Treatment of Small Cell Lung Cancer: Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

doi:10.1378/chest.12-2363

Chest

Volume 143, Issue 5, Supplement, May 2013, Pages e400S-e419S

https://doi.org/10.1378/chest.12-2363 Get rights and content

Background

Small cell lung cancer (SCLC) is a lethal disease for which there have been only small advances in diagnosis and treatment in the past decade. Our goal was to revise the evidence-based guidelines on staging and best available treatment options.

Methods

A comprehensive literature search covering 2004 to 2011 was conducted in MEDLINE, Embase, and five Cochrane databases using SCLC terms. This was cross-checked with the authors' own literature searches and knowledge of the literature. Results were limited to research in humans and articles written in English.

Results

The staging classification should include both the old Veterans Administration staging classification of limited stage (LS) and extensive stage (ES), as well as the new seventh edition American Joint Committee on Cancer/International Union Against Cancer staging by TNM. The use of PET scanning is likely to improve the accuracy of staging. Surgery is indicated for carefully selected stage I SCLC. LS disease should be treated with concurrent chemoradiotherapy in patients with good performance status. Thoracic radiotherapy should be administered early in the course of treatment, preferably beginning with cycle 1 or 2 of chemotherapy. Chemotherapy should consist of four cycles of a platinum agent and etoposide. ES disease should be treated primarily with chemotherapy consisting of a platinum agent plus etoposide or irinotecan. Prophylactic cranial irradiation prolongs survival in those individuals with both LS and ES disease who achieve a complete or partial response to initial therapy. To date, no molecularly targeted therapy agent has demonstrated proven efficacy against SCLC.

Conclusion

Evidence-based guidelines are provided for the staging and treatment of SCLC. LS-SCLC is treated with curative intent with 20% to 25% 5-year survival. ES-SCLC is initially responsive to standard treatment, but almost always relapses, with virtually no patients surviving for 5 years. Targeted therapies have no proven efficacy against SCLC.

Section snippets

Summary of Recommendations

2.4.1 In patients with small cell lung cancer (SCLC) (proven or suspected), a staging evaluation is recommended consisting of a medical history and physical examination, CBC and comprehensive chemistry panel with renal and hepatic function tests, CT of the chest and abdomen with intravenous contrast or CT scan of the chest extending through the liver and adrenal glands, MRI or CT of the brain, and bone scan (Grade 1B).

2.4.2. In patients with clinically limited-stage (LS)-SCLC, PET imaging is

Methods

To identify relevant studies, a team of research librarians and authors conducted a comprehensive literature search using SCLC terms and an adapted therapy hedge from MEDLINE's Clinical Queries, optimized for sensitivity.⁴ The search was conducted in MEDLINE, Embase, and five Cochrane databases (Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, Health Technology Assessment, and NHS Economic Evaluation Database).

Staging Systems

The Veterans Administration Lung Study Group (VALSG) two-stage classification scheme has been used routinely for the clinical staging of SCLC.⁵ The VALSG system defines LS disease as (1) disease confined to one hemithorax, although local extension may be present; (2) no extrathoracic metastases except for ipsilateral supraclavicular lymph nodes; and (3) primary tumor and regional nodes that can be encompassed adequately in a reasonably safe radiation portal. ES disease is defined as disease

Role of Surgery

A prospective randomized trial comparing surgery and radiotherapy in the 1960s and two subsequent meta-analyses demonstrating the benefits of radiotherapy led to the initial abandonment of surgery in the treatment of SCLC.38, 39, 40 After analyzing two randomized and eight nonrandomized comparative observational studies, the second edition of the ACCP Lung Cancer Guidelines found inadequate objective evidence to categorically support any recommendation regarding surgery for SCLC, although the

Use of RT for SCLC

The use of RT for SCLC can be thought of in terms of TRT, prophylactic cranial irradiation (PCI), and RT used for the palliation of various metastases. RT has long been established as an effective palliative therapy for metastases and thus will not be reviewed here (see the symptom management article of the lung cancer guidelines⁵³).

Use of Chemotherapy for SCLC

Two randomized phase 3 trials evaluated doxorubicin-based chemotherapy compared with platinum-based chemotherapy in SCLC. Baka and associates⁷² enrolled patients with either LS- or ES-SCLC who were randomized to either doxorubicin, cyclophosphamide, and etoposide (ACE) or EP for six cycles. There were no differences in response rates (72% vs 77%) or MST for LS (10.9 months vs 12.6 months) or ES (8.3 months vs 7.5 months). More grade 3/4 neutropenia and infections occurred on the ACE regimen. A

Novel Therapies

Thalidomide, believed to be an antiangiogenic agent, was tested in two trials. In a trial from the United Kingdom, 724 patients with LS (51%) or ES (49%) were randomized to thalidomide, 100 to 200 mg daily for 2 years, or placebo.⁸⁹ All patients received etoposide and carboplatin every 3 weeks for six cycles. The median overall survival was 10.5 months (placebo) and 10.1 months (thalidomide) with an HR of 1.09 (95% CI, 0.93-1.27; P = .28). Among patients with LS disease there was no difference

Second-line Treatment of SCLC

Most patients who present with LS-SCLC and nearly all with ES-SCLC will develop recurrent disease. Patients with recurrent SCLC can be divided into two categories based on the likelihood of response to second-line therapy: refractory/resistant disease (primary progression or recurrence within 3 months of initial therapy) or relapsed/sensitive disease (recurrence > 3 months after initial therapy). Patients with refractory/resistant disease exhibit much lower response rates with second-line

Treatment of SCLC in the Elderly

The definition of “elderly” varies throughout the oncology literature, but most studies, including the majority of those dealing with lung cancer, define elderly as 70 years of age or older. Among patients diagnosed with SCLC, about 43% are ≥ 70 years old and 10% are ≥ 80 years old.¹⁰⁸ Unfortunately, despite the frequent occurrence of SCLC in the elderly, the enrollment of elderly patients in clinical trials is low, and few high-quality, randomized trials have specifically focused on the

Acknowledgments

Author contributions: Dr Jett had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Jett: contributed to the uniform development of the guidelines and contributions from each contributing author and is responsible for the final manuscript.

Dr Schild: contributed to the writing of all sections related to radiotherapy.

Dr Kesler: contributed to the writing of sections related to thoracic surgery.

Dr Kalemkerian:

References (115)

SZ Lewis et al.
Methodology for development of guidelines for lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines
Chest
(2013)
S Cuffe et al.
Characteristics and outcomes of small cell lung cancer patients diagnosed during two lung cancer computed tomographic screening programs in heavy smokers
J Thorac Oncol
(2011)
RA Stahel et al.
Staging and prognostic factors in small cell lung cancer: a consensus report
Lung Cancer
(1989)
P Micke et al.
Staging small cell lung cancer: Veterans Administration Lung Study Group versus International Association for the Study of Lung Cancer—what limits limited disease?
Lung Cancer
(2002)
P Goldstraw et al.
The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumors
J Thorac Oncol
(2007)
FA Shepherd et al.
The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer
J Thorac Oncol
(2007)
E Vallières et al.
The IASLC Lung Cancer Staging Project: proposals regarding the relevance of TNM in the pathologic staging of small cell lung cancer in the forthcoming (seventh) edition of the TNM classification for lung cancer
J Thorac Oncol
(2009)
SH Ignatius Ou et al.
The applicability of the proposed IASLC staging revisions to small cell lung cancer (SCLC) with comparison to the current UICC 6th TNM Edition
J Thorac Oncol
(2009)
R Chin et al.
Whole body FDG-PET for the evaluation and staging of small cell lung cancer: a preliminary study
Lung Cancer
(2002)
BM Fischer 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)

M Vinjamuri et al.

Can positron emission tomography be used as a staging tool for small-cell lung cancer?

Clin Lung Cancer

(2008)

HP Hauber et al.

Positron emission tomography in the staging of small-cell lung cancer : a preliminary study

Chest

(2001)

S Niho et al.

Detection of unsuspected distant metastases and/or regional nodes by FDG-PET [corrected] scan in apparent limited-disease small-cell lung cancer

Lung Cancer

(2007)

J van Loon et al.

Selective nodal irradiation on basis of (18)FDG-PET scans in limited-disease small-cell lung cancer: a prospective study

Int J Radiat Oncol Biol Phys

(2010)

J van Loon et al.

18FDG-PET based radiation planning of mediastinal lymph nodes in limited disease small cell lung cancer changes radiotherapy fields: a planning study

Radiother Oncol

(2008)

BM Fischer et al.

PET/CT imaging in response evaluation of patients with small cell lung cancer

Lung Cancer

(2006)

W Fox et al.

Medical Research Council comparative trial of surgery and radiotherapy for primary treatment of small-celled or oat-celled carcinoma of bronchus. Ten-year follow-up

Lancet

(1973)

GR Simon et al.

Management of small cell lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition)

Chest

(2007)

K Karrer et al.

The importance of surgical and multimodality treatment for small cell bronchial carcinoma

J Thorac Cardiovasc Surg

(1989)

K Osterlind et al.

Influence of surgical resection prior to chemotherapy on the long-term results in small cell lung cancer. A study of 150 operable patients

Eur J Cancer Clin Oncol

(1986)

FA Shepherd et al.

Surgical treatment for limited small-cell lung cancer. The University of Toronto Lung Oncology Group experience

J Thorac Cardiovasc Surg

(1991)

JB Yu et al.

Surveillance epidemiology and end results evaluation of the role of surgery for stage I small cell lung cancer

J Thorac Oncol

(2010)

M Inoue et al.

Results of preoperative mediastinoscopy for small cell lung cancer

Ann Thorac Surg

(2000)

MJ Simoff et al.

Symptom management in patients with lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines

Chest

(2013)

J Wolf et al.

Controlled study of survival of patients with clinically inoperable lung cancer treated with radiation therapy

Am J Med

(1966)

SE Schild et al.

Long-term results of a phase III trial comparing once-daily radiotherapy with twice-daily radiotherapy in limited-stage small-cell lung cancer

Int J Radiat Oncol Biol Phys

(2004)

KK Fu et al.

A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003

Int J Radiat Oncol Biol Phys

(2000)

R Catane et al.

Follow-up neurological evaluation in patients with small cell lung carcinoma treated with prophylactic cranial irradiation and chemotherapy

Int J Radiat Oncol Biol Phys

(1981)

C Le Péchoux et al.

Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial

Lancet Oncol

(2009)

WK de Jong et al.

Phase III study of cyclophosphamide, doxorubicin, and etoposide compared with carboplatin and paclitaxel in patients with extensive disease small-cell lung cancer

Eur J Cancer

(2007)

P Zatloukal et al.

A multicenter international randomized phase III study comparing cisplatin in combination with irinotecan or etoposide in previously untreated small-cell lung cancer patients with extensive disease

Ann Oncol

(2010)

A Schmittel et al.

A German multicenter, randomized phase III trial comparing irinotecan-carboplatin with etoposide-carboplatin as first-line therapy for extensive-disease small-cell lung cancer

Ann Oncol

(2011)

JPSN Lima et al.

Camptothecins compared with etoposide in combination with platinum analog in extensive stage small cell lung cancer: systematic review with meta-analysis

J Thorac Oncol

(2010)

DR Spigel et al.

Phase II trial of irinotecan, carboplatin, and bevacizumab in the treatment of patients with extensive-stage small-cell lung cancer

J Thorac Oncol

(2009)

PE Postmus et al.

Testing the possible non-cross resistance of two equipotent combination chemotherapy regimens against small-cell lung cancer: a phase II study of the EORTC Lung Cancer Cooperative Group

Eur J Cancer

(1993)

JP Sculier et al.

A phase II randomised trial comparing the cisplatin-etoposide combination chemotherapy with or without carboplatin as second-line therapy for small-cell lung cancer

Ann Oncol

(2002)

N Howlander et al.

SEER Cancer Statistics Review, 1975-2008

(2011)

RB Haynes et al.

Optimal search strategies for retrieving scientifically strong studies of treatment from Medline: analytical survey

BMJ

(2005)

M Zelen

Keynote address on biostatistics and data retrieval

Cancer Chemother Rep 3

(1973)

MMH Hochstenbag et al.

Asymptomatic brain metastases (BM) in small cell lung cancer (SCLC): MR-imaging is useful at initial diagnosis

J Neurooncol

(2000)

T Seute et al.

Response of asymptomatic brain metastases from small-cell lung cancer to systemic first-line chemotherapy

J Clin Oncol

(2006)

B Campling et al.

Is bone marrow examination in small-cell lung cancer really necessary?

Ann Intern Med

(1986)

DB Tritz et al.

Bone marrow involvement in small cell lung cancer. Clinical significance and correlation with routine laboratory variables

Cancer

(1989)

N Levitan et al.

The value of the bone scan and bone marrow biopsy staging small cell lung cancer

Cancer

(1985)

I Brink et al.

Impact of [18F]FDG-PET on the primary staging of small-cell lung cancer

Eur J Nucl Med Mol Imaging

(2004)

JD Bradley et al.

Positron emission tomography in limited-stage small-cell lung cancer: a prospective study

J Clin Oncol

(2004)

V Kut et al.

Staging and monitoring of small cell lung cancer using [18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET)

Am J Clin Oncol

(2007)

A Azad et al.

High impact of 18F-FDG-PET on management and prognostic stratification of newly diagnosed small cell lung cancer

Mol Imaging Biol

(2010)

T Schumacher et al.

FDG-PET imaging for the staging and follow-up of small cell lung cancer

Eur J Nucl Med

(2001)

YY Shen et al.

Whole-body ¹⁸F-2-deoxyglucose positron emission tomography in primary staging small cell lung cancer

Anticancer Res

(2002)

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Re-examining prophylactic cranial irradiation in small cell lung cancer: a systematic review and meta-analysis
2024, eClinicalMedicine
Patients with small cell lung cancer (SCLC) are at high risk for brain metastases. Prophylactic cranial irradiation (PCI) is recommended in this population to reduce the incidence of brain metastases and prolong survival. We aimed to assesses the efficacy of PCI in this population in the era of routine brain imaging. To our knowledge, this is the first systematic review and meta-analysis to examine the use among patients who were radiographically confirmed not to have brain metastases after completion of first-line therapy.
In this systematic review and meta-analysis, cohort studies and controlled trials reporting on the use of PCI for patients SCLC were identified in EMBASE, MEDLINE, CENTRAL, and grey literature sources. The literature search was conducted on November 12, 2023. Summary data were extracted. Random-effects meta-analyses pooled hazard ratios (HR) for the primary outcome of overall survival between PCI and no intervention groups. This study is registered with the Open Science Framework, DOI:10.17605/OSF.IO/BC359, and PROSPERO, CRD42021249466.
Of 4318 identified records, 223 were eligible for inclusion. 109 reported on overall survival in formats amenable to meta-analysis; PCI was associated with longer survival in all patients with SCLC (HR 0.59; 95% CI, 0.55–0.63; p < 0.001; n = 56,770 patients), patients with limited stage disease (HR 0.60; 95% CI, 0.55–0.65; p < 0.001; n = 78 studies; n = 27,137 patients), and patients with extensive stage disease (HR 0.59; 95% CI, 0.51–0.70; p < 0.001; n = 28 studies; n = 26,467 patients). Between-study heterogeneity was significant when pooled amongst all studies (I2 = 73.6%; 95% CI 68.4%–77.9%). Subgroup analysis did not reveal sources of heterogeneity. In a subgroup analysis on studies that used magnetic resonance imaging to exclude presence of brain metastases at restaging among all patients, overall survival did not differ significantly between patients who did or did not receive PCI (HR 0.74; 95% CI, 0.52–1.05; p = 0.08; n = 9 studies; n = 1384 patients).
Our findings suggested that administration of PCI is associated with a survival benefit, but not when considering studies that radiographically confirmed absence of brain metastases, suggesting that the survival benefit conferred by PCI might be therapeutic rather than prophylactic.
No funding.
Efficacy and Safety of Anti–Programmed Death-Ligand 1 Monoclonal Antibody Socazolimab With Carboplatin and Etoposide for Extensive-Stage SCLC: Results From the Phase 1b Clinical Trial
2023, JTO Clinical and Research Reports
The study (ClinicalTrials.gov, NCT04346914) is an open label, single-arm, phase 1b clinical trial investigating the safety, tolerability, and efficacy of the recombinant human anti–programmed death-ligand 1 monoclonal antibody socazolimab in combination with carboplatin and etoposide in the first-line treatment of extensive-stage SCLC. Good safety and efficacy were found in previous phase 1 clinical trials of other cancers, such as cervix cancer.
Patients received socazolimab (5 mg/kg) every three weeks until disease progression or physician decision. Carboplatin (area under the curve: 5) was also administered every three weeks and etoposide (100 mg/m²) on days 1, 2, and 3 of the treatment cycle. The primary purpose of the study was safety measured by the Common Terminology Criteria for Adverse Events. Secondary purposes included objective response rate, progression-free survival, duration of response, and overall survival.
From April 15, 2020 (enrollment date), to December 30, 2021 (data cutoff), 20 patients with extensive-stage SCLC were administered with socazolimab, carboplatin, and etoposide. Objective response rate was 70.0% (95% confidence interval [CI]: 45.72%–88.11%). Median progression-free survival was 5.65 months (95% CI: 4.14–6.54), and the median duration of response was 4.29 months (95% CI: 2.76–5.85). Median overall survival was 14.88 months (95% CI: 10.09–not evaluated). The highest incidence of treatment-related adverse events included anemia (100%), decreased neutrophil count (95%), decreased platelet count (95%), and decreased white blood cell count (95%), which occurred during combination therapy. The most common grade 3 or 4 treatment-related adverse events were neutropenia (90%), decreased white blood cell count (65%), decreased platelet count (50%), and anemia (30%), which were also common adverse reactions of chemotherapy. No adverse events leading to death had occurred.
Results revealed that the combination therapy of socazolimab, carboplatin, and etoposide had preliminarily confirmed the safety of socazolimab in the first-line treatment of SCLC combined with EC chemotherapy. Currently, a phase 3, randomized, placebo-controlled trial (ClinicalTrials.gov, NCT04878016) is being conducted with 498 patients.
Hyperfractionated Accelerated Radiotherapy Versus Stereotactic Body Radiotherapy in the Treatment of Limited-Stage Small Cell Lung Cancer: A Matched-Pair Analysis
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Funding/Sponsors: The overall process for the development of these guidelines, including matters pertaining to funding and conflicts of interest, are described in the methodology article.¹ The development of this guideline was supported primarily by the American College of Chest Physicians. The lung cancer guidelines conference was supported in part by a grant from the Lung Cancer Research Foundation. The publication and dissemination of the guidelines was supported in part by a 2009 independent educational grant from Boehringer Ingelheim Pharmaceuticals, Inc.

COI Grids reflecting the conflicts of interest that were current as of the date of the conference and voting are posted in the online supplementary materials.

Disclaimer: American College of Chest Physician guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed at http://dx.doi.org/10.1378/chest.1435S1.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

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Chest

Treatment of Small Cell Lung Cancer: Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

Background

Methods

Results

Conclusion

Section snippets

Summary of Recommendations

Methods

Staging Systems

Role of Surgery

Use of RT for SCLC

Use of Chemotherapy for SCLC

Novel Therapies

Second-line Treatment of SCLC

Treatment of SCLC in the Elderly

Acknowledgments

Chest

J Thorac Oncol

Lung Cancer

Lung Cancer

J Thorac Oncol

J Thorac Oncol

J Thorac Oncol

J Thorac Oncol

Lung Cancer

Ann Oncol

Clin Lung Cancer

Chest

Lung Cancer

Int J Radiat Oncol Biol Phys

Radiother Oncol

Lung Cancer

Lancet

Chest

J Thorac Cardiovasc Surg

Eur J Cancer Clin Oncol

J Thorac Cardiovasc Surg

J Thorac Oncol

Ann Thorac Surg

Chest

Am J Med

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Lancet Oncol

Eur J Cancer

Ann Oncol

Ann Oncol

J Thorac Oncol

J Thorac Oncol

Eur J Cancer

Ann Oncol

SEER Cancer Statistics Review, 1975-2008

Optimal search strategies for retrieving scientifically strong studies of treatment from Medline: analytical survey

BMJ

Keynote address on biostatistics and data retrieval

Cancer Chemother Rep 3

Asymptomatic brain metastases (BM) in small cell lung cancer (SCLC): MR-imaging is useful at initial diagnosis

J Neurooncol

Response of asymptomatic brain metastases from small-cell lung cancer to systemic first-line chemotherapy

J Clin Oncol

Is bone marrow examination in small-cell lung cancer really necessary?

Ann Intern Med

Bone marrow involvement in small cell lung cancer. Clinical significance and correlation with routine laboratory variables

Cancer

The value of the bone scan and bone marrow biopsy staging small cell lung cancer

Cancer

Impact of [18F]FDG-PET on the primary staging of small-cell lung cancer

Eur J Nucl Med Mol Imaging

Positron emission tomography in limited-stage small-cell lung cancer: a prospective study

J Clin Oncol

Staging and monitoring of small cell lung cancer using [18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET)

Am J Clin Oncol

High impact of 18F-FDG-PET on management and prognostic stratification of newly diagnosed small cell lung cancer

Mol Imaging Biol

FDG-PET imaging for the staging and follow-up of small cell lung cancer

Eur J Nucl Med

Whole-body 18F-2-deoxyglucose positron emission tomography in primary staging small cell lung cancer

Anticancer Res

Whole-body ¹⁸F-2-deoxyglucose positron emission tomography in primary staging small cell lung cancer