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.

Inclusion Criteria:

1. Histologically confirmed cancer of the ovary, fallopian tube or peritoneum.

2. Women of all races and ethnicities are eligible for this trial.

3. Age > 18.

4. The patient must have documented disease limited to the abdomen and pelvis that is
amenable to complete CRS indicated by:

1. Disease confined to the peritoneal surfaces.

2. No clinical or radiological evidence of hematogenous or distant (extra-abdominal)
nodal metastasis.

5. Evidence of response to NACT must as documented by at least one of the following:
decline in serum CA125 level, at least a 30% decrease in the sum of the longest
diameter of target lesions on radiographic imaging, or resolution of ascites or
pleural effusion(s).

6. Gynecologic Oncology Group (GOG) performance status <= 2

7. Leukocytes >= 3,000/microliter (mcL), absolute neutrophil count >= 1,500/mcL,
platelets >= 100,000/mcL

8. Adequate hepatic function as measured by total bilirubin within normal institutional
limits, aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
(SGOT))/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT))
=< 2.5 x institutional upper limit of normal

9. Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min for
patients with creatinine levels above institutional normal

10. Albumin >= 2.5 mg/dL

11. Satisfactory cardiopulmonary function (no history of severe congestive heart failure
or severe pulmonary disease, as indicated by clinically acceptable risks to undergo
major abdominal surgery

12. Voluntary participation after getting written informed consent

Exclusion Criteria:

1. Prior chemotherapy (other than NACT) or whole abdomen radiation for ovarian, fallopian
tube or primary peritoneal cancers.

2. Patients with an active second malignancy regardless of site.

3. Uncontrolled inter-current illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

4. Pregnant or breast-feeding patients

5. Patients who are receiving other oncologic investigational therapeutic agents

6. Patients receiving NACT whose disease has progressed following at least 3 cycles of
platinum-based therapy, defined by at least one of the following: clinical
deterioration (new or worsening of existing ascites, carcinomatous ileus, malignant
bowel obstruction, declining performance status); new lesion(s) or increase in maximal
diameter of > 20% of the two largest target lesions; rising CA-125 (an increase of at
least 10% of baseline value that increases over 3 values obtained every 21 days).

7. Cardiac or pulmonary conditions that preclude aggressive cytoreductive surgery.

8. Patients found to have non-gynecologic cancer at the time of surgery.

9. Patients with gynecologic malignancy of low-grade serous or borderline histology.