Adjuvant Chemotherapy (Yes or No) After Colorectal Liver Metastases Resection

Abstract & Commentary

By William B. Ershler, MD, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.

Synopsis: The question of the role for systemic therapy in addition to surgical resection of liver metastases was addressed by Portier and colleagues from France by conducting a multicenter trial in which 173 patients with liver-only colorectal metastases had resection of the metastatic lesion(s) with or without additional systemic chemotherapy (fluorouracil and leucovorin). The 5-year disease-free survival rate of 33.5% for those receiving adjuvant therapy was significantly better than that for the surgery-only arm (26.7%).

Source: Portier G, 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. 2006;24:4976-4982.

There has remained some controversy on the advisability of systemic chemotherapy after resection of hepatic metastases from colorectal cancer. This, despite the demonstrated benefit of such in patients at high risk for recurrence after primary surgery or in those with stage IV disease. Yet, there had previously been no randomized clinical trial demonstrating benefit in terms of overall survival. In the current multicenter trial, 173 patients with completely resected hepatic metastases from colorectal cancer were randomized to surgery alone (observation, n = 87) or to surgery followed by 6 months of systemic adjuvant chemotherapy with fluorouracil and folinic acid (n = 86). Using an intention-to-treat analysis (171 patients evaluable), after a median follow-up of 87 months, the 5 year disease free survival rate was 33.5% for the patients in the chemotherapy group and 26.7% for patients in the control group (Cox multivariate analysis: odds ratio for recurrence or death = 0.66; 95% CI, 0.46-0.96; P = 0.28). With regard to secondary outcome measures, a trend towards increased overall survival was observed but did not reach statistical significance (5-year overall survival: chemotherapy group, 51.1% vs control group, 41.1%; odds ratio for death, 0.73; 95% CI, 0.48-1.10; P = 0.13).

Thus, adjuvant systemic chemotherapy provided a significant disease-free survival benefit for patients with resected liver metastases from colorectal cancer.

Commentary

Although chemotherapy may prolong survival in patients with hepatic recurrence of colorectal cancer, surgical excision offers the best and probably only chance for cure. Recent developments in radiofrequency ablation (RFA) and similar approaches are also likely to offer comparable results in selected patients. Yet, even with effective surgery or RFA, a substantial portion of the patients recur, either in the liver or at other sites. Accordingly, it would seem that such individuals would be excellent candidates for adjuvant therapy. However, only two randomized phase III trials in which the comparative group was surgery alone have been published,1,2 and the results of these were not definitive. In one of these, hepatic arterial infusion (HAI) of floxuridine (FUDR) or fluorouracil compared with either surgery alone or systemic therapy showed a recurrence free benefit of chemotherapy over surgery alone. However, this trial was not designed to assess an overall survival benefit. In the other trial, HAI of FU plus leucovorin was compared to surgery alone, and no benefit beyond surgery was observed.

The current report is the first adequately powered trial comparing systemic chemotherapy after surgery to surgery alone. The trial was projected to enroll 200 subjects, but was closed after ten years with only 173, due to slow accrual. Using disease-free survival as the primary end point, patients receiving postoperative chemotherapy fared significantly better than those receiving surgery alone. There was also a trend toward benefit in overall survival, though this had not reached a level of statistical difference.

In his editorial comments regarding this trial,3 Alberts highlights the problems that can occur in a trial that is slow to accrue, including the point that the chemotherapy used would be considered inferior to current standards that might include such agents as oxaliplatin, irinotecan, bevacizumab, or cetuximab. He points to the fact that the trial showed benefit with FU and leucovorin as a proof in concept that adjuvant therapy is useful in this setting, but that the trial needs to be validated using more modern systemic approaches. Fortunately, the EORTC trial 40983, in which patients with liver only colorectal metastases were randomly assigned to surgery alone or 3 months of oxaliplatin, leucovorin, and FU (FOLFOX4) before surgery and 3 months of FOLFOX 4 after surgery has recently completed its accrual of 300 patients, and overall survival is the primary end point.

Thus, it is likely that most experts today would agree that systemic adjuvant therapy is justified in the setting of hepatic resection of colorectal metastases. The question regarding the drugs to be administered and their scheduling remains unanswered, as does the impact of such an approach on overall survival.

References

1. Lorenz M, 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. 1998;228:756-762.

2. Kemeny MM, 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. 2002;20:1499-1505.

3. Alberts SR. Evolving role of chemotherapy in resected liver metastases. J Clin Oncol. 2006;24:4952-4953.