Condition category
Cancer
Date applied
02/08/2017
Date assigned
14/08/2017
Last edited
14/08/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Approximately a quarter of the patients who are diagnosed with colorectal cancer and metastases (when the cancer spreads to other parts of the body) have peritoneal (the tissue that lines the abdominal cavity) 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. This is 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 (a minimially invasive surgery done through a small incision) 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. The aim of this study is to investigate whether PIPAC is a safe, feasible, tolerable, and potentially effective treatment for patients with peritoneal metastases of colorectal cancer.

Who can participate?
Adults with peritoneal metises of colorectal cancer without metastases elsewhere (e.g. liver, lung), who cannot be cured by surgery due to too many peritoneal metastases.

What does the study involve?
Participants undergo the PIPAC procedure. This takes 90 minutes. After the procedure, participants stay in hospital for at least one night. This is repeated every six weeks until participants have three PIPAC procedures. This may be done more or less depending on the participatns response to the procedure. Four weeks after each procedure, participants have a CT-scan to evaluate if they can another PIPAC. If not, they receive the usual chemotherapy treatment. After participants undergo their last PIPAC, they visit the outpatient centre every three months to evaluate how the cancer responds to the treatment.

What are the possible benefits and risks of participating?
Participants may benefit from a similar or more effective treatment against peritoneal metastases than chemotherapy, as well as a lower risk of side-effects. There are risks of side-effects such as pain, nausea, fever, wound infection, diarrhea, obstipation (severe constipation) and minor damage to the kidney, liver and bone marrow. There is a rare risk of bowel perforation or bleeding during PIPAC. These severe side-effects have not been observed during PIPAC in patients with peritoneal metastases of colorectal cancer.

Where is the study run from?
Catharina Hospital (Netherlands)

When is the study starting and how long is it expected to run for?
January 2017 to October 2019

Who is funding the study?
Catharina Hospital (Netherlands)

Who is the main contact?
Dr Koen Rovers
koen.rovers@catharinaziekenhuis.nl

Trial website

Contact information

Type

Scientific

Primary contact

Dr Koen Rovers

ORCID ID

Contact details

Catharina Hospital
Department of Surgery
PO Box 1350
Eindhoven
5602 ZA
Netherlands
+31 402396350
koen.rovers@catharinaziekenhuis.nl

Additional identifiers

EudraCT number

2017-000927-29

ClinicalTrials.gov number

Protocol/serial number

NL60405.100.17

Study information

Scientific title

Safety, 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

Acronym

CRC-PIPAC

Study hypothesis

Upfront repeated laparoscopic PIPAC with oxaliplatin and simultaneous intravenous bolus 5-fluorouracil/leucovorin is a safe, feasible, and tolerable treatment for patients with isolated unresectable colorectal peritoneal metastases, with a potentially higher preliminary oncological efficacy compared to standard palliative systemic therapy.

Ethics approval

Ethics board: Medical Research Ethics Committees United, 31/07/2017, ref: R17.038

Study design

Interventional single arm single center phase I-II study

Primary study design

Interventional

Secondary study design

Non randomised study

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Isolated unresectable colorectal peritoneal metastases

Intervention

Instead 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.

After the last PIPAC-procedure, patients are radiologically and biochemically evaluated at the oncological outpatient clinic every 3 months for a total of 3 times. Thereafter, patients enter regular oncological follow-up according to local protocol.

Intervention type

Mixed

Phase

Drug names

Primary outcome measures

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 . Expected timepoint: +/- 16 weeks after inclusion.

Secondary outcome measures

1. 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. Expected timepoint: +/- 1 week after inclusion.
2. 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. Expected timepoint: +/- 1 week after inclusion.
3. 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. Expected timepoint: +/- 1 week after inclusion.
4. Platinum concentrations in excretes (urine, saliva) of the patient. Method: concentrations at t=1, t=3, t=5, and t=7 days after the first 10-20 PIPAC-procedures, depending on findings. Expected timepoint: +/- 1 week after inclusion.
5. 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. Expected timepoint: +/- 12 weeks after inclusion.
6. 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. Expected timepoint: +/- 16 weeks after inclusion.
7. Hospital stay. Method: time between PIPAC-procedure and discharge, measured after each PIPAC-procedure up to 4 weeks after the last PIPAC-procedure. Expected timepoint: +/- 16 weeks after inclusion.
8. Number of readmissions. Method: hospital readmission after initial discharge, measured after each PIPAC-procedure up to 4 weeks after the last PIPAC-procedure. Expected timepoint: +/- 16 weeks after inclusion.
9. Number of PIPAC-procedures. Method: measured in each patient with reasons for discontinuation of further PIPAC-procedures. Expected timepoint: +/- 52 weeks after inclusion.
10. Organ functions. Method: renal, liver, and haematological function, measured at baseline as well as 12 hours and 4 weeks after each PIPAC-procedure. Expected timepoint: +/- 16 weeks after inclusion.
11. Histopathological tumour response. Method: Peritoneal Regression Scale (PRGS), measured after each second and subsequent PIPAC-procedure. Expected timepoint: +/- 12 weeks after inclusion.
12. Macroscopic intraperitoneal tumour response. Method: Peritoneal Cancer Index (PCI), measured after each second and subsequent PIPAC-procedure. Expected timepoint: +/- 12 weeks after inclusion.
13. Tumour markers. Method: carcinoembryonic antigen, measured at baseline as well as 12 hours and 4 weeks after each PIPAC-procedure, and during follow-up every 3 months. Expected timepoint: +/- 52 weeks after inclusion.
14. Peritoneal progression free survival. Method: time between inclusion and macroscopic intraperitoneal disease progression during a second or subsequent PIPAC, or time between inclusion and radiological evidence of intraperitoneal disease progression on CT-scan 4 weeks after each PIPAC or during follow-up every 3 months. Expected timepoint: +/- 52 weeks after inclusion.
15. 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. Expected timepoint: +/- 52 weeks after inclusion.
16. Disease-specific survival. Method: time between inclusion and death due to colorectal cancer. Expected timepoint: +/- 52 weeks after inclusion.
17. Overall survival. Method: time between inclusion and death due to any cause. Expected timepoint: +/- 52 weeks after inclusion.
18. Quality of life. Method: EQ5D5L, EORTC-QLQC30, and EORTC-QLQCR29, measured at baseline, 4 weeks after each PIPAC-procedure, and during follow-up every 3 months. Expected timepoint: +/- 52 weeks after inclusion.
19. Costs. Method: iMTA Productivity Cost Questionnaire and iMTA Medical Consumption Questionnaire, measured at 3, 6, 9, and 12 months after inclusion. Expected timepoint: +/- 52 weeks after inclusion.
20. 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. Expected timepoint: +/- 12 weeks after inclusion.
21. Collection of blood for translational research. Method: an EDTA tube (10 ml) is drawn, processed, and frozen 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. Expected timepoint: +/- 52 weeks after inclusion.

Overall trial start date

01/01/2017

Overall trial end date

01/10/2019

Reason abandoned

Eligibility

Participant inclusion criteria

1. Histologically confirmed unresectable peritoneal metastases of a colorectal or appendiceal carcinoma
2. Asymptomatic presentation (i.e. no disabling malignant ascites or obstructive symptoms)
3. WHO performance score 0-1
4. Written informed consent

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

20

Participant exclusion criteria

1. Radiological evidence of extra-abdominal metastatic disease
2. 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)
3. Known pregnancy or lactation
4. Known unstable or uncompensated respiratory or cardiac disease
5. Known bleeding diathesis or coagulopathy
6. Serious active infections
7. Any other condition not allowing for a safe laparoscopy or a safe administration of oxaliplatin, 5-fluorouracil, or leucovorin
8. Enrolment in another clinical study

Recruitment start date

01/10/2017

Recruitment end date

01/10/2018

Locations

Countries of recruitment

Netherlands

Trial participating centre

Catharina Hospital
Michelangelolaan 2
Eindhoven
5623 EJ
Netherlands

Sponsor information

Organisation

Catharina Hospital

Sponsor details

Michelangelolaan 2
Eindhoven
5623 EJ
Netherlands

Sponsor type

Hospital/treatment centre

Website

https://www.catharinaziekenhuis.nl/

Funders

Funder type

Hospital/treatment centre

Funder name

Catharina Hospital

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Results are published in peer-reviewed journals and presented on scientific congresses, most likely journals and congresses that focus on surgery, oncology, and gastroenterology.

IPD sharing statement:
The datasets generated during and/or analysed during the current study are/will be available upon request from Koen Rovers, koen.rovers@catharinaziekenhuis.nl

Intention to publish date

01/10/2019

Participant level data

Available on request

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes