PIPAC for Peritoneal Metastases of Colorectal Cancer (CRC-PIPAC)

Repetitive Electrostatic Pressurised Intraperitoneal Aerosol Chemotherapy With Oxaliplatin (ePIPAC-OX) as a Palliative Monotherapy for Isolated Unresectable Colorectal Peritoneal Metastases: Protocol of a Multicentre, Open-label, Single-arm, Phase II Study (CRC-PIPAC)

This is multicentre, open-label, single-arm phase II study that investigates the feasibility, safety, tolerability, preliminary efficacy, costs, and pharmacokinetics or repetitive electrostatic pressurised intraperitoneal aerosol chemotherapy (ePIPAC-OX) as a palliative monotherapy for patients with isolated unresectable colorectal peritoneal metastases.

Study Overview

• Status: Completed
• Conditions: Colorectal Neoplasms; Peritoneal Neoplasms; Peritoneal Carcinomatosis; Appendiceal Neoplasms
• Intervention / Treatment: Combination product: repetitive ePIPAC-OX

Detailed Description

Rationale: repetitive electrostatic pressurised intraperitoneal aerosol chemotherapy with oxaliplatin (ePIPAC-OX) is offered as a palliative treatment option for patients with isolated unresectable colorectal peritoneal metastases (PM) in several centres worldwide. However, little is known about its feasibility, safety, tolerability, efficacy, costs, and pharmacokinetics in this setting.

Objectives: to prospectively explore the feasibility, safety, tolerability, preliminary efficacy, costs, and pharmacokinetic profile of repetitive ePIPAC-OX as a palliative monotherapy for isolated unresectable colorectal PM under controlled circumstances.

Study design: multicentre, open-label, single-arm, phase II study.

Setting: two Dutch tertiary referral hospitals for the surgical treatment of colorectal PM.

Study population: adults who have a World Health Organisation (WHO) performance status of 0 or 1, adequate organ functions, histologically or cytologically confirmed unresectable PM of a colorectal or appendiceal carcinoma, no systemic metastases, no symptoms of gastrointestinal obstruction, no contraindications for the planned intervention, and no previous pressurised intraperitoneal aerosol chemotherapy (PIPAC).

Intervention: instead of standard palliative treatment, enrolled patients receive laparoscopy-controlled ePIPAC-OX (92 mg/m2 body-surface area [BSA]) with intravenous leucovorin (20 mg/m2 BSA) and bolus 5-fluorouracil (400 mg/m2 BSA) every six weeks. Four weeks after each procedure, patients undergo clinical, radiological, and biochemical evaluation. ePIPAC-OX is repeated until clinical, radiological, or macroscopic disease progression, after which standard palliative treatment is (re)introduced.

Outcomes: the primary outcome is the number of patients with major toxicity (grade ≥3 according to the Common Terminology Criteria for Adverse Events v4.0) up to four weeks after the last procedure. Secondary outcomes are the environmental safety of ePIPAC-OX, procedure-related characteristics, the number of procedures in each patient and reasons for discontinuation, minor toxicity, organ-specific toxicity, postoperative complications, hospital stay, readmissions, quality of life, costs, progression-free survival, overall survival, and the radiological, histopathological, cytological, biochemical, and macroscopic tumour response. Atomic absorption spectrophotometry is used to measure concentrations of oxaliplatin in plasma, plasma ultrafiltrate, urine, ascites, PM, and normal peritoneum during and after ePIPAC-OX.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Eindhoven, Netherlands
    • Catharina Hospital
  • Nieuwegein, Netherlands
    • St. Antonius Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Eligible patients are adults who have:

• a World Health Organisation (WHO) performance status of ≤1;
• histological or cytological proof of PM of a colorectal or appendiceal carcinoma;
• unresectable disease determined by abdominal computed tomography (CT) and a diagnostic laparoscopy or laparotomy;
• adequate organ functions (haemoglobin ≥5.0 mmol/L, neutrophils ≥1.5 x 109/L, platelets ≥100 x 109/L, serum creatinine <1.5 x ULN, creatinine clearance ≥30 ml/min, and liver transaminases <5 x ULN);
• no symptoms of gastrointestinal obstruction;
• no radiological evidence of systemic metastases;
• no contraindications for oxaliplatin or 5-fluorouracil/leucovorin;
• no contraindications for a laparoscopy;
• no previous PIPAC-procedures.

Enrolled patients are excluded from the analyses in case they did not receive a first ePIPAC-OX, e.g.:

• due to systemic metastases on baseline thoracoabdominal CT, or;
• due to non-access during first ePIPAC-OX, or;
• due to resectable disease during first ePIPAC-OX.

Importantly, enrolment is allowed for patients with an unresected primary tumour (if asymptomatic) and for patients in various lines of palliative treatment, including patients who refuse, have not had, or do not qualify for first-line palliative systemic therapy. All potentially eligible patients are discussed by a multidisciplinary team. Enrolled patients are informed about the potential consequences of postponing or discontinuing standard palliative treatment by a medical oncologist prior to enrolment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: repetitive ePIPAC-OX

Combination product: repetitive ePIPAC-OX; Instead of standard palliative treatment, enrolled patients receive laparoscopy-controlled electrostatic pressurised intraperitoneal aerosol chemotherapy with oxaliplatin (ePIPAC-OX) (92 mg/m2 body-surface area [BSA]) with intravenous leucovorin (20 mg/m2 BSA) and bolus 5-fluorouracil (400 mg/m2 BSA) every six weeks. Four weeks after each procedure, patients undergo clinical, radiological, and biochemical evaluation. ePIPAC-OX is repeated until clinical, radiological, or macroscopic disease progression, after which standard palliative treatment is (re)considered.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major toxicity	Number of patients with Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grade III-V, up to 4 weeks after the last ePIPAC-OX	Expected (in case of three ePIPAC-OX): 16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Minor toxicity	Number of patients with Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grade II, up to 4 weeks after the last ePIPAC-OX	Expected (in case of three ePIPAC-OX): 16 weeks
Organ-specific toxicity	Number of patients that develops bone marrow, kidney, or liver function disorders, up to four weeks after the last ePIPAC-OX	Expected (in case of three ePIPAC-OX): 16 weeks
Major postoperative complications	Number of patients with Clavien-Dindo grade III-V postoperative complications, up to four weeks after the last ePIPAC	Expected (in case of three ePIPAC-OX): 16 weeks
Minor postoperative complications	Number of patients with Clavien-Dindo grade II postoperative complications, up to four weeks after the last ePIPAC-OX	Expected (in case of three ePIPAC-OX): 16 weeks
Hospital stay	Number of days between ePIPAC-OX and initial discharge, up to four weeks after the last ePIPAC-OX	Expected (in case of three ePIPAC-OX): 16 weeks
Readmissions	Number of hospital admissions after initial discharge after ePIPAC-OX, up to four weeks after the last ePIPAC-OX	Expected (in case of three ePIPAC-OX): 16 weeks
Radiological tumour response	Number of patients with radiological response/stable disease/progression, based on central review of thoracoabdominal CT and diffusion-weighted MRI at baseline and four weeks after each ePIPAC-OX, performed by two independent radiologists blinded to clinical outcomes (classification not defined a priori)	Expected (in case of three ePIPAC-OX): 16 weeks
Histopathological tumour response	Peritoneal Regression Grading Score (PRGS), based on central review of collected peritoneal biopsies during each ePIPAC-OX, performed by two independent pathologists blinded to clinical outcomes	Expected (in case of three ePIPAC-OX): 12 weeks
Cytological tumour response	Number of patients with positive/negative cytology, based on collected ascites or peritoneal washing cytology during each ePIPAC-OX	Expected (in case of three ePIPAC-OX): 12 weeks
Macroscopic tumour response	Peritoneal Cancer Index and ascites volume during each ePIPAC-OX	Expected (in case of three ePIPAC-OX): 12 weeks
Biochemical tumour response	Tumour marker value measured at baseline, each postoperative day, and four weeks after each ePIPAC-OX	Expected (in case of three ePIPAC-OX): 16 weeks
Quality of life: EQ-5D-5L	EQ-5D-5L at baseline and one and four weeks after each ePIPAC-OX	Expected (in case of three ePIPAC-OX): 16 weeks
Quality of life: QLQ-C30	QLQ-C30 at baseline and one and four weeks after each ePIPAC-OX	Expected (in case of three ePIPAC-OX): 16 weeks
Quality of life: QLQ-CR29	QLQ-CR29 at baseline and one and four weeks after each ePIPAC-OX	Expected (in case of three ePIPAC-OX): 16 weeks
Costs	Costs of treatment, based on questionnaires (iMTA PCQ, iMTA MCQ) four weeks after each ePIPAC-OX, derived from the Dutch costing guidelines for health care research at the time of analysis	Expected (in case of three ePIPAC-OX): 16 weeks
Progression-free survival	Time between enrolment and clinical, radiological, or macroscopic progression, or death	24 months
Overall survival	Time between enrolment and death	24 months
Environmental safety of ePIPAC-OX	Platinum concentrations in the air of the operating room and on the surface of the operating room during ePIPAC-OX	1 week (measured only during the first three procedures in the study)
Pharmacokinetics	Platinum concentrations in plasma and plasma ultrafiltrate (collected before ePIPAC-OX and 5, 10, 20, 30, 60, 120, 240, 360, and 1080 minutes after oxaliplatin injection), urine (collected before ePIPAC-OX and on postoperative days 1, 3, 5, and 7), and two pieces of normal peritoneum and two peritoneal metastases collected during each ePIPAC-OX.	Expected (in case of three ePIPAC-OX): 13 weeks
Procedure-related characteristics: intraoperative complications	Number of procedures with intraoperative complications determined during each ePIPAC-OX	Expected (in case of three ePIPAC-OX): 12 weeks
Procedure-related characteristics: adhesions	Zühlke score determined during each ePIPAC-OX	Expected (in case of three ePIPAC-OX): 12 weeks
Procedure-related characteristics: operating time	Operating time in minutes determined during each ePIPAC-OX	Expected (in case of three ePIPAC-OX): 12 weeks
Procedure-related characteristics: blood loss	Blood loss in minutes determined during each ePIPAC-OX	Expected (in case of three ePIPAC-OX): 12 weeks

Collaborators and Investigators

• Sponsor: Koen Rovers
• Investigators: Study Chair: Ignace de Hingh, MD, PhD, Catharina Hospital, Eindhoven, Netherlands; Principal Investigator: Djamila Boerma, MD, PhD, St Antonius Hospital, Nieuwegein, Netherlands

Publications and helpful links

General Publications

• Giger-Pabst U, Tempfer CB. How to Perform Safe and Technically Optimized Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC): Experience After a Consecutive Series of 1200 Procedures. J Gastrointest Surg. 2018 Dec;22(12):2187-2193. doi: 10.1007/s11605-018-3916-5. Epub 2018 Aug 21.
• Tempfer C, Giger-Pabst U, Hilal Z, Dogan A, Rezniczek GA. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) for peritoneal carcinomatosis: systematic review of clinical and experimental evidence with special emphasis on ovarian cancer. Arch Gynecol Obstet. 2018 Aug;298(2):243-257. doi: 10.1007/s00404-018-4784-7. Epub 2018 Jun 4.
• Grass F, Vuagniaux A, Teixeira-Farinha H, Lehmann K, Demartines N, Hubner M. Systematic review of pressurized intraperitoneal aerosol chemotherapy for the treatment of advanced peritoneal carcinomatosis. Br J Surg. 2017 May;104(6):669-678. doi: 10.1002/bjs.10521.
• Lurvink RJ, Rovers KP, Wassenaar ECE, Bakkers C, Burger JWA, Creemers GM, Los M, Mols F, Wiezer MJ, Nienhuijs SW, Boerma D, de Hingh IHJT. Patient-reported outcomes during repetitive oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy for isolated unresectable colorectal peritoneal metastases in a multicenter, single-arm, phase 2 trial (CRC-PIPAC). Surg Endosc. 2022 Jun;36(6):4486-4498. doi: 10.1007/s00464-021-08802-6. Epub 2021 Nov 10.
• Rovers KP, Wassenaar ECE, Lurvink RJ, Creemers GM, Burger JWA, Los M, Huysentruyt CJR, van Lijnschoten G, Nederend J, Lahaye MJ, Deenen MJ, Wiezer MJ, Nienhuijs SW, Boerma D, de Hingh IHJT. Pressurized Intraperitoneal Aerosol Chemotherapy (Oxaliplatin) for Unresectable Colorectal Peritoneal Metastases: A Multicenter, Single-Arm, Phase II Trial (CRC-PIPAC). Ann Surg Oncol. 2021 Sep;28(9):5311-5326. doi: 10.1245/s10434-020-09558-4. Epub 2021 Feb 5.
• Lurvink RJ, Tajzai R, Rovers KP, Wassenaar ECE, Moes DAR, Pluimakers G, Boerma D, Burger JWA, Nienhuijs SW, de Hingh IHJT, Deenen MJ. Systemic Pharmacokinetics of Oxaliplatin After Intraperitoneal Administration by Electrostatic Pressurized Intraperitoneal Aerosol Chemotherapy (ePIPAC) in Patients with Unresectable Colorectal Peritoneal Metastases in the CRC-PIPAC Trial. Ann Surg Oncol. 2021 Jan;28(1):265-272. doi: 10.1245/s10434-020-08743-9. Epub 2020 Jun 22.
• Rovers KP, Lurvink RJ, Wassenaar EC, Kootstra TJ, Scholten HJ, Tajzai R, Deenen MJ, Nederend J, Lahaye MJ, Huysentruyt CJ, van 't Erve I, Fijneman RJ, Constantinides A, Kranenburg O, Los M, Thijs AM, Creemers GM, Burger JW, Wiezer MJ, Boerma D, Nienhuijs SW, de Hingh IH. 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 Jul 27;9(7):e030408. doi: 10.1136/bmjopen-2019-030408.

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 1, 2017
• Primary Completion (ACTUAL): October 1, 2019
• Study Completion (ACTUAL): October 1, 2019

Study Registration Dates

• First Submitted: August 2, 2017
• First Submitted That Met QC Criteria: August 8, 2017
• First Posted (ACTUAL): August 11, 2017

Study Record Updates

• Last Update Posted (ACTUAL): October 15, 2019
• Last Update Submitted That Met QC Criteria: October 14, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: Survival; Quality of Life; Fluorouracil; Platinum; Costs and Cost Analysis; Mortality; Antineoplastic Agents; Drug-Related Side Effects and Adverse Reactions; Colorectal Neoplasms; Oxaliplatin; Leucovorin; Postoperative Complications; Laparoscopy; Peritoneum; Aerosols; Disease-free survival; Pressurized Intraperitoneal Aerosol Chemotherapy; Intraoperative Complications; PIPAC; Translational Medical Research; Peritoneal Neoplasms; Intraperitoneal Injections; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials, Phase II as topic; Pressurised Intraperitoneal Aerosol Chemotherapy; Cecal Neoplasms
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Peritoneal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Abdominal Neoplasms; Cecal Diseases; Cecal Neoplasms; Neoplasms; Carcinoma; Colorectal Neoplasms; Peritoneal Neoplasms; Appendiceal Neoplasms
• Other Study ID Numbers: NL60405.100.17 (OTHER: Dutch Competent Authority); 2017-000927-29 (EUDRACT_NUMBER); NTR6603 (REGISTRY: NTR); ISRCTN89947480 (REGISTRY: ISRCTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Available on request
• IPD Sharing Time Frame: End of the study
• IPD Sharing Access Criteria: Available on request
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No