CPT-11 in gastrointestinal cancer

Abstract

Colorectal, gastric and pancreatic cancers are major health problems worldwide. Although surgery is a curative option in 50% of patients with colorectal cancer, it is much less effective in gastric cancer (< 20% of patients) and virtually ineffective in pancreatic cancer. These three cancer types also respond poorly to chemotherapy. CPT-11 (irinotecan), a novel cytotoxic drug, is now available in many countries as a single agent for second-line therapy in metastatic colorectal cancer. The response rate in the pivotal European study of metastatic colorectal cancer patients was 14%, with a median duration of response of 8.5 months. There was also a high rate of disease stabilisation (44%), with a median duration of 4.8 months. Median survival time was 10.4 months. The dose-limiting toxicities (DLT) for CPT-11 are delayed diarrhoea and neutropenia, both of which are schedule dependent and non-cumulative. These encouraging data in second-line therapy support the further study of CPT-11 as first-line therapy for colorectal cancer in combination with other agents. Four Japanese trials of CPT-11 as first- and/or second-line single-agent therapy for advanced gastric cancer report response rates of 18-43%. The median durations for response and survival time in the late phase II trial were 2.3 months and 5.8 months, respectively. These results are in the range of those reported for sequential high-dose methotrexate and 5-fluorouracil (5-FU)/doxorubicin (FAMTX), etoposide/leucovorin/5-FU (ELF) or cisplatin/5-FU therapy in gastric cancer. Data are currently available from five phase II studies of CPT-11 in advanced pancreatic cancer: four Japanese and one European. The response rates ranged from 9 to 19%. The median duration of survival for all treated patients in the European study was 5.2 months. CPT-11 in combination with 5-FU is currently being investigated in Japan, the U.S.A. and Europe in patients with gastrointestinal tumours. CPT-11 is also being evaluated in combination with each of the following agents: oxaliplatin, docetaxel, raltitrexed, etoposide and mitomycin C. Japanese studies of CPT-11 plus cisplatin in patients with gastric cancer have produced response rates of 48-59%. These encouraging data highlight the potential for CPT-11 in combination therapy for gastrointestinal tumours.