Hypofractionated Stereotactic Radiosurgery in Treating Patients With Large Brain Metastasis

Study Overview
=================
Brief Summary
-----------------
This phase I trial studies the side effects and best dose of hypofractionated radiosurgery in treating patients with large brain metastasis. Stereotactic radiosurgery can send x-rays directly to the tumor and cause less damage to normal tissue. Giving fractionated stereotactic radiosurgery may kill more tumor cells.

Detailed Description
-----------------
PRIMARY OBJECTIVE: To demonstrate the safety and feasibility of treating brain metastases or resection cavities greater than 3 cm with hypofractionated radiosurgery and to determine the maximum-tolerated radiation dose for hypofractionated radiosurgery (HR) delivered in 5 fractions, 2-3 fractions per week. OUTLINE: This is a dose-escalation study. Patients undergo hypofractionated stereotactic radiosurgery 2-3 times weekly (5 fractions total) for 2-3 weeks. After completion of study treatment, patients are followed up at 1 month and then every 3 months thereafter.

Official Title
-----------------
Phase I Dose Escalation Trial of Hypofractionated Radiosurgery for Large Brain Metastasis

Conditions
-----------------
Metastatic Malignant Neoplasm to Brain, Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
-----------------
* Radiation: Hypofractionated Radiosurgery


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pathologic proven diagnosis of solid tumor malignancy One brain metastasis or brain metastasis resection cavity with maximal diameter ≥ 3 cm (or ≥ 14 cc.) and ≤ 6 cm (or ≤ 113 cc.) Recursive partitioning analysis (RPA) class I-II/ Karnofsky Performance status (KPS) ≥ 70% Exclusion Criteria: Prior stereotactic radiosurgery (SRS) to adjacent lesion such that planning target volume would have received more than 12 Gy RPA class III (KPS < 70%) Brain metastasis or resection cavity volume < 3 cm or > 6 cm Radiosensitive or non-solid (eg. small cell lung carcinomas, germ cell tumors, leukemias, or lymphomas) or unknown tumor histologies Concurrent chemotherapy (no chemotherapy starting 14 days before start of radiation) Evidence of leptomeningeal disease by magnetic resonance imaging (MRI) and/or cerebrospinal fluid (CSF) cytology Current pregnancy More than 8 weeks between resection and radiosurgical procedure Metastases to brain stem, midbrain, pons, or medulla or within 5 mm of the optic apparatus (optic nerves and chiasm) Inability to undergo MRI evaluation for treatment planning and follow-up

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hypofractionated Radiosurgery<br>HR (Hypofractionated Radiosurgery) delivered in 5 fractions, with a minimum of 2 and a maximum of 3 fractions being delivered per week, to patients with brain metastases or resection cavity greater than 3 cm and less than 6 cm. Dose escalation will proceed according to the Escalation with Overdose Control (EWOC) method with a planned total enrollment of 24 patients, in 8 patient cohorts with 3 patients per cohort. A 4 month observation period will occur for each completed cohort prior to dose escalation, with a goal timeline for trial completion of 4 years from first patient enrollment. | Radiation: Hypofractionated Radiosurgery<br>* Radiation Therapy will consist of partial brain irradiation delivered to the metastatic brain tumor or resection cavity, delivered in 5 treatments with 2-3 treatments delivered per week.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of hypofractionated radiosurgery defined as the highest dose level where a grade 3 or greater with an attribution score of ≥ 3 develops in ≤ 2 of 6 patients in a dose group | Graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The rate of toxicities will be calculated with 95% confidence interval (CI). | 4 months | 
| Neurologic toxicity due to treatment, graded according to the CTCAE version 4.03 | Calculated with 95% CI. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local control; lack of progression of disease in resection cavity as defined by Response Evaluation Criteria In Solid Tumors (RECIST) criteria | The median time to local brain progression will be calculated by Kaplan-Meier method with 95% CI. | 4 months | 
| Distant control: lack of progression of disease in surrounding brain as defined by RECIST criteria | The median time to distant brain progression will be calculated by Kaplan-Meier method with 95% CI. | 4 months | 
| Freedom from failure/progression free survival |  | Up to 2 years | 
| Overall survival (OS): death from any cause | The median of OS time with 95% CI will be calculated by Kaplan-Meier method. | Up to 2 years | 
| Long-term neurocognitive outcomes: using the Hopkins Verbal Learning Test-Revised (HVLT-R), Mini Mental Status Exam (MMSE) and Cognitive Functioning Subscale of the Medical Outcomes Scale (MOS) | Neurocognitive effect will be regressed over time using generalized estimating equation (GEE) model. The population change over time (slope) will be estimated with 95% CI. | Up to 2 years | 
| Quality of life (QOL) outcomes: using the quality of life questionnaire for the Functional Assessment of Cancer Therapy-Brain (FACT-Br). | QOL outcomes will be regressed over time using GEE model. The population change over time (slope) will be estimated with 95% CI. | Up to 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Brain metastasis