TOKYO, JapanNew phase III trial data suggest that irinotecan is
one of the most active agents available to treat extensive-disease
small-cell lung cancer, outperforming the standard etoposide
(VePesid)/cisplatin (Platinol) treatment, while causing less myelosuppression.
When given together with cisplatin, irinotecan produced a survival
benefit so significant that the phase III trial was stopped early,
according to Tomohide Tamura, MD, of the National Cancer Center
Hospital in Tokyo.
Based on these results, irinotecan and cisplatin is a new
standard treatment against extensive-stage small-cell lung cancer in
Japan, said Dr. Tamura.
Irinotecan, which works by direct inhibition of topoisomerase-I, is
converted to its active metabolite SN-38, which shows potent activity
in vivo across a wide variety of tumor types.
In the phase III study undertaken by the Japan Clinical Oncology
Group (JCOG 9511), irinotecan/cisplatin over four courses was
compared to etoposide/cisplatin in patients with extensive-stage
small-cell lung cancer. The planned sample size was 230 patients.
Clear Survival Benefit
Results from JCOG 9511, as described at the meeting by Dr. Tamura,
showed a clear survival benefit with the irinotecan/cisplatin
combination, while adverse effects varied between arms, with regard
to both hematologic and nonhematologic toxicity. Notably, there was
less myelosuppression in the irinotecan/cisplatin arm.
At a first prespecified interim analysis in August 1998, survival
difference was not statistically significant. Four months later, the
difference in mean survival time was 411 days for irinotecan plus
cisplatin vs 282 days for etoposide and cisplatin (P =
.00025). At this point the study was stopped. A total of 154 patients
had been enrolled (median age 63); most were male and had performance
As of March 2000, survival in JCOG 9511 was updated. Median survival
time was 390 days vs 287 days in favor of irinotecan/cisplatin (P
= .0021). Survival rates were 58.4% for the irinotecan/cis-platin
group at 1 year vs 37.3% for the etoposide/cisplatin arm, and 18.9%
vs 6.5% at 2 years.
The overall response rate was 85.3% for irinotecan plus cisplatin
(including 2.7% complete response), compared with 67.5% for etoposide
plus cis-platin (including 9.1% complete response).
The most common hematologic toxicity greater than grade 3 was
neutropenia (65% of patients on irinotecan/cisplatin vs 92% on
etoposide/cisplatin), followed by leukopenia (27% for
51% for etoposide/cisplatin). Thrombocytopenia occurred in 5% of
patients on irinotecan/cisplatin vs 18% on the reference treatment.
Regarding nonhematologic toxicities of grade 3 or greater, emesis of
grade 3 was observed in 10 irinotecan/cisplatin patients and 5
etoposide/cisplatin patients. Grade 3/4 diarrhea was seen in 12
irinotecan/cisplatin patients and no etoposide/cisplatin patients.
Dr. Tamura summarized additional irinotecan investigations underway:
A randomized phase II study (JCOG 9902) is evaluating a new
triplet regimen of irinotecan plus etoposide and cisplatin in
patients with extensive disease. The study will compare a weekly and
every-4-week schedule, both of which have already been evaluated in
phase I trials.
JCOG 9903 will look at an initial regimen of concurrent
etoposide/cisplatin plus radiotherapy twice daily, followed by
irinotecan/cisplatin, in patients with limited-stage disease.