The Safety of FOLFIRINOX Regimen: Oxaliplatin and Irinotecan Sequence of Administration

Presenter: Kara Kubli, PharmD, BCOP, Clinical Pharmacy Specialist–Bone Marrow Transplant, University of Rochester Medical Center, NY

Co-Authors: Frank Lattuca, PharmD, Hematology/Oncology Clinical Pharmacy Specialist, University of Rochester Medical Center; Teresa Napolitano, PharmD, BCOP, Oncology Pharmacy Manager, University of Rochester Medical Center; Paige Bloom, DNP, AGACNP-BC, RN-BC, Nurse Practitioner, University of Rochester Medical Center; Annie Steele, RN, Registered Nurse, University of Rochester Medical Center; Andrea Baran, MS, Associate Director, Biostatistical Consulting Service, University of Rochester Medical Center; Erika Ramsdale, MD, Associate Professor, Division of Hematology/Oncology, University of Rochester Medical Center; Aram Hezel, MD, Associate Professor, Chief, Division of Hematology/Oncology, University of Rochester Medical Center

BACKGROUND: The chemotherapy regimen FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin, irinotecan) is used in the treatment of pancreatic cancer and colorectal cancer. There is conflicting evidence in the literature regarding the sequencing of irinotecan and oxaliplatin. Historically, oxaliplatin has been administered first, followed by irinotecan. One review suggested that sequencing had no impact on efficacy or safety outcomes, whereas another recommended that irinotecan be given first to reduce cholinergic effects. An in-vitro study showed that oxaliplatin exerts maximal cytotoxicity when administered before SN-38, irinotecan’s active metabolite, suggesting giving irinotecan first only in cases of dysarthria. The FOLFOXIRI regimen contains the same medications; however, irinotecan is historically administered first. At our institution, we updated the sequencing of FOLFIRINOX to administer oxaliplatin first. Since that change, providers have noticed adverse effects, including dysarthria and dysphagia.

OBJECTIVES: The primary objective was to determine if the sequencing of oxaliplatin and irinotecan has an impact on the incidence of adverse reactions, including dysarthria, dysphagia, numbness, and gastrointestinal discomfort. The secondary objectives were to determine if age, gender, or presence of atropine had an impact on adverse reactions.

METHOD: This retrospective study included 84 adults receiving FOLFIRINOX, modified FOLFIRINOX, or FOLFOXIRI plus bevacizumab, from July 2017 to August 2020. We used mixed logistic regression models, including a fixed effect for regimen sequence, to estimate the infusion adverse reaction rate, while accounting for correlations in the data from multiple infusions on the same patient via a random intercept. Using these models, odds ratios were estimated to compare the risk of infusions between the 2 regimen sequences, while adjusting for other covariates, including age, gender, and use of atropine.

RESULTS: When oxaliplatin was administered first, the infusion reaction rate was 18.4% (95% confidence interval [CI], 10.7%-29.7%). When oxaliplatin was administered second, the infusion reaction rate was 2.8% (95% CI, 0.9%-8.0%). The odds ratio of infusion reactions when oxaliplatin was administered first was 7.94 (95% CI, 2.82-22.4; P <.0001). After adjusting for age, gender, and atropine, the effect of sequencing still holds (odds ratio = 7.62; 95% CI, 2.77-21.0; P <.0001).

CONCLUSION: These data suggest that there is a correlation between infusion reactions and administration sequence. These data may be beneficial in patients who have reactions; however, more data are needed to evaluate the efficacy of sequencing of irinotecan and oxaliplatin.

1. da Silva AA, Carlotto J, Rotta I. Standardization of the infusion sequence of antineoplastic drugs used in the treatment of breast and colorectal cancers. Einstein (Sao Paulo). 2018;16:eRW4074. doi: 10.1590/S1679-45082018RW4074.
2. Conroy T, Desseigne F, Ychou M, et al; for the Groupe Tumeurs Digestives of Unicancer and the PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817-1825.
3. Gil-Delgado MA, Bastian G, Guinet F, et al. Oxaliplatin plus irinotecan and FU-FOL combination and pharmacokinetic analysis in advanced colorectal cancer patients. Am J Clin Oncol. 2004;27:294-298.
4. Lambert A, Gavoille C, Conroy T. Current status on the place of FOLFIRINOX in metastatic pancreatic cancer and future directions. Therap Adv Gastroenterol. 2017;10:631-645.
5. Mancini R, Modlin J. Chemotherapy administration sequence: a review of the literature and creation of a sequencing chart. J Hematol Oncol Pharm. 2011;1(1):17-25.
6. Masi G, Vasile E, Loupakis F, et al. Randomized trial of two induction chemotherapy regimens in metastatic colorectal cancer: an updated analysis. J Natl Cancer Inst. 2011;103:21-30.
7. Matsuoka A, Maeda O, Inada-Inoue M, et al. FOLFIRINOX-induced reversible dysarthria: a case report and review of previous cases. Oncol Lett. 2015;10:2662-2664.
8. Valencak J, Raderer M, Kornek GV, et al. Irinotecan-related cholinergic syndrome induced by coadministration of oxaliplatin. J Natl Cancer Inst. 1998;90:160.
9. Zeghari-Squalli N, Raymond E, Cvitkovic E, Goldwasser F. Cellular pharmacology of the combination of the DNA topoisomerase I inhibitor SN-38 and the diaminocyclohexane platinum derivative oxaliplatin. Clin Cancer Res. 1999;5:1189-1196.