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Severe Sequence-Specific Toxicity When Capecitabine Is Given After Fluorouracil and Leucovorin

Ivo M. Hennig, Jay D. Naik, Sarah Brown, Alex Szubert, David A. Anthoney, David P. Jackson, Alan M. Melcher, S. Michael Crawford, Christopher Bradley, Julia M.B. Brown, Matthew T. Seymour

From the St James's Institute of Oncology, St James's University Hospital; Clinical Trials Research Unit, University of Leeds, Leeds; Airedale General Hospital, Keighley; Bradford Royal Infirmary, Bradford; and York District Hospital, York, United Kingdom

Corresponding author: Matthew Seymour, MA, MD, FRCP, Cancer Research UK Centre, St James's Institute of Oncology, St James's University Hospital, Leeds LS9 7TF, United Kingdom; e-mail: matt.seymour{at}leedsth.nhs.uk

Purpose Options for single-agent fluoropyrimidine adjuvant therapy after bowel cancer resection include intravenous fluorouracil with leucovorin (FU/LV) or oral capecitabine. These treatments have similar efficacy but differ in convenience and toxicity. We therefore wished to compare their overall acceptability to patients.

Patients and Methods Patients scheduled for adjuvant single-agent fluoropyrimidine therapy were randomly assigned to receive once-weekly FU/LV (425 mg/m² FU, 45 mg LV) for 6 weeks, followed by two 3-week cycles of capecitabine (1,250 mg/m² twice daily, days 1 through 14), or the same treatments but in reverse order. After 12 weeks, the patients were asked which treatment they preferred, and received the preferred treatment for an additional 12 weeks. The primary end point was patient preference.

Results After 40 of the planned 74 patients had been randomly assigned, real-time adverse event monitoring led to early trial closure because of excess sequence-specific toxicity. Eleven of 14 patients (79%) receiving capecitabine as their second treatment experienced grade 3 toxicity. This compared with five of 18 patients (28%) receiving capecitabine as the first treatment, and no patients receiving FU/LV as the first treatment (zero of 16) or the second treatment (zero of 12). Similar imbalances were seen in the proportion of patients requiring interruption of treatment.

Conclusion In chemotherapy-naïve patients, capecitabine produced more toxicity than FU/LV, but at levels in line with previously reported data. However, treatment with capecitabine after FU/LV caused markedly increased toxicity, indicating a sequence-specific interaction. The mechanism has not been determined, but interaction with intracellularly retained folate after FU/LV therapy is a possibility. Oncologists need to be aware of this risk if considering crossing patients over from FU/LV to capecitabine-based regimens.

Supported by Cancer Research (United Kingdom), and the National Health Service Trusts of each participating institution which include the St James's Institute of Oncology, St James's University Hospital, Leeds; Bradford Royal Infirmary, Bradford; Airedale General Hospital, Keighley; Harrogate District Hospital, Harrogate; York District Hospital, York; Huddersfield Royal Infirmary, Huddersfield; and the University of Leeds Clinical Trials Research Unit, Leeds, United Kingdom. Additional support by an unrestricted educational grant from Roche Pharmaceuticals.

J.D.N. and I.M.H. contributed equally to the writing of this article.

Presented at the European Society of Medical Oncology Conference, July 5-8, 2007, Lugano, Switzerland.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical Trials repository link available on www.JCO.org.

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