Irinotecan Plus Cisplatin Surpasses Previous Combinations in Extensive Small-Cell Lung Cancer

NASHVILLE, Tennessee—Irinotecan (Camptosar)/cisplatin (Platinol) combination therapy was significantly more effective and less toxic than standard etoposide (VePesid)/cisplatin in phase II trials, according to Alan B. Sandler, MD. The combination is now being tested in larger clinical studies. These confirmatory studies will use a 21-day cycle of irinotecan/cisplatin rather than the 28-day cycle used in preliminary studies.

Although small-cell lung cancer (SCLC) is typically quite chemosensitive, most patients relapse and 90% die within 2 years of relapse. "Early metastatic involvement is common, and 60% to 70% of patients present with extensive essentially incurable disease," Dr. Sandler said. He is associate professor of medicine and medical director of thoracic oncology at Vanderbilt University Medical Center in Nashville, Tennessee.

Current Outcomes Dismal

Etoposide has been considered the most active single agent, and most widely used combinations are etoposide based. Dr. Sandler said that outcomes with current standard regimens are dismal, with median overall survival of only 6 to 11 months and 2-year survival of 10% to 20% in patients with extensive disease.

"Prior to 2000, phase III trials in extensive SCLC showed no convincing data that any one regimen was superior," Dr. Sandler said. "Although somewhat longer median survival occurred with etoposide, ifosfamide (Ifex), and cisplatin (VIP), it has not become the standard of care because of the associated toxicity."

Single-Agent Activity

A number of new agents have significant single-agent activity in either first-line or second-line use. Dr. Sandler said that work with irinotecan has been carried forward in combination therapy, mostly in Japan. Kudoh and coworkers reported data on a phase II study of weekly irinotecan plus cisplatin as first-line therapy for patients with either limited or extensive SCLC.

"The most important toxicity was grade 3 or 4 neutropenia, which occurred in nearly 80% of patients. Grade 3 or 4 nausea related to cisplatin occurred in 35%, and grade 3 or 4 diarrhea, which is always at about 15% in lung cancer patients, was seen in 19% of these subjects," Dr. Sandler reported. Results in patients with extensive disease were median survival of 13.0 months and 2-year overall survival of 21.7%.

Phase III Trial

This work was followed by a phase III trial in extensive-disease SCLC comparing irinotecan (60 mg/m² on days 1, 8, and 15) plus cisplatin (60 mg/m² on day 1) to etoposide (100 mg/m² on days 1-3) plus cisplatin (60 mg/m² on day 1). Irinotecan/cisplatin cycles repeated every 4 weeks for 4 cycles. Etoposide/cisplatin cycles repeated every 3 weeks for 4 cycles. Dr. Sandler said that toxicity was significantly worse on the etoposide/cisplatin arm and that the day 15 irinotecan dose was not administered or was reduced in 50% of patients due to toxicity.

The overall response rate was 67% with etoposide/cisplatin vs 89% with irinotecan/cisplatin (P < 0.01). The complete response rate was 13% with etoposide/cisplatin vs 2% with irinotecan/cisplatin. This translated into significantly better progression-free survival for patients treated with irinotecan/cisplatin. Two-year overall survival was 18.9% with irinotecan/cisplatin and 6.5% with etoposide/cisplatin (P = 0.0021). "Fortunately, this was one of those trials where you don’t need a statistician to tell you the difference was highly significant," Dr. Sandler said.

Dr. Sandler and colleagues recently began enrolling patients into a trial comparing irinotecan and cisplatin on a 21-day schedule to etoposide and cisplatin on a similar schedule. The investigators hope this will reduce the "day 15" problem encountered in previous studies. Three hundred patients will be randomized to four cycles of either cisplatin 30 mg/m² on days 1 and 8 plus irinotecan 65 mg/m² on days 1 and 8, or cisplatin 80 mg/m² on day 1 plus etoposide 100 mg/m² on days 1 to 3.