University of Oulu

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, 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☆, ESMO Open, Volume 7, Issue 3, 2022, 100427, ISSN 2059-7029,

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

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Author: Osterlund, P.1,2,3; Kinos, S.1; Pfeiffer, P.4;
Organizations: 1Department of Oncology, Tampere University Hospital and University of Tampere, Tampere, Finland
2Department of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
3Department of Oncology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
4Department of Oncology, Odense University Hospital, Odense, Denmark
5Department of Oncology, Amsterdam University Medical Centre, Amsterdam, the Netherlands
6Department of Oncology, Karolinska University Hospital, Stockholm, Sweden
7Department of Oncology, Haukeland University Hospital and Department of Clinical Science, University of Bergen, Bergen, Norway
8Department of Oncology, Turku University Hospital and University of Turku, Turku, Finland
9Department of Oncology, Skåne University Hospital, Lund, Sweden
10Department of Oncology, St. Vincent’s University Hospital, Dublin, Ireland
11Department of Oncology, Uppsala University Hospital, Uppsala, Sweden
12Department of Oncology, Regional Hospital West Jutland, Herning, Denmark
13Department of Oncology, Oulu University Hospital, Oulu, Finland
14Department of Oncology, Sundsvall Hospital, Sundsvall, Sweden
15Department of Cardiology, University Medical Centre Utrecht, Utrecht, the Netherlands
16Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.6 MB)
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Language: English
Published: BMJ, 2022
Publish Date: 2023-07-11


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.

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Series: ESMO open
ISSN: 2059-7029
ISSN-E: 2059-7029
ISSN-L: 2059-7029
Volume: 7
Issue: 3
Article number: 100427
DOI: 10.1016/j.esmoop.2022.100427
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Funding: This work was supported by Finska Läkaresällskapet (2016, 2018-2022), the Finnish Cancer Foundation (2019-2023), the Competitive State Research Financing of the Expert Responsibility Area of Tampere, Turku, and Helsinki University Hospitals (2016-2022), Tampere University Hospital Fund (Tukisäätiö 2019, 2020, and OOO-project 2020), Research Fund of Helsinki University Hospital (2019, 2021, 2022), Relander’s Foundation (2020-2022), and the infrastructure for the database and study nurse was partly supported by Nordic Drugs. The funders had no role in the study design, analysis, interpretation of the data, decision to publish, or writing of this report. All authors had full access to the data and had final responsibility for the decision to submit it for publication. All authors report institutional research funding from Nordic drugs paid to Tampere University Hospital and support for database, during the conduct of the study.
Copyright information: © 2022 The Author(s). Published by Elsevier Ltd on behalf of European Society for Medical Oncology. This is an open access article under the CC BY license (