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PIPAC for peritoneal metastases of colorectal cancer


- candidate number27709
- NTR NumberNTR6603
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR1-aug-2017
- Secondary IDsNL60405.100.17 2017-000927-29
- Public TitlePIPAC for peritoneal metastases of colorectal cancer
- Scientific TitleSafety, feasibility, tolerability, and preliminary oncological efficacy of upfront repeated laparoscopic PIPAC with oxaliplatin and simultaneous intravenous bolus 5-fluorouracil/leucovorin for isolated unresectable colorectal peritoneal metastases: a single center, single arm phase I/II study
- ACRONYMCRC-PIPAC
- hypothesisUpfront repeated laparoscopic PIPAC with oxaliplatin and simultaneous intravenous bolus 5-fluorouracil/leucovorin is a safe, feasible, and tolerable treatment for patients with isolated unresectable peritoneal metastases, with a potentially higher preliminary oncological efficacy than standard palliative systemic therapy
- Healt Condition(s) or Problem(s) studiedColorectal cancer, Colorectal metastised cancer, Peritoneal metastasis
- Inclusion criteria- Adult
- Histologically confirmed unresectable peritoneal metastases of a colorectal or appendiceal carcinoma;
- Asymptomatic presentation (i.e. no disabling malignant ascites or obstructive symptoms);
- WHO performance score 0-1;
- Written informed consent.
- Exclusion criteria- Radiological evidence of extra-abdominal metastatic disease;
- Inadequate organ functions (hemoglobin <5.0 mmol/L, absolute neutrophil count <1.5 x 10(9)/L, platelet count <100 x 10(9)/L, serum creatinine >1.5 x ULN, creatinine clearance <30 ml/min, liver transaminases >5 x ULN).
- Known pregnancy or lactation;
- Known unstable or uncompensated respiratory or cardiac disease;
- Known bleeding diathesis or coagulopathy;
- Serious active infections;
- Any other condition not allowing for a safe laparoscopy or a safe administration of oxaliplatin, 5-fluorouracil, or leucovorin;
- Enrolment in another clinical study;
- mec approval receivedyes
- multicenter trialno
- randomisedno
- group[default]
- TypeSingle arm
- Studytypeintervention
- planned startdate 1-okt-2017
- planned closingdate1-okt-2019
- Target number of participants20
- InterventionsInstead of standard palliative systemic therapy, patients receive upfront laparoscopic PIPAC with oxaliplatin (92 mg/m2) and simultaneous intravenous bolus 5-fluorouracil/leucovorin (400/20 mg/m2), intentionally repeated with an interval of six weeks until intraperitoneal disease progression, unfitness for laparoscopy, or laparoscopic non-access. In case of intraperitoneal disease progression, unfitness for laparoscopy, or laparoscopic non-access, patients intentionally receive standard palliative systemic therapy, while further PIPAC-procedures are cancelled. In case of systemic disease progression with intraperitoneal disease response or stable disease, patients intentionally receive standard palliative systemic therapy, while further PIPAC-procedures are intentionally continued until intraperitoneal disease progression, unfitness for laparoscopy, or laparoscopic non-access.
- Primary outcome- Outcome: Major mobidity
- Method: Common Terminology Criteria for Adverse Events grade III-V, measured after each PIPAC-procedure up to 4 weeks after the last PIPAC-procedure
- Timepoint: 6 to 12 months
- Secondary outcome- Outcome: Platinum concentrations in the air of the operating room
- Method: Stationary measurements in the operating room and personal measurements at the working places of the personnel (e.g. surgeon, anesthesiologist) and at the position of the patient, measured during the first 3-5 PIPAC-procedures, depending on findings
- Timepoint: 1 to 2 months

- Outcome: Platinum concentrations on surfaces in the operating room
- Method: Measurements on the surface of equipment and devices (e.g. high pressure injector, filter system) and personal measurements at the working places of the personnel (e.g. clothing, gloves) and at the position of the patient, measured during the first 3-5 PIPAC-procedures, depending on findings
- Timepoint: 1 to 2 months

- Outcome: Platinum concentrations in plasma of the patient
- Method: Total and ultrafiltrated plasma concentrations of platinum, measured at t=0, t=0.5, t=0.75, t=1, t=2, t=4, t=6, and t=8 hours after start of oxaliplatin injection during/after the first 10-20 PIPAC-procedures, depending on findings
Timepoint: 2 to 4 months

- Outcome: Platinum concentrations in excretes (urine, saliva) of the patient
- Method: Measured at t=1, t=3, t=5, and t=7 days after the first 10-20 PIPAC-procedures, depending on findings
- Timepoint: 2 to 4 months

- Outcome: Intraoperative characteristics
- Method: Laparoscopic (non-)access, amount of adhesions (Zühlke), ascites volume (ml), blood loss (ml), operating time (minutes), any intraoperative complications (e.g. bleeding, perforation), and any PIPAC-specific technical difficulties, measured during each PIPAC-procedure
- Timepoint: 6 to 12 months

- Outcome: Minor morbidity
- Method: Common Terminology Criteria for Adverse Events grade II, measured after each PIPAC-procedure up to 4 weeks after the last PIPAC-procedure
- Timepoint: 6 to 12 months

- Outcome: Hospital stay
- Method: Days between PIPAC-procedure and discharge, measured after each PIPAC-procedure up to 4 weeks after the last PIPAC-procedure
- Timepoint: 6 to 12 months

- Outcome: Number of readmissions
- Method: Hospital readmission after initial discharge, measured after each PIPAC-procedure up to 4 weeks after the last PIPAC-procedure
- Timepoint: 6 to 12 months

- Outcome: Number of PIPAC-procedures
- Method: Measured in each patient with reasons for discontinuation of further PIPAC-procedures
- Timepoint: 6 to 12 months

- Outcome: Organ functions
- Method: Renal, liver, and haematological function, measured at baseline as well as 12 hours and 4 weeks after each PIPAC-procedure
- Timepoint: 6 to 12 months

- Outcome: Histopathological tumour response
- Method: Assessed with the Peritoneal Regression Scale (PRGS), measured after each second and subsequent PIPAC-procedure
- Timepoint: 6 to 12 months

- Outcome: Macroscopic intraperitoneal tumour response
- Method: Assessed with the Peritoneal Cancer Index (PCI), measured after each second and subsequent PIPAC-procedure
- Timepoint: 6 to 12 months

- Outcome: Tumour markers
- Method: Carcinoembryonic antigen (CEA), measured at baseline as well as 12 hours and 4 weeks after each PIPAC-procedure, and during follow-up every 3 months
- Timepoint: 12 to 24 months

- Outcome: Peritoneal progression free survival
- Method: Time between inclusion and macroscopic intraperitoneal disease progression during a second or subsequent PIPAC, or radiological evidence of intraperitoneal disease progression on CT-scan 4 weeks after each PIPAC or during follow-up every 3 months
- Timepoint: 12 to 24 months

- Outcome: Systemic progression free survival
- Method: Time between inclusion and radiological evidence of systemic disease progression on CT-scan 4 weeks after each PIPAC or during follow-up every 3 months
- Timepoint: 12 to 24 months

- Outcome: Disease-specific survival
- Method: Months between inclusion and death due to colorectal cancer
- Timepoint: 12 to 24 months

- Outcome: Overall survival
- Method: Months between inclusion and death due to any cause
- Timepoint: 12 to 24 months

- Outcome: Quality of life
- Method: Assessed with EQ5D5L, EORTC-QLQC30, and EORTC-QLQCR29, and measured at baseline, 4 weeks after each PIPAC-procedure, and during follow-up every 3 months
- Timepoint: 12 to 24 months

- Outcome: Costs
- Method: Assessed with the iMTA Productivity Cost Questionnaire and iMTA Medical Consumption Questionnaire, and measured at 3, 6, 9, and 12 months after inclusion
- Timepoint: 12 to 24 months

- Outcome: Collection of tissue and ascites for translational research
- Method: During each PIPAC-procedure, ascites or peritoneal fluid is sent for cytology and several peritoneal metastases are biopsied. After processing, these samples are frozen until analysis
- Timepoint: 6 to 12 months

- Outcome: Collection of blood for translational research
- Method: An EDTA tube (10 ml) is drawn at baseline, t=0, t=0.5, t=1, t=2, t=4, t=6, t=8 during/after each PIPAC, 4 weeks after each PIPAC, and during follow-up every 3 months. After processing, these samples are frozen until analysis
- Timepoint: 12 to 24 months
- TimepointsSee sections 'Primary outcome(s)' and 'secondary outcome(s)' above
- Trial web site
- statusplanned
- CONTACT FOR PUBLIC QUERIESDrs. Koen Rovers
- CONTACT for SCIENTIFIC QUERIESDrs. Koen Rovers
- Sponsor/Initiator Catharina Hospital Eindhoven
- Funding
(Source(s) of Monetary or Material Support)
Catharina Hospital Eindhoven,
- Publications
- Brief summarySummary intended for the lay public

Background of study
Approximately a quarter of the patients who are diagnosed with colorectal cancer and metastases have their metastases in the peritoneum, the so called peritoneal metastases. The vast majority of these patients cannot be cured by surgery, frequently due to too many peritoneal metastases. These incurable patients have a very short life expectancy. Nowadays, they are treated with chemotherapy through the veins. However, chemotherapy through the veins appears to be relatively ineffective against peritoneal metastases, probably because it does not reach the peritoneal metastases very well. Chemotherapy through the veins may also cause side effects that are sometimes severe. Recently, doctors developed PIPAC: a short laparoscopic operation during which chemotherapy is sprayed in the abdomen for 30 minutes, directly against the peritoneal metastases. As a result, PIPAC may be more effective against peritoneal metastases than chemotherapy through the veins. It may also have less side effects, because the chemotherapy mainly stays in the abdomen, not in the veins. PIPAC indeed shows promising results in the first European patients with peritoneal metastases of colorectal cancer who have been treated with this operation.

Aim of study
To investigate whether PIPAC is a safe, feasible, tolerable, and potentially effective treatment for patients with peritoneal metastases of colorectal cancer.

Participants
Patients with peritoneal metastases of colorectal cancer, without metastases elsewhere (e.g. liver, lung), who cannot be cured by surgery due to too many peritoneal metastases.

Treatment
Instead of chemotherapy through the veins, participants receive PIPAC. PIPAC is a laparoscopic operation under general anesthesia. The entire operation takes about 90 minutes. After the operation, patients stay in the hospital for at least one night. PIPAC is repeated every 6 weeks. The aim is to perform 3 PIPACs. If the peritoneal metastases respond well to PIPAC, participants may undergo more than 3 PIPACs. Participants may also undergo less than 3 PIPACs: for example if the peritoneal metastases do not respond PIPAC, if laparoscopy is unsafe for the patient, or if the surgeons cannot perform PIPAC due to adhesions in the abdomen. In case no further PIPACs can be performed, participants receive chemotherapy through the veins.

Other appointments
Four weeks after each PIPAC, participants visit the hospital for a CT-scan and an appointment at the oncological outpatient clinic to evaluate whether a next PIPAC can be performed. If not, participants receive chemotherapy through the veins. After the last PIPAC, patients visit the oncological outpatient clinic every 3 months to evaluate how the cancer responds to the treatment.

Potential risks for participants
PIPAC may cause side-effects. The most frequent potential side-effects are pain, nausea, fever, wound infection, diarrhea, obstipation, and minor damages to the kidney, liver, and bone marrow. These side-effects are mostly very mild. Moreover, the risk of side-effects of PIPAC is thought to be lower than the risk of side-effects of chemotherapy through the veins. Severe side-effects of PIPAC are extremely rare. The most important are a bowel perforation or a bleeding during PIPAC. So far, these severe side-effects have not been observed during PIPAC in patients with peritoneal metastases of colorectal cancer.

Potential benefits for participants
PIPAC may potentially be similarly or even more effective against peritoneal metastases than chemotherapy through the veins, with a potential lower risk of side-effects. There may be a small chance (+/- 10%) that the peritoneal metastases become so small that they can be cured by surgery. However, these potential benefits are uncertain. The cancer may deteriorate at any moment during treatment with PIPAC.

Hypothesis of study
The investigators expect that PIPAC is a safe, feasible, and tolerable treatment for patients with peritoneal metastases of colorectal cancer, with a potentially similar or higher efficacy against peritoneal metastases of colorectal cancer compared to chemotherapy through the veins.
- Main changes (audit trail)
- RECORD1-aug-2017 - 13-aug-2017


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