Hyperthermic Intraperitoneal Chemotherapy in Advanced Gastric Cancer: The End of Skepticism?

Abstract

Over the past two decades, novel therapeutic approaches to peritoneal carcinomatosis (PC) have emerged, combining cytoreductive surgery and peritonectomy procedures with perioperative intraperitoneal chemotherapy (PIC), including hyperthermic intraperitoneal chemotherapy (HIPEC) and/or early postoperative intraperitoneal chemotherapy (EPIC). Theoretically, cytoreductive surgery is performed to treat macroscopic disease and PIC to treat microscopic residual disease aiming to remove disease completely with a single procedure. Many consider it a standard of care for disease such as pseudomyxoma peritonei, peritoneal mesothelioma, or localized and resectable colorectal carcinomatosis. Because of its negative prognosis, the question regarding the efficiency of this combined procedure still remains controversial for carcinomatosis from gastric origin. Peritoneal dissemination is the most frequent pattern of metastasis and recurrence with gastric cancers. Traditionally, there was a mutual agreement in the oncologic community that those patients with gastric peritoneal dissemination were incurable. For the past 10 years, despite improvements in systemic chemotherapy with the development of new targeted therapy and encouraging tumor response rates, there have been no large phase III studies that demonstrated the real benefit of one regimen and really changed the negative prognosis of this disease evolution. With this phase III study including 68 patients with PC from gastric cancer, Yang et al. demonstrated that the use of HIPEC with the association cisplatinum-mitomycin C significantly improved survival. With HIPEC, the overall survival was extended by nearly 70% (6.5 vs 11.0 months) when compared with cytoreductive surgery alone. The authors compared their results and the design of their study to those reported by the Netherlands phase III study, conducted for the treatment of PC from colorectal origin and that compared the combination of CRS with HIPEC compared with systemic chemotherapy. This important study strongly influenced the oncologic community and precipitated the evolution to a new management of colorectal carcinomatosis with a curative intent. However, it demonstrated the potential benefit of CRS combined with HIPEC and not of HIPEC only. To our knowledge, Yang et al. is the first study that demonstrated the benefit of HIPEC in one phase III study for the treatment of PC, whatever the origin is. The experience of few single institutions, combined with phase II studies, reported encouraging survival results following treatment of PC with this therapeutic strategy. Recently, a collaborative effort of French institutions collected data from 159 patients and represents the largest experience of the treatment of PC from gastric origin. With a median follow-up of 20.4 months, the overall median survival was 9.2 months, which is close to that reported by Yang et al. in the experimental group (11 months). This median survival rate remains low, but the 5-year survival rate was 13% with some long-term survivors. These survival results are less encouraging than those obtained for other peritoneal surface malignancies, reflecting either a more aggressive disease process less responsive to this combined treatment modality or the need for better patient selection. However, the combination of cytoreductive surgery with HIPEC was the only therapeutic strategy that reported long-term survivors at 5 years. Prognostic factors are essential for a better patient selection for the combined procedure, and some have been identified in the phase III study. For intraperitoneal chemotherapy to be effective, residual disease following attempted cytoreductive surgery must be of low volume. In the recent French study, long-term survival, with a 5-year Society of Surgical Oncology 2011