Single vs Multiple Dose Radiation for Brain Metastases

(HYPOGRYPHE Trial)

Recruiting at 49 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

Trial Summary

What is the purpose of this trial?

This study is designed to see if we can lower the chance of side effects from radiation in patients with breast, kidney, small cell lung cancer, non-small cell lung cancer or melanoma that has spread to the brain and who are also being treated with immunotherapy, specifically immune checkpoint inhibitor (ICI) therapy. This study will compare the usual care treatment of single fraction stereotactic radiosurgery (SSRS) given on one day versus fractionated stereotactic radiosurgery (FSRS), which is a lower dose of radiation given over a few days to determine if FSRS is better or worse at reducing side effects than usual care treatment.

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 data supports the effectiveness of this treatment for brain metastases?

Research shows that both single-dose radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) are effective for treating brain metastases. FSRT is noted for better control and fewer side effects for larger lesions, while SRS is effective for smaller, limited metastases. ^{1 2 3 4 5}

Is stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT) safe for treating brain metastases?

Stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT) are generally considered safe for treating brain metastases, with advancements in technology improving their safety and accuracy. These treatments have been used effectively with a focus on patient safety and quality assurance to minimize risks. ^{3 4 6 7 8}

How does the treatment of single vs multiple dose radiation for brain metastases differ from other treatments?

This treatment uses precise, targeted radiation (stereotactic radiosurgery or fractionated stereotactic radiotherapy) to treat brain metastases, which can be more effective and cause less cognitive decline than traditional whole-brain radiation. It offers flexibility in dosing, with options for a single high dose or multiple smaller doses, allowing for tailored treatment based on the size and number of brain metastases. ^{1 3 5 9 10}

Research Team

Christina K. Cramer

Principal Investigator

Wake Forest University Health Sciences

Eligibility Criteria

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

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

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 have had brain radiation therapy before.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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 (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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Neuro-Oncology Practice Clinical Debate: stereotactic radiosurgery or fractionated stereotactic radiotherapy following surgical resection for brain metastasis. [2021]

2. Greece pubmed.ncbi.nlm.nih.gov

Survival After Stereotactic Radiosurgery (SRS) or Fractionated Stereotactic Radiotherapy (FSRT) for Cerebral Metastases in the Elderly. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Outcomes of Hypofractionated Stereotactic Radiotherapy for Small and Moderate-Sized Brain Metastases: A Single-Institution Analysis. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

A Comparison of Single Fraction and Multi Fraction Radiosurgery on the Gamma Knife ICON: A Single Institution Review. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Single-dose versus fractionated stereotactic radiotherapy for brain metastases. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Quality and Safety Considerations in Stereotactic Radiosurgery and Stereotactic Body Radiation Therapy: An ASTRO Safety White Paper Update. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Definition and quality requirements for stereotactic radiotherapy: consensus statement from the DEGRO/DGMP Working Group Stereotactic Radiotherapy and Radiosurgery. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Fractionated stereotactic radiosurgery for large brain metastases. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

Stereotactic radiosurgery and stereotactic radiotherapy for brain metastases. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Feasibility of linac-based fractionated stereotactic radiotherapy and stereotactic radiosurgery for patients with up to ten brain metastases. [2023]