a median overall survival
nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The responses did not of 7.7 months (95% CI, 5.2–10.1). Both overall survival and response rate
correlate with PD-L1 expression; studies indicate that SCLC has a lower were higher in those who were PD-L1 positive. Grade 3 or 4 adverse
rate of PD-L1 expression than NSCLC.166 Diarrhea was the most common events occurred in 12% of patients and two patients died from
grade 3 or 4 treatment-related adverse event. The overall frequency of treatment-related adverse events (pneumonitis and encephalitis). For the
grade 3 or 4 adverse events was about 20%, and fewer than 10% of 2019 update, the NCCN SCLC Panel added pembrolizumab as a new
patients discontinued treatment because of treatment-related adverse subsequent therapy option for patients with SCLC regardless of PD-L1
events. Updated preliminary data from an expansion cohort of this trial levels based on phase 1 and 2 data.170,171
reported a 1-year overall survival of 42% in patients receiving
nivolumab/ipilimumab and 30% in those receiving nivolumab alone.167 Immunotherapeutic agents, such as nivolumab, ipilimumab, and
Further data suggest that tumor mutational burden may be a useful pembrolizumab may cause unique immune-mediated adverse events that
biomarker for assessing whether patients will respond to nivolumab with or are not seen with traditional cytotoxic chemotherapy; therefore, health
without ipilimumab.168 care providers should be aware of the spectrum of potential
immune-mediated adverse events, know how to manage these adverse
A recent phase 3 trial (CheckMate 331) assessed nivolumab monotherapy events, and educate their patients about possible side effects.172,173 For
versus topotecan or amrubicin in 569 patients with relapsed SCLC.169 patients with immune-mediated adverse events, high-dose corticosteroids
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are generally recommended based on the severity of the reaction. improvement in 2-year overall survival when compared with chemotherapy
Nivolumab, ipilimumab, or pembrolizumab should be withheld or alone.63,64 However, achieving long-term local control using conventional
discontinued for severe or life-threatening immune-mediated adverse chemoradiotherapy for patients with limited-stage SCLC remains a
events when indicated (see prescribing information). challenge.
The optimal duration of subsequent systemic therapy has not been fully Timing of Radiation with Chemotherapy
explored. For cytotoxic chemotherapy agents, the duration of treatment is The administration of thoracic radiotherapy requires the assessment of
usually short and the cumulative toxicity is frequently limiting even in several factors, including the timing of chemotherapy and radiotherapy
patients who experience response. For these reasons, subsequent (concurrent vs. sequential), timing of radiotherapy (early vs. late), volume
systemic therapy should be continued until 2 cycles beyond best response of the radiation port (original tumor volume vs. shrinking field as the tumor
(for chemotherapy), progression of disease, or development of responds), dose of radiation, and fractionation of radiotherapy. Early
unacceptable toxicity. Additional subsequent systemic therapy (eg, third concurrent chemoradiotherapy is recommended for patients with
line) can be considered if patients are still PS 0 to 2. limited-stage SCLC based on randomized trials. A randomized phase 3
trial by the Japanese Cooperative Oncology Group assessed sequential
Radiotherapy versus concurrent thoracic radiotherapy combined with EP for patients
The Principles of Radiation Therapy section in the algorithm describes the with limited-stage disease. They reported that patients treated with
radiation doses, target volumes, and normal tissue dose-volume concurrent radiotherapy lived longer than those treated with sequential
constraints for limited-stage SCLC, and includes references to support the radiotherapy.76
recommendations; PCI and treatment of brain metastases are also
discussed (see the algorithm). The American College of Radiology (ACR) Another randomized phase 3 trial (by the National Cancer Institute of
Appropriateness Criteria are a useful resource.174 The Principles of Canada) comparing radiotherapy beginning with either cycle 2 or cycle 6
Radiation Therapy section in the NSCLC algorithm may also be useful (eg, of chemotherapy showed that early radiotherapy was associated with
general principles of radiotherapy, palliative radiotherapy) (see the NCCN improved local and systemic control and longer survival.175 Several
Guidelines for Non-Small Cell Lung Cancer, available at www.NCCN.org). systematic reviews and meta-analyses on the timing of thoracic
This section describes the studies supporting the NCCN RT radiotherapy in limited-stage SCLC have reported that early concurrent
recommendations for SCLC. radiotherapy results in a small, but significant improvement in overall
survival when compared with late concurrent or sequential
Thoracic Radiotherapy radiotherapy.176,177 Another meta-analysis in patients with limited-stage
The addition of thoracic radiotherapy has improved survival for patients SCLC showed that survival was improved with more rapid completion of
with limited-stage SCLC. Meta-analyses that included more than 2000 the chemoradiotherapy regimen (start of any chemotherapy until the end
patients show that thoracic radiation for limited-stage disease yields a 25% of radiotherapy).178 A meta-analysis of individual patient data from 12 trials
to 30% reduction in local failure, and a corresponding 5% to 7% (2668 patients) reported that early concurrent chemoradiotherapy
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increased 5-year overall survival (HR, 0.79; 95% CI, 0.69–0.91), although NCCN SCLC Panel recommends that either 45 Gy with twice-daily
severe acute esophagitis was also increased, when compared with late fractionation or 60 to 70 Gy with once-daily fractionation are acceptable
concurrent therapy.179 options depending on individual patient characteristics. For example,
twice-daily thoracic radiation is technically challenging for patients with
Radiation Fractionation bilateral mediastinal adenopathy, and logistically challenging for many
The ECOG/Radiation Therapy Oncology Group compared once-daily to patients and radiotherapy centers. Overall, patients selected for combined
twice-daily radiotherapy with EP.180 In this trial, 412 patients with modality treatment that incorporates twice-daily radiotherapy must have an
limited-stage SCLC were treated with concurrent chemoradiotherapy using excellent PS and good baseline pulmonary function.
a total dose of 45 Gy delivered either twice daily over 3 weeks or once
daily over 5 weeks. The twice-daily schedule produced a survival Radiation for Limited-Stage SCLC
advantage, but a higher incidence of grade 3 to 4 esophagitis was seen
External-Beam RT
when compared with the once-daily regimen. Median overall survivals
For limited-stage IIB to IIIC disease (T3–4,N0,M0; T1–4,N1–3,M0), the
were 23 versus 19 months (P = .04), and 5-year survival rates were 26%
NCCN Guidelines recommend that radiotherapy should be used
versus 16% in the twice-daily and once-daily radiotherapy arms,
concurrently with chemotherapy and that radiotherapy should start with the
respectively.180 A significant criticism of this trial is that the doses of
first or second cycle (category 1). The optimal dose and schedule of
radiation in the 2 arms were not biologically equivalent, with the 45 Gy
radiotherapy have not been established. For twice-daily radiotherapy, the
once-daily regimen providing suboptimal therapy.
recommended schedule is 1.5 Gy twice daily to a total dose of 45 Gy in 3
Another randomized phase 3 trial showed no survival difference between weeks. For once-daily radiotherapy, the recommended schedule is 2.0 Gy
once-daily thoracic radiotherapy to 50.4 Gy with concurrent EP and a split once daily to a total dose of 60 to 70 Gy (see Principles of Radiation
course of twice-daily thoracic radiotherapy to 48 Gy with concurrent EP.181 Therapy in the algorithm).182-184
However, split-course radiotherapy may be less efficacious because of
The minimum technical requirement for thoracic irradiation is CT-planned
interval tumor regrowth between courses. The CONVERT randomized
3-D conformal radiotherapy. For concurrent chemoradiation,
phase 3 trial assessed 45 Gy twice daily compared with 66 Gy once daily
intensity-modulated radiation therapy (IMRT) is preferred over
in 547 patients with limited-stage SCLC.73 Median overall survival was
3D-conformal external-beam RT because IMRT is less toxic (see
similar between the 2 arms (30 vs. 25 months; HR for death in the
Principles of Radiation Therapy in the algorithm and the NCCN Guidelines
once-daily group, 1.18 [95% CI, 0.95–1.45]; P = .14]). Although toxicity
for Non-Small Cell Lung Cancer, available at www.NCCN.org).185-190 More
was generally similar between the arms, patients receiving 45 Gy twice
advanced technologies may also be used when needed (eg, 4D-CT) (see
daily had more grade 4 neutropenia when compared with those receiving
Principles of Radiation Therapy in the algorithm). The radiation target
66 Gy once daily (49% vs. 38%; P = .05).
volumes can be defined on the PET/CT scan obtained at the time of
Based on the data from these randomized trials, the optimal dose and radiotherapy planning using definitions in reports 50 and 62 from the
fractionation of thoracic radiotherapy for SCLC remain unresolved. The International Commission on Radiation Units & Measurements
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(ICRU).191,192 However, the pre-chemotherapy PET/CT scan should be may be useful for SCLC (see Principles of Radiation Therapy in the NCCN
reviewed to include the originally involved lymph node regions in the Guidelines for NSCLC, available at www.NCCN.org).
treatment fields.184,193
Thoracic Radiation for Extensive-Stage SCLC
The normal tissue constraints used for NSCLC are appropriate for SCLC The addition of sequential (consolidative) thoracic radiotherapy may be
when using similar radiotherapy doses (see the NCCN Guidelines for considered in select patients with low-bulk metastatic extensive-stage
Non-Small Cell Lung Cancer, available at www.NCCN.org). When using disease who have a complete or near complete response after initial
accelerated schedules (eg, 3–5 weeks), the spinal cord constraints from systemic therapy. This recommendation was initially based on the results
the CALCB 30610/RTOG 0538 protocol can be used as a guide (see of a randomized trial by Jeremic et al,203 in which patients experiencing a
Principles of Radiation Therapy in the algorithm).194-196 complete response at distant metastatic sites after 3 cycles of EP were
randomized to receive either 1) further EP; or 2) accelerated
SABR hyperfractionated radiotherapy (ie, 54 Gy in 36 fractions over 18 treatment
Emerging data suggest that SABR (also known as stereotactic body days) in combination with carboplatin plus etoposide.203 The investigators
radiation therapy [SBRT]) may be useful for patients with clinical stage I to found that the addition of radiotherapy resulted in improved median overall
IIA (T1–2,N0) SCLC who are medically inoperable or refuse survival (17 vs. 11 months). Another phase 3 randomized trial in patients
surgery.11,197-201 One study of 43 patients with clinical stage I SCLC who with extensive-stage SCLC (Dutch CREST trial) reported that the addition
received SABR found that 31 patients were stage IA and 79% were of consolidative thoracic radiotherapy (30 Gy in 10 fractions) did not
medically inoperable.11 Patients typically received 48 to 50 Gy (4–5 improve the primary endpoint of 1-year overall survival (33% vs. 28%, P =
fractions), and only 8 patients received chemotherapy and PCI. The 2-year .066), but a secondary analysis did find improvement in 2-year overall
overall survival was 72.3% and 2-year PFS was 44.6%. Distant metastasis survival (13% vs. 3%, P = .004) and 6-month PFS when compared with
occurred in 47% of patients. A multicenter analysis of 74 patients patients who did not receive consolidative thoracic radiotherapy.204 A trial
suggested that the addition of chemotherapy typically after SABR involving 32 patients who received consolidative thoracic RT reported that
improves survival for patients with clinical limited-stage SCLC.12,202 Most of only 16% (5/32) of patients had symptomatic chest recurrences.205
these patients had PET staging, although they did not have pathologic Consolidative thoracic RT appears to mainly benefit patients with residual
nodal staging. Patients who received chemotherapy after SABR had a thoracic disease after systemic therapy, but with low-bulk extrathoracic
median overall survival of 31.4 months versus 14.3 months for those metastatic disease that has responded to systemic therapy.206
receiving SABR alone (P = .02). For the 2019 update, the NCCN SCLC
Panel now recommends (category 2A) SABR followed by systemic Prophylactic Cranial Irradiation
therapy as an option for select patients with clinical stage I to IIA (T1–2, Intracranial metastases occur in more than 50% of patients with SCLC.
N0) who are medically inoperable or decline surgery The NCCN Randomized studies have shown that PCI is effective in decreasing the
Guidelines for NSCLC provide detailed recommendations for SABR that incidence of cerebral metastases, but most individual studies did not have
sufficient power to show a meaningful survival advantage.207 A
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meta-analysis of all randomized PCI trials (using data from individual symptomatic brain metastases (14.6% vs. 40.4%) and increased the
patients) reported a nearly 50% reduction in the 3-year incidence of brain 1-year survival rate (27.1% vs. 13.3%) compared with controls.213
metastases, from 58.6% in the control group to 33.3% in the PCI-treated However, the study did not require brain imaging prior to PCI and did not
group.208 Thus, PCI seems to prevent (and not simply delay) the standardize the PCI dose or fractionation. Conflicting data come from a
emergence of brain metastases. This meta-analysis also reported a 5.4% randomized phase 3 trial from Japan, which found that median overall
increase in 3-year overall survival in patients treated with PCI, from 15.3% survival was not improved in patients receiving PCI when compared with
in the control group to 20.7% in the PCI group.208 Although the number of observation (11.6 months [95% CI, 9.5–13.3] versus 13.7 months [95% CI,
patients with extensive-stage disease was small in this meta-analysis, the 10.2–16.4]) (HR, 1.27; 95% CI, 0.96–1.68; P = .094).214 In this trial,
observed benefit was similar in patients with both limited-stage and patients were required to have an MRI to confirm that they did not have
extensive-stage disease. A retrospective study of patients with brain metastases prior to PCI, and the PCI regimen was standardized at
limited-stage disease also found that PCI increased survival at 2, 5, and 25 Gy in 10 fractions. In addition, the study required close MRI
10 years compared with those who did not receive PCI.209 A study in 184 surveillance imaging in patients to allow for the early treatment of brain
patients with limited-stage SCLC assessed PCI versus no PCI in patients metastases.
who responded to chemoradiotherapy and had no brain metastases on
brain MRI imaging before and after primary treatment.210 In patients Based on the conflicting trial results from Japan and the EORTC, the
receiving PCI, median overall survival was 26 months (range, 19.4–32.6 NCCN SCLC Panel recently softened the recommendation for PCI in
months) versus 14 months (range, 11.4–16.6 months; P < .0001) for those patients with extensive-stage disease to consider either PCI or close
without PCI. surveillance brain imaging. The NCCN SCLC Panel also added detailed
imaging recommendations for patients regardless of PCI (see Surveillance
For patients (4257) with extensive-stage SCLC, but without brain in this Discussion). Therefore, depending on individual patient factors,
metastases, a large retrospective analysis of 4257 patients showed that either PCI or close brain surveillance imaging (MRI preferred or CT with
PCI improved median overall survival compared with no PCI (13.9 vs. 11.1 contrast) appear to be reasonable options for patients with
months; P < .0001).211 Another analysis of patients with extensive-stage extensive-stage SCLC and good response to initial systemic therapy. For
SCLC (n = 397) reported that PCI improved overall survival compared with the 2019 update, the NCCN SCLC Panel added a caveat that the risks
no PCI (13.5 vs. 8.5 months, respectively; HR, 0.55; 95% CI, 0.39–0.77; and benefits of PCI versus brain surveillance imaging should be discussed
P= .0005); however, these patients did not receive routine surveillance with patients.
brain imaging.212
Late neurologic sequelae have been attributed to PCI, particularly in
In light of the paucity of data on the benefits of PCI in patients with studies using fractions greater than 3 Gy and/or administering PCI
extensive-stage SCLC, the EORTC performed a randomized trial that concurrently with chemotherapy.133,215,216 Thus, PCI is not recommended
assessed PCI versus no PCI in 286 patients with extensive-stage SCLC for patients with poor PS (3–4) or impaired neurocognitive function.217,218
whose disease had responded to initial chemotherapy; PCI decreased Older age (>60 years) has also been associated with chronic
MS-16

neurotoxicity.132,134 When given after the completion of chemotherapy and is recommended using either MRI (preferred) or CT with contrast. Detailed
at a low dose per fraction, PCI may cause less neurologic toxicity. brain imaging recommendations are provided in the algorithm.214
Memantine is a N-methyl-D-aspartate (NMDA) receptor antagonist that
may delay cognitive dysfunction in patients receiving whole-brain RT.219 Palliative Radiotherapy
Patients receiving memantine had a longer time before cognitive decline For patients with localized symptomatic sites of disease (ie, painful bony
(HR, 0.78; 95% CI, 0.62–0.99, P = .01). The NCCN SCLC Panel lesions, spinal cord compression, obstructive atelectasis) or with brain
recommends that memantine be considered for patients receiving PCI or metastases, radiotherapy can provide excellent palliation (see the
therapeutic whole-brain irradiation. For the 2019 update, the panel added algorithm and the NCCN Guidelines for Non-Small Cell Lung Cancer,
memantine dosing to the algorithm based on clinical trial data (RTOG available at www.NCCN.org).224-226 Orthopedic stabilization may be useful
0614).219 in patients at high risk for fracture because of osseous structural
impairment. Because patients with SCLC often have a short life span,
Before the decision is made to administer PCI, a balanced discussion surgery is not usually recommended for spinal cord compression.
between the patient and physician is necessary.133,220 The NCCN SCLC Whole-brain radiotherapy is recommended for brain metastases in
Panel recommends PCI (category 1) for patients with limited-stage patients with SCLC due to the frequent occurrence of multiple metastases
disease who attain a complete or partial response; PCI can be considered (see Principles of Radiation Therapy in the algorithm and the NCCN
(category 2A) for patients with extensive-stage disease.213,217 For the 2019 Guidelines for Central Nervous System Cancers, available at
update, the NCCN SCLC Panel added a caveat that it is not clear whether www.NCCN.org).227 Although late complications, such as neurocognitive
patients who have had surgical resection for stage I to IIA SCLC will impairment, may occur with whole-brain radiotherapy, this is less of an
benefit from PCI because these patients have a lower risk of developing issue in patients with SCLC because long-term survival is rare.133 The
brain metastases.202,221,222 The preferred dose for PCI is 25 Gy in 10 daily recommended dose for whole-brain radiotherapy is 30 Gy in 10 daily
fractions (2.5 Gy/fraction) (see Principles of Radiation Therapy in the fractions.227 In patients who develop brain metastases after PCI,
algorithm).208,213,223 The NCCN SCLC Panel feels that a shorter course of stereotactic radiosurgery (preferred) or whole-brain radiotherapy may be
PCI may be appropriate (eg, 20 Gy in 5 fractions) for selected patients considered.228,229
with extensive-stage disease.213 Higher doses (eg, 36 Gy) increased
mortality and toxicity when compared with lower doses (25 Gy).132,223 PCI Surgical Resection of Stage I to IIA SCLC
should not be given concurrently with chemotherapy, and high total The Principles of Surgical Resection for SCLC are described in the NCCN
radiotherapy dose (>30 Gy) should be avoided because of the increased algorithm; studies supporting these recommendations are described in this
risk of neurotoxicity.132 Fatigue, headache, and nausea/vomiting are the section. Briefly, the NCCN Guidelines state that surgery is only
most common acute toxic effects after PCI.218,223 After the acute toxicities recommended for patients with stage I to IIA (T1–2,N0) SCLC in whom
of initial systemic therapy have resolved, PCI can be administered. For mediastinal staging has confirmed that mediastinal lymph nodes are not
patients not receiving PCI, surveillance for metastases with brain imaging involved.10,230 Data show that patients with nodal disease (ie, T1–3,N1–3,
MS-17

M0–1) do not benefit from surgery.231 Note that fewer than 5% of patients those who did not undergo surgery is inherently flawed by selection bias.
with SCLC have true stage I to IIA disease.232 Ultimately, the role of surgery in SCLC will not be fully defined until trials
are done to compare surgery plus adjuvant chemotherapy to concurrent
For the 2019 update, the NCCN SCLC Panel expanded the indication for chemoradiotherapy in patients who are rigorously staged.
surgery to include patients with clinical stage IIA SCLC based on the
change in staging criteria such that tumors up to 5 cm in diameter (T2b) In patients with clinical stage I to IIA (T1–2,N0) SCLC who are being
without lymph node involvement (N0) are now classified as IIA. The Lung considered for surgical resection, occult nodal disease should be ruled out
Cancer Study Group conducted the only prospective randomized trial through mediastinal staging before resection.240 If resection is performed,
evaluating the role of surgery in SCLC.231 Patients with limited-stage the NCCN SCLC Panel recommends lobectomy with mediastinal lymph
disease, excluding those with solitary peripheral nodules, received 5 node dissection as the preferred operation and does not feel that
cycles of chemotherapy with CAV; those showing a response to segmental or wedge resections are appropriate for patients with SCLC.
chemotherapy were randomly assigned to undergo resection plus thoracic After complete resection, adjuvant chemotherapy or chemoradiation is
radiotherapy or thoracic radiotherapy alone. The overall survival rates of recommended.217,235,241,242 Adjuvant chemotherapy alone is recommended
patients on the two arms were equivalent, suggesting no benefit to surgery for patients without nodal metastases, whereas concurrent chemotherapy
in this setting. However, only 19% of enrolled patients had clinical stage I and postoperative mediastinal radiotherapy are recommended for patients
(T1–2,N0,M0) disease. with nodal metastases (see Adjuvant Treatment in the algorithm).
Although panel members agree that postoperative mediastinal
Most of the data regarding the role of surgery in SCLC are from radiotherapy is recommended in this setting, it should be based on the
retrospective reviews.230,233-237 These studies report favorable 5-year extent of nodal sampling/dissection and extent of nodal positivity;
survival rates of 40% to 60% in patients with stage I disease. In most however, there are no data to support this recommendation. The role of
series, survival rates decline significantly in patients with more advanced PCI is unclear in surgically resected early-stage patients, because they
disease with lymph node involvement, leading to the general appear to have a lower incidence of brain metastases (see Prophylactic
recommendation that surgery should only be considered in those with Cranial Irradiation in this Discussion and Adjuvant Treatment in the
stage I to IIA disease (T1–2,N0,M0). Interpretation of these results is algorithm).208 The NCCN SCLC Panel recommends new baseline disease
limited by the selection bias inherent in retrospective reviews and by the assessment after adjuvant therapy.
variable use of chemotherapy and radiotherapy. A meta-analysis
describes the evidence from currently available randomized trials in Surveillance
greater detail.238 The surveillance recommendations for patients with SCLC are outlined in
the algorithm. The frequency of surveillance decreases during subsequent
Analyses of the SEER database also suggest that surgery may be
years because of the declining risk of recurrence.243 If a new pulmonary
appropriate for some patients with localized disease.13,239 However, these
nodule develops, it should prompt evaluation for a new primary lung
studies are limited by the lack of information on chemotherapy use in the
cancer, because second primary tumors are a frequent occurrence in
database. In addition, comparison of the survival of surgical patients to all
MS-18

patients who are cured of SCLC.244,245 It is important to monitor for brain

metastases, which allows for early treatment prior to the development of
potentially debilitating neurologic symptoms. The NCCN SCLC Panel
recommends brain MRI (preferred) or brain CT with contrast every 3 to 4
months during year 1 for all patients. For the 2019 update, the panel
revised these imaging recommendations to every 6 months during year 2,
regardless of the PCI status. PET/CT is not recommended for routine
follow-up. Smoking cessation should be encouraged for all patients with
SCLC, because second primary tumors occur less commonly in patients
who quit smoking (see the NCCN Guidelines for Smoking Cessation,
available at www.NCCN.org).246-248 Former smokers should be encouraged
to remain abstinent. The NCCN SCLC Panel also recommends the
survivorship guidelines for appropriate patients (see the NCCN Guidelines
for Survivorship, available at www.NCCN.org).
Summary
SCLC is a poorly differentiated high-grade neuroendocrine carcinoma.21
Most cases of SCLC are caused by cigarette smoking.4 Management of
SCLC is described in the NCCN Guidelines for SCLC, which include the
algorithm and this supporting Discussion text. Revisions for the 2019
update of the NCCN Guidelines for SCLC are described in this Discussion
and outlined in the algorithm (see Summary of the Guidelines Updates in
the algorithm). For the 2019 update (Version 1), the NCCN SCLC Panel
now recommends atezolizumab/carboplatin/etoposide as a preferred
first-line systemic therapy option (category 1) for extensive-stage SCLC
based on clinical trial data and the FDA approval.65 The panel also added
pembrolizumab as a new subsequent therapy option for patients with
SCLC regardless of PD-L1 levels based on phase 1 and 2 data.170,171 In
addition, the panel added a new recommendation for SABR followed by
systemic therapy for select patients with clinical stage I to IIA SCLC (T1–2,
N0,M0) who are medically inoperable or decline surgery.11,12,197,202
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Small Cell Lung Cancer: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)

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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Small Cell Lung Cancer

NCCN Guidelines Version 3.2020 NCCN Guidelines Index

Apar Kishor P. Ganti, MD, Chair † Charles Florsheim Daniel Morgensztern, MD †

Wallace Akerley, MD † John C. Grecula, MD § Saraswati Pokharel, MD ≠

Jessica Bauman † The Sidney Kimmel Comprehensive Sonam Puri, MD † ‡ Þ

NCCN Guidelines Version 3.2020 NCCN Guidelines Index

NCCN Small Cell Lung Cancer Panel Members

NCCN Guidelines Version 3.2020 NCCN Guidelines Index

NCCN Guidelines Version 3.2020 NCCN Guidelines Index

NCCN Guidelines Version 3.2020 NCCN Guidelines Index

NCCN Guidelines Version 3.2020 NCCN Guidelines Index

DIAGNOSIS INITIAL EVALUATIONa STAGE

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

NCCN Guidelines Version 3.2020 NCCN Guidelines Index

STAGE ADDITIONAL WORKUP

• If pleural effusion is present,

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

NCCN Guidelines Version 3.2020 NCCN Guidelines Index

TESTING RESULTSk INITIAL TREATMENT ADJUVANT TREATMENT

Lobectomyi,l Systemic therapym

i See Principles of Surgical Resection (SCL-C).

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

NCCN Guidelines Version 3.2020 NCCN Guidelines Index

INITIAL TREATMENT ADJUVANT TREATMENT

Poor PS (3-4) Individualized treatment

m See Principles of Systemic Therapy (SCL-E).

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

NCCN Guidelines Version 3.2020 NCCN Guidelines Index

STAGE INITIAL TREATMENTq

Systemic therapym ± RTn to

May administer systemic therapy first, with

m See Principles of Systemic Therapy (SCL-E).

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

NCCN Guidelines Version 3.2020 NCCN Guidelines Index

RESPONSE ASSESSMENT FOLLOWING ADJUVANT SURVEILLANCEt

b See Signs and Symptoms of Small Cell Lung Cancer (SCL-A).

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

NCCN Guidelines Version 3.2020 NCCN Guidelines Index

PROGRESSIVE DISEASE SUBSEQUENT THERAPY/PALLIATIVE THERAPY

m See Principles of Systemic Therapy (SCL-E).

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

NCCN Guidelines Version 3.2020 NCCN Guidelines Index

SIGNS AND SYMPTOMS OF SMALL CELL LUNG CANCER

Signs and symptoms due to local primary tumor growth

Signs and symptoms due to extrathoracic (hematogenous) metastases

NCCN Guidelines Version 3.2020 NCCN Guidelines Index

SIGNS AND SYMPTOMS OF SMALL CELL LUNG CANCER

Signs and symptoms of paraneoplastic syndromes

• Neurologic: All specific syndromes are rare

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

NCCN Guidelines Version 3.2020 NCCN Guidelines Index

PRINCIPLES OF PATHOLOGIC REVIEW

NCCN Guidelines Version 3.2020 NCCN Guidelines Index

PRINCIPLES OF PATHOLOGIC REVIEW

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

NCCN Guidelines Version 3.2020 NCCN Guidelines Index

PRINCIPLES OF SURGICAL RESECTION

• Stage I-IIA SCLC is diagnosed in less than 5% of patients with SCLC.