Easier Regimen Effective for Advanced Gastroesophageal Cancer

By Judith Groch
LONDON, Jan. 3 -- There seems to be an alternative approach to untreated advanced gastroesophageal cancer that is easier on patients than a standard regimen, with no less efficacy. In a multicenter randomized trial, capecitabine (Xeloda) and oxaliplatin (Eloxatin), as alternatives to the standard infused fluorouracil and cisplatin (Platinol), matched the older regimen, researchers here reported in the Jan. 3 issue of the New England Journal of Medicine.
Capecitabine, an oral fluoropyrimidine, plus oxaliplatin, a platinum compound, was as effective in prolonging overall survival as fluorouracil and cisplatin, found David Cunningham, M.D., of Royal Marsden Hospital National Health Service Foundation here, and colleagues in Britain and Australia.
Triple chemotherapy with epirubicin (Ellence) plus cisplatin and fluorouracil is standard for advanced gastroesophageal cancer. However, fluorouracil must be infused through an ambulatory infusion pump, which impairs quality of life, while cisplatin, which is nephrotoxic, requires IV hydration, the researchers said.
The phase 3 noninferiority trial for overall survival was designed to determine whether infused fluorouracil can be replaced by oral capecitabine and cisplatin by IV oxaliplatin, which can be given by IV in two hours and does not require hydration. Cisplatin lengthens outpatient visits or may require overnight hospital admission, the researchers said.
From June 2000 through May 2005, 1,002 patients were randomly assigned in a two-by-two study to three-drug therapy with epirubicin and cisplatin plus either fluorouracil or capecitabine. A second group received epirubicin and oxaliplatin plus either fluorouracil or capecitabine.
For the capecitabine-fluorouracil comparison, the hazard ratio for death in the capecitabine group was 0.86 (95% confidence interval: 0.80 to 0.99).
For the oxaliplatin-cisplatin comparison, the hazard ratio for the oxaliplatin group was 0.92 (95% CI: 0.80 to 1.10). For all comparisons, P=0.36.
The upper limit of the confidence intervals for both hazard ratios were well below the predefined noninferiority margin of 1.23, thereby showing noninferiority of both capecitabine and oxaliplatin in the two-by-two comparisons, the researchers said.
Median follow-up was 17.1 months. All groups received epirubicin. Median survival times in the four groups -- cisplatin plus either fluorouracil or capecitabine and oxaliplatin plus either fluorouracil or capecitabine were 9.9 months, 9.9 months, 9.3 months, and 11.2 months, respectively.
Survival rates at one year were 37.7%, 40.8%, 40.4%, and 46.8%, respectively, the researchers reported.
In a secondary analysis, overall survival was longer with the oxaliplatin plus capecitabine group than with cisplatin plus fluorouracil group, with a hazard ratio for death of 0.80 in the oxaliplatin plus capecitabine group (95% CI: 0.66 to 0.97, P=0.02).
Progression-free survival and response rates did not differ significantly among the regimens, while the toxic effects of capecitabine and fluorouracil were similar, the researchers reported.
A planned multivariate analysis confirmed the robustness of the noninferiority result for the primary analysis. Performance status, extent of disease, and age were included in the model.
The subsite of the tumor (esophagus, gastroesophageal junction, or stomach) and the results of histologic analysis (adenocarcinoma or squamous-cell carcinoma) did not significantly affect survival. These variables were excluded from the model, the researchers said.
There was a nonsignificant trend toward improved survival in the capecitabine groups as compared with the fluorouracil groups in the intention-to-treat analysis, they reported.
Compared with cisplatin, oxaliplatin was associated with lower rates of grade 3 or 4 neutropenia, alopecia, renal toxicity, and thromboembolism, but with slightly higher rates of grade 3 or 4 diarrhea and neuropathy.
This study was supported in part by Hoffmann-La Roche, maker of capecitabine, and sanofi-aventis, maker of oxaliplatin, together with the Gastrointestinal Unit Clinical Research Fund of the Royal Marsden Hospital. The study was conducted under the auspices of the National Cancer Research Institute, of Britain, and the Royal Marsden Hospital.
Dr. Cunningham reported receiving consulting and lecture fees and research grants from Hoffmann-La Roche and sanofi-aventis, and serving as an expert witness for Roche.
Primary source: New England Journal of MedicineSource reference:Cunningham D, et al "Capecitabine and Oxaliplatin for Advanced Esophagogastric Cancer" N Engl J Med 2008; 358: 36-46.