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

• Published in: The lancet oncology 2020-03, Vol.21 (3), p.398-411
• Main Authors: Bridgewater, John A, Pugh, Siân A, Maishman, Tom, Eminton, Zina, Mellor, Jane, Whitehead, Amy, Stanton, Louise, Radford, Michael, Corkhill, Andrea, Griffiths, Gareth O, Falk, Stephen, Valle, Juan W, O'Reilly, Derek, Siriwardena, Ajith K, Hornbuckle, Joanne, Rees, Myrddin, Iveson, Timothy J, Hickish, Tamas, Garden, O James, Cunningham, David, Maughan, Timothy S, Primrose, John N, Shablack, Alaaeldin, O'Callaghan, Ann, Moody, (Margaret) Anne, Allen, Alex, Brewster, Alison, Brown, Alison, Mayer, Astrid, Davidson, Brian, Ton, Chan, Wilson, Charles, Lowdell, Charles, Rees, Charlotte, Baughan, Christopher, Barlow, Clare, Purcell, Colin, Smith, David, Tsang, David, Brown, Ewan, Walker, Georgina, Malik, Hassan, Cameron, Iain, Nolan, Luke, Hall, Marcia, Tomlinson, Marjorie, Hill, Mark, Peterson, Mark, Finch-Jones, Meg, Kumar, Nagappan, Karanjia, Nariman, Ali, Nasim, Heaton, Nigel, Ton, Nua Chan, Ross, Paul, Praseedom, Raaj, Thomas, Robert, Clive, Sally, Slater, Sarah, Smith, Sarah, Mudan, Satvinder, Bhattacharya, Satya, Essapen, Sharadah, Raouf, Sherif, Fenwick, Stephen, Cleator, Susan, Diamond, Tom, Potter, Vanessa
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cancer therapies; Capecitabine - administration & dosage; Cetuximab - administration & dosage; Chemotherapy; Clinical trials; Codons; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Diarrhea; Drug therapy; Female; Fluorouracil - administration & dosage; Folinic acid; Follow-Up Studies; Humans; Immunotherapy; Irinotecan; Irinotecan - administration & dosage; Leucovorin - administration & dosage; Liver; Liver Neoplasms - drug therapy; Liver Neoplasms - secondary; Male; Medical prognosis; Medical research; Metastases; Metastasis; Middle Aged; Monoclonal antibodies; Mucositis; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - pathology; Oxaliplatin; Oxaliplatin - administration & dosage; Peripheral neuropathy; Prognosis; Safety; Studies; Surgery; Survival Rate; Targeted cancer therapy; Thromboembolism; Vomiting
• ISSN: 1470-2045; 1474-5488
• DOI: 10.1016/S1470-2045(19)30798-3

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. 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/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. 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 protoco