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

Sponsor:	Children's Oncology Group
Collaborator:	National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00346164

Purpose

RATIONALE: 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. It is not yet known which regimen is more effective in treating soft tissue sarcoma.

PURPOSE: This phase III trial is studying observation to see how well it works compared with radiation therapy, combination chemotherapy, and/or surgery in treating patients with soft tissue sarcoma.

Condition	Intervention	Phase
Childhood Malignant Fibrous Histiocytoma of Bone Sarcoma	Drug: doxorubicin hydrochloride Drug: ifosfamide Procedure: observation Procedure: therapeutic conventional surgery Radiation: radiation therapy	Phase III

Study Type:	Interventional
Study Design:	Treatment, Open Label
Official Title:	Risk-Based Treatment for Non-Rhabdomyosarcoma Soft Tissue Sarcomas (NRSTS) in Patients Under 30 Years of Age

Resource links provided by NLM:

MedlinePlus related topics: Cancer Soft Tissue Sarcoma Surgery

Drug Information available for: Doxorubicin Doxorubicin hydrochloride Myocet Ifosfamide

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Long-term survival at 5 years [ Designated as safety issue: No ]
Event-free and overall survival at 5 years [ Designated as safety issue: No ]

Secondary Outcome Measures:

Local tumor control at 5 years [ Designated as safety issue: No ]
Feasibility of neoadjuvant chemoradiotherapy [ Designated as safety issue: No ]
Imaging and pathologic response after neoadjuvant chemoradiotherapy, and their relationship to survival and local outcomes [ Designated as safety issue: No ]

Estimated Enrollment:	400
Study Start Date:	February 2007
Estimated Primary Completion Date:	March 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Group 1: Experimental (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 receive regimen A (observation only). Patients with high-grade tumor ≤ 5 cm (in maximum diameter) with positive microscopic margins are assigned to receive regimen B (beginning between 6-42 days after surgical resection, patients undergo a total of 31 fractions of adjuvant radiotherapy).	Procedure: observation Patients undergo observation Radiation: radiation therapy Patients undergo radiotherapy
Group 2: Experimental (Intermediate risk [nonmetastatic, resected high-grade tumor > 5 cm or unresected disease]): Patients with grossly resected, high-grade tumor > 5 cm (in maximum diameter) are assigned to receive regimen C (adjuvant chemoradiotherapy) for approximately 19 weeks. Patients with unresected tumor are assigned to receive regimen D (neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy with or without radiotherapy) lasting approximately 25 weeks.	Drug: doxorubicin hydrochloride Given IV Drug: ifosfamide Given IV Procedure: therapeutic conventional surgery Patients undergo surgery Radiation: radiation therapy Patients undergo radiotherapy
Group 3: Experimental (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, with metastases 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.	Drug: doxorubicin hydrochloride Given IV Drug: ifosfamide Given IV Procedure: observation Patients undergo observation Procedure: therapeutic conventional surgery Patients undergo surgery Radiation: radiation therapy Patients undergo radiotherapy

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Detailed Description:

OBJECTIVES:

Primary

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).
Assess event-free and overall survival of patients treated with these regimens.
Assess the pattern of treatment failure in these patients.

Secondary

Assess the feasibility of a neoadjuvant chemoradiotherapy approach in patients with intermediate- or high-risk NRSTS.
Assess the imaging and pathologic responses to neoadjuvant chemoradiotherapy in patients with intermediate- or high-risk NRSTS.
Correlate imaging and pathologic response with clinical outcomes in patients with intermediate- or high-risk disease who undergo neoadjuvant chemoradiotherapy.
Prospectively define clinical prognostic factors associated with event-free survival, overall survival, local recurrence, and distant recurrence in these patients.
Correlate patient outcomes with findings of biologic studies performed on tissue specimens collected on protocol COG-D9902 from these patients.
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.
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.

PROJECTED ACCRUAL: A total of 400 patients will be accrued for this study.

Eligibility

Ages Eligible for Study:	up to 29 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Newly diagnosed non-rhabdomyosarcoma soft tissue sarcoma (STS), confirmed by central pathology review via concurrent enrollment on protocol COG-D9902
- Metastatic or nonmetastatic 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* NOTE: *Patients < 2 years of age with infantile fibrosarcoma not allowed
    - 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:
  - Nonmetastatic 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:
- Nonmetastatic 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
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*
- 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)
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.
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)

PATIENT CHARACTERISTICS:

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
Hemoglobin ≥ 10 g/dL (may be supported by transfusion)*
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)*
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
- 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
No evidence of dyspnea at rest*
No exercise intolerance*
Resting pulse oximetry reading > 94% on room air (for patients with respiratory symptoms)* NOTE: *Patients eligible for study regimen A (observation only) are not required to meet the organ function requirements; patients eligible for study regimen B are required to have adequate organ function in the organs that are within the radiotherapy field; patients eligible for study regimens C or D must meet all organ function requirements

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
Prior treatment for cancer allowed provided the patient meet the prior therapy requirements
No prior anthracycline (e.g., doxorubicin ir daunorubicin) or ifosfamide chemotherapy for patients enrolled on arm C or arm D
No prior radiotherapy to tumor-involved sites
No concurrent aprepitant during chemotherapy

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00346164

Show 155 Study Locations

Sponsors and Collaborators

Children's Oncology Group

National Cancer Institute (NCI)

Investigators

Study Chair:	Sheri L. Spunt, MD	St. Jude Children's Research Hospital
Investigator:	Karyn A. Goodman, MD	Stanford University

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Children's Oncology Group - Group Chair Office ( Gregory H. Reaman )
Study ID Numbers:	CDR0000483702, COG-ARST0332
Study First Received:	June 28, 2006
Last Updated:	November 25, 2009
ClinicalTrials.gov Identifier:	NCT00346164 History of Changes
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

adult malignant hemangiopericytoma
adult malignant mesenchymoma
adult neurofibrosarcoma
adult alveolar soft-part sarcoma
adult angiosarcoma
adult epithelioid sarcoma
adult extraskeletal chondrosarcoma
adult extraskeletal osteosarcoma
adult fibrosarcoma
adult leiomyosarcoma
adult liposarcoma
adult synovial sarcoma
childhood alveolar soft-part sarcoma
childhood angiosarcoma
childhood epithelioid sarcoma

childhood fibrosarcoma
childhood leiomyosarcoma
childhood liposarcoma
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
adult malignant fibrous histiocytoma
localized childhood malignant fibrous histiocytoma of bone
metastatic childhood malignant fibrous histiocytoma of bone
chondrosarcoma

Additional relevant MeSH terms:

Histiocytoma, Malignant Fibrous
Neoplasms by Histologic Type
Molecular Mechanisms of Pharmacological Action
Histiocytoma, Benign Fibrous
Antineoplastic Agents
Antibiotics, Antineoplastic
Pharmacologic Actions
Doxorubicin
Neoplasms, Connective and Soft Tissue

Neoplasms
Ifosfamide
Histiocytoma
Therapeutic Uses
Sarcoma
Antineoplastic Agents, Alkylating
Neoplasms, Connective Tissue
Neoplasms, Fibrous Tissue
Alkylating Agents

ClinicalTrials.gov processed this record on November 27, 2009