KANAGAWA, JapanAccording to the results of a randomized,
multicenter phase III trial, irinotecan (Camptosar) plus cisplatin
(Platinol) was associated with a highly significant improvement in
survival, with less myelosuppression, in patients with
extensive-disease small-cell lung cancer (SCLC), compared with the
standard therapy of etoposide/cisplatin. The findings were presented
at the 36th Annual Meeting of the American Society of Clinical
The overall response rate was 83% in the irinotecan/cisplatin arm vs
68% in the etoposide/cisplatin arm, said Kazumasa Noda, MD, of the
Kanagawa Cancer Center, Japan. The study was conducted by the Japan
Clinical Oncology Group (JCOG 9511).
Irinotecan/cisplatin every 4 weeks is considered a new standard
treatment regimen against extensive-disease SCLC.
Irinotecan/cisplatin is now being used as a standard regimen in
Japan, Dr. Noda told ONI.
The large difference in survival observed at the first interim
analysis prompted the second interim analysis to be performed earlier
than originally planned. The significant difference in survival
continued at the second interim analysis, done November 19, 1998.
The irinotecan/cisplatin arm was highly superior to the
etoposide/cisplatin arm in overall survival (P = .00025),
Dr. Noda said. This difference triggered early termination of the
In accordance with the recommendation of the independent
monitoring committee, enrollment into this study was terminated in
December 1998, Dr. Noda said. The study, which ended with 154
patients enrolled, had originally planned a sample size of 230 patients.
Much enthusiasm has greeted the Japanese study, and efforts are
underway to replicate its results in North America.
Thats a fabulous study, Alan Sandler, MD, of
Vanderbilt University, said in an ONI interview. It was
a nicely performed study, and it ended early because the results were
so disparate . . . really some of the most amazing results seen for
SCLC. Obviously it needs to be confirmed in other trials.
Two studies are planned to replicate the Japanese study. Dr. Sandler,
together with Paul Bunn, MD, of the University of Colorado Cancer
Center, Denver, is planning to repeat the study using a modified
About 50% of Dr. Nodas patients didnt receive day
15 of irinotecan because of hematologic toxicities, he said.
Were planning on doing a weekly two-out-of-three regimen
[for both platinum and irinotecan] rather than three out of
four. Dr. Sandler hopes to begin enrolling patients by the fall.
In addition, the Southwest Oncology Group (SWOG) is planning a
confirmatory study using doses identical to the regimen Dr. Noda described.
Giuseppe Giaccone, MD, PhD, of Free University Hospital, Amsterdam,
The Netherlands, who commented on Dr. Nodas report at the ASCO
session, expressed a few reservations.
He recommended that a multivariate analysis be performed. He also
recommended that if studies intended to replicate the results find
similarly promising results, they should nevertheless not be
This is extensive-disease SCLC, he said. For 20
years we did not see an improvement in survival with chemotherapy by
changing different cocktails. I wonder whether an interim analysis
should not have looked just simply at safety and response rate and
things like this, and not really have given advice about stopping the
study when a difference in survival is seen before the target accrual
He added, I think the study is clearly interesting but requires
repetition by another group.
Between November 1995 and November 1998, 154 patients were randomized
between the two arms, with 77 patients entered into each arm. The
regimen for the irinotecan/cisplatin arm was irinotecan 60 mg/m²
on days 1, 8, and 15 and cisplatin 60 mg/m² on day 1 every 4
weeks for four cycles. The etoposide/cisplatin arm regimen consisted
of etoposide 100 mg/m² on days 1, 2, and 3 and cisplatin 80
mg/m² on day 1 every 3 weeks for four cycles. Both arms required
hydration and administration of antiemetics and G-CSF (Neupogen) if
necessary until recovery.
The primary endpoint for the study was survival. The complete
remission rate was 2.7% in the irinotecan/cisplatin arm and 9.1% in
the etoposide/cisplatin arm. Partial remission rate was 80.5% in the
and 58.4% in the etoposide/cis-platin arm.
According to updated survival data presented by Dr. Noda at the
conference, median survival and 1-year survival were 390 days and
58.4% in the irinotecan/cisplatin arm vs 287 days and 37.7% in the
The irinotecan/cisplatin regimen is expected to prolong median
survival by up to 40%, compared to the etoposide/cisplatin
regimen, Dr. Noda said.
A difference in hematologic toxicities was seen between the two arms.
JCOG grade 3-4 leukopenia occurred in 27% of the patients in the
irinotecan/cisplatin arm and 52% of patients in the
etoposide/cisplatin arm (P = .003). Grade 3-4 neutropenia
developed in 66% of those in the irinotecan/cisplatin arm vs 92% in
the etoposide/cisplatin arm (P = .0002). Grade 3-4
thrombocytopenia occurred in 5% of patients in the
irinotecan/cisplatin arm and 19% of those in the etoposide/cisplatin
arm (P = .01).
Severe adverse events were observed more frequently in the
irinotecan/cisplatin arm; however, those were not beyond the expected
level, Dr. Noda said.
Except for diarrhea, nonhematologic toxicities occurred with a
similar severity in each arm. Grade 3-4 diarrhea was seen in 16% of
the irinotecan/cisplatin arm and in none of the patients in the
etoposide/cisplatin arm (P = .0001).
Four treatment-related deaths occurred, three in the
irinotecan/cisplatin arm and one in the etoposide/cisplatin arm. Two
deaths in the irinotecan/cisplatin arm were due to infection
accompanied by neutropenia. The third death in the
irinotecan/cisplatin arm was caused by bleeding from the metastatic
site. The death in the etoposide/cisplatin arm was due to pneumonitis.
A second randomization for complete or good partial responders was
also planned. It was designed to compare subsequent radiotherapy with
observation. However the second randomization was terminated
early because of poor accrual, Dr. Noda said. Only 20 patients
had been enrolled, he told ONI.