Small-cell lung cancer (SCLC) is one of the most aggressive solid tumors. Although its incidence is decreasing and modest improvements in outcome have been observed in the past 3 decades, long-term survival is observed only in approximately 10% of patients with limited disease. (In contrast, the outcome in patients with extensive disease is uniformly fatal.) The review by Drs. Ganti, Zhen, and Kessinger presents an excellent update on current therapeutic options for patients with limited-stage SCLC and provides insights into future clinical research developments. In this commentary, we would like to outline ongoing discussions with regard to challenges in the optimal management and current clinical trials in the disease.
The Japan Clinical Oncology Group (JCOG) reported with great enthusiasm the results of a phase III clinical trial comparing the combination of the topoisomerase I inhibitor irinotecan (Camptosar) and cisplatin (Platinol)—known as IP—to the standard etoposide/cisplatin regimen (EP) in extensive-stage SCLC patients. This trial was terminated after an interim analysis met predefined early-stopping rules favoring the experimental arm with irinotecan. An improvement in median survival from 9.4 to 12.8 months was observed, corresponding to a hazard ratio of 0.60 (95% confidence interval = 0.43-0.83). The results of this trial prompted the integration of irinotecan into chemoradiotherapy protocols in limited-stage SCLC.
Two phase II clinical studies evaluated concurrent radiotherapy (45 Gy twice daily) during the first cycle of EP chemotherapy followed by three cycles of IP.[3,4] Both studies showed acceptable toxicity and encouraging median survivals of 20 and 23 months. In both trials, isolated local relapses were extremely rare, and grade 3/4 esophagitis was noted in less than 10% of patients.
A phase III clinical trial (JCOG 0202) is currently randomizing limited-disease patients after upfront chemoradiotherapy during the first cycle of EP to either continuation of EP (standard arm) or three cycles of IP (experimental arm). Unfortunately, an extensive-disease phase III clinical study conducted in the United States with a slightly different IP schedule did not result in improved survival, compared to the EP regimen. The pharmacogenomic differences between US and Japanese populations are a potential cause of this discrepancy. A polymorphism of the UGT1A1 gene, which encodes a protein involved in irinotecan metabolism, is currently being studied and may account for ethnic differences in irinotecan efficacy.
A similar study of oral topotecan, another topoisomerase inhibitor, was conducted in Europe. In first-line treatment of patients with extensive SCLC, topotecan/cisplatin proved to have efficacy similar to that of the standard EP schedule.
Given the negative results of these phase III trials, evidence for further development of topoisomerase I inhibitors in limited-stage SCLC is less compelling. However, different dosing schedules of these drugs should be investigated before definitive conclusions can be made. Results from a large prospective randomized study of irinotecan/cisplatin vs etoposide/cisplatin in extensive-stage SCLC conducted in Norway will be presented at the 2007 annual meeting of the American Society of Clinical Oncology.
The role of radiation therapy as a means of improving local control and overall survival in the management of limited-stage SCLC was established in the early 1990s. Turrisi et al reported the landmark study of thoracic radiotherapy, showing that twice-daily irradiation to 45 Gy leads to a 10% improvement in the 5-year survival rate, compared to the same dose administered once daily. Twice-daily radiotherapy appears to better counteract accelerated repopulation of clonogenic tumor cells during radiotherapy. The control arm of this study used a dose regarded as suboptimal, and many radiation oncologists in the United States and Europe continue to treat their patients with doses ranging from 60 to 74 Gy using once-daily fractionation. A clinical trial comparing these two approaches is planned.
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Govindan R, Page N, Morgensztern D, et al: Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: Analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 24:4539-4544, 2006.
2. Noda K, Nishiwaki Y, Kawahara M, et al: Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 346:85-91, 2002.
3. Kubota K, Nishiwaki Y, Sugiura T, et al: Pilot study of concurrent etoposide and cisplatin plus accelerated hyperfractionated thoracic radiotherapy followed by irinotecan and cisplatin for limited-stage small cell lung cancer: Japan Clinical Oncology Group 9903. Clin Cancer Res 11:5534-5538, 2005.
4. Saito H, Takada Y, Ichinose Y, et al: Phase II study of etoposide and cisplatin with concurrent twice-daily thoracic radiotherapy followed by irinotecan and cisplatin in patients with limited-disease small-cell lung cancer: West Japan Thoracic Oncology Group 9902. J Clin Oncol 24:5247-5252, 2006.
5. Hanna N, Bunn PA Jr, Langer C, et al: Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 24:2038-2043, 2006.
6. Eckardt JR, von Pawel J, Papai Z, et al: Open-label, multicenter, randomized, phase III study comparing oral topotecan/cisplatin versus etoposide/cisplatin as treatment for chemotherapy-naive patients with extensive-disease small-cell lung cancer. J Clin Oncol 24:2044-2051, 2006.
7. Pignon JP, Arriagada R, Ihde DC, et al: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327:1618-1624, 1992.
8. Turrisi AT III, 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 340:265-271, 1999.
9. 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 94:625-630, 2006.
10. Auperin A, Arriagada R, Pignon JP, et al: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341:476-484, 1999.
11. Kakkar AK, Levine MN, Kadziola Z, et al: Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: The Fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol 22:1944-1948, 2004.
12. Klerk CP, Smorenburg SM, Otten HM, et al: The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 23:2130-2135, 2005.
13. Altinbas M, Coskun HS, Er O, et al: A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost 2:1266-1271, 2004.
14. Redman M, Crowley J: Small randomized trials. J Thorac Oncol 2:1-2, 2007.
15. Pujol JL, Breton J, Gervais M, et al: A prospective randomized phase III, double-blind, placebo controlled study of thalidomide in extended disease SCLC patients after response to chemotherapy: an Intergroup Study FNCLCC Cleo04-IFCT 00-01 (abstract 7057). J Clin Oncol 24(18S):378s, 2006.
16. Dy GK, Miller AA, Mandrekar SJ, et al: A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: A CALGB and NCCTG study. Ann Oncol 16:1811-1816, 2005.
17. Krug LM, Crapanzano JP, Azzoli CG, et al: Imatinib mesylate lacks activity in small cell lung carcinoma expressing c-kit protein: A phase II clinical trial. Cancer 103:2128-2131, 2005.
18. Warshamana-Greene GS, Litz J, Buchdunger E, et al: The insulin-like growth factor-I (IGF-I) receptor kinase inhibitor NVP-ADW742, in combination with STI571, delineates a spectrum of dependence of small cell lung cancer on IGF-I and stem cell factor signaling. Mol Cancer Ther 3:527-535, 2004.