Observation, Radiation Therapy, Combination Chemotherapy, and/or Surgery in Treating Young Patients With Soft Tissue Sarcoma

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00346164
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 588
• Locations: 187
• Arms: 4
• Actual Duration (Months): 181.8
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase III trial is studying observation to see how well a risk based treatment strategy works in patients with soft tissue sarcoma. In the study, patients are assigned to receive surgery +/- radiotherapy +/- chemotherapy depending on their risk of recurrence. Sometimes, after surgery, the tumor may not need additional treatment until it progresses. In this case, observation may be sufficient. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as ifosfamide and doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving chemotherapy and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments after surgery may kill any tumor cells that remain after surgery.

Condition or Disease	Intervention/Treatment	Phase
Adult Alveolar Soft-part Sarcoma; Adult Angiosarcoma; Adult Epithelioid Sarcoma; Adult Extraskeletal Chondrosarcoma; Adult Extraskeletal Osteosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Fibrous Histiocytoma; Adult Malignant Hemangiopericytoma; Adult Malignant Mesenchymoma; Adult Neurofibrosarcoma; Adult Synovial Sarcoma; Childhood Alveolar Soft-part Sarcoma; Childhood Angiosarcoma; Childhood Epithelioid Sarcoma; Childhood Fibrosarcoma; Childhood Leiomyosarcoma; Childhood Liposarcoma; Childhood Malignant Mesenchymoma; Childhood Neurofibrosarcoma; Childhood Synovial Sarcoma; Dermatofibrosarcoma Protuberans; Metastatic Childhood Soft Tissue Sarcoma; Nonmetastatic Childhood Soft Tissue Sarcoma; Stage I Adult Soft Tissue Sarcoma; Stage II Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma	Drug: doxorubicin hydrochloride; Other: clinical observation; Procedure: therapeutic conventional surgery; Radiation: 3-dimensional conformal radiation therapy; Drug: ifosfamide	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

1. Define a risk-based treatment strategy comprising observation only, adjuvant radiotherapy, or adjuvant chemoradiotherapy or neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy with or without radiotherapy in young patients with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS).

2. Assess event-free and overall survival of patients treated with these regimens.

3. Assess the pattern of treatment failure in these patients.

SECONDARY OBJECTIVES:

1. Assess the feasibility of a neoadjuvant chemoradiotherapy approach in patients with intermediate- or high-risk NRSTS.

2. Assess the imaging and pathologic responses to neoadjuvant chemoradiotherapy in patients with intermediate- or high-risk NRSTS.

3. Correlate imaging and pathologic response with clinical outcomes in patients with intermediate- or high-risk disease who undergo neoadjuvant chemoradiotherapy.

4. Prospectively define clinical prognostic factors associated with event-free survival, overall survival, local recurrence, and distant recurrence in these patients.

5. Correlate patient outcomes with findings of biologic studies performed on tissue specimens collected on protocol COG-D9902 from these patients.

6. Determine whether the diagnosis and histologic grade of NRSTS assigned by the enrolling institution correlates with the diagnosis and histologic grade established by central expert pathology reviewers.

7. Compare the Pediatric Oncology Group (POG) and Fédération Nationale des Centres de Lutte Contre le Cancer (French Federation of Cancer Centers [FNCLCC]) pathologic grading systems to determine which better correlates with clinical outcomes.

OUTLINE: This is a multicenter study. Patients are divided into 3 risk groups according to presence of metastatic disease (yes vs no), status of prior surgery (resected vs unresected), grade of tumor (low vs high), and size of primary tumor (≤ 5 cm vs > 5 cm). Patients are assigned to different treatment regimens based on disease extent (nonmetastatic vs metastatic), tumor size (≤ 5 cm vs > 5 cm), extent of resection of primary tumor (resected vs unresected), extent of resection of metastases (complete or microscopic residual vs gross residual), microscopic tumor margins (negative vs positive), and tumor grade (low vs high).

GROUP 1 (low risk [nonmetastatic, grossly resected disease, except high-grade tumor > 5 cm]):

Patients with low-grade tumor with either negative or positive microscopic margins or high-grade tumor ≤ 5 cm (in maximum diameter) with negative microscopic margins are assigned to regimen A. Patients with high-grade tumor ≤ 5 cm (in maximum diameter) with positive microscopic margins are assigned to regimen B.

REGIMEN A (observation only): Patients undergo observation only.

REGIMEN B (adjuvant radiotherapy): Beginning between 6-42 days after surgical resection, patients undergo a total of 31 fractions of adjuvant radiotherapy.

GROUP 2 (intermediate risk [nonmetastatic, resected or unresected disease]): Patients with grossly resected, high-grade tumor > 5 cm (in maximum diameter) are assigned to regimen C. Patients with unresected tumor are assigned to regimen D.

REGIMEN C (adjuvant chemoradiotherapy): Patients receive ifosfamide IV over 3 hours on days 1-3 in weeks 1, 4, 7, 10, 13, and 16 and doxorubicin hydrochloride IV over 24 hours on days 1 and 2 in weeks 1, 4, 13, 16, and 19. Beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy.

*NOTE: *Patients who receive brachytherapy will initiate radiotherapy in Week 1. If brachytherapy is administered, chemotherapy should begin within 2 weeks of completion of brachytherapy and the Weeks 1 and 19 doxorubicin should be given instead at Weeks 7 and 10.

REGIMEN D (neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy with or without radiotherapy): Neoadjuvant chemoradiotherapy and surgery: Patients receive ifosfamide IV over 3 hours on days 1-3 in weeks 1, 4, 7, and 10 and doxorubicin hydrochloride IV over 24 hours on days 1 and 2 in weeks 1 and 4. Beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy**. Patients undergo surgical resection in week 13.

NOTE: **Patients with primary hepatic tumors do not receive radiotherapy in week 4.

Adjuvant chemotherapy with or without radiotherapy: Patients receive ifosfamide IV over 3 hours on days 1-3 in weeks 16 and 19 and doxorubicin hydrochloride IV over 24 hours on days 1 and 2 in weeks 16, 19***, and 22. Beginning in week 16, patients achieving gross total resection with positive microscopic margins undergo a total of 6 fractions of adjuvant radiotherapy. Patients achieving less than total gross resection undergo a total of 11 fractions of adjuvant radiotherapy. Patients achieving total gross resection with negative microscopic margins do not receive adjuvant radiotherapy.

NOTE: ***Patients who receive adjuvant radiotherapy in week 16 receive doxorubicin hydrochloride in week 25 instead of week 19.

GROUP 3 (high risk [metastatic, resected, incompletely resected, or unresected disease]):

Patients with low-grade, all-sites resected tumor with either negative or positive microscopic margins are assigned to receive treatment as in group 1 regimen A. Patients with high-grade, grossly resected primary tumor, and metastatic disease are assigned to receive treatment as in group 2 regimen C. Patients with unresected, high-grade metastatic tumor are assigned to receive treatment as in group 2 regimen D.

In all groups, treatment continues in the absence of disease progression. After completing study treatment, patients are followed periodically for at least 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 588 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Risk-Based Treatment for Non-Rhabdomyosarcoma Soft Tissue Sarcomas (NRSTS) in Patients Under 30 Years of Age
• Actual Study Start Date: Feb 5, 2007
• Actual Primary Completion Date: Sep 5, 2014
• Actual Study Completion Date: Mar 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A: No adjuvant treatment Patients with low-grade tumor with either negative or positive microscopic margins or high-grade tumor ≤ 5 cm (in maximum diameter) with negative microscopic margins are assigned to arm A: (observation only).	Other: clinical observation; Patients undergo observation; Other Names: observation ; Procedure: therapeutic conventional surgery; Patients undergo surgery
Experimental: Arm B: Low risk; adjuvant radiotherapy Patients with high-grade tumor ≤ 5 cm (in maximum diameter) with positive microscopic margins are assigned to arm B: (adjuvant radiotherapy). Beginning between 6-42 days after surgical resection, patients undergo a total of 31 fractions of adjuvant radiotherapy.	Other: clinical observation; Patients undergo observation; Other Names: observation ; Procedure: therapeutic conventional surgery; Patients undergo surgery; Radiation: 3-dimensional conformal radiation therapy; Patients undergo radiotherapy; Other Names: 3D conformal radiation therapy 3D-CRT
Experimental: Arm C: Intermediate & High risk; adjuvant chemoradiotherapy High risk [metastatic, resected, incompletely resected, or unresected disease] patients with high-grade, grossly resected primary tumor, with metastases are assigned to receive arm C: (adjuvant chemoradiotherapy). Patients receive ifosfamide IV; doxorubicin hydrochloride IV; beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy.	Drug: doxorubicin hydrochloride; Given IV; Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF ; Other: clinical observation; Patients undergo observation; Other Names: observation ; Radiation: 3-dimensional conformal radiation therapy; Patients undergo radiotherapy; Other Names: 3D conformal radiation therapy 3D-CRT ; Drug: ifosfamide; Given IV; Other Names: Cyfos Holoxan IFF IFX IPP
Experimental: Arm D: Intermediate & High Risk; Neoadjuvant chemoradiotherapy High risk [metastatic, resected, incompletely resected, or unresected disease] patients with unresected, high-grade metastatic tumor are assigned to receive treatment as in arm D: (neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy with or without radiotherapy): Patients receive ifosfamide IV; doxorubicin hydrochloride IV. Beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy. Patients undergo surgical resection in week 13.	Drug: doxorubicin hydrochloride; Given IV; Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF ; Other: clinical observation; Patients undergo observation; Other Names: observation ; Procedure: therapeutic conventional surgery; Patients undergo surgery; Radiation: 3-dimensional conformal radiation therapy; Patients undergo radiotherapy; Other Names: 3D conformal radiation therapy 3D-CRT ; Drug: ifosfamide; Given IV; Other Names: Cyfos Holoxan IFF IFX IPP

Outcome Measures

Primary Outcome Measures

1. Probability for Event Free Survival. [5 years]

   Probability of no relapse, secondary malignancy or death after 5 years since enrollment.

Secondary Outcome Measures

1. Toxicity Rate [13 weeks]

   Percentage of Arm D patients experiencing grade 4+ adverse events.

2. Complete or Partial Response Rate [13 weeks]

   Tumor response by imaging. Complete Response (CR): Complete disappearance of the tumor. Partial Response (PR): At least 64% decrease in volume compared to the measurement obtained at study enrollment. Overall Response (OR)=CR+PR.

3. Percent Tumor Necrosis [13 weeks]

   Percent tumor necrosis by pathology review.

4. Event Free Survival Probability Disease Extent [5 years]

   Probability of no relapse, secondary malignancy or death after 5 years since enrollment.

5. Event Free Survival Probability Histologic Grade [5 years]

   Probability of no relapse, secondary malignancy or death after 5 years since enrollment

6. Overall Survival Probability Disease Extent [5 years]

   Probability of survival after 5 years since enrollment.

7. Overall Survival Probability Extent of Resection of the Primary Tumor [5 years]

   Probability of survival after 5 years since enrollment.

8. Incidence of Distant Metastasis [Up to 10 years]

   Percent of patients who had distant metastasis.

9. Genetic and Gene Expression Profiles [At diagnosis]

   The tumors from patients registered on D9902 will be analyzed for genetic and gene expression profiles. The study will prospectively evaluate each tumor and confirm newly defined sarcoma diagnostic criteria based on cancer signatures in NRSTS.

10. Degree of Agreement in Histologic Grade Determined by the Enrolling Institution Versus by Central Pathology Reviewers [At Diagnosis]

    Histologic grades were determined by the central pathology reviewers and institutional pathologists based on published standards. A higher grade is associated with a more severe disease.

11. Degree of Agreement in Histologic Grade Between Pediatric Oncology Group (POG) and Fédération Nationale Des Centres de Lutte Contre le Cancer (FNCLCC) Pathologic Grading Systems [At diagnosis]

    POG and FNCLCC grades were determined by pathologists based on published standards. A higher grade is associated with a more severe disease.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 29 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Newly diagnosed non-rhabdomyosarcoma soft tissue sarcoma (STS), confirmed by central pathology review via concurrent enrollment on protocol COG-D9902

• Metastatic or non metastatic disease

• Meets 1 of the following criteria:

• Intermediate (i.e., rarely metastasizing) or malignant STS, including any of the following:

• Adipocytic tumor, including liposarcoma of any of the following histology subtypes:

• Dedifferentiated

• Myxoid

• Round cell

• Pleomorphic type

• Mixed-type

• Not otherwise specified (NOS)

• Fibroblastic/myofibroblastic tumors, including any of the following:

• Solitary fibrous tumor

• Hemangiopericytoma

• Low-grade myofibroblastic sarcoma

• Myxoinflammatory fibroblastic sarcoma

• Adult fibrosarcoma*

• Myxofibrosarcoma

• Low-grade fibromyxoid sarcoma or hyalinizing spindle-cell tumor

• Sclerosing epithelioid fibrosarcoma

• So-called fibrohistiocytic tumors, including any of the following:

• Plexiform fibrohistiocytic tumor

• Giant cell tumor of soft tissues

• Pleomorphic malignant fibrous histiocytoma (MFH)/undifferentiated pleomorphic sarcoma

• Giant cell MFH/undifferentiated pleomorphic sarcoma with giant cells

• Inflammatory MFH/undifferentiated pleomorphic sarcoma with prominent inflammation

• Smooth muscle tumor (leiomyosarcoma)

• Pericytic [perivascular] tumor (malignant glomus tumor or glomangiosarcoma)

• Vascular tumor, including angiosarcoma

• Chondro-osseous tumors of any of the following types:

• Mesenchymal chondrosarcoma

• Extraskeletal osteosarcoma

• Tumors of uncertain differentiation, including any of the following:

• Angiomatoid fibrous histiocytoma

• Ossifying fibromyxoid tumor

• Myoepithelioma/parachordoma

• Synovial sarcoma

• Epithelioid sarcoma

• Alveolar soft-part sarcoma

• Clear cell sarcoma of soft tissue

• Extraskeletal myxoid chondrosarcoma ("chordoid type")

• Malignant mesenchymoma

• Neoplasms with perivascular epithelioid cell differentiation (PEComa)

• Clear cell myomelanocytic tumor

• Intimal sarcoma

• Malignant peripheral nerve sheath tumor

• Dermatofibrosarcoma protuberans meeting both of the following criteria:

• Non metastatic disease

• Tumor must be grossly resected prior to study enrollment

• Embryonal sarcoma of the liver

• Unclassified STS that is too undifferentiated to be placed in a specific pathologic category (undifferentiated STS or STS NOS)

• Gross resection of the primary tumor ≤ 42 days prior to enrollment required except if any of the following circumstances apply:

• Non metastatic high-grade tumor > 5 cm in maximal diameter and gross or microscopic residual tumor is anticipated after resection

• Tumor of either high- or- low-grade that cannot be grossly excised without unacceptable morbidity

• High-grade tumor with metastases

• Patients with metastatic low-grade tumor whose disease is amenable to gross resection at all sites must undergo gross resection of all sites prior to study entry

• Patients with a tumor recurrence after a gross total resection are not eligible

• Tumors arising in bone are not eligible

• Patients with epithelioid sarcoma, clear cell sarcoma, or clinical or radiologic evidence of regional lymph node enlargement must undergo sentinel lymph node biopsies or lymph node sampling to confirm the status of regional lymph nodes* NOTE: *Except in cases where the study radiologist reviews the imaging and indicates that a biopsy is not needed to confirm that the patient has lymph node involvement.

• If lymph node biopsies are positive for tumor (or the lymph nodes are classified as positive by the study radiologist), formal lymph node dissection must be done at the time of definitive surgery(prior to study entry for patients assigned to study regimen C)

• Patients with metastatic disease must undergo a biopsy to confirm the presence of metastatic tumor if all metastases are < 1 cm in maximal diameter (except in cases where the study radiologist reviews the imaging and indicated that a biopsy is not needed to confirm that the patient has metastatic disease)

• Lansky performance status (PS) 50-100% (for patients ≤ 16 years of age) OR Karnofsky PS 50-100% (for patients > 16 years of age)

• Life expectancy ≥ 3 months

• Absolute neutrophil count ≥ 1,000/mm³*

• Platelet count ≥ 100,000/mm³*

• Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min (≥ 40 mL/min for infants < 1 year of age)* or serum creatinine based on age and/or gender as follows:

• 0.4 mg/dL (1 month to < 6 months of age)

• 0.5 mg/dL (6 months to < 1 year of age)

• 0.6 mg/dL (1 year to < 2 years of age)

• 0.8 mg/dL (2 years to < 6 years of age)

• 1.0 mg/dL (6 years to < 10 years of age)

• 1.2 mg/dL (10 years to < 13 years of age)

• 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 years to < 16 years of age)

• 1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age)

• Patients with urinary tract obstruction by tumor must meet the renal function criteria listed above AND must have unimpeded urinary flow established via decompression of the obstructed portion of the urinary tract

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)*

• Shortening fraction ≥ 27% by echocardiogram* OR ejection fraction ≥ 50% by radionuclide angiogram*

• Not pregnant or nursing (patients undergoing radiotherapy and/or chemotherapy)

• No nursing for ≥ 1 month after completion of study treatment in study regimens C or D

• Fertile patients must use effective contraception during and for ≥ 1 month after completion of study treatment

• Negative pregnancy test

• No evidence of dyspnea at rest*

• No exercise intolerance*

• Resting pulse oximetry reading > 94% on room air (for patients with respiratory symptoms)*

• Prior treatment for cancer allowed provided the patient meet the prior therapy requirements

• No prior anthracycline (e.g., doxorubicin or daunorubicin) or ifosfamide chemotherapy for patients enrolled on arm C or arm D

• No prior radiotherapy to tumor-involved sites

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Phoenix Childrens Hospital	Phoenix	Arizona	United States	85016
3	University of Arizona Health Sciences Center	Tucson	Arizona	United States	85724
4	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
5	Children's Oncology Group	Arcadia	California	United States	91006-3776
6	Southern California Permanente Medical Group	Downey	California	United States	90242
7	City of Hope Medical Center	Duarte	California	United States	91010
8	Loma Linda University Medical Center	Loma Linda	California	United States	92354
9	Miller Children's Hospital	Long Beach	California	United States	90806
10	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
11	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
12	David Geffen School of Medicine at UCLA	Los Angeles	California	United States	90095
13	Children's Hospital Central California	Madera	California	United States	93636-8762
14	Children's Hospital and Research Center at Oakland	Oakland	California	United States	94609-1809
15	Kaiser Permanente-Oakland	Oakland	California	United States	94611
16	Childrens Hospital of Orange County	Orange	California	United States	92868-3874
17	Lucile Packard Children's Hospital Stanford University	Palo Alto	California	United States	94304
18	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
19	University of California San Francisco Medical Center-Parnassus	San Francisco	California	United States	94143
20	Children's Hospital Colorado	Aurora	Colorado	United States	80045
21	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado	United States	80218
22	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
23	Yale University	New Haven	Connecticut	United States	06520-8032
24	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
25	Children's National Medical Center	Washington	District of Columbia	United States	20010
26	Broward Health Medical Center	Fort Lauderdale	Florida	United States	33316
27	Lee Memorial Health System	Fort Myers	Florida	United States	33901
28	University of Florida	Gainesville	Florida	United States	32610
29	Memorial Healthcare System - Joe DiMaggio Children's Hospital	Hollywood	Florida	United States	33021
30	Nemours Children's Clinic - Jacksonville	Jacksonville	Florida	United States	32207-8426
31	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
32	Miami Children's Hospital	Miami	Florida	United States	33155
33	Baptist Hospital of Miami	Miami	Florida	United States	33176
34	Florida Hospital	Orlando	Florida	United States	32803
35	M D Anderson Cancer Center- Orlando	Orlando	Florida	United States	32806
36	Nemours Childrens Clinic - Orlando	Orlando	Florida	United States	32806
37	Nemours Children's Clinic - Pensacola	Pensacola	Florida	United States	32504
38	All Children's Hospital	Saint Petersburg	Florida	United States	33701
39	Saint Joseph Children's Hospital of Tampa	Tampa	Florida	United States	33607
40	Saint Mary's Hospital	West Palm Beach	Florida	United States	33407
41	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
42	Memorial Health University Medical Center	Savannah	Georgia	United States	31403
43	University of Hawaii	Honolulu	Hawaii	United States	96813
44	Tripler Army Medical Center	Honolulu	Hawaii	United States	96859
45	Saint Luke's Mountain States Tumor Institute	Boise	Idaho	United States	83712
46	University of Illinois	Chicago	Illinois	United States	60612
47	Childrens Memorial Hospital	Chicago	Illinois	United States	60614
48	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637-1470
49	Loyola University Medical Center	Maywood	Illinois	United States	60153
50	Advocate Hope Children's Hospital	Oak Lawn	Illinois	United States	60453
51	Advocate Lutheran General Hospital	Park Ridge	Illinois	United States	60068
52	Saint Jude Midwest Affiliate	Peoria	Illinois	United States	61602
53	Southern Illinois University	Springfield	Illinois	United States	62702
54	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
55	Saint Vincent Hospital and Health Services	Indianapolis	Indiana	United States	46260
56	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
57	University of Kentucky	Lexington	Kentucky	United States	40536
58	Kosair Children's Hospital	Louisville	Kentucky	United States	40202
59	Tulane University Health Sciences Center	New Orleans	Louisiana	United States	70112
60	Eastern Maine Medical Center	Bangor	Maine	United States	04401
61	Maine Children's Cancer Program	Scarborough	Maine	United States	04074
62	University of Maryland Greenebaum Cancer Center	Baltimore	Maryland	United States	21201-1595
63	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
64	Johns Hopkins University	Baltimore	Maryland	United States	21287-8936
65	Walter Reed National Military Medical Center	Bethesda	Maryland	United States	20889-5600
66	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
67	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
68	University of Massachusetts Medical School	Worcester	Massachusetts	United States	01655
69	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
70	Wayne State University	Detroit	Michigan	United States	48202
71	Saint John Hospital and Medical Center	Detroit	Michigan	United States	48236
72	Hurley Medical Center	Flint	Michigan	United States	48502
73	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
74	Kalamazoo Center for Medical Studies	Kalamazoo	Michigan	United States	49008
75	Michigan State University - Breslin Cancer Center	Lansing	Michigan	United States	48910
76	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
77	University of Minnesota Medical Center-Fairview	Minneapolis	Minnesota	United States	55455
78	Mayo Clinic	Rochester	Minnesota	United States	55905
79	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
80	University of Missouri-Columbia	Columbia	Missouri	United States	65212
81	The Childrens Mercy Hospital	Kansas City	Missouri	United States	64108
82	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
83	Saint John's Mercy Medical Center	Saint Louis	Missouri	United States	63141
84	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
85	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada	United States	89106
86	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
87	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
88	Saint Peter's University Hospital	New Brunswick	New Jersey	United States	08901
89	UMDNJ - Robert Wood Johnson University Hospital	New Brunswick	New Jersey	United States	08903
90	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
91	Saint Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
92	Overlook Hospital	Summit	New Jersey	United States	07902
93	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87106
94	Albany Medical Center	Albany	New York	United States	12208
95	Montefiore Medical Center	Bronx	New York	United States	10467-2490
96	Brooklyn Hospital Center	Brooklyn	New York	United States	11201
97	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
98	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York	United States	11040
99	New York University Langone Medical Center	New York	New York	United States	10016
100	Mount Sinai Medical Center	New York	New York	United States	10029
101	Columbia University Medical Center	New York	New York	United States	10032
102	University of Rochester	Rochester	New York	United States	14642
103	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
104	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
105	New York Medical College	Valhalla	New York	United States	10595
106	Mission Hospitals Inc	Asheville	North Carolina	United States	28801
107	University of North Carolina	Chapel Hill	North Carolina	United States	27599
108	Carolinas Medical Center	Charlotte	North Carolina	United States	28203
109	Presbyterian Hospital	Charlotte	North Carolina	United States	28204
110	Duke University Medical Center	Durham	North Carolina	United States	27710
111	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
112	Sanford Medical Center-Fargo	Fargo	North Dakota	United States	58122
113	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
114	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
115	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
116	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
117	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
118	The Children's Medical Center of Dayton	Dayton	Ohio	United States	45404
119	The Toledo Hospital/Toledo Children's Hospital	Toledo	Ohio	United States	43606
120	Mercy Children's Hospital	Toledo	Ohio	United States	43608
121	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
122	Legacy Emanuel Children's Hospital	Portland	Oregon	United States	97227
123	Legacy Emanuel Hospital and Health Center	Portland	Oregon	United States	97227
124	Oregon Health and Science University	Portland	Oregon	United States	97239
125	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania	United States	18017
126	Geisinger Medical Center	Danville	Pennsylvania	United States	17822-2001
127	Penn State Hershey Children's Hospital	Hershey	Pennsylvania	United States	17033
128	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
129	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
130	Rhode Island Hospital	Providence	Rhode Island	United States	02903
131	Palmetto Health Richland	Columbia	South Carolina	United States	29203
132	Greenville Cancer Treatment Center	Greenville	South Carolina	United States	29605
133	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
134	T C Thompson Children's Hospital	Chattanooga	Tennessee	United States	37403
135	East Tennessee Childrens Hospital	Knoxville	Tennessee	United States	37916
136	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
137	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
138	Texas Tech University Health Science Center-Amarillo	Amarillo	Texas	United States	79106
139	Dell Children's Medical Center of Central Texas	Austin	Texas	United States	78723
140	Driscoll Children's Hospital	Corpus Christi	Texas	United States	78411
141	Medical City Dallas Hospital	Dallas	Texas	United States	75230
142	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
143	Brooke Army Medical Center	Fort Sam Houston	Texas	United States	78234
144	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
145	Baylor College of Medicine	Houston	Texas	United States	77030
146	M D Anderson Cancer Center	Houston	Texas	United States	77030
147	Covenant Children's Hospital	Lubbock	Texas	United States	79410
148	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229-3900
149	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229
150	Scott and White Memorial Hospital	Temple	Texas	United States	76508
151	Primary Children's Medical Center	Salt Lake City	Utah	United States	84113
152	University of Vermont	Burlington	Vermont	United States	05401
153	University of Virginia	Charlottesville	Virginia	United States	22908
154	Inova Fairfax Hospital	Falls Church	Virginia	United States	22042
155	Childrens Hospital-King's Daughters	Norfolk	Virginia	United States	23507
156	Virginia Commonwealth University	Richmond	Virginia	United States	23298
157	Seattle Children's Hospital	Seattle	Washington	United States	98105
158	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington	United States	99204
159	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington	United States	98405
160	Madigan Army Medical Center	Tacoma	Washington	United States	98431
161	West Virginia University Charleston	Charleston	West Virginia	United States	25304
162	Saint Vincent Hospital	Green Bay	Wisconsin	United States	54301
163	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
164	Marshfield Clinic	Marshfield	Wisconsin	United States	54449
165	Midwest Children's Cancer Center	Milwaukee	Wisconsin	United States	53226
166	Sydney Children's Hospital	Randwick	New South Wales	Australia	2031
167	The Children's Hospital at Westmead	Sydney	New South Wales	Australia	2145
168	Royal Brisbane and Women's Hospital	Herston	Queensland	Australia	4029
169	Women's and Children's Hospital-Adelaide	North Adelaide	South Australia	Australia	5006
170	Royal Children's Hospital	Parkville	Victoria	Australia	3052
171	Princess Margaret Hospital for Children	Perth	Western Australia	Australia	6008
172	Alberta Children's Hospital	Calgary	Alberta	Canada	T3B 6A8
173	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2B7
174	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
175	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
176	Janeway Child Health Centre	Saint John's	Newfoundland and Labrador	Canada	A1B 3V6
177	IWK Health Centre	Halifax	Nova Scotia	Canada	B3J 3G9
178	Chedoke-McMaster Hospitals	Hamilton	Ontario	Canada	L8S 4L8
179	Cancer Centre of Southeastern Ontario at Kingston General Hospital	Kingston	Ontario	Canada	K7L 5P9
180	Children's Hospital of Eastern Ontario	Ottawa	Ontario	Canada	K1H 8L1
181	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
182	The Montreal Children's Hospital of the MUHC	Montreal	Quebec	Canada	H3H 1P3
183	Hospital Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5
184	Centre Hospitalier Universitaire de Quebec	Ste-Foy	Quebec	Canada	G1V 4G2
185	Saskatoon Cancer Centre	Saskatoon	Saskatchewan	Canada	S7N 4H4
186	Starship Children's Hospital	Grafton	Auckland	New Zealand	1145
187	San Jorge Children's Hospital	Santurce		Puerto Rico	00912

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Sheri Spunt, MD, Children's Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT00346164
• Other Study ID Numbers: ARST0332; NCI-2009-00426; COG-ARST0332; CDR0000483702; U10CA098543
• First Posted: Jun 29, 2006
• Last Update Posted: Apr 28, 2022
• Last Verified: Jun 1, 2021

• Additional relevant MeSH terms: Sarcoma; Osteosarcoma; Leiomyosarcoma; Liposarcoma; Chondrosarcoma; Sarcoma, Synovial; Hemangiosarcoma; Fibrosarcoma; Sarcoma, Alveolar Soft Part; Histiocytoma; Hemangiopericytoma; Solitary Fibrous Tumors; Histiocytoma, Benign Fibrous; Histiocytoma, Malignant Fibrous; Mesenchymoma; Neurofibrosarcoma; Dermatofibrosarcoma; Doxorubicin; Liposomal doxorubicin; Ifosfamide

Study Results

Participant Flow

Arm/Group Title	Arm A: No Adjuvant Treatment	Arm B: Low Risk; Adjuvant Radiotherapy	Arm C: Intermediate & High Risk; Adjuvant Chemoradiotherapy	Arm D: Intermediate & High Risk; Neoadjuvant Chemoradiotherapy
Arm/Group Description	Patients with low-grade tumor with either negative or positive microscopic margins or high-grade tumor ≤ 5 cm (in maximum diameter) with negative microscopic margins are assigned to arm A: (observation only). clinical observation: Patients undergo observation therapeutic conventional surgery: Patients undergo surgery	Patients with high-grade tumor ≤ 5 cm (in maximum diameter) with positive microscopic margins are assigned to arm B: (adjuvant radiotherapy). Beginning between 6-42 days after surgical resection, patients undergo a total of 31 fractions of adjuvant radiotherapy. clinical observation: Patients undergo observation therapeutic conventional surgery: Patients undergo surgery 3-dimensional conformal radiation therapy: Patients undergo radiotherapy	High risk [metastatic, resected, incompletely resected, or unresected disease] patients with high-grade, grossly resected primary tumor, with metastases are assigned to receive arm C: (adjuvant chemoradiotherapy). Patients receive ifosfamide IV; doxorubicin hydrochloride IV; beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy. doxorubicin hydrochloride: Given IV clinical observation: Patients undergo observation 3-dimensional conformal radiation therapy: Patients undergo radiotherapy ifosfamide: Given IV	High risk [metastatic, resected, incompletely resected, or unresected disease] patients with unresected, high-grade metastatic tumor are assigned to receive treatment as in arm D: (neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy with or without radiotherapy): Patients receive ifosfamide IV; doxorubicin hydrochloride IV. Beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy. Patients undergo surgical resection in week 13. doxorubicin hydrochloride: Given IV clinical observation: Patients undergo observation therapeutic conventional surgery: Patients undergo surgery 3-dimensional conformal radiation therapy: Patients undergo radiotherapy ifosfamide: Given IV
Period Title: Overall Study
STARTED	222	21	122	223
COMPLETED	205	14	96	117
NOT COMPLETED	17	7	26	106

Baseline Characteristics

Arm/Group Title	Arm A: No Adjuvant Treatment	Arm B: Low Risk; Adjuvant Radiotherapy	Arm C: Intermediate & High Risk; Adjuvant Chemoradiotherapy	Arm D: Intermediate & High Risk; Neoadjuvant Chemoradiotherapy	Total
Arm/Group Description	Patients with low-grade tumor with either negative or positive microscopic margins or high-grade tumor ≤ 5 cm (in maximum diameter) with negative microscopic margins are assigned to arm A: (observation only). clinical observation: Patients undergo observation therapeutic conventional surgery: Patients undergo surgery	Patients with high-grade tumor ≤ 5 cm (in maximum diameter) with positive microscopic margins are assigned to arm B: (adjuvant radiotherapy). Beginning between 6-42 days after surgical resection, patients undergo a total of 31 fractions of adjuvant radiotherapy. clinical observation: Patients undergo observation therapeutic conventional surgery: Patients undergo surgery 3-dimensional conformal radiation therapy: Patients undergo radiotherapy	High risk [metastatic, resected, incompletely resected, or unresected disease] patients with high-grade, grossly resected primary tumor, with metastases are assigned to receive arm C: (adjuvant chemoradiotherapy). Patients receive ifosfamide IV; doxorubicin hydrochloride IV; beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy. doxorubicin hydrochloride: Given IV clinical observation: Patients undergo observation 3-dimensional conformal radiation therapy: Patients undergo radiotherapy ifosfamide: Given IV	High risk [metastatic, resected, incompletely resected, or unresected disease] patients with unresected, high-grade metastatic tumor are assigned to receive treatment as in arm D: (neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy with or without radiotherapy): Patients receive ifosfamide IV; doxorubicin hydrochloride IV. Beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy. Patients undergo surgical resection in week 13. doxorubicin hydrochloride: Given IV clinical observation: Patients undergo observation therapeutic conventional surgery: Patients undergo surgery 3-dimensional conformal radiation therapy: Patients undergo radiotherapy ifosfamide: Given IV	Total of all reporting groups
Overall Participants	222	21	122	223	588
Age (Months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Months]	138.87 (60.88)	142.58 (59.46)	155.14 (69.20)	171.31 (68.90)	154.68 (67.10)
Sex: Female, Male (Count of Participants)
Female	124 55.9%	9 42.9%	60 49.2%	120 53.8%	313 53.2%
Male	98 44.1%	12 57.1%	62 50.8%	103 46.2%	275 46.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	29 13.1%	1 4.8%	22 18%	38 17%	90 15.3%
Not Hispanic or Latino	185 83.3%	19 90.5%	95 77.9%	178 79.8%	477 81.1%
Unknown or Not Reported	8 3.6%	1 4.8%	5 4.1%	7 3.1%	21 3.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.5%	0 0%	2 1.6%	3 1.3%	6 1%
Asian	7 3.2%	1 4.8%	2 1.6%	8 3.6%	18 3.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	1 0.4%	1 0.2%
Black or African American	23 10.4%	2 9.5%	21 17.2%	43 19.3%	89 15.1%
White	169 76.1%	16 76.2%	90 73.8%	137 61.4%	412 70.1%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	22 9.9%	2 9.5%	7 5.7%	31 13.9%	62 10.5%

Outcome Measures

1. Primary Outcome

Title	Probability for Event Free Survival.
Description	Probability of no relapse, secondary malignancy or death after 5 years since enrollment.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

Ineligible patients are excluded as well as patients who were treated on the incorrect arm.

Arm/Group Title	Arm A: No Adjuvant Treatment	Arm B: Low Risk; Adjuvant Radiotherapy	Arm C: Intermediate & High Risk; Adjuvant Chemoradiotherapy	Arm D: Intermediate & High Risk; Neoadjuvant Chemoradiotherapy
Arm/Group Description	Patients with low-grade tumor with either negative or positive microscopic margins or high-grade tumor ≤ 5 cm (in maximum diameter) with negative microscopic margins are assigned to arm A: (observation only). clinical observation: Patients undergo observation therapeutic conventional surgery: Patients undergo surgery	Patients with high-grade tumor ≤ 5 cm (in maximum diameter) with positive microscopic margins are assigned to arm B: (adjuvant radiotherapy). Beginning between 6-42 days after surgical resection, patients undergo a total of 31 fractions of adjuvant radiotherapy. clinical observation: Patients undergo observation therapeutic conventional surgery: Patients undergo surgery 3-dimensional conformal radiation therapy: Patients undergo radiotherapy	High risk [metastatic, resected, incompletely resected, or unresected disease] patients with high-grade, grossly resected primary tumor, with metastases are assigned to receive arm C: (adjuvant chemoradiotherapy). Patients receive ifosfamide IV; doxorubicin hydrochloride IV; beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy. doxorubicin hydrochloride: Given IV clinical observation: Patients undergo observation 3-dimensional conformal radiation therapy: Patients undergo radiotherapy ifosfamide: Given IV	High risk [metastatic, resected, incompletely resected, or unresected disease] patients with unresected, high-grade metastatic tumor are assigned to receive treatment as in arm D: (neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy with or without radiotherapy): Patients receive ifosfamide IV; doxorubicin hydrochloride IV. Beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy. Patients undergo surgical resection in week 13. doxorubicin hydrochloride: Given IV clinical observation: Patients undergo observation therapeutic conventional surgery: Patients undergo surgery 3-dimensional conformal radiation therapy: Patients undergo radiotherapy ifosfamide: Given IV
Measure Participants	205	17	110	196
Number (95% Confidence Interval) [Probability of EFS at 5 years]	0.8984	0.7647	0.6079	0.4873

2. Secondary Outcome

Title	Toxicity Rate
Description	Percentage of Arm D patients experiencing grade 4+ adverse events.
Time Frame	13 weeks

Outcome Measure Data

Analysis Population Description

Excluding ineligible patients and patients not treated based on the protocol.

Arm/Group Title	Arm D
Arm/Group Description	Intermediate & High Risk; Neoadjuvant chemoradiotherapy
Measure Participants	196
Number (95% Confidence Interval) [percentage of participants]	3.06 1.4%

3. Secondary Outcome

Title	Complete or Partial Response Rate
Description	Tumor response by imaging. Complete Response (CR): Complete disappearance of the tumor. Partial Response (PR): At least 64% decrease in volume compared to the measurement obtained at study enrollment. Overall Response (OR)=CR+PR.
Time Frame	13 weeks

Outcome Measure Data

Analysis Population Description

Only Arm D patients were evaluated for imaging response at week 13 after surgery. Ineligible and inevaluable Arm D patients were excluded.

Arm/Group Title	Arm D
Arm/Group Description	Intermediate & High Risk; Neoadjuvant chemoradiotherapy
Measure Participants	142
Number (95% Confidence Interval) [percentage of patients]	33.1

4. Secondary Outcome

Title	Percent Tumor Necrosis
Description	Percent tumor necrosis by pathology review.
Time Frame	13 weeks

Outcome Measure Data

Analysis Population Description

Only Arm D patients were evaluated at week 13 for percent tumor necrosis. Ineligible and inevaluable Arm D patients were excluded.

Arm/Group Title	Arm D
Arm/Group Description	Intermediate & High Risk; Neoadjuvant chemoradiotherapy
Measure Participants	129
Mean (Standard Deviation) [percentage of tumor necrosis]	59.4 (38.5)

5. Secondary Outcome

Title	Event Free Survival Probability Disease Extent
Description	Probability of no relapse, secondary malignancy or death after 5 years since enrollment.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

94 participants were excluded because of ineligibility, incorrect treatment, or absence of evaluation for tumor invasiveness and histologic grade.

Arm/Group Title	Non-metastatic	Metastatic
Arm/Group Description
Measure Participants	425	69
Number (95% Confidence Interval) [Probability]	0.7758	0.1960

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: No Adjuvant Treatment, Arm B: Low Risk; Adjuvant Radiotherapy
	Comments	The Cox proportional hazards model was used to evaluate prognostic impact of disease extent (non-metastatic; metastatic) after accounting for the effects of site of the primary tumor (body wall; extremity; head/neck; visceral), tumor size (<=5cm; >5cm), tumor depth (deep; superficial), tumor invasiveness (invasive; non-invasive), extent of resection of the primary tumor (less than total resection; margin -; margin +), and histologic (POG) grade.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Cox
	Comments

6. Secondary Outcome

Title	Event Free Survival Probability Histologic Grade
Description	Probability of no relapse, secondary malignancy or death after 5 years since enrollment
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

94 participants were excluded because of ineligibility, incorrect treatment, or absence of evaluation for tumor invasiveness and histologic grade.

Arm/Group Title	Histologic Grade 1	Histologic Grade 2	Histologic Grade 3
Arm/Group Description
Measure Participants	60	79	355
Number (95% Confidence Interval) [Probability]	0.9636	0.8505	0.6136

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: No Adjuvant Treatment, Arm B: Low Risk; Adjuvant Radiotherapy, Arm C: Intermediate & High Risk; Adjuvant Chemoradiotherapy
	Comments	The Cox proportional hazards model was used to evaluate prognostic impact of histologic (POG) grade after accounting for the effects of disease extent (non-metastatic; metastatic), site of the primary tumor (body wall; extremity; head/neck; visceral), tumor size (<=5cm; >5cm), tumor depth (deep; superficial), tumor invasiveness (invasive; non-invasive), and extent of resection of the primary tumor (less than total resection; margin -; margin +) .
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0049
	Comments
	Method	Regression, Cox
	Comments

7. Secondary Outcome

Title	Overall Survival Probability Disease Extent
Description	Probability of survival after 5 years since enrollment.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

94 participants were excluded because of ineligibility, incorrect treatment, or absence of evaluation for tumor invasiveness and histologic grade.

Arm/Group Title	Non-metastatic	Metastatic
Arm/Group Description
Measure Participants	425	69
Number (95% Confidence Interval) [Probability]	0.8752	0.3153

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: No Adjuvant Treatment, Arm B: Low Risk; Adjuvant Radiotherapy
	Comments	The Cox proportional hazards model was used to evaluate prognostic impact of disease extent (non-metastatic; metastatic) after accounting for the effects of site of the primary tumor (body wall; extremity; head/neck; visceral), tumor size (<=5cm; >5cm), tumor depth (deep; superficial), tumor invasiveness (invasive; non-invasive), extent of resection of the primary tumor (less than total resection; margin -; margin +), and histologic (POG) grade.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Cox
	Comments

8. Secondary Outcome

Title	Overall Survival Probability Extent of Resection of the Primary Tumor
Description	Probability of survival after 5 years since enrollment.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

94 participants were excluded because of ineligibility, incorrect treatment, or absence of evaluation for tumor invasiveness and histologic grade.

Arm/Group Title	Less Than Total Resection	Negative Margins	Positive Margins
Arm/Group Description
Measure Participants	163	247	84
Number (95% Confidence Interval) [Probability]	0.5975	0.9353	0.7764

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: No Adjuvant Treatment, Arm B: Low Risk; Adjuvant Radiotherapy, Arm C: Intermediate & High Risk; Adjuvant Chemoradiotherapy
	Comments	The Cox proportional hazards model was used to evaluate prognostic impact of the resection extent of the primary tumor (less than total resection; margin -; margin +) after accounting for the effects of site of the primary tumor (body wall; extremity; head/neck; visceral), disease extent (non-metastatic; metastatic), tumor size (<=5cm; >5cm), tumor depth (deep; superficial), tumor invasiveness (invasive; non-invasive), and histologic (POG) grade.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0096
	Comments
	Method	Regression, Cox
	Comments

9. Secondary Outcome

Title	Incidence of Distant Metastasis
Description	Percent of patients who had distant metastasis.
Time Frame	Up to 10 years

Outcome Measure Data

Analysis Population Description

94 participants were excluded because of ineligibility, incorrect treatment, or absence of evaluation for tumor invasiveness and histologic grade.

Arm/Group Title	Non-metastatic	Metastatic
Arm/Group Description
Measure Participants	425	69
Number (95% Confidence Interval) [Percentage of participants]	10.59 4.8%	60.87 289.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: No Adjuvant Treatment, Arm B: Low Risk; Adjuvant Radiotherapy
	Comments	The logistic regression model was used to evaluate prognostic impact of disease extent (non-metastatic; metastatic) after accounting for the effects of site of the primary tumor (body wall; extremity; head/neck; visceral), tumor size (<=5cm; >5cm), tumor depth (deep; superficial), tumor invasiveness (invasive; non-invasive), extent of resection of the primary tumor (less than total resection; margin -; margin +), and histologic (POG) grade.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Logistic
	Comments	Firth logistic regression is used to overcome the issue of quasi-complete separation of data points.

10. Secondary Outcome

Title	Incidence of Distant Metastasis
Description	Percent of patients who had distant metastasis.
Time Frame	Up to 10 years

Outcome Measure Data

Analysis Population Description

94 participants were excluded because of ineligibility, incorrect treatment, or absence of evaluation for tumor invasiveness and histologic grade.

Arm/Group Title	Histologic Grade 1	Histologic Grade 2	Histologic Grade 3
Arm/Group Description
Measure Participants	60	79	355
Number (95% Confidence Interval) [Percentage of participants]	0.00 0%	5.06 24.1%	23.38 19.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: No Adjuvant Treatment, Arm B: Low Risk; Adjuvant Radiotherapy, Arm C: Intermediate & High Risk; Adjuvant Chemoradiotherapy
	Comments	The logistic regression model was used to evaluate prognostic impact of histologic (POG) grade after accounting for the effects of disease extent (non-metastatic; metastatic), site of the primary tumor (body wall; extremity; head/neck; visceral), tumor size (<=5cm; >5cm), tumor depth (deep; superficial), tumor invasiveness (invasive; non-invasive), and extent of resection of the primary tumor (less than total resection; margin -; margin +) .
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0228
	Comments
	Method	Regression, Logistic
	Comments	Firth logistic regression is used to overcome the issue of quasi-complete separation of data points.

11. Secondary Outcome

Title	Genetic and Gene Expression Profiles
Description	The tumors from patients registered on D9902 will be analyzed for genetic and gene expression profiles. The study will prospectively evaluate each tumor and confirm newly defined sarcoma diagnostic criteria based on cancer signatures in NRSTS.
Time Frame	At diagnosis

Outcome Measure Data

Analysis Population Description

None of the tumors were analyzed for genetic and gene expression profiles. The analysis will not be completed. The time frame "At diagnosis" is the time frame for the gene expression profiles.

Arm/Group Title	All Patients
Arm/Group Description	All patients
Measure Participants	0

12. Secondary Outcome

Title	Degree of Agreement in Histologic Grade Determined by the Enrolling Institution Versus by Central Pathology Reviewers
Description	Histologic grades were determined by the central pathology reviewers and institutional pathologists based on published standards. A higher grade is associated with a more severe disease.
Time Frame	At Diagnosis

Outcome Measure Data

Analysis Population Description

Ineligible patients, as well as patients without histologic grade determined by enrolling institution or central pathology reviewers were excluded. The OM evaluates the degree of agreement of two pathology grading reviews at diagnosis. The time frame "At diagnosis" reflects the OM.

Arm/Group Title	Histologic Grade 1 by Enrolling Institution	Histologic Grade 2 by Enrolling Institution	Histologic Grade 3 by Enrolling Institution
Arm/Group Description
Measure Participants	45	71	278
Histologic grade 1 by central pathology reviewers	38 17.1%	5 23.8%	1 0.8%
Histologic grade 2 by central pathology reviewers	4 1.8%	56 266.7%	9 7.4%
Histologic grade 3 by central pathology reviewers	3 1.4%	10 47.6%	268 219.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: No Adjuvant Treatment, Arm B: Low Risk; Adjuvant Radiotherapy, Arm C: Intermediate & High Risk; Adjuvant Chemoradiotherapy
	Comments	Kappa statistic and its 95% confidence interval are used to assess agreement beyond random.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kappa statistic
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.76 to 0.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Degree of Agreement in Histologic Grade Between Pediatric Oncology Group (POG) and Fédération Nationale Des Centres de Lutte Contre le Cancer (FNCLCC) Pathologic Grading Systems
Description	POG and FNCLCC grades were determined by pathologists based on published standards. A higher grade is associated with a more severe disease.
Time Frame	At diagnosis

Outcome Measure Data

Analysis Population Description

Ineligible patients, as well as patients without histologic grade determined by POG or FNCLCC were excluded. The OM evaluates the degree of agreement of two pathology grading systems applied at diagnosis. The time frame "At diagnosis" reflects the OM.

Arm/Group Title	Histologic Grade 1 by FNCLCC	Histologic Grade 2 by FNCLCC	Histologic Grade 3 by FNCLCC
Arm/Group Description
Measure Participants	79	222	241
Histologic grade 1 by POG	46 20.7%	8 38.1%	1 0.8%
Histologic grade 2 by POG	24 10.8%	69 328.6%	0 0%
Histologic grade 3 by POG	9 4.1%	145 690.5%	240 196.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: No Adjuvant Treatment, Arm B: Low Risk; Adjuvant Radiotherapy, Arm C: Intermediate & High Risk; Adjuvant Chemoradiotherapy
	Comments	Kappa statistic and its 95% confidence interval are used to assess agreement beyond random.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kappa statistic
	Estimated Value	0.42
	Confidence Interval	(2-Sided) 95%; 0.36 to 0.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Adverse Event Reporting Description	Ineligible patients and patients who were not treated based on the protocol were excluded from AE reporting (both serious and other).
Arm/Group Title	Arm A: No Adjuvant Treatment		Arm B: Low Risk; Adjuvant Radiotherapy		Arm C: Intermediate & High Risk; Adjuvant Chemoradiotherapy		Arm D: Intermediate & High Risk; Neoadjuvant Chemoradiotherapy
Arm/Group Description	Patients with low-grade tumor with either negative or positive microscopic margins or high-grade tumor ≤ 5 cm (in maximum diameter) with negative microscopic margins are assigned to arm A: (observation only). clinical observation: Patients undergo observation therapeutic conventional surgery: Patients undergo surgery		Patients with high-grade tumor ≤ 5 cm (in maximum diameter) with positive microscopic margins are assigned to arm B: (adjuvant radiotherapy). Beginning between 6-42 days after surgical resection, patients undergo a total of 31 fractions of adjuvant radiotherapy. clinical observation: Patients undergo observation therapeutic conventional surgery: Patients undergo surgery 3-dimensional conformal radiation therapy: Patients undergo radiotherapy		High risk [metastatic, resected, incompletely resected, or unresected disease] patients with high-grade, grossly resected primary tumor, with metastases are assigned to receive arm C: (adjuvant chemoradiotherapy). Patients receive ifosfamide IV; doxorubicin hydrochloride IV; beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy. doxorubicin hydrochloride: Given IV clinical observation: Patients undergo observation 3-dimensional conformal radiation therapy: Patients undergo radiotherapy ifosfamide: Given IV		High risk [metastatic, resected, incompletely resected, or unresected disease] patients with unresected, high-grade metastatic tumor are assigned to receive treatment as in arm D: (neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy with or without radiotherapy): Patients receive ifosfamide IV; doxorubicin hydrochloride IV. Beginning in week 4, patients also undergo a total of 31 fractions of radiotherapy. Patients undergo surgical resection in week 13. doxorubicin hydrochloride: Given IV clinical observation: Patients undergo observation therapeutic conventional surgery: Patients undergo surgery 3-dimensional conformal radiation therapy: Patients undergo radiotherapy ifosfamide: Given IV
All Cause Mortality
	Arm A: No Adjuvant Treatment		Arm B: Low Risk; Adjuvant Radiotherapy		Arm C: Intermediate & High Risk; Adjuvant Chemoradiotherapy		Arm D: Intermediate & High Risk; Neoadjuvant Chemoradiotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm A: No Adjuvant Treatment		Arm B: Low Risk; Adjuvant Radiotherapy		Arm C: Intermediate & High Risk; Adjuvant Chemoradiotherapy		Arm D: Intermediate & High Risk; Neoadjuvant Chemoradiotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/205 (0%)		1/17 (5.9%)		1/110 (0.9%)		3/196 (1.5%)
Gastrointestinal disorders
Upper gastrointestinal hemorrhage	0/205 (0%)	0	0/17 (0%)	0	1/110 (0.9%)	1	0/196 (0%)	0
General disorders
Death NOS	0/205 (0%)	0	0/17 (0%)	0	0/110 (0%)	0	1/196 (0.5%)	1
Infections and infestations
Infections and infestations - Other, specify	0/205 (0%)	0	0/17 (0%)	0	0/110 (0%)	0	1/196 (0.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	0/205 (0%)	0	0/17 (0%)	0	0/110 (0%)	0	1/196 (0.5%)	1
Treatment related secondary malignancy	0/205 (0%)	0	1/17 (5.9%)	1	0/110 (0%)	0	0/196 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm A: No Adjuvant Treatment		Arm B: Low Risk; Adjuvant Radiotherapy		Arm C: Intermediate & High Risk; Adjuvant Chemoradiotherapy		Arm D: Intermediate & High Risk; Neoadjuvant Chemoradiotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/205 (0%)		0/17 (0%)		2/110 (1.8%)		7/196 (3.6%)
Cardiac disorders
Cardiac disorders - Other, specify	0/205 (0%)	0	0/17 (0%)	0	0/110 (0%)	0	1/196 (0.5%)	1
Pericardial effusion	0/205 (0%)	0	0/17 (0%)	0	0/110 (0%)	0	1/196 (0.5%)	1
Gastrointestinal disorders
Diarrhea	0/205 (0%)	0	0/17 (0%)	0	0/110 (0%)	0	1/196 (0.5%)	1
General disorders
General disorders and administration site conditions - Other, specify	0/205 (0%)	0	0/17 (0%)	0	0/110 (0%)	0	1/196 (0.5%)	1
Infections and infestations
Hepatic infection	0/205 (0%)	0	0/17 (0%)	0	0/110 (0%)	0	1/196 (0.5%)	1
Injury, poisoning and procedural complications
Dermatitis radiation	0/205 (0%)	0	0/17 (0%)	0	0/110 (0%)	0	1/196 (0.5%)	1
Wound dehiscence	0/205 (0%)	0	0/17 (0%)	0	0/110 (0%)	0	1/196 (0.5%)	1
Metabolism and nutrition disorders
Hypokalemia	0/205 (0%)	0	0/17 (0%)	0	0/110 (0%)	0	1/196 (0.5%)	1
Nervous system disorders
Encephalopathy	0/205 (0%)	0	0/17 (0%)	0	1/110 (0.9%)	1	1/196 (0.5%)	1
Seizure	0/205 (0%)	0	0/17 (0%)	0	0/110 (0%)	0	1/196 (0.5%)	1
Skin and subcutaneous tissue disorders
Skin ulceration	0/205 (0%)	0	0/17 (0%)	0	0/110 (0%)	0	1/196 (0.5%)	1
Vascular disorders
Hypotension	0/205 (0%)	0	0/17 (0%)	0	1/110 (0.9%)	1	1/196 (0.5%)	1
Thromboembolic event	0/205 (0%)	0	0/17 (0%)	0	0/110 (0%)	0	1/196 (0.5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Must obtain prior Sponsor approval.