Systemic therapy for patients with resectable hepatic colorectal metastases: improving patient selection.

The past three decades have seen great changes in the management of hepatic colorectal cancer metastases. While resection remains firmly established as the most effective therapy for selected patients, the emergence of more effective chemotherapeutic agents has been a practice changing development and has considerably altered the therapeutic approach to patients with this disease. In the palliative setting, the power of contemporary systemic agents is clear, with superior tumor response rates and prolonged survival well documented. Indeed, this greater efficacy translates into conversion to resectability in a significant proportion of patients with advanced, initially unresectable disease, a feature of systemic therapy only rarely seen in the past. There is thus little doubt that contemporary systemic chemotherapeutic agents, with their greater antitumor activity and ability to bring more patients to resection, have greatly improved long-term outcome in patients with advanced disease. As a result, there is a perception that advances in chemotherapy offer a similar benefit when used in the adjuvant or perioperative setting. Supporting this is a large body of retrospective data that suggests significantly better posthepatectomy survival over time. In the era before contemporary systemic agents, 5-year survival rates of 25– 40 % were reported routinely following hepatic resection. By contrast, several studies have demonstrated significantly greater 5-year survival rates for patients treated more contemporaneously. Of note, these analyses typically show improvements in overall survival over time, whereas changes in disease-free survival rates have been much less impressive. On the surface, these data would implicate a major contribution from systemic therapy in leading to better outcomes in patients in patients with resectable disease; however, prospective data do not reflect the same level of benefit seen in patients with advanced disease. In fact, the results of multiple prospective randomized trials examining adjuvant or perioperative chemotherapy after potentially curative hepatic resection have shown no improvement in overall survival. In two trials of adjuvant 5-FU after hepatic resection, a combined analysis of 302 randomized patients was unable to demonstrate significant improvements in recurrence-free or overall survival. Furthermore, a study of adjuvant FOLFIRI compared with 5-FU after hepatic resection in 306 patients showed absolutely no difference in recurrence free or overall survival. The most notable adjuvant trial, the EORTC study led by Nordlinger, randomized 364 patients to perioperative FOLFOX or observation following complete resection of four or fewer liver metastases, and showed a marginal benefit in progression free survival at 3 years (7 %, p = 0.058); this improved to 9 % (p = 0.025) when the analysis was restricted to resected patients. An updated analysis showed no improvement in overall survival. These seemingly discordant results between outcomes in the adjuvant and palliative settings are disappointing and somewhat surprising, particularly those reported in the EORTC study, which compared current, standard agents to a ‘‘no chemotherapy’’ group. Although many oncologists point to these data as justification for the routine use of adjuvant or perioperative systemic chemotherapy after potentially curative resection of colorectal liver metastases, the benefit, if present at all, is likely to be small, and the weight of published evidence does not necessarily support this approach. The reasons that these studies do not show a clear benefit of systemic therapy are unclear, but failure to account fully for the heterogeneity of patients with hepatic Society of Surgical Oncology 2013