1. Margin Reduction using IGRT For Soft-Tissue Sarcoma: Secondary Analysis of RTOG 0630 Dian Wang, MD., Ph.D. Rush University Medical Center CTOS October 17, 2014

2. Contributing Authors Allen Li, Ph.D., Medical College of Wisconsin, USA Xiaojian Chen, PhD Medical College of Wisconsin, USA Qiang Zhang, Ph.D. NRG Oncology Statistics, USA David G. Kirsch, MDDuke University Medical Center, USA Ivy Petersen, MDMayo Clinic, USA Thomas F. DeLaney, MD Massachusetts General Hospital, USA Carolyn R. Freeman, MD McGill University Health Centre, CA Andy Trotti, MD. H. Lee Moffitt Cancer Ct Res Inst, USA Ying Hitchcock, MD University of Utah, USA Meena Bedi, MD Medical College of Wisconsin, USA Michael Haddock, MD Mayo Clinic, USA Anurag Singh, MD Roswell Park Cancer Institute, USA George Dundas, MD Cross Cancer Institute, CA Dian Wang, MD Rush University Medical Center, USA

3. Disclosure None

4. IGRT, especially IG-IMRT, decreases late side effects of the patients with soft tissue sarcoma of the extremity –A multicenter phase II trial of preoperative image- guided radiotherapy for soft tissue sarcoma of the extremity (RTOG 0630) (Wang et al., ASTRO 2013) –A single institutional phase II trial of preoperative image-guided IMRT for soft tissue sarcoma of the lower extremity (O’Sullivan et al., Cancer 2013) –A retrospective review of a single institutional experience (Alektiar et al., JCO 2008) However, what is the impact of different pretreatment imaging modalities? Background

5. IMRT decreases RT side effects No of pts Med F/U (mo) RTLCFibrosisEdemaJoint stiffness Davis Radiol 2005 Phase III (multi-) 9439.6Preop vs. postop 2D >90%31.5% vs. 48.2% postop 15.1% vs. 23.2% postop 17.8% vs. 23.2% postop Alektiar JCO 2008 Retro- (single) 4135Postop IMRT 94%?12.2%17.2% O’Sullivan Cancer 2013 Phase II (single) 7049Preop IMRT 93%9.3%11.1%5.4% Wang ASTRO 2013 Phase II (multi- RTOG 0630) 8643Preop IMRT 75% 3DCRT 25% 93%5.3%3.5%5.3%

6. Primary objective: –Determine the effect of a reduced RT volume using 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 RTOG 0630 A phase II trial of preoperative image-guided radiotherapy for soft tissue sarcoma of the extremity

7. RTOG 0630 Schema ↓ Cohort A pre-operative IGRT + chemotherapy 50 Gy delivered in 25 fractions - 3DCRT or IMRT - IGRT: 3D or 2D imaging Chemotherapy: Neoadjuvant Concurrent or interdigitated Adjuvant Closed due to poor accrual (12 patients) Cohort B pre-operative IGRT only 50 Gy delivered in 25 fractions - 3DCRT or IMRT - IGRT: 3D or 2D imaging 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 ↓ ↓ Completed 03/2008-09/2010): 86 patients

8. 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 The following six pre-treatment images were collected from RTOG 0630 –3D images KV fan-beam CT (KVCT) MV fan-beam CT (MVCT) KV cone-beam (KVCB) MV cone-beam (MVCB) –2D orthogonal images KV Orthogonal images (KVorth) MV Orthogonal images (MVorth)

9. Clinical outcomes of Cohort B 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 borderline significance on late effects Rate of local failure after surgery (6.8% at 2.8 years) is within expected range and are all in-field failures Absence of marginal recurrences and the favorable late effect profile at 2 years indicates that the parameters of radiotherapy in RTOG 0630 can be utilized for pre- operative IGRT of extremity STS

10. Secondary Analysis: Objectives Six IGRT modalities were used in the RTOG 0630 trial. We analyzed all the daily patient-repositioning data collected in this trial to (1) compare the performance of the six IGRT modalities, (2) determine the impact of daily image guidance, and (3) estimate required CTV-to-PTV margins

11. Secondary Analysis: Data Collection Prospective Data Collection from participating institutions # of institutions: 18 # of patients: 98 All patients were repositioned daily based on bony anatomy registration using the pretreatment imaging, including KVCT, KVCB, MVCT, MVCB, KVorth and MVorth

12. Secondary Analysis: Methodology Daily patient repositioning data, including shifts in right-left (RL), superior-inferior (SI) and anterior-posterior (AP) directions and rotations in pitch, roll and yaw were analyzed The mean and standard deviations (SD) for each shift and rotation were calculated for each patient and for each IGRT modality. For the two most commonly used modalities MVCT (25/98) and KVorth (44/98), the t-test and F-test were performed to analyze the differences in their means and SDs The CTV-to-PTV margins were estimated using 2.5∑+0.7σ, where ∑ and σ were systematic and random positioning errors, respectively, based on the data for MVCT and KVorth

13. Secondary Analysis: Results Between MVCT and KVorth, there were no statistically significant differences in the shifts and rotations (p>0.1), except in the shifts in AP direction (2.2 vs - 0.5 mm, p<0.002) Daily Repositioning Shifts (mean ± SD) mm) : Modality Right-Left (RL)Superior-Inferior (SI)Anterior-Posterior (AP) KVCT 0.5±4.21.7±5.2-1.9±4.3 KVCB 0.35±3.5-0.4±1.82.5±5.6 MVCT 1.0±4.0-0.4±3.12.2±3.3 MVCB 1.1±8.01.2±1.3-0.9±4.4 KVorth -0.5±4.00.0±2.3-0.5±3.2 MVorth 1.0±2.73.7±6.50.1±4.0 For the two most commonly used modalities (MVCT and KVorth) the mean±SD of pitch rotations were -0.1±1.0 and 0.4±1.3 deg, respectively

14. Secondary Analysis: Results Average shifts in x, y, and z directions for each patients for six modalities

15. Secondary Analysis: Results Modality Systematic Error (  )Random Error (  ) Margin x (mm) y (mm) z (mm) x (mm) y (mm) z (mm) x (mm) y (mm) z (mm) KVCT4.25.24.35.14.85.014.216.514.3 KVCB3.51.85.63.32.94.611.16.517.3 MVCT4.03.13.34.23.84.913.010.411.7 MVCB8.01.34.46.82.93.224.65.313.2 KVorth4.02.33.24.54.04.113.18.610.8 MVorth2.76.54.04.53.84.410.019.013.0 The estimated CTV-to-PTV margins in RL, SI and AP directions required in the absence of daily IGRT would be 13.0, 10.4, and 11.7 mm from MVCT data, and 13.1, 8.6, and 10.8 mm from KVorth data, respectively

16. Secondary Analysis: Conclusions  Differences between six available IGRT modalities for positioning patients with soft-tissue sarcoma of the extremity based on bony anatomy were not significant except for  Shifts in AP were significantly different between MVCT and KVorth (2.2 vs. -0.5, p<0.002)  The observed large daily repositioning errors as well as large variations between institutions (data not shown) imply that daily IGRT is necessary for this tumor site, particularly in a multi-institutional trial  Otherwise, a CTV-to-PTV margin of 1.5 cm is required to account for daily variations

17. Acknowlegement NRG/RTOG HQ All investigators and patients from participating institutions This project was supported by RTOG grant U10 CA21661, CCOP grant U10 CA37422, and ATC grant U24 CA81647 from the National Cancer Institute (NCI)

18. Patient Characteristics Location –Thigh 58.3% – 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%

19. 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 Radiiotherapy ReviewPercent Per Protocol55.7% Acceptable Variation32.9% Unacceptable Variation10.1%

20. Outcomes for 79 patients Major Wound Complications: overall 36.6% (42% for LE) –Exclusively in lower extremity Median Follow-up: 2.82 years (0.09-4.7 years) Local Failure –5 patients without surgery –5 patients out of 74 with recurrence after surgery (6.8%) Metastasis and Survival Percent Distant Metastasis40.5% Death29.1%