Band 3, Heft 2 - Special Issue: PIPAC Clinical Trials (Part 1)

Background Peritoneal carcinomatosis (PC) is a common endpoint in both gastrointestinal and non-gastrointestinal cancers, and PC is treated as other systemic metastases – unfortunately with disappointing results and considerable side-effects. Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) is a new method of applying traditional chemotherapy, and preliminary data indicate that PIPAC is safe, able to stabilize or improve quality of life, and can induce an objectively measurable reduction in disease burden in PC. Methods PIPAC-OPC2 is a prospectively controlled Phase II, single center, one-arm, open-label clinical trial investigating the treatment effect of PIPAC in patients with histological or cytological proven PC from gastrointestinal, ovarian or primary peritoneal cancer. Eligible patients will receive PIPAC in series of three using a combination of doxorubicin (1.5 mg/m 2 ) and cisplatin (7.5 mg/m 2 ) for non-colorectal cancer patients (PIPAC C/D), and oxaliplatin (92 mg/m 2 ) in patients with PC of colorectal origin (PIPAC OX). Patients are monitored by: (1) repeated measurements of the Peritoneal Regression Grading Score (PRGS) in biopsies obtained from metal clips marked areas, (2) Quality-of-Life (QoL) questionnaires, (3) Magnetic Resonance Imaging (MRI) and (4) Prognostic Nutritional Index (PNI). Adverse events and surgical complications will be recorded according to the 30 days definition. Results The primary outcome of PIPAC-OPC2 is to evaluate if PIPAC can induce major or complete response (PRGS 1 or 2) within a series of three PIPAC procedures. Secondarily this study investigates changes in QoL and MRI as a staging and response evaluation tool. The secondary outcomes will be used to create a model that may predict which of the patients will benefit from PIPAC treatment. Conclusions It is expected that PIPAC directed therapy can induce major or complete response in 50 % of patients with PC of colorectal origin and in 30 % of patients with PC of non-colorectal origin – and at the same time stabilize or even improve quality of life. This trial may provide data regarding the utility of MRI as a staging and response evaluation tool in patients with PC. Trial registration The study is registered with ClinicalTrials.gov Identifier NCT03287375 and the European Clinical Trials Database (EudraCT) number 2016-003394-18.

Background Peritoneal metastasis (PM) is the second most common site of recurrence in colon cancer (CC) patients and accounts for approximately one-third of all recurrences. Patients with T4 or intraperitoneal perforated colon cancers have an increased risk of developing PM, and since manifest PM is difficult to treat, high-risk patients should be offered prophylactic treatment. Here, we propose a study of adjuvant oxaliplatin administered as pressurized intraperitoneal aerosol chemotherapy (PIPAC OX) in patients with high-risk colon cancer (T4, perforated tumors, ovarian metastasis). Methods PIPAC-OPC3 CC is a non-randomized, non-blinded phase 2 cohort study designed to treat high-risk colon cancer patients with adjuvant PIPAC-directed therapy. Based on an expected 90 % peritoneal recurrence-free survival with adjuvant PIPAC against the estimated 75 % without, 60 patients are needed (α: 0.05, power: 0.8). Eligible patients will receive two PIPAC treatments with oxaliplatin (92 mg/m 2 ) at 4–6 week intervals. During laparoscopy, the peritoneum is biopsied at two locations, and peritoneal lavage with 500 mL of saline and laparoscopic ultrasound is performed. The patients are screened for adverse medical events and surgery-related complications after each PIPAC procedure. After the second PIPAC procedure, the patients will be examined in the outpatient clinic and followed with CT scans 12, 24 and 36 months after resection. The primary outcome of the PIPAC-OPC3 CC trial is to evaluate if PIPAC-directed adjuvant therapy can reduce the risk of PM. Secondary outcomes include the number of conversions from positive to negative peritoneal lavage cytology after one PIPAC procedure, completion rate of two adjuvant PIPAC treatments, toxicity and complication rate and recurrence-free and overall survival rates after 1, 3 and 5 years. Results It is expected that PIPAC-directed adjuvant therapy can provide an absolute risk reduction of 15 % regarding the development of PM in high-risk colon cancer patients, and that this may result in increased survival rates. We expect that free intraperitoneal tumor cells (FITC) may be detected by peritoneal lavage performed just prior to the administration of PIPAC-directed therapy, and that this treatment may convert FITC-positive patients to a FITC-negative status. Conclusions This study may provide important knowledge to be used in designing additional studies on PIPAC in the adjuvant setting of other primary cancers. Trial registration ClinicalTrials.gov Identifier NCT03280511 (2017-09-12). European Clinical Trials Database (EudraCT) 2017-002637-37.

Background Nanoparticles hold considerable promise for aerosol-based intraperitoneal delivery in patients with carcinomatosis. Recently, results from preclinical and early clinical trials suggested that albumin-bound paclitaxel (ABP, Abraxane™) may result in superior efficacy in the treatment of peritoneal metastases (PM) compared to the standard solvent-based paclitaxel formulation (Taxol™). Here, we propose a phase I study of pressurized intraperitoneal aerosol chemotherapy (PIPAC) using ABP in patients with upper Gastrointestinal, breast, or ovarian cancer. Methods Eligible patients with advanced, biopsy-proven PM from ovarian, breast, gastric, hepatobiliary, or pancreatic origin will undergo three PIPAC treatments using ABP with a 4-week interval. The dose of ABP will be escalated from 35 to 140 mg/m² using a Bayesian approach until the maximally tolerated dose is determined. The primary end point is dose-limiting toxicity. Secondary analyses include surgical morbidity, non-access rate, pharmacokinetic and pharmacodynamic analyses, quality of life, and exploratory circulating biomarker analyses. Discussion ABP holds considerable promise for intraperitoneal aerosol delivery. The aim of this study is to determine the dose level for future randomized phase II trials using ABP in PIPAC therapy. Trial registration This trial is registered as EudraCT: 2017-001688-20 and Clinicaltrials.gov: NCT03304210.

Background Peritoneal metastasis is a common and dismal evolution of several gastrointestinal (GI) tumors, including gastric, colorectal, hepatobiliary, pancreatic, and other cancers. The therapy of peritoneal metastasis is largely palliative; with the aim of prolonging life and preserving its quality. In the meantime, a significant pharmacological advantage of intraperitoneal chemotherapy was documented in the preclinical model, and numerous clinical studies have delivered promising clinical results. Methods This is a prospective, open, randomized multicenter phase III clinical study with two arms that aims to evaluate the effects of pressurized intraperitoneal aerosol chemotherapy (PIPAC) combined with systemic chemotherapy vs. intravenous systemic chemotherapy alone on patients with metastatic upper GI tumors with a peritoneal seeding. Upper GI-adenocarcinomas originated from biliary tract, pancreas and stomach, or esophago- gastric junction are eligible. Patients in the study are treated with standard of care systemic palliative chemotherapy (mFOLFOX6) vs. PIPAC with intravenous (i.v.) chemotherapy (mFOLFOX6). Patients in first line with first diagnosed peritoneal seeding are eligible. Primary outcome is progression free survival (PFS). Conclusions PIPAC-procedure is explicit a palliative method but it delivers cytotoxic therapy like in hyperthermic intraperitoneal chemotherapy (HIPEC)-procedure directly to the tumor in a minimally invasive technique, without the need for consideration of the peritoneal-plasma barrier. The technique of PIPAC is minimally invasive and very gentle and the complete procedure takes only round about 45 min and, therefore, optimal in a clearly palliative situation where cure is not the goal. It is also ideal for using this approach in a first line situation, where deepest response should be achieved. The symbiosis of systemic therapy and potentially effective surgery has to be well-planned without deterioration of the patient due to aggressive way of surgery like in cytoreductive surgery (CRS)+HIPEC. Trial registration EudraCT: 2018-001035-40.

Background Peritoneal metastasis (PM) from gastric cancer often remains undiagnosed until it reaches an advanced stage. Despite curative management combining perioperative systemic chemotherapy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC), treated patients’ 5 year survival rate remains under 20 % when patients are carefully selected. Palliative intravenous chemotherapy in patients with non-resectable cancer is frequently associated with poor long-term benefit and an estimated survival time below 1 year. Recently, two retrospectives studies reported that Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) improves patients’ overall survival without impairing their quality of life (QoL). This promising result needs however to be studied on large randomized clinical trial to validate the effect of PIPAC on survival and QoL of patients with gastric PM. Methods PIPAC EstoK 01 is a prospective, open, randomized multicenter phase II clinical study with two arms that aims at evaluating the effects of PIPAC with doxorubicin and cisplatin on patients with PM of gastric cancer with peritoneal cancer index (PCI)>8, treated with systemic chemotherapy between two PIPAC procedures. Patients were randomized at the end of explorative laparoscopy and after signing a written consent. Patients received in the first experimental arm a treatment associating PIPAC and systemic chemotherapy (1 PIPAC then 2 IV Chemo) and systemic chemotherapy only in the control arm. Primary endpoint was progression-free survival from the date of surgery to the date of death, or to the end of the 5 year follow-up. Secondary endpoint was 2 year overall survival, morbidity, QoL and secondary resectability rate. The number of patients randomized was calculated to be 94. Trial registration Retrospectively registered.