Combination Chemotherapy in Treating Patients With Non-Metastatic Extracranial Ewing Sarcoma

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01231906
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 642
• Locations: 243
• Arms: 2
• Anticipated Duration (Months): 187.7
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This trial examined the outcome benefit to patients of adding a new chemotherapy drug combination to the established treatment approach for patients with extracranial Ewing sarcoma, that had not spread from the primary site to other places in the body. The trial randomly assigned patients at the time of study entry to receive established standard treatment with the following 5-drugs: vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, ifosfamide and etoposide. The outcome for patients receiving the standard 5-drug combination was compared to the outcome for patients who received the same 5-drugs with an additional drug, topotecan hydrochloride delivered in a novel combination with vincristine sulfate and cyclophosphamide.

Condition or Disease	Intervention/Treatment	Phase
Localized Extraskeletal Ewing Sarcoma; Peripheral Primitive Neuroectodermal Tumor of Bone; Peripheral Primitive Neuroectodermal Tumor of Soft Tissues	Drug: Cyclophosphamide; Drug: Dexrazoxane; Drug: Doxorubicin Hydrochloride; Drug: Etoposide; Drug: Ifosfamide; Other: Laboratory Biomarker Analysis; Drug: Topotecan Hydrochloride; Drug: Vincristine Sulfate	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

1. Test the effect of the combination of vincristine (vincristine sulfate), cyclophosphamide, and topotecan (topotecan hydrochloride) (VTC) added to the standard 5-drug interval-compressed chemotherapy backbone on event-free and overall survival of children and young adults with Ewing sarcoma.

CORRELATIVE SCIENCE OBJECTIVES:

1. To evaluate initial volumetric tumor size as a prognostic factor for event free survival (EFS) in patients with localized Ewing tumors.

2. To evaluate histologic response as a prognostic factor for EFS in patients with localized Ewing tumors.

3. To continue evaluation of biologic markers both as related to prognosis and as eventual therapeutic targets via encouraging concurrent enrollment on a Ewing sarcoma specimen-collection study.

4. To evaluate imaging response by fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) as a prognostic factor for EFS.

5. To evaluate the effects of the type of local therapy on EFS and overall survival.

6. To evaluate the effect of local surgical margins in conjunction with histologic response on EFS in patients with localized Ewing tumors.

7. To evaluate the effect of local therapy modality (surgery, radiotherapy, or a combination) as well as the type of surgical reconstruction on musculoskeletal complications.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A:

INDUCTION THERAPY: Patients receive vincristine sulfate intravenously (IV) on day 1 in weeks 1, 2, 5, 6, 9, and 10; doxorubicin hydrochloride IV over 1-15 minutes (or as per institutional policies up to 60-minutes) on days 1 and 2 and cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 5, and 9; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 7, and 11.

CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7, 8, 9, 10, 13, 14, 17, 18, 21, and 22; doxorubicin hydrochloride IV on days 1 and 2 in weeks 1 and 9; cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 7, 9, 13, 17, and 21; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 5, 11, 15, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 1 and 9.

ARM B:

INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, 10, 11 and 12; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1 and 9; cyclophosphamide IV over 15-30 minutes on days 1-5 in weeks 1 and 9, and over 30-60 minutes on day 1 of weeks 5 and 11; ifosfamide and etoposide as in arm A; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 5 and 11.

CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7-10, 13-16, 19, and 20; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1, 7, and 15; cyclophosphamide IV over 15-60 minutes on days 1-5 in weeks 1, 7, and 15, and over 30-60 minutes on day 1 in weeks 9, 13, and 19; ifosfamide IV over 1 hour and etoposide IV over 1- 2 hours on days 1-5 in weeks 3, 5, 11, 17, and 21; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 9,13, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 13 and 19.

Patients could undergo surgery alone after recovery from week 12 chemotherapy if the primary tumor could be completely resected with negative margins and with reasonable functional result. Patients with inadequate margins after surgery were to receive radiotherapy in addition. Patients with lesions in surgically difficult sites such as the spine, skull, and periacetabular pelvis, patients with a poor response to induction chemotherapy, or those patients in whom surgery would result in unacceptable functional results were recommended to receive radiation and not surgery. Radiotherapy was to be administered during weeks 1-7 of consolidation therapy or after recovery from surgery for patients with positive margins. Patients who received planned pre-operative radiation and had positive surgical margins were to receive additional radiotherapy.

After completion of study therapy, patients are followed up every 3 months for 3 years and then every 6 months for 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 642 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Randomized Trial of Adding Vincristine-Topotecan-Cyclophosphamide to Standard Chemotherapy in Initial Treatment of Non-Metastatic Ewing Sarcoma
• Actual Study Start Date: Nov 22, 2010
• Actual Primary Completion Date: Mar 31, 2020
• Anticipated Study Completion Date: Jul 14, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A (combination chemotherapy) INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, and 10; doxorubicin hydrochloride IV over 1-15 minutes (or as per institutional policies up to 60-minutes) on days 1 and 2 and cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 5, and 9; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 7, and 11. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7, 8, 9, 10, 13, 14, 17, 18, 21, and 22; doxorubicin hydrochloride IV on days 1 and 2 in weeks 1 and 9; cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 7, 9, 13, 17, and 21; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 5, 11, 15, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 1 and 9.	Drug: Cyclophosphamide; Given IV; Other Names: (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamide Monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 ; Drug: Dexrazoxane; Other Names: 2, 6-Piperazinedione, 4,4''-propylenedi-, (P)- (8CI) 2,6-Piperazinedione, 4, 4''-(1-methyl-1,2-ethanediyl)bis-, (S)- (9CI) ADR-529 ICRF-187 Razoxane (+)-form Soluble ICRF (L-isomer) ; 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 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 VP 16-213 VP-16 VP-16-213 VP16 ; 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 ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Vincristine Sulfate; Given IV; Other Names: Kyocristine Leurocristine Sulfate Leurocristine, sulfate Oncovin Vincasar Vincosid Vincrex Vincristine, sulfate
Experimental: Arm B (combination chemotherapy, topotecan hydrochloride) INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, 10, 11 and 12; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1 and 9; cyclophosphamide IV over 15-30 minutes on days 1-5 in weeks 1 and 9, and over 30-60 minutes on day 1 of weeks 5 and 11; ifosfamide and etoposide as in arm A; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 5 and 11. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7-10, 13-16, 19, and 20; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1, 7, and 15; cyclophosphamide IV over 15-60 minutes on days 1-5 in weeks 1, 7, and 15, and over 30-60 minutes on day 1 in weeks 9, 13, and 19; ifosfamide IV over 1 hour and etoposide IV over 1- 2 hours on days 1-5 in weeks 3, 5, 11, 17, and 21; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 9,13, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 13 and 19.	Drug: Cyclophosphamide; Given IV; Other Names: (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamide Monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 ; Drug: Dexrazoxane; Other Names: 2, 6-Piperazinedione, 4,4''-propylenedi-, (P)- (8CI) 2,6-Piperazinedione, 4, 4''-(1-methyl-1,2-ethanediyl)bis-, (S)- (9CI) ADR-529 ICRF-187 Razoxane (+)-form Soluble ICRF (L-isomer) ; 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 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 VP 16-213 VP-16 VP-16-213 VP16 ; 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 ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Topotecan Hydrochloride; Given IV; Other Names: Hycamptamine Hycamtin SKF S-104864-A Topotecan HCl topotecan hydrochloride (oral) ; Drug: Vincristine Sulfate; Given IV; Other Names: Kyocristine Leurocristine Sulfate Leurocristine, sulfate Oncovin Vincasar Vincosid Vincrex Vincristine, sulfate

Outcome Measures

Primary Outcome Measures

1. Event-Free Survival [5 years after enrollment]

   Estimated 5-year EFS where EFS is calculated as the time from study enrollment to disease progression, disease relapse, occurrence of a second malignant neoplasm, death from any cause or last follow-up whichever occurs first. Kaplan-Meier method is used for estimation. Patients without an event are censored at last contact.

Other Outcome Measures

1. Overall Survival [5 years after enrollment]

   Time from study enrollment to death or last patient contact.

2. Histological Response, in Terms of Event Free Survival After Local Control in Patients Who Received Local Control Therapy [At the end of INDUCTION THERAPY (84 days)]

   Percent of viable tumor in the resected tumor specimen after the patient receives 2 cycles of induction chemotherapy. Patients will be classified into groups according to: (1) good risk - less than 10% viable tumor in the resection specimen; and (2) standard risk - 10% or more viable tumor in the resection specimen. Patients who receive radiation therapy to the primary tumor prior to tumor resection or whose tumor is resected prior to the start of systemic therapy are not evaluable for this outcome measure.

3. SUVmax as Determined by Positron Emission Tomography (PET)-Determined Response at Enrollment [At study enrollment]

   Patients will be classified into two groups according to SUVmax as: (1) study population median or greater; and (2) less than the study population median.

4. SUVmax as Determined by Positron Emission Tomography (PET)-Determined Response After Induction [At the end of INDUCTION THERAPY (84 days)]

   Patients will be classified into two groups according to SUVmax as: (1) study population median or greater; and (2) less than the study population median. Patients who receive radiation therapy to the primary tumor prior to the completion of 2 cycles of induction or who do not receive 2 cycles of induction chemotherapy are not evaluable for this outcome measure.

5. Tumor Volume in Milliliters (ml) at Enrollment [At study enrollment]

   Patients will be classified into two groups: (1) tumor volume 200 ml or greater and (2) tumor volume less than 200 ml.

6. Radiological Response of Soft Tissue Component of Mass by Radiological Evaluation at the End of Induction Chemotherapy [At the end of INDUCTION THERAPY (84 days)]

   Patients will be classified into two groups: (1) complete resolution of soft tissue mass; and (2) soft tissue mass present after induction chemotherapy. Patients who receive radiation therapy to the primary tumor prior to the completion of 2 cycles of induction, who do not receive 2 cycles of induction chemotherapy or who do not have soft tissue involvement detected at enrollment or at any time prior to the end of induction chemotherapy are not evaluable for this outcome measure.

7. Type of Local Control Modality Used for Removal of Primary Tumor Site at Any Time up to the End of the First 6 Cycles of Consolidation Chemotherapy [126 days after enrollment]

   Patients will be categorized into the following groups: (1) surgery as the local control modality; (2) radiation therapy as the local control modality; (3) surgery and radiation therapy as the local control modality; and (4) no local control modality administered to the primary tumor site. Patients who do not complete induction chemotherapy will not be evaluable for this outcome measure.

8. Occurrence of Grade 2 or Higher Musculoskeletal Event (ME), or Surgery Required to Treat a Complication of Local Therapy [132 days after enrollment]

   Any National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 ME of grade 2 or greater or ME of any grade where surgery is required to treat a complication of local therapy. Patients who do not complete induction chemotherapy or do not have any local control modality administered to the primary tumor site will not be evaluable for this outcome measure.

9. Presence of Tumor at the Margin of Resection for Patients Who Have Surgery as the Only Local Control Modality [126 days after enrollment]

   Patients will be categorized into the following groups: (1) tumor present at the margin of resection; and (2) no tumor present at the margin of resection. Patients who are not classified as having surgery as the only local control modality will not be evaluable for this outcome measure.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with newly diagnosed, biopsy confirmed, extracranial, non-metastatic Ewing sarcoma or primitive neuroectodermal tumor (PNET) of bone or soft tissue are eligible for this study; note:

• For the purpose of this study, chest wall tumors with ipsilateral pleural effusions, ipsilateral positive pleural fluid cytology or ipsilateral pleural based secondary tumor nodules will be considered localized disease

• Patients with regional node involvement, based on clinical suspicion confirmed by pathologic documentation are considered to be non-metastatic

• Patients with discontinuous osseous lesions within the same bone are considered to be non-metastatic

• Tumors arising in the bony skull (extra-dural) are considered to be extracranial

• Patient eligibility will be based on a diagnosis of Ewing sarcoma or PNET by institutional pathologist

• No prior chemotherapy or radiation therapy is allowed; patients should only have had a biopsy of the primary tumor without an attempt at complete or partial resection; patients will still be eligible if unplanned excision was attempted or accomplished as long as adequate imaging was obtained prior to surgery

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70mL/min/1.73 m^2 or serum creatinine based on age/gender as follows:

• 1 month to < 6 months: 0.4 mg/dL

• 6 months to < 1 year: 0.5 mg/dL

• 1 to < 2 years: 0.6 mg/dL

• 2 to < 6 years: 0.8 mg/dL

• 6 to < 10 years: 1 mg/dL

• 10 to < 13 years: 1.2 mg/dL

• 13 to < 16 years: 1.5 mg/dL (male), 1.4 mg/dL (female)

• = 16 years: 1.7 mg/dL (male), 1.4 mg/dL (female)

• Total bilirubin < 1.5 x upper limit of normal (ULN) for age

• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x upper limit of normal (ULN) for age

• Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by radionuclide angiogram

Exclusion Criteria:

• Patients must have no evidence of metastatic disease; metastatic disease are lesions which are discontinuous from the primary tumor, are not regional lymph nodes and do not share a body cavity with the primary tumor; if there is any doubt whether lesions are metastatic, a biopsy of those lesions should be taken

• Skeletal lesions in adjacent bones (trans-articular)

• Contralateral pleural effusion and contralateral pleural nodules

• Distant lymph node involvement

• Patients with pulmonary nodules are considered to have metastatic disease if the patient has:

• Solitary nodule > 0.5 cm or multiple nodules of > 0.3 cm unless biopsied and negative for Ewing's

• Biopsies of solitary nodule =< 0.5 cm or multiple nodules =< 0.3 cm are not required but if performed and positive indicate metastatic disease

• Patients whose tumors arise in the dural and intra-dural soft tissues of the cranium and spine are not eligible

• Patients with pathologic diagnoses other than Ewing sarcoma will be excluded

• Patients diagnosed with Ewing Sarcoma as a second malignant neoplasm are not eligible if they have received chemotherapy or radiation for the treatment of their primary malignancy

• Pregnant women will not be entered on this study; pregnancy tests must be obtained in female patients who are post-menarchal; lactating females may not participate unless they have agreed not to breastfeed their infants; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of the study treatment

• All patients and/or their parents or legal guardians must sign a written informed consent

• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

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	USA Health Strada Patient Care Center	Mobile	Alabama	United States	36604
4	Providence Alaska Medical Center	Anchorage	Alaska	United States	99508
5	Phoenix Childrens Hospital	Phoenix	Arizona	United States	85016
6	Banner University Medical Center - Tucson	Tucson	Arizona	United States	85719
7	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202-3591
8	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
9	Kaiser Permanente Downey Medical Center	Downey	California	United States	90242
10	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010
11	Loma Linda University Medical Center	Loma Linda	California	United States	92354
12	Miller Children's and Women's Hospital Long Beach	Long Beach	California	United States	90806
13	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
14	Los Angeles County-USC Medical Center	Los Angeles	California	United States	90033
15	USC / Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
16	Cedars Sinai Medical Center	Los Angeles	California	United States	90048
17	Mattel Children's Hospital UCLA	Los Angeles	California	United States	90095
18	UCLA / Jonsson Comprehensive Cancer Center	Los Angeles	California	United States	90095
19	Valley Children's Hospital	Madera	California	United States	93636
20	Children's Hospital and Research Center at Oakland	Oakland	California	United States	94609-1809
21	Kaiser Permanente-Oakland	Oakland	California	United States	94611
22	Children's Hospital of Orange County	Orange	California	United States	92868
23	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California	United States	92868
24	Lucile Packard Children's Hospital Stanford University	Palo Alto	California	United States	94304
25	Sutter Medical Center Sacramento	Sacramento	California	United States	95816
26	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
27	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
28	UCSF Medical Center-Parnassus	San Francisco	California	United States	94143
29	UCSF Medical Center-Mission Bay	San Francisco	California	United States	94158
30	Children's Hospital Colorado	Aurora	Colorado	United States	80045
31	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado	United States	80218
32	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
33	Yale University	New Haven	Connecticut	United States	06520
34	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
35	MedStar Georgetown University Hospital	Washington	District of Columbia	United States	20007
36	Children's National Medical Center	Washington	District of Columbia	United States	20010
37	Broward Health Medical Center	Fort Lauderdale	Florida	United States	33316
38	Lee Memorial Health System	Fort Myers	Florida	United States	33901
39	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida	United States	33908
40	University of Florida Health Science Center - Gainesville	Gainesville	Florida	United States	32610
41	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida	United States	33021
42	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida	United States	32207
43	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
44	Miami Cancer Institute	Miami	Florida	United States	33176
45	AdventHealth Orlando	Orlando	Florida	United States	32803
46	Arnold Palmer Hospital for Children	Orlando	Florida	United States	32806
47	Nemours Children's Clinic - Orlando	Orlando	Florida	United States	32806
48	Orlando Health Cancer Institute	Orlando	Florida	United States	32806
49	Nemours Children's Hospital	Orlando	Florida	United States	32827
50	Nemours Children's Clinic - Pensacola	Pensacola	Florida	United States	32504
51	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida	United States	33701
52	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida	United States	33607
53	Saint Mary's Hospital	West Palm Beach	Florida	United States	33407
54	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
55	Augusta University Medical Center	Augusta	Georgia	United States	30912
56	Memorial Health University Medical Center	Savannah	Georgia	United States	31404
57	Straub Clinic and Hospital	Honolulu	Hawaii	United States	96813
58	University of Hawaii Cancer Center	Honolulu	Hawaii	United States	96813
59	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii	United States	96826
60	Tripler Army Medical Center	Honolulu	Hawaii	United States	96859
61	Saint Luke's Cancer Institute - Boise	Boise	Idaho	United States	83712
62	Lurie Children's Hospital-Chicago	Chicago	Illinois	United States	60611
63	Northwestern University	Chicago	Illinois	United States	60611
64	University of Illinois	Chicago	Illinois	United States	60612
65	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
66	Loyola University Medical Center	Maywood	Illinois	United States	60153
67	Advocate Children's Hospital-Oak Lawn	Oak Lawn	Illinois	United States	60453
68	Advocate Children's Hospital-Park Ridge	Park Ridge	Illinois	United States	60068
69	Advocate Lutheran General Hospital	Park Ridge	Illinois	United States	60068
70	Saint Jude Midwest Affiliate	Peoria	Illinois	United States	61637
71	Saint John's Hospital	Springfield	Illinois	United States	62702
72	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62702
73	Memorial Medical Center	Springfield	Illinois	United States	62781
74	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
75	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
76	Saint Vincent Hospital and Health Care Center	Indianapolis	Indiana	United States	46260
77	Blank Children's Hospital	Des Moines	Iowa	United States	50309
78	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
79	Siouxland Regional Cancer Center	Sioux City	Iowa	United States	51101
80	Mercy Medical Center-Sioux City	Sioux City	Iowa	United States	51102
81	Saint Luke's Regional Medical Center	Sioux City	Iowa	United States	51104
82	University of Kentucky/Markey Cancer Center	Lexington	Kentucky	United States	40536
83	Norton Children's Hospital	Louisville	Kentucky	United States	40202
84	Tulane University Health Sciences Center	New Orleans	Louisiana	United States	70112
85	Children's Hospital New Orleans	New Orleans	Louisiana	United States	70118
86	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
87	Eastern Maine Medical Center	Bangor	Maine	United States	04401
88	Maine Children's Cancer Program	Scarborough	Maine	United States	04074
89	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
90	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
91	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
92	Walter Reed National Military Medical Center	Bethesda	Maryland	United States	20889-5600
93	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
94	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
95	Baystate Medical Center	Springfield	Massachusetts	United States	01199
96	UMass Memorial Medical Center - University Campus	Worcester	Massachusetts	United States	01655
97	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
98	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan	United States	48201
99	Ascension Saint John Hospital	Detroit	Michigan	United States	48236
100	Michigan State University Clinical Center	East Lansing	Michigan	United States	48824-7016
101	Hurley Medical Center	Flint	Michigan	United States	48503
102	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
103	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
104	Beaumont Children's Hospital-Royal Oak	Royal Oak	Michigan	United States	48073
105	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
106	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
107	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905
108	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
109	Columbia Regional	Columbia	Missouri	United States	65201
110	Children's Mercy Hospitals and Clinics	Kansas City	Missouri	United States	64108
111	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
112	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
113	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska	United States	68114
114	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
115	University Medical Center of Southern Nevada	Las Vegas	Nevada	United States	89102
116	Sunrise Hospital and Medical Center	Las Vegas	Nevada	United States	89109
117	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada	United States	89135
118	Summerlin Hospital Medical Center	Las Vegas	Nevada	United States	89144
119	Nevada Cancer Research Foundation NCORP	Las Vegas	Nevada	United States	89169
120	Saint Mary's Regional Medical Center	Reno	Nevada	United States	89503
121	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
122	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
123	Saint Barnabas Medical Center	Livingston	New Jersey	United States	07039
124	Morristown Medical Center	Morristown	New Jersey	United States	07960
125	Saint Peter's University Hospital	New Brunswick	New Jersey	United States	08901
126	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey	United States	08903
127	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
128	Saint Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
129	Overlook Hospital	Summit	New Jersey	United States	07902
130	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87102
131	Albany Medical Center	Albany	New York	United States	12208
132	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
133	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
134	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York	United States	11040
135	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York	United States	10016
136	Mount Sinai Hospital	New York	New York	United States	10029
137	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York	United States	10032
138	University of Rochester	Rochester	New York	United States	14642
139	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
140	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
141	New York Medical College	Valhalla	New York	United States	10595
142	Mission Hospital	Asheville	North Carolina	United States	28801
143	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
144	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina	United States	28203
145	Novant Health Presbyterian Medical Center	Charlotte	North Carolina	United States	28204
146	Duke University Medical Center	Durham	North Carolina	United States	27710
147	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
148	Sanford Broadway Medical Center	Fargo	North Dakota	United States	58122
149	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
150	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
151	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
152	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
153	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
154	Dayton Children's Hospital	Dayton	Ohio	United States	45404
155	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio	United States	43606
156	Mercy Children's Hospital	Toledo	Ohio	United States	43608
157	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
158	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma	United States	74136
159	Providence Saint Vincent Medical Center	Portland	Oregon	United States	97225
160	Legacy Emanuel Children's Hospital	Portland	Oregon	United States	97227
161	Legacy Emanuel Hospital and Health Center	Portland	Oregon	United States	97227
162	Oregon Health and Science University	Portland	Oregon	United States	97239
163	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania	United States	18017
164	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
165	Penn State Children's Hospital	Hershey	Pennsylvania	United States	17033
166	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
167	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
168	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States	19134
169	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
170	Rhode Island Hospital	Providence	Rhode Island	United States	02903
171	Medical University of South Carolina	Charleston	South Carolina	United States	29425
172	Prisma Health Richland Hospital	Columbia	South Carolina	United States	29203
173	BI-LO Charities Children's Cancer Center	Greenville	South Carolina	United States	29605
174	Greenville Cancer Treatment Center	Greenville	South Carolina	United States	29605
175	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
176	T C Thompson Children's Hospital	Chattanooga	Tennessee	United States	37403
177	East Tennessee Childrens Hospital	Knoxville	Tennessee	United States	37916
178	Saint Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
179	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
180	Dell Children's Medical Center of Central Texas	Austin	Texas	United States	78723
181	Driscoll Children's Hospital	Corpus Christi	Texas	United States	78411
182	Medical City Dallas Hospital	Dallas	Texas	United States	75230
183	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
184	El Paso Children's Hospital	El Paso	Texas	United States	79905
185	Brooke Army Medical Center	Fort Sam Houston	Texas	United States	78234
186	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
187	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas	United States	77030
188	M D Anderson Cancer Center	Houston	Texas	United States	77030
189	Covenant Children's Hospital	Lubbock	Texas	United States	79410
190	Children's Hospital of San Antonio	San Antonio	Texas	United States	78207
191	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229
192	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
193	Scott and White Memorial Hospital	Temple	Texas	United States	76508
194	Primary Children's Hospital	Salt Lake City	Utah	United States	84113
195	University of Vermont and State Agricultural College	Burlington	Vermont	United States	05405
196	University of Virginia Cancer Center	Charlottesville	Virginia	United States	22908
197	Inova Fairfax Hospital	Falls Church	Virginia	United States	22042
198	Children's Hospital of The King's Daughters	Norfolk	Virginia	United States	23507
199	Naval Medical Center - Portsmouth	Portsmouth	Virginia	United States	23708-2197
200	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
201	Carilion Children's	Roanoke	Virginia	United States	24014
202	Seattle Children's Hospital	Seattle	Washington	United States	98105
203	University of Washington Medical Center - Montlake	Seattle	Washington	United States	98195
204	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington	United States	99204
205	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington	United States	98405
206	Madigan Army Medical Center	Tacoma	Washington	United States	98431
207	United Hospital Center	Bridgeport	West Virginia	United States	26330
208	West Virginia University Charleston Division	Charleston	West Virginia	United States	25304
209	West Virginia University Healthcare	Morgantown	West Virginia	United States	26506
210	Camden Clark Medical Center	Parkersburg	West Virginia	United States	26101
211	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin	United States	54301
212	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
213	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin	United States	54449
214	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226
215	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
216	John Hunter Children's Hospital	Hunter Regional Mail Centre	New South Wales	Australia	2310
217	Sydney Children's Hospital	Randwick	New South Wales	Australia	2031
218	The Children's Hospital at Westmead	Westmead	New South Wales	Australia	2145
219	Royal Brisbane and Women's Hospital	Herston	Queensland	Australia	4029
220	Royal Children's Hospital-Brisbane	Herston	Queensland	Australia	4029
221	Queensland Children's Hospital	South Brisbane	Queensland	Australia	4101
222	Women's and Children's Hospital-Adelaide	North Adelaide	South Australia	Australia	5006
223	Princess Margaret Hospital for Children	Perth	Western Australia	Australia	6008
224	Alberta Children's Hospital	Calgary	Alberta	Canada	T3B 6A8
225	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2B7
226	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
227	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
228	Janeway Child Health Centre	Saint John's	Newfoundland and Labrador	Canada	A1B 3V6
229	IWK Health Centre	Halifax	Nova Scotia	Canada	B3K 6R8
230	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8N 3Z5
231	Kingston Health Sciences Centre	Kingston	Ontario	Canada	K7L 2V7
232	Children's Hospital	London	Ontario	Canada	N6A 5W9
233	Children's Hospital of Eastern Ontario	Ottawa	Ontario	Canada	K1H 8L1
234	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
235	The Montreal Children's Hospital of the MUHC	Montreal	Quebec	Canada	H3H 1P3
236	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5
237	Allan Blair Cancer Centre	Regina	Saskatchewan	Canada	S4T 7T1
238	Saskatoon Cancer Centre	Saskatoon	Saskatchewan	Canada	S7N 4H4
239	Centre Hospitalier Universitaire de Quebec	Quebec		Canada	G1V 4G2
240	Starship Children's Hospital	Grafton	Auckland	New Zealand	1145
241	Christchurch Hospital	Christchurch		New Zealand	8011
242	San Jorge Children's Hospital	San Juan		Puerto Rico	00912
243	King Faisal Specialist Hospital and Research Centre	Riyadh		Saudi Arabia	11211

Sponsors and Collaborators

• Children's Oncology Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Patrick J Leavey, Children's Oncology Group

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 4, 2016

More Information

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT01231906
• Other Study ID Numbers: AEWS1031; NCI-2011-02611; S12-01231; CDR0000687639; COG-AEWS1031; AEWS1031; AEWS1031; P30CA013330; U10CA180830; U10CA180886; U10CA098543
• First Posted: Nov 1, 2010
• Last Update Posted: May 23, 2022
• Last Verified: Mar 1, 2022

• Additional relevant MeSH terms: Sarcoma; Sarcoma, Ewing; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Soft Tissue Neoplasms; Cyclophosphamide; Ifosfamide; Isophosphamide mustard; Doxorubicin; Liposomal doxorubicin; Etoposide; Vincristine; Etoposide phosphate; Topotecan; Podophyllotoxin; Dexrazoxane; Razoxane; 3,6-bis(5-chloro-2-piperidyl)-2,5-piperazinedione

Study Results

Participant Flow

Arm/Group Title	Arm A (Combination Chemotherapy)	Arm B (Combination Chemotherapy, Topotecan Hydrochloride)
Arm/Group Description	INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, and 10; doxorubicin hydrochloride IV over 1-15 minutes (or as per institutional policies up to 60-minutes) on days 1 and 2 and cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 5, and 9; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 7, and 11. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7, 8, 9, 10, 13, 14, 17, 18, 21, and 22; doxorubicin hydrochloride IV on days 1 and 2 in weeks 1 and 9; cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 7, 9, 13, 17, and 21; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 5, 11, 15, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 1 and 9.	INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, 10, 11 and 12; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1 and 9; cyclophosphamide IV over 15-30 minutes on days 1-5 in weeks 1 and 9, and over 30-60 minutes on day 1 of weeks 5 and 11; ifosfamide and etoposide as in arm A; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 5 and 11. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7-10, 13-16, 19, and 20; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1, 7, and 15; cyclophosphamide IV over 15-60 minutes on days 1-5 in weeks 1, 7, and 15, and over 30-60 minutes on day 1 in weeks 9, 13, and 19; ifosfamide IV over 1 hour and etoposide IV over 1- 2 hours on days 1-5 in weeks 3, 5, 11, 17, and 21; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 9,13, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 13 and 19.
Period Title: Overall Study
STARTED	319	323
Received Therapy	308	318
COMPLETED	198	222
NOT COMPLETED	121	101

Baseline Characteristics

Arm/Group Title	Arm A (Combination Chemotherapy)	Arm B (Combination Chemotherapy, Topotecan Hydrochloride)	Total
Arm/Group Description	INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, and 10; doxorubicin hydrochloride IV over 1-15 minutes (or as per institutional policies up to 60-minutes) on days 1 and 2 and cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 5, and 9; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 7, and 11. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7, 8, 9, 10, 13, 14, 17, 18, 21, and 22; doxorubicin hydrochloride IV on days 1 and 2 in weeks 1 and 9; cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 7, 9, 13, 17, and 21; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 5, 11, 15, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 1 and 9.	INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, 10, 11 and 12; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1 and 9; cyclophosphamide IV over 15-30 minutes on days 1-5 in weeks 1 and 9, and over 30-60 minutes on day 1 of weeks 5 and 11; ifosfamide and etoposide as in arm A; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 5 and 11. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7-10, 13-16, 19, and 20; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1, 7, and 15; cyclophosphamide IV over 15-60 minutes on days 1-5 in weeks 1, 7, and 15, and over 30-60 minutes on day 1 in weeks 9, 13, and 19; ifosfamide IV over 1 hour and etoposide IV over 1- 2 hours on days 1-5 in weeks 3, 5, 11, 17, and 21; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 9,13, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 13 and 19.	Total of all reporting groups
Overall Participants	319	323	642
Age (Count of Participants)
<=18 years	272 85.3%	280 86.7%	552 86%
Between 18 and 65 years	47 14.7%	43 13.3%	90 14%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	13	13	13
Sex: Female, Male (Count of Participants)
Female	145 45.5%	130 40.2%	275 42.8%
Male	174 54.5%	193 59.8%	367 57.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	45 14.1%	44 13.6%	89 13.9%
Not Hispanic or Latino	269 84.3%	275 85.1%	544 84.7%
Unknown or Not Reported	5 1.6%	4 1.2%	9 1.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	3 0.9%	3 0.5%
Asian	11 3.4%	6 1.9%	17 2.6%
Native Hawaiian or Other Pacific Islander	3 0.9%	2 0.6%	5 0.8%
Black or African American	10 3.1%	4 1.2%	14 2.2%
White	267 83.7%	280 86.7%	547 85.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	28 8.8%	28 8.7%	56 8.7%
Region of Enrollment (Count of Participants)
United States	286 89.7%	286 88.5%	572 89.1%
Australia	17 5.3%	20 6.2%	37 5.8%
Canada	14 4.4%	13 4%	27 4.2%
New Zealand	2 0.6%	2 0.6%	4 0.6%
Saudi Arabia	0 0%	2 0.6%	2 0.3%

Outcome Measures

1. Primary Outcome

Title	Event-Free Survival
Description	Estimated 5-year EFS where EFS is calculated as the time from study enrollment to disease progression, disease relapse, occurrence of a second malignant neoplasm, death from any cause or last follow-up whichever occurs first. Kaplan-Meier method is used for estimation. Patients without an event are censored at last contact.
Time Frame	5 years after enrollment

Outcome Measure Data

Analysis Population Description

Only eligible patients are considered in the calculation of this outcome measure.

Arm/Group Title	Arm A (Combination Chemotherapy)	Arm B (Combination Chemotherapy, Topotecan Hydrochloride)
Arm/Group Description	INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, and 10; doxorubicin hydrochloride IV over 1-15 minutes (or as per institutional policies up to 60-minutes) on days 1 and 2 and cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 5, and 9; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 7, and 11. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7, 8, 9, 10, 13, 14, 17, 18, 21, and 22; doxorubicin hydrochloride IV on days 1 and 2 in weeks 1 and 9; cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 7, 9, 13, 17, and 21; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 5, 11, 15, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 1 and 9.	INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, 10, 11 and 12; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1 and 9; cyclophosphamide IV over 15-30 minutes on days 1-5 in weeks 1 and 9, and over 30-60 minutes on day 1 of weeks 5 and 11; ifosfamide and etoposide as in arm A; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 5 and 11. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7-10, 13-16, 19, and 20; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1, 7, and 15; cyclophosphamide IV over 15-60 minutes on days 1-5 in weeks 1, 7, and 15, and over 30-60 minutes on day 1 in weeks 9, 13, and 19; ifosfamide IV over 1 hour and etoposide IV over 1- 2 hours on days 1-5 in weeks 3, 5, 11, 17, and 21; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 9,13, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 13 and 19.
Measure Participants	309	320
Number (95% Confidence Interval) [Percent Probability]	77.64	78.79

2. Other Pre-specified Outcome

Title	Overall Survival
Description	Time from study enrollment to death or last patient contact.
Time Frame	5 years after enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Other Pre-specified Outcome

Title	Histological Response, in Terms of Event Free Survival After Local Control in Patients Who Received Local Control Therapy
Description	Percent of viable tumor in the resected tumor specimen after the patient receives 2 cycles of induction chemotherapy. Patients will be classified into groups according to: (1) good risk - less than 10% viable tumor in the resection specimen; and (2) standard risk - 10% or more viable tumor in the resection specimen. Patients who receive radiation therapy to the primary tumor prior to tumor resection or whose tumor is resected prior to the start of systemic therapy are not evaluable for this outcome measure.
Time Frame	At the end of INDUCTION THERAPY (84 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Other Pre-specified Outcome

Title	SUVmax as Determined by Positron Emission Tomography (PET)-Determined Response at Enrollment
Description	Patients will be classified into two groups according to SUVmax as: (1) study population median or greater; and (2) less than the study population median.
Time Frame	At study enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Other Pre-specified Outcome

Title	SUVmax as Determined by Positron Emission Tomography (PET)-Determined Response After Induction
Description	Patients will be classified into two groups according to SUVmax as: (1) study population median or greater; and (2) less than the study population median. Patients who receive radiation therapy to the primary tumor prior to the completion of 2 cycles of induction or who do not receive 2 cycles of induction chemotherapy are not evaluable for this outcome measure.
Time Frame	At the end of INDUCTION THERAPY (84 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Other Pre-specified Outcome

Title	Tumor Volume in Milliliters (ml) at Enrollment
Description	Patients will be classified into two groups: (1) tumor volume 200 ml or greater and (2) tumor volume less than 200 ml.
Time Frame	At study enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Radiological Response of Soft Tissue Component of Mass by Radiological Evaluation at the End of Induction Chemotherapy
Description	Patients will be classified into two groups: (1) complete resolution of soft tissue mass; and (2) soft tissue mass present after induction chemotherapy. Patients who receive radiation therapy to the primary tumor prior to the completion of 2 cycles of induction, who do not receive 2 cycles of induction chemotherapy or who do not have soft tissue involvement detected at enrollment or at any time prior to the end of induction chemotherapy are not evaluable for this outcome measure.
Time Frame	At the end of INDUCTION THERAPY (84 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Type of Local Control Modality Used for Removal of Primary Tumor Site at Any Time up to the End of the First 6 Cycles of Consolidation Chemotherapy
Description	Patients will be categorized into the following groups: (1) surgery as the local control modality; (2) radiation therapy as the local control modality; (3) surgery and radiation therapy as the local control modality; and (4) no local control modality administered to the primary tumor site. Patients who do not complete induction chemotherapy will not be evaluable for this outcome measure.
Time Frame	126 days after enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Occurrence of Grade 2 or Higher Musculoskeletal Event (ME), or Surgery Required to Treat a Complication of Local Therapy
Description	Any National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 ME of grade 2 or greater or ME of any grade where surgery is required to treat a complication of local therapy. Patients who do not complete induction chemotherapy or do not have any local control modality administered to the primary tumor site will not be evaluable for this outcome measure.
Time Frame	132 days after enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Presence of Tumor at the Margin of Resection for Patients Who Have Surgery as the Only Local Control Modality
Description	Patients will be categorized into the following groups: (1) tumor present at the margin of resection; and (2) no tumor present at the margin of resection. Patients who are not classified as having surgery as the only local control modality will not be evaluable for this outcome measure.
Time Frame	126 days after enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Up to 6 months post-treatment planned as 252 days; All-Cause Mortality: up to 9 years
Adverse Event Reporting Description	Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.
Arm/Group Title	Arm A (Combination Chemotherapy)		Arm B (Combination Chemotherapy, Topotecan Hydrochloride)
Arm/Group Description	INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, and 10; doxorubicin hydrochloride IV over 1-15 minutes (or as per institutional policies up to 60-minutes) on days 1 and 2 and cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 5, and 9; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 7, and 11. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7, 8, 9, 10, 13, 14, 17, 18, 21, and 22; doxorubicin hydrochloride IV on days 1 and 2 in weeks 1 and 9; cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 7, 9, 13, 17, and 21; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 5, 11, 15, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 1 and 9.		INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, 10, 11 and 12; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1 and 9; cyclophosphamide IV over 15-30 minutes on days 1-5 in weeks 1 and 9, and over 30-60 minutes on day 1 of weeks 5 and 11; ifosfamide and etoposide as in arm A; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 5 and 11. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7-10, 13-16, 19, and 20; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1, 7, and 15; cyclophosphamide IV over 15-60 minutes on days 1-5 in weeks 1, 7, and 15, and over 30-60 minutes on day 1 in weeks 9, 13, and 19; ifosfamide IV over 1 hour and etoposide IV over 1- 2 hours on days 1-5 in weeks 3, 5, 11, 17, and 21; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 9,13, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 13 and 19.
All Cause Mortality
	Arm A (Combination Chemotherapy)		Arm B (Combination Chemotherapy, Topotecan Hydrochloride)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	51/308 (16.6%)		42/318 (13.2%)
Serious Adverse Events
	Arm A (Combination Chemotherapy)		Arm B (Combination Chemotherapy, Topotecan Hydrochloride)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/308 (2.6%)		11/318 (3.5%)
Blood and lymphatic system disorders
Anemia	0/308 (0%)	0	1/318 (0.3%)	1
Febrile neutropenia	1/308 (0.3%)	1	1/318 (0.3%)	1
Cardiac disorders
Heart failure	1/308 (0.3%)	1	0/318 (0%)	0
Left ventricular systolic dysfunction	1/308 (0.3%)	1	0/318 (0%)	0
Right ventricular dysfunction	0/308 (0%)	0	1/318 (0.3%)	1
Sinus tachycardia	0/308 (0%)	0	1/318 (0.3%)	1
Gastrointestinal disorders
Ascites	0/308 (0%)	0	2/318 (0.6%)	2
Colitis	0/308 (0%)	0	1/318 (0.3%)	1
Diarrhea	0/308 (0%)	0	1/318 (0.3%)	1
Mucositis oral	1/308 (0.3%)	1	0/318 (0%)	0
Nausea	0/308 (0%)	0	1/318 (0.3%)	1
Stomach pain	0/308 (0%)	0	1/318 (0.3%)	1
Typhlitis	1/308 (0.3%)	1	1/318 (0.3%)	1
Hepatobiliary disorders
Hepatic failure	0/308 (0%)	0	1/318 (0.3%)	1
Portal hypertension	0/308 (0%)	0	1/318 (0.3%)	1
Immune system disorders
Allergic reaction	0/308 (0%)	0	1/318 (0.3%)	1
Infections and infestations
Enterocolitis infectious	0/308 (0%)	0	1/318 (0.3%)	1
Infections and infestations - Other, specify	0/308 (0%)	0	1/318 (0.3%)	1
Sepsis	4/308 (1.3%)	4	2/318 (0.6%)	2
Soft tissue infection	0/308 (0%)	0	1/318 (0.3%)	1
Urinary tract infection	0/308 (0%)	0	1/318 (0.3%)	1
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications - Other, specify	0/308 (0%)	0	1/318 (0.3%)	1
Investigations
Alanine aminotransferase increased	0/308 (0%)	0	1/318 (0.3%)	1
Aspartate aminotransferase increased	0/308 (0%)	0	1/318 (0.3%)	1
Blood bilirubin increased	0/308 (0%)	0	1/318 (0.3%)	1
INR increased	0/308 (0%)	0	1/318 (0.3%)	1
Lymphocyte count decreased	0/308 (0%)	0	1/318 (0.3%)	1
Neutrophil count decreased	0/308 (0%)	0	1/318 (0.3%)	1
Platelet count decreased	0/308 (0%)	0	1/318 (0.3%)	1
White blood cell decreased	0/308 (0%)	0	1/318 (0.3%)	1
Musculoskeletal and connective tissue disorders
Soft tissue necrosis lower limb	0/308 (0%)	0	1/318 (0.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Leukemia secondary to oncology chemotherapy	1/308 (0.3%)	1	1/318 (0.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	1/308 (0.3%)	1	0/318 (0%)	0
Renal and urinary disorders
Acute kidney injury	1/308 (0.3%)	1	0/318 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pleural effusion	0/308 (0%)	0	1/318 (0.3%)	1
Pulmonary hypertension	0/308 (0%)	0	1/318 (0.3%)	1
Respiratory failure	2/308 (0.6%)	2	1/318 (0.3%)	1
Vascular disorders
Capillary leak syndrome	0/308 (0%)	0	1/318 (0.3%)	1
Hypotension	2/308 (0.6%)	2	0/318 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm A (Combination Chemotherapy)		Arm B (Combination Chemotherapy, Topotecan Hydrochloride)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	105/308 (34.1%)		91/318 (28.6%)
Blood and lymphatic system disorders
Anemia	16/308 (5.2%)	16	16/318 (5%)	16
Blood and lymphatic system disorders - Other, specify	1/308 (0.3%)	1	1/318 (0.3%)	1
Bone marrow hypocellular	0/308 (0%)	0	1/318 (0.3%)	1
Febrile neutropenia	28/308 (9.1%)	28	25/318 (7.9%)	25
Cardiac disorders
Left ventricular systolic dysfunction	2/308 (0.6%)	2	0/318 (0%)	0
Pericardial effusion	1/308 (0.3%)	1	0/318 (0%)	0
Gastrointestinal disorders
Abdominal distension	0/308 (0%)	0	1/318 (0.3%)	1
Abdominal pain	3/308 (1%)	3	1/318 (0.3%)	1
Anal pain	0/308 (0%)	0	1/318 (0.3%)	1
Cecal hemorrhage	1/308 (0.3%)	1	0/318 (0%)	0
Colitis	2/308 (0.6%)	2	1/318 (0.3%)	1
Diarrhea	4/308 (1.3%)	4	0/318 (0%)	0
Dysphagia	1/308 (0.3%)	1	0/318 (0%)	0
Esophageal obstruction	1/308 (0.3%)	1	0/318 (0%)	0
Esophagitis	1/308 (0.3%)	1	0/318 (0%)	0
Gastrointestinal disorders - Other, specify	0/308 (0%)	0	1/318 (0.3%)	1
Mucositis oral	14/308 (4.5%)	14	7/318 (2.2%)	7
Nausea	1/308 (0.3%)	1	1/318 (0.3%)	1
Rectal pain	0/308 (0%)	0	1/318 (0.3%)	1
Vomiting	3/308 (1%)	3	0/318 (0%)	0
General disorders
Fever	3/308 (1%)	3	1/318 (0.3%)	1
Gait disturbance	0/308 (0%)	0	2/318 (0.6%)	2
Infusion site extravasation	1/308 (0.3%)	1	0/318 (0%)	0
Pain	5/308 (1.6%)	5	0/318 (0%)	0
Hepatobiliary disorders
Bile duct stenosis	0/308 (0%)	0	1/318 (0.3%)	1
Cholecystitis	1/308 (0.3%)	1	0/318 (0%)	0
Portal hypertension	1/308 (0.3%)	1	0/318 (0%)	0
Infections and infestations
Anorectal infection	0/308 (0%)	0	1/318 (0.3%)	1
Bone infection	1/308 (0.3%)	1	0/318 (0%)	0
Catheter related infection	2/308 (0.6%)	2	0/318 (0%)	0
Device related infection	1/308 (0.3%)	1	0/318 (0%)	0
Endocarditis infective	1/308 (0.3%)	1	0/318 (0%)	0
Infections and infestations - Other, specify	15/308 (4.9%)	15	6/318 (1.9%)	6
Lung infection	1/308 (0.3%)	1	0/318 (0%)	0
Mucosal infection	0/308 (0%)	0	1/318 (0.3%)	1
Otitis media	1/308 (0.3%)	1	0/318 (0%)	0
Pelvic infection	0/308 (0%)	0	1/318 (0.3%)	1
Pleural infection	0/308 (0%)	0	1/318 (0.3%)	1
Sepsis	4/308 (1.3%)	4	3/318 (0.9%)	3
Skin infection	2/308 (0.6%)	2	2/318 (0.6%)	2
Soft tissue infection	2/308 (0.6%)	2	0/318 (0%)	0
Upper respiratory infection	1/308 (0.3%)	1	0/318 (0%)	0
Urinary tract infection	1/308 (0.3%)	1	0/318 (0%)	0
Wound infection	4/308 (1.3%)	4	2/318 (0.6%)	2
Injury, poisoning and procedural complications
Dermatitis radiation	2/308 (0.6%)	2	2/318 (0.6%)	2
Fracture	2/308 (0.6%)	2	0/318 (0%)	0
Intraoperative neurological injury	1/308 (0.3%)	1	0/318 (0%)	0
Radiation recall reaction (dermatologic)	2/308 (0.6%)	2	0/318 (0%)	0
Wound complication	0/308 (0%)	0	2/318 (0.6%)	2
Investigations
Alanine aminotransferase increased	3/308 (1%)	3	2/318 (0.6%)	2
Aspartate aminotransferase increased	1/308 (0.3%)	1	0/318 (0%)	0
Blood bilirubin increased	2/308 (0.6%)	2	1/318 (0.3%)	1
Lymphocyte count decreased	5/308 (1.6%)	5	4/318 (1.3%)	4
Neutrophil count decreased	26/308 (8.4%)	26	26/318 (8.2%)	26
Platelet count decreased	23/308 (7.5%)	23	22/318 (6.9%)	22
Weight loss	1/308 (0.3%)	1	0/318 (0%)	0
White blood cell decreased	17/308 (5.5%)	17	13/318 (4.1%)	13
Metabolism and nutrition disorders
Anorexia	3/308 (1%)	3	2/318 (0.6%)	2
Dehydration	4/308 (1.3%)	4	0/318 (0%)	0
Hyperglycemia	3/308 (1%)	3	0/318 (0%)	0
Hyperkalemia	1/308 (0.3%)	1	0/318 (0%)	0
Hypocalcemia	1/308 (0.3%)	1	0/318 (0%)	0
Hypokalemia	7/308 (2.3%)	7	5/318 (1.6%)	5
Hyponatremia	1/308 (0.3%)	1	0/318 (0%)	0
Hypophosphatemia	3/308 (1%)	3	1/318 (0.3%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/308 (0%)	0	3/318 (0.9%)	3
Back pain	6/308 (1.9%)	6	3/318 (0.9%)	3
Bone pain	5/308 (1.6%)	5	1/318 (0.3%)	1
Chest wall pain	5/308 (1.6%)	5	4/318 (1.3%)	4
Generalized muscle weakness	1/308 (0.3%)	1	3/318 (0.9%)	3
Joint effusion	1/308 (0.3%)	1	0/318 (0%)	0
Joint range of motion decreased	6/308 (1.9%)	6	7/318 (2.2%)	7
Muscle weakness lower limb	2/308 (0.6%)	2	3/318 (0.9%)	3
Muscle weakness right-sided	0/308 (0%)	0	1/318 (0.3%)	1
Muscle weakness upper limb	0/308 (0%)	0	1/318 (0.3%)	1
Musculoskeletal and connective tissue disorder - Other, specify	3/308 (1%)	3	2/318 (0.6%)	2
Musculoskeletal deformity	1/308 (0.3%)	1	0/318 (0%)	0
Myalgia	1/308 (0.3%)	1	0/318 (0%)	0
Myositis	1/308 (0.3%)	1	0/318 (0%)	0
Neck pain	0/308 (0%)	0	1/318 (0.3%)	1
Pain in extremity	9/308 (2.9%)	9	13/318 (4.1%)	13
Pelvic soft tissue necrosis	0/308 (0%)	0	1/318 (0.3%)	1
Soft tissue necrosis lower limb	3/308 (1%)	3	3/318 (0.9%)	3
Trismus	2/308 (0.6%)	2	0/318 (0%)	0
Nervous system disorders
Peripheral motor neuropathy	3/308 (1%)	3	1/318 (0.3%)	1
Peripheral sensory neuropathy	0/308 (0%)	0	3/318 (0.9%)	3
Syncope	1/308 (0.3%)	1	1/318 (0.3%)	1
Psychiatric disorders
Depression	1/308 (0.3%)	1	0/318 (0%)	0
Psychosis	1/308 (0.3%)	1	0/318 (0%)	0
Suicidal ideation	1/308 (0.3%)	1	1/318 (0.3%)	1
Renal and urinary disorders
Renal and urinary disorders - Other, specify	1/308 (0.3%)	1	0/318 (0%)	0
Reproductive system and breast disorders
Pelvic pain	0/308 (0%)	0	2/318 (0.6%)	2
Perineal pain	1/308 (0.3%)	1	0/318 (0%)	0
Respiratory, thoracic and mediastinal disorders
Atelectasis	0/308 (0%)	0	1/318 (0.3%)	1
Hypoxia	1/308 (0.3%)	1	0/318 (0%)	0
Tracheal mucositis	1/308 (0.3%)	1	0/318 (0%)	0
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders - Other, specify	2/308 (0.6%)	2	1/318 (0.3%)	1
Skin ulceration	1/308 (0.3%)	1	0/318 (0%)	0
Surgical and medical procedures
Surgical and medical procedures - Other, specify	0/308 (0%)	0	1/318 (0.3%)	1
Vascular disorders
Hypotension	3/308 (1%)	3	5/318 (1.6%)	5
Thromboembolic event	1/308 (0.3%)	1	2/318 (0.6%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Must obtain prior sponsor approval