Repetitive electrostatic pressurised intraperitoneal aerosol chemotherapy (ePIPAC) with oxaliplatin as a palliative monotherapy for isolated unresectable colorectal peritoneal metastases: protocol of a Dutch, multicentre, open-label, single-arm, phase II study (CRC-PIPAC)

Rovers, Koen P.; Lurvink, Robin J.; Wassenaar, Emma C. E.; Kootstra, Thomas J.M.; Scholten, Harm J.; Tajzai, Rudaba; Deenen, Maarten J.; Nederend, Joost; Lahaye, Max J.; Huysentruyt, Clément J.R.; Erve, Iris van ‘t; Fijneman, Remond J.A.; Constantinides, Alexander; Kranenburg, Onno; Los, Maartje; Thijs, Anna M.J.; Creemers, G.J.; Burger, Jacobus W. A.; Wiezer, Marinus J.; Boerma, Djamila; Nienhuijs, Simon W.; Hingh, Ignace H. J. T. de

doi:10.1136/bmjopen-2019-030408

Cited by 21 publications

(18 citation statements)

References 52 publications

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“…Blood from patients with histologically proven CRC with isolated, initially unresectable liver metastases was collected in the multicenter CAIRO5 trial (NCT02162563) [14]. Blood and peritoneal fluid were obtained from patients with histologically proven isolated and unresectable CRC-PM, participating in the CRC-PIPAC trial (NCT03246321) [15]. Both trials were approved by a medical ethical committee, and all patients signed written informed consent for study participation, as well as liquid biopsy and tumor tissue collection for translational research.…”

Section: Methodsmentioning

confidence: 99%

Detection of tumor‐derived cell‐free DNA from colorectal cancer peritoneal metastases in plasma and peritoneal fluid

Erve

Rovers

Constantinides

et al. 2021

The Journal of Pathology CR

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Tumor-derived cell-free DNA (cfDNA) is an emerging biomarker for guiding the personalized treatment of patients with metastatic colorectal cancer (CRC). While patients with CRC liver metastases (CRC-LM) have relatively high levels of plasma cfDNA, little is known about patients with CRC peritoneal metastases (CRC-PM). This study evaluated the presence of tumor-derived cfDNA in plasma and peritoneal fluid (i.e. ascites or peritoneal washing) in 20 patients with isolated CRC-PM and in the plasma of 100 patients with isolated CRC-LM. Among tumor tissue KRAS/BRAF mutation carriers, tumor-derived cfDNA was detected by droplet digital polymerase chain reaction (ddPCR) in plasma of 93% of CRC-LM and 20% of CRC-PM patients and in peritoneal fluid in all CRC-PM patients. Mutant allele fraction (MAF) and mutant copies per ml (MTc/ml) were lower in CRC-PM plasma than in CRC-LM plasma (median MAF = 0.28 versus 18.9%, p < 0.0001; median MTc/ml = 21 versus 1,758, p < 0.0001). Within patients with CRC-PM, higher cfDNA levels were observed in peritoneal fluid than in plasma (median MAF = 16.4 versus 0.28%, p = 0.0019; median MTc/ml = 305 versus 21, p = 0.0034). These data imply that tumor-derived cfDNA in plasma is a poor biomarker to monitor CRC-PM. Instead, cfDNA detection in peritoneal fluid may offer an alternative to guide CRC-PM treatment decisions.

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Section: Methodsmentioning

confidence: 99%

Detection of tumor‐derived cell‐free DNA from colorectal cancer peritoneal metastases in plasma and peritoneal fluid

Erve

Rovers

Constantinides

et al. 2021

The Journal of Pathology CR

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“…The procedure has been extensively described in the protocol of the CRC-PIPAC study. 19 20 In summary, after creating a 12 mm Hg pneumoperitoneum with two balloon trocars using an open introduction, an explorative laparoscopy is performed with adhesiolysis if needed to create enough working space. If ePIPAC-OX seems feasible, leucovorin (20 mg/m 2 BSA in 10 min) and 5-fluorouracil (400 mg/m 2 BSA in 15 min) are administered intravenously, since these drugs are thought to increase the efficacy of oxaliplatin.…”

Section: Methods and Analysismentioning

confidence: 99%

“…Given the absence of data to guide a sample size calculation, the central ethics committee approved a pragmatically determined sample size of 20 patients as a sufficient number to explore the safety, feasibility and antitumour activity of the study treatment, similar to the CRC-PIPAC study. 19 20 Enrolled patients who are unable to receive the first ePIPAC-OX are replaced to enrol a total number of 20 patients who receive at least one cycle of bidirectional therapy.…”

Section: Methods and Analysismentioning

confidence: 99%

“…Previously, a multicentre, single-arm, phase II study (CRC-PIPAC) investigated the safety, feasibility antitumour activity, patient-reported outcomes (PROs), costs and pharmacokinetics of repetitive electrostatic PIPAC with oxaliplatin (ePIPAC-OX) as a palliative monotherapy in 20 patients with isolated unresectable CPM in any line of palliative treatment. 19 20 …”

Section: Introductionmentioning

confidence: 99%

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First-line palliative systemic therapy alternated with electrostatic pressurised intraperitoneal aerosol chemotherapy (oxaliplatin) for isolated unresectable colorectal peritoneal metastases: protocol of a multicentre, single-arm, phase II study (CRC-PIPAC-II)

et al. 2021

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IntroductionDespite its increasing use, first-line palliative systemic therapy alternated with electrostatic pressurised intraperitoneal aerosol chemotherapy with oxaliplatin (ePIPAC-OX), hereinafter referred to as first-line bidirectional therapy, has never been prospectively investigated in patients with colorectal peritoneal metastases (CPM). As a first step to address this evidence gap, the present study aims to assess the safety, feasibility, antitumour activity, patient-reported outcomes, costs and systemic pharmacokinetics of first-line bidirectional therapy in patients with isolated unresectable CPM.Methods and analysisIn this single-arm, phase II study in two Dutch tertiary referral centres, 20 patients are enrolled. Key eligibility criteria are a good performance status, pathologically proven isolated unresectable CPM, no previous palliative systemic therapy for colorectal cancer, no (neo)adjuvant systemic therapy ≤6 months prior to enrolment and no previous pressurised intraperitoneal aerosol chemotherapy (PIPAC). Patients receive three cycles of bidirectional therapy. Each cycle consists of 6 weeks first-line palliative systemic therapy at the medical oncologists’ decision (CAPOX-bevacizumab, FOLFOX-bevacizumab, FOLFIRI-bevacizumab or FOLFOXIRI-bevacizumab) followed by ePIPAC-OX (92 mg/m2) with an intraoperative bolus of intravenous leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2). Study treatment ends after the third ePIPAC-OX. The primary outcome is the number of patients with—and procedures leading to—grade ≥3 adverse events (Common Terminology Criteria for Adverse Events V.5.0) up to 4 weeks after the last procedure. Key secondary outcomes include the number of bidirectional cycles in each patient, treatment-related characteristics, grade ≤2 adverse events, tumour response (histopathological, cytological, radiological, biochemical, macroscopic and ascites), patient-reported outcomes, systemic pharmacokinetics of oxaliplatin, costs, progression-free survival and overall survival.Ethics and disseminationThis study is approved by the Dutch competent authority, a medical ethics committee and the institutional review boards of both study centres. Results will be submitted for publication in peer-reviewed medical journals and presented to patients and healthcare professionals.Trial registration numberNL8303.

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“…All three components are now part of PIPAC [57]. Starting with the first preclinical experiments through technology development, first in-human use [58], Phase 1 [59][60][61] and Phase 2 [62][63][64][65][66][67] trials, PIPAC is currently being evaluated in randomized controlled trials [68][69][70][71][72] for palliative therapy of PM [73]. PIPAC ( Figure 3) is applied through laparoscopic access using two balloon trocars in an operating room equipped with laminar air flow.…”

Section: Pressurized Intraperitoneal Aerosol Chemotherapy (Pipac)mentioning

confidence: 99%

Overcoming Drug Resistance by Taking Advantage of Physical Principles: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)

Nadiradze

Horvath

Sautkin

et al. 2019

Cancers

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Theoretical considerations as well as comprehensive preclinical and clinical data suggest that optimizing physical parameters of intraperitoneal drug delivery might help to circumvent initial or acquired resistance of peritoneal metastasis (PM) to chemotherapy. Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is a novel minimally invasive drug delivery system systematically addressing the current limitations of intraperitoneal chemotherapy. The rationale behind PIPAC is: (1) optimizing homogeneity of drug distribution by applying an aerosol rather than a liquid solution; (2) applying increased intraperitoneal hydrostatic pressure to counteract elevated intratumoral interstitial fluid pressure; (3) limiting blood outflow during drug application; (4) steering environmental parameters (temperature, pH, electrostatic charge etc.) in the peritoneal cavity for best tissue target effect. In addition, PIPAC allows repeated application and objective assessment of tumor response by comparing biopsies between chemotherapy cycles. Although incompletely understood, the reasons that allow PIPAC to overcome established chemoresistance are probably linked to local dose intensification. All pharmacological data published so far show a superior therapeutic ratio (tissue concentration/dose applied) of PIPAC vs. systemic administration, of PIPAC vs. intraperitoneal liquid chemotherapy, of PIPAC vs. Hyperthermic Intraperitoneal Chemotherapy (HIPEC) or PIPAC vs. laparoscopic HIPEC. In the initial introduction phase, PIPAC has been used in patients who were quite ill and had already failed multiple treatment regimes, but it may not be limited to that group of patients in the future. Rapid diffusion of PIPAC in clinical practice worldwide supports its potential to become a game changer in the treatment of chemoresistant isolated PM of various origins.

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Repetitive electrostatic pressurised intraperitoneal aerosol chemotherapy (ePIPAC) with oxaliplatin as a palliative monotherapy for isolated unresectable colorectal peritoneal metastases: protocol of a Dutch, multicentre, open-label, single-arm, phase II study (CRC-PIPAC)

Cited by 21 publications

References 52 publications

Detection of tumor‐derived cell‐free DNA from colorectal cancer peritoneal metastases in plasma and peritoneal fluid

Detection of tumor‐derived cell‐free DNA from colorectal cancer peritoneal metastases in plasma and peritoneal fluid

First-line palliative systemic therapy alternated with electrostatic pressurised intraperitoneal aerosol chemotherapy (oxaliplatin) for isolated unresectable colorectal peritoneal metastases: protocol of a multicentre, single-arm, phase II study (CRC-PIPAC-II)

Overcoming Drug Resistance by Taking Advantage of Physical Principles: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)

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