Single vs Multiple Dose Radiation for Brain Metastases

(HYPOGRYPHE Trial)

Recruiting at 54 trial locations

Overseen By Karen Craver, MT, MHA

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Wake Forest University Health Sciences

Must be taking: Immune checkpoint inhibitors

Must not be taking: Bevacizumab

Disqualifiers: Prior brain radiation, Leptomeningeal carcinomatosis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

Duration: 1-2 weeks

244 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two radiation methods to determine which causes fewer side effects for people with specific cancers that have spread to the brain and are also receiving immune checkpoint inhibitor therapy. It compares single-dose radiation (SSRS, or Stereotactic Radiosurgery) to a multi-dose approach (FSRS, or Fractionated Stereotactic Radiosurgery) to identify which better reduces side effects. Suitable participants have breast, kidney, or lung cancer, or melanoma that has spread to the brain and are undergoing immune therapy. The trial aims to improve treatment by easing the burden on the body while effectively targeting brain metastases. As an unphased trial, this study allows patients to contribute to innovative research that could enhance future cancer treatments.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, it mentions that patients must not have planned or prior therapy with bevacizumab within 30 days of starting the study treatment.

What prior data suggests that these radiation techniques are safe for treating brain metastases?

Research has shown that both FSRS (fractionated stereotactic radiosurgery) and SSRS (single fraction stereotactic radiosurgery) are generally safe for treating brain metastases, which is cancer that has spread to the brain. Studies have found that FSRS, which spreads the radiation dose over several days, is well-tolerated. This approach reduces side effects by using smaller doses of radiation over time.

In contrast, SSRS delivers a high dose in one session but remains safe. A large study found that SSRS is safe even for patients with many brain metastases and often helps maintain brain function.

Both treatments are noninvasive, meaning they do not involve surgery. They target radiation precisely at the tumors, protecting healthy brain tissue. This precision makes them a preferred option for many patients with brain metastases.

In summary, both FSRS and SSRS have demonstrated safety, focusing on maintaining quality of life by minimizing side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the trial comparing FSRS and SSRS for treating brain metastases because it explores different radiation delivery methods that could enhance patient outcomes. Unlike traditional whole brain radiotherapy, which can affect the entire brain and impair neurocognitive function, these techniques target only the cancerous lesions. FSRS administers lower doses of radiation over several sessions, potentially reducing side effects, while SSRS delivers a high dose in a single session, offering convenience and precision. This trial could help determine which approach offers the best balance of effectiveness and quality of life for patients.

What evidence suggests that this trial's treatments could be effective for reducing side effects in patients with brain metastases?

This trial will compare fractionated stereotactic radiosurgery (FSRS) with single fraction stereotactic radiosurgery (SSRS) for treating brain metastases. Research has shown that both FSRS and SSRS effectively treat cancer that has spread to the brain. FSRS involves administering lower doses of radiation over several days and has successfully controlled brain cancer. Studies suggest FSRS is particularly useful for treating brain metastases that have not been surgically removed. In contrast, SSRS delivers a high dose of radiation in one session and is a common treatment for brain metastases, with studies indicating it controls cancer well in about 70% of patients after one year. Both treatments precisely target the cancer to minimize harm to healthy brain tissue. ^{5 6 7 8 9}

Who Is on the Research Team?

Glenn Lesser, MD

Principal Investigator

Wake Forest University Health Sciences

Are You a Good Fit for This Trial?

This trial is for adults with certain cancers (melanoma, kidney, non-small cell lung cancer, or breast cancer) that have spread to the brain. They must have at least one brain tumor of a specific size and are on or will be on immunotherapy. Pregnant women and those who can't undergo MRI scans are excluded.

Inclusion Criteria

I have 15 or fewer brain tumors suitable for specific radiation treatments.

Negative serum or urine pregnancy test within 14 days of randomization for women of child-bearing potential

Ability to understand and the willingness to sign written informed consent

Exclusion Criteria

Serious intercurrent illness or medical condition judged by the local investigator to compromise the patient's safety, preclude safe administration of the planned protocol treatment, or would not permit the patient to be managed according to the protocol guidelines

I've had radiation for brain tumors, but they were treated far from where my current cancer would be targeted.

I have had brain radiation therapy before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either single fraction stereotactic radiosurgery (SSRS) or fractionated stereotactic radiosurgery (FSRS) while on immune checkpoint inhibitor (ICI) therapy

1-2 weeks

3 to 5 visits (in-person) for FSRS, 1 visit (in-person) for SSRS

Follow-up

Participants are monitored for safety and effectiveness, including adverse radiation effects and symptom burden

9 months

Regular follow-up visits as per study protocol

What Are the Treatments Tested in This Trial?

Interventions

• FSRS
• SSRS

Trial Overview The study compares two types of radiation treatments for patients with brain metastases from certain cancers also receiving immunotherapy: a single high-dose session versus multiple lower-dose sessions over several days to see which better reduces side effects.

How Is the Trial Designed?

Group I: FSRS = fractionated stereotactic radiosurgery Experimental Treatment 1 Intervention

FSRS is an advanced radiation technique that uses a lower dose precision radiation delivered over 3 to 5 treatments given daily or every other day to intracranial lesions.

Group II: SSRS = single fraction stereotactic radiosurgery Active Control 1 Intervention

SSRS is an advanced radiation technique that delivers high dose precision radiation in a single dose to discrete intracranial lesions. SSRS has recently become a standard-of-care treatment for patients with 1-4 brain metastases and is also commonly used for patients with up to 15 metastases, due to improved neurocognitive outcomes compared to whole brain radiotherapy.

FSRS is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Fractionated Stereotactic Radiosurgery for:

• Brain metastases from various cancers including breast, kidney, lung, and melanoma

Approved in United States as Fractionated Stereotactic Radiosurgery for:

• Brain metastases from various cancers including breast, kidney, lung, and melanoma

Approved in Canada as Fractionated Stereotactic Radiosurgery for:

• Brain metastases from various cancers including breast, kidney, lung, and melanoma

Who Is Running the Clinical Trial?

Wake Forest University Health Sciences

Lead Sponsor

Trials

1,432

Recruited

2,506,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Stereotactic radiosurgery (SRS) and hypofractionated stereotactic radiotherapy (HFSRT) are effective treatment options for brain metastases, but their use in patients with life-limiting diseases remains a topic of debate.

This review highlights the need for careful consideration of the indications and challenges associated with SRS and HFSRT to optimize patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic radiosurgery and stereotactic radiotherapy for brain metastases. Halasz, LM., Rockhill, JK.[2022]

Stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT) have advanced significantly, necessitating updated best practices for safety and quality assurance due to their complexity and precision in delivering high doses of radiation.

A team-based approach with trained specialists and a comprehensive quality assurance program is essential for the safe and effective implementation of SRS and SBRT, emphasizing that patient safety is a collective responsibility among all stakeholders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality and Safety Considerations in Stereotactic Radiosurgery and Stereotactic Body Radiation Therapy: An ASTRO Safety White Paper Update. Das, IJ., Dawes, SL., Dominello, MM., et al.[2022]

In a study of 176 patients with 1 to 10 brain metastases treated with linac-based fractionated stereotactic radiotherapy (fSRT) or stereotactic radiosurgery (SRS), those with 1 brain metastasis had a significantly better median overall survival of 19.8 months compared to 7.3 months for 2-4 metastases and 5.1 months for 5-10 metastases.

The study found that the safety profile was acceptable, with only 13.5% of patients experiencing radiation necrosis of grade 2 or higher, and no cases of grade 4 or 5 necrosis, suggesting that linac-based fSRT and SRS can be safely used even in patients with multiple brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility of linac-based fractionated stereotactic radiotherapy and stereotactic radiosurgery for patients with up to ten brain metastases. Hirata, M., Yasui, K., Oota, N., et al.[2023]

In a study of 104 elderly patients with 1-3 cerebral metastases treated with stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT), factors like a high Karnofsky Performance Status (KPS), having a single lesion, and smaller cumulative lesion size were significantly associated with better survival outcomes.

A newly developed survival score demonstrated high accuracy in predicting death within 12 months, with a 95% positive predictive value, although it was less effective in predicting survival beyond that timeframe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival After Stereotactic Radiosurgery (SRS) or Fractionated Stereotactic Radiotherapy (FSRT) for Cerebral Metastases in the Elderly. Rades, D., Nguyen, T., Blanck, O., et al.[2021]

Stereotactic radiotherapy, including SRS, FSRT, and SBRT, is recognized as a guideline-recommended treatment for both malignant and benign tumors, as well as for certain neurological and vascular disorders.

The German Society for Radiation Oncology and the German Society for Medical Physics have established consensus statements outlining the necessary definitions and quality standards for stereotactic radiotherapy to ensure optimal clinical outcomes and treatment quality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Definition and quality requirements for stereotactic radiotherapy: consensus statement from the DEGRO/DGMP Working Group Stereotactic Radiotherapy and Radiosurgery. Guckenberger, M., Baus, WW., Blanck, O., et al.[2020]

Fractionated stereotactic radiosurgery (fSRS) is a safe and effective treatment option for patients with larger brain metastases (tumor volume >2.061 cm3) who are not suitable for single fraction stereotactic radiosurgery (SRS).

Delays in treatment can negatively impact local control of the tumors, with a significant difference in local control rates observed based on whether treatment occurred within 10 days of planning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Comparison of Single Fraction and Multi Fraction Radiosurgery on the Gamma Knife ICON: A Single Institution Review. Loftus, JP., Shepard, M., Liang, Y., et al.[2023]

Fractionated stereotactic radiosurgery (SRS) for large brain metastases (over 3 cm) is both feasible and safe, with no reported acute or late complications in a study of 36 patients.

The treatment showed improved local control rates, with 73% progression-free survival at 6 months and 63% at 12 months, suggesting it may be more effective than single fraction SRS for these larger tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fractionated stereotactic radiosurgery for large brain metastases. Wegner, RE., Leeman, JE., Kabolizadeh, P., et al.[2018]

In a study of 98 patients with brain metastases, fractionated stereotactic radiotherapy (FSRT) showed similar survival rates and local progression-free survival (LPFS) compared to single-dose radiosurgery (SRS), despite being used for larger and more challenging lesions.

FSRT was associated with a significantly lower risk of toxicity (5%) compared to SRS (17%), suggesting it may be a safer option for patients with difficult-to-treat brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-dose versus fractionated stereotactic radiotherapy for brain metastases. Kim, YJ., Cho, KH., Kim, JY., et al.[2022]

Fractionated stereotactic radiotherapy (FSRT) is a safe and effective treatment for brain metastases of any size, showing excellent local control with a 12-month local failure rate of 17.8% overall.

In a study of 60 patients treated with FSRT, the median survival was 20.5 months, and the risk of radionecrosis was relatively low at 7.1%, indicating favorable toxicity outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of Hypofractionated Stereotactic Radiotherapy for Small and Moderate-Sized Brain Metastases: A Single-Institution Analysis. Yan, M., Zalay, O., Kennedy, T., et al.[2022]

Recent clinical trials indicate that stereotactic radiosurgery (SRS) leads to less cognitive decline and provides equivalent survival rates compared to whole-brain radiotherapy (WBRT) for treating resected brain metastasis.

There is ongoing debate in the medical community regarding the use of fractionated stereotactic radiotherapy (FSRT) versus SRS, with some evidence suggesting FSRT may enhance local control at the tumor site, but SRS is currently defended as the standard of care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuro-Oncology Practice Clinical Debate: stereotactic radiosurgery or fractionated stereotactic radiotherapy following surgical resection for brain metastasis. Palmer, JD., Greenspoon, J., Brown, PD., et al.[2021]

Citations

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Stereotactic Radiation Therapy for Brain Metastases Data from 87 analyzed patients treated at our institution suggest that this technique is characterized by a good effectiveness in local control ...

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Stereotactic Radiosurgery and Stereotactic Fractionated ... This review highlights the evidence and the emerging role of SRS-SRT in patients diagnosed with intact intracranial metastases.

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Response of treatment-naive brain metastases to ... Our results demonstrate that brain metastases ≤3 cm are not uniformly responsive to SRS and suggest that prospective studies to evaluate the effect of SRS alone

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Optimal radiotherapy dose and fractionation for stereotactic ... We investigated efficacy and safety outcomes of such treatment and the impact of radiotherapy dose fractionations in a real-world multi-center cohort.

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1053429623000048

Precision Radiation for Brain Metastases With a Focus on ... There are multiple published randomized controlled trials supporting single-fraction stereotactic radiosurgery (SF-SRS) for patients presenting with 1 to 4 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7216666/

Radiosurgery and fractionated stereotactic body radiotherapy ... The aim of this study was to analyze treatment outcomes after single fraction radiosurgery (SFRS) and fractionated SBRT (fSBRT) in patients with lung ...

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A Phase 1 Study of Stereotactic Ablative Radiation Therapy ... The ARREST study demonstrated that SABR treatment for all sites of polymetastatic disease is safe and feasible in selected patients.

8. thegreenjournal.com thegreenjournal.com/article/S0167-8140(25)04611-0/fulltext

Definition and requirements for stereotactic radiotherapy Stereotactic radiation therapy (SRT) has evolved from its initial application in the treatment of benign, vascular, and malignant brain lesions.

9. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK542166/

Stereotactic Radiosurgery (SRS) and Stereotactic Body ... - NCBI These noninvasive modalities offer effective management for a range of conditions, including brain metastases, benign brain tumors (such as ...