FOLFIRI (folinic acid, fluorouracil, and irinotecan) increases not efficacy but toxicity compared with single-agent irinotecan as a second-line treatment in metastatic colorectal cancer patients: a randomized clinical trial

Xiaowei Zhang, Ran Duan, Yusheng Wang, Xin Liu, Wen Zhang, Xiaodong Zhu, Zhiyu Chen, Wei Shen, Yifu He, Hong Qiang Wang, Mingzhu Huang, Chenchen Wang, Zhe Zhang, Xiaoying Zhao, Lixin Qiu, Jianfeng Luo, Xuedan Sheng, Weijian Guo, Xiaowei Zhang, Ran Duan, Yusheng Wang, Xin Liu, Wen Zhang, Xiaodong Zhu, Zhiyu Chen, Wei Shen, Yifu He, Hong Qiang Wang, Mingzhu Huang, Chenchen Wang, Zhe Zhang, Xiaoying Zhao, Lixin Qiu, Jianfeng Luo, Xuedan Sheng, Weijian Guo

Abstract

Background: FOLFIRI [irinotecan, folinic acid (CF), and fluorouracil] is considered a standard second-line chemotherapy regimen for patients with metastatic colorectal cancer (mCRC) who failed first-line XELOX/FOLFOX regimens. However, it remains unknown whether fluorouracil is still necessary in this case. This trial was designed to test the superiority of FOLFIRI over single-agent irinotecan as a second-line treatment for patients with mCRC.

Methods: This randomized clinical trial was conducted in five hospitals in China. From 4 November 2016 to 17 January 2020, patients aged 18 years or older with histologically confirmed unresectable mCRC and who had failed first-line XELOX/FOLFOX regimens were screened and enrolled. Patients were randomized to receive either FOLFIRI or irinotecan. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and toxicity. Data were analyzed on an intention-to-treat basis.

Results: A total of 172 patients with mCRC were randomly treated with FOLFIRI (n = 88) or irinotecan (n = 84). The median PFS was 104 and 112 days (3.5 and 3.7 months) in the FOLFIRI and irinotecan groups, respectively [hazard ratio (HR) = 1.084, 95% confidence interval (CI) = 0.7911-1.485; p = 0.6094], and there was also no significant difference in OS and ORR between the two groups. The incidence of the following adverse events (AEs) was significantly higher in the FOLFIRI group than in the irinotecan group: any grade AEs including leucopenia (73.9% versus 55.4%), neutropenia (72.7% versus 56.6%), thrombocytopenia (31.8% versus 18.1%), jaundice (18.2% versus 7.2%), mucositis (40.9% versus 14.5%), vomiting (37.5% versus 21.7%), and fever (19.3% versus 7.2%) and grade 3-4 neutropenia (47.7% versus 21.7%).

Conclusion: This is the first head-to-head trial showing that single-agent irinotecan yielded PFS, OS, and ORR similar to FOLFIRI, with a more favorable toxicity profile; therefore, it might be a more favorable standard chemotherapy regimen for mCRC patients who failed first-line XELOX/FOLFOX regimens.

Trial registration: This study is registered with ClinicalTrials.gov, number NCT02935764, registered 17 October 2016, https://ichgcp.net/clinical-trials-registry/NCT02935764.

Keywords: FOLFIRI; chemotherapy; irinotecan; metastatic colorectal cancer.

Conflict of interest statement

Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

© The Author(s), 2022.

Figures

Figure 1.
Figure 1.
Patient flow diagram.
Figure 2.
Figure 2.
Kaplan–Meier survival estimates in the intention-to-treat population. (a) Progression-free survival and (b) overall survival in patients receiving FOLFIRI compared with patients receiving IRI.
Figure 3.
Figure 3.
Forest plots of exploratory subgroup analysis of (a) disease-free survival and (b) overall survival.

References

    1. Mo S, Cai X, Zhou Z, et al.. Nomograms for predicting specific distant metastatic sites and overall survival of colorectal cancer patients: a large population-based real-world study. Clin Transl Med 2020; 10: 169–181.
    1. Zhang J, Yan S, Liu X, et al.. Gender-related prognostic value and genomic pattern of intra-tumor heterogeneity in colorectal cancer. Carcinogenesis 2017; 38: 837–846.
    1. Mo S, Zhou Z, Dai W, et al.. Development and external validation of a predictive scoring system associated with metastasis of T1-2 colorectal tumors to lymph nodes. Clin Transl Med 2020; 10: 275–287.
    1. Latest global cancer data: cancer burden rises to 19.3 million new cases and 10.0 million cancer deaths in 2020. International Agency for Research on Cancer, World Health Organization,
    1. Siegel RL, Miller KD, Fedewa SA, et al.. Colorectal cancer statistics, 2017. CA Cancer J Clin 2017; 67: 177–193.
    1. Aparicio J, Esposito F, Serrano S, et al.. Metastatic colorectal cancer. First line therapy for unresectable disease. J Clin Med 2020; 9: E3889.
    1. Gustavsson B, Carlsson G, Machover D, et al.. A review of the evolution of systemic chemotherapy in the management of colorectal cancer. Clin Colorectal Cancer 2015; 14: 1–10.
    1. Grothey A, Sargent D, Goldberg RM, et al.. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004; 22: 1209–1214.
    1. Xu RH, Muro K, Morita S, et al.. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol 2018; 19: 660–671.
    1. Xu J, Kim TW, Shen L, et al.. Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: the TERRA study. J Clin Oncol 2018; 36: 350–358.
    1. Li J, Qin S, Xu RH, et al.. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA 2018; 319: 2486–2496.
    1. Li J, Qin S, Xu R, et al.. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2015; 16: 619–629.
    1. Tournigand C, André 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: 229–237.
    1. Rothenberg ML, Oza AM, Bigelow RH, et al.. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 2003; 21: 2059–2069.
    1. Cunningham D, Glimelius B. A phase III study of irinotecan (CPT-11) versus best supportive care in patients with metastatic colorectal cancer who have failed 5-fluorouracil therapy. V301 Study Group. Semin Oncol 1999; 26(1, Suppl. 5): 6–12.
    1. Van Cutsem E, Blijham GH. Irinotecan versus infusional 5-fluorouracil: a phase III study in metastatic colorectal cancer following failure on first-line 5-fluorouracil. V302 Study Group. Semin Oncol 1999; 26(1, Suppl. 5): 13–20.
    1. Satoh T, Ura T, Yamada Y, et al.. Genotype-directed, dose-finding study of irinotecan in cancer patients with UGT1A1*28 and/or UGT1A1*6 polymorphisms. Cancer Sci 2011; 102: 1868–1873.
    1. Sobrero AF, Maurel J, Fehrenbacher L, et al.. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26: 2311–2319.
    1. Kim JH, Park SJ, Park MI, et al.. FOLFIRI as second-line chemotherapy after failure of FOLFOX4 in advanced colorectal cancer: a Korean single-center experience. Korean J Gastroenterol 2014; 63: 18–24.
    1. Van Cutsem E, Tabernero J, Lakomy R, et al.. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012; 30: 3499–3506.
    1. Seymour MT, Maughan TS, Ledermann JA, et al.. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial [published correction appears in Lancet 2007; 370: 566]. Lancet 2007; 370: 143–152.
    1. Raymond E, Buquet-Fagot C, Djelloul S, et al.. Antitumor activity of oxaliplatin in combination with 5-fluorouracil and the thymidylate synthase inhibitor AG337 in human colon, breast and ovarian cancers. Anticancer Drugs 1997; 8: 876–885.
    1. deBraud F, Munzone E, Nolè F, et al.. Synergistic activity of oxaliplatin and 5-fluorouracil in patients with metastatic colorectal cancer with progressive disease while on or after 5-fluorouracil. Am J Clin Oncol 1998; 21: 279–283.
    1. de Gramont A, Figer M, Seymour M, et al.. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: 2938–2947.
    1. Giacchetti S, Perpoint B, Zidani R, et al.. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000; 18: 136–147.
    1. Garufi C, Brienza S, Pugliese P, et al.. Overcoming resistance to chronomodulated 5-fluorouracil and folinic acid by the addition of chronomodulated oxaliplatin in advanced colorectal cancer patients. Anticancer Drugs 2000; 11: 495–501.
    1. Azrak RG, Cao S, Slocum HK, et al.. Therapeutic synergy between irinotecan and 5-fluorouracil against human tumor xenografts. Clin Cancer Res 2004; 10: 1121–1129.
    1. Yamada T, Furukawa K, Yokoi K, et al.. Effects of irinotecan and 5-FU combination therapy in gastric cancer – is combination therapy synergic? Gan To Kagaku Ryoho 2010; 37: 2125–2129.
    1. Goldberg RM, Erlichman C. Irinotecan plus 5-FU and leucovorin in advanced colorectal cancer: North American trials. Oncology 1998; 12(8, Suppl. 6): 59–63.
    1. Muro K, Boku N, Shimada Y, et al.. Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2/3 non-inferiority study (FIRIS study). Lancet Oncol 2010; 11: 853–860.
    1. Yasui H, Muro K, Shimada Y, et al.. A phase 3 non-inferiority study of 5-FU/l-leucovorin/irinotecan (FOLFIRI) versus irinotecan/S-1 (IRIS) as second-line chemotherapy for metastatic colorectal cancer: updated results of the FIRIS study. J Cancer Res Clin Oncol 2015; 141: 153–160.
    1. Miyamoto Y, Tsuji A, Tanioka H, et al.. S-1 and irinotecan plus bevacizumab as second-line chemotherapy for patients with oxaliplatin-refractory metastatic colorectal cancer: a multicenter phase II study in Japan (KSCC1102) [published correction appears in Int J Clin Oncol 2017]. Int J Clin Oncol 2016; 21: 705–712.
    1. Takaoka T, Kimura T, Shimoyama R, et al.. Panitumumab in combination with irinotecan plus S-1 (IRIS) as second-line therapy for metastatic colorectal cancer. Cancer Chemother Pharmacol 2016; 78: 397–403.
    1. Cassidy J, Clarke S, Díaz-Rubio E, et al.. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 2008; 26: 2006–2012.
    1. Saltz LB, Clarke S, Díaz-Rubio E, et al.. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study [published correction appears in J Clin Oncol 2008; 26: 3110] [published correction appears in J Clin Oncol 2009; 27: 653]. J Clin Oncol 2008; 26: 2013–2019.
    1. Fuchs CS, Marshall J, Mitchell E, et al.. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C study. J Clin Oncol 2007; 25: 4779–4786.

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