Condition category
Cancer
Date applied
26/04/2016
Date assigned
11/05/2016
Last edited
02/09/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Background and study aims
Surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment option for patients with colon and rectal cancer with metastases in the peritoneum (addominal cavity). During this treatment, all visible metastases in the abdomen are removed. Subsequently, the abdominal (peritoneal) cavity is filled with chemotherapy drugs that have been heated, in order to destroy remaining invisible tumour cells in the abdomen. Nowadays, some patients also receive chemotherapy before or after surgery with HIPEC. However, many doctors worldwide do not agree about the benefit of chemotherapy in these patients, since it has never been investigated. However, it has potential benefits. Chemotherapy before HIPEC is thought to make the tumour(s) smaller, so it is easier to remove during surgery. Chemotherapy after HIPEC is thought to stop the cancer from coming back by destroying invisible tumour cells that may be left behind in the body. This study aims to investigate the potential benefit of chemotherapy before and after surgery for patients with colon/rectal cancer and metastases in the peritoneum who undergo surgery with HIPEC.

Who can participate?
Patients aged 18 and over with colon cancer and metastases in the peritoneum, who are candidate for surgery with HIPEC.

What does the study involve?
Participants are randomly allocated into two groups. One group receives the standard treatment of surgery with HIPEC: the control arm. The other group receives preoperative before surgery) chemotherapy, followed by surgery with HIPEC, followed by postoperative (after surgery) chemotherapy: the experimental arm. The used chemotherapy drugs are standard drugs for colon cancer with metastases.

What are the possible benefits and risks of participating?
In the experimental arm, the most important possible benefit of the experimental treatment is a prolonged life expectancy. The most important risks of the experimental arm are the side effects of chemotherapy. In the control arm, the most important possible risk is a reduced life expectancy.

Where is the study run from?
1. Catharina Hospital (Eindhoven, the Netherlands)
2. VU University Medical Centre (Amsterdam, the Netherlands)
3. Antoni van Leeuwenhoek Hospital (Amsterdam, the Netherlands)
4. Erasmus University Medical Centre (Rotterdam, the Netherlands)
5. University Medical Centre Groningen (Groningen, the Netherlands)
6. University Medical Centre Utrecht (Utrecht, the Netherlands)
7. Radboud University Medical Center (Nijmegen, the Netherlands)
8. Sint Antonius Hospital (Nieuwegein, the Netherlands)
9. Medisch Spectrum Twente (Enschede, the Netherlands)

When is the study starting and how long is it expected to run for?
January 2017 to January 2026

Who is funding the study?
Roche Netherlands B.V.

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

Trial website

Contact information

Type

Scientific

Primary contact

Dr Koen P.B. Rovers

ORCID ID

Contact details

PO Box 1350
Eindhvoen
5602 ZA
Netherlands
+31 (0)402 396 350
koen.rovers@catharinaziekenhuis.nl

Additional identifiers

EudraCT number

2016-001865-99

ClinicalTrials.gov number

NCT02758951

Protocol/serial number

NL57644.100.16

Study information

Scientific title

Investigating the benefit of perioperative systemic therapy in patients undergoing cytoreductive surgery with HIPEC for peritoneal metastases of colorectal cancer: the multicentre, phase II-III, prospective, randomised CAIRO6 study.

Acronym

CAIRO6

Study hypothesis

Perioperative systemic therapy and cytoreductive surgery with HIPEC will result in an overall survival benefit compared to cytoreductive surgery and HIPEC alone in patients with peritoneal metastases of colorectal cancer.

Ethics approval

Not provided at time of registration

Study design

Interventional open-label multicentre phase II-III prospective randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

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

Colorectal cancer, colon cancer, rectal cancer, peritoneal cancer, peritoneal metastases, peritoneal carcinomatosis, colorectal peritoneal metastases, colorectal peritoneal carcinomatosis, colorectal carcinomatosis

Intervention

As of 02/09/2016:
Experimental arm:
1. Patients in the experimental arm will receive neoadjuvant combination chemotherapy plus bevacizumab for three 3-weekly (CAPOX + BEV) or four 2-weekly (FOLFOX + BEV) cycles, followed by restaging with thoraco-abdominal CT-scan. In case of progressive and unresectable disease, the best possible palliative treatment will be offered. In case of progressive but resectable disease, patients will undergo explorative laparotomy and subsequent cytoreductive surgery with HIPEC at least 6 weeks after the last cycle of bevacizumab is administered. In case of responsive or stable disease, one 3-weekly (CAPOX) or two 2-weekly (FOLFOX) neoadjuvant cycles of combination chemotherapy without bevacizumab will be administered. Subsequently, not earlier than 3 weeks after the last day of the last cycle of combination chemotherapy, explorative laparotomy and subsequent cytoreductive surgery with HIPEC will be performed.
2. Cytoreductive surgery with HIPEC.
3. Adjuvant systemic therapy: Only in patients with stable disease or response upon neoadjuvant treatment, adjuvant combination chemotherapy will be given according to the neoadjuvant regimen, but without bevacizumab, for four 3-weekly cycles (CAPOX) or six 2-weekly cycles (FOLFOX).

Control arm:
1. Cytoreductive surgery with HIPEC

Initial
Experimental arm:
1. Neoadjuvant systemic therapy: Combination chemotherapy with the addition of bevacizumab for three 3-weekly (CAPOX + Bevacizumab) or four 2-weekly (FOLFOX + BEV) cycles, followed by restaging with thoracoabdominal CT-scan. In case of progressive disease, the best possible treatment will be offered. In case of responsive or stable disease, one 3-weekly (CAPOX) or two 2-weekly (FOLFOX) additional cycles of combination chemotherapy alone will be administered.
2. Cytoreductive surgery and HIPEC.
3. Adjuvant systemic therapy: Combination chemotherapy for four 3-weekly (CAPOX) or six 2-weekly (FOLFOX) cycles.

Control arm:
1. Cytoreductive surgery and HIPEC

Intervention type

Drug

Phase

Phase II/III

Drug names

1. 5-Fluorouracil; 5-FU; Fluorouracil; L01BC02
2. Leucovorin; Calcium Folinate; V03AF03
3. Oxaliplatin; L01XA03
4. Capecitabine; Xeloda; L01BC06
5. Irinotecan; L01XX19
6. Bevacizumab; Avastin; L01XC07

Primary outcome measures

As of 02/09/2016:
1. Primary outcome of the phase II study (n=80): major postoperative complications, defined as Clavien-Dindo grade III-V, at 90 days postoperatively.
2. Primary outcome of the phase III study (n=340): overall survival after 3-years follow-up.

Initial
1. Primary outcome of the phase II study (n=80): major morbidity, defined as Clavien-Dindo grade III-V, at 90 days post-op
2. Primary outcome of the phase III study (n=340): 3-year overall survival (regular oncological follow-up at 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54 and 60 months post-op)

Secondary outcome measures

As of 02/09/2016:
1.Secondary outcome of the phase II study (n=80):
1.1 feasibility of randomisation, defined as inclusion of 80 patients 1 year after the start of accrual at the last participating centre.
1.2 Minor postoperative complications, defined as Clavien-Dindo grade II, at 90 days postoperatively.
1.3 Systemic therapy related toxicity, defined as NCICTCAE v4.0 grade II-V.
2. Secondary outcomes of the phase III study (n=340):
2.1. 5-year overall survival
2.2. 3-year and 5-year disease-free survival
2.3. Procedure-related characteristics of cytoreductive surgery with HIPEC (i.e. operating time, blood loss)
2.4. Peritoneal Cancer Index (PCI) at start of cytoreductive surgery.
2.5. Completeness of Cytoreduction (CC) Score directly after cytoreductive surgery
2.6. Severe postoperative complications, defined as Clavien-Dindo ≥3 at 90 days postoperatively
2.7. Postoperative mortality at 90 days postoperatively.
2.8. Hospital stay, until 12 months postoperatively.
2.9. Quality of life (EQ5D questionnaire, EORTC QLQ C30 questionnaire, EORTC QLQ CR29 questionnaire) at inclusion, and 3, 6, 12, 24, 36 and 60 months postoperatively.
2.10. Cost-effectiveness (iMTA Productivity Cost Questionnaire, iMTA Medical Consumption Questionnaire) at inclusion, and 3, 6, 12, 24, 36 and 60 months postoperatively.
2.11. Severe systemic therapy related toxicity (NCICTCAE v4.0 grade 3-5) of neoadjuvant combination chemotherapy with bevacizumab (experimental arm)
2.12. Severe systemic therapy related toxicity (NCICTCAE v4.0 grade 3-5) of adjuvant combination chemotherapy (experimental arm)
2.13. Number of patients with disease progression, stable disease, or responsive disease to neoadjuvant combination chemotherapy/bevacizumab.

Initial
1. Secondary outcome of the phase II study (n=80): feasibility of randomisation, defined as inclusion of 80 patients in 1 year after the start of accrual at the last participating centre
2. Secondary outcomes of the phase III study (n=340):
2.1. 5-year overall survival (regular oncological follow-up at 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54 and 60 months post-op)
2.2. 3-year and 5-year disease-free survival (regular oncological follow-up at 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54 and 60 months post-op)
2.3. Procedure-related characteristics of CRS + HIPEC (i.e. operating time, blood loss)
2.4. Peritoneal Cancer Index (PCI) Score during diagnostic laparoscopy and directly after laparotomy
2.5. Completeness of Cytoreduction (CC) Score directly after cytoreductive surgery
2.6. Treatment-related severe postoperative complications, defined as Clavien-Dindo ≥3 (in-hospital, 30-day, 90-day)
2.7. Treatment-related postoperative complications, defined as Clavien-Dindo <3 (in-hospital, 30-day, 90-day)
2.8. Treatment-related mortality (in-hospital, 30-day, 90-day)
2.9. ICU stay and hospital stay
2.10. Quality of life (EQ5D questionnaire, EORTC QLQ C30 questionnaire, EORTC QLQ CR29 questionnaire) at 6, 12, 36 and 60 months post-op
2.11. Cost-effectiveness (iMTA Productivity Cost Questionnaire, iMTA Medical Consumption Questionnaire) at 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57 and 60 months post-op
2.12. % of patients able to complete their full neoadjuvant treatment, and reasons for not completing and/or dose reduction (experimental arm)
2.13. % of patients able to complete their full adjuvant treatment, and reasons for not completing and/or dose reduction (experimental arm)
2.14. Treatment-related toxicity of neoadjuvant systemic treatment (experimental arm)
2.15. Treatment-related toxicity of adjuvant systemic treatment (experimental arm)
2.16. % of patient eligible for CRS + HIPEC after neoadjuvant treatment (experimental arm)
2.17. Overall survival in patients with progressive disease during neoadjuvant therapy (experimental arm) at 3 and 5 years after diagnosis with PMCRC
2.18. Morphological tumour response to neoadjuvant systemic therapy (experimental arm) after 3 (CAPOX + Bevacizumab) or 4 (FOLFOC + Bevacizumab) courses of neoadjuvant systemic therapy
2.19. Pathological tumour response to neoadjuvant systemic therapy (experimental arm) (Mandard score)

Overall trial start date

01/01/2017

Overall trial end date

01/01/2026

Reason abandoned

Eligibility

Participant inclusion criteria

1. Peritoneal Cancer Index (PCI) score ≤20, determined by diagnostic staging laparoscopy
2. Achievability of complete cytoreduction, determined by diagnostic staging laparoscopy
3. Pathological confirmation of non-signet adenocarcinoma in peritoneal deposits or ascites
4. 18 years or older
5. WHO performance score 0-1
6. Adequate clinical condition to undergo CRS + HIPEC and neoadjuvant systemic therapy within 4 and 3 weeks after staging laparoscopy, respectively
7. Neutrophil count of at least 3.000/mm3, platelet count of at least 100,000/mm3 (<3 months before inclusion)
8. No bleeding diathesis or coagulopathy
9. Normal creatinine or creatinine clearance, determined by the MDRD-formula, of at least 50 ml/min (<3 months before inclusion)
10. Written informed consent
11. Expected adequacy of follow-up

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

340

Participant exclusion criteria

As of 02/09/2016:
1. Signet ring cell histology (>50% of the cells have signet ring cell histology) of the primary tumour.
2. Systemic metastases (i.e. liver, lung)
3. Known pregnancy or lactation.
4. Known unstable or uncompensated respiratory or cardiac disease.
5. Serious active infections.
6. Adjuvant chemotherapy after primary resection of colorectal cancer used within 6 months prior to randomisation.
7. Any condition not allowing the safe administration of the planned systemic treatment (bevacizumab, 5-fluorouracil, leucovorin, capecitabine, oxaliplatin, irinotecan).
8. Stomatitis, ulceration in the mouth or gastrointestinal tract.
9. Severe diarrhoea.
10. Known pernicious anaemia or other anaemias due to vitamin B12 deficiency.
11. Known previous peripheral sensory neuropathy with functional impairment after previous use of oxaliplatin.
12. Impaired liver function (serum bilirubin ≤2 x ULN, serum transaminases ≤5 x ULN), assessment only if indicated.
13. Known dihydropyrimidine dehydrogenase deficiency, determined by dihydropyrimidine dehydrogenase genotyping.

Initial
1. Signet ring cell histology (>50% of the cells have signet ring cell histology) of the primary tumour
2. Pregnant or lactating women
3. Unstable or uncompensated respiratory or cardiac disease
4. Serious active infections
5. Other concurrent chemotherapy used within 6 months prior to inclusion
6. Any condition not allowing the safe administration of the planned systemic treatment (bevacizumab, fluorouracil, folinic acid, capecitabine or oxaliplatin/irinotecan)
7. Stomatitis, ulceration in the mouth or gastrointestinal tract
8. Severe diarrhoea
9. Severe hepatic and/or renal dysfunction
10. Plasma bilirubin concentrations greater than 85 μmol/L

Recruitment start date

01/01/2017

Recruitment end date

01/01/2021

Locations

Countries of recruitment

Netherlands

Trial participating centre

Catharina Hospital
PO Box 1350
Eindhoven
5602 ZA
Netherlands

Trial participating centre

Medisch Spectrum Twente
PO Box 50000
Enschede
7500 KA
Netherlands

Trial participating centre

VU University Medical Centre
PO Box 7057
Amsterdam
1007 MB
Netherlands

Trial participating centre

Antoni van Leeuwenhoek Hospital
PO Box 90203
Amsterdam
1006 BE
Netherlands

Trial participating centre

Erasmus University Medical Centre
PO Box 2040
Rotterdam
3000 CA
Netherlands

Trial participating centre

University Medical Centre Groningen
PO Box 30001
Groningen
9700 RB
Netherlands

Trial participating centre

University Medical Centre Utrecht
PO Box 85500
Utrecht
3508 GA
Netherlands

Trial participating centre

Radboud University Medical Center
PO Box 9101
Nijmegen
6500 HB
Netherlands

Trial participating centre

Sint Antonius Hospital
PO Box 2500
Nieuwegein
3430 EM
Netherlands

Sponsor information

Organisation

Catharina Hospital (Netherlands)

Sponsor details

Michelangelolaan 2
Eindhoven
5623 EJ
Netherlands
+31 (0)402 396 350
koen.rovers@catharinaziekenhuis.nl

Sponsor type

Hospital/treatment centre

Website

www.catharinaziekenhuis.nl

Funders

Funder type

Industry

Funder name

Roche Netherlands B.V.

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

1. Results of the phase II trial will be published after the first 80 patients completed their 90 day follow-up.
2. Results of the phase III trial will be published after 340 patients completed their 3-year and 5-year follow-up

Intention to publish date

01/10/2018

Participant level data

To be made available at a later date

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

02/09/2016: Changed scientific title from "Investigating the role of systemic therapy in patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal metastases of colorectal cancer: the multicenter, phase II-III, prospective, randomised CAIRO-6 trial". Made amendments to interventions, outcome measures and exclusion criteria as time stamped in the relevant field. Removed "Academic Medical Centre" as trial participating centre and added "Medisch Spectrum Twente". Changed overall start date from 01/11/2016 to 01/01/2017. Changed overall end date from 01/11/2025 to 01/01/2026. Changed recruitment start date from 01/11/2016 to 01/01/2017. Changed recruitment end date from 01/11/2020 to 01/01/2021.