Stereotactic Radiosurgery vs Whole-Brain Radiotherapy for Brain Metastasis from Lung Cancer

Recruiting at 227 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: NRG Oncology

Must not be taking: NMDA antagonists

Disqualifiers: Leptomeningeal metastases, Demyelinating disease, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: 2-24 weeks

200 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial compares two radiation treatments for small cell lung cancer that has spread to the brain. One treatment uses stereotactic radiosurgery, a precise, high-dose radiation that targets tumors directly and may reduce damage to normal brain tissue. The other treatment combines whole-brain radiation therapy with memantine, a drug that may help protect memory by avoiding radiation to the hippocampus. This trial is open to individuals diagnosed with small cell lung cancer that has spread to the brain, with brain tumors visible on an MRI and measuring 4 cm or smaller. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot use certain drugs like amantadine, ketamine, or dextromethorphan during the trial.

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

Research has shown that stereotactic radiosurgery (SRS) is generally well-tolerated for treating brain tumors that have spread from lung cancer. Studies indicate that patients with fewer than five brain tumors respond well to SRS, suggesting it can manage the cancer without causing many new problems. However, patients with more than five tumors might face a higher risk of additional brain issues.

Whole-brain radiation therapy that avoids the hippocampus (HA-WBRT) aims to reduce memory-related side effects. HA-WBRT is often used with memantine, a drug that may help protect memory and thinking skills. Past treatments have safely combined memantine with HA-WBRT.

In summary, research has shown that both SRS and HA-WBRT with memantine are safe treatment options, each aiming to minimize side effects related to memory and thinking. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer targeted and potentially less invasive options for brain metastasis from lung cancer. Stereotactic Radiosurgery (SRS) is unique because it delivers highly focused radiation to tumors in just one or a few sessions, minimizing exposure to surrounding healthy brain tissue. This precision can reduce side effects compared to traditional whole-brain radiotherapy, which often affects the entire brain. Meanwhile, the combination of Whole-Brain Radiotherapy with memantine aims to protect cognitive function, an area of concern with standard treatments. These approaches hold promise for improving patient outcomes by potentially offering more effective and kinder alternatives.

What evidence suggests that this trial's treatments could be effective for brain metastasis from lung cancer?

Research has shown that stereotactic radiosurgery (SRS), a treatment available in this trial, effectively treats brain tumors that have spread from lung cancer. Studies have found that SRS can control cancer in patients with fewer than five brain tumors. This treatment delivers a high dose of radiation directly to the tumor, potentially causing fewer side effects than treatments targeting the whole brain. Another treatment option in this trial is whole-brain radiation therapy (HA-WBRT) combined with memantine, a drug that can help protect memory by avoiding the brain areas involved in memory and thinking. Both treatments offer important options for managing brain tumors in lung cancer patients. ^{1 2 3 6 7}

Who Is on the Research Team?

Vinai Gondi

Principal Investigator

NRG Oncology

Are You a Good Fit for This Trial?

Adults with small cell lung cancer that has spread to the brain, who have not had prior brain radiotherapy or certain other cancers in the last 5 years. Participants must be able to undergo MRI scans, have a good performance status (able to carry out daily activities), and can't be pregnant. They should also not have severe medical conditions or history of allergic reactions to memantine.

Inclusion Criteria

My small cell lung cancer has spread to my brain.

REQUIRED MRI ELEMENTS

Proficiency in English or French Canadian

Exclusion Criteria

My cancer has spread to the lining of my brain and spinal cord.

You have a serious, ongoing health problem.

I have a history of cancer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo either stereotactic radiosurgery (SRS) over 1 day or hippocampal-avoidant whole brain radiotherapy (HA-WBRT) once daily for 2 weeks, with memantine administered for up to 24 weeks

2-24 weeks

Daily visits for 2 weeks for HA-WBRT, single or multiple visits for SRS

Follow-up

Participants are monitored for safety and effectiveness after treatment, including neurocognitive assessments and imaging

1 year

Every 2-3 months for 1 year, then every 6 months

Long-term follow-up

Participants are monitored for long-term outcomes such as overall survival and incidence of adverse events

Up to 10 years

What Are the Treatments Tested in This Trial?

Interventions

• Memantine Hydrochloride
• Stereotactic Radiosurgery
• Whole-Brain Radiotherapy

Trial Overview The trial is testing if stereotactic radiosurgery, which targets only tumor sites in the brain, is more effective at preserving memory and thinking than whole-brain radiation therapy avoiding the hippocampus combined with memantine hydrochloride.

How Is the Trial Designed?

Group I: Arm I (SRS) Experimental Treatment 5 Interventions

Patients undergo SRS over 1 day (in some cases several days). Patients undergo blood sample collection and MRI throughout the study.

Group II: Arm II (HA-WBRT, memantine) Active Control 5 Interventions

Patients also undergo HA-WBRT QD for 2 weeks in the absence of disease progression or unacceptable toxicity. Patients will also receive memantine PO QD or BID for up to 24 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection and MRI throughout the study.

Stereotactic Radiosurgery is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Stereotactic Radiosurgery for:

• Brain tumors
• Metastatic brain tumors
• Arteriovenous malformations (AVMs)
• Trigeminal neuralgia
• Acoustic neuromas

Approved in United States as Stereotactic Radiosurgery for:

• Brain tumors
• Metastatic brain tumors
• Arteriovenous malformations (AVMs)
• Trigeminal neuralgia
• Acoustic neuromas
• Liver tumors
• Lung tumors
• Spinal cord tumors

Approved in Canada as Stereotactic Radiosurgery for:

• Brain tumors
• Metastatic brain tumors
• Arteriovenous malformations (AVMs)
• Trigeminal neuralgia
• Acoustic neuromas

Approved in Japan as Stereotactic Radiosurgery for:

• Brain tumors
• Metastatic brain tumors
• Arteriovenous malformations (AVMs)
• Trigeminal neuralgia
• Acoustic neuromas

Approved in China as Stereotactic Radiosurgery for:

• Brain tumors
• Metastatic brain tumors
• Arteriovenous malformations (AVMs)
• Trigeminal neuralgia
• Acoustic neuromas

Approved in Switzerland as Stereotactic Radiosurgery for:

• Brain tumors
• Metastatic brain tumors
• Arteriovenous malformations (AVMs)
• Trigeminal neuralgia
• Acoustic neuromas

Who Is Running the Clinical Trial?

NRG Oncology

Lead Sponsor

Trials

242

Recruited

105,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Stereotactic radiosurgery (SRS) is a safe and effective treatment for patients with limited, inoperable brain metastases from non-small cell lung cancer (NSCLC), showing positive outcomes in local control.

Combining whole-brain radiotherapy (WBRT) with SRS did not improve overall survival rates, although it did enhance locoregional control, indicating that SRS alone may be sufficient for managing these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Limited Cerebral Metastases in NSCLC: A Literature Review of SRS Versus Whole-brain Radiotherapy. Grenzelia, M., Zygogianni, A., Grapsa, D., et al.[2022]

A meta-analysis of two trials involving 358 participants found that adding stereotactic radiosurgery (SRS) to whole brain radiation therapy (WBRT) did not significantly improve overall survival compared to WBRT alone, although it did show better local control of brain metastases.

Patients receiving the combination of WBRT and SRS had improved performance status and reduced need for steroids, with a notable increase in the percentage of patients maintaining or improving their Karnofsky Performance Scale scores at 6 months (43% vs. 28% for WBRT alone).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery for the treatment of brain metastases. Patil, CG., Pricola, K., Sarmiento, JM., et al.[2022]

In a study involving 40 patients treated with stereotactic radiosurgery (SRS) and a historical control group of 70 patients receiving whole-brain radiotherapy (WBRT), SRS showed a median overall survival (OS) of 10.4 months compared to 6.5 months for WBRT, although the difference was not statistically significant.

SRS was associated with no grade III toxicities, suggesting it may be a safer option compared to WBRT, which indicates the need for further randomized trials to explore its efficacy and safety in the context of modern cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic radiosurgery versus whole-brain radiotherapy in patients with 4-10 brain metastases: A nonrandomized controlled trial. Bodensohn, R., Kaempfel, AL., Boulesteix, AL., et al.[2023]

The study proposes a new treatment approach called HA-SIB-WBRT, which combines hippocampal avoidance with a simultaneous integrated boost of radiation to improve tumor control in patients with multiple brain metastases, aiming to recruit 100 patients over 2 years.

The primary goal of the trial is to assess whether this technique leads to better target lesion control and improved cognitive outcomes compared to traditional HA-WBRT, highlighting the importance of maintaining quality of life for patients with brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomised prospective phase II trial in multiple brain metastases comparing outcomes between hippocampal avoidance whole brain radiotherapy with or without simultaneous integrated boost: HA-SIB-WBRT study protocol. Chia, BSH., Leong, JY., Ong, ALK., et al.[2021]

Out of 40,803 patients with brain metastases from non-small cell lung cancer, 83.8% received whole brain radiation therapy (WBRT), while only 16.2% were treated with stereotactic radiosurgery (SRS), indicating that WBRT is still the predominant treatment method.

The use of SRS has significantly increased from 7% in 2004 to 37% in 2014, with factors such as the year of diagnosis, type of facility (academic vs. community), and insurance status influencing the likelihood of receiving SRS over WBRT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disparities in the Use of Single-fraction Stereotactic Radiosurgery for the Treatment of Brain Metastases From Non-small Cell Lung Cancer. Modh, A., Doshi, A., Burmeister, C., et al.[2023]

Combining stereotactic radiosurgery (SRS) with whole brain radiation therapy (WBRT) does not significantly improve overall survival for patients with brain metastases compared to WBRT alone, based on a meta-analysis of two studies involving 358 participants.

However, patients receiving the combined treatment of SRS and WBRT showed better local control of the disease and improved performance status, particularly those with a single brain metastasis, indicating that while survival may not be extended, quality of life and disease management can be enhanced.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery for the treatment of brain metastases. Patil, CG., Pricola, K., Sarmiento, JM., et al.[2020]

In a study of 710 patients with small cell lung cancer brain metastases, stereotactic radiosurgery (SRS) showed a median overall survival of 8.5 months, comparable to whole-brain radiotherapy (WBRT), which had a median survival of 6.5 months, indicating SRS is a viable first-line treatment option.

SRS resulted in a shorter time to central nervous system progression (TTCP) compared to WBRT, with a hazard ratio of 0.38, suggesting that while SRS may lead to quicker progression, it does not compromise overall survival or central nervous system progression-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of First-line Radiosurgery vs Whole-Brain Radiotherapy for Small Cell Lung Cancer Brain Metastases: The FIRE-SCLC Cohort Study. Rusthoven, CG., Yamamoto, M., Bernhardt, D., et al.[2022]

Gamma knife radiosurgery (GKRS) is an effective local treatment for brain metastases from small cell lung carcinoma (SCLC), achieving a local control rate of 76.4% in treated lesions.

Despite the effectiveness of GKRS, the overall survival benefit is limited, with a median survival of only 4.8 months after treatment, as most patients ultimately succumb to systemic organ failure rather than neurological decline.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of radiosurgery in patients with brain metastasis from small cell lung carcinoma. Jo, KW., Kong, DS., Lim, DH., et al.[2022]

Whole-brain radiotherapy (WBRT) is a common treatment for lung cancer patients with brain metastases, but it can lead to cognitive decline due to radiation damage to the hippocampus.

Hippocampal-sparing WBRT is a promising technique that aims to reduce cognitive side effects while still effectively treating brain metastases, supported by both preclinical and clinical evidence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hippocampal-Sparing Whole-Brain Radiotherapy for Lung Cancer. Zhao, R., Kong, W., Shang, J., et al.[2022]

A meta-analysis of two trials involving 358 participants found that adding stereotactic radiosurgery (SRS) to whole brain radiation therapy (WBRT) did not significantly improve overall survival compared to WBRT alone, although it did show benefits for specific patient groups.

Patients receiving the combination of WBRT and SRS experienced better local control of brain metastases, improved performance status, and reduced need for steroids, indicating that while overall survival may not differ, the quality of life and treatment effectiveness could be enhanced with the combined approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery for the treatment of brain metastases. Patil, CG., Pricola, K., Garg, SK., et al.[2018]

In a study of 156 non-small cell lung cancer patients with 1-4 brain metastases, stereotactic radiosurgery (LINAC-SRS) did not show significantly better overall survival compared to whole-brain radiotherapy (WBRT) or WBRT plus radiotherapy boost (WBRT+RTB).

The median overall survival was not reached for the LINAC-SRS group, while it was 33.3 months for WBRT and 27.9 months for WBRT+RTB, indicating that LINAC-SRS may not provide a clear advantage in treatment outcomes for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world analysis of different intracranial radiation therapies in non-small cell lung cancer patients with 1-4 brain metastases. Chen, Z., Zhou, L., Zhao, M., et al.[2022]

The novel Spatially Partitioned Adaptive Radiosurgery (SPARE) technique significantly reduces radiation exposure to the hippocampus and normal brain tissue compared to traditional hippocampal-avoidance whole brain radiation therapy (HA-WBRT), with reductions of up to 93% in dose metrics.

In a study of 10 cases, the GKI-Spr method not only outperformed HA-WBRT but also showed superior dosimetry compared to single-fraction single-day SRS, indicating it may be a safer and more effective option for treating multiple brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-Fraction Stereotactic Radiosurgery Versus Hippocampal-Avoidance Whole Brain Radiation Therapy for Patients With 10 to 30 Brain Metastases: A Dosimetric Analysis. Nguyen, TK., Sahgal, A., Detsky, J., et al.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10526239/

Modern Stereotactic Radiotherapy for Brain Metastases from ... In this review, we offer an overview of the current trends in the treatment of BMs from lung cancer, with a secondary focus on future perspectives based on ...

2. advancesradonc.org advancesradonc.org/article/S2452-1094(23)00066-0/fulltext

Stereotactic Radiosurgery for Brain Metastases in Patients ... SRS for SCLC in patients with <5 BM appears to offer acceptable control rates. Patients with >5 BM have high rates of subsequent brain failure and are not ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6355452/

Gamma Knife radiosurgery for brain metastases from small ... Stereotactic radiosurgery is a reasonable treatment option for patients with brain metastases of SCLC who had PCI or WBRT failure.

4. sciencedirect.com sciencedirect.com/journal/radiotherapy-and-oncology/vol/206/suppl/S1?page=6

Radiotherapy and Oncology | ESTRO 2025, 2-6 May ... 3808 Clinical outcomes in patients with HER2-positive Breast Cancer Brain Metastases treated with Stereotactic Radiosurgery. Eva Ruane, Guhan ...

5. nature.com nature.com/articles/s41598-022-13853-3

Clinical outcomes of patients with multiple courses ... We investigated the long-term clinical outcomes of patients who underwent multiple courses (≥ 5) of gamma knife radiosurgery (GKRS) due to ...

6. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2835449

Therapy, Safety, and Logistics of Preoperative vs ... Preoperative SRT was safe and logistically feasible with the potential benefit of expediting treatment.

7. practicalradonc.org practicalradonc.org/article/S1879-8500(22)00054-6/fulltext

Radiation Therapy for Brain Metastases: An ASTRO ... A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung ...