Clinical trial NCT01606098: The Role of Surgery of the Primary Tumour in Patients With Synchronous Unresectable Metastases of Colorectal Cancer
Official title: The Role of Surgery of the Primary Tumour With Few or Absent Symptoms in Patients With Synchronous Unresectable Metastases of Colorectal Cancer, a Randomized Phase III Study. A Study of the Dutch Colorectal Cancer Group (DCCG)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Colon Cancer
Primary Tumour
Rectal Cancer
Keywords: Surgery
Chemotherapy
Lead sponsor: Dutch Colorectal Cancer Group
Sponsor class: OTHER
Collaborators: name: Hoffmann-La Roche
First posted: 2012-05-25
Enrollment: 206
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The clinical benefit of resection of the primary tumour in patients with synchronous unresectable metastases is not known. In the literature studies usually describe retrospective selected patients with synchronous metastases treated with or without resection of the primary tumour. All these studies are biased in patient selection and there are no prospective randomized studies on this topic. In patients with few or absent symptoms of the primary tumour, arguments both in favour and against initial resection have been presented, and therefore a randomized trial is warranted. Although recent publications suggest that resection of the primary tumour in synchronous metastasized colon cancer patients might not be necessary, this appears to be based on feasibility and not on clinical outcome. Several studies comparing large groups of patients with or without resection of the primary tumour suggest an improved survival when the primary tumour is resected. A potential benefit of resection of the primary tumour is to prevent complications of the primary tumour during chemotherapy treatment or during later stages of the disease. A recent analysis of the CAIRO and CAIRO2 data showed that metastatic colon cancer patients who had a resection of the primary tumour prior to study entry, had an improved survival compared to patients without a resection of the primary tumour. However, these patients were selected after the primary tumour was resected and therefore these results are not corrected for surgical morbidity and mortality. The investigators here propose a randomized trial in order to demonstrate that resection of the primary tumour does improve overall survival.


Eligibility criteria: Inclusion Criteria:

* Histological proof of colorectal cancer
* Resectable primary tumour in situ with unresectable distant metastases
* No indication for neo-adjuvant (chemo)radiation
* No severe signs or symptoms related to the primary tumour (i.e. severe bleeding, obstruction, severe abdominal pain) that require immediate surgery or other symptomatic treatment (e.g. stenting)
* No prior systemic treatment for advanced disease
* Age ≥ 18 years
* WHO performance status 0-2
* Laboratory values obtained ≤ 4 weeks prior to randomization: Adequate bone marrow function (Hb ≥ 6.0 mmol/L, absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L), renal function (serum creatinine ≤ 1.5x ULN and creatinine clearance, Cockroft formula, ≥ 30 ml/min), liver function (serum bilirubin ≤ 2 x ULN, serum transaminases ≤ 3 x ULN without presence of liver metastases or ≤ 5x ULN with presence of liver metastases)
* Expected adequacy of follow-up
* Written informed consent
* CT scan abdomen and CT thorax/X-thorax performed ≤ 4 weeks prior to randomization

Exclusion Criteria:

* Pregnancy, lactation
* Unresectable primary tumour (i.e. neurovascular encasement, substantial ingrowth in pancreatic head), or any condition preventing the safety or feasibility of resection of the primary tumour, i.e. massive ascites or extensive peritoneal disease
* Requirement of neoadjuvant (chmo)radiation therapy
* Second primary malignancy within the past 5 years with the exception of adequately treated in situ carcinoma of any organ or basal cell carcinoma of the skin
* Any medical condition that prevents the safe administration of systemic treatment
* Previous intolerance of fluoropyrimidines, known dihydropyrimidine dehydrogenase (DPD) deficiency
* Planned radical resection of all metastatic disease
* Uncontrolled hypertension, i.e. values consistently \> 150/100 mmHg
* Use of ≥ 3 antihypertensive drugs
* Significant cardiovascular disease \< 1 yr before randomization (symptomatic congestive heart failure, myocardial infarction, unstable angina pectoris, serious uncontrolled cardiac arrhythmia, cerebro vascular event)
* Chronic active infection
* Concurrent treatment with any other anti-cancer therapy as described per protocol

Primary outcomes:
measure: Overall survival
timeFrame: Time from randomisation until death, assessed up to 5 years
Secondary outcomes:
measure: Progression-free survival
timeFrame: Time from randomisation until first progression or death whichever comes first, asessed up to 5 years
measure: Response to chemotherapy
timeFrame: Fist-line chemotherapy, assessed until progression
measure: Systemic therapy related toxicity
timeFrame: Every 3 weeks during first-line treatment
measure: Surgery related morbidity and mortality
timeFrame: 30 days
measure: Quality of life
timeFrame: Every 6 months from randomisation until first progression
measure: Interval between randomization and initiation of systemic treatment
timeFrame: Number of days between randomization and initiation of systemic treatment
measure: Cost-benefit analyses
timeFrame: Until end of first-line systemic treatment
measure: Patients requiring resection of the primary tumour in the non-resection arm
timeFrame: Time from randomisation until death, assessed up to 5 years
measure: Overall survival in patients in whom treatment according to protocol was initiated
timeFrame: Time form randomisation until death, assessed up to 5 years
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: University Hospital Aalborg
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Herlev
country: Denmark
facility: Herlev Hospital
city: Herning
country: Denmark
facility: Regionshospital Herning
city: Roskilde
country: Denmark
facility: Roskilde hospital
city: Alkmaar
country: Netherlands
facility: Medisch Centrum Alkmaar
city: Almelo
country: Netherlands
facility: Ziekenhuisgroep Twente
city: Almere
country: Netherlands
facility: Flevoziekenhuis
city: Amstelveen
country: Netherlands
facility: Ziekenhuis Amstelland
city: Amsterdam
country: Netherlands
facility: Academic Medical Centre
city: Amsterdam
country: Netherlands
facility: OLVG
city: Amsterdam
country: Netherlands
facility: VUMC
city: Apeldoorn
country: Netherlands
facility: Gelre Ziekenhuis
city: Assen
country: Netherlands
facility: Wilhelmina Ziekenhuis
city: Beverwijk
country: Netherlands
facility: Rode Kruis Ziekenhuis
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
city: Den Bosch
country: Netherlands
facility: Jeroen Bosch
city: Den Haag
country: Netherlands
facility: MC Haaglanden en Bronovo Nebo
city: Doetinchem
country: Netherlands
facility: Slingeland Ziekenhuis
city: Dordrecht
country: Netherlands
facility: Albert Schweitzer Ziekenhuis
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
city: Eindhoven
country: Netherlands
facility: Maxima Medisch Centrum
city: Geldrop
country: Netherlands
facility: St Annaziekenhuis
city: Gouda
country: Netherlands
facility: Groene Hart Ziekenhuis
city: Groningen
country: Netherlands
facility: Martini Ziekenhuis
city: Groningen
country: Netherlands
facility: UMCG
city: Haarlem
country: Netherlands
facility: Spaarne Gasthuis
city: Harderwijk
country: Netherlands
facility: St Jansdal
city: Helmond
country: Netherlands
facility: Elkerliek Ziekenhuis
city: Hoofddorp
country: Netherlands
facility: Spaarne Gasthuis
city: Nieuwegein
country: Netherlands
facility: St Antonius Ziekenhuis
city: Nijmegen
country: Netherlands
facility: Radboudumc
city: Purmerend
country: Netherlands
facility: Waterland Ziekenhuis
city: Roermond
country: Netherlands
facility: Laurentius Ziekenhuis
city: Rotterdam
country: Netherlands
facility: Maasstad Ziekenhuis
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Rotterdam
country: Netherlands
facility: Fransicus Gastuis & Vlietland
city: Sneek
country: Netherlands
facility: Antonius Ziekenhuis
city: Tiel
country: Netherlands
facility: Ziekenhuis Rivierenland
city: Tilburg
country: Netherlands
facility: Elisabeth-Tweesteden
city: Uden
country: Netherlands
facility: Bernhoven Ziekenhuis
city: Utrecht
country: Netherlands
facility: University Medical Centre Utrecht
city: Veghel
country: Netherlands
facility: Bernhoven Ziekenhuis
city: Venlo
country: Netherlands
facility: VieCuri Medisch Centrum
city: Zaandam
country: Netherlands
facility: Zaans Medisch Centrum
city: Zwolle
country: Netherlands
facility: Isala Klinieken
Study officials:
affiliation: UMC Utrecht
name: M. Koopman, Prof MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Radboud University Medical Center
name: H. JW de Wilt, Prof MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: van der Kruijssen DEW, Elias SG, Vink GR, van Rooijen KL, 't Lam-Boer J, Mol L, Punt CJA, de Wilt JHW, Koopman M; CAIRO4 Working Group. Sixty-Day Mortality of Patients With Metastatic Colorectal Cancer Randomized to Systemic Treatment vs Primary Tumor Resection Followed by Systemic Treatment: The CAIRO4 Phase 3 Randomized Clinical Trial. JAMA Surg. 2021 Dec 1;156(12):1093-1101. doi: 10.1001/jamasurg.2021.4992.
citation: 't Lam-Boer J, Mol L, Verhoef C, de Haan AF, Yilmaz M, Punt CJ, de Wilt JH, Koopman M. The CAIRO4 study: the role of surgery of the primary tumour with few or absent symptoms in patients with synchronous unresectable metastases of colorectal cancer--a randomized phase III study of the Dutch Colorectal Cancer Group (DCCG). BMC Cancer. 2014 Oct 2;14:741. doi: 10.1186/1471-2407-14-741.