1. Evaluation of Femur Fracture Risk in Soft-Tissue Sarcoma of the Thigh Treated with Intensity- Modulated Radiation Therapy (IMRT) Michael R. Folkert, MD PhD, Samuel Singer, MD, Murray F. Brennan, MD, Patrick J. Boland MD, Kaled M. Alektiar, MD Departments of Radiation Oncology, Surgery, and Orthopedic Surgery Memorial Sloan-Kettering Cancer Center New York NY USA

2. Disclosures None of the authors have anything to disclose.

3. Introduction Researchers at PMH 1 have previously examined the risk of femur fracture in patients treated with adjuvant conventional RT for thigh sarcoma. 101 patients were identified with 22 RT- associated fractures; risk factors were assessed and incorporated into a nomogram. 1.Gortzak et al, Cancer 2010; 116(6):1553-1559.

4. Objective: Preliminary data has suggested a lower risk of fracture when using IMRT. We compared the observed risk of femoral fracture in primary soft-tissue sarcoma (STS) of the thigh treated with adjuvant IMRT at MSKCC to the expected risk using the Princess Margaret Hospital (PMH) nomogram.

5. Methods Patients treated with limb-sparing surgery and adjuvant IMRT between 2/2002 and 11/2009 for primary STS of the thigh were included (84); those receiving prophylactic internal fixation were excluded (2). –Median followup was 44 months (range 6-129 months) –Mean of 52 months. Expected femoral fracture risk was calculated using the PMH nomogram. –Direct calculation using maximum likelihood estimates, with P(fracture) = 1/(1+e -Σ(MLE) ) Cumulative risk of fracture was estimated using Kaplan-Meier statistics; univariate and multivariate analysis was performed.

6. N (%)PMH N (%) 82101 GenderFemale35 (43%)52 (51.5%) Male47 (57%)49 (48.5%) Age range(19-88)(20-89) CompartmentAnterior38 (46%)44 (43.6%) Posterior26 (32%)13 (12.9%) Medial/Adductor18 (22%)20 (19.8%) "Other"024 (23.8%) Tumor size range (cm)(2.5-31)(1-28) Extent of Periosteal Stripping<10cm66 (80.5%)80 (79.2%) 10-20cm9 (11%)16 (15.8%) >20cm7 (8.5%)5 (5%) Radiation Dose (Gy) Dose ≥ 60 Gy69 (84.1%)65 (64.4%) Dose < 60 Gy13 (15.9%)36 (35.6%) ChemotherapyYes31 (38%)0 (0%) No51 (62%)101 (100%) Patients

7. Results At a median followup of 44 months: –There were 5 (6.1%) fractures. –The median time to fracture was 12.2 months (range 6.9-54.9 months). –The cumulative risk of fracture using IMRT at 5 years was 8.6% (95% CI 0.6- 16.6%).

8. Results – Comparison to PMH Crude Rates Median time to fracture in PMH cohort was 4 years. The 5 year crude risk in PMH cohort (15/22 fractures in 101 patients) was 14.8%, compared to 6.1% in the current study using IMRT. 1.Gortzak et al, Cancer 2010; 116(6):1553-1559.

9. Observed vs. Expected Fracture Risk The PMH femur fracture nomogram was predictive in the IMRT cohort. The observed crude risk of fractures was 6.1% compared to 26.4% expected crude risk from the PMH nomogram.

10. Predictors of fracture: univariate analysis (5 years) P value Gender.403 Age (continuous).315 Compartment of Thigh.191 Tumor Size (continuous).012 Periosteal stripping.049 Dose > 60 Gy.519 Chemotherapy.818 - On MVA, these factors did not retain significance.

11. Conclusions In this study, the crude observed risk of femoral fracture in patients treated with IMRT (6.1%) is less than the expected risk using the PMH nomogram (26.4%). Longer followup duration in the PMH cohort may contribute to this difference, but even reporting cumulative 5-year risk in the IMRT cohort, the rate was only 8.6%; longer followup in our cohort is still needed. Established predictors of femoral fracture such as gender, age, tumor size, and periosteal stripping seem to exert less influence when using IMRT.

12. Thank you for your kind attention. Any questions?

13. PMH Nomogram The PMH nomogram for prediction of femur fracture risk was based on variables found to be associated on multivariate logistic regression analysis. 1 The fit of their model on the basis of the receiver-operating characteristic (ROC) curve was excellent, with an area under the curve (AUC) of 0.90. 1.Gortzak et al, Cancer 2010; 116(6):1553-1559.

14. Dosimetric Concerns When expanding GTV to CTV, nearby bone is excluded. A longitudinal strip of skin is spared to protect lymphatic drainage. Total Dose or Volume ≤To: 64%V 40 Gy 37 GyMean Dose 66 GyMax Point Dose

15. Prophylactic IM Nail Prophylactic femoral intramedullary (IM) nailing has been raised as a consideration for patients at high risk of fracture. While this may potentially benefit high-risk patients treated with conventional radiation therapy, there is no clear indication at this time for patients treated with IMRT.

16. Dose to Fracture Site Performing dosimetric analysis on site of fracture relative to initial treatment (ongoing).

17. Results, Univariate Analysis Predictors of fracture on univariate analysis (at 5 years); on MVA, these factors did not retain significance. 5 Year Cumulative RiskP value Female13.7% (0-30.5%).392 Male4.8% (0-11.6%) Age ≤ 50 0%.100 Age > 5013.2% (0-25.6%) Compartment, Anterior19.9% (1.5-38.3%).037 Compartment, Posterior0.0% Compartment, Medial0.0% Tumor Size, ≤ 10cm0.0%.038 Tumor Size, > 10 cm 16.9% (0.1-33.7%) <10 cm periosteal stripping7.5% (0-16.5%).001 10-20 cm periosteal stripping0.0% > 20 cm periosteal stripping31.4% (0-68.6%) Dose ≤ 60 Gy 0.0%.305 Dose > 60 Gy10.2% (0-19.6%) No Chemotherapy9.1% (0-19.9%).817 Chemotherapy6.6% (0-15.6%)