MADISON, WisconsinAlthough topotecan (Hycamtin) has clear
activity in small-cell lung cancer, the optimal combinations,
schedule, and route of administration for use of this topoisomerase-I
inhibitor as first-line therapy are yet to be determined, according
to Joan H. Schiller, MD, of the University of Wisconsin Comprehensive
Cancer Center, Madison, Wisconsin.
Further efforts need to be directed at identifying optimal ways
of combining topotecan up front with other cytotoxic agents,
Dr. Schiller said.
As second-line treatment, topotecan is active and well tolerated in
patients with SCLC that relapses 60 days or more after first-line
treatment. But in the first-line setting, topotecan after four cycles
of etoposide (VePesid)/cisplatin (Platinol) does not seem to improve
overall survival, Dr. Schiller explained.
ECOG Phase III Trial
402 patients with previously untreated extensive stage SCLC
completed an Eastern Cooperative Oncology Group (ECOG) phase III
trial (EST 7593) with a two-step chemotherapy protocol (see table).
First, all patients received four cycles of etoposide/cisplatin every
3 weeks. The 223 patients with responses or stable disease were then
randomized to either four cycles of topotecan or observation.
The overall response rate to induction etoposide/cisplatin was 33%,
including 3% complete response and 30% partial response. Additional
responses were noted among patients randomized to topotecan in the
second step, including 2% complete and 5% partial response.
Median survival, however, was 9.5 months for all patients completing
the trial and there was no significant difference in overall survival
from date of randomization to the second part of the trial. Likewise,
there was no significant difference in a variety of quality of life
One variable suggesting a benefit of the additional chemotherapy was
progression-free survival, significantly longer in the
topotecan-treated group (3.4 months vs 2.3 months for the observation
arm, P = .0001).
This result was somewhat surprising. After all, topotecan was
the most active single agent in small-cell lung cancer that ECOG has
ever seen, Dr. Schiller said. Topotecan was shown in another
ECOG trial to have a considerable level of activity in extensive
stage SCLC; of 48 eligible patients, 19 (40%) had a partial response
and an additional 17 patients had stable disease. Median survival was
10 months and 1-year survival was 39 months.
The result was also disappointing in light of the fact that there is
at least a theoretical rationale for why combining a topoisomerase-I
and topoisomerase-II inhibitor would be beneficial in SCLC. Both
topotecan and etoposide are active in the disease, and preclinically,
sequences of topoisomerase-I and topoisomerase-II have had a
synergistic effect on tumors.
Perhaps the problem, Dr. Schiller said, is that there are very little
data to show that so-called maintenance therapy, as
illustrated by the EST 7593 protocol, actually works in SCLC. Indeed,
the chemotherapeutic agent irinotecan (Camptosar), which is also a
topoisomerase-I inhibitor, has shown better activity up front,
combined with cisplatin versus the standard etoposide/cisplatin
Other directions of study may be indicated for topotecan. Maybe
a topoisomerase-II inhibitor (etoposide) followed by a
topoisomerase-I inhibitor (topotecan) is the wrong sequence,
Dr. Schiller said.