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Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial

Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial
Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial
Background

Surgery for colorectal liver metastases results in an overall survival of about 40% at 5 years. Progression-free survival is increased with the addition of oxaliplatin and fluorouracil chemotherapy. The addition of cetuximab to these chemotherapy regimens results in an overall survival advantage in patients with advanced disease who have the KRAS exon 2 wild-type tumour genotype. We aimed to assess the benefit of addition of cetuximab to standard chemotherapy in patients with resectable colorectal liver metastasis.

Methods

Patients with KRAS exon 2 wild-type resectable or suboptimally resectable colorectal liver metastases were randomised in a 1:1 ratio to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done using minimisation with factors of surgical centre, poor prognostic tumour (one or more of: ?4 metastases, N2 disease, or poor differentiation of primary tumour), and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m2 intravenously over 2 h and fluorouracil bolus 400 mg/m2 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 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 as an intravenous dose of 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 was progression-free survival. This is an interim analysis, up to Nov 1, 2012, when the trial was closed, having met protocol-defined futility criteria. This trial is registered, ISRCTN22944367.

Findings

128 KRAS exon 2 wild-type patients were randomised to chemotherapy alone and 129 to chemotherapy with cetuximab between Feb 26, 2007, and Nov 1, 2012. 117 patients in the chemotherapy alone group and 119 in the chemotherapy plus cetuximab group were included in the primary analysis. The median follow-up was 21·1 months (95% CI 12·6–33·8) in the chemotherapy alone group and 19·8 months (12·2–28·7) in the chemotherapy plus cetuximab group. With an overall median follow-up of 20·7 months (95% CI 17·9–25·6) and 123 (58%) of 212 required events observed, progression-free survival was significantly shorter in the chemotherapy plus cetuximab group than in the chemotherapy alone group (14·1 months [95% CI 11·8–15·9] vs 20·5 months [95% CI 16·8–26·7], hazard ratio 1·48, 95% CI 1·04–2·12, p=0·030). The most common grade 3 or 4 adverse events were low neutrophil count (15 [11%] preoperatively in the chemotherapy alone group vs six [4%] in the chemotherapy plus cetuximab group; four [4%] vs eight [8%] postoperatively), embolic events (six [4%] vs eight [6%] preoperatively; two [2%] vs three [3%] postoperatively), peripheral neuropathy (six [4%] vs one [1%] preoperatively; two [2%] vs four [4%] postoperatively), nausea or vomiting (four [3%] vs six [4%] preoperatively; four [4%] vs two [2%] postoperatively), and skin rash (two [1%] vs 21 [15%] preoperatively; 0 vs eight [8%] postoperatively). There were three deaths in the chemotherapy plus cetuximab group (one interstitial lung disease and pulmonary embolism, one bronchopneumonia, and one pulmonary embolism) and one in the chemotherapy alone group (heart failure) that might have been treatment related.

Interpretation

Addition of cetuximab to chemotherapy and surgery for operable colorectal liver metastases in KRAS exon 2 wild-type patients results in shorter progression-free survival. Translational investigations to explore the molecular basis for this unexpected interaction are needed but at present the use of cetuximab in this setting cannot be recommended.

Funding

Cancer Research UK.
601-611
Primrose, John
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Falk, Stephen
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Finch-Jones, Meg
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Valle, Juan
33830bc4-19fa-4140-af0d-1b1add1fbc6b
O'Reilly, Derek
e7fee95c-4b75-4c86-903d-ea9d2af3298e
Siriwardena, Ajith
6df89e5e-c7e1-48d1-bb8d-4f688d05fc2a
Hornbuckle, Joanne
7bbf81dc-bcc7-4598-a5e4-313c8460a9af
Peterson, Mark
634b554c-3350-40da-ae1b-6927e7a7551e
Rees, Myrddin
f35b89e2-e207-439f-b685-7b6dcbaea214
Iveson, Tim
867cb6c5-ea9a-4521-a4cc-4cd4d2503b3a
Hickish, Tamas
585e80ad-7670-4fcd-9448-a454744ed486
Butler, Rachel
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Stanton, Louise
8b827763-d839-4b4b-bbf2-358a84110294
Dixon, Elizabeth
f2e33dd1-36f5-4a82-8d3b-ebd5b14cb675
Little, Louisa
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Bowers, Megan
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Pugh, Siân
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Garden, O. James
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Cunningham, David
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Maughan, Tim
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Bridgewater, John
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Primrose, John
d85f3b28-24c6-475f-955b-ec457a3f9185
Falk, Stephen
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Finch-Jones, Meg
5e1f7fc9-5be8-4d7a-9ccc-7b1b6a1f7f80
Valle, Juan
33830bc4-19fa-4140-af0d-1b1add1fbc6b
O'Reilly, Derek
e7fee95c-4b75-4c86-903d-ea9d2af3298e
Siriwardena, Ajith
6df89e5e-c7e1-48d1-bb8d-4f688d05fc2a
Hornbuckle, Joanne
7bbf81dc-bcc7-4598-a5e4-313c8460a9af
Peterson, Mark
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Rees, Myrddin
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Iveson, Tim
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Hickish, Tamas
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Butler, Rachel
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Stanton, Louise
8b827763-d839-4b4b-bbf2-358a84110294
Dixon, Elizabeth
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Little, Louisa
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Bowers, Megan
e76368dc-819f-4069-93f2-e1eee7bc691e
Pugh, Siân
83010563-0865-446c-ba71-95e2a45d9562
Garden, O. James
d2499653-2d0e-4ee8-86b9-cae6cc852324
Cunningham, David
c40c8fe4-7eac-4b98-aaa5-b866da1e32ab
Maughan, Tim
9f5b1ca4-9ed7-4100-bf04-c4026e4b5395
Bridgewater, John
a7c51f93-a80e-4b89-828f-34f477259d5c

Primrose, John, Falk, Stephen, Finch-Jones, Meg, Valle, Juan, O'Reilly, Derek, Siriwardena, Ajith, Hornbuckle, Joanne, Peterson, Mark, Rees, Myrddin, Iveson, Tim, Hickish, Tamas, Butler, Rachel, Stanton, Louise, Dixon, Elizabeth, Little, Louisa, Bowers, Megan, Pugh, Siân, Garden, O. James, Cunningham, David, Maughan, Tim and Bridgewater, John (2014) Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial. The Lancet Oncology, 15 (6), 601-611. (doi:10.1016/S1470-2045(14)70105-6). (PMID:24717919)

Record type: Article

Abstract

Background

Surgery for colorectal liver metastases results in an overall survival of about 40% at 5 years. Progression-free survival is increased with the addition of oxaliplatin and fluorouracil chemotherapy. The addition of cetuximab to these chemotherapy regimens results in an overall survival advantage in patients with advanced disease who have the KRAS exon 2 wild-type tumour genotype. We aimed to assess the benefit of addition of cetuximab to standard chemotherapy in patients with resectable colorectal liver metastasis.

Methods

Patients with KRAS exon 2 wild-type resectable or suboptimally resectable colorectal liver metastases were randomised in a 1:1 ratio to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done using minimisation with factors of surgical centre, poor prognostic tumour (one or more of: ?4 metastases, N2 disease, or poor differentiation of primary tumour), and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m2 intravenously over 2 h and fluorouracil bolus 400 mg/m2 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 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 as an intravenous dose of 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 was progression-free survival. This is an interim analysis, up to Nov 1, 2012, when the trial was closed, having met protocol-defined futility criteria. This trial is registered, ISRCTN22944367.

Findings

128 KRAS exon 2 wild-type patients were randomised to chemotherapy alone and 129 to chemotherapy with cetuximab between Feb 26, 2007, and Nov 1, 2012. 117 patients in the chemotherapy alone group and 119 in the chemotherapy plus cetuximab group were included in the primary analysis. The median follow-up was 21·1 months (95% CI 12·6–33·8) in the chemotherapy alone group and 19·8 months (12·2–28·7) in the chemotherapy plus cetuximab group. With an overall median follow-up of 20·7 months (95% CI 17·9–25·6) and 123 (58%) of 212 required events observed, progression-free survival was significantly shorter in the chemotherapy plus cetuximab group than in the chemotherapy alone group (14·1 months [95% CI 11·8–15·9] vs 20·5 months [95% CI 16·8–26·7], hazard ratio 1·48, 95% CI 1·04–2·12, p=0·030). The most common grade 3 or 4 adverse events were low neutrophil count (15 [11%] preoperatively in the chemotherapy alone group vs six [4%] in the chemotherapy plus cetuximab group; four [4%] vs eight [8%] postoperatively), embolic events (six [4%] vs eight [6%] preoperatively; two [2%] vs three [3%] postoperatively), peripheral neuropathy (six [4%] vs one [1%] preoperatively; two [2%] vs four [4%] postoperatively), nausea or vomiting (four [3%] vs six [4%] preoperatively; four [4%] vs two [2%] postoperatively), and skin rash (two [1%] vs 21 [15%] preoperatively; 0 vs eight [8%] postoperatively). There were three deaths in the chemotherapy plus cetuximab group (one interstitial lung disease and pulmonary embolism, one bronchopneumonia, and one pulmonary embolism) and one in the chemotherapy alone group (heart failure) that might have been treatment related.

Interpretation

Addition of cetuximab to chemotherapy and surgery for operable colorectal liver metastases in KRAS exon 2 wild-type patients results in shorter progression-free survival. Translational investigations to explore the molecular basis for this unexpected interaction are needed but at present the use of cetuximab in this setting cannot be recommended.

Funding

Cancer Research UK.

Full text not available from this repository.

More information

e-pub ahead of print date: 7 April 2014
Published date: May 2014
Organisations: Cancer Sciences, Clinical Trials Unit

Identifiers

Local EPrints ID: 368206
URI: http://eprints.soton.ac.uk/id/eprint/368206
PURE UUID: 0700665a-6a02-4e4e-b29b-6f488f4e6f6b
ORCID for John Primrose: ORCID iD orcid.org/0000-0002-2069-7605
ORCID for Louise Stanton: ORCID iD orcid.org/0000-0001-8181-840X

Catalogue record

Date deposited: 28 Aug 2014 14:46
Last modified: 01 Feb 2020 01:30

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Contributors

Author: John Primrose ORCID iD
Author: Stephen Falk
Author: Meg Finch-Jones
Author: Juan Valle
Author: Derek O'Reilly
Author: Ajith Siriwardena
Author: Joanne Hornbuckle
Author: Mark Peterson
Author: Myrddin Rees
Author: Tim Iveson
Author: Tamas Hickish
Author: Rachel Butler
Author: Louise Stanton ORCID iD
Author: Elizabeth Dixon
Author: Louisa Little
Author: Megan Bowers
Author: Siân Pugh
Author: O. James Garden
Author: David Cunningham
Author: Tim Maughan
Author: John Bridgewater

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