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Original Investigation
September 4, 2019

Patterns of Recurrence After Resection of Pancreatic Ductal Adenocarcinoma: A Secondary Analysis of the ESPAC-4 Randomized Adjuvant Chemotherapy Trial

Author Affiliations
  • 1The Royal Liverpool University Hospital, Liverpool, England
  • 2University of Liverpool, Liverpool, England
  • 3The Clatterbridge Cancer Centre, Wirral, England
  • 4University of Manchester/The Christie, Manchester, England
  • 5Manchester University Foundation Trust, Manchester, England
  • 6Royal Marsden Hospital, London, England
  • 7Weston Park Hospital, Sheffield, England
  • 8Royal Free Hospital, London, England
  • 9St. James's University Hospital, Leeds, England
  • 10Clinical Research Sörmland, Karolinska Institutet, Stockholm, Sweden
  • 11Clinical Research Sörmland, University of Uppsala, Uppsala, Sweden
  • 12Bristol Haematology and Oncology Centre, Bristol, England
  • 13University of Hamburg Medical Institutions UKE, Hamburg, Germany
  • 14Royal Surrey County Hospital, Guildford, England
  • 15Guy's Hospital, London, England
  • 16Hammersmith Hospital, London, England
  • 17The Beatson West of Scotland Cancer Centre, Glasgow, Scotland
  • 18Velindre Hospital, Cardiff, Wales
  • 19Queen Elizabeth Hospital, Birmingham, England
  • 20Churchill Hospital, Oxford, England
  • 21Derriford Hospital, Plymouth, England
  • 22Jersey General Hospital, Jersey, England
  • 23Skåne University Hospital, Lund, Sweden
  • 24University Hospital Coventry, Coventry, England
  • 25Hôpital Beaujon, Clichy, France
  • 26Greifswald University, Medicine, Greifswald, Germany
  • 27University Hospital Munich, Ludwig-Maximilians-University Munich, Germany
  • 28University of Heidelberg, Heidelberg, Germany
JAMA Surg. Published online September 4, 2019. doi:10.1001/jamasurg.2019.3337
Key Points

Question  What are the patterns of disease recurrence after resection of pancreatic cancer followed by systemic chemotherapy?

Findings  In this secondary analysis of a randomized clinical trial, median recurrence-free survival, median survival after recurrence, and the median overall survival were similar. Adjuvant gemcitabine plus capecitabine was associated with reduced rate of local recurrence compared with gemcitabine monotherapy and improved overall survival.

Meaning  Pancreatic cancer can be regarded as a systemic disease, irrespective of site of recurrence, requiring adjuvant systemic therapy after resection for effective treatment.


Importance  The patterns of disease recurrence after resection of pancreatic ductal adenocarcinoma with adjuvant chemotherapy remain unclear.

Objective  To define patterns of recurrence after adjuvant chemotherapy and the association with survival.

Design, Setting, and Participants  Prospectively collected data from the phase 3 European Study Group for Pancreatic Cancer 4 adjuvant clinical trial, an international multicenter study. The study included 730 patients who had resection and adjuvant chemotherapy for pancreatic cancer. Data were analyzed between July 2017 and May 2019.

Interventions  Randomization to adjuvant gemcitabine or gemcitabine plus capecitabine.

Main Outcomes and Measures  Overall survival, recurrence, and sites of recurrence.

Results  Of the 730 patients, median age was 65 years (range 37-81 years), 414 were men (57%), and 316 were women (43%). The median follow-up time from randomization was 43.2 months (95% CI, 39.7-45.5 months), with overall survival from time of surgery of 27.9 months (95% CI, 24.8-29.9 months) with gemcitabine and 30.2 months (95% CI, 25.8-33.5 months) with the combination (HR, 0.81; 95% CI, 0.68-0.98; P = .03). The 5-year survival estimates were 17.1% (95% CI, 11.6%-23.5%) and 28.0% (22.0%-34.3%), respectively. Recurrence occurred in 479 patients (65.6%); another 78 patients (10.7%) died without recurrence. Local recurrence occurred at a median of 11.63 months (95% CI, 10.05-12.19 months), significantly different from those with distant recurrence with a median of 9.49 months (95% CI, 8.44-10.71 months) (HR, 1.21; 95% CI, 1.01-1.45; P = .04). Following recurrence, the median survival was 9.36 months (95% CI, 8.08-10.48 months) for local recurrence and 8.94 months (95% CI, 7.82-11.17 months) with distant recurrence (HR, 0.89; 95% CI, 0.73-1.09; P = .27). The median overall survival of patients with distant-only recurrence (23.03 months; 95% CI, 19.55-25.85 months) or local with distant recurrence (23.82 months; 95% CI, 17.48-28.32 months) was not significantly different from those with only local recurrence (24.83 months; 95% CI, 22.96-27.63 months) (P = .85 and P = .35, respectively). Gemcitabine plus capecitabine had a 21% reduction of death following recurrence compared with monotherapy (HR, 0.79; 95% CI, 0.64-0.98; P = .03).

Conclusions and Relevance  There were no significant differences between the time to recurrence and subsequent and overall survival between local and distant recurrence. Pancreatic cancer behaves as a systemic disease requiring effective systemic therapy after resection.

Trial Registration  Clinicaltrials.gov Identifier: NCT00058201, EudraCT 2007-004299-38, and ISRCTN 96397434.

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