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

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 Lewis. Ann Surg Singer. Ann Surg 2003

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 van Dalen. EJSO 2006

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

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

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%)

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

Results: Patient/Tumor Characteristics VariableMedianRange Age (yrs)6024~84 Tumor Size (cm)275~70 Time to LR (mo)212~160 VariableCategoryN% Total SexFemale Histologic GradeHigh Histologic SubtypeWell-differentiated Dedifferentiated Myxoid43.8 Round cell32.9

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

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< Primary Size0.1 LR Resection< Contig Organ0.1 Primary Grade< Age0.2 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

Multivariate Analysis of Disease-Specific Survival for First LR (N=105) VariablepHRLCI 0.95UCI 0.95 LR Growth Rate LR Resection Primary Low Grade

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< Micro 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

Multivariate Analysis of Disease-Specific Survival for Complete Resection of First LR (N=61) VariablepHRLCI 0.95UCI 0.95 LR Growth Rate LR Low Grade Primary Low Grade LR Size LR Low Grade Primary Low Grade

Univariate Analysis of Disease-Free Survival for Complete Resection of First LR (N=61) Variablep p LR Growth Rate< Sex0.2 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

Multivariate Analysis of Disease-Free Survival for Complete Resection of First LR (N=61) VariablepHRLCI 0.95UCI 0.95 LR Growth Rate< LR Low Grade LR Size LR Low Grade

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

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

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

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

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