title: Combined topoisomerase I inhibition for the treatment of metastatic colon cancer.
abstract: The objective of this study was to define the maximally tolerated dose (MTD) and response rate of a combination of two topoisomerase I inhibitors, topotecan and irinotecan, in patients with metastatic colon cancer. Eleven patients, the majority with previously progressive disease on 5-fluorouracil-based regimens, were enrolled onto a phase I/II dose escalation trial utilizing continuous infusion topotecan for 2 weeks and weekly irinotecan x 3 with cycles repeated every 28 days. Dosages of topotecan utilized included 0.2 and 0.25mg/m2/day. Irinotecan was administered at a dose of 62 mg/m2 by i.v. bolus. Patients were followed for toxicity and response. The MTD of the combination of agents was found to be 0.25mg/m2/day for topotecan and 62 mg/m2 for irinotecan. The most common serious toxicities were diarrhea and nausea/vomiting. Only one patient experienced grade III neutropenia. There were no complete or partial responses. However, four patients had prolonged disease stabilization (SD) of up to 324 days and this group remained on protocol therapy for an average of 227 days (p=0.0005 versus patients not achieving SD). We concluded that the MTD for this combination of topoisomerase I inhibitors, given on this particular schedule, has been defined. This combination cannot be recommended as a first- or second-line therapy for patients with metastatic colon cancer based on the responses observed. However, approximately one-third of patients achieved prolonged disease stabilization. Topotecan with irinotecan may be useful as a palliative regimen for a subgroup of colon cancer patients.
authors.affiliation: Division of Hematology/Oncology, University of California, Irvine and Chao Family Comprehensive Cancer Center, Irvine, CA, USA. rholocomb@uci.edu
authors.forename: Randall F
authors.initials: RF
authors.lastname: Holcombe
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Kong
authors.forename: Donna
authors.initials: D
authors.lastname: Wimmer
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D004264:DNA Topoisomerases, Type I / Q000494:pharmacology / Q000627:therapeutic use*; D003967:Diarrhea / Q000139:chemically induced / Q000150:complications; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D000077146:Irinotecan; D020714:Maximum Tolerated Dose; D009325:Nausea / Q000139:chemically induced / Q000150:complications; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D009367:Neoplasm Staging / Q000379:methods; D009503:Neutropenia / Q000139:chemically induced / Q000150:complications; D018579:Patient Selection; D012074:Remission Induction; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced / Q000150:complications
chemical_list: D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D019772:Topotecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin