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

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ClinicalTrials.gov Identifier: NCT00346164
Recruitment Status : Completed
First Posted : June 29, 2006
Results First Posted : October 6, 2017
Last Update Posted : October 6, 2017
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Study Description
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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

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Study Design
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Study Type : Interventional  (Clinical Trial)
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
Study Start Date : February 2007
Actual Primary Completion Date : September 2014

Resource links provided by the National Library of Medicine


Arms and Interventions
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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 Name: 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 Name: 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 Name: 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 Name: 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
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Primary Outcome Measures :
  1. Probability for Event Free Survival. [ Time Frame: 5 years ]
    Probability of no relapse, secondary malignancy or death after 5 years since enrollment.


Secondary Outcome Measures :
  1. Toxicity Rate [ Time Frame: 13 weeks ]
    Percentage of Arm D patients experiencing grade 4+ adverse events.

  2. Complete or Partial Response Rate [ Time Frame: 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 [ Time Frame: 13 weeks ]
    Percent tumor necrosis by pathology review.

  4. Event Free Survival Probability Disease Extent [ Time Frame: 5 years ]
    Probability of no relapse, secondary malignancy or death after 5 years since enrollment.

  5. Event Free Survival Probability Histologic Grade [ Time Frame: 5 years ]
    Probability of no relapse, secondary malignancy or death after 5 years since enrollment

  6. Overall Survival Probability Disease Extent [ Time Frame: 5 years ]
    Probability of survival after 5 years since enrollment.

  7. Overall Survival Probability Extent of Resection of the Primary Tumor [ Time Frame: 5 years ]
    Probability of survival after 5 years since enrollment.

  8. Incidence of Distant Metastasis [ Time Frame: Up to 10 years ]
    Percent of patients who had distant metastasis.

  9. Genetic and Gene Expression Profiles [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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
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Information from the National Library of Medicine

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Ages Eligible for Study:   up to 29 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00346164


  Show 187 Study Locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
Principal Investigator: Sheri Spunt, MD Children's Oncology Group
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT00346164     History of Changes
Other Study ID Numbers: ARST0332
NCI-2009-00426 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
COG-ARST0332 ( Other Identifier: Children's Oncology Group )
CDR0000483702 ( Other Identifier: Clinical Trials.gov )
U10CA098543 ( U.S. NIH Grant/Contract )
First Posted: June 29, 2006    Key Record Dates
Results First Posted: October 6, 2017
Last Update Posted: October 6, 2017
Last Verified: December 2016

Additional relevant MeSH terms:
Sarcoma
Osteosarcoma
Leiomyosarcoma
Liposarcoma
Chondrosarcoma
Sarcoma, Synovial
Hemangiosarcoma
Fibrosarcoma
Hemangiopericytoma
Sarcoma, Alveolar Soft Part
Histiocytoma
Histiocytoma, Benign Fibrous
Histiocytoma, Malignant Fibrous
Mesenchymoma
Liver Neoplasms
 Neurofibrosarcoma
Neurilemmoma
Dermatofibrosarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Muscle Tissue
Neoplasms, Adipose Tissue
Neoplasms, Vascular Tissue
Neoplasms, Fibrous Tissue
Neoplasms, Complex and Mixed
Digestive System Neoplasms
Neoplasms by Site