Home › Trials › NCT04804644

High dose radiation for brain cancer vs whole brain radiation to protect memory

Phase III Trial of Stereotactic Radiosurgery (SRS) Versus Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) for Brain Metastases From Small Cell Lung Cancer

Phase 3 Interventional NRG Oncology · NCT04804644

This study is testing whether a high dose radiation treatment for brain cancer can better protect memory compared to the standard whole brain radiation therapy for patients with small cell lung cancer that has spread to the brain.

Quick facts

PhasePhase 3
Study typeInterventional
Enrollment200 (estimated)
Ages18 Years and up
SexAll
SponsorNRG Oncology Academic / other
Drugs / interventionschemotherapy, immunotherapy, radiation
Locations227 sites (Phoenix, Arizona and 226 other locations)
Trial IDNCT04804644 on ClinicalTrials.gov

What this trial studies

This phase III trial compares the effectiveness of stereotactic radiosurgery (SRS) against whole brain radiation therapy with hippocampal avoidance (HA-WBRT) plus memantine for patients with small cell lung cancer that has metastasized to the brain. The study aims to determine whether SRS can better prevent cognitive decline and preserve memory function compared to the standard treatment. Participants will undergo various cognitive assessments and symptom evaluations to measure the impact of each treatment approach. The trial includes patients with brain metastases that meet specific size and location criteria.

Who should consider this trial

Good fit: Ideal candidates are patients with a confirmed diagnosis of small cell lung cancer and brain metastases that meet specific size and location criteria.

Not a fit: Patients with larger brain metastases or those whose cancer has progressed beyond the eligibility criteria may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could lead to improved cognitive outcomes and quality of life for patients with brain metastases from small cell lung cancer.

How similar studies have performed: Other studies have shown promise in using stereotactic radiosurgery for brain metastases, suggesting potential benefits in cognitive preservation.

Eligibility criteria

Show full inclusion / exclusion criteria 
Inclusion Criteria:

* Pathologically (histologically or cytologically) proven diagnosis of small cell lung cancer within 5 years of registration. If the original histologic proof of malignancy is greater than 5 years, then pathological (i.e., more recent) confirmation is required (e.g., from a systemic or brain metastasis);

  * Patients with de novo or recurrent small cell lung cancer are permitted.
* Brain metastases =\< 4 cm in largest diameter and outside a 5-mm margin around either hippocampus must be visible on contrast-enhanced magnetic resonance imaging (MRI) performed =\< 21 days prior to study entry.

  * The total tumor volume must be 30 cm\^3 or less. Lesion volume will be approximated by measuring the lesion's three perpendicular diameters on contrast enhanced, T1-weighted MRI and the product of those diameters will be divided by 2 to estimate the lesion volume (e.g. xyz/2). Alternatively, direct volumetric measurements via slice by slice contouring on a treatment planning software package can be used to calculate the total tumor volume.
  * Brain metastases can be diagnosed synchronous to the initial diagnosis of small cell lung cancer or metachronous to the initial diagnosis and management of small cell lung cancer.
  * Brain metastases must be diagnosed on MRI, which will include the following elements:

    * REQUIRED MRI ELEMENTS

      * Post gadolinium contrast-enhanced T1-weighted three-dimensional (3D) spoiled gradient (SPGR). Acceptable 3D SPGR sequences include magnetization prepared 3D gradient recalled echo (GRE) rapid gradient echo (MP-RAGE), turbo field echo (TFE) MRI, BRAVO (Brain Volume Imaging) or 3D Fast FE (field echo). The T1-weighted 3D scan should use the smallest possible axial slice thickness, not to exceed 1.5 mm.
      * Pre-contrast T1 weighted imaging (3D imaging sequence strongly encouraged).
      * A minimum of one axial T2 FLAIR (preferred) or T2 sequence is required. This can be acquired as a two dimensional (2D) or 3D image. If 2D, the images should be obtained in the axial plane.
    * ADDITIONAL RECOMMENDATIONS

      * Recommendation is that an axial T2 FLAIR (preferred) sequence be performed instead of a T2 sequence.
      * Recommendation is that that pre-contrast 3D T1 be performed with the same parameters as the post-contrast 3D T1.
      * Recommendation is that imaging be performed on a 3 Tesla (3T) MRI.
      * Recommendation is that the study participants be scanned on the same MRI instrument at each time point.
      * Recommendation is that if additional sequences are obtained, these should meet the criteria outlined in Kaufmann et al., 2020.
      * If additional sequences are obtained, total imaging time should not exceed 60 minutes.
      * If additional metastases not known at the time of registration/randomization or seen in the MRI used for eligibility are subsequently found on the radiation therapy (RT) planning MRI such that the total intacranial volume exceeds 30 cm\^3, the patient is still considered eligible.
* History/physical examination
* Age \>= 18
* Karnofsky performance status of \>= 70
* Creatinine clearance \>= 30 ml/min
* Following the diagnosis of brain metastases, patients can initiate and treat with systemic (chemotherapy and/or immunotherapy) before enrollment only if their brain metastases are asymptomatic and not located in eloquent locations (e.g., brainstem, pre-/post-central gyrus, visual cortex). However, within 21 days prior to enrollment, brain MRI must be repeated to confirm eligibility.

  * Patients with symptomatic brain metastases and/or brain metastases in eloquent locations (e.g., brainstem, pre-/post central gyrus, visual cortex) are eligible for enrollment on the trial; however, the specific treatment approach of starting with systemic therapy alone and delaying brain radiation is not recommended for these patients.
* Concurrent immunotherapy with brain radiation (SRS or HA-WBRT) is permitted.
* Negative urine or serum pregnancy test (in women of childbearing potential) within 14 days prior to registration. Women of childbearing potential and men who are sexually active must use contraception while on study.
* Patients may have had prior intracranial surgical resection.
* Because neurocognitive testing is the primary goal of this study, patients must be proficient in English or French Canadian.
* The patient must provide study-specific informed consent prior to study entry.

  * Patients with impaired decision-making capacity are not permitted on study.
* ELIGIBILITY CRITERIA PRIOR TO STEP 2 REGISTRATION
* The following baseline neurocognitive tests must be completed within 21 days prior to Step 2 registration: HVLT-R, TMT, and COWA. The neurocognitive test will be uploaded into RAVE for evaluation by Dr. Wefel. Once the upload is complete, within 3 business days a notification will be sent via email to the RA to proceed to Step 2.

  * NOTE: Completed baseline neurocognitive tests can be uploaded at the time of Step 1 registration.
* PRIOR TO STEP 2 REGISTRATION: The following baseline neurocognitive tests must be completed within 21 days prior to Step 2 registration: HVLT-R, TMT, and COWA. The neurocognitive tests will be uploaded into RAVE for evaluation by Dr. Wefel. Once the upload is complete, within 3 business days a notification will be sent via email to the RA to proceed to Step 2.

NOTE: Completed baseline neurocognitive tests can be uploaded at the time of Step 1 registration.

Exclusion Criteria:

* Planned infusion of cytotoxic chemotherapy on the same day as SRS or HA-WBRT treatment. Patients may have had prior chemotherapy. Concurrent immunotherapy is permitted.

  * For patients receiving fractionated SRS on an every-other-day basis, planned infusion of cytotoxic chemotherapy is not permitted between SRS treatments.
* Brainstem metastasis \> 10 cm\^3
* Prior allergic reaction to memantine.
* Patients with definitive leptomeningeal metastases.
* Known history of demyelinating disease such as multiple sclerosis.
* Contraindication to MR imaging such as implanted metal devices that are MRI-incompatible, allergy to MRI contrast that cannot be adequately addressed with pre-contrast medications, or foreign bodies that preclude MRI imaging. (Questions regarding MRI compatibility of implanted objects should be reviewed with the Radiology Department performing the MRI).
* Current use of (other N-methyl-D-aspartate \[NMDA\] antagonists) amantadine, ketamine, or dextromethorphan.
* Radiographic evidence of hydrocephalus or other architectural change of the ventricular system resulting in significant anatomic distortion of the hippocampus, including placement of external ventricular drain or ventriculoperitoneal shunt.

  * Mild cases of hydrocephalus not resulting in significant anatomic distortion of the hippocampus are permitted.
* Prior radiotherapy to the brain, including SRS, WBRT, or prophylactic cranial irradiation (PCI).

Where this trial is running

Phoenix, Arizona and 226 other locations

+177 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Metastatic Lung Small Cell CarcinomaMetastatic Malignant Neoplasm in the BrainRecurrent Lung Small Cell CarcinomaStage IV Lung Cancer AJCC v8
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.