Clinical advances with topoisomerase I inhibitors in gastrointestinal malignancies.

Phase III studies have shown irinotecan prolongs survival significantly when compared with either best supportive care or best infusional 5-fluorouracil (5-FU)-based chemotherapy in patients with 5-FU-resistant colorectal cancer. Phase I/II studies are investigating the combination of irinotecan with 5-FU, with thymidylate synthase inhibitors, notably raltitrexed, and with the oral fluoropyrimidines. Preliminary results suggest irinotecan and raltitrexed can safely be combined in the clinic and that this combination is active. The combination of irinotecan with the oral fluoropyrimidines also has produced promising results. A phase I study of irinotecan plus 5-FU/folinic acid showed high activity in first-line metastatic disease and further trials using the doses of 80 mg/m2 irinotecan plus 2 g 5-FU weekly are recommended. The combination of irinotecan with the De Gramont 5-FU regimen is feasible and active in patients with 5-FU-resistant metastatic disease. Alternating exposure to irinotecan and 5-FU may be as active as either treatment alone, and has been associated with overall response rates (ORRs) greater than 30% and encouraging median survival. The combination of irinotecan with oxaliplatin is also feasible and levels of response rates are in the region of 50% (especially with a 2-weekly administration schedule). In patients with advanced gastric cancer (including those with pretreated disease) ORRs of around 50% have been reported following administration of either cisplatin plus irinotecan or cisplatin plus docetaxel.