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Together with neoadjuvant systemic therpay PIPAC will be performed twice and regional chemotherpay will be administered before planned CRS/HIPEC

Pressurized Intraperitoneal Aerosol Chemotherapy will be delivered to the abdominal cavity by means of laparoscopy.

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)

Gal Levi, M.Sc

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel drug-delivery system developed to deliver, effectively and safely, small doses of cytotoxic agents into peritoneal tumor deposits. It is currently used for palliation and for down-staging of patients who are non-eligible for cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy (HIPEC).

The aim of this study is to evaluate the efficacy of PIPAC used in neoadjuvant setting to enhance the response of patients with colorectal peritoneal metastasis when combined with neoadjuvant systemic therapy for patients eligible to CRS/HIPEC prior to planned surgery.

This is an open label, single arm, single center, phase II trial to study the added efficacy benefit of PIPAC administered in the neoadjuvant setting in combination with systemic therapy for patients eligible for CRS/HIPEC.

the following procedures will be done to all study population. Visit 0 (Week #0) screening - Clinical evaluation and baseline cross-sectional imaging. Patients will be evaluated for their eligibility and recruited if found suitable.

(Week #1) tumor board discussion to ensure eligibility and staging (Week #2-4) Initiation of systemic therapy, if not been already started (2 cycles): Systemic therapy will be administered and tailored by the treating oncologist as per patient tolerability. If already on chemotherapy at visit 0, patients will continue chemotherapy until first PIPAC.

Visit 1 (Week #4) first PIPAC: Diagnostic laparoscopy, staging, PCI evaluation and biopsies will be taken as described earlier.

Systemic therapy (2 cycles, Week #4-8): Systemic therapy will be administered and tailored by the treating oncologist as per patient tolerability.

Visit 2 (Week #6) - post first PIPAC - Surgical Oncology Clinic: evaluation of PIPAC tolerability and possible side effects or complications. Cross sectional imaging to monitor progression prior to the upcoming second PIPAC.

Visit 3 (Week #8) - second PIPAC: Diagnostic laparoscopy, staging, PCI evaluation and biopsies will be taken as described earlier.

Systemic therapy (2 cycles, Week #8-12): Systemic therapy will be administered and tailored by the treating oncologist as per patient tolerability. Systemic therapy will be stopped at week#12 (2-4 weeks) prior to planned CRS/HIPEC Visit 4 (Week #10) - post second PIPAC - Surgical Oncology Clinic: evaluation of PIPAC tolerability, quality of life, and possible side effects or complications after PIPAC.

Visit 5 (Week #12-14) - Surgical evaluation and cross-sectional imaging - Surgical Oncology Clinic: Planning for upcoming CRS/HIPEC Visit 6 (Week #14-16) - CRS/HIPEC: proper PCI evaluation, complete tumor cytoreduction and HIPEC will be targeted. The extent of surgery, technical difficulties including OR time and blood loss will be documented.

Visit 7 follow up visit: will be conducted within 1 month after hospital discharge. Tolerability and possible complications post-surgery will be evaluated.

Visit 8-11 follow up visits: Surgical Oncology Clinic evaluation: cross sectional imaging, Tumor markers and clinical evaluation will be conducted for any signs of possible recurrence on 3 monthly bases Visit 12-13 follow up: Surgical oncology clinic: cross sectional imaging, Tumor markers and clinical evaluation will be conducted for any signs of possible recurrence on 6 monthly bases. The follow up for the trial will be concluded at this stage (total of 3 years follow up).

To be noted that patient systemic chemotherapy would not be interrupted throughout the treatment protocol and PIPAC therapy will be delivered in-between chemotherapy cycles.

Combined Neoadjuvant Systemic and PIPAC Therapy (NASPIT) for Patients With Colorectal Peritoneal Metastasis Eligible for CRS and HIPEC: A Prospective Phase II Trial

Clinically, at time of laparoscopic exploration, tumor burden and distribution will be assessed. Peritoneal cancer index (PCI) will be documented. Final evaluation of tumor burden, PCI and clinical response will be evaluated at time of CRS/HIPEC. Radiologically, a baseline abdominal computed tomography (CT) scan will be acquired \<4 weeks before the initiation of the treatment plan and will be repeated before CRS/HIPEC. Response will be evaluated by an independent radiologist as per RECIST criteria 1.1. Pathologically, biopsies from representative lesions will be taken. During the first procedure, before PIPAC delivery one sample from each abdominal quadrant and will be submitted to histopathology examination. Each biopsy site will be marked by a sliver clip for subsequent biopsies in the following PIPAC. Final pathological assessment will be done from specimens obtained at time of cytoreductive surgery .

Recurrence free survival (RFS) will be calculated from the date of CRS/HIPEC to the date of documented disease recurrence. Events for the RFS endpoint include clinical, radiological (CT, PET), serological (CEA, CA-19-9, CA-125) and/or surgical exploration.

Prof. Aviram Nissan

Proffesor

Antineoplastic Agents

All Drugs and Chemicals

Doxorubicin

Liposomal doxorubicin

Cisplatin

After insufflation of a 12 mmHg of capnoperitoneum at 37°C, two balloons safety trocars (10 and 12mm) are inserted into the abdominal wall. Injection of Doxorubicin (2.1 mg/m2 in 50 ml NaCl 0.9%) and Cisplatin (10.5 mg/m2 body surface in 150 ml NaCl 0.9%) with a flow rate of 0.7ml/s, the therapeutic capnoperitoneum is maintained for 30 min at body temperature.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC)

Patient will receive standard poly chemotherapy proposed by the oncologist or any new standard validated during the study, until progression or toxicity.

Standard chemotherapy

Peritoneal metastasis is a common pattern in advanced gastric cancer leading to a terminal condition in a very short time. Whatever recent progress regarding systemic chemotherapy using multi drugs association median survival is limited to 6 months with altered quality of life (QoL) after 4 months for all patients. We postulated that a new innovative health technology for delivering intraperitoneal pressurized aerosol of chemotherapy (Doxorubicin and Cisplatin) during laparoscopy can transform that situation offering to double the survival with QoL preservation. Interestingly, PIPAC procedure is made to be applied repeatedly, every 4 to 6 weeks. This therapeutic strategy allows to improved Intra Peritoneal (IP) drugs impregnation and maintained Intra-Veinous (IV) chemotherapy meanwhile. The primary objective of this study is to evaluate and compare 24-month progression free-survival in patients with peritoneal carcinomatosis of gastric cancer treated either with IV chemotherapy and Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) or with IV chemotherapy alone, with preservation of quality of life.

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in Gastric Carcinomatosis. Phase II Randomized Study

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in Gastric Carcinomatosis. Phase II Randomized Study - PIPAC EstoK 01

24-month progression free-survival, defined as time from randomization to any clinical (ascites, abdominal pain, weight loss \> 10% of total body weight) and/or morphological signs (systemic metastases, ascites, progression with RECIST criteria) of recurrence (local or systemic) or death.

Postoperative pain with a numeric rating scale from 0 to 10 (0 being no pain and 10 the worst possible pain)

Secondary resectability rate after the treatment

Quality of life evaluated monthly by the patient with the EORTC QLQ-STO22 questionnaire

Quality of health status evaluated monthly by the patient with the EQ-5D-5L questionnaire

Rate of treatment-related toxicity at 60 days of each PIPAC procedure

Morbidity will be evaluated on post-operative day 60 by the Clavien-Dindo classification (I to V)

Morbidity will be evaluated by the Comprehensive Complication Index, ranging from 0 to 100 (https://www.assessurgery.com/about_cci-calculator)

The time of discontinuation defined as the time from randomization to therapy change or dose reduction because of progression of disease or intolerance or adverse effects or patient refusal or death.

Assistance Publique - Hôpitaux de Paris

Rectal Diseases

Neoplastic Processes

Micronutrients

Pharmaceutical Solutions

Hematinics

Vitamins

Oxaliplatin

Leucovorin

Fluorouracil

Levoleucovorin

Folic Acid

Folinic Acid

Folate

Vitamin B9

Preliminary laparoscopic exploration of the abdominal cavity and adjuvant pressurized intraperitoneal aerosol chemotherapy (PIPAC) with oxaliplatin and concurrent intravenous infusion of 5-fluorouracil and folinic acid.

Laparoscopic exploration of the abdominal cavity with dissection of adhesions and biopsies of suspect findings (if needed).

PIPAC will be administered with oxaliplatin (92 mg/m2 body surface area in 150 ml dextrose solution) for 30 minutes under the following spraying conditions: cytostatic application at a rate of 30 ml/min, pressure of 1380 kilo-pascal over 30 minutes, and temperature of 22°C. One hour before the beginning of PIPAC, intravenous infusion of 5-fluorouracil (400 mg/m2) and folinic acid (20mg/m2) will be initiated. Standard protectionist procedures will be adopted to avoid contamination of operators and the environment with nebulized chemotherapy.

Dario Baratti, MD

The objective of this clinical trial is to demonstrate the feasibility and safety of pressurized intraperitoneal aerosol chemotherapy (PIPAC) for the prevention of peritoneal metastases after curative-intent surgery for high-risk colorectal cancer.

This single-arm, single-center, open-label trial enrolls patients after curative-intent surgery for colon adenocarcinoma (proximal to peritoneal reflection), intestinal or mucinous histological type, associated with the following clinical-pathological risk factors for the development of peritoneal metastases: a) stage pT4a, N0-2b, M0 of the Tumor Node Metastasis classification; b) stage pT4b, N0-2b, M0; and c) primary perforated tumor (any T, any N, M0). Eligible patients who will give informed consent undergo laparoscopic pressurized intraperitoneal aerosol chemotherapy (PIPAC) 4 to 8 weeks after primary surgery, followed by adjuvant systemic chemotherapy according to according to current guidelines. After the procedure, patients will be followed-up to assess occurrence of adverse events,survival, peritoneal and systemic disease relapse, and quality of life.

Adjuvant Pressurized Intraperitoneal Aerosol Chemotherapy to Prevent Colorectal Peritoneal Metastases (ProphyPIPAC)

Pilot Study of Adjuvant Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) for the Prevention of Peritoneal Metastases After Curative-intent Surgery for High-risk Colorectal Cancer.

I confirm that we have a plan to make individual participant data (IPD) available to other researchers through publicly available database

The adjuvant PIPAC performed in an early setting after primary surgery will be considered feasible if:

* the laparoscopic procedure can be completed in 9 patients;
* the postoperative stay will be three days or shorter in ≥6 patients;
* the post-operative adjuvant s-CT will begin within 12 weeks of primary surgery in ≥ 9 patients.

The adjuvant PIPAC will be considered a well tolerated procedure if:

* a maximum of one serious treatment-related complication will occur;
* a maximum of one laparotomy conversion will occur;
* a maximum of one hospital readmission will occur within 30 days.

Overall survival will be measured from the date of primary surgery to the date of death for any cause or, for patients still alive at the date of the last available follow-up.

Disease-free survival will be measured from the date of primary surgery to the date of peritoneal metastasis diagnosis, systemic metastases or death.

Peritoneal disease-free survival will be measured from the date of primary surgery to the date of peritoneal metastasis diagnosis,

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Combined Neoadjuvant Systemic and PIPAC Therapy (NASPIT) for Patients With Colorectal Peritoneal Metastasis Eligible for CRS and HIPEC: A Prospective Phase II Trial	NCT04475159	Metastatic Colo... Peritoneal Carc... Colon Adenocarc...	Pressurized Int...	18 Years -	Sheba Medical Center
Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in Gastric Carcinomatosis. Phase II Randomized Study	NCT04065139	Gastric Adenoca... Cancer Metastat... Chemotherapy Ef...	Pressurized int... Standard chemot...	18 Years - 75 Years	Assistance Publique - Hôpitaux de Paris
Adjuvant Pressurized Intraperitoneal Aerosol Chemotherapy to Prevent Colorectal Peritoneal Metastases (ProphyPIPAC)	NCT06091683	Peritoneal Meta...	Pressurized int...	18 Years - 75 Years	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Adjuvant Pressurized Intraperitoneal Aerosol Chemotherapy to Prevent Colorectal Peritoneal Metastases (ProphyPIPAC)	NCT06091683	Peritoneal Meta...	Pressurized int...	18 Years - 75 Years	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in Gastric Carcinomatosis. Phase II Randomized Study	NCT04065139	Gastric Adenoca... Cancer Metastat... Chemotherapy Ef...	Pressurized int... Standard chemot...	18 Years - 75 Years	Assistance Publique - Hôpitaux de Paris
Combined Neoadjuvant Systemic and PIPAC Therapy (NASPIT) for Patients With Colorectal Peritoneal Metastasis Eligible for CRS and HIPEC: A Prospective Phase II Trial	NCT04475159	Metastatic Colo... Peritoneal Carc... Colon Adenocarc...	Pressurized Int...	18 Years -	Sheba Medical Center

Spots Global Cancer Trial Database for pressurized intraperitoneal aerosol chemotherapy (pipac)