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Journal of Clinical Oncology, Vol 24, No 31 (November 1), 2006: pp. 4952-4953 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.9236
Evolving Role of Chemotherapy in Resected Liver MetastasesMedical Oncology, Mayo Clinic, Rochester, MN 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 Waugh1 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,2 a growing body of evidence has now made surgery an accepted practice.3-6 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%.7,8 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.8 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.9,10 In one of these trials, HAI FUDR alternating with systemic FU after surgery showed a recurrence-free benefit of chemotherapy over surgery alone.10 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.9 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 al11 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 al11 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 al11 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 of FOLFOX4 after surgery. This trial recently completed its accrual of approximately 300 patients with overall survival as the primary end point. It is unlikely—and potentially inappropriate—that a trial will now be performed in patients with resected liver metastases without considering some form of systemic chemotherapy for all patients. While the trials of HAI therapy did not show clear evidence of improvement in overall survival, and the current reported trial shows statistical benefit for disease-free survival, but not overall survival, there is a large body of clinical trial data supporting the use of chemotherapy in both resected stage III and in unresectable stage IV colorectal cancer. As Portier et al11 point out, it is no longer feasible to use overall survival as the primary end point in a first-line trial for stage IV colorectal cancer. Given the multiple options available to patients, it is very likely that patients with resected liver-only metastases who develop recurrence will be offered additional chemotherapy that will likely impact their overall survival. In addition, a portion of patients with recurrence will be candidates for repeat surgery or ablation. As such, it is unlikely that any future trial will be able to use overall survival as a meaningful end point, but must instead use other meaningful end points such as disease-free survival. Finally, it is important to address the question of both benefits and risks of treatment, when using a combined modality approach for patients with potentially resectable liver metastases. Chemotherapy alone offers the potential for control and improved survival, but not potential cure. Surgery is still the one modality that offers the potential of cure, but is likely reaching its limit of benefit. The potential morbidity and mortality of surgery in a modern era and in a high volume center is low and therefore appears justified. The addition of chemotherapy to surgery has the potential of enhancing outcome and reducing the risk of recurrence. The optimal manner in which therapy is given remains an unanswered question. Does HAI therapy alternating with systemic therapy enhance outcome over systemic therapy alone? At least one prior trial supports an added benefit of HAI therapy to systemic therapy over systemic therapy alone.12 However, with more active systemic regimens, it is unclear if this benefit is of a large enough degree to outweigh the added cost, toxicities and technical issues associated with placement of an HAI pump. The recently activated National Surgical Adjuvant Breast and Bowel Project trial C-09, which randomly assigns patients to either systemic capecitabine and oxaliplatin alone or with alternating HAI FUDR after resection of liver-only metastases, may help address this question. Ultimately, it is critical that we as a research community and as care providers for patients with liver-only metastases from colorectal cancer conduct trials with relevant clinical questions and adequate sample size and with appropriately rapid accrual. Trials that accrue slowly or fail to meet their planned accrual hinder our ability to provide meaningful answer to our patients when they ask if there is a benefit to therapy after surgical resection and, if so, what type of therapy is likely to be of greatest benefit. The outcome of patients with liver-only metastases has improved dramatically from 50 years ago, but there is much left to do to ensure benefit for all of our patients. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES 1. Woodington GF, Waugh JM: Results of resection of metastatic tumors of the liver. Am J Surg 105:24-29, 1963[CrossRef][Medline] 2. Silen W: Hepatic resection for metastases from colorectal carcinoma is of dubious value. Arch Surg 124:1021-1022, 1989 3. Belli G, D'Agostino A, Ciciliano F, et al: Liver resection for hepatic metastases: 15 years of experience. J Hepatobiliary Pancreat Surg 9:607-613, 2002[CrossRef][Medline] 4. Fong Y, Fortner J, Sun RL, et al: Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: Analysis of 1001 consecutive cases. Ann Surg 230:309-318, 1999; discussion 318-321, 1999[CrossRef][Medline] 5. Nordlinger B, Guiguet M, Vaillant JC, et al: Surgical resection of colorectal carcinoma metastases to the liver: A prognostic scoring system to improve case selection, based on 1568 patients. Association Francaise de Chirurgie Cancer 77:1254-1262, 1996 6. Hughes KS, Rosenstein RB, Songhorabodi S, et al: Resection of the liver for colorectal carcinoma metastases: A multi-institutional study of long-term survivors. Dis Colon Rectum 31:1-4, 1988[Medline] 7. Scheele J, Altendorf-Hofmann A: Resection of colorectal liver metastases. Langenbeck's Arch Surg 384:313-327, 1999[CrossRef][Medline] 8. Fong Y, Cohen AM, Fortner JG, et al: Liver resection for colorectal metastases. J Clin Oncol 15:938-946, 1997 9. Lorenz M, Muller HH, Schramm H, et al: Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer: German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen). Ann Surg 228:756-762, 1998[CrossRef][Medline] 10. Kemeny MM, Adak S, Gray B, et al: Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: Surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy–an Intergroup study. J Clin Oncol 20:1499-1505, 2002 11. Portier G, Elias D, Bouche O, et al: Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol 24:4976-4982, 2006 12. Kemeny N, Huang Y, Cohen AM, et al: Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 341:2039-2048, 1999
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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