Early Tumor Shrinkage and Clinical Outcome in Metastatic Colorectal Cancer: Analysis of Predictive Utility in the CRYSTAL and OPUS Studies

Background: This study was carried out to assess the effect of cetuximab plus chemotherapy in first-line treatment of unresectable colorectal liver metastases (CLM).Methods: After resection of the primary focus, patients from Zhongshan Hospital with non-resectable synchronous liver-limited metastases from wild-type KRAS colorectal cancer were randomly assigned to receive chemotherapy (FOLFIRI or mFOLFOX6) plus cetuximab (arm A) or chemotherapy alone (arm B).The primary end point was the rate of secondary resection for liver metastases.Secondary end points included tumor response, survival and BRAF analysis.Results: From June 2008 to December 2011, 116 patients were assessable (59 in arm A and 57 in arm B).The 3-year overall survival (OS) rate and median survival time (MST) of the total patients was 32% and 27.5 months, respectively.The R0 resection rate for liver metastases was 30.5% (18/59) in arm A and 8.8% (5/57) in arm B, with significant difference (P < 0.01).The patients in arm A had improved objective response (66.1% versus 33.3%, P < 0.01), increased 3-year OS rate (43% versus 21%, P = 0.01) and prolonged MST (32.8 versus 22.8 months, P = 0.01) compared with those in arm B. Furthermore, for the patients without liver surgery, people from arm A also got more survival benefit than those from arm B on 3-year OS rate (25% versus 17%, P = 0.047), MST (28.2 versus 21.2 months, P = 0.047) and progression-free survival (8.3 versus 5.2 months, P = 0.03).In addition, in arm A, patients who experienced resection of liver metastases were significantly improved 3-year OS rate (74% versus 25%, P = 0.02) and MST (46.6 versus 28.2 months; P = 0.02) than those without liver surgery, and the patients with wild-type BRAF tumors had better 3-year OS rate (49% versus 29%, P = 0.01) or MST (35.7 versus 25.2 months, P = 0.01) than those with mutated BRAF tumors.Conclusions: For initially unresectable CLM with KRAS wild-type, cetuximab combined with chemotherapy could improve resectability of liver metastases, response rates and survival compared with chemotherapy alone.The mutation status of the BRAF gene may be a predictor of outcome in the cetuximab group (ClinicalTrials.govnumber NCT01564810).