Testing a New Regimen for Metastatic Colorectal Cancer

Abstract & Commentary

By William B. Ershler, MD, Editor

Synopsis: Rather than infusional 5 fluorouracil, the use of capecitabine in combination with irinotecan and oxaliplatin (COI) was explored to establish appropriate dose (of irinotecan) and efficacy in terms of response rate and progression-free survival. Toxicity was primarily gastrointestinal and was manageable with no episodes of severe neutropenia or neutropenic fever and response rates were comparable to published phase II reports of FOLFOXIRI.

Source: Bajetta E, et al. Ann Oncol. 2007;18:1810-1816.

Although there have been significant advances in the management of metastatic colorectal cancer, there remains plenty of room for improvement in terms of response rates and toxicity. Phase II trials combining irinotecan and oxaliplatin concurrently with 5FU infusion (FOLFOXIRI) showed promising activity in the first-line setting, achieving response rates of 58-69%, median time to progression of 10-11 months and overall survival of 22-26 months.1,2 The 5FU infusion, however, is cumbersome, requiring an indwelling central venous catheter and portable infusion pump. Because Capecitabine, an oral fluoropyrimidine pro-drug that achieves tumor-selective generation of 5FU through exploitation of the higher activity of the thymidine phosphorylase enzyme in tumors, compared with healthy tissue3 has the additional advantage of oral formulation, efforts have been made to substitute it for infusional 5FU in newer regimens.4-6 The current report from Milan details one such new regimen utilizing capecitabine, oxaliplatin and irinotecan (COI) in a novel schedule.

The study consisted of a phase I, open-label, dose-finding part followed by a phase II trial. The primary objective was to determine the maximum-tolerated dose (MTD) of irinotecan when administered concurrently with oxaliplatin and Capecitabine in close sequence in a 6-day schedule biweekly. Patients received irinotecan on day 1, oxaliplatin (85 mg/m2) on day 2 and Capecitabine 1000 mg/m2 orally twice daily) on days 2-6 of a biweekly cycle. Three dose levels ranging from 150 to 180 mg/m2 were explored for irinotecan in sequential cohorts of three to six patients. The recommended dose for irinotecan was 180 mg/m2.

A total of 38 patients received a median of six cycles. The majority of patients (76%) completed six or more cycles and early discontinuation due to dose-limiting gastrointestinal toxicity occurred in only two patients. Four patients discontinued therapy to undergo resection of metastases. Toxicity was present but manageable and included diarrhea (grade 3 or 4 in 9 patients [24%]) and nausea (grade 1 or 2 in 6 patients [16%]). Grade 3 or 4 neutropenia did not occur and one patient had grade 3 or 4 thrombocytopenia and another grade 3 or 4 anemia.

Of 27 assessable patients treated at the recommended dose, 17 achieved a partial response (overall response rate [ORR] 63%; 95% confidence interval [CI], 44 to 78%) with a total of eight patients undergoing metastasectomy. Estimated progression-free survival and overall median survival were 8.5 and 23.5 months, respectively.

Commentary

Thus, Bajetta and colleagues have provided an alternative to FOLFOXIRI; one that is both more convenient (two days of intravenous chemotherapy per cycle, compared with one day and a five day infusion) and less myelosuppressive (with no patients experiencing grade 3/4 neutropenia or neutropenic fever). The lack of neutropenia compares favorably with FOLFOXIRI during which severe neutropenia occurs in the majority of treated patients.1,2

Regarding efficacy, it appears that COI is comparable to FOLFOXIRI as well as with FOLFIRI7 in terms of both response rate and progression-free survival. However, to be confident of this would require a randomized trial. Nonetheless, the current data are promising, and the regimen may prove particularly useful for downsizing hepatic colorectal metastases before curative surgery.

References

1. Falcone A, et al. Biweekly chemotherapy with oxaliplatin, irinotecan, infusional Fluorouracil, and leucovorin: a pilot study in patients with metastatic colorectal cancer. J Clin Oncol. 2002;20(19):4006-4014.

2. Souglakos J, et al. Triplet combination with irinotecan plus oxaliplatin plus continuous-infusion fluorouracil and leucovorin as first-line treatment in metastatic colorectal cancer: a multicenter phase II trial. J Clin Oncol. 2002;20(11):2651-2657.

3. Walko CM, Lindley C. Capecitabine: a review. Clin Ther. 2005;27(1):23-44.

4. Cassidy J, et al. XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol. 2004;22(11):2084-91.

5. Koopman M, et al. Randomised study of sequential versus combination chemotherapy with capecitabine, irinotecan and oxaliplatin in advanced colorectal cancer, an interim safety analysis. A Dutch Colorectal Cancer Group (DCCG) phase III study. Ann Oncol. 2006;17(10):1523-1528.

6. Rea DW, et al. A phase I/II and pharmacokinetic study of irinotecan in combination with capecitabine as first-line therapy for advanced colorectal cancer. Ann Oncol. 2005;16(7):1123-1132.

7. Souglakos J, et al. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006;94(6):798-805.