Adjuvant intraperitoneal 5-fluorouracil in high-risk colon cancer: A multicenter phase III trial.

Patients with stage II and III colon cancers are considered at high risk of tumor recurrence and constitute the target population for adjuvant therapy. Systemic postoperative chemotherapy has been shown to be effective in increasing survival rates in patients with stage III colon cancer. 1,2 The recognition of predominant patterns of spread, especially the fact that 50% of recurrences are hepatic metastases and that 20% to 50% occur in the peritoneum, 3 has provided the impetus for a series of adjuvant locoregional approaches using portal vein infusion or intraperitoneal perfusion of 5-fluorouracil (5-FU). The main advantage of locoregional chemotherapy is that it achieves high regional and hepatic concentrations of drug, whereas systemic passage and thus toxicity are reduced because of the high extraction by the liver. Dissemination of colorectal cancer to the liver through the portal vein makes the liver one of the major sites of recurrence after colorectal cancer resection, accounting for 25% to 50% of recurrences. 4 As a consequence, the first attempts at adjuvant regional therapy in colorectal cancer used the portal route, even though the vascularization of micrometastases remains controversial. 5 Despite promising initial results, 6 several studies of adjuvant intraportal chemotherapy produced controversial results. 7–10 Moreover, a meta-analysis 11 of 10 trials comprising 3,500 patients has shown that intraportal adjuvant chemotherapy offered a limited benefit. More recently, a large study comprising 1,235 patients demonstrated that low-dose intraportal 5-FU could not improve overall and disease-free survival rates or reduce the occurrence of liver metastases. 12 There has been little experience with adjuvant intraperitoneal chemotherapy. 13–15 It can theoretically add a local action to the liver effect and thus prevent both liver and peritoneal recurrences. We report in this article early and long-term results of a multicenter prospective randomized study comparing resection and early postoperative adjuvant intraperitoneal chemotherapy with 5-FU versus surgery alone in patients undergoing resection of stage II and III colon cancers. This is the largest series of this type. It is likely to remain unique: phase III trials now cannot have a control arm with surgical resection alone because systemic adjuvant chemotherapy has become the standard treatment.