Technical Feasibility of Modified Early Post-Operative Intraperitoneal Chemotherapy (mEPIC)

The goal of this prospective phase II unicentric Canadian clinical trial is to clarify the feasibility of modified early post-operative intraperitoneal chemotherapy (mEPIC) following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in the clinical context of peritoneal carcinomatosis from colorectal and appendicular neoplasms.

The primary objective of this study is to confirm the feasibility of mEPIC by evaluating its completion rate compared to the one of historical standard early post-operative intraperitoneal chemotherapy (EPIC) cohorts. The secondary objectives of the study are to evaluate the safety of the mEPIC protocol by monitoring adverse events arising during the protocol and to assess logistical implementation barriers for the nursing and Oncology pharmacy teams, respectively.

Participants will undergo a modified schedule of EPIC (mEPIC) designed to maximize therapeutic benefit by exploiting the known pharmacokinetics and pharmacodynamics properties of fluorouracil (5-FU) while limiting the logistical issues of the standard protocol. mEPIC consists in shortening the original protocol from five to two days of postoperative intraperitoneal chemotherapy. Additionally, instead of solely administering a singular 5-FU bolus per 24 hours-period, mEPIC is based on the De Gramont intravenous regimen and consists of administering one intraperitoneal bolus of 5-FU (400 mg/m2) followed by a 24 hours-intraperitoneal infusion of 5-FU (1200 mg/m2) on postoperative days 1 and 2.

Early postoperative intraperitoneal chemotherapy (EPIC) was first introduced by Sugarbaker in the 1990s in an effort to reduce disease recurrence and to prolong long-term survival of patients with peritoneal carcinomatosis from colorectal and appendicular malignancies including pseudomyxoma peritonei (PMP). Given the high risk of peritoneal recurrence, even after optimal cytoreduction, EPIC was a simple way of delivering high doses of cytotoxic agents targeted at the peritoneal surfaces without systemic compromise and eliminating any residual microscopic tumor deposits before the formation of fibrinous adhesions. The original protocol consists of administering 650 mg / m2 of intraperitoneal Fluorouracil (5-FU) in hypertonic, high molecular weight solution on postoperative days one to five. This solution is administered as an intraperitoneal bolus, remains for 23 hours with the surgical drains clamped before one hour of free drainage. Currently, there is no definitive randomised data comparing the benefit of EPIC versus no EPIC in any indication. One study that evaluated repeated cycles of intraperitoneal 5-FU in colon cancer demonstrated improved survival, but the study was discontinued early due to poor recruitment. Non-randomised data from the St George Hospital Peritoneal Surface Malignancy Program suggests a benefit for the addition of EPIC to hyperthermic intraperitoneal chemotherapy (HIPEC) with respect to survival outcomes in low-grade appendiceal cancers with no differences in morbidity but requires increased time in high dependency care unit. A recent study also demonstrates that in low-grade appendiceal neoplasms with pseudomyxoma peritonei, the addition of EPIC to HIPEC with cytoreductive surgery (CRS) improves overall survival in propensity score matched cases but results in prolonged hospitalisation. There is also conflicting data showing no advantage for the addition of EPIC to HIPEC in colorectal and high grade appendiceal cancer and an increased rate of grade III/IV complications.

From a therapeutic perspective, the use of intraperitoneal 5-FU benefits from the high peritoneal to plasma area under the curve, hence allowing the administration of higher intraperitoneal doses than intravenous doses with a resultant 250-fold increased tissue exposure. Even with significantly higher doses of 5-FU, systemic toxicities are much lower than systemic infusion due in part from the first pass metabolism through the liver. However, the standard EPIC protocol does not take into account the short perfusate half-life of 5-FU (0.75-1.5 hour). Consequently, by administering it as a large bolus, the majority of 5-FU is metabolized from the intraperitoneal compartment within 4-7.5 hours even though the solution remains intraperitoneally for 23 hours. In comparison to systemic therapy, infusions regimens of 5-FU based on protracted venous infusion or the so-called De Gramont regimen have essentially replaced bolus regimens such as the Mayo and Roswell Park regimens due to superior efficacy and better toxicity profiles. It consists in administering a bolus of 5-FU to achieve therapeutic concentrations followed by protracted venous infusion of 5-FU. This mode of administration also maximizes the inhibition of thymidylate synthase and other targets of 5-FU.

Additionally, there are clinical and administrative down-sides to the existing standard EPIC. These include: protracted occupancy of high dependency unit beds with a high nurse to patient ratio, which aggravates existing access issues. Furthermore, there are risks of abdominal tamponade, generalised discomfort during the procedure, prolonged ileus and increased risk of fistula and collection, hence prolonging length of stay. For these mentioned reasons, many patients do not complete every day of the planned treatment. For instance, out of the 435 patients who received EPIC in a high-volume center (St George Hospital) between 1996 and 2017, 269 (61.8%) completed the 5-day protocol, 33 (7.6%), 30 (6.9%), 45 (10.3%) and 58 (13.3%) completed 1, 2, 3 and 4 days of EPIC, respectively.

Rationale for Performing this Study:

Although, there is no randomised evidence to support EPIC, it has become one of the standard therapies for management of colorectal and appendicular neoplasms with peritoneal carcinomatosis in many high-volume surgical oncology centers. There is a need to devise a logistically more feasible regimen and also exploit the known pharmacokinetics and pharmacodynamics properties of 5-FU. Our phase II trial proposes a modified schedule of EPIC (mEPIC) designed to maximize therapeutic advantages and reduce logistical barriers. This modified EPIC (mEPIC) consists in shortening the original protocol from five to two days of postoperative intraperitoneal chemotherapy. Additionally, instead of solely administering a singular 5-FU bolus per 24 hours-period, mEPIC is based on the De Gramont intravenous regimen and consists of administering one intraperitoneal bolus of 5-FU (400 mg/m2) followed by a 24 hours-intraperitoneal infusion of 5-FU (1200 mg/m2) on postoperative days 1 and 2. The total proposed intraperitoneal dose of 1600 mg / m2 per day is comparable to and/or lower than described dosing ranges of 5-FU described in the literature. These doses are equivalent to systemic (intravenous) doses but the systemic exposure would be significantly less due to the known intraperitoneal to plasma area under the curve (AUC) ratios of up to 1000-fold. In this regard, the proposed dose is considered to be toxicologically safe.

The purpose of the study is to confirm the feasibility of mEPIC by evaluating its completion rate compared to the one of historical EPIC cohorts in patients with colorectal and appendicular neoplasms with peritoneal carcinomatosis treated with CRS and HIPEC. The hypothesis of this study is that mEPIC will be superior to the standard EPIC protocol in terms of completion rate. The safety of mEPIC (adverse events) and logistical nursing or pharmaceutical problems will also be recorded and assessed. Demonstrating feasibility of mEPIC will facilitate development of subsequent clinical trials evaluating its efficacy (recurrence free survival) and safety (30-day morbidity/mortality) compared to the standard EPIC protocol.

Eligibility Criteria:
Inclusion Criteria:

* Patient's age 18 years or older, both genders.
* In good general health as evidenced by an ECOG score of 0 or 1.
* Histological diagnosis of appendicular or colorectal tumors with peritoneal carcinomatosis, either synchronous (\< 12 months after primary diagnosis) or metachronous (\>12 months after the primary diagnosis)
* Complete staging defined as: (1)Computed tomography (CT) scan of the chest, abdomen and pelvis. (2) Positron emission tomography (PET) scan when clinically appropriate. (3) Diagnostic laparoscopy reporting Peritoneal carcinomatosis index (PCI) +/- biopsy
* Meets criteria for recommendation by combined multidisciplinary team and tumor board for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) followed by mEPIC
* Surgery must be performed within 4-6 weeks following the end of neoadjuvant therapy or 4-6 weeks following the patient's enrollment if no neoadjuvant therapy needed.
* Provision of signed and dated informed consent form
* Stated willingness to comply with all study procedures and availability for the study duration
* Hematology: Absolute neutrophil count (ANC) ≥ 1,500/ μL; Platelets \> 75,000/ μL.
* Adequate Renal function Creatinine \<1.5 x the upper limit of normal (ULN) or calculated creatinine clearance of ≥ 50ml/min.
* Adequate Hepatic function: Bilirubin less than 1.5mg/dL; (except in patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0mg/dL).

Exclusion Criteria:

Pre-cytoreductive surgery:

* Other malignancies other than appendicular and colorectal neoplasms with peritoneal involvement
* Inability to complete cytoreductive surgery (ECOG 2 or above) or any patient deemed unfit for surgery
* Known allergic reaction or major toxicity to Fluorouracil
* Contraindications to Fluorouracil, including history of coronary spasm and/or known dihydropyrimidine dehydrogenase deficiency
* Pregnancy
* Evidence of extensive intraperitoneal adhesions at the time of surgery which prohibits intraperitoneal therapy, as determined by the operating surgeon.
* Any condition that would preclude the ability to deliver appropriate intraperitoneal (IP) therapy.

Post-cytoreductive surgery:

* Patient deemed not medically suitable to receive mEPIC protocol according to surgical team
* Uncorrected coagulopathy and/or thrombocytopenia and/or neutropenia
* Active infection
* Hemodynamic and / or respiratory compromise
* Evidence of extensive intraperitoneal adhesions at the time of surgery which prohibits intraperitoneal therapy, as determined by the operating surgeon.
* Any condition that would preclude the ability to deliver appropriate IP therapy.