1. Medical treatment of uterine sarcomas Amant Frederic MD PhD Gynaecological Oncologist UZ Gasthuisberg Katholieke Universiteit Leuven Belgium March 23, 2007 Turku, Finland

2. ENDOMETRIAL STROMAL SARCOMA ENDOMETRIAL CARCINOSARCOMA UTERINE LEIOMYOSARCOMA

5. Hormone receptors in endometrial adenosarcoma Amant et al., Gynecol Oncol 2004;93:680-5 PR sarcoma PR epithelial ER sarcoma ER epithelial N (%) 0 (0) NA 2 (100) NA Recurrent UA (n=2) 1 (12) 2 (25) 0 (0) 4 (50) UA + S (n=8) 12 (60) 13 (65) 16 (80) 17 (85) UA (n=20)

8. Adjuvant progestins? Chu et al., Gynecol Oncol 2003:90:170-6 No adjuvant progestins Adjuvant Progestins 6/9 (67%) 4/13 (31%) Recurrence

10. Retrospective study in ESS (n= 31) Amant et al, submitted

11. Retrospective study in ESS (n= 31) Amant et al, submitted

12. Indolent growth and hormone sensitivity Hysterectomy Secondary and tertiary debulking including organ resection and thoracotomy Chemotherapy Radiotherapy Progestins AI GnRHa 36% +

13. ENDOMETRIAL STROMAL SARCOMA ENDOMETRIAL CARCINOSARCOMA UTERINE LEIOMYOSARCOMA

16. Intraepithelial carcinoma Endometrial carcinoma Carcinosarcoma Monoclonal theory Carcinosarcoma Immunohistochemistry Clinicopathologic findings In vitro and in vivo studies Molecular findings

17. Overview on spread pattern in different subtypes of endometrial cancer as reported in literature Amant et al. Gynecol Oncol 2005;98:274-80 9/20 (45) 3/6 (50) 3/32 (9) 7/20 (35) Clear cell 72/244 (30) 47/202 (23) 27/125 (22) 17/57 (13) Serous 80/423 (19) 15/96 (16) 75/512 (15) 72/373 (19) Carcinosarcoma 78/734 (11) 3/25 (12) 41/721 (6) 86/668 (13) Grade 3 E Pelvic LN Omental Adnexal Peritoneal cytology N (%)

19. Ovarian carcinosarcoma tumorigenesis: composition of metastatic lesions Amant et al., Gynecol Oncol 2003;90:372-7 8 (100) 3 (37) 4 (50) 1 (13) 0 (0) Recurrent 107 (100) 2 (2) 13(12) 21(20) 71(66) Primary Total S CS (>50% S) CS (>50% C) C N(%)

20. Improved survival in surgical stage I UPSC treated with adjuvant platinum based chemotherapy Kelly et al., Gynecol Oncol 2005;98:353-359 Recurrence rate: 1/33 (3%) vs 20/43 (47%) 5-year survival: 46 vs 100% (p<0.01) 1/7 (14) 4/5 (80) Ic 0/15 (0) 10/12 (77) Ib 0/7 (0) 6/14 (43) Ia, residual 0/3 (0) 0/9 (0) Ia, no residual Adj chemo N (%) No adjuvant R/ N (%)

24. Single agent chemotherapy in carcinosarcoma 19% 11% 8% 50mg/m² Cisplatin 63 Thigpen et al., 1991 18% 9% 9% 175 mg/m² Paclitaxel 44 Curtin et al., 2001 32% 14% 18% 1,5mg/m²/5d Ifosfamide 28 Sutton et al., 1989 42% 33% 8% 75-100mg/m² Cisplatin 18 Gershenson et al., 1987 18% 11% 7% 50mg/m² Cisplatin 28 Thierri et al., 1986 RR PR CR Dosage Cytotoxic N

25. Combination chemotherapy in carcinosarcoma 80% 0 4/5 175mg/m² AUC 6 Paclitaxel Carboplatin 6 Toyoshima, 2004 33% 2/6 0 75mg/m² 1,2mg/m² Too toxic Cisplatin Ifosfamide 16 Ramondetta, 2003 100% 2/4 2/4 2x100 mg/m² 50 mg/m² 50 mg/m² Etoposide Cisplatin adriamycin 4 Resnik, 1995 16% 3/32 2/32 2g 100mg/m² 2x100mg/m² Hydroxyurea Dacarbazine Etoposide 32 Currie, 1996 RR PR CR Dosage Cytotoxic N

27. Single agent or combination chemotherapy in carcinosarcoma? 42% 75-100mg/m² Cisplatin 18 Gershenson et al., 1987 32% 1,5mg/m²/5d Ifosfamide 28 Sutton et al., 1989 80% 175mg/m² AUC 6 Paclitaxel Carboplatin 6 Toyoshima, 2004 45% 1.6 g/m² x3 135 mg/m² Ifosfamide Paclitaxel 179 Homesley, 2007 RR Dosage Cytotoxic N

29. ENDOMETRIAL STROMAL SARCOMA ENDOMETRIAL CARCINOSARCOMA UTERINE LEIOMYOSARCOMA

31. Leiomyosarcoma: spread pattern 4 (3.1) 130 5 (5.0) 101 Total 2 (2.8) 71 0 (0.0) 27 Leitao et al, (2003) - - 0 (0.0) 4 Gadduci et al., (1996) - - 3 (75.0) 4 Chen et al., (1989) - - 0 (0.0) 9 Goff et al., (1993) 2 (3.4) 59 2 (3.5) 57 Major et al., (1993) Nr pos (%) N Nr pos (%) N Ovarian Meta Lymph node Meta Series

33. Leiomyosarcoma: prognosis Gadducci et al., Gynecol Oncol 1996;62:25-32 N = 126

34. Single agent activity in leiomyosarcoma 1 CR, 4 PR/35 (16%) 50mg/m² Liposomal doxorubicin Sutton et al., (2005) 1 PR 1.2 mg/m² ET-743 (Yondelis) Tewari et al., (2006) 1CR/13 (8%) variable Temozolomide Anderson et al., (2005) 1 CR, 8 PR/ 42 (20%) 1000mg/m² (1-8-15) Gemcitabine Look et al., (2004) 3 CR/33 (9%) 175mg/m² Paclitaxel Sutton et al., (1999) 4 CR, PR/48 (8%) 175mg/m² Paclitaxel Gallup et al., 2003 6 PR/35 (17%) 1.5 mg/m², 5d Ifosfamide Sutton et al., (1992) 7/28 (25%) 60mg/m² Doxorubicin Omura et al., (1983) Response Shedule Drug Series

35. Combination chemotherapy in leiomyosarcoma 18/34 (53%) RR 900mg/m², d1&8 100mg/m², d8 Gemcitabine Docetaxel Hensley et al., 2002 28% Too toxic Dacarbazine Mitomycin Doxorubicin Cisplatin Long et al., 2005 18% RR (34 % RR when PS 0) 900mg/m², d1&8 100mg/m², d8 Gemcitabine Docetaxel Bay et al., 2006 Response Shedule Drug Series

42. ENDOMETRIAL STROMAL SARCOMA Adjuvant progestins Repeat surgery ENDOMETRIAL CARCINOSARCOMA ~ UPSC Adjuvant platin based chemotherapy Paclitaxel-carboplatin UTERINE LEIOMYOSARCOMA Doxo, gemcitabine +/- docetaxel Low grade: hormonal with resection Yondelis/trabectedin/ET-743?

44. Survival time (months) 140 120 100 80 60 40 20 0 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0 Histotype carcinosarcoma non- endometrioid endometrioid Actuarial survival in stage I-II disease Amant et al., Gynecol Oncol 2005;98:274-80

48. Signal transduction continues Signal transduction blocked Exon 17 activating mutation Exon 11 activating mutation KIT receptor Imatinib Imatinib Rushing et al., Gynecol Oncol 2003;91:9-14 Raspollini et al., Clin Cancer Res 2004;10:3500-3

50. Immunohistochemistry Meis & Lawrence Am J Clin Pathol 1990;94:1-7 George et al., Hum Pathol 1991;22:215-223 100 35-76 Vimentin 48-57 100 Keratin 22-57 100 EMA Sa component Ca component %

52. Molecular genetic evidence N T Identical alleles were lost in the epithelial and mesenchymal component Abeln et al., J Pathol 1997;183:424-31 Identical TP53 point mutational genotype in the epithelial and mesenchymal component Kounelis et al., Hum Pathol 1998;29:82-87

53. USPC: a single institution review of 129 cases Slomovitz et al., Gynecol Oncol 2003;463-9 5y OS (%) n 20 31 Stage IV 37 41 Stage III 5 Stage II 34 7 Ic 59 26 Ib 81 19 Ia 63 52 Stage I

55. USPC: Outcomes in 60 surgical stage I patients with and without adjuvant treatment Huh et al., Gynecol Oncol 2003;91:470-5 * Differences are not statistically significant 66% 65% 7 (17%) Conservative N=40 (66%) Chemo + RT N=1 (2%) 100% 100% 0 (0%) ChemoR/ N=7(12%) 59% 60% 2 (16%) Radiotherapy N=12 (20%) 5-y-OS* 5-y-DFS* Rec

57. Efficacy of adjuvant chemotherapy in 29 stage I UPSC Dietrich et al., Gynecol Oncol 2005;99:557-63 100% NED 0 3 NED 0 1 DOD 1 1 Ic 100% NED 1 (8 %) 13 NED 0 1 100% NED 1 (33%) 3 Ib 100% NED 0 5 100% NED 0 2 Ia Actual Rec, % n Actual Rec, % n Actual Rec, % n Paclitaxel-Carbo N=21 Cispl-cycloph N=2 Carbo OR Cispl N=6

58. Homesley, H. D. et al. J Clin Oncol; 25:526-531 2007 Fig 1. Progression-free (PF) survival by two randomized treatment groups

59. Clinicopathologic data of women in whom the diagnosis of endometrial stromal sarcoma was initially missed Amant et al., Gynecol Oncol 2003;90:37-43