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Small-Cell Lung Cancer: Therapeutic Changes

Small-Cell Lung Cancer: Therapeutic Changes

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.)[1] 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.

Chemotherapy

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.[2] 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.[5] 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.[6] 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.

 

Radiotherapy

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.[7] 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.[8] 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.

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