Phase I trial of combined irinotecan and oxaliplatin given every three weeks to patients with metastatic colorectal cancer.
BACKGROUND
Both irinotecan and oxaliplatin are active agents in the treatment of patients with metastatic colorectal cancer (MCC). There is a strong preclinical rationale for combining these two agents. We sought to determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of combined irinotecan and oxaliplatin given every three weeks.


METHODS
Cohorts of patients with MCC previously treated with 5-fluorouracil received escalating doses of irinotecan (150, 175, and 200 mg/m(2)) and a fixed dose of oxaliplatin (130 mg/m(2)), both given intravenously every 3 weeks. DLT was evaluated within the first course of treatment. Objective responses were evaluated every two courses and were confirmed at least four weeks later.


RESULTS
Fourteen patients were treated and evaluated for toxicity. The DLT was neutropenia, with or without fever, and delayed recovery of neutrophil counts was frequent (13 courses in six patients). Other toxic effects (peripheral neuropathy, nausea, vomiting, diarrhea, and fatigue) were mild to moderate. Among 13 patients evaluable for activity, four achieved partial responses and nine had stable disease.


CONCLUSIONS
The combination of irinotecan and oxaliplatin is safe and apparently active in the treatment of MCC patients. The recommended dose for phase II studies is 175 mg/m(2) irinotecan plus 130 mg/m(2) oxaliplatin, given every 3 weeks. Neutropenia and delayed recovery of neutrophil counts are the predominant early toxicities with this schedule.
Hoff
Paulo M
PM
Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. phoff@mdanderson.org
Saad
Everardo D
ED
Pazdur
Richard
R
Wolff
Robert
R
Lassere
Yvonne
Y
Bogaard
Karla R
KR
Abbruzzese
James L
JL
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009503:Neutropenia / Q000139:chemically induced; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D016896:Treatment Outcome
D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D002166:Camptothecin