Annals of Oncology 13:566-575, 2002
© 2002 European Society for Medical Oncology
Original Paper |
First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin
1Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, UK; 2Cancer Research Campaign Department, University of Glasgow, and Beatson Oncology Centre, Glasgow, UK; 3University Hospital Gasthuisberg, Leuven, Belgium; 4MD Anderson Cancer Center, Houston, TX, USA; 5Istituto Nazionale Tumori, Milan, Italy; 6Department of Medical Oncology, Royal Prince Alfred Hospital, Camperdown, Australia; 7Department D’Oncologie Medicale, Center Claudius Regaud, Toulouse, France; 8F. Hoffmann-La Roche Ltd, Basel, Switzerland; 9Russian Research Center, Moscow, Russia; 10Medizinische Universitätsklinik, Knappschaftskrankenhaus, Bochum, Germany; 11Department of Oncology, Box Hill Hospital, Melbourne, Australia; 12Ottawa Regional Cancer Center, Ottawa, Canada; 13Developmental Therapeutics and Gastroenterology Oncology, Lombardi Cancer Center, Washington, DC, USA; 14Servicio de Oncologia, Hospital Gregorio Marañón, Madrid, Spain; 15Oncologia Medica, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; 16Department of Gastroenterology, Hospital Ambroise Pare, Boulogne, France; 17Biological Sciences Division, University of Chicago, Chicago, IL, USA
Received 2 May 2001; revised 26 September 2001; accepted 10 October 2001.
Purpose
To evaluate the safety profile of capecitabine using data from a large, well-characterized population of patients with metastatic colorectal cancer treated in two phase III studies. In these trials, capecitabine achieved significantly superior response rates, equivalent time to disease progression and equivalent survival compared with 5-fluorouracil (5-FU)/leucovorin.
Patients and methods
Patients (n = 1207) were randomized to either oral capecitabine (1250 mg/m2 twice daily, on days 1–14 every 21 days) or intravenous (i.v.) bolus 5-FU/leucovorin (Mayo Clinic regimen).
Results
Capecitabine demonstrated a safety profile superior to that of 5-FU/leucovorin, with a significantly lower incidence of diarrhea, stomatitis, nausea, alopecia and grade 3 or 4 neutropenia leading to significantly fewer neutropenic fever/sepsis cases and fewer hospitalizations. All patients in the capecitabine group received a starting dose of 1250 mg/m2 twice daily and the majority (66%) did not require dose modification for adverse events. In the 5-FU/leucovorin group, 58% of patients did not require dose reduction for toxicities. The capecitabine dose-modification scheme reduced the recurrence of key toxicities without compromising efficacy. In both treatment arms, patients with moderate renal impairment at baseline (estimated creatinine clearance 30–50 ml/min) experienced a higher incidence of grade 3 or 4 toxicities. This increase was more pronounced with 5-FU/leucovorin.
Conclusions
Capecitabine is at least as effective, better tolerated and more convenient than i.v. 5-FU/leucovorin as treatment for patients with metastatic colorectal cancer. Analysis of data from two large phase III trials demonstrates that efficacy is not compromised in patients requiring a dose reduction for adverse events. The phase III data and an additional pharmacokinetic study support a lower starting dose in patients with moderate renal impairment at baseline (calculated creatinine clearance 30–50 ml/min) and a contra-indication in patients with severely impaired creatinine clearance at baseline (<30 ml/min). For patients with normal or mildly impaired renal function at baseline, the standard starting dose is well tolerated. The incidence and severity of adverse events in patients with moderate renal impairment at baseline who were treated with 5-FU/leucovorin was more pronounced, indicating that capecitabine provides a better-tolerated alternative.
Key words: capecitabine, colorectal cancer, fluoropyrimidine, tolerability
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