Limited stage small cell lung cancer: Initial management
- Elizabeth H Baldini, MD, MPH
Elizabeth H Baldini, MD, MPH
- Associate Professor of Radiation Oncology
- Harvard Medical School
- Gregory P Kalemkerian, MD
Gregory P Kalemkerian, MD
- Professor of Medicine
- Co-Director, Thoracic Oncology
- University of Michigan Medical Center
- Section Editors
- Rogerio C Lilenbaum, MD, FACP
Rogerio C Lilenbaum, MD, FACP
- Section Editor — Lung Cancer
- Yale Cancer Center
- James R Jett, MD
James R Jett, MD
- Section Editor — Lung Cancer
- Professor of Medicine Emeritus
- National Jewish Health
- Steven E Schild, MD
Steven E Schild, MD
- Section Editor — Radiation Therapy
- Professor of Radiation Oncology
- Mayo Clinic College of Medicine
Small cell lung cancer (SCLC) is a neuroendocrine tumor that represents about 15 percent of all lung cancers. SCLC occurs predominantly in smokers. (See "Cigarette smoking and other possible risk factors for lung cancer".)
SCLC is distinguished from non-small cell lung cancer (NSCLC) by its rapid doubling time and high growth fraction, and the early development of metastases. SCLC usually presents with disseminated disease, and treatment strategies have focused on systemic therapy. For patients with limited stage disease, treatment also includes radiation therapy directed toward thoracic disease, as well as prophylactic treatment of the brain.
The initial management of patients with limited stage SCLC is reviewed here. Related topics include:
- Cohen MH, Ihde DC, Bunn PA Jr, et al. Cyclic alternating combination chemotherapy for small cell bronchogenic carcinoma. Cancer Treat Rep 1979; 63:163.
- Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992; 327:1618.
- Warde P, Payne D. Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 1992; 10:890.
- Gaspar LE, Gay EG, Crawford J, et al. Limited-stage small-cell lung cancer (stages I-III): observations from the National Cancer Data Base. Clin Lung Cancer 2005; 6:355.
- Jänne PA, Freidlin B, Saxman S, et al. Twenty-five years of clinical research for patients with limited-stage small cell lung carcinoma in North America. Cancer 2002; 95:1528.
- Evans WK, Shepherd FA, Feld R, et al. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol 1985; 3:1471.
- Fukuoka M, Furuse K, Saijo N, et al. Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer. J Natl Cancer Inst 1991; 83:855.
- Sundstrøm S, Bremnes RM, Kaasa S, et al. Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years' follow-up. J Clin Oncol 2002; 20:4665.
- Pujol JL, Carestia L, Daurès JP. Is there a case for cisplatin in the treatment of small-cell lung cancer? A meta-analysis of randomized trials of a cisplatin-containing regimen versus a regimen without this alkylating agent. Br J Cancer 2000; 83:8.
- Mascaux C, Paesmans M, Berghmans T, et al. A systematic review of the role of etoposide and cisplatin in the chemotherapy of small cell lung cancer with methodology assessment and meta-analysis. Lung Cancer 2000; 30:23.
- Rossi A, Di Maio M, Chiodini P, et al. Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. J Clin Oncol 2012; 30:1692.
- Skarlos DV, Samantas E, Kosmidis P, et al. Randomized comparison of etoposide-cisplatin vs. etoposide-carboplatin and irradiation in small-cell lung cancer. A Hellenic Co-operative Oncology Group study. Ann Oncol 1994; 5:601.
- Lee SM, James LE, Qian W, et al. Comparison of gemcitabine and carboplatin versus cisplatin and etoposide for patients with poor-prognosis small cell lung cancer. Thorax 2009; 64:75.
- Kubota K, Hida T, Ishikura S, et al. Etoposide and cisplatin versus irinotecan and cisplatin in patients with limited-stage small-cell lung cancer treated with etoposide and cisplatin plus concurrent accelerated hyperfractionated thoracic radiotherapy (JCOG0202): a randomised phase 3 study. Lancet Oncol 2014; 15:106.
- Reck M, von Pawel J, Macha HN, et al. Randomized phase III trial of paclitaxel, etoposide, and carboplatin versus carboplatin, etoposide, and vincristine in patients with small-cell lung cancer. J Natl Cancer Inst 2003; 95:1118.
- Levitan N, Dowlati A, Shina D, et al. Multi-institutional phase I/II trial of paclitaxel, cisplatin, and etoposide with concurrent radiation for limited-stage small-cell lung carcinoma. J Clin Oncol 2000; 18:1102.
- Ettinger DS, Berkey BA, Abrams RA, et al. Study of paclitaxel, etoposide, and cisplatin chemotherapy combined with twice-daily thoracic radiotherapy for patients with limited-stage small-cell lung cancer: a Radiation Therapy Oncology Group 9609 phase II study. J Clin Oncol 2005; 23:4991.
- Horn L, Bernardo P, Sandler A, et al. A phase II study of paclitaxel + etoposide + cisplatin + concurrent radiation therapy for previously untreated limited stage small cell lung cancer (E2596): a trial of the Eastern Cooperative Oncology Group. J Thorac Oncol 2009; 4:527.
- Hainsworth JD, Gray JR, Stroup SL, et al. Paclitaxel, carboplatin, and extended-schedule etoposide in the treatment of small-cell lung cancer: comparison of sequential phase II trials using different dose-intensities. J Clin Oncol 1997; 15:3464.
- Baas P, Belderbos JS, Senan S, et al. Concurrent chemotherapy (carboplatin, paclitaxel, etoposide) and involved-field radiotherapy in limited stage small cell lung cancer: a Dutch multicenter phase II study. Br J Cancer 2006; 94:625.
- Le QT, Moon J, Redman M, et al. Phase II study of tirapazamine, cisplatin, and etoposide and concurrent thoracic radiotherapy for limited-stage small-cell lung cancer: SWOG 0222. J Clin Oncol 2009; 27:3014.
- Lee SM, Woll PJ, Rudd R, et al. Anti-angiogenic therapy using thalidomide combined with chemotherapy in small cell lung cancer: a randomized, double-blind, placebo-controlled trial. J Natl Cancer Inst 2009; 101:1049.
- Arnold AM, Seymour L, Smylie M, et al. Phase II study of vandetanib or placebo in small-cell lung cancer patients after complete or partial response to induction chemotherapy with or without radiation therapy: National Cancer Institute of Canada Clinical Trials Group Study BR.20. J Clin Oncol 2007; 25:4278.
- Spigel DR, Hainsworth JD, Yardley DA, et al. Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab. J Clin Oncol 2010; 28:43.
- Shepherd FA, Giaccone G, Seymour L, et al. Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group and the European Organization for Research and Treatment of Cancer. J Clin Oncol 2002; 20:4434.
- Rigas JR, Denham CA, Rinaldi DA, et al. Randomized, placebo-controlled trials of the matrix metalloproteinase inhibitor BAY12-9566 as adjuvant therapy for patients with small cell and non-small cell lung cancer. Proc ASCO 2003; 22:628.
- McClay EF, Bogart J, Herndon JE 2nd, et al. A phase III trial evaluating the combination of cisplatin, etoposide, and radiation therapy with or without tamoxifen in patients with limited-stage small cell lung cancer: Cancer and Leukemia Group B Study (9235). Am J Clin Oncol 2005; 28:81.
- Giaccone G, Debruyne C, Felip E, et al. Phase III study of adjuvant vaccination with Bec2/bacille Calmette-Guerin in responding patients with limited-disease small-cell lung cancer (European Organisation for Research and Treatment of Cancer 08971-08971B; Silva Study). J Clin Oncol 2005; 23:6854.
- Corso CD, Rutter CE, Park HS, et al. Role of Chemoradiotherapy in Elderly Patients With Limited-Stage Small-Cell Lung Cancer. J Clin Oncol 2015; 33:4240.
- Choi NC, Carey RW. Importance of radiation dose in achieving improved loco-regional tumor control in limited stage small-cell lung carcinoma: an update. Int J Radiat Oncol Biol Phys 1989; 17:307.
- Papac RJ, Son Y, Bien R, et al. Improved local control of thoracic disease in small cell lung cancer with higher dose thoracic irradiation and cyclic chemotherapy. Int J Radiat Oncol Biol Phys 1987; 13:993.
- Choi NC, Herndon JE 2nd, Rosenman J, et al. Phase I study to determine the maximum-tolerated dose of radiation in standard daily and hyperfractionated-accelerated twice-daily radiation schedules with concurrent chemotherapy for limited-stage small-cell lung cancer. J Clin Oncol 1998; 16:3528.
- Bogart JA, Herndon JE 2nd, Lyss AP, et al. 70 Gy thoracic radiotherapy is feasible concurrent with chemotherapy for limited-stage small-cell lung cancer: analysis of Cancer and Leukemia Group B study 39808. Int J Radiat Oncol Biol Phys 2004; 59:460.
- Kies MS, Mira JG, Crowley JJ, et al. Multimodal therapy for limited small-cell lung cancer: a randomized study of induction combination chemotherapy with or without thoracic radiation in complete responders; and with wide-field versus reduced-field radiation in partial responders: a Southwest Oncology Group Study. J Clin Oncol 1987; 5:592.
- Liengswangwong V, Bonner JA, Shaw EG, et al. Limited-stage small-cell lung cancer: patterns of intrathoracic recurrence and the implications for thoracic radiotherapy. J Clin Oncol 1994; 12:496.
- Bonner JA, Sloan JA, Shanahan TG, et al. Phase III comparison of twice-daily split-course irradiation versus once-daily irradiation for patients with limited stage small-cell lung carcinoma. J Clin Oncol 1999; 17:2681.
- De Ruysscher D, Bremer RH, Koppe F, et al. Omission of elective node irradiation on basis of CT-scans in patients with limited disease small cell lung cancer: a phase II trial. Radiother Oncol 2006; 80:307.
- van Loon J, De Ruysscher D, Wanders R, 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; 77:329.
- Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999; 340:265.
- Takada M, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 2002; 20:3054.
- Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S. Initial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small-cell lung cancer: a randomized study. J Clin Oncol 1997; 15:893.
- Schild SE, Bonner JA, Shanahan TG, 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; 59:943.
- Turrisi AT 3rd, Glover DJ, Mason BA. A preliminary report: concurrent twice-daily radiotherapy plus platinum-etoposide chemotherapy for limited small cell lung cancer. Int J Radiat Oncol Biol Phys 1988; 15:183.
- Johnson BE, Salem C, Nesbitt J, et al. Limited stage small cell lung cancer treated with concurrent hyperfractionated chest radiotherapy and etoposide/cisplatin. Lung Cancer 1993; 9:S21.
- Armstrong JG, Rosenstein MM, Kris MG, et al. Twice daily thoracic irradiation for limited small cell lung cancer. Int J Radiat Oncol Biol Phys 1991; 21:1269.
- Johnson DH, Turrisi AT, Chang AY, et al. Alternating chemotherapy and twice-daily thoracic radiotherapy in limited-stage small-cell lung cancer: a pilot study of the Eastern Cooperative Oncology Group. J Clin Oncol 1993; 11:879.
- Mornex F, Trillet V, Chauvin F, et al. Hyperfractionated radiotherapy alternating with multidrug chemotherapy in the treatment of limited small cell lung cancer (SCLC). Groupe Lyonnais d'Oncologie Thoracique. Int J Radiat Oncol Biol Phys 1990; 19:23.
- Sloan JA, Bonner JA, Hillman SL, et al. A quality-adjusted reanalysis of a Phase III trial comparing once-daily thoracic radiation vs. twice-daily thoracic radiation in patients with limited-stage small-cell lung cancer(1). Int J Radiat Oncol Biol Phys 2002; 52:371.
- Perry MC, Eaton WL, Propert KJ, et al. Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med 1987; 316:912.
- Bunn PA Jr, Lichter AS, Makuch RW, et al. Chemotherapy alone or chemotherapy with chest radiation therapy in limited stage small cell lung cancer. A prospective, randomized trial. Ann Intern Med 1987; 106:655.
- Perez CA, Einhorn L, Oldham RK, et al. Randomized trial of radiotherapy to the thorax in limited small-cell carcinoma of the lung treated with multiagent chemotherapy and elective brain irradiation: a preliminary report. J Clin Oncol 1984; 2:1200.
- Rosenthal S, Tattersall MH, Fox RM, et al. Adjuvant thoracic radiotherapy in small cell lung cancer: Ten year follow-up of a randomized study. Lung Cancer 1991; 7:235.
- Gregor A, Drings P, Burghouts J, et al. Randomized trial of alternating versus sequential radiotherapy/chemotherapy in limited-disease patients with small-cell lung cancer: a European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group Study. J Clin Oncol 1997; 15:2840.
- Perry MC, Herndon JE 3rd, Eaton WL, Green MR. Thoracic radiation therapy added to chemotherapy for small-cell lung cancer: an update of Cancer and Leukemia Group B Study 8083. J Clin Oncol 1998; 16:2466.
- Murray N, Coy P, Pater JL, et al. Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1993; 11:336.
- Spiro SG, James LE, Rudd RM, et al. Early compared with late radiotherapy in combined modality treatment for limited disease small-cell lung cancer: a London Lung Cancer Group multicenter randomized clinical trial and meta-analysis. J Clin Oncol 2006; 24:3823.
- Skarlos DV, Samantas E, Briassoulis E, et al. Randomized comparison of early versus late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-cell lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology Group (HeCOG). Ann Oncol 2001; 12:1231.
- Work E, Nielsen OS, Bentzen SM, et al. Randomized study of initial versus late chest irradiation combined with chemotherapy in limited-stage small-cell lung cancer. Aarhus Lung Cancer Group. J Clin Oncol 1997; 15:3030.
- Pijls-Johannesma MC, De Ruysscher D, Lambin P, et al. Early versus late chest radiotherapy for limited stage small cell lung cancer. Cochrane Database Syst Rev 2005; :CD004700.
- De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al. Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol 2006; 24:1057.
- Fried DB, Morris DE, Poole C, et al. Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol 2004; 22:4837.
- Videtic GM, Fung K, Tomiak AT, et al. Using treatment interruptions to palliate the toxicity from concurrent chemoradiation for limited small cell lung cancer decreases survival and disease control. Lung Cancer 2001; 33:249.
- STAGING AND GENERAL APPROACH TO TREATMENT
- Limited stage disease
- Extensive stage disease
- BENEFIT OF TREATMENT
- Etoposide plus cisplatin
- - Carboplatin versus cisplatin
- Other regimens
- - Irinotecan-containing regimens
- - Paclitaxel-containing regimens
- - Novel agents
- THORACIC RADIATION THERAPY
- Benefit of RT
- Treatment volume
- Fractionation schedule
- - Accelerated hyperfractionation
- - Split course treatment
- PROPHYLACTIC CRANIAL IRRADIATION
- INTEGRATION WITH CHEMOTHERAPY
- Sequential, concurrent, and alternating approaches
- Early versus late thoracic RT
- - Rationale
- - Clinical trials
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS