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
- Conditions
- Metastatic MelanomaPrognostic Stage IV Breast Cancer AJCC v8Metastatic Digestive System CarcinomaStage IV Renal Cell Cancer AJCC v8Stage IVA Lung Cancer AJCC v8Anatomic Stage IV Breast Cancer AJCC v8Metastatic Breast CarcinomaMetastatic Malignant Neoplasm in the BrainStage IVB Lung Cancer AJCC v8Metastatic Lung Non-Small Cell Carcinoma
- Interventions
- Other: Quality-of-Life AssessmentOther: Questionnaire AdministrationRadiation: Stereotactic RadiosurgeryRadiation: Whole-Brain Radiotherapy
- Registration Number
- NCT04588246
- Lead Sponsor
- NRG Oncology
- Brief Summary
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.
- Detailed Description
PRIMARY OBJECTIVE:
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.
SECONDARY OBJECTIVES:
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.
EXPLORATORY OBJECTIVES:
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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 350
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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
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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
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Distant brain relapse lesions must be diagnosed on MRI, which will include the following elements:
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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
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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
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-
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Brain metastasis velocity (BMV) since upfront SRS must be >= 4 brain metastases/year
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The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
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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
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History and physical examination within 28 days prior to randomization
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Karnofsky performance status of >= 70 within 28 days prior to randomization
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Calculated creatinine clearance (CrCl) >= 30 ml/min (within 28 days prior to randomization)
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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)
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Negative urine or serum pregnancy test (in women of childbearing potential) within 14 days prior to randomization
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Prior WBRT or prophylactic cranial irradiation
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Local relapse of metastasis previously treated with upfront SRS (i.e., relapse outside previously SRS-treated metastases is allowed)
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Brain metastases from primary germ cell tumor, small cell carcinoma, or lymphoma
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Definitive leptomeningeal metastasis
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Planned cytotoxic chemotherapy on the same day as SRS or HA-WBRT; concurrent immunotherapy is permitted
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Radiographic evidence of enlargement or other architectural distortion of the lateral ventricles, including placement of external ventricular drain or ventriculoperitoneal shunt
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Known history of demyelinating disease such as multiple sclerosis
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Inability to swallow pills
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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
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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
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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
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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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm I (salvage SRS, memantine, HA-WBRT) Whole-Brain Radiotherapy 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 PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Arm II (salvage SRS) Quality-of-Life Assessment Patients undergo salvage SRS. Arm I (salvage SRS, memantine, HA-WBRT) Quality-of-Life Assessment 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 PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Arm I (salvage SRS, memantine, HA-WBRT) Questionnaire Administration 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 PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Arm II (salvage SRS) Questionnaire Administration Patients undergo salvage SRS. Arm II (salvage SRS) Stereotactic Radiosurgery Patients undergo salvage SRS. Arm I (salvage SRS, memantine, HA-WBRT) Stereotactic Radiosurgery 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 PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Arm I (salvage SRS, memantine, HA-WBRT) Memantine 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 PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity.
- Primary Outcome Measures
Name Time Method Time to Neurologic Death From randomization until progressive neurologic decline at time of death, irrespective of status of extracranial disease, or death from inter-current disease in patients with severe neurologic dysfunction, assessed up to 3 years The primary comparison of treatment effect on neurologic deaths will be based a one-sided 0.05-level (score) test for cause-specific hazard ratio in a Cox proportional hazards model. Additional analyses will involve estimating the median time to neurologic death using the cumulative incidence function estimator in the presence of precluding events such as non-neurologic deaths in the two arms, separately. The Gray's test will be used to evaluate the difference in the distribution of neurologic deaths. These results will be interpreted in light of the competing non-neurologic deaths, which may be frequent.
- Secondary Outcome Measures
Name Time Method Symptom Burden Up to 1 year Measured by the MD Anderson Symptom Inventory - Brain Tumor (MDASI-BT). The MDASI-BT rates symptoms on an 11- point scale (0 to 10) to indicate the presence and severity of the symptom, with 0 being "not present" and 10 being "as bad as you can imagine." Each symptom is rated at its worst in the last 24 hours.
Overall Survival (OS) From randomization to death from any cause, assessed up to 3 years Analysis will consist of estimation of the OS curves via the Kaplan-Meier method and a stratified log-rank test. Additional analyses may consist of estimating the hazard ratio via the Cox proportional hazards model, accounting for other prognostic covariates (and evaluating whether the proportional hazards assumption holds or whether any treatment effect is notably time-varying), and evaluating for potential treatment by prognostic covariate interactions.
Intracranial Progression-Free Survival (IPFS) From randomization to intracranial progression or death from any cause, assessed up to 3 years Analysis will consist of estimation of the IPFS curves via the Kaplan-Meier method and a stratified log-rank test. Additional analyses may consist of estimating the hazard ratio via the Cox proportional hazards model, accounting for other prognostic covariates (and evaluating whether the proportional hazards assumption holds or whether any treatment effect is notably time-varying), and evaluating for potential treatment by prognostic covariate interactions.
Health Status Up to 1 year Measured by the European Quality of Life Five Dimension Five Level Scale Questionnaire (EQ-5D-5L). The EQ-5D-5L uses 5 levels (no problems, slight problems, moderate problems, severe problems, and extreme problems) to assess current health status.
Cognitive Abilities Up to 1 year Measured by the Patient Reported Outcomes Measurement Information System Cognitive Function Short Form 4a version 2.0.
Brain Metastasis Velocity (BMV) at subsequent relapse Up to 3 years The Wilcoxon rank-sum test will be used to compare the distributions of BMVs between the two treatment arms at 2-sided 0.05 level.
Incidence of Adverse Events associated with the interventions Up to 3 years Adverse Events (AEs) will be graded according to Common Terminology Criteria for Adverse Events version 5.0. Comprehensive summaries of all AEs by treatment arm will be generated and examined. Counts and frequencies of worst (highest score) AE per patient will be presented overall and by AE type category, separately by assigned treatment group. The proportion of patients with at least one grade 3 or higher AE will be compared between treatment arm.
Trial Locations
- Locations (76)
Banner University Medical Center - Tucson
🇺🇸Tucson, Arizona, United States
University of Arizona Cancer Center-North Campus
🇺🇸Tucson, Arizona, United States
City of Hope Corona
🇺🇸Corona, California, United States
City of Hope Comprehensive Cancer Center
🇺🇸Duarte, California, United States
City of Hope at Irvine Lennar
🇺🇸Irvine, California, United States
City of Hope Antelope Valley
🇺🇸Lancaster, California, United States
Sutter Cancer Centers Radiation Oncology Services-Roseville
🇺🇸Roseville, California, United States
Sutter Roseville Medical Center
🇺🇸Roseville, California, United States
Sutter Medical Center Sacramento
🇺🇸Sacramento, California, United States
City of Hope South Pasadena
🇺🇸South Pasadena, California, United States
City of Hope South Bay
🇺🇸Torrance, California, United States
City of Hope Upland
🇺🇸Upland, California, United States
Delaware Clinical and Laboratory Physicians PA
🇺🇸Newark, Delaware, United States
Helen F Graham Cancer Center
🇺🇸Newark, Delaware, United States
Medical Oncology Hematology Consultants PA
🇺🇸Newark, Delaware, United States
Christiana Care Health System-Christiana Hospital
🇺🇸Newark, Delaware, United States
UM Sylvester Comprehensive Cancer Center at Coral Gables
🇺🇸Coral Gables, Florida, United States
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
🇺🇸Deerfield Beach, Florida, United States
Mayo Clinic in Florida
🇺🇸Jacksonville, Florida, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
🇺🇸Miami, Florida, United States
Memorial Hospital West
🇺🇸Pembroke Pines, Florida, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
University of Chicago Comprehensive Cancer Center
🇺🇸Chicago, Illinois, United States
Carle at The Riverfront
🇺🇸Danville, Illinois, United States
Northwestern Medicine Cancer Center Kishwaukee
🇺🇸DeKalb, Illinois, United States
Carle Physician Group-Effingham
🇺🇸Effingham, Illinois, United States
Northwestern Medicine Cancer Center Delnor
🇺🇸Geneva, Illinois, United States
Carle Physician Group-Mattoon/Charleston
🇺🇸Mattoon, Illinois, United States
Carle Cancer Center
🇺🇸Urbana, Illinois, United States
The Carle Foundation Hospital
🇺🇸Urbana, Illinois, United States
Northwestern Medicine Cancer Center Warrenville
🇺🇸Warrenville, Illinois, United States
University of Maryland/Greenebaum Cancer Center
🇺🇸Baltimore, Maryland, United States
MedStar Franklin Square Medical Center/Weinberg Cancer Institute
🇺🇸Baltimore, Maryland, United States
UM Upper Chesapeake Medical Center
🇺🇸Bel Air, Maryland, United States
Central Maryland Radiation Oncology in Howard County
🇺🇸Columbia, Maryland, United States
UM Baltimore Washington Medical Center/Tate Cancer Center
🇺🇸Glen Burnie, Maryland, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
Saint Joseph Mercy Hospital
🇺🇸Ann Arbor, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology - Brighton
🇺🇸Brighton, Michigan, United States
Saint Joseph Mercy Chelsea
🇺🇸Chelsea, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
🇺🇸Chelsea, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
🇺🇸Ypsilanti, Michigan, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
Siteman Cancer Center at West County Hospital
🇺🇸Creve Coeur, Missouri, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Siteman Cancer Center-South County
🇺🇸Saint Louis, Missouri, United States
Siteman Cancer Center at Christian Hospital
🇺🇸Saint Louis, Missouri, United States
Siteman Cancer Center at Saint Peters Hospital
🇺🇸Saint Peters, Missouri, United States
Northwell Health/Center for Advanced Medicine
🇺🇸Lake Success, New York, United States
University of Rochester
🇺🇸Rochester, New York, United States
Wake Forest University Health Sciences
🇺🇸Winston-Salem, North Carolina, United States
Sanford Bismarck Medical Center
🇺🇸Bismarck, North Dakota, United States
Sanford Broadway Medical Center
🇺🇸Fargo, North Dakota, United States
Sanford Roger Maris Cancer Center
🇺🇸Fargo, North Dakota, United States
Ohio State University Comprehensive Cancer Center
🇺🇸Columbus, Ohio, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Christiana Care Health System-Concord Health Center
🇺🇸Chadds Ford, Pennsylvania, United States
Geisinger Medical Center
🇺🇸Danville, Pennsylvania, United States
UPMC Cancer Centers - Arnold Palmer Pavilion
🇺🇸Greensburg, Pennsylvania, United States
Geisinger Medical Oncology-Lewisburg
🇺🇸Lewisburg, Pennsylvania, United States
Riddle Memorial Hospital
🇺🇸Media, Pennsylvania, United States
UPMC-Shadyside Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
Geisinger Cancer Services-Pottsville
🇺🇸Pottsville, Pennsylvania, United States
Lankenau Medical Center
🇺🇸Wynnewood, Pennsylvania, United States
UPMC Memorial
🇺🇸York, Pennsylvania, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Prisma Health Cancer Institute - Faris
🇺🇸Greenville, South Carolina, United States
Covenant Medical Center-Lakeside
🇺🇸Lubbock, Texas, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸Richmond, Virginia, United States
West Virginia University Healthcare
🇺🇸Morgantown, West Virginia, United States
University of Wisconsin Carbone Cancer Center
🇺🇸Madison, Wisconsin, United States
Froedtert Menomonee Falls Hospital
🇺🇸Menomonee Falls, Wisconsin, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Drexel Town Square Health Center
🇺🇸Oak Creek, Wisconsin, United States
Froedtert West Bend Hospital/Kraemer Cancer Center
🇺🇸West Bend, Wisconsin, United States