Clinical advances with topoisomerase I inhibitors in gastrointestinal malignancies

Phase III studies have shown irinotecan prolongs survival significantly whe n compared with either best supportive care or best infusional 5-fluorourac il (5-FU)-based chemotherapy in patients with 5-FU-resistant colorectal can cer. Phase mi studies are investigating the combination of irinotecan with 5-FU, with thymidylate synthase inhibitors, notably raltitrexed, and with t he oral fluoropyrimidines. Preliminary results suggest irinotecan and ralti trexed can safely be combined in the clinic and that this combination is ac tive. The combination of irinotecan with the oral fluoropyrimidines also ha s produced promising results. A phase I study of irinotecan plus 5-FU/folin ic acid showed high activity in first-line metastatic disease and further t rials using the doses of 80 mg/m(2) irinotecan plus 2 g 5-FU weekly are rec ommended. The combination of irinotecan with the De Gramont 5-FU regimen is feasible and active in patients with 5-FU-resistant metastatic disease. Al ternating exposure to irinotecan and 5-FU may be as active as either treatm ent alone, and has been associated with overall response rates (ORRs) great er than 30% and encouraging median survival. The combination of irinotecan with oxaliplatin is also feasible and levels of response rates are in the r egion of 50% (especially with a 2-weekly administration schedule). In patie nts with advanced gastric cancer (including those with pretreated disease) ORRs of around 50% have been reported following administration of either ci splatin plus irinotecan or cisplatin plus docetaxel. [(C) 1999 Lippincott W illiams & Wilkins.].