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,ENDOMETRIAL STROMAL SARCOMA ENDOMETRIAL CARCINOSARCOMA UTERINE LEIOMYOSARCOMA,New
2、 classification,Low-grade ESSESS,High-grade ESSUndifferentiated or poorly differentiated uterine sarcoma,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., Obs
3、tet Gynecol 2004;104:1182-4,14mm,12mm,28 mts MPA,Role of BSO in ESS: Recurrence rates,Adjuvant progestins? Chu et al., Gynecol Oncol 2003:90:170-6,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 s
4、tage 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),Retrospective study in ESS (n= 31) submitted,Indolent growth and hormone sensitivity: proposal for treatment,Hysterectomy,
5、Secondary and tertiary debulking including organ resection and thoracotomy,Chemotherapy Radiotherapy,Progestins AI GnRHa,36%,+,Adj progestins?,ENDOMETRIAL STROMAL SARCOMA ENDOMETRIAL CARCINOSARCOMA UTERINE LEIOMYOSARCOMA,Adjuvant chemotherapy Omura et al., J Clin Oncol 1985;3:1240-5,156 uterine sarc
6、omas (CS + LMS) Stage I-II disease Pelvic irradiation was optional Adriamycin 60mg/m, 3 weekly, x8 No survival benefit Different pattern of recurrence: pulmonary (LMS) vs extrapulmonary (CS),Benefit for multimodality adjuvant treatment of endometrial carcinosarcoma,Authors:-Manolitsas et al., Cancer
7、 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;16:1364-9Postoperative chemotherapy and radiotherapy Problem:-retrospective-small series-inadequate staging (!),EORTC 55874: RT vs observation,Overview on spr
8、ead pattern in different subtypes of endometrial cancer as reported in literature Amant et al. Gynecol Oncol 2005;98:274-80,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.),Recurrenc
9、e rate: 20/43 (47%) vs 1/33 (3%) 5-year survival: 46 vs 100% (p0.01),Adjuvant chemotherapy for surgical stage I CS in Leuven,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 cispl
10、atin chemotherapy in advanced endometrial carcinoma Randall et al., JCO 2006;24:36-44,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 (s
11、tage III): chemotherapy followed by pelvic radiotherapy Stage IV: systemic treatment,Single agent chemotherapy in carcinosarcoma,Combination chemotherapy in carcinosarcoma,Randomised trial! Homesley et al., J Clin Oncol 2007;25:526-31,N = 179 Ifosfamide 2g/m 3days vs ifosfamide 1.6g/m 3 days + pacli
12、taxel 135mg/m; 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,Single agent or combination chemotherapy in carcinosarcoma?,Trastuzumab in endometrial carcinosarcoma?,Amant et al., Gynecol Oncol 2004;95:583-
13、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 tra
14、stuzumab to weekly paclitaxel Leuven: 1 case: no response in UPSC (single and trastuzumab-paclitaxel) 1 case: primary FISH +, lungM+ IHC ERBB2 -,ENDOMETRIAL STROMAL SARCOMA ENDOMETRIAL CARCINOSARCOMA UTERINE LEIOMYOSARCOMA,Leiomyosarcoma: spread pattern,Single agent activity in leiomyosarcoma,Combin
15、ation chemotherapy in leiomyosarcoma,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 o
16、f 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
17、 Oncol 2003;91:9-14; Serrano et al., Clin Cancer Res 2005;11:4977-8),Imatinib mesylate no option,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
18、 et al., Obstet Gynecol 2007;109:512-4),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/m, 3-weekly,Yondelis in Leuven: 2 US PD, 1/3 LMS responded,3 cycli Yondelis,3 cycli Yondelis,15mm,105mm,11mm,84mm,11 mm,15 mm,
