Intraperitoneal chemotherapy: Hot, timely, and relevant?

Abstract

Only 45% of women diagnosed with epithelial ovarian cancer (EOC) will remain alive 5 years after their diagnosis. 1 For several decades, we have seen little progress in terms of overall survival (OS). However, we have now entered a new era with increased knowledge of ovarian cancer biology, and this has led to new therapeutic options and an understanding that 1 size does not fit all for women diagnosed with this disease. 2 Our current challenge is how to interpret the emerging data to inform treatment decisions for the individual women that we see in the clinic. Nowhere is this more apparent than in the role of the combination of optimal cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). The use of HIPEC has been growing in popularity in recent years, although initially there were no randomized data to support its use. Even with a positive randomized trial, issues concerning the study design and the statistical analysis raise questions about whether HIPEC should be recommended as a standard-of-care approach. There are many questions that remain unanswered. They include the fundamental question of whether there is a role for intraperitoneal (IP) chemotherapy, hot or cold, as our use of targeted agents becomes more sophisticated. If there is a role for HIPEC, when should it be considered, and is hyperthermia necessary? Ultimately, we need to understand which women will derive a benefit from this approach or, perhaps more importantly, identify those who will not benefit. For implementing HIPEC, the real-world analyses provided by Ghirardi et al 3 are important because they can help us to understand patient selection and tolerability and help to guide physicians and women in making a choice. IP delivery of chemotherapy relies on the presumption that the cancer cells are inherently chemosensitive and that there is a dose-response relationship (ie, "more is better"). EOC lends itself to this approach because the residual disease after surgery and the initial recurrence are primarily confined to the abdominal cavity. Certain chemotherapeutic agents have a pharmacokinetic advantage with higher IP concentrations and a longer half-life of the drug in the peritoneal cavity in comparison with intravenous (IV) administration. For cisplatin, this translates into 10-to 20-fold greater exposure, and for other drugs such as paclitaxel, this ratio is even higher. 4 In 2006, the National Cancer Institute issued an alert after reviewing the data from 7 randomized clinical trials exploring the combination of serial cold IP and IV administration versus IV administration alone after optimal cytoreductive surgery for EOC. IP/IV chemotherapy was associated with a 21.6% decrease in the risk of death and an approximately 12-month increase in median OS. However, IP delivery also resulted in greater complexity, more toxicity, and significant resource implications. In addition, the design and statistical analysis of individual studies raised questions about the true benefit of this approach. IP/IV administration was ...

Hyperthermic Intraperitoneal Chemotherapy–Induced Molecular Changes in Humans Validate Preclinical Data in Ovarian Cancer

“… 5 - 7 However, questions remain regarding optimal patient selection, drug choice, toxicities, and HIPEC timing in EOC. 3 , 8 - 10 …”

“…[5][6][7] However, questions remain regarding optimal patient selection, drug choice, toxicities, and HIPEC timing in EOC. 3,[8][9][10] Theoretical advantages of hyperthermia include an increased cytotoxic effect, strengthened by synergy with cisplatin through increased cellular uptake of cisplatin and improved crosslinking to DNA. Other heat-induced effects include increased vascular flow and enhanced cell membrane permeability leading to cytokine release.…”

“…1,2 Nonetheless, IP therapy has not been widely adopted. 3 Support for hyperthermic intraperitoneal chemotherapy (HIPEC) has increased. 4 HIPEC is the delivery of heated chemotherapy (42°C) into the IP cavity immediately after optimal cytoreductive surgery (CRS).…”

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

“…However, there were criticisms of OVHIPEC questioning the use of HIPEC. Some of the significant criticisms include: (1) long accrual time (9 years) with the trial being performed in the era of anti-angiogenesis therapy and poly (adenosine diphosphate ribose) polymerase (PARP) inhibitors, (2) lack of stratification (e.g., BRCA status, histology), (3) small study size, leading to a difference of 15 deaths between groups and (4) use of the RFS as the primary endpoint, while the OS was a secondary endpoint [ 34 , 35 , 36 , 37 ]. The randomized phase III trial in recurrent EOC by Spiliotis et al was also criticized for its study design.…”