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Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: Long-term results of the New EPOC randomised clinical trial

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  • John Bridgewater
  • Siân Pugh
  • Tom Maishman
  • Zina Eminton
  • Jane Mellor
  • Amy Whitehead
  • Louise Stanton
  • Mike Radford
  • Andrea Corkhill
  • Gareth O Giffiths
  • Stephen Falk
  • Juan Valle
  • Derek O'Reilly
  • Ajith Siriwardena
  • Joanne Hornbuckle
  • Myrddin Rees
  • Timothy Iveson
  • Tamas Hickish
  • David Cunningham
  • Timothy Maughan
  • John N. Primrose
  • New EPOC Investigators

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Original languageEnglish
JournalThe Lancet Oncology
DOIs
Publication statusPublished - 21 Mar 2020

Abstract

Background The interim analysis of the multicentre New EPOC trial demonstrated a significant reduction in progression free survival (PFS) for the group allocated to cetuximab (HR=1.48 95% CI 1.04-2.12, p=0.030). The focus of the present analysis was to determine the impact on overall survival (OS). Methods Patients with KRAS wild-type (codons 12, 13 and 61) 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. The trial was open label and randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer (one or more of: ≥ 4 metastases, N2 disease or poor differentiation of primary cancer), and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m intravenously over 2 h and fluorouracil bolus 400 mg/m intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m repeated every 2 weeks (regimen one) or oxaliplatin 130 mg/m intravenously over 2 h and oral capecitabine 1000 mg/m twice daily on days 1–14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m every 2 weeks with regimen one and three or a loading dose of 400 mg/m followed by a weekly infusion of 250 mg/m with regimen two. The primary trial endpoint was progression free survival. The objective of this present study was to assess the secondary endpoint of overall survival. The trial completed recruitment on 1 Nov 2012 and these data are now presented at a median follow-up of 67 months. Secondary endpoints also included preoperative cancer response (response after the end of the preoperative treatment period using RECIST), pathological resection status (margin ≥1 cm, <1 cm, or cancer on cut surface), and safety findings during chemotherapy. Since the trial was negative, the quality of life and cost effectiveness analyses were not done. All analyses (except AE and SAE analyses) were performed on the intention-to-treat population including all patients with known KRAS (codons 12, 13, 61) wild-type status who had data available for the analysis being performed. AE and SAE analyses included all randomised patients. This trial is registered, ISRCTN 22944367. Findings Between 26 February 2007 and 12 October 2012, 257 eligible patients were randomly assigned to chemotherapy with cetuximab (n=129) or no cetuximab (n=128). This analysis was carried out five years after the last patient was recruited, as defined in the protocol. The updated PFS analysis demonstrated a hazard ratio of 1.17 (in favour of chemotherapy alone), 95% CI 0.87-1.56, p=0.304 with an observed median progression free survival of 22.2 months (95% CI 18.3 to 26.8) in the chemotherapy alone group and 15.5 months (95% CI 13.8 to 18.0) in the chemotherapy with cetuximab group. Median OS was shorter in the chemotherapy with cetuximab group (55 months) compared to the chemotherapy alone group (81 months, HR 1.45 95% CI 1.02-2.05, p=0.036), with an observed median OS of 81.0 months (95% CI 59.6 to not reached) in the chemotherapy alone group and 55.4 months (95% CI 43.5 to 71.5) in the cetuximab group. The detriment in OS was most notable in patients with <4 metastases/well differentiated cancers/N stage<2 (HR 2.35 95%CI 1.37-4.03, p=0.012). There was no statistically significant difference in the secondary outcomes of pre-operative response or pathological resection status between groups. There were a total of five deaths that may have been treatment related (one in the chemotherapy alone group and four in the chemotherapy and cetuximab group). The most common grade 3-4 adverse events reported were Neutrophil count decreased (47/271 patients), Diarrhea (27/271), Skin Rash (23/271), Thromboembolic event (21/271), Lethargy (19/271), Mucositis Oral (17/271), Vomiting (14/271), Peripheral Neuropathy (13/271) and pain (12/271). The most common serious adverse events reported of any grade were Diarrhoea (16/271 patients), thromboembolic event (16/271), vomiting (12/271), fever (9/271), sepsis (7/271) and device related infection (7/271). Interpretation Although the addition of cetuximab to chemotherapy improves the overall survival improves the overall survival in some studies on patients with advanced inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant overall survival disadvantage. Cetuximab should not be used in this setting. Funding Cancer Research UK (C317/A7275).

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