Multiagent Regimens for Metastatic Colorectal Cancer: If Some Is Good, More Must Be Better

Abstract

The management of patients with metastatic colorectal cancer has undergone substantial evolution over the past two decades. The advent of several new classes of therapeutics that have been approved for use in patients with colorectal cancer since the mid1990s has resulted in tangible clinical benefit, with median survival currently expected to be in excess of 20 months (1–3). In an era not so long ago, 5-fluorouracil was the sole agent with generally recognized benefit in managing patients with colorectal cancer. The use of this agent was associated with a median survival of less than 1 year. Thus, recent advances have been substantial; however, it is humbling to realize that we still have considerable room for improvement in our therapeutic armamentarium. In addition to the development of new cytotoxic agents including oxaliplatin and irinotecan along with the antibody inhibitors of vascular endothelial growth factor and the epidermal growth factor receptor, we have learned that patients with metastatic colorectal cancer should not all be treated similarly nor should the goals of therapy be singular, namely palliation, as it was in a bygone era. We have also learned that the approximately 40% of patients whose tumors contain a mutation in the KRAS oncogene will not derive benefit from the use of antibody therapy directed against epidermal growth factor receptor (4). With the introduction of modern therapeutic approaches, it has become apparent that patients with metastatic colorectal cancer can be classified into at least three broad therapeutic groups: 1) patients with organ-isolated disease (eg, liver only), who can be managed with surgical and ablative approaches with curative intent; 2) patients with organ-isolated disease, who may be “converted” to a state that is amenable to surgical and ablative approaches with curative intent; and 3) patients whose disease is so widespread or in inaccessible locations that preclude intervention with anything but palliative intent. Clearly, the goals of therapy must be considered in selecting the optimal therapeutic intervention. For patients in whom palliation is the goal, regimens that are associated with the longest survival balanced by their attendant toxicity profile may be preferred. Conversely, for patients in whom “conversion” to an operable state is the goal, regimens with the highest response rate and at least a tolerable short-term toxicity profile may be considered optimal. The report by Masi et al. (5) in this issue of the Journal details the long-term outcomes (median follow-up of 5 years) in 244 patients with metastatic colorectal cancer who were randomly assigned to treatment with either FOLFIRI or FOLFOXIRI as first-line therapy. Antibody therapy was not used with either of these regimens because the study was conducted before the widespread availability of these agents. The authors report that the use of the three-drug regimen (FOLFOXIRI) was superior to the doublet (FOLFIRI) in all measures of clinical efficacy, including response rate (60% vs 34%; P < .001), progression-free survival (9.8 vs 6.9 months; P < .001), and overall survival (22.6 vs 16.7 months; P = .026). They also report that among patients with hepatic metastases, those treated with the three-drug regimen had a greater incidence of resections with curative intent compared with those treated with the doublet (36% vs 12%; P = .017). The higher resectability rate, although determined retrospectively, presumably reflects a higher response rate achieved with the triplet regimen. Given that response is the critical factor in enabling resection with curative intent, the FOLFOXIRI regimen is certainly a strong contender as a “conversion” regimen given the available agents. However, the 60% response rate reported by Masi et al. must be considered in context with results of the Hellenic Oncology Research Group (HORG) trial, in which 283 patients were randomly assigned to either the FOLFOXIRI or FOLFIRI regimen (6). Souglakos et al. (6) reported that the FOLFOXIRI regimen was associated with a 43% response rate among 137 patients. Although numerically superior, this rate was not statistically significantly different from the response rate of patients treated on the control arm using FOLFIRI (33.6%) and is similar to other contemporaneously conducted trials using the FOLFIRI regimen that have been reported to have response rates in the 31%–56% range (7–11). What about the patients for whom palliation is the goal of therapy? For this population, which represents the largest proportion of patients with metastatic colorectal cancer, regimens that are associated with the best survival balanced with an acceptable toxicity profile are preferred. The trial presented by Masi et al. dem onstrates a clear advantage in progression-free survival and overall survival for the FOLFOXIRI arm, whereas the HORG trial failed to demonstrate the superiority of FOLFOXIRI over FOLFIRI for either progression-free survival (6.9 vs 8.4 months; P = .17) or overall survival (19.5 vs 21.5 months; P = .34) (6). Although the progression-free survival (9.8 months) and overall survival (23.4