Should the results of the new EPOC trial change practice in the management of patients with resectable metastatic colorectal cancer confined to the liver?

Biologic agents, specifically epidermal growth factor receptor blockers and vascular endothelial growth factor inhibitors, combined with cytotoxic agents have become a standard of care for the treatment of metastatic colorectal cancer (CRC) but lack proven benefit as adjuvant treatment of primary colon cancer. Patients with resectable CRC metastases limited to the liver represent an intermediate group in terms of their burden of disease and prognosis. In those patients, the 5-year life expectancy after surgery is approximately 35% to 40% compared with 75% in patients with stage III disease and 10% in unselected patients with stage IV disease. In patients with resectable liver-limited CRC randomly assigned to treatment with surgery alone or perioperative chemotherapy with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX), the risk of cancer relapse after surgery in the cohort randomly assigned to perioperative FOLFOX was reduced by one quarter. A logical next step is to raise the question, Can outcomes be improved further by combining treatment with biologic and cytotoxic agents in the perioperative setting in this increasingly common patient population? The New EPOC (Eloxatin Peri-Operative Chemotherapy) trial was organized in the United Kingdom to address this question, and the results were published and recently updated. The trial compared two groups of patients who were determined to have resectable liver metastases, all of whom received perioperative chemotherapy with FOLFOX, oxaliplatin and capecitabine (XELOX), or fluorouracil, leucovorin, and irinotecan (FOLFIRI) with a random assignment to treatment with or without the addition of the epidermal growth factor receptor–blocking antibody cetuximab. The trial initially enrolled patients regardless of KRAS mutation status in the tumor but was later restricted to patients whose tumors were found to be KRAS (exon 2) wild type. On the basis of their study’s outcome, the investigators concluded that combinations of cetuximab with chemotherapy in the perioperative setting for treatment of patients with potentially resectable colorectal liver metastases conferred no survival benefit and were actually detrimental. Data from studies in patients with advanced disease show that the addition of cetuximab or panitumumab to combination chemotherapy in patients whose tumors harbor a KRAS (exon 2) or other RAS mutations can be detrimental, although overall, patients without RAS mutations benefit from the combination. If this biology applies in the setting of resected stage IV disease, the initial inclusion of patients who did not have RAS testing may have influenced the outcome. In the N0147 (Comparison of Combination Chemotherapy Regimens With or Without Cetuximab in Treating Patients Who Have Undergone Surgery for Stage III Colon Cancer) study, which assigned patients with resected stage III CRC to FOLFOX with or without cetuximab, there was a statistically nonsignificant trend toward a detrimental effect that was independent of RAS status in the cetuximab-treated cohort. The New EPOC investigators hypothesize that molecular interactions may be playing a role in the observed outcomes in both N0147 and New EPOC, suggesting that the interplay of chemotherapy with cetuximab is different in patients with microscopic residual disease than it is in those with gross residual disease. Organizing randomized clinical trials that involve surgery and chemotherapy is difficult, and few such combined modality studies have been completed. We congratulate the investigators for meeting their accrual goal, but we are concerned that the data they published may not support the conclusions that they drew from their study because of issues surrounding surgical quality control, inclusion of patients whose surgical outcomes did not meet the predetermined study goals, incomplete data, and diversity in both the population enrolled and the regimens they received. Surgery is both an art and a science, and its practice depends on the judgment and skills of the surgeons. Studies have shown that the experience of the surgeon and the surgical team can be an important variable in patient outcomes. The impact of quality assurance of the operative procedures performed in cancer surgery trials has been explicitly demonstrated in two large, randomized Dutch trials that addressed gastric and rectal cancer surgery, both of which were practice changing. In those trials, surgeons could only recruit to the JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 33 NUMBER 3 JANUARY 2