Neoadjuvant Radiosurgery for Resectable Brain Metastases: Phase I/II Study

Study Overview
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Brief Summary
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This Phase I/II trial studies the ability to stop brain metastases from coming back after treatment with radiosurgery followed by surgical resection. It will also evaluate the side effects of these combined treatments and help determine the best radiosurgery dose. Radiosurgery focuses the x-rays directly to the tumor and cause less damage to the normal tissue in the brain.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the safety (risk of acute and long-term toxicities) of neoadjuvant radiosurgery at escalating doses followed by surgical resection of brain metastases. (Phase I) II. To determine the local control of brain metastases treated with neoadjuvant radiosurgery followed by surgical resection. (Phase II) SECONDARY OBJECTIVES: I. To determine the rate of distant brain failure when brain metastases are managed with neoadjuvant radiosurgery followed by surgical resection. II. To estimate the rate of salvage surgery, whole brain radiation therapy (WBRT), or stereotactic radiosurgery (SRS) for participants treated with neoadjuvant radiosurgery followed by surgical resection. III. To determine the rate of radiation necrosis/steroid dependency. IV. To determine the radiobiologic impact of neoadjuvant radiosurgery for resected brain metastases. OUTLINE: This is a phase I, dose-escalation study of radiosurgery followed by a phase II study. The following outcomes were removed from the protocol in an amendment: Changes in neurocognitive function as measured by the Hopkins Verbal Learning Test (HVLT), Controlled Oral Word Association (COWA) & Trailmaking Test B, and Trailmaking Test A QOL measured by FACT-BR and EORTC-QLQ30

Official Title
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Neoadjuvant Radiosurgery for Resectable Brain Metastases: Phase I/II Study

Conditions
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Tumors Metastatic to Brain

Intervention / Treatment
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* Radiation: radiosurgery
* Procedure: therapeutic conventional surgery
* Procedure: quality-of-life assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a prior histologic diagnosis of cancer other than small cell lung cancer, lymphoma, and germ cell histologies Magnetic resonance imaging (MRI) evidence of 1-4 brain metastases, with at least one lesion > 20 mm and ≤ 50 mm in maximal diameter and determined to be appropriate for SRS and gross total resection; all other brain metastases are appropriate for SRS Patient can have prior SRS to lesions other than the one planned for neoadjuvant SRS and resection Patient must have a Karnofsky performance score of ≥ 70 Exclusion Criteria: Patient deemed medically unfit to undergo surgical resection of brain metastasis Prior whole brain radiotherapy Patient with contraindication for imaging with MRI Inability to participate in study activities due to physical or mental limitations Inability or unwillingness to return for all the required follow-up visits At the time of planning, unable to deliver 10 Gray (Gy) or less to optic nerve/chiasm Tumor located in the brainstem Imaging or cytologic evidence of leptomeningeal disease

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (radiosurgery, surgery)<br>Patients undergo radiosurgery on day 0. Within 2 weeks, patients undergo surgical resection. | Radiation: radiosurgery<br>* Undergo radiosurgery<br>* Other names: radiation surgery;Procedure: therapeutic conventional surgery<br>* Undergo surgical resection<br>Procedure: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) | MTD of radiosurgery determined by dose-limiting toxicities graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 (Phase I) | Day 0 | 
| Proportion of participants without local failure (Phase II) | Local control of brain metastases, as measured by proportion of participants without local failure (Local failure is tumor progression of the metastasis treated on the study) (Phase II) The Kaplan-Meier method will be used. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with distant brain failure | Rate of distant brain failure, defined as progression of brain metastases outside of the brain metastasis treated on study. The Kaplan-Meier method will be used. | Up to 3 years | 
| Rate of radiation necrosis/steroid dependency | Rate of radiation necrosis/steroid dependency | Up to 3 years | 
| Rate of salvage treatment | Number of patients that have any salvage treatment, including surgery, stereotactic radiosurgery (SRS), or whole brain radiation therapy (WBRT) | Up to 3 years |