Dr. Alan Sandler’s sweeping review of the role of irinotecan(Drug information on irinotecan) (CPT-11, Camptosar) in the treatment of small-cell lung cancer (SCLC) leaves few stones unturned. Some perspective, however, is necessary. To date, with the exception of the Japan Clinical Oncology Group trial, which demonstrated the superiority of irinotecan in combination with cisplatin(Drug information on cisplatin) compared to standard therapy with etoposide(Drug information on etoposide) and cisplatin, no other new platinum agent combination has proven superior to standard therapy in the treatment of extensive SCLC. The Noda study, published recently in the New England Journal of Medicine, has sparked considerable interest and anticipation in the medical oncology community.
Extensive-Stage, Chemonaive SCLC
In a randomized phase III study, Noda and colleagues compared standard etoposide and cisplatin to an experimental regimen of irinotecan and cisplatin, as piloted by Kudoh and others in Japan. The study originally intended to randomize responders secondarily to either observation or radical thoracic radiotherapy (50 Gy in 2-Gy fractions per day × 5 weeks), but this component of the study was abandoned. Updated analyses demonstrated a significant benefit for irinotecan/cisplatin compared to etoposide/cisplatin, with 1- and 2-year survival rates, respectively, of 58.4% and 19.5% for the irinotecan-containing regimen vs 37.7% and 5.2% for the etoposide-containing regimen (P = .0021).
This difference could not be attributed to an imbalance in the delivery of treatment: 69% of those receiving irinotecan/cisplatin tolerated all four cycles, compared to 71% of those receiving etoposide/cisplatin. Also, there was no obvious discrepancy in baseline demographics. As expected, the irinotecan/cisplatin regimen produced significantly more grade 3 or higher diarrhea (16% vs 0%, P = .001) but significantly less neutropenia (66% vs 92%, P = .0002) and grade 3 or higher thrombocytopenia (5% vs 18%, P = .01).
Thus, in Japan, the irinotecan/cisplatin combination has become the standard for comparison in future studies of extensive disease. However, it should be noted that patients over age 70 were excluded, and the study precluded prior radiotherapy. Two separate North American trials alluded to by Dr. Sandlerone ongoing and one plannedwill either refute or corroborate the Japanese results. An intergroup trial will recapitulate the Japanese effort, using identical doses. The other trial employs a more standard 3-week schedule, comparing etoposide (100 mg/m²/d × 3) and cisplatin (80 mg/m² on day 1) to irinotecan (65 mg/m² on days 1 and 8) and cisplatin (30 mg/m² on days 1 and 8) every 3 weeks.
The rationale for this altered schedule of irinotecan and cisplatin is fourfold: (1) elimination of day 15 irinotecan dosing, which was omitted or reduced in 50% of patients enrolled in the Japanese study; (2) symmetrical 3-week schedules for both arms; (3) reduced dose of cisplatin in an effort to reduce toxicity; (4) exploitation of putative cisplatin/irinotecan synergy using a weekly combination schedule. This study employs a 2:1 irinotecan/cisplatin vs etoposide/cisplatin randomization and targets a 50% 1-year and 15% 2-year survival rate for the irinotecan/cisplatin arm vs 37.5% and 7.5%, respectively for the control arm.