CPT-11: an original spectrum of clinical activity

Due to its novel mechanism of action, CPT-11 (irinotecan) has significant in vitro activity against a variety of solid tumors, including those particularly resistant to other cytotoxic agents. This activity has been confirmed in clinical trials of single-agent CPT-11 conducted in Japan, Europe, and the United States. In chemotherapy-naive patients with advanced non-small cell lung cancer, a response rate of 32% to 34% has been shown in Japan with CPT-11 monotherapy, although this has been improved to within the range of 43% to 54% using CPT-11 in combination with cisplatin. Prior chemotherapy appears to reduce the response rate substantially in this setting, although the mechanisms of cross-resistance are unknown. CPT-11 is also active in small cell lung cancer, with a single agent response rate of 47% in patients previously treated with cisplatin. As might be expected, CPT-11 is more active when combined with cisplatin as first-line chemotherapy for small cell lung cancer, with Japanese investigators reporting an average response rate of 85%. Consistent results from studies of colorectal cancer in Japan, the United States, and Europe, indicate that CPT-11 is active as a single agent in patients who have developed progressive disease following 5-fluorouracil (5-FU)-based treatment. In patients with metastatic colorectal cancer, approximately 18% to 27% of patients with 5-FU refractory disease and 15% to 32% of patients who are chemotherapy-naive respond to single agent therapy. Efforts to combine CPT-11 with 5-FU with or without folinic acid are ongoing. There is less clinical experience with CPT-11 in the treatment of other solid tumors, but activity has been reported in phase II trials of patients with squamous cell carcinoma of the uterine cervix or skin, and in those with cancer of the ovary, stomach, or pancreas and in patients with lymphoma. While notable objective response rates have been reported for single agent CPT-11, the precise role of this drug in the treatment of patients with solid tumors has yet to be defined, especially as part of first-line therapy. CPT-11 appears to be one of the most exciting new drugs to reach clinical development in the past decade, and its seemingly wide spectrum of clinical activity suggests that it may have a substantial impact on the treatment of many of the most common epithelial malignancies.