Study of Fractionated Stereotactic Radiosurgery to Treat Large Brain Metastases

• Sponsor: Stanford University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00928226
• Collaborator: (none)
• Enrollment: 56
• Location: 1
• Arms: 4
• Actual Duration (Months): 128
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Brain Cancer; Neoplasm Metastasis; Cancer of Brain and Nervous System; Metastatic Malignant Neoplasm to Brain	Radiation: Fractionated Stereotactic Radiosurgery (SRS); Procedure: Surgical resection	N/A

Detailed Description

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:

1. Determine the local control rate as assessed on MRI and clinical exam.

2. Determine short- and long-term adverse effects.

3. Determine the distant intra-cranial control rate.

4. Determine the overall survival rate.

5. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 56 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of Fractionated Stereotactic Radiosurgery to Treat Large Brain Metastases
• Actual Study Start Date: Apr 1, 2009
• Actual Primary Completion Date: Oct 31, 2017
• Actual Study Completion Date: Dec 1, 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Stereotactic Radiosurgery (SRS) Maximum-tolerated Dose (MTD) [60 days]

   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.

Secondary Outcome Measures

1. Local Disease Control [12 months]

   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.

2. Distant Intra-cranial Disease Control [12 months]

   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.

3. Adverse Effects Within 30 Days [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.

4. Adverse Effects More Than 30 Days up to 1 Year [after 30 days and 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.

5. Overall Survival (OS) [3 years]

   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.

6. Health-related Quality of Life (HR-QoL), as Measured by EORTC QLQ-C30 [6 months]

   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.

7. Health-related Quality of Life (HR-QoL), as Measured by EORTC Brain Cancer Module QLQ-BN20 [6 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University School of Medicine	Stanford	California	United States	94305

Sponsors and Collaborators

• Stanford University

Investigators

• Principal Investigator: Clara Choi, Stanford University
• Principal Investigator: Scott Soltys, Stanford University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 18, 2013
• Informed Consent Form - Dec 16, 2014

More Information

Publications

None provided.

• Responsible Party: Scott Soltys, Assistant Professor of Radiation Oncology, Stanford University
• ClinicalTrials.gov Identifier: NCT00928226
• Other Study ID Numbers: IRB-15107; SU-04272009-2418; BRN0010
• First Posted: Jun 25, 2009
• Last Update Posted: Jan 22, 2020
• Last Verified: Jan 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Additional relevant MeSH terms: Neoplasms; Neoplasm Metastasis; Brain Neoplasms

Study Results

Participant Flow

Arm/Group Title	Arm 1 - 24 Grey SRS	Arm 2 - 27 Grey SRS	Arm 3 - 30 Grey SRS	Arm 4 - 33 Grey SRS
Arm/Group Description	24 Grey administered as 8 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	27 Grey administered as 9 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	30 Grey administered as 10 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	33 Grey administered as 11 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care
Period Title: Overall Study
STARTED	20	12	12	12
Strata A: Small Tumor, Resected	6	6	6	6
Strata B: Small Tumor, Not Resected	5	0	0	0
Strata C: Large Tumor, Resected	8	6	6	6
Strata D: Large Tumor, Not Resected	1	0	0	0
COMPLETED	20	12	12	12
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Arm 1 - 24 Grey SRS	Arm 2 - 27 Grey SRS	Arm 3 - 30 Grey SRS	Arm 4 - 33 Grey SRS	Total
Arm/Group Description	24 Grey administered as 8 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	27 Grey administered as 9 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	30 Grey administered as 10 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	33 Grey administered as 11 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	Total of all reporting groups
Overall Participants	20	12	12	12	56
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	16 80%	5 41.7%	7 58.3%	7 58.3%	35 62.5%
>=65 years	4 20%	7 58.3%	5 41.7%	5 41.7%	21 37.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.8 (11.0)	67.2 (12.0)	58.9 (12.2)	59.2 (12.1)	61.1 (11.9)
Sex: Female, Male (Count of Participants)
Female	8 40%	5 41.7%	5 41.7%	6 50%	24 42.9%
Male	12 60%	7 58.3%	7 58.3%	6 50%	32 57.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 5%	1 8.3%	2 16.7%	2 16.7%	6 10.7%
Not Hispanic or Latino	15 75%	6 50%	10 83.3%	10 83.3%	41 73.2%
Unknown or Not Reported	4 20%	5 41.7%	0 0%	0 0%	9 16.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	1 5%	0 0%	1 8.3%	0 0%	2 3.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%
White	13 65%	5 41.7%	11 91.7%	11 91.7%	40 71.4%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	6 30%	7 58.3%	0 0%	1 8.3%	14 25%
Region of Enrollment (participants) [Number]
United States	20 100%	12 100%	12 100%	12 100%	56 100%

Outcome Measures

1. Primary Outcome

Title	Stereotactic Radiosurgery (SRS) Maximum-tolerated Dose (MTD)
Description	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.
Time Frame	60 days

Outcome Measure Data

Analysis Population Description

There were few participants who did not receive tumor resection, and these were restricted to Arm 1 (24 Grey SRS).

Arm/Group Title	Arm 1 - 24 Grey SRS	Arm 2 - 27 Grey SRS	Arm 3 - 30 Grey SRS	Arm 4 - 33 Grey SRS
Arm/Group Description	24 Grey administered as 8 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	27 Grey administered as 9 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	30 Grey administered as 10 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	33 Grey administered as 11 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care
Measure Participants	20	12	12	12
Strata A: Small tumor, resected	0	0	0	0
Strata B: Small tumor, not resected	0
Strata C: Large tumor, resected	0	0	0	0
Strata D: Large tumor, not resected	0

2. Secondary Outcome

Title	Local Disease Control
Description	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.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

There were few participants who did not receive tumor resection, and these were restricted to Arm 1 (24 Grey SRS). Only participants with 12-month treatment response data are included.

Arm/Group Title	Arm 1 - 24 Grey SRS	Arm 2 - 27 Grey SRS	Arm 3 - 30 Grey SRS	Arm 4 - 33 Grey SRS
Arm/Group Description	24 Grey administered as 8 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	27 Grey administered as 9 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	30 Grey administered as 10 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	33 Grey administered as 11 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care
Measure Participants	11	10	12	12
Strata A: Small tumor, resected	4 20%	6 50%	5 41.7%	6 50%
Strata B: Small tumor, not resected	0 0%
Strata C: Large tumor, resected	5 25%	4 33.3%	6 50%	4 33.3%

3. Secondary Outcome

Title	Distant Intra-cranial Disease Control
Description	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.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

There were few participants who did not receive tumor resection, and these were restricted to Arm 1 (24 Grey SRS). Only participants with 12-month disease status data are included.

Arm/Group Title	Arm 1 - 24 Grey SRS	Arm 2 - 27 Grey SRS	Arm 3 - 30 Grey SRS	Arm 4 - 33 Grey SRS
Arm/Group Description	24 Grey administered as 8 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	27 Grey administered as 9 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	30 Grey administered as 10 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	33 Grey administered as 11 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care
Measure Participants	11	10	9	12
Strata A: Small tumor, resected	4 20%	3 25%	2 16.7%	2 16.7%
Strata B: Small tumor, not resected	2 10%
Strata C: Large tumor, resected	3 15%	3 25%	3 25%	3 25%

4. Secondary Outcome

Title	Adverse Effects Within 30 Days
Description	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.
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

There were few participants who did not receive tumor resection, and these were restricted to Arm 1 (24 Grey SRS).

Arm/Group Title	Arm 1 - 24 Grey SRS	Arm 2 - 27 Grey SRS	Arm 3 - 30 Grey SRS	Arm 4 - 33 Grey SRS
Arm/Group Description	24 Grey administered as 8 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	27 Grey administered as 9 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	30 Grey administered as 10 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	33 Grey administered as 11 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care
Measure Participants	20	12	12	12
Strata A: Small tumor, resected	3	4	4	2
Strata B: Small tumor, not resected	3
Strata C: Large tumor, resected	4	2	2	3
Strata D: Large tumor, not resected	1

5. Secondary Outcome

Title	Adverse Effects More Than 30 Days up to 1 Year
Description	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.
Time Frame	after 30 days and up to 1 year

Outcome Measure Data

Analysis Population Description

There were few participants who did not receive tumor resection, and these were restricted to Arm 1 (24 Grey SRS). Only participants surviving more than 30 days are included.

Arm/Group Title	Arm 1 - 24 Grey SRS	Arm 2 - 27 Grey SRS	Arm 3 - 30 Grey SRS	Arm 4 - 33 Grey SRS
Arm/Group Description	24 Grey administered as 8 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	27 Grey administered as 9 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	30 Grey administered as 10 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	33 Grey administered as 11 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care
Measure Participants	19	12	12	12
Strata A: Small tumor, resected	6	1	3	2
Strata B: Small tumor, not resected	1
Strata C: Large tumor, resected	3	4	6	5

6. Secondary Outcome

Title	Overall Survival (OS)
Description	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.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

There were few participants who did not receive tumor resection, and these were restricted to Arm 1 (24 Grey SRS).

Arm/Group Title	Arm 1 - 24 Grey SRS	Arm 2 - 27 Grey SRS	Arm 3 - 30 Grey SRS	Arm 4 - 33 Grey SRS
Arm/Group Description	24 Grey administered as 8 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	27 Grey administered as 9 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	30 Grey administered as 10 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	33 Grey administered as 11 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care
Measure Participants	20	12	12	12
Strata A: Small tumor, resected	3 15%	4 33.3%	3 25%	5 41.7%
Strata B: Small tumor, not resected	2 10%
Strata C: Large tumor, resected	5 25%	2 16.7%	4 33.3%	2 16.7%
Strata D: Large tumor, not resected	0 0%

7. Secondary Outcome

Title	Health-related Quality of Life (HR-QoL), as Measured by EORTC QLQ-C30
Description	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.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

There were few participants who did not receive tumor resection, and these were restricted to Arm 1 (24 Grey SRS). Only participants providing 6-month European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life of Cancer Patients (QLQ-C30) health-related quality of life (HR-QoL) data are included.

Arm/Group Title	Arm 1 - 24 Grey SRS	Arm 2 - 27 Grey SRS	Arm 3 - 30 Grey SRS	Arm 4 - 33 Grey SRS
Arm/Group Description	24 Grey administered as 8 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	27 Grey administered as 9 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	30 Grey administered as 10 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	33 Grey administered as 11 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care
Measure Participants	15	11	6	12
Strata A: Small tumor, resected	100	83.3	75	50
Strata B: Small tumor, not resected	75
Strata C: Large tumor, resected	87.5	75	83.3	83.3

8. Secondary Outcome

Title	Health-related Quality of Life (HR-QoL), as Measured by EORTC Brain Cancer Module QLQ-BN20
Description	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.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

There were few participants who did not receive tumor resection, and these were restricted to Arm 1 (24 Grey SRS). Only participants with 6-month European Organisation for Research and Treatment of Cancer (EORTC) Brain Cancer Module (QLQ-BN20) health-related quality of life (HR-QoL) data are included.

Arm/Group Title	Arm 1 - 24 Grey SRS	Arm 2 - 27 Grey SRS	Arm 3 - 30 Grey SRS	Arm 4 - 33 Grey SRS
Arm/Group Description	24 Grey administered as 8 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	27 Grey administered as 9 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	30 Grey administered as 10 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care	33 Grey administered as 11 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care
Measure Participants	16	11	6	12
Strata A: Small tumor, resected	0	16.7	16.5	16.7
Strata B: Small tumor, not resected	0
Strata C: Large tumor, resected	12.5	33.3	8.3	8.3

Adverse Events

Time Frame	3 years
Arm/Group Title	Arm 1 - 24 Grey SRS		Arm 2 - 27 Grey SRS		Arm 3 - 30 Grey SRS		Arm 4 - 33 Grey SRS
Arm/Group Description	24 Grey administered as 8 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care		27 Grey administered as 9 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care		30 Grey administered as 10 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care		33 Grey administered as 11 Gy x 3 fractions Fractionated Stereotactic Radiosurgery (SRS): Standard of care Surgical resection: Standard of care
All Cause Mortality
	Arm 1 - 24 Grey SRS		Arm 2 - 27 Grey SRS		Arm 3 - 30 Grey SRS		Arm 4 - 33 Grey SRS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/20 (50%)		6/12 (50%)		5/12 (41.7%)		5/12 (41.7%)
Serious Adverse Events
	Arm 1 - 24 Grey SRS		Arm 2 - 27 Grey SRS		Arm 3 - 30 Grey SRS		Arm 4 - 33 Grey SRS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/20 (65%)		6/12 (50%)		12/12 (100%)		3/12 (25%)
Cardiac disorders
Chest pain - cardiac	0/20 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0
Gastrointestinal disorders
Enterocolitis	0/20 (0%)	0	1/12 (8.3%)	2	0/12 (0%)	0	0/12 (0%)	0
Rectal Pain	0/20 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0
Gastrointestinal disorders-Others, retrosigmoid stent migration to colon wall	0/20 (0%)	0	1/12 (8.3%)	2	0/12 (0%)	0	0/12 (0%)	0
Constipation	0/20 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0
Nausea	0/20 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0
General disorders
Pain-leg pain	0/20 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0
Multi-organ failure	1/20 (5%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0
Death NOS	2/20 (10%)	2	1/12 (8.3%)	1	1/12 (8.3%)	1	0/12 (0%)	0
Infections and infestations
Infection and infectations-other, fever	0/20 (0%)	0	0/12 (0%)	0	2/12 (16.7%)	3	0/12 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified-Other disease progression	9/20 (45%)	9	3/12 (25%)	3	0/12 (0%)	0	0/12 (0%)	0
Nervous system disorders
Nervous system disorders	0/20 (0%)	0	0/12 (0%)	0	2/12 (16.7%)	2	2/12 (16.7%)	2
Seizure	1/20 (5%)	2	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0
Cognitive disturbance	0/20 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1
Altered mental status	0/20 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0
Renal and urinary disorders
Renal and urinary disorders -Others, Renal Failure	0/20 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm 1 - 24 Grey SRS		Arm 2 - 27 Grey SRS		Arm 3 - 30 Grey SRS		Arm 4 - 33 Grey SRS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/20 (100%)		12/12 (100%)		12/12 (100%)		12/12 (100%)
Ear and labyrinth disorders
Ear and labyrinth disorders-Other, imbalance	1/20 (5%)	1	2/12 (16.7%)	2	1/12 (8.3%)	1	1/12 (8.3%)	1
Eye disorders
Watering eyes	0/20 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0
Eye disorders - Other, diplopia	0/20 (0%)	0	1/12 (8.3%)	1	2/12 (16.7%)	2	0/12 (0%)	0
Eye disorders - Other, visual field loss	2/20 (10%)	2	1/12 (8.3%)	1	1/12 (8.3%)	1	3/12 (25%)	3
Gastrointestinal disorders
Nausea	0/20 (0%)	0	1/12 (8.3%)	1	4/12 (33.3%)	4	2/12 (16.7%)	2
Dysphagia	0/20 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0
Vomitting	1/20 (5%)	1	1/12 (8.3%)	1	1/12 (8.3%)	1	0/12 (0%)	0
General disorders
Fatigue	2/20 (10%)	2	2/12 (16.7%)	2	3/12 (25%)	3	4/12 (33.3%)	4
Metabolism and nutrition disorders
Anorexia	0/20 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	4/20 (20%)	4	2/12 (16.7%)	2	1/12 (8.3%)	1	0/12 (0%)	0
Pain in extremity	1/20 (5%)	1	3/12 (25%)	3	2/12 (16.7%)	2	0/12 (0%)	0
Nervous system disorders
Headache	4/20 (20%)	4	3/12 (25%)	3	2/12 (16.7%)	2	1/12 (8.3%)	1
Paresthesia	1/20 (5%)	1	2/12 (16.7%)	2	0/12 (0%)	0	0/12 (0%)	0
Dysarthria	0/20 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0
Memory impairment	0/20 (0%)	0	1/12 (8.3%)	1	1/12 (8.3%)	1	1/12 (8.3%)	1
Central nervous system necrosis	2/20 (10%)	2	2/12 (16.7%)	2	1/12 (8.3%)	1	5/12 (41.7%)	5
Ataxia	0/20 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0
Psychiatric disorders
Confusion	1/20 (5%)	1	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0
Respiratory, thoracic and mediastinal disorders
Tracheal mucositis	0/20 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0
Hoarseness	0/20 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0
Skin and subcutaneous tissue disorders
Allopecia	1/20 (5%)	1	5/12 (41.7%)	5	7/12 (58.3%)	7	4/12 (33.3%)	4
Pruritus	0/20 (0%)	0	1/12 (8.3%)	1	1/12 (8.3%)	1	1/12 (8.3%)	1

Limitations/Caveats

[Not Specified]

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.