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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Colon Cancer, Primary Tumour, Rectal Cancer

Intervention / Treatment
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* Procedure: Surgery of the primary tumour
* Drug: Systemic treatment


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Systemic treatment<br>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. | Drug: Systemic treatment<br>* First line fluoropyrimidine-based chemotherapy with bevacizumab. The chemotherapy regimen is to the discretion of the local investigator, who may choose between: 5FU/LV or capecitabine or capecitabine + oxaliplatin(CAPOX)or 5FU + oxaliplatin(FOLFOX 4 or FOLFOX 7)or 5FU + irinotecan (FOLFIRI) or capecitabine + irinotecan(CAPIRI)<br>* Other names: Bevacizumab in combination with fluoropyrimidine-based schedules;|
| Experimental: Surgery followed by systemic treatment<br>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 | Procedure: Surgery of the primary tumour<br>* Surgical resection of the colon tumour<br>Drug: Systemic treatment<br>* First line fluoropyrimidine-based chemotherapy with bevacizumab. The chemotherapy regimen is to the discretion of the local investigator, who may choose between: 5FU/LV or capecitabine or capecitabine + oxaliplatin(CAPOX)or 5FU + oxaliplatin(FOLFOX 4 or FOLFOX 7)or 5FU + irinotecan (FOLFIRI) or capecitabine + irinotecan(CAPIRI)<br>* Other names: Bevacizumab in combination with fluoropyrimidine-based schedules;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival of the intent-to-treat population | Time from randomisation until death, assessed up to 5 years | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Surgery, Chemotherapy