|- candidate number||27167|
|- NTR Number||NTR6301|
|- ISRCTN||ISRCTN no longer applicable|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||4-mei-2017|
|- Secondary IDs||NCT02758951 ISRCTN15977568|
|- Public Title||Chemotherapy and surgery versus surgery alone for colorectal cancer with metastases in the peritoneum|
|- Scientific Title||Perioperative systemic therapy and surgery versus surgery alone for resectable colorectal peritoneal metastases: the multicentre, open-label, parallel-group, randomised controlled CAIRO6 trial|
|- hypothesis||Perioperative systemic therapy and surgery results in improved oncological outcomes compared to surgery alone in patients with resectable colorectal peritoneal metastases|
|- Healt Condition(s) or Problem(s) studied||Colorectal metastised cancer|
|- Inclusion criteria||• Histological confirmation of non-appendiceal colorectal cancer with non-signet histology in peritoneal deposits or ascites;|
• PCI score ≤20 and CC-0 or CC-1 achievable, determined by adequate preoperative work-up;
• 18 years or older;
• WHO performance score 0-1;
• Adequate clinical condition to undergo cytoreductive surgery with HIPEC and/or neoadjuvant combination chemotherapy with bevacizumab within 4 weeks after randomisation;
• 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;
• No known bleeding diathesis or coagulopathy;
• Written informed consent;
• Able and willing to adhere to follow-up.
|- Exclusion criteria||• Signet ring cell histology (>50% of the cells have signet ring cell histology) of the primary tumour;|
• Systemic metastases (i.e. liver, lung);
• Known pregnancy or lactation, wish for pregnancy, and not willing to use contraceptives;
• Known unstable or uncompensated respiratory or cardiac disease;
• Serious active infections;
• Adjuvant chemotherapy after primary resection of colorectal cancer within 6 months prior to randomisation;
• Any condition not allowing the safe administration of the planned systemic treatment (bevacizumab, 5-fluorouracil, leucovorin, capecitabine, oxaliplatin, irinotecan);
• Stomatitis, ulceration in the mouth or gastrointestinal tract;
• Severe diarrhoea;
• Known pernicious anaemia or other anaemias due to vitamin B12 deficiency;
• Known previous peripheral sensory neuropathy with functional impairment after previous use of oxaliplatin;
• Impaired liver function (serum bilirubin ≤2 x ULN, serum transaminases ≤5 x ULN), assessment only if indicated.
|- mec approval received||yes|
|- multicenter trial||yes|
|- Type||2 or more arms, randomized|
|- planned startdate ||1-jun-2017|
|- planned closingdate||1-aug-2021|
|- Target number of participants||358|
|- Interventions||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. 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).
|- Primary outcome||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
|- Secondary outcome||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
|- Timepoints||Timepoints of primary endpoints:|
Phase II study:
Major postoperative complications (Clavien-Dindo III-V): after 80 patients completed their 90 days follow-up after cytoreductive surgery with HIPEC
Phase III study:
Number of patients alive three years after randomisation: after 358 patients are 3 years after randomisation
|- Trial web site||www.dccg.nl/trial/cairo6|
|- status||open: patient inclusion|
|- CONTACT FOR PUBLIC QUERIES||Drs. Koen Rovers|
|- CONTACT for SCIENTIFIC QUERIES||Drs. Koen Rovers|
|- Sponsor/Initiator ||Catharina Hospital Eindhoven|
(Source(s) of Monetary or Material Support)
|Dutch Cancer Society, Roche Nederland BV|
|- Publications||Rovers KP, Simkens GA, Punt CJ, van Dieren S, Tanis PJ, de Hingh IH. Perioperative systemic therapy for resectable colorectal peritoneal metastases: sufficient evidence for its widespread use? A critical review. Crit Rev Oncol Hematol. 2017;114:53-62|
|- Brief summary||Rationale: In the absence of randomised studies, there is a worldwide controversy on the clinical benefit of perioperative systemic therapy in patients with colorectal peritoneal metastases who are candidate for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS & HIPEC).|
Primary objective: To compare the prognosis of patients who receive perioperative systemic therapy and CRS & HIPEC versus CRS & HIPEC alone.
Study design: This is a prospective, multicenter, randomised, parallel group, phase II-III study that randomizes patients with resectable colorectal peritoneal metastases to perioperative systemic therapy and CRS & HIPEC (experimental arm) or upfront CRS & HIPEC alone (control arm). The study starts as a randomized phase II study (n=80) in order to investigate the safety of perioperative systemic therapy in this setting.
Study population: Patients with non-signet ring cell colorectal cancer with histologically proven peritoneal metastases without systemic metastases, in whom a complete cytoreduction seems achievable.
Primary endpoints – phase II: Primary endpoints are major postoperative complications and the number of complete cytoreductions.
Primary and secondary endpoints – phase III: The primary endpoint is 3-year overall survival. Secondary endpoints are 5-year overall survival, 1- and 3-year progression-free survival, number of complete cytoreductions, CRS & HIPEC related characteristics (e.g. PCI-score, number of resections, operating time), major postoperative complications, quality of life, and cost-effectiveness. In the experimental arm, additional secondary endpoints are severe systemic therapy related toxicity and radiological/histological response to neoadjuvant systemic therapy. Blood and tissue is collected at pre-specified time points for future translational research.
Sample size: The phase II study includes 80 patients, with 40 patients in each arm. The expected 3-year overall survival in the control arm is 50%. We hypothesize that the experimental treatment results in a 15% increase in overall survival rate if analysed according to an intention-to-treat principle. With a 0.05 two-sided significance level, 80% power and a drop-out of 5%, a sample size of 179 patients in each arm is needed, resulting in a total of 358 patients, including the 80 patients from the phase II study.
|- Main changes (audit trail)|
|- RECORD||4-mei-2017 - 19-mei-2017|