EGFR antibodies in resectable metastatic colorectal liver metastasis: more harm than benefit?
Mené sur 257 patients atteints d'un cancer colorectal sans mutation KRAS et présentant des métastases hépatiques, cet essai de phase III évalue l'efficacité, du point de vue de la survie globale, de la réponse pré-opératoire, du statut des marges de résection, et la toxicité de l'ajout du cétuximab à une chimiothérapie dispensée avant et après une résection hépatique
The current standard of care for resectable liver-limited colorectal cancer is perioperative chemotherapy followed by curative resection, based on the EORTC trial, which showed a modest improvement in 3-year progression-free survival. Since the addition of a biological agent to systemic therapy leads to increased proportions of patients achieving a response in the metastatic setting, a logical subsequent trial would investigate the role of biological agents in the perioperative setting.
In the New EPOC study, the results of which were published by John A Bridgewater and colleagues in The Lancet Oncology, patients with resectable KRAS exon 2 wild-type colorectal liver-limited metastases were randomly assigned to perioperative chemotherapy (oxaliplatin plus fluorouracil, oxaliplatin plus capecitabine, or irinotecan plus fluorouracil) with or without addition of the epidermal growth factor receptor (EGFR) antibody cetuximab.Although the concept was rational and the trial well designed, the initially reported results were rather unexpected and controversial. Although the addition of cetuximab to chemotherapy numerically increased the proportion of patients with a response, it showed shorter progression-free survival, with a hazard ratio of 1·48 (95% CI 1·04–2·12; p=0·030) in patients given chemotherapy with cetuximab versus those who had chemotherapy alone. Overall survival was similar (HR 1·49, 95% CI 0·86–2·60; p=0·16) but was not significant, conceivably because of short follow-up. On the basis of these data, the trial was stopped early. These results led to a controversial debate reflected in an exchange of letters in a different journal. In their long-term analysis, Bridgewater and colleagues now confirm the initial results, showing shorter overall survival in patients given chemotherapy plus cetuximab compared with patients given chemotherapy alone (55·4 months [95% CI 43·5–71·5] vs 81·0 months [59·6 to not reached]; HR 1·45, 95% CI 1·02–2·05; p=0·036). The detrimental effects were more pronounced in patients with more favourable clinical tumour characteristics, potentially indicating an adverse effect in a true adjuvant (micrometastatic) setting. Finally, the results were largely driven by post-recurrence survival, suggesting either the development of a more aggressive disease phenotype or imbalances in post-recurrence treatment approaches.
The Lancet Oncology , commentaire, 2019