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

• Sponsor: Radiation Therapy Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00589121
• Collaborator: National Cancer Institute (NCI) (NIH), NRG Oncology (Other)
• Enrollment: 98
• Locations: 17
• Arms: 2
• Actual Duration (Months): 122.6
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Lymphedema; Musculoskeletal Complications; Radiation Fibrosis; Radiation Toxicity; Sarcoma	Drug: Chemotherapy; Radiation: Radiation therapy; Procedure: Surgery	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 98 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Image Guided Preoperative Radiotherapy for Primary Soft Tissue Sarcomas of the Extremity
• Actual Study Start Date: Mar 1, 2008
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: May 21, 2018

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. 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 [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.

Secondary Outcome Measures

1. Local Failure Rate at Two Years [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.

2. Regional Failure Rate at Two Years [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.

3. Distant Failure Rate at Two Years [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.

4. Distant Disease-free Survival Rate at Two Years [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.

5. Disease-free Survival Rate at Two Years [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.

6. Overall Survival Rate at Two Years [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.

7. Second Primary Tumor Rate at Two Years [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.

8. 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 [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.

9. Percentage of Patients With Wound Complications [From date of surgery to 4 months post-surgery]

   Estimate rate of patients with acute wound complications with 95% confidence interval assuming binomial distribution.

10. Pattern of First Failure [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.

11. Mean Musculoskeletal Tumor Rating Scale (MSTS) by Late Radiation Morbidity at Two Years [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.

12. Percentage of Patients With Other CTCAE, v.3.0 Grade 3-5 Adverse Events [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.

Other Outcome Measures

1. 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)]

2. 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)]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

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

Sponsors and Collaborators

• Radiation Therapy Oncology Group
• National Cancer Institute (NCI)
• NRG Oncology

Investigators

• 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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT00589121
• Other Study ID Numbers: RTOG-0630; CDR0000582196
• First Posted: Jan 9, 2008
• Last Update Posted: Jun 12, 2019
• Last Verified: Jun 1, 2018

• Keywords provided by Radiation Therapy Oncology Group: 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
• Additional relevant MeSH terms: Sarcoma; Radiation Pneumonitis; Lymphedema; Fibrosis

Study Results

Participant Flow

Arm/Group Title	Cohort A - Chemotherapy	Cohort B - No Chemotherapy
Arm/Group Description	Radiation therapy with neoadjuvant or adjuvant or concurrent or interdigitated chemotherapy followed by surgery followed by, for patients with positive margins, radiation therapy boost	Radiation therapy followed by surgery followed by, for patients with positive margins, radiation therapy boost
Period Title: Overall Study
STARTED	12	86
COMPLETED	10	79
NOT COMPLETED	2	7

Baseline Characteristics

Arm/Group Title	Cohort A - Chemotherapy	Cohort B - No Chemotherapy	Total
Arm/Group Description	Radiation therapy with neoadjuvant or adjuvant or concurrent or interdigitated chemotherapy followed by surgery followed by, for patients with positive margins, radiation therapy boost	Radiation therapy followed by surgery followed by, for patients with positive margins, radiation therapy boost	Total of all reporting groups
Overall Participants	10	79	89
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	52	61	61
Sex: Female, Male (Count of Participants)
Female	5 50%	37 46.8%	42 47.2%
Male	5 50%	42 53.2%	47 52.8%

Outcome Measures

1. Primary Outcome

Title	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
Description	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.
Time Frame	2 years after start of treatment (+/- 3 months)

Outcome Measure Data

Analysis Population Description

All eligible patients on Cohort B who started study treatment and had an assessment of toxicity at 2 years. (See limitations and caveats, Cohort A is not included.)

Arm/Group Title	Cohort B - No Chemotherapy
Arm/Group Description	Radiation therapy followed by surgery followed by, for patients with positive margins, radiation therapy boost
Measure Participants	57
Number (95% Confidence Interval) [percentage of participants]	10.5 105%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort B - No Chemotherapy
	Comments	Initially designed to test for a 20% absolute improvement from 37% (fixed rate) to 17% using Fisher's exact test, requiring 41 patients per cohort (51 with 20% ineligibility) with 5% type I error and 90% statistical power. During accrual, the sample size for cohort B was increased to 66 (83 with 20% ineligibility) to test for a 15% improvement with 5% type I error and 85% power.
	Type of Statistical Test	Superiority or Other
	Comments	The fixed rate of 37% comes from the published National Cancer Institute of Canada trial SR2 (CAN-NCIC-SR2: Phase III Randomized Study of Pre- vs Postoperative Radiotherapy in Curable Extremity Soft Tissue Sarcoma) receiving preoperative radiation therapy without image-guided radiation therapy (IGRT).
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	Fisher Exact
	Comments

2. Secondary Outcome

Title	Local Failure Rate at Two Years
Description	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.
Time Frame	From registration to date of failure (local progression) or death or last follow-up. Report at time of primary outcome measure analysis.

Outcome Measure Data

Analysis Population Description

All eligible patients on Cohort B who started study treatment. (See limitations and caveats, Cohort A is not included.)

Arm/Group Title	Cohort B - No Chemotherapy
Arm/Group Description	Radiation therapy followed by surgery followed by, for patients with positive margins, radiation therapy boost
Measure Participants	79
Number (95% Confidence Interval) [percentage of participants]	11.4 114%

3. Secondary Outcome

Title	Regional Failure Rate at Two Years
Description	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.
Time Frame	From registration to date of failure (regional progression) or death or last follow-up. Report at time of primary outcome measure analysis.

Outcome Measure Data

Analysis Population Description

All eligible patients on Cohort B who started study treatment. (See limitations and caveats, Cohort A is not included.)

Arm/Group Title	Cohort B - No Chemotherapy
Arm/Group Description	Radiation therapy followed by surgery followed by, for patients with positive margins, radiation therapy boost
Measure Participants	79
Number (95% Confidence Interval) [percentage of participants]	0 0%

4. Secondary Outcome

Title	Distant Failure Rate at Two Years
Description	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.
Time Frame	From registration to date of failure (distant progression) or death or last follow-up. Report at time of primary outcome measure analysis.

Outcome Measure Data

Analysis Population Description

All eligible patients on Cohort B who started study treatment. (See limitations and caveats, Cohort A is not included.)

Arm/Group Title	Cohort B - No Chemotherapy
Arm/Group Description	Radiation therapy followed by surgery followed by, for patients with positive margins, radiation therapy boost
Measure Participants	79
Number (95% Confidence Interval) [percentage of participants]	37.3 373%

5. Secondary Outcome

Title	Distant Disease-free Survival Rate at Two Years
Description	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.
Time Frame	From registration to date of failure (distant progression or death) or last follow-up. Report at time of primary outcome measure analysis.

Outcome Measure Data

Analysis Population Description

All eligible patients on Cohort B who started study treatment. (See limitations and caveats, Cohort A is not included.)

Arm/Group Title	Cohort B - No Chemotherapy
Arm/Group Description	Radiation therapy followed by surgery followed by, for patients with positive margins, radiation therapy boost
Measure Participants	79
Number (95% Confidence Interval) [percentage of participants]	61.4 614%

6. Secondary Outcome

Title	Disease-free Survival Rate at Two Years
Description	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.
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.

Outcome Measure Data

Analysis Population Description

All eligible patients on Cohort B who started study treatment. (See limitations and caveats, Cohort A is not included.)

Arm/Group Title	Cohort B - No Chemotherapy
Arm/Group Description	Radiation therapy followed by surgery followed by, for patients with positive margins, radiation therapy boost
Measure Participants	79
Number (95% Confidence Interval) [percentage of participants]	58.1 581%

7. Secondary Outcome

Title	Overall Survival Rate at Two Years
Description	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.
Time Frame	From registration to date of death or last follow-up. Report at time of primary outcome measure analysis.

Outcome Measure Data

Analysis Population Description

All eligible patients on Cohort B who started study treatment. (See limitations and caveats, Cohort A is not included.)

Arm/Group Title	Cohort B - No Chemotherapy
Arm/Group Description	Radiation therapy followed by surgery followed by, for patients with positive margins, radiation therapy boost
Measure Participants	79
Number (95% Confidence Interval) [percentage of participants]	80.6 806%

8. Secondary Outcome

Title	Second Primary Tumor Rate at Two Years
Description	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.
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.

Outcome Measure Data

Analysis Population Description

All eligible patients on Cohort B who started study treatment. (See limitations and caveats, Cohort A is not included.)

Arm/Group Title	Cohort B - No Chemotherapy
Arm/Group Description	Radiation therapy followed by surgery followed by, for patients with positive margins, radiation therapy boost
Measure Participants	79
Number (95% Confidence Interval) [percentage of participants]	5.1 51%

9. Secondary Outcome

Title	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
Description	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.
Time Frame	2 years after start of treatment (+/- 3 months)

Outcome Measure Data

Analysis Population Description

All eligible patients on Cohort B who started study treatment and had an assessment of toxicity at 2 years. (See limitations and caveats, Cohort A is not included.)

Arm/Group Title	Cohort B - No Chemotherapy
Arm/Group Description	Radiation therapy followed by surgery followed by, for patients with positive margins, radiation therapy boost
Measure Participants	57
Number (95% Confidence Interval) [percentage of participants]	8.8 88%

10. Secondary Outcome

Title	Percentage of Patients With Wound Complications
Description	Estimate rate of patients with acute wound complications with 95% confidence interval assuming binomial distribution.
Time Frame	From date of surgery to 4 months post-surgery

Outcome Measure Data

Analysis Population Description

All eligible patients on cohort B that had surgery and a wound assessment. (See limitations and caveats, Cohort A is not included.)

Arm/Group Title	Cohort B - No Chemotherapy
Arm/Group Description	Radiation therapy followed by surgery followed by, for patients with positive margins, radiation therapy boost
Measure Participants	71
Number (95% Confidence Interval) [percentage of participants]	36.6 366%

11. Secondary Outcome

Title	Pattern of First Failure
Description	Pattern of first failure including local failure (in-field, marginal, and outside-field failure), regional failure, distant failure, and death without disease progression.
Time Frame	From registration to date of local, regional or distant progression. Report at time of primary outcome measure analysis.

Outcome Measure Data

Analysis Population Description

All eligible patients on Cohort B who started study treatment. All eligible patients on Cohort B. (See limitations and caveats, Cohort A is not included.)

Arm/Group Title	Cohort A - Chemotherapy	Cohort B - No Chemotherapy
Arm/Group Description	Radiation therapy with neoadjuvant or adjuvant or concurrent or interdigitated chemotherapy followed by surgery followed by, for patients with positive margins, radiation therapy boost	Radiation therapy followed by surgery followed by, for patients with positive margins, radiation therapy boost
Measure Participants	10	79
Local	1 10%	8 10.1%
Regional	0 0%	1 1.3%
Distant	1 10%	29 36.7%
Dead without disease progression	0 0%	2 2.5%
Alive without disease progression	8 80%	39 49.4%

12. Secondary Outcome

Title	Mean Musculoskeletal Tumor Rating Scale (MSTS) by Late Radiation Morbidity at Two Years
Description	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.
Time Frame	From start of treatment to 2 years.

Outcome Measure Data

Analysis Population Description

All eligible patients on Cohort B who had a 2-year MSTS assessment. (See limitations and caveats, Cohort A is not included.)

Arm/Group Title	No Late Radiation Morbitity	Has Late Radiation Toxicity
Arm/Group Description
Measure Participants	18	2
Mean (Standard Deviation) [units on a scale]	31.3 (4.5)	25.0 (0)

13. Secondary Outcome

Title	Percentage of Patients With Other CTCAE, v.3.0 Grade 3-5 Adverse Events
Description	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.
Time Frame	From start of treatment to last follow-up. Analysis can occur at or after time of primary outcome measure analysis.

Outcome Measure Data

Analysis Population Description

All eligible patients on Cohort B who started study treatment. (See limitations and caveats, Cohort A is not included.)

Arm/Group Title	Cohort B - No Chemotherapy
Arm/Group Description	Radiation therapy followed by surgery followed by, for patients with positive margins, radiation therapy boost
Measure Participants	79
Number (95% Confidence Interval) [percentage of patients]	38.0

14. Other Pre-specified Outcome

Title	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Other Pre-specified Outcome

Title	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Other Pre-specified Outcome

Title	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Adverse Event Reporting Description	Subjects experiencing more than one of a given adverse event (AE) are counted only once for that adverse event. Data is reported for eligible patients with adverse event data who started study treatment.
Arm/Group Title	Cohort A - Chemotherapy		Cohort B - No Chemotherapy
Arm/Group Description	Radiation therapy with neoadjuvant or adjuvant or concurrent or interdigitated chemotherapy followed by surgery followed by, for patients with positive margins, radiation therapy boost		Radiation therapy followed by surgery followed by, for patients with positive margins, radiation therapy boost
All Cause Mortality
	Cohort A - Chemotherapy		Cohort B - No Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Cohort A - Chemotherapy		Cohort B - No Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/10 (20%)		13/79 (16.5%)
Blood and lymphatic system disorders
Blood disorder	1/10 (10%)		1/79 (1.3%)
Hemoglobin decreased	1/10 (10%)		0/79 (0%)
Gastrointestinal disorders
Nausea	1/10 (10%)		0/79 (0%)
Vomiting	1/10 (10%)		0/79 (0%)
General disorders
Edema limbs	0/10 (0%)		2/79 (2.5%)
Fatigue	1/10 (10%)		0/79 (0%)
Infections and infestations
Infection [other]	1/10 (10%)		0/79 (0%)
Opportunistic infection	0/10 (0%)		1/79 (1.3%)
Skin infection [with normal or Grade 1-2 ANC]	0/10 (0%)		3/79 (3.8%)
Wound infection [with normal or Grade 1-2 ANC]	0/10 (0%)		1/79 (1.3%)
Injury, poisoning and procedural complications
Arterial injury - Extremity-lower	1/10 (10%)		0/79 (0%)
Dermatitis radiation	0/10 (0%)		1/79 (1.3%)
Late RT Toxicity: subcutaneous tissue: NOS	0/10 (0%)		1/79 (1.3%)
Postoperative hemorrhage	1/10 (10%)		0/79 (0%)
Investigations
Laboratory test abnormal	1/10 (10%)		0/79 (0%)
Leukopenia	1/10 (10%)		1/79 (1.3%)
Lymphopenia	1/10 (10%)		1/79 (1.3%)
Neutrophil count decreased	2/10 (20%)		1/79 (1.3%)
Platelet count decreased	0/10 (0%)		1/79 (1.3%)
Musculoskeletal and connective tissue disorders
Joint disorder	1/10 (10%)		1/79 (1.3%)
Late RT Toxicity: joint: NOS	1/10 (10%)		1/79 (1.3%)
Muscle weakness	1/10 (10%)		0/79 (0%)
Pain in extremity	1/10 (10%)		1/79 (1.3%)
Nervous system disorders
Dizziness	1/10 (10%)		0/79 (0%)
Hydrocephalus	0/10 (0%)		1/79 (1.3%)
Neuralgia	1/10 (10%)		0/79 (0%)
Peripheral motor neuropathy	0/10 (0%)		2/79 (2.5%)
Psychiatric disorders
Confusion	0/10 (0%)		1/79 (1.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/10 (0%)		1/79 (1.3%)
Skin and subcutaneous tissue disorders
Decubitus ulcer	1/10 (10%)		0/79 (0%)
Skin disorder	0/10 (0%)		1/79 (1.3%)
Skin induration	0/10 (0%)		1/79 (1.3%)
Vascular disorders
Hematoma	0/10 (0%)		1/79 (1.3%)
Hemorrhage	0/10 (0%)		1/79 (1.3%)
Hypertension	1/10 (10%)		0/79 (0%)
Thrombosis	1/10 (10%)		0/79 (0%)
Vascular disorder	1/10 (10%)		0/79 (0%)
Other (Not Including Serious) Adverse Events
	Cohort A - Chemotherapy		Cohort B - No Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/10 (80%)		73/79 (92.4%)
Blood and lymphatic system disorders
Blood disorder	1/10 (10%)		1/79 (1.3%)
Febrile neutropenia	1/10 (10%)		0/79 (0%)
Hemoglobin decreased	3/10 (30%)		19/79 (24.1%)
Hemolysis	1/10 (10%)		0/79 (0%)
Cardiac disorders
Arrhythmia supraventricular	1/10 (10%)		0/79 (0%)
Left ventricular failure	1/10 (10%)		0/79 (0%)
Palpitations	1/10 (10%)		0/79 (0%)
Premature ventricular contractions	1/10 (10%)		0/79 (0%)
Sinus tachycardia	1/10 (10%)		0/79 (0%)
Supraventricular tachycardia	1/10 (10%)		0/79 (0%)
Ear and labyrinth disorders
Tinnitus	1/10 (10%)		0/79 (0%)
Eye disorders
Diplopia	1/10 (10%)		0/79 (0%)
Vision blurred	1/10 (10%)		0/79 (0%)
Gastrointestinal disorders
Abdominal pain	1/10 (10%)		1/79 (1.3%)
Constipation	2/10 (20%)		4/79 (5.1%)
Diarrhea	1/10 (10%)		5/79 (6.3%)
Ear, nose and throat examination abnormal	2/10 (20%)		1/79 (1.3%)
Gastritis	1/10 (10%)		1/79 (1.3%)
Gastrointestinal disorder	1/10 (10%)		1/79 (1.3%)
Nausea	2/10 (20%)		13/79 (16.5%)
Vomiting	2/10 (20%)		5/79 (6.3%)
General disorders
Chills	1/10 (10%)		3/79 (3.8%)
Edema limbs	0/10 (0%)		11/79 (13.9%)
Edema limbs	6/10 (60%)		59/79 (74.7%)
Fatigue	3/10 (30%)		27/79 (34.2%)
Fever	1/10 (10%)		5/79 (6.3%)
Gait abnormal	1/10 (10%)		6/79 (7.6%)
General symptom	1/10 (10%)		1/79 (1.3%)
Ill-defined disorder	1/10 (10%)		0/79 (0%)
Localized edema [trunk/genital]	1/10 (10%)		3/79 (3.8%)
Pain [NOS]	1/10 (10%)		1/79 (1.3%)
Pain [other]	3/10 (30%)		10/79 (12.7%)
Stern's Scale Toxicity: edema: NOS	6/10 (60%)		59/79 (74.7%)
Infections and infestations
Gastric infection [with unknown ANC]	1/10 (10%)		0/79 (0%)
Infection [other]	0/10 (0%)		4/79 (5.1%)
Skin infection [with normal or Grade 1-2 ANC]	1/10 (10%)		1/79 (1.3%)
Wound infection [with normal or Grade 1-2 ANC]	2/10 (20%)		10/79 (12.7%)
Wound infection [with unknown ANC]	1/10 (10%)		1/79 (1.3%)
Injury, poisoning and procedural complications
Dermatitis radiation	2/10 (20%)		22/79 (27.8%)
Fracture	0/10 (0%)		5/79 (6.3%)
Late RT Toxicity: subcutaneous tissue: NOS	5/10 (50%)		25/79 (31.6%)
Postoperative hemorrhage	1/10 (10%)		0/79 (0%)
Radiation recall reaction (dermatologic)	1/10 (10%)		10/79 (12.7%)
Seroma	1/10 (10%)		10/79 (12.7%)
Wound dehiscence	0/10 (0%)		5/79 (6.3%)
Investigations
Activated partial thromboplastin time prolonged	1/10 (10%)		1/79 (1.3%)
Alanine aminotransferase increased	2/10 (20%)		1/79 (1.3%)
Alkaline phosphatase increased	2/10 (20%)		2/79 (2.5%)
Aspartate aminotransferase increased	1/10 (10%)		1/79 (1.3%)
Gamma-glutamyltransferase increased	1/10 (10%)		1/79 (1.3%)
Hyperbilirubinemia	1/10 (10%)		1/79 (1.3%)
Laboratory test abnormal	1/10 (10%)		2/79 (2.5%)
Leukopenia	3/10 (30%)		4/79 (5.1%)
Lymphopenia	4/10 (40%)		7/79 (8.9%)
Neutrophil count decreased	1/10 (10%)		1/79 (1.3%)
Platelet count decreased	4/10 (40%)		1/79 (1.3%)
Weight loss	1/10 (10%)		5/79 (6.3%)
Metabolism and nutrition disorders
Acidosis	1/10 (10%)		0/79 (0%)
Anorexia	2/10 (20%)		7/79 (8.9%)
Dehydration	1/10 (10%)		0/79 (0%)
Hyperglycemia	2/10 (20%)		4/79 (5.1%)
Hyperkalemia	1/10 (10%)		2/79 (2.5%)
Hypoalbuminemia	2/10 (20%)		4/79 (5.1%)
Hypocalcemia	1/10 (10%)		4/79 (5.1%)
Hypokalemia	2/10 (20%)		3/79 (3.8%)
Hyponatremia	3/10 (30%)		3/79 (3.8%)
Musculoskeletal and connective tissue disorders
Back pain	1/10 (10%)		6/79 (7.6%)
Buttock pain	1/10 (10%)		3/79 (3.8%)
Joint disorder	1/10 (10%)		1/79 (1.3%)
Joint disorder	6/10 (60%)		33/79 (41.8%)
Joint pain	1/10 (10%)		7/79 (8.9%)
Late RT Toxicity: joint: NOS	6/10 (60%)		30/79 (38%)
Muscle weakness	1/10 (10%)		4/79 (5.1%)
Muscle weakness lower limb	2/10 (20%)		5/79 (6.3%)
Musculoskeletal disorder	2/10 (20%)		5/79 (6.3%)
Myalgia	1/10 (10%)		1/79 (1.3%)
Neck pain	2/10 (20%)		0/79 (0%)
Pain in extremity	2/10 (20%)		40/79 (50.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/10 (10%)		2/79 (2.5%)
Nervous system disorders
Depressed level of consciousness	1/10 (10%)		0/79 (0%)
Dizziness	1/10 (10%)		3/79 (3.8%)
Extrapyramidal disorder	1/10 (10%)		0/79 (0%)
Headache	1/10 (10%)		4/79 (5.1%)
Neuralgia	2/10 (20%)		4/79 (5.1%)
Neurological disorder NOS	0/10 (0%)		4/79 (5.1%)
Peripheral motor neuropathy	0/10 (0%)		8/79 (10.1%)
Peripheral sensory neuropathy	1/10 (10%)		18/79 (22.8%)
Phantom pain	1/10 (10%)		0/79 (0%)
Speech disorder	1/10 (10%)		0/79 (0%)
Taste alteration	1/10 (10%)		1/79 (1.3%)
Psychiatric disorders
Anxiety	0/10 (0%)		4/79 (5.1%)
Depression	2/10 (20%)		2/79 (2.5%)
Insomnia	0/10 (0%)		4/79 (5.1%)
Renal and urinary disorders
Proteinuria	1/10 (10%)		0/79 (0%)
Urinary retention	0/10 (0%)		4/79 (5.1%)
Reproductive system and breast disorders
Erectile dysfunction	1/10 (10%)		0/79 (0%)
Gynecomastia	1/10 (10%)		0/79 (0%)
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary hemorrhage	1/10 (10%)		0/79 (0%)
Cough	1/10 (10%)		6/79 (7.6%)
Dyspnea	2/10 (20%)		4/79 (5.1%)
Hemorrhage nasal	1/10 (10%)		0/79 (0%)
Hypoxia	1/10 (10%)		1/79 (1.3%)
Pleural effusion	1/10 (10%)		1/79 (1.3%)
Pneumothorax	1/10 (10%)		0/79 (0%)
Respiratory disorder	1/10 (10%)		0/79 (0%)
Skin and subcutaneous tissue disorders
Alopecia	4/10 (40%)		3/79 (3.8%)
Decubitus ulcer	1/10 (10%)		4/79 (5.1%)
Erythema multiforme	1/10 (10%)		2/79 (2.5%)
Pain of skin	0/10 (0%)		7/79 (8.9%)
Pruritus	1/10 (10%)		2/79 (2.5%)
Rash desquamating	2/10 (20%)		7/79 (8.9%)
Skin disorder	1/10 (10%)		9/79 (11.4%)
Skin hyperpigmentation	2/10 (20%)		14/79 (17.7%)
Skin induration	1/10 (10%)		1/79 (1.3%)
Skin induration	5/10 (50%)		38/79 (48.1%)
Sweating	1/10 (10%)		0/79 (0%)
Telangiectasia	1/10 (10%)		0/79 (0%)
Vascular disorders
Hematoma	2/10 (20%)		3/79 (3.8%)
Hypertension	1/10 (10%)		0/79 (0%)
Hypotension	1/10 (10%)		1/79 (1.3%)
Thrombosis	1/10 (10%)		4/79 (5.1%)
Vascular disorder	2/10 (20%)		1/79 (1.3%)

Limitations/Caveats

Due to unmet accrual goals for Cohort A, the decision was made to close this cohort and to increase the sample size of Cohort B. Due to the small sample size for Cohort A results were not reported.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.