Incidence of cardiotoxicity with the oral fluoropyrimidine capecitabine is typical of that reported with 5-fluorouracil

Texte intégral

(1)Annals of Oncology 13: 484–485, 2002. Letters to the Editor. Incidence of cardiotoxicity with the oral fluoropyrimidine capecitabine is typical of that reported with 5-fluorouracil Acute cardiotoxicity has recently been reported in two patients receiving capecitabine [1, 2], an oral fluoropyrimidine that undergoes a three-step enzymatic conversion to 5-fluorouracil (5-FU). Cardiotoxicity due to 5-FU is a rare but serious side effect, reported in 1–18% of patients [3]. The most common symptom of fluorouracil-associated cardiotoxicity is anginalike chest pain [3]. Less common symptoms include cardiac arrythmias, congestive heart failure, myocardial infarction, dilatative cardiomyopathy, cardiogenic shock, cardiac arrest or sudden death syndrome. The mechanism of 5-FU-induced cardiotoxicity has not been completely elucidated. Most cases occur during or following initial courses of fluorouracil treatment and are generally reversible on treatment discontinuation. Only a proportion (18%) of patients developing cardiotoxicity following 5-FU exposure have a history of underlying cardiac disease. To enable a direct comparison between the incidence of cardiotoxic events in patients receiving capecitabine mono-. therapy (1250 mg/m2 twice daily, days 1–14, followed by a 7-day rest period) and i.v. 5-FU/LV (Mayo Clinic regimen), a retrospective analysis was performed on two randomized phase III studies comparing the two regimens as first-line therapy for patients with metastatic colorectal cancer (MCRC) (n = 1189) [4, 5]. Two large phase II studies evaluating capecitabine monotherapy in patients with taxane-pretreated metastatic breast cancer (MBC) (n = 236) [6, 7] were also analyzed. This analysis revealed a similar low incidence (3%) of capecitabine-related cardiotoxic events in patients with MCRC and MBC (Table 1). Among patients with MCRC treated in the two phase III trials, 3% of patients in each of the treatment arms experienced treatment-related cardiotoxic events (all grades). Grade 3–4 treatment-related cardiotoxic events occurred in four patients in the 5-FU/LV arm (0.7%) and five patients in the capecitabine arm (0.8%). One fatal cardiac event related to study treatment occurred in each treatment arm. One patient with a prior history of ischaemic heart disease experienced a fatal myocardial infarction while receiving capecitabine, while the second patient experienced cardiac failure 12 days after completion of their 5-FU/LV treatment. Treatment-related cardiotoxic events (all grades) also occurred at a similar incidence (3%) in patients with taxane-pretreated MBC who received capecitabine in two phase II trials (n = 236) [6, 7]. None of the. Table 1. Incidence of treatment-related cardiotoxic adverse events in patients treated in clinical trials evaluating capecitabine monotherapy (1250 mg/m2 twice daily on days 1–14, followed by a 7-day rest period) Treatment-related grade 3–4 cardiac adverse events Patients with MCRC [4, 5]. Patients with MBC [6, 7]. 5-FU/LV (Mayo Clinic regimen) (n = 593). capecitabine (n = 596). capecitabine (n = 236). 20 (3). 19 (3). 7 (3). Incidence: no. of patients (%) All grades Grade 3–4 adverse events Myocardial infarction. a. a. a. 4 (1). 5 (1). 0 (0). 2. 1. –. Angina pectoris. 1. 1. –. Myocardial ischaemia. –. 1. –. Myocarditis. –. 1. –. Cardiac failure. 1. –. –. Tachycardia. –. 1. –. Chest pain (cardiac). 1. –. –. Individual patients may have had ≥1 event.. © 2002 European Society for Medical Oncology.

(2) 485 236 patients treated in these trials experienced serious treatment-related or fatal cardiac events. In conclusion, these data show that the incidence of cardiotoxicity in patients receiving capecitabine monotherapy is within the range that occurs with 5-FU. Physicians administering any fluoropyrimidine should be aware of the potential for cardiotoxicity and discontinue treatment promptly in patients developing clinical signs of such toxicity. E. Van Cutse m 1, P. M. Hoff 2, J. L. Blum3, M. Abt4 & B. Osterwalder 5 1. University Hospital Gasthuisberg, Leuven, Belgium (E-mail: eric.vancutsem@uz.kuleuven.ac.be); 2Centro Paulista de Oncologia, Albert Einstein Hospital, Sâo Paulo, Brazil; 3Baylor-Charles A. Sammons Cancer Center, US Oncology, Dallas, Texas, USA; 4 Biostatistics, F. Hoffmann-La Roche Ltd, Basel, Switzerland; 5 Clinical Science, F. Hoffmann-La Roche Ltd, Basel, Switzerland (E-mail: Eric.VanCutsem@uz.kuleuven.ac.be). References 1. Schnetzler B, Popova N, Collao Lamb C et al. Coronary spasm induced by capecitabine. Ann Oncol 2001; 12: 723–725. 2. Bertolini A, Fiumano M, Fusco O et al. Acute cardiotoxicity during capecitabine treatment: a case report. Tumori 2001; 87: 200–206. 3. Becker K, Erckenbrecht JF, Haussinger D et al. Cardiotoxicity of the antiproliferative compound fluorouracil. Drugs 1999; 57: 475–484. 4. Hoff PM, Ansari R, Batist G et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 2001; 19: 2282–2292. 5. Van Cutsem E, Twelves C, Cassidy J et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin (Mayo Clinic regimen) in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 2001; 19: 4093–4096. 6. Blum JL, Jones SE, Buzdar AU et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999; 17: 485–493. 7. Blum JL, Dieras V, La Russo PM et al. Multicenter, phase II study of capecitabine in taxane-pretreated metastatic breast cancer patients. Cancer 2001; 92: 1759–1768.. DOI: 10.1093/annonc/mdf108.

(3)