Colorectal Liver Metastases: Treat Effectively Up Front and Consider the Borderline Resectable
Authors: Jean-Nicolas Vauthey
Journal: Journal of Clinical Oncology (2007)

In this issue of the Journal of Clinical Oncology (JCO), two articles focusing on colorectal liver metastases (CLM) contribute to advances in a rapidly evolving field. In the first article, Tomlinson et al report only one disease-specific death among 102 survivors from a cohort of 612 patients who underwent resection, with a minimum 10-year follow-up. This is in contrast to a 34% incidence of disease-related death among the 5-year survivors, suggesting that patients who survive 5 years after liver resection have a low risk of recurrence and death from CLM. Studies from the Mayo Clinic and Erlangen, Germany have suggested that the likelihood of cure can be assessed after 5 and 7 years, respectively, but survival at 10 years appears to be the litmus test for reaching the plateau in disease-specific survival, which admittedly is the best presumptive evidence of cure. This 10-year interval defines the appropriate follow-up time for patients after resection, because 16% (16 of 102) of these 10-year survivors benefited from liver or lung reresection for recurrence in the interim. Importantly, none of the traditional adverse prognostic indicators of recurrence, such as carcinoembryonic antigen more than 200 ng/mL, short disease-free interval, node-positive primary, tumor size more than 5 cm, multiple tumors, or synchronous presentation precluded long-term survival, except for a positive resection margin. In the second article, Adam et al report on the outcome of 25 patients who underwent resection for CLM after stabilization or response using cetuximab with irinotecanor oxaliplatin-containing regimens. In this study, patients were treated with cetuximab as second-line or higher line chemotherapy after the failure of firstline chemotherapy. Among 133 patients treated solely at the authors’ institution for unresectable or marginally resectable disease, nine (7%) subsequently underwent successful resection. Thus, the addition of cetuximab allowed 7% of patients with disease refractory to first-line therapy to undergo resection, thereby increasing the number of patients able to undergo resection from the previously reported 14% resectability rate achieved by the same institution after first-line, oxaliplatin-based chemotherapy without biologic therapy for unresectable disease. This improvement in resectability is consistent with the 10% to 16% additional response rate achieved with the biologic agents cetuximab and bevacizumab, and with a previous analysis reporting an almost linear correlation between response and resectability for metastases confined to the liver. The two articles presented in this issue of JCO raise several important questions regarding patient selection, perioperative outcome, and survival in patients with CLM. First, for patients with resectable disease, no single risk factor precludes resection, and long-term follow-up reveals survivors among those with adverse prognostic factors. A recent consensus conference on CLM proposed that resectability can be defined on the basis of three oncosurgical criteria distinct from prognostic factors: the ability to obtain a complete resection (negative margin); the ability to preserve two contiguous liver segments, with adequate vascular inflow and outflow; and the ability to preserve adequate future liver remnant ( 20% in a healthy liver). Second, patients should be referred early for evaluation for resection, and perhaps more aggressive chemotherapy including biologic agents up front is appropriate for patients with multiple or large metastases and liver-only disease. Although Adam et al do not report the total number of chemotherapy cycles that their patients received, the perioperative complication rate, including hepatobiliary complications (50%), was twice that reported in other studies for patients receiving short-duration (3 to 4 months) preoperative chemotherapy, and was likely related to the prolonged and sequential use of multiple regimens. Third, with an increasing number of patients undergoing resection as a result of more effective chemotherapy, patients with limited synchronous extrahepatic disease (such as perihepatic nodes, peritoneal implants, or lung or ovarian metastases) are now included in resection series. In the report by Adam et al, more than half of the patients who underwent resection had extrahepatic disease, and at least one third had positive margins. Previous experience suggests a 5-year overall survival rate of less than 20% in the subset of patients with extrahepatic disease or positive margins, in contrast to the 53% to 58% 5-year survival rate currently reported from multicenter and single-center studies using traditional selection criteria for resection of CLM. Thus, from an anatomic and prognostic perspective, it seems appropriate to recommend that patients with combined liver and extrahepatic disease be reported separately from those meeting the traditional resectable criteria, and be designated as borderline resectable. Surgeons who have affected the natural history of CLM in patients with stage IV hepatic-only disease are now surfing on the chemotherapy wave, which has shifted the earlier part of the survival curve to the right in this disease. As a result, the resection criteria have not only expanded (resection of extrahepatic disease and reresection), but have moved toward criteria based on biologic information derived from chemotherapy (stable disease or JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 29 OCTOBER 1