A retrospective cohort study of patients presenting with cardiotoxicity after treatment with fluoropyrimidines suggests that switching to S-1 (i.e. a combination of tegafur, gimeracil, and oteracil, at a molar ratio of 1:0.4:1) is safe for these patients and supports treatment continuation.
Fluoropyrimidines (e.g. capecitabine, 5-fluorouracil) are widely used to treat solid tumors but are linked to clinical cardiotoxicity in about 5% of patients, often leading to discontinuation. In addition, subclinical cardiotoxicity may be much more common; present in up to one-third of patients. Cardiotoxicity may be less frequent in patients treated with S-1 as compared with 5-fluorouracil and capecitabine, but head-to-head comparisons are lacking.
Prof. Pia Österlund (Tampere University Hospital, Finland) presented a 6-country, 12-center retrospective cohort study including patients with solid tumors (ICD10 C15-C21, C24-25, C50, C80) who experienced fluoropyrimidine-related cardiotoxicity (cardiac event grade 1-4), and who were re-challenged with a different fluoropyrimidine or S-1 and then assessed for cardiotoxicity .
The underlying mechanisms of cardiotoxicity are not well understood, but they may include abnormal coronary artery contractility or spasm, and myocardial toxicity. The purpose of this retrospective study is to compare different 5-fluorouracil-based dosing modalities and S-1 and to compare cardiotoxicity during these treatments. The primary endpoint was recurrent cardiotoxicity during S-1 therapy after switching from any other fluoropyrimidine.
Cardiotoxicity during capecitabine (n=124), continuous (n=13), or bolus 5-fluorouracil (n=4) was reported for 141 patients prior to switching to S-1 therapy. Cardiotoxicity was defined as chest pain including vasospasm without cardiac findings (55%), acute coronary syndrome or myocardial infarction (32%), atrial fibrillation (4%), heart failure/cardiomyopathy (4%), tachycardia/bradycardia (3%), and/or other (15%). Cardiotoxicity was grade 3-4 in 55%, appeared on cycle 1-2 in 89%, and at a median 4 days (range 0-466) from fluoropyrimidine initiation. Causality was judged to be related in 26%, probable in 60%, and possible in 14%. Action with fluoropyrimidine causing cardiotoxicity was permanent discontinuation in 91%. Treatment intent was curative in 70%. Cumulative incidence of recurrent cardiotoxicity with S-1 was 3.5% (95% CI 1.2-8.4%) and the median time to recurrent cardiotoxicity was 11 (range 6-195) days.
Four (out of 141) participants had grade 1 and one grade 2 recurrent cardiotoxicity. Three participants were judged possibly related to S-1 and 2 were not judged to be related. S-1 was discontinued in one patient and continued in 4 (for 63-252 days) without action (n = 2), with dose reduction (n=1), or delay (n=1). There were no differences in demographic or risk factors regarding recurrent cardiotoxicity on S-1.
In conclusion, fluoropyrimidine-related cardiotoxicity is often severe, occurs early, and leads to permanent fluoropyrimidine discontinuation. Switching to an S-1-based therapy is safe, is only associated with grade 1-2 recurrent cardiotoxicity in 3.5% of patients, and rarely leads to treatment discontinuation (0.7%), allowing patients to continue a fluoropyrimidine-based regimen.
1. Österlund P, et al. Feasibility of switching to S-1 upon other fluoropyrimidine-related cardiotoxicity in chemotherapy for solid tumors. ASCO Virtual Meeting, 29-31 May 2020, Poster 7037.