Optimal Topotecan Sequence and Combination in First-Line SCLC Treatment Elusive

MADISON, Wisconsin—Although 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

Recently, 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 measures.

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).

Surprising Result

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 combination.

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.