Clinical Review & Education

JAMA | Review

Small Cell Lung Cancer

A Review
So Yeon Kim, MD; Henry S. Park, MD, MPH; Anne C. Chiang, MD, PhD

Multimedia
IMPORTANCE Small cell lung cancer (SCLC) is a high-grade neuroendocrine carcinoma with an Supplemental content
incidence of 4.7 cases per 100 000 individuals in 2021 in the US and a 5-year overall survival
of 12% to 30%. CME at jamacmelookup.com

OBSERVATIONS Cigarette smoking is the primary risk factor for development of SCLC, as 95%
of patients diagnosed with SCLC have a history of tobacco use. Patients with SCLC may
present with respiratory symptoms such as cough (40%), shortness of breath (34%),
hemoptysis (10%), or metastases with corresponding local symptoms (30%) such as pleuritis
or bone pain; approximately 60% of patients with SCLC may be asymptomatic at diagnosis.
Chest imaging may demonstrate central hilar (85%) or mediastinal lymphadenopathy (75%).
At diagnosis, approximately 15% of patients have brain metastases, which may present as
headache or focal weakness. Diagnosis is confirmed by biopsy of a primary lung mass,
thoracic lymph node, or metastatic lesion. Small cell lung cancer is classified into limited stage
(LS-SCLC; 30%) vs extensive stage (ES-SCLC; 70%) based on whether the disease can be
treated within a radiation field that is typically confined to 1 hemithorax but may include
contralateral mediastinal and supraclavicular nodes. For patients with LS-SCLC, surgery or
concurrent chemotherapy with platinum-etoposide and radiotherapy is potentially curative in
30% of patients. More recently, median survival for LS-SCLC has reached up to 55.9 months
with the addition of durvalumab, an immunotherapy. First-line treatment for ES-SCLC is
combined treatment with platinum-etoposide chemotherapy and immunotherapy with the
programmed cell death 1 ligand 1 (PD-L1) inhibitors durvalumab or atezolizumab followed by
maintenance immunotherapy until disease progression or toxicity. Although initial rates of
tumor shrinkage are 60% to 70% with platinum-etoposide and immunotherapy treatment,
the median overall survival of patients treated for ES-SCLC is approximately 12 to 13 months,
with 60% of patients relapsing within 3 months. Second-line therapy for patients with
ES-SCLC includes the DNA-alkylating agent lurbinectedin (35% overall response rate; median
progression-free survival, 3.7 months) and a bispecific T-cell engager against delta-like ligand
3, tarlatamab (40% overall response rate; median progression-free survival, 4.9 months).

CONCLUSIONS AND RELEVANCE Small cell lung cancer is a smoking-related malignancy that
presents at an advanced stage in 70% of patients. Three-year overall survival is
approximately 56.5% for LS-SCLC and 17.6% for ES-SCLC. First-line treatment for LS-SCLC is
radiation targeting the tumor given concurrently with chemotherapy and followed by
consolidation immunotherapy. For ES-SCLC, first-line treatment is chemotherapy and
immunotherapy followed by maintenance immunotherapy.

Author Affiliations: Department of

Medicine, Yale University School
of Medicine, New Haven, Connecticut
(Kim, Chiang); Department of
Therapeutic Radiology, Yale
University School of Medicine,
New Haven, Connecticut (Park).
Corresponding Author: Anne C.
Chiang, MD, PhD, Yale University
School of Medicine, 333 Cedar St,
JAMA. doi:10.1001/jama.2025.0560 New Haven, CT 06510 (anne.chiang
Published online March 31, 2025. @yale.edu).

(Reprinted) E1
© 2025 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies.
Downloaded from jamanetwork.com by Fudan University, li bai on 04/01/2025
 Clinical Review & Education Review Small Cell Lung Cancer

I
n 2024, lung cancer was the leading cause of cancer-related 100 000 individuals).2 Small cell lung cancer is strongly associated
mortality in the US and the second most commonly diag- with tobacco smoking (95% of patients with SCLC have a history of
nosed cancer.1 Small cell lung cancer (SCLC), previously re- tobacco use), and although the risk of SCLC decreases with smok-
ferred to as “oat cell” carcinoma, represents 10% to 15% of all lung ing cessation, incidence of SCLC remains elevated after quitting for
cancers, with an incidence of 4.7 per 100 000 individuals in 2021 more than 30 years.4 Approximately 2.5% to 13% of SCLC has been
in the US.2 The incidence of SCLC has decreased over the last de- reported in individuals who have never smoked, and these patients
cade from 6.6 to 4.7 per 100 000 individuals, corresponding to may have a better prognosis. Among 391 cases from a multicenter
a decrease in tobacco smoking over this period.2 case-control study in South Korea, survival was 18.2 months among
Diagnosis is confirmed by biopsy of the primary tumor, in- patients with no smoking history vs 13.1 months among people who
volved thoracic lymph nodes, or metastatic lesion. Due to the high smoked (P = .054).5,6
proliferative rate of SCLC, 70% of patients have advanced-stage dis-
ease at diagnosis.2 The recommended treatment for patients with Molecular Characteristics of SCLC
limited-stage (LS-SCLC) disease (stage I-III) is radiotherapy to the tu- Small cell lung cancer is characterized by near universal loss of the
mor and chemotherapy.3 Patients with extensive-stage (ES-SCLC) tumor suppressor genes RB1 and TP53,7 and disease heterogeneity
disease (distant metastatic disease or disease that cannot be treated is characterized by expression of epigenetically regulated transcrip-
within a safe radiation field) should receive palliative care with com- tional factors. Subtypes include A and N, characterized by expres-
bination chemotherapy and immunotherapy (Figure). sion of neuroendocrine transcription factors ASCL1 and NeuroD1,
Treatment on relapse includes the DNA-alkylating agent lurbi- respectively, and subtype P, characterized by expression of non-
nectedin, re-treatment with platinum-etoposide chemotherapy, mi- neuroendocrine transcription factor POU2F3.8 A fourth subtype,
crotubule inhibitors such as taxanes, or alternative DNA-alkylating subtype I, is characterized by a lack of expression of ASCL1,
agents such as temozolomide. The US Food and Drug Administra- NeuroD1, or POU2F3 and has been characterized by expression of
tion (FDA) recently granted accelerated approval for tarlatamab, a genes associated with response to immune checkpoint inhibitors, a
bispecific antibody engaging in T cell–mediated destruction for re- class of drugs that block tumors from inactivating T cells (eFigure 1
lapsed SCLC. This Review summarizes the epidemiology, molecu- in the Supplement).9 YAP1 has also been proposed as a potential
lar characteristics, clinical presentation, and management of SCLC. subtype associated with upregulation of interferon-γ.10 Unlike in
Some common clinical questions and answers are shown in the Box. non-SCLC, programmed cell death 1 ligand 1 (PD-L1), a surface gly-
coprotein expressed in tumor cells or antigen-presenting cells that
allows tumor cells to escape immune destruction, is variably
expressed in SCLC (0%-80%) and is not a predictive biomarker of
Methods
response to checkpoint inhibitors in SCLC.11,12
We searched PubMed for articles with the term small cell lung cancer; Rarely, non-SCLC with genetic variants referred to as “onco-
the search was limited to English-language articles published be- genic drivers,” such as EGFR or ALK variants, that promote cancer
tween March 16, 2014, and October 13, 2024. Articles were se- growth may undergo histologic transformation from adenocarci-
lected with a focus on primary prospective data. A total of 95 ar- noma to SCLC, especially with tumors that also have TP53 or RB1
ticles were included. Articles comprised 24 randomized clinical trials, variants.13,14 Such tumors are associated with decreased survival
2 long-term updates of randomized clinical trials, 2 secondary or (6 to 8.5 months vs 13 months with de novo SCLC),15,16 and mecha-
pooled analyses of randomized clinical trials, 11 nonrandomized pro- nisms for the worse prognosis are poorly understood.13,17
spective trials, 1 update of a nonrandomized prospective trial, 11 meta-
analyses and systematic reviews, 10 retrospective studies, 3 clini- Clinical Presentation
cal practice guidelines, 3 reviews, and 9 translational studies. The Patients with SCLC may present with cough (40%), shortness of
remaining 19 articles were identified by the authors based on knowl- breath (34%), or hemoptysis (10%), although up to 60% of
edge of the literature before 2014 and from review of citations in patients may be asymptomatic. Pain at the site of disease involve-
retrieved articles. ment (30%) or constitutional symptoms such as weight loss
(24%), anorexia (9%), and fatigue (15%) may be observed, espe-
cially in ES-SCLC.18,19 Approximately 15% of patients with SCLC
have brain metastases at diagnosis, which may present with
Discussion
headache or focal weakness. These patients have decreased sur-
Epidemiology vival compared with patients with ES-SCLC without brain metas-
Approximately 16 000 new cases of SCLC were diagnosed in the tases (6 months vs 13 months; P < .001).20 Approximately 10% of
US in 2024.2 The median age at diagnosis in the US is 69 years, patients present with superior vena cava syndrome, character-
with a higher incidence in males compared with females (5.1 vs 4.6 ized by headaches, facial or neck swelling, upper extremity
cases per 100 000 individuals). Higher incidence of SCLC is edema, or voice changes due to compression of the superior vena
observed among non-Hispanic American Indian and Alaska Native cava from adenopathy.21 Patients with SCLC may also have para-
individuals (8.5 cases per 100 000 individuals), non-Hispanic Black neoplastic endocrinopathies, including syndrome of inappropri-
individuals (3.9 cases per 100 000 individuals), and non-Hispanic ate antidiuretic hormone secretion (24% of SCLC) presenting
White individuals (6.0 cases per 100 000 individuals) compared with hyponatremia due to production of vasopressin, or Cushing
with non-Hispanic Asian and Pacific Islander individuals (1.9 cases syndrome (2%-6% of SCLC) presenting with edema, weakness,
per 100 000 individuals) or Hispanic individuals (2.2 cases per hypertension, or hypokalemia due to ectopic production of

E2 JAMA Published online March 31, 2025 (Reprinted) jama.com

© 2025 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies.
Downloaded from jamanetwork.com by Fudan University, li bai on 04/01/2025
 Small Cell Lung Cancer Review Clinical Review & Education

Figure. Overview of Incidence and General Management of Limited-Stage SCLC and Extensive-Stage SCLC

Limited-stage small cell lung cancer (SCLC) Extensive-stage SCLC

Incidence Survival Treatment intent Incidence Survival Treatment intent
Stages I-IIA: <5.0% Median: 25.0-55.9 months Curative Stage IV: 70.0% Median: 12.3-13.0 months 5-Year: 12.0% Palliative
Stages IIB-III: 25.0% 3-Year: 56.5% 3-Year: 17.6%
5-Year: 16.1%-27.7%
Palliative care referral should be considered at diagnosis and throughout treatment

Stage I-IIA Stage IIB-III No or asymptomatic CNS metastases Symptomatic CNS metastases

Surgery Stereotactic ablative Chemoradiotherapy First-line chemoimmunotherapy Stereotactic radiosurgery or

radiotherapy whole brain radiation therapy
Consider lobectomy Platinum-etoposide plus immune checkpoint
with mediastinal For nonoperable Prophylactic cranial inhibitors (durvalumab or atezolizumab) Followed by systemic therapy
dissection candidates irradiation
Followed by adjuvant Followed by adjuvant Consider surveillance brain MRI brain surveillance
chemotherapy chemotherapy magnetic resonance imaging
(MRI) for patients with risk Consider prophylactic cranial irradiation for selected patients
Mediastinal nodal of neurocognitive decline
involvement found (eg, aged 60 years or older)
at time of surgery Second-line therapy and beyond for relapse
Postoperative
radiotherapy Consolidation ECOG score 0-2 ECOG score 3-4
immunotherapy
Residual disease
after surgery Clinical trial referral Best supportive care
Concurrent Per National Comprehensive Cancer Network, clinical trials
chemoradiotherapy are the preferred therapy if first-line therapy is not effective

If not a candidate for a clinical trial

Chemosensitive: disease Chemoresistant: disease progression

progression after 90 days before 90 days

• Platinum-etoposide Preferred agents

rechallenge • Tarlatamab or lurbinectedin
• Tarlatamab (DLL3 Other agents including
bispecific T-cell engager) • Temozolomide (alkylating agent)
• Lurbinectedin • Taxane (microtubule inhibitor)
(alkylating agent)
• Topotecan or irinotecan (topoisomerase I inhibitor)

CNS indicates central nervous system and ECOG, Eastern Cooperative Oncology safe radiation field. Extensive stage includes patients with malignant pleural
Group. Staging is categorized as limited stage based on whether the disease is effusion or distant metastases or disease not classified as limited.
confined to 1 hemithorax and supraclavicular region that can be treated within a

adrenocorticotropic hormone from the tumor.22-24 Two to three (37%), CD56 (90%-100%), and insulinoma-associated protein 1
percent of patients with SCLC may present with Lambert-Eaton (92%).27-30 Small cell lung cancer may be distinguished from less-
myasthenic syndrome, characterized by muscle weakness, ataxia, proliferative neuroendocrine tumors such as carcinoid and large cell
and hyporeflexia from autoimmune destruction of voltage-gated neuroendocrine carcinomas by morphology and mitotic count as de-
calcium channels, which leads to impaired release of acetylcho- fined by the World Health Organization.31
line in the neuromuscular junction.25,26
Staging
Diagnostic Evaluation For staging after diagnosis of SCLC, patients should undergo CT of
Chest imaging with x-ray or computed tomography (CT) typically the abdomen, brain magnetic resonance imaging (MRI), and posi-
demonstrates a central, bronchial, or hilar mass with bulky adenopa- tron emission tomography (PET)/CT. Bone scan may be used to
thy. Diagnosis is made by biopsy of the primary tumor and/or lymph rule out bone metastases if PET/CT is not available. Small cell lung
nodes with an endoscopic bronchial ultrasound or by biopsy of a cancer is classified as LS-SCLC or ES-SCLC based on whether the
metastatic lesion. Pathologic diagnosis is confirmed by morpho- disease is confined to 1 hemithorax (with or without hilar nodal
logic, immunohistochemical, and proliferative characteristics. involvement) encompassed by 1 radiation portal.32 The definition
Hematoxylin-eosin–stained slides of biopsied cytology or tissue dem- of LS-SCLC was expanded by the International Association for the
onstrate clusters of small, round, blue cells with a high nuclear to cy- Study of Lung Cancer in 1986 to include disease involving contra-
toplasm ratio and mitotic rate (ⱖ10 mitoses per 10 high-power lateral mediastinal and supraclavicular nodes and ipsilateral pleural
field).18 Ki-67, or the proliferation index, which demonstrates how effusion.33,34 The TNM system, which stages tumors by primary
quickly a cell is dividing, typically ranges from 50% to 100%.18 Im- tumor size, node positivity, and distant metastases, aligns closely
munohistochemistry stains of SCLC may be positive for cytokera- with the International Association for the Study of Lung Cancer
tin (50%-60%), thyroid transcription factor 1 (80%), and neuroen- staging system and includes stages I through III (limited stage) and
docrine markers such as synaptophysin (54%), chromogranin A stage IV (extensive stage).3

jama.com (Reprinted) JAMA Published online March 31, 2025 E3

© 2025 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies.
Downloaded from jamanetwork.com by Fudan University, li bai on 04/01/2025
 Clinical Review & Education Review Small Cell Lung Cancer

ard ratio, 0.94; 95% CI, 0.76-1.17]).36,38 Given similar outcomes,

Box. Clinical Questions and Answers once-daily or twice-daily radiotherapy regimens are reasonable,
with the twice-daily regimen still considered first-line treatment
How Does SCLC Typically Present? because randomized trials have yet to show superiority in survival
Approximately 60% of patients with small cell lung cancer (SCLC) for a once-daily radiotherapy regimen. The twice-daily regimen
are asymptomatic at presentation. However, SCLC may present
may be appealing to those preferring a shorter treatment dura-
with symptoms of cough, shortness of breath, or hemoptysis.
Patients may also have bulky mediastinal adenopathy causing
tion (3 weeks), and once-daily regimens (6.5-7 weeks) may be
superior vena cava syndrome (10%) or brain metastases (15%). preferred based on factors such as transportation and radio-
Paraneoplastic syndromes such as syndrome of inappropriate therapy machine availability.
antidiuretic hormone secretion (25%), Cushing syndrome Patients with node-negative (no lymph node involvement) stage I
(2%-6%), or Lambert-Eaton myasthenic syndrome (2%-3%) may to IIA (T1-2N0M0) SCLC may be considered for thoracoscopic lo-
also occur in patients with SCLC. bectomy if no tumor is detected in mediastinal and hilar lymph node
What Are the First-Line Treatments for LS-SCLC and ES-SCLC? biopsies. Fitness for resection is determined by evaluation of car-
First-line therapy for limited-stage (LS) SCLC is chemotherapy and diac and pulmonary comorbidities (eg, pulmonary function
radiotherapy followed by consolidation immunotherapy. Surgery testing).41-43 Stereotactic body radiotherapy, a form of high-dose ra-
followed by adjuvant chemotherapy can be considered for
diotherapy, is an effective and safe alternative to surgery for stage I
patients with LS-SCLC without lymph node involvement after
to IIA (T1-2N0M0) disease.44 After undergoing surgery or stereo-
multidisciplinary discussion with surgical, radiation, and medical
oncology specialists. First-line therapy for extensive-stage (ES) tactic body radiotherapy, patients are treated with adjuvant plati-
SCLC is a combination of chemotherapy and immunotherapy, num-etoposide chemotherapy for 4 cycles.43,45 For patients with
followed by maintenance immunotherapy. positive resection margins, adjuvant radiation is recommended per
National Comprehensive Cancer Network (NCCN) and American So-
What Are the Prognoses of LS-SCLC and ES-SCLC?
With treatment, the median overall survival is approximately 4.7 ciety for Radiation Oncology (ASTRO) guidelines.3,46 Evidence does
years for patients with LS-SCLC and approximately 13 months not currently support neoadjuvant chemotherapy for SCLC.47
for patients with ES-SCLC. Three-year survival is currently
approximately 56.5% for LS-SCLC and 17.6% for ES-SCLC. Consolidation Immunotherapy After Chemoradiation
To improve quality of life and overall survival, all patients Consolidation immunotherapy after chemoradiation is recom-
diagnosed with SCLC should establish care with a palliative care
mended per the NCCN for LS-SCLC.47 The phase 3 ADRIATIC trial
team, and patients with relapsed SCLC are encouraged to enroll
in clinical trials, if available.
compared up to 2 years of consolidation durvalumab, an anti–
PD-L1 inhibitor, given as monotherapy and in combination with
tremelimumab, a checkpoint (cytotoxic T-lymphocyte–associated
protein 4 [CTLA-4]) inhibitor, with placebo in 939 patients with
Treatment inoperable stage I to III SCLC after chemoradiation.39 The study
reported improved overall survival and progression-free survival,
Limited-Stage SCLC defined as the time to disease progression or death with consoli-
First-Line Treatment dation durvalumab relative to placebo (overall survival, 55.9
Limited-stage SCLC can be treated definitively with a combina- months with durvalumab vs 33.4 months with placebo [P = .01];
tion of chemotherapy, local therapy such as radiation therapy or progression-free survival, 16.6 months with durvalumab vs 9.2
surgery, and consolidation immunotherapy with the goal of cure months with placebo [P = .02]).39 Frequency of adverse events
(Table 1). Multidisciplinary discussions involving oncologists, was reported as follows: any grade of adverse events possibly
radiation oncologists, and thoracic surgeons can identify optimal related to study treatment: 67.2% with durvalumab and 48.7%
treatment approaches and individualized care for patients with with placebo; grade 1 to 2 hypothyroidism: 14.9% with dur-
LS-SCLC. valumab and 3.4% with placebo; any grade of pneumonitis: 9.2%
Treatment for LS-SCLC is high-dose radiotherapy targeted to with durvalumab and 5.3% with placebo; and grade 3 to 4 pneu-
the primary tumor and involved lymph nodes concurrently with monitis: 1.1% with durvalumab and 0.8% with placebo (P values
either cycle 1 or 2 of platinum-etoposide chemotherapy, adminis- for comparisons not reported).39
tered for 4 to 6 cycles.40 Initial response rates, defined as tumor
reduction by at least 30%, are 70% to 90%.36 Twice-daily radia- Prophylactic Cranial Irradiation
tion with 45 Gy in 30 fractions was previously established to have Small cell lung cancer metastasizes to the brain in approximately
superior survival outcomes compared with once-daily radio- 60% of patients within 3 years of LS-SCLC diagnosis.48 Although
therapy with 45 Gy in 25 fractions.35 Two phase 3 trials of patients prophylactic cranial irradiation is not typically administered to
with LS-SCLC compared twice-daily radiotherapy with once-daily patients with early-stage LS-SCLC (stage I-IIA) due to limited sur-
high-dose radiotherapy (66-70 Gy in 33-35 fractions) and did not vival advantage for these patients,49,50 daily low-dose prophylac-
report superiority of once-daily high-dose radiotherapy (Table 1) tic cranial irradiation to the whole brain is recommended for
in overall survival or adverse events (CONVERT trial [n = 547]: patients with LS-SCLC (stage IIB-IIIC) on confirmation of tumor
overall survival, 25 months for once-daily vs 30 months for twice- shrinkage on imaging following chemoradiation, per NCCN and
daily radiotherapy [hazard ratio, 1.18; 95% CI, 0.95-1.45]; CALGB ASTRO guidelines.3,46 In a meta-analysis of 7 randomized trials of
30610/RTOG 0538 trial [n = 638]: overall survival, 30.1 months 987 patients with SCLC in complete remission, compared with no
for once-daily vs 28.5 months for twice-daily radiotherapy [haz- prophylactic cranial irradiation, prophylactic cranial irradiation

E4 JAMA Published online March 31, 2025 (Reprinted) jama.com

© 2025 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies.
Downloaded from jamanetwork.com by Fudan University, li bai on 04/01/2025
 Small Cell Lung Cancer Review Clinical Review & Education

was associated with decreased cumulative incidence of brain

as standard of care vs low-dose daily

Established twice-daily radiotherapy

prophylactic cranial irradiation as an

Terminology Criteria for Adverse Events as severe or medically significant but not immediately life-threatening.
Demonstrated hippocampal-sparing

immunotherapy for up to 2 y after

metastases (58.6% vs 33.3%; P < .001) and an increase in overall

radiotherapy; outcomes generally

radiotherapy; outcomes generally

No superiority of high-dose daily

No superiority of high-dose daily

survival at 3 years (15.3% vs 20.7%; P = .01).48 A follow-up meta-

radiotherapy over twice-daily

radiotherapy over twice-daily

and relevance to clinical care. Grade 3 adverse events are defined by National Cancer Institute Common
option to spare memory loss
analysis of 28 retrospective studies including 18 575 patients with

Established consolidation
LS-SCLC demonstrated an overall survival benefit associated with
Clinical implications

chemoradiotherapy
prophylactic cranial irradiation (overall survival, 27.8 months) vs

appeared similar

appeared similar
without prophylactic cranial irradiation (overall survival, 18.8
radiotherapy

months; pooled adjusted hazard ratio, 0.62; 95% CI, 0.57-0.69).51

Adverse effects from prophylactic cranial irradiation include in-
creased risk of neurocognitive decline such as memory loss and de-
crease in executive function in up to 65% of patients at 6 months.52
Grade ≥3 esophagitis: 17.5% (once-daily
No grade ≥3 toxicities were observed in
Grade ≥3 esophagitis: 19% (once-daily

Memantine, an inhibitor of N-methyl-D-aspartate receptor, may be

(twice-daily radiotherapy) vs 16.3%

pneumonitis: 3.1% (durvalumab) vs

radiotherapy) vs 18% (twice-daily

radiotherapy) vs 16% (twice-daily

(once-daily radiotherapy) vs 1.9%
radiotherapy); pneumonitis: 2.3%

considered for 6 months during and after prophylactic cranial irra-

Grade ≥3 treatment-emergent
diation per NCCN guidelines, based on its association with de-
Grade ≥3 esophagitis: 32.5%

(twice-daily radiotherapy)
(once-daily radiotherapy)

creased risk of cognitive decline at 24 weeks compared with pla-

Grade ≥3 adverse events

cebo (53.8% vs 64.9%; P = .01).52 Although hippocampal avoidance

of radiation to bilateral hippocampi is recommended by the NCCN,
2.6% (placebo)
radiotherapy)

studies have reported conflicting data about reducing risk of cog-

either group

nitive decline with this technique.37,53,54 For patients who decline

prophylactic cranial irradiation or do not undergo prophylactic cra-
nial irradiation due to increased risk of neurocognitive decline (age
(hazard ratio, 0.76; 95% CI, 0.61-0.95;

ⱖ60 years or baseline neurocognitive impairment), close surveil-

Median, 23 mo vs 19 mo (hazard ratio,

Median, 25 mo vs 30 mo (hazard ratio,

0.57-0.93; P = .01); progression-free

5.8% vs 23.5% (odds ratio, 5; 95% CI,

Median, 30.1 mo vs 28.5 mo (hazard

33.4 mo (hazard ratio, 0.73; 95% CI,

Overall survival: median, 55.9 mo vs

survival: median, 16.6 mo vs 9.2 mo

lance for brain metastases with brain MRI every 3 to 6 months is rec-
1.18; 95% CI, 0.95-1.45; P = .14)

ratio, 0.94; 95% CI, 0.76-1.17;

ommended per the NCCN.

1.57-15.86; P = .003)

Extensive-Stage SCLC
First-Line Treatment
First-line treatment for patients with ES-SCLC is chemotherapy
0.83; P = .04)

with platinum-etoposide and an anti–PD-L1 inhibitor (atezolizumab

Outcome

P = .59)

P = .16)
Table 1. Summary of Selected Phase 3 Randomized Clinical Trials for Limited-Stage Small Cell Lung Cancera

or durvalumab) (Table 2). Two studies evaluating newly diagnosed

within a safe radiation field. Studies are ordered by year of publication. Studies were selected based on quality

ES-SCLC reported that addition of atezolizumab or durvalumab to

Limited-stage disease is defined as confined to 1 hemithorax and supraclavicular region that can be treated

chemotherapy, respectively, resulted in improved overall survival

No. of patients with
delayed short-term
Primary end point

progression-free

compared with platinum-etoposide chemotherapy alone. Addition

memory at 3 mo

Overall survival,
Overall survival

Twice-daily radiotherapy Overall survival

Overall survival

of atezolizumab to platinum-etoposide chemotherapy resulted in a

2-month increased survival (10.3 vs 12.3 months; hazard ratio,
survival

0.70; 95% CI, 0.54-0.91) at a median follow-up of 13.9 months

(n = 403).15 The addition of durvalumab to platinum-etoposide
to 45 Gy in 30 twice-daily

twice-daily fractions over

to 45 Gy in 25 once-daily

Twice-daily radiotherapy

chemotherapy resulted in a similar increase in overall survival by 2.7

Once-daily radiotherapy

months (10.3 vs 13.0 months; hazard ratio, 0.73; 95% CI, 0.59-0.91)
followed by placebo
Prophylactic cranial

Chemoradiotherapy
fractions over 5 wk

fractions over 3 wk

at a median follow-up of 18 months (n = 537).15,16 Some patients

to 45-Gy in 30

had durable responses, with 3-year overall survival of 5.8% with

Comparator

irradiation

placebo vs 17.6% with addition of durvalumab (hazard ratio, 0.71;

95% CI, 0.60-0.86) at a median follow-up of 39.4 months.64 The
3 wk

incidence of treatment-related adverse events was similar in

ligand 1 [PD-L1] inhibitor) for

patients who received combination chemoimmunotherapy and

Chemoradiotherapy followed
by consolidation durvalumab
Twice-daily radiotherapy to

Once-daily radiotherapy to

Once-daily radiotherapy to

(programmed cell death 1

66 Gy in 33 fractions over

70 Gy in 35 fractions over

chemotherapy, including grade 3 or higher adverse effects of neu-

45 Gy in 30 twice-daily

Hippocampal-sparing

tropenia (23.2% with atezolizumab vs 24.5% with placebo; 23%

prophylactic cranial
fractions over 3 wk

with durvalumab plus chemotherapy vs 32% with chemotherapy

alone), anemia (14.1% with atezolizumab vs 12.2% with placebo;
irradiation

8% with durvalumab plus chemotherapy vs 14% with chemo-

Regimen

up to 2 y
6.5 wk

therapy alone), and thrombocytopenia (10.1% with atezolizumab

7 wk

vs 7.7% with placebo; 5% with durvalumab plus chemotherapy vs

9% with chemotherapy).15,16 The presence of anti–PD-1, expressed
CALGB 30610/RTOG
Turrisi et al,35 1999

ADRIATIC,39 2024
CONVERT,36 2017

PREMER,37 2021

on T cells and a receptor for PD-L1, also has demonstrated clinical

0538,38 2023

benefit as a target of therapy in some but not all studies.55-57 Addi-

(n = 417)

(n = 547)

(n = 150)

(n = 638)

(n = 530)

tion of other checkpoint inhibitors such as T-cell immunoglobulin

Source

and immunoreceptor tyrosine–based inhibitory motif domain

(TIGIT), which inhibit activation and proliferation of T cells, to
a

jama.com (Reprinted) JAMA Published online March 31, 2025 E5

© 2025 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies.
Downloaded from jamanetwork.com by Fudan University, li bai on 04/01/2025
 E6
Table 2. Summary of Selected Clinical Trials for Extensive-Stage Small Cell Lung Cancera

Source Trial type Regimen Comparator Primary end point Outcomes Grade ≥3 AEs FDA approval
First-line treatment
IMpower133,16 Phase 3, Atezolizumab plus Placebo plus Progression-free • Progression-free survival: • Grade ≥3 neutropenia: 23.2% (atezolizumab) vs 24.5% 2019
2018 (n = 403) randomized carboplatin-etoposide for carboplatin-etoposide survival, overall 5.2 mo vs 4.3 mo (hazard (placebo)
4 cycles, plus for 4 cycles, plus survival ratio, 0.77; 95% CI, • Grade ≥3 anemia: 14.1% (atezolizumab) vs 12.2%
maintenance maintenance placebo 0.62-0.96) (placebo)
atezolizumab • Overall survival: 12.3 mo vs • Grade ≥3 immune-mediated AE: 10.6% (atezolizumab)
10.3 mo (hazard ratio, 0.70; vs 2.6% (placebo)
95% CI, 0.54-0.91)
CASPIAN,15 2019 Phase 3, Durvalumab plus Platinum-etoposide for Overall survival 13 mo vs 10.3 mo (hazard ratio, • Grade ≥3 neutropenia: 24% (durvalumab plus 2020
Clinical Review & Education Review

(n = 537) randomized platinum-etoposide up to up to 6 cycles with or 0.73; 95% CI, 0.59-0.91) platinum-etoposide) vs 33% (platinum-etoposide)
4 cycles, plus without prophylactic • Grade ≥3 anemia: 9% (durvalumab plus
maintenance durvalumab cranial irradiation platinum-etoposide) vs 18% (platinum-etoposide)
• Grade ≥3 immune-mediated AE: 5% (durvalumab plus
platinum-etoposide) vs <1% (platinum-etoposide)
KEYNOTE-604,55 Phase 3, Pembrolizumab plus Platinum-etoposide for Progression-free • Progression-free survival: • Grade ≥3 neutropenia: 43.5% (pembrolizumab) vs Not FDA

JAMA Published online March 31, 2025 (Reprinted)

2020 (n = 453) randomized platinum-etoposide for 4 4 cycles plus survival, overall 4.5 mo vs 4.3 mo (hazard 40.8% (placebo) approved
cycles plus maintenance maintenance placebo survival ratio, 0.75; 95% CI, • Grade ≥3 anemia: 15.7% (pembrolizumab) vs 15.2%
pembrolizumab 0.61-0.91) (placebo)
• Overall survival: 10.8 mo vs • Grade ≥3 immune-mediated AE: 7.2%
9.7 mo (hazard ratio, 0.80; (pembrolizumab) vs 0.9% (placebo)
95% CI, 0.64-0.98; P = .02)

Downloaded from jamanetwork.com by Fudan University, li bai on 04/01/2025

ASTRUM-005,56 Phase 3, Serplulimab plus Placebo plus Overall survival 15.4 mo vs 10.9 mo (hazard • Grade ≥3 neutropenia: 14.1% (serplulimab) vs 13.8% Approved in
2022 (n = 585) randomized carboplatin-etoposide for carboplatin-etoposide ratio, 0.63; 95% CI, 0.49-0.82; (placebo) China, 2022
up to 4 cycles plus for up to 4 cycles plus P < .001) • Grade ≥3 anemia: 5.4% (serplulimab) vs 5.6%
maintenance serplulimab maintenance placebo (placebo)
• Grade ≥3 immune-mediated AE: 9.5% (serplulimab) vs
5.6% (placebo)
CAPSTONE-1,57 Phase 3, Adebrelimab plus Placebo plus Overall survival 15.3 mo vs 12.8 mo (hazard • Grade ≥3 neutropenia: 76% (adebrelimab) vs 75% Approved in
2022 (n = 462) randomized carboplatin-etoposide for carboplatin-etoposide ratio, 0.72; 95% CI, 0.58-0.90; (placebo) China, 2023
6 cycles plus for 6 cycles plus P = .002) • Grade ≥3 anemia: 28% (adebrelimab) vs 28%
maintenance adebrelimab maintenance placebo (placebo)
• Grade ≥3 immune-mediated AE: 4.8% (adebrelimab)
vs 3% (placebo)
ETER701,58 2024 Phase 3, Benmelstobart plus Placebo plus placebo Progression-free • Progression-free survival: • Grade ≥3 neutropenia: 69.9% (benmelstobart plus Not FDA
(n = 738) randomized anlotinib plus carboplatin plus carboplatin plus survival, overall 6.9 mo vs 4.2 mo (hazard anlotinib plus carboplatin plus etoposide) vs 68.7% approved
plus etoposide or placebo etoposide survival ratio, 0.32; 95% CI, 0.26-0.41; (placebo plus placebo plus carboplatin plus
plus anlotinib plus P < .001) etoposide)
carboplatin plus • Overall survival: 19.3 mo vs • Grade ≥3 thrombocytopenia: 49.6% (benmelstobart
etoposide 11.9 mo (hazard ratio, 0.61; plus anlotinib plus carboplatin plus etoposide) vs
95% CI, 0.47-0.79; P < .001) 35.8% (placebo plus placebo plus carboplatin plus
etoposide)
• Grade ≥3 anemia: 25.2% (benmelstobart plus
anlotinib plus carboplatin plus etoposide) vs 24.0%
(placebo plus placebo plus carboplatin plus
etoposide)
• Grade ≥3 hypertension: 15.9% (benmelstobart plus
anlotinib plus carboplatin plus etoposide) vs 2.4%
(placebo plus placebo plus carboplatin plus
etoposide)
• Grade ≥3 proteinuria: 0.8% (benmelstobart plus
anlotinib plus carboplatin plus etoposide) vs 0.4%
(placebo plus placebo plus carboplatin plus
etoposide)

(continued)
Small Cell Lung Cancer

jama.com

© 2025 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies.
 Table 2. Summary of Selected Clinical Trials for Extensive-Stage Small Cell Lung Cancera (continued)

Source Trial type Regimen Comparator Primary end point Outcomes Grade ≥3 AEs FDA approval

jama.com
Maintenance
SWOG S1929,59 Phase 2, Maintenance talazoparib Maintenance Progression-free 4.2 mo vs 2.8 mo (hazard ratio, Grade 3 anemia: 37% (talazoparib plus atezolizumab) vs Not FDA
2023 (n = 106) randomized plus atezolizumab atezolizumab survival 0.70; 80% CI, 0.52-0.94) 2% (atezolizumab) approved
Small Cell Lung Cancer

Relapse
Trigo et al,60 2020 Phase 2, Lurbinectedin, Not applicable Overall response rate 35.2% • Grade ≥3 neutropenia: 46% Accelerated FDA
(n = 105) single-group 3.2 mg/m2 • Grade ≥3 anemia: 9% approval, 2020
basket • Grade ≥3 thrombocytopenia: 7%
Baize et al,61 2020 Phase 3, Carboplatin-etoposide for Oral topotecan for 6 Progression-free 4.7 mo vs 2.7 mo (hazard ratio, • Grade ≥3 neutropenia: 13.6% (chemotherapy) vs Recommended
(n = 164) randomized 6 cycles cycles survival 0.57; 90% CI, 0.41-0.73) 24.7% (topotecan) per NCCN
• Grade ≥3 anemia: 30.9% (chemotherapy) vs 35.8% guidelines
(topotecan)
• Grade ≥3 thrombocytopenia: 24.7% (chemotherapy)
vs 21% (topotecan)
• Grade ≥3 febrile neutropenia: 6.2% (chemotherapy) vs
13.6% (topotecan)
ATLANTIS,62 2023 Phase 3, Lurbinectedin, Physician choice of Overall survival 8.6 mo vs 7.6 mo (hazard ratio, • Grade ≥3 neutropenia: 37% (lurbinectedin plus Combination not
(n = 613) randomized 2.0 mg/m2, plus topotecan or 0.97; 95% CI, 0.82-1.15) doxorubicin) vs 69% (control) FDA approved
doxorubicin cyclophosphamide, • Grade ≥3 anemia: 19% (lurbinectedin plus
doxorubicin, and doxorubicin) vs 38% (control)
vincristine • Grade ≥3 thrombocytopenia: 14% (lurbinectedin plus

Downloaded from jamanetwork.com by Fudan University, li bai on 04/01/2025

doxorubicin) vs 31% (control)
DeLLphi-301,63 Phase 2, Tarlatamab Not applicable Overall response rate 40% with 10 mg; 32% with 100 • Cytokine-release syndrome: 51%; grade ≥3, 0.75% Accelerated FDA
2023 (n = 220) single-group mg (10-mg subgroup) approval, 2024
• Immune effector cell–associated neurotoxicity
syndrome: 8.3%; grade ≥3: 0% (10-mg subgroup)
• Grade ≥3 neutropenia: 6.0%
Abbreviations: AE, adverse event; FDA, US Food and Drug Administration; NCCN, National Comprehensive extending beyond a single radiation field for treatment. Trials are ordered by year of publication per type of
Cancer Network. treatment. Studies were selected based on quality and relevance to clinical care.
a
Extensive-stage small cell lung cancer is defined as disease extending beyond a single hemithorax or disease
Review Clinical Review & Education

(Reprinted) JAMA Published online March 31, 2025

© 2025 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies.
E7
 Clinical Review & Education Review Small Cell Lung Cancer

combination platinum-etoposide and anti–PD-1 therapy has not resistance mechanisms that are difficult to target with 1 class of drug.72
demonstrated a survival benefit in patients with ES-SCLC.65 Clinical trial enrollment for all patients upon relapse is strongly rec-
ommended by NCCN guidelines. If clinical trials are not available, per
Maintenance Therapy the NCCN the recommended subsequent therapy after progression
After initial cytoreduction with chemoimmunotherapy, monthly with first-line therapy depends on tumor sensitivity to chemo-
maintenance therapy with atezolizumab or durvalumab until tu- therapy, assessed by how long a patient has maintained tumor shrink-
mor progression and/or treatment intolerance is recommended for age without subsequent chemotherapy (Table 2). In a randomized
patients with ES-SCLC per NCCN guidelines to prolong control of phase 3 trial of 162 patients with ES-SCLC who had disease progres-
tumor growth.15,16 Most patients with ES-SCLC have regrowth of tu- sion or relapse after 90 days of treatment with platinum-etoposide,
mor after prior tumor shrinkage or development of new metasta- re-treatment with platinum-etoposide improved progression-free
ses on imaging within 3 to 4 months of initiation of maintenance survival compared with topotecan (4.7 vs 2.7 months; hazard ratio,
treatment, and maintenance therapies with nivolumab (an anti– 0.57; 90% CI, 0.41-0.73), with lower frequency of neutropenia (14%
PD-1 inhibitor) or nivolumab with ipilimumab (an anti–CTLA-4 in- vs 22%) and febrile neutropenia (6% vs 11%).61 Re-treatment with
hibitor) have not improved overall survival.66 Additional mainte- platinum-etoposide chemotherapy can be considered for relapsing
nance strategies with poly–adenosine diphosphate ribose patients who had a prior treatment response of greater than 6 months
polymerase (PARP) inhibitors59 and delta-like ligand 3–targeting an- to first-line platinum-etoposide chemotherapy.3
tibody drug conjugates67 have also not demonstrated survival ben- For patients who had a poor prior treatment response to
efit in patients with ES-SCLC. platinum-etoposide, lurbinectedin, a DNA-alkylating agent, is an
Consolidative thoracic radiation, radiation given within 6 weeks FDA-approved second-line therapy for SCLC. In a single-group
after initial chemotherapy or chemoimmunotherapy, may be used phase 2 trial, lurbinectedin had an overall response rate (tumor
to treat residual or persistent intrathoracic disease in patients with shrinkage of at least 30%) in 35.2% (95% CI, 26.2%-45.2%) of 105
ES-SCLC who have initial tumor reduction or tumor stability on previously treated patients with SCLC without brain metastases.60
imaging with platinum-etoposide therapy.46 In a trial of 495 pa- In patients with a chemotherapy-free treatment interval of 180
tients with ES-SCLC who had tumor shrinkage with induction che- days or longer, the overall response rate with lurbinectedin was
motherapy, low-dose consolidative thoracic radiotherapy of 30 Gy 60% (95% CI, 36.1%-86.9%). 73 The phase 3 ATLANTIS trial
in 10 fractions given with chemotherapy conferred a 2-year overall (n = 613) did not demonstrate improved survival with lurbinectedin
survival benefit compared with chemotherapy alone (13% vs 3%; in combination with doxorubicin compared with physician choice
P = .004).68 The most common serious adverse effects were fa- of topotecan or cyclophosphamide/doxorubicin/vincristine
tigue (4.5%) and shortness of breath (1.2%).68 There are limited pro- (Table 2), with negative results attributed to a lower dose of lurbi-
spective data on the efficacy of consolidative radiation after che- nectedin used in combination with doxorubicin relative to standard
moimmunotherapy. Consolidative thoracic radiation may be monotherapy dosing.62
considered for patients with ES-SCLC who have residual or persis- Alternative second-line treatments for ES-SCLC include
tent intrathoracic disease after chemoimmunotherapy per ASTRO topotecan, 74 irinotecan-based therapy, 75-7 7 taxanes, 78-80
guidelines.15,16,46 temozolomide,81 and gemcitabine-based therapies.78 Tarlatamab,
a bispecific T-cell engager against immune T cells and delta-like li-
Prophylactic Cranial Irradiation gand 3, a transmembrane protein abnormally expressed in 85% to
Prophylactic cranial irradiation for ES-SCLC is controversial. Based 94% of SCLC, recently gained accelerated FDA approval for pa-
on NCCN and ASTRO guidelines, either prophylactic cranial irradia- tients with SCLC who progress despite treatment with platinum-
tion or brain MRI surveillance every 3 to 6 months can be consid- etoposide chemotherapy and immunotherapy.63 In a phase 2 trial
ered; MRI surveillance is used more commonly than prophylactic of 220 patients with ES-SCLC, tarlatamab led to an overall re-
cranial irradiation in current clinical practice in the US.3,46,69,70 A sponse rate, defined as at least 30% tumor reduction from base-
phase 3 trial of 224 patients with ES-SCLC without brain metasta- line, of 40% with a 10-mg dose and 32% with a 100-mg dose.63 Fifty-
ses who had tumor shrinkage after treatment with platinum- nine percent of patients had a treatment response for 6 months or
etoposide chemotherapy did not demonstrate a survival benefit longer, and 68% of patients taking the 10-mg dose had a 9-month
with prophylactic cranial irradiation compared with close MRI sur- overall survival of 68%.63 Grade 1 or 2 cytokine-release syndrome,
veillance (every 3 months for up to 12 months followed by 18 and a systemic inflammatory syndrome characterized by sudden re-
24 months after enrollment), with overall survival of 11.6 months lease of cytokines, which presents as fever with or without hypo-
with prophylactic cranial irradiation and 13.7 months with MRI sur- tension or hypoxia, was observed in at least half of patients and was
veillance (hazard ratio, 1.27; 95% CI, 0.96-1.68).70 treatable.63 Future directions for SCLC treatment include tailored
approaches targeting DNA repair pathways, surface proteins ex-
Relapse pressed in SCLC such as seizure-related 6 homologue (SEZ6)82,83
Second-Line Treatment/Relapsed SCLC or B7H3,84 and immune modulation such as inhibiting lysine-
Approximately 50% of patients relapse after 9 months of concur- specific demethylase 1 (LSD1),85 which enhances antigen presen-
rent chemoradiation for LS-SCLC and after 4 to 5 months of mainte- tation to immune cells (eFigures 1 and 2 in the Supplement).
nance immunotherapy for ES-SCLC.15,16,39 Survival upon progres-
sion or relapse is 3 to 4 months without treatment.71 Poor prognosis Brain Metastases in ES-SCLC
despite initial response to first-line therapy may be due to the clonal Chemoimmunotherapy penetrates the blood-brain barrier and is
diversity of SCLC that emerges after treatment, which may confer the recommended initial approach per the NCCN for patients with

E8 JAMA Published online March 31, 2025 (Reprinted) jama.com

© 2025 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies.
Downloaded from jamanetwork.com by Fudan University, li bai on 04/01/2025
 Small Cell Lung Cancer Review Clinical Review & Education

ES-SCLC with asymptomatic brain metastases. For patients with intravenous immunoglobulin or amifampridine (potassium channel
neurologic symptoms such as headache, nausea, or vomiting, dexa- blocker).25,91
methasone, 4 mg every 6 hours, and stereotactic radiosurgery or
whole-brain radiotherapy prior to systemic therapy is recom- Treatment With Palliative Radiotherapy
mended.3 Brain metastases that develop after initiation of systemic Palliative radiotherapy may be considered for patients with SCLC who
therapy in ES-SCLC have conventionally been treated with whole- have airway compromise due to tumor mass effect, clinically sig-
brain radiation. However, gamma-knife radiation, a type of stereo- nificant hemoptysis due to vascular involvement of tumor, or extra-
tactic radiosurgery that provides precise high-dose radiation to the cranial metastases associated with pain or spinal cord compromise.3
tumor, may also be used and is increasingly preferred due to
decreased risk of neurocognitive decline.86 For selected patients Chemotherapy-Induced Myelosuppression
with an isolated large, symptomatic brain metastasis, craniotomy Chemotherapy-induced myelosuppression, which may present
and resection of the metastasis may be considered. with anemia, thrombocytopenia, or neutropenia, is usually man-
A cohort study of patients with ES-SCLC with brain metastases aged with prophylactic granulocyte colony-stimulating factor after
compared treatment with stereotactic radiosurgery (n = 710) vs completion of each cycle of chemotherapy. Another option to pre-
whole-brain radiation (n = 219).87 Although whole-brain radiation vent myelosuppression is trilaciclib, a cyclin-dependent kinase 4/6
was associated with a longer time to central nervous system pro- inhibitor, which arrests hemopoietic progenitor cells in the G1 stage
gression, defined as time from radiation to development of new of the cell cycle. In a pooled analysis of 242 patients with ES-SCLC,
central nervous system lesions, overall survival was greater with trilaciclib, administered as a 30-minute infusion within 4 hours
stereotactic radiosurgery vs whole-brain radiation (6.5 months vs prior to chemoimmunotherapy or prior to every cycle of chemo-
5.2 months; P = .003).87 However, a subsequent meta-analysis of 7 therapy, reduced the use of granulocyte colony-stimulating factor
retrospective studies that included 18 050 patients with SCLC with (28.5% vs 56.3% with placebo; P < .001), erythropoiesis-
brain metastases reported similar overall survival (hazard ratio, stimulating agents (3.3% vs 11.8% with placebo; P = .03), and red
0.87; 95% CI, 0.76-1.01) among patients receiving whole-brain blood cell transfusion (14.6% vs 26.1%; P = .03).92
radiation therapy and stereotactic radiosurgery.88 The threshold
for the number of brain metastases indicated for stereotactic radio- Tumor Lysis Syndrome
surgery over whole-brain radiation has not been prospectively Duetorapidapoptosisoftumorcellswithchemotherapy,patientswith
established; stereotactic radiosurgery may be considered for 10 or ES-SCLC may develop tumor lysis syndrome, which may result in elec-
fewer brain metastases.86,87 trolyte imbalances. Therefore, potassium, phosphate, calcium, uric
acid, and kidney function should be closely monitored in patients with
Prognosis ES-SCLC who are starting chemotherapy. Patients with signs of ac-
For patients with LS-SCLC, 5-year overall survival with chemo- tive tumor lysis should be hospitalized to treat electrolyte imbal-
therapy and radiation therapy was 16.1% to 27.7%2 prior to intro- ances and for close monitoring of cardiac and kidney function. Pro-
duction of durvalumab. With the addition of 2 years of consolida- phylaxis with allopurinol is not usually indicated for patients with
tion durvalumab, overall survival for LS-SCLC has improved from a normal or mildly elevated uric acid. Allopurinol and rasburicase, a urate
median of 33.4 months to 55.9 months, with 3-year overall sur- oxidase enzyme that transforms uric acid into an inactive metabo-
vival of 56.5%.39 Patients with ES-SCLC have an initial response lite, may be indicated for patients with spontaneous tumor lysis syn-
rate of approximately 60% to 80% to chemoimmunotherapy, drome (signs of tumor lysis prior to initiating chemotherapy).
with 3-year overall survival of 17.6% and 5-year overall survival of
12%.15,16,64,89 Palliative Care
Given the poor prognosis of SCLC, all patients should establish care
Practical Considerations with a palliative care team at the time of diagnosis. Early palliative
Treatment of Superior Vena Cava Syndrome care has been associated with improved physical, functional, emo-
First-line treatment for symptomatic superior vena cava syndrome tional, and social well-being in patients with lung cancer as as-
is chemotherapy.90 Patients with superior vena cava syndrome who sessed by the Functional Assessment of Cancer Therapy–Lung scale
have dyspnea, dysphagia, or cyanosis may also be treated with dexa- (score range, 0-136, with higher scores reflecting improved quality
methasone, 4 mg every 6 hours, or radiation if chemotherapy can- of life; clinically meaningful change is 2-3 points) (score, 98 vs 91.5;
not be initiated expeditiously. Stenting is typically not recom- P = .03) and improved survival (11.6 months vs 8.9 months;
mended as initial therapy for superior vena cava syndrome as SCLC P = .02).93,94 Patients with SCLC should have ongoing conversa-
is responsive to chemotherapy and radiation. tions about goals of care including desire for cardiopulmonary re-
suscitation and mechanical ventilation, and consideration of hos-
Treatment of Paraneoplastic Syndromes pice as an alternative to treatment.
For patients with paraneoplastic Cushing syndrome, steroidogen-
esis inhibitors such as ketoconazole may be used if Cushing syn- Limitations
drome does not improve with chemoimmunotherapy. Patients This Review has limitations. First, it may have missed some rel-
with syndrome of inappropriate antidiuretic hormone secretion evant articles. Second, a formal quality assessment of the included
may be treated with fluid restriction, and if not improved, salt tab- literature was not performed. Third, due to the poor prognosis of
lets, demeclocycline (tetracycline antibiotic), or tolvaptan can be SCLC and challenges in patient recruitment, there are few random-
considered.3,22 Lambert-Eaton syndrome may be treated with ized phase 3 treatment trials for SCLC.

jama.com (Reprinted) JAMA Published online March 31, 2025 E9

© 2025 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies.
Downloaded from jamanetwork.com by Fudan University, li bai on 04/01/2025
 Clinical Review & Education Review Small Cell Lung Cancer

tumor, given concurrently with chemotherapy, followed by consoli-

Conclusions dation immunotherapy for 2 years. First-line treatment for ES-SCLC
is a combination of chemotherapy and immunotherapy followed
Small cell lung cancer is a smoking-related malignancy that pre- by maintenance immunotherapy. Participation in clinical trials, if
sents at an advanced stage in 70% of patients. Three-year overall available, should be encouraged, and palliative care is associated
survival is approximately 56.5% for LS-SCLC and 17.6% for ES-SCLC. with improvements in quality of life and overall survival for pa-
Treatment for LS-SCLC is once- or twice-daily radiation targeting the tients with SCLC.

ARTICLE INFORMATION 2019;19(5):289-297. doi:10.1038/s41568-019- 21. Sculier JP, Evans WK, Feld R, et al. Superior vena
Accepted for Publication: January 15, 2025. 0133-9 caval obstruction syndrome in small cell lung
9. Gay CM, Stewart CA, Park EM, et al. Patterns of cancer. Cancer. 1986;57(4):847-851. doi:10.1002/
Published Online: March 31, 2025. 1097-0142(19860215)57:4<847::AID-
doi:10.1001/jama.2025.0560 transcription factor programs and immune pathway
activation define four major subtypes of SCLC with CNCR2820570427>3.0.CO;2-H
Conflict of Interest Disclosures: Dr Kim reported distinct therapeutic vulnerabilities. Cancer Cell. 22. Li Y, Li C, Qi X, Yu L, Lin L. Management of small
receipt of personal fees from Genentech and 2021;39(3):346-360. doi:10.1016/j.ccell.2020.12.014 cell lung cancer complicated with paraneoplastic
Revolution Medicine and institutional funding from Cushing’s syndrome: a systematic literature review.
Loxo@Lilly, Mirati/Bristol Myers Squibb, BridgeBio, 10. Owonikoko TK, Dwivedi B, Chen Z, et al. YAP1
expression in SCLC defines a distinct subtype with Front Endocrinol (Lausanne). 2023;14:1177125.
Genmab, BioInvent, AstraZeneca, MonteRosa, doi:10.3389/fendo.2023.1177125
Boehringer Ingelheim, Dynamicure, Seagen, Gilead, T-cell-inflamed phenotype. J Thorac Oncol. 2021;16
Takeda, and Vaccibody. Dr Park reported receipt of (3):464-476. doi:10.1016/j.jtho.2020.11.006 23. Bartalis E, Gergics M, Tinusz B, et al. Prevalence
personal fees from RefleXion, AstraZeneca, Bristol 11. Acheampong E, Abed A, Morici M, et al. Tumour and prognostic significance of hyponatremia in
Myers Squibb, Daiichi Sankyo, G1 Therapeutics, and PD-L1 expression in small-cell lung cancer: patients with lung cancer: systematic review and
Regeneron and grants from Merck and RefleXion. a systematic review and meta-analysis. Cells. 2020; meta-analysis. Front Med (Lausanne). 2021;8:671951.
Dr Chiang reported receipt of personal fees from 9(11):2393. doi:10.3390/cells9112393 doi:10.3389/fmed.2021.671951
AstraZeneca, Genentech, Daiichi Janssen, Amgen, 12. Yu H, Boyle TA, Zhou C, Rimm DL, Hirsch FR. 24. Nagy-Mignotte H, Shestaeva O, Vignoud L,
Zai Lab, and AbbVie and grants from Bristol Myers PD-L1 expression in lung cancer. J Thorac Oncol. et al; Multidisciplinary Thoracic Oncology Group at
Squibb. 2016;11(7):964-975. doi:10.1016/j.jtho.2016.04.014 Grenoble University Hospital, France. Prognostic
Submissions: We encourage authors to submit impact of paraneoplastic Cushing’s syndrome in
13. Roca E, Gurizzan C, Amoroso V, Vermi W, Ferrari small-cell lung cancer. J Thorac Oncol. 2014;9(4):
papers for consideration as a Review. Please V, Berruti A. Outcome of patients with lung
contact Kristin Walter, MD, at kristin.walter@ 497-505. doi:10.1097/JTO.0000000000000116
adenocarcinoma with transformation to small-cell
jamanetwork.org. lung cancer following tyrosine kinase inhibitors 25. Briggs SE, Gozzard P, Talbot DC. The
treatment: a systematic review and pooled analysis. association between Lambert-Eaton myasthenic
REFERENCES Cancer Treat Rev. 2017;59:117-122. doi:10.1016/j. syndrome and small cell lung carcinoma.
1. Siegel RL, Giaquinto AN, Jemal A. Cancer ctrv.2017.07.007 Immunotargets Ther. 2013;2:31-37. doi:10.2147/ITT.
statistics, 2024. CA Cancer J Clin. 2024;74(1):12-49. S31971
14. Offin M, Chan JM, Tenet M, et al. Concurrent
doi:10.3322/caac.21820 RB1 and TP53 alterations define a subset of 26. Payne M, Bradbury P, Lang B, et al. Prospective
2. Surveillance, Epidemiology, and End Results. EGFR-mutant lung cancers at risk for histologic study into the incidence of Lambert Eaton
Small cell carcinoma of the lung and bronchus. transformation and inferior clinical outcomes. myasthenic syndrome in small cell lung cancer.
Accessed March 31, 2024, 2024. https://seer. J Thorac Oncol. 2019;14(10):1784-1793. doi:10.1016/ J Thorac Oncol. 2010;5(1):34-38. doi:10.1097/JTO.
cancer.gov/statistics j.jtho.2019.06.002 0b013e3181c3f4f1

3. National Comprehensive Cancer Network. Small 15. Paz-Ares L, Dvorkin M, Chen Y, et al; CASPIAN 27. Dingemans AC, Früh M, Ardizzoni A, et al;
cell lung cancer. Accessed February 21, 2025. Investigators. Durvalumab plus platinum-etoposide ESMO Guidelines Committee. Small-cell lung
https://seer.cancer.gov/statistics/ versus platinum-etoposide in first-line treatment of cancer: ESMO clinical practice guidelines for
extensive-stage small-cell lung cancer (CASPIAN): diagnosis, treatment and follow-up. Ann Oncol.
4. Pesch B, Kendzia B, Gustavsson P, et al. 2021;32(7):839-853. doi:10.1016/j.annonc.2021.03.
Cigarette smoking and lung cancer—relative risk a randomised, controlled, open-label, phase 3 trial.
Lancet. 2019;394(10212):1929-1939. doi:10.1016/ 207
estimates for the major histological types from a
pooled analysis of case-control studies. Int J Cancer. S0140-6736(19)32222-6 28. Misch D, Blum T, Boch C, et al. Value of thyroid
2012;131(5):1210-1219. doi:10.1002/ijc.27339 16. Horn L, Mansfield AS, Szczęsna A, et al; transcription factor (TTF)-1 for diagnosis and
IMpower133 Study Group. First-line atezolizumab prognosis of patients with locally advanced or
5. Torres-Durán M, Ruano-Ravina A, Kelsey KT, metastatic small cell lung cancer. Diagn Pathol.
et al. Small cell lung cancer in never-smokers. Eur plus chemotherapy in extensive-stage small-cell
lung cancer. N Engl J Med. 2018;379(23):2220-2229. 2015;10:21. doi:10.1186/s13000-015-0250-z
Respir J. 2016;47(3):947-953. doi:10.1183/
13993003.01524-2015 doi:10.1056/NEJMoa1809064 29. Chu P, Wu E, Weiss LM. Cytokeratin 7 and
17. Xu J, Xu L, Wang B, Kong W, Chen Y, Yu Z. cytokeratin 20 expression in epithelial neoplasms:
6. Sun JM, Choi YL, Ji JH, et al. Small-cell lung a survey of 435 cases. Mod Pathol. 2000;13(9):
cancer detection in never-smokers: clinical Outcomes in patients with lung adenocarcinoma
with transformation to small cell lung cancer after 962-972. doi:10.1038/modpathol.3880175
characteristics and multigene mutation profiling
using targeted next-generation sequencing. Ann EGFR tyrosine kinase inhibitors resistance: 30. Sakakibara R, Kobayashi M, Takahashi N, et al.
Oncol. 2015;26(1):161-166. doi:10.1093/annonc/ a systematic review and pooled analysis. Front Oncol. Insulinoma-associated protein 1 (INSM1) is a better
mdu504 2022;11:766148. doi:10.3389/fonc.2021.766148 marker for the diagnosis and prognosis estimation
18. Abeloff MD. Abeloff’s Clinical Oncology. Elsevier; of small cell lung carcinoma than neuroendocrine
7. Meuwissen R, Linn SC, Linnoila RI, Zevenhoven J, phenotype markers such as chromogranin a,
Mooi WJ, Berns A. Induction of small cell lung 2020.
synaptophysin, and CD56. Am J Surg Pathol. 2020;
cancer by somatic inactivation of both Trp53 and 19. Ruano-Raviña A, Provencio M, Calvo de Juan V, 44(6):757-764. doi:10.1097/PAS.
Rb1 in a conditional mouse model. Cancer Cell. et al. Lung cancer symptoms at diagnosis: results of 0000000000001444
2003;4(3):181-189. doi:10.1016/S1535-6108(03) a nationwide registry study. ESMO Open. 2020;5
00220-4 (6):e001021. doi:10.1136/esmoopen-2020-001021 31. Rindi G, Mete O, Uccella S, et al. Overview of the
2022 WHO classification of neuroendocrine
8. Rudin CM, Poirier JT, Byers LA, et al. Molecular 20. Li N, Chu Y, Song Q. Brain metastasis in neoplasms. Endocr Pathol. 2022;33(1):115-154. doi:
subtypes of small cell lung cancer: a synthesis of patients with small cell lung cancer. Int J Gen Med. 10.1007/s12022-022-09708-2
human and mouse model data. Nat Rev Cancer. 2021;14:10131-10139. doi:10.2147/IJGM.S342009

E10 JAMA Published online March 31, 2025 (Reprinted) jama.com

© 2025 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies.
Downloaded from jamanetwork.com by Fudan University, li bai on 04/01/2025
 Small Cell Lung Cancer Review Clinical Review & Education

32. Zelen M. Keynote address on biostatistics and 45. Zhou N, Bott M, Park BJ, et al; Small Cell Lung 57. Wang J, Zhou C, Yao W, et al; CAPSTONE-1
data retrieval. Cancer Chemother Rep 3. 1973;4 Cancer Working Group. Predictors of survival Study Group. Adebrelimab or placebo plus
(2):31-42. following surgical resection of limited-stage small carboplatin and etoposide as first-line treatment for
33. Stahel RA, Ginsberg R, Havemann K, et al. cell lung cancer. J Thorac Cardiovasc Surg. 2021;161 extensive-stage small-cell lung cancer
Staging and prognostic factors in small cell lung (3):760-771. doi:10.1016/j.jtcvs.2020.10.148 (CAPSTONE-1): a multicentre, randomised,
cancer: a consensus report. Lung Cancer. 1989;5 46. Simone CB II, Bogart JA, Cabrera AR, et al. double-blind, placebo-controlled, phase 3 trial.
(4):119-126. doi:10.1016/0169-5002(89)90156-6 Radiation therapy for small cell lung cancer: an Lancet Oncol. 2022;23(6):739-747. doi:10.1016/
ASTRO clinical practice guideline. Pract Radiat Oncol. S1470-2045(22)00224-8
34. Micke P, Faldum A, Metz T, et al. Staging small
cell lung cancer: Veterans Administration Lung 2020;10(3):158-173. doi:10.1016/j.prro.2020.02.009 58. Cheng Y, Chen J, Zhang W, et al.
Study Group versus International Association for 47. Duan H, Shi L, Shao C, et al. A multicenter, Benmelstobart, anlotinib and chemotherapy in
the Study of Lung Cancer—what limits limited single-arm, open study of neoadjuvant or extensive-stage small-cell lung cancer:
disease? Lung Cancer. 2002;37(3):271-276. doi:10. conversion atezolizumab in combination with a randomized phase 3 trial. Nat Med. 2024;30(10):
1016/S0169-5002(02)00072-7 chemotherapy in resectable small cell lung cancer 2967-2976. doi:10.1038/s41591-024-03132-1

35. Turrisi AT III, Kim K, Blum R, et al. Twice-daily (cohort study). Int J Surg. 2023;109(9):2641-2649. 59. Karim NFA, Miao J, Reckamp KL, et al. SWOG
compared with once-daily thoracic radiotherapy in doi:10.1097/JS9.0000000000000501 S1929: phase II randomized study of maintenance
limited small-cell lung cancer treated concurrently 48. Aupérin A, Arriagada R, Pignon JP, et al; atezolizumab (A) versus atezolizumab + talazoparib
with cisplatin and etoposide. N Engl J Med. 1999; Prophylactic Cranial Irradiation Overview (AT) in patients with SLFN11 positive extensive
340(4):265-271. doi:10.1056/ Collaborative Group. Prophylactic cranial irradiation stage small cell lung cancer (ES-SCLC). J Clin Oncol.
NEJM199901283400403 for patients with small-cell lung cancer in complete 2023;41(16)(suppl):8504. doi:10.1200/JCO.2023.41.
remission. N Engl J Med. 1999;341(7):476-484. doi: 16_suppl.8504
36. Faivre-Finn C, Snee M, Ashcroft L, et al;
CONVERT Study Team. Concurrent once-daily 10.1056/NEJM199908123410703 60. Trigo J, Subbiah V, Besse B, et al. Lurbinectedin
versus twice-daily chemoradiotherapy in patients 49. Yang Y, Zhang D, Zhou X, et al. Prophylactic as second-line treatment for patients with small-cell
with limited-stage small-cell lung cancer cranial irradiation in resected small cell lung cancer: lung cancer: a single-arm, open-label, phase 2
(CONVERT): an open-label, phase 3, randomised, a systematic review with meta-analysis. J Cancer. basket trial. Lancet Oncol. 2020;21(5):645-654. doi:
superiority trial. Lancet Oncol. 2017;18(8):1116-1125. 2018;9(2):433-439. doi:10.7150/jca.21465 10.1016/S1470-2045(20)30068-1
doi:10.1016/S1470-2045(17)30318-2 50. Verma V, Simone CB II, Allen PK, Lin SH. 61. Baize N, Monnet I, Greillier L, et al; Groupe
37. Rodríguez de Dios N, Couñago F, Murcia-Mejía Outcomes of stereotactic body radiotherapy for Français de Pneumo-Cancérologie 01-13
M, et al. Randomized phase III trial of prophylactic T1-T2N0 small cell carcinoma according to addition Investigators. Carboplatin plus etoposide versus
cranial irradiation with or without hippocampal of chemotherapy and prophylactic cranial topotecan as second-line treatment for patients
avoidance for small-cell lung cancer (PREMER): irradiation: a multicenter analysis. Clin Lung Cancer. with sensitive relapsed small-cell lung cancer: an
a GICOR-GOECP-SEOR study. J Clin Oncol. 2021;39 2017;18(6):675-681. doi:10.1016/j.cllc.2017.03.009 open-label, multicentre, randomised, phase 3 trial.
(28):3118-3127. doi:10.1200/JCO.21.00639 Lancet Oncol. 2020;21(9):1224-1233. doi:10.1016/
51. Tomassen ML, Pomp J, van der Stap J, et al. The S1470-2045(20)30461-7
38. Bogart J, Wang X, Masters G, et al. High-dose overall survival impact of prophylactic cranial
once-daily thoracic radiotherapy in limited-stage irradiation in limited-stage small-cell lung cancer: 62. Aix SP, Ciuleanu TE, Navarro A, et al.
small-cell lung cancer: CALGB 30610 a systematic review and meta-analysis. Clin Transl Combination lurbinectedin and doxorubicin versus
(Alliance)/RTOG 0538. J Clin Oncol. 2023;41(13): Radiat Oncol. 2022;33:145-152. doi:10.1016/j.ctro. physician’s choice of chemotherapy in patients with
2394-2402. doi:10.1200/JCO.22.01359 2022.02.002 relapsed small-cell lung cancer (ATLANTIS):
a multicentre, randomised, open-label, phase 3
39. Cheng Y, Spigel DR, Cho BC, et al; ADRIATIC 52. Brown PD, Pugh S, Laack NN, et al; Radiation trial. Lancet Respir Med. 2023;11(1):74-86. doi:10.
Investigators. Durvalumab after chemoradio- Therapy Oncology Group. Memantine for the 1016/S2213-2600(22)00309-5
therapy in limited-stage small-cell lung cancer. prevention of cognitive dysfunction in patients
N Engl J Med. 2024;391(14):1313-1327. doi:10.1056/ receiving whole-brain radiotherapy: a randomized, 63. Ahn MJ, Cho BC, Felip E, et al; DeLLphi-301
NEJMoa2404873 double-blind, placebo-controlled trial. Neuro Oncol. Investigators. Tarlatamab for patients with
2013;15(10):1429-1437. doi:10.1093/neuonc/not114 previously treated small-cell lung cancer. N Engl J
40. Salem A, Mistry H, Hatton M, et al. Association Med. 2023;389(22):2063-2075. doi:10.1056/
of chemoradiotherapy with outcomes among 53. Brown PD, Gondi V, Pugh S, et al; NRG NEJMoa2307980
patients with stage I to II vs stage III small cell lung Oncology. Hippocampal avoidance during
cancer: secondary analysis of a randomized clinical whole-brain radiotherapy plus memantine for 64. Paz-Ares L, Chen Y, Reinmuth N, et al.
trial. JAMA Oncol. 2019;5(3):e185335-e185335. doi: patients with brain metastases: phase III trial NRG Durvalumab, with or without tremelimumab, plus
10.1001/jamaoncol.2018.5335 Oncology CC001. J Clin Oncol. 2020;38(10):1019- platinum-etoposide in first-line treatment of
1029. doi:10.1200/JCO.19.02767 extensive-stage small-cell lung cancer: 3-year
41. Doerr F, Stange S, Michel M, et al. Stage I and II overall survival update from CASPIAN. ESMO Open.
small-cell lung cancer-new challenge for surgery. 54. Belderbos JSA, De Ruysscher DKM, De Jaeger 2022;7(2):100408. doi:10.1016/j.esmoop.2022.
Lung. 2022;200(4):505-512. doi:10.1007/s00408- K, et al. Phase 3 randomized trial of prophylactic 100408
022-00549-8 cranial irradiation with or without hippocampus
avoidance in SCLC (NCT01780675). J Thorac Oncol. 65. Rudin CM, Liu SV, Soo RA, et al.
42. Wakeam E, Acuna SA, Leighl NB, et al. Surgery SKYSCRAPER-02: tiragolumab in combination with
versus chemotherapy and radiotherapy for early 2021;16(5):840-849. doi:10.1016/j.jtho.2020.12.024
atezolizumab plus chemotherapy in untreated
and locally advanced small cell lung cancer: 55. Rudin CM, Awad MM, Navarro A, et al; extensive-stage small-cell lung cancer. J Clin Oncol.
a propensity-matched analysis of survival. Lung KEYNOTE-604 Investigators. Pembrolizumab or 2024;42(3):324-335. doi:10.1200/JCO.23.01363
Cancer. 2017;109:78-88. doi:10.1016/j.lungcan.2017. placebo plus etoposide and platinum as first-line
04.021 therapy for extensive-stage small-cell lung cancer: 66. Owonikoko TK, Park K, Govindan R, et al.
randomized, double-blind, phase III KEYNOTE-604 Nivolumab and ipilimumab as maintenance therapy
43. Yang CF, Chan DY, Speicher PJ, et al. Role of in extensive-disease small-cell lung cancer:
adjuvant therapy in a population-based cohort of study. J Clin Oncol. 2020;38(21):2369-2379. doi:
10.1200/JCO.20.00793 CheckMate 451. J Clin Oncol. 2021;39(12):1349-1359.
patients with early-stage small-cell lung cancer. doi:10.1200/JCO.20.02212
J Clin Oncol. 2016;34(10):1057-1064. doi:10.1200/ 56. Cheng Y, Han L, Wu L, et al; ASTRUM-005
JCO.2015.63.8171 Study Group. Effect of first-line serplulimab vs 67. Johnson ML, Zvirbule Z, Laktionov K, et al.
placebo added to chemotherapy on survival in Rovalpituzumab tesirine as a maintenance therapy
44. Safavi AH, Mak DY, Boldt RG, Chen H, Louie AV. after first-line platinum-based chemotherapy in
Stereotactic ablative radiotherapy in T1-2N0M0 patients with extensive-stage small cell lung cancer:
the ASTRUM-005 randomized clinical trial. JAMA. patients with extensive-stage-SCLC: results from
small cell lung cancer: a systematic review and the phase 3 MERU Study. J Thorac Oncol. 2021;16
meta-analysis. Lung Cancer. 2021;160:179-186. 2022;328(12):1223-1232. doi:10.1001/jama.2022.
16464 (9):1570-1581. doi:10.1016/j.jtho.2021.03.012
doi:10.1016/j.lungcan.2021.07.007
68. Slotman BJ, van Tinteren H, Praag JO, et al. Use
of thoracic radiotherapy for extensive stage

jama.com (Reprinted) JAMA Published online March 31, 2025 E11

© 2025 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies.
Downloaded from jamanetwork.com by Fudan University, li bai on 04/01/2025
 Clinical Review & Education Review Small Cell Lung Cancer

small-cell lung cancer: a phase 3 randomised 78. Yun T, Kim HT, Han JY, et al. A phase II study of trial. Lancet Oncol. 2009;10(11):1037-1044. doi:10.
controlled trial. Lancet. 2015;385(9962):36-42. weekly paclitaxel plus gemcitabine as a second-line 1016/S1470-2045(09)70263-3
doi:10.1016/S0140-6736(14)61085-0 therapy in patients with metastatic or recurrent 87. Rusthoven CG, Yamamoto M, Bernhardt D,
69. Slotman B, Faivre-Finn C, Kramer G, et al; small cell lung cancer. Cancer Res Treat. 2016;48(2): et al. Evaluation of first-line radiosurgery vs
EORTC Radiation Oncology Group and Lung Cancer 465-472. doi:10.4143/crt.2015.061 whole-brain radiotherapy for small cell lung cancer
Group. Prophylactic cranial irradiation in extensive 79. Gelsomino F, Tiseo M, Barbieri F, et al. Phase 2 brain metastases: the FIRE-SCLC cohort study.
small-cell lung cancer. N Engl J Med. 2007;357(7): study of NAB-paclitaxel in sensitive and refractory JAMA Oncol. 2020;6(7):1028-1037. doi:10.1001/
664-672. doi:10.1056/NEJMoa071780 relapsed small cell lung cancer (SCLC) (NABSTER jamaoncol.2020.1271
70. Takahashi T, Yamanaka T, Seto T, et al. trial). Br J Cancer. 2020;123(1):26-32. doi:10.1038/ 88. Gaebe K, Li AY, Park A, et al. Stereotactic
Prophylactic cranial irradiation versus observation s41416-020-0845-3 radiosurgery versus whole brain radiotherapy in
in patients with extensive-disease small-cell lung 80. Ikeda N, Arai R, Soda S, et al. Carboplatin plus patients with intracranial metastatic disease and
cancer: a multicentre, randomised, open-label, nab-paclitaxel for recurrent small cell lung cancer: small-cell lung cancer: a systematic review and
phase 3 trial. Lancet Oncol. 2017;18(5):663-671. doi: a phase II study. Thorac Cancer. 2022;13(9):1342- meta-analysis. Lancet Oncol. 2022;23(7):931-939.
10.1016/S1470-2045(17)30230-9 1348. doi:10.1111/1759-7714.14394 doi:10.1016/S1470-2045(22)00271-6
71. O’Brien ME, Ciuleanu TE, Tsekov H, et al. 81. Pietanza MC, Waqar SN, Krug LM, et al. 89. Reck M, Dziadziuszko R, Sugawara S, et al.
Phase III trial comparing supportive care alone with Randomized, double-blind, phase II study of Five-year survival in patients with extensive-stage
supportive care with oral topotecan in patients with temozolomide in combination with either veliparib small cell lung cancer treated with atezolizumab in
relapsed small-cell lung cancer. J Clin Oncol. 2006; or placebo in patients with relapsed-sensitive or the phase III IMpower133 study and the phase III
24(34):5441-5447. doi:10.1200/JCO.2006.06.5821 refractory small-cell lung cancer. J Clin Oncol. 2018; IMbrella A extension study. Lung Cancer. 2024;196:
72. George J, Maas L, Abedpour N, et al. 36(23):2386-2394. doi:10.1200/JCO.2018.77.7672 107924. doi:10.1016/j.lungcan.2024.107924
Evolutionary trajectories of small cell lung cancer 82. Wiedemeyer WR, Gavrilyuk J, Schammel A, 90. Wright K, Digby GC, Gyawali B, et al. Malignant
under therapy. Nature. 2024;627(8005):880-889. et al. ABBV-011, a novel, calicheamicin-based superior vena cava syndrome: a scoping review.
doi:10.1038/s41586-024-07177-7 antibody-drug conjugate, targets SEZ6 to eradicate J Thorac Oncol. 2023;18(10):1268-1276. doi:10.1016/
73. Subbiah V, Paz-Ares L, Besse B, et al. Antitumor small cell lung cancer tumors. Mol Cancer Ther. j.jtho.2023.04.019
activity of lurbinectedin in second-line small cell 2022;21(6):986-998. doi:10.1158/1535-7163.MCT-21- 91. Oh SJ, Shcherbakova N, Kostera-Pruszczyk A,
lung cancer patients who are candidates for 0851 et al; LEMS Study Group. Amifampridine phosphate
re-challenge with the first-line treatment. Lung 83. Morgensztern D, Ready N, Johnson ML, et al. (Firdapse) is effective and safe in a phase 3 clinical
Cancer. 2020;150:90-96. doi:10.1016/j.lungcan. A phase I first-in-human study of ABBV-011, trial in LEMS. Muscle Nerve. 2016;53(5):717-725.
2020.10.003 a seizure-related homolog protein 6-targeting doi:10.1002/mus.25070
74. Horita N, Yamamoto M, Sato T, et al. Topotecan antibody-drug conjugate, in patients with small cell 92. Ferrarotto R, Anderson I, Medgyasszay B, et al.
for relapsed small-cell lung cancer: systematic lung cancer. Clin Cancer Res. 2024;30(22):5042- Trilaciclib prior to chemotherapy reduces the usage
review and meta-analysis of 1347 patients. Sci Rep. 5052. doi:10.1158/1078-0432.CCR-24-1547 of supportive care interventions for
2015;5:15437. doi:10.1038/srep15437 84. Fabrizio FP, Muscarella LA, Rossi A. chemotherapy-induced myelosuppression in
75. Kondo R, Watanabe S, Shoji S, et al. A phase II B7-H3/CD276 and small-cell lung cancer: what’s patients with small cell lung cancer: Pooled analysis
study of irinotecan for patients with previously new? Transl Oncol. 2024;39:101801. doi:10.1016/j. of three randomized phase 2 trials. Cancer Med.
treated small-cell lung cancer. Oncology. 2018;94 tranon.2023.101801 2021;10(17):5748-5756. doi:10.1002/cam4.4089
(4):223-232. doi:10.1159/000486622 85. Nguyen EM, Taniguchi H, Chan JM, et al. 93. Temel JS, Greer JA, Muzikansky A, et al. Early
76. Edelman MJ, Dvorkin M, Laktionov K, et al; Targeting lysine-specific demethylase 1 rescues palliative care for patients with metastatic
DISTINCT Study Investigators. Randomized phase 3 major histocompatibility complex class I antigen non-small-cell lung cancer. N Engl J Med. 2010;363
study of the anti-disialoganglioside antibody presentation and overcomes programmed (8):733-742. doi:10.1056/NEJMoa1000678
dinutuximab and irinotecan vs irinotecan or death-ligand 1 blockade resistance in SCLC. J Thorac 94. Cella D, Eton DT, Fairclough DL, et al. What is
topotecan for second-line treatment of small cell Oncol. 2022;17(8):1014-1031. doi:10.1016/j.jtho. a clinically meaningful change on the Functional
lung cancer. Lung Cancer. 2022;166:135-142. doi:10. 2022.05.014 Assessment of Cancer Therapy-Lung (FACT-L)
1016/j.lungcan.2022.03.003 86. Chang EL, Wefel JS, Hess KR, et al. questionnaire? results from Eastern Cooperative
77. Paz-Ares L, Spigel DR, Chen Y, et al. RESILIENT Neurocognition in patients with brain metastases Oncology Group (ECOG) Study 5592. J Clin Epidemiol.
part 1: a phase 2 dose-exploration and treated with radiosurgery or radiosurgery plus 2002;55(3):285-295. doi:10.1016/S0895-4356(01)
dose-expansion study of second-line liposomal whole-brain irradiation: a randomised controlled 00477-2
irinotecan in adults with small cell lung cancer. Cancer.
2022;128(9):1801-1811. doi:10.1002/cncr.34123

E12 JAMA Published online March 31, 2025 (Reprinted) jama.com

© 2025 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies.
Downloaded from jamanetwork.com by Fudan University, li bai on 04/01/2025