Oral Capecitabine as an Alternative to IV 5-fluorouracil-Based Adjuvant Therapy for Colon Cancer: Safety Results of a Randomized, Phase III Trial

Abstract & Commentary

Synopsis: Based on its improved safety profile, capecitabine has the potential to replace 5-FU/LV as standard adjuvant treatment for patients with colon cancer.

Source: Scheithauer, et al. Ann Oncol. 2003;14: 1735-1743.

Numerous clinical trials have demonstrated that adjuvant treatment with fluoropyrimidines improves outcomes for patients with resected colon cancer. There have been pooled analyses confirming increases in event-free and overall survival from therapy with 5-fluorouracil plus leucovorin.1

It is currently accepted that treatment with 5-FU/LV for 6-8 months is the standard adjuvant therapy for Dukes’ C (stage III) colon cancer, with trials showing no difference in the efficacy of weekly and monthly 5-FU/LV regimens.2 The efficacy of adjuvant therapy for high-risk Dukes’ B has also been demonstrated.3 Adjuvant treatment has also been shown to benefit older patients despite their low participation in clinical trials.4,5 There is also evidence that there is a considerable discrepancy between consensus recommendations and the use of adjuvant treatment in the community, particularly for older patients.6,7

In a randomized trial, treatment was discontinued in 24% of patients, primarily due to toxicity and lack of compliance.8 Capecitabine is an oral fluoropyrimidine that generates 5-FU preferentially in tumor tissue via a 3-step enzymatic sequence. Oral capecitabine is effective in the treatment of metastatic colorectal cancer.9,10 Capecitabine achieves a superior response rate and at least equivalent time to disease progression and overall survival compared with 5-FU/LV and an improved safety profile.11 The majority of patients prefer oral- and homebased therapy as long as efficacy is not compromised. The current international, multicenter, randomized, open-label phase III study evaluated capecitabine vs IV 5-FU/LV (Mayo Clinic regimen) as adjuvant therapy for patients with Dukes’ C colon cancer. This paper reports the planned safety analysis of 1987 patients.

Comment by Stuart M. Lichtman, MD

The study eligibility included patients aged 18-75 years who had histologically confirmed Dukes’ C colon carcinoma after surgery with curative intent. Patients were randomized to receive 24 weeks of treatment with either oral capecitabine 1250 mg/m2 twice daily, given on days 1-14 every 21 days or IV leucovorin 20 mg/m2 followed by IV bolus 5-FU 425 mg/m2, days 1-5 every 28 days. In all, 1987 patients were enrolled in 164 centers. Patients receiving capecitabine experienced significantly less diarrhea (46% vs 64%), nausea/vomiting (36% vs 51%), stomatitis (22% vs 60%), alopecia (6% vs 22%), and neutropenia (2% vs 8%). Only hand-foot syndrome was more common with capecitabine (62% vs 10%). Grade 3 hyperbilirubinemia was more common with capecitabine (18.6% vs 5.9%). Capecitabine showed a more favorable safety profile than 5-FU/LV in both younger and older patients. Older patients had more severe toxicity with the 5-FU/LV regimen; in capecitabine-treated patients there was no age difference. Premature withdrawal due to adverse events occurred in 12% of patients receiving capecitabine and 8% of those receiving 5-FU/LV. Overall, there was a low incidence of all-cause, 60-day mortality, with 5 deaths in the capecitabine arm and 4 in the 5-FU/LV arm.

The current study is the first step to try to determine whether an oral regimen can replace IV therapy for the adjuvant treatment of colon cancer. A less-toxic regimen would hopefully lead to greater compliance and allow more patients to benefit from therapy. This study showed that capecitabine might fulfill some of these criteria when compared to the Mayo Clinic adjuvant regimen. This regimen may have been a too-toxic comparator for single-agent capecitabine. There are alternative 5-FU/LV regimens that have less toxicity, particularly in older patients, which may have also been appropriate.12,13 There are emerging results from oxaliplatin combined with bolus/infusion 5-FU/LV as adjuvant treatment.14 Capecitabine may be an attractive alternative to replace 5-FU/LV in this regimen. A large, international study has shown that capecitabine in combination with oxaliplatin is active, first-line treatment for metastatic colorectal cancer, achieving similar efficacy.15 The conclusion is that from a safety perspective, capecitabine can replace 5-FU/LV as the standard adjuvant treatment for patients with colon cancer.

Dr. Lichtman is Associate Professor of Medicine NYU School of Medicine Division of Oncology; Don Monti Division of Medical Oncology North Shore University Hospital, Manhasset, NY.


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