The University of Southampton
University of Southampton Institutional Repository

Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial

Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial
Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial
Background
The interim analysis of the multicentre New EPOC trial showed a significant reduction in progressionfree survival for the group allocated to cetuximab plus chemotherapy compared with patients given chemotherapy alone. The focus of the present analysis was to assess the effect on overall survival.

Methods
New EPOC was a multicentre, open-label, randomised, controlled, phase 3 trial. Patients with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases were randomly assigned (1:1) to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer, and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m² administered intravenously over 2 h, l-folinic acid (175 mg flat dose administered intravenously over 2 h) or d,l-folinic acid (350 mg flat dose administered intravenously over 2 h), and fluorouracil bolus 400 mg/m² administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m² repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m² administered intravenously over 2 h and oral capecitabine 1000 mg/m² twice daily on days 1–14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m² intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m² every 2 weeks with regimen one and three or a loading dose of 400 mg/m² followed by a weekly infusion of 250 mg/m² with regimen two. The primary endpoint of progression-free survival was published previously. Secondary endpoints were overall survival, preoperative response, pathological resection status, and safety. Trial recruitment was halted prematurely on the advice of the Trial Steering Committee on Nov 1, 2012. All analyses (except safety) were done on the intention-to-treat population. Safety analyses included all randomly assigned patients. This trial is registered with ISRCTN, number 22944367.

Findings
Between Feb 26, 2007, and Oct 12, 2012, 257 eligible patients were randomly assigned to chemotherapy with cetuximab (n=129) or without cetuximab (n=128). This analysis was carried out 5 years after the last patient was recruited, as defined in the protocol, at a median follow-up of 66·7 months (95% CI 63·2–69·4). Median progression-free survival was 22·2 months (18·3–26·8) in the chemotherapy alone group and 15·5 months (13·8–18·0) in the chemotherapy plus cetuximab group (hazard ratio [HR] 1·17, 0·87–1·56; p=0·304). Median overall survival was 81·0 months (59·6 to not reached) in the chemotherapy alone group and 55·4 months (43·5–71·5) in the chemotherapy plus cetuximab group (HR 1·45, 1·02–2·05; p=0·036). There was no significant difference in the secondary outcomes of preoperative response or pathological resection status between groups. Five deaths might have been treatment-related (one in the chemotherapy alone group and four in the chemotherapy plus cetuximab group). The most common grade 3–4 adverse events reported were: neutrophil count decreased (26 [19%] of 134 in the chemotherapy alone group vs 21 [15%] of 137 in the chemotherapy plus cetuximab group), diarrhoea (13 [10%] vs 14 [10%]), skin rash (one [1%] vs 22 [16%]), thromboembolic events (ten [7%] vs 11 [8%]), lethargy (ten [7%] vs nine [7%]), mucositis oral (three [2%] vs 14 [10%]), vomiting (seven [5%] vs seven [5%]), peripheral neuropathy (eight [6%] vs five [4%]), and pain (six [4%] vs six [4%]).

Interpretation
Although the addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting.
1470-2045
398-411
Bridgewater, John
a7c51f93-a80e-4b89-828f-34f477259d5c
Pugh, Siân A.
7c46dc51-7cee-4914-8dc6-df31fc66e16e
Maishman, Tom
cf4259a4-0eef-4975-9c9d-a2c3d594f989
Eminton, Zina
44904d98-97be-4080-9a84-bf5742525f8e
Mellor, Jane M.
748aff30-b9fb-420a-8c4b-8b95beb6ecd0
Whitehead, Amy
7bd4e1d1-078b-4f2b-bfc9-ed44ba0a195a
Stanton, Louise
8b827763-d839-4b4b-bbf2-358a84110294
Radford, Michael
72cf921a-9179-430e-80d0-9970ae4099bb
Corkhill, Andrea
e74ed394-38fb-4bfb-883d-681b2aeaf931
Griffiths, Gareth
7fd300c0-d279-4ff6-842d-aa1f2b9b864d
Falk, Stephen
6bda4f5d-d5b0-4558-89d3-9e32cacf202a
Valle, Juan
33830bc4-19fa-4140-af0d-1b1add1fbc6b
O'Reilly, Derek
e7fee95c-4b75-4c86-903d-ea9d2af3298e
Siriwardena, Ajith K.
57af352c-f928-44e2-a68d-31e2a1b5f577
Hornbuckle, Joanne
7bbf81dc-bcc7-4598-a5e4-313c8460a9af
Rees, Myrddin
f35b89e2-e207-439f-b685-7b6dcbaea214
Iveson, Timothy
867cb6c5-ea9a-4521-a4cc-4cd4d2503b3a
Hickish, Tamas
585e80ad-7670-4fcd-9448-a454744ed486
Garden, O. James
d2499653-2d0e-4ee8-86b9-cae6cc852324
Cunningham, David
c40c8fe4-7eac-4b98-aaa5-b866da1e32ab
Maughan, Timothy
195bfe69-ebc3-4093-94fc-599733589530
Primrose, John
d85f3b28-24c6-475f-955b-ec457a3f9185
New EPOC investigators
Bridgewater, John
a7c51f93-a80e-4b89-828f-34f477259d5c
Pugh, Siân A.
7c46dc51-7cee-4914-8dc6-df31fc66e16e
Maishman, Tom
cf4259a4-0eef-4975-9c9d-a2c3d594f989
Eminton, Zina
44904d98-97be-4080-9a84-bf5742525f8e
Mellor, Jane M.
748aff30-b9fb-420a-8c4b-8b95beb6ecd0
Whitehead, Amy
7bd4e1d1-078b-4f2b-bfc9-ed44ba0a195a
Stanton, Louise
8b827763-d839-4b4b-bbf2-358a84110294
Radford, Michael
72cf921a-9179-430e-80d0-9970ae4099bb
Corkhill, Andrea
e74ed394-38fb-4bfb-883d-681b2aeaf931
Griffiths, Gareth
7fd300c0-d279-4ff6-842d-aa1f2b9b864d
Falk, Stephen
6bda4f5d-d5b0-4558-89d3-9e32cacf202a
Valle, Juan
33830bc4-19fa-4140-af0d-1b1add1fbc6b
O'Reilly, Derek
e7fee95c-4b75-4c86-903d-ea9d2af3298e
Siriwardena, Ajith K.
57af352c-f928-44e2-a68d-31e2a1b5f577
Hornbuckle, Joanne
7bbf81dc-bcc7-4598-a5e4-313c8460a9af
Rees, Myrddin
f35b89e2-e207-439f-b685-7b6dcbaea214
Iveson, Timothy
867cb6c5-ea9a-4521-a4cc-4cd4d2503b3a
Hickish, Tamas
585e80ad-7670-4fcd-9448-a454744ed486
Garden, O. James
d2499653-2d0e-4ee8-86b9-cae6cc852324
Cunningham, David
c40c8fe4-7eac-4b98-aaa5-b866da1e32ab
Maughan, Timothy
195bfe69-ebc3-4093-94fc-599733589530
Primrose, John
d85f3b28-24c6-475f-955b-ec457a3f9185

Bridgewater, John, Pugh, Siân A., Maishman, Tom, Eminton, Zina, Mellor, Jane M., Whitehead, Amy, Stanton, Louise, Radford, Michael, Corkhill, Andrea, Griffiths, Gareth, Falk, Stephen, Valle, Juan, O'Reilly, Derek, Siriwardena, Ajith K., Hornbuckle, Joanne, Rees, Myrddin, Iveson, Timothy, Hickish, Tamas, Garden, O. James, Cunningham, David, Maughan, Timothy and Primrose, John , New EPOC investigators (2020) Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial. The Lancet Oncology, 21 (3), 398-411. (doi:10.1016/S1470-2045(19)30798-3).

Record type: Article

Abstract

Background
The interim analysis of the multicentre New EPOC trial showed a significant reduction in progressionfree survival for the group allocated to cetuximab plus chemotherapy compared with patients given chemotherapy alone. The focus of the present analysis was to assess the effect on overall survival.

Methods
New EPOC was a multicentre, open-label, randomised, controlled, phase 3 trial. Patients with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases were randomly assigned (1:1) to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer, and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m² administered intravenously over 2 h, l-folinic acid (175 mg flat dose administered intravenously over 2 h) or d,l-folinic acid (350 mg flat dose administered intravenously over 2 h), and fluorouracil bolus 400 mg/m² administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m² repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m² administered intravenously over 2 h and oral capecitabine 1000 mg/m² twice daily on days 1–14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m² intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m² every 2 weeks with regimen one and three or a loading dose of 400 mg/m² followed by a weekly infusion of 250 mg/m² with regimen two. The primary endpoint of progression-free survival was published previously. Secondary endpoints were overall survival, preoperative response, pathological resection status, and safety. Trial recruitment was halted prematurely on the advice of the Trial Steering Committee on Nov 1, 2012. All analyses (except safety) were done on the intention-to-treat population. Safety analyses included all randomly assigned patients. This trial is registered with ISRCTN, number 22944367.

Findings
Between Feb 26, 2007, and Oct 12, 2012, 257 eligible patients were randomly assigned to chemotherapy with cetuximab (n=129) or without cetuximab (n=128). This analysis was carried out 5 years after the last patient was recruited, as defined in the protocol, at a median follow-up of 66·7 months (95% CI 63·2–69·4). Median progression-free survival was 22·2 months (18·3–26·8) in the chemotherapy alone group and 15·5 months (13·8–18·0) in the chemotherapy plus cetuximab group (hazard ratio [HR] 1·17, 0·87–1·56; p=0·304). Median overall survival was 81·0 months (59·6 to not reached) in the chemotherapy alone group and 55·4 months (43·5–71·5) in the chemotherapy plus cetuximab group (HR 1·45, 1·02–2·05; p=0·036). There was no significant difference in the secondary outcomes of preoperative response or pathological resection status between groups. Five deaths might have been treatment-related (one in the chemotherapy alone group and four in the chemotherapy plus cetuximab group). The most common grade 3–4 adverse events reported were: neutrophil count decreased (26 [19%] of 134 in the chemotherapy alone group vs 21 [15%] of 137 in the chemotherapy plus cetuximab group), diarrhoea (13 [10%] vs 14 [10%]), skin rash (one [1%] vs 22 [16%]), thromboembolic events (ten [7%] vs 11 [8%]), lethargy (ten [7%] vs nine [7%]), mucositis oral (three [2%] vs 14 [10%]), vomiting (seven [5%] vs seven [5%]), peripheral neuropathy (eight [6%] vs five [4%]), and pain (six [4%] vs six [4%]).

Interpretation
Although the addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting.

Text
19TLO1227_Primrose_proof_revised4 LS - Proof
Download (1MB)
Text
19TLO1227_Primrose_final - Proof
Restricted to Repository staff only
Request a copy

More information

Accepted/In Press date: 25 October 2019
e-pub ahead of print date: 31 January 2020
Published date: March 2020

Identifiers

Local EPrints ID: 437424
URI: http://eprints.soton.ac.uk/id/eprint/437424
ISSN: 1470-2045
PURE UUID: 0bbf57c7-1355-421c-bda3-e48e7e52c9b1
ORCID for Louise Stanton: ORCID iD orcid.org/0000-0001-8181-840X
ORCID for Gareth Griffiths: ORCID iD orcid.org/0000-0002-9579-8021
ORCID for Timothy Iveson: ORCID iD orcid.org/0000-0002-4681-2712
ORCID for John Primrose: ORCID iD orcid.org/0000-0002-2069-7605

Catalogue record

Date deposited: 29 Jan 2020 17:37
Last modified: 28 Apr 2022 06:29

Export record

Altmetrics

Contributors

Author: John Bridgewater
Author: Siân A. Pugh
Author: Tom Maishman
Author: Zina Eminton
Author: Jane M. Mellor
Author: Amy Whitehead
Author: Louise Stanton ORCID iD
Author: Michael Radford
Author: Andrea Corkhill
Author: Stephen Falk
Author: Juan Valle
Author: Derek O'Reilly
Author: Ajith K. Siriwardena
Author: Joanne Hornbuckle
Author: Myrddin Rees
Author: Timothy Iveson ORCID iD
Author: Tamas Hickish
Author: O. James Garden
Author: David Cunningham
Author: Timothy Maughan
Author: John Primrose ORCID iD
Corporate Author: New EPOC investigators

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×