Synchronous Colorectal Liver Metastases: Triumph Of Prospective Randomized Trials Over Observational Bias Leads To Paradigm Shift

The last one and a half decade has witnessed an exciting era for the management of advanced colorectal cancer, with emergence of effective combination chemotherapy, potent biologic agents, surgical techniques for safe hepatic resection and ancillary procedures such as portal vein embolization and radiofrequency ablation. Integration of these various interventions within the context of a multidisciplinary approach has fostered an aggressive stance amongst oncologists. This approach continues to be pushed forward with attempts to ‘‘tease out’’ additional patients who may become candidate for curative hepatic resection and hence alter the natural history of their disease. In this issue, Reddy et al comprehensively review the current evidence for outcomes in the management of synchronous colorectal liver metastases (CRLM) and inquire whether a paradigm shift is necessary. Let us examine some of the controversial issues that the authors raise in this review and then determine whether a paradigm change is justified. The traditional approach to the management of the asymptomatic primary tumor with synchronous CRLM has been to resect it to avoid future obstruction, perforation or bleeding. This notion is particularly evident for rectal primaries where surgeons believe that at minimum a diverting colostomy is necessary to prevent eventual obstruction during systemic chemotherapy/chemoradiation. Given that even primary tumors are now commonly considered quite responsive to current multiagent chemotherapy, potential complications are an unlikely event as evidenced by the report from the BRiTE registry. Additional evidence will hopefully become available from the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-10, a phase II trial evaluating FOLFOX6 with bevacizumab in patients who present with untreated primary colon cancer and concomitant metastatic disease not considered surgically resectable for cure. Downsizing to resectable disease has been extensively investigated by the Paul Brousse group in France. Adam et al reported their experience of a multimodality approach where patients received multiple cycles of chemotherapy and, if deemed resectable, then integrating a combination of hepatic resection, resection of extrahepatic disease, portal vein embolization, radiofrequency ablation, cryotherapy, two-stage hepatectomy, and repeat hepatectomy to achieve cure. When one critically examines this most aggressive approach for CRLM with an intention-to-treat analysis, the percentage of long-term survivors at a mean follow-up of 48.7 months was very low (3.5% alive and 2.2% alive without disease). This appears to be a long run for a short slide. When the same data are used to claim that chemotherapy will nullify the biologic effects of portal lymph node metastases, the reservations expressed by Wagman have to be echoed. Inoperable colorectal metastases may be considered a declining entity, but when one examines the published series on ‘‘conversion chemotherapy’’, patient selection is an important variable and it is clear that, the criteria for non-resectability not only differed between the studies but were often poorly defined. Until the report of the multi-institutional phase III trial by Portier et al, there had been no clear evidence from a randomized trial that adjuvant chemotherapy, either systemic or by hepatic artery infusion, added benefit over surgery alone. This trial was marred by slow accrual and inadequate sample size (173 of the planned 200 patients over a period of 10 years) but nonetheless did show The Author(s) 2009. This article is published with open access at Springerlink.com