CPT-11 in the treatment of small-cell lung cancer

Abstract

Small cell lung cancer is extremely sensitive to chemotherapy. Etoposide, a topoisomerase II inhibitor, is one of the most active single agents in chemotherapy, with a 45% response rate as a single agent. Polychemotherapy regimens which include etoposide can be expected to increase responses to 70% to 90% of cases. Despite these high response rates, however, median survival for patients with SCLC is only 9 to 12 months, and over 90% of patients will die of the disease. Identification of new, more active drugs is clearly crucial. CPT-I 1, a derivative of Camptothecin, which inhibits DNA topoisomerase I, has shown a significant antineoplastic activity in a broad spectrum of experimental tumor models. CPT-11 has also been found to be active in leukemia, lymphoma, SCLC, non-small cell lung cancer, colorectal cancer, ovarian cancer, and cervical cancer. CPT-11 has also demonstrated schedule-dependent antitumor activity and toxicity in preclinical animal models. On this basis, we carried out a phase I study and a phase II study of CPT-11 given as a single weekly intravenous infusion to patients with SCLC. In a phase II study of SCLC with conducted by a multicenter lung cancer study group (l), of 35 assessable patients, 2 achieved a complete response (CR) and 11 attained a parial response (PR), resulting in an overall response rate of 37%. The response rate for the 27 previously treated patients was 33%, and 50% in the 8 previously untreated patients. The median duration of survival was 3.5 weeks for all patients and 28 weeks for those with extensive disease (ED). The major toxicities were leukopenia and diarrhea. Grade 3-4 leukopenia affected 31% of the patients and grade 3 or 4 diarrhea occurred in 15%, being persistent in some patients. In a phase II study in previously treated patients with SCLC by Masuda et al (2), 7 patients had a PR (47%) and none a CR in the 15 assessable patients. The median survival time in the 15 assessable patients was 26.7 weeks. In this study, the most frequent toxicity was myelosuppression, and 33% developed severe leukopenia (WHO ? 3 grade), whereas 20% had grade 3 anemia. Diarrhea developed in one patient (7%) and grade > 3 pulmonary toxicity was observed in 2 patients (13%). A phase II study of CPT-11 (SO-SO mg/m’, days 1, 8 & 15) and cisplatin (60 mg/m*, day 1) in patients with previously untreated SCLC was conducted by a multicenter lung cancer study group (3). The response rates were 78% (4 CR & 10 PR) in 18 limited disease patients and 79% (3 CR & 8 PR) in the 14 extensive disease patients. Median survival time has not yet been reached. The common toxicities were leukopenia (grade 3 3, 46%), and 15% had grade 2 3 diarrhea. In a phase II study of CPT-11 (60 mg/m*, days 1, 8, & 15) and cisplatin (60 mg/m*, day 1) in 15 patients with previously treated SCLC, objective response was observed in 14. Of the 15 assessable patients, 5 (33%) had a PR and the median survival duration was over 150 days. To evaluate whether the effect of CPT-11 combined with cisplatin can improve the outcome of the chemotherapy in SCLC, we were conducting a phase Ill study of CPT-11 and cisplatin versus cisplatin and etoposide in previously untreated patients with ED SCLC by a multicenter lung cancer study group.