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

Sponsor

NRG Oncology (Other)

Overall Status

Recruiting

CT.gov ID

NCT04804644

Collaborator

National Cancer Institute (NCI) (NIH)

200

Enrollment

Locations

Arms

111.2

Anticipated Duration (Months)

2.4

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Lung Small Cell Carcinoma Metastatic Malignant Neoplasm in the Brain Recurrent Lung Small Cell Carcinoma Stage IV Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8	Drug: Memantine Hydrochloride Other: Neurocognitive Assessment Radiation: Stereotactic Radiosurgery Radiation: Whole-Brain Radiotherapy	Phase 3

Detailed Description

PRIMARY OBJECTIVE:

Determine whether stereotactic radiosurgery (SRS) relative to whole brain radiotherapy with hippocampal avoidance (HA-WBRT) plus memantine hydrochloride (memantine) for brain metastases from small cell lung cancer (SCLC) prevents cognitive function failure as measured by cognitive decline on a battery of tests: the Hopkins Verbal Learning Test - Revised (HVLT-R), Controlled Oral Word Association (COWA) test, and the Trail Making Test (TMT).

SECONDARY OBJECTIVES:

Determine whether SRS relative to HA-WBRT plus memantine for brain metastases from SCLC preserves cognitive function as separately measured by the HVLT-R, COWA, TMT Parts A and B, and Clinical Trial Battery Composite (CTB COMP).
Assess perceived difficulties in cognitive abilities using Patient Reported Outcomes Measurement Information System (PROMIS) after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC.
Assess symptom burden using the MD Anderson Symptom Inventory for brain tumor (MDASI-BT) after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC.
Compare cumulative incidence of intracranial disease progression after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC.
Compare overall survival after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC.
Compare cumulative incidence of neurologic death after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC.
Compare the number of salvage procedures used to manage recurrent intracranial disease following SRS relative to HA-WBRT plus memantine for SCLC brain metastases.
Compare adverse events between the treatment arms according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 criteria.
Compare the risk of developing cerebral necrosis between SRS and HA-WBRT plus memantine in patients receiving concurrent immunotherapy.

EXPLORATORY OBJECTIVES:

Compare cumulative incidence of local brain recurrence, distant brain relapse, and leptomeningeal dissemination after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC.
Compare the cost of brain-related therapies and quality-adjusted life years in patients who receive SRS relative to HA-WBRT plus memantine for brain metastases from SCLC.
Evaluate the time delay to salvage WBRT or HA-WBRT in patients enrolled on the SRS arm.
Evaluate whether a time delay for chemotherapy in patients receiving HA-WBRT plus memantine relative to SRS for brain metastases from SCLC has an effect on overall survival.
Evaluate baseline magnetic resonance (MR) imaging biomarkers of white matter injury and hippocampal volumetry as potential predictors of cognitive decline and differential benefit from SRS relative to HA-WBRT plus memantine for brain metastases from SCLC.
Evaluate the correlation between neurocognitive functioning and patient-reported outcomes.
Collect serum, plasma and imaging studies for future translational research analyses.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo SRS over 1 day (in some cases several days).

ARM II: Patients undergo HA-WBRT once daily (QD) for 2 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive memantine orally (PO) QD or twice daily (BID) for up to 24 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2-3 months for 1 year, and then every 6 months thereafter.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

200 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Supportive Care

Official Title:

Phase III Trial of Stereotactic Radiosurgery (SRS) Versus Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) for 10 or Fewer Brain Metastases From Small Cell Lung Cancer

Actual Study Start Date :

Mar 24, 2021

Anticipated Primary Completion Date :

Jul 1, 2025

Anticipated Study Completion Date :

Jul 1, 2030

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (SRS) Patients undergo SRS over 1 day (in some cases several days).	Other: Neurocognitive Assessment Ancillary studies Radiation: Stereotactic Radiosurgery Undergo SRS Other Names: Stereotactic External Beam Irradiation stereotactic external-beam radiation therapy Stereotactic Radiation Therapy Stereotactic Radiotherapy stereotaxic radiation therapy stereotaxic radiosurgery
Active Comparator: Arm II (HA-WBRT, memantine) Patients also undergo HA-WBRT QD for 2 weeks in the absence of disease progression or unacceptable toxicity. Patients will also receive memantine PO QD or BID for up to 24 weeks in the absence of disease progression or unacceptable toxicity.	Drug: Memantine Hydrochloride Given PO Other Names: Ebixia Namenda Other: Neurocognitive Assessment Ancillary studies Radiation: Whole-Brain Radiotherapy Undergo HA-WBRT Other Names: WBRT whole-brain radiation therapy

Arm

Intervention/Treatment

Experimental: Arm I (SRS)

Patients undergo SRS over 1 day (in some cases several days).

Other: Neurocognitive Assessment

Ancillary studies

Radiation: Stereotactic Radiosurgery

Undergo SRS

Other Names:

Stereotactic External Beam Irradiation

stereotactic external-beam radiation therapy

Stereotactic Radiation Therapy

Stereotactic Radiotherapy

stereotaxic radiation therapy

stereotaxic radiosurgery

Active Comparator: Arm II (HA-WBRT, memantine)

Patients also undergo HA-WBRT QD for 2 weeks in the absence of disease progression or unacceptable toxicity. Patients will also receive memantine PO QD or BID for up to 24 weeks in the absence of disease progression or unacceptable toxicity.

Drug: Memantine Hydrochloride

Given PO

Other Names:

Ebixia

Namenda

Other: Neurocognitive Assessment

Ancillary studies

Radiation: Whole-Brain Radiotherapy

Undergo HA-WBRT

Other Names:

WBRT

whole-brain radiation therapy

Outcome Measures

Primary Outcome Measures

Time to Neurocognitive Failure [1 year]
Neurocognitive failure is the first failure, defined as neurocognitive decline (decline vs. no decline) using the reliable change index (RCI) on at least one of the following tests: Hopkins Verbal Learning Test - Revised (HVLT-R), Controlled Oral Word Association (COWA) test, or Trail Making Test (TMT) Parts A and B.

Secondary Outcome Measures

Preservation of Neurocognitive Function [1 year]
A mixed effects model will be used to assess changes of standardized neurocognitive scores across time using all available data while adjusting for stratification variables and other baseline characteristics. For discrete time point analyses, the change from baseline to each follow-up time point, will be calculated and compared between treatment arms using a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.
Perceived Difficulties in Cognition [1 year]
Measured by Patient Reported Outcomes Measurement Information System (PROMIS). For discrete time point analyses, the change from baseline to each follow-up time point, will be calculated and compared between treatment arms using a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.
Symptom Burden [1 year]
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. Mixed effects models will be used to assess changes of the four subscale scores (symptom severity, symptom interference, neurologic factor, and cognitive factor score) across time using all available data while adjusting for stratification variables and other baseline characteristics. For discrete time point analyses, the change from baseline to each follow-up time point, will be calculated and compared between treatment arms using a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.
Overall Survival [From the date of randomization to the date of death, or otherwise, the last follow-up date on which the patient was reported alive, assessed up to 10 years]
Will be estimated using the Kaplan-Meier method (Kaplan 1958), and differences between treatment arms will be tested using the log rank test (Mantel 1966). The Cox proportional hazard model (Cox 1972) will be performed with the stratification variables and other baseline characteristics as fixed variables to assess the treatment effect while adjusting for patient specific risk factors such as number of brain metastases and its interaction with treatment, KPS, and time to salvage chemotherapy as a time varying covariate. A two-sided significance level of 0.05 will be used.
Time to Neurologic Death [From the date of randomization to the date of neurologic death, assessed up to 10 years]
Gray's test will be used to assess between treatment arm comparisons (Gray 1988). Cause-specific Cox proportional hazards models will be used to evaluate the effect of stratification variables (DS-GPA and prior NCF testing exposure) and other baseline characteristics, such as KPS, and number of brain metastases and its interaction with treatment arm. A two-sided significance level of 0.05 will be used.
Salvage procedures used to manage recurrent intracranial disease [10 years]
Will be collected and descriptively compared between arms using Chi-square tests.
Incidence of adverse events [10 years]
Graded by Common Terminology Criteria for Adverse Events version 5.0. Counts of all adverse events (AEs) by grade will be provided by treatment arm. Counts and frequencies will be provided for the worst grade AE experienced by the patient by treatment arm. The rate of grade 3+ AEs related to treatment and the rate of grade 3+ AEs regardless of relationship to treatment will be compared between treatment arms using a Chi-square test at a two-sided significance level of 0.05.

Other Outcome Measures

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]) [10 years]
Time to incidence of distant brain relapses [10 years]
Time to leptomeningeal dissemination [10 years]
Time delay to salvage WBRT or HA-WBRT in patients on the SRS arm [Baseline to first salvage treatment, assessed up to 10 years]
Gray's test will be used to compare treatment arms (Gray 1988).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.
Ten or fewer brain metastases =< 3 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.
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.
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 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.
History/physical examination within 28 days prior to registration
Age >= 18
Karnofsky performance status of >= 70 within 28 days prior to registration
Creatinine clearance >= 30 ml/min (within 28 days prior to registration)
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. Patients must have completed prior intracranial surgical resection at least 14 days prior to registration.
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 1 business day 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.
Prior allergic reaction to memantine.
Intractable seizures while on adequate anticonvulsant therapy; more than 1 seizure per month for the past 2 months.
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).
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 registration
Chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy at the time of registration
Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Hospital in Arizona	Phoenix	Arizona	United States	85054
2	Los Angeles County-USC Medical Center	Los Angeles	California	United States	90033
3	USC / Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
4	University of Colorado Hospital	Aurora	Colorado	United States	80045
5	UCHealth Memorial Hospital Central	Colorado Springs	Colorado	United States	80909
6	Memorial Hospital North	Colorado Springs	Colorado	United States	80920
7	University of Florida Health Science Center - Gainesville	Gainesville	Florida	United States	32610
8	Emory University Hospital Midtown	Atlanta	Georgia	United States	30308
9	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia	United States	30322
10	Northside Hospital	Atlanta	Georgia	United States	30342
11	Northside Hospital-Cherokee	Canton	Georgia	United States	30115
12	Northside Hospital-Forsyth	Cumming	Georgia	United States	30041
13	Centralia Oncology Clinic	Centralia	Illinois	United States	62801
14	Rush University Medical Center	Chicago	Illinois	United States	60612
15	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
16	Carle on Vermilion	Danville	Illinois	United States	61832
17	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois	United States	62526
18	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
19	Northwestern Medicine Cancer Center Kishwaukee	DeKalb	Illinois	United States	60115
20	Carle Physician Group-Effingham	Effingham	Illinois	United States	62401
21	Crossroads Cancer Center	Effingham	Illinois	United States	62401
22	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois	United States	60134
23	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois	United States	61938
24	Cancer Care Center of O'Fallon	O'Fallon	Illinois	United States	62269
25	Carle Cancer Center	Urbana	Illinois	United States	61801
26	The Carle Foundation Hospital	Urbana	Illinois	United States	61801
27	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois	United States	60555
28	Mary Greeley Medical Center	Ames	Iowa	United States	50010
29	McFarland Clinic PC - Ames	Ames	Iowa	United States	50010
30	Mary Bird Perkins Cancer Center	Baton Rouge	Louisiana	United States	70809
31	Anne Arundel Medical Center	Annapolis	Maryland	United States	21401
32	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
33	MedStar Franklin Square Medical Center/Weinberg Cancer Institute	Baltimore	Maryland	United States	21237
34	UM Upper Chesapeake Medical Center	Bel Air	Maryland	United States	21014
35	Central Maryland Radiation Oncology in Howard County	Columbia	Maryland	United States	21044
36	University of Maryland Shore Medical Center at Easton	Easton	Maryland	United States	21601
37	Boston Medical Center	Boston	Massachusetts	United States	02118
38	Saint Joseph Mercy Hospital	Ann Arbor	Michigan	United States	48106
39	IHA Hematology Oncology Consultants-Brighton	Brighton	Michigan	United States	48114
40	Saint Joseph Mercy Brighton	Brighton	Michigan	United States	48114
41	IHA Hematology Oncology Consultants-Canton	Canton	Michigan	United States	48188
42	Saint Joseph Mercy Canton	Canton	Michigan	United States	48188
43	IHA Hematology Oncology Consultants-Chelsea	Chelsea	Michigan	United States	48118
44	Saint Joseph Mercy Chelsea	Chelsea	Michigan	United States	48118
45	Saint Mary Mercy Hospital	Livonia	Michigan	United States	48154
46	IHA Hematology Oncology Consultants-Ann Arbor	Ypsilanti	Michigan	United States	48197
47	Sanford Joe Lueken Cancer Center	Bemidji	Minnesota	United States	56601
48	Mercy Hospital	Coon Rapids	Minnesota	United States	55433
49	Unity Hospital	Fridley	Minnesota	United States	55432
50	Saint Francis Medical Center	Cape Girardeau	Missouri	United States	63703
51	Parkland Health Center - Farmington	Farmington	Missouri	United States	63640
52	Missouri Baptist Medical Center	Saint Louis	Missouri	United States	63131
53	Sainte Genevieve County Memorial Hospital	Sainte Genevieve	Missouri	United States	63670
54	Mercy Hospital Springfield	Springfield	Missouri	United States	65804
55	Missouri Baptist Sullivan Hospital	Sullivan	Missouri	United States	63080
56	Missouri Baptist Outpatient Center-Sunset Hills	Sunset Hills	Missouri	United States	63127
57	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana	United States	59405
58	Montefiore Medical Center-Einstein Campus	Bronx	New York	United States	10461
59	Montefiore Medical Center-Weiler Hospital	Bronx	New York	United States	10461
60	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
61	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
62	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
63	Sanford Bismarck Medical Center	Bismarck	North Dakota	United States	58501
64	Sanford Broadway Medical Center	Fargo	North Dakota	United States	58122
65	Sanford Roger Maris Cancer Center	Fargo	North Dakota	United States	58122
66	University of Cincinnati Cancer Center-UC Medical Center	Cincinnati	Ohio	United States	45219
67	Case Western Reserve University	Cleveland	Ohio	United States	44106
68	University of Cincinnati Cancer Center-West Chester	West Chester	Ohio	United States	45069
69	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
70	Saint Vincent Hospital	Erie	Pennsylvania	United States	16544
71	Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212
72	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania	United States	18711
73	McLeod Regional Medical Center	Florence	South Carolina	United States	29506
74	Gibbs Cancer Center-Gaffney	Gaffney	South Carolina	United States	29341
75	Self Regional Healthcare	Greenwood	South Carolina	United States	29646
76	Gibbs Cancer Center-Pelham	Greer	South Carolina	United States	29651
77	Spartanburg Medical Center	Spartanburg	South Carolina	United States	29303
78	MGC Hematology Oncology-Union	Union	South Carolina	United States	29379
79	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota	United States	57104
80	Avera Cancer Institute	Sioux Falls	South Dakota	United States	57105
81	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
82	Langlade Hospital and Cancer Center	Antigo	Wisconsin	United States	54409
83	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
84	Aspirus Regional Cancer Center	Wausau	Wisconsin	United States	54401