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Clinical Trial
. 2019 Nov 1;154(11):1038-1048.
doi: 10.1001/jamasurg.2019.3337.

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

Robert P Jones  1 , Eftychia-Eirini Psarelli  2 , Richard Jackson  2 , Paula Ghaneh  1   2 , Christopher M Halloran  1   2 , Daniel H Palmer  2   3 , Fiona Campbell  1 , Juan W Valle  4 , Olusola Faluyi  3 , Derek A O'Reilly  5 , David Cunningham  6 , Jonathan Wadsley  7 , Suzanne Darby  7 , Tim Meyer  8 , Roopinder Gillmore  8 , Alan Anthoney  9 , Pehr Lind  10 , Bengt Glimelius  11 , Stephen Falk  12 , Jakob R Izbicki  13 , Gary William Middleton  14 , Sebastian Cummins  14 , Paul J Ross  15 , Harpreet Wasan  16 , Alec McDonald  17 , Tom Crosby  18 , Yuk Ting  19 , Kinnari Patel  20 , David Sherriff  21 , Rubin Soomal  22 , David Borg  23 , Sharmila Sothi  24 , Pascal Hammel  25 , Markus M Lerch  26 , Julia Mayerle  26   27 , Christine Tjaden  28 , Oliver Strobel  28 , Thilo Hackert  28 , Markus W Büchler  28 , John P Neoptolemos  28 ; European Study Group for Pancreatic Cancer
Affiliations
Clinical Trial

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

Robert P Jones et al. JAMA Surg. .

Abstract

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Neoptolemos has received grants from Cancer Research UK, Pancreas Cancer UK, National Institutes for Health Research, the European Union, Immunovia, Nucana, Taiho Pharma (Japan), KAEL GemVax (Korea), AstraZeneca, Clovis Oncology and Ventana, and Pharma Nord; payment for lectures from Amgen and Mylan; paid consultancy from Targovax, Erytech, Redhill Biopharma, Boehringer Ingelheim Pharma GmbH & Co KG, Novartis Pharma AG, KAEL GemVax, and Astellas; and educational travel grants from NuCana; Dr Neoptolemos was a National Institutes for Health Research senior investigator and was partly funded by the National Institutes for Health Biomedical Research Centre at the Royal Liverpool University, Liverpool, England. Dr Ghaneh has grants from Cancer Research UK and the National Institutes for Health Research. Dr Palmer has grants from Cancer Research UK, Nucana, and the National Institutes for Health Research and educational travel grants from NuCana. Dr Halloran has grants from Cancer Research UK, the National Institutes for Health Research, and the Royal College of Surgeons of England. Dr Cunningham is funded by the National Institutes of Health at the Royal Marsden Hospital. Dr Glimelius has funds from the Swedish Cancer Society. Dr Büchler is on the Board of B Braun, Melsungen AG. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram of European Study Group for Pancreatic Cancer 4
Figure 2.
Figure 2.. Kaplan-Meier Curves Showing Survival From Time of Recurrence
A, Recurrence stratified by local vs distant disease. B, Recurrence stratified by organ of recurrence.
Figure 3.
Figure 3.. Forest Plot Comparing Competing Risks Results for Local Recurrence, Distant Recurrence, and Overall Survival (OS)
See this image and copyright information in PMC

Comment in

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