Testing if High Dose Radiation Only to the Sites of Brain Cancer Compared to Whole Brain Radiation That Avoids the Hippocampus is Better at Preventing Loss of Memory and Thinking Ability

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of small cell lungcancer within 5 years of registration. If the original histologic proof ofmalignancy 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 eitherhippocampus 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 beapproximated by measuring the lesion's three perpendicular diameters oncontrast enhanced, T1-weighted MRI and the product of those diameters will bedivided by 2 to estimate the lesion volume (e.g. xyz/2). Alternatively, directvolumetric measurements via slice by slice contouring on a treatment planningsoftware package can be used to calculate the total tumor volume.

• Brain metastases can be diagnosed synchronous to the initial diagnosis of smallcell lung cancer or metachronous to the initial diagnosis and management ofsmall cell lung cancer.

• Brain metastases must be diagnosed on MRI, which will include the followingelements:

• REQUIRED MRI ELEMENTS

• Post gadolinium contrast-enhanced T1-weighted three-dimensional (3D)spoiled gradient (SPGR). Acceptable 3D SPGR sequences includemagnetization prepared 3D gradient recalled echo (GRE) rapid gradientecho (MP-RAGE), turbo field echo (TFE) MRI, BRAVO (Brain VolumeImaging) or 3D Fast FE (field echo). The T1-weighted 3D scan shoulduse the smallest possible axial slice thickness, not to exceed 1.5mm.

• Pre-contrast T1 weighted imaging (3D imaging sequence stronglyencouraged).

• A minimum of one axial T2 FLAIR (preferred) or T2 sequence isrequired. 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 beperformed instead of a T2 sequence.

• Recommendation is that that pre-contrast 3D T1 be performed with thesame 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 sameMRI instrument at each time point.

• Recommendation is that if additional sequences are obtained, theseshould meet the criteria outlined in Kaufmann et al., 2020.

• If additional sequences are obtained, total imaging time should notexceed 60 minutes.

• If additional metastases not known at the time ofregistration/randomization or seen in the MRI used for eligibilityare subsequently found on the radiation therapy (RT) planning MRIsuch that the total intacranial volume exceeds 30 cm^3, the patientis 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 withsystemic (chemotherapy and/or immunotherapy) before enrollment only if their brainmetastases are asymptomatic and not located in eloquent locations (e.g., brainstem,pre-/post-central gyrus, visual cortex). However, within 21 days prior toenrollment, brain MRI must be repeated to confirm eligibility.

• Patients with symptomatic brain metastases and/or brain metastases in eloquentlocations (e.g., brainstem, pre-/post central gyrus, visual cortex) areeligible for enrollment on the trial; however, the specific treatment approachof starting with systemic therapy alone and delaying brain radiation is notrecommended 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 aresexually 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 beproficient 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 priorto Step 2 registration: HVLT-R, TMT, and COWA. The neurocognitive test will beuploaded 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

• NOTE: Completed baseline neurocognitive tests can be uploaded at the time ofStep 1 registration.

• PRIOR TO STEP 2 REGISTRATION: The following baseline neurocognitive tests must becompleted within 21 days prior to Step 2 registration: HVLT-R, TMT, and COWA. Theneurocognitive tests will be uploaded into RAVE for evaluation by Dr. Wefel. Oncethe upload is complete, within 3 business days a notification will be sent via emailto 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-WBRTtreatment. Patients may have had prior chemotherapy. Concurrent immunotherapy ispermitted.

• For patients receiving fractionated SRS on an every-other-day basis, plannedinfusion 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 areMRI-incompatible, allergy to MRI contrast that cannot be adequately addressed withpre-contrast medications, or foreign bodies that preclude MRI imaging. (Questionsregarding MRI compatibility of implanted objects should be reviewed with theRadiology 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 theventricular 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 ofthe hippocampus are permitted.

• Prior radiotherapy to the brain, including SRS, WBRT, or prophylactic cranialirradiation (PCI).