NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Small Cell Lung Cancer

Version 1.2027 — July 1, 2026

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Small Cell Lung Cancer Discussion

*Apar Kishor P. Ganti, MD, Chair † John C. Grecula, MD § Tejas Patil, MD †

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

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Table of Contents
Small Cell Lung Cancer Discussion

Find an NCCN Member Institution:

NCCN Small Cell Lung Cancer Panel Members [Link]
Summary of the Guidelines Updates institutions.
Initial Evaluation and Staging (SCL-1) NCCN Categories of Evidence and
Limited Stage, Workup, and Treatment (SCL-2) Consensus: All recommendations
Extensive Stage, Primary Treatment (SCL-5) are category 2A unless otherwise
Response Assessment Following Primary Treatment and Adjuvant Therapy (SCL-6) indicated.
Progressive Disease: Subsequent Therapy and Palliative Therapy (SCL-8)
See NCCN Categories of Evidence
Signs and Symptoms of Small Cell Lung Cancer (SCL-A) and Consensus.
Principles of Pathologic Review (SCL-B) NCCN Categories of Preference:
Principles of Surgical Resection (SCL-C) All recommendations are considered
Principles of Supportive Care (SCL-D) appropriate.
Principles of Systemic Therapy (SCL-E)
Principles of Radiation Therapy (SCL-F) See NCCN Categories of
Principles of Imaging (SCL-G) 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. ©2026.

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Small Cell Lung Cancer Discussion

Updates in Version 1.2027 of the NCCN Guidelines for Small Cell Lung Cancer:
General
• References updated.
SCL-1
• Initial evaluation, bullet 7: Consider molecular profiling biomarker testing
• Footnote f: If FDG-PET/CT is not available, bone scan may be used to identify bone metastases. Pathologic confirmation is recommended for isolated or equivocal
lesions if their involvement would change clinical management.
• Footnote g: Comprehensive molecular profiling Biomarker testing via blood, tissue, or both 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-2
• Footnote k: Lymph node staging procedures include endobronchial ultrasound-guided biopsy (preferred, if expertise exists), mediastinoscopy, mediastinotomy,
esophageal ultrasound-guided biopsy, and video-assisted thoracoscopy. If endobronchial lymph node biopsy is positive, additional mediastinal staging is not required.
If nodal involvement is established by one modality of mediastinal staging, additional modalities are not necessary, but staging biopsies of visible nodes in all
accessible nodal stations is encouraged to inform radiotherapy targeting. (also for SCL-3)
SCL-5
• Primary treatment, row 1: Combination Systemic therapy including supportive care
SCL-6
• Page extensively revised.
SCL-6A
• Footnote aa added: Imaging every 8 weeks for the first 18 months and every 12 weeks after.
SCL-8
• Footnote cc: Consider genomic profiling biomarker testing, if not previously done, to determine clinical trial eligibility.
SCL-B 1 of 2
• Pathologic Evaluation, bullet 8: Comprehensive molecular profiling Biomarker testing via blood, tissue, or both can be considered in rare cases...
• Immunohistochemical Staining, bullet 3 added: Carcinoid tumors generally retain RB1 expression and show a wild-type p53 staining pattern. In contrast, most high-grade
neuroendocrine carcinomas demonstrate loss of RB1 expression and/or aberrant (mutation-type) p53 expression, characterized by either diffuse strong nuclear staining
(overexpression) or complete absence of staining (null pattern).
SCL-D
• Lambert-Eaton myasthenic syndrome, sub-bullet 1: Consider amifampridine or intravenous immunoglobulin (IVIG) in consultation with neurology
SCL-E 1 of 6
• Primary or Adjuvant Therapy for Limited-Stage SCLC
Table heading: Four cycles of cytotoxic chemotherapy are recommended. Planned cycle length should be every 21–28 days during concurrent RT. During cytotoxic
chemotherapy + RT, Cisplatin/Etoposide is recommended (category 1)...
Consolidation Therapy: Durvalumab 1500 mg Day 1 every 28 Days for up to 24 months (category 1)
The following regimens were changed from a Category 1 to a Category 2A recommendation:
◊ Cisplatin 75 mg/m2 Day 1 and Etoposide 100 mg/m2 Days 1, 2, 3
◊ Cisplatin 60 mg/m2 Day 1 and Etoposide 120 mg/m2 Days 1, 2, 3
• Primary Therapy for Extensive Stage SCLC
Regimen changed from category 2A to category 1: 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 Lurbinectedin 3.2 mg/m2 and Atezolizumab 1200 mg Day 1, every 21 days

Continued
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Small Cell Lung Cancer Discussion

Updates in Version 1.2027 of the NCCN Guidelines for Small Cell Lung Cancer:
SCL-E 3 of 6
• Footnote d: Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or concurrent use of
immunosuppressive agents. If TKI is continued, for transformed SCLC from NSCLC with oncogenic driver, ICI should be avoided due to known toxicity.
• Footnote added: NCCN Guidelines for Management of CAR T-Cell and Lymphocyte Engager-Related Toxicities.
• Footnote added: Pembrolizumab and berahyaluronidase alfa-pmph subcutaneous injection may be substituted for IV pembrolizumab. Pembrolizumab and
berahyaluronidase alfa-pmph has different dosing and administration instructions compared to IV pembrolizumab.
MS-1
• Discussion section updated to reflect changes within the algorithm

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DIAGNOSIS INITIAL EVALUATIONa,b STAGE

• History and physical (H&P)c

• Pathology reviewd Limited stage
• Complete blood count (CBC) (see ST-1 for TNM Additional
Small cell lung • Electrolytes, liver function tests Classification) Workup (SCL-2)
cancer (SCLC) or (LFTs), blood urea nitrogen (BUN),
combined SCLC/ creatinine
non-small cell lung • Imaging studies based on
cancer (NSCLC) on Principles of Imaging (SCL-G)a,e,f
biopsy or cytology • Smoking cessation counseling and
of primary or intervention. See NCCN Guidelines Extensive stage
(see ST-1 for TNM Primary
metastatic site for Smoking Cessation
Treatment (SCL-5)
• Consider biomarker testingg Classification)
• Integrate palliative care. See NCCN
Guidelines for Palliative Care

a If extensive stage is established, further staging evaluation is optional and dependent on the clinical situation. However, brain imaging—MRI (preferred) or CT with
contrast—is recommended.
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. See Principles of Imaging (SCL-G).
f If FDG-PET/CT is not available, bone scan may be used to identify bone metastases. Pathologic confirmation is recommended for isolated or equivocal lesions if their
involvement would change clinical management.
g Biomarker testing via blood, tissue, or both 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.

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Small Cell Lung Cancer Discussion

STAGE ADDITIONAL WORKUPb

• If pleural effusion is present,

thoracentesis is
Limited stage:
recommended; if Pathologic lymph Primary
Clinical stage
thoracentesis inconclusive, node stagingj,k Treatment (SCL-3)
I–IIA (T1–2,N0,M0)
consider thoracoscopyh
• Pulmonary function tests
(PFTs) during evaluation
for surgery or definitive Limited stage
Limited stage radiation therapy (RT) IIB–IIIC (T3–4,N0,M0; T1–4,N1–3,M0).
• Multidisciplinary evaluation Primary
(see ST-1 for TNM Consider pathologic lymph node
is recommended before Treatment (SCL-4)
Classification) staging (especially for cN0) if it would
surgery help determine RT fieldsj,k
• Bone imaging (radiographs
or MRI) as appropriate if
FDG-PET/CT equivocal
(consider biopsy if bone Bone marrow biopsy,
imaging is equivocal) thoracentesis, or any Extensive-stage
• Unilateral marrow compelling evidence of Disease (SCL-5)
aspiration/biopsy in select distant disease consistent
patientsi 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.
Perform bone marrow biopsy only if it changes clinical management.
j Principles of Surgical Resection (SCL-C).
k Lymph node staging procedures include endobronchial ultrasound-guided biopsy (preferred, if expertise exists), mediastinoscopy, mediastinotomy, esophageal
ultrasound-guided biopsy, and video-assisted thoracoscopy. If nodal involvement is established by one modality of mediastinal staging, additional modalities are not
necessary, but staging biopsies of visible nodes in all accessible nodal stations is encouraged to inform radiotherapy targeting.

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

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TESTING RESULTSk PRIMARY TREATMENT ADJUVANT TREATMENT

N0 Systemic therapym

R0

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

Pathologic lymph node stagingj,k positive SCL-4

j Principles of Surgical Resection (SCL-C).

k Lymph node staging procedures include endobronchial ultrasound-guided biopsy (preferred, if expertise exists), mediastinoscopy, mediastinotomy, esophageal
ultrasound-guided biopsy, and video-assisted thoracoscopy. If nodal involvement is established by one modality of mediastinal staging, additional modalities are not
necessary, but staging biopsies of visible nodes in all accessible nodal stations is encouraged to inform radiotherapy targeting.
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 Systemic therapy may be initiated first if time to initiation of stereotactic body radiotherapy (SABR) will be prolonged.
p Principles of Imaging (SCL-G).

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

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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 Poor PS (3–4) Systemic therapym ± RTn
IIB–IIlC (T3–4,N0,M0; due to SCLC (concurrent or sequential)
T1–4,N1–3,M0)

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

not due to SCLC See NCCN Guidelines for Palliative Care

m Principles of Systemic Therapy (SCL-E).

n Principles of Radiation Therapy (SCL-F).
p Principles of Imaging (SCL-G).
q Principles of Supportive Care (SCL-D).

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

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SCL-4
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STAGE PRIMARY TREATMENT

• Good PS (0–2) Systemic therapym including supportive
• Poor PS (3–4) careq
Without localized due to SCLC See NCCN Guidelines for Palliative Care
symptomatic sites
or brain metastases
• Poor PS (3–4) Individualized therapy including
not due to supportive careq
SCLC See NCCN Guidelines for Palliative Care
Systemic therapym ± RTn to
• Superior vena
symptomatic sites
cava (SVC)
If high risk of fracture due to osseous
syndrome
structural impairment, consider
• Lobar obstruction
Extensive stage orthopedic stabilization and
Localized • Bone metastases
(see ST-1 for TNM palliative external beam RT (EBRT)n Response
Classification)r symptomatic sites
• Initiate steroidst Assessment
• Systemic therapym + RTn (typically Following Primary
Spinal cord
sequential)u Treatment (SCL-6)p
compression
• See NCCN Guidelines for Central
Nervous System Cancers
Administer systemic therapy before
Asymptomatic
initiating brain RTm,n,s
With brain
• Brain RTn before systemic therapy,u
metastases
unless immediate systemic therapy
Symptomatic
is indicated
• Initiate steroidst
m Principles of Systemic Therapy (SCL-E).
n Principles of Radiation Therapy (SCL-F).
p Principles of Imaging (SCL-G).
q Principles of Supportive Care (SCL-D).
r For transformation to SCLC from NSCLC, consider referral to a center with expertise (SCL-E 4 of 6).
s If brain metastases progress while on systemic therapy, it is recommended that brain RT is initiated before completion of systemic therapy.
t Initiate steroids for patients with symptomatic neurologic disease. Eg, dexamethasone 10 mg loading dose followed by 4–6 mg maintenance dose (IV or PO every 4–6 hours [or
as appropriate]). Kumar A, et al. Clin Spine Surg 2017;4:156-163.
u 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.

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

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RESPONSE ASSESSMENT FOLLOWING ADJUVANT THERAPY

PRIMARY TREATMENT

Durvalumabm,y,z,aa (category 1)
Good
PS
Prophylactic cranial
Limited irradiation (PCI)c,n,v,w,y
stage
or consider MRI brain Durvalumabm,y,z,aa (category 1)
surveillancee,v
Complete
response or Poor
partial response Consider MRI brain surveillancee,v
PS
or stable
disease
Extensive stage Surveillance
• Continue maintenance • MRI brain surveillancee,v ± (SCL-7)
• See Consider PCIn,v
Treatment immunotherapy, if
patient was started on Consider thoracic RTn,x
Response
Assessment chemoimmunotherapy
in Principles
of Imaging
(SCL-G)
• CBC
• Electrolytes,
LFTs, BUN,
creatinine
Primary progressive disease Subsequent Therapy/Palliative Therapy (SCL-8)

Footnotes

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

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FOOTNOTES
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. See Principles of Imaging (SCL-G)
m Principles of Systemic Therapy (SCL-E).
n Principles of Radiation Therapy (SCL-F).
v PCI is not recommended in patients with poor PS or impaired neurocognitive function. Increased cognitive decline after PCI has been observed in older adults (≥60
years) in prospective trials; the risks and benefits of PCI versus close brain surveillance, MRI (preferred), or CT with contrast should be carefully discussed with these
patients. Edelman MJ, Am Soc Clin Oncol Educ Book 2020:40:24-28.
w The benefit of PCI is unclear in patients who have undergone definitive therapy for pathologic stage I (T1–2a,N0,M0) SCLC. See Principles of Radiation Therapy
(SCL-F).
x Sequential RT to thorax in selected patients, especially with residual thoracic disease and low-bulk extrathoracic metastatic disease that has responded to systemic
therapy.
y If PCI is considered, it should be given prior to durvalumab.
z For those with good PS who are medically inoperable or decision was made not to pursue surgical resection.
aa Imaging every 8 weeks for the first 18 months and every 12 weeks after.

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

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SURVEILLANCE

After completion of initial

therapy:
Limited • Oncology follow-up
stage visits every 3 mo during
y 1–2, every 6 mo during
y 3, then annually • Provide survivorship care plan after completion of initial
therapybb
• H&Pc; blood work only as clinically indicated Relapse,
• Surveillance CT, brain MRI (preferred). See Principles of Imaging see
(SCL-G). New pulmonary nodule should initiate workup for Subsequent
potential new primary Therapy
After completion of initial • Smoking cessation intervention, see Guidelines for Smoking (SCL-8)
or subsequent therapy: Cessation
• Oncology follow-up
Extensive visits every 2 mo during
stage y 1, every 3–4 mo
during y 2–3, every 6
mo during y 4–5, then
annually

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

bb NCCN Guidelines for Survivorship.

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

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PROGRESSIVE DISEASE SUBSEQUENT THERAPY/PALLIATIVE THERAPY

• Consider subsequent
systemic therapym,p
• Palliative symptom
Continue until PS 0–2 management,q,dd
progressionee including localized
Subsequent Response or development RTn to symptomatic
systemic therapym,p of unacceptable sites
toxicity
or
PS 0–2
Palliative symptom
managementq,dd No
including localized response or
RTn to symptomatic Palliative symptom
Relapse unacceptable management,q,dd
or primary sites toxicity PS 3–4 including localized RTn
progressive to symptomatic sites
diseasecc

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

m Principles of Systemic Therapy (SCL-E).

n Principles of Radiation Therapy (SCL-F).
p Principles of Imaging (SCL-G).
q Principles of Supportive Care (SCL-D).
cc Consider biomarker testing, if not previously done, to determine clinical trial eligibility.
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 (SCL-F).

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

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Small Cell Lung Cancer Discussion

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
Note: All recommendations are category 2A unless otherwise indicated.
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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
Subacute cerebellar degeneration – ataxia, dysarthria
Encephalomyelitis – confusion, obtundation, dementia
Sensory neuropathy – pain, sensory loss
Lambert-Eaton myasthenic syndrome (LEMS)a – proximal muscle weakness, autonomic dysfunction
◊ Neurologic workup, preferably in consultation with neurology, may include but is not limited to tests for PQ- and N-type voltage-gated
calcium channel (VGCC) antibodies.
Cancer-associated retinopathy – visual loss, photosensitivity
• 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

Hematologic:
• Anemia
• Leukemoid reaction – leukocytosis
• Trousseau syndrome – migratory thrombophlebitis

a Principles of Supportive Care (SCL-D).

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

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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
• Biomarker testing via blood, tissue, or both 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.
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 For cases with suspicious SCLC morphology
without expression of neuroendocrine markers, POU2F3 immunohistochemical staining can be considered.13,14
Thyroid transcription factor-1 (TTF-1) is positive in 85% to 90% of SCLCs.15-18
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
• Carcinoid tumors generally retain RB1 expression and show a wild-type p53 staining pattern. In contrast, most high-grade neuroendocrine carcinomas
demonstrate loss of RB1 expression and/or aberrant (mutation-type) p53 expression, characterized by either diffuse strong nuclear staining (overexpression) or
complete absence of staining (null pattern). References
Note: All recommendations are category 2A unless otherwise indicated.
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PRINCIPLES OF PATHOLOGIC REVIEW – REFERENCES

1 WHO Classification of Tumours Editorial Board. Thoracic Tumours. In: WHO classification or tumours series. 5th ed. Lyon, 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 Wang Y, Jin Y, Shen X, et al. POU2F3: A sensitive and specific diagnostic marker for neuroendocrine-low/negative small cell lung cancer. Am J Surg Pathol
2023;47;1059-1066.
14 Baine MK, Febres-Aldana CA, Chang JC, et al. POU2F3 in SCLC: clinicopathologic and genomic analysis with a focus on its diagnostic utility in neuroendocrine-low
SCLC. J Thorac Oncol 2022;17:1109-1121.
15 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.
16 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.
17 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.
18 Wick MR. Immunohistology of neuroendocrine and neuroectodermal tumors. Semin Diagn Pathol 2000;17:194-203.

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

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PRINCIPLES OF SURGICAL RESECTION

• Stage I–IIA SCLC is diagnosed in <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, FDG-PET/CT imaging, and lymph node staging).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).3-7
• 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 (see 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. Pneumonectomy should not be
performed 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.

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

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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 ([Link]
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

• Lambert-Eaton myasthenic syndrome

Consider amifampridine or intravenous immunoglobulin (IVIG) in consultation with neurology

• Pain management: See NCCN Guidelines for Adult Cancer Pain

• Nausea/vomiting: See NCCN Guidelines for Antiemesis

• Psychosocial distress: See NCCN Guidelines for Distress Management

Refer to the NCCN Distress Thermometer and Problem List, which includes social determinants of health

• 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.

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

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PRINCIPLES OF SYSTEMIC THERAPY

PRIMARY OR ADJUVANT THERAPY FOR LIMITED-STAGE SCLC:
Four cycles of cytotoxic chemotherapy are recommended.
Planned cycle length should be every 21–28 days during concurrent RT.
The use of myeloid growth factors is not recommended during concurrent cytotoxic chemotherapy plus RT (category 1 for not using GM-CSF).1
Preferred
• Cisplatin 75 mg/m2 Day 1 and Etoposide 100 mg/m2 Days 1, 2, 32
• Cisplatin 60 mg/m2 Day 1 and Etoposide 120 mg/m2 Days 1, 2, 33
• Carboplatin area under the curve (AUC) 5–6 Day 1 and Etoposide 100 mg/m2 Days 1, 2, 3a,4

• Consolidation Therapy
Durvalumab 1500 mg Day 1 every 28 Days for up to 24 months (category 1)b,5

Other Recommended
• Cisplatin 25 mg/m2 Days 1, 2, 3 and Etoposide 100 mg/m2 Days 1, 2, 32

PRIMARY THERAPY FOR EXTENSIVE-STAGE SCLCc:

Four cycles of cytotoxic chemotherapy are recommended, but some patients may receive up to 6 cycles based on response and tolerability after 4 cycles.
Preferred
• 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)d,e,f,6
• 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 daysd,e,f
• 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
Lurbinectedin 3.2 mg/m2 and Atezolizumab 1200 mg Day 1, every 21 days (category 1 for all)g,h,7
• 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)d,e,i,8
• 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)d,e,i,8
Other Recommended
• Carboplatin AUC 5–6 Day 1 and Etoposide 100 mg/m2 Days 1, 2, 39 Footnotes (SCL-E 2 of 6)
• Cisplatin 75 mg/m2 Day 1 and Etoposide 100 mg/m2 Days 1, 2, 310 Subsequent Systemic Therapy (SCL-E 3 of 6)
• Cisplatin 80 mg/m2 Day 1 and Etoposide 80 mg/m2 Days 1, 2, 311 References (SCL-E 5 of 6)
• Cisplatin 25 mg/m2 Days 1, 2, 3 and Etoposide 100 mg/m2 Days 1, 2, 312
Useful in Certain Circumstances
• Carboplatin AUC 5 Day 1 and Irinotecan 50 mg/m2 Days 1, 8, 1513
• Cisplatin 60 mg/m2 Day 1 and Irinotecan 60 mg/m2 Days 1, 8, 1514
• Cisplatin 30 mg/m2 Days 1, 8 and Irinotecan 65 mg/m2 Days 1, 815

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

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PRINCIPLES OF SYSTEMIC THERAPY – FOOTNOTES

a Cisplatin contraindicated or not tolerated.
b Those who did not experience disease progression after systemic therapy + concurrent RT may continue durvalumab until disease progression or intolerable toxicity,
or for a maximum of 24 months.
c For transformation to SCLC from NSCLC, consider referral to a center with expertise (SCL-E 4 of 6).
d Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or concurrent use of
immunosuppressive agents. If TKI is continued for transformed SCLC from NSCLC with oncogenic driver, ICI should be avoided due to known toxicity.
e Maintenance immunotherapy with either atezolizumab or durvalumab should continue until progression or intolerable toxicity.
f Atezolizumab and hyaluronidase-tqjs subcutaneous injection may be substituted for IV atezolizumab. Atezolizumab and hyaluronidase-tqjs has different dosing and
administration instructions compared to atezolizumab for intravenous infusion.
g Consider adding lurbinectedin to maintenance atezolizumab in patients who have achieved at least stable disease following four cycles of induction
chemoimmunotherapy, have an ECOG PS of 0–1, and no history of brain metastases.
h This regimen is not for use as re-treatment in subsequent-line therapy if lurbinectedin has been used previously.
i Included patients with asymptomatic untreated brain metastases.

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

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SCLC SUBSEQUENT SYSTEMIC THERAPY (PS 0–2)j

Consider dose reduction or growth factor support for patients with PS 2
Preferred
• Tarlatamab-dllek,l,16 (category 1)
• Clinical trial enrollment
• Irinotecanm,17,18
• Lurbinectedin (if not previously used)19,20
• If prolonged disease-free time, re-treatment with platinum-based doublet with or without immunotherapy21-25
• Topotecan Oral (PO) or Intravenous (IV)17,23,26-28

Other Recommended
• CAV (Cyclophosphamide/Doxorubicin/Vincristine)26
• Docetaxel29
• Gemcitabine30,31,32
• Nivolumabn or Pembrolizumabo (if not previously treated with an ICI)d,33-36
• Oral Etoposide37,38
• Paclitaxel39,40
• Temozolomide40-42

d Contraindications for treatment with PD-1/PD-L1 inhibitors may include active

or previously documented autoimmune disease and/or concurrent use of m For patients with CNS disease, consider using irinotecan.
immunosuppressive agents. If TKI is continued for transformed SCLC from n Nivolumab and hyaluronidase-nvhy subcutaneous injection may be substituted
NSCLC with oncogenic driver, ICI should be avoided due to known toxicity. for IV nivolumab. Nivolumab and hyaluronidase-nvhy has different dosing and
j Subsequent systemic therapy refers to second-line and beyond therapy. administration instructions compared to IV nivolumab.
k For extensive stage with disease progression on or after platinum-based o Pembrolizumab and berahyaluronidase alfa-pmph subcutaneous injection may
chemotherapy. be substituted for IV pembrolizumab. Pembrolizumab and berahyaluronidase
l NCCN Guidelines for Management of CAR T-Cell and Lymphocyte Engager- alfa-pmph has different dosing and administration instructions compared to IV
Related Toxicities. pembrolizumab.
References on (SCL-E 5 of 6)
Note: All recommendations are category 2A unless otherwise indicated.
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Small Cell Lung Cancer Discussion

PRINCIPLES 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.43-46
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.43-46
If tyrosine kinase inhibitor (TKI) is continued, ICI should be avoided, due to known toxicity.45,47,48
Consider referral to a center with experience managing transformed SCLC.

References on (SCL-E 5 of 6)

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

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PRINCIPLES OF SYSTEMIC THERAPY – REFERENCES

1 Bunn PA, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte- 14 Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with
macrophage colony-stimulating factor in the treatment of limited stage small-cell lung etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 2002;346:85-
cancer: a prospective phase III randomized study of the Southwest Oncology Group. J Clin 91.
Oncol 1995;13:1632-1641. 15 Hanna N, Bunn Jr, PA, Langer C, et al. Randomized phase III trial comparing irinotecan/
2 Faivre-Finn C, Snee M, Ashcroft L, et al. Concurrent once-daily versus twice-daily cisplatin with etoposide/cisplatin in patients with previously untreated extensive stage
chemoradiotherapy in patients with limited stage small-cell lung cancer (CONVERT): an disease small-cell lung cancer. J Clin Oncol 2006;24:2038-2043.
open-label, phase 3, randomised, superiority trial. Lancet Oncol 2017;18:1116-1125. 16 Ahn MJ, Cho BC, Felip E, et al. Tarlatamab for patients with previously treated small-cell
3 Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic lung cancer. N Engl J Med 2023;389:2063-2075.
radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and 17 Edelman MJ, Dvorkin M, Laktionov K, et al. Randomized phase 3 study of the anti-
etoposide. N Engl J Med 1999;340:265-271. disialoganglioside antibody dinutuximab and irinotecan vs irinotecan or topotecan for
4 Skarlos DV, Samantas E, Briassoulis E, et al. Randomized comparison of early versus late second-line treatment of small cell lung cancer. Lung Cancer 2022;166:135-142.
hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease 18 Masuda N, Fukuoka M, Kusunoki Y, et al. CPT-11: a new derivative of camptothecin for
small-cell lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 1992;10:1225-
Group (HeCOG). Ann Oncol 2001;12:1231-1238. 1229.
5 Cheng Y, Spigel D, Cho BC, et al. Durvalumab after chemoradiotherapy in limited-stage 19 Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients
small-cell lung cancer. N Engl J Med 2024;39;1313-1327. with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol
6 Horn L, Mansfield A, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in 2020;21:645-654.
extensive stage small-cell lung cancer. N Engl J Med 2018;379:2220-2229. 20 Subbiah V, Paz-Ares L, Besse B, et al. Antitumor activity of lurbinectedin in second-
7 Paz-Ares L, Borghaei H, Liu SV, et al. Efficacy and safety of first-line maintenance therapy line small cell lung cancer patients who are candidates for re-challenge with the first-line
with lurbinectedin plus atezolizumab in extensive-stage small-cell lung cancer (IMforte): a treatment. Lung Cancer 2020;150:90-96.
randomised, multicentre, open-label, phase 3 trial. Lancet 2025;405:2129-2143. 21 Postmus PE, Berendsen HH, van Zandwijk N, et al. Retreatment with the induction
8 Goldman JW, Dvorkin M, Chen Y, et al. Durvalumab, with or without tremelimumab, plus regimen in small cell lung cancer relapsing after an initial response to short term
platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive chemotherapy. Eur J Cancer Clin Oncol 1987;23:1409-1411.
stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, 22 Giaccone G, Ferrati P, Donadio M, et al. Reinduction chemotherapy in small cell lung
open-label, phase 3 trial. Lancet Oncol 2021;22:51-65. cancer. Eur J Cancer Clin Oncol 1987;23:1697-1699.
9 Okamoto H, Watanabe K, Nishiwaki Y, et al. Phase II study of area under the plasma- 23 Baize N, Monnet I, Greillier L, et al. Carboplatin plus etoposide versus topotecan as
concentration-versus-time curve-based carboplatin plus standard-dose intravenous second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-
etoposide in elderly patients with small cell lung cancer. J Clin Oncol 1999;17:3540-3545. label, multicentre, randomised, phase 3 trial. Lancet Oncol 2020;21:1224-1233.
10 Spigel DR, Townley PM, Waterhouse DM, et al. Randomized phase II study of 24 Naito Y, Yamada K, Imamura Y, et al. Rechallenge treatment with a platinum‑based
bevacizumab in combination with chemotherapy in previously untreated extensive stage regimen in patients with sensitive relapsed small‑cell lung cancer. Med Oncol 2018;35:61.
small-cell lung cancer: results from the SALUTE trial. J Clin Oncol 2011;29:2215-2222. 25 Genestreti G, Tiseo M, Kenmotsu H, et al. Outcomes of platinum‑sensitive small‑cell
11 Niell HB, Herndon JE 2nd, Miller AA, et al. Randomized phase III Intergroup trial of lung cancer patients treated with platinum/etoposide rechallenge: a multi‑institutional
etoposide and cisplatin with or without paclitaxel and granulocyte-colony stimulating factor retrospective analysis. Clin Lung Cancer 2015;16:e223‑e228.
in patients with extensive stage small-cell lung cancer: Cancer and Leukemia Group B trial 26 von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide,
9732. J Clin Oncol 2005;23:3752-3759. doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin
12 Evans WK, Shepherd FA, Feld R, et al. VP-16 and cisplatin as first-line therapy for small- Oncol 1999;17:658-667.
cell lung cancer. J Clin Oncol 1985;3:1471-1477. 27 O’Brien ME, Ciuleanu TE, Tsekov H, et al. Phase III trial comparing supportive care alone
13 Schmittel A, Fischer von Weikersthal L, Sebastian M, et al. A randomized phase II trial with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J
of irinotecan plus carboplatin versus etoposide plus carboplatin treatment in patients with Clin Oncol 2006;24:5441-5447.
extended disease small-cell lung cancer. Ann Oncol 2006;17:663-667.

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

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Table of Contents
Small Cell Lung Cancer Discussion

PRINCIPLES OF SYSTEMIC THERAPY – REFERENCES

28 Eckardt JR, von Pawel J, Pujol JL, et al. Phase III study of oral compared with 43 Marcoux N, Gettinger SN, O'Kane G, et al. EGFR-mutant adenocarcinomas that
intravenous topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol transform to small-cell lung cancer and other neuroendocrine carcinomas: Clinical
2007;25:2086-2092. outcomes. J Clin Oncol 2019;37:278-285.
29 Smyth JF, Smith IE, Sessa C, et al. Activity of docetaxel (Taxotere) in small cell lung 44 Ferrer L, Giaj Levra M, Brevet M, et al. A brief report of transformation from NSCLC to
cancer. The Early Clinical Trials Group of the EORTC. Eur J Cancer 1994;30A:1058-1060. SCLC: Molecular and therapeutic characteristics. J Thorac Oncol 2019;14:130-134.
30 Masters GA, Declerck L, Blanke C, et al. Phase II trial of gemcitabine in refractory or 45 Chai X, Zhang X, Li W, Chai J. Small cell lung cancer transformation during antitumor
relapsed small-cell lung cancer: Eastern Cooperative Oncology Group Trial 1597. J Clin therapies: A systematic review. Open Med (Wars) 2021;16:1160-1167.
Oncol 2003;21:1550-1555. 46 Zhang CY, Sun H, Su JW, et al. A potential treatment option for transformed small-
31 Van der Lee I, Smit EF, van Putten JW, et al. Single-agent gemcitabine in patients with cell lung cancer on PD-L1 inhibitor-based combination therapy improved survival. Lung
resistant small-cell lung cancer. Ann Oncol 2001;12:557-561. Cancer 2023;175:68-78.
32 Hoang T, Kim K, Jaslowski A, et al. Phase II study of second-line gemcitabine in sensitive 47 Schoenfeld AJ, Arbour KC, Rizvi H, et al. Severe immune-related adverse events are
or refractory small cell lung cancer. Lung Cancer 2003;42:97-102. common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol 2019;30:839-844.
33 Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus 48 Oshima Y, Tanimoto T, Yuji K, Tojo A. EGFR-TKI-associated interstitial pneumonitis in
ipilimumab in recurrent small-cell lung cancer (Checkmate 032): a multicentre, open-label nivolumab-treated patients with non-small cell lung cancer JAMA Oncol 2018;4:1112-1115.
phase 1/2 trial. Lancet Oncol 2016;17:883-895.
34 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.
35 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.
36 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.
37 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.
38 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.
39 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.
40 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.
41 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.
42 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.

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

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Small Cell Lung Cancer Discussion

PRINCIPLES OF RADIATION THERAPY

General Principles:
• General principles of RT for lung cancer—including commonly used abbreviations; standards for clinical and technologic expertise and
quality assurance; and principles of RT simulation, planning, and delivery—are provided in the NCCN Guidelines for Non-Small Cell Lung
Cancer (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
three-dimensional (3D)-CRT. 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) four-dimensional (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-CRT 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.2-4

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 N25 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).6-8
• Timing: RT concurrent with systemic therapy is standard and preferred to sequential chemo/RT.9 RT should start early, with cycle 1 or 2 of
systemic therapy (category 1).10 A shorter time from the start of any therapy to the end of RT (SER) is significantly associated with improved
survival.11
• 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 7)

Normal Tissue Dose Constraints, Prophylactic Cranial Irradiation (SCL-F 3 of 7)
Brain Metastasis (SCL-F 4 of 7) Continued
References on
(SCL-F 5 of 7)
Note: All recommendations are category 2A unless otherwise indicated.
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PRINCIPLES OF RADIATION THERAPY

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%).12-17 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.14,18
• 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).19,20 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 from Norway and Canada 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, though regional practice between
daily and twice daily fractionation has diverged between those countries after subsequent experience.21-23
If using once-daily conventionally fractionated RT, higher doses of 66–70 Gy are preferred. 24-27 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.28-30
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.31,32 Another randomized phase
3 trial demonstrated a survival advantage of high-dose accelerated RT given as 54 Gy simultaneous integrated boost (SIB) to the GTV in 30
BID fractions over 3 weeks compared to standard 45 Gy in 30 BID fractions over 3 weeks. These studies indicate an advantage of higher
dose accelerated RT with concurrent chemotherapy.33,34
Adjuvant immunotherapy with durvalumab in patients who have not progressed after the completion of chemoRT has been shown to
provide a significant survival advantage. The optimal dose and schedule of RT in the context of immunotherapy is currently undefined.35
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.36,37 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.38 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.39
• 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.

Normal Tissue Dose Constraints, Prophylactic Cranial Irradiation (SCL-F 3 of 7) Continued

Brain Metastasis (SCL-F 4 of 7) References on
(SCL-F 5 of 7)
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PRINCIPLES OF RADIATION THERAPY

Extensive Stage (continued):
Based on two randomized trials, immunotherapy during and after chemotherapy is a first-line approach,40,41 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
chemoimmunotherapy 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 in the NCCN Guidelines for Non-Small Cell Lung Cancer).
• 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
survival42,43 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 used 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).44
These patients have a lower risk of developing brain metastases than patients with more advanced LS-SCLC and may not benefit from PCI.44 Brain
MRI surveillance is recommended in patients not receiving PCI.42 However, PCI may have a benefit in patients who are found to have pathologic
stage IIB or III SCLC after complete resection.43,44 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 ([Link] 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.45 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.46 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.47,48
• 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).47 PCI is not
recommended in patients with poor PS or impaired neurocognitive function.47 The role of PCI in MRI and FDG-PET staged SCLC in patients who
are fit 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://
[Link]/ct2/show/NCT04155034).

Brain Metastasis (SCL-F 4 of 7) Continued

References on
(SCL-F 5 of 7)
Note: All recommendations are category 2A unless otherwise indicated.
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PRINCIPLES OF RADIATION THERAPY

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 RT (WBRT) for brain metastases.48 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.49 Conflicting data have been reported with HA-PCI
versus conventional PCI in SCLC with one trial reporting no differences in cognition50 and a separate trial reporting improved cognitive
preservation with HA-PCI.51 A larger randomized trial of HA-PCI versus conventional PCI, NRG CC003,52 has completed accrual with results
pending.53
• An ongoing randomized trial, SWOG S1827/MAVERICK, is evaluating whether brain MRI surveillance alone is noninferior to MRI surveillance
plus PCI with regard to overall survival for LS-SCLC and ES-SCLC.54

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 RT (SRT)/radiosurgery (SRS).55,56,57 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).58
• In patients who develop brain metastases after PCI, repeat WBRT may be considered in carefully selected patients.59,60 SRS is preferred, if
feasible.61,62
• 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.49 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 CC001.49
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, reirradiation, or better prognosis).
References on
(SCL-F 5 of 7)

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

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Small Cell Lung Cancer Discussion

PRINCIPLES OF RADIATION THERAPY – REFERENCES

1 Chun SG, Hu C, Choy H, et al. Impact of intensity-modulated radiation therapy 12 De Ruysscher D, Bremer RH, Koppe F, et al. Omission of elective node
technique for locally advanced non-small-cell lung cancer: a secondary analysis of irradiation on basis of CT-scans in patients with limited disease small cell lung
the NRG Oncology RTOG 0617 randomized clinical trial. J Clin Oncol 2017;35:56- cancer: a phase II trial. Radiother Oncol 2006;80:307-312.
62. 13 van Loon J, De Ruysscher D, Wanders R, et al. Selective nodal irradiation
2 Simone CB 2nd, Bogart JA, Cabrera AR, et al. Radiation Therapy for Small on basis of (18)FDG-PET scans in limited-disease small-cell lung cancer: a
Cell Lung Cancer: An ASTRO Clinical Practice Guideline. Pract Radiat Oncol prospective study. Int J Radiat Oncol Biol Phys 2010;77:329-336.
2020;10:158-173. 14 Hu X, Bao Y, Xu YJ, et al. Final report of a prospective randomized study on
3 Chun SG, Simone CB 2nd, Amini A, et al. American Radium Society Appropriate thoracic radiotherapy target volume for limited stage small cell lung cancer with
Use Criteria: Radiation Therapy for Limited‑Stage SCLC 2020. J Thorac Oncol radiation dosimetric analyses. Cancer 2020;126:840-849.
2021;16:66‑75. 15 Shirvani SM, Komaki R, Heymach JV, et al. Positron emission tomography/
4 Higgins KA, Simone CB 2nd, Amini A, et al. American Radium Society Appropriate computed tomography-guided intensity-modulated radiotherapy for limited stage
Use Criteria on Radiation Therapy for Extensive‑Stage SCLC. J Thorac Oncol small-cell lung cancer. Int J Radiat Oncol Biol Phys 2012;82:e91-97.
2021;16:54‑65. 16 Xia B, Chen GY, Cai XW, et al. Is involved-field radiotherapy based on CT
5 Zhang C, Zhao G, Wu H, et al. Application of postoperative adjuvant radiotherapy safe for patients with limited stage small-cell lung cancer? Radiother Oncol
in limited stage small cell lung cancer: A systematic review and meta-analysis. 2012;102:258-262.
Radiother Oncol 2024;193:110123. 17 Colaco R, Sheikh H, Lorigan P, et al. Omitting elective nodal irradiation during
6 Shioyama Y, Onishi H, Takayama K, et al. Clinical outcomes of stereotactic body thoracic irradiation in limited stage small cell lung cancer - Evidence from a phase
radiotherapy for patients with stage I small-cell lung cancer: Analysis of a subset II trial. Lung Cancer 2012;76:72-77.
of the Japanese Radiological Society Multi-Institutional SBRT Study Group 18 Liengswangwong V, Bonner JA, Shaw EG, et al. Limited stage small-cell lung
Database. Technol Cancer Res Treat 2018;17:1533033818783904. cancer: patterns of intrathoracic recurrence and the implications for thoracic
7 Verma V, Simone CB 2nd, Allen PK, Lin SH. Outcomes of stereotactic body radiotherapy. J Clin Oncol 1994;12:496-502.
radiotherapy for T1-T2N0 small cell carcinoma according to addition of 19 Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily
chemotherapy and prophylactic cranial irradiation: a multicenter analysis. Clin thoracic radiotherapy in limited small-cell lung cancer treated concurrently with
Lung Cancer 2017;18:675-681.e1. cisplatin and etoposide. N Engl J Med 1999;340:265-271.
8 Verma V, Simone CB 2nd, Allen PK, et al. Multi-institutional experience of 20 Schild SE, Bonner JA, Shanahan TG, et al. Long-term results of a phase III trial
stereotactic ablative radiation therapy for stage I small cell lung cancer. Int J comparing once-daily radiotherapy with twice-daily radiotherapy in limited stage
Radiat Oncol Biol Phys 2017;97:362-371. small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004;59:943-951.
9 Takada M, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus 21 Grønberg BH, Halvorsen TO, Fløtten Ø, et al. Randomized phase II trial
sequential thoracic radiotherapy in combination with cisplatin and etoposide for comparing twice daily hyperfractionated with once daily hypofractionated thoracic
limited stage small-cell lung cancer: results of the Japan Clinical Oncology Group radiotherapy in limited disease small cell lung cancer. Acta Oncol 2016;55:591-
Study 9104. J Clin Oncol 2002;20:3054-3060. 597.
10 Fried DB, Morris DE, Poole C, et al. Systematic review evaluating the timing of 22 Turgeon GA, Souhami L, Kopek N, et al. Thoracic irradiation in 3 weeks for
thoracic radiation therapy in combined modality therapy for limited stage small-cell limited stage small cell lung cancer: Is twice a day fractionation really needed?
lung cancer. J Clin Oncol 2004;22:4837-4845. Cancer Radiother 2017;21:89-98.
11 De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al. Time between the 23 Graabak G, Grønberg BH, Sandvei MS, et al. Thoracic Radiotherapy in Limited
first day of chemotherapy and the last day of chest radiation is the most important stage SCLC-a Population-Based Study of Patterns of Care in Norway From 2000
predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol Until 2018 JTO Clin Res Rep 2022;3:100270.
2006;24:1057-1063.

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

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Small Cell Lung Cancer Discussion

PRINCIPLES OF RADIATION THERAPY – REFERENCES

24 Choi NC, Herndon JE 2nd, Rosenman J, et al. Phase I study to determine the 34 Jiayi Y, Zhang J, Chang X, et al. Real-world clinical outcomes in patients with
maximum-tolerated dose of radiation in standard daily and hyperfractionated- limited-stage Small cell lung cancer who received high-dose hyperfractionated
accelerated twice-daily radiation schedules with concurrent chemotherapy for simultaneous integrated boost radiation therapy versus standard-dose radiation
limited stage small-cell lung cancer. J Clin Oncol 1998;16:3528-3536. therapy. Pract Radiat Oncol 2026;S1879-8500:00120-7.
25 Miller KL, Marks LB, Sibley GS, et al. Routine use of approximately 60 Gy once- 35 Cheng Y, Spigel DR, Cho BC, et al; ADRIATIC Investigators. Durvalumab
daily thoracic irradiation for patients with limited stage small-cell lung cancer. Int J after chemoradiotherapy in limited-stage small-cell lung cancer. N Engl J Med
Radiat Oncol Biol Phys 2003;56:355-359. 2024;391:1313-1327.
26 Roof KS, Fidias P, Lynch TJ, et al. Radiation dose escalation in limited stage 36 Jeremic B, Shibamoto Y, Nikolic N, et al. Role of radiation therapy in the
small-cell lung cancer. Int J Radiat Oncol Biol Phys 2003;57:701-708. combined-modality treatment of patients with extensive disease small-cell lung
27 Bogart JA, Herndon JE, Lyss AP, et al. 70 Gy thoracic radiotherapy is feasible cancer: A randomized study. J Clin Oncol 1999;17:2092-2099.
concurrent with chemotherapy for limited stage small-cell lung cancer: analysis 37 Yee D, Butts C, Reiman A, et al. Clinical trial of post-chemotherapy consolidation
of Cancer and Leukemia Group B study 39808. Int J Radiat Oncol Biol Phys thoracic radiotherapy for extensive stage small cell lung cancer. Radiother Oncol
2004;59:460-468. 2 012;102:234-238.
28 Faivre-Finn C, Snee M, Ashcroft L, et al. Concurrent once-daily versus twice- 38 Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for
daily chemoradiotherapy in patients with limited stage small-cell lung cancer extensive stage small-cell lung cancer: a phase 3 randomised controlled trial.
(CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncol Lancet 2015;385:36-42.
2017;18:1116-1125. 39 Slotman BJ, van Tinteren H, Praag JO, et al. Radiotherapy for extensive stage
29 Bogart JA, Wang XF, Masters GA, et al. High-dose once-daily thoracic small-cell lung cancer-Authors’ reply. Lancet 2015;385:1292-1293.
radiotherapy in limited stage small-cell lung cancer: CALGB 30610 (Alliance)/ 40 Horn L, Mansfield A, Szczęsna A, et al. First-line atezolizumab plus
RTOG 0538. J Clin Oncol 2023;41:2394-2402. chemotherapy in extensive stage small-cell lung cancer. N Engl J Med
30 Ganti A, Dueck AC, Fruth B, et al. Comparison of quality of life in patients 2018;379:2220-2229.
randomized to high-dose once daily (QD) thoracic radiotherapy (TRT) with 41 Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide
standard twice daily (BID) TRT in limited stage small cell lung cancer (LS-SCLC) versus platinum-etoposide in first-line treatment of extensive stage small-cell lung
on CALGB 30610 (Alliance, Sub-study CALGB 70702) [abstract]. J Clin Oncol cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet
2022;40(Suppl):Abstract 8504. 2019;394:1929-1939.
31 Grønberg BH, Killingberg KT, Fløtten Ø, et al. High-dose versus standard dose 42 Arriagada R, Le Chevalier T, Rivière A, et al. Patterns of failure after prophylactic
twice-daily thoracic radiotherapy in limited stage small-cell lung cancer: final cranial irradiation in small-cell lung cancer: analysis of 505 randomized patients.
survival data, long-term toxicity and relapse patterns in a randomised, open-label, Ann Oncol 2002;13:748-754.
phase II trial. J Thorac Oncol 2025;S1556-0864;00696-3. 43 Aupérin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for
32 Qiu B, Li QW, Liu JL, et al. Moderately hypofractionated once-daily compared patients with small-cell lung cancer in complete remission. Prophylactic Cranial
with twice-daily thoracic radiation therapy concurrently with etoposide and Irradiation Overview Collaborative Group. N Engl J Med 1999;341:476-484.
cisplatin in limited stage small-cell lung cancer: a multi-center, Phase II, 44 Yang Y, Zhang D, Zhou X, et al. Prophylactic cranial irradiation in resected small
randomized trial. Int J Radiat Oncol Biol Phys 2021;111:424-435. cell lung cancer: A systematic review with meta-analysis. J Cancer 2018;9:433-
33 Yu J, Jiang L, Zhao L, et al. High-dose hyperfractionated simultaneous 439.
integrated boost radiotherapy versus standard-dose radiotherapy for limited-stage 45 Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in
small-cell lung cancer in China: a multicentre, open-label, randomised, phase 3 extensive small-cell lung cancer. N Engl J Med 2007;357:664-672.
trial. Lancet Respir Med 2024;12:799-809.

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

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Small Cell Lung Cancer Discussion

PRINCIPLES OF RADIATION THERAPY – REFERENCES

46 Takahashi T, Yamanaka T, Seto T, et al. Prophylactic cranial irradiation 57 Aizer AA, Shin K, Catalano PK. Treatment for brain metastases with stereotactic
versus observation in patients with extensive-disease small-cell lung cancer: a radiation vs hippocampal-avoidance whole brain radiation: A randomized clinical
multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2017;18:663- trial. JAMA 2026:335;1127-1136.
671. 58 Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of cognitive
47 Le Péchoux C, Dunant A, Senan S, et al. Standard-dose versus higher-dose
dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-
prophylactic cranial irradiation (PCI) in patients with limited stage small-cell lung blind, placebo-controlled trial. Neuro Oncol 2013;10:1429-1437.
cancer in complete remission after chemotherapy and thoracic radiotherapy 59 Sadikov E, Bezjak A, Yi QL, et al. Value of whole brain re-irradiation for brain
(PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised metastases--single centre experience. Clin Oncol (R Coll Radiol) 2007;19:532-
clinical trial. Lancet Oncol 2009;10:467-474. 538.
48 Wolfson AH, Bae K, Komaki R, et al. Primary analysis of a phase II randomized 60 Son CH, Jimenez R, Niemierko A, et al. Outcomes after whole brain reirradiation
trial Radiation Therapy Oncology Group (RTOG) 0212: Impact of different total in patients with brain metastases. Int J Radiat Oncol Biol Phys 2012;82:e167-
doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity 172.
and quality of life for patients with limited-disease small-cell lung cancer. Int J 61 Harris S, Chan MD, Lovato JF, et al. Gamma knife stereotactic radiosurgery as
Radiat Oncol Biol Phys 2011;81:77-84. salvage therapy after failure of whole-brain radiotherapy in patients with small-cell
49 Brown P, Gondi V, Pugh S, et al. Hippocampal avoidance during whole-brain
lung cancer. Int J Radiat Oncol Biol Phys 2012;83:e53-e59.
radiotherapy plus memantine for patients with brain metastases: Phase III trial 62 Wegner RE, Olson AC, Kondziolka D, et al. Stereotactic radiosurgery for
NRG Oncology CC001. J Clin Oncol 2020;38:1019-1029. patients with brain metastases from small cell lung cancer. Int J Radiat Oncol Biol
50 Belderbos JSA, De Ruysscher DKM, De Jaeger K, et al. Phase 3 randomized
Phys 2011;81:e21-e27.
trial of prophylactic cranial irradiation with or without hippocampus avoidance in
SCLC (NCT01780675). J Thorac Oncol 2021;16:840-849.
51 Rodriguez De Dios N, Murcia M, Counago F, et al. Phase III trial of prophylactic
cranial irradiation with or without hippocampal avoidance for small-cell lung
cancer. Int J Radiat Oncol Biol Phys 2019;105:S35-S36.
52 Gondi V, Pugh S, Mehta MP, et al. Primary endpoint results of NRG CC003:
Phase IIR/III trial of prophylactic cranial irradiation (PCI) with or without
hippocampal avoidance (HA) for small cell lung cancer (SCLC) [abstract 2023].
Int J Radiat Oncol Biol Phys 2023;117:E3.
53 Gondi V, Pugh SL, Mehta MP, et al. NRG Oncology CC003: A randomized
phase II/III trial of prophylactic cranial irradiation with or without hippocampal
avoidance for small cell lung cancer. J Clin Oncol 2019;37:TPS 8578-TPS 8578.
54 SWOG S1827 (MAVERICK) Testing whether the use of brain scans alone
instead of brain scans plus preventive brain radiation affects lifespan in patients
with small cell lung cancer. Available at: [Link]
NCT04155034.
55 Rusthoven CG, Yamamoto M, Bernhardt D, et al. Evaluation of first-line
radiosurgery vs whole-brain radiotherapy for small cell lung cancer brain
metastases: the FIRE-SCLC cohort study. JAMA Oncol 2020;6:1028-1037.
56 Aizer AA, Tanguturi SK, Shi DD, et al. Stereotactic radiosurgery in patients with
small cell lung cancer and 1-10 brain metastases: A multi-institutional, phase II,
prospective clinical trial. J Clin Oncol 2025;43:2986-2997.

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

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PRINCIPLES OF IMAGING
General Principles:
• Both CT and MRI are performed with contrast, unless clinically contraindicated.
• Workup of SCLC should be expedited, with studies done in parallel whenever possible.
• If extensive stage is established, brain imaging MRI (preferred) or CT with contrast is recommended. Further evaluation is dependent on the
clinical situation.
• Brain MRI is more sensitive than CT for identifying brain metastases and is preferred over CT.

Workup:
• Chest/abdomen/pelvis (C/A/P) CT with contrast
• Brain MRI (preferred) or CT with contrast
• FDG-PET/CT scan (skull base to mid-thigh), if needed to clarify extent of disease

Additional Workup:
• Bone imaging (radiographs or MRI) as appropriate, if FDG-PET/CT equivocal

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

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PRINCIPLES OF IMAGING
Recommendations for scanning are based on patients without altered symptoms or with stable symptoms

Treatment Response Assessment

• Limited Stage
For patients receiving adjuvant systemic therapy ± RT, response assessment is recommended only after completion of adjuvant therapy
(SCL-6).
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
(SCL-6).
Repeating scans to assess response during adjuvant or initial treatment is not recommended in the absence of new symptoms.
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).

• Extensive Stage
In known brain metastases, if systemic therapy was initiated prior to brain RT, brain MRI (preferred) or CT with contrast is recommended to
be repeated after every 2 cycles of systemic therapy until brain RT is initiated (SCL-6).
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 known brain metastases, brain MRI (preferred) or brain CT with contrast should be obtained
every 3–4 months, or at a frequency based on clinical indication.

Follow-up/Surveillance
• Most NCCN Member Institutions use chest CT ± abdomen/pelvis every 2–6 months (more frequently in years 1–2 and less frequently
thereafter).
• Brain MRI or CT with contrast every 3–4 months during year 1, then every 6 months in year 2, then after year 2, as clinically indicated
(regardless of PCI status).
Surveillance for all patients consists of:
◊ CT chest ± abdomen/pelvis
◊ Brain MRI (preferred) or brain CT
• Imaging for known metastases (eg, CT neck or MRI spine) should be repeated for follow-up. Other imaging studies may be obtained based
on individual clinical scenarios.
• New pulmonary nodule should initiate workup for potential new primary.
• FDG-PET/CT is not recommended for routine follow-up unless a contrast CT or MRI is contraindicated.

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

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PRINCIPLES OF IMAGING – REFERENCES

Bradley JD, Dehdashti F, Mintun MA, et al. Positron emission tomography in limited stage small-cell lung cancer: a prospective study. J Clin Oncol 2004;22:3248-3254.
Farooqi AS, Holliday EB, Allen PK, et al. Prophylactic cranial irradiation after definitive chemoradiotherapy for limited stage small cell lung cancer: Do all patients
benefit? Radiother Oncol 2017;122:307-312.
Fischer BM, Mortensen J, Langer SW, et al. A prospective study of PET/CT in initial staging of small-cell lung cancer: comparison with CT, bone scintigraphy and bone
marrow analysis. Ann Oncol 2007;18:338-345.
Jett JR, Schild SE, Kesler KA, Kalemkerian GP. Treatment of small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest
Physicians evidence-based clinical practice guidelines. Chest 2013;143:e400S-e419S.
Johnson BE. Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 1998;90:1335-1345.
Johnson BE, Linnoila RI, Williams JP, et al. Risk of second aerodigestive cancers increases in patients who survive free of small-cell lung cancer for more than 2 years.
J Clin Oncol 1995;13:101-111.
Kalemkerian GP. Staging and imaging of small cell lung cancer. Cancer Imaging 2012;11:253-258.
Kalemkerian GP, Gadgeel SM. Modern staging of small cell lung cancer. J Natl Compr Canc Netw 2013;11:99-104.
Le Pechoux C, Laplanche A, Faivre-Finn C, et al. Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different
doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01). Ann Oncol 2011;22:1154-1163.
Lok BH, Ma J, Foster A, et al. Factors influencing the utilization of prophylactic cranial irradiation in patients with limited stage small cell lung cancer. Adv Radiat Oncol
2017;2:548-554.
Manapov F, Klocking S, Niyazi M, et al. Timing of failure in limited disease (stage I-III) small-cell lung cancer patients treated with chemoradiotherapy: a retrospective
analysis. Tumori 2013;99:656-660.
Podoloff DA, Ball DW, Ben-Josef E, et al. NCCN task force: clinical utility of PET in a variety of tumor types. J Natl Compr Canc Netw 2009;7 Suppl 2:S1-26.
Seute T, Leffers P, ten Velde GP, Twijnstra A. Detection of brain metastases from small cell lung cancer: consequences of changing imaging techniques (CT versus
MRI). Cancer 2008;112:1827-1834.
Takahashi T, Yamanaka T, Seto T, et al. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre,
randomised, open-label, phase 3 trial. Lancet Oncol 2017;18:663-671.
Wolfson AH, Bae K, Komaki R, et al. Primary analysis of a phase II randomized trial Radiation Therapy Oncology Group (RTOG) 0212: impact of different total doses
and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer. Int J Radiat Oncol
Biol Phys 2011;81:77-84.

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

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

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

©, 2017, American College of Surgeons, All Rights Reserved. Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this
information is the AJCC Cancer Staging System.
Continued

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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.
©, 2017, American College of Surgeons, All Rights Reserved. Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this
information is the AJCC Cancer Staging System.

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Table of Contents
Small Cell Lung Cancer Discussion

ABBREVIATIONS
3D-CRT three dimensional conformal ICI immune checkpoint inhibitor SRS stereotactic radiosurgery
radiation therapy SRT stereotactic radiation therapy
IGRT image-guided radiation therapy
4D-CT four-dimensional computed SVC superior vena cava
tomography IMRT intensity-modulated radiation
therapy TKI tyrosine kinase inhibitor
ACTH adrenocorticotropic hormone
INSM1 insulinoma-associated protein 1 TNM tumor node metastasis
ADH antidiuretic hormone
IVIG intravenous immunoglobulin TTF-1 thyroid transcription factor-1
AIS adenocarcinoma in situ
LCNEC large-cell neuroendocrine
AUC area under the curve VGCC voltage-gated calcium channel
carcinoma
BUN blood urea nitrogen VMAT volumetric modulated arc therapy
LEMS Lambert-Eaton myasthenic
C/A/P chest/abdomen/pelvis syndrome WBRT whole brain radiation therapy
CBC complete blood count LFT liver function test
CNS central nervous system LS-SCLC limited stage small cell lung
CRT conformal radiation therapy cancer
EBRT external beam radiation therapy NSCLC non-small cell lung cancer
ENI elective nodal irradiation PCI prophylactic cranial irradiation
EORTC European Organisation for PD-1 programmed cell death protein 1
Research and Treatment of PD-L1 programmed death ligand 1
Cancer
PFT pulmonary function test
ES-SCLC extensive-stage small cell lung
cancer PS performance status
FDG fluorodeoxyglucose RBC red blood cell
G-CSF granulocyte colony-stimulating SABR stereotactic ablative radiotherapy
factor
SBRT stereotactic body radiation
GM-CSF granulocyte-macrophage colony-
stimulating factor therapy
GTV gross tumor volume SCIS squamous cell carcinoma in situ
H&E hematoxylin and eosin SCLC small cell lung cancer
H&P history and physical SER start of any therapy to the end of
RT
HA hippocampal avoidance
SIB simultaneous integrated boost

SIADH syndrome of inappropriate

antidiuretic hormone secretion

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Small Cell Lung Cancer Discussion

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 affordability.
Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
Other recommended 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.

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

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Small Cell Lung Cancer Discussion

Discussion
• The Discussion on the following pages describes the data and clinical information that support the recommendations in the algorithm.
• The presence of a "Discussion update in progress" watermark indicates that the section is being updated. The date of the last update is shown on MS-2.

Guidelines Update Methodology

• For complete details, refer to Development and Update of Guidelines.
• Prior to the update of the NCCN Guidelines, an electronic search of the PubMed database ([Link] using relevant search
terms was performed to obtain key literature in the field published since the previous Guidelines update. The PubMed database was chosen because
it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature. The search results were narrowed by
selecting studies in humans published in English. Results were confined to select article types including, but not limited to: Clinical Trial; Randomized
Controlled Trial; Meta-Analysis; Systematic Review; and Validation Study. The data from key PubMed articles as well as articles from additional
sources deemed as relevant to these Guidelines as discussed by the Panel during the Guidelines update have been included in the Discussion section.
Recommendations for which high-level evidence is lacking are based on the Panel’s review of lower-level evidence and expert opinion.
• NCCN Guidelines strive to use language that is person-first, non-stigmatizing, and inclusive and representative of all individuals to whom the Guideline
recommendations may apply. Therefore, NCCN Guidelines incorporate organ-specific, non-gendered recommendations and respectful terminology that
avoids harmful or disparaging stereotypes. NCCN's Guidance on Inclusive Language can be found at [Link]
advocacy-program/advancing-cancer-equity.
• For information about systemic therapy regimen naming methods used within the NCCN Guidelines algorithm, refer to the NCCN Chemotherapy Order
Templates® Systemic Therapy Regimen Naming Methods: Appendix I.
• For information about standardized use of biomarker terminology within the NCCN Guidelines algorithm, refer to Tjota MY, et al. J Natl Compr Canc
Netw.

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Discussion This discussion corresponds to the NCCN Guidelines for Small Cell Lung Cancer. Last updated: July 1, 2026

Table of Contents

Overview ..........................................................................................................................................................................................................MS-3

Diagnosis .........................................................................................................................................................................................................MS-4

Screening ................................................................................................................................................................................................................................ MS-4

Manifestations ......................................................................................................................................................................................................................... MS-4

Pathology ................................................................................................................................................................................................................................ MS-5

Evaluation ........................................................................................................................................................................................................MS-6

Staging Systems ..................................................................................................................................................................................................................... MS-6

Initial Evaluation ...................................................................................................................................................................................................................... MS-6

Prognostic Factors ...........................................................................................................................................................................................MS-8

Treatment.........................................................................................................................................................................................................MS-8

Surgical Resection of Stage I–IIA SCLC ................................................................................................................................................................................. MS-8

Systemic Therapy ................................................................................................................................................................................................................... MS-9

Older Patients ....................................................................................................................................................................................................................... MS-14

Surveillance for Relapse ....................................................................................................................................................................................................... MS-15

Subsequent Systemic Therapy ............................................................................................................................................................................................. MS-15

Radiation Therapy ................................................................................................................................................................................................................. MS-20

Radiation for Extensive-Stage SCLC .................................................................................................................................................................................... MS-23

Summary........................................................................................................................................................................................................ MS-27

References ..................................................................................................................................................................................................... MS-28

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Overview
Approximately 13% of lung tumors will be classified as small cell lung cancer (SCLC) in 2026.1 In 2026, an estimated 30,000 new cases of SCLC will be
diagnosed in the United States.1 Although the incidence of SCLC has been decreasing, the frequency in females is increasing and the male-to-female
incidence ratio has been close to 1:1 in the last few years.2 Nearly all cases of SCLC are attributable to cigarette smoking.3 Patients with SCLC who also
continue to smoke tobacco during treatment have increased toxicity and shorter survival.4 Therefore, tobacco smoking cessation counseling and
intervention should be strongly promoted in patients with SCLC and other high-grade neuroendocrine carcinomas (see the NCCN Clinical Practice
Guidelines in Oncology [NCCN Guidelines®] for Smoking Cessation, available at [Link]).5 Patients who previously smoked tobacco should be
strongly encouraged to remain abstinent. Programs using behavioral counseling combined with U.S. Food and Drug Administration (FDA)-approved
medications that promote smoking cessation can be very useful.

SCLC is characterized by a rapid doubling time, high growth fraction, and early development of widespread metastases. While most patients with SCLC
present with hematogenous metastases; approximately one third present with limited disease confined to the chest. Although 95% of small cell
carcinomas originate in the lung, they can also arise from extrapulmonary sites, including the nasopharynx, gastrointestinal tract, and genitourinary
tract.6,7 Both pulmonary and extrapulmonary small cell carcinomas have a similar clinical and biologic behavior with increased potential for widespread
metastases. Management of SCLC is described in the NCCN Guidelines® for Small Cell Lung Cancer that includes the algorithm and this supporting
Discussion text. Management of other lung neuroendocrine tumors (LNTs) and non-small cell lung cancer (NSCLC) are described in the NCCN
Guidelines for Neuroendocrine and Adrenal Tumors and NCCN Guidelines for Non-Small Cell Lung Cancer, respectively, available at [Link].

The definitions for limited- and extensive-stage SCLC incorporate tumor, node, metastasis (TNM) staging. The Panel recommends that the workup for
SCLC should be expedited and if possible, studies should be performed in parallel. In patients with limited-stage SCLC, the goal of treatment is cure
using chemotherapy plus thoracic radiation therapy (RT). However, some patients with resectable tumors (stage I–IIA) are eligible for curative surgery
followed by systemic therapy with or without mediastinal RT.8,9 The Panel recommends multidisciplinary evaluation before any surgery. In patients with
stage I–IIA SCLC, including medically inoperable circumstances or when the decision not to pursue surgical resection is made, stereotactic ablative
radiotherapy (SABR) followed by systemic therapy is an option.10-15 The benefits of prophylactic cranial irradiation (PCI) are unclear in patients with stage
I SCLC (T1–2a, N0, M0) who have received definitive therapy. The Panel recommends that MRI brain surveillance be considered for all patients with
limited-stage SCLC who do not receive PCI. In most patients with extensive-stage SCLC, systemic therapy with or without RT can palliate symptoms and
prolong survival; however, long-term survival is rare.16 SCLC is highly sensitive to initial chemotherapy and RT; however, most patients eventually die of
recurrent disease.17 Despite recent advances, the recommended therapy options for SCLC need improvement. Clinical trials generally represent
state-of-the-art treatment for patients with SCLC. Thus, participation in clinical trials is strongly encouraged.

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Diagnosis
Screening
Ideally, a screening test should detect disease at an early stage while it is still curable. The National Lung Screening Trial reported that screening with
annual, low-dose, spiral CT scans detected early-stage NSCLC and decreased lung cancer-specific mortality in individuals who are asymptomatic and at
high risk (see the NCCN Guidelines for Lung Cancer Screening, available at [Link]).18 Low-dose CT may be less effective for SCLC screening,
because symptomatic disease can develop between annual scans due to the aggressive nature of the disease, thereby limiting the potential for reducing
mortality through screening.18-21 Nevertheless, the same population of patients is eligible for and should benefit from LDCT screening for mortality
reduction from NSCLC.

Manifestations
Patients with SCLC typically present with a large hilar mass and bulky mediastinal lymphadenopathy that causes cough and dyspnea.22 Frequently,
patients present with symptoms of widespread metastatic disease, such as weight loss, debility, bone pain, and neurologic compromise. It is uncommon
for patients to present with a solitary peripheral nodule without central adenopathy. In this situation, fine-needle aspiration (FNA) may not adequately
differentiate small cell carcinoma (which is a high-grade neuroendocrine carcinoma) from low-grade (typical carcinoid), intermediate-grade (atypical
carcinoid), or large-cell neuroendocrine carcinoma (LCNEC) (which is also a high-grade neuroendocrine carcinoma) (see Neuroendocrine Tumors of the
Lung in the NCCN Guidelines for Neuroendocrine and Adrenal Tumors, available at [Link]).23,24

Many neurologic and endocrine paraneoplastic syndromes, including Lambert-Eaton myasthenic syndrome (LEMS), encephalomyelitis, and sensory
neuropathy, are associated with SCLC. 25-27 Patients with LEMS present with proximal leg weakness that is caused by antibodies directed against the
voltage-gated calcium channels. 28,29 Neurologic workup may include but is not limited to tests for PQ- and N-type voltage-gated calcium channel
(VGCC) antibodies. In consultation with neurology, amifampridine or intravenous immunoglobulin (IVIG) can be considered for LEMS treatment. The
Panel clarified that both the tests for syndrome and treatment should be performed in consultation with neurology. Paraneoplastic encephalomyelitis
may precede a diagnosis of SCLC. 30 Given the occurrence of paraneoplastic neurologic syndromes in individuals with SCLC, the Panel recommends
considering early subspecialty consultation for most recent management and a comprehensive paraneoplastic antibody panel and/or neurologic
consultation if neurologic paraneoplastic syndrome is suspected.

SCLC tumors sometimes produce polypeptide hormones, including vasopressin and adrenocorticotropic hormone, that cause syndrome of inappropriate
antidiuretic hormone secretion (SIADH) and Cushing syndrome, respectively.31,32 SIADH occurs more frequently than Cushing syndrome in patients with
SCLC. Primary treatment for SIADH includes fluid restriction (which is difficult for patients because of increased thirst) and demeclocycline. Cancer
treatment (eg, cisplatin) and/or supportive care (e.g., opiates) may also cause hyponatremia.33 Hyponatremia usually improves after successful treatment
of SCLC. However, vasopressin receptor inhibitors (i.e., conivaptan, tolvaptan) can be used for refractory hyponatremia.33-35

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Pathology
SCLC is a poorly differentiated malignant epithelial tumor that is categorized as a high-grade neuroendocrine carcinoma.23,36 Up to 30% of tumors from
patients with SCLC, particularly those who received treatment, reveal areas of NSCLC differentiation (mainly large cell carcinoma).37 In cases of
diagnostic dilemma, including carcinoids, the Panel strongly recommends getting a second opinion from a pathologist specializing in diagnosis of thoracic
malignancies. In good-quality samples, the classic and distinctive histology on hematoxylin and eosin (H&E), including small blue cells with scant
cytoplasm, high nuclear/cytoplasmic ratio, fine granular nuclear chromatin, and absent or inconspicuous nucleoli, may be sufficient for identifying
SCLC.23,38 Compared to atypical and typical carcinoids, the mitotic count is high in SCLC. However, mitotic figures are difficult to count in small biopsy
samples with crushed or necrotic cells; immunohistochemistry is useful in such samples.39

Using immunohistochemistry as one of the tools to diagnose and distinguish SCLC from NSCLC or other neuroendocrine tumors is important, especially
because these cancer types have different treatment recommendations.23,39-43 Ki-67 is useful for distinguishing SCLC from carcinoid tumors.39,43-45 Nearly
all SCLCs are immunoreactive for cytokeratin (AE1/AE3, CAM5.2) and 85% to 90% of SCLCs are positive for thyroid transcription factor-1 (TTF-1).23,46-48
Most SCLCs (~95%) stain positively for markers of neuroendocrine differentiation, including insulinoma-associated protein 1 (INSM1), chromogranin A,
NCAM (CD56), and synaptophysin.23,49,50 However, approximately 10% of NSCLCs will be immunoreactive for at least one of these neuroendocrine
markers and therefore cannot be used alone to distinguish SCLC from NSCLC.51 For suspicious cases of SCLC morphology without any expression of
neuroendocrine markers, POU2F3 IHC staining can be considered.52,53 Napsin A (adenocarcinoma marker) and p40 (or p63, squamous cell carcinoma
marker) are generally negative in SCLC and useful for distinguishing SCLC from poorly differentiated NSCLC and combined SCLC.54 It is important to
note that p40 (or p63) can be focally positive in SCLC. Immunohistochemical stains for Rb1 and p53 can also be used to differentiate atypical carcinoid
and SCLC. While the carcinoid tumors retain RB1 expression and show a wild-type p53 expression, most high-grade neuroendocrine tumors of the lung
show RB1 loss and/or p53 mutation-type expression with either strong and diffuse nuclear staining or null (null) type staining. The Panel clarified that
biomarker testing via blood, tissue, or both may be considered in rare cases, particularly for patients with extensive-stage/relapsed SCLC who have
never smoked or lightly smoked, remote smoking history, diagnostic/therapeutic dilemma, or at time of relapse if not done previously (as this may change
management).55-60

The WHO classification recognizes two types of SCLC: pure and combined SCLC.43,56,61-64 Combined SCLC, which consists of both SCLC and NSCLC
histology (squamous cell, adenocarcinoma, spindle/pleomorphic, and/or large cell carcinoma), is more frequent in patients with limited-stage
SCLC.43,56,63,65 Any presence of NSCLC histology (no minimal percentage) results in a classification of combined SCLC. The only exception is combined
SCLC and LCNEC where at least 10% of the tumor should show LCNEC morphology.37,66 Patients with combined SCLC are treated using regimens for
SCLC, because it is the more aggressive cancer.66 Patients with NSCLC can also transform to SCLC after treatment with epidermal growth factor
receptor (EGFR) tyrosine kinase inhibitors or immune checkpoint inhibitors (ICIs).67,68

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Evaluation
Staging Systems
The Veterans Administration (VA) Lung Study Group’s 2-stage classification scheme has historically been used to define the extent of disease in patients
with SCLC: 1) limited-stage is disease confined to the ipsilateral hemithorax, which can be safely encompassed within a radiation field; and 2)
extensive-stage is disease beyond the ipsilateral hemithorax, including malignant pleural/pericardial effusion or hematogenous metastases.69
Contralateral mediastinal and ipsilateral supraclavicular lymphadenopathy are generally classified as limited-stage SCLC, whereas the classification of
contralateral hilar and supraclavicular lymphadenopathy is more controversial and treatment is individualized.17,70,71 Approximately 66% of patients
present with overt hematogenous metastases, which commonly involve the contralateral lung, liver, adrenal glands, brain, bones, and/or bone marrow.
Most studies use the VA definitions of limited- or extensive-stage SCLC for clinical decision-making. But the TNM system is particularly useful for
selecting patients with T1–2, N0 disease who are eligible for surgery and RT.70 The American Joint Committee on Cancer (AJCC) revised the TNM
staging system (8th edition) for lung cancer in 2017.72,73 Clinical studies that include the TNM system will allow for more precise assessments of prognosis
and specific therapy.72

The Panel adopted a combined approach of using the AJCC TNM staging system and the older VA scheme for SCLC staging.17,70 Limited-stage SCLC is
defined as stage I–III (T any, N any, 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. Extensive-stage SCLC is defined as stage IV (T any,
N any, M1a/b/c) or T3–4 as described above.

Initial Evaluation
The workup for SCLC should be expedited with studies done in parallel whenever possible. Staging primarily provides a therapeutic guideline for thoracic
RT for patients with limited-stage SCLC. However, staging should not delay the onset of treatment for >1 week because of the aggressive nature of
SCLC. Many patients may become more seriously ill in the interval with a significant decline in performance status (PS). The Panel recommends early
integration of palliative care so that management of cancer-related symptoms and goals of care are discussed during initial evaluation.

The initial diagnostic evaluation includes a history and physical examination; pathology review; clinical laboratory tests; CT scan with contrast of the
chest/abdomen/pelvis (C/A/P); and MRI is preferred over CT scan with contrast for brain imaging.71,74 An FDG-PET/CT scan (skull base to mid-thigh),
which is superior to PET alone, is recommended, if needed, to clarify the extent of disease.17,70,75 For most metastatic sites, FDG-PET/CT is superior to
CT imaging; however, for the detection of brain metastases FDG-PET/CT is inferior to MRI (or contrast-enhanced CT as an alternative when MRI is not
possible) (see the NCCN Guidelines for Central Nervous System Cancers, available at [Link]).76 FDG-PET scans can also increase staging
accuracy because SCLC is a highly metabolically active disease.75,77,78 Approximately 19% of patients who undergo FDG-PET are upstaged from
limited-stage to extensive-stage SCLC, whereas 8% are downstaged from extensive-stage to limited-stage SCLC.71 Although FDG-PET/CT seems to
improve staging accuracy in SCLC, pathologic confirmation is recommended for isolated or equivocal lesions if their involvement changes clinical

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management. In select studies, FDG-PET staging improved detection of intrathoracic disease sites in approximately 27% of patients and led to alteration
of the planned radiation field.71,78,79

Once extensive-stage SCLC has been established, further staging is optional and dependent on the clinical situation. Further brain imaging with MRI
(preferred) or CT with contrast is recommended. Brain imaging can identify central nervous system (CNS) metastases in 10% to 15% of patients at
diagnosis, of which approximately 30% are asymptomatic. Early treatment of brain metastases results in less chronic neurologic morbidity, arguing for
the usefulness of early diagnosis in asymptomatic patients. Therefore, staging should broaden from sites of symptomatic disease, or those sites
suggested by laboratory tests.

Bone imaging with radiographs or MRI can be performed if FDG-PET/CT is equivocal or not available. Bone scans are positive in <30% of patients
without bone pain or abnormal alkaline phosphatase levels. However, <5% of patients have bone marrow involvement as the only site of extensive-stage
SCLC. Unilateral bone marrow aspirates and biopsies may be indicated in select patients with no other evidence of metastatic disease, with nucleated
red blood cells on peripheral blood smear and neutropenia, or thrombocytopenia suggestive of bone marrow infiltration. The Panel recommends
performing bone marrow biopsy in select patients with pathologic confirmation for isolated or equivocal lesions, only if it changes clinical management.
Any compelling evidence of distant disease consistent with malignancy should change the diagnosis to extensive-stage SCLC.

To confirm FDG-PET/CT scan results and rule out occult nodal disease before surgical resection, pathologic lymph node staging is recommended in
patients with clinical limited-stage I–IIA SCLC (T1–2, N0, M0).17 Pathologic lymph node staging can be considered to help determine RT fields in patients
with clinical stage IIB–IIIC SCLC (T1–4, N0, M0; T1–4, N1–3, M0), especially for those with clinical N0 disease. Lymph node staging procedures include
endobronchial ultrasound-guided biopsy (preferred, if expertise exists), mediastinoscopy, mediastinotomy, esophageal ultrasound-guided biopsy, and
video-assisted thoracoscopy.80,81 The Panel modified these recommendations to consider endoscopic procedures first, when expertise exists, before
other invasive staging procedures are performed. Staging biopsies of visible nodes in all accessible nodal stations should be performed to inform RT
targeting, but additional modalities for mediastinal staging are not necessary. The Panel further clarified that if nodal involvement is established by one
modality of mediastinal staging, additional modalities are not necessary, but staging biopsies of visible nodes in all accessible nodal stations is
encouraged to inform radiotherapy targeting.

Thoracentesis with cytologic analysis is recommended if pleural effusion is large enough to be safely accessed via ultrasound guidance. If thoracentesis
does not show malignant cells, then thoracoscopy can be considered to document pleural involvement, which is suggestive of extensive-stage SCLC.
The effusion should be excluded as a staging element if: 1) multiple cytopathologic examinations of the pleural fluid are negative for cancer; 2) the fluid is
not bloody and not an exudate; and 3) clinical judgment concludes that the effusion is not directly related to the cancer. Pericardial effusions are
classified using the same criteria.

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Prognostic Factors
Age <70 years, normal lactate dehydrogenase (LDH), and stage I disease are associated with favorable prognosis in patients with limited-stage SCLC.
Younger age, good PS, normal creatinine level, normal LDH, and a single metastatic site are favorable prognostic factors in patients with extensive-stage
SCLC.82,83 Poor PS (3–4), extensive-stage SCLC, weight loss, and markers (such as LDH) associated with bulky disease are the most important adverse
prognostic factors.

Treatment
Surgical Resection of Stage I–IIA SCLC
Fewer than 5% of patients with SCLC have true stage I–IIA disease.84 The general recommendation for surgery is restricted to certain patients with stage
I–IIA disease (T1–2, N0, M0). Most of the data regarding the role of surgery in SCLC are from retrospective studies.85-90 These studies report favorable
5-year survival rates of 40% to 60% in patients with stage I disease. In most series, survival rates decline significantly in patients with advanced disease
and lymph node involvement. Analyses of the SEER database suggest that surgery is appropriate for some patients with localized disease.15,91 However,
retrospective studies and analyses of the SEER database are limited by the lack of information on chemotherapy. In addition, comparison of the survival
of surgical patients to those who did not undergo surgery is inherently flawed by selection bias. Ultimately, the role of surgery in SCLC will not be fully
delineated until prospective trials compare surgery plus adjuvant chemotherapy with concurrent chemoradiotherapy in patients who are rigorously
staged. SABR, discussed later, is another option for stage I–IIA SCLC.

The Lung Cancer Study Group conducted the only prospective randomized trial evaluating the role of surgery in SCLC.92 Patients with limited-stage
SCLC, excluding those with solitary peripheral nodules, that responded to 5 cycles of chemotherapy with CAV (cyclophosphamide, doxorubicin, and
vincristine) were randomly assigned to undergo thoracic RT with or without resection. The overall survival (OS) rates of patients in the two arms were
equivalent, suggesting no benefit to surgery in this setting. However, only 19% of enrolled patients had clinical limited-stage I (T1–2, N0, M0) disease.
Additionally, data show that patients with SCLC who have nodal disease (i.e., T1–3, N1–3, M0–1) do not benefit from surgery.92

The Panel recommends that small lesions that are presumed to be small cell carcinoma on biopsy in patients who do not smoke tobacco should be
resected, because they are likely carcinoids that have been misdiagnosed (see the NCCN Guidelines for Neuroendocrine and Adrenal Tumors, available
at [Link]). The Panel also recommends surgery for certain patients with clinical stage I–IIA (T1–2, N0) SCLC with negative nodes that have
been confirmed by pathologic lymph node staging.13,85,93 Surgery can include patients with clinical limited-stage IIA SCLC based on the staging criteria
that includes tumors <5 cm in diameter (T2b) without lymph node involvement (N0). The Panel added recommendations for patients who did not have a
preoperative biopsy but have an intraoperative diagnosis of likely SCLC. If resection is performed, the Panel recommends lobectomy (preferred) with
mediastinal lymph node dissection or systematic lymph node sampling (e.g., ≥3 N2 and ≥1 N1 stations). The Panel does not recommend
pneumonectomy if nodal metastatic disease needs to be encompassed or under other circumstances. Chemoradiation is the preferred alternative over
any resection requiring pneumonectomy.

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Following surgery, adjuvant chemotherapy is recommended for patients with limited-stage I–IIA (T1–2, N0) SCLC with negative margins (R0
resection).88,94-96 Concurrent or sequential chemotherapy and postoperative mediastinal RT are recommended for patients with N+ disease.97 Although
Panel members agree that postoperative mediastinal RT is recommended for nodal metastases, it should be based on the extent of nodal
sampling/dissection and extent of nodal positivity. For patients with limited-stage I–IIA (T1–2, N0) SCLC with positive margins (R1/R2 resection), the
Panel recommends concurrent chemoradiation following surgery.

Systemic Therapy
For all patients with SCLC, systemic therapy is an essential component of primary/adjuvant treatment. Adjuvant chemotherapy is recommended for
patients with limited-stage SCLC who have had surgery or SABR. Systemic therapy following concurrent chemoradiation or SABR is also recommended
for patients with limited-stage I–IIA (T1–2, N0, M0) SCLC who are medically inoperable or do not want to pursue surgical resection. For patients with
limited-stage SCLC who are not eligible for surgery or SABR or have positive lymph node staging, chemotherapy with concurrent thoracic RT (category 1
for patients with PS 0–2) is the recommended primary treatment.9,98,99 For patients with extensive-stage SCLC, systemic therapy alone is recommended.
RT may be used in select patients with extensive-stage disease for palliation of symptoms (see NCCN Guidelines for Palliative Care, available at
[Link]). The systemic therapy recommendations are based on studies described in the following sections.

Cisplatin Versus Carboplatin

Randomized trials and retrospective analyses of patients with SCLC suggest similar efficacy between cisplatin and carboplatin regimens.100-102 In a meta-
analysis of 663 patients with limited- (32%) and extensive-stage SCLC (68%), no significant difference was observed in response rate (67% vs. 66%),
progression-free survival (PFS) (5.5 vs. 5.3 months), or OS (9.6 vs. 9.4 months) between cisplatin- versus carboplatin-containing regimens.103
Carboplatin is frequently substituted for cisplatin to reduce the risk of emesis, neuropathy, and nephropathy.104 The use of carboplatin carries a greater
risk of myelosuppression.104

Limited-Stage SCLC
Adjuvant chemotherapy alone is recommended for patients who have undergone surgical resection or SABR for limited-stage SCLC.
Cisplatin/etoposide is the most commonly used first-line combination chemotherapy regimen for patients with limited-stage SCLC.105,106
Cisplatin/etoposide replaced alkylator/anthracycline-based regimens based on its superiority in both efficacy and toxicity. 107-109 If pathologic lymph
node involvement is found at surgery (N+) for patients with stage I–IIA (T1–2, N0, M0), then thoracic RT can be added concurrently or sequentially to
cisplatin/etoposide. Treatment with cisplatin/etoposide plus definitive thoracic RT showed response rates of 70% to 90% with a median OS of 25 to 30
months and 5-year OS rates of 31% to 34%.105 Cisplatin/etoposide in combination with thoracic RT increases the risk of esophagitis, as well as
pulmonary and hematologic toxicity. 110 Thoracic RT improved local control rates by 25% and is associated with improved survival in patients with
limited-stage SCLC.98,99 Data suggest that chemoradiotherapy may also be indicated for patients with limited-stage SCLC who have cytologically
negative or indeterminate pleural effusions but not for those with pericardial effusions.111,112

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For patients with limited-stage IIB–IIIC (T3–4, N0, M0; T1–4, N1–3, M0) SCLC, the Panel recommends different cisplatin/etoposide regimens plus
concurrent thoracic RT (category 1). 98,99,113,114 The preferred cisplatin/etoposide regimens for limited-stage SCLC are based on the dosing used in the
CONVERT trial. 105 Carboplatin/etoposide is also listed as a preferred option based on the subgroup analysis in the ADRIATIC trial.115,116 Other
recommended options for limited-stage SCLC include additional cisplatin/etoposide doses. The use of myeloid growth factors is not recommended in
patients undergoing concurrent chemoradiation (category 1 for not using granulocyte-macrophage colony-stimulating factor [GM-CSF]).117

Response assessment is an important aspect of the management of SCLC. For patients with limited-stage SCLC, the Panel recommends response
assessment using CT with contrast after completion of adjuvant chemotherapy alone or chemotherapy with concurrent RT. Response assessment can
be measured using CT with contrast of the C/A/P and brain MRI (preferred) or brain CT with contrast. For systemic therapy alone or sequential
systemic therapy followed by RT in patients with limited-stage SCLC, the Panel recommends response assessment using CT with contrast of the
C/A/P after every 2 cycles of systemic therapy and at completion of therapy. In the absence of new symptoms, repeating scans to assess response
during adjuvant or initial treatment is not recommended.

Durvalumab Consolidation Therapy

The ADRIATIC trial included patients with stage I–III limited-stage SCLC, PS 0–1 and no disease progression on chemoradiation. The median OS
was 55.9 months in those patients receiving consolidation therapy (n = 264) compared to 33.4 months (P = .01) in patients receiving placebo (n =
266).115 The study revealed a statistically significant and clinically meaningful OS and PFS (16.6 vs. 9.2 months, P = .02) improvement in patients
receiving consolidation durvalumab compared to placebo. Based on these data, the Panel recommends durvalumab consolidation therapy in those
patients with limited-stage SCLC who did not experience disease progression after systemic therapy + concurrent RT (category 1). Durvalumab may
be continued until disease progression or intolerable toxicity, or for a maximum of 24 months. The Panel advises imaging every 8 weeks for the first
18 months and every 12 weeks after. Additionally, the Panel recommends if PCI is being considered in this setting it should be given prior to
consolidation durvalumab.

Extensive-Stage SCLC
The Panel recommends certain combination chemotherapy plus immunotherapy regimens as preferred options for patients with extensive-stage
SCLC.118-120 In patients with extensive-stage SCLC and brain metastases, systemic therapy can be given either before or after brain RT depending on
whether the patient has neurologic symptoms.16,121 The Panel recommends steroid initiation for patients with spinal cord compression or brain metastasis
who have symptomatic neurologic disease. For example, dexamethasone 10 mg loading dose followed by 4 to 6 mg maintenance dose (IV or oral [PO]
every 4–6 hours [or as appropriate]) can be initiated.122 If systemic therapy is given first, brain RT is administered after completion of systemic therapy.
However, if brain metastases progress while on systemic therapy, it is recommended that brain RT is initiated before completion of systemic therapy.
Systemic therapy with or without RT to localized symptomatic sites is recommended for patients with extensive disease, which includes the superior vena
cava (SVC), lobar obstruction, and bone metastasis. Prophylactic RT can be considered for patients with high fracture risk due to osseous structural
impairment.
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During systemic therapy for patients with extensive-stage SCLC, the Panel recommends response assessment using CT with contrast of the C/A/P after
every 2 to 3 cycles of systemic therapy and at completion of therapy.

For patients with known brain metastases, brain MRI (preferred) or brain CT with contrast should be obtained every 3–4 months, or at a frequency based
on clinical indication. If systemic therapy was initiated prior to brain RT, brain MRI (preferred) or CT with contrast is recommended to be repeated after
every 2 cycles of systemic therapy until brain RT is initiated.

The preferred regimens for patients with extensive-stage SCLC include etoposide/platinum regimens in combination with the programmed death ligand 1
(PD-L1)–targeted ICIs, atezolizumab or durvalumab. Contraindications for treatment with programmed cell death protein 1 (PD-1)/PD-L1 inhibitors may
include active or previously documented autoimmune disease and/or concurrent use of immunosuppressive agents. The Panel recommends continuation
of maintenance immunotherapy until disease progression or intolerable toxicity. Atezolizumab or durvalumab may cause unique immune-mediated
adverse events that are not seen with traditional cytotoxic chemotherapy. Therefore, health care providers should be aware of the spectrum and
management of potential immune-mediated adverse events and have a discussion with patients about possible side effects (see the NCCN Guidelines
for Management of Immune Checkpoint Inhibitor-Related Toxicities, available at [Link]). High-dose corticosteroids are generally recommended
for immune-mediated adverse events based on the severity of the reaction. Atezolizumab or durvalumab should be withheld or discontinued for severe or
life-threatening immune-mediated adverse events when indicated (see prescribing information).

Chemotherapy + Atezolizumab
IMpower133, a phase 3 randomized trial, assessed the addition of atezolizumab (treatment and maintenance) to carboplatin/etoposide in 403 patients
with previously untreated extensive-stage SCLC and compared outcomes to carboplatin/etoposide alone.120 The 1-year OS rate was 51.9% for the
atezolizumab regimen versus 39.0% for chemotherapy alone. The median OS was 12.3 months (95% CI, 10.8–15.8) with the addition of atezolizumab
versus 10.3 months (95% CI, 9.3–11.3) with chemotherapy alone (hazard ratio [HR], 0.76; 95% CI, 0.6–0.95; P = .0154).118 Response rates were similar
in both arms (60% with atezolizumab/chemotherapy vs. 64% with chemotherapy alone). The rate of grade 3 or 4 adverse events was similar in both
groups (67.7% for the atezolizumab regimen vs. 63.3% for chemotherapy alone). There were 4 deaths (2%) in the atezolizumab group versus 11 deaths
(5.6%) in the chemotherapy alone group. Different doses for maintenance atezolizumab have been FDA-approved for patients with extensive-stage
SCLC. In light of these data and FDA approval, the Panel recommends carboplatin/etoposide + atezolizumab as a category 1 and preferred first-line
systemic therapy option followed by maintenance atezolizumab for patients with extensive-stage SCLC.118,120 The Panel recommends either 1200 (every
3 weeks) or 1680 mg (every 4 weeks) of maintenance atezolizumab. The category 1 recommendation is only for 1200 mg of maintenance atezolizumab
based on the dose used in the clinical trial.118,120

IMforte, a phase 3 randomized trial, assessed the addition of lurbinectedin to the carboplatin/etoposide + atezolizumab regimen during the maintenance
phase with atezolizumab. PFS (stratified HR, 0.54; 95% CI, 0.43–0.67; P < .0001) and OS (stratified HR, 0.73; 95% CI, 0.57–0.95; P = .017) were longer
in the lurbinectedin plus atezolizumab group than in the atezolizumab group. The patients in this trial were randomized after platinum therapy only if they

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had either a response or stable disease; <10% of patients on the control arm received lurbinectedin after progression. The trial excluded patients with
brain metastases at diagnosis. Based on these data, the Panel recommends the addition of lurbinectedin to maintenance atezolizumab only in patients
who have achieved at least stable disease following four cycles of induction chemoimmunotherapy, have an Eastern Cooperative Oncology Group
(ECOG) PS of 0–1, and have no history of brain metastases. The Panel indicates that atezolizumab and hyaluronidase-tqjs subcutaneous injection may
be substituted for IV atezolizumab, and notes that atezolizumab and hyaluronidase-tqjs has different dosing and administration instructions compared to
IV atezolizumab infusion.

Chemotherapy + Durvalumab
CASPIAN, a phase 3 randomized trial, assessed adding durvalumab to etoposide and either carboplatin or cisplatin followed by maintenance
durvalumab in 537 patients with previously untreated extensive-stage SCLC and compared response to etoposide/platinum regimens.119,123 Most patients
received carboplatin (78%). A 3-year analysis showed that the median OS was 13.0 months (95% CI, 11.5–14.8) in the chemotherapy + durvalumab
group and 10.3 months (95% CI, 9.3–11.2) in the chemotherapy alone group (HR, 0.73; 95% CI, 0.59–0.91; P = .0047).124 The 1-year OS rate was
52.8% for the durvalumab regimen versus 39.3% for chemotherapy alone. The rate of serious adverse events was similar in both groups (32% vs. 36%).
The death rate from adverse events was also similar (2% vs. 1%). In this trial, adding tremelimumab to carboplatin (or cisplatin)/etoposide + durvalumab
did not improve OS compared with platinum/etoposide (10.4 vs. 10.5 months; HR, 0.82; 95% CI, 0.68–1.0). Based on the data and FDA approval, the
Panel recommends carboplatin or cisplatin/etoposide + durvalumab as a category 1 and preferred first-line systemic therapy option followed by
maintenance durvalumab for patients with extensive-stage SCLC, including those with asymptomatic untreated brain metastases.119,123,125

Other Primary Systemic Therapies

Other recommended first-line systemic therapy regimens for extensive-stage SCLC include cisplatin or carboplatin/etoposide combinations. Additional
chemotherapy combination regimens evaluated in patients with extensive-stage SCLC show inconsistent evidence of benefit compared with
cisplatin/etoposide. For example, a phase 3 trial in Japan reported that patients with extensive-stage SCLC treated with cisplatin/irinotecan had a median
survival of 12.8 months compared with 9.4 months for patients treated with cisplatin/etoposide (P = .002).126 The 2-year survival was 19.5% in the
cisplatin/irinotecan group versus 5.2% in the cisplatin/etoposide group.126 Two subsequent large phase 3 trials performed in the United States comparing
cisplatin/irinotecan versus cisplatin/etoposide showed no significant difference in response rate or OS.127,128 A phase 3 randomized trial of 220 patients
with extensive-stage SCLC found that median OS slightly improved with carboplatin/irinotecan compared with carboplatin/oral etoposide (8.5 vs. 7.1
months; P = .04).129 In addition, a meta-analysis suggested an improvement in PFS and OS with irinotecan/platinum regimens compared with
etoposide/platinum regimens.130 The Panel recommends the irinotecan-based regimens as primary therapy options (useful in certain circumstances) for
patients with extensive-stage SCLC. However, the relatively small absolute survival benefit needs to be balanced against the toxicity profile of
irinotecan-based regimens.

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The use of maintenance or consolidation chemotherapy beyond the recommended 4 to 6 cycles results in a minor increase in the duration of response
without improving survival and carries a greater risk of cumulative toxicity.131,132 The inability to destroy residual cells, despite the initial chemosensitivity
of SCLC, suggests the existence of cancer stem cells that are relatively resistant to cytotoxic therapy. Alternating or sequential combination therapies
have been designed to overcome drug resistance by exposing the tumor to as many active cytotoxic agents as possible during initial treatment.133
However, this approach has not improved PFS or OS in randomized trials.134,135 Therefore, the Panel recommends 4 cycles of systemic cytotoxic therapy
for patients with limited- (with concurrent radiation) and extensive-stage (with concurrent immunotherapy) SCLC. However, some patients with extensive-
stage SCLC may receive up to 6 cycles based on response and tolerability.

Attempts to improve long-term survival rates in patients with SCLC through the addition of more agents or the use of dose-intense chemotherapy,
maintenance therapy, or alternating non-cross-resistant chemotherapy regimens have not shown significant advantages compared to recommended
approaches. In two trials, the addition of ifosfamide (or anthracycline/cyclophosphamide) to cisplatin/etoposide showed a modest survival
advantage.136,137 However, these findings have not been uniformly observed, and the addition of an alkylating agent, with or without an anthracycline,
significantly increases hematologic toxicity when compared to cisplatin/etoposide alone.138 Two different phase 3 trials assessing the combination of
epirubicin/etoposide/ifosfamide versus cisplatin/etoposide, and carboplatin/etoposide with or without palifosfamide confirmed the lack of improvement in
survival with three-drug chemotherapy regimens in patients with extensive-stage SCLC.139,140 Similarly, the addition of paclitaxel to either cisplatin or
carboplatin/etoposide yielded promising results in phase 2 studies, but did not improve survival and was associated with unacceptable toxicity in a phase
3 trial.141

The role of high chemotherapy doses for patients with SCLC remains controversial. Patients receiving high chemotherapy doses compared with those
given conventional doses of the same agents had higher complete and partial response rates, and modestly longer median survival times.142 However,
randomized trials comparing conventional chemotherapy doses to incremental increases in dose intensity (up to 2 times the conventional dose) have not
consistently shown an increase in response rate or survival.143-146 In addition, a meta-analysis of trials that studied dose-intense variations of the CAV
and cisplatin/etoposide regimens found that increased relative dose intensity resulted in only a small, clinically insignificant enhancement of median
survival in patients with extensive-stage SCLC.147 Early phase 2 results designed to increase dose intensity by weekly cyclic multidrug chemotherapy
were promising, but favorable patient selection was of some concern.148,149 No survival benefit was documented in randomized trials, and excessive
treatment-related mortality was noted with weekly cyclic multidrug chemotherapy regimens.150-153

Despite the success with chemotherapy + atezolizumab or chemotherapy + durvalumab regimens, other immunotherapy-based strategies have not been
as favorable. A phase 3 randomized trial in patients with extensive-stage SCLC reported that the addition of ipilimumab to cisplatin or
carboplatin/etoposide as first-line therapy did not improve either OS or PFS compared with chemotherapy alone.154 Likewise, another phase 3
randomized trial showed no improvement in OS in patients with extensive-stage SCLC treated with first-line etoposide/platinum + pembrolizumab
followed by maintenance pembrolizumab compared with chemotherapy alone.56

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Antiangiogenic therapy has also been evaluated in SCLC. In patients with limited-stage SCLC, a phase 2 study of irinotecan, carboplatin, and
bevacizumab with concurrent RT followed by maintenance bevacizumab was terminated early because of an unacceptable incidence of
tracheoesophageal fistulae. In extensive-stage SCLC, phase 2 trials of platinum-based chemotherapy plus bevacizumab showed promising response
and survival data.155-158 However, at least two randomized trials have demonstrated no survival benefit for the addition of bevacizumab to standard
chemotherapy.159,160 Currently, the Panel does not recommend use of bevacizumab in patients with SCLC.

Cytokines (e.g., GM-CSF, granulocyte colony-stimulating factor [G-CSF]) can ameliorate chemotherapy-induced myelosuppression and reduce the
incidence of febrile neutropenia, but cumulative thrombocytopenia remains dose-limiting. Although trials involving patients with SCLC were instrumental
in obtaining FDA approval for the clinical use of cytokines,161 maintenance of dose intensity with growth factors does not prolong disease-free survival or
OS.162,163 The Panel does not recommend GM-CSF (category 1 for not using it) or G-CSF for patients with limited-stage SCLC receiving systemic
therapy/RT.117,164 Trilaciclib or G-CSF may be used as prophylactic supportive care options to decrease the incidence of chemotherapy-induced
myelosuppression when administering certain regimens for patients with extensive-stage SCLC.117,164-169 Trilaciclib is a transient cyclin-dependent kinase
(CDK) 4/6 inhibitor that has been shown to reduce chemotherapy-induced myelosuppression in patients with extensive stage SCLC. In clinical trials,
trilaciclib demonstrated reductions in the incidence and duration of severe neutropenia, as well as reductions in the incidence of severe anemia and
thrombocytopenia.167,170 It is important to note that trilaciclib or G-CSF are not treatment options.

Transformed SCLC from NSCLC with an Oncogenic Driver

The Panel recognizes that transformed SCLC from NSCLC is a rare population of patients with limited data including treatment options. The Panel
recommends considering referral to a center with expertise in managing transformed SCLC with an oncogenic driver, that can be actionable genomic
alterations. The Panel recommends systemic cytotoxic chemotherapy using the NCCN Guidelines for Small Cell Lung Cancer due to lack of data for
transformed SCLC. The role of immunotherapy in transformed SCLC is unclear and should be avoided if tyrosine kinase inhibitors are being used.
The Panel clarified that in patients who develop SCLC as a resistance mechanism to tyrosine kinase inhibitors used for actionable genomic alteration-
driven NSCLC, ICIs should be avoided if tyrosine kinase inhibitors are continued. This is due to known toxicity that is primarily driven by the long half-
life of ICIs.

Older Patients
The incidence of SCLC increases with age with the median age at diagnosis being >70 years.171 The functional status of an individual patient is more
useful than chronologic age in guiding clinical decision-making that includes considering treatment tolerance (see the NCCN Guidelines for Older Adult
Oncology, available at [Link]). Greater attention to the needs and support systems of a patient’s functional status is recommended to provide
optimal care. Patients who are able to perform activities of daily living (ADLs) should be treated with combination systemic therapy and RT, if
indicated.172-174 For example, a subgroup analysis of the CONVERT trial suggests that concurrent chemoradiation yields equivalent median survival in
patients <70 years and ≥70 years with limited-stage SCLC (29 vs. 30 months; P = .38).172 However, myelosuppression, fatigue, and lower organ reserves

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are encountered more frequently in patients ≥70 years. Therefore, the study recommended closer surveillance for patients ≥70 years during treatment to
avoid excessive risk.172

Randomized trials have indicated that less-intense treatment (e.g., single-agent etoposide) is inferior to combination chemotherapy (e.g.,
etoposide/platinum) in patients of all ages with good PS (0–2).175,176 A retrospective analysis in 8637 patients ≥70 years with limited-stage SCLC reported
that chemoradiation increased survival compared with chemotherapy alone.173 Several other strategies have been evaluated in patients ≥65 years with
SCLC.102,177-179 The use of 4 cycles of carboplatin/etoposide seems to yield favorable results, because the area-under-the-curve (AUC) dosing of
carboplatin takes into account the declining renal function of the patient.179 Targeting carboplatin to an AUC of 5, rather than 6, is more reasonable in the
population >70 years.180 A short, 2-week, full-intensity course of chemotherapy showed 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.181

PCI should be used with caution in older patients. A Dutch analysis of >5000 patients suggests that median survival is lower in patients ≥70 years
compared with patients <70 years treated with PCI, regardless of stage.182 Patients aged ≥60 years are at increased risk for cognitive decline after PCI;
therefore, the risks and benefits of PCI versus close MRI surveillance need to be discussed.183-186

Surveillance for Relapse

Although SCLC responds to initial treatment, disease relapse is observed in most patients.187,188 Most NCCN Member Institutions use chest CT (±
abdomen/pelvis) every 2 to 6 months (more frequently in years 1–2 and less frequently thereafter). The frequency of surveillance decreases during
subsequent years because of the declining risk of recurrence.189 If a new pulmonary nodule develops, it should prompt evaluation for a new primary lung
cancer, because second primary tumors post-treatment frequently occur in patients with no evidence of SCLC.190,191 It is important to monitor for brain
metastases prior to the development of potentially debilitating neurologic symptoms and to allow for early treatment. The Panel recommends brain MRI
(preferred) or CT with contrast every 3 to 4 months during year 1 for all patients and then every 6 months in year 2, and as clinically indicated thereafter,
regardless of the PCI status. MRI is more sensitive than CT for identifying brain metastases.74 The Panel maintains that FDG-PET/CT is not
recommended for routine follow-up unless contrast CT C/A/P or MRI is contraindicated. Tobacco smoking cessation intervention is recommended for all
patients with SCLC, because second primary tumors occur less commonly in patients who quit smoking (see the NCCN Guidelines for Smoking
Cessation, available at [Link]).192-194 Patients who previously smoked tobacco should be encouraged to remain abstinent. The Panel also
recommends the NCCN Guidelines for Survivorship for appropriate patients (available at [Link]).

Subsequent Systemic Therapy

Patients with disease relapse or with primary progressive disease may be treated with subsequent systemic therapy. Consider genomic profiling of
relapsed tumors, if not previously performed, to determine clinical trial eligibility. The Panel no longer recommends treatment based on the time frame for
chemotherapy free intervals (CTFI). Subsequent therapy options for all patients with SCLC should be chosen based on clinical expertise and trial data

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regardless of CTFI. The optimal duration of subsequent systemic therapy has not been fully explored. For cytotoxic chemotherapy agents, the duration of
treatment is usually short, and the cumulative toxicity is frequently limiting even in patients who experience response. For these reasons, subsequent
systemic therapy should be continued until progression of disease or development of unacceptable toxicity. For CNS progression only, the Panel
recommends continuing systemic therapy and treating brain metastases with RT. Additional subsequent systemic therapy (e.g., third line) can be
considered if patients are still PS 0–2. The Panel recommends response assessment using CT with contrast of the C/A/P after every 2 to 3 cycles. Dose
reduction or growth factor support should be considered for patients with a PS of 2.

Tarlatamab-dlle
Initial phase 1 and 2 trials in patients heavily pretreated for relapsed/refractory SCLC showed promising durability and acceptable safety profile with
tarlatamab, a bispecific T-cell engager antibody that targets delta-like ligand 3 (DLL3) and CD3.195 DLL3 is abnormally expressed on the surface of the
majority of SCLC cells (85-94%) and inhibits Notch. Because of the favorable benefit to risk ratio in patients who received 10 mg versus 100 mg, the
lower dose has been chosen for subsequent studies. In the phase 3 trial, patients were randomly assigned to receive tarlatamab (n = 254) or
chemotherapy (n = 255, topotecan or lurbinectedin depending on the site). Tarlatamab-dlle significantly improved median OS compared to the
chemotherapy group (13.6 vs 8.3 months).196 OS in the tarlatamab group was 76% at 6 months and 53% at 12 months as compared with 62% at 6
months and 37% at 12 months in the chemotherapy group. Grade 3 or higher adverse events were lower with tarlatamab compared to chemotherapy
(54% vs 80%). The most common treatment-related adverse events in the tarlatamab group included neutropenia, lymphopenia, lymphocyte count
decrease, fatigue, neutrophil count decrease, hyponatremia, and anemia. Additionally, cytokine release syndrome were observed in 56% of the patients
treated with tarlatamab. To manage unique toxicities with tarlatamab-dlle administration, the Panel refers to the NCCN Guidelines for Management of
Car T-Cell and Lymphocyte Engager-Related Toxicities (available at [Link]). The Panel recommends tarlatamab-dlle (10 mg dosing schedule)
as a category 1, preferred regimen for subsequent therapy.

Irinotecan
In a phase 2 study, disease responded to irinotecan in 47% of patients (95% CI, 21.4%–1.9%) with relapsed or refractory SCLC.197 Myelosuppression,
diarrhea, and pulmonary toxicity were reported in patients receiving irinotecan.197 Another phase 2/3 trial showed that irinotecan and topotecan had
comparable activity in patients with relapsed or refractory SCLC and metastasis.198 The Panel recommends irinotecan as a subsequent therapy option
(preferred) for patients with SCLC. The Panel added a consideration for irinotecan for patients with CNS disease.

Lurbinectedin
A phase 2 basket trial assessed lurbinectedin (3.2 mg/m2 every 3 weeks) as second-line therapy in 105 patients with SCLC who previously received
etoposide/platinum; 57% of patients had not received chemotherapy for ≥3 months.199 The overall response rate with lurbinectedin was 35% (95% CI,
26.2%–45.2%). The response rate ranged from 22% (95% CI, 11.2%–37.1%) to 45% (95% CI, 32.1%–58.4%). Common grade 3–4 adverse events
included anemia, leukopenia, neutropenia, and thrombocytopenia. There were no reported treatment-related deaths. In a subset analysis of this trial, the

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overall response rate associated with lurbinectedin was 60% (95% CI, 36.1%–86.9%). The median OS was 16.2 months (95% CI, 9.6–upper level not
reached).200 After 1 year, 60.9% of patients were alive and after 2 years, 27.1% were alive. Common grade 3–4 adverse events included neutropenia,
anemia, thrombocytopenia, fatigue, and increased liver function tests (including gamma-glutamyl transferase [GGT], alanine aminotransferase [ALT] and
alkaline phosphatase [ALP]). The FDA granted approval for lurbinectedin at a dose of 3.2 mg/m2 every 3 weeks based on clinical trial data.199 The Panel
recommends lurbinectedin as a subsequent therapy option (preferred) and if not previously used for patients with SCLC.199,200

Platinum-Based Therapy
A phase 3 randomized trial assessed carboplatin/etoposide compared with oral topotecan in 162 patients with SCLC relapse after >3 months on first-line
etoposide/platinum therapy.201 The median PFS was 4.7 months (90% CI, 3.9–5.5) in the carboplatin/etoposide group versus 2.7 months (90% CI, 2.3–
3.2) in the oral topotecan group (HR, 0.57; 90% CI, 0.41–0.73; P = .004). Grade 3–4 adverse events included thrombocytopenia, neutropenia, anemia,
febrile neutropenia, and asthenia. In the topotecan group, two treatment-related deaths occurred; no deaths occurred in the carboplatin/etoposide group.
The Panel recommends subsequent therapy with platinum-based regimens based on the clinical trial data.201-205 The Panel maintains that rechallenging
with the original regimen with or without immunotherapy, or similar platinum-based regimen, is recommended as an option (preferred) if there has been
prolonged disease-free time.201-205

Topotecan
Topotecan is also recommended as a subsequent therapy option based on clinical trial data.201 A randomized phase 3 trial for subsequent treatment
compared single-agent IV topotecan with CAV in patients with SCLC relapse at least 60 days after therapy.206 Both arms had similar response rates
(topotecan, 24.3%; CAV, 18.3%) and survival (25.0 vs. 24.7 weeks). Compared to CAV, topotecan caused less grade 4 neutropenia (37.8% vs. 51.4%; P
< .001) and improved symptoms of dyspnea, anorexia, hoarseness, and fatigue. There are conflicting data regarding the usefulness of weekly topotecan
in patients with relapsed SCLC.207,208 Many practicing oncologists have noted excessive toxicity when using 1.5 mg/m2 of IV topotecan for 5 days, and
studies suggest that an attenuated dose may be equally efficacious with lower toxicity.209 In another phase 3 trial, oral topotecan improved OS compared
with best supportive care (26 vs. 14 weeks).210 The efficacy and toxicity of oral and IV topotecan seem to be similar and therefore either route may be
used.210,211 The Panel recommends oral or IV topotecan as a subsequent therapy option (preferred) for patients with SCLC.201,206,210,212,213

Other Recommended Subsequent Therapy Options

CAV
A phase 3 trial (JCOG0605) from Japan in patients with sensitive, relapsed SCLC reported that the combination of cisplatin/etoposide/irinotecan
improved survival compared with topotecan (median survival, 18.2 vs. 12.5 months; HR, 0.67; 90% CI, 0.51–0.88; P = .0079). However, the toxicity of
this regimen was significant.214 The Panel recommends CAV as a subsequent therapy option based on clinical trial data.206

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Docetaxel and Paclitaxel

Docetaxel and paclitaxel, which belong to the taxane class of drugs, have been assessed in patients with refractory or relapsed SCLC. In a phase 2
study in patients with refractory or relapsed SCLC, 24% of patients’ disease responded to paclitaxel.215 Grade 3–4 toxicity included neutropenia,
infection, rash, neuropathy, and pulmonary toxicity. Another phase 2 study of paclitaxel in patients with refractory SCLC yielded a response rate of 29%
(95% CI, 12%–51%).216 A retrospective study in 185 patients showed a response rate of 17% during third-line or fourth-line therapy with paclitaxel.
Toxicity rates were similar in patients with PS 2 compared with PS 0–1 (63% vs. 62%).217 Twenty-five percent of patients’ disease responded to
docetaxel in a phase 2 trial in patients with previously treated SCLC. Reported toxicities included neutropenia and asthenia.218

Gemcitabine
Gemcitabine was assessed in a phase 2 trial in 42 patients with sensitive or refractory SCLC.219 The median survival was 7.1 months. The overall
objective response rate was 11.9%. One patient with refractory SCLC and four patients with sensitive SCLC had disease respond to therapy. Grade 3–4
toxicities included neutropenia (27%), thrombocytopenia (27%), neurologic toxicity (14%), and pulmonary toxicity (9%). Another phase 2 trial assessed
gemcitabine in 38 patients with resistant SCLC that progressed within 3 months of last therapy.220 The median survival was 17 weeks (range, 4–84). The
response rate was 13% (95% CI, 6%–27%); there were five partial responses and no complete responses. Grade 3 toxicities included thrombocytopenia
(29%) and leukopenia (18%).

Nivolumab and Pembrolizumab

ICIs have been evaluated in patients with relapsed SCLC.221-224 CheckMate 032, a phase 1/2 trial, assessed nivolumab alone (n = 147) or various doses
of ipilimumab + nivolumab (n = 96) for relapsed SCLC.221,222 Response rates were 11.6% for nivolumab and 21.9% for ipilimumab + nivolumab.221 The
12- and 24-month OS rates were similar (nivolumab, 30.5% and 17.9%; ipilimumab + nivolumab, 30.2% and 16.9%, respectively). Grade 3–4 adverse
events were 12.9% for nivolumab alone and 37.5% for ipilimumab + nivolumab. In patients receiving nivolumab alone, the most common grade 3 or 4
treatment-related adverse events were pneumonitis and increased levels of lipase and aspartate aminotransferase.

CheckMate 331, a randomized phase 3 trial, assessed nivolumab monotherapy versus amrubicin or topotecan in 569 patients with relapsed SCLC.213
Data show that OS was 7.5 months in patients receiving nivolumab versus 8.4 months in those receiving chemotherapy (HR, 0.86; 95% CI, 0.72–1.04; P
= .11).213 OS was similar regardless of PD-L1 levels. Response rates were 13.7% for nivolumab compared with 16.5% for chemotherapy.
Treatment-related deaths occurred in two patients receiving nivolumab and in three patients receiving chemotherapy. Fewer grade 3–4 adverse events
occurred in patients receiving nivolumab compared with chemotherapy (14% vs. 73%, respectively). A study reported that third-line therapy with
nivolumab was associated with longer survival (5.7 months; 95% CI, 3.5–8.0) compared with other treatments such as paclitaxel or topotecan (3.8
months; 95% CI, 2.8–4.9; HR, 0.63; 95% CI, 0.44–0.90).225 The 1-year OS rate is 28% with nivolumab versus 4% with the other treatments.

A combined analysis of two trials, phase Ib (KEYNOTE-028) and phase 2 (KEYNOTE-158), evaluated the activity of pembrolizumab in 83 patients with
relapsed SCLC who had received ≥2 lines of therapy. PD-L1 positivity (≥1%) was found in 56.6% of tumors and 84.3% patients did not have brain

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metastases.226 This analysis reported an objective response rate of 19.3% (95% CI, 11.4%–29.4%). The median OS was 7.7 months (95% CI, 5.2–10.1);
the estimated 12-month OS rate was 34.3%. Both OS and response rate were higher in those who were PD-L1 positive; however, one patient with a
complete response had a tumor that was PD-L1 negative. Grade 3 or 5 adverse events occurred in 9.6% (8/83) of patients; two patients died from
treatment-related adverse events (pneumonitis and encephalitis).

The FDA has withdrawn the subsequent therapy indications for nivolumab or pembrolizumab for patients with relapsed SCLC, because phase 3
randomized trial data did not show an improvement in OS.213,221-223,226,227 The Panel decided that nivolumab or pembrolizumab are just as effective as
(sometimes better than) and less toxic than the other subsequent therapy options.213,225 In addition, many agents recommended as subsequent therapy
options for patients with SCLC do not have an FDA indication in this setting, but data show that they are effective. Patients who have not previously
received ICIs may benefit from subsequent therapy with nivolumab or pembrolizumab. Nivolumab and hyaluronidase-nvhy subcutaneous injection may
be substituted for IV nivolumab. Nivolumab and hyaluronidase-nvhy has different dosing and administration instructions compared to IV nivolumab.
Similarly, pembrolizumab and berahyaluronidase alfa-pmph subcutaneous injection may be substituted for IV pembrolizumab. Pembrolizumab and
berahyaluronidase alfa-pmph has different dosing and administration instructions compared to IV pembrolizumab. The use of nivolumab and
pembrolizumab is discouraged in patients whose disease progresses while on maintenance atezolizumab or durvalumab as part of first-line therapy.
There are no data to suggest that giving patients subsequent ICIs is effective if their disease previously progressed on other ICIs.

Health care providers should be aware of the spectrum of potential immune-mediated adverse events unique to immunotherapeutic agents, such as
nivolumab and pembrolizumab, know how to manage these events, and discuss possible side effects with patients (see the NCCN Guidelines for
Management of Immune Checkpoint Inhibitor-Related Toxicities, available at [Link]).228,229 For patients with immune-mediated adverse events,
high-dose corticosteroids are generally recommended based on the severity of the reaction. Nivolumab or pembrolizumab should be withheld or
discontinued for severe or life-threatening immune-mediated adverse events (see prescribing information).

Etoposide
Oral etoposide was assessed in a phase 2 trial in 22 patients with recurrent SCLC.230 Ten patients (45%; 95% CI, 27%–65%) had a complete or partial
response. Median survival was ≥3.5 (range, 1 to 15+). Five patients were hospitalized because of neutropenia and fever. Two patients died from sepsis.
Another phase 2 trial assessed oral etoposide in 26 patients with refractory SCLC.231 The overall response rate was 23%; there was one complete
response and five partial responses.

Temozolomide
Data suggest that temozolomide may be useful for patients with SCLC, especially those with brain metastases and methylated O 6-methylguanine-DNA
methyltransferase (MGMT).232-234 Temozolomide was assessed in a phase 2 trial in patients with relapsed or refractory SCLC. In patients with sensitive
SCLC, the overall response rate was 23% (95% CI, 12%–37%). The response rate improved for patients with methylated MGMT compared to those with
unmethylated MGMT (38% vs. 7%; P = .08).

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Radiation Therapy
The American Radium Society appropriate use criteria and the American Society for Radiation Oncology (ASTRO) guidelines are useful resources.235-238
The Principles of Radiation Therapy section in the NSCLC algorithm may also be useful (see the NCCN Guidelines for Non-Small Cell Lung Cancer,
available at [Link]).

Thoracic Radiation Therapy for Limited-Stage SCLC

Achieving long-term local control using conventional chemoradiotherapy for patients with limited-stage SCLC remains a challenge. The addition of
thoracic RT has improved survival for patients with limited-stage SCLC. Meta-analyses that include >2000 patients show that thoracic radiation for
limited-stage SCLC yields a 25% to 30% reduction in local progression, and a corresponding 5% to 7% improvement in 2-year OS compared with
chemotherapy alone.98,99 A phase 3 trial reported 5-year OS of >30%, which is close to outcomes of locally advanced NSCLC of similar stage.105

Timing of Radiation with Chemotherapy

Optimal thoracic RT is impacted by several factors, including the timing of chemotherapy and RT (concurrent vs. sequential), timing of RT (early vs. late),
RT target volume (original tumor volume vs. shrinking field as the tumor responds), radiation dose, and RT fractionation. Early concurrent
chemoradiotherapy is recommended for patients with limited-stage SCLC based on randomized trials. A randomized phase 3 trial by the Japanese
Cooperative Oncology Group (9104) assessed sequential versus concurrent thoracic RT combined with cisplatin/etoposide for 231 patients with
limited-stage SCLC. OS was 27.2 months for those receiving concurrent chemoradiation versus 19.7 months for those receiving sequential
chemoradiation (P = .097).110 Patients receiving concurrent chemoradiation had more severe hematologic toxicity. Severe esophagitis occurred in 9% of
patients receiving concurrent chemoradiation and 4% receiving sequential chemoradiation.

Several systematic reviews and meta-analyses on the timing of thoracic RT in limited-stage SCLC have reported that early concurrent chemoradiation
results in a small, but significant improvement in OS compared with late concurrent or sequential chemoradiation.239,240 A randomized phase 3 trial (by
the National Cancer Institute of Canada) compared RT beginning with either cycle 2 or cycle 6 of chemotherapy and showed that early RT was
associated with improved local and systemic control and longer survival.241 Meta-analysis in patients with limited-stage SCLC showed that survival
improved with rapid completion of the chemoradiotherapy regimen (start of any chemotherapy until the end of RT).242 Another meta-analysis of individual
patient data from 12 trials (n = 2668) reported that early concurrent chemoradiation, associated with increase in acute esophagitis, had higher 5-year OS
(HR, 0.79; 95% CI, 0.69–0.91) compared with late concurrent chemoradiation.243

Radiation Fractionation
The ECOG/Radiation Therapy Oncology Group (RTOG) compared accelerated to conventionally fractionated RT with cisplatin/etoposide.244 In this trial,
412 patients with limited-stage SCLC were treated with concurrent chemoradiation using a total dose of 45 Gy delivered either twice daily over 3 weeks
(accelerated) or once daily over 5 weeks (conventional). Median OS was 23 versus 19 months (P = .04), and 5-year survival rates were 26% versus 16%

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in the accelerated and conventional RT arms, respectively.244 A higher incidence of grade 3–4 esophagitis was seen with the accelerated regimen
compared with the conventional regimen (when including elective mediastinal irradiation as was done during this era).244 A criticism of this trial in
retrospect is that the 45 Gy conventional regimen provided suboptimal dose intensity compared to modern conventionally fractionated regimens using
higher total doses.

CONVERT, a phase 3 randomized trial, compared accelerated 45 Gy (given twice daily over 3 weeks) with higher dose conventionally fractionated 66 Gy
(given once daily over 6.5 weeks) in 547 patients with limited-stage SCLC.105 Median OS was similar between the 2 groups (30 vs. 25 months,
accelerated vs. conventional). However, the CONVERT trial was not powered to show equivalence. Toxicity was generally similar between the arms;
however, patients receiving accelerated 45 Gy had more grade 4 neutropenia compared with those receiving conventional 66 Gy (49% vs. 38%; P = .05).

CALGB 30610 (Alliance)/RTOG 0538, a randomized phase 3 trial, compared high-dose conventional 70 Gy (once daily over 7 weeks) with accelerated
45 Gy (twice daily over 3 weeks) in 638 patients with limited-stage SCLC.245 Originally, there was a 61.2 Gy concomitant boost group in this trial, but it
was removed based on a planned interim toxicity analysis.246 Median OS was 30.5 months in the conventional 70 Gy arm versus 28.5 months in the
accelerated 45 Gy arm (HR, 0.94; 95% CI, 0.75–1.17; P = .591). There were 5 deaths in the conventional 70 Gy arm and 2 deaths in the accelerated 45
Gy arm. OS and toxicity were similar, although it did not demonstrate superiority of the high-dose conventional arm. The conventional 70 Gy arm had
better quality-of-life (QOL) scores at 3 weeks with patients reporting it to be more convenient.245

A randomized phase 2 trial assessed concurrent chemoradiation with two similarly accelerated regimens, 42 Gy given as once-daily fractions over 3
weeks compared with 45 Gy given as twice-daily fractions also over 3 weeks in 157 patients with limited-stage SCLC.247 The OS curves overlapped with
median OS of 18.8 months in the once-daily arm and 25.1 months in the twice-daily arm (P = .61). A retrospective study assessed concurrent
chemoradiation with accelerated 40 Gy in 3 weeks given as once-daily fractionation in 68 patients with limited-stage SCLC.248 The median survival was
28 months, which is comparable to outcomes of similarly accelerated twice-daily fractionation.

Despite multiple trials, high-dose conventional RT (66–70 Gy over 6.5–7 weeks) has not been shown to be superior to standard-dose accelerated RT (45
Gy over 3 weeks), though survival and toxicity appear to be comparable.105,245,249 Studies have also evaluated the potential advantage of high-dose
accelerated RT. Two randomized phase 2 trials compared high-dose accelerated RT with standard-dose accelerated RT. One trial in 182 patients with
limited-stage SCLC compared concurrent chemoradiation with high-dose accelerated 65 Gy given as once-daily fractions over approximately 5 weeks
with standard-dose accelerated 45 Gy given as twice-daily fractions over 3 weeks.250 Estimated PFS was 17.2 months in the high-dose group versus
13.4 months in the standard-dose group (P = .031). OS was 39.3 months in the high-dose group versus 33.6 months in the standard-dose group (P =
.137). Grade 3 or higher esophagitis (high-dose, 17.4% vs. standard-dose, 15.3%), grade 3 or higher pneumonitis (high-dose, 3.3% vs. standard-dose,
2.4%), and treatment-related deaths (high-dose, 2.2% vs. standard-dose, 1.2%) were similar in each group. The second trial in 176 patients with
limited-stage SCLC compared concurrent chemoradiation using high-dose accelerated RT with 60 Gy given as twice-daily fractions over 4 weeks with
accelerated standard-dose 45 Gy given as twice-daily fractions over 3 weeks.251 After 2 years, 74.2% of patients were alive in the 60 Gy group (95% CI,

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63.8%–82.9%) versus 48.1% in the 45 Gy group (95% CI, 36.9%–59.5%). The 5-year survival rates were 39.3% (60 Gy) and 28.4% (45 Gy). Three
treatment-related deaths occurred in each group. A randomized phase 3 trial demonstrated a significant survival advantage of high-dose accelerated RT
given as 54 Gy simultaneous integrated boost to the gross tumor volume in 30 twice-daily fractions over 3 weeks compared to standard 45 Gy in 30
twice-daily fractions over 3 weeks (60.7 months vs. 39.5 months, P = .003) in patients with limited-stage disease.252 Radiotherapy-related toxicities were
similar between the two groups. This outcome was similar to conclusions from a retrospective study that investigated a real-world cohort study of patients
with limited-stage SCLC and found that median PFS was higher in the high-dose accelerated RT (29.7 months; 95% CI, 15.9–not reached]) compared to
standard RT (15.0 months; 95% CI, 11.8–30.4).253

In general, accelerated RT (whether given once or twice daily) is superior to similar doses of conventionally fractionated RT and comparable to higher
dose conventionally fractionated RT. The Panel recommends accelerated 45 Gy given as twice-daily fractions over 3 weeks (category 1) or
conventionally fractionated 66 to 70 Gy given as once-daily fractions over 6.5 to 7 weeks as acceptable options depending on individual
circumstances105,245,249 since the twice-daily thoracic RT can be logistically challenging for patients and RT centers. The Panel maintains that higher
doses of 66 to 70 Gy are preferred if using once-daily fractionation.249

Patients with no disease progression after chemoradiation and who receive adjuvant immunotherapy with durvalumab have a significant survival
advantage.115 High-dose accelerated RT appears superior to standard-dose accelerated RT when delivered concurrently with chemotherapy.250-252 The
lack of increased toxicity with these regimens suggests that the historical determination of 45 Gy in 3 weeks as the maximum tolerated dose is no longer
applicable with modern conformal radiotherapy techniques and the omission of elective nodal irradiation. The role of high-dose accelerated RT in the
context of the new standard of adjuvant immunotherapy remains to be determined.

Technical Considerations
The minimum technical requirement for thoracic irradiation is CT-planned three dimension (3D)-conformal RT. Intensity-modulated RT (IMRT) is
preferred over 3D-conformal external-beam RT (EBRT) because of lower toxicity. The normal tissue constraints used for NSCLC are appropriate for
SCLC when using similar RT doses (see Principles of Radiation Therapy in the algorithm and the NCCN Guidelines for Non-Small Cell Lung Cancer,
available at [Link]).254-259 More advanced technologies, such as four dimensional (4D)-CT and proton therapy, may also be appropriate to limit
normal tissue toxicity. The radiation target volumes can be defined on the FDG-PET/CT scan obtained at the time of RT planning, as well as any positive
biopsies, using definitions in Reports 50 and 62 from the International Commission on Radiation Units & Measurements.255 However, the
pre-chemotherapy FDG-PET/CT scan should be reviewed to include the original involved lymph node regions in the treatment fields if chemotherapy
begins before RT.260,261 When using accelerated schedules (e.g., 3–5 weeks), the spinal cord constraints from the CALGB 30610/RTOG 0538 protocol
can be used as a guide.249,262-264

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SABR
Emerging data suggest that SABR (stereotactic ablative radiotherapy, also known as stereotactic body RT (SBRT) is effective for patients with clinical
limited-stage I–IIA (T1–2, N0) SCLC, especially for medically inoperable circumstances or in those who refuse surgery.12,265-270 A meta-analysis of 7
studies (399 patients) summarized outcomes in patients with limited-stage SCLC who received SABR; 94% of the patients in this study were deemed
inoperable.270 Forty-four percent of patients received chemotherapy and 13.8% of patients received PCI. OS was 86% (95% CI, 74%–95%) at 1 year and
64% (95% CI, 46%–80%) at 2 years. Nodal recurrence rate was 18% (95% CI, 7.5%–31%) and distal recurrence rate was 27% (95% CI, 7.4%–53%).
Grade 3 toxicity was observed in 1.4% of patients (95% CI, 0%–5.3%). A multicenter analysis of 74 patients suggested that the addition of chemotherapy
typically after SABR improves survival for patients with clinically limited-stage SCLC.14,271 Most of these patients had FDG-PET staging but not pathologic
nodal staging. Patients who received chemotherapy after SABR had a median OS of 31.4 months versus 14.3 months for those who received SABR
alone (P = .02).

An analysis of 2107 patients with histologically confirmed T1–T2, N0, M0 from the National Cancer Database found that 7.1% had upfront SABR followed
by adjuvant chemotherapy and 92.9% had concurrent chemoradiation.10 Compared with patients receiving upfront concurrent chemoradiation, those
receiving SABR were often older, had T1 disease, and were treated recently in academic medical settings. Median survival was 29.2 months in those
receiving SABR/chemotherapy versus 31.2 months in those receiving chemoradiation (P = .77). Both ASTRO and the American Radium Society
recommend SABR followed by adjuvant chemotherapy as an option for medically inoperable patients with clinically limited-stage I–IIA SCLC (T1–2,
N0).236,237

The Panel recommends SABR followed by systemic therapy as an option for select patients with clinically limited-stage I–IIA (T1–2, N0) SCLC who are
medically inoperable or decline surgery.12,271 The Panel added a caveat that systemic therapy may be initiated first, if time to initiation of SABR will be
prolonged. The NCCN Guidelines for Non-Small Cell Lung Cancer provide detailed recommendations for SABR that may be useful for SCLC (see
Principles of Radiation Therapy in the NCCN Guidelines for Non-Small Cell Lung Cancer, available at [Link]).

Radiation for Extensive-Stage SCLC

Sequential Thoracic Radiation for Extensive-Stage SCLC
A randomized trial by Jeremic et al assessed sequential (consolidative) thoracic RT in patients experiencing a complete response at distant metastatic
sites after 3 cycles of cisplatin/etoposide.274 Patients were randomized to receive either 1) further cisplatin/etoposide; or 2) accelerated hyperfractionated
RT (i.e., 54 Gy in 36 fractions over 18 treatment days) in combination with carboplatin/etoposide.274 The addition of RT resulted in improved median OS
(17 vs. 11 months). The Dutch CREST trial, a phase 3 randomized trial in patients with extensive-stage SCLC, reported that the addition of consolidative
thoracic RT (30 Gy in 10 fractions) did not improve the primary endpoint of 1-year OS (33% vs. 28%; P = .066). However, a secondary analysis found
improvement in 2-year OS (13% vs. 3%; P = .004) and 6-month PFS compared with patients who did not receive consolidative thoracic RT.275 A trial
involving 32 patients who received consolidative thoracic RT reported that only 16% of patients had symptomatic chest recurrences.276 Consolidative

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thoracic RT appears to mainly benefit patients with residual thoracic disease after chemotherapy (without immunotherapy) and low-bulk extrathoracic
metastatic disease that has responded to systemic therapy.277 Based on the limited data, the American Radium Society recommends that consolidative
thoracic RT be considered for select patients with extensive-stage SCLC.235 International experts (International Association for the Study of Lung Cancer
[IASLC] and European Society for Radiotherapy and Oncology [ESTRO]) recommend consolidative thoracic RT in select patients with stage IV SCLC
(that has responded to first-line chemotherapy) and limited extrathoracic tumor burden.278

The Panel recommends that consolidative thoracic RT be considered in select patients with low-bulk, extrathoracic, metastatic, extensive-stage disease
who have a complete or near complete response after initial systemic therapy before maintenance immunotherapy.235,274,275 Sequential thoracic RT can
be considered for selected patients, during or before maintenance immunotherapy; however, there are limited data on optimal sequencing. The benefit of
thoracic RT in the context of chemoimmunotherapy is under evaluation in the RAPTOR/NRG LU007 trial (NCT04402788).

Radiotherapy for brain metastases

Prophylactic Cranial Irradiation (PCI)
Intracranial metastases occur in >50% of patients with SCLC. Randomized studies show that PCI is effective in decreasing the incidence of cerebral
metastases, but most individual studies did not have sufficient power to show a meaningful survival advantage.279 Several meta-analyses suggest that
PCI after complete resection may benefit patients with pathologic stage IIB or stage III SCLC.280-282 A meta-analysis of all randomized PCI trials reported
a reduction in the 3-year incidence of brain metastases, from 58.6% in the control group to 33.3% in the PCI-treated group.281 Thus, PCI seems to
prevent, and not simply delay, the emergence of brain metastases. This meta-analysis also reported an increase in 3-year OS from 15.3% in the control
group to 20.7% in the PCI group.281 Although the number of patients with extensive-stage SCLC was small, the observed benefit was similar in patients
with both limited-stage and extensive-stage SCLC. A retrospective study of patients with limited-stage SCLC also found that PCI increased survival at 2,
5, and 10 years compared with those who did not receive PCI.283

None of the abovementioned studies in limited-stage SCLC used MRI of the brain with FDG-PET scans for staging. A retrospective study (n = 184) with
limited-stage SCLC assessed PCI versus no PCI in patients whose disease responded to chemoradiotherapy, and who had no brain metastases on MRI
imaging before and after primary treatment.284 In patients receiving PCI, median OS was 26 months (range, 19.4–32.6 months) versus 14 months for
those without PCI (range, 11.4–16.6 months; P < .0001). A more modern retrospective study included 49 patients with limited-stage SCLC who were
staged with brain MRI before treatment.285 The median OS was 55 months in patients with limited-stage SCLC who received PCI versus 24 months in
those who did not receive PCI (P < .05). At 1 year, the probability of developing symptomatic brain metastases was 4% in patients with limited-stage
SCLC who received PCI versus 22% in those who did not receive PCI (P < .05). To date, there is a lack of studies on PCI in the context of adjuvant
immunotherapy to treat limited-stage SCLC.

For patients with extensive-stage SCLC, but without brain metastases, a large retrospective analysis of 4257 patients showed that PCI improved median
OS compared with no PCI (13.9 vs. 11.1 months; P < .0001).286 Another analysis of patients with extensive-stage SCLC (n = 397) reported that PCI
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improved OS compared with no PCI (13.5 vs. 8.5 months; HR, 0.55; 95% CI, 0.39–0.77; P = .0005); however, these patients did not receive routine brain
imaging surveillance.287

The EORTC performed a randomized trial that assessed PCI versus no PCI in 286 patients with extensive-stage SCLC that had responded to initial
chemotherapy. PCI decreased symptomatic brain metastases (14.6% vs. 40.4%) and increased the 1-year survival rate (27.1% vs. 13.3%) compared
with controls.288 However, the study did not require brain imaging prior to PCI and did not standardize the PCI dose or fractionation. Conflicting data from
a randomized phase 3 trial found that median OS is not improved in patients receiving PCI compared with MRI surveillance (11.6 months; 95% CI, 9.5–
13 vs. 13.7 months; 95% CI, 10.2–16.4) (HR, 1.27; 95% CI, 0.96–1.68; P = .094).289 In this trial, patients were required to have an MRI to confirm that
they did not have brain metastases prior to PCI, and the PCI regimen was standardized at 25 Gy in 10 fractions. The study also required close MRI
surveillance in patients to allow for early treatment of brain metastases. Based on the limited data, the American Radium Society recommends either PCI
or brain MRI surveillance for patients with extensive-stage SCLC and without brain metastases.235 Early prevention of brain metastases does not directly
correlate to greater QOL or neurocognitive function in these trials. A review article summarizing the use of PCI in SCLC notes that prospective trials
demonstrating the benefits of PCI over MRI surveillance in the modern era are needed.290 A randomized trial (SWOG S1827/MAVERICK) is currently
addressing this exact question and assessing brain MRI surveillance alone compared to brain MRI surveillance plus PCI for patients with limited- and
extensive-stage SCLC. Late neurologic sequelae have been attributed to PCI, particularly in studies using fractions >3 Gy and/or administering PCI
concurrently with chemotherapy.184,291,292 Thus, PCI is not recommended for patients with poor PS (3–4) or impaired neurocognitive function.96,293 PCI has
also been associated with chronic neurotoxicity in patients who are aged ≥60 years.183,185

The Panel has gradually revised the adjuvant recommendations for patients whose disease showed a complete or partial response after primary
treatment based on conflicting clinical trial data and concerns about the neurocognitive toxicity of PCI. Before a decision is made to administer PCI, a
balanced discussion is necessary between the patient and physician.184,294 The Panel recommends considering PCI for patients with limited-stage SCLC
that has achieved a complete or partial response.96,281,288 PCI should be administered prior to consolidation durvalumab therapy. The Panel maintains
that the benefit of PCI is unclear in patients with very-early-stage SCLC (pathologic limited-stage I [T1–2a, N0, M0]) who have had definitive therapy (ie,
surgery, SABR). These patients have a lower risk of developing brain metastases than patients with more advanced limited-stage SCLC and may not
benefit from PCI.271,280,295 The Panel recommends MRI brain surveillance for all patients with limited-stage SCLC who do not receive PCI, as well as for
post-treatment surveillance in those receiving PCI. In patients with extensive-stage SCLC, the Panel recommends MRI brain surveillance with or without
consideration of PCI based on the conflicting trial results from Japan and the EORTC.288,289 Brain imaging surveillance for metastases is recommended
using either MRI (preferred) or CT with contrast in patients who are unable to undergo MRI. 289

Technical Considerations
Higher PCI doses (e.g., 36 Gy) increased mortality and toxicity compared with lower doses (25 Gy).183,296 Therefore, the preferred dose for PCI is 25 Gy
in 10 daily fractions (2.5 Gy/fraction).281,288,296 A shorter course of PCI may be appropriate (e.g., 20 Gy in 5 fractions) for selected patients with

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extensive-stage SCLC.288 PCI should not be given concurrently with chemotherapy, and high total RT dose (>30 Gy) should be avoided because of the
increased risk of neurotoxicity.183 After the acute toxicities of initial systemic therapy have resolved, PCI can be administered. When given after the
completion of chemotherapy and at a low dose per fraction, PCI may cause less neurologic toxicity. Fatigue, headache, and nausea/vomiting are the
most common acute toxic effects after PCI.293,296

The Panel recommends that memantine be considered for patients receiving PCI or therapeutic whole-brain irradiation. Memantine is a
N-methyl-D-aspartate (NMDA) receptor antagonist that may delay cognitive dysfunction in patients receiving brain RT.297 Patients receiving memantine
have a longer time before cognitive decline (HR, 0.78; 95% CI, 0.62–0.99; P = .01). NRG Oncology CC001, a phase 3 randomized trial, assessed HA
whole-brain IMRT/memantine compared with conventional whole-brain RT/memantine in patients with brain metastases who were not diagnosed with
SCLC.298 Cognitive preservation and patient-reported outcomes were improved with HA-IMRT (HR, 0.74; 95% CI, 0.58–0.95; P =.02). However,
conflicting data have been reported with HA-PCI versus conventional PCI. PREMER, a phase 3 randomized trial, reported improved cognitive
preservation with HA-PCI.299 However, another phase 3 randomized trial reported no differences in cognition with HA-PCI.300 A large randomized trial
(NRG CC003) assessed HA-PCI versus conventional PCI and found that addition of HA to PCI prevented neurocognitive functioning failure (adjusted
HR, 0.78; 95% CI, 0.61–0.99; P = .039).301 Overall, hippocampal avoidance should be considered when administering whole brain radiotherapy for PCI
or treatment of brain metastases.

Brain metastases
Brain metastases have conventionally been treated with whole brain RT (WBRT) in patients with SCLC due to the frequent occurrence of multiple
metastases. The recommended dose for WBRT is 30 Gy in 10 daily fractions.305 Also, see the NCCN Guidelines for Non-Small Cell Lung Cancer,
available at [Link]). IMRT, SABR, or stereotactic radiosurgery (SRS) may be appropriate for select patients (e.g., those whose tumors are in
close proximity to organs at risk).

A retrospective multicenter cohort study assessed stereotactic radiosurgery (SRS) versus WBRT in 710 patients with SCLC who had a limited number of
brain metastases; OS was 6.5 months (95% CI, 5.5–8.0) for SRS and 5.2 months (95% CI, 4.4–6.7) for whole-brain RT (P = .003).306 A meta-analysis of
nine observational studies (1638 patients) also reported favorable lesion control and survival outcomes with SRS versus whole-brain RT.307 Phase 2 and
phase 3 trials in patients with brain metastases, who did not receive any prior brain directed radiation, investigated whether SRS improves symptoms or
neurological death compared to WBRT (historical controls or in a randomized controlled trial).272,273 Neurologic death in the phase 2 trial was defined as
marked, progressive, radiologic brain progression accompanied by corresponding neurologic symptomatology without systemic disease progression or
systemic symptoms of a life-threatening nature. This trial studying patients with small cell lung cancer and 1-10 brain metastases showed that SRS
resulted in lower neurologic death compared to historical WBRT controls (11% vs 17.5%). The phase 3 trial showed that compared to
hippocampal-avoidance (HA) WBRT in patients with mostly non-small cell lung cancer, breast, melanoma, or others with 5 to 20 brain metastases, SRS
was associated with less severe symptoms and interference with daily functioning.

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A randomized trial (NRG CC009) is comparing SRS to HA whole-brain IMRT/memantine in this setting. The Panel recommends that SRS may be used
for selected patients with limited brain metastases based on available data, pending outcomes of the ongoing trials.306 In patients who develop brain
metastases after PCI, SRS (preferred) or repeat WBRT (in carefully selected patients) may be considered.308,309 For patients with a better prognosis (e.g.,
≥4 months), HA whole-brain IMRT/memantine is preferred to conventional WBRT/memantine because it produces less of a decrease in cognitive
function. However, patients with metastases within 5 mm of the hippocampi, leptomeningeal metastases, and other high-risk features were not eligible for
HA whole-brain IMRT in the phase 3 NRG CC001 trial.298

Palliative Radiation Therapy

For patients with localized symptomatic sites of disease (i.e., painful bony lesions, spinal cord compression, obstructive atelectasis) or with brain
metastases, RT can provide excellent palliation (see the algorithm and the NCCN Guidelines for Non-Small Cell Lung Cancer, available at
[Link]).302-304 Orthopedic stabilization may be useful in patients at high risk for fracture because of osseous structural impairment. Because
patients with SCLC often have a short life span, surgery is usually not recommended for spinal cord compression. Radiation dose and fractionation for
extracranial metastases include 30 Gy in 10 fractions, 20 Gy in 5 fractions, or 8 Gy in 1 fraction based on common dose-fractionation regimens used for
other solid tumors, and more definitive doses may be appropriate in selected circumstances.

Summary
In summary, the V.1.2027 NCCN Guidelines for Small Cell Lung Cancer have recommendations for diagnosis, evaluation, therapy, and surveillance for
limited- and extensive-stage SCLC based on data from clinical trials and Panel expertise.

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NCCN Guidelines Version 1.2027

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NCCN Guidelines Version 1.2027

Small Cell Lung Cancer

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NCCN Guidelines Version 1.2027

Small Cell Lung Cancer

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NCCN Guidelines Version 1.2027

Small Cell Lung Cancer

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NCCN Guidelines Version 1.2027

Small Cell Lung Cancer

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NCCN Guidelines Version 1.2027

Small Cell Lung Cancer

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Small Cell Lung Cancer

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Small Cell Lung Cancer

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NCCN Guidelines Version 1.2027

Small Cell Lung Cancer

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NCCN Guidelines Version 1.2027

Small Cell Lung Cancer

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NCCN Guidelines Version 1.2027

Small Cell Lung Cancer

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NCCN Guidelines Version 1.2027

Small Cell Lung Cancer

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NCCN Guidelines Version 1.2027

Small Cell Lung Cancer

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Small Cell Lung Cancer

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Small Cell Lung Cancer

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Small Cell Lung Cancer

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NCCN Guidelines Version 1.2027

Small Cell Lung Cancer

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