Fractionated Stereotactic Radiotherapy vs. Single Session Radiosurgery in Patients With Larger Brain Metastases

Study Overview
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Brief Summary
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Phase III trial comparing local control and side effects after fractionated stereotactic radiotherapy and single session radiosurgery in patients with larger brain metastases (2-4 cm)

Detailed Description
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This is a prospective, multicenter randomized trial comparing local control and side effects after fractionated stereotactic radiotherapy with 12 x 4 Gy and single session radiosurgery according to RTOG 9005 in patients with larger brain metastases (2-4 cm). Patients will be randomized to either fractionated stereotactic radiotherapy with 12 x 4 Gy or radiosurgery with 1 x 18 Gy (2-3 cm) or 1 x 15 Gy (3-4 cm) as defined by the RTOG 9005. Randomization will be stratified by metastasis volume and histology.

Official Title
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Efficacy and Safety of Fractionated Stereotactic Radiotherapy (FSRT) in Comparison to Single Session Radiosurgery in Patients With Larger Brain Metastases (2-4 cm)

Conditions
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Cerebral Metastases of Solid Cancers

Intervention / Treatment
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* Radiation: Radiosurgery
* Radiation: Fractionated stereotactic radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years, no upper age limit Karnofsky Performance Score > 50 points Expected Survival > 3 months 1-10 cerebral metastases of metastatic solid cancer Indication for local radiotherapy Patients must be able to understand the protocol and provide informed consent Exclusion Criteria: Whole Brain radiotherapy no longer than 6 weeks before the start of stereotactic radiotherapy or planned whole brain radiotherapy after stereotactic radiotherapy Prior irradiation of the cerebral metastasis that is to be treated in the study Relevant overlap of prior radiation fields with the metastasis that is to be treated in the study Metastasis in the brainstem Contraindication for cerebral MRI Metastasis that is to be treated in the study can't be visualized in contrast-enhanced T1 MRI sequence Pregnant or lactating women Abuse of illicit drugs, alcohol or medication Patient not able or willing to behave according to protocol Participation in another clinical trial

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
Interventional Model Description: Prospective, multicenter, Open-Label, randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Radiosurgery with 1 x 18 Gy (2-3 cm) or 1 x 15 Gy (3-4 cm) and<br>Radiosurgery with 1 x 18 Gy (2-3 cm) or 1 x 15 Gy (3-4 cm) and no margin as defined by the RTOG 9005 | Radiation: Radiosurgery<br>* Radiosurgery with 1 x 18 Gy (2-3 cm) or 1 x 15 Gy (3-4 cm)<br>|
| Other: Fractionated stereotactic radiotherapy with 12 x 4 Gy and 2 mm<br>Fractionated stereotactic radiotherapy with 12 x 4 Gy and 2 mm margin | Radiation: Fractionated stereotactic radiotherapy<br>* Fractionated stereotactic radiotherapy with 12 x 4 Gy and 2 mm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to local progression - TTLP | Local progression will be defined according to the RANO-BM criteria by an increase of at least 20% in the longest diameter of the metastasis relative to nadir or baseline. In addition to the relative increase of 20% the lesion must increase by an absolute value of 5 mm or more. TTLP is defined as the time from randomization until the detection of progression as per the RANO-BM criteria. Patients will be censored if they have no signs of local progression at the time of last tumor monitoring during follow-up or at the onset of one of the following competing risk events not associated with local progression: death, lost to follow up, unauthorized non-protocol treatment of the target lesion. Confirmatory analysis of the primary endpoint variable will be performed using a p-value of p≤0.05 as the global significance level. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CNS toxicity according to CTCAE v5.0 | CNS toxicity according to CTCAE v5.0 | 12 months | 
| Time to local progression (Volumetric RANO-BM criteria) | Based on the RANO-BM criteria, progression is defined as an increase in volume of 72.8% or more (corresponds to a 20% increase in diameter for a perfect sphere). | 12 months | 
| Quality of Life according to EORTC QLQ-C30 | Quality of life measured by European Organization for Research and Treatment of Cancer (EORTC) questionnaire QLQ C30 | Change from baseline to 3, 6, 12 and 24 months | 
| Local-Progression-Free Survival | Local-Progression-Free Survival is defined like TTLP except that death not associated with local progression will not be censored but assessed as a separate event | 12 months | 
| Overall Survival | Overall Survival | 24 months | 
| Quality of Life according to EORTC QLQ-BN20 | Quality of life measured by European Organization for Research and Treatment of Cancer (EORTC) questionnaire QLQ BN20 | Change from baseline to 3, 6, 12 and 24 months |