Observation, Radiation Therapy, Combination Chemotherapy, and/or Surgery in Treating Young Patients With Soft Tissue Sarcoma
- Conditions
- Adult Extraskeletal OsteosarcomaAdult Malignant Fibrous HistiocytomaChildhood FibrosarcomaChildhood LiposarcomaMetastatic Childhood Soft Tissue SarcomaNonmetastatic Childhood Soft Tissue SarcomaStage I Adult Soft Tissue SarcomaStage III Adult Soft Tissue SarcomaAdult AngiosarcomaAdult Epithelioid Sarcoma
- Interventions
- Other: clinical observationProcedure: therapeutic conventional surgeryRadiation: 3-dimensional conformal radiation therapy
- Registration Number
- NCT00346164
- Lead Sponsor
- Children's Oncology Group
- Brief Summary
This phase III trial is studying observation to see how well a risk based treatment strategy works in patients with soft tissue sarcoma. In the study, patients are assigned to receive surgery +/- radiotherapy +/- chemotherapy depending on their risk of recurrence. Sometimes, after surgery, the tumor may not need additional treatment until it progresses. In this case, observation may be sufficient. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as ifosfamide and doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving chemotherapy and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments after surgery may kill any tumor cells that remain after surgery.
- Detailed Description
PRIMARY OBJECTIVES:
I. Define a risk-based treatment strategy comprising observation only, adjuvant radiotherapy, or adjuvant chemoradiotherapy or neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy with or without radiotherapy in young patients with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS).
II. Assess event-free and overall survival of patients treated with these regimens.
III. Assess the pattern of treatment failure in these patients.
SECONDARY OBJECTIVES:
I. Assess the feasibility of a neoadjuvant chemoradiotherapy approach in patients with intermediate- or high-risk NRSTS.
II. Assess the imaging and pathologic responses to neoadjuvant chemoradiotherapy in patients with intermediate- or high-risk NRSTS.
III. Correlate imaging and pathologic response with clinical outcomes in patients with intermediate- or high-risk disease who undergo neoadjuvant chemoradiotherapy.
IV. Prospectively define clinical prognostic factors associated with event-free survival, overall survival, local recurrence, and distant recurrence in these patients.
V. Correlate patient outcomes with findings of biologic studies performed on tissue specimens collected on protocol COG-D9902 from these patients.
VI. Determine whether the diagnosis and histologic grade of NRSTS assigned by the enrolling institution correlates with the diagnosis and histologic grade established by central expert pathology reviewers.
VII. Compare the Pediatric Oncology Group (POG) and Fédération Nationale des Centres de Lutte Contre le Cancer (French Federation of Cancer Centers \[FNCLCC\]) pathologic grading systems to determine which better correlates with clinical outcomes.
OUTLINE: This is a multicenter study. Patients are divided into 3 risk groups according to presence of metastatic disease (yes vs no), status of prior surgery (resected vs unresected), grade of tumor (low vs high), and size of primary tumor (≤ 5 cm vs \> 5 cm). Patients are assigned to different treatment regimens based on disease extent (nonmetastatic vs metastatic), tumor size (≤ 5 cm vs \> 5 cm), extent of resection of primary tumor (resected vs unresected), extent of resection of metastases (complete or microscopic residual vs gross residual), microscopic tumor margins (negative vs positive), and tumor grade (low vs high).
GROUP 1 (low risk \[nonmetastatic, grossly resected disease, except high-grade tumor \> 5 cm\]): Patients with low-grade tumor with either negative or positive microscopic margins or high-grade tumor ≤ 5 cm (in maximum diameter) with negative microscopic margins are assigned to regimen A. Patients with high-grade tumor ≤ 5 cm (in maximum diameter) with positive microscopic margins are assigned to regimen B.
REGIMEN A (observation only): Patients undergo observation only.
REGIMEN B (adjuvant radiotherapy): Beginning between 6-42 days after surgical resection, patients undergo a total of 31 fractions of adjuvant radiotherapy.
GROUP 2 (intermediate risk \[nonmetastatic, resected or unresected disease\]): Patients with grossly resected, high-grade tumor \> 5 cm (in maximum diameter) are assigned to regimen C. Patients with unresected tumor are assigned to regimen D.
REGIMEN C (adjuvant chemoradiotherapy): Patients receive ifosfamide IV over 3 hours on days 1-3 in weeks 1, 4, 7, 10, 13, and 16 and doxorubicin hydrochloride IV over 24 hours on days 1 and 2 in weeks 1, 4, 13, 16, and 19. Beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy.
\*NOTE: \*Patients who receive brachytherapy will initiate radiotherapy in Week 1. If brachytherapy is administered, chemotherapy should begin within 2 weeks of completion of brachytherapy and the Weeks 1 and 19 doxorubicin should be given instead at Weeks 7 and 10.
REGIMEN D (neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy with or without radiotherapy): Neoadjuvant chemoradiotherapy and surgery: Patients receive ifosfamide IV over 3 hours on days 1-3 in weeks 1, 4, 7, and 10 and doxorubicin hydrochloride IV over 24 hours on days 1 and 2 in weeks 1 and 4. Beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy\*\*. Patients undergo surgical resection in week 13.
NOTE: \*\*Patients with primary hepatic tumors do not receive radiotherapy in week 4.
Adjuvant chemotherapy with or without radiotherapy: Patients receive ifosfamide IV over 3 hours on days 1-3 in weeks 16 and 19 and doxorubicin hydrochloride IV over 24 hours on days 1 and 2 in weeks 16, 19\*\*\*, and 22. Beginning in week 16, patients achieving gross total resection with positive microscopic margins undergo a total of 6 fractions of adjuvant radiotherapy. Patients achieving less than total gross resection undergo a total of 11 fractions of adjuvant radiotherapy. Patients achieving total gross resection with negative microscopic margins do not receive adjuvant radiotherapy.
NOTE: \*\*\*Patients who receive adjuvant radiotherapy in week 16 receive doxorubicin hydrochloride in week 25 instead of week 19.
GROUP 3 (high risk \[metastatic, resected, incompletely resected, or unresected disease\]): Patients with low-grade, all-sites resected tumor with either negative or positive microscopic margins are assigned to receive treatment as in group 1 regimen A. Patients with high-grade, grossly resected primary tumor, and metastatic disease are assigned to receive treatment as in group 2 regimen C. Patients with unresected, high-grade metastatic tumor are assigned to receive treatment as in group 2 regimen D.
In all groups, treatment continues in the absence of disease progression. After completing study treatment, patients are followed periodically for at least 5 years.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 588
-
Newly diagnosed non-rhabdomyosarcoma soft tissue sarcoma (STS), confirmed by central pathology review via concurrent enrollment on protocol COG-D9902
- Metastatic or non metastatic disease
-
Meets 1 of the following criteria:
-
Intermediate (i.e., rarely metastasizing) or malignant STS, including any of the following:
-
Adipocytic tumor, including liposarcoma of any of the following histology subtypes:
- Dedifferentiated
- Myxoid
- Round cell
- Pleomorphic type
- Mixed-type
- Not otherwise specified (NOS)
-
Fibroblastic/myofibroblastic tumors, including any of the following:
- Solitary fibrous tumor
- Hemangiopericytoma
- Low-grade myofibroblastic sarcoma
- Myxoinflammatory fibroblastic sarcoma
- Adult fibrosarcoma*
- Myxofibrosarcoma
- Low-grade fibromyxoid sarcoma or hyalinizing spindle-cell tumor
- Sclerosing epithelioid fibrosarcoma
-
So-called fibrohistiocytic tumors, including any of the following:
- Plexiform fibrohistiocytic tumor
- Giant cell tumor of soft tissues
- Pleomorphic malignant fibrous histiocytoma (MFH)/undifferentiated pleomorphic sarcoma
- Giant cell MFH/undifferentiated pleomorphic sarcoma with giant cells
- Inflammatory MFH/undifferentiated pleomorphic sarcoma with prominent inflammation
-
Smooth muscle tumor (leiomyosarcoma)
-
Pericytic [perivascular] tumor (malignant glomus tumor or glomangiosarcoma)
-
Vascular tumor, including angiosarcoma
-
Chondro-osseous tumors of any of the following types:
- Mesenchymal chondrosarcoma
- Extraskeletal osteosarcoma
-
Tumors of uncertain differentiation, including any of the following:
- Angiomatoid fibrous histiocytoma
- Ossifying fibromyxoid tumor
- Myoepithelioma/parachordoma
- Synovial sarcoma
- Epithelioid sarcoma
- Alveolar soft-part sarcoma
- Clear cell sarcoma of soft tissue
- Extraskeletal myxoid chondrosarcoma ("chordoid type")
- Malignant mesenchymoma
- Neoplasms with perivascular epithelioid cell differentiation (PEComa)
- Clear cell myomelanocytic tumor
- Intimal sarcoma
-
-
Malignant peripheral nerve sheath tumor
-
Dermatofibrosarcoma protuberans meeting both of the following criteria:
- Non metastatic disease
- Tumor must be grossly resected prior to study enrollment
-
Embryonal sarcoma of the liver
-
Unclassified STS that is too undifferentiated to be placed in a specific pathologic category (undifferentiated STS or STS NOS)
-
-
Gross resection of the primary tumor ≤ 42 days prior to enrollment required except if any of the following circumstances apply:
-
Non metastatic high-grade tumor > 5 cm in maximal diameter and gross or microscopic residual tumor is anticipated after resection
-
Tumor of either high- or- low-grade that cannot be grossly excised without unacceptable morbidity
-
High-grade tumor with metastases
- Patients with metastatic low-grade tumor whose disease is amenable to gross resection at all sites must undergo gross resection of all sites prior to study entry
-
-
Patients with a tumor recurrence after a gross total resection are not eligible
-
Tumors arising in bone are not eligible
-
Patients with epithelioid sarcoma, clear cell sarcoma, or clinical or radiologic evidence of regional lymph node enlargement must undergo sentinel lymph node biopsies or lymph node sampling to confirm the status of regional lymph nodes* NOTE: *Except in cases where the study radiologist reviews the imaging and indicates that a biopsy is not needed to confirm that the patient has lymph node involvement.
- If lymph node biopsies are positive for tumor (or the lymph nodes are classified as positive by the study radiologist), formal lymph node dissection must be done at the time of definitive surgery(prior to study entry for patients assigned to study regimen C)
-
Patients with metastatic disease must undergo a biopsy to confirm the presence of metastatic tumor if all metastases are < 1 cm in maximal diameter (except in cases where the study radiologist reviews the imaging and indicated that a biopsy is not needed to confirm that the patient has metastatic disease)
-
Lansky performance status (PS) 50-100% (for patients ≤ 16 years of age) OR Karnofsky PS 50-100% (for patients > 16 years of age)
-
Life expectancy ≥ 3 months
-
Absolute neutrophil count ≥ 1,000/mm³*
-
Platelet count ≥ 100,000/mm³*
-
Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min (≥ 40 mL/min for infants < 1 year of age)* or serum creatinine based on age and/or gender as follows:
- 0.4 mg/dL (1 month to < 6 months of age)
- 0.5 mg/dL (6 months to < 1 year of age)
- 0.6 mg/dL (1 year to < 2 years of age)
- 0.8 mg/dL (2 years to < 6 years of age)
- 1.0 mg/dL (6 years to < 10 years of age)
- 1.2 mg/dL (10 years to < 13 years of age)
- 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 years to < 16 years of age)
- 1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age)
-
Patients with urinary tract obstruction by tumor must meet the renal function criteria listed above AND must have unimpeded urinary flow established via decompression of the obstructed portion of the urinary tract
-
Bilirubin ≤ 1.5 times upper limit of normal (ULN)*
-
Shortening fraction ≥ 27% by echocardiogram* OR ejection fraction ≥ 50% by radionuclide angiogram*
-
Not pregnant or nursing (patients undergoing radiotherapy and/or chemotherapy)
- No nursing for ≥ 1 month after completion of study treatment in study regimens C or D
-
Fertile patients must use effective contraception during and for ≥ 1 month after completion of study treatment
-
Negative pregnancy test
-
No evidence of dyspnea at rest*
-
No exercise intolerance*
-
Resting pulse oximetry reading > 94% on room air (for patients with respiratory symptoms)*
-
Prior treatment for cancer allowed provided the patient meet the prior therapy requirements
-
No prior anthracycline (e.g., doxorubicin or daunorubicin) or ifosfamide chemotherapy for patients enrolled on arm C or arm D
-
No prior radiotherapy to tumor-involved sites
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm A: No adjuvant treatment clinical observation Patients with low-grade tumor with either negative or positive microscopic margins or high-grade tumor ≤ 5 cm (in maximum diameter) with negative microscopic margins are assigned to arm A: (observation only). Arm B: Low risk; adjuvant radiotherapy clinical observation Patients with high-grade tumor ≤ 5 cm (in maximum diameter) with positive microscopic margins are assigned to arm B: (adjuvant radiotherapy). Beginning between 6-42 days after surgical resection, patients undergo a total of 31 fractions of adjuvant radiotherapy. Arm C: Intermediate & High risk; adjuvant chemoradiotherapy 3-dimensional conformal radiation therapy High risk \[metastatic, resected, incompletely resected, or unresected disease\] patients with high-grade, grossly resected primary tumor, with metastases are assigned to receive arm C: (adjuvant chemoradiotherapy). Patients receive ifosfamide IV; doxorubicin hydrochloride IV; beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy. Arm A: No adjuvant treatment therapeutic conventional surgery Patients with low-grade tumor with either negative or positive microscopic margins or high-grade tumor ≤ 5 cm (in maximum diameter) with negative microscopic margins are assigned to arm A: (observation only). Arm C: Intermediate & High risk; adjuvant chemoradiotherapy clinical observation High risk \[metastatic, resected, incompletely resected, or unresected disease\] patients with high-grade, grossly resected primary tumor, with metastases are assigned to receive arm C: (adjuvant chemoradiotherapy). Patients receive ifosfamide IV; doxorubicin hydrochloride IV; beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy. Arm B: Low risk; adjuvant radiotherapy therapeutic conventional surgery Patients with high-grade tumor ≤ 5 cm (in maximum diameter) with positive microscopic margins are assigned to arm B: (adjuvant radiotherapy). Beginning between 6-42 days after surgical resection, patients undergo a total of 31 fractions of adjuvant radiotherapy. Arm B: Low risk; adjuvant radiotherapy 3-dimensional conformal radiation therapy Patients with high-grade tumor ≤ 5 cm (in maximum diameter) with positive microscopic margins are assigned to arm B: (adjuvant radiotherapy). Beginning between 6-42 days after surgical resection, patients undergo a total of 31 fractions of adjuvant radiotherapy. Arm D: Intermediate & High Risk; Neoadjuvant chemoradiotherapy therapeutic conventional surgery High risk \[metastatic, resected, incompletely resected, or unresected disease\] patients with unresected, high-grade metastatic tumor are assigned to receive treatment as in arm D: (neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy with or without radiotherapy): Patients receive ifosfamide IV; doxorubicin hydrochloride IV. Beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy. Patients undergo surgical resection in week 13. Arm D: Intermediate & High Risk; Neoadjuvant chemoradiotherapy 3-dimensional conformal radiation therapy High risk \[metastatic, resected, incompletely resected, or unresected disease\] patients with unresected, high-grade metastatic tumor are assigned to receive treatment as in arm D: (neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy with or without radiotherapy): Patients receive ifosfamide IV; doxorubicin hydrochloride IV. Beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy. Patients undergo surgical resection in week 13. Arm D: Intermediate & High Risk; Neoadjuvant chemoradiotherapy clinical observation High risk \[metastatic, resected, incompletely resected, or unresected disease\] patients with unresected, high-grade metastatic tumor are assigned to receive treatment as in arm D: (neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy with or without radiotherapy): Patients receive ifosfamide IV; doxorubicin hydrochloride IV. Beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy. Patients undergo surgical resection in week 13. Arm C: Intermediate & High risk; adjuvant chemoradiotherapy doxorubicin hydrochloride High risk \[metastatic, resected, incompletely resected, or unresected disease\] patients with high-grade, grossly resected primary tumor, with metastases are assigned to receive arm C: (adjuvant chemoradiotherapy). Patients receive ifosfamide IV; doxorubicin hydrochloride IV; beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy. Arm C: Intermediate & High risk; adjuvant chemoradiotherapy ifosfamide High risk \[metastatic, resected, incompletely resected, or unresected disease\] patients with high-grade, grossly resected primary tumor, with metastases are assigned to receive arm C: (adjuvant chemoradiotherapy). Patients receive ifosfamide IV; doxorubicin hydrochloride IV; beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy. Arm D: Intermediate & High Risk; Neoadjuvant chemoradiotherapy doxorubicin hydrochloride High risk \[metastatic, resected, incompletely resected, or unresected disease\] patients with unresected, high-grade metastatic tumor are assigned to receive treatment as in arm D: (neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy with or without radiotherapy): Patients receive ifosfamide IV; doxorubicin hydrochloride IV. Beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy. Patients undergo surgical resection in week 13. Arm D: Intermediate & High Risk; Neoadjuvant chemoradiotherapy ifosfamide High risk \[metastatic, resected, incompletely resected, or unresected disease\] patients with unresected, high-grade metastatic tumor are assigned to receive treatment as in arm D: (neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy with or without radiotherapy): Patients receive ifosfamide IV; doxorubicin hydrochloride IV. Beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy. Patients undergo surgical resection in week 13.
- Primary Outcome Measures
Name Time Method Probability for Event Free Survival. 5 years Probability of no relapse, secondary malignancy or death after 5 years since enrollment.
- Secondary Outcome Measures
Name Time Method Overall Survival Probability Extent of Resection of the Primary Tumor 5 years Probability of survival after 5 years since enrollment.
Complete or Partial Response Rate 13 weeks Tumor response by imaging. Complete Response (CR): Complete disappearance of the tumor. Partial Response (PR): At least 64% decrease in volume compared to the measurement obtained at study enrollment. Overall Response (OR)=CR+PR.
Toxicity Rate 13 weeks Percentage of Arm D patients experiencing grade 4+ adverse events.
Event Free Survival Probability Histologic Grade 5 years Probability of no relapse, secondary malignancy or death after 5 years since enrollment
Incidence of Distant Metastasis Up to 10 years Percent of patients who had distant metastasis.
Overall Survival Probability Disease Extent 5 years Probability of survival after 5 years since enrollment.
Genetic and Gene Expression Profiles At diagnosis The tumors from patients registered on D9902 will be analyzed for genetic and gene expression profiles. The study will prospectively evaluate each tumor and confirm newly defined sarcoma diagnostic criteria based on cancer signatures in NRSTS.
Event Free Survival Probability Disease Extent 5 years Probability of no relapse, secondary malignancy or death after 5 years since enrollment.
Degree of Agreement in Histologic Grade Between Pediatric Oncology Group (POG) and Fédération Nationale Des Centres de Lutte Contre le Cancer (FNCLCC) Pathologic Grading Systems At diagnosis POG and FNCLCC grades were determined by pathologists based on published standards. A higher grade is associated with a more severe disease.
Percent Tumor Necrosis 13 weeks Percent tumor necrosis by pathology review.
Degree of Agreement in Histologic Grade Determined by the Enrolling Institution Versus by Central Pathology Reviewers At Diagnosis Histologic grades were determined by the central pathology reviewers and institutional pathologists based on published standards. A higher grade is associated with a more severe disease.
Trial Locations
- Locations (187)
Driscoll Children's Hospital
🇺🇸Corpus Christi, Texas, United States
New York Medical College
🇺🇸Valhalla, New York, United States
Children's Hospital Central California
🇺🇸Madera, California, United States
Childrens Memorial Hospital
🇺🇸Chicago, Illinois, United States
University of Chicago Comprehensive Cancer Center
🇺🇸Chicago, Illinois, United States
Massachusetts General Hospital Cancer Center
🇺🇸Boston, Massachusetts, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
University of Iowa Hospitals and Clinics
🇺🇸Iowa City, Iowa, United States
Saint Luke's Mountain States Tumor Institute
🇺🇸Boise, Idaho, United States
Maine Children's Cancer Program
🇺🇸Scarborough, Maine, United States
Michigan State University - Breslin Cancer Center
🇺🇸Lansing, Michigan, United States
Hurley Medical Center
🇺🇸Flint, Michigan, United States
University of Massachusetts Medical School
🇺🇸Worcester, Massachusetts, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
St. Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States
Penn State Hershey Children's Hospital
🇺🇸Hershey, Pennsylvania, United States
The Children's Hospital at Westmead
🇦🇺Sydney, New South Wales, Australia
The Children's Medical Center of Dayton
🇺🇸Dayton, Ohio, United States
Sydney Children's Hospital
🇦🇺Randwick, New South Wales, Australia
Sanford USD Medical Center - Sioux Falls
🇺🇸Sioux Falls, South Dakota, United States
Royal Brisbane and Women's Hospital
🇦🇺Herston, Queensland, Australia
M D Anderson Cancer Center
🇺🇸Houston, Texas, United States
Rady Children's Hospital - San Diego
🇺🇸San Diego, California, United States
Riley Hospital for Children
🇺🇸Indianapolis, Indiana, United States
Nevada Cancer Research Foundation CCOP
🇺🇸Las Vegas, Nevada, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
University of Texas Health Science Center at San Antonio
🇺🇸San Antonio, Texas, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Geisinger Medical Center
🇺🇸Danville, Pennsylvania, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸Minneapolis, Minnesota, United States
University of Minnesota Medical Center-Fairview
🇺🇸Minneapolis, Minnesota, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States
Children's Hospital and Research Center at Oakland
🇺🇸Oakland, California, United States
Children's Healthcare of Atlanta - Egleston
🇺🇸Atlanta, Georgia, United States
Memorial Health University Medical Center
🇺🇸Savannah, Georgia, United States
University of New Mexico Cancer Center
🇺🇸Albuquerque, New Mexico, United States
Saint John's Mercy Medical Center
🇺🇸Saint Louis, Missouri, United States
Brooklyn Hospital Center
🇺🇸Brooklyn, New York, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
The Steven and Alexandra Cohen Children's Medical Center of New York
🇺🇸New Hyde Park, New York, United States
New York University Langone Medical Center
🇺🇸New York, New York, United States
Mount Sinai Medical Center
🇺🇸New York, New York, United States
University of Rochester
🇺🇸Rochester, New York, United States
Stony Brook University Medical Center
🇺🇸Stony Brook, New York, United States
Mission Hospitals Inc
🇺🇸Asheville, North Carolina, United States
Carolinas Medical Center
🇺🇸Charlotte, North Carolina, United States
Children's Hospital Medical Center of Akron
🇺🇸Akron, Ohio, United States
Rainbow Babies and Childrens Hospital
🇺🇸Cleveland, Ohio, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
The Toledo Hospital/Toledo Children's Hospital
🇺🇸Toledo, Ohio, United States
Mercy Children's Hospital
🇺🇸Toledo, Ohio, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸Pittsburgh, Pennsylvania, United States
Texas Tech University Health Science Center-Amarillo
🇺🇸Amarillo, Texas, United States
Medical City Dallas Hospital
🇺🇸Dallas, Texas, United States
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Brooke Army Medical Center
🇺🇸Fort Sam Houston, Texas, United States
Cook Children's Medical Center
🇺🇸Fort Worth, Texas, United States
Baylor College of Medicine
🇺🇸Houston, Texas, United States
Covenant Children's Hospital
🇺🇸Lubbock, Texas, United States
Methodist Children's Hospital of South Texas
🇺🇸San Antonio, Texas, United States
Scott and White Memorial Hospital
🇺🇸Temple, Texas, United States
Inova Fairfax Hospital
🇺🇸Falls Church, Virginia, United States
Childrens Hospital-King's Daughters
🇺🇸Norfolk, Virginia, United States
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸Spokane, Washington, United States
Mary Bridge Children's Hospital and Health Center
🇺🇸Tacoma, Washington, United States
Madigan Army Medical Center
🇺🇸Tacoma, Washington, United States
Southern California Permanente Medical Group
🇺🇸Downey, California, United States
University of Arizona Health Sciences Center
🇺🇸Tucson, Arizona, United States
Primary Children's Medical Center
🇺🇸Salt Lake City, Utah, United States
Children's Oncology Group
🇺🇸Arcadia, California, United States
City of Hope Medical Center
🇺🇸Duarte, California, United States
Loma Linda University Medical Center
🇺🇸Loma Linda, California, United States
Miller Children's Hospital
🇺🇸Long Beach, California, United States
Cedars-Sinai Medical Center
🇺🇸Los Angeles, California, United States
David Geffen School of Medicine at UCLA
🇺🇸Los Angeles, California, United States
Kaiser Permanente-Oakland
🇺🇸Oakland, California, United States
Childrens Hospital of Orange County
🇺🇸Orange, California, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸Palo Alto, California, United States
University of California San Francisco Medical Center-Parnassus
🇺🇸San Francisco, California, United States
Connecticut Children's Medical Center
🇺🇸Hartford, Connecticut, United States
Broward Health Medical Center
🇺🇸Fort Lauderdale, Florida, United States
Memorial Healthcare System - Joe DiMaggio Children's Hospital
🇺🇸Hollywood, Florida, United States
Nemours Children's Clinic - Jacksonville
🇺🇸Jacksonville, Florida, United States
Miami Children's Hospital
🇺🇸Miami, Florida, United States
University of Illinois
🇺🇸Chicago, Illinois, United States
Advocate Hope Children's Hospital
🇺🇸Oak Lawn, Illinois, United States
Loyola University Medical Center
🇺🇸Maywood, Illinois, United States
Saint Jude Midwest Affiliate
🇺🇸Peoria, Illinois, United States
Saint Vincent Hospital and Health Services
🇺🇸Indianapolis, Indiana, United States
Eastern Maine Medical Center
🇺🇸Bangor, Maine, United States
Princess Margaret Hospital for Children
🇦🇺Perth, Western Australia, Australia
Sanford Medical Center-Fargo
🇺🇸Fargo, North Dakota, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
Albany Medical Center
🇺🇸Albany, New York, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
State University of New York Upstate Medical University
🇺🇸Syracuse, New York, United States
Presbyterian Hospital
🇺🇸Charlotte, North Carolina, United States
Lehigh Valley Hospital - Muhlenberg
🇺🇸Bethlehem, Pennsylvania, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
CancerCare Manitoba
🇨🇦Winnipeg, Manitoba, Canada
Wayne State University
🇺🇸Detroit, Michigan, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
Phoenix Childrens Hospital
🇺🇸Phoenix, Arizona, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Legacy Emanuel Children's Hospital
🇺🇸Portland, Oregon, United States
Legacy Emanuel Hospital and Health Center
🇺🇸Portland, Oregon, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
🇺🇸Denver, Colorado, United States
All Children's Hospital
🇺🇸Saint Petersburg, Florida, United States
Helen DeVos Children's Hospital at Spectrum Health
🇺🇸Grand Rapids, Michigan, United States
Johns Hopkins University
🇺🇸Baltimore, Maryland, United States
Baptist Hospital of Miami
🇺🇸Miami, Florida, United States
University of Arkansas for Medical Sciences
🇺🇸Little Rock, Arkansas, United States
Alfred I duPont Hospital for Children
🇺🇸Wilmington, Delaware, United States
Lee Memorial Health System
🇺🇸Fort Myers, Florida, United States
Sinai Hospital of Baltimore
🇺🇸Baltimore, Maryland, United States
UMDNJ - Robert Wood Johnson University Hospital
🇺🇸New Brunswick, New Jersey, United States
Saint Joseph's Regional Medical Center
🇺🇸Paterson, New Jersey, United States
Newark Beth Israel Medical Center
🇺🇸Newark, New Jersey, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
🇺🇸Miami, Florida, United States
Nemours Children's Clinic - Pensacola
🇺🇸Pensacola, Florida, United States
Southern Illinois University
🇺🇸Springfield, Illinois, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
Saint Mary's Hospital
🇺🇸West Palm Beach, Florida, United States
T C Thompson Children's Hospital
🇺🇸Chattanooga, Tennessee, United States
University of Maryland Greenebaum Cancer Center
🇺🇸Baltimore, Maryland, United States
Advocate Lutheran General Hospital
🇺🇸Park Ridge, Illinois, United States
Dartmouth Hitchcock Medical Center
🇺🇸Lebanon, New Hampshire, United States
Saint John Hospital and Medical Center
🇺🇸Detroit, Michigan, United States
Kalamazoo Center for Medical Studies
🇺🇸Kalamazoo, Michigan, United States
University of Missouri-Columbia
🇺🇸Columbia, Missouri, United States
Saint Peter's University Hospital
🇺🇸New Brunswick, New Jersey, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Overlook Hospital
🇺🇸Summit, New Jersey, United States
Hospital Sainte-Justine
🇨🇦Montreal, Quebec, Canada
Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
Greenville Cancer Treatment Center
🇺🇸Greenville, South Carolina, United States
Women's and Children's Hospital-Adelaide
🇦🇺North Adelaide, South Australia, Australia
West Virginia University Charleston
🇺🇸Charleston, West Virginia, United States
Marshfield Clinic
🇺🇸Marshfield, Wisconsin, United States
Alberta Children's Hospital
🇨🇦Calgary, Alberta, Canada
Saint Vincent Hospital
🇺🇸Green Bay, Wisconsin, United States
British Columbia Children's Hospital
🇨🇦Vancouver, British Columbia, Canada
Royal Children's Hospital
🇦🇺Parkville, Victoria, Australia
University of Vermont
🇺🇸Burlington, Vermont, United States
Palmetto Health Richland
🇺🇸Columbia, South Carolina, United States
East Tennessee Childrens Hospital
🇺🇸Knoxville, Tennessee, United States
Vanderbilt-Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States
Centre Hospitalier Universitaire de Quebec
🇨🇦Ste-Foy, Quebec, Canada
Janeway Child Health Centre
🇨🇦Saint John's, Newfoundland and Labrador, Canada
Starship Children's Hospital
🇳🇿Grafton, Auckland, New Zealand
IWK Health Centre
🇨🇦Halifax, Nova Scotia, Canada
Cancer Centre of Southeastern Ontario at Kingston General Hospital
🇨🇦Kingston, Ontario, Canada
Saskatoon Cancer Centre
🇨🇦Saskatoon, Saskatchewan, Canada
The Montreal Children's Hospital of the MUHC
🇨🇦Montreal, Quebec, Canada
San Jorge Children's Hospital
🇵🇷Santurce, Puerto Rico
University of Alberta Hospital
🇨🇦Edmonton, Alberta, Canada
University of Virginia
🇺🇸Charlottesville, Virginia, United States
Children's Hospital of Eastern Ontario
🇨🇦Ottawa, Ontario, Canada
Chedoke-McMaster Hospitals
🇨🇦Hamilton, Ontario, Canada
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Midwest Children's Cancer Center
🇺🇸Milwaukee, Wisconsin, United States
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
Saint Joseph Children's Hospital of Tampa
🇺🇸Tampa, Florida, United States
Walter Reed National Military Medical Center
🇺🇸Bethesda, Maryland, United States
C S Mott Children's Hospital
🇺🇸Ann Arbor, Michigan, United States
Wake Forest University Health Sciences
🇺🇸Winston-Salem, North Carolina, United States
Yale University
🇺🇸New Haven, Connecticut, United States
The Childrens Mercy Hospital
🇺🇸Kansas City, Missouri, United States
Kosair Children's Hospital
🇺🇸Louisville, Kentucky, United States
Florida Hospital
🇺🇸Orlando, Florida, United States
M D Anderson Cancer Center- Orlando
🇺🇸Orlando, Florida, United States
Nemours Childrens Clinic - Orlando
🇺🇸Orlando, Florida, United States
University of North Carolina
🇺🇸Chapel Hill, North Carolina, United States
University of Florida
🇺🇸Gainesville, Florida, United States
University of Hawaii
🇺🇸Honolulu, Hawaii, United States
Tripler Army Medical Center
🇺🇸Honolulu, Hawaii, United States
University of Kentucky
🇺🇸Lexington, Kentucky, United States
Tulane University Health Sciences Center
🇺🇸New Orleans, Louisiana, United States
Dell Children's Medical Center of Central Texas
🇺🇸Austin, Texas, United States
Virginia Commonwealth University
🇺🇸Richmond, Virginia, United States
University of Wisconsin Hospital and Clinics
🇺🇸Madison, Wisconsin, United States
Montefiore Medical Center
🇺🇸Bronx, New York, United States
Rhode Island Hospital
🇺🇸Providence, Rhode Island, United States