Should we continue intra-peritoneal chemotherapy in advanced ovarian cancer patients?

Ovarian cancer has the highest mortality of all gynecologic malignancies in the United States. Ovarian cancer is often diagnosed at advanced stage. Optimal cytoreduction, followed by intravenous chemotherapy consisting of platinum taxol containing agents represents the mainstay of ovarian cancer therapy. The introduction of intraperitoneal chemotherapy utilized a novel route of administration showing promise in treating ovarian cancer both in vitro studies and clinical trials. Currently, in gynecologic oncology practice, the efficacy and toxicity of intraperitoneal chemotherapy is not yet widely agreed upon. The major clinical trials and future therapies utilizing intraperitoneal chemotherapy will be review here. Introduction and background Ovarian cancer is the number one cause of death from gynecologic malignancies in the United States, and is typically diagnosed at an advanced stage with an exceedingly low five-year survival [1,2]. The low survival rate of ovarian cancer has stimulated many studies to identify new, improved chemotherapy dosing regimens, routes of administration and chemotherapy agents. The current standard of care are platinum agents combined with taxane agents administered through the intravenous route. These therapies are typically administered every three weeks for six cycles. In 1996, the GOG 104 study evaluated a new route of administration. The trial was conducted given that survival outcomes remained poor in advanced stage ovarian cancer despite aggressive surgical and intravenous chemotherapeutic management. The GOG 104 was based on a number of diverse studies which all supported the use of intraperitoneal (IP) chemotherapy [3]. Some of the studies were theoretical, using pharmacokinetic modeling, while other studies utilized successful in-vivo mouse and rat models which led to additional pilot clinical studies 4–6. In these early clinical pilot studies, radioisotopes were given intraperitoneally and showed an advantage for early stage ovarian cancer. In its infancy IP chemotherapy was frequently restricted to patients who needed palliative treatment of their advanced malignant ascites [4,5]. Eventually the technique and chemotherapy improved leading to a phase III trial from the GOG. This initial phase III study displayed a survival advantage in the IP arm for the treatment of advanced ovarian cancer. Since that initial randomized controlled trial there have been a number of similar trials, the four most influential being, GOG 104, GOG 114, GOG 172 and now GOG 252. These trials have been completed to help determine the efficacy, toxicity and plausibility of intraperitoneal chemotherapy. There have been a number of metaand post hoc analyses to determine the safety, efficacy and tolerability of IP chemotherapy [7-9]. In gynecologic oncology, the debate over IP chemotherapy has been ongoing since its inception. The debate continues as these studies are largely heterogeneous with relation to chemotherapy dosing, toxicities, study design and delivery methods. These issues and variable results have led to slow uptake of IP chemotherapy in the clinical setting. The three clinical trials will be reviewed here, as will the biochemical and pharmacokinetic rationale Correspondence to: Masoud Azodi, Professor, Department of Obstetrics, Gynecology and Reproductive Science, Division of Gynecologic Oncology, Yale University School of Medicine, PO Box 20063, New Haven, CT 06520, USA, Tel: 203-384-4870, Fax: 203-384-3579, E-mail: [email protected] Received: August 01, 2016; Accepted: September 14, 2016; Published: September 17, 2016 to use intraperitoneal chemotherapy, the toxicities associated with intraperitoneal chemotherapy, the possibility of improving the IP delivery system and the future of intraperitoneal chemotherapy. This is an important discussion in the gynecologic oncology field as the current questions regarding the future of IP chemotherapy [10]. Biochemical and pharmacokinetic reasonings for intraperitoneal chemotherapy Ovarian cancer at advanced stages will metastasizes to many different areas in the peritoneal cavity and thus portend a poor survival. The single most important prognostic factor in prolonging survival is achieving complete cytoreductive surgery to no visible residual disease. Unfortunately, it is not feasible to remove all microscopic residual tumor cells from the peritoneal cavity. Additionally, it may not be feasible to remove innumerable small tumors less than 1 cm from all peritoneal surfaces. Due to the difficulty, at times, of achieving complete cytoreduction, the idea of intraperitoneal (IP) chemotherapy was born. IP chemotherapy is thought to achieve higher concentrations of chemotherapy at and within the residual tumor surface. As stated above, the theory with IP chemotherapy is to administer high doses of chemotherapy to the peritoneal cavity. Once in the peritoneal cavity, the therapy can directly act on both the individual microscopic tumor cells, and the surfaces of residual sub-centimeter tumoral implants. The concept of placing medical therapy into the peritoneal cavity is not new, in fact, peritoneal dialysis was first used with patients who had renal insufficiency in 1923 [6,11]. With this technique in mind, theoretical models were developed to determine the distribution and elimination of chemotherapy when applied through an IP route [6,12]. Altwerger G (2016) Should we continue intra-peritoneal chemotherapy in advanced ovarian cancer patients? Volume 3(5): 565-574 Integr Cancer Sci Therap, 2016 doi: 10.15761/ICST.1000206 Consistently, in-vivo studies nicely complimented and supported the theoretical models [12,13]. With encouraging results in-vivo, other areas of medicine began to apply this technique. One example was found in central nervous system (CNS) tumors. The subarachnoid space is known for being relatively difficult to be penetrated by chemotherapy. When neuro-oncologists found that IV treatment with methotrexate was ineffective for CNS leukemia, it was suggested that the therapy be placed directly into the subarachnoid space. In 1957 methotrexate was used intrathecally where they achieved a high concentration and altered the course of CNS leukemia [6,14]. Similarly, to the CSF, the peritoneal fluid has low concentrations of chemotherapeutics after intravenous administration. Conversely, IP infusion of chemotherapy achieved high levels of chemotherapeutics both systemically and intraperitoneally. Thus, the technique of bathing intraperitoneal tumors with IP chemotherapy was employed. In-vivo mouse models using IP administration of therapy revealed that the IP route not only maintained a high concentration intraperitoneally but also led to a maintained distribution systemically over a longer time interval [12,13]. The high systemic concentration can be explained by the fact that the chemotherapeutics are absorbed into the systemic circulation due to the large surface area of the peritoneal membrane and abundant blood supply [12,13]. Intraperitoneal injection also allows for a slowrelease to the systemic circulation, allowing for similar sustainable systemic concentrations ast IV chemotherapy [12,13,15]. Thus, IP administration of chemotherapy should be efficient in targeting tumor cells directly in the intraperitoneal cavity as well as the tumor cells in the systemic circulation. Along these lines, in advanced ovarian carcinoma, higher concentrations of chemotherapy can be both directly delivered to the tumor’s surface and to the core of the tumor through systemic circulation leading to improved cytotoxic effects [12,13,16].