Switch to oral S-1 in metastatic colorectal cancer patients with 5FU/capecitabine-induced cardiovascular toxicity

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Abstract Background 5FU and capecitabine are cytotoxic fluoropyrimidines that are effective in several cancer types, and are associated in approx. 4%-6% with cardiovascular toxicity (CVT). This usually occurs in the first treatment cycle, and may be serious. Rechallenge with 5FU/capecitabine under cardioprophylaxis and monitoring may reduce, but not prevent recurrence of CVT and risk of death, and is laborious. Raltitrexed is another fluoropyrimidine that was developed in colorectal cancer (CRC) but is not recommended anymore in international guidelines due to a poor safety profile. However since the incidence of CVT is low, a switch to raltitrexed is sometimes used in patients with 5FU/capecitabine-induced CVT. However published data show recurrent CVT in up to 16% of patients who switched to raltitrexed after 5FU/capecitabine-induced CVT, which may be serious and even fatal. S-1 is an oral fluoropyrimidine (a combination of tegafur with the metabolic inhibitors gimeracil and oteracil) with similar efficacy to 5FU/capecitabine, but serious CVT has not been documented. Purpose To investigate the recurrence of CVT after switch to S-1 in cancer patients experiencing 5FU/capecitabine-induced CVT. Methods We performed a retrospective cohort analysis of 200 cancer patients treated between 2011 and 2020 in 13 centers in 6 European countries who experienced CVT during 5FU or capecitabine-based treatment and subsequently switched to S-1. Previous cardiovascular comorbidities were present in 99 (50%) patients. CVT 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). CVT was severe or life-threatening in 112 (56%) patients and led to permanent capecitabine/5-FU discontinuation in 192 (96%). Results After switch to S-1, recurrent CVT was observed in 8 (4%) patients (95% CI 2.02-7.89). 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 6.2, 95% CI 1.4-28). 99% of patients were able to continue the planned duration of treatment. Conclusions We conclude that a switch to S-1 is safe and feasible in cancer patients with 5FU/capecitabine-induced CVT, and allows patients continuation of effective fluoropyrimidine treatment. Our data compare favorably to a rechallenge with 5FU/capecitabine, and to a switch to raltitrexed in CRC patients. The use of S-1 has recently been approved by European Medicines Agency (EMA) in CRC patients experiencing 5FU/capecitabine-induced CVT, and is recommended in these patients in the 2023 guideline of the European Society of Medical Oncology (ESMO).

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