Pre-Surgical Radiosurgery for Brain Metastases

Overseen By Zachary Buchwald, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Emory University

Must not be taking: Immunosuppressants, Investigational agents

Disqualifiers: HIV, Uncontrolled illness, Pregnancy, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the safety and effectiveness of using focused radiation treatment (stereotactic radiosurgery) before surgery (resection) for patients with cancer that has spread to the brain. This approach may enhance the body's immune response against the cancer and reduce the likelihood of recurrence after surgery. Participants will receive either high or low doses of the steroid dexamethasone alongside the radiation and surgery. Suitable candidates for this trial are those with brain cancer visible on an MRI scan who can perform daily activities independently. As an Early Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative approach.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on immunosuppressive medications other than dexamethasone or if you are receiving other investigational agents.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have shown that stereotactic radiosurgery (SRS) is a well-tolerated treatment for cancer that has spread to the brain. Research indicates a high success rate of 86% in controlling the cancer, effectively targeting it with minimal need for additional treatment. Side effects are generally manageable and less severe compared to other radiation methods.

For dexamethasone, a steroid used to reduce brain swelling, studies suggest that lower doses usually lead to fewer side effects. High doses may increase the risk of negative effects without improving results. Therefore, dosage is crucial when assessing its safety. Both SRS and dexamethasone have been studied extensively and are considered safe when used correctly. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the pre-surgical radiosurgery approach for brain metastases because it combines stereotactic radiosurgery (SRS) with varying doses of dexamethasone before surgical resection. Unlike traditional treatment options, which may involve whole-brain radiation therapy or surgery alone, this method targets brain metastases with precise, high-dose radiation while minimizing damage to surrounding tissue. Additionally, the use of dexamethasone, a potent anti-inflammatory medication, helps reduce swelling and improve surgical outcomes. This innovative combination aims to enhance the effectiveness of surgery and improve patient recovery, providing a potentially superior alternative to current standards of care.

What evidence suggests that this trial's treatments could be effective for brain metastases?

This trial will compare two treatment approaches for brain metastases. Research has shown that stereotactic radiosurgery (SRS), which participants in this trial will receive, effectively treats cancer that has spread to the brain. This treatment uses focused radiation to target tumors, helping to control their growth. Studies indicate that SRS can be as effective as whole-brain radiation for many patients. In this trial, participants will also receive either high or low doses of dexamethasone. Both doses can help reduce symptoms like brain swelling, though higher doses may cause more side effects without providing better results. Both SRS and dexamethasone show promise in reducing symptoms and improving the quality of life for patients with brain metastases. ^{1 5 6 7 8}

Who Is on the Research Team?

Zachary Buchwald, MD, PhD

Principal Investigator

Emory University Hospital/Winship Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults over 18 with cancer that has spread to the brain, visible on MRI. They must have a life expectancy of more than 12 weeks, be able to undergo surgery, and follow study procedures. Pregnant or nursing women, those on immunosuppressants (except dexamethasone), or with certain serious illnesses can't participate.

Inclusion Criteria

Life expectancy > 12 weeks as determined by the investigator

I am willing and able to follow the study's schedule and procedures.

I can take care of myself but might not be able to do heavy physical work.

Exclusion Criteria

Pregnant or nursing women are excluded

I am taking immunosuppressive medication, but not dexamethasone.

Human immunodeficiency virus (HIV)-positive

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Patients undergo stereotactic radiosurgery (SRS) to the brain metastasis for 1-3 fractions over 1-5 days and receive dexamethasone until the day of surgical resection

1-3 weeks

Surgery

Patients undergo surgical resection of the brain metastasis

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

120 days, then every 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Dexamethasone
• Resection
• Stereotactic Radiosurgery

Trial Overview The trial tests if stereotactic radiosurgery before surgery can prevent cancer from returning in patients with brain metastases. It's an early phase I trial focused on understanding side effects and how well this pre-surgery radiation works as a treatment.

How Is the Trial Designed?

Group I: Arm B (SRS, high dose dexamethasone, surgery) Experimental Treatment 2 Interventions

Patients undergo SRS to the brain metastasis for 1-3 fractions over 1-5 days. Patients also receive high dose dexamethasone PO or IV for 2-21 days until the day of surgical resection. Patients then undergo surgical resection.

Group II: Arm A (SRS, low dose dexamethasone, surgery) Experimental Treatment 3 Interventions

Patients undergo SRS to the brain metastasis for 1-3 fractions over 1-5 days. Patients also receive low dose dexamethasone PO or IV for 2-21 days until the day of surgical resection. Patients then undergo surgical resection.

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

Approved in United States as Surgical Resection for:

• Colorectal Cancer
• Liver Metastases
• Lung Metastases

Approved in European Union as Surgical Excision for:

• Colorectal Cancer
• Liver Metastases
• Lung Metastases

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 130 patients treated with CyberKnife Radiosurgery for brain metastases, a cumulative tumor volume greater than 7cc was linked to worse outcomes, including higher rates of death and neurological defects.

The addition of whole brain radiation therapy (WBRT) was associated with improved survival rates in patients with a higher tumor burden, suggesting that WBRT may play a beneficial role in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cumulative volumetric analysis as a key criterion for the treatment of brain metastases. Kim, IK., Starke, RM., McRae, DA., et al.[2018]

Stereotactic radiosurgery for brain metastases from breast cancer showed a high tumor control rate of 93% and a median survival of 13 months post-treatment, indicating its efficacy as a treatment option.

The absence of multiple brain metastases was the only significant factor associated with longer survival, while the treatment had a low complication rate, with only a few cases of radiation-induced edema that did not require further surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic radiosurgery for brain metastases from breast cancer. Firlik, KS., Kondziolka, D., Flickinger, JC., et al.[2019]

Stereotactic radiosurgery (SRS) is an effective non-invasive technique for targeting deep brain lesions with high doses of radiation, but it does not provide benefits for newly diagnosed malignant gliomas.

For patients with brain metastases, SRS can improve median survival when combined with whole-brain radiation therapy (WBRT), and in some cases, SRS alone may be a viable treatment option without compromising survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of radiosurgery in the management of malignant brain tumors. Stieber, VW., Ellis, TL.[2019]

In a study of 4,327 patients with brain metastases from non-small cell lung cancer, it was found that treatment at non-academic facilities significantly increased the likelihood of receiving LINAC SRS over Gamma Knife SRS, especially in the Midwestern, Northeastern, and Southern US regions.

Patients receiving higher doses of radiation (18-24 Gy) were also more likely to receive LINAC SRS, and those living within 20 miles of a treatment facility had a 27% higher chance of receiving LINAC, suggesting that geographic accessibility plays a role in treatment modality choice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of linear accelerator versus Gamma Knife stereotactic radiosurgery use for brain metastases in the United States. McClelland Iii, S., Degnin, C., Chen, Y., et al.[2022]

Moderately dosed stereotactic radiosurgery (SRS) for one to four brain metastases showed a median overall survival of 7.5 months, with high local brain control rates of 87% at 6 months and 79% at 12 months, indicating its efficacy in treating limited brain metastases.

The study suggests that initial SRS alone can be a safe treatment option, as only 22% of patients required additional whole-brain radiotherapy, and significant predictors of survival included the time between the primary diagnosis and brain metastases, as well as the volume of the treated metastasis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome of moderately dosed radiosurgery for limited brain metastases. Report of a single-center experience. Meisner, J., Meyer, A., Polivka, B., et al.[2021]

Hypofractionated Gamma Knife radiosurgery is effective for treating large metastatic brain tumors (average volume of 18.3 cm³), achieving a local control rate of 90% and a median survival time of 16.2 months.

The treatment demonstrated low toxicity, with only 8.3% of patients experiencing grade 1 side effects and a single case of radiation necrosis, indicating it is a safe option for patients who cannot undergo surgical resection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fractionated Stereotactic Gamma Knife Radiosurgery for Large Brain Metastases: A Retrospective, Single Center Study. Kim, JW., Park, HR., Lee, JM., et al.[2022]

Pre-operative stereotactic radiosurgery (SRS) for brain metastases significantly reduces dose exposure to healthy brain tissue compared to post-operative SRS, with a median volume receiving 28 Gy being lower in the pre-operative setting (6.79 ccm) than in the extended field post-operative setting (10.79 ccm).

The study found that the morphology of the resection cavity post-surgery differs significantly from the original lesion, which could complicate treatment planning; thus, pre-operative SRS may provide better delineation and treatment planning advantages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pre-Operative Versus Post-Operative Radiosurgery of Brain Metastases-Volumetric and Dosimetric Impact of Treatment Sequence and Margin Concept. El Shafie, RA., Tonndorf-Martini, E., Schmitt, D., et al.[2020]

In a study comparing two treatment methods for patients with one or two brain metastases, whole-brain radiotherapy plus stereotactic radiosurgery (WBRT+SRS) showed similar survival and control rates to surgery plus whole-brain radiotherapy with a boost (OP+WBRT+boost), with 1-year survival rates of 65% and 63%, respectively.

WBRT+SRS is less invasive than OP+WBRT+boost, making it a potentially preferable option for patients, although further confirmation through randomized trials is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A matched-pair analysis comparing whole-brain radiotherapy plus stereotactic radiosurgery versus surgery plus whole-brain radiotherapy and a boost to the metastatic site for one or two brain metastases. Rades, D., Kueter, JD., Pluemer, A., et al.[2009]

Stereotactic radiosurgery (SRS) using CyberKnife for large brain metastasis cavities (≥2 cm) showed a local failure rate of 24%, indicating it can effectively control local disease after surgery.

Patients with synchronous metastases had a higher risk of distant brain failure, suggesting that while SRS can delay the need for whole brain radiation therapy (WBRT), careful monitoring is needed for those with multiple metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracranial control after Cyberknife radiosurgery to the resection bed for large brain metastases. Vogel, J., Ojerholm, E., Hollander, A., et al.[2018]

The implementation of a safety checklist for Gamma Knife stereotactic radiosurgery (SRS) over 1500 procedures in 8 years has resulted in no reported human errors, highlighting its effectiveness in enhancing safety.

The checklist addresses specific indications for irradiating tissue volumes and functional disorders, promoting a zero-tolerance approach to errors and fostering multidisciplinary cooperation in neurosurgical practices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lausanne checklist for safe stereotactic radiosurgery. Tuleasca, C., Zeverino, M., Patin, D., et al.[2020]

Patients with newly diagnosed brain metastases showed significantly better survival outcomes when treated with stereotactic radiosurgery (SRS) alone compared to whole brain radiation therapy (WBRT) alone, indicating SRS may be a more effective treatment option (p<0.001).

The study highlights the importance of considering patient factors such as age, performance status (ECOG-PS), and primary tumor type when determining treatment plans, as these factors significantly influenced survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multimodality treatment of brain metastases: an institutional survival analysis of 275 patients. Elaimy, AL., Mackay, AR., Lamoreaux, WT., et al.[2022]

Stereotactic radiosurgery (SRS) significantly improved overall survival (OS) for patients with multiple brain metastases, with a median OS of 15.7 months compared to 8.0 months for those receiving whole-brain radiotherapy (WBRT).

SRS also demonstrated a high local control rate of 91.7% for individual brain metastases, indicating it is an effective treatment option for managing multiple brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A matched-pair analysis comparing stereotactic radiosurgery with whole-brain radiotherapy for patients with multiple brain metastases. El Shafie, RA., Celik, A., Weber, D., et al.[2021]

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]

Citations

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Practice Variation in Perioperative Dexamethasone Use ... The findings of this study suggest that variations in perioperative dexamethasone dosing across centers may affect outcomes and stricter dosing protocols ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2808527/

The role of steroids in the management of brain metastases The authors conclude that for the majority of patients, the lower doses of 4 and 8 mg dexamethasone per day have an equivalent effect on improving neurologic ...

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Dexamethasone in brain tumor patients - PubMed Central - NIH Higher doses were linked to poorer overall survival and greater toxicity as indicated by multiple large-scale studies: Mistry et al. reported ...

4. neurology.org neurology.org/doi/10.1212/WNL.44.4.675

Dose‐effect relationship of dexamethasone on Karnofsky ... We conclude that administration of 4 mg dexamethasone per day for treatment of brain tumor edema results in the same degree of improvement as does ...

5. nature.com nature.com/articles/s41467-024-53034-6

a two-arm pilot study evaluating clinical outcomes and ... The secondary clinical endpoints of overall survival, distant brain failure, leptomeningeal disease and local recurrence at 12-months were 66%, ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6700052/

Evidence-based dexamethasone dosing in malignant brain ... Best available evidence suggests that higher doses of DXM may give more adverse events, but may not necessarily result in better clinical condition.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT00188864

Dexamethasone for Palliation - Brain Metastases Steroids (such as Decadron or Dexamethasone) are medication used to reduce swelling around the tumour, and thus symptoms improve. Steroids could be very helpful ...

8. apm.amegroups.org apm.amegroups.org/article/view/7757/html

Brain metastases: advances over the decades - Tsao The steroid of choice is dexamethasone and the starting dose of 4-8 mg per day was suggested. However, if a patient experiences severe symptoms of increased ...