Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies and the fifth most common cause of cancer death in women. In 2015, it is estimated that there will be 21,980 new cases of ovarian cancer with 14,270 deaths from this disease (1). Currently, there are no effective screening strategies and over 60% of patients present with stage III or IV disease (2). Management of patients with advanced EOC includes aggressive surgical cytoreduction followed by platinum-based chemotherapy (3,4). Between 70% and 80% of patients will achieve clinical remission; however, most patients will relapse and are not curable (5). Multiple advancements have occurred over the last several decades for women with EOC including: the incorporation of taxanes into chemotherapy regimens, the introduction of intraperitoneal (IP) and dose-dense treatment regimens, and the development of biologic agents such as bevacizumab and olaparib (4,6-9). Three Gynecologic Oncology Group (GOG) phase III clinical trials have demonstrated a significant improvement in both progression-free (PFS) and overall survival (OS) in the primary treatment of those patients with optimally cytoreduced EOC who undergo subsequent treatment with a combination of intravenous and intraperitoneal (IV/IP) chemotherapy (10-12). The most recent of these trials, GOG 172, demonstrated a 15.9-month improvement in OS when IP chemotherapy was used for the treatment of optimally cytoreduced, advanced EOC as compared to standard intravenous (IV) therapy (10). The results of this trial prompted an announcement by the National Cancer Institute (NCI) in 2006 recommending IP chemotherapy as the standard of care for adjuvant treatment of optimally cytoreduced, advanced EOC. However, the full benefit of IP chemotherapy for the treatment of advanced EOC has not been realized, as toxicity, IP catheter complications, and complicated dosing regimens have limited widespread adoption of this method. Variable uptake has led to interest in incorporation of hyperthermic intraperitoneal chemotherapy (HIPEC) into the treatment plan given the ease of administration at the time of surgery and the lack of an indwelling IP catheter.
Interest in HIPEC has been largely driven by success in the treatment of carcinomatosis from gastrointestinal malignancies by Sugarbaker and others (13-16). EOC exhibits a pattern of dissemination similar to that of advanced gastrointestinal malignancies in that metastases tend to develop diffusely via direct tumor spread within the peritoneal cavity as opposed to hematologic or lymphatic routes. This makes the use of HIPEC in the treatment of these patients a logical consideration. In the treatment of ovarian cancer, HIPEC has the potential benefit of overcoming some of the toxicities and challenges of administering IP chemotherapy. Hyperthermia may increase cytotoxicity of chemotherapeutic agents by increasing intracellular drug penetration and overcoming platinum resistance with hyperthermia (17). Additionally, hyperthermia itself may have a direct cytotoxic effect that acts in synergy with cytotoxic chemotherapy agents (18). Several studies have demonstrated that concentrations of chemotherapy agents within the peritoneal cavity are several times higher when chemotherapy is administered intra-abdominally than when given intravenously (19-21). IP drug delivery overcomes the peritoneal-plasma barrier and concentrates cytotoxic agents within the peritoneal cavity for prolonged periods of time which may enhance cancer cell death with the potential for less systemic toxicity.
Despite the proposed benefits of HIPEC in the treatment of EOC, the data with regard to clinical applicability remain quite heterogeneous. In a study by Deraco et al., patients with advanced primary ovarian cancer who underwent primary debulking received HIPEC with doxorubicin and cisplatin followed by standard chemotherapy. Five-year OS was 60.7% and 5-year PFS survival was 15.2% (22). In another study, Coccolini et al., reported outcomes of 54 patients with primary or recurrent EOC who underwent surgical cytoreduction followed by HIPEC with cisplatin and paclitaxel. At median follow-up of 20 months, PFS and OS were 12.5 and 32.9 months, respectively (23). Fagotti et al. reported a series of 42 patients with recurrent, platinum-sensitive EOC who were treated with cytoreduction and HIPEC with oxaliplatin followed by adjuvant IV oxaliplatin and taxotere. The toxicity profile was reasonable with a 34.8% complication rate and no perioperative deaths reported. At a median follow-up of 18 months, disease-free and OS were 24 and 38 months, respectively (24).
There is clearly a growing interest in HIPEC given the increasing number of prospective trials incorporating HIPEC; however, the ideal cytotoxic regimen and timing remains unclear. This study aims to examine patients with EOC treated with HIPEC with a particular focus on the cytotoxic regimen and treatment outcomes to guide future prospective trial design.
MATERIALS AND METHODS
University of Pittsburgh Institutional Review Board approval was obtained. Patients diagnosed with EOC between January 1, 2004 and December 31, 2013 who were treated with HIPEC were identified from a prospectively maintained HIPEC database. The indication for treatment and the HIPEC regimen given were left to the discretion of the treating physician. HIPEC was administered via the closed-abdomen technique as previously described in the literature (25). Patients were excluded from this study if the indication for HIPEC was a non-epithelial histology or a tumor of low malignant potential. However, patients with an initial diagnosis of a low-malignant potential tumor that recurred as an invasive malignancy that was subsequently treated with HIPEC were included.
Charts were abstracted for demographic information, disease characteristics, treatment characteristics, and patient outcomes. For each patient, available treatment details were collected for all regimens given prior to and following HIPEC administration. Indications for HIPEC treatment include front-line treatment, consolidation therapy following treatment of primary or recurrent disease, and treatment of recurrence. Unless otherwise stated, all patients underwent optimal cytoreduction prior to the administration of HIPEC. In cases where HIPEC was given as consolidative treatment after completion of therapy for primary or recurrent disease, the patient was confirmed to have no evidence of IP disease via a second-look surgery prior to administering HIPEC. Information on surgical outcomes was collected with a focus on perioperative complications and perioperative mortality. Patient outcomes were collected including time to progression following HIPEC and OS following HIPEC treatment. Toxicities were compared between treatment regimens using Fisher’s exact test with significance set at a P value of P<0.05.