Korean J Gastroenterol.  2023 Dec;82(6):288-294. 10.4166/kjg.2023.114.

Leucovorin-induced Hypersensitivity Reaction in a Patient with Metastatic Colorectal Cancer Treated with Cetuximab Plus FOLFOX Chemotherapy: A Case Report

• Kim M
• Kim DH
• Lee JY
• Nam YH
• Lee JH

• KMID: 2549812
• DOI: http://doi.org/10.4166/kjg.2023.114

Abstract

The FOLFOX regimen (combination of leucovorin, 5-fluorouracil, and oxaliplatin) is the first-line treatment for high-risk stage 2 and 3 colorectal cancer patients. While hypersensitivity reactions (HSRs) caused by oxaliplatin are commonly reported, HSRs due to leucovorin have been infrequently reported. This report aims to investigate the clinical presentation, diagnosis, and management of leucovorin induced HSRs. A 60-year-old female developed generalized edema, dyspnea, and facial redness during cetuximab plus FOLFOX chemotherapy administered for management of metastatic colorectal cancer. Because HSRs induced by oxaliplatin are commonly reported, we initially presumed an oxaliplatin-induced HSR. However, despite undergoing oxaliplatin desensitization, HSRs persisted, and they were still observed when leucovorin was administered without oxaliplatin. The patient was diagnosed with leucovorin-induced HSR and underwent leucovorin desensitization. However, the reactions recurred within 30 minutes of the initiating the desensitization. Considering unsuccessful leucovorin desensitization, leucovorin was excluded. The patient received cetuximab and oxaliplatin chemotherapy without leucovorin to date without any adverse effects. While leucovorin-induced HSRs are infrequently reported, they should still be regarded as potential adverse effects.

Keyword

Colorectal cancer; Leucovorin; Hypersensitivity

Figure

• 

  Fig. 1 Red rash papules on the trunk appeared after administrating leucovorin within 30 minutes.

Reference

1. Benson AB, Venook AP, Al-Hawary MM, et al. 2021; Colon cancer, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 19:329–359.

2. Van Cutsem E, Cervantes A, Adam R, et al. 2016; ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 27:1386–1422. DOI: 10.1093/annonc/mdw235. PMID: 27380959.

3. Cassidy J, Misset JL. 2002; Oxaliplatin-related side effects: characteristics and management. Semin Oncol. 29(5 Suppl 15):11–20. DOI: 10.1053/sonc.2002.35524. PMID: 12422304.

4. Bano N, Najam R, Qazi F, Mateen A. 2016; Clinical features of oxaliplatin induced hypersensitivity reactions and therapeutic approaches. Asian Pac J Cancer Prev. 17:1637–1641. DOI: 10.7314/APJCP.2016.17.4.1637. PMID: 27221832.

5. Vermeulen C, Mathelier-Fusade P, Gaouar H, Leynadier F. 2003; Two cases of allergy to leucovorin. Revue Française d'Allergologie et d'Immunologie Clinique. 43:342–343. DOI: 10.1016/S0335-7457(03)00115-1.

6. Apraxine M, Van den Eynde M, De Cuyper A, Pirson F. 2022; Hypersensitivity reactions to folinic acid: mechanisms involved based on two case reports and a literature review. Allergy Asthma Clin Immunol. 18:107. DOI: 10.1186/s13223-022-00752-5. PMID: 36550565. PMCID: PMC9783773.

7. Florit-Sureda M, Conde-Estévez D, Vidal J, Montagut C. 2016; Hypersensitivity reaction caused by folinic acid administration: a case report and literature review. J Chemother. 28:500–505. DOI: 10.1179/1973947815Y.0000000048. PMID: 26042586.

8. Ureña-Tavera A, Zamora-Verduga M, Madrigal-Burgaleta R, Angel-Pereira D, Berges-Gimeno MP, Alvarez-Cuesta E. 2015; Hypersensitivity reactions to racemic calcium folinate (leucovorin) during FOLFOX and FOLFIRI chemotherapy administrations. J Allergy Clin Immunol. 135:1066–1067. DOI: 10.1016/j.jaci.2014.09.045. PMID: 25457996.

9. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. 2017 Nov 27. Available from: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf.

10. Siegel RL, Miller KD, Wagle NS, Jemal A. 2023; Cancer statistics, 2023. CA Cancer J Clin. 73:17–48. DOI: 10.3322/caac.21763. PMID: 36633525.

11. Siu SW, Chan RT, Au GK. 2006; Hypersensitivity reactions to oxaliplatin: experience in a single institute. Ann Oncol. 17:259–261. DOI: 10.1093/annonc/mdj042. PMID: 16282245.

12. Damaske A, Ma N, Williams R. 2012; Leucovorin-induced hypersensitivity reaction. J Oncol Pharm Pract. 18:136–139. DOI: 10.1177/1078155210396577. PMID: 21248170.

13. Gudimetla V, Daw J, Almhana F, Haddad A. 2019; Delayed hypersensitivity reaction to leucovorin. Am J Ther. 26:e533–e534. DOI: 10.1097/MJT.0000000000000977. PMID: 31045877.

14. Benchalal M, Yahchouchy-Chouillard E, Fouere S, Fingerhut A. 2002; Anaphylactic shock secondary to intravenous administration of folinic acid: a first report. Ann Oncol. 13:480–481. DOI: 10.1093/annonc/mdf023. PMID: 11996482.

15. Zhu L, Li H, Du Q, Ye X, Yu S, Luo X, Zhai Q. 2021; Meta-analysis of risk factors associated with oxaliplatin hypersensitivity reactions in cancer patients. Int J Clin Oncol. 26:2194–2204. DOI: 10.1007/s10147-021-02034-3. PMID: 34625844. PMCID: PMC8580899.

16. Nucera E, Aruanno A, Mezzacappa S, Pascolini L, Buonomo A, Schiavino D. Hypersensitivity reactions to folic acid: Three case reports and a review of the literature. Int J Immunopathol Pharmacol. 2018; doi: https://doi.org/10.1177/2058738418817704. DOI: 10.1177/2058738418817704. PMCID: PMC6299334.

17. Kidera Y, Satoh T, Ueda S, et al. 2011; High-dose dexamethasone plus antihistamine prevents colorectal cancer patients treated with modified FOLFOX6 from hypersensitivity reactions induced by oxaliplatin. Int J Clin Oncol. 16:244–249. DOI: 10.1007/s10147-010-0170-6. PMID: 21243395.

18. Gammon D, Bhargava P, McCormick MJ. 2004; Hypersensitivity reactions to oxaliplatin and the application of a desensitization protocol. Oncologist. 9:546–549. DOI: 10.1634/theoncologist.9-5-546. PMID: 15477639.

19. Cortijo-Cascajares S, Nacle-López I, García-Escobar I, et al. 2013; Effectiveness of oxaliplatin desensitization protocols. Clin Transl Oncol. 15:219–225. DOI: 10.1007/s12094-012-0909-9. PMID: 22855191.

20. de Las Vecillas Sánchez L, Alenazy LA, Garcia-Neuer M, Castells MC. 2017; Drug hypersensitivity and desensitizations: Mechanisms and new approaches. Int J Mol Sci. 18:1316. DOI: 10.3390/ijms18061316. PMID: 28632196. PMCID: PMC5486137.