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Adjuvant Chemotherapy for Resected Periampullary Adenocarcinoma—Reply

Adjuvant Chemotherapy for Resected Periampullary Adenocarcinoma—Reply In Reply: The ESPAC-3 periampullary cancer trial demonstrated a significant survival benefit for adjuvant chemotherapy, adjusting for prognostic variables. Dr Overman and colleagues have suggested a central pathology review to be more certain about the origin of the primary tumor in the patients enrolled in the trial. Such a review was not possible in a large trial spanning several continents because of logistical considerations and, for certain countries, regulatory constraints governing the international transport of clinical samples. To minimize error, the trial was restricted to pancreatic cancer centers and required completion of a detailed histopathology registration form as well as the pathology report itself being faxed to the central, international Clinical Trials Unit prior to any patient being considered against the eligibility criteria. The EORTC study1 comprised 92 patients with periampullary and 104 patients with pancreatic ductal adenocarcinoma who were recruited from only 4 neighboring countries. Central pathology review in 178 (82%) of 218 patients initially recruited revised the diagnosis in 9 (5%) patients but only between periampullary and pancreatic cancers and not among periampullary tumor types. This level of error would not have influenced the outcome in either trial. Of the 434 patients with periampullary cancer initially randomized in ESPAC-3, only 3 patients were found to have pancreatic cancer and were excluded. In the subsequent central review of the pathology reports, there was no reclassification between periampullary and pancreatic ductal adenocarcinomas. At the start of this trial (July 2000), there was no distinction between intestinal and pancreatobiliary histological phenotypes for patients with ampullary cancer. This classification was developed in later years; therefore, there has been a tendency more recently to vary the treatment based on such a dichotomy. We were able to explore this by retrospectively classifying 135 (46%) of the 196 ampullary cancers, reflecting the quality of the pathology reporting over this 11-year period. This specific hypothesis is being tested in the ESPAC-4 periampullary cancer trial by prospective histological classification. The relative distribution of the different tumor types in the trial should not be taken as representative of the actual distribution because the patients entered in the trial were not consecutive. The skewed distribution of the different tumor types reflects local and shifting prejudices to adjuvant treatment of specific tissue types during the conduct of the trial rather than discrepancies in histological reporting. The protocol stated that treatment should be started up to 8 weeks following resection but commencement beyond this time point would also be permitted judged on individual case circumstances at the discretion of the central Clinical Trials Unit. The ESPAC investigator team is conducting a detailed analysis of the effect of timing on the start of chemotherapy and the dose intensity on outcomes. Restaging imaging was not mandated (although 4 patients did not start adjuvant treatment because of the interim development of metastases) because this was a large randomized study that included an observation control group and was analyzed on an intention-to-treat basis. Back to top Article Information Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. References 1. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC Gastrointestinal Tract Cancer Cooperative Group. Ann Surg. 1999;230(6):776-78410615932PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Adjuvant Chemotherapy for Resected Periampullary Adenocarcinoma—Reply

JAMA , Volume 308 (18) – Nov 14, 2012

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Publisher
American Medical Association
Copyright
Copyright © 2012 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.2012.13955
Publisher site
See Article on Publisher Site

Abstract

In Reply: The ESPAC-3 periampullary cancer trial demonstrated a significant survival benefit for adjuvant chemotherapy, adjusting for prognostic variables. Dr Overman and colleagues have suggested a central pathology review to be more certain about the origin of the primary tumor in the patients enrolled in the trial. Such a review was not possible in a large trial spanning several continents because of logistical considerations and, for certain countries, regulatory constraints governing the international transport of clinical samples. To minimize error, the trial was restricted to pancreatic cancer centers and required completion of a detailed histopathology registration form as well as the pathology report itself being faxed to the central, international Clinical Trials Unit prior to any patient being considered against the eligibility criteria. The EORTC study1 comprised 92 patients with periampullary and 104 patients with pancreatic ductal adenocarcinoma who were recruited from only 4 neighboring countries. Central pathology review in 178 (82%) of 218 patients initially recruited revised the diagnosis in 9 (5%) patients but only between periampullary and pancreatic cancers and not among periampullary tumor types. This level of error would not have influenced the outcome in either trial. Of the 434 patients with periampullary cancer initially randomized in ESPAC-3, only 3 patients were found to have pancreatic cancer and were excluded. In the subsequent central review of the pathology reports, there was no reclassification between periampullary and pancreatic ductal adenocarcinomas. At the start of this trial (July 2000), there was no distinction between intestinal and pancreatobiliary histological phenotypes for patients with ampullary cancer. This classification was developed in later years; therefore, there has been a tendency more recently to vary the treatment based on such a dichotomy. We were able to explore this by retrospectively classifying 135 (46%) of the 196 ampullary cancers, reflecting the quality of the pathology reporting over this 11-year period. This specific hypothesis is being tested in the ESPAC-4 periampullary cancer trial by prospective histological classification. The relative distribution of the different tumor types in the trial should not be taken as representative of the actual distribution because the patients entered in the trial were not consecutive. The skewed distribution of the different tumor types reflects local and shifting prejudices to adjuvant treatment of specific tissue types during the conduct of the trial rather than discrepancies in histological reporting. The protocol stated that treatment should be started up to 8 weeks following resection but commencement beyond this time point would also be permitted judged on individual case circumstances at the discretion of the central Clinical Trials Unit. The ESPAC investigator team is conducting a detailed analysis of the effect of timing on the start of chemotherapy and the dose intensity on outcomes. Restaging imaging was not mandated (although 4 patients did not start adjuvant treatment because of the interim development of metastases) because this was a large randomized study that included an observation control group and was analyzed on an intention-to-treat basis. Back to top Article Information Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. References 1. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC Gastrointestinal Tract Cancer Cooperative Group. Ann Surg. 1999;230(6):776-78410615932PubMedGoogle ScholarCrossref

Journal

JAMAAmerican Medical Association

Published: Nov 14, 2012

References