FOLFIRI-3: A New Second-Line Regimen for Advanced Colon Cancer

Abstract & Commentary

By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.

Synopsis: Optimal second-line therapy for patients with metastatic colorectal cancer who were initially treated with FOLFOX has yet to be established. In this phase II multicenter French trial, a new iteration of FOLFIRI (FOLFIRI-3) was introduced and its efficacy and safety were examined in 65 patients who had initially been treated with the FOLFOX regimen. There was a 23% objective response rate and a median progression-free survival of 4.7 months observed; parameters that compare favorably with other second-line regimens. Toxicity included diarrhea and neutropenia, but these were less frequently observed than with FOLFIRI-2 used in a similar setting. Thus, FOLFIRI-3 is a promising regimen for patients with advanced colorectal cancer, particularly in the setting of progression after 5FU/LV or FOLOFOX.

Source: Mabro M, et al. A phase II study of FOLFIRI-3 (double infusion of irinotecan combined with LV5FU) after FOLFOX in advanced colorectal cancer patients. Br J Cancer. 2006;94:1287-1292.

Treatment of metastatic colorectal cancer has evolved over the past 2 decades with the introduction of such agents as irinotecan, oxaliplatin, bevacizumab, and cetuximab. In a recently published large, phase III study, FOLFOX4 achieved better response rate, progression-free survival and overall survival than the irinotecan-based IFL regimen as first-line treatment for metastatic colorectal cancer.1 Although irinotecan has definite activity against colorectal cancer, there are limited data about irinotecan-based treatment in those previously treated with FOLFOX. Accordingly, Mabro and colleagues throughout France designed FOLFIRI-3 and conducted a phase II study to establish its efficacy and safety in advanced colorectal cancer patients previously treated with FOLFOX.

FOLFIRI-3 consisted of irinotecan 100 mg/m2 as a 60-minute infusion on day 1 running concurrently with leucovorin 200 mg/m2 as a 2-hour infusion on day 1, followed by 46-hour continuous infusion of 5-fluorouracil (5FU) 2000 mg/m2, and irinotecan 100 mg/m2 repeated on day 3 (upon the completion of the 5FU infusion. The regimen was scheduled every 2 weeks).

Sixty-five patients entered the study. The intent-to-treat objective response rate was 23% (95% CI, 13-33%). Disease was stable in 37% of patients, progressed in 26% and was not assessable in 14%. From the start of FOLFIRI-3, median progression-free survival was 4.7 months and median overall survival 10.5 months. Main toxicities were grade 3-4 diarrhea (23%), and grade 4 neutropenia (11%).


There have been several phase II and III studies that have established evidence for efficacy of irinotecan after 5FU failure.2-5 Additional studies, such as recently reported by Seymour and colleagues6 have shown that adding 5FU with leucovorin results in enhancement (albeit, minor) with regard to response rate and overall survival in patients previously treated with 5FU. However, until the current study, there was limited data demonstrating efficacy in patients previously treated with FOLFOX. For patients that received first-line 5FU and second-line FOLFOX4, single-agent irinotecan achieved a 4% response rate and progression-free survival of 2.7 months.6

In the current study the progression-free survival was 4.7 months and the response rate 23%. Furthermore, when comparing response rates and other outcome parameters, FOLFIRI-3 would seem to be more efficacious and less toxic, at least with regard to diarrhea and neutropenia than the earlier renditions of this combination (FOLFIRI, AND FOLFIRI-2). For example, in a similar setting of second-line treatment, FOLFIRI-2 was associated with 31% grade 3-4 diarrhea, 52% neutropenia, and 14% febrile neutropenia.7

Thus, FOLFIRI-3 appears to be a reasonable combination for second-line treatment of metastatic colorectal cancer, particularly when patients receive 5FU/LV or FOLFOX as initial treatment. It remains to be seen, however, how patients who were previously treated with targeted therapies such as bevacizumab or cetuximab will respond to this regimen, or, for that matter, whether the addition of these agents will enhance the FOLFIRI-3 response.


1. Goldberg RM, et al. Scheduling of fluorouracil: a forget-me-not in the jungle of doublets. J Clin Oncol. 2004;22:4-6.

2. Pitot HC, et al. Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol. 1997;15:2910-2919.

3. Van Custem E, et al. Clinical activity and benefit of irinotecan (CPT-11) in patients with colorectal cancer truly resistant to 5-fluorouracil (5-FU). Eur J Cancer. 1999;35:54-59.

4. Cunningham D, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998;352:1413-1418.

5. Rougier P, et al. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet. 1998;352:1407-1412; Erratum in: Lancet. 1998;352:1634.

6. Rowland KM, et al. Proc Am Soc Clin Oncol. 2005;24;3519a (abstract).

7. Mabro M, et al. Bimonthly leucovorin, infusion 5-fluorouracil, hydroxyurea, and irinotecan (FOLFIRI-2) for pretreated metastatic colorectal cancer. Am J Clin Oncol. 2003;26:254-258.