Chemotherapy following removal of periampullary cancer may improve survival
The results of ESPAC-3 randomised study
- Date : 19 Jul 2012
- Topic : Gastrointestinal cancers
Patients who had surgery for periampullary cancer and received chemotherapy had a statistically significant survival benefit, compared to patients who did not receive chemotherapy, after adjusting for prognostic variables, according to a study in the July 11 issue of JAMA.
Periampullary carcinomas arise from the head of the pancreas. The clinical presentation is similar to that of pancreatic ductal adenocarcinoma, and together they represent a major cause of death. Around 80% of periampullary adenocarcinomas are resectable and thus comprise around 30% to 40% of all resections for cancers in the head of the pancreas. Although chemotherapy after surgery has been shown to have a survival benefit for pancreatic cancer, there have been no randomised trials for periampullary adenocarcinomas.
Dr John Neoptolemos of the University of Liverpool, England, and colleagues conducted the European Study Group for Pancreatic Cancer (ESPAC)-3 periampullary trial, an open-label, phase III, randomised controlled study to determine whether adjuvant chemotherapy (fluorouracil or gemcitabine) provides improved overall survival following resection. The study was conducted from July 2000 to May 2008 in 100 centres in Europe, Australia, Japan, and Canada. Of the 428 patients included in the primary analysis, 297 had ampullary, 96 had bile duct, and 35 had other cancers.
One hundred forty-four patients were assigned to the observation group, 143 patients to receive folinic acid via intravenous bolus injection followed by fluorouracil via intravenous bolus injection administered 1 to 5 days every 28 days, and 141 patients to receive intravenous infusion of gemcitabine once a week for 3 of every 4 weeks for 6 months.
Two hundred forty-four patients (57%) had died at the time of analysis, 88 (61%) in the observation group, 83 (58%) in the fluorouracil plus folinic acid group, and 73 (52%) in the gemcitabine group. For the primary analysis, in the observation group, the median survival was 35.2 months and in the chemotherapy group 43.1 months.
Multivariate analysis found a statistically significant survival benefit to chemotherapy, but these results should be considered hypothesis generating
This is the largest randomised trial conducted in this group of patients. Based on the null hypothesis the unadjusted primary analysis of the primary outcome of survival did not demonstrate a significant benefit for adjuvant chemotherapy. Multivariate analysis, correcting for prognostic variables, found a statistically significant survival benefit to chemotherapy and specifically for gemcitabine compared with observation, notwithstanding the better safety profile compared with fluorouracil plus folinic acid, but these results should be considered hypothesis generating. There were different survival outcomes by tumour type, although age, poorly differentiated tumour grade, and lymph node involvement were also independent survival factors.
A clear survival advantage for each specific tumour type could not be embraced in the trial design because the relative low incidence for each of the tumour types would have demanded a very large number of patients with unreasonably long and unattainable timelines. Therefore, from a pragmatic point of view, there were strong arguments to combine the different tumour types because the clinical presentation is very similar and they are treated in exactly the same way by surgery. Moreover, tissue and molecular profiling cuts across these tumour types and have been productively combined in previous studies. From this trial, however, it is clear that improving survival results in the adjuvant setting for intrapancreatic bile duct cancer is much more challenging and may need to be considered as a completely separate entity. Thus grouping may need to be avoided not only with ampullary cancer but also more proximal bile duct cancers.
The authors discussed that although there was no single review of histological sections, all the pathology reports were reviewed centrally by several experienced pathologists, so this is unlikely to be a source of systemic error. In the absence of controlled trials, there has been a recent tendency to vary the treatment of patients with ampullary cancer based on whether the tumour displayed an intestinal or pancreatobiliary histological phenotype. At the start of this trial, this dichotomised classification was not being widely applied. In the present study, there were no statistically significant differences in survival between these ampullary subtypes.
The modest effect of adjuvant therapy
In patients with resectable disease attempts at improving survival have included more extensive surgery and adjuvant chemoradiation but have not been successful. At the time of designing this study, the best evidence for adjuvant therapy for pancreatic cancer was from the ESPAC-1 trial, demonstrating a significant improvement in survival with the addition of fluorouracil plus folinic acid using the Mayo regimen. In other cancer types, infusional fluorouracil regimens are commonly used. Although there are differences in toxicity profile, evidence of superior efficacy over the Mayo regimen in the adjuvant setting is lacking. Indeed in the parallel ESPAC-3 version 2 trial for pancreatic ductal adenocarcinoma of the pancreas, gemcitabine was not superior to the Mayo regimen with respect to the primary end point of overall survival.
The authors concluded that this study found support for the use adjuvant chemotherapy to improve survival in patients with periampullary cancers, this effect was modest, indicating a need for further improvements and warranting the testing of combination chemotherapies.
The study was supported by Cancer Research United Kingdom; 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 and The Australasian Gastro-Intestinal Trials Group. JPN is part funded Liverpool NIHR Pancreas Biomedical Research Unit. MM is part funded Oxford NIHR Biomedical Research Centre.
None of the sponsors or funders influenced the design and conduct of the study nor the collection, management, analysis, and interpretation of the data or in the preparation, review, or approval of the manuscript.
Dr Neoptolemos had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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