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Irinotecan Therapy for Small-Cell Lung Cancer

Irinotecan Therapy for Small-Cell Lung Cancer

Dr. Alan Sandler’s sweeping review of the role of
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
compared to standard therapy with etoposide and cisplatin, no other new platinum
agent combination has proven superior to standard therapy in the treatment of
extensive SCLC.[1] 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,[1] as piloted by Kudoh and others in Japan.[2] 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. Sandler—one
ongoing and one planned—will 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.

Relapsed SCLC

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