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

Study Overview
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Brief Summary
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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.

Detailed Description
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PRIMARY OBJECTIVES: I. 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). II. Assess event-free and overall survival of patients treated with these regimens. III. Assess the pattern of treatment failure in these patients. SECONDARY OBJECTIVES: I. Assess the feasibility of a neoadjuvant chemoradiotherapy approach in patients with intermediate- or high-risk NRSTS. II. Assess the imaging and pathologic responses to neoadjuvant chemoradiotherapy in patients with intermediate- or high-risk NRSTS. III. Correlate imaging and pathologic response with clinical outcomes in patients with intermediate- or high-risk disease who undergo neoadjuvant chemoradiotherapy. IV. Prospectively define clinical prognostic factors associated with event-free survival, overall survival, local recurrence, and distant recurrence in these patients. V. Correlate patient outcomes with findings of biologic studies performed on tissue specimens collected on protocol COG-D9902 from these patients. VI. 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. VII. 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.

Official Title
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Risk-Based Treatment for Non-Rhabdomyosarcoma Soft Tissue Sarcomas (NRSTS) in Patients Under 30 Years of Age

Conditions
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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

Intervention / Treatment
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* Drug: doxorubicin hydrochloride
* Other: clinical observation
* Procedure: therapeutic conventional surgery
* Radiation: 3-dimensional conformal radiation therapy
* Drug: ifosfamide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 29 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: No adjuvant treatment<br>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<br>* Patients undergo observation<br>* Other names: observation;Procedure: therapeutic conventional surgery<br>* Patients undergo surgery<br>|
| Experimental: Arm B: Low risk; adjuvant radiotherapy<br>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<br>* Patients undergo observation<br>* Other names: observation;Procedure: therapeutic conventional surgery<br>* Patients undergo surgery<br>Radiation: 3-dimensional conformal radiation therapy<br>* Patients undergo radiotherapy<br>* Other names: 3D-CRT;|
| Experimental: Arm C: Intermediate & High risk; adjuvant chemoradiotherapy<br>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<br>* Given IV<br>* Other names: Adriamycin RDF;Other: clinical observation<br>* Patients undergo observation<br>* Other names: observation;Radiation: 3-dimensional conformal radiation therapy<br>* Patients undergo radiotherapy<br>* Other names: 3D-CRT;Drug: ifosfamide<br>* Given IV<br>* Other names: IPP;|
| Experimental: Arm D: Intermediate & High Risk; Neoadjuvant chemoradiotherapy<br>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<br>* Given IV<br>* Other names: Adriamycin RDF;Other: clinical observation<br>* Patients undergo observation<br>* Other names: observation;Procedure: therapeutic conventional surgery<br>* Patients undergo surgery<br>Radiation: 3-dimensional conformal radiation therapy<br>* Patients undergo radiotherapy<br>* Other names: 3D-CRT;Drug: ifosfamide<br>* Given IV<br>* Other names: IPP;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity Rate | Percentage of Arm D patients experiencing grade 4+ adverse events. | 13 weeks | 
| Complete or Partial Response Rate | 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. | 13 weeks | 
| Percent Tumor Necrosis | Percent tumor necrosis by pathology review. | 13 weeks | 
| Event Free Survival Probability Disease Extent | Probability of no relapse, secondary malignancy or death after 5 years since enrollment. | 5 years | 
| Event Free Survival Probability Histologic Grade | Probability of no relapse, secondary malignancy or death after 5 years since enrollment | 5 years | 
| Overall Survival Probability Disease Extent | Probability of survival after 5 years since enrollment. | 5 years | 
| Overall Survival Probability Extent of Resection of the Primary Tumor | Probability of survival after 5 years since enrollment. | 5 years | 
| Incidence of Distant Metastasis | Percent of patients who had distant metastasis. | Up to 10 years | 
| Genetic and Gene Expression Profiles | 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. | At diagnosis | 
| Degree of Agreement in Histologic Grade Determined by the Enrolling Institution Versus by Central Pathology Reviewers | 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. | At Diagnosis | 
| 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 | POG and FNCLCC grades were determined by pathologists based on published standards. A higher grade is associated with a more severe disease. | At diagnosis |