Trial of Differential Margins in Single Isocenter Radiosurgery of Brain Metastases

UAB 2507 - Randomized Phase II Study of Differential Margins in Single Isocenter Radiosurgery of Brain Metastases

Radiosurgery is the use of a focal high dose of radiation therapy to ablate or kill a tumor. This trial will enroll patients with brain metastases 4 cm or less in greatest diameter and will compare 0mm margin to a 2mm margin for treatment.

Study Overview

• Status: Recruiting
• Conditions: Brain Metastases
• Intervention / Treatment: Procedure: brain metastases radiosurgery

Detailed Description

Without a stereotactic frame there is considerable variation in practice in the use of planning target volume (PTV) margins for linac radiosurgery. In particular, the use of a single isocenter for multiple targets geometrically increases the risk that rotational errors will result in significant dosimetric errors, and many centers have considered adding margin. A recent AAPM task group survey has found that ~90% of centers worldwide add a PTV margin to account for error and that 8% add more than 2 mm. The most common margin is 2 mm. Other potential reasons to add a margin include spacial MRI error, couch walkout, CBCT to linac isocenter mismatch, and undetected intrafraction motion. Treatment volume is the greatest predictor of radiation toxicity associated with radiosurgery and potentially unnecessary margins will lead to increased risk to the patient. This trial will incorporate a composite endpoint that includes control of the tumor and toxicity.

Uncomplicated tumor control probability (UTCP) is defined as the chance the tumor is locally controlled (TCP) without grade 3 or greater CNS toxicity (1-NTCP). The investigators hypothesize a 2 mm margin will worsen uncomplicated control compared to a 0 mm PTV margin in the treatment multiple metastases in a single fraction.

This trial will inform the standard of care margin (0 mm vs 2 mm) for single isocenter treatment of multiple targets.

• Study Type: Interventional
• Enrollment (Estimated): 180
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: John Fiveash, MD; Phone Number: 205-975-0224; Email: jfiveash@uabmc.edu

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • Recruiting
      • University of Alabama at Birmingham (UAB) Hazelrig-Salter Radiation Oncology Center
      • Principal Investigator: John Fiveash, MD
      • Sub-Investigator: Kristen Riley, MD
      • Sub-Investigator: Richard Popple, MD
      • Sub-Investigator: Christopher Willey, MD
      • Sub-Investigator: Samual Marcrom, MD
      • Sub-Investigator: Hunter Boggs, MD
      • Sub-Investigator: Christopher Dobbelbower, MD
      • Sub-Investigator: James Markert, MD
      • Sub-Investigator: Phillip Schmalz, MD
      • Sub-Investigator: Winfield Fisher, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Stated willingness to comply with all study procedures and availability for the duration of the study
2. Male or female, aged 19 and older
3. Brain metastases diagnosis not requiring retreatment to the same tumor
4. For females of reproductive potential should undergo pregnancy testing as per UAB Radiation Oncology standard policies
5. Ability of subject or Legally Authorized Representative (LAR)) to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Current use of cytotoxic chemotherapy within 3 days of treatment. There are no restrictions on the use of immunotherapy during treatment. TKIs known to be radiation sensitizers such as BRAF should be held at least 24 hours prior to treatment.
2. Inability to have MRI imaging
3. Pregnancy
4. Treatment with another investigational drug 14 days of enrollment
5. Radiosurgery planned for post-operative adjuvant cavity only. Patients with any gross residual after surgery are eligible. Patients with at least one intact metastasis may enroll but adjuvant cavity will not be evaluable.
6. At the time of Radiation Oncology consultation more than twenty targets are identified. Note that it is common that a few additional metastases may be identified during the treatment planning or peer review processes. More than twenty targets may be included if this number is found after the initial clinical review of the treatment planning MRI.
7. Tumor maximal diameter > 4 cm.
8. Prior SBRT or SRS to a lesion planned for retreatment. Note that patients with prior whole brain radiation alone are eligible.
9. Patients with diffuse leptomeningeal tumor are not eligible. Patients with a focal dural or pachymeningeal tumor are eligible if other intra-axial tumors are planned to be treated. Similar to postoperative cavities, the pachymeningeal tumor deposit will be treated but not evaluable for the assessment of local control or toxicity.

INCLUSION OF VULNERABLE PARTICIPANTS Vulnerable populations as defined by the NIH including children, prisoners, and adult subjects who lack capacity to consent to research participation are not eligible.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 0mm margin; For each patient two radiation treatment plans will be created. One will have 0 mm margin for the planning target volume. Tumors will be prescribed based upon the maximum diameter of the largest tumor and location at the discretion of the treating radiation oncologist with the following guidance: < 2.0 cm diameter 16-20 Gy 2.0-4.0 cm diameter 3 fractions of 9 Gy for total 27 Gy.	Procedure: brain metastases radiosurgery; Radiosurgery is the use of a focal high dose of radiation therapy to ablate or kill a tumor. This trial will enroll patients with brain metastases 4 cm or less in greatest diameter and will compare 0mm margin to a 2mm margin for treatment.
Active Comparator: 2mm margin; For each patient two radiation treatment plans will be created. One will be 2 mm margin for the planning target volume. Tumors will be prescribed based upon the maximum diameter of the largest tumor and location at the discretion of the treating radiation oncologist with the following guidance: < 2.0 cm diameter 16-20 Gy 2.0-4.0 cm diameter 3 fractions of 9 Gy for total 27 Gy.	Procedure: brain metastases radiosurgery; Radiosurgery is the use of a focal high dose of radiation therapy to ablate or kill a tumor. This trial will enroll patients with brain metastases 4 cm or less in greatest diameter and will compare 0mm margin to a 2mm margin for treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference between 0mm and 2mm	Fisher's Exact Test to determine if (per patient) uncomplicated control is improved or worsened with the addition of a 2mm PTV margin in the treatment of brain metastases with single isocenter radiosurgery.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum margin size of the tumor	To compare 0mm margin and 2mm margin radiosurgery for local tumor control, RANO assessment by individual tumor calculated by multiplying the longest diameter on an axial slice and its longest perpendicular diameter on the same slice	12 months
Percentage of toxicity	To compare 0mm margin and 2mm margin radiosurgery for toxicity. NTCP - assessed per tumor and per patient, assign to all tumors if attribution ambiguous (only grade 3 or greater CNS toxicity included)	12 months
Change in normal brain dosimetry	To compare 0mm margin and 2mm margin radiosurgery for normal brain dosimetry.; Dosimetry of normal brain (2 mm vs 0 mm); Dosimetry of hippocampi (2 mm vs 0 mm)	12 months

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Investigators: Principal Investigator: John A Fiveash, MD, The University of Alabama at Birmingham

Study record dates

Study Major Dates

• Study Start (Actual): April 8, 2025
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): August 1, 2028

Study Registration Dates

• First Submitted: February 26, 2025
• First Submitted That Met QC Criteria: February 26, 2025
• First Posted (Actual): March 4, 2025

Study Record Updates

• Last Update Posted (Estimated): October 15, 2025
• Last Update Submitted That Met QC Criteria: October 14, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: Brain Metastases; radiosurgery (RS); stereotactic radiosurgery (SRS); edge linear accelerator; single isocenter 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
• Other Study ID Numbers: IRB-300014291 (UAB2507); Robert Award (Other Identifier: Robert Award)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No