SCLC

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

Version 3.2024 — June 11, 2024
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NCCN Guidelines Version 3.2024 NCCN Guidelines Index

Table of Contents
Small Cell Lung Cancer Discussion
*Apar Kishor P. Ganti, MD, Chair † John C. Grecula, MD § Chinh Phan, DO Ξ

Fred & Pamela Buffett Cancer Center The Ohio State University Comprehensive Cancer UC Davis Comprehensive Cancer Center
Center - James Cancer Hospital
*Billy W. Loo, Jr., MD, PhD/Vice Chair § Saraswati Pokharel, MD ≠
and Solove Research Institute
Stanford Cancer Institute Roswell Park Comprehensive Cancer Center
Christine Hann, MD, PhD †
Shahed Badiyan, MD § Sonam Puri, MD † ‡ Þ
The Sidney Kimmel Comprehensive
UT Southwestern Simmons Comprehensive Cancer Huntsman Cancer Institute
Cancer Center at Johns Hopkins
Center at the University of Utah
Wade Iams, MD †
Michael Bassetti, MD § Angel Qin, MD †
Vanderbilt-Ingram Cancer Center
University of Wisconsin Carbone Cancer Center University of Michigan Rogel Cancer Center
Maya Khalil, MD † Þ
Christine Bestvina, MD † Jacob Sands, MD †
O'Neal Comprehensive Cancer Center at UAB
The UChicago Medicine Comprehensive Cancer Dana Farber/Brigham and
Center Jyoti Malhotra, MD † Women's Cancer Center
City of Hope National Medical Center
Anne Chiang, MD, PhD † Rafael Santana-Davila, MD †
Yale Cancer Center/Smilow Cancer Hospital Robert E. Merritt, MD ¶ Fred Hutchinson Cancer Center
The Ohio State University Comprehensive Cancer
Christopher A. D'Avella, MD † Michael Shafique, MD †
Center - James Cancer Hospital
Abramson Cancer Center Moffitt Cancer Center
and Solove Research Institute
at the University of Pennsylvania Misty Shields, MD, PhD †
Nisha Mohindra, MD †
Megan Daly, MD § Indiana University Melvin and Bren Simon
Robert H. Lurie Comprehensive Cancer
UC Davis Comprehensive Cancer Center Comprehensive Cancer Center
Center of Northwestern University
Afshin Dowlati, MD † Tina Tailor, MD ф
Julian R. Molina, MD, PhD †
Case Comprehensive Cancer Center/ Duke Cancer Institute
Mayo Clinic Comprehensive Cancer Center
University Hospitals Seidman Cancer Center and Saiama N. Waqar, MD †
Cleveland Clinic Taussig Cancer Institute Cesar Moran, MD ≠
Siteman Cancer Center at Barnes-
The University of Texas
Robert J. Downey, MD ¶ Jewish Hospital and Washington
MD Anderson Cancer Center
Memorial Sloan Kettering Cancer Center University School of Medicine
Claire Mulvey, MD ‡ Þ
Martin Edelman, MD † UCSF Helen Diller Family
Fox Chase Cancer Center NCCN
Comprehensive Cancer Center
Carly J. Cassara, MSc
Charles Florsheim, JD ¥ Evan Osmundson, MD § Swathi Ramakrishnan, PhD
Patient Advocate Vanderbilt-Ingram Cancer Center
Kathryn A. Gold, MD † Shiven Patel, MD ‡ ‡ Hematology/Hematology oncology
UC San Diego Moores Cancer Center Huntsman Cancer Institute at the University of Utah Þ Internal medicine
Jonathan W. Goldman, MD † Tejas Patil, MD ‡ † Medical oncology
UCLA Jonsson Comprehensive Cancer Center University of Colorado Cancer Center ≠ Pathology
¥ Patient advocacy
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Ξ Pulmonary medicine
§ Radiotherapy/Radiation oncology
NCCN Guidelines Panel Disclosures ¶ Surgery/Surgical oncology
ф Diagnostic Radiology
* Discussion writing committee member

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NCCN Small Cell Lung Cancer Panel Members Find an NCCN Member Institution:
Summary of the Guidelines Updates https://www.nccn.org/home/member-
Initial Evaluation and Staging (SCL-1) institutions.
Limited Stage, Workup and Treatment (SCL-2) NCCN Categories of Evidence and
Extensive Stage, Primary Treatment (SCL-5) Consensus: All recommendations
Response Assessment Following Primary Treatment and Surveillance (SCL-6) are category 2A unless otherwise
Progressive Disease: Subsequent Therapy and Palliative Therapy (SCL-7) indicated.
Signs and Symptoms of Small Cell Lung Cancer (SCL-A) See NCCN Categories of Evidence
Principles of Pathologic Review (SCL-B) and Consensus.
Principles of Surgical Resection (SCL-C)
Principles of Supportive Care (SCL-D) NCCN Categories of Preference:
Principles of Systemic Therapy (SCL-E) All recommendations are considered
Principles of Radiation Therapy (SCL-F) appropriate.
See NCCN Categories of Preference.
Staging (ST-1)
Lung Neuroendocrine Tumors – See NCCN Guidelines for Neuroendocrine and Adrenal Tumors
Abbreviations (ABBR-1)
The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.
Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical
circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or
warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not
be reproduced in any form without the express written permission of NCCN. ©2024.

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Terminologies in all NCCN Guidelines are being actively modified to advance the goals of equity, inclusion, and representation.
Updates in Version 3.2024 of the NCCN Guidelines for Small Cell Lung Cancer from Version 2.2024 include:
SCL-E 3 of 6
• Chemotherapy-free interval (CTFI) >6 months, other recommended regimen added: tarlatamab-dlle
• CTFI ≤6 months, preferred regimen added: tarlatamab-dlle
• Footnote i added: For extensive-stage with disease progression on or after platinum-based chemotherapy.
SCL-E 6 of 6
• Reference added: Ahn MJ, Cho BC, Felip E, et al. Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer N Engl J Med 2023;389:2063-75
MS-1
• The discussion section has been updated to reflect the changes in the algorithm.
SCL-1
• Initial Evaluation
Bullet 9 modified: Consider molecular profiling (only for patients who have never smoked tobacco with extensive stage SCLC)
Bullet 10 added: Integrate palliative care. See NCCN Guidelines for Palliative Care.
• Footnote g modified: Molecular testing can be considered in rare cases for patients with extensive-stage SCLC who do not smoke tobacco, lightly smoke, or for pathologic
dilemma because this may change management. Comprehensive molecular profiling can be considered in rare cases—particularly for patients with extensive-stage/
relapsed SCLC who do not smoke tobacco, lightly smoke, have remote smoking history, or have diagnostic or therapeutic dilemma, or at time of relapse—if not previously
done, because this may change management.
SCL-3
• Adjuvant Treatment
Branch modified: N1+
Branch removed: N2, Systemic therapy + mediastinal RT (sequential or concurrent)
SCL-5
• Primary treatment, spinal cord compression
Bullet 1 added: Initiate steroids
Bullet 2 modified: Systemic therapy + RT (typically sequential to symptomatic sites before systemic therapy unless immediate systemic therapy is required)
• Footnotes added
u: For transformation to SCLC from NSCLC, consider referral to a center with expertise (SCL-E 4 of 6).
v: Initiate steroids for patients with symptomatic neurologic disease.
w: With neurologic symptoms, RT is preferred before systemic therapy. Systemic therapy may start first if RT cannot be started expeditiously or if controlling systemic
symptoms is more urgent.
SCL-6
• Surveillance
Bullet 4 modified: Brain MRI (preferred) or CT with contrast every 3–4 mo during y 1, then every 6 mo during y 2 and after y 2 afterwards, then as clinically indicated
(regardless of PCI status)
Bullet 7 modified: FDG-PET/CT is not recommended for routine follow-up unless contrast CT C/A/P is contraindicated
Continued
UPDATES

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SCL-7
• Footnotes added
ee: For CNS progression only, continue systemic therapy and treat the brain metastases with RT (see Principles of Radiation Therapy).
ff: Consider genomic profiling, if not previously done, to determine clinical trial eligibility.
SCL-A 2 of 2
• Neurologic
Sub-bullet 1 added: Consider early subspecialty consultation for unusual paraneoplastic neurologic syndromes to ensure the most recent management is done
Sub-bullet 2 modified: If paraneoplastic neurologic syndrome is suspected, consider obtaining a neurologic consultation and/or comprehensive paraneoplastic antibody
panel
• Footnote added: Principles of Supportive Care (SCL-D).
SCL-B 1 of 2
• Bullet 5 modified: Careful counting of mitoses is essential, because it is the most important histologic criterion for distinguishing SCLC from typical and atypical carcinoids.
Strongly recommend a second opinion—with a pathologist specializing in the diagnosis of thoracic malignancies—for diagnostic dilemma, including carcinoid.
• Bullet 8 modified: Molecular testing can be considered in rare cases for patients with extensive-stage SCLC who do not smoke tobacco, lightly smoke (<10 cigarettes/
day), or for pathologic dilemma because this may change management Comprehensive molecular profiling can be considered in rare cases—particularly for patients with
extensive-stage/relapsed SCLC who do not smoke tobacco, lightly smoke (<10 cigarettes/day), with remote smoking history, or diagnostic or therapeutic dilemma or at time
of relapse—if not previously done, because this may change management.
SCL-C
• Bullet 2, sub-bullet 2 modified: For patients undergoing definitive surgical resection, the preferred operation is lobectomy with mediastinal lymph node dissection or
systematic lymph node sampling (eg, ≥3 N2 and ≥1 N1 stations).
• References added
3: Katz MHG, Francescatti AB, Hunt KK; Cancer Surgery Standards Program of the American College of Surgeons. Technical Standards for Cancer Surgery: Commission
on Cancer Standards 5.3-5.8. Ann Surg Oncol 2022;29:6549-6558.
4: Darling GE, Allen MS, Decker PA, et al. Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the
patient with N0 or N1 (less than hilar) non-small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 Trial. J Thorac Cardiovasc Surg
2011;141:662-670.
5: Darling GE, Allen MS, Decker PA, et al. Number of lymph nodes harvested from a mediastinal lymphadenectomy: results of the randomized, prospective American
College of Surgeons Oncology Group Z0030 trial. Chest 2011;139:1124-1129.
6: Osarogiagbon RU, Decker PA, Ballman K, et al. Survival Implications of Variation in the Thoroughness of Pathologic Lymph Node Examination in American College of
Surgeons Oncology Group Z0030 (Alliance). Ann Thorac Surg 2016;102:363-369.
7: Su S, Scott WJ, Allen MS, et al. Patterns of survival and recurrence after surgical treatment of early stage non-small cell lung carcinoma in the ACOSOG Z0030
(ALLIANCE) trial. J Thorac Cardiovasc Surg 2014;147:747-752: Discussion 752-753.
SCL-D
• Bullet 2 modified: Granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) is or granulocyte colony–stimulating
factor (G-CSF) are not recommended during concurrent systemic therapy plus RT (category 1 for not using GM-CSF).
• SIADH, sub-bullet removed: Antineoplastic therapy
• Cushing syndrom, sub-bullet 2 modified: Try to control before initiation of antineoplastic therapy. Consider referral to an appropriate endocrinology subspecialist.
• Bullet added: Consider early subspecialty consultation for unusual paraneoplastic neurologic syndromes to ensure the most recent management is done.
• Reference added: Wang C, Zhu S, Miao C, et al. Safety and efficacy of pegylated recombinant human granulocyte colony-stimulating factor during concurrent Continued
chemoradiotherapy for small-cell lung cancer: a retrospective, cohort-controlled trial. BMC Cancer 2022;22:542.
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SCL-E 2 of 6
• Footnote b modified: Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or concurrent use
of immunosuppressive agents. For safety reasons, do not use ICIs in patients who have recently received tyrosine kinase inhibitors (TKIs).
• Footnotes added:
c: Included patients with asymptomatic untreated brain metastases.
d: Maintenance immunotherapy with either atezolizumab or durvalumab should continue until progression or intolerable toxicity.
e: For transformation to SCLC from NSCLC, consider referral to a center with expertise (SCL-E 4 of 6).
SCL-E 3 of 6
• Page extensively revised.
• Vinorelbine and bendamustine (category 2B) were removed as subsequent therapy options.
SCL-E 4 of 6
• Bullet added: Transformed SCLC from NSCLC with an Oncogenic Driver
• Sub-bullets added
This is a rare population of patients with very limited data to guide treatment.
Systemic cytotoxic chemotherapy is recommended using the NCCN Guidelines for Small Cell Lung Cancer.
The role of immunotherapy in this setting is unclear based on limited data.
If TKI is continued, ICI should be avoided, due to known toxicity.
Consider referral to a center with experience managing transformed SCLC.
SCL-E 6 of 6
• References added
28: Edelman MJ, Dvorkin M, Laktionov K, et al. Randomized phase 3 study of the anti-disialoganglioside antibody dinutuximab and irinotecan vs irinotecan or topotecan
for second-line treatment of small cell lung cancer. Lung Cancer 2022;166:135-142.
40: Hoang T, Kim K, Jaslowski A, et al. Phase II study of second-line gemcitabine in sensitive or refractory small cell lung cancer. Lung Cancer 2003;42:97-102.
41: Schoenfeld AJ, Arbour KC, Rizvi H, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol
2019;30:839-844.
42: Oshima Y, Tanimoto T, Yuji K, Tojo A et al. EGFR-TKI-associated interstitial pneumonitis in nivolumab-treated patients with non-small cell lung cancer. JAMA Oncol
2018;4:1112-1115.
43: Marcoux N, Gettinger SN, O'Kane G, et al. EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: Clinical
outcomes. J Clin Oncol 2019;37:278-285.
44: Ferrer L, Giaj Levra M, Brevet M, et al. A brief report of transformation from NSCLC to SCLC: Molecular and therapeutic characteristics. J Thorac Oncol 2019;14:130-
134.
45: Chai X, Zhang X, Li W, Chai J. Small cell lung cancer transformation during antitumor therapies: A systematic review. Open Med (Wars) 2021;16:1160-1167.
46: Zhang CY, Sun H, Su JW, et al. A potential treatment option for transformed small-cell lung cancer on PD-L1 inhibitor-based combination therapy improved survival.
Lung Cancer 2023;175:68-78.
• References removed:
Furuse K, Kuboa K, Kawahara M, et al. Phase II study of vinorelbine in heavily previously treated small cell lung cancer. Japan Lung Cancer Vinorelbine Study Group.
Oncology 1996;53:169-172
Continued
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Jassem J, Karnicka-Mlodkowska H, van Pottelsberghe C, et al. Phase II study of vinorelbine (Navelbine) in previously treated small cell lung cancer patients. EORTC Lung
Cancer Cooperative Group. Eur J Cancer 1993;29A:1720-1722.
Lammers PE, Shyr Y, Li CI, et al. Phase II study of bendamustine in relapsed chemotherapy sensitive or resistant small-cell lung cancer. J Thorac Oncol 2014;9:559-562.
Oxnard GR, Yang JCH, Yu H, et al. TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer.
Ann Oncol 2020;31:507-516.
SCL-F 1 of 6
• General treatment information, limited stage, bullet 2 modified: 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 radiotherapy (SABR), also known as stereotactic body RT (SBRT), 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).
SCL-F 2 of 6
• Extensive stage, bullet 1 modified: Consolidative thoracic RT is beneficial for selected patients with ES-SCLC with complete response or good response to systemic therapy
before immunotherapy, 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. The Dutch CREST randomized
trial of modest-dose thoracic RT (30 Gy in 10 fractions) in patients with ES-SCLC that responded to systemic therapy chemotherapy (without immunotherapy) 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. 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.
SCL-F 3 of 6
• Extensive stage
Bullet removed: Dosing and fractionation of consolidative thoracic RT should be individualized within the range of 30 Gy in 10 daily fractions up to definitive dosing
regimens in patients with a longer life expectancy.
Bullet 1 modified: Based on two randomized trials, immunotherapy during and after chemotherapy is a first-line approach, but these studies did not include consolidative
thoracic RT. Nevertheless, consolidative thoracic RT after chemoimmunotherapy can be considered for selected patients as above, during or before maintenance
immunotherapy (there are no limited data on optimal sequencing or safety). The benefit of thoracic RT in the context of chemoimmunotherapy is under evaluation in the
RAPTOR/NRG LU007 trial.
SCL-F 4 of 6
• Prophylactic Cranial Irradiation
Bullet 2 modified: When administering PCI, consider adding memantine during and after RT, which has been shown to decrease neurocognitive impairment following
whole brain radiation therapy (WBRT) for brain metastases. 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 (see the NCCN
Guidelines for Central Nervous System Cancers)
Bullet 3 modified: Hippocampal-avoidance (HA) PCI using IMRT may be considered as a potential strategy to improve cognitive preservation. A phase III randomized trial
of HA-WBRT versus conventional WBRT demonstrated improved cognitive preservation and patient-reported outcomes with HA-WBRT in patients with brain metastases
from mixed histologies. Conflicting data have been reported with HA-PCI versus conventional PCI in SCLC with one trial reporting no differences in cognition and a
separate trial reporting improved cognitive preservation with HA-PCI. A larger randomized trial of HA-PCI versus conventional PCI, NRG CC003, is ongoing has completed
accrual with results pending.
• Brain Metastases, bullet 4 modified: For patients with a better prognosis (eg, ≥4 months), hippocampal-sparing WBRT using IMRT plus memantine is preferred because
it produces less cognitive function failure than conventional WBRT plus memantine. However, patients with metastases within 5 mm of the hippocampi, leptomeningeal
Continued
Version 3.2024, 6/11/24 © 2024 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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metastases, and other high risk features were not eligible for hippocampal-sparing WBRT on NRG CC001. Although CC001 did not include patients with brain metastases
from SCLC, it is reasonable to extrapolate the findings to SCLC.
SCL-F 5 of 6
• Reference modified: Bogart JA, Wang XF, Masters GA, et al. Phase 3 comparison of high-dose once daily (QD) thoracic radiotherapy (TRT) with standard twice-daily (BID)
TRT in limited stage small cell lung cancer (LSCLC): CALGB 30610 (Alliance)/RTOG 0538. J Clin Oncol 2021;39:8505-8505. High-dose once-daily thoracic radiotherapy in
limited-stage small-cell lung cancer: CALGB 30610 (Alliance)/RTOG 0538. J Clin Oncol 2023;41:2394-2402.
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DIAGNOSIS INITIAL EVALUATIONa,b STAGE
• History and physical (H&P)c

• Pathology reviewd
• Complete blood count (CBC)
• Electrolytes, liver function tests
(LFTs), blood urea nitrogen (BUN), Limited stage
creatinine (See ST-1 for TNM Additional
Small cell lung Workup (SCL-2)
• Chest/abdomen/pelvis (C/A/P) CT Classification)
cancer (SCLC) or
with contrast
combined SCLC/
• Brain MRIa,e (preferred) or CT with
non-small cell lung
contrast
cancer (NSCLC) on
• FDG-PET/CT scan (skull base to
biopsy or cytology
mid-thigh), if needed to clarify
of primary or
extent of diseasea,f Extensive stage
metastatic site Primary
• Smoking cessation counseling (See ST-1 for TNM
and intervention. See the NCCN Classification) Treatment (SCL-5)
Guidelines for Smoking Cessation.
• Consider molecular profilingg
• Integrate palliative care. See NCCN
Guidelines for Palliative Care
a If extensive stage is established, further staging evaluation is optional. However, brain imaging MRI (preferred), or CT with contrast is recommended in all patients.
b Workup of SCLC should be expedited, with studies done in parallel whenever possible.
c Signs and Symptoms of Small Cell Lung Cancer (SCL-A).
d Principles of Pathologic Review (SCL-B).
e Brain MRI is more sensitive than CT for identifying brain metastases and is preferred over CT.
f If FDG-PET/CT is not available, bone scan may be used to identify metastases. Pathologic confirmation is recommended for lesions detected by FDG-PET/CT that alter stage.
g Comprehensive molecular profiling can be considered in rare cases—particularly for patients with extensive-stage/relapsed SCLC who do not smoke tobacco, lightly smoke, have remote
smoking history, or have diagnostic or therapeutic dilemma, or at time of relapse—if not previously done, because this may change management.
Note: All recommendations are category 2A unless otherwise indicated.
SCL-1

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STAGE ADDITIONAL WORKUPb
• If pleural effusion is present,

thoracentesis is
recommended; if
thoracentesis inconclusive, Limited stage:
consider thoracoscopyh Pathologic mediastinal Primary
Clinical stage
• Pulmonary function tests stagingj,k Treatment (SCL-3)
I–IIA (T1–2,N0,M0)
(PFTs) during evaluation for
surgery or definitive RT
• Multidisciplinary evaluation
Limited stage is recommended before Limited stage
(see ST-1 for TNM surgery IIB–IIIC (T3–4,N0,M0; T1–4,N1–3,M0).
Classification) Primary Treatment
• Bone imaging (radiographs Consider pathologic mediastinal
(SCL-4)
or MRI) as appropriate if staging (especially for cN0) if it would
FDG-PET/CT equivocal help determine RT fieldsj,k
(consider biopsy if bone
imaging is equivocal)
• Unilateral marrow
aspiration/biopsy in select Bone marrow biopsy, Extensive-Stage
patientsi thoracentesis, or bone studies Disease (SCL-5)
consistent with malignancy
b Workup of SCLC should be expedited, with studies done in parallel whenever possible.
h 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.
i Selection criteria include: nucleated red blood cells (RBCs) on peripheral blood smear, neutropenia, or thrombocytopenia suggestive of bone marrow infiltration.
j Principles of Surgical Resection (SCL-C).
k 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.
SCL-2

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TESTING RESULTSk PRIMARY TREATMENT ADJUVANT TREATMENT
N0 Systemic therapym
R0
Lobectomyj,l
Pathologic (preferred) and
mediastinal mediastinal lymph
stagingj,k negative node dissection or
sampling Systemic therapym
± mediastinal RTn
N+ Response
(sequential or
concurrent) Assessment
Following
Limited stage: Primary
R1/R2 Systemic therapym + concurrent RTn Treatment
clinical stage
I–IIA (T1–2,N0,M0) (SCL-6)o,p
SABRn Systemic therapym,q
Medically inoperable or
decision made not to
pursue surgical resection Systemic therapym
+ concurrent RTn
(SCL-4)
Pathologic mediastinal stagingj,k positive SCL-4
Footnotes
(SCL-3A)
SCL-3

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FOOTNOTES
j Principles of Surgical Resection (SCL-C).
k 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.
l Select patients may be treated with systemic therapy/RT as an alternative to surgical resection.
m Principles of Systemic Therapy (SCL-E).
n Principles of Radiation Therapy (SCL-F).
o For patients receiving adjuvant systemic therapy ± RT, response assessment is recommended 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 is recommended 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 C/A/P
CT with contrast is recommended after every 2 cycles of systemic therapy and at completion of therapy(SCL-6).
q Systemic therapy may be initiated first if time to initiation of stereotactic body radiotherapy (SABR) will be prolonged.
SCL-3A

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PRIMARY TREATMENT
Good
performance Systemic therapym +
status (PS) (0–2) concurrent RTn (category 1)
Response
Assessment
Following Primary
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 including supportive carer

not due to SCLC NCCN Guidelines for Palliative Care

p For patients receiving systemic therapy + concurrent RT, response assessment is recommended 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 C/A/P
CT with contrast is recommended after every 2 cycles of systemic therapy and at completion of therapy (SCL-6).
r Principles of Supportive Care (SCL-D).
SCL-4

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STAGE PRIMARY TREATMENTu

• Good PS (0–2) Combination systemic therapym including
• Poor PS (3–4) supportive carer
Extensive stage
due to SCLC NCCN Guidelines for Palliative Care
without localized
symptomatic sites
or brain metastases • Poor PS (3–4) Individualized therapy including
not due to supportive carer
SCLC 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
• Lobar obstruction
Extensive stage orthopedic stabilization and
Extensive stage + • Bone metastases
(see ST-1 for TNM palliative external beam RT (EBRT)n Response
localized
Classification)u symptomatic sites • Initiate steroidsv Assessment
• Systemic therapym + RTn (typically Following Primary
Spinal cord
sequential)w Treatment (SCL-6)t
compression
• NCCN Guidelines for Central
Nervous System Cancers
Administer systemic therapy before

Asymptomatic
initiating brain RTm,n,s
Extensive stage
with brain • Brain RTn before systemic therapy,w
metastases unless immediate systemic therapy
Symptomatic is indicated
m Principles of Systemic Therapy (SCL-E). • Initiate steroidsv
o For patients receiving adjuvant systemic therapy ± RT, response assessment is recommended only after completion of adjuvant therapy (SCL-6); do not repeat scans to assess response during adjuvant
treatment.
s Brain MRI (preferred) or CT with contrast is recommended to be repeated after every 2 cycles of systemic therapy until brain RT is initiated or systemic therapy is completed, whichever is first (SCL-6). If brain
metastases progress while on systemic therapy, it is recommended that brain RT is initiated before completion of systemic therapy. Principles of Radiation Therapy (SCL-F).
t During systemic therapy, response assessment by C/A/P CT with contrast should occur after every 2–3 cycles of systemic therapy and at completion of therapy (SCL-6).
u For transformation to SCLC from NSCLC, consider referral to a center with expertise (SCL-E 4 of 6).
v Initiate steroids for patients with symptomatic neurologic disease.
w With neurologic symptoms, RT is preferred before systemic therapy. Systemic therapy may start first if RT cannot be started expeditiously or if controlling systemic symptoms is more urgent.
SCL-5

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RESPONSE ASSESSMENT FOLLOWING ADJUVANT RT SURVEILLANCE

PRIMARY TREATMENT
Prophylactic • Provide survivorship
cranial irradiation After completion of initial care plan after
(PCI)n,y,z therapy: completion of initial
Limited • Oncology follow-up visits therapyx
or every 3 mo during y 1–2,
stage Consider • H&Pc; blood work only
Complete every 6 mo during y 3, as clinically indicated
MRI brain then annually
response surveillancee,y • Surveillance CTbb
or partial
After completion of initial or • Brain MRI (preferred)e or
response MRI brain subsequent therapy: CT with contrast every
surveillancee,y ± • Oncology follow-up visits 3–4 mo during y 1, then
Extensive every 6 mo afterwards,
stage • Consider PCIn,y every 2 mo during y 1,
• Consider every 3–4 mo during y 2–3, then as clinically Relapse,
• C/A/P CT with then every 6 mo during indicated (regardless of see
contrast thoracic RTn,aa
4–5, then annually PCI status) Subsequent
• Brain MRIe • New pulmonary nodule
(preferred) Therapy
After completion of initial therapy: should initiate workup (SCL-7)
or CT with Limited • Oncology follow-up visits every 3 mo for potential new
contrast stage during y 1–2, every 6 mo during y 3, primary
• CBC then annually • Smoking cessation
• Electrolytes, Stable intervention, see the
LFTs, BUN, disease After completion of initial or NCCN Guidelines for
creatinine subsequent therapy: Smoking Cessation
Extensive • Oncology follow-up visits every 2 • FDG-PET/CT is not
stage mo during y 1, every 3–4 mo during recommended for
y 2–3, then every 6 mo during y 4–5, routine follow-up unless
then annually contrast CT C/A/P is
contraindicated
Subsequent Therapy/
Primary progressive disease
Palliative Therapy (SCL-7)
c Signs and Symptoms of Small Cell Lung Cancer (SCL-A).
e Brain MRI is more sensitive than CT for identifying brain metastases and is
preferred over CT. z The benefit of PCI is unclear in patients who have undergone definitive therapy
n Principles of Radiation Therapy (SCL-F). for pathologic stage I (T1-2a,N0,M0) SCLC. See Principles of Radiation Therapy
x NCCN Guidelines for Survivorship. (SCL-F).
y PCI is not recommended in patients with poor PS or impaired neurocognitive aa Sequential RT to thorax in selected patients, especially with residual thoracic
function. Increased cognitive decline after PCI has been observed in older adults disease and low-bulk extrathoracic metastatic disease that has responded to
(≥60 years) in prospective trials; the risks and benefits of PCI versus close brain systemic therapy.
surveillance, MRI (preferrred) or CT with contrast, should be carefully discussed bb Most NCCN Member Institutions use CT chest ± abdomen/pelvis every 2–6
with these patients. months (more frequently in years 1–2 and less frequently thereafter).
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PROGRESSIVE DISEASE SUBSEQUENT THERAPY/PALLIATIVE THERAPY
• Consider subsequent
systemic therapym,cc
• Palliative symptom
Continue until PS 0–2 management,r,dd
progressionee including localized
Subsequent RTn to symptomatic
systemic Response or development
of unacceptable sites
therapym,cc
toxicity
or
PS 0–2
Palliative symptom
managementr,dd No
including localized response or Palliative symptom
Relapse RTn to symptomatic unacceptable management,r,dd
or primary PS 3–4
sites toxicity including localized RTn
progressive to symptomatic sites
diseaseff
PS 3–4 Palliative symptom management,r,dd including localized RTn to symptomatic sites

cc Response assessment by C/A/P CT with contrast is recommended after every 2–3 cycles of systemic therapy.
dd NCCN Guidelines for Palliative Care.
ee For central nervous system (CNS) progression only, continue systemic therapy and treat the brain metastases with RT (see Principles of Radiation Therapy).
ff Consider genomic profiling, if not previously done, to determine clinical trial eligibility.
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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 (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
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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)a:
◊ 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 syndromea:
◊ 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

Consider early subspecialty consultation for unusual paraneoplastic neurologic syndromes to ensure the most recent management is done
If paraneoplastic neurologic syndrome is suspected, consider obtaining a neurologic consultation and/or 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
Lambert-Eaton myasthenic syndrome (LEMS)a (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 syndrome – migratory thrombophlebitis
a Principles of Supportive Care (SCL-D).

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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. Strongly recommend a
second opinion—with a pathologist specializing in the diagnosis of thoracic malignancies—for diagnostic dilemma, including carcinoid.
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
• SCLC is often associated with necrosis. However, necrosis, usually punctate, is also seen in atypical carcinoid tumors. Counting mitotic figures helps to distinguish these two
entities.
• 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, except in combination with LCNEC. At least 10% of the tumor
should show LCNEC morphology to be classified as combined SCLC and LCNEC.1
• Comprehensive molecular profiling can be considered in rare cases—particularly for patients with extensive-stage/relapsed SCLC who do not smoke tobacco, lightly smoke
(<10 cigarettes/day), have remote smoking history, or have diagnostic or therapeutic dilemma, or at time of relapse—if not previously done, because this may change
management.
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 insulinoma-associated protein 1 (INSM1), CD56/NCAM, synaptophysin, and
chromogranin A. Fewer than 5% of SCLCs are negative for all neuroendocrine markers.11,12
Thyroid transcription factor-1 (TTF-1) is positive in 85% to 90% of SCLCs.13-16
Additional immunohistochemical markers are useful in distinguishing small cell carcinoma from poorly differentiated non-small cell carcinoma and combined carcinoma using
Napsin A as a marker of adenocarcinoma, and p40 or p63 as a marker of squamous differentiation.10 It should, however, be noted that p40 and p63 can be focally positive in small
cell carcinoma.
• 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
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REFERENCES
1 WHO Classification of Tumours Editorial Board. Thoracic Tumours. In: WHO classification or tumours series. 5th ed. Lyron, France. International Agency for Research
on Cancer; 2021.
2 Travis 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.
3 Travis 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.
4 Pelosi 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.
5 Pelosi 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.
6 Rindi G, Klersy C, Inzani F, et al. Grading the neuroendocrine tumors of the lung: an evidence-based proposal. Endocr Relat Cancer 2013;21:1-16.
7 Travis WD. Advances in neuroendocrine lung tumors. Ann Oncol 2010;21 Suppl 7:vii65-vii71.
8 Zakowski MF. Pathology of small cell carcinoma of the lung. Semin Oncol 2003;30:3-8.
9 Nicholson 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.
10 Masai 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;21:292-297.
11 Rooper LM, Sharma R, Li QK, et al. INSM1 demonstrates superior performance to the individual and combined use of synaptophysin, chromogranin and CD56 for
diagnosing neuroendocrine tumors of the thoracic cavity. Am J Surg Pathol 2017;41:1561-1569.
12 Bellizzi AM. Immunohistochemistry in the diagnosis and classification of neuroendocrine neoplasms: what can brown do for you? Hum Pathol 2020;96:8-33.
13 Ordonez 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.
14 Kaufmann 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.
15 Lantuejoul 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.
16 Wick 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 FDG-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 or
systematic lymph node sampling (eg, ≥3 N2 and ≥1 N1 stations).3,4,5,6,7
• In patients who do not smoke, small lesions that are presumed to be small cell carcinoma on biopsy should be resected because they are
likely carcinoids that have been misdiagnosed (NCCN Guidelines for Neuroendocrine and Adrenal Tumors).
• Surgery may be considered for selected patients with T3 (based on size), N0 SCLC, if invasive mediastinal lymph node staging is negative.
• Intraoperative diagnosis of likely SCLC in a patient with no prior biopsy
Mediastinal lymph node dissection or systematic lymph node sampling with frozen section is recommended to assess extent of disease
and overall burden of disease.
If primary site and lymph nodes appear resectable, perform anatomic resection, preferably lobectomy. Should not do pneumonectomy if
needed to encompass nodal metastatic disease.
• Patients who undergo complete resection should be treated with postoperative systemic therapy.8 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 unclear in patients who have undergone definitive therapy for pathologic stage I (T1-2a,N0,M0); see SCL-F.
1 Lad 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-323S.
2 Yang 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.
3 Katz MHG, Francescatti AB, Hunt KK; Cancer Surgery Standards Program of the American College of Surgeons. Technical Standards for Cancer Surgery: Commission on Cancer
Standards 5.3-5.8. Ann Surg Oncol 2022;29:6549-6558.
4 Darling GE, Allen MS, Decker PA, et al. Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1
(less than hilar) non-small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 Trial. J Thorac Cardiovasc Surg 2011;141:662-670.
5 Darling GE, Allen MS, Decker PA, et al. Number of lymph nodes harvested from a mediastinal lymphadenectomy: results of the randomized, prospective American College of Surgeons
Oncology Group Z0030 trial. Chest 2011;139:1124-1129.
6 Osarogiagbon RU, Decker PA, Ballman K, et al. Survival Implications of Variation in the Thoroughness of Pathologic Lymph Node Examination in American College of Surgeons
Oncology Group Z0030 (Alliance). Ann Thorac Surg 2016;102:363-369.
7 Su S, Scott WJ, Allen MS, et al. Patterns of survival and recurrence after surgical treatment of early stage non-small cell lung carcinoma in the ACOSOG Z0030 (ALLIANCE) trial. J
Thorac Cardiovasc Surg 2014;147:747-752: Discussion 752-753.
8 Yang CE, Chan DY, Speicher PJ, et al. Role of adjuvant therapy in a population-based cohort of patients with early-stage small-cell lung cancer. J Clin Oncol 2016;34:1057-1064.
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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-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony–stimulating factor (G-CSF) are not recommended during
concurrent systemic therapy plus RT (category 1 for not using GM-CSF).1,2
• Trilaciclib or G-CSF may be used as prophylactic options to decrease the incidence of chemotherapy-induced myelosuppression when
administering platinum/etoposide ± immune checkpoint inhibitor (ICI)-containing regimens or a topotecan-containing regimen for extensive-
stage SCLC (ES-SCLC).
• SIADH
Fluid restriction
Saline infusion for symptomatic patients
Demeclocycline
Vasopressin receptor inhibitors (ie, conivaptan, tolvaptan) for refractory hyponatremia
• Cushing syndrome
Consider ketoconazole. If not effective, consider metyrapone.
Consider referral to an appropriate endocrinology subspecialist.
• 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
• Consider early subspecialty consultation for unusual paraneoplastic neurologic syndromes to ensure the most recent management is done
1 Bunn PA, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell
lung cancer: a prospective phase III randomized study of the Southwest Oncology Group. J Clin Oncol 1995;13:1632-1641.
2 Wang C, Zhu S, Miao C, et al. Safety and efficacy of pegylated recombinant human granulocyte colony-stimulating factor during concurrent chemoradiotherapy for
small-cell lung cancer: a retrospective, cohort-controlled trial. BMC Cancer 2022;22:542.
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PRINCIPLES OF SYSTEMIC THERAPY

PRIMARY OR ADJUVANT THERAPY FOR LIMITED-STAGE SCLC:
Four cycles of systemic therapy are recommended.
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).1
Preferred Regimens
• Cisplatin 75 mg/m2 day 1 and etoposide 100 mg/m2 days 1, 2, 32
Other Recommended Regimens
• Cisplatin 25 mg/m2 days 1, 2, 3 and etoposide 100 mg/m2 days 1, 2, 32
• Carboplatin area under the curve (AUC) 5–6 day 1 and etoposide 100 mg/m2 days 1, 2, 3a,4
PRIMARY THERAPY FOR EXTENSIVE-STAGE SCLC e :

Four cycles of therapy are recommended, but some patients may receive up to 6 cycles based on response and tolerability after 4 cycles.
Preferred Regimens
• Carboplatin AUC 5 day 1 and etoposide 100 mg/m2 days 1, 2, 3 and atezolizumab 1200 mg day 1 every 21 days x 4 cycles followed by
maintenance atezolizumab 1200 mg day 1, every 21 days (category 1 for all)b,d,5
• Carboplatin AUC 5 day 1 and etoposide 100 mg/m² days 1, 2, 3 and atezolizumab 1200 mg day 1 every 21 days x 4 cycles followed by
maintenance atezolizumab 1680 mg day 1, every 28 daysb,d
• Carboplatin AUC 5–6 day 1 and etoposide 80–100 mg/m2 days 1, 2, 3 and durvalumab 1500 mg day 1 every 21 days x 4 cycles followed by
maintenance durvalumab 1500 mg day 1 every 28 days (category 1 for all)b,c,d,6
• Cisplatin 75–80 mg/m2 day 1 and etoposide 80–100 mg/m2 days 1, 2, 3 and durvalumab 1500 mg day 1 every 21 days x 4 cycles followed by
maintenance durvalumab 1500 mg day 1 every 28 days (category 1 for all)b,c,d,6
• Carboplatin AUC 5–6 day 1 and etoposide 100 mg/m2 days 1, 2, 37
• Cisplatin 25 mg/m2 days 1, 2, 3 and etoposide 100 mg/m2 days 1, 2, 310
Useful in Certain Circumstances
• Carboplatin AUC 5 day 1 and irinotecan 50 mg/m2 days 1, 8, 1511
• Cisplatin 60 mg/m2 day 1 and irinotecan 60 mg/m2 days 1, 8, 1512
• Cisplatin 30 mg/m2 days 1, 8 and irinotecan 65 mg/m2 days 1, 813
Footnotes (SCL-E 2 of 6)
Subsequent Systemic Therapy (SCL-E 3 of 6)
Response Assessment (SCL-E 4 of 6)
References (SCL-E 5 of 6)

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FOOTNOTES
a Cisplatin contraindicated or not tolerated.
b Contraindications for treatment with programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors may include active or previously
documented autoimmune disease and/or concurrent use of immunosuppressive agents. For safety reasons, do not use ICIs in patients who have recently received
tyrosine kinase inhibitors (TKIs).
c Included patients with asymptomatic untreated brain metastases.
d Maintenance immunotherapy with either atezolizumab or durvalumab should continue until progression or intolerable toxicity.
e For transformation to SCLC from NSCLC, consider referral to a center with expertise (SCL-E 4 of 6).

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SCLC SUBSEQUENT SYSTEMIC THERAPY (PS 0–2)f,

Consider dose reduction or growth factor support for patients with PS 2.
CHEMOTHERAPY-FREE INTERVAL (CTFI) >6 MONTHS
Preferred Regimens
• Clinical trial enrollment
• Re-treatment with platinum-based doubletg,34,35,37-39

• Lurbinectedin17,36
• Topotecan oral (PO) or intravenous (IV)14-16,28
• Irinotecanh,21,28
• Tarlatamab-dllei,47
CTFI ≤6 MONTHS
Preferred Regimens
• Clinical trial enrollment
• Lurbinectedin17,36
• Topotecan oral (PO) or intravenous (IV)14-16,28,37
• Irinotecanh,21,28
• Tarlatamab-dllei,47
• Re-treatment with platinum-based doublet may be considered for CTFI 3–6 monthsg,37,38,39

• Nivolumab or pembrolizumab (if not previously treated with an ICI)b, 29,30,31,32,33
• Paclitaxel18,19
• Temozolomide22,23
• Cyclophosphamide/doxorubicin/vincristine (CAV)14
• Docetaxel20
• Gemcitabine26,27,40
• Oral etoposide24,25
g Rechallenging with the original regimen or similar platinum-based regimen, as shown on

b Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or SCL-E 1, is recommended if there has been a CTFI of more than 6 months and may be
previously documented autoimmune disease and/or concurrent use of immunosuppressive considered if there has been a CTFI of at least 3 to 6 months.
agents. For safety reasons, do not use ICIs in patients who have recently received TKIs. h For patients with CNS disease, consider using irinotecan.
f Subsequent systemic therapy refers to second-line and beyond therapy.. i For extensive-stage with disease progression on or after platinum-based chemotherapy.
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PRINCIPLES OF SYSTEMIC THERAPY

Response Assessment
• Limited stage
For patients receiving adjuvant therapy, response assessment is recommended only after completion of adjuvant therapy; do not repeat
scans to assess response during adjuvant treatment.
Response assessment after adjuvant therapy involves C/A/P CT with contrast and brain MRI (preferred) with contrast or brain CT with
contrast (SCL-6).
For patients receiving systemic therapy + concurrent RT, response assessment is recommended 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 C/A/P CT with
contrast is recommended after every 2–3 cycles of systemic therapy and at completion of therapy.
• Extensive stage
During systemic therapy, response assessment by C/A/P CT with contrast is recommended after every 2–3 cycles of systemic therapy and
at completion of therapy.
For patients with asymptomatic brain metastases receiving systemic therapy before brain RT, it is recommended that brain MRI (preferred)
or CT with contrast is repeated after every 2 cycles of systemic therapy and at completion of therapy.
• Subsequent systemic therapy

Response assessment by C/A/P CT with contrast is recommended after every 2–3 cycles of systemic therapy.
• Transformed SCLC from NSCLC with an Oncogenic Driver

This is a rare population of patients with very limited data to guide treatment.43,44,45,46
Systemic cytotoxic chemotherapy is recommended using the NCCN Guidelines for Small Cell Lung Cancer.43,44
The role of immunotherapy in this setting is unclear based on limited data.43,44,45,46
If TKI is continued, ICI should be avoided, due to known toxicity.41,42,45
Consider referral to a center with experience managing transformed SCLC.

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PRINCIPLES OF SYSTEMIC THERAPY – References

1 Bunn PA, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a
prospective phase III randomized study of the Southwest Oncology Group. J Clin Oncol 1995;13:1632-1641.
2 Faivre-Finn C, Snee M, Ashcroft L, et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label,
phase 3, randomised, superiority trial. Lancet Oncol 2017;18:1116-1125.
3 Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl
J Med 1999;340:265-271.
4 Skarlos DV, Samantas E, Briassoulis E, et al. Randomized comparison of early versus late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-
cell lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology Group (HeCOG). Ann Oncol 2001;12:1231-1238.
5 Horn L, Mansfield A, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med 2018;379:2220-2229.
6 Goldman JW, Dvorkin M, Chen Y, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage
small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2021;22:51-65.
7 Okamoto H, Watanabe K, Nishiwaki Y, et al. Phase II study of area under the plasma-concentration-versus-time curve-based carboplatin plus standard-dose intravenous etoposide in
elderly patients with small cell lung cancer. J Clin Oncol 1999;17:3540-3545.
8 Spigel DR, Townley PM, Waterhouse DM, et al. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung
cancer: results from the SALUTE trial. J Clin Oncol 2011;29:2215-2222.
9 Niell HB, Herndon JE 2nd, Miller AA, et al. Randomized phase III Intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte-colony stimulating factor in patients
with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B trial 9732. J Clin Oncol 2005;23:3752-3759.
10 Evans WK, Shepherd FA, Feld R, et al. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol 1985;3:1471-1477.
11 Schmittel A, Fischer von Weikersthal L, Sebastian M, et al. A randomized phase II trial of irinotecan plus carboplatin versus etoposide plus carboplatin treatment in patients with
extended disease small-cell lung cancer. Ann Oncol 2006;17:663-667.
12 Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 2002;346:85-91.
13 Hanna N, Bunn Jr. PA, Langer C, et al. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease
small-cell lung cancer. J Clin Oncol 2006;24:2038-2043.
14 von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol
1999;17:658-667.
15 O’Brien ME, Ciuleanu TE, Tsekov H, et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin
Oncol 2006;24:5441-5447.
16 Eckardt JR, von Pawel J, Pujol JL, et al. Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol 2007;25:2086-2092.
17 Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol
2020;21:645-654.
18 Smit EF, Fokkema E, Biesma B, et al. A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer. Br J Cancer 1998;77:347-351.
19 Yamamoto N, Tsurutani J, Yoshimura N, et al. Phase II study of weekly paclitaxel for relapsed and refractory small cell lung cancer. Anticancer Res 2006;26:777-781.
20 Smyth JF, Smith IE, Sessa C, et al. Activity of docetaxel (Taxotere) in small cell lung cancer. The Early Clinical Trials Group of the EORTC. Eur J Cancer 1994; 30A:1058-1060.
21 Masuda N, Fukuoka M, Kusunoki Y, et al. CPT-11: a new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 1992;10:1225-1229.
22 Pietanza MC, Kadota K, Huberman K, et al. Phase II trial of temozolomide with relapsed sensitive or refractory small cell lung cancer, with assessment of methylguanine-DNA
methyltransferase as a potential biomarker. Clin Cancer Res 2012;18:1138-1145.
23 Zauderer MG, Drilon A, Kadota K, et al. Trial of a 5-day dosing regimen of temozolomide in patients with relapsed small cell lung cancers with assessment of methylguanine-DNA
methyltransferase. Lung Cancer 2014;86:237-240.
24 Einhorn LH, Pennington K, McClean J. Phase II trial of daily oral VP-16 in refractory small cell lung cancer: a Hoosier Oncology Group study. Semin Oncol 1990;17:32-35.

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PRINCIPLES OF SYSTEMIC THERAPY – References

25 Johnson DH, Greco FA, Strupp J, et al. Prolonged administration of oral etoposide in patients with relapsed or refractory small-cell lung cancer: a phase II trial. J Clin Oncol
1990;8:1613-1617.
26 Van der Lee I, Smit EF, van Putten JW, et al. Single-agent gemcitabine in patients with resistant small-cell lung cancer. Ann Oncol 2001;12:557-561.
27 Masters GA, Declerck L, Blanke C, et al. Phase II trial of gemcitabine in refractory or relapsed small-cell lung cancer: Eastern Cooperative Oncology Group Trial 1597. J Clin Oncol
2003;21:1550-1555.
28 Edelman MJ, Dvorkin M, Laktionov K, et al. Randomized phase 3 study of the anti-disialoganglioside antibody dinutuximab and irinotecan vs irinotecan or topotecan for second-line
treatment of small cell lung cancer. Lung Cancer. 2022;166:135-142.
29 Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (Checkmate 032): a multicentre, open-label phase 1/2
trial. Lancet Oncol 2016;17:883-895.
30 Ready NE, Ott PA, Hellmann MD, et al. Nivolumab monotherapy and nivolumab plus ipilimumab in recurrent small cell lung cancer: results from the CheckMate 032 randomized cohort.
J Thorac Oncol 2020;15:426-435.
31 Chung HC, Lopez-Martin JA, Kao S, et al. Phase 2 study of pembrolizumab in advanced small-cell lung cancer (SCLC): KEYNOTE-158 [abstract]. J Clin Oncol 2018;36(Suppl):
Abstract 8506.
32 Chung HC, Piha-Paul SA, Lopez-Martin J, et al. Pembrolizumab After Two or More Lines of Previous Therapy in Patients With Recurrent or Metastatic SCLC: Results From the
KEYNOTE-028 and KEYNOTE-158 Studies J Thorac Oncol 2020;15:618-627.
33 Ott PA, Elez E, Hiret S, et al. Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ib KEYNOTE-028 study. J Clin Oncol 2017;35:3823-3829.
34 Postmus PE, Berendsen HH, van Zandwijk N, et al. Retreatment with the induction regimen in small cell lung cancer relapsing after an initial response to short term chemotherapy. Eur
J Cancer Clin Oncol 1987;23:1409-1411.
35 Giaccone G, Ferrati P, Donadio M, et al. Reinduction chemotherapy in small cell lung cancer. Eur J Cancer Clin Oncol 1987;23:1697-1699.
36 Subbiah V, Paz-Ares L, Besse B, et al. Antitumor activity of lurbinectedin in second-line small cell lung cancer patients who are candidates for re-challenge with the first-line treatment.
Lung Cancer 2020;150:90-96.
37 Baize N, Monnet I, Greillier L, et al. Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label,
multicentre, randomised, phase 3 trial. Lancet Oncol 2020;21:1224-1233.
38 Naito Y, Yamada K, Imamura Y, et al. Rechallenge treatment with a platinum‑based regimen in patients with sensitive relapsed small‑cell lung cancer. Med Oncol 2018;35:61.
39 Genestreti G, Tiseo M, Kenmotsu H, et al. Outcomes of platinum‑sensitive small‑cell lung cancer patients treated with platinum/etoposide rechallenge: a multi‑institutional retrospective
analysis. Clin Lung Cancer 2015;16:e223‑e228.
40 Hoang T, Kim K, Jaslowski A, et al. Phase II study of second-line gemcitabine in sensitive or refractory small cell lung cancer. Lung Cancer 2003;42:97-102.
41 Schoenfeld AJ, Arbour KC, Rizvi H, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol 2019;30:839-844.
42 Oshima Y, Tanimoto T, Yuji K, Tojo A EGFR-TKI-associated interstitial pneumonitis in nivolumab-treated patients with non-small cell lung cancer JAMA Oncol 2018;4:1112-1115.
43 Marcoux N, Gettinger SN, O'Kane G, et al. EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: Clinical outcomes. J Clin
Oncol 2019;37:278-285.
44 Ferrer L, Giaj Levra M, Brevet M, et al. A brief report of transformation from NSCLC to SCLC: Molecular and therapeutic characteristics. J Thorac Oncol 2019;14:130-134.
45 Chai X, Zhang X, Li W, Chai J. Small cell lung cancer transformation during antitumor therapies: A systematic review. Open Med (Wars) 2021;16:1160-1167.
46 Zhang CY, Sun H, Su JW, et al. A potential treatment option for transformed small-cell lung cancer on PD-L1 inhibitor-based combination therapy improved survival. Lung Cancer
2023;175:68-78.
47 Ahn MJ, Cho BC, Felip E, et al. Tarlatamab for patients with previously treated small-cell lung cancer. N Engl J Med 2023;389:2063-2075.

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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 (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 (CRT) planning, and ensuring accurate delivery of the planned treatment. A minimum standard is CT‑planned
3D-CRT 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 FDG-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 (NSCL‑C).
• Useful references include the ASTRO Guidelines and the American Radium Society.2,53,54
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 radiotherapy (SABR), also known as stereotactic body RT (SBRT), 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).3-5
• Timing: RT concurrent with systemic therapy is standard and preferred to sequential chemo/RT.6 RT should start early, with cycle 1 or 2 of
systemic therapy (category 1).7 A shorter time from the start of any therapy to the end of RT (SER) is significantly associated with improved
survival.8
• Target definition: RT target volumes should be defined based on the pretreatment FDG-PET scan and CT scan obtained at the time of RT
planning, as well as any positive biopsies. FDG-PET/CT is recommended, preferably within 4 weeks and no more than 8 weeks, before
treatment. Ideally, FDG-PET/CT should be obtained in the treatment position.
Limited Stage (continued), Extensive Stage (SCL-F 2 of 6)

Normal Tissue Dose Constraints, Prophylactic Cranial Irradiation (SCL-F 3 of 6)
Brain Metastasis (SCL-F 4 of 6) Continued
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Limited Stage (continued):
• Historically, clinically uninvolved mediastinal nodes have been included in the RT target volume, whereas uninvolved supraclavicular nodes
generally have not been included. Several more modern series, both retrospective and prospective, suggest that omission of elective nodal
irradiation (ENI) results in low rates of isolated nodal recurrences (0%–11%, most <5%), particularly when incorporating FDG-PET staging/
target definition (1.7%–3%).10-15 ENI has been omitted in recent 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.
• 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.12,16
• 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).17,18 When BID fractionation is used, there should be at least a 6‑hour interfraction interval to allow for repair of normal
tissue.
Retrospective and randomized phase II studies suggest that similarly accelerated doses of 40–42 Gy in 3 weeks but given in once-daily
fractionation produce similar outcomes as 45 Gy in 3 weeks in BID fractionation.19,20
If using once-daily conventionally fractionated RT, higher doses of 66–70 Gy are preferred. 21-24 Two randomized phase III trials did not
demonstrate superiority of 66 Gy in 6.5 weeks/2 Gy daily (the European CONVERT trial) or 70 Gy in 7 weeks/2 Gy daily (CALGB 30610/RTOG
0538) over 45 Gy in 3 weeks/1.5 Gy BID, but overall survival and toxicity were similar.25,26,27
Recent randomized phase II trials suggest that higher dose accelerated RT of 60–65 Gy in 4–5 weeks given in BID or daily fractionation may
produce increased overall or progression-free survival compared to 45 Gy in 3 weeks in BID fractionation.28,29
Extensive Stage:
• Consolidative thoracic RT is beneficial for selected patients with ES-SCLC with complete response or good response to systemic therapy
before immunotherapy, 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.30,31 The Dutch CREST randomized trial of modest-dose thoracic RT (30 Gy in 10 fractions) in patients
with ES-SCLC that responded to chemotherapy (without immunotherapy) 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.32 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.33
• Dosing and fractionation of consolidative thoracic RT should be individualized within the range of 30 Gy in 10 daily fractions up to definitive
dosing regimens in patients with a longer life expectancy.
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Extensive Stage (continued):
• Based on two randomized trials, immunotherapy during and after chemotherapy is a first-line approach,34,35 but these studies did not include consolidative
thoracic RT. Nevertheless, consolidative thoracic RT after chemoimmunotherapy can be considered for selected patients as above, during or before
maintenance immunotherapy (there are limited data on optimal sequencing or safety). The benefit of thoracic RT in the context of chemo-immunotherapy
is under evaluation in the RAPTOR/NRG LU007 trial.
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 (LS-SCLC) who have a good response to initial therapy, PCI decreases brain metastases and increased overall
survival36,37 in meta-analyses of past clinical trials. Of note, none of the past studies that have been used as the basis for PCI recommendations in LS-
SCLC employed MRI staging of the brain nor did any utilize FDG-PET scans for overall staging.
• The benefit of PCI is unclear in patients who have undergone definitive therapy for very early LS-SCLC, ie, pathologic stage I–IIA (T1–2,N0,M0).9 These
patients have a lower risk of developing brain metastases than patients with more advanced, LS-SCLC and may not benefit from PCI.9 Brain MRI
surveillance is recommended in patients not receiving PCI.9 However, PCI may have a benefit in patients who are found to have pathologic stage IIB
or III SCLC after complete resection.9,37 This issue is being evaluated in the ongoing NCI cooperative group trial SWOG S1827/MAVERICK (brain MRI
surveillance ± PCI), which includes the population undergoing surgical resection (https://clinicaltrials.gov/ct2/show/NCT04155034).
• In patients with ES-SCLC that has responded to systemic therapy, PCI decreases brain metastases. A randomized trial conducted by the European
Organisation for Research and Treatment of Cancer (EORTC) found improved overall survival with PCI.38 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.39 Surveillance imaging for brain metastases is recommended for all patients regardless of PCI status.
• 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.40,41
• Neurocognitive function: Increasing age and higher doses are the most predictive factors for development of chronic neurotoxicity. In trial RTOG 0212, 83%
of patients >60 years experienced chronic neurotoxicity 12 months after PCI versus 56% of patients <60 years (P = .009).41 PCI is not recommended in
patients with poor PS or impaired neurocognitive function.40 The role of PCI in MRI and FDG-PET staged SCLC in fit patients with normal neurocognitive
function is the subject of ongoing debate, particularly in limited stage, and is being evaluated in the phase III SWOG S1827/MAVERICK trial comparing PCI
(active comparator) to MRI surveillance (experimental) in both limited and extensive stage (https://clinicaltrials.gov/ct2/show/NCT04155034).

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Prophylactic Cranial Irradiation (continued):
• Administer PCI after resolution of acute toxicities of initial therapy. PCI is not recommended in patients with poor PS or impaired
neurocognitive functioning.
• When administering PCI, consider adding memantine during and after RT, which has been shown to decrease neurocognitive impairment
following whole brain radiation therapy (WBRT) for brain metastases.42 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 (see NCCN Guidelines for Central Nervous System Cancers).
• Hippocampal-avoidance (HA) PCI using IMRT may be considered as a potential strategy to improve cognitive preservation. A phase
III randomized trial of HA-WBRT versus conventional WBRT demonstrated improved cognitive preservation and patient-reported
outcomes with HA-WBRT in patients with brain metastases from mixed histologies.43 Conflicting data have been reported with HA-PCI
versus conventional PCI in SCLC with one trial reporting no differences in cognition44 and a separate trial reporting improved cognitive
preservation with HA-PCI.45 A larger randomized trial of HA-PCI versus conventional PCI, NRG CC003, has completed accrual with results
pending.46
• An ongoing randomized trial, SWOG S1827/MAVERICK, is evaluating whether brain MRI surveillance alone is non-inferior to MRI surveillance
plus PCI with regard to overall survival for LS-SCLC and ES-SCLC.47
Brain Metastases:
• Brain metastases have conventionally been treated with WBRT; however, selected patients with a small number of metastases may be
appropriately treated with stereotactic radiotherapy (SRT)/radiosurgery (SRS).48 A current randomized trial, NRG CC009, is comparing SRS
to hippocampal-sparing WBRT plus memantine in this setting.
• 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).42
• In patients who develop brain metastases after PCI, repeat WBRT may be considered in carefully selected patients.49,50 SRS is preferred, if
feasible.51,52
• For patients with a better prognosis (eg, ≥4 months), hippocampal-sparing WBRT using IMRT plus memantine is preferred because it
produces less cognitive function failure than conventional WBRT plus memantine.43 However, patients with metastases within 5 mm of the
hippocampi, leptomeningeal metastases, and other high-risk features were not eligible for hippocampal-sparing WBRT on NRG CC001.43
Although CC001 did not include patients with brain metastases from SCLC, it is reasonable to extrapolate the findings to SCLC.
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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PRINCIPLES OF RADIATION THERAPY – References

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31 Yee D, Butts C, Reiman A, et al. Clinical trial of post-chemotherapy consolidation thoracic 45 Rodriguez De Dios N, Murica M, Counago F, et al. Phase III trial of prophylactic cranial
radiotherapy for extensive-stage small cell lung cancer. Radiother Oncol 2012;102:234-238. irradiation with or without hippocampal avoidance for small-cell lung cancer. Int J Radiat Oncol
32 Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage Biol Phys 2019;105:S35-S36.
small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 2015;385:36-42. 46 Gondi V, Pugh SL, Mehta MP, et al. NRG Oncology CC003: A randomized phase II/III trial of
33 Slotman BJ, van Tinteren H, Praag JO, et al. Radiotherapy for extensive stage small-cell lung prophylactic cranial irradiation with or without hippocampal avoidance for small cell lung cancer. J
cancer-Authors’ reply. Lancet 2015;385:1292-1293. Clin Oncol 2019;37:TPS 8578-TPS 8578.
34 Horn L, Mansfield A, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive- 47 SWOG S1827 (MAVERICK) Testing whether the use of brain scans alone instead of brain
stage small-cell lung cancer. N Engl J Med 2018;379:2220-2229. scans plus preventive brain radiation affects lifespan in patients with small cell lung cancer.
35 Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum- https://clinicaltrials.gov/ct2/show/NCT04155034
etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a 48 Rusthoven CG, Yamamoto M, Bernhardt D, et al. Evaluation of first-line radiosurgery vs whole-
randomised, controlled, open-label, phase 3 trial. Lancet 2019;394:1929-1939. brain radiotherapy for small cell lung cancer brain metastases: the FIRE-SCLC cohort study.
36 Arriagada R, Le Chevalier T, Rivière A, et al. Patterns of failure after prophylactic cranial JAMA Oncol 2020;6:1028-1037.
irradiation in small-cell lung cancer: analysis of 505 randomized patients. Ann Oncol 49 Sadikov E, Bezjak A, Yi QL, et al. Value of whole brain re-irradiation for brain metastases--single
2002;13:748-754. centre experience. Clin Oncol (R Coll Radiol) 2007;19:532-538.
37 Aupérin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small- 50 Son CH, Jimenez R, Niemierko A, et al. Outcomes after whole brain reirradiation in patients with
cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative brain metastases. Int J Radiat Oncol Biol Phys 2012;82:e167-172.
Group. N Engl J Med 1999;341:476-484. 51 Harris S, Chan MD, Lovato JF, et al. Gamma knife stereotactic radiosurgery as salvage therapy
38 Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell after failure of whole-brain radiotherapy in patients with small-cell lung cancer. Int J Radiat Oncol
lung cancer. N Engl J Med 2007;357:664-672. Biol Phys 2012;83:e53-e59.
39 Takahashi T, Yamanaka T, Seto T, et al. Prophylactic cranial irradiation versus observation in 52 Wegner RE, Olson AC, Kondziolka D, et al. Stereotactic radiosurgery for patients with brain
patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, metastases from small cell lung cancer. Int J Radiat Oncol Biol Phys 2011;81:e21-e27.
phase 3 trial. Lancet Oncol 2017;18:663-671. 53 Chun SG, Simone CB 2nd, Amini A, et al. American Radium Society Appropriate Use
40 Le Péchoux C, Dunant A, Senan S, et al. Standard-dose versus higher-dose prophylactic Criteria: Radiation Therapy for Limited‑Stage SCLC 2020. J Thorac Oncol 2021;16:66‑75.
cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission 54 Higgins KA, Simone CB 2nd, Amini A, et al. American Radium Society Appropriate Use
after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, Criteria on Radiation Therapy for Extensive‑Stage SCLC. J Thorac Oncol 2021;16:54‑65.
and IFCT 99-01): a randomised clinical trial. Lancet Oncol 2009;10:467-474.

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Table of Contents
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/c), 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 of Contents
Table 2. Definitions for T, N, M (continued) Table 3. AJCC Prognostic Groups Prognostic Stage Groups
N Regional Lymph Nodes T N M T N M
NX Regional lymph nodes cannot be assessed Occult TX N0 M0 Stage IIIB T1a N3 M0
N0 No regional lymph node metastasis carcinoma T1b N3 M0
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral Stage 0 Tis N0 M0 T1c N3 M0
hilar lymph nodes and intrapulmonary nodes, including Stage IA1 T1mi N0 M0
involvement by direct extension T2a N3 M0
T1a N0 M0 T2b N3 M0
N2 Metastasis in ipsilateral mediastinal and/or subcarinal
lymph node(s) Stage IA2 T1b N0 M0 T3 N2 M0
N3 Metastasis in contralateral mediastinal, contralateral hilar, Stage IA3 T1c N0 M0 T4 N2 M0
ipsilateral or contralateral scalene, or supraclavicular lymph Stage IB T2a N0 M0 Stage IIIC T3 N3 M0
node(s)
Stage IIA T2b N0 M0 T4 N3 M0
Stage IIB T1a N1 M0 Stage IV Any T Any N M1
M Distant Metastasis
T1b N1 M0 Stage IVA Any T Any N M1a
MX Distant metastasis cannot be assessed
T1c N1 M0 Any T Any N M1b
M0 No distant metastasis
T2a N1 M0 Stage IVB Any T Any N M1c
M1 Distant metastasis
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
a Most 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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Table of Contents
ABBREVIATIONS
ACTH adrenocorticotropic hormone IGRT image-guided radiation therapy TNM tumor node metastasis
AIS adenocarcinoma in situ IMRT intensity-modulated radiation TTF-1 thyroid transcription factor-1
therapy
ANNA-1 antineuronal nuclear antibody- VMAT volumetric modulated arc therapy
type 1 (also known as anti-Hu INSM1 insulinoma-associated protein 1
antibody) WBRT whole brain radiation therapy
LCNEC large-cell neuroendocrine
AUC area under the curve carcinoma
BUN blood urea nitrogen LEMS Lambert-Eaton myasthenic
C/A/P chest/abdomen/pelvis syndrome
CBC complete blood count LFT liver function test
CNS central nervous system LS-SCLC limited-stage small cell lung
CONVERT concurrent once-daily versus cancer
twice-daily radiotherapy NSCLC non-small cell lung cancer
CREST carotid revascularization PCI prophylactic cranial irradiation
endarterectomy versus Stenting
Trial PD-1 programmed cell death protein 1
CRT conformal radiation therapy PD-L1 programmed death ligand 1
CTFI chemotherapy-free interval PFT pulmonary function test
EBRT external beam radiation therapy PS performance status
ENI elective nodal irradiation RBC red blood cell
ES-SCLC extensive-stage small cell lung SABR stereotactic ablative radiotherapy
cancer
SBRT stereotactic body radiation
4D-CT four-dimensional computed therapy
tomography
SCIS squamous cell carcinoma in situ
FDG fluorodeoxyglucose
G-CSF granulocyte colony-stimulating SCLC small cell lung cancer
factor SER start of any therapy to the end of
GM-CSF granulocyte-macrophage colony- RT
stimulating factor SIADH syndrome of inappropriate
GTV gross tumor volume antidiuretic hormone secretion
H&E hematoxylin and eosin SRS stereotactic radiosurgery
H&P history and physical SRT stereotactic radiation therapy
HA hippocampal avoidance SVC superior vena cava
ICIs immune checkpoint inhibitors
3D three dimensional
TKIs tyrosine kinase inhibitors
ABBR-1

Table of Contents
NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is
uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the
intervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus (≥50%, but <85% support of the Panel) 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 3.2024

This discussion corresponds to the NCCN Guidelines for Subsequent Systemic Therapy .................................................................................14
Discussion Small Cell Lung Cancer. Last updated: November 21,
2023 Platinum-Based Therapy ......................................................................................14
Table of Contents Lurbinectedin ........................................................................................................15
Overview ............................................................................................... 2
Topotecan ............................................................................................................15
Guidelines Update Methodology ........................................................... .3
Irinotecan .............................................................................................................16
Literature Search Criteria....................................................................... 3
Nivolumab and Pembrolizumab ............................................................................16
Sensitive/Inclusive Language Usage ..................................................... 3 Other Subsequent Therapy Options ......................................................................17
Diagnosis .............................................................................................. 3 Radiation Therapy ....................................................................................................18
Screening ................................................................................................................... 3 Thoracic Radiation Therapy ..................................................................................18
Manifestations ............................................................................................................ 3 Radiation for Limited-Stage SCLC ............................................................................20
Pathology ................................................................................................................... 4 Radiation for Extensive-Stage SCLC.........................................................................21
Evaluation ............................................................................................. 5 Summary ............................................................................................. 24

Staging Systems ........................................................................................................ 5 References .......................................................................................... 25
Initial Evaluation ......................................................................................................... 6
Prognostic Factors ................................................................................ 7
Treatment.............................................................................................. 7
Surgical Resection of Stage I to IIA SCLC .................................................................. 7
Systemic Therapy....................................................................................................... 8
Cisplatin Versus Carboplatin .................................................................................. 8
Limited-Stage SCLC............................................................................................... 9
Extensive-Stage SCLC ........................................................................................... 9
Older Patients .......................................................................................................... 13
Surveillance for Relapse ........................................................................................... 13
Version 3.2024 © 2024 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.
MS-1

Overview Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Small

Neuroendocrine tumors account for approximately 20% of lung cancers; of Cell Lung Cancer that includes the algorithm and this supporting
which nearly 14% are small cell lung cancer (SCLC).1-3 In 2023, an Discussion text. Management of other lung neuroendocrine tumors (LNTs)
estimated 33,000 new cases of SCLC were diagnosed in the United and Non-Small Cell Lung Cancer (NSCLC) are described in the NCCN
States.1,2,4 During the COVID-19 pandemic, the diagnosis and treatment of Guidelines for Neuroendocrine and Adrenal Tumors and Non-Small Cell
lung cancer were hampered; however, this has not been reflected in the Lung Cancer, respectively, available at www.NCCN.org.
2023 estimates for incidence and mortality because of the typical delays in
The definitions for limited-stage and extensive-stage SCLC incorporate
collecting, calculating, and reporting of data.1 Although the incidence of
TNM staging (see the algorithm and Staging in this Discussion). The panel
SCLC has been decreasing, the frequency in females is increasing and
recommends that the workup for SCLC should be expedited and if
the male-to-female incidence ratio is now 1:1.1-3
possible, studies should be performed in parallel. In patients with
Nearly all cases of SCLC are attributable to cigarette smoking.5 Patients limited-stage SCLC, the goal of treatment is cure using chemotherapy plus
with SCLC who also continue to smoke tobacco during treatment have thoracic radiation therapy (RT). However, some patients with resectable
increased toxicity and shorter survival.6 Therefore, tobacco smoking tumors (stage I–IIA) are eligible for curative surgery followed by systemic
cessation counseling and intervention should be strongly promoted in therapy with or without mediastinal RT.10,11 The panel recommends
patients with SCLC and other high-grade neuroendocrine carcinomas (see multidisciplinary evaluation before any surgery. In other patients with stage
the NCCN Guidelines for Smoking Cessation, available at I–IIA SCLC, including medically inoperable circumstances or when the
www.NCCN.org).7 Patients who previously smoked tobacco should be decision not to pursue surgical resection is made, stereotactic ablative
strongly encouraged to remain abstinent. Programs using behavioral radiotherapy (SABR) followed by systemic therapy is an option.12-17 The
counseling combined with U.S. Food and Drug Administration benefits of prophylactic cranial irradiation (PCI) are unclear in patients with
(FDA)-approved medications that promote smoking cessation can be very stage I SCLC (T1–2a, N0, M0) who have received definitive therapy. The
useful. NCCN Panel recommends that MRI brain surveillance be considered for
all patients with limited-stage SCLC who do not receive PCI. In most
SCLC is characterized by a rapid doubling time, high growth fraction, and patients with extensive-stage SCLC, systemic therapy with or without RT
early development of widespread metastases. Most patients with SCLC can palliate symptoms and prolong survival; however, long-term survival is
present with hematogenous metastases; approximately one third present rare.18 SCLC is highly sensitive to initial chemotherapy and RT; however,
with limited disease confined to the chest. Although 95% of small cell most patients eventually die of recurrent disease.19 Despite recent
carcinomas originate in the lung, they can also arise from extrapulmonary advances, the recommended therapy options for SCLC need
sites, including the nasopharynx, gastrointestinal tract, and genitourinary improvement. Clinical trials generally represent state-of-the-art treatment
tract.8,9 Both pulmonary and extrapulmonary small cell carcinomas have a for patients with SCLC. Thus, participation in clinical trials is strongly
similar clinical and biologic behavior with increased potential for encouraged.
widespread metastases. Management of SCLC is described in the NCCN
MS-2

Guidelines Update Methodology NCCN Guidelines incorporate non-gendered language, instead focusing
The NCCN Guidelines® for Small Cell Lung Cancer were originally on organ-specific recommendations. This language is both more accurate
published in 1996 and have been subsequently updated at least once and more inclusive and can help fully address the needs of individuals of
every year.20 The complete details of the Development and Update of the all sexual orientations and gender identities. NCCN Guidelines will
NCCN Guidelines are available at www.NCCN.org. continue to use the terms men, women, female, and male when citing
statistics, recommendations, or data from organizations or sources that do
Literature Search Criteria not use inclusive terms. Most studies do not report how sex and gender
Prior to the update of the NCCN Guidelines for Small Cell Lung data are collected and use these terms interchangeably or inconsistently.
If sources do not differentiate gender from sex assigned at birth or organs
Carcinoma, an electronic search of the PubMed database was performed
to obtain key literature in SCLC using the following search term: (small cell present, the information is presumed to predominantly represent cisgender
lung cancer OR small cell carcinoma lung) NOT (non-small). The PubMed individuals. NCCN encourages researchers to collect more specific data in
database was chosen because it is the most widely used resource for future studies and organizations to use more inclusive and accurate
medical literature and it indexes peer-reviewed biomedical literature. language in subsequent analyses.
The search results were narrowed by selecting studies in humans Diagnosis

published in English. Results were confined to the following article types: Screening
Clinical Trial, Phase 1; Clinical Trial, Phase 2; Clinical Trial, Phase 3; Ideally, a screening test should detect disease at an early stage when it is
Clinical Trial, Phase 4; Guideline; Practice Guidelines; Randomized still curable. The National Lung Screening Trial reported that screening
Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation with annual, low-dose, spiral CT scans detected early-stage NSCLC and
Studies. The data from key PubMed articles as well as articles from decreased lung cancer-specific mortality in asymptomatic high-risk
additional sources deemed as relevant to these NCCN Guidelines and individuals (see the NCCN Guidelines for Lung Cancer Screening,
discussed by the NCCN SCLC Panel have been included in this version of available at www.NCCN.org).22 Low-dose CT is probably not useful for
the Discussion section. Recommendations for which high-level evidence is SCLC screening because symptomatic disease can develop between
lacking are based on the panel’s review of lower-level evidence and expert annual scans due to the aggressive nature of the disease; thereby limiting
opinion. the potential reduction of mortality through screening.22-25
Sensitive/Inclusive Language Usage Manifestations

NCCN Guidelines strive to use language that advances the goals of Patients with SCLC typically present with a large hilar mass and bulky
equity, inclusion, and representation.21 NCCN Guidelines endeavor to use mediastinal lymphadenopathy that causes cough and dyspnea.26
language that is person-first; not stigmatizing; anti-racist, anti-classist, Frequently, patients present with symptoms of widespread metastatic
anti-misogynist, anti-ageist, anti-ableist, and anti-weight-biased; and disease, such as weight loss, debility, bone pain, and neurologic
inclusive of individuals of all sexual orientations and gender identities. compromise. The Signs and Symptoms of Small Cell Lung Cancer section
MS-3

in the algorithm lists the manifestations based on tumor location and type than Cushing syndrome. Primary treatment for SIADH includes fluid
of metastases. It is uncommon for patients to present with a solitary restriction (which is difficult for patients because of increased thirst) and
peripheral nodule without central adenopathy. In this situation, fine-needle demeclocycline. Cancer treatment (eg, cisplatin) and/or supportive care
aspiration (FNA) may not adequately differentiate small cell carcinoma (eg, opiates) may also cause hyponatremia.37 Hyponatremia usually
(which is a high-grade neuroendocrine carcinoma) from low-grade (typical improves after successful treatment of SCLC. However, vasopressin
carcinoid), intermediate-grade (atypical carcinoid), or large-cell receptor inhibitors (ie, conivaptan, tolvaptan) can be used for refractory
neuroendocrine carcinoma (LCNEC) (which is also a high-grade hyponatremia (see Principles of Supportive Care in the algorithm).37-39
neuroendocrine carcinoma) (see Lung Neuroendocrine Tumors in the
NCCN Guidelines for Neuroendocrine and Adrenal Tumors, available at Pathology
www.NCCN.org).27,28 SCLC is a poorly differentiated malignant epithelial tumor that is
categorized as a high-grade neuroendocrine carcinoma.27,40 Up to 30% of
Many neurologic and endocrine paraneoplastic syndromes, including tumors from patients with SCLC reveal areas of NSCLC differentiation
Lambert-Eaton myasthenic syndrome, encephalomyelitis, and sensory (mainly large cell carcinoma).41 This finding is more common in patients
neuropathy, are associated with SCLC.29-31 Given the occurrence of who have received previous treatment. The classic and distinctive
paraneoplastic neurologic syndromes in individuals with SCLC, the panel histology on hematoxylin and eosin (H&E), including small blue cells with
recommends considering early subspecialty consultation for most recent scant cytoplasm, high nuclear/cytoplasmic ratio, fine granular nuclear
management in v1.2024. Patients with Lambert-Eaton Myasthenic chromatin, and absent or inconspicuous nucleoli, may be sufficient for
Syndrome present with proximal leg weakness that is caused by identifying SCLC in good-quality histologic samples.27,42 The mitotic count
antibodies directed against the voltage-gated calcium channels.32,33 is high in SCLC compared with the count in atypical and typical carcinoids.
Paraneoplastic encephalomyelitis and sensory neuropathy-related However, mitotic figures are difficult to count in small biopsy samples with
neurologic deficits are caused by the production of an antibody (anti-Hu) crushed or necrotic cells. In such samples immunohistochemistry is
that cross-reacts with both small cell carcinoma antigens and human useful.43 In cases of diagnostic dilemma, including carcinoids, the panel
neuronal RNA-binding proteins. Paraneoplastic encephalomyelitis may strongly recommends getting a second opinion with a pathologist
precede a diagnosis of SCLC.34 The NCCN SCLC Panel recommends specializing in diagnosis of thoracic malignancies.
considering a comprehensive paraneoplastic antibody panel and/or
neurologic consultation if neurologic paraneoplastic syndrome is Using immunohistochemistry as one of the tools to diagnose and
suspected. distinguish SCLC from NSCLC or other neuroendocrine tumors is
important; especially because these cancer types have different treatment
SCLC tumors sometimes produce polypeptide hormones, including recommendations. 27,43-47 Ki-67 is useful for distinguishing SCLC from
vasopressin and adrenocorticotropic hormone that cause syndrome of carcinoid tumors.43,47-49 Nearly all SCLCs are immunoreactive for
inappropriate ADH secretion (SIADH) and Cushing syndrome, cytokeratin (AE1/Ae3, CAM5.2) and 85% to 90% of SCLCs are positive for
respectively.35,36 In patients with SCLC, SIADH occurs more frequently thyroid transcription factor-1 (TTF-1).27,50-52 Most SCLCs (~95%) stain
MS-4

positively for markers of neuroendocrine differentiation, including Evaluation

insulinoma-associated protein 1 (INSM1), chromogranin A, NCAM (CD56), Staging Systems
and synaptophysin.27,53,54 However, at least one of these neuroendocrine
The Veterans Administration (VA) Lung Study Group’s 2-stage
markers will be immunoreactive in approximately 10% of NSCLCs and
classification scheme has historically been used to define the extent of
therefore cannot be used alone to distinguish SCLC from NSCLC.55
disease in patients with SCLC: 1) limited-stage is disease confined to the
Napsin A (adenocarcinoma marker) and p40 (or p63, squamous cell
ipsilateral hemithorax, which can be safely encompassed within a radiation
carcinoma marker) are generally negative in SCLC and useful for
field; and 2) extensive-stage is disease beyond the ipsilateral hemithorax,
distinguishing SCLC from poorly differentiated NSCLC and combined
including malignant pleural/pericardial effusion or hematogenous
SCLC.56 However, p40 (or p63) can be focally positive in SCLC. For the
metastases.71 Contralateral mediastinal and ipsilateral supraclavicular
v1.2024 update, the panel clarified that molecular profiling may be
lymphadenopathy are generally classified as limited-stage SCLC, whereas
considered in rare cases, particularly for patients with
the classification of contralateral hilar and supraclavicular
extensive-stage/relapsed SCLC who have never smoked or lightly
lymphadenopathy is more controversial and treatment is
smoked, remote smoking history, for diagnostic/pathologic dilemma, or at
individualized.19,72,73 Approximately 66% of patients present with overt
time of relapse if not done previously because this may change
hematogenous metastases, which commonly involve the contralateral
management.57-62
lung, liver, adrenal glands, brain, bones, and/or bone marrow. Most
The WHO classification recognizes two types of SCLC: pure and studies use the VA definitions of limited-stage or extensive-stage SCLC,
combined SCLC.47,58,63-66 Combined SCLC, which consists of both SCLC for clinical decision-making. However, the TNM system is useful for
and NSCLC histology (squamous cell, adenocarcinoma, selecting patients with T1–2, N0 disease who are eligible for surgery and
spindle/pleomorphic, and/or large cell carcinoma), is more frequent in RT.72 The American Joint Committee on Cancer (AJCC) revised the TNM
patients with limited-stage SCLC.47,58,65,67 Any presence of NSCLC staging system (8th edition) for lung cancer in 2017 (see Staging in the
histology (no minimal percentage) results in a classification of combined algorithm).74,75 Clinical research studies that include use of the TNM
SCLC. The only exception is combined SCLC and LCNEC where at least system will allow for more precise assessments of prognosis and specific
10% of the tumor should show LCNEC morphology.41,68 Patients with therapy.74
combined SCLC are treated using regimens for SCLC, because it is the
The NCCN SCLC Panel adopted a combined approach of using both the
more aggressive cancer.68 Patients with NSCLC can also transform to
AJCC TNM staging system and the older VA scheme for SCLC
SCLC after treatment with epidermal growth factor receptor (EGFR)
staging.19,72 Limited-stage SCLC is defined as stage I to III (T any, N any,
tyrosine kinase inhibitors or immune checkpoint inhibitors.69,70
M0) that can be safely treated with definitive RT. This excludes T3–4 due
to multiple extensive lung nodules or disease with tumor/nodal volume that
is too large to be encompassed in a tolerable radiation plan (see Table 1
in the algorithm). Extensive-stage SCLC is defined as stage IV (T any, N
any, M1a/b/c) or T3–4 as previously described.
MS-5

Initial Evaluation Once a patient has been found to have extensive-stage SCLC, further
The workup for SCLC should be expedited with studies done in parallel staging is optional, except for brain imaging.19 Brain imaging (preferably
whenever possible. Staging should not delay the onset of treatment for MRI or CT with contrast) can identify central nervous system (CNS)
more than 1 week because of the aggressive nature of SCLC. Many metastases in 10% to 15% of patients at diagnosis, of which
patients may become more seriously ill in the interval, with a significant approximately 30% are asymptomatic. Therefore, staging should not focus
decline in their performance status (PS). Staging primarily provides a only on sites of symptomatic disease or on sites suggested by laboratory
therapeutic guideline for thoracic RT for patients with limited-stage SCLC. tests. Early treatment of brain metastases results in less chronic
For v1.2024, the panel recommends integration of palliative care so that neurologic morbidity, arguing for the usefulness of early diagnosis in
management of cancer-related symptoms and goals of care are discussed asymptomatic patients.
during initial evaluation.
Bone imaging with radiographs or MRI can be performed if FDG-PET/CT
The initial diagnostic evaluation includes a history and physical is equivocal or not available; bone biopsy can be further considered if
examination; pathology review; clinical laboratory tests; CT scan with bone imaging is also equivocal. Bone scans are positive in up to 30% of
intravenous contrast of the chest/abdomen/pelvis; and MRI (preferred) or patients without bone pain or without abnormal alkaline phosphatase
CT scan with intravenous contrast for brain imaging.73,76 An FDG-PET/CT levels. However, less than 5% of patients have bone marrow involvement
scan (skull base to mid-thigh), which is superior to PET alone, is as the only site of extensive-stage SCLC. Unilateral bone marrow
recommended to clarify the extent of disease if needed.19,72,77 For most aspirates and biopsies may be indicated in select patients with no other
metastatic sites, FDG-PET/CT is superior to CT imaging; however, FDG- evidence of metastatic disease, with nucleated red blood cells on
PET/CT is inferior to MRI (or contrast-enhanced CT as an alternative peripheral blood smear and neutropenia, or thrombocytopenia suggestive
when MRI is not possible) for the detection of brain metastases (see the of bone marrow infiltration.
NCCN Guidelines for Central Nervous System Cancers, available at
Before surgical resection in patients with clinical limited stage I–IIA SCLC
www.NCCN.org).78 FDG-PET scans can also increase staging accuracy in
(T1–2, N0, M0), pathologic mediastinal staging is recommended to confirm
patients with SCLC, because SCLC is a highly metabolic disease.77,79,80
FDG-PET/CT scan results and rule out occult nodal disease.19 To help
Approximately 19% of patients who undergo FDG-PET are upstaged from
determine RT fields, mediastinal staging can be considered for clinical
limited-stage to extensive-stage SCLC, whereas 8% are down staged from
stage IIB–IIIC SCLC (T1–4, N0, M0; T1-4, N1-3, M0), especially for those
extensive-stage to limited-stage SCLC.73 Although FDG-PET/CT seems to
with clinical N0 disease. Invasive mediastinal staging can be performed
improve staging accuracy in SCLC, pathologic confirmation is still required
either by conventional mediastinoscopy or by minimally invasive
for FDG-PET/CT-detected lesions. Additionally, FDG-PET staging altered
techniques such as transesophageal endoscopic ultrasound-guided FNA
the planned radiation field because of improved detection of intrathoracic
(EUS-FNA), endobronchial ultrasound-guided transbronchial needle
disease sites in approximately 27% of patients.73,80,81
aspiration (EBUS-TBNA), or video-assisted thoracic surgery (VATS).82,83 If
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the endoscopic lymph node biopsy is positive, then additional mediastinal Surgical Resection of Stage I to IIA SCLC
staging is not recommended. The Principles of Surgical Resection for SCLC are described in the
algorithm and the studies supporting these recommendations are
Thoracentesis with cytologic analysis is recommended if pleural effusion is
described in this section. Most of the data regarding the role of surgery in
large enough to be safely accessed via ultrasound guidance. If
SCLC are from retrospective studies.86-91 These studies report favorable
thoracentesis does not show malignant cells, then thoracoscopy can be
5-year survival rates of 40% to 60% in patients with stage I disease. In
considered to document pleural involvement, which is suggestive of
most series, survival rates decline significantly in patients with advanced
extensive-stage SCLC. The effusion should be excluded as a staging
disease with lymph node involvement. Therefore, the general
element if: 1) multiple cytopathologic examinations of the pleural fluid are
recommendation for surgery is restricted to certain patients with stage I–
negative for cancer; 2) the fluid is not bloody and not an exudate; and 3)
IIA disease (T1–2, N0, M0). Fewer than 5% of patients with SCLC have
clinical judgment concludes that the effusion is not directly related to the
true stage I–IIA disease.92 Analyses of the SEER database suggest that
cancer. Pericardial effusions are classified using the same criteria.
surgery is appropriate for some patients with localized disease.17,93
Prognostic Factors However, retrospective studies and analyses of the SEER database are
limited by the lack of information on chemotherapy. In addition,
Poor PS (3–4), extensive-stage SCLC, weight loss, and markers, such as
comparison of the survival of surgical patients to those who did not
lactate dehydrogenase (LDH), associated with bulky disease are the most
undergo surgery is inherently flawed by selection bias. Ultimately, the role
important adverse prognostic factors. Age <70 years, normal LDH, and
of surgery in SCLC will not be fully delineated until prospective trials in
stage I disease are associated with favorable prognosis in patients with
patients who are rigorously staged compare surgery plus adjuvant
limited-stage SCLC. Younger age, good PS, normal creatinine level,
chemotherapy versus concurrent chemoradiotherapy.
normal LDH, and a single metastatic site are favorable prognostic factors
in patients with extensive-stage SCLC.84,85 The Lung Cancer Study Group conducted the only prospective
randomized trial evaluating the role of surgery in SCLC.94 Patients with
Treatment limited-stage SCLC, excluding those with solitary peripheral nodules, that
Surgery is only recommended for certain patients with stage I–IIA SCLC; responded to 5 cycles of chemotherapy with cyclophosphamide,
with only about 5% of patients eligible for surgery. Concurrent doxorubicin, and vincristine (CAV) were randomly assigned to undergo
chemoradiation or SABR is recommended for patients with limited-stage I– thoracic RT with or without resection. The overall survival rates of patients
IIA (T1–2, N0) SCLC who are medically inoperable or do not want to on the two arms were equivalent, suggesting no benefit to surgery in this
pursue surgical resection (see Systemic Therapy, Radiation Therapy, and setting. However, only 19% of enrolled patients had clinical limited stage I
SABR in this Discussion). Systemic therapy alone (with or without (T1–2, N0, M0) disease. Data show that patients with SCLC who have
palliative RT) is recommended for patients with extensive-stage SCLC. nodal disease (ie, T1–3, N1–3, M0–1) do not benefit from surgery.94
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The NCCN Panel recommends that in patients who do not smoke tobacco, therapy (see Prophylactic Cranial Irradiation in this Discussion and
small lesions—that are presumed to be small cell carcinoma on biopsy— Adjuvant Treatment in the algorithm).99,100 For patients with limited stage I–
should be resected because they are likely carcinoids that have been IIA (T1–2, N0) SCLC with positive margins (R1/R2 resection), the panel
misdiagnosed (see the NCCN Guidelines for Neuroendocrine and Adrenal recommends concurrent chemoradiation following surgery. The NCCN
Tumors, available at www.NCCN.org). The NCCN SCLC Panel also SCLC Panel recommends response assessment following adjuvant
recommends surgery for certain patients with clinical stage I to IIA (T1–2, therapy to establish new disease baseline.
N0) SCLC with negative mediastinal lymph nodes that have been
confirmed by mediastinal staging.15,86,95 Surgery can include patients with Systemic Therapy
clinical limited stage IIA SCLC based on the staging criteria that includes For all patients with SCLC, systemic therapy is an essential component of
tumors up to 5 cm in diameter (T2b) without lymph node involvement (N0). appropriate treatment (see Principles of Systemic Therapy in the
The NCCN Panel added recommendations for patients who did not have a algorithm). The NCCN SCLC Panel has preference stratified the adjuvant,
preoperative biopsy but have an intraoperative diagnosis of likely SCLC. If first-line, and subsequent therapy options for patients with SCLC into 1)
resection is performed, the NCCN SCLC Panel recommends lobectomy Preferred, 2) Other recommended, and 3) Useful under certain
(preferred) with mediastinal lymph node dissection or systematic lymph circumstances.
node sampling (eg, >3 N2 and >1 N1 stations). The panel does not
recommend pneumonectomy if nodal metastatic disease needs to be Adjuvant chemotherapy is recommended for patients with early-stage
encompassed or under other circumstances. Chemoradiation is the SCLC who have had surgery or SABR. For patients with limited-stage
preferred alternative over any resection requiring pneumonectomy. SCLC who are not eligible for surgery or SABR, chemotherapy with
concurrent thoracic RT (category 1 for patients with PS 0–2) is the
Following surgery, adjuvant chemotherapy or chemoradiation is recommended primary treatment.11,101,102 For patients with extensive-stage
recommended based on the absence or presence of nodal metastases for SCLC, systemic therapy alone is recommended. RT may be used in select
patients with limited stage I to IIA (T1–2, N0) SCLC with negative margins patients for palliation of symptoms (see NCCN Guidelines for Palliative
(R0 resection) (see Systemic Therapy in this Discussion).89,96-98 Adjuvant Care, available at www.NCCN.org). These options are rationalized based
chemotherapy alone is recommended for patients without nodal on studies described in the following sections.
metastases (N0). Concurrent or sequential chemotherapy and
Cisplatin Versus Carboplatin
postoperative mediastinal RT are recommended for patients with N+
disease (see Adjuvant Treatment in the algorithm). Although panel Randomized trials in a small number of patients with SCLC and
members agree that postoperative mediastinal RT is recommended for retrospective analysis of patients with extensive-stage SCLC suggest
nodal metastases, it should be based on the extent of nodal similar efficacy between cisplatin and carboplatin regimens.103-105 In a
sampling/dissection and extent of nodal positivity; however, there are no meta-analysis of 663 patients with limited-stage SCLC (32%) and
data to support this recommendation. The benefit of PCI is unclear in extensive-stage SCLC (68%), no significant difference was observed in
patients with pathologic stage I (T1–2a, N0, M0) who have had definitive response rate (67% vs. 66%), progression-free survival (PFS) (5.5 vs. 5.3
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months), or overall survival (9.6 vs. 9.4 months) between cisplatin- versus preferred etoposide/cisplatin regimens for limited-stage SCLC are based
carboplatin-containing regimens.106 Carboplatin is frequently substituted on the dosing used in the CONVERT trial. 108 Other recommended
for cisplatin to reduce the risk of emesis, neuropathy, and nephropathy.107 options for limited-stage SCLC include carboplatin/etoposide and other
However, the use of carboplatin carries a greater risk of cisplatin/etoposide doses. The use of myeloid growth factors is not
myelosuppression.107 recommended in patients undergoing concurrent chemoradiation
(category 1 for not using granulocyte-macrophage colony-stimulating
Limited-Stage SCLC
factor [GM-CSF]).118 Thus far, there are no data to support the use of
Adjuvant chemotherapy alone is recommended for patients who have immunotherapy in patients with limited-stage SCLC.
undergone surgical resection (N0) or SABR for early-stage SCLC (see
Principles of Systemic Therapy in the algorithm). However, most patients Response assessment is an important aspect of the management of
with limited-stage SCLC are not eligible for surgery or SABR. Etoposide SCLC. For patients with limited-stage SCLC, the panel recommends
plus cisplatin is the most commonly used first-line combination response assessment using CT with contrast only after completion of
chemotherapy regimen for patients with limited-stage SCLC.108,109 adjuvant chemotherapy alone or chemotherapy with concurrent RT and
Etoposide plus cisplatin replaced alkylator plus anthracycline-based not during therapy. Response assessment can be measured using CT
regimens based on its superiority in both efficacy and toxicity. 110-112 If with contrast of the chest/abdomen/pelvis and brain MRI (preferred) or
pathologic lymph node involvement is found at surgery (N1 or N2) for brain CT with contrast. For systemic therapy alone or sequential
patients with stage I–IIA (T1–2, N0, M0), then thoracic RT can be added systemic therapy followed by RT in patients with limited-stage SCLC, the
concurrently or sequentially to etoposide/cisplatin. Treatment with panel recommends response assessment using CT with contrast of the
etoposide/cisplatin plus definitive thoracic RT showed response rates of chest/abdomen/pelvis after every 2 to 3 cycles of systemic therapy and
70% to 90% with a median overall survival of 25 to 30 months and 5-year again at completion of therapy.
overall survival rates of 31% to 34%.108 Thoracic RT improves local
control rates by 25% in patients with limited-stage SCLC and is associated Extensive-Stage SCLC
with improved survival.101,102 Data suggest that chemoradiotherapy may The NCCN SCLC Panel recommends certain combination chemotherapy
also be indicated for patients with limited-stage SCLC who have plus immunotherapy regimens as preferred options for patients with
cytologically negative or indeterminate pleural effusions but not for those extensive-stage SCLC.119-121 In patients with extensive-stage SCLC and
with pericardial effusions.113,114 Etoposide/cisplatin in combination with brain metastases, systemic therapy can be given either before or after
thoracic RT increases the risk of esophagitis, pulmonary toxicity, and brain RT depending on whether the patient has neurologic symptoms (see
hematologic toxicity. 115 Primary Treatment in the algorithm).18,122 If systemic therapy is given first,
brain RT is administered after completion of systemic therapy.
For patients with limited-stage IIB–IIIC (T3–4, N0, M0; T1–4, N1–3, M0)
SCLC, the NCCN Guidelines recommends different etoposide/cisplatin For many years, platinum plus etoposide had been the only recommended
regimens plus concurrent thoracic RT (category 1). 101,102,116,117 The therapy for patients with extensive-stage SCLC; however, the preferred
regimens now include the programmed death ligand 1 (PD-L1)–targeted
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immune checkpoint inhibitors, atezolizumab or durvalumab. for patients with extensive-stage SCLC who have asymptomatic brain
Contraindications for treatment with programmed cell death protein 1 metastases and are receiving systemic therapy before brain RT. Brain
(PD-1)/PD-L1 inhibitors may include active or previously documented MRI (preferred) or brain CT with contrast is recommended after every 2
autoimmune disease and/or concurrent use of immunosuppressive cycles of systemic therapy and again at completion of therapy.
agents. For v1.2024, recent use of tyrosine kinase inhibitors (TKIs) is
added as a contraindication for treatment with immune checkpoint Atezolizumab Plus Chemotherapy
inhibitors. The panel recommends continuation of maintenance IMpower133, a phase 3 randomized trial, assessed the addition of
immunotherapy until disease progression or intolerable toxicity. atezolizumab (treatment and maintenance) to carboplatin plus etoposide
Atezolizumab or durvalumab may cause unique immune-mediated in 403 patients with previously untreated extensive-stage SCLC and
adverse events that are not seen with traditional cytotoxic chemotherapy. compared outcomes to carboplatin plus etoposide alone.121 The 1-year
Therefore, health care providers should be aware of the spectrum and overall survival rate was 51.9% for the atezolizumab regimen versus
management of potential immune-mediated adverse events and have a 39.0% for chemotherapy alone. The median overall survival was 12.3
discussion with patients about possible side effects. High-dose months (95% CI, 10.8–15.8) with the addition of atezolizumab versus 10.3
corticosteroids are generally recommended for immune-mediated adverse months (95% CI, 9.3–11.3) with chemotherapy alone (hazard ratio [HR],
events based on the severity of the reaction. Atezolizumab or durvalumab 0.76; 95% CI, 0.6–0.95; P = .0154).119 Response rates were similar in both
should be withheld or discontinued for severe or life-threatening arms (60% with chemotherapy plus atezolizumab vs. 64% with
immune-mediated adverse events when indicated (see prescribing chemotherapy alone). The rate of grade 3 or 4 adverse events was similar
information) (see the NCCN Guidelines for Management of in both groups (67.7% for the atezolizumab regimen vs. 63.3% for
Immunotherapy-Related Toxicities, available at www.NCCN.org). chemotherapy alone). There were 4 deaths (2%) in the atezolizumab
group versus 11 deaths (5.6%) in the chemotherapy alone group. Different
The panel recommends steroid initiation for patients with spinal cord doses for maintenance atezolizumab have been FDA-approved for
compression or brain metastasis who have symptomatic neurologic patients with extensive-stage SCLC. In light of these data and FDA
disease. Systemic therapy with or without RT to localized symptomatic approval, the NCCN SCLC Panel recommends carboplatin plus etoposide
sites is recommended for patients with extensive disease, which includes plus atezolizumab as a category 1 and preferred first-line systemic therapy
the superior vena cava (SVC), lobar obstruction, and bone metastasis. option followed by maintenance atezolizumab for patients with
Prophylactic external beam RT (EBRT) can be considered for patients with extensive-stage SCLC.119,121 The NCCN Panel recommends either 1200 or
high fracture risk due to osseous structural impairment. 1680 mg of maintenance atezolizumab. The category 1 recommendation
is only for 1200 mg of maintenance atezolizumab based on the dose used
During systemic therapy for patients with extensive-stage SCLC, the panel
in the clinical trial.119,121
recommends response assessment using CT with contrast of the
chest/abdomen/pelvis after every 2 to 3 cycles of systemic therapy and
again at completion of therapy. Serial brain imaging is also recommended
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Durvalumab Plus Chemotherapy etoposide/cisplatin (P = .002).126 The 2-year survival was 19.5% in the
CASPIAN, a phase 3 randomized trial, assessed adding durvalumab to irinotecan plus cisplatin group versus 5.2% in the etoposide/cisplatin
etoposide and either carboplatin or cisplatin followed by maintenance group.126 Two subsequent large phase 3 trials performed in the United
durvalumab in 537 patients with previously untreated extensive-stage States comparing irinotecan plus cisplatin versus etoposide/cisplatin
SCLC and compared response to platinum plus etoposide alone showed no significant difference in response rate or overall survival.127,128
regimens.120,123 Most patients received carboplatin (78%). A 3-year A phase 3 randomized trial of 220 patients with extensive-stage SCLC
analysis showed that the median overall survival was 13.0 months (95% found that median overall survival slightly improved with irinotecan and
CI, 11.5–14.8) in the durvalumab plus chemotherapy group and 10.3 carboplatin compared with carboplatin and oral etoposide (8.5 vs. 7.1
months (95% CI, 9.3–11.2) in the chemotherapy alone group (HR, 0.73; months; P = .04).129 In addition, a meta-analysis suggested an
95% CI, 0.59–0.91; P = .0047).124 The 1-year overall survival rate was improvement in PFS and overall survival with irinotecan plus platinum
52.8% for the durvalumab regimen versus 39.3% for chemotherapy alone. regimens compared with etoposide plus platinum regimens.130 The NCCN
The rate of serious adverse events was similar in both groups (32% vs. SCLC Panel recommends the irinotecan-based regimens as primary
36%). The death rate from adverse events was also similar (2% vs. 1%). therapy options (useful in certain circumstances) for patients with
In this trial, adding tremelimumab to durvalumab/etoposide carboplatin (or extensive-stage SCLC. However, the relatively small absolute survival
cisplatin) did not improve overall survival compared with benefit needs to be balanced against the toxicity profile of
platinum/etoposide (10.4 vs. 10.5 months; HR, 0.82; 95% CI, 0.68–1.0). irinotecan-based regimens.
Based on the data and FDA approval, the NCCN SCLC Panel
The use of maintenance or consolidation chemotherapy beyond the
recommends durvalumab plus etoposide plus (carboplatin or cisplatin) as
recommended 4 to 6 cycles results in a minor increase in the duration of
a category 1 and preferred first-line systemic therapy option followed by
response without improving survival and carries a greater risk of
maintenance durvalumab for patients with extensive-stage SCLC,
cumulative toxicity.131,132 The inability to destroy residual cells, despite the
including those with asymptomatic untreated brain metastases.120,123-125
initial chemosensitivity of SCLC, suggests the existence of cancer stem
Other Primary Systemic Therapies cells that are relatively resistant to cytotoxic therapy. Alternating or
Other recommended first-line systemic therapy regimens for sequential combination therapies have been designed to overcome drug
extensive-stage SCLC include etoposide with either cisplatin or resistance by exposing the tumor to as many active cytotoxic agents as
carboplatin. Additional chemotherapy combination regimens evaluated in possible during initial treatment.133 However, this approach has not
patients with extensive-stage SCLC show inconsistent evidence of benefit improved PFS or overall survival in randomized trials.134,135 Therefore, the
compared with etoposide/cisplatin. For example, the combination of NCCN SCLC Panel recommends 4 cycles of systemic cytotoxic therapy
irinotecan and cisplatin initially appeared to be better than for patients with limited-stage (with concurrent radiation) and extensive-
etoposide/cisplatin. A phase 3 trial in Japan reported that patients with stage (with concurrent immunotherapy) SCLC. However, some patients
extensive-stage SCLC treated with irinotecan plus cisplatin had a median with extensive-stage SCLC may receive up to 6 cycles based on response
survival of 12.8 months compared with 9.4 months for patients treated with and tolerability.
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Attempts to improve long-term survival rates in patients with SCLC favorable patient selection was of some concern.148,149 No survival benefits
through the addition of more agents or the use of dose-intense were documented in randomized trials, and excessive treatment-related
chemotherapy, maintenance therapy, or alternating non-cross-resistant mortality were noted with weekly cyclic multidrug chemotherapy
chemotherapy regimens have not shown significant advantages compared regimens.150-153
to recommended approaches. In two trials, the addition of ifosfamide (or
cyclophosphamide plus an anthracycline) to etoposide/cisplatin showed a Despite the recent success with atezolizumab/chemotherapy or
modest survival advantage.136,137 However, these findings have not been durvalumab/chemotherapy regimens, other immunotherapy-based
uniformly observed, and the addition of an alkylating agent, with or without strategies have not been as favorable. A phase 3 randomized trial in
an anthracycline, significantly increases hematologic toxicity when patients with extensive-stage SCLC reported that the addition of
compared to etoposide/cisplatin alone.138 Two different phase 3 trials ipilimumab to etoposide with either cisplatin or carboplatin as first-line
assessing the combination of ifosfamide, etoposide, and epirubicin versus therapy did not improve either overall survival or PFS compared with
etoposide/cisplatin, and carboplatin plus etoposide with or without chemotherapy alone.154 Likewise, another phase 3 randomized trial
palifosfamide confirmed the lack of improvement in survival with showed no improvement in overall survival in patients with extensive-stage
three-drug chemotherapy regimens in patients with extensive-stage SCLC treated with first-line pembrolizumab plus etoposide/platinum
SCLC.139,140 Similarly, the addition of paclitaxel to either cisplatin or followed by maintenance pembrolizumab compared with chemotherapy
carboplatin plus etoposide yielded promising results in phase 2 studies, alone.58
but did not improve survival and was associated with unacceptable toxicity
Antiangiogenic therapy has also been evaluated in SCLC. In patients with
in a phase 3 trial.141
limited-stage SCLC, a phase 2 study of irinotecan, carboplatin, and
The role of high dose chemotherapy for patients with SCLC remains bevacizumab with concurrent RT followed by maintenance bevacizumab
controversial. Patients receiving high chemotherapy doses compared with was terminated early because of an unacceptable incidence of
those given conventional doses of the same agents had higher complete tracheoesophageal fistulae. In extensive-stage SCLC, phase 2 trials of
and partial response rates, and modestly longer median survival times.142 platinum-based chemotherapy plus bevacizumab showed promising
However, randomized trials comparing conventional chemotherapy doses response and survival data.155-158 However, at least two randomized trials
to incremental increases in dose intensity (up to 2 times the conventional have demonstrated no survival benefit for the addition of bevacizumab to
dose) have not consistently shown an increase in response rate or standard chemotherapy.159,160 Currently, the NCCN SCLC Panel does not
survival.143-146 In addition, a meta-analysis of trials that studied recommend use of bevacizumab in patients with SCLC.
dose-intense variations of the CAV and etoposide/cisplatin regimens found
Cytokines (eg, GM-CSF, granulocyte colony-stimulating factor [G-CSF])
that increased relative dose intensity resulted in only a small, clinically
can ameliorate chemotherapy-induced myelosuppression and reduce the
insignificant enhancement of median survival in patients with
incidence of febrile neutropenia, but cumulative thrombocytopenia remains
extensive-stage SCLC.147 Early phase 2 results designed to increase dose
dose-limiting. Although trials involving patients with SCLC were
intensity by weekly cyclic multidrug chemotherapy were promising, but
instrumental in obtaining FDA approval for the clinical use of cytokines,161
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maintenance of dose intensity with growth factors does not prolong >70 years and limited-stage SCLC (29 vs. 30 months; P = .38).170
disease-free survival or overall survival.162,163 The panel does not However, myelosuppression, fatigue, and lower organ reserves are
recommend GM-CSF (category 1 for not using it) or G-CSF for patients encountered more frequently in patients >70 years. Therefore, the study
with limited-stage SCLC receiving systemic therapy/RT.118,164 Trilaciclib or recommended closer surveillance for patients >70 years during treatment
G-CSF may be used as prophylactic supportive care options to decrease to avoid excessive risk.170
the incidence of chemotherapy-induced myelosuppression when
administering certain regimens for patients with extensive-stage SCLC Randomized trials have indicated that less-intense treatment (eg,
(see Principles of Supportive Care in the algorithm).118,164-168 It is important single-agent etoposide) is inferior to combination chemotherapy (eg,
to note that trilaciclib or G-CSF are not treatment options. platinum plus etoposide) in patients of all ages with good PS (0–2).173,174 A
retrospective analysis in 8637 patients >70 years with limited-stage SCLC
Transformed SCLC from NSCLC with an Oncogenic Driver reported that chemoradiation increased survival compared with
The panel recognizes that transformed SCLC from NSCLC is a rare chemotherapy alone.171 Several other strategies have been evaluated in
population of patients with limited data including treatment options. The patients >65 years with SCLC.105,175-177 The use of 4 cycles of carboplatin
panel recommends considering referral to a center with expertise in plus etoposide seems to yield favorable results, because the
managing transformed SCLC. The panel recommends systemic cytotoxic area-under-the-curve (AUC) dosing of carboplatin takes into account the
chemotherapy using SCLC Guidelines due to lack of data for declining renal function of the patient.177 However, targeting carboplatin to
transformed SCLC. The role of immunotherapy in transformed SCLC is an AUC of 5, rather than 6, is more reasonable in the population >70
unclear and should be avoided if tyrosine kinase inhibitors are being years.178 A short 2-week course, full-intensity chemotherapy showed
used. acceptable results in patients (median age, 73 and poor PS); but this
approach has not been directly compared with 4 to 6 cycles of therapy.179
Older Patients
The incidence of SCLC increases with age with the median age at PCI should be used with caution in older patients. A Dutch analysis of
diagnosis being >70 years.169 The functional status of an individual patient more than 5000 patients suggests that median survival is lower in patients
is more useful than chronological age in guiding clinical decision-making >70 years compared with patients <70 years treated with PCI, regardless
that includes considering treatment tolerance (see the NCCN Guidelines of stage.180 Patients aged ≥60 years are at increased risk for cognitive
for Older Adult Oncology, available at www.NCCN.org). Greater attention decline after PCI; therefore, the risks and benefits of PCI versus close MRI
to the needs and support systems of a patient’s functional status is surveillance need to be discussed.181-184
recommended to provide optimal care. Patients who are able to perform
activities of daily living (ADLs) should be treated with combination Surveillance for Relapse
systemic therapy and RT, if indicated.170-172 For example, a subgroup Although SCLC responds to initial treatment, disease relapse is observed
analysis of the CONVERT trial suggests that concurrent chemoradiation in most patients.185,186 Therefore, surveillance recommendations to assess
yields equivalent median survival in patients <70 years versus patients for relapse in patients with SCLC are outlined in the algorithm. Most
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NCCN Member Institutions use chest CT (± abdomen/pelvis) every 2 to 6 Subsequent systemic therapy provides significant palliation in many
months (more frequently in years 1 to 2 and less frequently thereafter). patients, although the likelihood of response is highly dependent on the
The frequency of surveillance decreases during subsequent years time from initial therapy to relapse.193 If the interval is 6 months or less
because of the declining risk of recurrence.187 If a new pulmonary nodule (refractory or resistant disease), response to most agents or regimens is
develops, it should prompt evaluation for a new primary lung cancer, poor (≤10%). If more than 6 months have elapsed (sensitive disease),
because second primary tumors frequently occur in patients with no expected response rates are approximately 25%. Response rates are
evidence of SCLC post-treatment.188,189 It is important to monitor for brain higher with newer agents, such as lurbinectedin. Unfortunately, most
metastases, prior to the development of potentially debilitating neurologic patients relapse in 6 months or less.194,195 Note that the European Society
symptoms, which allows for early treatment. The NCCN SCLC Panel for Medical Oncology (ESMO) Guidelines use cutoffs of 3 months or more
recommends brain MRI (preferred) or CT with contrast every 3 to 4 for sensitive SCLC and less than 3 months for resistant SCLC.196 The
months during year 1 for all patients and then every 6 months as clinically NCCN SCLC Panel recommends additional subsequent therapy options
indicated, regardless of the PCI status. MRI is more sensitive than CT for for patients with SCLC based on clinical expertise and trial data. Other
identifying brain metastases.76 The panel maintains that FDG-PET/CT is recommended subsequent therapy options, described in the following
not recommended for routine follow-up unless contrast CT sections, include topotecan (oral [PO] or IV), lurbinectedin, CAV,
chest/abdomen/pelvis is contraindicated. Tobacco smoking cessation docetaxel, oral etoposide, gemcitabine, irinotecan, nivolumab, paclitaxel,
intervention is recommended for all patients with SCLC, because second pembrolizumab, and temozolomide (category 2A for all agents).The
primary tumors occur less commonly in patients who quit smoking (see the optimal duration of subsequent systemic therapy has not been fully
NCCN Guidelines for Smoking Cessation, available at explored. For cytotoxic chemotherapy agents, the duration of treatment is
www.NCCN.org).190-192 Patients who previously smoked tobacco should be usually short, and the cumulative toxicity is frequently limiting even in
encouraged to remain abstinent. The NCCN SCLC Panel also patients who experience response. For these reasons, subsequent
recommends the survivorship guidelines for appropriate patients (see the systemic therapy should be continued until progression of disease or
NCCN Guidelines for Survivorship, available at www.NCCN.org). development of unacceptable toxicity. The panel recommends response
assessment using CT with contrast of the chest/abdomen/pelvis after
Subsequent Systemic Therapy every 2 to 3 cycles. Dose reduction or growth factor support should be
Patients with disease relapse or with primary progressive disease may be considered for patients with a PS of 2. For CNS progression only, the
treated with subsequent systemic therapy. Recommended subsequent panel recommends continuing systemic therapy and treat brain
systemic therapy options are based on chemotherapy-free interval (CTFI) metastases with RT. Additional subsequent systemic therapy (eg, third
of 1) 6 months or less; or 2) more than 6 months (see Principles of line) can be considered if patients are still PS 0 to 2.
Systemic Therapy in the algorithm). Clinical trial enrollment is the
preferred regimen for both CTFI >6 months and CTFI <6 months. For Platinum-Based Therapy
v1.2024, the panel recommends considering genomic profiling of relapsed A phase 3 randomized trial assessed carboplatin plus etoposide compared
tumors, if not previously performed, to determine clinical trial eligibility. with oral topotecan in 162 patients with SCLC relapse after more than 3
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months on first-line platinum/etoposide therapy.197 The median PFS was 3–4 adverse events included neutropenia, anemia, thrombocytopenia,
4.7 months (90% CI, 3.9–5.5) in the carboplatin/etoposide group versus fatigue, and increased liver function tests. The FDA granted approval for
2.7 months (90% CI, 2.3–3.2) in the oral topotecan group (HR, 0.57; 90% lurbinectedin at a dose of 3.2 mg/m2 every 3 weeks based on clinical trial
CI, 0.41–0.73; P = .004). Grade 3–4 adverse events included data.201
thrombocytopenia, neutropenia, anemia, febrile neutropenia, and asthenia.
In the topotecan group, two treatment-related deaths occurred; no deaths ATLANTIS, a phase 3 randomized trial, assessed lurbinectedin plus
occurred in the carboplatin/etoposide group. The NCCN SCLC Panel doxorubicin versus control therapy with either CAV or topotecan in 613
recommends subsequent therapy with platinum-based regimens based on patients with relapsed SCLC.202 Most patients had received first-line
the clinical trial data.194,197-200 The NCCN Panel maintains that platinum-based therapy more than 3 months ago. The median overall
rechallenging with the original regimen, or similar platinum-based regimen, survival was 8.6 months (95% CI, 7.1–9.4) with lurbinectedin/doxorubicin
is recommended for subsequent systemic therapy, if CTFI >6 months and versus 7.6 months (95% CI, 6.6–8.2) with CAV or topotecan (HR, 0.97;
may be considered if there has been a CTFI of at least 3 to 6 95% CI, 0.82–1.15). Grade 3 or higher adverse events occurred in 66% of
months.194,197-200 The NCCN Panel maintained that platinum-based patients receiving lurbinectedin/doxorubicin versus 86.5% of patients in
doublets are the preferred subsequent therapy options for patients with the control group. Grade 3 or worse adverse events included neutropenia
SCLC and a PS of 0 to 2.194,197,198 (lurbinectedin/doxorubicin: 37%; control: 69%). Two patients (<1%) died
because of treatment-related adverse events in the
Lurbinectedin lurbinectedin/doxorubicin group and 10 (3%) patients died in the control
A phase 2 basket trial assessed lurbinectedin (3.2 mg/m2 every 3 weeks) group. The dose of lurbinectedin was 2 mg/m2 in the ATLANTIS trial, which
as second-line therapy in 105 patients with SCLC who previously received is less than the dose used in the phase 2 trial discussed earlier.195,201
platinum/etoposide; 57% of patients had not received chemotherapy for 3
months or more.201 The overall response rate with lurbinectedin was 35% The NCCN SCLC Panel recommends lurbinectedin as a subsequent
(95% CI, 26.2%–45.2%). The response rate was 22% (95% CI, 11.2%– therapy option for patients with SCLC with CTFI >6 months (other
37.1%) if CTFI was less than 3 months. The response rate was 45% (95% recommended regimens) and CTFI <6 months (preferred).195,201 The
CI, 32.1%–58.4%) if CTFI was 3 months or more. Common grade 3–4 NCCN Panel decided to continue recommending lurbinectedin at the
adverse events included anemia, leucopenia, neutropenia, and higher dose based on the FDA approval and since the lower dose of
thrombocytopenia. There were no reported treatment-related deaths. In a lurbinectedin did not perform well in ATLANTIS.201,202
subset analysis of this trial, lurbinectedin was assessed as second-line
Topotecan
therapy in 20 patients with SCLC who had received platinum/etoposide
Topotecan is also recommended as a subsequent therapy option based
more than 6 months ago.195 The overall response rate with lurbinectedin
on clinical trial data.197 A randomized phase 3 trial for subsequent
was 60% (95% CI, 36.1%–86.9%). The median overall survival was 16.2
treatment for patients with SCLC relapse at least 60 days after therapy
months (95% CI, 9.6–upper level not reached). After 1 year, 60.9% of
compared single-agent IV topotecan with the combination regimen CAV.203
patients were alive and after 2 years, 27.1% were alive. Common grade
Both arms had similar response rates (topotecan, 24.3%; CAV, 18.3%)
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and survival (25.0 vs. 24.7 weeks). Compared to CAV, topotecan caused nivolumab and 21.9% for nivolumab plus ipilimumab.212 The 12- and
less grade 4 neutropenia (37.8% vs. 51.4%; P < .001) and improved 24-month overall survival rates were similar (nivolumab, 30.5% and
symptoms of dyspnea, anorexia, hoarseness, and fatigue. There is 17.9%; nivolumab plus ipilimumab, 30.2% and 16.9%, respectively).
conflicting data regarding the usefulness of weekly topotecan in patients Grade 3–4 adverse events were 12.9% for nivolumab alone and 37.5% for
with relapsed SCLC.204,205 Many practicing oncologists have noted nivolumab plus ipilimumab. In patients receiving nivolumab alone, the
excessive toxicity when using 1.5 mg/m2 of IV topotecan for 5 days, and most common grade 3 or 4 treatment-related adverse events were
studies suggest that an attenuated dose may be equally efficacious with pneumonitis and increased levels of lipase and aspartate
lower toxicity.206 In another phase 3 trial, oral topotecan improved overall aminotransferase.
survival compared with best supportive care (26 vs. 14 weeks).207 The
efficacy and toxicity of oral and IV topotecan seem to be similar and CheckMate 331, a randomized phase 3 trial, assessed nivolumab
therefore either route may be used.207,208 The NCCN SCLC Panel monotherapy versus topotecan or amrubicin in 569 patients with relapsed
recommends oral or IV topotecan as a subsequent therapy option for SCLC.209,216 Data show that overall survival was 7.5 months in patients
patients with SCLC with CTFI >6 months (other recommended regimens) receiving nivolumab versus 8.4 months in those receiving chemotherapy
and CTFI < 6 months (preferred).197,202,203,207,209 (HR, 0.86; 95% CI, 0.72–1.04; P = .11).209 Overall survival was similar
regardless of PD-L1 levels. Response rates were 13.7% for nivolumab
Irinotecan compared with 16.5% for chemotherapy. Treatment-related deaths
47% of patients responded (95% CI, 21.4%–71.9%) to irinotecan in a occurred in two patients receiving nivolumab and in three patients
phase 2 study in patients with refractory or relapsed SCLC.210 receiving chemotherapy. Fewer grade 3–4 adverse events occurred in
Myelosuppression, diarrhea, and pulmonary toxicity were reported in patients receiving nivolumab compared with chemotherapy (14% vs. 73%,
patients receiving irinotecan.210 Another phase 2/3 trial showed that respectively). A study reported that third-line therapy with nivolumab was
irinotecan and topotecan had comparable activity in patients with relapsed associated with longer survival (5.7 months; 95% CI, 3.5–8.0) compared
or refractory SCLC and metastasis.211 The NCCN SCLC Panel with other treatments such as paclitaxel or topotecan (3.8 months; 95% CI,
recommends irinotecan as a subsequent therapy option for patients with 2.8–4.9; HR, 0.63; 95% CI, 0.44–0.90).217 The 1-year overall survival rate
SCLC with CTFI >6 months (other recommended regimens) and CTFI <6 is 28% with nivolumab versus 4% with the other treatments.
months (preferred). The panel added a consideration for irinotecan for
patients with CNS disease. A combined analysis of two trials, phase Ib (KEYNOTE-028) and phase 2
(KEYNOTE-158), evaluated the activity of pembrolizumab in 83 patients
Nivolumab and Pembrolizumab with relapsed SCLC who had received two or more lines of therapy. 56%
Immune checkpoint inhibitors have been evaluated in patients with of patients were positive for PD-L1 (≥1%) and 84% patients did not have
relapsed SCLC.212-215 CheckMate 032, a phase 1/2 trial, assessed brain metastases.218,219 This analysis reported a response rate of 19.3%
nivolumab alone (n = 147) or various doses of nivolumab plus ipilimumab (95% CI, 11.4%–29.4%). The median overall survival was 7.7 months
(n = 96) for relapsed SCLC.212,213 Response rates were 11.6% for (95% CI, 5.2–10.1); the estimated 12-month overall survival rate was 34%.
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Both overall survival and response rate were higher in those who were Immunotherapy-Related Toxicities, available at www.NCCN.org).222,223 For
PD-L1 positive; however, one patient with a complete response had a patients with immune-mediated adverse events, high-dose corticosteroids
tumor that was PD-L1 negative. Grade 3 or 4 adverse events occurred in are generally recommended based on the severity of the reaction.
9.6% (8/83) of patients; two patients died from treatment-related adverse Nivolumab or pembrolizumab should be withheld or discontinued for
events (pneumonitis and encephalitis). severe or life-threatening immune-mediated adverse events when
indicated (see prescribing information).
The FDA has withdrawn the subsequent therapy indications for nivolumab
or pembrolizumab for patients with relapsed SCLC, because phase 3 Other Subsequent Therapy Options
randomized trial data did not show an improvement in overall survival. Paclitaxel and docetaxel that belong to the taxane class of drugs have
209,213,214,216,218-221 However, the NCCN SCLC Panel lists these agents as been assessed in patients with refractory or relapsed SCLC. In a phase 2
subsequent systemic therapy options (other recommended regimens) for study in patients with refractory or relapsed SCLC; 24% of patients
patients with CTFI <6 months. The panel decided that nivolumab or responded to paclitaxel.224 Grade 3–4 toxicity included neutropenia,
pembrolizumab are just as effective as (sometimes better than) and less infection, rash, neuropathy, and pulmonary toxicity. Another phase 2 study
toxic than the other subsequent therapy options.209,217 In addition, many of paclitaxel in patients with refractory SCLC yielded a response rate of
agents recommended as subsequent therapy options for patients with 29% (95% CI, 12%–51%).225 A retrospective study in 185 patients showed
SCLC do not have an FDA indication in this setting but data show that a response rate of 17% during third-line or fourth-line therapy with
they are effective (see Other Subsequent Therapy Options in this paclitaxel. Toxicity rates were similar in patients with PS 2 compared with
Discussion). Patients with limited-stage SCLC who relapse and have not PS 0 to 1 (63% vs. 62%).226 25% of patients responded to docetaxel in a
previously received immune checkpoint inhibitors may benefit from phase 2 trial in patients with previously treated SCLC. Reported toxicities
subsequent therapy with nivolumab or pembrolizumab. However, the use included neutropenia and asthenia.227
of nivolumab and pembrolizumab is discouraged in patients whose
disease progresses while on maintenance atezolizumab or durvalumab as Oral etoposide was assessed in a phase 2 trial in 22 patients with
part of first-line therapy. There are no data to suggest that giving patients recurrent SCLC.228 Ten patients (45%; 95% CI, 27%–65%) had a
subsequent immune checkpoint inhibitors is effective if their disease complete or partial response. Median survival was 3.5 or more months
previously progressed on other immune checkpoint inhibitors. (range, 1 to 15+). Five patients were hospitalized because of neutropenia
and fever. Two patients died from sepsis. Another phase 2 trial assessed
Immunotherapeutic agents, such as nivolumab and pembrolizumab, may oral etoposide in 26 patients with refractory SCLC.229 The overall response
cause unique immune-mediated adverse events that are not seen with rate was 23%; there was one complete response and five partial
traditional cytotoxic chemotherapy. Therefore, health care providers responses.
should be aware of the spectrum of potential immune-mediated adverse
events, know how to manage these events, and discuss possible side Gemcitabine was assessed in a phase 2 trial in 42 patients with sensitive
effects with patients (see the NCCN Guidelines for Management of or refractory SCLC.230 The median survival was 7.1 months. The overall
objective response rate was 11.9%. One patient with refractory SCLC and
MS-17

four patients with sensitive SCLC responded. Grade 3–4 toxicities SCLC, however consolidative or palliative RT is an option for these
included neutropenia (27%), thrombocytopenia (27%), neurologic toxicity patients. The American Radium Society appropriate use criteria and the
(14%), and pulmonary (9%). Another phase 2 trial assessed gemcitabine American Society for Radiation Oncology (ASTRO) guidelines are useful
in 38 patients with resistant SCLC that progressed within 3 months of last resources.236-239 The Principles of Radiation Therapy section in the NSCLC
therapy.231 The median survival was 17 weeks (range, 4–84). The algorithm may also be useful (see the NCCN Guidelines for Non-Small
response rate was 13% (95% CI, 6%–27%); there were five partial Cell Lung Cancer, available at www.NCCN.org).
responses and no complete responses. Grade 3 toxicities included
Thoracic Radiation Therapy
thrombocytopenia (29%) and leukopenia (18%).
Achieving long-term local control using conventional chemoradiotherapy
Data suggest that temozolomide may be useful for patients with SCLC, for patients with limited-stage SCLC remains a challenge. The addition of
especially those with brain metastases and methylated thoracic RT has improved survival for patients with limited-stage SCLC.
O6-methylguanine-DNA methyltransferase (MGMT).232-234 Temozolomide Meta-analyses that include more than 2000 patients show that thoracic
was assessed in a phase 2 trial in patients with relapsed or refractory radiation for limited-stage SCLC yields a 25% to 30% reduction in local
SCLC. In patients with sensitive SCLC, the overall response rate was 23% progression, and a corresponding 5% to 7% improvement in 2-year overall
(95% CI, 12%–37%). The response rate improved for patients with survival compared with chemotherapy alone.101,102 A phase 3 trial has
methylated MGMT compared to those with unmethylated MGMT (38% vs. reported 5-year overall survival of more than 30%, which is close to
7%; P = .08). outcomes of locally advanced NSCLC of similar stage.108
A phase 3 trial (JCOG0605) from Japan in patients with sensitive, Timing of Radiation with Chemotherapy
relapsed SCLC reported that the combination of cisplatin, etoposide, and Optimal thoracic RT is impacted by several factors, including the timing of
irinotecan improved survival compared with topotecan (median survival, chemotherapy and RT (concurrent vs. sequential), timing of RT (early vs.
18.2 vs. 12.5 months; HR, 0.67; 90% CI, 0.51–0.88; P = .0079). However, late), the RT target volume (original tumor volume vs. shrinking field as the
the toxicity of this regimen was significant and it is not recommended for tumor responds), dose of radiation, and fractionation of RT. Early
subsequent therapy.235 The NCCN Panel recommends CAV as a concurrent chemoradiotherapy is recommended for patients with
subsequent therapy options based on clinical trial data.203 limited-stage SCLC based on randomized trials. A randomized phase 3
trial by the Japanese Cooperative Oncology Group (9104) assessed
Radiation Therapy sequential versus concurrent thoracic RT combined with
The Principles of Radiation Therapy section in the algorithm, including PCI etoposide/cisplatin for 231 patients with limited-stage SCLC. Overall
and treatment of brain metastasis, describes the radiation doses, target survival was 27.2 months for those receiving concurrent chemoradiation
volumes, and normal tissue dose-volume constraints for limited-stage versus 19.7 months for those receiving sequential chemoradiation (P =
SCLC and includes references to support the recommendations. RT is not .097).115 Patients receiving concurrent chemoradiation had more severe
recommended as primary treatment for patients with extensive-stage hematologic toxicity. Severe esophagitis occurred in 9% of patients
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receiving concurrent chemoradiation and 4% receiving sequential dose intensity compared to modern conventionally fractionated regimens
chemoradiation. using higher total doses.
Several systematic reviews and meta-analyses on the timing of thoracic CONVERT, a phase 3 randomized trial, compared accelerated 45 Gy
RT in limited-stage SCLC have reported that early concurrent (given twice daily over 3 weeks) with higher dose conventionally
chemoradiation results in a small, but significant improvement in overall fractionated 66 Gy (given once daily over 6.5 weeks) in 547 patients with
survival compared with late concurrent or sequential chemoradiation.240,241 limited-stage SCLC.108 Median overall survival was similar between the 2
A randomized phase 3 trial (by the National Cancer Institute of Canada) groups (30 vs. 25 months). However, the CONVERT trial was not powered
compared RT beginning with either cycle 2 or cycle 6 of chemotherapy to show equivalence. Although toxicity was generally similar between the
and showed that early RT was associated with improved local and arms, patients receiving accelerated 45 Gy had more grade 4 neutropenia
systemic control and longer survival.242 Another meta-analysis in patients compared with those receiving conventional 66 Gy (49% vs. 38%; P =
with limited-stage SCLC showed that survival improved with rapid .05).
completion of the chemoradiotherapy regimen (start of any chemotherapy
until the end of RT [SER]).243 A meta-analysis of individual patient data CALGB 30610 (Alliance)/RTOG 0538, a randomized phase 3 trial,
from 12 trials (2668 patients) reported that early concurrent compared high-dose conventional 70 Gy (once daily over 7 weeks) with
chemoradiation, associated with increase in acute esophagitis, had higher accelerated 45 Gy (twice daily over 3 weeks) in 638 patients with
5-year overall survival (HR, 0.79; 95% CI, 0.69–0.91) compared with late limited-stage SCLC.246 Originally, there was a 61.2 Gy concomitant boost
concurrent chemoradiation.244 group in this trial, but it was removed based on a planned interim toxicity
analysis.247 Median overall survival was 30.5 months in the conventional
Radiation Fractionation 70 Gy arm versus 28.5 months in the accelerated 45 Gy arm (HR, 0.94;
The Eastern Cooperative Oncology Group (ECOG)/Radiation Therapy 95% CI, 0.75–1.17; P = .591). There were 5 deaths in the conventional 70
Oncology Group (RTOG) compared accelerated to conventionally Gy arm and 2 deaths in the accelerated 45 Gy arm. Overall survival and
fractionated RT with etoposide/cisplatin.245 In this trial, 412 patients with toxicity were similar. The conventional 70 Gy arm had better quality-of-life
limited-stage SCLC were treated with concurrent chemoradiation using a scores at 3 weeks with patients reporting it to be more convenient. The
total dose of 45 Gy delivered either twice daily over 3 weeks (accelerated) study was not designed to assess whether the conventional 70 Gy arm
or once daily over 5 weeks (conventional). Median overall survival was 23 was superior to the accelerated 45 Gy arm.
versus 19 months (P = .04), and 5-year survival rates were 26% versus
A randomized phase 2 trial assessed concurrent chemoradiation with two
16% in the accelerated and conventional RT arms, respectively.245 A
similarly accelerated regimens, 42 Gy given as once-daily fractions over 3
higher incidence of grade 3–4 esophagitis was seen with the accelerated
weeks compared with 45 Gy given as twice-daily fractions also over 3
regimen compared with the conventional regimen.245 A significant criticism
weeks in 157 patients with limited-stage SCLC.248 The overall survival
of this trial is that the 45 Gy conventional regimen provided suboptimal
curves overlapped with median overall survival of 18.8 months in the
once-daily arm and 25.1 months in the twice-daily arm (P = .61). A
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retrospective study assessed concurrent chemoradiation with accelerated similar.108,246,252 Overall, accelerated RT (whether given once or twice
40 Gy in 3 weeks given as once-daily fractionation in 68 patients with daily) is superior to similar doses of conventionally fractionated RT and
limited-stage SCLC.249 The median survival was 28 months which is comparable to higher dose conventionally fractionated RT. The NCCN
comparable to outcomes of similarly accelerated twice-daily fractionation. SCLC Panel recommends that either accelerated 45 Gy given as
twice-daily fractions over 3 weeks (category 1) or conventionally
Two randomized phase 2 trials compared high-dose accelerated RT with fractionated 66 to 70 Gy given as once-daily fractions over 6.5 to 7 weeks
standard-dose accelerated RT. One trial compared concurrent are acceptable options depending on individual patient
chemoradiation with high-dose accelerated 65 Gy given as once-daily circumstances.108,246,252 The NCCN SCLC Panel maintains that higher
fractions over approximately 5 weeks with standard-dose accelerated 45 doses of 66 to 70 Gy are preferred if using once-daily fractionation,252
Gy given as twice-daily fractions over 3 weeks in 182 patients with since the twice-daily thoracic radiation is logistically challenging for many
limited-stage SCLC.250 Estimated PFS was 17.2 months in the high-dose patients and RT centers.
group versus 13.4 months in the standard-dose group (P = .031). Overall
survival was 39.3 months in the high-dose group versus 33.6 months in Radiation for Limited-Stage SCLC
the standard-dose group (P = .137). Grade 3 or higher esophagitis External-Beam RT
(high-dose, 17.4% vs. standard-dose, 15.3%), grade 3 or higher For limited-stage IIB to IIIC disease (T3–4, N0, M0; T1–4, N1–3, M0), the
pneumonitis (high-dose, 3.3% vs. standard-dose, 2.4%), and NCCN Guidelines recommend that RT should be used concurrently with
treatment-related deaths (high-dose, 2.2% vs. standard-dose, 1.2%) were chemotherapy and that RT should start with the first or second cycle
similar in each group. The second trial compared concurrent (category 1 for patients with PS 0–2).237,240 The optimal dose and schedule
chemoradiation using high-dose accelerated RT with 60 Gy given as of RT have not been established. For accelerated RT, the recommended
twice-daily fractions over 4 weeks with standard-dose accelerated 45 Gy schedule is 1.5 Gy twice daily to a total dose of 45 Gy in 3 weeks. For
given as twice-daily fractions over 3 weeks in 176 patients with conventionally fractionated RT, the recommended schedule is 2.0 Gy once
limited-stage SCLC.251 After 2 years, 74.2% (95% CI, 63.8%–82.9%) of daily to a total dose of 66 to 70 Gy.108,252-255
patients were alive in the 60 Gy group versus 48.1% (95% CI, 36.9%–
59.5%) in the 45 Gy group. Three treatment-related deaths occurred in The minimum technical requirement for thoracic irradiation is CT-planned
each group. 3D-conformal RT. Intensity-modulated RT (IMRT) is preferred over
3D-conformal external-beam RT (EBRT) because of lower toxicity. The
Despite multiple trials, the optimal dose and fractionation of thoracic RT for normal tissue constraints used for NSCLC are appropriate for SCLC when
SCLC remains unresolved. Higher dose accelerated RT may be using similar RT doses (see Principles of Radiation Therapy in the
advantageous, and this remains to be confirmed in larger studies. Two algorithm and the NCCN Guidelines for Non-Small Cell Lung Cancer,
randomized trials have not shown that high dose without acceleration (66 available at www.NCCN.org).256-261 More advanced technologies, such as
Gy or 70 Gy over 6.5–7 weeks) is superior to moderate dose accelerated 4D-CT and proton therapy, may also be appropriate to limit normal tissue
fractionation (45 Gy over 3 weeks); however, survival and toxicity are toxicity. The radiation target volumes can be defined on the FDG-PET/CT
MS-20

scan obtained at the time of RT planning, as well as any positive biopsies, chemoradiation, those receiving SABR were often older, had T1 disease,
using definitions in Reports 50 and 62 from the International Commission and treated recently in academic medical settings. Median survival was
on Radiation Units & Measurements (ICRU).262,263 However, the 29.2 months in those receiving SABR/chemotherapy versus 31.2 months
pre-chemotherapy FDG-PET/CT scan should be reviewed to include the in those receiving chemoradiation (P = .77). Both ASTRO and the
original involved lymph node regions in the treatment fields if American Radium Society recommend SABR followed by adjuvant
chemotherapy begins before RT.255,264 When using accelerated schedules chemotherapy as an option for medically inoperable patients with clinical
(eg, 3–5 weeks), the spinal cord constraints from the CALGB limited stage I–IIA SCLC (T1–2, N0).237,238
30610/RTOG 0538 protocol can be used as a guide.252,265-267
The NCCN SCLC Panel recommends (category 2A) SABR followed by
SABR systemic therapy as an option for select patients with clinical limited stage
Emerging data suggest that SABR (also known as stereotactic body RT I–IIA (T1–2, N0) ie who are medically inoperable or decline surgery.14,274
[SBRT]) is effective for patients with clinical limited-stage I–IIA (T1–2, N0) The NCCN SCLC Panel added a caveat that systemic therapy may be
SCLC, especially for medically inoperable circumstances or refuse initiated first, if time to initiation of SABR will be prolonged. The NCCN
surgery.14,268-273 A meta-analysis of 7 studies (399 patients) summarized Guidelines for NSCLC provide detailed recommendations for SABR that
outcomes in patients with early-stage SCLC who received SABR; 94% of may be useful for SCLC (see Principles of Radiation Therapy in the NCCN
the patients in this study were deemed inoperable.273 44% of patients Guidelines for NSCLC, available at www.NCCN.org).
received chemotherapy and 13.8% of patients received PCI. Overall
survival was 86% (95% CI, 74%–95%) and 64% (95% CI, 46%–80%) at 1 Radiation for Extensive-Stage SCLC
year and 2 years, respectively. The nodal and distal recurrence rates were Sequential Thoracic Radiation for Extensive-Stage SCLC
18% (95% CI, 7.5%–31%) and 27% (95% CI, 7.4%–53%), respectively. A randomized trial by Jeremic et al275 assessed sequential (consolidative)
Grade 3 toxicity was observed in 1.4% of patients (95% CI, 0%–5.3%). A thoracic RT in patients experiencing a complete response at distant
multicenter analysis of 74 patients suggested that the addition of metastatic sites after 3 cycles of etoposide/cisplatin. Patients were
chemotherapy typically after SABR improves survival for patients with randomized to receive either 1) further etoposide/cisplatin; or 2)
clinical limited-stage SCLC.16,274 Most of these patients had FDG-PET accelerated hyperfractionated RT (ie, 54 Gy in 36 fractions over 18
staging but not pathologic nodal staging. Patients who received treatment days) in combination with carboplatin plus etoposide.275 The
chemotherapy after SABR had a median overall survival of 31.4 months addition of RT resulted in improved median overall survival (17 vs. 11
versus 14.3 months for those who received SABR alone (P = .02). months). The Dutch CREST trial, a phase 3 randomized trial in patients
with extensive-stage SCLC, reported that the addition of consolidative
An analysis of 2107 patients with histologically confirmed T1–T2, N0, M0 thoracic RT (30 Gy in 10 fractions) did not improve the primary endpoint of
from the National Cancer Database found that 7.1% had upfront SABR 1-year overall survival (33% vs. 28%; P = .066). A secondary analysis
followed by adjuvant chemotherapy and 92.9% had concurrent found improvement in 2-year overall survival (13% vs. 3%; P = .004) and
chemoradiation.12 Compared with patients receiving upfront concurrent 6-month PFS compared with patients who did not receive consolidative
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thoracic RT.276 A trial involving 32 patients who received consolidative incidence of brain metastases, from 58.6% in the control group to 33.3% in
thoracic RT reported that only 16% of patients had symptomatic chest the PCI-treated group.100 Thus, PCI seems to prevent, and not simply
recurrences.277 Consolidative thoracic RT appears to mainly benefit delay, the emergence of brain metastases. This meta-analysis also
patients with residual thoracic disease after chemotherapy (without reported an increase in 3-year overall survival from 15.3% in the control
immunotherapy) and low-bulk extrathoracic metastatic disease that has group to 20.7% in the PCI group.100 Although the number of patients with
responded to systemic therapy.278 The American Radium Society extensive-stage SCLC was small, the observed benefit was similar in
recommends that consolidative thoracic RT be considered for select patients with both limited-stage and extensive-stage SCLC. A
patients with extensive-stage SCLC based on the limited data.236 retrospective study of patients with limited-stage SCLC also found that PCI
European experts (International Association for the Study of Lung Cancer increased survival at 2, 5, and 10 years compared with those who did not
[IASLC] and European Society Radiation Oncology [ESTRO]) recommend receive PCI.282 A study of 184 patients with limited-stage SCLC assessed
consolidative thoracic RT in select patients with stage IV SCLC who have PCI versus no PCI in patients who responded to chemoradiotherapy and
responded to first-line chemotherapy and have limited extrathoracic tumor had no brain metastases on MRI imaging, before and after primary
burden.279 treatment.283 In patients receiving PCI, median overall survival was 26
months (range, 19.4–32.6 months) versus 14 months (range, 11.4–16.6
The NCCN SCLC Panel recommends that consolidative thoracic RT be months; P < .0001) for those without PCI.
considered in select patients with low bulk extra thoracic metastatic
extensive stage disease who have a complete or near complete response None of the abovementioned studies in limited-stage SCLC used MRI
after initial systemic therapy before maintenance immunotherapy.236,275,276 staging of the brain or FDG-PET scans for overall staging. A retrospective
Sequential thoracic RT can be considered for selected patients, during or study included 49 patients with limited-stage SCLC who were staged with
before maintenance immunotherapy; however, there are limited data on brain MRI before treatment.284 The median overall survival was 55 months
optimal sequencing. The benefit of thoracic RT in the context of in patients with limited-stage SCLC who received PCI versus 24 months in
chemoimmunotherapy is under evaluation in the RAPTOR/NRG LU007 those who did not receive PCI (P < .05). At 1 year, the probability of
trial (NCT04402788). developing symptomatic brain metastases was 4% in patients with
limited-stage SCLC who received PCI versus 22% in those who did not
Prophylactic Cranial Irradiation
receive PCI (P < .05). For patients with extensive-stage SCLC, but without
Intracranial metastases occur in greater than 50% of patients with SCLC. brain metastases, a large retrospective analysis of 4257 patients showed
Randomized studies show that PCI is effective in decreasing the incidence that PCI improved median overall survival compared with no PCI (13.9 vs.
of cerebral metastases, but most individual studies did not have sufficient 11.1 months; P < .0001).285 Another analysis of patients with
power to show a meaningful survival advantage.280 Several meta-analyses extensive-stage SCLC (n = 397) reported that PCI improved overall
suggest that PCI after complete resection may benefit patients with survival compared with no PCI (13.5 vs. 8.5 months, respectively; HR,
pathologic stage IIB or stage III SCLC.99,100,281 A meta-analysis of all 0.55; 95% CI, 0.39–0.77; P = .0005); however, these patients did not
randomized PCI trials reported a nearly 50% reduction in the 3-year receive routine surveillance brain imaging.286
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The EORTC performed a randomized trial that assessed PCI versus no limited-stage SCLC that shows a complete or partial response.98,100,287 The
PCI in 286 patients with extensive-stage SCLC that had responded to NCCN Panel maintains that the benefit of PCI is unclear in patients with
initial chemotherapy. PCI decreased symptomatic brain metastases very early-stage SCLC (pathologic limited-stage I [T1–2a, N0, M0]) who
(14.6% vs. 40.4%) and increased the 1-year survival rate (27.1% vs. have had definitive therapy (ie, surgery, SABR). These patients have a
13.3%) compared with controls.287 However, the study did not require lower risk of developing brain metastases than patients with more
brain imaging prior to PCI and did not standardize the PCI dose or advanced limited-stage SCLC and may not benefit from PCI.99,274,293 The
fractionation. Conflicting data from a randomized phase 3 trial in Japan NCCN Panel recommends MRI brain surveillance for all patients with
found that median overall survival is not improved in patients receiving PCI limited-stage SCLC who do not receive PCI. In patients with
compared with MRI surveillance (11.6 months; 95% CI, 9.5–13 vs. 13.7 extensive-stage SCLC, the NCCN Panel recommends MRI brain
months; 95% CI, 10.2–16.4) (HR, 1.27; 95% CI, 0.96–1.68; P = .094).288 In surveillance with or without consideration of PCI based on the conflicting
this trial, patients were required to have an MRI to confirm that they did not trial results from Japan and the EORTC.287,288 Brain imaging surveillance
have brain metastases prior to PCI, and the PCI regimen was for metastases is recommended using either MRI (preferred) or CT with
standardized at 25 Gy in 10 fractions. In addition, the study required close contrast in patients who are unable to undergo MRI.288
MRI surveillance imaging in patients to allow for the early treatment of
brain metastases. The American Radium Society recommends either PCI Higher PCI doses (eg, 36 Gy) increased mortality and toxicity compared
or brain MRI surveillance for patients with extensive-stage SCLC and with lower doses (25 Gy).181,294 Therefore, the preferred dose for PCI is 25
without brain metastases based on the limited data.236 A randomized trial Gy in 10 daily fractions (2.5 Gy/fraction).100,287,294 A shorter course of PCI
(SWOG S1827/MAVERICK) is currently assessing brain MRI surveillance may be appropriate (eg, 20 Gy in 5 fractions) for selected patients with
alone compared to brain MRI surveillance plus PCI for patients with extensive-stage SCLC.287 PCI should not be given concurrently with
late-stage SCLC and early-stage SCLC. Late neurologic sequelae have chemotherapy, and high total RT dose (>30 Gy) should be avoided
been attributed to PCI, particularly in studies using fractions greater than 3 because of the increased risk of neurotoxicity.181 After the acute toxicities
Gy and/or administering PCI concurrently with chemotherapy.182,289,290 of initial systemic therapy have resolved, PCI can be administered. When
Thus, PCI is not recommended for patients with poor PS (3–4) or impaired given after the completion of chemotherapy and at a low dose per fraction,
neurocognitive function.98,291 PCI has also been associated with chronic PCI may cause less neurologic toxicity. Fatigue, headache, and
neurotoxicity in patients who are aged ≥60 years.181,183 nausea/vomiting are the most common acute toxic effects after PCI.291,294
The NCCN SCLC Panel has gradually revised the adjuvant The NCCN SCLC Panel recommends that memantine be considered for
recommendations for patients whose disease showed a complete or patients receiving PCI or therapeutic whole-brain irradiation. Memantine is
partial response after primary treatment based on conflicting clinical trial a N-methyl-D-aspartate (NMDA) receptor antagonist that may delay
data and concerns about using PCI. Before a decision is made to cognitive dysfunction in patients receiving brain RT.295 Patients receiving
administer PCI, a balanced discussion is necessary between the patient memantine have a longer time before cognitive decline (HR, 0.78; 95% CI,
and physician.182,292 The NCCN Panel recommends PCI for patients with 0.62–0.99; P = .01). NRG Oncology CC001, a phase 3 randomized trial,
MS-23

assessed hippocampal-avoidance (HA) whole-brain IMRT plus memantine www.NCCN.org).303 The recommended dose for whole-brain RT is 30 Gy
compared with conventional whole-brain RT plus memantine in patients in 10 daily fractions.303
with brain metastases who were not diagnosed with SCLC.296 Cognitive
preservation and patient-reported outcomes were improved with HA IMRT A retrospective multicenter cohort study assessed SRS versus
(HR, 0.74; 95% CI, 0.58–0.95; P=.02). However, conflicting data have whole-brain RT in 710 patients with SCLC who had a limited number of
been reported with HA PCI versus conventional PCI. PREMER, a phase 3 brain metastases; overall survival was 6.5 months (95% CI, 5.5–8.0) for
randomized trial, reported improved cognitive preservation with HA PCI.297 SRS and 5.2 months (95% CI, 4.4–6.7) for whole-brain RT (P = .003).304 A
However, another phase 3 randomized trial (NCT01780675) reported no meta-analysis of nine observational studies (1638 patients) also reported
differences in cognition with HA PCI.298 A large randomized trial (NRG favorable lesion control and survival outcomes with SRS versus
CC003) is assessing HA-PCI versus conventional PCI.299 whole-brain RT.305 A randomized trial (NRG CC009) is comparing SRS to
HA whole-brain IMRT plus memantine in this setting. The NCCN Panel
Palliative Radiation Therapy decided that SRS may be used for selected patients with a small number
For patients with localized symptomatic sites of disease (ie, painful bony of brain metastases based on available data, pending outcomes of the
lesions, spinal cord compression, obstructive atelectasis) or with brain ongoing trials.304 In patients who develop brain metastases after PCI, SRS
metastases, RT can provide excellent palliation (see the algorithm and the (preferred) or repeat whole-brain RT (in carefully selected patients) may
NCCN Guidelines for Non-Small Cell Lung Cancer, available at be considered.306,307 For patients with a better prognosis (eg, ≥4 months),
www.NCCN.org).300-302 Orthopedic stabilization may be useful in patients HA whole-brain IMRT plus memantine is preferred because it produces
at high risk for fracture because of osseous structural impairment. less of a decrease in cognitive function than conventional whole-brain RT
Because patients with SCLC often have a short life span, surgery is not plus memantine. However, patients with metastases within 5 mm of the
usually recommended for spinal cord compression. Radiation dose and hippocampi, leptomeningeal metastases, and other high-risk features were
fractionation for extracranial metastases include 30 Gy in 10 fractions, 20 not eligible for HA whole-brain IMRT in the phase 3 NRG CC001 trial.296
Gy in 5 fractions, or 8 Gy in 1 fraction based on common
dose-fractionation regimens used for other solid tumors (see the NCCN Summary
Guidelines for NSCLC, available at www.NCCN.org). IMRT, SABR, or In summary, the NCCN Guidelines for SCLC v1.2024 has
stereotactic radiosurgery (SRS) may be appropriate for select patients (eg, recommendations for diagnosis, evaluation, therapy options and
those whose tumors are in close proximity to organs at risk). surveillance for both limited-stage and extensive-stage SCLC. These
recommendations are based on data from clinical trials and panel
Brain metastases have conventionally been treated with whole brain RT in expertise.
patients with SCLC due to the frequent occurrence of multiple metastases
(see Principles of Radiation Therapy in the algorithm and the NCCN
Guidelines for Central Nervous System Cancers, available at
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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Small Cell Lung Cancer

NCCN Guidelines for Patients® available at www.nccn.org/patients

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

*Apar Kishor P. Ganti, MD, Chair † John C. Grecula, MD § Chinh Phan, DO Ξ

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

DIAGNOSIS INITIAL EVALUATIONa,b STAGE

• History and physical (H&P)c

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

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

STAGE ADDITIONAL WORKUPb

• If pleural effusion is present,

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

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

TESTING RESULTSk PRIMARY TREATMENT ADJUVANT TREATMENT

Pathologic mediastinal stagingj,k positive SCL-4

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

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

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

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

Poor PS (3–4) Individualized treatment including supportive carer

m Principles of Systemic Therapy (SCL-E).

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

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

STAGE PRIMARY TREATMENTu

Administer systemic therapy before

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

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

RESPONSE ASSESSMENT FOLLOWING ADJUVANT RT SURVEILLANCE

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

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

PROGRESSIVE DISEASE SUBSEQUENT THERAPY/PALLIATIVE THERAPY

PS 3–4 Palliative symptom management,r,dd including localized RTn to symptomatic sites

m Principles of Systemic Therapy (SCL-E).

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

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

SIGNS AND SYMPTOMS OF SMALL CELL LUNG CANCER

Signs and Symptoms Due to Extrathoracic (Hematogenous) Metastases

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

SIGNS AND SYMPTOMS OF SMALL CELL LUNG CANCER

• Neurologic: All specific syndromes are rare

a Principles of Supportive Care (SCL-D).

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

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

PRINCIPLES OF PATHOLOGIC REVIEW

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

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

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

PRINCIPLES OF SURGICAL RESECTION

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

NCCN Guidelines Version 3.2024 NCCN Guidelines Index

PRINCIPLES OF SUPPORTIVE CARE

• Pain management: See NCCN Guidelines for Adult Cancer Pain