This phase III trial compares the effect of stereotactic radiosurgery to standard of care memantine and whole brain radiation therapy that avoids the hippocampus (the memory zone of the brain) for the treatment of small cell lung cancer that has spread to the brain. Stereotactic radiosurgery is a specialized radiation therapy that delivers a single, high dose of radiation directly to the tumor and may cause less damage to normal tissue. Whole brain radiation therapy delivers a low dose of radiation to the entire brain including the normal brain tissue. Hippocampal avoidance during whole-brain radiation therapy (HA-WBRT) decreases the amount of radiation that is delivered to the hippocampus which is a brain structure that is important for memory. The drug, memantine, is also often given with whole brain radiotherapy because it may decrease the risk of side effects related to thinking and memory. Stereotactic radiosurgery may decrease side effects related to memory and thinking compared to standard of care HA-WBRT plus memantine.
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.
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.
Parallel
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Memantine Hydrochloride
DrugGiven PO
Neurocognitive Assessment
Other interventionAncillary studies
Stereotactic Radiosurgery
RadiationUndergo SRS
Survey Administration
Other interventionAncillary studies
Whole-Brain Radiotherapy
RadiationUndergo HA-WBRT
Time to neurocognitive failure
A failure is defined using the reliable change index (RCI) criteria, as measured by the Hopkins Verbal Learning Test - Revised (HVLT-R), Controlled Oral Word Association (COWA) test, and Trail Making Test (TMT) Parts A and B. The cumulative incidence approach will be used to estimate the percentage of failures while accounting for the competing risk of death.
Preservation of neurocognitive function
Neurocognitive function will be measured by the HVLT-R, COWA, and TMT. The HVLT-R has 3 parts that will be analyzed separately: Total Recall, Delayed Recall, and Delayed Recognition. The TMT also has 2 parts that will be analyzed separately: TMT Part A and TMT Part B. The COWA has a single outcome measure that will be analyzed. Standardized scores that adjust for age, education, and sex when necessary will be analyzed.
Perceived difficulties in cognition
Measured by Patient Reported Outcomes Measurement Information System (PROMIS). The total raw score for a PROMIS short form would be the sum of the values of the response to each question (therefore, for a short form which all questions are answered, the lowest possible score is 4 and the highest possible raw score is 20).
Symptom burden
Measured by MD Anderson Symptom Inventory for brain tumor (MDASI-BT). Four subscales (symptom severity, symptom interference, neurologic factor, and cognitive factor score) as well as certain individual items (fatigue, neurologic factor items, and cognitive factor items) of the MDASI-BT will be analyzed.
Time to intracranial disease progression
Time to any intracranial progression will be measured from the date of randomization to the date of intracranial disease progression. Death without an event will be treated as a competing risk. Alive patients without an event will be censored at their last known follow-up time. The percentage of patients with a failure will be determined using cumulative incidence.
Time to local brain recurrence (in brain lesions present at trial enrollment and treated with either stereotactic radiosurgery [SRS] or hippocampal-avoidant whole brain radiotherapy [HA-WBRT])
Time to incidence of distant brain relapses
Time to leptomeningeal dissemination
White matter injury and hippocampal volume
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NRG Oncology
Lead sponsor
National Cancer Institute (NCI)
Collaborator
