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Update on treatment modalities of uterine sarcomas

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

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Update on treatment modalities of uterine sarcomas

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  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 14mm 12mm 28 mts MPA • 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

  5. Role of BSO in ESS: Recurrence rates

  6. Adjuvant progestins?Chu et al., Gynecol Oncol 2003:90:170-6

  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 36% Secondary and tertiary debulking including organ resection and thoracotomy Chemotherapy Radiotherapy Hysterectomy Adj progestins? + Progestins AI GnRHa

  10. ENDOMETRIAL STROMAL SARCOMA ENDOMETRIAL CARCINOSARCOMA UTERINE LEIOMYOSARCOMA

  11. Adjuvant chemotherapyOmura 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 treatmentof 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 literatureAmant et al. Gynecol Oncol 2005;98:274-80

  15. Improved survival in surgical stage I UPSC treated with adjuvant platinum based chemotherapyKelly et al., Gynecol Oncol 2005;98:353-359(Huh et al., Dietrich et al.) 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

  17. 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 Randall, M. E. et al. J Clin Oncol; 24:36-44 2006 Fig 4. Survival by treatment and stage

  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

  20. Combination chemotherapy in carcinosarcoma

  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?

  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

  26. Single agent activity in leiomyosarcoma

  27. Combination chemotherapy in leiomyosarcoma

  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 11mm 11 mm 15 mm 15mm 3 cycli Yondelis° 105mm 84mm 3 cycli Yondelis°

  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?

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