Comparison of Radiation Therapy Regimens in Combination With Chemotherapy in Treating Young Patients With Newly Diagnosed Standard-Risk Medulloblastoma

Phase 3

Completed

Conditions: Medulloblastoma

Interventions: Drug: Cisplatin
Radiation: Craniospinal Irradiation
Drug: Cyclophosphamide
Radiation: Involved-Field Radiation Therapy
Drug: Lomustine
Other: Laboratory Biomarker Analysis
Other: Quality-of-Life Assessment
Radiation: Radiation Therapy
Drug: Vincristine Sulfate

Registration Number: NCT00085735

Lead Sponsor: Children's Oncology Group

Brief Summary: This randomized phase III trial is studying how well standard-dose radiation therapy works compared to reduced-dose radiation therapy in children 3-7 years of age AND how well standard volume boost radiation therapy works compared to smaller volume boost radiation therapy when given together with chemotherapy in treating young patients who have undergone surgery for newly diagnosed standard-risk medulloblastoma. Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in chemotherapy, such as vincristine, cisplatin, lomustine, and cyclophosphamide, work in different ways to stop tumor cells from dividing so they stop growing or die. Giving radiation therapy with chemotherapy after surgery may kill any remaining tumor cells. It is not yet known whether standard-dose radiation therapy is more effective than reduced-dose radiation therapy when given together with chemotherapy after surgery in treating young patients with medulloblastoma.

Detailed Description: PRIMARY OBJECTIVE:

I. To determine whether reducing the craniospinal dose of radiation therapy to 18.00 Gy in children 3-7 years of age does not compromise event-free survival and overall survival as compared to treatment with 23.40 Gy of craniospinal radiation; and to determine if reducing the irradiated volume of the primary site tumor boost from the whole posterior fossa to the tumor bed only will not compromise event-free and overall survival.

SECONDARY OBJECTIVES:

I. To evaluate patterns of failure in children treated with an irradiation boost volume smaller than conventional posterior fossa volumes.

II. To reduce the cognitive, auditory and endocrinologic effects of treatment of average-risk medulloblastoma by reducing the dose of craniospinal irradiation therapy.

III. To determine if the audiologic and endocrinologic toxicity will be reduced with the use of limited tumor boost volume irradiation compared to patients treated with conventional target volumes of radiation.

IV. To develop an optimal gene expression medulloblastoma outcome predictor, validated prospectively in a multi-institution randomized clinical trial.

V. To improve compliance with long-term quality of life and functional status data submission by educating institutional nurses to administer and submit for analysis a battery of four instruments: Behavior Assessment System for Children- 2nd Edition (BASC-2), Adaptive Behavior Assessment System - 2nd Edition (ABAS-II), Behavior Rating Inventory of Executive Function (BRIEF), PedsQLTM 4.0.

OUTLINE: Patients 3-7 years of age are randomized to 1 of 4 arms (Arm I-IV). Patients 8-21 years of age are randomized to 1 of 2 arms (Arm V or VI).

Within 31 days after definitive surgery, all patients begin therapy. Patients undergo radiation therapy with doses according to their Arm randomization on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, and 43-47 (weeks 0-6). All patients receive vincristine intravenously (IV) over 1 minute (or infusion via minibag as per institutional policy) on days 8, 15, 22, 29, 36, and 43 (weeks 1-6).

ARM I: Patients 3-7 years of age undergo lowered dose craniospinal irradiation (LDCSI) with involved-field radiation therapy (IFRT) boost.

ARM II: Patients 3-7 years of age undergo LDCSI with whole posterior fossa radiation therapy (PFRT) boost.

ARM III: Patients 3-7 years of age undergo standard dose craniospinal irradiation (SDCSI) with IFRT boost.

ARM IV: Patients 3-7 years of age undergo SDCSI with PFRT boost.

ARM V: Patients 8-21 years of age undergo SDCSI with IFRT boost.

ARM VI: Patients 8-21 years of age undergo SDCSI with PFRT boost.

MAINTENANCE CHEMOTHERAPY: Beginning 4 weeks after completion of chemoradiotherapy, patients receive 2 different regimens of maintenance chemotherapy for a total of 9 courses. Each course in regimen A is 6 weeks (42 days) in duration. Each course in regimen B is 4 weeks (28 days) in duration.

REGIMEN A (courses 1, 2, 4, 5, 7, and 8): Patients receive lomustine orally and cisplatin IV over 6 hours on day 1 and vincristine IV on days 1, 8, and 15 of weeks 11, 17, 27, 33, 43, and 49.

REGIMEN B (courses 3, 6, and 9): Patients receive cyclophosphamide IV over 1 hour on days 1 and 2 and vincristine IV on days 1 and 8 of weeks 23, 39, and 55.

Treatment continues in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at 3-6 months after completion of radiotherapy and at 3-4 years after study entry. Neurocognitive function may also be assessed.

Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

OUTLINE: Patients 3-7 years of age are randomized to 1 of 4 arms (Arm I-IV). Patients 8-21 years of age are randomized to 1 of 2 arms (Arm V or VI).

Within 31 days after definitive surgery, all patients begin therapy. Patients undergo radiation therapy with doses according to their Arm randomization on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, and 43-47 (weeks 0-6). All patients receive vincristine intravenously (IV) over 1 minute (or infusion via minibag as per institutional policy) on days 8, 15, 22, 29, 36, and 43 (weeks 1-6).

ARM I: Patients 3-7 years of age undergo lowered dose craniospinal irradiation (LDCSI) with involved-field radiation therapy (IFRT) boost.

ARM II: Patients 3-7 years of age undergo LDCSI with whole posterior fossa radiation therapy (PFRT) boost.

ARM III: Patients 3-7 years of age undergo standard dose craniospinal irradiation (SDCSI) with IFRT boost.

ARM IV: Patients 3-7 years of age undergo SDCSI with PFRT boost.

ARM V: Patients 8-21 years of age undergo SDCSI with IFRT boost.

ARM VI: Patients 8-21 years of age undergo SDCSI with PFRT boost.

MAINTENANCE CHEMOTHERAPY: Beginning 4 weeks after completion of chemoradiotherapy, patients receive 2 different regimens of maintenance chemotherapy for a total of 9 courses. Each course in regimen A is 6 weeks (42 days) in duration. Each course in regimen B is 4 weeks (28 days) in duration.

REGIMEN A (courses 1, 2, 4, 5, 7, and 8): Patients receive lomustine orally and cisplatin IV over 6 hours on day 1 and vincristine IV on days 1, 8, and 15 of weeks 11, 17, 27, 33, 43, and 49.

REGIMEN B (courses 3, 6, and 9): Patients receive cyclophosphamide IV over 1 hour on days 1 and 2 and vincristine IV on days 1 and 8 of weeks 23, 39, and 55.

Treatment continues in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at 3-6 months after completion of radiotherapy and at 3-4 years after study entry. Neurocognitive function may also be assessed.

Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 549

Inclusion Criteria

Histologically confirmed medulloblastoma located in the posterior fossa
- Standard-risk disease
Minimal volume, non-disseminated disease, defined by the following:
- Residual tumor ≤ 1.5 cm^2 confirmed by MRI with contrast imaging within 21 days after surgery
- No metastatic disease in the head, spine, or cerebrospinal fluid (CSF) confirmed by both of the following:
  - Enhanced MRI of the spine within 5 days before surgery OR within 28 days after surgery
  - Negative cytological examination of CSF after surgery, but before study enrollment
Brain stem involvement allowed
Performance status - Karnofsky 50-100% (> 16 years of age)
Performance status - Lansky 30-100% (≤ 16 years of age)
Absolute neutrophil count > 1,500/uL
Platelet count > 100,000/uL (transfusion independent)
Hemoglobin > 10 g/dL (transfusions allowed)
Bilirubin < 1.5 times upper limit of normal (ULN) for age
AST or ALT < 1.5 times ULN for age
Creatinine clearance OR radioisotope glomerular filtration rate >= 70 mL/min/1.73m^2 or a serum creatinine based on age/gender as follows:

Age Maximum Serum Creatine (mg/dL)

1month to < 6 months male: 0.4 female: 0.4
6 months to <1 year male: 0.5 female: 0.5
1 year to < 2 years male: 0.6 female: 0.6
2 to < 6 years male: 0.8 female: 0.8
6 to < 10 years male: 1 female: 1
10 to < 13 years male: 1.2 female: 1.2
13 to < 16 years male: 1.5 female: 1.4
>= 16 years male: 1.7 female: 1.4
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- No prior chemotherapy
- Prior corticosteroids allowed
- No prior radiotherapy

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm III (3-7 years of age, SDCSI, IFRT)	Vincristine Sulfate	See Detailed Description (Arm III)
Arm IV (3-7 years of age, SDCSI, PFRT)	Vincristine Sulfate	See Detailed Description (Arm IV)
Arm V (8-21 years of age, SDCSI, IFRT)	Vincristine Sulfate	See Detailed Description (Arm V)
Arm I (3-7 years of age, LDCSI, IFRT)	Vincristine Sulfate	See Detailed Description (Arm I)
Arm II (3-7 years of age, LDCSI, PFRT)	Vincristine Sulfate	See Detailed Description (Arm II)
Arm II (3-7 years of age, LDCSI, PFRT)	Quality-of-Life Assessment	See Detailed Description (Arm II)
Arm II (3-7 years of age, LDCSI, PFRT)	Lomustine	See Detailed Description (Arm II)
Arm I (3-7 years of age, LDCSI, IFRT)	Cisplatin	See Detailed Description (Arm I)
Arm I (3-7 years of age, LDCSI, IFRT)	Craniospinal Irradiation	See Detailed Description (Arm I)
Arm I (3-7 years of age, LDCSI, IFRT)	Cyclophosphamide	See Detailed Description (Arm I)
Arm I (3-7 years of age, LDCSI, IFRT)	Involved-Field Radiation Therapy	See Detailed Description (Arm I)
Arm I (3-7 years of age, LDCSI, IFRT)	Laboratory Biomarker Analysis	See Detailed Description (Arm I)
Arm I (3-7 years of age, LDCSI, IFRT)	Lomustine	See Detailed Description (Arm I)
Arm I (3-7 years of age, LDCSI, IFRT)	Quality-of-Life Assessment	See Detailed Description (Arm I)
Arm II (3-7 years of age, LDCSI, PFRT)	Cisplatin	See Detailed Description (Arm II)
Arm II (3-7 years of age, LDCSI, PFRT)	Craniospinal Irradiation	See Detailed Description (Arm II)
Arm II (3-7 years of age, LDCSI, PFRT)	Cyclophosphamide	See Detailed Description (Arm II)
Arm II (3-7 years of age, LDCSI, PFRT)	Laboratory Biomarker Analysis	See Detailed Description (Arm II)
Arm II (3-7 years of age, LDCSI, PFRT)	Radiation Therapy	See Detailed Description (Arm II)
Arm III (3-7 years of age, SDCSI, IFRT)	Cisplatin	See Detailed Description (Arm III)
Arm III (3-7 years of age, SDCSI, IFRT)	Craniospinal Irradiation	See Detailed Description (Arm III)
Arm III (3-7 years of age, SDCSI, IFRT)	Cyclophosphamide	See Detailed Description (Arm III)
Arm III (3-7 years of age, SDCSI, IFRT)	Involved-Field Radiation Therapy	See Detailed Description (Arm III)
Arm III (3-7 years of age, SDCSI, IFRT)	Laboratory Biomarker Analysis	See Detailed Description (Arm III)
Arm III (3-7 years of age, SDCSI, IFRT)	Lomustine	See Detailed Description (Arm III)
Arm III (3-7 years of age, SDCSI, IFRT)	Quality-of-Life Assessment	See Detailed Description (Arm III)
Arm IV (3-7 years of age, SDCSI, PFRT)	Craniospinal Irradiation	See Detailed Description (Arm IV)
Arm IV (3-7 years of age, SDCSI, PFRT)	Cyclophosphamide	See Detailed Description (Arm IV)
Arm IV (3-7 years of age, SDCSI, PFRT)	Laboratory Biomarker Analysis	See Detailed Description (Arm IV)
Arm IV (3-7 years of age, SDCSI, PFRT)	Lomustine	See Detailed Description (Arm IV)
Arm IV (3-7 years of age, SDCSI, PFRT)	Quality-of-Life Assessment	See Detailed Description (Arm IV)
Arm IV (3-7 years of age, SDCSI, PFRT)	Radiation Therapy	See Detailed Description (Arm IV)
Arm V (8-21 years of age, SDCSI, IFRT)	Cisplatin	See Detailed Description (Arm V)
Arm V (8-21 years of age, SDCSI, IFRT)	Craniospinal Irradiation	See Detailed Description (Arm V)
Arm V (8-21 years of age, SDCSI, IFRT)	Cyclophosphamide	See Detailed Description (Arm V)
Arm V (8-21 years of age, SDCSI, IFRT)	Involved-Field Radiation Therapy	See Detailed Description (Arm V)
Arm V (8-21 years of age, SDCSI, IFRT)	Laboratory Biomarker Analysis	See Detailed Description (Arm V)
Arm V (8-21 years of age, SDCSI, IFRT)	Lomustine	See Detailed Description (Arm V)
Arm V (8-21 years of age, SDCSI, IFRT)	Quality-of-Life Assessment	See Detailed Description (Arm V)
Arm VI (8-21 years of age, SDCSI, PFRT)	Cisplatin	See Detailed Description (Arm VI)
Arm VI (8-21 years of age, SDCSI, PFRT)	Craniospinal Irradiation	See Detailed Description (Arm VI)
Arm VI (8-21 years of age, SDCSI, PFRT)	Cyclophosphamide	See Detailed Description (Arm VI)
Arm VI (8-21 years of age, SDCSI, PFRT)	Laboratory Biomarker Analysis	See Detailed Description (Arm VI)
Arm VI (8-21 years of age, SDCSI, PFRT)	Lomustine	See Detailed Description (Arm VI)
Arm VI (8-21 years of age, SDCSI, PFRT)	Quality-of-Life Assessment	See Detailed Description (Arm VI)
Arm VI (8-21 years of age, SDCSI, PFRT)	Radiation Therapy	See Detailed Description (Arm VI)
Arm VI (8-21 years of age, SDCSI, PFRT)	Vincristine Sulfate	See Detailed Description (Arm VI)

Primary Outcome Measures

Name	Time	Method
Event-free Survival (EFS)	Assessed at 3 years	EFS was defined as the time interval from date of study entry to date of disease progression, disease recurrence, second malignant neoplasm or death from any cause, whichever occurs first, or to the date of last follow-up for patients without events. EFS was estimated using the method of Kaplan and Meier. 3-year estimates are reported with 95% confidence intervals (CI's).
Overall Survival (OS)	3 years	OS was defined as the time interval from date of study entry to date of death from any cause or to the date of last follow-up for survivors. OS was estimated using the method of Kaplan and Meier. 3-year estimates are reported with 95% CI's. For purposes of this analysis, arms I, III and V (involved field radiation therapy \[IFRT\]) are combined and compared to arms II, IV and VI (posterior fossa irradiation \[PFRT\]).

Secondary Outcome Measures

Name	Time	Method
Non-local Posterior Fossa (NLPF) Failure Rate	3 years	NLPF failure was defined as tumor recurrence/progression outside the radiation therapy clinical target volume boost (CTV-boost) but within the posterior fossa CTV (CTV-PF). The cumulative incidence (CI) of NLPF failure was estimated; 3-year estimates were reported with 95% confidence intervals. Patients with other failure types (e.g., NPF, LPF) and with other events prior to NLPF failure (e.g., death, second malignancy) were considered as having competing events.
Overall Survival (OS) by Molecular Subgroup Based on Methylation Arrays	3 years	OS was defined as the time interval from date of study entry to date of death from any cause or to date of last contact for survivors. OS was estimated using the method of Kaplan and Meier. 3-year estimates are reported with 95% CI's.
Progression-free Survival (PFS) by Molecular Subgroup Based on Methylation Arrays	3 years	PFS was defined as the time interval from date of study entry to disease progression, relapse or death due to cancer or to last follow-up. Second malignancies and deaths from causes clearly not associated with tumor progression or recurrence were censored. PFS was estimated using the method of Kaplan and Meier. 3-year estimates are reported with 95% CI's.
Post-treatment Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) by CSI Group Within Time Window 1 (4-15 Months Post Diagnosis)	4 - 15 months post diagnosis	Metacognition index (MI) was measured by BRIEF test. Assessments within the time window, from eligible and evaluable patients are reported. If the patient had disease progression, only the assessments before progression date were reported. The MI is a standard T- score, and it ranges from 0 to 100. The higher score reported suggests a higher level of dysfunction.
Post-treatment Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) by CSI Group Within Time Window 3 (49 - 72 Months Post Diagnosis)	49 - 72 months post diagnosis	Metacognition index (MI) was measured by BRIEF test. Assessments within the time window, from eligible and evaluable patients are reported. If the patient had disease progression, only the assessments before progression date were reported. The MI is a standard T- score, and it ranges from 0 to 100. The higher score reported suggests a higher level of dysfunction.
Non-posterior Fossa (NPF) Failure Rate	3 years	NPF failure was defined as tumor recurrence within the neuroaxis but outside the radiation therapy clinical target volume (CTV). The cumulative incidence (CI) of NPF failure was estimated; 3-year estimates were reported with 95% confidence intervals. Patients with other failure types (e.g., LPF failure) and with other events prior to NPF failure (e.g., death, second malignancy) were considered as having competing events.
Post-treatment Neurocognitive Function as Measured by the Estimated Full-scale IQ (FSIQ) by CSI Group Within Time Window 1 (4 - 15 Months Post Diagnosis).	4 -15 months post diagnosis	Post-treatment neurocognitive function was assessed. Full-scale IQ (FSIQ) is a representative measurement for neurocognitive function. FSIQ was measured by IQ tests. Assessments within the time window, from eligible and evaluable patients are reported. The time window is 4-15 months post diagnosis, only the assessments before progression date were reported. The Range of FSIQ is 50-150. A higher FSIQ is better.
Post-treatment Neurocognitive Function as Measured by the Estimated Full-scale IQ (FSIQ) by CSI Group Within Time Window 2 (27 - 48 Months Post Diagnosis)	27 - 48 months post diagnosis	Post-treatment neurocognitive function was assessed. Full-scale IQ (FSIQ) is a representative measurement for neurocognitive function. FSIQ was measured by IQ tests. Assessments within the time window, from eligible and evaluable patients are reported. The time window is 27-48 months post diagnosis, only the assessments before progression date were reported. The range of FSIQ is 50 - 150. A higher FSIQ is better.
Compliance Rates for All Eligible and Evaluable Patients Enrolled Within Time Window 1 (4-15 Months Post Diagnosis)	4-15 months post diagnosis	Compliance rates are calculated to monitor the compliance with long-term quality of life and functional status data submission. A patient will be compliant if the patient has metacognition index score. Compliance rates will be assessed at each of the 3 neurocognitive/quality of life assessment time windows. All eligible and evaluable patients enrolled will be used. Patients removed from treatment prior to the time of neuropsychological assessment (for reasons such as disease progression, death, withdrawal of consent, etc.) will not be included in the denominator to assess the compliance rate. The time window is 4 - 15 months post diagnosis.
Compliance Rates for All Eligible and Evaluable Patients Enrolled Within Time Window 2 (27-48 Months Post Diagnosis)	27-48 months post diagnosis	Compliance rates are calculated to monitor the compliance with long-term quality of life and functional status data submission. A patient will be compliant if the patient has metacognition index score. Compliance rates will be assessed at each of the 3 neurocognitive/quality of life assessment time windows. All eligible and evaluable patients enrolled will be used. Patients removed from treatment prior to the time of neuropsychological assessment (for reasons such as disease progression, death, withdrawal of consent, etc.) will not be included in the denominator to assess the compliance rate. The time window is 27 - 48 months post diagnosis.
Local Posterior Fossa (LPF) Failure Rate	3 years	LPF failure was defined as tumor recurrence/progression within the tumor bed. The cumulative incidence (CI) of LPF failure was estimated; 3-year estimates were reported with 95% confidence intervals. Patients with other failure types (e.g., NPF) and with other events prior to LPF failure (e.g., death, second malignancy) were considered as having competing events.
Post-treatment Grade 3+ Hearing Loss as Measured by Common Terminology Criteria for Adverse Events (CTCAE) Version (v)4	Up to 3 years	Proportions of patients with grade 3+ hearing loss after the completion of therapy will be calculated and reported separately for low dose craniospinal irradiation (LDCSI) versus (vs.) standard dose craniospinal irradiation (SDCSI) patients. Eligible and evaluable patients 3-7 years of age will be used.
Compliance Rates for All Eligible and Evaluable Patients Enrolled Within Time Window 3 (49 - 72 Months Post Diagnosis)	49 - 72 months post diagnosis	Compliance rates are calculated to monitor the compliance with long-term quality of life and functional status data submission. A patient will be compliant if the patient has metacognition index score. Compliance rates will be assessed at each of the 3 neurocognitive/quality of life assessment time windows. All eligible and evaluable patients enrolled will be used. Patients removed from treatment prior to the time of neuropsychological assessment (for reasons such as disease progression, death, withdrawal of consent, etc.) will not be included in the denominator to assess the compliance rate. The time window is 49 - 72 months post diagnosis.
Post-treatment Endocrine Function by CSI Group	Up to 3 years	Post-treatment endocrine function was measured by laboratory assessment of the thyroid stimulating hormone (TSH). The mean TSH will be reported.
Incidence of Grade 3+ Hearing Loss at 1-year Post Treatment as Assessed by CTCAE v4	Up to 3 years	Proportions of patients with grade 3+ hearing impairment as assessed by CTCAE v4 at 1-year post treatment were calculated.
Incidence of Endocrine Dysfunction as Measured by Growth Hormone Stimulation Tests at the Time of Completion of Therapy by Radiotherapy (RT) Group	Post-treatment up to 3 years	Endocrine dysfunction was assessed by growth hormone stimulation (GHS) tests. We report the percentage of patients with abnormal growth hormone stimulation tests.
Post-treatment Neurocognitive Function as Measured by the Estimated Full-scale IQ (FSIQ) by CSI Group Within Time Window 3 (49 - 72 Months Post Diagnosis)	49 - 72 months post diagnosis	Post-treatment neurocognitive function was assessed. Full-scale IQ (FSIQ) is a representative measurement for neurocognitive function. FSIQ was measured by IQ tests. Assessments within the time window, from eligible and evaluable patients are reported. The time window is 49-72 months post diagnosis, only the assessments before progression date were reported. The Range of FSIQ is 50-150. A higher FSIQ is better.
Post-treatment Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) by CSI Group Within Time Window 2 (27-48 Months Post Diagnosis)	27-48 months post diagnosis	Metacognition index (MI) was measured by BRIEF test. Assessments within the time window, from eligible and evaluable patients are reported. If the patient had disease progression, only the assessments before progression date were reported. The MI is a standard T- score, and it ranges from 0 to 100. The higher score reported suggests a higher level of dysfunction.

Trial Locations

Locations (197): Henry Ford Health Saint John Hospital
🇺🇸
Detroit, Michigan, United States
Children's Hospital of Alabama
🇺🇸
Birmingham, Alabama, United States
University of Alabama at Birmingham Cancer Center
🇺🇸
Birmingham, Alabama, United States
Phoenix Childrens Hospital
🇺🇸
Phoenix, Arizona, United States
Banner University Medical Center - Tucson
🇺🇸
Tucson, Arizona, United States
Kaiser Permanente Downey Medical Center
🇺🇸
Downey, California, United States
Loma Linda University Medical Center
🇺🇸
Loma Linda, California, United States
Miller Children's and Women's Hospital Long Beach
🇺🇸
Long Beach, California, United States
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
Cedars Sinai Medical Center
🇺🇸
Los Angeles, California, United States
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Henry Ford Health Saint John Hospital
🇺🇸Detroit, Michigan, United States