1. IMPACT OF CHEMOTHERAPY IN UTERINE SARCOMA (UTS): REVIEW OF 12 CLINICAL TRIALS FROM EORTC INVOLVING ADVANCED UTS COMPARED TO OTHER SOFT TISSUE SARCOMA (STS) I Ray-Coquard, A Natukunda, JY Blay, P Casali, I Judson, A Krarup Hansen, LH Lindner, AP dei Tos, H Gelderblom, S Marreaud, S Litière, P Rutkowski, P Hohenberger, A Gronchi, W van der Graaf.

2. Background Uterine sarcoma :  Age 40-60 y  5-10 % of uterine corpus malignancies  7% of all STS, 70% LMS Active drugs reported in litt (phase II)*:  Doxorubicin, PLD, ifosfamide, gemcitabine, trabectedin & combo Dox-Ifos, Gem-Tax, Gem- DTIC, Dox-Trabectedin  RR 11 – 54% & median PFS 3 to 6 months No data from phase III trials in first line on RR, PFS and OS (except Muss, Cancer 1985, 100 pts) *Omura 83, Sutton 88, Look 04, Sutton 05, Sutton 09, Hensley 08, Duffaud 10, Garcia del Muro 11, Pautier 13

3. Objectives To give an overview of uterine sarcoma patient characteristics compared to other sarcoma sub-types. To evaluate the factors associated with the clinical behavior of patients with advanced or metastatic uterine sarcoma treated by first line chemotherapy Using data of 12 EORTC pooled sarcoma trials, from 1977 to 2001.

4. Methods Categorical variables were summarized by frequencies and percentages, continuous variables were summarized by median, range, interquartile range (IQR). Comparisons between factors was done using chi-square or Kruskal-wallis tests. Survival was estimated by Kaplan Meier method Univariate and multivariate analyses were done using  Cox regression for PFS and OS  Logistic regression for RR

5. Selection of uterine sarcoma patients 3002 patients in the EORTC sarcoma database 175 received prior treatment 2827 received no prior treatment 225 Uterine Sarcoma patients 2602 Other subtypes From 1977 to 2001

6. Results (charact. of Ut. Sarcoma pts compared to all others)

7. Results (charact. of UtS patients compared to others)

8. Overall Survival Uterine vs. other sub types

9. Overall Survival - univariate analysis Covariates Patients (N) Observed Events (O) Hazard Ratio (95% CI) P-Value Performance status PS 0 103 791.00 <0.001 PS 1 98 881.67 (1.23, 2.27) PS 2+ 21 3.25 (1.99, 5.30) Prior Surgery No 11 101.00 0.46 Partial 73 600.66 (0.34, 1.30) Total 89 750.66 (0.34, 1.29) Prior radiotherapy No 155 1271.00 0.674 Yes 68 621.07 (0.79, 1.45) Primary site involved No 121 1031.00 0.394 Yes 81 70.87 (0.64, 1.19) Histopathological grade Grade I&II 52 411.00 0.002 Grade III 90 811.84 (1.25, 2.71) Treatment Anthracyclins 96 841.00 DOX+IFO 66 581.07 (0.77, 1.51)0.96 CYVADIC 23 200.95 (0.58, 1.55) IFO ALONE 40 291.01 (0.66, 1.54) Age (cts.) 2181851.02(1.00, 1.03)0.037 HistologyLeiomyo 159 1381.00 Other 57 450.73 (0.51, 1.03)0.072

10. Overall Survival multivariate analysis Factor Hazard Ratio 95% Lower CL for Hazard Ratio 95% Upper CL for Hazard Ratio P Histopathological grade I& II vs. III0.61 0.410.910.014 Performance status PS 1 vs. PS 01.871.262.75 0.002 PS 2+ vs. PS 02.411.294.51  Better outcome for patients with WHO performance status 0 vs. 1 & 2.  Better outcome was observed for uterine patients with histopathological grade I&II compared to grade III  No significant effect of chemotherapy regimen in first line treatment observed for OS

11. Overall Survival by prognostic factors (Grade /PS) Grade Median (95% CI) (Months) GRADE I&II12.53 (9.00, 21.65) GRADE III9.23 (7.46, 11.93) Performance status Median (95% CI) (Months) 0 13.83 (10.38, 17.38) 19.07 (6.77, 11.01) 2+3.35 (2.04, 7.95)

12. PFS Uterine vs. other sub types

13. PFS univariate analysis Covariates Patients (N) Observed Events (O) Hazard Ratio (95% CI) P-Value Performance status Missing data n = 3 PS 0103931.00 0.022 PS 198961.31 (0.99, 1.75) PS 2+21 1.85 (1.15, 2.98) Prior Surgery Missing data n= 52 No11 1.00 0.030 Partial73690.49 (0.26, 0.94) Total89840.42 (0.22, 0.80) Histopathological grade Grade I&II52481.00 0.099 Grade III90871.36 (0.94, 1.95) Missing83 Chemotherapy regimen Anthracyclins96891.00 0.451 DOX+IFO66631.10 (0.80, 1.52) CYVADIC23 0.82 (0.51, 1.30) IFO ALONE40381.22 (0.83, 1.78) Age Missing data n =7 < 40 yrs23181.00 0.028 40-50 yrs56541.85 (1.07, 3.19) 50-60 yrs79772.24 (1.32, 3.79) >=60 yrs60571.98 (1.16, 3.39) Histology Missing data n = 9 Leiomyo sarcoma1591541.00 0.034 Other57510.71 (0.51, 0.98) Prior RT, CT regimen, histological grade, primary site involved are not prognostic factors

14. PFS Multivariate analysis Factor Hazard Ratio 95% Hazard Ratio Confidence Limits P Prior surgeryPartial vs. No0.340.150.790.022 Total vs. No0.310.130.71 Histopathological grade I &II vs. III0.610.390.950.027  Better outcome for patients who had prior partial or total surgery vs. no prior surgery  Better outcome was observed for uterine patients with histopathological grade I&II compared to grade III  No significant effect of chemotherapy regimen in first line treatment observed for PFS

15. Response to chemotherapy  52 (23.2%) patients responded to chemotherapy  Few response among Ifosfamide alone patients  Univariate analysis identified high grade (RR 30%) vs low grade (RR 13%), non leiomyosarcoma (RR 33%) vs leio (RR 20%) and anthracyclins containing CT (RR 27%) vs ifo alone (RR 5%) as predictive factors for RR 25% 27%35%5%

16. Conclusions Poor prognosis for PFS (median 4 months) & OS (10 months) Prognostic impact of performance status and grade on OS There was no significant effect of chemotherapy regimen observed neither for PFS nor OS.  Anthra alone remains a standard of care  Do not used Ifosfamide alone for Ut sarcoma pts Only 25% responders to chemotherapy among the uterine sarcoma patients. Need for new strategies !