Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Overview of the Molecular and Cellular Mechanisms of Actions and Effects on Epithelial Ovarian Cancers

Abstract

Most patients with epithelial ovarian cancers (EOCs) are at advanced stages (stage III–IV), for which the recurrence rate is high and the 5-year survival rate is low. The most effective treatment for advanced diseases involves a debulking surgery followed by adjuvant intravenous chemotherapy with carboplatin and paclitaxel. Nevertheless, systemic treatment with intravenous chemotherapeutic agents for peritoneal metastasis appears to be less effective due to the poor blood supply to the peritoneal surface with low drug penetration into tumor nodules. Based on this reason, hyperthermic intraperitoneal chemotherapy (HIPEC) emerges as a new therapeutic alternative. By convection and diffusion, the hyperthermic chemotherapeutic agents can directly contact intraperitoneal tumors and produce cytotoxicity. In a two-compartment model, the peritoneal–plasma barrier blocks the leakage of chemotherapeutic agents from peritoneal cavity and tumor tissues to local vessels, thus maintaining a higher concentration of chemotherapeutic agents within the tumor tissues to facilitate tumor apoptosis and a lower concentration of chemotherapeutic agents within the local vessels to decrease systemic toxicity. In this review, we discuss the molecular and cellular mechanisms of HIPEC actions and the effects on EOCs, including the progression-free survival (PFS), disease-free survival (DFS) and overall survival (OS). For primary advanced ovarian cancers, more studies are agreeing that patients undergoing HIPEC have better surgical and clinical (PFS; OS) outcomes than those not, although one study reported no differences in the PFS and OS. For recurrent ovarian cancers, studies have revealed better DFS and OS in patients undergoing HIPEC than those in patients not undergoing HIPEC, although one study reported no differences in the PFS. HIPEC appears comparable to traditional intravenous chemotherapy in treating advanced EOCs. Overall, HIPEC has demonstrated some therapeutic benefits in many randomized phase III trials when combined with the standard cytoreductive surgeries for advanced EOCs. Nevertheless, many unknown aspects of HIPEC, including detailed mechanisms of actions, along with the effectiveness and safety for the treatment of EOCs, warrant further investigation.

Survival and complications of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in patients with intra-abdominal malignancies: A meta-analysis of randomized controlled trials

“…HIPEC prevents and treats PM by combining three main mechanisms: chemotherapy, hyperthermia and mechanical flushing ( Sugarbaker, 2005 ; Garofalo et al, 2006 ; Chiva and Gonzalez-Martin, 2015 ). Because the tolerance of normal cells and tumor cells to temperature is different ( Garofalo et al, 2006 ), thermochemotherapeutic drugs can directly contact tumor cells in the peritoneum and produce cytotoxicity after convection and diffusion ( Lim P. Q. et al, 2022 ). HIPEC can eradicate single cancer cells or microscopic nodules, but because the peritoneal penetration of chemotherapy drugs is limited, the tumor must be eliminated as thoroughly as possible first.…”

FMO family may serve as novel marker and potential therapeutic target for the peritoneal metastasis in gastric cancer

“…Unfortunately, there is no effective therapeutic strategy for treating PM in GC. Due to the blood–peritoneal barrier, systemic chemotherapy is ineffective in treating PM ( 30 ). Importantly, cytoreductive surgery (CRS) + hyperthermic introperitoneal chemotherapy (HIPEC) may improve the prognosis of PM in GC to some extent, but more clinical studies are warranted ( 1 ).…”

Polyploidy, EZH2 upregulation, and transformation in cytomegalovirus-infected human ovarian epithelial cells

“…Optimal surgery and platinum-based chemotherapy (such as carboplatin and cisplatin) remain the mainstay of treatment often combined with paclitaxel, gemcitabine, a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF) bevacizumab, pegylated liposomal doxorubicin, cyclophosphamide, topotecan, poly-ADP-ribose- polymerase (PARP) inhibitors, and immune check point inhibitors especially for recurrent OC [ 2 – 4 ]. In some cases, due to the poor blood supply to the peritoneal surface, hyperthermic intraperitoneal chemotherapy (HIPEC) has been used as a therapeutic alternative [ 5 ].…”