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Rofecoxib associated with weekly irinotecan and infusional 5-fluorouracil as second-line treatment for metastatic colorectal cancer.

3686 Background:We performed this Phase I -II study to determine the feasibility and activity of a "methronomic" schedule of chemotherapy with weekly irinotecan (CPT 11) and 5-fluorouracil (5-FU) by continuos infusion associated with a selective inhibitor of cyclooxygenase-2 (COX-2) as second-line therapy for advanced colorectal cancer.


METHODS
The patients (pts) had metastatic disease progressing after an oxaliplatin-based chemotherapy, age ≥ 18 to ≤ 75 years, good performance status and measurable lesions. A cycle of treatment consisted of two phases: induction (weeks 1 to 5), with rofecoxib at the oral dose of 50 mg/day combined with intravenous weekly CPT-11 on days 1-8-15-22 and infusional 5-FU at the dose of 200 mg/m2/day for 5 weeks, and maintenance (weeks 6 to 8) with rofecoxib alone. The starting dose of CPT-11 was of 87.5 mg/m2, further dose escalations were by increments of 12.5 mg/m2 per level up to 125 mg/m2.


RESULTS
Fifteen pts have been enrolled in the Phase I study. The dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) were defined by conventional criteria. At the fourth dose level (125 mg/m2) a pt out of the 6 enrolled presented grade 3 reversible diarrhea as one DLT. During the 35 cycles administered, side-effects were moderate, only 7 being complicated by grade 3-4 toxicities. Therefore the dose of the irinotecan of 125 mg/m2 was closen for the Phase II study. Seven of the 15 assessable pts obtained a partial response (46.7%; 95% exact confidence limits: 21 to 71%) with a median duration of 5 months. Thirty-two pts have been enrolled up to now into the Phase II and 26 are evaluable for toxicity and response. No complete response was observed: 11 pts had partial response (42.3 % ) and 10 stable disease (38,5 %). To date, grade 3 diarrhea in 6 pts, grade 3-4 neutropenia in 5 pts, and grade 3 peripheral neuropathy in 1 pt were observed.


CONCLUSIONS
Rofecoxib associated with weekly irinotecan and infusional 5-fluorouracil is a safe and active second line treatment for metastatic colorectal cancer. The recruitment is ongoing. No significant financial relationships to disclose.