1. Local Recurrence Growth Rate Predicts Outcome In Locally Recurrent Retroperitoneal Liposarcoma James Park, MD, Li-Xuan Qin, PhD, Francesco Prete, MD Murray Brennan, MD, Samuel Singer, MD

2. Background: Retroperitoneal Liposarcoma Retroperitoneal sarcoma (RPS) 15% of soft tissue sarcomas (STS) 1 Liposarcoma (LS) most common; 20% of all STS, up to 50% of RPS 2 Complete resection feasible in 80% of primary RPLS 3 Local recurrence 40~80%; local effects cause of death in 75% 1,2 1. Stoeckle. Cancer 20012. Lewis. Ann Surg 19983. Singer. Ann Surg 2003

3. Background: Retroperitoneal Liposarcoma Gross margin, grade, and histologic subtype predict survival 1,2 Subtype and contiguous organ resection, predict local recurrence 1 No objective consensus to guide re-resection of local recurrence following complete resection 1. Singer. Ann Surg 20032. van Dalen. EJSO 2006

4. Histologic subtype defines grade and predicts local recurrence and survival in RPLS 1. Singer. Ann Surg 2003 Grade5-yr DSS (%)5-yr LRFS (%) Well-differentiatedlow8345 Dedifferentiatedhigh2012 Myxoid (<5% round cell)low7540 Round cell (>5% round cell)high35NA

5. Purpose Determine prognostic factors for survival and recurrence in patients with locally recurrent retroperitoneal liposarcoma Use these factors to guide therapy and define subset of patients with locally recurrent retroperitoneal liposarcoma most likely to benefit from surgical resection

6. Methods Prospective sarcoma database reviewed 7/82~10/05 All STS treated N=6682 All RPS treated N=607 All RPLS treated N=355 Primary RPLS treated N=207 Complete resection N=180 (180/207 87%) Local recurrence (LR) N=105 (105/180 58%) Complete resection of LR N=61 (61/105 58%)

7. Methods Endpoints: Disease-specific survival (from time of first local recurrence) for all 105 patients Local recurrence-free survival for 61 patients re-resected Statistics:  Univariate analysis- Kaplan Meier curve and Log-rank test  Multivariate analysis- Cox’s PH model and Score test  Cut-point finding- Minimum P value method Patient/tumor variablesTreatment variables  Age  Sex  Microscopic Margins  Histologic Subtype  Grade  Contiguous organ resection  Tumor Size (sum largest dimensions)  Adjuvant Radiation  Time to LR  Adjuvant Chemotherapy

8. Results: Patient/Tumor Characteristics VariableMedianRange Age (yrs)6024~84 Tumor Size (cm)275~70 Time to LR (mo)212~160 VariableCategoryN% Total SexFemale3634.3 Histologic GradeHigh5249.5 Histologic SubtypeWell-differentiated4845.7 Dedifferentiated4946.7 Myxoid43.8 Round cell32.9

9. VariableN% Total Microscopic Margin Negative5351 Contiguous Organ Resection6562 Adjuvant Radiation EBRT Brachy 9898 8787 Adjuvant Chemotherapy109 Results: Treatment characteristics

10. Univariate Analysis of Disease-Specific Survival for First LR (N=105)  Start time: First LR  End point: Dead of disease  LR Growth Rate = Variablep p LR Growth Rate<0.00001Primary Size0.1 LR Resection<0.00001Contig Organ0.1 Primary Grade<0.00001Age0.2 Primary Subtype<0.0001Chemo0.3 LR Size<0.0001Micro Margin0.4 Time to LR0.01Radiation0.6 Sex0.9 Tumor size (sum of max dimensions on imaging) Time from primary resection to LR

11. Multivariate Analysis of Disease-Specific Survival for First LR (N=105) VariablepHRLCI 0.95UCI 0.95 LR Growth Rate0.0151.21.01.4 LR Resection0.0100.40.20.8 Primary Low Grade0.0100.40.20.8

12. Univariate Analysis of Disease-Specific Survival for Complete Resection of First LR (N=61)  Start time: LR resection  End point: Dead of disease Second recurrence  LR Growth Rate = Variablep p LR Growth Rate<0.00001Micro Margin0.3 LR Grade<0.0001Primary Size0.4 LR Subtype0.001Sex0.4 LR Size0.009Age0.4 Primary Grade0.02Radiation0.7 Primary Subtype0.1Chemo0.9 Time to LR0.2 Tumor size (sum of max dimensions on pathology) Time from primary resection to LR

13. Multivariate Analysis of Disease-Specific Survival for Complete Resection of First LR (N=61) VariablepHRLCI 0.95UCI 0.95 LR Growth Rate0.0022.21.33.6 LR Low Grade0.0200.20.10.8 Primary Low Grade0.9901.00.42.8 LR Size0.0011.0 1.1 LR Low Grade0.0010.20.10.5 Primary Low Grade0.2900.60.21.6

14. Univariate Analysis of Disease-Free Survival for Complete Resection of First LR (N=61) Variablep p LR Growth Rate<0.00001Sex0.2 LR Size0.002Micro Margin0.2 LR Grade0.06Primary Subtype0.7 LR Subtype0.07Primary Size0.8 Age0.09Primary Grade0.8 Time to LR0.12LR Resection1.0

15. Multivariate Analysis of Disease-Free Survival for Complete Resection of First LR (N=61) VariablepHRLCI 0.95UCI 0.95 LR Growth Rate<0.0012.71.74.3 LR Low Grade0.3900.70.41.5 LR Size0.0011.11.01.1 LR Low Grade0.0240.50.20.9

16. Finding a cutoff for LR growth rate using the Minimum p value method 0.9 1. Mazumdar. Statist Med 2003

17. Disease-Specific Survival by LR Growth Rate All 105 Patients 61 Re-resected

18. Resection does not improve Disease-specific survival for LR Growth Rate ≥ 0.9 (N=105)

19. Summary  LR growth rate and primary grade are independent predictors of disease-specific survival in locally recurrent RPLS  Patients with LR growth rate ≥ 0.9 cm/month had significantly worse disease-specific survival  Re-resection of the recurrence did not alter the poor outcome for patients with LR growth rate ≥ 0.9 cm/month

20. Conclusion  LR growth rate predicts disease-specific survival and local control following complete resection of locally recurrent RPLS  Patients with LR growth rate ≥ 0.9cm/month did not benefit from aggressive operative management and should be considered for trials of novel targeted therapies