Image-Guided Radiation Therapy in Treating Patients With Primary Soft Tissue Sarcoma of the Shoulder, Arm, Hip, or Leg

Study Overview
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Brief Summary
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RATIONALE: Image-guided radiation therapy uses high-energy x-rays to kill tumor cells. Specialized radiation therapy that delivers a lower dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. PURPOSE: This phase II trial is studying the side effects and how well image-guided radiation therapy works in treating patients with primary soft tissue sarcoma of the shoulder, arm, hip, or leg.

Detailed Description
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OBJECTIVES: Primary To determine the effect of reduced radiation volume using image-guided radiotherapy (IGRT) on lymphedema ≥ grade 2, subcutaneous fibrosis, and joint stiffness at 2 years in patients with primary soft tissue sarcoma of the extremity. Secondary To estimate the rates of other grade 3-5 adverse events as measured by Common Toxicity Criteria for Adverse Effects (CTCAE) v3.0. To determine the pattern of first failure, including local failure (in-field, marginal, and outside-field failure), regional failure, distant failure, and death without disease progression. To estimate the rates of local failure, local-regional failure, distant failure, distant disease-free survival, disease-free survival, overall survival, and second primary tumor. To estimate the rate of wound complications. To correlate the degree of late radiation morbidity (defined as any lymphedema, subcutaneous fibrosis, or joint stiffness) at 2 years with scores on the clinical measure, Musculoskeletal Tumor Rating Scale (MSTS). OUTLINE: This is a multicenter study. Neoadjuvant radiotherapy: Patients are assigned to 1 of 2 treatment groups (group 1 closed to accrual as of 01/08/10). Group 1 (closed to accrual as of 01/08/10): Patients undergo 3-D conformal radiotherapy (3D-CRT) or intensity-modulated therapy (IMRT) once daily, 5 days a week, for 4½-5 weeks. Patients also receive up to 6 courses of neoadjuvant, adjuvant, concurrent, or interdigitated chemotherapy. Group 2: Patients undergo 3D-CRT or IMRT once daily, 5 days a week, for 5 weeks. Surgery: At 4-8 weeks after completion of neoadjuvant radiotherapy, patients undergo surgical resection of the tumor. Patients with positive tumor margins (residual tumor) undergo intraoperative radiotherapy boost or proceed to adjuvant radiotherapy within 2 weeks after surgery. Adjuvant radiotherapy: Patients undergo either external-beam radiotherapy (EBRT) once daily for 8 fractions or brachytherapy. After completion of study treatment, patients are followed at least every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Official Title
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A Phase II Trial of Image Guided Preoperative Radiotherapy for Primary Soft Tissue Sarcomas of the Extremity

Conditions
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Lymphedema, Musculoskeletal Complications, Radiation Fibrosis, Radiation Toxicity, Sarcoma

Intervention / Treatment
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* Drug: Chemotherapy
* Radiation: Radiation therapy
* Procedure: Surgery


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed primary soft tissue sarcoma of the upper extremity (including shoulder) or lower extremity (including hip) Incisional or core biopsy required within the past 8 weeks No histopathological diagnosis of any of the following: Rhabdomyosarcoma Extraosseous primitive neuroectodermal tumor (PNET) Soft tissue Ewing sarcoma Osteosarcoma Kaposi sarcoma Angiosarcoma Aggressive fibromatosis (desmoid tumor) Dermatofibrosarcoma protuberans Chondrosarcoma Extraskeletal myxoid chondrosarcoma allowed Tumor must be surgically resectable, as determined by a surgeon within the past 8 weeks Limb-preservation surgery alone would not provide adequate local control, as determined by the surgeon No sarcoma of the hand, foot, head, neck, or intra-abdominal or retroperitoneal region or body wall No sarcoma ≥ 32 cm in any direction No lymph node or distant metastases, according to the following within the past 8 weeks: History/physical examination, including a detailed description of the location, size, and stage of the sarcoma MRI with contrast of the primary tumor The maximum dimension of the primary tumor is measured in MRI images CT scan of the chest Multiple pulmonary nodules < 8 mm without a histological diagnosis detected incidentally on a non-screening CT scan may be allowed CT scan with contrast of the abdomen and pelvis in patients with intermediate- or high-grade sarcoma of the upper thigh No recurrent tumor after prior potentially curative therapy PATIENT CHARACTERISTICS: Zubrod performance status 0-1 Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 8.0 g/dL (transfusion or other intervention allowed) Bilirubin ≤ 1.5 mg/dL* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2 times upper limit of normal* Serum creatinine ≤ 1.6 mg/dL OR creatinine clearance ≥ 55 mL/min* Left ventricular ejection fraction (LVEF) ≥ 50% by multiple gated acquisition scan (MUGA) or echocardiogram* Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No other invasive malignancy within the past 3 years, except nonmelanomatous skin cancer or carcinoma in situ of the breast, oral cavity, or cervix No severe, active co-morbidity, including any of the following*: Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months Transmural myocardial infarction within the past 6 months Acute bacterial infection or fungal infection requiring intravenous antibiotics Acquired Immune Deficiency Syndrome (AIDS) or immunocompromised patients HIV testing not required No NCI CTCAE v 3.0 grade 3-4 electrolyte abnormalities, including any of the following*: Calcium < 7 mg/dL or > 12.5 mg/dL Glucose < 40 mg/dL or > 250 mg/dL Magnesium < 0.9 mg/dL or > 3 mg/dL Potassium < 3mmol/L or > 6 mmol/L Sodium < 130 mmol/L or > 155 mmol/L NOTE: *Applies to group 1 only, which was closed to accrual as of 01/08/10) PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior excisional biopsy in which the majority of the tumor (≥ 50%) is removed No prior radiotherapy to the region of the study cancer that would result in overlap of radiotherapy fields No other concurrent investigational agents

Ages Eligible for Study
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Minimum Age: 18 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: Cohort A - Chemotherapy<br>Radiation therapy with neoadjuvant or adjuvant or concurrent or interdigitated chemotherapy followed by surgery followed by, for patients with positive margins, radiation therapy boost | Drug: Chemotherapy<br>* Up to 6 courses of investigator's choice of neoadjuvant, adjuvant, concurrent, or interdigitated chemotherapy<br>Radiation: Radiation therapy<br>* Preoperative IGRT (3D-CRT or IMRT): If receiving neoadjuvant or adjuvant chemotherapy or no chemotherapy: 50 Gy (2 Gy once a day, 5 times a week). If receiving concurrent or interdigitated chemotherapy: 44 Gy (2 Gy once a day, 5 times a week). Postoperative radiotherapy boost for patients with positive margins following surgery: 16 Gy (2 Gy once a day, 5 times a week) external beam radiation therapy or 16 Gy at ≤ 80 cGy per hour brachytherapy or 3.4 Gy/fraction in 4 fractions brachytherapy or 10-12.5 Gy in a single fraction intraoperative radiation therapy boost.<br>Procedure: Surgery<br>* Resection of the sarcoma with the goal of having negative pathologic margins. Every effort should be made to have limb preservation surgery unless there is documented evidence of tumor progression that would require amputation for an appropriate negative margin resection. All lesions of the extremities should be treated with wide excision.<br>|
| Experimental: Cohort B - No Chemotherapy<br>Radiation therapy followed by surgery followed by, for patients with positive margins, radiation therapy boost | Radiation: Radiation therapy<br>* Preoperative IGRT (3D-CRT or IMRT): If receiving neoadjuvant or adjuvant chemotherapy or no chemotherapy: 50 Gy (2 Gy once a day, 5 times a week). If receiving concurrent or interdigitated chemotherapy: 44 Gy (2 Gy once a day, 5 times a week). Postoperative radiotherapy boost for patients with positive margins following surgery: 16 Gy (2 Gy once a day, 5 times a week) external beam radiation therapy or 16 Gy at ≤ 80 cGy per hour brachytherapy or 3.4 Gy/fraction in 4 fractions brachytherapy or 10-12.5 Gy in a single fraction intraoperative radiation therapy boost.<br>Procedure: Surgery<br>* Resection of the sarcoma with the goal of having negative pathologic margins. Every effort should be made to have limb preservation surgery unless there is documented evidence of tumor progression that would require amputation for an appropriate negative margin resection. All lesions of the extremities should be treated with wide excision.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Late Radiation Morbidity (≥ Grade 2 Lymphedema, Subcutaneous Fibrosis, or Joint Stiffness) at 2 Years From the Start of Radiotherapy as Measured by EORTC/RTOG Criteria | The rate of patients with late radiation morbidity (≥ grade 2 lymphedema, subcutaneous fibrosis, or joint stiffness) at 2 years from the start of radiotherapy as measured by EORTC(European Organisation for Research and Treatment of Cancer)/RTOG (Radiation Therapy Oncology Group) criteria. Grade refers to the severity of the morbidity. The RTOG/EORTC Late Radiation Morbidity Scoring Schema assigns Grades 1 through 5 with unique clinical descriptions of severity for each morbidity based on this general guideline: Grade 1 Mild , Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to morbidity. | 2 years after start of treatment (+/- 3 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local Failure Rate at Two Years | Local failure is defined as the time from registration to date of failure (local progression) or death or last follow-up. Two year rate and 95% confidence interval were estimated by the cumulative incidence method. | From registration to date of failure (local progression) or death or last follow-up. Report at time of primary outcome measure analysis. | 
| Regional Failure Rate at Two Years | Regional failure is defined as the time from registration to date of failure (regional progression) or death or last follow-up. Two year rate and 95% confidence interval were estimated by the cumulative incidence method. | From registration to date of failure (regional progression) or death or last follow-up. Report at time of primary outcome measure analysis. | 
| Distant Failure Rate at Two Years | Distant failure is defined as the time from registration to date of failure (distant progression) or death or last follow-up. Two year rate and 95% confidence interval were estimated by the cumulative incidence method. | From registration to date of failure (distant progression) or death or last follow-up. Report at time of primary outcome measure analysis. | 
| Distant Disease-free Survival Rate at Two Years | Distant disease-free survival is defined as the time from registration to date of failure (distant progression or death) or last follow-up. Two year rate and 95% confidence interval were estimated by the Kaplan-Meier method. | From registration to date of failure (distant progression or death) or last follow-up. Report at time of primary outcome measure analysis. | 
| Disease-free Survival Rate at Two Years | Disease-free survival is defined as the time from registration to date of failure (local, regional, or distant progression or death) or last follow-up. Two year rate and 95% confidence interval were estimated by the Kaplan-Meier method. | From registration to date of failure (local, regional or distant progression or death) or last follow-up. Report at time of primary outcome measure analysis. | 
| Overall Survival Rate at Two Years | Overall survival is defined as the time from registration to date of death or last follow-up. Two year survival rate and 95% confidence interval were estimated by the Kaplan-Meier method. | From registration to date of death or last follow-up. Report at time of primary outcome measure analysis. | 
| Second Primary Tumor Rate at Two Years | Second primary tumor is defined as the time from registration to date of failure (second primary tumor) or death or last follow-up. Two year rate and 95% confidence interval were estimated by the cumulative incidence method. | From registration to date of failure (second primary tumor) or death or last follow-up. Report at time of primary outcome measure analysis. | 
| Late Radiation Morbidity Rate (≥ Grade 2 Lymphedema, Subcutaneous Fibrosis or Joint Stiffness) at 2 Years From the Start of Radiotherapy as Measured by CTCAE v3.0 | Adverse events are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. | 2 years after start of treatment (+/- 3 months) | 
| Percentage of Patients With Wound Complications | Estimate rate of patients with acute wound complications with 95% confidence interval assuming binomial distribution. | From date of surgery to 4 months post-surgery | 
| Pattern of First Failure | Pattern of first failure including local failure (in-field, marginal, and outside-field failure), regional failure, distant failure, and death without disease progression. | From registration to date of local, regional or distant progression. Report at time of primary outcome measure analysis. | 
| Mean Musculoskeletal Tumor Rating Scale (MSTS) by Late Radiation Morbidity at Two Years | The Musculoskeletal Tumor Rating Scale (MSTS) is a measure of physical function across 7 items, completed by the physician (preferably by the Orthopedic Surgeon or Surgical Oncologist) or the physician's designated staff. The 7 items are: pain, range of motion, strength, joint stability, joint deformity, emotional, acceptance, and overall function. Each item is scored from 0-5 (worst possible to best possible condition). The item scores are summed to get the total score which ranges from 0-35. Late radiation morbidity is defined as ≥ grade 2 lymphedema, subcutaneous fibrosis, or joint stiffness. Adverse events are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. | From start of treatment to 2 years. | 
| Percentage of Patients With Other CTCAE, v.3.0 Grade 3-5 Adverse Events | Adverse events are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. | From start of treatment to last follow-up. Analysis can occur at or after time of primary outcome measure analysis. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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radiation fibrosis, radiation toxicity, lymphedema, musculoskeletal complications, stage I adult soft tissue sarcoma, stage II adult soft tissue sarcoma, adult extraskeletal chondrosarcoma, stage III adult soft tissue sarcoma