1. Update on treatment modalities of uterine sarcomas Amant Frederic MD PhD Gynaecological Oncologist UZ Gasthuisberg Katholieke Universiteit Leuven Belgium Second Update in Gynaecological Oncology Leuven, 5th of may 2007

2. ENDOMETRIAL STROMAL SARCOMA ENDOMETRIAL CARCINOSARCOMA UTERINE LEIOMYOSARCOMA

3. New classification Low-grade ESS ESS High-grade ESS Undifferentiated or poorly differentiated uterine sarcoma

4. Effective hormonal agents in recurrent setting Progestins Aromatase inhibitor –Maluf et al., Gynecol Oncol 2001;82:384-8 –Leunen et al., Gynecol Oncol 2004;95:769-71 GnRH analogue –Burke et al., Obstet Gynecol 2004;104:1182-4 14mm12mm 28 mts MPA

5. Role of BSO in ESS: Recurrence rates N (%)BSONo BSO Gaducci, 19962/6 (33)1/6 (17) Chu, 20036/14 (43)4/8 (50) Li, 200510/24 (42)4/12 (33) Leuven, submitted3/15 (20)1/7 (14)

6. Adjuvant progestins? Chu et al., Gynecol Oncol 2003:90:170-6 Recurrence Adjuvant Progestins4/13 (31%) No adjuvant progestins6/9 (67%)

7. Retrospective study in ESS (n= 31) submitted Hormonal treatment at diagnosis –7/7 (100%) with Horm R/ stage I –15/24 (63%) without Horm R/ stage I BSO in stage I premenopausal –With BSO 3/15 (20%) relapses vs 1/7 (14%) Vast majority no lymphadenectomy –1/31 (3%) isolated retroperitoneal recurrence (lung and abdominal M+ 9 mts later)

8. Retrospective study in ESS (n= 31) submitted

9. Indolent growth and hormone sensitivity: proposal for treatment Hysterectomy Secondary and tertiary debulking including organ resection and thoracotomy ChemotherapyRadiotherapy ProgestinsAIGnRHa 36% + Adj progestins?

10. ENDOMETRIAL STROMAL SARCOMA ENDOMETRIAL CARCINOSARCOMA UTERINE LEIOMYOSARCOMA

11. Adjuvant chemotherapy Adjuvant chemotherapy Omura et al., J Clin Oncol 1985;3:1240-5 156 uterine sarcomas (CS + LMS) Stage I-II disease Pelvic irradiation was optional Adriamycin 60mg/m², 3 weekly, x8 No survival benefit Different pattern of recurrence: pulmonary (LMS) vs extrapulmonary (CS)

12. Benefit for multimodality adjuvant treatment of endometrial carcinosarcoma Authors: -Manolitsas et al., Cancer 2001;91:1437-43 -Peters et al., Gynecol Oncol 1989;34:323-7 -Menczer et al., Gynecol Oncol 2005;97:166-70 -Wong et al., Int J Gynecol Ca 2006;16:1364-9 Postoperative chemotherapy and radiotherapy Problem:-retrospective -small series -inadequate staging (!)

13. EORTC 55874: RT vs observation

14. Overview on spread pattern in different subtypes of endometrial cancer as reported in literature Amant et al. Gynecol Oncol 2005;98:274-80 N (%)Peritoneal cytology AdnexalOmentalPelvic LN Grade 3 E86/668 (13)41/721 (6)3/25 (12)78/734 (11) Carcinosarc oma 72/373 (19)75/512 (15)15/96 (16)80/423 (19) Serous17/57 (13)27/125 (22)47/202 (23)72/244 (30) Clear cell7/20 (35)3/32 (9)3/6 (50)9/20 (45)

15. Improved survival in surgical stage I UPSC treated with adjuvant platinum based chemotherapy Kelly et al., Gynecol Oncol 2005;98:353-359 (Huh et al., Dietrich et al.) No adjuvant R/ N (%) Adj chemo N (%) Ia, no residual0/9 (0)0/3 (0) Ia, residual6/14 (43)0/7 (0) Ib10/12 (77)0/15 (0) Ic4/5 (80)1/7 (14) Recurrence rate: 20/43 (47%) vs 1/33 (3%) 5-year survival: 46 vs 100% (p<0.01)

16. Adjuvant chemotherapy for surgical stage I CS in Leuven DrugSurgeryAdequate stagingStatus BLHAP7-2004NED UMnone10-2004AWED BB3HAP, 1EpiC11-2004NED LMEpiC1-2005NED BMHAP1-2005NED RAEpiC3-2005NED OJnone1-2006DOD HEpiC1-2006No omentectomyCR BAEpiC2-2006No omentectomyCR VMEpiC1-2007-

17. Randall, M. E. et al. J Clin Oncol; 24:36-44 2006 Fig 4. Survival by treatment and stage Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma Randall et al., JCO 2006;24:36-44

18. Treatment of apparent early stage endometrial carcinosarcoma Surgical staging including HT, BSO, pelvic lymphadenectomy, peritoneal bx and omentectomy Stage I-II: Platin based adjuvant chemotherapy Node positive (stage III): chemotherapy followed by pelvic radiotherapy Stage IV: systemic treatment

19. Single agent chemotherapy in carcinosarcoma NCytotoxicDosageCRPRRR Sutton et al., 1989 28Ifosfamide1,5mg/m²/5d18%14%32% Thierri et al., 1986 28Cisplatin50mg/m²7%11%18% Gershenson et al., 1987 18Cisplatin75-100mg/m²8%33%42% Thigpen et al., 1991 63Cisplatin50mg/m²8%11%19% Curtin et al., 2001 44Paclitaxel175 mg/m²9% 18%

20. Combination chemotherapy in carcinosarcoma NCytotoxicDosageCRPRRR Resnik, 19954Etoposide Cisplatin adriamycin 2x100 mg/m² 50 mg/m² 2/4 100% Currie, 199632Hydroxyurea Dacarbazine Etoposide 2g 100mg/m² 2x100mg/m² 2/323/3216% Ramondetta, 2003 16Cisplatin Ifosfamide 75mg/m² 1,2mg/m² Too toxic 02/633% Toyoshima, 2004 6Paclitaxel Carboplatin 175mg/m² AUC 6 4/5080%

21. Randomised trial! Homesley et al., J Clin Oncol 2007;25:526-31 N = 179 Ifosfamide 2g/m² 3days vs ifosfamide 1.6g/m² 3 days + paclitaxel 135mg/m²; three weekly Response –PS 0: 39 vs 51% –PS 1: 23 vs 45% –PS 2: 0 vs 31% –Overall: 29 vs 45% Median PFS: 3.6 vs 5.8 mts Median OS: 8.4 vs 13.5 mts

22. Single agent or combination chemotherapy in carcinosarcoma? NCytotoxicDosageRR Sutton et al., 1989 28Ifosfamide1,5mg/m²/5d32% Gershenson et al., 1987 18Cisplatin75-100mg/m²42% Toyoshima, 2004 6Paclitaxel Carboplatin 175mg/m² AUC 6 80% Homesley, 2007 179Ifosfamide Paclitaxel 1.6 g/m² x3 135 mg/m² 45%

23. Trastuzumab in endometrial carcinosarcoma? Amant et al., Gynecol Oncol 2004;95:583-7 –7/22 CS ERBB-2 ++ or +++; 3/7 FISH+, 3/22 (14%) –Sarcoma component negative Raspollini et al., Int J Gynecol Ca 2006;16:416-22 –9/22 (32%) CS ERBB-2 +; all four ++/+++ FISH+ Endometrial cancer: Jewell et al., Int J Gynecol Ca 2006;16:1370-3 –Gr2 endometrioid, ER-, PR-: dramatic respons after addition of trastuzumab to weekly paclitaxel Leuven: –1 case: no response in UPSC (single and trastuzumab-paclitaxel) –1 case: primary FISH +, lungM+ IHC ERBB2 -

24. ENDOMETRIAL STROMAL SARCOMA ENDOMETRIAL CARCINOSARCOMA UTERINE LEIOMYOSARCOMA

25. Leiomyosarcoma: spread pattern SeriesLymph node MetaOvarian Meta NNr pos (%)N Major et al., (1993) 572 (3.5)592 (3.4) Goff et al., (1993) 90 (0.0)-- Chen et al., (1989) 43 (75.0)-- Gadduci et al., (1996) 40 (0.0)-- Leitao et al, (2003) 270 (0.0)712 (2.8) Total1015 (5.0)1304 (3.1)

26. Single agent activity in leiomyosarcoma SeriesDrugSheduleResponse Omura et al., (1983)Doxorubicin60mg/m²7/28 (25%) Sutton et al., (1992)Ifosfamide1.5 mg/m², 5d6 PR/35 (17%) Sutton et al., (1999)Paclitaxel175mg/m²3 CR/33 (9%) Gallup et al., 2003Paclitaxel175mg/m²4 CR, PR/48 (8%) Look et al., (2004)Gemcitabine1000mg/m² (1-8-15)1 CR, 8 PR/ 42 (20%) Anderson et al., (2005) Temozolomidevariable1CR/13 (8%) Sutton et al., (2005)Liposomal doxorubicin 50mg/m²1 CR, 4 PR/35 (16%) Tewari et al., (2006)ET-743 (Yondelis)1.2 mg/m²1 PR

27. Combination chemotherapy in leiomyosarcoma SeriesDrugSheduleResponse Long et al., 2005 Dacarbazine Mitomycin Doxorubicin Cisplatin Too toxic28% Hensley et al., 2002 Gemcitabine Docetaxel 900mg/m², d1&8 100mg/m², d8 18/34 (53%) RR Leu et al., 2004Gemcitabine Docetaxel 65mg/m², d1&8 100mg/m², d8 5 CR + 10 PR / 35 (43%) RR Bay et al., 2006Gemcitabine Docetaxel 900mg/m², d1&8 100mg/m², d8 18% RR (34 % RR when PS 0)

28. C-kit as a target for anti-tyrosine- kinase in LMS? 17/32 (53%) c-KIT expression (Raspollini et al., Clin Ca Res 2004;10:3500-3) also Wang 2003, Winter 2003, Leath 2004. But: KIT needs to be phosporylated to start its signaling cascade –Absence of phosphorylation of KIT in uterine LMS, probably not involved in tumorigenesis and not likely to be a target for anti-tyrosine-kinase drug therapy (Serrano et al., Clin Cancer Res 2005;11:4977-8) But: tumors with mutations in exon 11 are likely to respond –Lack of mutations in uterine sarcomas (Rushing et al., Gynecol Oncol 2003;91:9-14; Serrano et al., Clin Cancer Res 2005;11:4977-8) Imatinib mesylate no option

29. Hormonal agents? Progestins –USMN-LMP, recurrence after 4y as LMS, PR +++: 250 mg MPA (Amant et al., Int J Gyn Cancer 2005;15:1210-12) Mifeprostone –1/3 3y stabilisation in PR +++ LMS (2 PD) (Koivisto-Korander et al., Obstet Gynecol 2007;109:512-4)

30. ET-743/ecteinascidin/Yondelis Le Cesne et al., J Clin Oncol 2005;23:576-84 –soft tissue sarcomas –24/43 (56%) LMS progression arrest rate; 5 responses in LMS –OS unusual long in these heavily pretreated patients –TTP 105 days, 6-mts DFS 29%, median OS 9.2mts Tewari et al., Gynecol Oncol 2006;102:421-4 –8 months SD in metastatic uterine LMS –1.2 mg/m², 3-weekly

31. Yondelis in Leuven: 2 US PD, 1/3 LMS responded 3 cycli Yondelis° 15mm 105mm 11mm 84mm 11 mm 15 mm

32. ENDOMETRIAL STROMAL SARCOMA Hysterectomy only (no BSO) Adjuvant progestins? Repeat surgery ENDOMETRIAL CARCINOSARCOMA Adequate surgical staging Adjuvant platin based chemotherapy Paclitaxel-carboplatin UTERINE LEIOMYOSARCOMA Hysterectomy only Doxo, gemcitabine +/- docetaxel Low grade: hormonal with resection Yondelis/trabectedin/ET-743?