Hyperthermic Intraperitoneal Chemotherapy and Cytoreductive Surgery in the Management of Peritoneal Carcinomatosis

Rahul Rajeev, MBBS; Kiran K. Turaga, MD


Cancer Control. 2016;23(1):36-46. 

In This Article

Hyperthermic Intraperitoneal Chemotherapy

Early attempts at treatment for peritoneal carcinomatosis with surgery alone produced rapid rates of progression and treatment failure.[13,14] The tumor cell entrapment theory proposed that intraperitoneal tumor emboli generated during surgery seeded on the peritoneal surface and aided by the growth factors associated with wound healing and peritoneal vasculature, forming metastases.[15] Chemotherapy intraperitoneally delivered at the time of surgery can theoretically kill the tumor emboli, thus avoiding tumor progression.

Chemoperfusion has continued to progress since the HIPEC delivery system was first trialed.[16] The benefits of the intraperitoneal delivery of antineoplastic drugs are manifold; hyperthermia aids in increased cellular penetration of the drug while synergistically enhancing cytotoxicity. Moreover, vascular stasis of microcirculation occurs in neoplastic cells at temperatures produced by HIPEC, while normal cells experience increased flow. This, combined with the selective accumulation of lactic acid and the resulting lowered level of pH in neoplastic tissue, results in cell death.[17] Drug concentrations achieved through this route cannot be replicated by intravenous chemotherapy and, to some extent, systemic toxicities are avoided.

Verwaal et al[18] compared cytoreductive surgery/HIPEC followed by systemic chemotherapy vs systemic chemotherapy with or without palliative surgery in patients with colorectal cancer and peritoneal carcinomatosis (CRC-PC) and found that those in the HIPEC group had better survival rates than their counterparts. After 8 years of follow-up, the 5-year survival rate was 45% and significant differences in progression-free survival and disease-free survival rates between the HIPEC and control arms were also noted.[10]

A phase 3 randomized trial comparing cytoreductive surgery/HIPEC with cytoreductive surgery alone for the management of gastric cancer reported improved rates of survival and acceptable rates of morbidity with cytoreduction/HIPEC.[19] Another trial compared cytoreductive surgery/HIPEC plus systemic chemotherapy with systemic chemotherapy alone and demonstrated that the combined modality achieved modest rates of prolonged survival in carefully selected patients with gastric cancer.[20] The evidence continues to accumulate, with numerous observational and retrospective studies supporting the superiority of multimodality treatment with cytoreductive surgery/HIPEC in the setting of peritoneal carcinomatosis (Fig 2).[11,18,19,21–37] Although this combination treatment began as experimental therapy, cytoreductive surgery/HIPEC is now the standard of care in peritoneal carcinomatosis, which is now being viewed as a treatable entity rather than a terminal condition.[11,18,19,21–37] Appendiceal mucinous neoplasms, colorectal adenocarcinoma, mesothelioma, and epithelial ovarian carcinoma are histologies that most benefit from intraperitoneal chemotherapy.[11,18,19,21–37] For patients with high-grade disease or poor prognostic factors, multidisciplinary treatment using systemic chemotherapy is often employed (Table 1). Select ongoing and recently completed trials involving cytoreductive surgery and HIPEC are described in Table 2.

Figure 2.

Selected evidence supporting use of cytoreductive surgery and HIPEC for the management of peritoneal carcinomatosis. CRS = cytoreductive surgery, DPAM = diffuse peritoneal adenomucinosis, EPIC = early postoperative intraperitoneal chemotherapy, HIPEC = hyperthermic intraperitoneal chemotherapy, OS = overall survival, PC = peritoneal carcinomatosis, PCI = Peritoneal Cancer Index, PMCA = peritoneal mucinous carcinoma, PMP = Pseudomyxoma peritonei infection, RCT = randomized controlled trial.
Information from references 18, 19, and 21 to 37.