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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00589121
Recruitment Status : Completed
First Posted : January 9, 2008
Results First Posted : July 17, 2017
Last Update Posted : June 12, 2019
Sponsor:
Collaborators:
National Cancer Institute (NCI)
NRG Oncology
Information provided by (Responsible Party):
Radiation Therapy Oncology Group

Tracking Information
First Submitted Date  ICMJE January 5, 2008
First Posted Date  ICMJE January 9, 2008
Results First Submitted Date  ICMJE August 25, 2016
Results First Posted Date  ICMJE July 17, 2017
Last Update Posted Date June 12, 2019
Actual Study Start Date  ICMJE March 2008
Actual Primary Completion Date December 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 19, 2017)
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 [ Time Frame: 2 years after start of treatment (+/- 3 months) ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: January 5, 2008)
Effect of reduced radiation volume using image-guided radiotherapy (IGRT) on 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
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 3, 2019)
  • Local Failure Rate at Two Years [ Time Frame: From registration to date of failure (local progression) or death or last follow-up. Report at time of primary outcome measure analysis. ]
    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.
  • Regional Failure Rate at Two Years [ Time Frame: From registration to date of failure (regional progression) or death or last follow-up. Report at time of primary outcome measure analysis. ]
    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.
  • Distant Failure Rate at Two Years [ Time Frame: From registration to date of failure (distant progression) or death or last follow-up. Report at time of primary outcome measure analysis. ]
    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.
  • Distant Disease-free Survival Rate at Two Years [ Time Frame: 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 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.
  • Disease-free Survival Rate at Two Years [ Time Frame: 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. ]
    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.
  • Overall Survival Rate at Two Years [ Time Frame: From registration to date of death or last follow-up. Report at time of primary outcome measure analysis. ]
    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.
  • Second Primary Tumor Rate at Two Years [ Time Frame: From registration to date of failure (second primary tumor) or death or last follow-up. Report at time of primary outcome measure analysis. ]
    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.
  • 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 [ Time Frame: 2 years after start of treatment (+/- 3 months) ]
    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.
  • Percentage of Patients With Wound Complications [ Time Frame: From date of surgery to 4 months post-surgery ]
    Estimate rate of patients with acute wound complications with 95% confidence interval assuming binomial distribution.
  • Pattern of First Failure [ Time Frame: From registration to date of local, regional or distant progression. Report at time of primary outcome measure analysis. ]
    Pattern of first failure including local failure (in-field, marginal, and outside-field failure), regional failure, distant failure, and death without disease progression.
  • Mean Musculoskeletal Tumor Rating Scale (MSTS) by Late Radiation Morbidity at Two Years [ Time Frame: From start of treatment to 2 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.
  • Percentage of Patients With Other CTCAE, v.3.0 Grade 3-5 Adverse Events [ Time Frame: From start of treatment to last follow-up. Analysis can occur at or after time of primary outcome measure analysis. ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 5, 2008)
  • Effect of reduced radiation volume using IGRT on late radiation morbidity (≥ grade 2 lymphedema, subcutaneous fibrosis, and joint stiffness) at 2 years from the start of radiotherapy as measured by CTCAE v3.0 criteria
  • Other grade 3-5 adverse events as measured by CTCAE v3.0 criteria
  • Pattern of first failure, including local failure (in-field, marginal, and outside-field failure), regional failure, distant failure, and death without disease progression
  • Time to local failure
  • Time to regional failure
  • Time to distant failure
  • Distant disease-free survival
  • Disease-free survival
  • Overall survival
  • Time to second primary tumor
  • Rate of wound complications
  • Impact of late radiation morbidity (≥ grade 2 lymphedema, subcutaneous fibrosis, or joint stiffness) at 2 years on the clinical measure, Musculoskeletal Tumor Rating Scale (MTRS)
Current Other Pre-specified Outcome Measures
 (submitted: June 19, 2017)
  • Correlation of Late Radiation Morbidity at 2 Years With the 3 Quality of Life Assessments [Functional Assessment of Cancer Therapy-General (FACTG), Toronto Extremity Salvage Score (TESS), and Sexual Adjustment Questionnaire (SAQ)] [ Time Frame: 2 years after start of treatment (+/- 3 months) ]
  • Comparison of TESS and the MSTS Scores at 2 Years Between Cohort B Patients and the Preoperative Radiotherapy Patients in the NCIC CTG Trial [National Cancer Institute of Canada Clinical Trials Group] [ Time Frame: 2 years after start of treatment (+/- 3 months) ]
  • Comparison of SAQ Scores at 2 Years for Cohort A Patients With Cohort B Patients [ Time Frame: 2 years after start of treatment (+/- 3 months) ]
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Image-Guided Radiation Therapy in Treating Patients With Primary Soft Tissue Sarcoma of the Shoulder, Arm, Hip, or Leg
Official Title  ICMJE A Phase II Trial of Image Guided Preoperative Radiotherapy for Primary Soft Tissue Sarcomas of the Extremity
Brief Summary

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

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Lymphedema
  • Musculoskeletal Complications
  • Radiation Fibrosis
  • Radiation Toxicity
  • Sarcoma
Intervention  ICMJE
  • Drug: Chemotherapy
    Up to 6 courses of investigator's choice of neoadjuvant, adjuvant, concurrent, or interdigitated chemotherapy
  • Radiation: Radiation therapy
    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.
  • Procedure: Surgery
    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.
Study Arms  ICMJE
  • Experimental: Cohort A - Chemotherapy
    Radiation therapy with neoadjuvant or adjuvant or concurrent or interdigitated chemotherapy followed by surgery followed by, for patients with positive margins, radiation therapy boost
    Interventions:
    • Drug: Chemotherapy
    • Radiation: Radiation therapy
    • Procedure: Surgery
  • Experimental: Cohort B - No Chemotherapy
    Radiation therapy followed by surgery followed by, for patients with positive margins, radiation therapy boost
    Interventions:
    • Radiation: Radiation therapy
    • Procedure: Surgery
Publications * Wang D, Zhang Q, Eisenberg BL, Kane JM, Li XA, Lucas D, Petersen IA, DeLaney TF, Freeman CR, Finkelstein SE, Hitchcock YJ, Bedi M, Singh AK, Dundas G, Kirsch DG. Significant Reduction of Late Toxicities in Patients With Extremity Sarcoma Treated With Image-Guided Radiation Therapy to a Reduced Target Volume: Results of Radiation Therapy Oncology Group RTOG-0630 Trial. J Clin Oncol. 2015 Jul 10;33(20):2231-8. doi: 10.1200/JCO.2014.58.5828. Epub 2015 Feb 9.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 22, 2015)
98
Original Enrollment  ICMJE
 (submitted: January 5, 2008)
102
Actual Study Completion Date  ICMJE May 21, 2018
Actual Primary Completion Date December 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00589121
Other Study ID Numbers  ICMJE RTOG-0630
CDR0000582196
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Radiation Therapy Oncology Group
Study Sponsor  ICMJE Radiation Therapy Oncology Group
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • NRG Oncology
Investigators  ICMJE
Principal Investigator: Dian Wang, MD, PhD Medical College of Wisconsin
Study Chair: Scott Okuno, MD Mayo Clinic
Study Chair: Burton L. Eisenberg, MD Norris Cotton Cancer Center
Study Chair: John M. Kane, MD Roswell Park Cancer Institute
Study Chair: David G. Kirsch, MD, PhD Duke Cancer Institute
PRS Account Radiation Therapy Oncology Group
Verification Date June 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP