Improving Long-Term Outcomes for Patients With Liver Metastases From Colorectal Cancer

Abstract

Despite improved screening and adjuvant therapy for primary colorectal cancers, synchronous and metachronous liver metastases remain a significant problem for patients with this disease. Approximately 40% of patients who develop metastatic disease have tumor confined to the liver, which has driven interest in regional therapies targeting the liver. These include chemotherapy delivered via hepatic arterial infusion (HAI), destructive therapies such as radiofrequency ablation (RFA), and surgical metastasectomy. Surgical techniques for liver resection have improved significantly during the last decade; therefore, this has become an attractive method for rendering suitable patients macroscopically disease free. Studies showing prolonged diseasefree survival, overall survival—and possibly cure—in selected patients have demonstrated the efficacy of this approach. Systemic chemotherapy has been shown to downsize a proportion of initially unresectable liver metastases to the point of resectability. Adam et al reported a single-institution series of 872 patients with colorectal liver metastases who were assessed for resectability: 171 (19.6%) had resectable disease initially and underwent immediate surgery; 701 patients who had unresectable disease initially were treated with preoperative chemotherapy, which was mainly oxaliplatin based. After restaging, 95 patients (13.6%) were considered resectable, and underwent surgery. The actuarial 5-year survival for this downstaged group was 34%, with the survival curve almost exactly replicating that of patients who had initially resectable disease who underwent immediate surgery. This nonrandomized, yet innovative comparison has been a major rationale in support of surgery for patients with initially unresectable disease that responds adequately to preoperative chemotherapy. Response to this therapy is also predictive for long-term outcome. Adam et al found that patients who had liver metastasectomy after tumor progression on preoperative chemotherapy had significantly poorer survival than responders or those with tumor stabilization. Postoperative therapy is an accepted and rational component of treatment for patients requiring preoperative downsizing before resection. However, even patients with initially resectable liver metastases may benefit from postoperative therapy. The largest study was performed by the Federation Francophone de Cancerologie Digestive, which randomly assigned 167 patients to intravenous fluorouracil (FU)/leucovorin (LV) or observation after complete liver metastasectomy. Preliminary results suggested a nonstatistically significant trend toward improved disease-free and overall survival. An Intergroup study of 109 patients compared postoperative HAI floxuridine plus continuousinfusion intravenous FU versus observation. Although there was no difference in overall survival, both time to recurrence and time to recurrence in the liver were prolonged in the postoperative therapy arm. Additional support for the notion of more intensive postoperative therapy was provided by a study that demonstrated improved 2-year survival for patients randomly assigned to postoperative HAI floxuridine plus systemic FU versus systemic FU alone. Long-term follow-up has confirmed superior progression-free survival and a trend to improved overall survival for the combination arm. There are few prospective trials of preoperative systemic chemotherapy for patients with unresectable liveronly metastases. Pozzo et al conducted a single-institution nonrandomized study that comprised 40 patients with unresectable disease defined by local criteria. These criteria were more than six metastases (or three per lobe; 14 patients); more than 5 cm diameter of at least one lesion if six metastases (or three per lobe; 10 patients); and contiguity with at least two hepatic veins, inferior vena cava or liver hilum (14 patients). The response rate to irinotecan/FU/ LV) was 47.5%, and 13 (32.5%) patients underwent R0 liver resection. Six cycles of postoperative chemotherapy were administered to all patients who underwent resection JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 36 DECEMBER 2