Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4)

TY - JOUR

T1 - Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4)

T2 - a multicentre, open-label, randomised, phase 3 trial

AU - Neoptolemos, John P

AU - Palmer, Daniel H

AU - Ghaneh, Paula

AU - Psarelli, Eftychia E

AU - Valle, Juan W

AU - Halloran, Christopher M

AU - Faluyi, Olusola

AU - O'Reilly, Derek A

AU - Cunningham, David

AU - Wadsley, Jonathan

AU - Darby, Suzanne

AU - Meyer, Tim

AU - Gillmore, Roopinder

AU - Anthoney, Alan

AU - Lind, Pehr

AU - Glimelius, Bengt

AU - Falk, Stephen

AU - Izbicki, Jakob R

AU - Middleton, Gary William

AU - Cummins, Sebastian

AU - Ross, Paul J

AU - Wasan, Harpreet

AU - McDonald, Alec

AU - Crosby, Tom

AU - Ma, Yuk Ting

AU - Patel, Kinnari

AU - Sherriff, David

AU - Soomal, Rubin

AU - Borg, David

AU - Sothi, Sharmila

AU - Hammel, Pascal

AU - Hackert, Thilo

AU - Jackson, Richard

AU - Büchler, Markus W

AU - European Study Group for Pancreatic Cancer

N1 - Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND license. Published by Elsevier Ltd.. All rights reserved.

PY - 2017/3/11

Y1 - 2017/3/11

N2 - 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/m2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m2 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.

AB - 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/m2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m2 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.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antimetabolites, Antineoplastic/administration & dosage

KW - Antineoplastic Combined Chemotherapy Protocols/administration & dosage

KW - Capecitabine/administration & dosage

KW - Carcinoma, Pancreatic Ductal/drug therapy

KW - Chemotherapy, Adjuvant

KW - Deoxycytidine/administration & dosage

KW - Female

KW - Humans

KW - Kaplan-Meier Estimate

KW - Male

KW - Middle Aged

KW - Pancreatic Neoplasms/drug therapy

KW - Treatment Outcome

U2 - 10.1016/S0140-6736(16)32409-6

DO - 10.1016/S0140-6736(16)32409-6

M3 - SCORING: Journal article

C2 - 28129987

VL - 389

SP - 1011

EP - 1024

JO - LANCET

JF - LANCET

SN - 0140-6736

IS - 10073

ER -