Study of Fractionated Stereotactic Radiosurgery to Treat Large Brain Metastases

January 6, 2024 updated by: Scott Soltys, Stanford University

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

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).

Study Overview

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 Type

Interventional

Enrollment (Actual)

56

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • California
      • Stanford, California, United States, 94305
        • Stanford University School of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Arm 1 - 24 Grey SRS
24 Grey administered as 8 Gy x 3 fractions
Standard of care
Other Names:
  • Cyberknife surgery
Standard of care
Experimental: Arm 2 - 27 Grey SRS
27 Grey administered as 9 Gy x 3 fractions
Standard of care
Other Names:
  • Cyberknife surgery
Standard of care
Experimental: Arm 3 - 30 Grey SRS
30 Grey administered as 10 Gy x 3 fractions
Standard of care
Other Names:
  • Cyberknife surgery
Standard of care
Experimental: Arm 4 - 33 Grey SRS
33 Grey administered as 11 Gy x 3 fractions
Standard of care
Other Names:
  • Cyberknife surgery
Standard of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Stereotactic Radiosurgery (SRS) Maximum-tolerated Dose (MTD)
Time Frame: 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.

60 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Local Disease Control
Time Frame: 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.

12 months
Distant Intra-cranial Disease Control
Time Frame: 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.
12 months
Adverse Effects Within 30 Days
Time Frame: 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
Time Frame: 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.
after 30 days and up to 1 year
Overall Survival (OS)
Time Frame: 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.
3 years
Health-related Quality of Life (HR-QoL), as Measured by EORTC QLQ-C30
Time Frame: 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.

  1. Not at all
  2. A Little
  3. Quite a Bit
  4. 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
Time Frame: 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.

  1. Not at all
  2. A Little
  3. Quite a Bit
  4. 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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 1, 2009

Primary Completion (Actual)

October 31, 2017

Study Completion (Actual)

December 1, 2019

Study Registration Dates

First Submitted

June 23, 2009

First Submitted That Met QC Criteria

June 24, 2009

First Posted (Estimated)

June 25, 2009

Study Record Updates

Last Update Posted (Actual)

January 30, 2024

Last Update Submitted That Met QC Criteria

January 6, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Other Study ID Numbers

  • IRB-15107
  • SU-04272009-2418 (Other Identifier: Stanford University)
  • BRN0010 (Other Identifier: OnCore)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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