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Oncology
Protocol
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)
  1. Robin J. Lurvink1,
  2. Paulien Rauwerdink2,
  3. Koen P. Rovers1,
  4. Emma C.E. Wassenaar2,
  5. Maarten J. Deenen3,
  6. Joost Nederend4,
  7. Clément J.R. Huysentruyt5,
  8. Iris van 't Erve6,
  9. Remond J.A. Fijneman6,
  10. Erik J.R.J. van der Hoeven7,
  11. Cornelis A. Seldenrijk8,
  12. Alexander Constantinides9,
  13. Onno Kranenburg9,
  14. Maartje Los10,
  15. Karin H. Herbschleb10,
  16. Anna M.J. Thijs11,
  17. Geert-Jan M. Creemers11,
  18. Jacobus W.A. Burger1,
  19. Marinus J. Wiezer2,
  20. Simon W. Nienhuijs1,
  21. Djamila Boerma2,
  22. Ignace H.J.T. de Hingh1,12
  1. 1Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands
  2. 2Department of Surgery, Sint Antonius Ziekenhuis, Nieuwegein, The Netherlands
  3. 3Department of Clinical Pharmacy, Catharina Hospital, Eindhoven, The Netherlands
  4. 4Department of Radiology, Catharina Hospital, Eindhoven, The Netherlands
  5. 5Department of Pathology, Catharina Hospital, Eindhoven, The Netherlands
  6. 6Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
  7. 7Department of Radiology, Sint Antonius Ziekenhuis, Nieuwegein, The Netherlands
  8. 8Department of Pathology DNA, Sint Antonius Ziekenhuis, Nieuwegein, The Netherlands
  9. 9Department of Imaging and Cancer, UMC Utrecht, Utrecht, The Netherlands
  10. 10Department of Medical Oncology, Sint Antonius Ziekenhuis, Nieuwegein, The Netherlands
  11. 11Department of Medical Oncology, Catharina Hospital, Eindhoven, The Netherlands
  12. 12School for Oncology and Developmental Biology, GROW, Maastricht, The Netherlands
  1. Correspondence to Professor Ignace H.J.T. de Hingh; ignace.d.hingh{at}catharinaziekenhuis.nl

Abstract

Introduction Despite 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 analysis In 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 dissemination This 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 number NL8303.

  • colorectal surgery
  • gastrointestinal tumours
  • chemotherapy
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjopen-2020-044811

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    Strengths and limitations of this study

    • First prospective phase II study assessing the safety, feasibility and antitumour activity of first-line palliative systemic therapy with bevazicumab alternated with pressurised intraperitoneal aerosol chemotherapy (oxaliplatin) for colorectal peritoneal metastases (CPM).

    • Inclusion of a clinically homogenous population of patients with CPM receiving first-line palliative treatment.

    • Assessment of multiple secondary outcomes, for example, patient-reported outcomes, costs and the systemic pharmacokinetics of oxaliplatin.

    • Translational side studies of the present study may open new opportunities for research in understanding and treating CPMs.

    • Potential limitation: histopathological heterogeneity (ie, enrolment allowed for both appendiceal and colorectal primary tumours and signet ring cell carcinoma).

    Introduction

    The peritoneum is a common metastatic site in colorectal cancer, and the presence of colorectal peritoneal metastases (CPM) is characterised by a poor prognosis.1 2 Most patients with CPM are treated with palliative intent.3 When treated with systemic therapy, patients with CPM have a shorter survival than patients with systemic metastases of colorectal cancer.4

    Theoretically, intraperitoneal chemotherapy could be an interesting palliative treatment option due to a favourable peritoneum–plasma concentration ratio.5 However, the use of intraperitoneal chemotherapy is limited by poor direct tumour penetration, inhomogeneous intraperitoneal drug distribution and dose-limiting local toxicity.6 7 Pressurised intraperitoneal aerosol chemotherapy (PIPAC) has been developed to overcome these limitations.8–11 PIPAC is a laparoscopic method for the repetitive intraperitoneal administration of low-dose chemotherapy as a pressurised aerosol, claiming enhanced tumour penetration, homogeneous intraperitoneal drug distribution and low toxicity in preliminary studies.8–11 The first clinical reports have suggested that PIPAC is feasible, safe and well tolerated in patients with peritoneal metastases of various primary tumours.12 13 Given these results, PIPAC is currently implemented in a rapidly increasing number of centres worldwide.12 14 In these centres, patients with CPM are generally treated with PIPAC with oxaliplatin (92 mg/m2) every 6–8 weeks, with or without concomitant systemic therapy.14 Electrostatic precipitation of the aerosol is thought to enhance tissue penetration and is practised in several centres.15–18

    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

    Repetitive ePIPAC-OX could also be added to first-line systemic therapy with the aim to maximise intraperitoneal tumour response and eliminate systemic micrometastases. The combination of first-line systemic therapy (including bevacizumab) and repetitive ePIPAC-OX, hereinafter referred to as first-line bidirectional therapy, is already offered to patients with isolated unresectable CPM in several PIPAC centres worldwide.14

    Despite its increasing use, the feasibility, safety and antitumour activity of first-line bidirectional therapy has never been prospectively investigated in patients with isolated unresectable CPM in clinical trials with predefined eligibility criteria, interventions and outcomes. Moreover, nothing is known about PROs and costs of—and the systemic pharmacokinetics of oxaliplatin during—first-line bidirectional therapy in this setting. As a first step to address this evidence gap, the present multicentre, single-arm, phase II study (CRC-PIPAC-II) aims to assess the safety, feasibility antitumour activity, PROs, costs and systemic pharmacokinetics of first-line bidirectional therapy in patients with isolated unresectable CPM.

    Methods and analysis

    Setting

    This study is performed in two Dutch tertiary referral centres for the surgical treatment of CPM.

    Eligibility criteria

    Eligibility criteria are:

    • ≥18 years of age.

    • WHO performance status of 0–1.

    • Histologically or cytologically proven peritoneal metastases of a colorectal or appendiceal carcinoma.

    • Unresectable disease, defined as a Peritoneal Cancer Index (PCI) >20 or if complete resection of peritoneal metastases is surgically not feasible, based on abdominal CT, laparoscopy or laparotomy.

    • Adequate organ functions (hemoglobin ≥5.0 mmol/L, neutrophils ≥1.5×109/L, platelets ≥100×109/L, serum creatinine <1.5 × upper limit of normal (ULN), creatinine clearance ≥30 mL/min and liver transaminases <5 × ULN).

    • No symptoms of gastrointestinal obstruction.

    • No systemic metastases.

    • No contraindications for the planned systemic therapy or laparoscopy.

    • No previous PIPAC.

    • No previous palliative systemic therapy for colorectal cancer.

    • No (neo)adjuvant systemic therapy for colorectal cancer ≤6 months prior to enrolment.

    Interventions and procedures

    The study flow chart is shown in figure 1. The schedule of enrolment, interventions and assessments is shown in table 1.

    Figure 1
    Figure 1

    Study flow chart. B, bloods (organ functions and tumor markers); C, cytology (ascites or peritoneal lavage); CRS, cytoreductive surgery; ePIPAC-OX, electrostatic pressurized intraperitoneal aerosol chemotherapy with oxaliplatin; H, histopathology (peritoneal biopsies); MDT, multidisciplinary tumor board; HIPEC, hyperthermic intraperitoneal chemotherapy; P, pharmacokinetic sampling; Q, questionnaires (costs and patient-reported outcomes); Q*, questionnaires (patient-reported outcomes); R, radiology (thoracoabdominal CT and diffusion-weighted MRI peritoneum); R*, thoracoabdominal CT; T, translational research (blood and ascites or peritoneal lavage); T*, translational research (blood).

    View this table:
    Table 1

    Schedule of enrolment, interventions and assessments

    All patients receive three cycles of first-line bidirectional therapy. Each cycle consists of 6 weeks of first-line systemic therapy followed by one ePIPAC-OX. Study treatment ends after the third ePIPAC-OX in all patients.

    First-line palliative systemic therapy

    The treating medical oncologist determines which of the following first-line regimens will be used:

    • Two 3-weekly cycles of CAPOX-bevacizumab (intravenous oxaliplatin (130 mg/m2 body surface area (BSA)) on day 1, oral capecitabine (1000 mg/m2 BSA) twice daily on days 1–14, intravenous bevacizumab (7.5 mg/kg body weight) on day 1).

    • Three 2-weekly cycles of FOLFOX-bevacizumab (intravenous oxaliplatin (85 mg/m2 BSA) on day 1, intravenous leucovorin (400 mg/m2 BSA) on day 1, intravenous bolus/continuous 5-fluorouracil (400/2400 mg/m2 BSA) on days 1–2, intravenous bevacizumab (5 mg/kg body weight) on day 1).

    • Three 2-weekly cycles of FOLFIRI-bevacizumab (intravenous irinotecan [180 mg/m2 BSA) on day 1, intravenous leucovorin (400 mg/m2 BSA) on day 1, intravenous bolus/continuous 5-fluorouracil (400/2400 mg/m2 BSA) on days 1–2, intravenous bevacizumab (5 mg/kg body weight) on day 1).

    • Three 2-weekly cycles of FOLFOXIRI-bevacizumab (intravenous oxaliplatin (85 mg/m2 BSA) on day 1, intravenous irinotecan (165 mg/m2 BSA) on day 1, intravenous leucovorin (400 mg/m2 BSA) on day 1, intravenous continuous 5-fluorouracil (2400 mg/m2 BSA) on days 1–2, intravenous bevacizumab (5 mg/kg body weight) on day 1).

    These regimens are based on the European Society for Medical Oncology (ESMO) and the Dutch guideline for the treatment of metastatic colorectal cancer.21 22 According to the ESMO guideline, both bevacizumab and anti-EGFR therapy can be added to first-line systemic chemotherapy when disease control is the main goal of treatment. According to the Dutch guideline, bevacizumab is the first-choice biological agent for the treatment of metastatic colorectal cancer, as it can be administered to patients with wildtype KRAS and patients with mutated KRAS, in contrast to anti-EGFR therapy.

    Dose reductions, switches between allowed regimens and management of toxicity are left to the discretion of the treating medical oncologist. Dihydropyrimidine dehydrogenase status is assessed by genotyping before the first administration of systemic therapy, and dosages of capecitabine or 5-fluorouracil are modified accordingly.23

    ePIPAC-OX

    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/m2 BSA in 10 min) and 5-fluorouracil (400 mg/m2 BSA in 15 min) are administered intravenously, since these drugs are thought to increase the efficacy of oxaliplatin.24 25 Meanwhile, ascites (or peritoneal lavage using saline if ascites is absent) is evacuated and sent for cytology, the PCI and ascites volume are registered26 and three peritoneal metastases from different intra-abdominal areas (if possible) are biopsied and sent for histopathology. Biopsy locations are marked with clips to enable similar biopsies during subsequent procedures.

    Then, after building the PIPAC setup and ensuring a leak-free pneumoperitoneum, oxaliplatin (92 mg/m2 BSA (maximum 184 mg) diluted to a total volume of 150 mL in a 5% dextrose solution) is aerosolised into the peritoneal cavity through a nebuliser (CapnoPen, Capnomed GmbH, Villingendorf, Germany) using an angiographic injector at a maximum pressure of 200 psi and a flow of 30 mL/min, all according to internationally used protocols.14 After formation of the aerosol in 5 min, it is electrostatically precipitated for another 25 min using Ultravision technology (Alesi Surgical, Cardiff, UK) as described by others,16 as this could enhance tumour penetration of oxaliplatin.15

    Then, the peritoneal cavity is exsufflated through a closed aerosol waste system, instruments are removed, and incisions are closed.

    Postoperatively, patients receive analgesics and antiemetics according to local protocol. Standard postoperative clinical evaluations are performed a few hours after ePIPAC-OX and on every postoperative day until discharge. Postoperative laboratory tests are only performed if indicated. Patients are intentionally discharged on the day of ePIPAC-OX or on the first postoperative day.

    Evaluations

    Before each cycle of systemic therapy, patients undergo clinical and biochemical (ie, tumour markers and organ functions) evaluation by the treating medical oncologist. Before each ePIPAC-OX, patients undergo clinical evaluation by the treating surgeon. During and shortly after ePIPAC-OX, patients undergo macroscopic (ie, peritoneal cancer index (PCI)26) and ascites volume), histopathological (ie, peritoneal regression grading score (PRGS) of peritoneal biopsies27 28) and cytological evaluation. Radiological evaluation is performed 1 week before the second ePIPAC-OX and 4 weeks after the third ePIPAC-OX.29 Patients are discussed by a multidisciplinary tumour board after the second and third ePIPAC-OX.

    After completing 6 weeks of systemic therapy, the subsequent ePIPAC-OX is planned within 1–4 weeks thereafter. After ePIPAC-OX, systemic therapy is restarted 1–4 weeks postoperatively. Study treatment is discontinued in case of physician-determined disease progression, unacceptable toxicity or physician’s or patient’s decision to discontinue participation. Study treatment ends after the third ePIPAC-OX, regardless of response to therapy, after which patients receive standard supportive, palliative or curative care according to the Dutch national guideline without further ePIPAC-OX.22

    Pharmacokinetic sampling

    Four millilitres of whole blood samples are collected in heparin tubes at multiple time points during and after the first ePIPAC-OX as well as during and after the first cycle of systemic therapy:

    • ePIPAC-OX: at t=0, t=0.5, t=1, t=2 and t=16 hours and t=1 week after intraperitoneal oxaliplatin injection.

    • CAPOX-bevacizumab: at t=0, t=0.5, t=1 and t=2 hours and t=3 weeks after intravenous administration of oxaliplatin.

    • FOLFOX-bevacizumab or FOLFOXIRI-bevacizumab: at t=0, t=0.5, t=1, t=2, t=48 hours and t=2 weeks after intravenous administration of oxaliplatin.

    After direct centrifuging, a plasma aliquot is stored at −80°C until analysis. To obtain the free fraction of oxaliplatin, a second 1 mL plasma aliquot is centrifuged through an ultrafiltration membrane and stored at −80°C until analysis. Oxaliplatin concentrations are measured using atomic absorption spectrometry performed on a Thermo Fisher Solaar ICE 3500 graphite-furnace spectrophotometer with Zeeman correction (Thermo Fisher Scientific, Bremen, Germany).

    Translational research

    Two 10 mL cell-free DNA BCT tubes (Streck, La Vista, Nebraska, USA) are used to collect 20 mL of whole blood at baseline and before each ePIPAC-OX. Tubes are sent to a central laboratory for isolation and storage (−80°C) of plasma and cell pellet according to the manufacturer’s instructions. Collected ascites or peritoneal lavage is centrifuged twice (5 min, 420 g, zero break) under sterile conditions. The supernatant is snap frozen and stored (−80°C) until further analysis. The cell pellet is suspended into an organoid culture medium at 4°C for transport and further preparation.

    Outcomes

    The primary outcome is the number of patients with—and procedures leading to—grade ≥3 adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE) V.5.0 (primary classification) and Clavien-Dindo (secondary classification) up to 4 weeks after the last ePIPAC-OX.30 31

    Secondary outcomes are:

    • The number of completed cycles of bidirectional therapy in each patient and reasons for discontinuation.

    • Characteristics of systemic therapy (eg, administered regimens, number of completed cycles and dose reductions).

    • Characteristics of ePIPAC-OX (eg, intraoperative complications and operating time).

    • The number of patients with—and procedures leading to—grade ≤2 adverse events according to the CTCAE V.5.0 (primary classification) and Clavien-Dindo (secondary classification) up to 4 weeks after the last ePIPAC-OX.30 31

    • Hospital stay, defined as the number of days between ePIPAC-OX and initial discharge.

    • Readmissions, defined as any unplanned hospital admission after initial discharge up to 4 weeks after the last ePIPAC-OX.

    • Radiological tumour response, centrally evaluated by two assessors blinded to clinical outcomes, using the Response Evaluation Criteria In Solid Tumors V.1.1 and the radiological PCI.29

    • Histopathological tumour response, centrally evaluated by two assessors blinded to clinical outcomes, using the four-tier PRGS of collected peritoneal biopsies during each ePIPAC-OX.27 28

    • Macroscopic tumour response, based on the PCI during each ePIPAC-OX.

    • Ascites response, based on ascites volume during each ePIPAC-OX.

    • Biochemical tumour response, based on carcinoembryonic antigen levels at baseline and before each ePIPAC-OX.

    • Cytological tumour response, based on the presence or absence of malignant cells in ascites or peritoneal lavage collected during each ePIPAC-OX.

    • PROs, based on the EQ-5D-5L,32 EORTC QLQ-C3033 and EORTC QLQ-CR2934 questionnaires at baseline, 1 week before the first ePIPAC-OX and 1 and 4 weeks after each ePIPAC-OX.

    • The bioavailability of oxaliplatin, based on the systemic pharmacokinetics of oxaliplatin during and after one intravenous administration, as well as during and after one ePIPAC-OX.

    • Costs, derived from the Dutch cost guideline for healthcare research at the time of analysis, based on hospital information systems, case report forms and the iMTA Productivity cost questionnaire35 and the iMTA Medical consumption questionnaire36 at baseline and 4 weeks after each ePIPAC-OX.

    • Progression-free survival, defined as the time between enrolment and physician-determined disease progression or death.

    • Overall survival, defined as the time between enrolment and death.

    Sample size

    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.

    Recruitment

    The study commenced on 30 January 2020 and the first patient was enrolled on 5 February 2020. The investigators expect to complete accrual within a maximum of 3 years. Strategies for achieving adequate patient accrual are not defined a priori.

    Data collection and data management

    Outcomes are collected in all patients who complete at least one cycle of bidirectional therapy. All baseline characteristics and outcomes are prospectively collected by a local investigator in each study centre using standardised electronic case report forms linked to an ISO 27001 certified central study database (De Research Manager, Deventer, the Netherlands). This ISO 27001 certified system optimises data quality by standardised data entry, coding, security and storage.

    Statistical methods

    Continuous data are presented as a median with (interquartile) range, and categorical data are presented as number (percentage). Due to the single-arm design of the present study and the explorative nature of the analysed outcomes, basic statistical methods are not defined a priori. These methods will be defined before data analysis. Time-to-event variables, such as progression-free and overall survival, are analysed and presented using the Kaplan-Meier method.

    Data monitoring

    Interim analyses are performed 4 weeks after the 5th, 15th, 30th and 45th procedure. The study is terminated, or temporarily halted for evaluation and potential adaption of the study protocol, if more than three CTCAE grade 3 or 4 adverse events occur or more than one CTCAE grade 5 adverse event occur that are considered directly related to ePIPAC-OX. Adverse events related to systemic therapy are not included in the stopping rules. If the study is terminated, enrolled patients do not receive any further ePIPAC-OX. The principal investigators (IHJTH and DB) have access to the interim results and make the final decision to terminate or continue the study. No data monitoring committee was formed for this study.

    Harms

    All serious adverse events (SAEs) or suspected unexpected serious adverse reactions (SUSARs) that occur from enrolment up to 4 weeks after the last ePIPAC-OX are reported by local investigators to the coordinating investigator within 24 hours. The coordinating investigator reports these SAEs/SUSARs to the central ethics committee within 7 days of first knowledge for lethal or life-threatening SAEs/SUSARs and within 15 days for other SAEs/SUSARs.

    Auditing

    Auditing is performed by independent qualified monitors of the study centres. The study is considered a medium-risk study according to the brochure ‘Kwaliteitsborging mensgebonden onderzoek 2.0’ by the Dutch Federation of University Medical Centers, meaning that study centres are audited two to three times per year, depending on enrolment, with 25% auditing of the study master file, investigator site files, informed consent forms, eligibility criteria, source data verification and SAEs/SUSARs.

    Patient and public involvement

    Patients are not involved in the design, recruitment and conduct of the study but will be involved in the dissemination of study results.

    Ethics and dissemination

    Research ethics approval

    The present study is approved by a central ethics committee (MEC-U, Nieuwegein, Netherlands, number R19.087) and the institutional review boards of both study centres.

    Protocol amendments

    Important modifications to the study protocol need to be authorised by the central ethics committee. After authorisation, these modifications are communicated to the Dutch competent authority, the institutional review boards of both study centres, all investigators, study registries and patients (if required by the central ethics committee).

    Informed consent

    Patients are enrolled by their treating physician and provide written informed consent. Patients are able to give separate consent for participation in translational side studies.

    Confidentiality

    Personal data of patients is collected, shared and maintained according to the Dutch law.

    Access to data

    All authors have access to the final dataset, without any contractual agreements that limit such access.

    Ancillary and poststudy care

    One of the study centres (Catharina Hospital, Eindhoven, the Netherlands) is insured to cover harms caused by study participation in either participating hospital. After stopping study treatment, patients receive further supportive, palliative or curative intent treatment according to Dutch guideline.22

    Dissemination policy

    Study results will be personally communicated to participants, submitted for publication in peer-reviewed medical journals and presented to patients, healthcare professionals and the public during (inter)national meetings. Authorship eligibility guidelines are not defined a priori. The full study protocol and the Dutch informed consent form are available from the corresponding author. After study completion, the participant-level dataset and statistical code will be available on reasonable request.

    Discussion

    To the knowledge of the authors, CRC-PIPAC-II is the first study that prospectively investigates the safety, feasibility, antitumour activity, PROs, costs and systemic pharmacokinetics of first-line systemic chemotherapy and bevacizumab alternated with repetitive ePIPAC-OX (ie, first-line bidirectional therapy) in patients with isolated unresectable CPM.

    The present study has several strengths. All patients in the present study receive standard first-line systemic regimens based on the ESMO guideline for the treatment of metastatic colorectal cancer,21 which contrasts the heterogeneity in treatment lines in available studies on (e)PIPAC-OX for CPM. The homogeneity in first-line treatment may facilitate a comparison between the present study and other first-line studies in metastatic colorectal cancer. Furthermore, assessment of outcomes such as PROs, costs and systemic pharmacokinetics will provide further insight in the tolerability, costs and pharmacokinetic profile of first-line bidirectional therapy in this setting. Translational side studies may open new opportunities for research in understanding and treating CPM.

    A potential limitation of the present study is the histopathological heterogeneity of the study population, since the eligibility criteria allow the enrolment of patients with both colorectal and appendiceal carcinomas, as well as including distinct pathological features such as signet ring cell histology. Furthermore, different first-line palliative systemic regimens are allowed, including FOLFOXIRI-bevacizumab, which might result in clinical heterogeneity. Although the potential clinical and histopathological heterogeneity could impede the interpretation of preliminary efficacy outcomes, this is not the major focus of this study.

    With regards to the chemotherapy regimen used in this study, the results of the recently published PRODIGE-7 trial may question the intraperitoneal use of oxaliplatin (combined with 5-fluorouracil and leucovorin) in patients with CPM.37 However, in contrast with PRODIGE-7, patients in the present study are either systemic therapy-naïve or had undergone a mandatory 6-month wash-out period of systemic therapy. As a result, the previously untreated patients in this study may be more sensitive to intraperitoneal oxaliplatin than patients in the PRODIGE-7 trial.

    Most importantly, patients in the present study undergo palliative instead of curative intent treatment and receive repetitive instead of a single administration of intraperitoneal oxaliplatin. Repetitive PIPAC-OX (with or without intraoperative intravenous bolus 5-fluorouracil/leucovorin) is increasingly offered and frequently combined with first-line systemic chemotherapy and bevacizumab in many centres worldwide.12 14 38 39 Despite the increasing use, the safety and feasibility of this combination has never been prospectively investigated in clinical trials. Altogether, it remains important to assess the feasibility and safety of the combination of first-line palliative systemic therapy and repetitive PIPAC-OX, hence the major focus of this study.

    With regards to the oxaliplatin dose during PIPAC, two phase I dose-escalation trials recently assessed the maximum tolerated dose of repetitive PIPAC-OX for unresectable peritoneal metastases of various origins.40 41 The French PIPOX trial observed two dose-limiting toxicities of systemic therapy with repetitive PIPAC-OX at 140 mg/m2 and the investigators defined a maximum tolerated dose of repetitive PIPAC-OX of 90 mg/m2. The PIPAC-OX trial from Singapore reported no dose-limiting toxicities with repetitive PIPAC-OX 120 mg/m2 monotherapy; however, this trial was prematurely terminated due to the dose-limiting toxicities of the PIPOX trial. As a result, both trials are currently recruiting phase II expansion cohorts to investigate various systemic regimens combined with repetitive PIPAC-OX at 90 mg/m2: a dose similar to the oxaliplatin dose in the current trial.

    Results of several other ongoing single-arm, phase II studies are closely monitored. The first study primarily assesses the histopathological response of PIPAC with various drugs for peritoneal metastases of various origins (including PIPAC-OX for CPM), with or without concomitant systemic therapy, in 137 patients in any line of palliative treatment.42 The second study assesses the safety of PIPAC with various drugs for peritoneal metastases of various origins (including PIPAC-OX for CPM), with or without concomitant systemic therapy, in 16 patients in a later line of palliative treatment (ClinicalTrials.gov, NCT04329494). The third study assesses progression-free survival of 30 patients with CPM receiving PIPAC-OX, with or without concomitant systemic therapy, in any line of palliative treatment (ClinicalTrials.gov, NCT03868228). Results of the previous CRC-PIPAC study, the present CRC-PIPAC-II study, and these ongoing studies may help designing future randomised trials to determine the role of (e)PIPAC-OX in the palliative treatment of patients with isolated unresectable CPM.

    References

    1. ↵
      1. van der Geest LGM,
      2. Lam-Boer Jorine't,
      3. Koopman M, et al
      . Nationwide trends in incidence, treatment and survival of colorectal cancer patients with synchronous metastases. Clin Exp Metastasis 2015;32:457–65.doi:10.1007/s10585-015-9719-0pmid:http://www.ncbi.nlm.nih.gov/pubmed/25899064
      OpenUrlCrossRefPubMed
    2. ↵
      1. Lurvink RJ,
      2. Bakkers C,
      3. Rijken A
      . Increase in the incidence of synchronous and metachronous peritoneal metastases in patients with colorectal cancer: a nationwide study. Eur J Surg Oncol 2021.
    3. ↵
      1. Razenberg LGEM,
      2. Lemmens VEPP,
      3. Verwaal VJ, et al
      . Challenging the dogma of colorectal peritoneal metastases as an untreatable condition: results of a population-based study. Eur J Cancer 2016;65:113–20.doi:10.1016/j.ejca.2016.07.002pmid:http://www.ncbi.nlm.nih.gov/pubmed/27497343
      OpenUrlPubMed
    4. ↵
      1. Franko J,
      2. Shi Q,
      3. Meyers JP, et al
      . Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the analysis and research in cancers of the digestive system (ARCAD) database. Lancet Oncol 2016;17:1709–19.doi:10.1016/S1470-2045(16)30500-9pmid:http://www.ncbi.nlm.nih.gov/pubmed/27743922
      OpenUrlPubMed
    5. ↵
      1. Dedrick RL,
      2. Myers CE,
      3. Bungay PM, et al
      . Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian cancer. Cancer Treat Rep 1978;62:1–11.pmid:http://www.ncbi.nlm.nih.gov/pubmed/626987
      OpenUrlPubMedWeb of Science
    6. ↵
      1. Dedrick RL,
      2. Flessner MF
      . Pharmacokinetic problems in peritoneal drug administration: tissue penetration and surface exposure. J Natl Cancer Inst 1997;89:480–7.doi:10.1093/jnci/89.7.480pmid:http://www.ncbi.nlm.nih.gov/pubmed/9086004
      OpenUrlCrossRefPubMedWeb of Science
    7. ↵
      1. Markman M
      . Intraperitoneal antineoplastic drug delivery: rationale and results. Lancet Oncol 2003;4:277–83.doi:10.1016/S1470-2045(03)01074-Xpmid:http://www.ncbi.nlm.nih.gov/pubmed/12732164
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      1. Solaß W,
      2. Hetzel A,
      3. Nadiradze G, et al
      . Description of a novel approach for intraperitoneal drug delivery and the related device. Surg Endosc 2012;26:1849–55.doi:10.1007/s00464-012-2148-0pmid:http://www.ncbi.nlm.nih.gov/pubmed/22580869
      OpenUrlCrossRefPubMed
    9. ↵
      1. Solass W,
      2. Herbette A,
      3. Schwarz T, et al
      . Therapeutic approach of human peritoneal carcinomatosis with Dbait in combination with capnoperitoneum: proof of concept. Surg Endosc 2012;26:847–52.doi:10.1007/s00464-011-1964-ypmid:http://www.ncbi.nlm.nih.gov/pubmed/22042585
      OpenUrlPubMed
    10. ↵
      1. Solass W,
      2. Kerb R,
      3. Mürdter T, et al
      . Intraperitoneal chemotherapy of peritoneal carcinomatosis using pressurized aerosol as an alternative to liquid solution: first evidence for efficacy. Ann Surg Oncol 2014;21:553–9.doi:10.1245/s10434-013-3213-1pmid:http://www.ncbi.nlm.nih.gov/pubmed/24006094
      OpenUrlCrossRefPubMed
    11. ↵
      1. Blanco A,
      2. Giger-Pabst U,
      3. Solass W, et al
      . Renal and hepatic toxicities after pressurized intraperitoneal aerosol chemotherapy (PIPAC). Ann Surg Oncol 2013;20:2311–6.doi:10.1245/s10434-012-2840-2pmid:http://www.ncbi.nlm.nih.gov/pubmed/23377563
      OpenUrlPubMed
    12. ↵
      1. Alyami M,
      2. Hübner M,
      3. Grass F, et al
      . Pressurised intraperitoneal aerosol chemotherapy: rationale, evidence, and potential indications. Lancet Oncol 2019;20:e368–77.doi:10.1016/S1470-2045(19)30318-3pmid:http://www.ncbi.nlm.nih.gov/pubmed/31267971
      OpenUrlPubMed
    13. ↵
      1. Grass F,
      2. Vuagniaux A,
      3. Teixeira-Farinha H, et al
      . Systematic review of pressurized intraperitoneal aerosol chemotherapy for the treatment of advanced peritoneal carcinomatosis. Br J Surg 2017;104:669–78.doi:10.1002/bjs.10521pmid:http://www.ncbi.nlm.nih.gov/pubmed/28407227
      OpenUrlCrossRefPubMed
    14. ↵
      1. Nowacki M,
      2. Alyami M,
      3. Villeneuve L, et al
      . Multicenter comprehensive methodological and technical analysis of 832 pressurized intraperitoneal aerosol chemotherapy (PIPAC) interventions performed in 349 patients for peritoneal carcinomatosis treatment: An international survey study. Eur J Surg Oncol 2018;44:991–6.doi:10.1016/j.ejso.2018.02.014pmid:http://www.ncbi.nlm.nih.gov/pubmed/29526367
      OpenUrlPubMed
    15. ↵
      1. Kakchekeeva T,
      2. Demtröder C,
      3. Herath NI, et al
      . In vivo feasibility of electrostatic precipitation as an adjunct to pressurized intraperitoneal aerosol chemotherapy (ePIPAC). Ann Surg Oncol 2016;23:592–8.doi:10.1245/s10434-016-5108-4pmid:http://www.ncbi.nlm.nih.gov/pubmed/26842487
      OpenUrlPubMed
    16. ↵
      1. Willaert W,
      2. Van de Sande L,
      3. Van Daele E, et al
      . Safety and preliminary efficacy of electrostatic precipitation during pressurized intraperitoneal aerosol chemotherapy (PIPAC) for unresectable carcinomatosis. Eur J Surg Oncol 2019;45:2302–9.doi:10.1016/j.ejso.2019.06.018pmid:http://www.ncbi.nlm.nih.gov/pubmed/31221459
      OpenUrlPubMed
    17. ↵
      1. Graversen M,
      2. Detlefsen S,
      3. Ellebaek SB, et al
      . Pressurized intraperitoneal aerosol chemotherapy with one minute of electrostatic precipitation (ePIPAC) is feasible, but the histological tumor response in peritoneal metastasis is insufficient. Eur J Surg Oncol 2020;46:155–9.doi:10.1016/j.ejso.2019.08.024pmid:http://www.ncbi.nlm.nih.gov/pubmed/31493986
      OpenUrlPubMed
    18. ↵
      1. Reymond M,
      2. Demtroeder C,
      3. Solass W, et al
      . Electrostatic precipitation pressurized intraperitoneal aerosol chemotherapy (ePIPAC): first in-human application. Pleura Peritoneum 2016;1:109–16.doi:10.1515/pp-2016-0005pmid:http://www.ncbi.nlm.nih.gov/pubmed/30911614
      OpenUrlPubMed
    19. ↵
      1. Rovers KP,
      2. Lurvink RJ,
      3. Wassenaar EC, et al
      . 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). BMJ Open 2019;9:e030408. doi:10.1136/bmjopen-2019-030408pmid:http://www.ncbi.nlm.nih.gov/pubmed/31352425
      OpenUrlAbstract/FREE Full Text
    20. ↵
      1. Rovers KP,
      2. Wassenaar ECE,
      3. Lurvink RJ
      . Pressurized intraperitoneal aerosol chemotherapy (oxaliplatin) for unresectable colorectal peritoneal metastases: a multicenter, single-arm, phase II trial (CRC-PIPAC). Ann Surg Oncol 2021;58.doi:10.1245/s10434-020-09558-4
    21. ↵
      1. Van Cutsem E,
      2. Cervantes A,
      3. Adam R, et al
      . ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016;27:1386–422.doi:10.1093/annonc/mdw235pmid:http://www.ncbi.nlm.nih.gov/pubmed/27380959
      OpenUrlCrossRefPubMed
    22. ↵
      1. Landelijke werkgroep Gastro Intestinale Tumoren
      . Richtlijn colorectaal carcinoom, 2014. Available: https://www. oncoline. nl/colorectaalcarcinoom [Accessed 01 Sep 2020].
    23. ↵
      1. Lunenburg CATC,
      2. van der Wouden CH,
      3. Nijenhuis M, et al
      . Dutch pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of DPYD and fluoropyrimidines. Eur J Hum Genet 2020;28:508–17.doi:10.1038/s41431-019-0540-0pmid:http://www.ncbi.nlm.nih.gov/pubmed/31745289
      OpenUrlPubMed
    24. ↵
      1. Elias D,
      2. Bonnay M,
      3. Puizillou JM, et al
      . Heated intra-operative intraperitoneal oxaliplatin after complete resection of peritoneal carcinomatosis: pharmacokinetics and tissue distribution. Ann Oncol 2002;13:267–72.doi:10.1093/annonc/mdf019pmid:http://www.ncbi.nlm.nih.gov/pubmed/11886004
      OpenUrlCrossRefPubMed
    25. ↵
      1. Giacchetti S,
      2. Perpoint B,
      3. Zidani R, et al
      . Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000;18:136–47.doi:10.1200/JCO.2000.18.1.136pmid:http://www.ncbi.nlm.nih.gov/pubmed/10623704
      OpenUrlAbstract/FREE Full Text
    26. ↵
      1. Jacquet P,
      2. Sugarbaker PH
      . Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis. Cancer Treat Res 1996;82:359–74.doi:10.1007/978-1-4613-1247-5_23pmid:http://www.ncbi.nlm.nih.gov/pubmed/8849962
      OpenUrlCrossRefPubMed
    27. ↵
      1. Solass W,
      2. Sempoux C,
      3. Detlefsen S, et al
      . Peritoneal sampling and histological assessment of therapeutic response in peritoneal metastasis: proposal of the peritoneal regression grading score (PRGS). Pleura Peritoneum 2016;1:99–107.doi:10.1515/pp-2016-0011pmid:http://www.ncbi.nlm.nih.gov/pubmed/30911613
      OpenUrlCrossRefPubMed
    28. ↵
      1. Solass W,
      2. Sempoux C,
      3. Carr NJ, et al
      . Reproducibility of the peritoneal regression grading score for assessment of response to therapy in peritoneal metastasis. Histopathology 2019;74:1014–24.doi:10.1111/his.13829pmid:http://www.ncbi.nlm.nih.gov/pubmed/30687944
      OpenUrlCrossRefPubMed
    29. ↵
      1. Eisenhauer EA,
      2. Therasse P,
      3. Bogaerts J, et al
      . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–47.doi:10.1016/j.ejca.2008.10.026pmid:http://www.ncbi.nlm.nih.gov/pubmed/19097774
      OpenUrlCrossRefPubMedWeb of Science
    30. ↵
      1. National Cancer Institute
      . Common terminology criteria for adverse events (CTCAE) v5.0, 2017. Available: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf [Accessed 01 Sep 2020].
    31. ↵
      1. Dindo D,
      2. Demartines N,
      3. Clavien P-A
      . Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205–13.doi:10.1097/01.sla.0000133083.54934.aepmid:http://www.ncbi.nlm.nih.gov/pubmed/15273542
      OpenUrlCrossRefPubMedWeb of Science
    32. ↵
      1. Herdman M,
      2. Gudex C,
      3. Lloyd A, et al
      . Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:1727–36.doi:10.1007/s11136-011-9903-xpmid:http://www.ncbi.nlm.nih.gov/pubmed/21479777
      OpenUrlCrossRefPubMedWeb of Science
    33. ↵
      1. Aaronson NK,
      2. Ahmedzai S,
      3. Bergman B, et al
      . The European organization for research and treatment of cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365–76.doi:10.1093/jnci/85.5.365pmid:http://www.ncbi.nlm.nih.gov/pubmed/8433390
      OpenUrlCrossRefPubMedWeb of Science
    34. ↵
      1. Stiggelbout AM,
      2. Kunneman M,
      3. Baas-Thijssen MCM, et al
      . The EORTC QLQ-CR29 quality of life questionnaire for colorectal cancer: validation of the Dutch version. Qual Life Res 2016;25:1853–8.doi:10.1007/s11136-015-1210-5pmid:http://www.ncbi.nlm.nih.gov/pubmed/26711791
      OpenUrlPubMed
    35. ↵
      1. Bouwmans C,
      2. Krol M,
      3. Severens H, et al
      . The iMTA productivity cost questionnaire: a standardized instrument for measuring and Valuing health-related productivity losses. Value Health 2015;18:753–8.doi:10.1016/j.jval.2015.05.009pmid:http://www.ncbi.nlm.nih.gov/pubmed/26409601
      OpenUrlPubMed
    36. ↵
      1. iMTA Productivity and Health Research Group
      . Handleiding iMTA medical cost questionnaire (iMCQ). Rotterdam: iMTA, Erasmus Universiteit Rotterdam, 2018.
    37. ↵
      1. Quénet F,
      2. Elias D,
      3. Roca L, et al
      . Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:256–66.doi:10.1016/S1470-2045(20)30599-4pmid:http://www.ncbi.nlm.nih.gov/pubmed/33476595
      OpenUrlPubMed
    38. ↵
      1. Siebert M,
      2. Alyami M,
      3. Mercier F, et al
      . Pressurized intraperitoneal aerosol chemotherapy (PIPAC) in association with systemic chemotherapy and bevacizumab, evaluation of safety and feasibility. A single center comparative study. Eur J Surg Oncol 2021;47:139–42.doi:10.1016/j.ejso.2019.03.021pmid:http://www.ncbi.nlm.nih.gov/pubmed/30914289
      OpenUrlPubMed
    39. ↵
      1. Sgarbura O,
      2. Villeneuve L,
      3. Alyami M, et al
      . Current practice of pressurized intraperitoneal aerosol chemotherapy (PIPAC): still standardized or on the verge of diversification? Eur J Surg Oncol 2021;47:149–56.doi:10.1016/j.ejso.2020.08.020pmid:http://www.ncbi.nlm.nih.gov/pubmed/32900609
      OpenUrlPubMed
    40. ↵
      1. Dumont F,
      2. Passot C,
      3. Raoul J-L, et al
      . A phase I dose-escalation study of oxaliplatin delivered via a laparoscopic approach using pressurised intraperitoneal aerosol chemotherapy for advanced peritoneal metastases of gastrointestinal tract cancers. Eur J Cancer 2020;140:37–44.doi:10.1016/j.ejca.2020.09.010pmid:http://www.ncbi.nlm.nih.gov/pubmed/33039812
      OpenUrlPubMed
    41. ↵
      1. Kim G,
      2. Tan HL,
      3. Sundar R, et al
      . PIPAC-OX: a phase I study of oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy in patients with peritoneal metastases. Clin Cancer Res 2020. doi:doi:10.1158/1078-0432.CCR-20-2152. [Epub ahead of print: 04 Nov 2020].pmid:http://www.ncbi.nlm.nih.gov/pubmed/33148667
      OpenUrlPubMed
    42. ↵
      1. Graversen M,
      2. Detlefsen S,
      3. Asmussen J, et al
      . Treatment of peritoneal carcinomatosis with Pressurized IntraPeritoneal Aerosol Chemotherapy - PIPAC-OPC2. Pleura Peritoneum 2018;3:20180108.doi:10.1515/pp-2018-0108pmid:http://www.ncbi.nlm.nih.gov/pubmed/30911656
      OpenUrlPubMed

    Footnotes

    • RJL and PR are joint first authors.

    • RJL and PR contributed equally.

    • Contributors RJL and PR are the coordinating investigators. RJL, KPR, AMJT, GJMC, JWAB, SWN and IHJTdH are the local investigators of the first study center. PR, ECEW, KHH, ML, MJW and DB are the local investigators of the second study center. MJD is the study pharmacologist supervising the pharmacokinetic analyses. JN and EJRJvdH are the study radiologists performing the central radiological review. CJRH and CAS are the study pathologists performing the central histopathological review. IvE and RJAF are responsible for translational research on blood. AC and OK are responsible for translational research on ascites and peritoneal lavage. IHJTdH is the principal investigator. RJL, PR, DB, and IHJTdH made substantial contributions to the conception and design of the study, drafted the protocol and drafted the manuscript. KPR, AMJT, GJMC, JWAB, SWN, ECEW, KHH, ML, MJW, MJD, JN, EJRJvdH, CJRH, CAS, IvE, RJAF, AC and OK made substantial contributions to conception and design of the study and critically revised the protocol and the manuscript for important intellectual content. All authors gave final approval of the version to be published and agree to be accountable for all aspects of the work.

    • Funding This study is supported by the Catharina Research Foundation (unrestricted grant, grant number CZE-2020.02) and the St. Antonius Research Foundation (unrestricted grant, local funding number 2019.01).

    • Competing interests IHJTH received grants, paid to the institute, from Roche, QP&S and RanD Biotech outside the submitted work. This manuscript is based on the study protocol version 4.0, 15 June 2020.

    • Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

    • Provenance and peer review Not commissioned; externally peer reviewed.