Continuation of fluoropyrimidine treatment with S-1 after cardiotoxicity on capecitabine- or 5-fluorouracil-based therapy in patients with solid tumours: a multicentre retrospective observational cohort study

P Osterlund, S Kinos, P Pfeiffer, T Salminen, J J M Kwakman, J-E Frödin, C H Shah, H Sorbye, R Ristamäki, P Halonen, L M Soveri, E Heervä, A Ålgars, M Bärlund, H Hagman, R McDermott, M O'Reilly, R Röckert, G Liposits, R Kallio, P Flygare, A J Teske, E van Werkhoven, C J A Punt, B Glimelius, P Osterlund, S Kinos, P Pfeiffer, T Salminen, J J M Kwakman, J-E Frödin, C H Shah, H Sorbye, R Ristamäki, P Halonen, L M Soveri, E Heervä, A Ålgars, M Bärlund, H Hagman, R McDermott, M O'Reilly, R Röckert, G Liposits, R Kallio, P Flygare, A J Teske, E van Werkhoven, C J A Punt, B Glimelius

Abstract

Background: Capecitabine- or 5-fluorouracil (5-FU)-based chemotherapy is widely used in many solid tumours, but is associated with cardiotoxicity. S-1 is a fluoropyrimidine with low rates of cardiotoxicity, but evidence regarding the safety of switching to S-1 after 5-FU- or capecitabine-associated cardiotoxicity is scarce.

Patients and methods: This retrospective study (NCT04260269) was conducted at 13 centres in 6 countries. The primary endpoint was recurrence of cardiotoxicity after switch to S-1-based treatment due to 5-FU- or capecitabine-related cardiotoxicity: clinically meaningful if the upper boundary of the 95% confidence interval (CI; by competing risk) is not including 15%. Secondary endpoints included cardiac risk factors, diagnostic work-up, treatments, outcomes, and timelines of cardiotoxicity.

Results: Per protocol, 200 patients, treated between 2011 and 2020 [median age 66 years (range 19-86); 118 (59%) males], were included. Treatment intent was curative in 145 (73%). Initial cardiotoxicity was due to capecitabine (n = 170), continuous infusion 5-FU (n = 22), or bolus 5-FU (n = 8), which was administered in combination with other chemotherapy, targeted agents, or radiotherapy in 133 patients. Previous cardiovascular comorbidities were present in 99 (50%) patients. Cardiotoxic events (n = 228/200) included chest pain (n = 125), coronary syndrome/infarction (n = 69), arrhythmia (n = 22), heart failure/cardiomyopathy (n = 7), cardiac arrest (n = 4), and malignant hypertension (n = 1). Cardiotoxicity was severe or life-threatening in 112 (56%) patients and led to permanent capecitabine/5-FU discontinuation in 192 (96%). After switch to S-1, recurrent cardiotoxicity was observed in eight (4%) patients (95% CI 2.02-7.89, primary endpoint met). Events were limited to grade 1-2 and occurred at a median of 16 days (interquartile range 7-67) from therapy switch. Baseline ischemic heart disease was a risk factor for recurrent cardiotoxicity (odds ratio 6.18, 95% CI 1.36-28.11).

Conclusion: Switching to S-1-based therapy is safe and feasible after development of cardiotoxicity on 5-FU- or capecitabine-based therapy and allows patients to continue their pivotal fluoropyrimidine-based treatment.

Keywords: S-1; cardiac toxicity; cardiotoxicity; colorectal cancer; fluoropyrimidines; gastrointestinal cancer.

Conflict of interest statement

Disclosure PO, SK, PP, TS, JJMK, JEF, CHS, HS, RR, PH, LMS, EH, AÅ, MB, HH, RMD, MOR, RR, GL, RK, PF, AJK, EvW, CJAP, and BG report grants, personal fees, or non-financial support from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Clovis Oncology, Eli Lilly, Eisai, Erytech Pharma, Fresenius, Incyte, Janssen-Cilag, Merck, Merck Sharp & Dohme, Nordic Drugs, Nordic Pharma, Nordic Group, Nutricia, Pierre-Fabre, Roche, Sanofi, Servier, Sobi, or Varian. Data sharing The data collected for this study can be made available to others in de-identified form after all primary and secondary endpoints have been published, in the presence of a data transfer agreement, and if the purpose of use complies with Finnish and European legislation. Requests for data sharing can be made to the corresponding author, including a proposal that must be approved by the steering committee.

Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Time to appearance of cardiotoxicity from initiation of treatment during initial capecitabine or 5-fluorouracil (5-FU)-based therapy (n = 200; red) and during S-1-based therapy after switching due to cardiotoxicity on 5-FU or capecitabine (blue).
Figure 2
Figure 2
Time to appearance of worst cardiotoxicity (n = 200), i.e. chest pain (blue), acute coronary syndrome/myocardial infarction (red), heart failure/cardiomyopathy (green), or cardiac arrest/arrhythmia (orange) during fluoropyrimidine-based (solid lines) and time to appearance of recurrent cardiotoxicity (n = 8) colour-separated as above (dotted lines) and time without recurrent cardiotoxicity (n = 192; turquoise) on S-1-based therapy. MI, myocardial infarction; sdr, syndrome.

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