Condition category
Cancer
Date applied
26/04/2016
Date assigned
11/05/2016
Last edited
04/05/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Cancer of the colon or rectum may spread (metastasise) to the peritoneum, the thin layer of tissue that lines the abdomen. Doctors treat these metastases by combining surgery with hyperthermic intraperitoneal chemotherapy (HIPEC), which involves filling the abdominal (peritoneal) cavity with chemotherapy drugs that have been heated. Many patients also receive chemotherapy before and after surgery with HIPEC. This has several advantages. It may make the metastases in the peritoneum smaller before surgery, so that they are easier to remove completely. Furthermore, it may eliminate any cancer that has already spread elsewhere in the body. Chemotherapy after surgery may help to stop the cancer coming back by eliminating invisible cancer cells that may have been left behind in the body. Chemotherapy before and after surgery with HIPEC also has potential disadvantages. It may cause side effects, which may be so severe that they decrease quality of life or make surgery impossible. Furthermore, doctors are still not sure if chemotherapy is effective against metastases in the peritoneum. If not, the metastases in the peritoneum will only grow during chemotherapy. Nowadays, many doctors do not agree about whether to give chemotherapy before and after surgery with HIPEC, because the potential advantages and disadvantages have never been properly investigated. Therefore, this study aims to find out whether chemotherapy before and after surgery with HIPEC is of benefit for patients with colon or rectal cancer with peritoneal metastases.

Who can participate?
Patients aged 18 and over with colon or rectal cancer and metastases in the peritoneum, who are candidates for surgery with HIPEC. This is determined by the treating doctor.

What does the study involve?
Participants are randomly allocated into two groups. One group receives surgery with HIPEC without chemotherapy (the standard treatment). The other group receives surgery with HIPEC with chemotherapy before and after surgery (the experimental treatment). Additionally, participants in both groups are asked to fill in questionnaires about their quality of life and health care costs.

What are the possible benefits and risks of participating?
The experimental treatment may lead to an increased life expectancy and an increased chance of being cured. These possible benefits have to be weighed against the most important risks of the experimental treatment, which are side effects that make surgery impossible and/or decrease quality of life.

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

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

Who is funding the study?
1. Dutch Cancer Society
2. Roche Netherlands B.V.

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

Trial website

www.dccg.nl/trial/cairo-6

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

Perioperative systemic therapy and surgery versus surgery alone for resectable colorectal peritoneal metastases: a multicentre, phase II-III, randomised controlled study

Acronym

CAIRO6

Study hypothesis

Current hypothesis as of 04/05/2017:
Perioperative systemic therapy and surgery with HIPEC results in improved overall survival compared to surgery with HIPEC alone.

Previous 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

MEC-U (Medical Research Ethics Committees United), Nieuwegein, the Netherlands, 22/12/2016, ref: R15.056

Study design

Open-label parallel-group multicentre randomised controlled phase II-III 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 with isolated peritoneal metastases

Intervention

Current interventions as of 04/05/2017:
Experimental arm: Perioperative systemic therapy:
1. Neoadjuvant systemic therapy: combination chemotherapy plus bevacizumab for three 3-weekly (CAPOX + bevacizumab) or four 2-weekly (FOLFOX + bevacizumab) cycles, followed by restaging. In case of systemic disease progression (e.g. liver or lung metastases), the best possible palliative treatment is offered. In case of stable or responsive disease, one 3-weekly (CAPOX) or two 2-weekly (FOLFOX) neoadjuvant cycles of combination chemotherapy without bevacizumab are administered.
2. Cytoreductive surgery with HIPEC.
3. Adjuvant systemic therapy: Only in case of a sufficiently good clinical condition and stable or responsive disease upon neoadjuvant treatment, adjuvant combination chemotherapy is intentionally administered according to the neoadjuvant regimen without bevacizumab for four 3-weekly cycles (CAPOX) or six 2-weekly cycles (FOLFOX).

Control arm:
1. Cytoreductive surgery with HIPEC

Previous interventions from 02/09/2016 to 04/05/2017:
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

Original interventions:
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

5-fluorouracil, capecitabine, leucovorin, oxaliplatin, bevacizumab

Primary outcome measures

Current primary outcome measures as of 04/05/2017:
Phase II study (n=80):
1. Both arms: number of patients who undergo a complete or near-complete cytoreduction (CC0 or CC1)
2. Both arms: major postoperative complications 90 days after surgery with HIPEC (Clavien-Dindo III-V)

Phase III study (n=358):
1. Both arms: number of patients alive three years after randomisation

Primary outcome measures from 02/09/2016 to 04/05/2017:
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

Original primary outcome measures:
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

Current secondary outcome measures as of 04/05/2017:
Phase II study (n=80):
1. Both arms: minor postoperative complications 90 days after surgery with HIPEC (Clavien-Dindo II)
2. Experimental arm: moderate/severe systemic therapy related toxicity until one month after the last administration of systemic therapy (CTCAE II-V)

Phase III study (n=358):
1. Both arms: number of patients without disease progression one and three years after randomisation.
2. Both arms: number of patients alive five years after randomisation
3. Both arms: extent of peritoneal disease during surgery (PCI score)
4. Both arms: number of complete or near complete cytoreductions (CC0 or CC1)
5. Both arms: procedure-related characteristics of surgery with HIPEC (e.g. blood loss, operating time)
6. Both arms: major postoperative complications 90 days after surgery with HIPEC (Clavien-Dindo III-V)
7. Both arms: quality of life (EQ-5D, EORTC QLQ-C30, EORTC QLQ-CR29)
8. Both arms: cost-effectiveness (iMTA Medical Consumption Questionnaire, iMTA Productivity Cost Questionnaire)
9. Experimental arm: severe systemic therapy related toxicity until one month after the last administration of systemic therapy (CTCAE III-V)
10. Experimental arm: radiological response to neoadjuvant systemic therapy
11. Experimental arm: pathological response to neoadjuvant systemic therapy

Previous secondary outcome measures from 02/09/2016 to 04/05/2017:
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.

Original secondary outcome measures:
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

01/06/2017

Overall trial end date

01/08/2026

Reason abandoned

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 04/05/2017:
1. PCI score ≤20 and CC-0 or CC-1 achievable, determined by adequate preoperative work-up
2. Histological confirmation of non-appendiceal colorectal cancer with non-signet histology in peritoneal deposits or ascites
3. 18 years or older
4. WHO performance score 0-1
5. Adequate clinical condition to undergo cytoreductive surgery with HIPEC and/or neoadjuvant combination chemotherapy with bevacizumab within 4 weeks after randomisation
6. Adequate organ functions: normal bone marrow function (Hb ≥6.0 mmol/L, absolute neutrophil count ≥1.5 x 109/L, platelet count ≥100 x 109/L), renal function (serum creatinine ≤1.5 x ULN and creatinine clearance [Cockroft formula] ≥30 ml/min), determined <3 months prior to randomisation;
7. No known bleeding diathesis or coagulopathy
8. Written informed consent
9. Able and willing to adhere to follow-up

Previous 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

80 in phase II and then an additional 278 in phase III

Participant exclusion criteria

Current exclusion criteria as of 04/05/2017:
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, wish for pregnancy, and not willing to use contraceptives
4. Known unstable or uncompensated respiratory or cardiac disease
5. Serious active infections
6. Adjuvant chemotherapy after primary resection of colorectal cancer 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

Previous exclusion criteria from 02/09/2016 to 04/05/2017:
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

Original exclusion criteria:
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

01/06/2017

Recruitment end date

01/08/2021

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

Funder name

KWF Kankerbestrijding

Alternative name(s)

Dutch Cancer Society

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

Netherlands

Results and Publications

Publication and dissemination plan

1. Phase II trial: after 80 patients completed their 90 day follow-up after surgery with HIPEC (01/12/2018)
2. Phase II trial: after 358 patients are 3 years after randomisation, and then again after 358 patients are 5 years after randomisation (01/09/2024)

IPD sharing plan
The datasets generated and/or analysed during the current study will be included in the subsequent results publication

Intention to publish date

01/12/2018

Participant level data

Other

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

04/05/2017: The following changes were made to the trial record: 1. Changed public title from "Addition of systemic therapy to surgery and hyperthermic intraperitoneal chemotherapy for colon cancer with peritoneal metastases". 2. Changed scientific title from "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". 3. Changed study design from "Interventional open-label multicentre phase II-III prospective randomised controlled trial". 4. Changed condition from "Colorectal cancer, colon cancer, rectal cancer, peritoneal cancer, peritoneal metastases, peritoneal carcinomatosis, colorectal peritoneal metastases, colorectal peritoneal carcinomatosis, colorectal carcinomatosis". 5. Changed overall trial start date from 01/01/2017 to 01/06/2017. 6. Changed overall trial end date from 01/01/2026 to 01/08/2026. 7. Changed recruitment start date from 01/01/2017 to 01/06/2017. 8. Changed recruitment end date from 01/01/2021 to 01/08/2021. 9. Changed target number of participants from 340 to "80 in phase II and then an additional 278 in phase III". 10. Dutch Cancer Society was added as a funder. 02/09/2016: The following changes were made to the trial record: 1. 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". 2. Removed "Academic Medical Centre" as trial participating centre and added "Medisch Spectrum Twente". 3. Changed overall start date from 01/11/2016 to 01/01/2017. 4. Changed overall end date from 01/11/2025 to 01/01/2026. 5. Changed recruitment start date from 01/11/2016 to 01/01/2017. 6. Changed recruitment end date from 01/11/2020 to 01/01/2021.