Colorectal Pulmonary Metastases: Pulmonary Metastasectomy Versus Stereotactic Ablative Radiotherapy

Study Overview
=================
Brief Summary
-----------------
COPPER is an international, multicenter, parallel-arm, phase III randomized controlled trial comparing two local treatment strategies (SABR or metastasectomy) for patients with an indication for local treatment for limited (max. three) colorectal pulmonary metastases

Detailed Description
-----------------
The study is formally endorsed by the Dutch Society of Lung Surgery (NVvL), the Dutch Society of Cardiothoracic Surgery (NVT), the Dutch Society of Radiation Oncology (NVRO). The main objective of the proposed randomized trial is to compare efficacy of SABR to the efficacy of metastasectomy with regards to the primary endpoint (local recurrence free survival at 5 years) in patients with limited colorectal pulmonary metastases. This will determine the most effective local treatment modality. The investigators hypothesize that patients with limited colorectal pulmonary metastases will have non-inferior overall survival after pulmonary metastasectomy compared to SABR, however metastasectomy will result in superior local recurrence free survival at five years when compared to SABR. In addition, the investigators hypothesize that SABR is associated with lower morbidity, comparable quality of life and comparable health care costs compared to metastasectomy. Recurrent metastases are preferably treated by the index treatment to which the patient was randomized, local recurrent metastases are preferably treated by means of cross-over between both arms. Comparing metastasectomy to SABR for patients with colorectal pulmonary metastases will present the international community the evidence needed to better select patients for local radical treatment, while diminishing uncertainty for patients and care givers.

Official Title
-----------------
Colorectal Pulmonary Metastases: Pulmonary Metastasectomy Versus Stereotactic Ablative Radiotherapy: a Phase III Multicenter Randomized Controlled Trial

Conditions
-----------------
Lung Metastases, Colorectal Cancer Metastatic

Intervention / Treatment
-----------------
* Procedure: Minimally invasive pulmonary metastasectomy
* Radiation: Stereotactic ablative radiotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years Eastern Cooperative Oncology Group (ECOG)-Performance status 0 - 2 Willing to provide informed consent Patients with 1 to 3 lung metastases from colorectal cancer eligible for both a minimally invasive surgical resection and SABR, as assessed by the multidisciplinary tumor board (MDT) Radically treated primary colorectal cancer Patient is able and willing to complete the quality-of-life questionnaires Previous liver metastases are radically treated with curative intent Histologically confirmed malignancy with metastatic disease detected on imaging. Biopsy of metastasis is preferred, but not required. Exclusion Criteria: Previous or present metastases outside liver or lungs Concurrent malignant cancer, or history of other malignant cancers within the past 5 years (excluding prespecified low-risk cancers) Hilar or mediastinal lymph node metastases Poor cardiopulmonary function test Inability to treat all colorectal metastases Surgical resection by means of a bilobectomy or pneumonectomy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicenter, parallel-arm, phase III randomized controlled trial Patients will be randomized in a 1:1 manner to SABR or minimally invasive metastasectomy for the local treatment of three or less colorectal pulmonary metastases
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Minimally invasive pulmonary metastasectomy<br>Minimally invasive parenchymal sparing pulmonary metastasectomy Surgical approach by means of video-assisted thoracic surgery (VATS), robot-assisted (RATS), or uniportal VATS | Procedure: Minimally invasive pulmonary metastasectomy<br>* Surgical margin is equal to tumor size, if possible The goal is a parenchymal-sparing resection<br>* Other names: Lung metastasectomy;|
| Experimental: Stereotactic ablative radiotherapy<br>Gross tumor volume = tumor visible on CT (+/- PET) No CTV margin will be added (Clinical target volume (CTV) = Gross target volume (GTV)) Planning Target Volume (PTV): GTV plus margins of 3-5mm (varying depending on site, motion, SABR delivery approach) | Radiation: Stereotactic ablative radiotherapy<br>* Depending on tumor location, 54 Gy in 3 fractions, 55 Gy in 5 fractions, 60 Gy in 8 fractions.<br>* Other names: Stereotactic body radiation therapy (SBRT);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local recurrence-free survival | Time from randomization to local recurrence or death from any cause | From date of randomization through study completion, up to 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Time from randomization to death from any cause | 5 years | 
| Progression-free survival (PFS) | Time from randomization to disease progression at any site or death | 5 years | 
| Local recurrence rate (LRR) per tumor | Proportion of treated metastases with local recurrence | 5 years | 
| Quality of life (QoL) assessment - EuroQoL (EQ-5D-5L) | [0-5 for 5 dimensions, higher score = worse QoL] | 5 years | 
| Quality of life assessment - Functional Assessment of Cancer Therapy: General (FACT-G) | [27 questions in 4 subscales, higher score = better QoL] | 5 years | 
| Health economic evaluation - Institute for Medical Technology Assessment (iMTA) - iMTA Medical Cost Questionnaire (iMCQ) | Medical costs [Euro] | 5 years | 
| Health economic evaluation - iMTA Productivity Cost Questionnaire (iPCQ) | Productivity costs [Euro] | 5 years | 
| Tumor patterns of failure | Local, regional and distant disease control based on surveillance imaging | 5 years | 
| Rate of adverse events | Frequency of adverse events and serious adverse events | 2 years | 
| Multiparameter flow cytometric analyses (FACS) | Peripheral blood mononuclear cell (PBMC) concentration | 1 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Colorectal pulmonary metastases, Pulmonary metastasectomy, Stereotactic radiotherapy, Randomized controlled trial, Colorectal cancer metastases