HIPEC After Initial CRS in Patients Who Have Received NACT

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.

Because of the tendency for EOC to remain confined within the peritoneal cavity for much of the course of disease, the use of post-operative intra-peritoneal (IP) chemotherapy has been extensively evaluated in women who have undergone successful cytoreductive surgery (CRS). Four large randomized clinical trials have been performed by the Gynecologic Oncology Group (GOG), three of which demonstrate improved overall survival in patients treated with an IP regimen. GOG 172 demonstrated a striking 16 month improvement in overall survival in patient's receiving IP cisplatin and paclitaxel when compared to patients receiving intravenous cisplatin and paclitaxel, a survival difference that was sustained in a follow-up publication after a median 10 year survival . Despite randomized controlled trial (RCT) evidence supporting a survival advantage for IP chemotherapy, its use remains low, largely due to potential toxicity and possible IP catheter complications. Despite optimal CRS and systemic chemotherapy the majority of patients will ultimately experience recurrence of the disease.

Heated intra-operative peritoneal chemotherapy (HIPEC) has garnered interest in the international oncology community for the treatment of peritoneal surface malignancies. HIPEC has demonstrated clinical efficacy for the treatment of pseudomyxoma peritonei, appendiceal cancer, colon cancer and malignant mesothelioma. HIPEC allows for the treatment of residual microscopic disease at the completion of CRS. HIPEC takes advantage of the plasma-peritoneal barrier to allow for peritoneal drug levels 20-1000 times that seen in plasma . HIPEC to >41°C may have anti-tumor effects as well as allow for better penetration of the drug into residual tumor . The use of HIPEC at the time of surgery, prior to the formation of adhesions, may allow for improved distribution of chemotherapy throughout the peritoneal cavity.

HIPEC has been investigated as a treatment for patients with newly diagnosed EOC as well as for patients with recurrent disease. Retrospective and case-control studies show a survival advantage for patients in both the primary and recurrent disease setting.

A recent randomized controlled study performed in Europe was the first well-designed, randomized, prospective clinical trial to demonstrate a survival advantage for HIPEC in EOC . This phase 3 randomized trial evaluated the administration of HIPEC using cisplatin in women undergoing interval cytoreductive surgery after NACT and demonstrated a significant improvement in progression free and overall survival with acceptable toxicity.

By far, the most common drug evaluated in HIPEC for EOC is Cisplatin. Cisplatin (CDDP) is a heavy metal complex containing a central atom of platinum surrounded by two chloride atoms and two ammonia molecules in the cis- position. It has biochemical properties similar to that of bifunctional alkylating agents producing inter- and intra-strand cross-links in DNA. It is non-cell-cycle specific. Approximately 95% of the dose is absorbed from the peritoneal cavity in 1.0 hour. CDDP concentrates in the liver, kidney and intestine and is excreted by the kidneys. The dose of CDDP recommended for normothermic intraperitoneal administration is the same as that recommended for intravenous administration and ranges from 75 -100 mg/m2. The major dose-limiting toxicity of CDDP is dose-related cumulative renal insufficiency. Other toxicities include ototoxicity, myelosuppression, nausea and vomiting, hair loss and peripheral neuropathy.

A recent phase I multicenter trial of NACT followed by HIPEC in EOC using CDDP established a dose of 70 mg/m2 as a tolerable dose in patients who had received 6 cycles of carboplatin and paclitaxel neoadjuvant chemotherapy . The results of this recently published phase I clinical trial are encouraging. However, in current clinical practice, patients tend to receive 3 cycles of NACT with carboplatin and paclitaxel based regimens followed by CRS, as opposed to 6 initial cycles of NACT given in the phase I study.

The investigators propose a pilot study evaluating the feasibility of HIPEC in women undergoing interval CRS and achieving optimal tumor cytoreduction after 3 cycles of NACT. The safety, tolerability and efficacy of HIPEC will be evaluated in this cohort of EOC patients with historically inferior outcomes.