Fluoropyrimidine-induced hand-foot syndrome and cardiotoxicity: recommendations for the use of the oral fluoropyrimidine S-1 in metastatic colorectal cancer

Background: Fluoropyrimidines (FPs) are an essential part of the majority of systemic regimens in the treatment of metastatic colorectal cancer (CRC). The use of the oral FP S-1 has been approved by the European Medicines Agency as monotherapy or in combination with oxaliplatin or irinotecan, with or without bevacizumab, for the treatment of patients with metastatic CRC in whom it is not possible to continue treatment with another FP due to hand-foot syndrome (HFS) or cardiovascular toxicity (CVT). Subsequently, this indication has been included in the 2022 ESMO guidelines for metastatic CRC. Recommendations for use in daily practice are not available. Patients and methods: Based on peer-reviewed published data on the use of S-1 in Western patients with metastatic CRC who switched from infusional 5-fluorouracil (5-FU) or capecitabine to S-1 for reasons of HFS or CVT, recommendations for its use were formulated by an international group of medical oncologists with expertise in the treatment of metastatic CRC and a cardio-oncologist. Results: In patients who experience pain and/or functional impairment due to HFS during treatment with capecitabine or infusional 5-FU, a switch to S-1 is recommended without prior dose reduction of capecitabine/5-FU. S-1 should preferably be initiated at full dose when HFS has decreased to grade ≤1. In patients with cardiac complaints, in whom an association with capecitabine or infusional 5-FU treatment cannot be excluded, capecitabine/5-FU should be discontinued and a switch to S-1 is recommended. Conclusions: These recommendations should guide clinicians in daily practice in the treatment of patients with metastatic CRC with FP-containing regimens.