Frameless Stereotactic Radiosurgery for Intact Brain Metastases

The Clinical Relevance of Margins in Frameless Stereotactic Radiosurgery for Intact Brain Metastases: a Randomized Trial of 0 vs 2 mm Margins

This is a randomized study to determine if not treating planning target volume (PTV) margins during radiation therapy worsens progression free survival rates in patients with brain metastases.

Study Overview

• Status: Recruiting
• Conditions: Brain Metastases
• Intervention / Treatment: Procedure: Stereotactic Radiosurgery

• Study Type: Interventional
• Enrollment (Estimated): 166
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Robyn Hseu; Phone Number: 773-834-3198; Email: rhseu@radonc.uchicago.edu

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Recruiting
      • University of Chicago
      • Contact: Robyn Hseu; Email: rhseu@radonc.uchicago.edu
      • Principal Investigator: Steven J. Chmura, M.D., Ph.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult patients (≥ 18 years old) with an ECOG Performance Status 0-2 and a life expectancy of 3 months or more.
• Histologically confirmed systemic malignancy with gadolinium contrast-enhanced MRI scan demonstrating 1-5 intraparenchymal brain metastases.
• Well-circumscribed, measureable intraparenchymal brain lesion(s) with maximum tumor diameter ≤3.0 cm. If multiple lesions are present, the other(s) must not exceed 3.0 cm in maximum diameter. At least one lesion must be ≥1.0 cm in maximum diameter and ≥0.5 cm in a perpendicular diameter to be considered measurable disease.
• Negative urine or serum pregnancy test done ≤ 14 days prior to CT simulation, for women of child-bearing potential only.
• Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

• Diagnosis of germ cell tumor, small cell carcinoma or hematologic malignancy.
• Metastases in the brain stem, midbrain, pons, medulla, or within 7 mm of the optic apparatus (optic nerves, chiasm and optic tracts).
• Diagnosis of leptomeningeal disease.
• Prior cranial radiotherapy within 90 days of trial enrollment or prior SRS at any time to any lesion to be treated on protocol
• Chemotherapy (including oral agents and targeted agents) or immunotherapy given within 14 days of SRS. Hormonal therapy is permitted. For Her2+ breast cancer patients, anti-Her2 therapy cannot be given within 14 days of SRS. Patients who are scheduled to receive trastuzumab emtansine after SRS cannot be enrolled.
• Contraindications to gadolinium contrast-enhanced MRI (eg, non-compatible pacemaker, eGFR<30, gadolinium allergy).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Stereotactic Radiosurgery to 2 mm GTV to PTV margins	Procedure: Stereotactic Radiosurgery; The SRS dose will depend on the maximum diameter of the gross tumor volume (GTV)
Experimental: Stereotactic Radiosurgery to 0 mm GTV to PTV margins	Procedure: Stereotactic Radiosurgery; The SRS dose will depend on the maximum diameter of the gross tumor volume (GTV)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (PFS) rates estimated by the Kaplan-Meier method at 6 months	Progression free survival (PFS) rates will be estimated by the Kaplan-Meier method and the 0-mm and 2-mm groups will be compared via the log-rank statistic with a one-sided test of significance, using follow-up data up to 6 months.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (PFS) rates estimated by the Kaplan-Meier method	Progression free survival (PFS) rates will be estimated by the Kaplan-Meier method and the 0-mm, and 2-mm groups will be compared via the log-rank statistic with a one-sided test of significance, using follow-up data up to 6 months.	2 years
Rates of radiation necrosis	To evaluate the superiority of frameless LINAC-based SRS using 0 mm margins compared to 2 mm margins in reducing rates of radiation necrosis.	2 years
Rates of pseudoprogression	To evaluate the superiority of frameless LINAC-based SRS using 0 mm margins compared to 2 mm margins in reducing rates of radiation pseudoprogression.	2 years
Local failure rates	Local failure and OS rates at 6 months, 1 year and 2 years will be estimated by the Kaplan-Meier method, comparing arms via the log-rank statistic.	2 years
Rate of acute central nervous system (CNS) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grade 2 and higher toxicities	Any acute CTCAE v4.0 CNS Grade 2+ and Grade 3+ toxicities, within 90 days of SRS completion (toxicity must be specified).	90 days
Rates of distant intracranial failure	The appearance of new non-target lesions ≥5 mm following completion of radiotherapy will be considered distant intracranial failure. If a non-target lesion <5 mm is found on a later scan to have increased to ≥ 5 mm, distant intracranial failure will be declared at the date of the earliest scan showing the new lesion.	2 years
Rates of salvage therapy	Time to initiation of any combination of salvage Stereotactic Radiosurgery (SRS), Whole Brain Radiation Therapy WBRT, or neurosurgical resection for intracranial failure.	2 years
Association between dose and risk of radionecrosis or pseudoprogression	To determine association between V10Gy and V12Gy all tissue, whole brain and normal brain parameters and risk of radionecrosis or pseudoprogression.	2 years
Overall survival rates	Time from Stereotactic Radiosurgery (SRS) completion to death.	2 years
Rate of late central nervous system (CNS) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grade 2 and higher toxicities	To compare rates of late (greater than 90 days from SRS) CTCAE v4.0 CNS Grade 2+ and Grade 3+ toxicities.	2 years

Collaborators and Investigators

• Sponsor: University of Chicago
• Investigators: Principal Investigator: Steven J. Chmura, M.D., Ph.D., University of Chicago

Study record dates

Study Major Dates

• Study Start (Actual): September 5, 2023
• Primary Completion (Estimated): August 22, 2028
• Study Completion (Estimated): August 22, 2028

Study Registration Dates

• First Submitted: April 19, 2016
• First Submitted That Met QC Criteria: April 19, 2016
• First Posted (Estimated): April 21, 2016

Study Record Updates

• Last Update Posted (Estimated): December 29, 2025
• Last Update Submitted That Met QC Criteria: December 19, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: brain metastases; Stereotactic Radiosurgery
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms; Nervous System Neoplasms; Central Nervous System Neoplasms; Brain Neoplasms; Investigative Techniques; Therapeutics; Surgical Procedures, Operative; Radiotherapy; Stereotaxic Techniques; Neurosurgical Procedures; Radiosurgery
• Other Study ID Numbers: IRB15-1476

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No