Hypofractionated Versus Single Fraction Stereotactic Adjuvant Radiotherapy to the Resection Cavity of Brain Metastases

Study Overview
=================
Brief Summary
-----------------
This prospective, randomized, controlled, monocentric clinical phase III study focuses on stereotactic irradiation of resection cavities of brain metastases after surgical resection and seeks to demonstrate the superiority of fractionated irradiation schemes in terms of local control.

Detailed Description
-----------------
There is a growing scientific focus on single fraction stereotactic (SRS) and hypofractionated stereotactic irradiation (HFSRT) after surgical resection of brain metastasis and its use is more frequently recommended in international guidelines. Despite intensive research, the optimal fractionation scheme and dose prescription for adjuvant irradiation of the resection cavity remains unclear. Based on our own institutional data [Cit.1] and a recently published metaanalysis [Cit.2], we hypothesize that local control (LC) after HFSRT is superior compared to SRS in terms of LC. To evaluate the hypothesis in a prospective, randomized, controlled setting we designed the SATURNUS study. A total of 126 patients will be randomized 1:1 to either HFSRT (dose 6-7 x 5 Gy) or SRS (dose 1 x 12-20 Gy). If further unresected brain metastases are present, they will be treated with SRS (1 x 14 - 22 Gy). Irradiation is carried out with a Gamma Knife or a Linear Accelerator. In line with current clinical practice, the choice of positioning method for SRS with the Gamma Knife (mask or stereotactic frame) is left to the patient. In the case of SRS with the Linear Accelerator or HFSRT, fixation is done with a mask as technically not otherwise feasible. Follow-up-MRI will be at least carried out 6 weeks and 3, 6, 9 and 12 months after treatment. Primary endpoint of the study is local control (LC) at the irradiated resection cavity after 12 months. Locoregional control (LRC) and overall survival (OS) as well as salvage-treatments, irradiation-associated toxicities (especially rate of radionecrosis) and quality-of-life parameters are investigated as secondary endpoints. To the best of our knowledge, the SATURNUS study is the only randomized phase III study comparing different techniques of postoperative stereotactic radiotherapy after resection of brain metastases adequately powered to detect a superiority of HSFRT regarding LC.

Official Title
-----------------
Hypofractionated Stereotactic Radiotherapy Versus Single Fraction Stereotactic Radiosurgery to the Resection Cavity of Brain Metastases After Surgical Resection - A Prospective, Randomized, Controlled, Monocentric Phase III Trial

Conditions
-----------------
Brain Metastases, Resection Cavity

Intervention / Treatment
-----------------
* Radiation: Hypofractionated stereotactic radiotherapy (HFSRT) versus single fraction stereotactic radiotherapy radiosurgery (SRS)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed solid tumor disease One to three resected brain metastases Consent to perform adjuvant irradiation by an interdisciplinary tumor board Completed wound healing Resection within the last six weeks at the time of study inclusion Diameter of the resection cavity ≤ 4 cm (on Planning MRI) Age > 18 years KPS > 60% Adequate contraceptive measures for fertile women / men Written informed consent (must be available before enrolment in the trial) Exclusion Criteria: Contraindication for repetitive contrast enhanced MRI Leptomeningeal disease Small cell histology, hematological malignancies and / or germ cell malignancies Previous irradiation of the brain Pregnant and lactating women Inability to understand the character and consequences of the study Withdrawal of consent

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: 1:1 Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: HSFRT<br>Hypofractionated stereotactic radiotherapy to the resection cavity, dose prescription: 6-7 x 5 Gy | Radiation: Hypofractionated stereotactic radiotherapy (HFSRT) versus single fraction stereotactic radiotherapy radiosurgery (SRS)<br>* intervention description see above<br>|
| Active Comparator: Arm B: SRS<br>Single fraction stereotactic radiotherapy to the resection cavity, dose prescription: 1 x 12-20 Gy | Radiation: Hypofractionated stereotactic radiotherapy (HFSRT) versus single fraction stereotactic radiotherapy radiosurgery (SRS)<br>* intervention description see above<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local control | Local control at the resected site(s) | 12 months after adjuvant radiotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LC | Local control at all treated site(s) | 12 months after adjuvant radiotherapy | 
| LRC | Locoregional control=CNS progression free survival | 12 months after adjuvant radiotherapy | 
| OS | Overall survival | 12 months after adjuvant radiotherapy | 
| Salvage-free survival | Overall survival | 12 months after adjuvant radiotherapy | 
| Intracranial salvage therapy | Number and kind of intracranial salvage treatments | 12 months after adjuvant radiotherapy | 
| Pseudoprogression | Rate of pseudoprogression | up to 12 months after adjuvant radiotherapy | 
| Irradiation-related toxicity | according to CTCAE v4.03, especially rate of radionecrosis | up to 12 months after adjuvant radiotherapy | 
| QoL | Quality of life according to EORTC QLQ-C30 and EORTC QLQ-B20 | up to 12 months after adjuvant radiotherapy | 
| Time to loss of independence | defined as decrease in Barthel index by > 20 points | up to 12 months after adjuvant radiotherapy | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Brain Metastases, Resection Cavity, Radiotherapy, Stereotactic Irradiation, Gamma Knife