Dataset Information

Multicenter dose-escalation Phase I trial of mitomycin C pressurized intraperitoneal aerosolized chemotherapy in combination with systemic chemotherapy for appendiceal and colorectal peritoneal metastases: rationale and design.

ABSTRACT:

Objectives

Peritoneal metastasis (PM) from appendiceal cancer or colorectal cancer (CRC) has significant morbidity and limited survival. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a minimally invasive approach to treat PM. We aim to conduct a dose-escalation trial of mitomycin C (MMC)-PIPAC combined with systemic chemotherapy (FOLFIRI) in patients with PM from appendiceal cancer or CRC.

Methods

This is a multicenter Phase I study of MMC-PIPAC (NCT04329494). Inclusion criteria include treatment with at least 4 months of first- or second-line systemic chemotherapy with ineligibility for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Exclusion criteria are: progression on chemotherapy; extraperitoneal metastases; systemic chemotherapy intolerance; bowel obstruction; or poor performance status (ECOG>2). Escalating MMC-PIPAC doses (7-25 mg/m²) will be administered in combination with standard dose systemic FOLFIRI. Safety evaluation will be performed on 15 patients (dose escalation) and six expansion patients: 21 evaluable patients total.

Results

The primary endpoints are recommended MMC dose and safety of MMC-PIPAC with FOLFIRI. Secondary endpoints are assessment of response (by peritoneal regression grade score; Response Evaluation Criteria in Solid Tumors [RECIST 1.1], and peritoneal carcinomatosis index), progression free survival, overall survival, technical failure rate, surgical complications, conversion to curative-intent CRS-HIPEC, patient-reported outcomes, and functional status. Longitudinal blood and tissue specimens will be collected for translational correlatives including pharmacokinetics, circulating biomarkers, immune profiling, and single-cell transcriptomics.

Conclusions

This Phase I trial will establish the recommended dose of MMC-PIPAC in combination with FOLFIRI. Additionally, we expect to detect an early efficacy signal for further development of this therapeutic combination.

SUBMITTER: Raoof M

PROVIDER: S-EPMC9742457 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

Multicenter dose-escalation Phase I trial of mitomycin C pressurized intraperitoneal aerosolized chemotherapy in combination with systemic chemotherapy for appendiceal and colorectal peritoneal metastases: rationale and design.

Raoof Mustafa M Sullivan Kevin M KM Frankel Paul H PH Fakih Marwan M Synold Timothy W TW Lim Dean D Woo Yanghee Y Paz Isaac Benjamin IB Fong Yuman Y Thomas Rebecca Meera RM Chang Sue S Eng Melissa M Tinsley Raechelle R Whelan Richard L RL Deperalta Danielle D Reymond Marc A MA Jones Jeremy J Merchea Amit A Dellinger Thanh H TH

Pleura and peritoneum 20220621 4

<h4>Objectives</h4>Peritoneal metastasis (PM) from appendiceal cancer or colorectal cancer (CRC) has significant morbidity and limited survival. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a minimally invasive approach to treat PM. We aim to conduct a dose-escalation trial of mitomycin C (MMC)-PIPAC combined with systemic chemotherapy (FOLFIRI) in patients with PM from appendiceal cancer or CRC.<h4>Methods</h4>This is a multicenter Phase I study of MMC-PIPAC (NCT04329494). In ...[more]

PMID: 36560966

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Project description:Pressurized intraperitoneal aerosol chemotherapy with oxaliplatin (PIPAC-OX) is increasingly used as a palliative treatment option for patients with colorectal peritoneal metastases (CPM). The present study aimed to systematically review all clinical studies reporting safety and efficacy outcomes of PIPAC-OX in patients with CPM. PubMed, EMBASE, The Cochrane Library, and CINAHL were systematically searched to identify all clinical studies that included at least one patient with CPM treated with PIPAC-OX and reported one of the following outcomes: adverse events, tumor response, quality of life, secondary cytoreductive surgery, progression-free survival, overall survival, and environmental safety of PIPAC-OX. Results were narratively described. Of 28 included studies, only 14 non-comparative studies separately reported at least one outcome of PIPAC-OX for CPM, of which only two studies specifically focused on this group. These 14 studies reported adverse events (5 studies), tumor response (5 studies), secondary cytoreductive surgery (4 studies), progression-free survival (1 study), overall survival (5 studies), and environmental safety (2 studies). Except for 5 studies (describing 26 patients), none of the included studies stratified their results for PIPAC-OX monotherapy and PIPAC-OX with concomitant systemic therapy, and none of the studies reporting survival outcomes stratified results for line of palliative treatment, complicating interpretation. No PIPAC-OX related deaths were reported. No occupational platinum was detected during PIPAC-OX. The available evidence regarding PIPAC-OX for CPM is limited and difficult to interpret. Despite these limitations, PIPAC-OX appears safe in patients with CPM and safe for operating personnel. To increase insight in the role of PIPAC-OX in this setting, investigators of ongoing and future studies are encouraged to report separate outcomes of PIPAC-OX for CPM, to stratify their results for PIPAC-OX monotherapy and PIPAC-OX with concomitant systemic therapy, and to stratify survival results for line of palliative treatment.

Project description:BackgroundThe annual incidence of gastrointestinal carcinomas (stomach, small bowel, colon and rectum) is increasing in Western countries, reaching 50,000 new cases each year in France. Peritoneal carcinomatosis (PC) is diagnosed in 15% of these patients. Complete cytoreductive surgery (CCS) plus Hyperthermic IntraPeritoneal Chemotherapy (HIPEC) is the only therapy that can offer patients with PC a chance for long-term survival with a 5 year overall survival (OS) rate of 30-60% versus 0-5% with systemic chemotherapy alone. However, CCS plus HIPEC still presents serious limitations and very few patients (10%) are candidates for these radical treatments. PC remains a palliative setting for 90% of patients with a median survival ranging from 15 to 25 months. Innovative surgical therapies such as Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) therefore need to be developed to improve the prognosis. Potential benefits were obtained after intraperitoneal nebulization of oxaliplatin in patients with advanced PC from colorectal cancer. Innovative surgical therapies such as pressurized intraperitoneal aerosol chemotherapy (PIPAC) have been proposed as palliative locoregional treatment with some promising results. The dose of oxaliplatin currently established by nebulization (PIPAC) is really low at 92 mg/m2. However, the peritoneum acts as a barrier limiting the systemic passage of intraperitoneal drug. Oxaliplatin used at higher doses during PIPAC procedures could be a safe option and allow better intratumoral penetration of chemotherapy.Method and designThe proposed study is a multicenter phase I/II trial of oxaliplatin dose escalation during PIPAC. The aim is to determine the maximum tolerated dose of pressurized oxaliplatin administered by the intraperitoneal route (PIPAC) during two consecutive procedures at a 4-6 week interval for patients with extended peritoneal carcinomatosis from the gastrointestinal tract. Dose started at 90 mg/m2 and escalation was in 50 mg/m2 steps up to a maximum of 300 mg/m2.DiscussionOxaliplatin is an effective drug in gastrointestinal cancer and high doses given by the intraperitoneal route during HIPEC are well tolerated. In this phase I trial, we hypothesized that high-dose oxaliplatin during PIPAC is feasible and safe. The repeated local administration of high doses of oxaliplatin could improve tumor response and prognosis.Trial registrationProspective study. ClinicalTrials.gov: NCT03294252. EudraCT: 2016-003666-49.

Project description:BackgroundPeritoneal 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.MethodsPIPAC-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/m2) and cisplatin (7.5 mg/m2) for non-colorectal cancer patients (PIPAC C/D), and oxaliplatin (92 mg/m2) 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.ResultsThe 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.ConclusionsIt 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 registrationThe study is registered with ClinicalTrials.gov Identifier NCT03287375 and the European Clinical Trials Database (EudraCT) number 2016-003394-18.

Project description:Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is an emerging palliative treatment for patients with unresectable peritoneal metastases. Potential advantages of PIPAC over current treatment options are a homogeneous intraperitoneal distribution, low local and systemic toxicity, and enhanced tumour penetration. Given these possible benefits, PIPAC is increasingly implemented in many centres worldwide. Scientific research into PIPAC is currently available from in vitro/in vivo/in animal studies, retrospective cohorts in humans, and phase I and II studies in humans. There are no results from randomised trials comparing PIPAC with conventional treatment, such as palliative systemic therapy. This narrative review aimed to provide an overview of the currently available literature on PIPAC. In general, repetitive PIPAC was feasible and safe for patients and operating room personnel. Primary and secondary non-access rates varied from 0-17% and 0-15%, respectively. Iatrogenic bowel injury was observed in 0-3% of PIPAC procedures. CTCAE grade 1-2 complications were common, mostly consisting of abdominal pain, nausea, vomiting, and fatigue. CTCAE grade 3-4 complications were uncommon, occurring on 0-15% of PIPAC procedures. Post-operative mortality rates of 0-2% were reported. The risk of occupational exposure to cytotoxic drugs was very low when strict safety guidelines were followed. Clinical heterogeneity was high in most studies, since, in general, patients with unresectable peritoneal metastases from a variety of primary tumours were included. Also, patients received either PIPAC monotherapy or PIPAC combined with concomitant systemic therapy, and were able to receive PIPAC in any line of palliative treatment. Since the results were generally not stratified for these three important factors, this severely complicates the interpretation of results. Based on the current literature, PIPAC may be regarded as a promising palliative treatment option in patients with diffuse peritoneal metastases. Initial results show that it is feasible and safe. However, well designed and (ideally) randomized controlled trials are urgently needed to determine the additional value of PIPAC in this setting. Until then, PIPAC should preferably be performed in the setting of clinical trials.

Dataset Information

Multicenter dose-escalation Phase I trial of mitomycin C pressurized intraperitoneal aerosolized chemotherapy in combination with systemic chemotherapy for appendiceal and colorectal peritoneal metastases: rationale and design.

Objectives

Methods

Results

Conclusions

Publications

Multicenter dose-escalation Phase I trial of mitomycin C pressurized intraperitoneal aerosolized chemotherapy in combination with systemic chemotherapy for appendiceal and colorectal peritoneal metastases: rationale and design.

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