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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 in patients with resectable colorectal liver metastasis showed a significant reduction in progression-free survival in patients allocated to cetuximab plus chemotherapy compared with those 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. Adult patients (aged ≥18 years) with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases and a WHO performance status of 0–2 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/m 2 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/m 2 administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m 2 repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m 2 administered intravenously over 2 h and oral capecitabine 1000 mg/m 2 twice daily on days 1–14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m 2 intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m 2 every 2 weeks with regimen one and three or a loading dose of 400 mg/m 2 followed by a weekly infusion of 250 mg/m 2 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 (IQR 58·0–77·5). Median progression-free survival was 22·2 months (95% CI 18·3–26·8) in the chemotherapy alone group and 15·5 months (13·8–19·0) in the chemotherapy plus cetuximab group (hazard ratio [HR] 1·17, 95% CI 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%]), oral mucositis (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. Funding: Cancer Research UK.

1470-2045
398-411
Bridgewater, John
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Pugh, Siân A.
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Maishman, Tom
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Eminton, Zina
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Mellor, Jane M.
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Whitehead, Amy
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Stanton, Louise
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Radford, Michael
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Corkhill, Andrea
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Griffiths, Gareth
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Falk, Stephen
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Valle, Juan
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O'Reilly, Derek
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Siriwardena, Ajith K.
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Hornbuckle, Joanne
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Rees, Myrddin
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Iveson, Timothy
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Hickish, Tamas
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Garden, O. James
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Cunningham, David
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Maughan, Timothy
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Primrose, John
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New EPOC investigators
Bridgewater, John
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Pugh, Siân A.
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Maishman, Tom
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Eminton, Zina
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Mellor, Jane M.
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Whitehead, Amy
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Stanton, Louise
8b827763-d839-4b4b-bbf2-358a84110294
Radford, Michael
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Corkhill, Andrea
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Griffiths, Gareth
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Falk, Stephen
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Valle, Juan
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O'Reilly, Derek
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Siriwardena, Ajith K.
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Hornbuckle, Joanne
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Rees, Myrddin
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Iveson, Timothy
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Hickish, Tamas
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Garden, O. James
d2499653-2d0e-4ee8-86b9-cae6cc852324
Cunningham, David
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Maughan, Timothy
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Primrose, John
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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 in patients with resectable colorectal liver metastasis showed a significant reduction in progression-free survival in patients allocated to cetuximab plus chemotherapy compared with those 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. Adult patients (aged ≥18 years) with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases and a WHO performance status of 0–2 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/m 2 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/m 2 administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m 2 repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m 2 administered intravenously over 2 h and oral capecitabine 1000 mg/m 2 twice daily on days 1–14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m 2 intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m 2 every 2 weeks with regimen one and three or a loading dose of 400 mg/m 2 followed by a weekly infusion of 250 mg/m 2 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 (IQR 58·0–77·5). Median progression-free survival was 22·2 months (95% CI 18·3–26·8) in the chemotherapy alone group and 15·5 months (13·8–19·0) in the chemotherapy plus cetuximab group (hazard ratio [HR] 1·17, 95% CI 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%]), oral mucositis (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. Funding: Cancer Research UK.

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Accepted/In Press date: 25 October 2019
e-pub ahead of print date: 31 January 2020
Published date: March 2020
Additional Information: Funding Information: JAB has received speakers' fees from Merck Serono. JWV reports grants from Cancer Research UK during the conduct of the study; personal fees from Ipsen, Novartis, AstraZeneca, Merck, Delcath, Agios, Pfizer, PCI Biotech, Incyte, Keocyt, QED, Pieris Pharmaceuticals, Genoscience Pharma, Mundipharma EDO, Wren Laboratories, Nucana, and Imaging Equipment Limited outside the submitted work; and travel grants from Celgene and Nucana. TH is a medical director for iQHealth Tech, has received research funding (to institution) from Pfizer, Pierre Fabre and has attended advisory boards for Lilly and Sobi. DC reports research funding from Amgen, Sanofi, Merrimack, AstraZeneca, Celgene, MedImmune, Bayer, 4SC, Clovis, Eli Lilly, Janssen and Merck. All other authors declare no competing interests. Funding Information: We thank the patients for their participation in this study and their families, and all investigators and onsite personnel. This research study was funded by Cancer Research UK ( C317/A7275 ), and supported by the UK National Institute of Health Research Clinical Research Network: Cancer. This study was also supported by a medical grant from Merck KGaA (Darmstadt, Germany), which also supported the provision of cetuximab for the study and the original KRAS testing. DC is funded partly from the NIHR BRC at the Royal Marsden and Institute of Cancer Research. Publisher Copyright: © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license

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

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Date deposited: 29 Jan 2020 17:37
Last modified: 12 Aug 2022 04:01

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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

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