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

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

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.

Study Overview

• Status: Completed
• Conditions: Sarcoma; Lymphedema; Radiation Toxicity; Radiation Fibrosis; Musculoskeletal Complications
• Intervention / Treatment: Drug: Chemotherapy; Radiation: Radiation therapy; Procedure: Surgery

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: Interventional
• Enrollment (Actual): 98
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute at University of Alberta
  • Ontario
    • London, Ontario, Canada, N6A 4L6
      • London Regional Cancer Program at London Health Sciences Centre
  • Quebec
    • Montreal, Quebec, Canada, H2W 1S6
      • McGill Cancer Centre at McGill University
• United States
  • Delaware
    • Newark, Delaware, United States, 19713
      • CCOP - Christiana Care Health Services
  • Florida
    • Gainesville, Florida, United States, 32610-0232
      • University of Florida Shands Cancer Center
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic - Jacksonville
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center - Miami
    • Tampa, Florida, United States, 33612-9497
      • H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • Norton Suburban Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Royal Oak, Michigan, United States, 48073
      • William Beaumont Hospital - Royal Oak Campus
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756-0002
      • Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center
  • New York
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center
  • Vermont
    • Saint Johnsbury, Vermont, United States, 05819
      • Norris Cotton Cancer Center - North
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	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.
Experimental: Cohort B - No Chemotherapy; Radiation therapy followed by surgery followed by, for patients with positive margins, radiation therapy boost	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.

What is the study measuring?

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.

Other Outcome Measures

Outcome Measure	Time Frame
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)]	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]	2 years after start of treatment (+/- 3 months)
Comparison of SAQ Scores at 2 Years for Cohort A Patients With Cohort B Patients	2 years after start of treatment (+/- 3 months)

Collaborators and Investigators

• Sponsor: Radiation Therapy Oncology Group
• Collaborators: National Cancer Institute (NCI); NRG Oncology
• Investigators: Principal Investigator: Dian Wang, MD, PhD, Medical College of Wisconsin; 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

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2008
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): May 21, 2018

Study Registration Dates

• First Submitted: January 5, 2008
• First Submitted That Met QC Criteria: January 5, 2008
• First Posted (Estimate): January 9, 2008

Study Record Updates

• Last Update Posted (Actual): June 12, 2019
• Last Update Submitted That Met QC Criteria: June 3, 2019
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: radiation toxicity; lymphedema; stage III adult soft tissue sarcoma; stage II adult soft tissue sarcoma; stage I adult soft tissue sarcoma; musculoskeletal complications; adult extraskeletal chondrosarcoma; radiation fibrosis
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Lymphatic Diseases; Lung Diseases; Wounds and Injuries; Lung Diseases, Interstitial; Lung Injury; Radiation Injuries; Fibrosis; Sarcoma; Lymphedema; Radiation Pneumonitis
• Other Study ID Numbers: RTOG-0630; CDR0000582196