Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial

Research output: Contribution to journalArticlepeer-review

Authors

  • John P Neoptolemos
  • Daniel H Palmer
  • Paula Ghaneh
  • Eftychia E Psarelli
  • Juan W Valle
  • Christopher M Halloran
  • Olusola Faluyi
  • Derek A O'Reilly
  • David Cunningham
  • Jonathan Wadsley
  • Suzanne Darby
  • Tim Meyer
  • Roopinder Gillmore
  • Alan Anthoney
  • Pehr Lind
  • Bengt Glimelius
  • Stephen Falk
  • Jakob R Izbicki
  • Gary Middleton
  • Sebastian Cummins
  • Paul J Ross
  • Harpreet Wasan
  • Alec McDonald
  • Tom Crosby
  • Yuk Ting Ma
  • Kinnari Patel
  • David Sherriff
  • Rubin Soomal
  • David Borg
  • Sharmila Sothi
  • Pascal Hammel
  • Thilo Hackert
  • Richard Jackson
  • Markus W Büchler
  • European Study Group for Pancreatic Cancer

Colleges, School and Institutes

External organisations

  • University of Liverpool
  • The Royal Liverpool and Broadgreen University Hospital Trust
  • University of Liverpool
  • The Clatterbridge Cancer Centre, Wirral, UK.
  • Manchester Royal Infirmary
  • Royal Marsden NHS Foundation Trust
  • Weston Park Hospital
  • Royal Free London NHS Foundation Trust
  • Karolinska Institutet
  • University of Uppsala
  • Bristol Oncology and Haematology Centre
  • University of Hamburg
  • Royal Surrey County Hospital, Guildford, UK.
  • Guy's and St Thomas' NHS Foundation Trust
  • Beatson West Scotland Cancer Centre
  • Velindre Hospital, Cardiff, UK.
  • University of Oxford
  • Derriford Hospital, Plymouth, UK.
  • Ipswich Hospital NHS Trust
  • Skåne University Hospital
  • Hôpital Beaujon, Clichy, France.
  • Heidelberg University

Abstract

BACKGROUND: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer.

METHODS: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m(2) gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m(2) oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434.

FINDINGS: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group.

INTERPRETATION: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma.

FUNDING: Cancer Research UK.

Details

Original languageEnglish
Pages (from-to)1011–1024
JournalThe Lancet
Volume389
Issue number10073
Early online date25 Jan 2017
Publication statusPublished - 11 Mar 2017

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