Combination Chemotherapy, PEG-Interferon Alfa-2b, and Surgery in Treating Patients With Osteosarcoma

Sponsor

Children's Oncology Group (Other)

Overall Status

Unknown status

CT.gov ID

NCT00134030

Collaborator

National Cancer Institute (NCI) (NIH), University College London Hospitals (Other)

1,164

Enrollment

218

Locations

Arms

5.3

Patients Per Site

Study Details

Study Description

Brief Summary

This randomized phase III trial is studying combination chemotherapy followed by surgery and two different combination chemotherapy regimens with or without PEG-interferon alfa-2b to compare how well they work in treating patients with osteosarcoma. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Biological therapies, such as PEG-interferon alfa-2b, may interfere with the growth of tumor cells. Giving combination chemotherapy before surgery may shrink the tumor so it can be removed. Giving combination chemotherapy together with PEG-interferon alfa-2b after surgery may kill any remaining tumor cells. It is not yet known whether giving combination therapy together with PEG-interferon alfa-2b is more effective than two different combination chemotherapy regimens alone after surgery in treating osteosarcoma.

Condition or Disease	Intervention/Treatment	Phase
Localized Osteosarcoma Metastatic Osteosarcoma	Drug: Cisplatin Drug: Doxorubicin Hydrochloride Drug: Etoposide Drug: Ifosfamide Drug: Methotrexate Biological: Peginterferon Alfa-2b Other: Quality-of-Life Assessment Other: Questionnaire Administration Procedure: Therapeutic Conventional Surgery	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

Compare whether adjuvant maintenance therapy comprising doxorubicin, cisplatin, and high-dose methotrexate (MAP) alone vs MAP combined with ifosfamide and etoposide improves event-free survival of patients with resectable high-grade osteosarcoma who achieve a poor histological response (HR) to neoadjuvant induction therapy comprising MAP.
Compare whether adjuvant maintenance therapy comprising MAP alone vs MAP and PEG-interferon alfa-2b improves event-free survival of patients with resectable high-grade osteosarcoma who achieve a good HR to neoadjuvant induction therapy comprising MAP.

SECONDARY OBJECTIVES:

Compare overall survival of patients treated with these regimens. II. Compare short- and long-term toxicity of these regimens in these patients. III. Compare quality of life of patients treated with these regimens. IV. Compare event-free survival and overall survival of patients with localized osteosarcoma treated with these regimens.
Correlate biological or clinical changes with histological response and outcomes in patients treated with these regimens.
Determine outcomes of patients treated with these regimens.

OUTLINE: This is a randomized, controlled, multicenter study.

INDUCTION THERAPY: (MAP; weeks 1-10) Patients receive doxorubicin IV continuously over 48 hours on days 1-2 and cisplatin IV over 4 hours on days 1 and 2 in weeks 1 and 6. Patients also receive high-dose methotrexate (MTX)* IV over 4 hours on day 1 in weeks 4, 5, 9, and 10. Patients then proceed to surgery.

NOTE: *Patients must receive >= 2 but =< 6 doses of high-dose MTX.

SURGERY: Patients undergo amputation or limb salvage surgery in week 11. Tumor tissue is evaluated for histological response to induction therapy. Patients whose tumor is not amenable to macroscopically complete surgical resection undergo radiotherapy and/or other investigational therapy off study. Patients who undergo macroscopically complete surgical resection of the primary tumor or metastases AND who have no disease progression or unacceptable toxicity proceed to maintenance therapy.

MAINTENANCE THERAPY: Patients are assigned to 1 of 2 groups according to histological response (good [< 10% viable tumor] vs poor [? 10% viable tumor]). Patients in each group are stratified according to site of primary tumor and presence of metastases.

GROUP 1: (good histological response) Patient are randomized to 1 of 2 treatment arms within 35 days after surgery.

ARM I: (MAP; weeks 12-29) Patients receive doxorubicin IV continuously over 48 hours on days 1-2 in weeks 12, 17, 22, and 26 and cisplatin IV over 4 hours on days 1 and 2 in weeks 12 and 17. Patients also receive high-dose MTX IV over 4 hours on day 1 in weeks 15, 16, 20, 21, 24, 25, 28, and 29.

ARM II: (MAPifn; weeks 12-104) Patients receive doxorubicin, cisplatin, and high-dose MTX as in arm I. Patients than receive PEG-interferon alfa-2b subcutaneously once daily on day 1 in weeks 30-104.

GROUP 2: (poor histological response) Patients are randomized to 1 of 2 treatment arms within 35 days after surgery.

ARM I: (MAP; weeks 12-29) Patients receive doxorubicin, cisplatin, and high-dose MTX as in group 1 arm I.

ARM II: (MAPIE; weeks 12-40) Patients receive doxorubicin IV continuously over 48 hours on days 1-2 in weeks 12, 20, 28, and 36 and cisplatin IV over 4 hours on days 1 and 2 in weeks 12 and 28. Patients also receive high-dose MTX IV over 4 hours on day 1 in weeks 15, 19, 23, 27, 31, 35, 39, and 40. Patients receive ifosfamide IV over 4 hours on days 1-5 in weeks 16, 24, and 32 and on days 1-3 in weeks 20 and 36 and etoposide IV over 1 hour on days 1-5 in weeks 16, 24, and 32.

In both groups, treatment continues in the absence of disease progression or unacceptable toxicity. Quality of life is assessed periodically.

After completion of study treatment, patients are followed every 1?-3 months for 2 years, every 2-4 months for 2 years, every 6 months for 6 years, and then every 6-12 months thereafter. Peer Reviewed and Funded or Endorsed by Cancer Research UK

Study Design

Study Type:

Interventional

Actual Enrollment :

1164 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized Trial of the European and American Osteosarcoma Study Group to Optimize Treatment Strategies for Resectable Osteosarcoma Based on Histological Response to Pre-operative Chemotherapy

Actual Study Start Date :

Nov 14, 2005

Actual Primary Completion Date :

Jan 31, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Maintenance therapy group 1 arm I Patients receive doxorubicin IV continuously over 48 hours on days 1-2 in weeks 12, 17, 22, and 26 and cisplatin IV over 4 hours on days 1 and 2 in weeks 12 and 17. Patients also receive high-dose MTX IV over 4 hours on day 1 in weeks 15, 16, 20, 21, 24, 25, 28, and 29.	Drug: Cisplatin Given IV Other Names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Cis-dichloroammine Platinum (II) Cis-platinous Diamine Dichloride Cis-platinum Cis-platinum II Cis-platinum II Diamine Dichloride Cismaplat Cisplatina Cisplatinum Cisplatyl Citoplatino Citosin Cysplatyna DDP Lederplatin Metaplatin Neoplatin Peyrone's Chloride Peyrone's Salt Placis Plastistil Platamine Platiblastin Platiblastin-S Platinex Platinol Platinol- AQ Platinol-AQ Platinol-AQ VHA Plus Platinoxan Platinum Platinum Diamminodichloride Platiran Platistin Platosin Drug: Doxorubicin Hydrochloride Given IV Other Names: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI) ADM Adriacin Adriamycin Adriamycin Hydrochloride Adriamycin PFS Adriamycin RDF ADRIAMYCIN, HYDROCHLORIDE Adriamycine Adriblastina Adriblastine Adrimedac Chloridrato de Doxorrubicina DOX DOXO-CELL Doxolem Doxorubicin.HCl Doxorubin Farmiblastina FI 106 FI-106 hydroxydaunorubicin Rubex Drug: Methotrexate Given IV Other Names: Abitrexate Alpha-Methopterin Amethopterin Brimexate CL 14377 CL-14377 Emtexate Emthexat Emthexate Farmitrexat Fauldexato Folex Folex PFS Lantarel Ledertrexate Lumexon Maxtrex Medsatrexate Metex Methoblastin Methotrexate LPF Methotrexate Methylaminopterin Methotrexatum Metotrexato Metrotex Mexate Mexate-AQ MTX Novatrex Rheumatrex Texate Tremetex Trexeron Trixilem WR-19039 Other: Quality-of-Life Assessment Ancillary studies Other Names: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies Procedure: Therapeutic Conventional Surgery Undergo amputation or limb salvage surgery
Experimental: Maintenance therapy group 1 arm II Patients receive doxorubicin, cisplatin, and high-dose MTX as in arm I. Patients than receive PEG-interferon alfa-2b subcutaneously once daily on day 1 in weeks 30-104.	Drug: Cisplatin Given IV Other Names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Cis-dichloroammine Platinum (II) Cis-platinous Diamine Dichloride Cis-platinum Cis-platinum II Cis-platinum II Diamine Dichloride Cismaplat Cisplatina Cisplatinum Cisplatyl Citoplatino Citosin Cysplatyna DDP Lederplatin Metaplatin Neoplatin Peyrone's Chloride Peyrone's Salt Placis Plastistil Platamine Platiblastin Platiblastin-S Platinex Platinol Platinol- AQ Platinol-AQ Platinol-AQ VHA Plus Platinoxan Platinum Platinum Diamminodichloride Platiran Platistin Platosin Drug: Doxorubicin Hydrochloride Given IV Other Names: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI) ADM Adriacin Adriamycin Adriamycin Hydrochloride Adriamycin PFS Adriamycin RDF ADRIAMYCIN, HYDROCHLORIDE Adriamycine Adriblastina Adriblastine Adrimedac Chloridrato de Doxorrubicina DOX DOXO-CELL Doxolem Doxorubicin.HCl Doxorubin Farmiblastina FI 106 FI-106 hydroxydaunorubicin Rubex Drug: Methotrexate Given IV Other Names: Abitrexate Alpha-Methopterin Amethopterin Brimexate CL 14377 CL-14377 Emtexate Emthexat Emthexate Farmitrexat Fauldexato Folex Folex PFS Lantarel Ledertrexate Lumexon Maxtrex Medsatrexate Metex Methoblastin Methotrexate LPF Methotrexate Methylaminopterin Methotrexatum Metotrexato Metrotex Mexate Mexate-AQ MTX Novatrex Rheumatrex Texate Tremetex Trexeron Trixilem WR-19039 Biological: Peginterferon Alfa-2b Given subcutaneously Other Names: PEG Interferon Alpha-2b PEG Intron PEG-IFN Alfa-2b PEG-IFN-a 2b PEG-interferon alfa-2b PEG-Intron Pegylated Interferon Alpha-2b Polyethylene Glycol IFN-A2b Polyethylene Glycol Interferon Alfa-2b SCH 54031 Sylatron Other: Quality-of-Life Assessment Ancillary studies Other Names: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies Procedure: Therapeutic Conventional Surgery Undergo amputation or limb salvage surgery
Active Comparator: Maintenance therapy group 2 arm I Patients receive doxorubicin, cisplatin, and high-dose MTX as in group 1 arm I.	Drug: Cisplatin Given IV Other Names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Cis-dichloroammine Platinum (II) Cis-platinous Diamine Dichloride Cis-platinum Cis-platinum II Cis-platinum II Diamine Dichloride Cismaplat Cisplatina Cisplatinum Cisplatyl Citoplatino Citosin Cysplatyna DDP Lederplatin Metaplatin Neoplatin Peyrone's Chloride Peyrone's Salt Placis Plastistil Platamine Platiblastin Platiblastin-S Platinex Platinol Platinol- AQ Platinol-AQ Platinol-AQ VHA Plus Platinoxan Platinum Platinum Diamminodichloride Platiran Platistin Platosin Drug: Doxorubicin Hydrochloride Given IV Other Names: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI) ADM Adriacin Adriamycin Adriamycin Hydrochloride Adriamycin PFS Adriamycin RDF ADRIAMYCIN, HYDROCHLORIDE Adriamycine Adriblastina Adriblastine Adrimedac Chloridrato de Doxorrubicina DOX DOXO-CELL Doxolem Doxorubicin.HCl Doxorubin Farmiblastina FI 106 FI-106 hydroxydaunorubicin Rubex Drug: Methotrexate Given IV Other Names: Abitrexate Alpha-Methopterin Amethopterin Brimexate CL 14377 CL-14377 Emtexate Emthexat Emthexate Farmitrexat Fauldexato Folex Folex PFS Lantarel Ledertrexate Lumexon Maxtrex Medsatrexate Metex Methoblastin Methotrexate LPF Methotrexate Methylaminopterin Methotrexatum Metotrexato Metrotex Mexate Mexate-AQ MTX Novatrex Rheumatrex Texate Tremetex Trexeron Trixilem WR-19039 Other: Quality-of-Life Assessment Ancillary studies Other Names: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies Procedure: Therapeutic Conventional Surgery Undergo amputation or limb salvage surgery
Experimental: Maintenance therapy group 2 arm II Patients receive doxorubicin IV continuously over 48 hours on days 1-2 in weeks 12, 20, 28, and 36 and cisplatin IV over 4 hours on days 1 and 2 in weeks 12 and 28. Patients also receive high-dose MTX IV over 4 hours on day 1 in weeks 15, 19, 23, 27, 31, 35, 39, and 40. Patients receive ifosfamide IV over 4 hours on days 1-5 in weeks 16, 24, and 32 and on days 1-3 in weeks 20 and 36 and etoposide IV over 1 hour on days 1-5 in weeks 16, 24, and 32.	Drug: Cisplatin Given IV Other Names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Cis-dichloroammine Platinum (II) Cis-platinous Diamine Dichloride Cis-platinum Cis-platinum II Cis-platinum II Diamine Dichloride Cismaplat Cisplatina Cisplatinum Cisplatyl Citoplatino Citosin Cysplatyna DDP Lederplatin Metaplatin Neoplatin Peyrone's Chloride Peyrone's Salt Placis Plastistil Platamine Platiblastin Platiblastin-S Platinex Platinol Platinol- AQ Platinol-AQ Platinol-AQ VHA Plus Platinoxan Platinum Platinum Diamminodichloride Platiran Platistin Platosin Drug: Doxorubicin Hydrochloride Given IV Other Names: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI) ADM Adriacin Adriamycin Adriamycin Hydrochloride Adriamycin PFS Adriamycin RDF ADRIAMYCIN, HYDROCHLORIDE Adriamycine Adriblastina Adriblastine Adrimedac Chloridrato de Doxorrubicina DOX DOXO-CELL Doxolem Doxorubicin.HCl Doxorubin Farmiblastina FI 106 FI-106 hydroxydaunorubicin Rubex Drug: Etoposide Given IV Other Names: Demethyl Epipodophyllotoxin Ethylidine Glucoside EPEG Lastet Toposar Vepesid VP 16-213 VP-16 VP-16-213 Drug: Ifosfamide Given IV Other Names: Asta Z 4942 Asta Z-4942 Cyfos Holoxan Holoxane Ifex IFO IFO-Cell Ifolem Ifomida Ifomide Ifosfamidum Ifoxan IFX Iphosphamid Iphosphamide Iso-Endoxan Isoendoxan Isophosphamide Mitoxana MJF 9325 MJF-9325 Naxamide Seromida Tronoxal Z 4942 Z-4942 Drug: Methotrexate Given IV Other Names: Abitrexate Alpha-Methopterin Amethopterin Brimexate CL 14377 CL-14377 Emtexate Emthexat Emthexate Farmitrexat Fauldexato Folex Folex PFS Lantarel Ledertrexate Lumexon Maxtrex Medsatrexate Metex Methoblastin Methotrexate LPF Methotrexate Methylaminopterin Methotrexatum Metotrexato Metrotex Mexate Mexate-AQ MTX Novatrex Rheumatrex Texate Tremetex Trexeron Trixilem WR-19039 Other: Quality-of-Life Assessment Ancillary studies Other Names: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies Procedure: Therapeutic Conventional Surgery Undergo amputation or limb salvage surgery

Outcome Measures

Primary Outcome Measures

Event-free survival [From date of randomization to date of the event, assessed up to 10 years]
Will be assessed using the logrank test and expressed using hazard ratios with appropriate confidence intervals.

Secondary Outcome Measures

Overall survival [From date of randomization to date of death, assessed up to 10 years]
Will be assessed using the logrank test and expressed using hazard ratios with appropriate confidence intervals.
Toxicity as measured by CTCAE v3.0 [Up to 10 years]
Proportions of patients experiencing grade 3 and 4 toxicities will be compared using chi-square tests or Fisher's exact tests where appropriate.
Quality of life [Up to 3 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

5 Years to 40 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed high-grade osteosarcoma, including second malignancies
Localized or metastatic disease
The primary tumor must be located in the limbs or axial skeleton, including any of the following sites*:
Long bone of upper limb
Short bone of upper limb
Long bone of lower limb
Short bone of lower limb
Vertebral column
Ribs, sternum, clavicle, or scapula
Pelvic bones, sacrum, or coccyx
Tumor (primary, metastatic, or both) resectable OR is expected to become resectable after neoadjuvant induction chemotherapy
Suitable for neoadjuvant chemotherapy
Performance status - Lansky 50-100% (for patients under 16 years of age)
Performance status - Karnofsky 50-100%*
Performance status - WHO or ECOG 0-2*
Platelet count ? 100,000/mm?
Neutrophil count ? 1,500/mm?
WBC ? 3,000/mm?
Bilirubin ? 1.5 times upper limit of normal
Creatinine clearance ? 70 mL/min
Creatinine based on age as follows:
No greater than 1.0 mg/dL (for patients 5 to 10 years of age)
No greater than 1.2 mg/dL (for patients 11 to 15 years of age)
No greater than 1.5 mg/dL (for patients over 15 years of age)
Ejection fraction ? 50% by radionuclide angiogram
Shortening fraction ? 28% by echocardiogram
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No known HIV positivity
No prior chemotherapy for any disease
Prior radiotherapy for another malignancy allowed
No prior treatment for osteosarcoma

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Alabama	Birmingham	Alabama	United States	35233
2	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama	United States	35233
3	Phoenix Childrens Hospital	Phoenix	Arizona	United States	85016
4	The University of Arizona Medical Center-University Campus	Tucson	Arizona	United States	85724
5	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202-3591
6	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
7	Southern California Permanente Medical Group	Downey	California	United States	90242
8	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010
9	Loma Linda University Medical Center	Loma Linda	California	United States	92354
10	Miller Children's and Women's Hospital Long Beach	Long Beach	California	United States	90806
11	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
12	Cedars Sinai Medical Center	Los Angeles	California	United States	90048
13	Mattel Children's Hospital UCLA	Los Angeles	California	United States	90095
14	UCLA / Jonsson Comprehensive Cancer Center	Los Angeles	California	United States	90095
15	Children's Hospital Central California	Madera	California	United States	93636-8762
16	Children's Hospital and Research Center at Oakland	Oakland	California	United States	94609-1809
17	Kaiser Permanente-Oakland	Oakland	California	United States	94611
18	Children's Hospital of Orange County	Orange	California	United States	92868
19	Lucile Packard Children's Hospital Stanford University	Palo Alto	California	United States	94304
20	Sutter Medical Center Sacramento	Sacramento	California	United States	95816
21	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
22	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
23	UCSF Medical Center-Mount Zion	San Francisco	California	United States	94115
24	UCSF Medical Center-Parnassus	San Francisco	California	United States	94143
25	UCSF Medical Center-Mission Bay	San Francisco	California	United States	94158
26	Harbor-University of California at Los Angeles Medical Center	Torrance	California	United States	90502
27	Children's Hospital Colorado	Aurora	Colorado	United States	80045
28	University of Connecticut	Farmington	Connecticut	United States	06030
29	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
30	Yale University	New Haven	Connecticut	United States	06520
31	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
32	MedStar Georgetown University Hospital	Washington	District of Columbia	United States	20007
33	Children's National Medical Center	Washington	District of Columbia	United States	20010
34	Broward Health Medical Center	Fort Lauderdale	Florida	United States	33316
35	Lee Memorial Health System	Fort Myers	Florida	United States	33901
36	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida	United States	33908
37	University of Florida Health Science Center - Gainesville	Gainesville	Florida	United States	32610
38	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida	United States	33021
39	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida	United States	32207
40	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
41	Miami Cancer Institute	Miami	Florida	United States	33176
42	Florida Hospital Orlando	Orlando	Florida	United States	32803
43	Arnold Palmer Hospital for Children	Orlando	Florida	United States	32806
44	Nemours Children's Clinic - Orlando	Orlando	Florida	United States	32806
45	UF Cancer Center at Orlando Health	Orlando	Florida	United States	32806
46	Nemours Children's Hospital	Orlando	Florida	United States	32827
47	Nemours Children's Clinic - Pensacola	Pensacola	Florida	United States	32504
48	Sacred Heart Hospital	Pensacola	Florida	United States	32504
49	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida	United States	33701
50	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida	United States	33607
51	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
52	Augusta University Medical Center	Augusta	Georgia	United States	30912
53	Memorial Health University Medical Center	Savannah	Georgia	United States	31404
54	University of Hawaii Cancer Center	Honolulu	Hawaii	United States	96813
55	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii	United States	96826
56	Tripler Army Medical Center	Honolulu	Hawaii	United States	96859
57	Lurie Children's Hospital-Chicago	Chicago	Illinois	United States	60611
58	Rush University Medical Center	Chicago	Illinois	United States	60612
59	University of Illinois	Chicago	Illinois	United States	60612
60	Loyola University Medical Center	Maywood	Illinois	United States	60153
61	Advocate Children's Hospital-Oak Lawn	Oak Lawn	Illinois	United States	60453
62	Saint Jude Midwest Affiliate	Peoria	Illinois	United States	61637
63	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62702
64	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
65	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
66	Saint Vincent Hospital and Health Care Center	Indianapolis	Indiana	United States	46260
67	Blank Children's Hospital	Des Moines	Iowa	United States	50309
68	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
69	University of Kansas Cancer Center	Kansas City	Kansas	United States	66160
70	University of Kentucky/Markey Cancer Center	Lexington	Kentucky	United States	40536
71	Norton Children's Hospital	Louisville	Kentucky	United States	40202
72	Tulane University Health Sciences Center	New Orleans	Louisiana	United States	70112
73	Children's Hospital New Orleans	New Orleans	Louisiana	United States	70118
74	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
75	Eastern Maine Medical Center	Bangor	Maine	United States	04401
76	Maine Children's Cancer Program	Scarborough	Maine	United States	04074
77	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
78	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
79	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
80	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
81	University of Massachusetts Medical School	Worcester	Massachusetts	United States	01655
82	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
83	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan	United States	48201
84	Saint John Hospital and Medical Center	Detroit	Michigan	United States	48236
85	Michigan State University Clinical Center	East Lansing	Michigan	United States	48824-7016
86	Hurley Medical Center	Flint	Michigan	United States	48503
87	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
88	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan	United States	49503
89	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
90	Kalamazoo Center for Medical Studies	Kalamazoo	Michigan	United States	49008
91	Beaumont Children's Hospital-Royal Oak	Royal Oak	Michigan	United States	48073
92	William Beaumont Hospital-Royal Oak	Royal Oak	Michigan	United States	48073
93	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
94	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
95	Mayo Clinic	Rochester	Minnesota	United States	55905
96	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
97	The Childrens Mercy Hospital	Kansas City	Missouri	United States	64108
98	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri	United States	63104
99	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
100	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska	United States	68114
101	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
102	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada	United States	89106
103	Children's Specialty Center of Nevada II	Las Vegas	Nevada	United States	89109
104	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
105	Saint Barnabas Medical Center	Livingston	New Jersey	United States	07039
106	Morristown Medical Center	Morristown	New Jersey	United States	07960
107	Saint Peter's University Hospital	New Brunswick	New Jersey	United States	08901
108	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey	United States	08903
109	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
110	Saint Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
111	Overlook Hospital	Summit	New Jersey	United States	07902
112	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87102
113	Albany Medical Center	Albany	New York	United States	12208
114	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
115	Brooklyn Hospital Center	Brooklyn	New York	United States	11201
116	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
117	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York	United States	11040
118	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York	United States	10016
119	Mount Sinai Hospital	New York	New York	United States	10029
120	Columbia University/Herbert Irving Cancer Center	New York	New York	United States	10032
121	University of Rochester	Rochester	New York	United States	14642
122	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
123	New York Medical College	Valhalla	New York	United States	10595
124	Mission Hospital-Memorial Campus	Asheville	North Carolina	United States	28801
125	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
126	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina	United States	28203
127	Novant Health Presbyterian Medical Center	Charlotte	North Carolina	United States	28204
128	Duke University Medical Center	Durham	North Carolina	United States	27710
129	East Carolina University	Greenville	North Carolina	United States	27858
130	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
131	Sanford Broadway Medical Center	Fargo	North Dakota	United States	58122
132	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
133	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
134	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
135	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
136	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
137	Dayton Children's Hospital	Dayton	Ohio	United States	45404
138	The Toledo Hospital/Toledo Children's Hospital	Toledo	Ohio	United States	43606
139	Mercy Children's Hospital	Toledo	Ohio	United States	43608
140	University of Toledo	Toledo	Ohio	United States	43614
141	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
142	Legacy Emanuel Children's Hospital	Portland	Oregon	United States	97227
143	Legacy Emanuel Hospital and Health Center	Portland	Oregon	United States	97227
144	Oregon Health and Science University	Portland	Oregon	United States	97239
145	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania	United States	18017
146	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
147	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
148	Penn State Children's Hospital	Hershey	Pennsylvania	United States	17033
149	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
150	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States	19134
151	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
152	Medical University of South Carolina	Charleston	South Carolina	United States	29425
153	Palmetto Health Richland	Columbia	South Carolina	United States	29203
154	BI-LO Charities Children's Cancer Center	Greenville	South Carolina	United States	29605
155	Greenville Cancer Treatment Center	Greenville	South Carolina	United States	29605
156	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
157	T C Thompson Children's Hospital	Chattanooga	Tennessee	United States	37403
158	East Tennessee Childrens Hospital	Knoxville	Tennessee	United States	37916
159	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
160	Texas Tech University Health Sciences Center-Amarillo	Amarillo	Texas	United States	79106
161	Driscoll Children's Hospital	Corpus Christi	Texas	United States	78411
162	Medical City Dallas Hospital	Dallas	Texas	United States	75230
163	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
164	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
165	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas	United States	77030
166	M D Anderson Cancer Center	Houston	Texas	United States	77030
167	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229
168	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
169	Scott and White Memorial Hospital	Temple	Texas	United States	76508
170	Primary Children's Hospital	Salt Lake City	Utah	United States	84113
171	University of Vermont College of Medicine	Burlington	Vermont	United States	05405
172	University of Virginia Cancer Center	Charlottesville	Virginia	United States	22908
173	Inova Fairfax Hospital	Falls Church	Virginia	United States	22042
174	Childrens Hospital-King's Daughters	Norfolk	Virginia	United States	23507
175	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
176	Carilion Clinic Children's Hospital	Roanoke	Virginia	United States	24014
177	Seattle Children's Hospital	Seattle	Washington	United States	98105
178	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington	United States	99204
179	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington	United States	98405
180	Madigan Army Medical Center	Tacoma	Washington	United States	98431
181	West Virginia University Charleston Division	Charleston	West Virginia	United States	25304
182	Cabell-Huntington Hospital	Huntington	West Virginia	United States	25701
183	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin	United States	54301
184	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
185	Marshfield Clinic	Marshfield	Wisconsin	United States	54449
186	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226
187	John Hunter Children's Hospital	Hunter Regional Mail Centre	New South Wales	Australia	2310
188	The Children's Hospital at Westmead	Westmead	New South Wales	Australia	2145
189	Westmead Hospital	Westmead	New South Wales	Australia	2145
190	Royal Brisbane and Women's Hospital	Herston	Queensland	Australia	4029
191	Royal Children's Hospital-Brisbane	Herston	Queensland	Australia	4029
192	Lady Cilento Children's Hospital	South Brisbane	Queensland	Australia	4101
193	Women's and Children's Hospital-Adelaide	North Adelaide	South Australia	Australia	5006
194	Royal Children's Hospital	Parkville	Victoria	Australia	3052
195	Princess Margaret Hospital for Children	Perth	Western Australia	Australia	6008
196	Alberta Children's Hospital	Calgary	Alberta	Canada	T3B 6A8
197	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2B7
198	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
199	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
200	Janeway Child Health Centre	Saint John's	Newfoundland and Labrador	Canada	A1B 3V6
201	IWK Health Centre	Halifax	Nova Scotia	Canada	B3K 6R8
202	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8N 3Z5
203	Kingston Health Sciences Centre	Kingston	Ontario	Canada	K7L 2V7
204	Children's Hospital	London	Ontario	Canada	N6A 5W9
205	Victoria Hospital	London	Ontario	Canada	N6K 1C2
206	Children's Hospital of Eastern Ontario	Ottawa	Ontario	Canada	K1H 8L1
207	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
208	The Montreal Children's Hospital of the MUHC	Montreal	Quebec	Canada	H3H 1P3
209	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5
210	Saskatoon Cancer Centre	Saskatoon	Saskatchewan	Canada	S7N 4H4
211	Centre Hospitalier Universitaire de Quebec	Quebec		Canada	G1V 4G2
212	Starship Children's Hospital	Grafton	Auckland	New Zealand	1145
213	Christchurch Hospital	Christchurch		New Zealand	8011
214	Wellington Children's Hospital	Wellington		New Zealand	6002
215	San Jorge Children's Hospital	San Juan		Puerto Rico	00912
216	Swiss Pediatric Oncology Group - Bern	Bern		Switzerland	3010
217	Swiss Pediatric Oncology Group - Geneva	Geneva		Switzerland	1205
218	Swiss Pediatric Oncology Group - Lausanne	Lausanne		Switzerland	1011