Evolving role of chemotherapy in resected liver metastases.

There are now over 50 years of publications reporting benefits from the resection of liver metastases from colorectal cancer. In one of the earliest reports published in 1963, Drs Woodington and Waugh described a case series of patients undergoing resection of liver metastases. Seven of the patients included in this series had liver metastases from colon cancer, and they survived an average of 3.1 years after surgery. Despite this positive outcome, early attempts at surgical resection of liver metastases were frequently accompanied by high rates of morbidity and mortality. Over the ensuing next four decades, surgical advances have allowed an increasing number of patients with liver metastases from colorectal cancer to undergo surgery with much improved rates of morbidity and mortality. While some physicians have raised doubts about the benefits and generalizability of such therapy, a growing body of evidence has now made surgery an accepted practice. With these successes, the current 5-year overall survival rates with surgery alone for liver metasatases appears to be in the range of 25% to 40%, while 5-year disease-free survival is in the range of 20%. When patients develop a recurrence of their metastatic disease after surgery approximately one half of the recurrences occur in the liver. For many patients this may be the only site of recurrence. Based on these observations, clinical trials assessing the potential role of chemotherapy after liver resection have been performed in an attempt to lessen the rate of recurrence and increase survival. However, until recently the role of adjuvant chemotherapy in the perioperative setting has been of unclear benefit. Despite the several decades of advances in surgery, few large prospective or randomized trials of adjuvant chemotherapy have been undertaken in this group of patients. Given the high proportion of patients with liver-only recurrence, several randomized trials have assessed intrahepatic therapy using hepatic artery infusion (HAI) of floxuridine (FUDR) or fluorouracil (FU) compared with either liver resection alone or systemic therapy. Only two adequately powered randomized phase III trials with a surgery only-arm have been reported to date. In one of these trials, HAI FUDR alternating with systemic FU after surgery showed a recurrence-free benefit of chemotherapy over surgery alone. However, this trial was not designed to assess an overall survival benefit. In an intent-to-treat analysis, overall survival was worse in those patients who received chemotherapy compared with those who underwent surgery alone. When the analysis was confined to those patients who were able to have a pump placed (30 of 53 randomized patients) compared with those who underwent surgery alone, there was a trend toward improvement in overall survival. In a separate trial comparing HAI FU and leucovorin (LV) to surgery alone, no benefit was seen over surgery alone. How about Kemeny’s study of HAI FUDR FU/LV versus FU/LV originally reported in the New England Journal of Medicine in 1999 and updated in a letter to the New England Journal of Medicine last year? Until the current report of the trial by Portier et al in this issue of the Journal of Clinical Oncology, there has been no clear evidence that chemotherapy, either systemic or by HAI, added benefit over surgery alone from a randomized trial. The report of the results of the trial led by Portier et al represents the first publication of an adequately powered randomized phase III trial comparing systemic chemotherapy after surgery to surgery alone. This trial enrolled 173 of the planned 200 patients over a period of 10 years. Enrollment to the trial was suspended after 173 patients due to slow accrual. Using disease-free survival as the predefined primary end point, patients receiving postoperative systemic FU plus LV fared significantly better than those receiving surgery alone (24.4 months v 17.6 months, respectively). There was also a trend toward benefit in overall survival, though this has not reached a level of statistical difference. Given the results of this trial, what should be the standard of care in 2006? The trial of Portier et al and the trials of others assessing the use of chemotherapy in the postoperative setting have been hindered by slow accrual and by inadequate sample size to appropriately evaluate the benefit of chemotherapy. When a trial takes 10 years to complete accrual, the original question may become outdated. In this trial, the original question of “Does chemotherapy benefit patients after resection of liver-only metastases from colorectal cancer?” remains important. However, the chemotherapy used in this trial is now considered inferior to currently available regimens containing potentially more active agents such as oxaliplatin, irinotecan, bevacizumab, or cetuximab. The fact that this trial showed benefit with FU and LV, based on the predefined end point of this trial, provides a proof of concept of adjuvant chemotherapy in this patient population. It would be helpful to have this trial validated through additional trials, using more modern systemic approaches, similar to those tested in high-risk resected primary colorectal cancer. This will be accomplished, in part, by the European Organisation for Research and Treatment of Cancer trial 40983, which randomly assigned patients with potentially resectable liver-only metastases to surgery alone or 3 months of oxaliplatin, LV, and FU (FOLFOX4) before surgery and 3 months JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 31 NOVEMBER 1 2006