The Randomized Trial of Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemoperfusion: What It Does and Does Not Tell Us

Peritoneal dissemination or ‘‘carcinomatosis’’ from colorectal carcinoma is a problem all oncologists must face. Natural history studies have shown that peritoneal carcinomatosis is uniformly fatal, with a median survival in the range of 6 months. This has led some to therapeutic nihilism. For more than a decade, a handful of centers have pursued aggressive cytoreductive surgery combined with intraperitoneal hyperthermic chemotherapy (HIPEC) as an alternative approach to this disease. Single-institution trials of HIPEC show survival with peritoneal carcinomatosis from colorectal carcinoma well in excess of a year with this approach. While doubling to tripling the survival time compared with historical controls represents a significant accomplishment in this group of patients, these results have been treated with a healthy degree of skepticism. Strict selection criteria, variation in intraperitoneal chemotherapy, and the vagaries of what represents ‘‘cytoreductive surgery,’’ made many of our colleagues, particularly those in medical oncology, reticent to refer patients for such an aggressive therapy. To bring cytoreductive surgery and intraperitoneal chemotherapy into the mainstream, a randomized trial was sorely needed. Conducting a randomized trial in patients with peritoneal carcinomatosis is a difficult undertaking, as most patients presenting for cytoreductive surgery and HIPEC are not willing to be randomized to a nonHIPECarm. Several centers have initiated randomized trials, only to fail due to inadequate accrual.However, investigators from the Netherlands Cancer Institute in Amsterdam have succeeded where other institutions had failed. Their prospective randomized trial was initially published in the Journal ofClinicalOncology in 2003, with striking results, but limited follow-up. In this issue of the Annals of Surgical Oncology, the group from the Netherlands Cancer Institute updates the results of their initial study to a median follow-up of 8 years. This represents a verymature experience for this disease process. In their study, conducted over a 3-year period, 105 patients were randomized to receive ‘‘standard treatment’’ consisting of fluorouracil and leucovorin with or without palliative surgery, or the same chemotherapy with aggressive cytoreductive surgery and intraperitoneal hyperthermic chemotherapy with mitomycin c (HIPEC). The median diseasespecific and progression-free survival was 12.6 and 7.7 months in the standard chemotherapy arm and increased to 22.2 and 12.6 months in the cytoreduction and chemoperfusion arm (P = .028 for each). Treatment morbidity for cytoreductive surgery and HIPEC in this study was similar to other centers with a mortality rate of 8%. An exciting finding of this trial was a 5-year survival of 20% (50% for those who can be completely cytoreduced), which confirmed the results of several of the single-institution phase II trials. The trial tells us, with class I evidence, that this survival benefits accrues to patients despite this significant postoperative mortality rate. This study also confirmed the universal finding that the prognosis following cytoreductive surgery and intraperitoneal hyperthermic chemotherapy is closely related to the completeness of the cytoreduction. Published online August 12, 2008. Address correspondence and reprint requests to: Edward A. Levine, MD; E-mail: elevine@wfubmc.edu