A Pilot Study of Heated Intraperitoneal Chemotherapy (HIPEC) After Interval Cytoreductive Surgery (CRS) in Patients Who Have Received Neoadjuvant Chemotherapy (NACT) for Epithelial Ovarian, Fallopian Tube and Primary Peritoneal Cancers

Cancer of the ovary, fallopian tube and peritoneum (referred to as epithelial ovarian cancer, EOC) remains the leading cause of death from gynecologic cancer in the US and is expected to account for 22,000 cases and 14,000 deaths in 2016. Patients classically present with peritoneal carcinomatosis and ascites, a reflection of the dissemination pattern of this cancer in the peritoneal cavity. Malignant cells in EOC disseminate throughout the peritoneal cavity forming tumors on the parietal and visceral peritoneum. The majority of patients will be found to have advanced International Federation of Gynecology and Obstetrics (FIGO) stage III and IV disease at initial presentation. Patients with peritoneal carcinomatosis from EOC most often succumb to advanced locoregional disease in the form of intractable ascites, malignant visceral obstruction and cancer cachexia.

Primary cytoreductive surgery (PCS) followed by systemic chemotherapy has been the standard of care for women presenting with advanced EOC. The ability to achieve optimal surgical cytoreduction is historically the most important prognostic factor for women with EOC. The Gynecologic Oncology Group defines optimal cytoreduction as a post-operative residual disease of ≤ 1 cm in largest diameter . Wide variability in the extent and effort of cytoreductive surgery is seen in clinical practice with surgical cytoreductive efforts ranging from standard procedures (hysterectomy, salpingo-opherectomy, omentectomy) to complex multiviceral resections that may require radical upper abdominal surgery. There is increasing evidence that the patients who ultimately gain the most benefit from surgery are those with no gross residual disease (R0 resection) at the completion of PCS . An examination of 2,655 patients with epithelial ovarian cancer or primary peritoneal cancer enrolled in the Gynecologic Oncology Group 182 study demonstrated improved OS and PFS in those patients with in whom PCS resulted in a complete gross resection . Patients presenting with bulky upper abdominal disease (UAD) have a particularly poor prognosis. Women presenting with bulky UAD have been shown to have inferior PFS and OS survival compared to patents with no or limited UAD even among patients in whom optimal debulking surgery is successfully performed . Importantly, the presence of bulky UAD is associated with diminishing rates of successful PCS.

Advanced stage EOC is heterogenous, ranging from limited intra-abdominal disease to diffuse carcinomatosis involving the majority of the peritoneal surfaces. Use of a universal staging system for peritoneal malignancy may aid the clinician in treatment planning and prognostication. While several attempts have been made to develop peritoneal cancer scoring systems, the most widely used is the Peritoneal Cancer Index (PCI) as described by Jacquet and Sugarbaker in 1996 . The PCI quantitates the volume of tumor implants in 13 different abdomino-pelvic regions which are added up to form a score ranging from 0-39. While the PCI may be used as a prognostic indicator, it does not directly correlate with resectability of the disease. Tumor involvement of critical anatomic sites, for example regions 9, 10 and 11, representing the jejunum and ileum, may be associated with unresectable disease despite a low PCI score .

Two recently published randomized controlled trials demonstrated that neoadjuvant chemotherapy (NACT) and interval cytoreductive surgery (ICS) was non-inferior to PCS and adjuvant chemotherapy and resulted in a lower incidence of treatment related morbidity and mortality. These trials, however, have been criticized for lower optimal debulking rates and significantly lower median overall survival rates compared to prior trials in advanced EOC. The choice between PCS and NACT remains controversial and clinical guidelines have recently been published to aid clinicians in the choice between these treatment plans .

Patients who are not candidates for PCS due to medical comorbidities, poor performance status or clinically apparent or obvious unresectable disease constitute a group with a particularly poor prognosis. These patients are preferentially treated with neoadjuvant chemotherapy (NACT). NACT is associated with decreased peri-operative morbidity and an increased likelihood of optimal cytoreduction at surgery compared with primary surgery, however, to date a survival benefit or improvement has not been demonstrated . A recent multi-institutional observational study evaluating the use of NACT in patients with stage III/IV EOC at 6 NCI designated cancer centers demonstrated a significant increase in the use of NACT since 2010, from 16 - 34% in stage III and from 41 - 62% in stage IV EOC . Patients who received NACT were more likely to undergo optimal CRS but were less likely to require ICU admission or re-hospitalization. Among women with stage IIIC disease who had optimal CRS to ≤1 cm, NACT was associated with decreased overall survival when compared to PCS. This difference in survival, however, did not persist in NACT patients in whom CRS resulted in no gross residual disease.