Background: Combined therapy with irinotecan/fluorouracil/levoleucovorin (calcium levofolinate) [IFL] has lost its position as the standard regimen for metastatic colorectal cancer because its toxicity and effectiveness have become controversial.
Objective: To (i) identify the optimal regimen for IFL therapy in terms of irinotecan dosage, and (ii) determine the maximum tolerated dose and efficacy of the modified-IFL regimen in patients with histologically confirmed advanced colorectal cancer.
Methods: In a phase I study, nine patients with advanced colorectal cancer received IFL treatment modified such that irinotecan was administered every 2 weeks, as opposed to the more toxic once-weekly administration. The study evaluated three escalating dose levels of irinotecan (100,125 and 150 mg/m2). Each treatment cycle consisted of irinotecan on days 1 and 15; fluorouracil 600 mg/m2 on days 1,8, 15 and 22; and levoleucovorin 250 mg/m2 on days 1, 8, 15 and 22. Data from the phase I study were used to determine the recommended dose of irinotecan for the phase II study. The latter study evaluated the effectiveness (overall response rate, median time to disease progression and median survival time) and tolerability of this modified-IFL therapy as ambulatory treatment in 22 patients with advanced colorectal cancer.
Results: The dose-limiting toxicity of irinotecan was grade 3 neutropenia, which occurred in three patients at dose level 2 (125 mg/m2); furthermore, a fourth patient developed grade 4 neutropenia at this dose level. Therefore, 125 mg/m2 was considered to be the maximum tolerated dose, and the dose of irinotecan for the phase II study was set at 100 mg/m2. Fourteen patients achieved partial response using this modified-IFL regimen, and the overall response rate was 63.6% (95% CI 43.5, 83.7). The median time to progression was 197 days (range 111–283 days) and the median survival time was 414 days (95% CI 116, 712). Toxicities were acceptable and manageable.
Conclusions: Modified-IFL therapy is a practical, effective and tolerable option for ambulatory treatment of advanced colorectal cancer.
Poon MA, O’Connell MJ, Moertel CG, et al. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 1989; 7: 1407–18PubMedGoogle Scholar
Buroker TR, O’Connell MJ, Wieand HS, et al. Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol 1994; 12: 14–20PubMedGoogle Scholar
Leichman CG, Fleming TR, Muggia FM, et al. Phase II study of fluorouracil and its modulation in advanced colorectal cancer. J Clin Oncol 1995; 13: 1303–11PubMedGoogle Scholar
Petrelli N, Douglass Jr HO, Herrera L, et al. The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group. J Clin Oncol 1989; 7:1419–26PubMedGoogle Scholar
de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: 2938–47PubMedGoogle Scholar
Shimada Y, Yoshino M, Wakui A, et al. Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer. CPT-11 Gastrointestinal Cancer Study Group. J Clin Oncol 1993; 11: 909–13PubMedGoogle Scholar
Saltz LB, Douillard JY, Pirotta N, et al. Irinotecan plus fluorouracil/leucovorin for metastatic colorectal cancer: a new survival standard. Oncologist 2001; 6: 81–91PubMedCrossRefGoogle Scholar
Rothenberg ML, Meropol NJ, Poplin EA, et al. Mortality associated with irinotecan plus bolus fluorouracil/ leucovorin: summary findings of an independent panel. J Clin Oncol 2001; 19: 3801–7PubMedGoogle Scholar
Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluor-ouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000; 343: 905–14PubMedCrossRefGoogle Scholar
Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000; 25: 1041–7CrossRefGoogle Scholar
Ohtsu A, Boku N, Yoshioka T, et al. Phase II study of irinotecan in combination with 120-h infusion of 5-fluor-ouracil in patients with metastatic colorectal carcinoma: Japan Clinical Oncology Group Study (JCOG9703). Jpn J Clin Oncol 2003; 33: 28–32PubMedCrossRefGoogle Scholar
Komatsu M, Takei T, Kato T, et al. Phase I/II study of irinotecan (CPT-11) combined with l-leucovorin (l-LV) and 5FU in patients with advanced colorectal cancer. In: Hokkaido Gastrointestinal Cancer Study Group, editor. Proceedings of the 18th UICC International Cancer Congress; 2002 Jun 30–Jul 5; HokkaidoGoogle Scholar
Andre T, Louvet C, Maindrault-Goebel F, et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOL-FIRI) for pretreated metastatic colorectal cancer. GER-COR. Eur J Cancer 1999; 35: 1343–7PubMedCrossRefGoogle Scholar
National Cancer Institute. National Cancer Institute common toxicity criteria version 2.0 [online]. Available from URL: http://ctep.cancer.gov/ [Accessed 2010 Feb 1]
Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000; 92: 205–16PubMedCrossRefGoogle Scholar
Mori K, Kondo T, Kamiyama Y, et al. Preventive effect of Kampo medicine (Hangeshashin-to) against irinotecaninduced diarrhea in advanced non-small-cell lung cancer. Cancer Chemother Pharmacol 2003; 51: 403–6PubMedGoogle Scholar
Saltz LB, Kanowitz J, Kemeny NE, et al. Phase I clinical and pharmacokinetic study of irinotecan, fluorouracil, and leucovorin in patients with advanced solid tumors. J Clin Oncol 1996; 14: 2959–67PubMedGoogle Scholar
Goldberg RM, Sargent DJ, Morton RF, et al. Early detection of toxicity and adjustment of ongoing clinical trials: the history and performance of the North Central Cancer Treatment Group’s real-time toxicity monitoring program. J Clin Oncol 2002; 20: 4591–6PubMedCrossRefGoogle Scholar
Saltz LB, Niedzwiecki D, Hollis D, et al. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol 2007; 25: 3456–61PubMedCrossRefGoogle Scholar
Delaunoit T, Goldberg RM, Sargent DJ, et al. Mortality associated with daily bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan or oxaliplatin: results from Intergroup Trial N9741. Cancer 2004; 15: 2170–6CrossRefGoogle Scholar
Dy GK, Krook JE, Green EM, et al. Impact of complete response to chemotherapy on overall survival in advanced colorectal cancer: results from Intergroup N9741. J Clin Oncol 2007; 25: 3469–74PubMedCrossRefGoogle Scholar
Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22: 229–37PubMedCrossRefGoogle Scholar
Goldberg RM, Sargent DJ, Morton RF, et al. Randomized controlled trial of reduced-dose bolus fluorouracil plus leucovorin and irinotecan or infused fluorouracil plus leucovorin and oxaliplatin in patients with previously untreated metastatic colorectal cancer: a North American Intergroup Trial. J Clin Oncol 2006; 24: 3347–53PubMedCrossRefGoogle Scholar
Goto A, Yamada Y, Hosokawa A, et al. Phase I/II study of irinotecan, 5-fluorouracil, and l-leucovorin combination therapy (modified Saltz regimen) in patients with metastatic colorectal cancer. Int J Clin Oncol 2004; 9: 364–8PubMedCrossRefGoogle Scholar
Kohne CH, Wils J, Lorenz M, et al. Randomized phase III study of high-dose fluorouracil given as a weekly 24-hour infusion with or without leucovorin versus bolus fluorouracil plus leucovorin in advanced colorectal cancer: European Organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952. J Clin Oncol 2003; 21: 3721–8PubMedCrossRefGoogle Scholar
Wasserman E, Myara A, Lokie F, et al. Severe CPT-11 toxicity in patients with Gilbert’s syndrome: two case reports. Ann Oncol 1997; 8: 1049–51PubMedCrossRefGoogle Scholar
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: 2335–42PubMedCrossRefGoogle Scholar