In the largest adjuvant trial conducted in pancreatic cancer to date, patients treated with fluorouracil plus folinic acid had a median survival of 23.0 months, compared with 23.6 months for those treated with gemcitabine. The median progression-free survival was 14.1 and 14.3 months, respectively.
The study results, initially presented at the 2009 annual meeting of the American Society of Clinical Oncology and reported by Medscape Medical News at that time, appear in the September 8 issue of JAMA.
"Gemzar arrived in 1996 and changed the treatment landscape for advanced pancreatic cancer. It acquired a mythical status," lead author John P. Neoptolemos, MD, head of the Division of Surgery and Oncology at the University of Liverpool in the United Kingdom, told Medscape Medical News at that time.
Dr. Neoptolemos noted that American clinicians tend to feel that fluorouracil might not be as effective. Gemcitabine combined with radiation has become the treatment of choice in the United States, whereas fluorouracil remains the preferred therapy in Europe and other regions, he explained.
In addition to similar overall and progression-free survival, the authors found that there were no significant differences between treatment groups in global quality-of-life scores.
However, more toxic effects were reported by patients receiving fluorouracil plus folinic acid. A total of 77 patients (14%) in that group reported 97 treatment-related serious adverse events, whereas 40 patients (7.5%) in the gemcitabine group reported 52 events (P < .001).
How Do Results Affect Treatment?
This study is the third trial conducted by the European Study Group for Pancreatic Cancer investigators (ESPAC-3), and they have "sequentially evaluated important questions involving adjuvant therapy," writes Eileen M. O'Reilly, MD, from the Memorial Sloan-Kettering Cancer Center in New York City in an accompanying editorial.
"Adjuvant therapy for resected pancreatic adenocarcinoma is now firmly established as offering a modest but real improvement in overall survival at 5 years with about double the number of patients alive compared with no treatment," she writes, adding that the "ESPAC investigators have significantly contributed to the establishment of standard adjuvant therapy."
But how do the results of ESPAC-3 affect current adjuvant treatment for pancreatic adenocarcinoma? Dr. O'Reilly points out that consensus favors gemcitabine: the results of the CONKO-001 (Charité Onkologie) study demonstrated a survival advantage for gemcitabine over observation alone; gemcitabine's toxicity profile is more favorable than bolus fluorouracil; and the results of RTOG 97-04 (Radiation Therapy Oncology Group) reported a survival trend favoring gemcitabine.
However, for patients unable to tolerate gemcitabine, "there is now a clearly validated alternative," she writes.
The ESPAC-4 trial, which is currently in progress, is a logical progression from the questions that the ESPAC investigators have been methodically exploring, notes Dr. O'Reilly. The study examines whether the combination of capecitabine plus gemcitabine, compared with gemcitabine alone, will improve survival. These results will probably be available in 5 to 7 years.
Over the next decade, practice will be refined by results from the ongoing European and American studies, but "there is much to be done, including identification of new and active drugs for treating pancreatic cancer that may be translated into the adjuvant setting," she notes.
Study Details
ESPAC-3 trial was conducted in 159 pancreatic cancer centers in Europe, Australasia, Japan, and Canada, and consisted of 1088 patients with pancreatic ductal adenocarcinoma who had undergone resection.
From July 2000 to January 2007, participants were randomized to 1 of 2 groups: 551 patients received fluorouracil plus folinic acid (an intravenous bolus injection of folinic acid, 20 mg/m2, followed by an intravenous bolus injection fluorouracil, 425 mg/m2, given 1 to 5 days every 28 days); and 537 patients received gemcitabine (an intravenous infusion, 1000 mg/m2, once a week for 3 of every 4 weeks) for 6 months. All patients were followed for at least 2 years.
The final analysis was conducted on an intention-to-treat basis after a median of 34.2 months and after 753 (69%) of the patients had died.
Estimates of survival at 12 and 24 months were 78.5% and 48.1%, respectively, for patients receiving fluorouracil plus folinic acid, and 80.1% and 49.1% for those receiving gemcitabine. There was no statistically significant difference in survival estimates between groups.
For progression-free survival, estimates at 12 and 24 months were 56.1% and 30.7%, respectively, for the fluorouracil plus folinic acid group and 61.3% and 29.6% for the gemcitabine group.
A total of 117 patients (11%) reported 149 treatment-related serious adverse events, with the majority attributable to inpatient hospitalization. Patients in the fluorouracil plus folinic acid group reported a significantly higher rate of grade 3/4 stomatitis (10% vs 0%) and diarrhea (13% vs 2%), whereas patients in the gemcitabine group reported significantly more grade 3/4 hematologic toxicity (P = .003).
This study was supported by Cancer Research UK; National Cancer Institute of Canada, Canadian Cancer Society; Fonds de Recherche de la Société Nationale Française de Gastroentérologie; Fondazioone Italiana Malattie del Pancreas; Health and Medical Research Council of Australia, Cancer Councils of New South Wales, Queensland, Victoria, and South Australia. The work of coauthor David Cunningham, MD, from the Royal Marsden National Health Service Foundation Trust, London and Surrey, United Kingdom, is funded in part by the National Institute for Health Research Biomedical Research Centre at the Royal Marsden Hospital. The remaining authors have disclosed no relevant financial relationships. Dr. O'Reilly reports receiving research funding from Sanofi-Aventis and consulting fees from Genentech.
JAMA. 2010;304:1073-1081, 1124-1125.
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