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Objectives

Late Effects of Pre-Operative Imaged-Guided Radiation Therapy (IGRT) in Extremity Sarcoma Patients: Results OF RTOG 0630.

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Objectives

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  1. Late Effects of Pre-Operative Imaged-Guided Radiation Therapy (IGRT) in Extremity Sarcoma Patients: Results OF RTOG 0630 Dian Wang, MD., Ph.D.; Qiang Zhang, Ph.D.; Burton L. Eisenberg, MD. ; John Kane III, MD.; X Allen Li, Ph.D.; David Lucas, MD.; Carolyn R. Freeman, MD.; Andy Trotti, MD.; Ying Hitchcock, MD.,; David G. Kirsch, MD., Ph.D.

  2. Objectives • Primary objective: • Determine the effect of reduced RT volume through IGRT on late radiation morbidity at 2 years from the start of RT • Late morbidity defined as Grade 2 or higher: (1) edema scored by Stern’s scale (2) subcutaneous fibrosis scored by RTOG/EORTC criteria (3) joint stiffness scored by RTOG/EORTC criteria • Secondary objectives: • Determine the pattern of failure

  3. RTOG 0630 Schema Cohort B pre-operative IGRT only Cohort A pre-operative IGRT + chemotherapy ↓ ↓ 50 Gy delivered in 25 fractions - 3DCRT or IMRT - IGRT: 3D or 2D imaging 50 Gy delivered in 25 fractions - 3DCRT or IMRT - IGRT: 3D or 2D imaging ↓ Chemotherapy: Neoadjuvant Concurrent or interdigitated Adjuvant • Surgery 4-8 weeks later • For a positive margin • EBRT: 16 Gy in 8 fx • Brachytherapy: LDR (16 Gy) or HDR (3.4 Gy X 4 fx) • IORT: 10 -12.5 Gy in 1 fx Closed to poor accrual (12 patients)

  4. IGRT: Daily Pre-treatment Images • Daily pretreatment images were required: • Bony structure adjacent to the gross tumor PTV: standard for position adjustment • An error of > 5 mm after shifts based on the pretreatment images is unacceptable • 3D images • KV and MV fan-beam CT • KV and MV cone-beam CT • 2D orthogonal images • KV • MV • Fiducial markers (optional)

  5. Target Definitions • Gross Tumor Volume (GTV): defined by MRI T1 plus contrast images. • Clinical Tumor Volume (CTV): GTV plus area at risk for microscopic disease • Intermediate-High grade tumors ≥ 8cm: CTV = GTV plus 3 cm longitudinal margins + suspicious edema defined by T2 MRI and 1.5 cm radial margins • CTV for all other tumors: Typically CTV = GTV plus 2 cm longitudinal margins + suspicious edema defined by T2 MRI and 1.0 cm radial margins • Planning Target Volume (PTV): CTV plus 5 mm • Dose constraints for normal tissue structures: • TD5/5 (target dose to cause 5% toxicity in 5 years)

  6. Protocol Summary • Patient accrual: March 2008 through September 2010 • Cohort B: 86 patients • 7 patients excluded from analysis: • 6 ineligible • 2 not extremity sarcoma, 2 MRI>8 weeks prior to study entry, 1 no labs prior to study entry, 1 started protocol tx prior to study entry) • 1 no protocol treatment • 79 patients eligible: analyzed for this late toxicity report • Sample size of 66 needed to detect a 15% absolute improvement in late toxicity compared to pre-operative RT arm of the NCIC SR2 trial 37% (27/73) to 22%

  7. Patient Characteristics • Location • Upper leg 58.3% • Lower leg 20.3% • Median Size 10.5 cm (3.5-30 cm) • Histology • UPS 21.5% • Myxofibrosarcoma 20.3% • Myxoid Liposarcoma 12.7% • LMS 10.2% • Grade: G3 46.8%, G2 24.1%

  8. Treatment Delivered for 79 patients • Radiation Type • 3DCRT - 20 (25.3%) • IMRT - 59 (74.7%) • Surgery • 74 (93.7%) • R0 - 54 (73%) • R1 - 18 (24.3%) • R2 - 2.7% • 5 patients did not undergo surgery because of metastatic disease

  9. Outcomes for 79 patients • Major Wound Complications: 36.6% • Median Follow-up: 2.82 years (0.09-4.7 years) • Local Failure • 5 patients without surgery • 5 patients out of 74 with local recurrence after surgery (6.8%)

  10. Patterns of Local Failure (Cohort B) 5 patients did not have surgery due to systemic progression

  11. Toxicities Definitively, Probably or Possibly Related to Protocol • Grade 3/4 by CTCAE: mainly due to skin and bleeding • Grade 3: 20 (25.3%) • Grade 4: 4 (5.1%) • For the 2-year late toxicities (subcutaneous fibrosis, edema and joint stiffness) • 22 patients excluded: • 13 died<1.75 years • 3 <1.75 years F/U • 6 have at least 1.75 year F/U but without 2-year toxicity assessment • 57 patients are evaluable for the 2-year late toxicity endpoints (between 1.75 and 2.25 years). Subjects analyzed for this report

  12. Summary of 2-year Late Morbidities (N=57 eligible) • Subcutaneous fibrosis and joint stiffness were scored by the RTOG/EORTC criteria, and edema by Stern’s Scale. • Rate of the 2-year Grade 2+ late toxicity events (at least one event of the above three) was reported to be 37% (27/73) in the NCIC SR2 trial preoperative arm. A significant reduction of these late toxicities was observed when compared with the NCIC SR2 Trial Preoperative arm (6/57 vs. 27/73, p=0.0005, Fisher’s Exact test)

  13. Late Effects and Tumor Characteristics/ Treatment Factors • Resection of blood vessels associated with late effects • p=0.08 for subcutaneous fibrosis • p=0.03 for joint stiffness • p=1.0 for edema • No other treatment-related or tumor-specific factors correlated with late effects

  14. Summary • RTOG 0630 Target Definitions and IGRT: Significant reduction of late radiation morbidities (Grade 2+ subcutaneous fibrosis, joint stiffness and edema) when compared to NCIC SR2 Trial Preoperative RT Arm • 10.5% RTOG 0630 vs. 37% NCIC SR2 (p=0.0005) • Resection of blood vessels has a borderline significance on late effects • Rate of Local Failure after surgery (6.8% at 2.8 years) is within expected range and all are in-field failures • Absence of marginal-field local failures reported to-date and the favorable late effect profile indicates that the parameters of radiotherapy in RTOG 0630 can be utilized for pre-operative IGRT of extremity STS

  15. Acknowlegement • RTOG HQ • All investigators and patients from participating institutions • Colleagues in the RTOG sarcoma working group • This project was supported by RTOG grant U10 CA21661, CCOP grant U10 CA37422, and ATC grant U24 CA81647 from the National Cancer Institute (NCI)

  16. Radiation Therapy: 3DCRT or IMRT • Prescription: 50 Gy in 25 fractions prescribed to 95% of the PTV • Variations • No variation: Prescription dose per protocol • Minor variation: greater than 20%, but no more than 25% of PTV received ≥110% prescription dose. • Major variation: more than 25% of PTV received ≥110% prescription dose or dose to the above normal tissue structures is more than the TD5/5 limit.

  17. RTOG 0630 Schema Cohort B: patients receiving pre-operative IGRT only Tumor Grade: Low Intermediate High Tumor Stage: T1 (≤ 5 cm) or T2 (>5 cm) Superficial (a) or deep (b) Histology Type: IG-RT: 3DCRT or IMRT 3D or 2D imaging Chemotherapy: Neoadjuvant Concurrent or interdigitated Adjuvant ↓ 50 Gy delivered in 25 fractions - 3DCRT or IMRT -IGRT: 3D or 2D imaging ↓ • Surgery performed 4-8 weeks later. • For a positive margin • EBRT: 16 Gy in 8 fx • Brachytherapy: LDR (16 Gy) or HDR (3.4 Gy X 4 fx) • IORT: 10 -12.5 Gy in 1 fx

  18. Late Morbidities By tumor characteristics and other potential treatment factors

  19. Late Morbidities By Tumor Characteristics and Treatment 1. Only 1 unacceptable variation

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