The Role of Surgery of the Primary Tumour in Patients With Synchronous Unresectable Metastases of Colorectal Cancer

Phase 3

Completed

• Conditions: Colon Cancer; Rectal Cancer; Primary Tumour
• Interventions: Procedure: Surgery of the primary tumour; Drug: Systemic treatment

• Registration Number: NCT01606098
• Lead Sponsor: Dutch Colorectal Cancer Group

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2012-05-23
• Study First Submitted QC: 2012-05-24
• Study First Posted: 2012-05-25
• Study Start: 2012-07
• Primary Completion: 2022-06
• Study Completion: 2022-12
• Status Verified: 2023-09
• Last Update Submitted: 2023-09-11
• Last Update Posted: 2023-09-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 206

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Surgery followed by systemic treatment	Systemic treatment	Surgery within 4 weeks of randomization followed by fluoropyrimidine-based chemotherapy with bevacizumab until progression or unacceptable toxicity, followed by salvage therapy upon progression at the discretion of the local investigator
Systemic treatment	Systemic treatment	First-line fluoropyrimidine-based chemotherapy with bevacizumab initiated within 4 weeks of randomization, followed by salvage therapy upon progression at the discretion of the local investigator. Surgery of primary tumour will be performed only when indicated by local signs or symptoms.
Surgery followed by systemic treatment	Surgery of the primary tumour	Surgery within 4 weeks of randomization followed by fluoropyrimidine-based chemotherapy with bevacizumab until progression or unacceptable toxicity, followed by salvage therapy upon progression at the discretion of the local investigator

Primary Outcome Measures

Name	Time	Method
Overall survival	Time from randomisation until death, assessed up to 5 years	Overall survival of the intent-to-treat population

Secondary Outcome Measures

Name	Time	Method
Surgery related morbidity and mortality	30 days
Patients requiring resection of the primary tumour in the non-resection arm	Time from randomisation until death, assessed up to 5 years	Number of patients requiring resection of the primary tumour in the non-resection arm
Systemic therapy related toxicity	Every 3 weeks during first-line treatment	Adverse events grade 3-4 according to NCI-CTC 4.0
Progression-free survival	Time from randomisation until first progression or death whichever comes first, asessed up to 5 years
Quality of life	Every 6 months from randomisation until first progression	EORTC QLQ-C30 and CR38
Interval between randomization and initiation of systemic treatment	Number of days between randomization and initiation of systemic treatment
Cost-benefit analyses	Until end of first-line systemic treatment
Response to chemotherapy	Fist-line chemotherapy, assessed until progression	Response rate according to RECIST 1.1
Overall survival in patients in whom treatment according to protocol was initiated	Time form randomisation until death, assessed up to 5 years	Having received at least one cycle of systemic treatment in arm A and surgery in arm B

Trial Locations

Locations (44)

OLVG; 🇳🇱 Amsterdam, Netherlands

Slingeland Ziekenhuis; 🇳🇱 Doetinchem, Netherlands

Albert Schweitzer Ziekenhuis; 🇳🇱 Dordrecht, Netherlands

Martini Ziekenhuis; 🇳🇱 Groningen, Netherlands

Ziekenhuis Rivierenland; 🇳🇱 Tiel, Netherlands

VUMC; 🇳🇱 Amsterdam, Netherlands

Academic Medical Centre; 🇳🇱 Amsterdam, Netherlands

Catharina Ziekenhuis; 🇳🇱 Eindhoven, Netherlands

St Annaziekenhuis; 🇳🇱 Geldrop, Netherlands

Zaans Medisch Centrum; 🇳🇱 Zaandam, Netherlands

Amphia Ziekenhuis; 🇳🇱 Breda, Netherlands

MC Haaglanden en Bronovo Nebo; 🇳🇱 Den Haag, Netherlands

Maxima Medisch Centrum; 🇳🇱 Eindhoven, Netherlands

Elkerliek Ziekenhuis; 🇳🇱 Helmond, Netherlands

Medisch Centrum Alkmaar; 🇳🇱 Alkmaar, Netherlands

Flevoziekenhuis; 🇳🇱 Almere, Netherlands

Gelre Ziekenhuis; 🇳🇱 Apeldoorn, Netherlands

Wilhelmina Ziekenhuis; 🇳🇱 Assen, Netherlands

Rode Kruis Ziekenhuis; 🇳🇱 Beverwijk, Netherlands

Ziekenhuisgroep Twente; 🇳🇱 Almelo, Netherlands

Jeroen Bosch; 🇳🇱 Den Bosch, Netherlands

Groene Hart Ziekenhuis; 🇳🇱 Gouda, Netherlands

Maasstad Ziekenhuis; 🇳🇱 Rotterdam, Netherlands

Bernhoven Ziekenhuis; 🇳🇱 Veghel, Netherlands

University Medical Centre Utrecht; 🇳🇱 Utrecht, Netherlands

VieCuri Medisch Centrum; 🇳🇱 Venlo, Netherlands

Spaarne Gasthuis; 🇳🇱 Hoofddorp, Netherlands

St Antonius Ziekenhuis; 🇳🇱 Nieuwegein, Netherlands

Radboudumc; 🇳🇱 Nijmegen, Netherlands

Laurentius Ziekenhuis; 🇳🇱 Roermond, Netherlands

University Hospital Aalborg; 🇩🇰 Aalborg, Denmark

Rigshospitalet; 🇩🇰 Copenhagen, Denmark

Regionshospital Herning; 🇩🇰 Herning, Denmark

Roskilde hospital; 🇩🇰 Roskilde, Denmark

Ziekenhuis Amstelland; 🇳🇱 Amstelveen, Netherlands

Herlev Hospital; 🇩🇰 Herlev, Denmark

Waterland Ziekenhuis; 🇳🇱 Purmerend, Netherlands

UMCG; 🇳🇱 Groningen, Netherlands

St Jansdal; 🇳🇱 Harderwijk, Netherlands

Erasmus MC; 🇳🇱 Rotterdam, Netherlands

Fransicus Gastuis & Vlietland; 🇳🇱 Rotterdam, Netherlands

Antonius Ziekenhuis; 🇳🇱 Sneek, Netherlands

Elisabeth-Tweesteden; 🇳🇱 Tilburg, Netherlands

Isala Klinieken; 🇳🇱 Zwolle, Netherlands