Topoisomerase I inhibitors in the treatment of colorectal cancer

Over the past 10 years, a number of topoisomerase I inhibitors have entered into clinical trials and several of these have been evaluated in phase II and III studies to determine their activity in patients with advanced colorectal cancer. The most extensively studied of these has been irinotecan (CPT-II). In phase II trials in patients with colorectal cancer that was recurrent or refractory to 5-Fluorouracil (5-FU)-based front-line therapy, response rates of 14% to 22% and median survival times of 8 to 10 months have been consistently reported by groups from Japan, Europe, and the United States using a variety of drug administration schedules. Two recently reported phase III trials comparing CPT-II against infusional 5-FU or best supportive care demonstrated that CPT-II confers a survival advantage over either of the two other approaches. In front-line treatment of colorectal cancer, CPT-II produces response rates of 19% to 32% and median survival times of 11 to 12 months, figures quite similar to those achievable with bolus 5-FU and leucovorin. Further evaluation in the front-line setting has concentrated on the integration of CPT-II with 5-FU-based regimens. The role of other topoisomerase I inhibitors in colorectal cancer has been more difficult to characterize. Using a standard daily x 5 schedule, topotecan has little objective activity against relapsed or refractory colorectal cancer. Infusional topotecan appears more promising in the treatment of patients with advanced colorectal cancer. The development of an oral formulation of topotecan may make this approach more feasible and is likely to undergo clinical evaluation in the near future. Phase II evaluation of 9- aminocamptothecin (9-AC) has focused on infusional schedules of varying lengths. Despite this, little antitumor activity has been observed against colorectal cancer. Other topoisomerase I inhibitors, such as DX-8951f and 9- nitrocamptothecin (9-NC, RFS2000), have not been formally tested in phase II trials against colorectal cancer. In summary, extensive evaluation of topoisomerase I inhibitors has identified a significant degree of variability in clinical activity in patients with advanced colorectal cancer. To date, only one topoisomerase I inhibitor, CPT-II, has demonstrated a level of activity sufficient for it to become an integral component of treatment for patients with 5-FU-refractory colorectal cancer. Current and future studies will focus on the development of front-line regimens combining CPT-II and 5- FU for treatment of patients with advanced-stage disease, moving topoisomerase I inhibitors into the adjuvant therapy setting and developing combined modality regimens of surgery, radiation, and topoisomerase I inhibitors for patients with locally advanced colorectal cancer.