Neoadjuvant vs. Intraoperative vs. Adjuvant Resection Cavity Radiotherapy of Brain Metastases

Study Overview
=================
Brief Summary
-----------------
Patients suffering from malignancies in advanced stages often develop brain metastases, which limit both the life span and the quality of life. Combining surgery and radiotherapy for resectable brain metastases is standard of care but there is a lot of controversy on which kind of radiotherapy is best suitable. Recently, first volumetric in-silico analyses point to theoretical advantages of neoadjuvant stereotactic radiotherapy of brain metastases. Special about this trial is the direct comparison between the three currently discussed radiotherapy options for resectable brain metastases: Neoadjuvant stereotactic radiotherapy, intraoperative radiotherapy and adjuvant stereotactic radiotherapy.

Detailed Description
-----------------
This trial approach allows for detailed comparison of resected tissue samples, cerebrospinal fluid and blood of all patient groups. So, the investigators will investigate biomaterial of recently irradiated (neoadjuvant and intraoperative arms) and non-irradiated (adjuvant arm) tissue. All this prompts the main issues of the explorative randomized controlled phase 2 RADCAV trial: Is there a difference between neoadjuvant stereotactic radiotherapy vs. intraoperative radiotherapy vs. adjuvant stereotactic radiotherapy regarding the factors immune profiling, dosimetry, efficacy and toxicity. It can be hypothesized that the resected tissue differs between recently irradiated and non-irradiated brain metastases, for example regarding different histopathologic and molecular pathologic markers including immune environment, markers for cell death and markers for tumor invasion. Are there histopathologic and molecular pathologic markers of tumor cell response and prognosis so the investigators can better understand the effects of irradiation on metastatic brain tissue? And are there relevant differences in dosimetry that put patients at different risks for efficacy and toxicity?

Official Title
-----------------
Neoadjuvant vs. Intraoperative vs. Adjuvant Resection Cavity Radiotherapy of Brain Metastases - A Prospective Randomized Explorative Phase II Trial

Conditions
-----------------
Brain Metastases, Radiotherapy

Intervention / Treatment
-----------------
* Radiation: Preoperative Radiotherapy
* Radiation: Intraoperative Radiation
* Radiation: Postoperative Radiotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed solid malignancy Metastatic brain disease (1-10 brain metastases), with at least one brain metastasis in a non-eloquent location (i.e. motor or speech) planned for resection Maximum size of the brain metastasis <5cm Eligibility of patients for both stereotactic radiotherapy and resection Time interval from resection to adjuvant stereotactic radiosurgery of 2-6 weeks Time interval from neoadjuvant stereotactic radiosurgery to resection of 1-7 days Possibility to postpone resection for neoadjuvant stereotactic radiosurgery, if applicable Karnofsky performance scores >= 70 or Eastern Cooperative Oncology Group (ECOG) >= 2 at enrollment Age ≥ 18 years of age For women with childbearing potential, (and men) adequate contraception. Ability of subject to understand character and individual consequences of the clinical trial Written informed consent (must be available before enrolment in the trial) Exclusion Criteria: Necessity of immediate surgical resection due to life threatening symptoms brain metastasis directly located (≤10mm) next to the optic system or brain stem Refusal of the patients to take part in the study Small-cell lung cancer (SCLC) or hematologic malignancy as primary malignant illness Leptomeningeal disease suspected RadCav Trial Protocol Version 1.1, 01.07.2022 18 Previous radiotherapy of the brain Contraindication for contrast-enhanced MRI Pregnant or lactating women Participation in another competing clinical study or observation period of competing trials, respectively

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Arm A (Preoperativ SRS)<br>Preoperative stereotatic radiosurgery following resection of brain metastases after 1-7 days | Radiation: Preoperative Radiotherapy<br>* Resection of brain mestases following<br>|
| Experimental: Experimental Arm B (Intraoperativ SRS)<br>Intraoperative stereotactic radiotherapy after resection of brain metastases | Radiation: Intraoperative Radiation<br>* While Resection<br>|
| Active Comparator: Standard Treatment Arm C (Posoperativ SRS)<br>Resection of brain metastases following stereotactic radiotherapy after 2-6 weeks | Radiation: Postoperative Radiotherapy<br>* After resection<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of treatment response | number of patients without progresion according to RANO-BM | through study completion, an avarage of 60 month | 
| local tumor control | events of tumor progression or recurrence in the area of 1cm surrounding the resection cavity and surrounding the surgical access | through study completion, an avarage of 60 month | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Brain Metastases, Radiotherapy