Study of Fractionated Stereotactic Radiosurgery to Treat Large Brain Metastases

Study Overview
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Brief Summary
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The maximum tolerated dose of 3-session (ie, treatment) stereotactic radiosurgery (SRS) to treat brain metastases greater than 4.2 cm³ in size will be determined. This study investigates if increasing radiation dose improves outcome for patients without greater toxicity (side effects).

Detailed Description
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Brain metastases are the most common intracranial tumors and occur in approximately 25% of patients with cancer. In the US, approximately 170,000 cancer patients a year are diagnosed with brain metastases. The prognosis of patients with brain metastases is variable and depends on several factors, including performance status, age, control of the primary tumor, and extent of extracranial disease. Historically, patients with brain metastases who receive supportive care only have median survival of 1 to 2 months. However, a subgroup of patients with favorable prognosis who undergo treatment can enjoy an extended life expectancy with median survival of 10 to 16 months. Treatment options for brain metastases include medical management, surgery, and radiation therapy (radiotherapy). Both surgery and radiotherapy have an important role in management of brain metastases, and an optimized treatment plan may include both. It is well-established that surgery followed by conventional whole brain radiation (WBRT) decreases local recurrence and improves median survival compared to WBRT alone. Conventional WBRT is administered as radiotherapy to the whole cranium delivered in 10 to 20 daily treatments. For this study, radiotherapy will be delivered using stereotactic radiosurgery (SRS) to treat individual metastases. SRS has the advantage of sparing normal brain tissue. In SRS, high energy radiation is precisely directed at the target lesion. Due to the steep fall-off of the radiation dose away from the target, the advantage of relative sparing of the normal brain may be realized. The present study is based on a rationale of treating brain metastases with surgical resection followed by adjuvant SRS to the resection cavity, while deferring conventional WBRT for salvage therapy. WBRT is associated with a short-term decline in quality of life and long-term deficits in neurocognitive function (late effects). Late toxicity of WBRT, such as memory impairment and dementia, is usually irreversible and is likely due to demyelination, vascular damage, and necrosis. Following WBRT, the actuarial rate of neurocognitive toxicity at 2 years can be up to 49%. Recipients of WBRT may demonstrate a > 2 standard deviation decline in their performance at 6 months. Compared to SRS alone, WBRT was reported to be associated with a marked decline in learning and memory function at 4 months (49% vs 23%, in favor of SRS). To minimize the potential late effects of WBRT, investigators have explored the use of SRS alone, deferring the use of WBRT for salvage treatment if needed. Both retrospective analyses and a prospective randomized trial reported no apparent survival benefit to combining WBRT with SRS compared to SRS alone Primary Objectives: Determine the maximum tolerated dose (MTD) of stereotactic radiosurgery (SRS). Secondary Objectives: Determine the local control rate as assessed on MRI and clinical exam. Determine short- and long-term adverse effects. Determine the distant intra-cranial control rate. Determine the overall survival rate. Assess the patient's health related quality of life. Treatment Group assignment will be by SRS dose level. SRS will be administered as 3 fractions. Radiation dose is administered as Greys (or Grays; abbreviated Gy), a unit by which radiation is measured. Treatment Groups are as follows: Group 1 = 24 Gy (administered as 8 Gy x 3) Group 2 = 7 Gy (9 Gy x 3); Group 3 = 30 Gy (10 Gy x 3); Group 4 = 33 Gy (11 Gy x 3). Within each Treatment Group, analysis may be stratified by tumor size and suitability for surgical resection, as below. For those participants eligible for surgical resection, the procedure will be conducted in advance of the SRS treatment. Strata A will be those with tumors 4.2 to 14.1 cm³, and suitable for resection. Strata B will be those with tumors 4.2 to 14.1 cm³, but not suitable for resection. Strata C will be those with tumors 14.2 to 33.5 cm³, and suitable for resection. Strata D will be those with tumors 14.2 to 33.5 cm³, but not suitable for resection.

Official Title
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A Phase I/II Study of Fractionated Stereotactic Radiosurgery to Treat Large Brain Metastases

Conditions
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Brain Cancer, Neoplasm Metastasis, Cancer of Brain and Nervous System, Metastatic Malignant Neoplasm to Brain

Intervention / Treatment
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* Radiation: Fractionated Stereotactic Radiosurgery (SRS)
* Procedure: Surgical resection


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Age 18 years and older Pathologically-proven solid tumor malignancy 1 to 4 brain metastases, one of which is 4.2 to 33.5 cm³. Prior surgery or SRS is allowed as long as the target metastatic lesion in this study has not previously been treated with SRS. Prior cytotoxic systemic therapy must be completed ≥ 5 days prior to radiosurgery. No concurrent cytotoxic systemic therapy along with SRS. Cytotoxic systemic therapy to start ≥ 5 days after the completion of SRS. Life expectancy of ≥ 12 weeks. Ability to understand and the willingness to sign a written informed consent. EXCLUSION CRITERIA Previously treated with whole brain irradiation Target metastatic lesion previously been treated with SRS. > 4 total brain metastases at the time of initial evaluation. Pregnant Unable to give informed consent.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 - 24 Grey SRS<br>24 Grey administered as 8 Gy x 3 fractions | Radiation: Fractionated Stereotactic Radiosurgery (SRS)<br>* Standard of care<br>* Other names: Cyberknife surgery;Procedure: Surgical resection<br>* Standard of care<br>|
| Experimental: Arm 2 - 27 Grey SRS<br>27 Grey administered as 9 Gy x 3 fractions | Radiation: Fractionated Stereotactic Radiosurgery (SRS)<br>* Standard of care<br>* Other names: Cyberknife surgery;Procedure: Surgical resection<br>* Standard of care<br>|
| Experimental: Arm 3 - 30 Grey SRS<br>30 Grey administered as 10 Gy x 3 fractions | Radiation: Fractionated Stereotactic Radiosurgery (SRS)<br>* Standard of care<br>* Other names: Cyberknife surgery;Procedure: Surgical resection<br>* Standard of care<br>|
| Experimental: Arm 4 - 33 Grey SRS<br>33 Grey administered as 11 Gy x 3 fractions | Radiation: Fractionated Stereotactic Radiosurgery (SRS)<br>* Standard of care<br>* Other names: Cyberknife surgery;Procedure: Surgical resection<br>* Standard of care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stereotactic Radiosurgery (SRS) Maximum-tolerated Dose (MTD) | The maximum-tolerated Dose (MTD) of stereotactic radiosurgery (SRS) was assessed based on the number of dose-limiting toxicities (DLTs). DLT was defined as any treatment-related grade 3, 4, or 5 central nervous system (CNS) radiation morbidity observed within 30 days of radiosurgery. CNS radiation morbidity was further defined as. 5 = Death 4 = Serious neurologic impairment such as paralysis, coma, or seizures > 3/week 3 = Neurologic findings requiring hospitalization 2 = Neurologic findings present sufficient to require attendant care 1 = Fully functional status (ie, able to work) with minor neurologic findings; no medication needed 0 = No Change The outcome is expressed as number of DLTs experienced by participants, by radiotherapy dose cohort and tumor size, a number without dispersion. Per protocol, the MTD of SRS was defined as either the dose level below that at which 4+ DLTs were experienced by 12 subjects, or the maximum dose administered without MTD. | 60 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local Disease Control | Local disease control (treatment response) was assessed on the basis of tumor size before and 12 months after treatment. Treatment response was based on the following criteria. Tumor area is determined as the product of 2 measurements of lesion diameter. Complete response (CR): The tumor is no longer seen within the radiosurgical target volume Partial response (PR): Decrease of > 50% in tumor area Minor response (MR): Decrease of < 50% in tumor area Stable disease (SD): The scan shows no change. Progression (P): A > 25% increase in tumor area, or any new lesion within the radiosurgical target volume. Local control is defined as as any treatment response other than progression. The outcome is as the number of participants that did not progress, by radiotherapy dose cohort and tumor size, a number without dispersion. | 12 months | 
| Distant Intra-cranial Disease Control | Distant treatment failure (failure to achieve or maintain disease control) is defined as the radiographic appearance of a new or enhancing lesion more than 5 mm from the radiosurgical target volume. The outcome is expressed as the number of participants who have distant treatment failure after radiotherapy dose cohort and tumor size, a number without dispersion. | 12 months | 
| Adverse Effects Within 30 Days | Short-term adverse effects are defined as any adverse event related to the stereotactic radiosurgery (SRS), and occurring within 30 days of SRS. The outcome is expressed as the number of events experienced by participants, by radiotherapy dose cohort and tumor size, a number without dispersion. | 30 days | 
| Adverse Effects More Than 30 Days up to 1 Year | Long-term adverse effects are defined as any adverse event related to the stereotactic radiosurgery (SRS), and occurring more 30 days but within 12 months of SRS. The outcome is expressed as the number of events experienced by participants, by radiotherapy dose cohort and tumor size, a number without dispersion. | after 30 days and up to 1 year | 
| Overall Survival (OS) | Overall survival (OS) is assessed as remaining alive 3 years after stereotactic radiosurgery (SRS) therapy. The outcome is expressed as the number of participants alive 3 years after SRS, by radiotherapy dose cohort and tumor size, a number without dispersion. | 3 years | 
| Health-related Quality of Life (HR-QoL), as Measured by EORTC QLQ-C30 | Health-related quality of life (HR-QoL), was assessed based on the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life of Cancer Patients (QLQ-C30) survey, a survey of 28 questions with the following responses / numerical values. Not at all A Little Quite a Bit Very Much Response range is 28 to 112, normalized to a 100 point scale. Lower values indicate little effect of disease, and higher values indicate greater effect. The outcome is expressed as the median value with full range, by radiotherapy dose cohort and tumor size. | 6 months | 
| Health-related Quality of Life (HR-QoL), as Measured by EORTC Brain Cancer Module QLQ-BN20 | Health-related quality of life (HR-QoL), was assessed based on the European Organisation for Research and Treatment of Cancer (EORTC) Brain Cancer Module (QLQ-BN20), a survey of 20 questions with the following responses / numerical values. Not at all A Little Quite a Bit Very Much Response range is 20 to 80, normalized to a 0 to 100 scale. Lower values indicate little effect of disease, and higher values indicate greater effect. The outcome is expressed as the median value with full range, by radiotherapy dose cohort and tumor size. | 6 months |