Breast Cancer Clinical Trial
Testing the Addition of Whole Brain Radiotherapy Using a Technique That Avoids the Hippocampus to Stereotactic Radiosurgery in People With Cancer That Has Spread to the Brain and Come Back in Other Areas of the Brain After Earlier Stereotactic Radiosurgery
This phase III trial compares the effect of adding whole brain radiotherapy with hippocampal avoidance and memantine to stereotactic radiosurgery versus stereotactic radiosurgery alone in treating patients with cancer that has spread to the brain and come back in other areas of the brain after earlier stereotactic radiosurgery. Hippocampus avoidance during whole-brain radiation therapy decreases the amount of radiation that is delivered to the hippocampus, which is a brain structure that is important for memory. The medicine memantine is also often given with whole brain radiation therapy because it may decrease the risk of side effects of radiation on thinking and memory. Stereotactic radiosurgery delivers a high dose of radiation only to the small areas of cancer in the brain and avoids the surrounding normal brain tissue. Adding whole brain radiotherapy with hippocampal avoidance and memantine to stereotactic radiosurgery may be effective in shrinking or stabilizing cancer that has spread to the brain and returned in other areas of the brain after receiving stereotactic radiosurgery.
I. To determine if salvage stereotactic radiosurgery (SRS) plus whole brain radiotherapy with hippocampal avoidance (HA-WBRT) in patients with brain metastasis velocity >= 4 new brain metastases/year at time of first or second distant brain failure following upfront SRS prolongs time to neurologic death as compared to salvage SRS alone.
I. To determine if salvage SRS + HA-WBRT in patients with brain metastasis velocity >= 4 new brain metastases/year at time of first or second distant brain failure following upfront SRS prolongs overall survival as compared to salvage SRS alone.
II. To evaluate if salvage SRS + HA-WBRT in patients with brain metastasis velocity >= 4 new brain metastases/year at time of first or second distant brain failure following upfront SRS prolongs intracranial progression-free survival as compared to salvage SRS alone.
III. To evaluate if salvage SRS + HA-WBRT in patients with brain metastasis velocity >= 4 new brain metastases/year at time of first or second distant brain failure following upfront SRS improves brain metastasis velocity at subsequent relapse as compared to salvage SRS alone.
IV. To assess perceived difficulties in cognitive abilities, symptom burden and health status after salvage SRS + HA-WBRT, as compared to salvage SRS alone, in patients with brain metastasis velocity >= 4 new brain metastases/year at time of first or second distant brain failure following upfront SRS.
V. To compare neurocognitive function outcomes following salvage SRS + HA-WBRT, as compared to salvage SRS alone, in patients with brain metastasis velocity >= 4 new brain metastases/year at time of first or second distant brain failure following upfront SRS.
VI. To tabulate and descriptively compare the adverse events associated with the interventions.
VII. To tabulate and descriptively compare the number of salvage procedures used to manage recurrent intracranial disease following the interventions.
I. To collect serum, plasma, and whole blood for translational research analyses.
II. To collect baseline and all follow-up magnetic resonance (MR) imaging for hippocampal volume, memory center substructures, axial T2 volumes, and quantitative texture analysis.
III. To collect baseline and follow-up MR imaging to extract whole brain volume, white matter volume and volume of metastatic disease to correlate with cognitive change at 4 months.
IV. To evaluate dose-volume histogram parameters to correlate with radiation toxicity.
V. To assess in patients receiving immunotherapy or targeted therapy, if salvage SRS + HA-WBRT in patients with brain metastasis velocity >= 4 new brain metastases/year at time of first or second distant brain failure following upfront SRS improves brain metastasis velocity and/or overall survival at subsequent relapse as compared to salvage SRS.
VI. To compare the estimated cost of brain-related therapies and quality-adjusted life years in patients who receive salvage SRS + HA-WBRT, as compared to salvage SRS alone, in patients with metastasis velocity >= 4 new brain metastases/year at time of first or second distant brain failure following upfront SRS.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Within 1 week prior to or following HA-WBRT, patients undergo salvage SRS. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine orally (PO) once daily (QD) or twice daily (BID) for 24 weeks in the absence of disease progression or unacceptable toxicity.
ARM II: Patients undergo salvage SRS.
After completion of study treatment, patients are followed up every 2-3 months for at least 1 year.
Patients must have developed their first or second distant brain relapse(s) at least 8 weeks after upfront SRS and within 21 days prior to randomization
Distant brain relapse lesions to be treated must measure =< 3.0 cm in maximal extent and total volume of distant brain relapses to be treated must measure < 30 mL on the contrast-enhanced diagnostic magnetic resonance imaging (MRI) brain scan obtained within 21 days prior to randomization
Distant brain relapse lesions 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 fluid attenuated inversion recovery (FLAIR) (preferred) or T2 sequence is required. This can be acquired as a 2D or 3D image. If 2D, the images should be obtained in the axial plane
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
Brain metastasis velocity (BMV) since upfront SRS must be >= 4 brain metastases/year
The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
Pathologically (histologically or cytologically) proven diagnosis of non-small cell lung cancer, melanoma, breast cancer, renal cell carcinoma, or gastrointestinal cancer within 10 years prior to randomization. If the original histologic proof of malignancy is greater than 10 years, then pathological (i.e., more recent) confirmation is required (e.g., from a systemic metastasis or brain metastasis)
Other histologies are not permitted
History and physical examination within 28 days prior to randomization
Karnofsky performance status of >= 70 within 28 days prior to randomization
Calculated creatinine clearance (CrCl) >= 30 ml/min (within 28 days prior to randomization)
Blood urea nitrogen (BUN) within 1.5 times the institutional upper limit of normal (ULN) (e.g., if the ULN is 20 mg/dL, then BUN up to 30 mg/dL is permitted) (within 28 days prior to randomization)
Negative urine or serum pregnancy test (in women of childbearing potential) within 14 days prior to randomization
Prior WBRT or prophylactic cranial irradiation
Local relapse of metastasis previously treated with upfront SRS (i.e., relapse outside previously SRS-treated metastases is allowed)
Brain metastases from primary germ cell tumor, small cell carcinoma, or lymphoma
Definitive leptomeningeal metastasis
Planned cytotoxic chemotherapy on the same day as SRS or HA-WBRT; concurrent immunotherapy is permitted
Radiographic evidence of enlargement or other architectural distortion of the lateral ventricles, including placement of external ventricular drain or ventriculoperitoneal shunt
Known history of demyelinating disease such as multiple sclerosis
Inability to swallow pills
Contraindication to MR imaging such as non-MR conditional implanted metal devices or unknown metallic foreign bodies, or contraindication to gadolinium contrast administration during MR imaging, such as anaphylactic allergy that cannot be adequately addressed with pre-contrast medications or acute kidney injury
Contraindications to memantine, including:
Allergy, including prior allergic reaction to memantine
Intractable seizures on adequate anticonvulsive therapy-more than 1 seizure per month for the past 2 months
Current use of N-methyl-D-aspartate (NMDA) agonist
Current alcohol or drug abuse, which can exacerbate lethargy/dizziness with memantine
Severe, active co-morbidity defined as follows:
Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
Transmural myocardial infarction within the last 6 months
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of randomization
Chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy at the time of randomization
Severe hepatic disease defined as a diagnosis of Child-Pugh class B or C hepatic disease
Renal tubular acidosis or metabolic acidosis
Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count >= 200 cells/microliter within 30 days prior to randomization. Note also that HIV testing is not required for eligibility for this protocol
Pregnant or lactating women, or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the medication and radiation involved in this study has unknown effects on the unborn fetus
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There are 45 Locations for this study
Ann Arbor Michigan, 48106, United States
Brighton Michigan, 48114, United States
Chelsea Michigan, 48118, United States
Chelsea Michigan, 48118, United States
Ypsilanti Michigan, 48197, United States
Jackson Mississippi, 39216, United States
Greensburg Pennsylvania, 15601, United States
Pittsburgh Pennsylvania, 15232, United States
York Pennsylvania, 17408, United States
Morgantown West Virginia, 26506, United States
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