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

• Published in: ESMO open 2022-06, Vol.7 (3), p.100427-100427, Article 100427
• Main Authors: Osterlund, P., Kinos, S., Pfeiffer, P., Salminen, T., Kwakman, J.J.M., Frödin, J.-E., Shah, C.H., Sorbye, H., Ristamäki, R., Halonen, P., Soveri, L.M., Heervä, E., Ålgars, A., Bärlund, M., Hagman, H., McDermott, R., O’Reilly, M., Röckert, R., Liposits, G., Kallio, R., Flygare, P., Teske, A.J., van Werkhoven, E., Punt, C.J.A., Glimelius, B.
• Format: Article
• Language: English
• Subjects: cardiac toxicity; cardiotoxicity; colorectal cancer; fluoropyrimidines; gastrointestinal cancer; Medicin och hälsovetenskap; Original Research; S-1
• ISSN: 2059-7029; 2059-7029
• DOI: 10.1016/j.esmoop.2022.100427

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. 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. 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). 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. [Display omitted] •Cardiotoxicity occurs in 4%-6% during capecitabine- or 5-FU-based treatment and often leads to treatment discontinuation.•This is the largest patient series switched to S-1-based treatment after cardiotoxicity on fluoropyrimidine treatment.•We show that 96% of 200 patients had no recurrent cardio