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Postgraduaatcursus CHGV en VVOG “Het Endometrium”

Postgraduaatcursus CHGV en VVOG “Het Endometrium”. Sarcoom van de uterus 1/ 60000 Prof . Wiebren A. A. Tjalma. Grobbendonk, 4 December 2009. Wiebren.Tjalma@uza.be. Challenge. 45 j Dikke buik Pijn HK: 3/9/09 optimaal LMS. Mesenchymal Uterine Tumors Smooth Muscle Leiomyoma

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Postgraduaatcursus CHGV en VVOG “Het Endometrium”

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  1. Postgraduaatcursus CHGV en VVOG“Het Endometrium” Sarcoom van de uterus 1/ 60000 Prof.Wiebren A. A. Tjalma Grobbendonk, 4 December 2009 Wiebren.Tjalma@uza.be

  2. Challenge 45 j Dikke buik Pijn HK: 3/9/09 optimaal LMS

  3. Mesenchymal Uterine Tumors Smooth Muscle Leiomyoma Leiomyosarcoma Endometrial Stroma stromal nodules endometrial stromal sarcoma Definition of uterine sarcoma A disease arising from mesodermal derivatives (uterine smooth muscle, endometrial stroma and blood and lymphatic vessel walls)

  4. Classified * According to the types of elements involved Pure: only mesodermal elements present Mixed: both mesodermal and epithelial elements * Malignant Mesodermal element normal present Homologous (only smooth muscle and stroma) Heterologous (striated muscle and cartilage)

  5. Histologic Classification

  6. Uterine sarcoma classification (NCCN) • Leiomyosarcoma4 • Endometrial stromal sarcoma1 • Undifferentiated sarcoma high grade (HGUD) 2 or pure hetelogous sarcoma 3

  7. l

  8. Carcinosarcoma • Overall 5 year survival poor (25%) and strongly associated with degree of myometrial invasion. • ~60% have spread outside the uterus at time of diagnosis • ~35% regional lymph node spread in clinical stage 1pts • Early hematogenous spread to liver and lung is common • In pts without extrauterine disease, 40% chance of distant recurrence

  9. LMS • 1 for every 800 leiomyomas

  10. LMS Comprise 35% to 40% of uterine sarcomas Prognostic factors: size (>5 cm) and mitotic index Even confined to the uterus, 5 –years survival: 50% Median survival of women with advanced or recurrent disease: < 10 months

  11. Treatment ? Hysterectomy + BSO

  12. LMS • 208 LMS pts treated at the Mayo Clinic (1976-1999) • case control analysis on 62 pts receiving or not pelvic RT: • significant decrease in local recurrences in RT group • no statistical difference in DSS or RFS • multivariate analysis: no improved survival for pelvic RT • larger prospective randomized trials are needed Giuntoli RL et al Gynecol Oncol, 89:460, 2003

  13. 300 CS pts treated at MDACC (1954-1998) surgery alone 113 surgery + RT 160 RT alone 27 pelvic recurrence (5 y): 38% distant recurrence (5 y) 54% (abdomen 55%) lower rate of local recurrence in RT group (28% vs 48%, p 0.0002) no difference in OS Callister M et al. IJROBP, 58:786–796, 2004

  14. adjuvant pelvic RT decreased the risk of pelvic recurrence... however the survival rates remain poor because of a high rate of distant metastases. as more effective CHT is developed to control distant disease, the role of RT in local control in the pelvis may increase. future research should consider programs that integrate surgery, RT, and chemotherapy to maximize the probability of cure. Callister M et al. IJROBP, 58:786–796, 2004

  15. pts eligible (12/1993 – 3/2005) 206 CS stage I – IV Whole Abdominal Irradiation (WAI) 105 CDDP + IFX + Mesna (CIM) 101 Wolfson AH et al Gynecol Oncol 107:177, 2007

  16. chronic adverse events G2 G3 G4 WAI 17 14 2 CIM 6 4 0 Wolfson AH et al Gynecol Oncol 107:177, 2007

  17. no significant difference in recurrence rate or survival chronic adverse events were higher in WAI regimen the observed difference favor the use of chemotherapy in future trials Wolfson AH et al Gynecol Oncol 107:177, 2007

  18. pts eligible (7/1988 – 7/2001) 224 LMS 99 CS 92 ESS 15 Pelvic RT 112 observation 112 Reed N et al EJC 44:808, 2008

  19. Overall survival

  20. no difference in OS or DFS increased LC for CS patients receiving RT, no benefit for LMS no indication on adjuvant RT for LMS. CS  aggressive variants of endometrial epithelial tumours and management reflects the treatment of endometrial carcinomas. these results will help to shape future management and clinical trials in uterine sarcomas, distinguishing between LMS and CS. Reed N et al EJC 44:808, 2008

  21. Advanced or Recurrence Treatment is palliative only

  22. UTERINE SARCOMAS SINGLE –AGENTS ACTIVITY IN PHASE II TRIALS

  23. UTERINE LEIOMYOSARCOMASSINGLE-AGENTS ACTIVITY IN PHASE II TRIALS

  24. LMS: DFS interval < 6 months or > 6 months Tumour biology: gene alterations < 6 months: CT > 6 months: HT and/or S before CT (medroxyprogesterone, anastrazole, letrozole, mifepristone)

  25. Target Therapy : the future !?

  26. A PHASE II EVALUATION OF PACLITAXEL AND CARBOPLATIN IN THE TREATMENT OF CARCINOSARCOMA OF THE UTERUS: A GYNECOLOGIC ONCOLOGY GROUP (GOG) STUDY M.A. Powell, V.L. Filiaci, P.G. Rose, R.S. Mannel, P. Hanjani, K. DeGeest, B.E. Miller, N. Susumu, F.R. Ueland (JCO 2009)

  27. COMBINATION CHEMOTHERAY FOR UTERINE CARCINOSARCOMA Ifosfamide vs isosfamide-cisplatin (n = 197) RR: 36% versus 54% PFS: 4 versus 6 months* (Sutton, 2000) Ifosfamide to ifosfamide-paclitaxel-filgastrim (n = 179) RR: 29% and 45%* PFS: 4 versus 6 months* OS: 8 versus 14 months* (Homesley, 2007) * P < .05

  28. CARBOPLATIN – PACLITAXEL FOR UTERINE CARCINOSARCOMA: RETROSPECTIVE STUDIES & PRELIMINARY REPORTS Toyoshima, 2004: RR 80% (4 of 5) Ramondetta, 2007: RR 64% (7 of 11) Hoskins, 2008: 20 up-front tx, 11 recurrent - RR: 60% (12 of 20, CR 5, PR 7): Up-front - RR: 55% (6 of 11, CR 2, PR 4): recurrent - median PFS of 16 and 12 months Pectasides, 2008: carboplatin/paclitaxel/liposamal-doxrubicin - (n = 29) RR: 62%, PFS: 8.2, OS: 16.4 months

  29. Confirmed Response N (%) Complete response 6 (13.0) Partial response 19 (41.3) Stable disease 11 (23.9) Increasing disease 6 (13.0) Not evaluated for response 4 (8.7)

  30. CONCLUSION Carboplatin-paclitaxel is effective against uterine carcinosarcoma (MMMT) with response rates and survival similar to those achieved with ifosfamide Advantage: more convenient, less requirement for growth factor support, likely less toxicicity, and potentially more easily combined with biological therapies

  31. SUMMARY The most active chemotherapy agents vary according to histologic subtype LMS: gemcitabine/docetaxel or doxorubicin/ifosfamide are the regimens with the highest response rates Carcinosarcoma: ifosfamide and cisplatin are the most active agents Biologics will be next subject of investigation Novel clinical trials are needed

  32. ESS History Current practice: Hysterectomy LN ? Yes / No LN involvement 7-9 % No survival benefit 5 years survival LN+ 86 % ; LN – 95% BSO ? Yes / No Logical : yes ; Proven ? No Premenopausal HRT (5 pts)

  33. ESS retrospective study • LG HG • n. 72 31 • recurrence rate 37% 38% • isolated pelvis 40% 58% • total pelvis 66% 58% • total abdomen 37% 25% • total distant 36% 25% • the utility of adjuvant radiation therapy (22 cases) is unclear Leath CA, 3rd et al Gynecol Oncol, 105:630, 2007

  34. Adjuvant therapy Progestin or AI No prospective studies Limited retrospective data Duration? Medroxyprogesterone 250 mg ; megestrol 160 mg Daily 2 years survival benefit Sight effects

  35. Recurrence Indolent growth Recurrence 36 – 56 % Median time stage 1: 65 months Stage 3-4: 9 months Aggressive Surgery and Repeated surgery

  36. Adenosarcoma Benign epithelial component Stromal: low-grade sarcoma Behaviour ESS Ovaries preservation yes/no

  37. Conclusions Uncommon – surprise Trials are missing LMS & ESS: Hysterectomy LN : No BSO discuss Adjuvant therapy: no Advanced & Recurrent LMS: CT / HT ESS: HT

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