Capecitabine Should Replace 5-FU in Adjuvant Treatment of Dukes’ C Colon Cancer, Investigator Avers

NEW ORLEANS-Oral capecitabine(Drug information on capecitabine) (Xeloda) should supplant the current standard intravenous fluorouracil(Drug information on fluorouracil)/ leucovorin (5-FU/LV) regimen, owing to its superior safety, and efficacy that is at least equivalent to the standard of care, according to James Cassidy, MD. "At least in my opinion, capecitabine should replace bolus 5-FU and leucovorin in the adjuvant treatment of Dukes' C colon cancer patients," said Dr. Cassidy, chair of the Cancer Research United Kingdom Department of Medical Oncology, Glasgow University, at the 40th Annual Meeting of the American Society of Clinical Oncology. Dr. Cassidy reported new results from the X-ACT trial (Xeloda in Adjuvant Colon Cancer Therapy) that included nearly 2,000 patients with (stage III)/Dukes' C colon cancer who underwent curative surgery followed by chemotherapy (abstract 3509) (Figure 1). The study met its primary endpoint of achieving disease-free survival at least equivalent to standard 5-FU/leucovorin, while other clinical endpoints suggested superiority to the standard of care. In addition, capecitabine-treated patients had a significantly lower incidence of the most severe toxicities. "There is a trend to improved diseasefree survival, and almost superiority in overall survival," Dr. Cassidy said. Relapse-free survival was superior. "There is definitely improved safety. In every important side effect, capecitabine is better," Dr. Cassidy noted. Potential for Change
Findings of the X-ACT trial have the "potential to bring a change to the current standard of adjuvant treat- ment" for colon cancer, according to Howard A. Burris III, MD, of the Sarah Cannon Cancer Center, Nashville, Tennessee. Dr. Burris, one of more than 160 investigators in the X-ACT study, said results show that "a convenient oral regimen can be used in place of hours of cumbersome chemotherapy." By intent-to-treat analysis, 3-year disease-free survival was 64.2% in the capecitabine arm vs 60.6% for 5-FU/ leucovorin (hazard ratio [HR] = 0.87, 95% confidence interval [CI], 0.75- 1.00, P = .0528, see Figure 2). "Certainly, I think one could interpret this as showing at least equivalence-certainly not inferiority, and almost certainly a degree of superiority," Dr. Cassidy said. These results show that treatment with capecitabine produced a 13% reduction in the risk of disease relapse or death from any cause when compared to IV 5-FU. The X-ACT trial is an "excellent equivalence trial" that has indeed achieved its primary objective of showing equivalence to 5-FU/LV, said Eric Van Cutsem, MD, PhD, of the Digestive Oncology Unit, University Hospital Gathuisberg; Leuven, Belgium. "The conclusions of the X-ACT trial are that capecitabine is at least as effective as bolus 5-FU/folinic acid, with a trend to improved activity," Dr. Van Cutsem said. "Also, Dr. Cassidy has shown us that capecitabine is less toxic than bolus 5-FU." All Chemotherapy-Naive
All patients in X-ACT had chemotherapy- naive Dukes' C colon cancer with curative resection and were randomized to capecitabine or bolus 5- FU/leucovorin. Capecitabine was given at a dosage of 1,250 mg/m² twice daily for 14 days in a 21-day cycle. Alternatively, patients received the Mayo Clinic regimen of 5-FU 425 mg/m² and leucovorin 20 mg/m², given on days 1 to 5 every 28 days. In total, both patient groups received 24 weeks of treatment (eight cycles of capecitabine or six cy cles of 5-FU/LV). Median age of patients in X-ACT was approximately 62 years and 85% were Eastern Clinical Oncology Group (ECOG) performance status (PS) 0, with 15% having a PS of 1. More than 80% of patients had normal carcinoembyronic antigen (CEA) and the majority (76%) had T3 disease. Median follow-up at the time of this analysis was 3.8 years. While the primary endpoint of equivalence in disease-free survival was met, relapse-free survival actually met statistical criteria for superiority favoring capecitabine. Three-year relapse- free survival was 65.5% for capecitabine vs 61.9% for 5-FU/leucovorin (HR = 0.86, 95% CI 0.74- 0.99, P = .0407). "At least for this particular endpoint, capecitabine is clearly superior to the Mayo Clinic regimen," Dr. Cassidy said. The difference translates into a 14% reduction in risk of relapse from colon can- cer among patients treated with capecitabine. Overall survival also showed a trend in improvement favoring capecitabine. Three-year overall survival was 81.3% for capecitabine and 77.6% for 5-FU/leucovorin (HR = 0.84, 95% CI 0.69-1.01, P = .0706). This difference translates into a 16% reduction in risk of death compared to IV 5-FU. "We need to follow the patients longer," Dr. Cassidy said, "[but] the separation [in survival curves] is in the direction of an advantage for capecitabine." Capecitabine also offered an improved side effect profile. Previously published safety results (Ann Oncol 14(12):1735-1743, 2003), show that there was significantly less diarrhea, stomatitis, neutropenia, nausea/vomiting, and alopecia in the capecitabine arm vs the 5-FU/leucovorin arm (P < .001). Hand-foot syndrome was significantly more common in the capecitabine arm. This responded "very well" to dose reductions "and of course, it's an inconvenience, but not a serious side effect, at least in my opinion," Dr. Cassidy said. Potential Criticisms Addressed
According to Dr. Van Cutsem, one point of discussion for X-ACT is the use of bolus 5-FU/leucovorin instead of infusional 5-FU/leucovorin as a control arm. "We have data from some studies-an intergroup study in the United States and a French study- that show an identical activity of bolus vs infusional 5-FU regimen in the adjuvant setting," he said. The X-ACT investigators also addressed another potential criticism up front-whether the performance of the Mayo Clinic regimen was inferior to what has been observed in other studies. In fact, the Mayo arm in X-ACT had comparable efficacy with other trial data in Dukes' C patients. For example, the 3-year disease-free survival of 61% was comparable to findings of 61%, 62%, and 63% in three other trials comprising a total of more than 1,300 patients. "There really is no difference here, so that potential explanation is not valid," Dr. Cassidy said. One other potential criticism was that the desired chemotherapy duration or intensity may not have been achieved in one or both arms. There was no difference, however, in the number of patients completing the full course of treatment (84% for capecitabine and 88% for bolus 5-FU/ leucovorin), the number of patients needing dose reduction (42% and 44%), or the number needing interruption or delay (57% and 52%). FDA Approval Sought
This report on X-ACT was one of two suggesting an important role for oral fluoropyrimidines in the adjuvant treatment of colon cancer. Also reported was a randomized trial of tegafur(Drug information on tegafur)-uracil (UFT) vs 5-FU/leucovorin (see report on abstract 3508 on page 13). "The data for capecitabine, based on the trials that we have seen today, are more solid," Dr. Van Cutsem added. For the future, a major question will be whether capecitabine can replace 5-FU/leucovorin in combination regimens in the adjuvant setting. In particular, Dr. Van Cutsem suggested potential combinations can be explored with oral fluoropyrimidines plus oxaliplatin(Drug information on oxaliplatin) (Eloxatin) or irinotecan (CPT-11, Camptosar), or with novel targeted agents such as bevacizumab(Drug information on bevacizumab) (Avastin) and cetuximab(Drug information on cetuximab) (Erbitux). "We can conclude that the oral fluoropyrimidines are to be preferred to bolus intravenous 5-FU/folinic acid in the adjuvant treatment of colon cancer," he said. Capecitabine is currently indicated as first-line treatment of metastatic colorectal cancer when treatment with fluoropyrimidine therapy alone is preferred. Results of the X-ACT trial were submitted to the FDA in August to support the use of capecitabine for adjuvant treatment of colon cancer.