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

E. Van Cutsem1, P. M. Hoff2, J. L. Blum3, M. Abt4 and B. Osterwalder5

1University 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; 4Biostatistics, F. Hoffmann-La Roche Ltd, Basel, Switzerland; 5Clinical Science, F. Hoffmann-La Roche Ltd, Basel, Switzerland (E-mail: eric.vancutsem@uz.kuleuven.ac.be)

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 angina-like 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 monotherapy (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).


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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)
 
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 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 m1, P. M. Hoff2, J. L. Blum3, M. Abt4 & B. Osterwalder5

1University 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; 4Biostatistics, F. Hoffmann-La Roche Ltd, Basel, Switzerland; 5Clinical Science, F. Hoffmann-La Roche Ltd, Basel, Switzerland (E-mail: Eric.VanCutsem@uz.kuleuven.ac.be)

References

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