• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
Medical Treatment Of Uterine Sarcomas
 

Medical Treatment Of Uterine Sarcomas

on

  • 3,287 views

 

Statistics

Views

Total Views
3,287
Views on SlideShare
3,278
Embed Views
9

Actions

Likes
1
Downloads
65
Comments
0

3 Embeds 9

http://www.slideshare.net 6
http://radiotherapyhome-fondas.blogspot.com 2
http://radiotherapyhome-fondas.blogspot.in 1

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

    Medical Treatment Of Uterine Sarcomas Medical Treatment Of Uterine Sarcomas Presentation Transcript

    • Medical treatment of uterine sarcomas Amant Frederic MD PhD Gynaecological Oncologist UZ Gasthuisberg Katholieke Universiteit Leuven Belgium March 23, 2007 Turku, Finland
    • ENDOMETRIAL STROMAL SARCOMA ENDOMETRIAL CARCINOSARCOMA UTERINE LEIOMYOSARCOMA
    • New classification
      • Low-grade ESS
      • ESS
      • High-grade ESS
      • Undifferentiated or poorly differentiated uterine sarcoma
    • ESS: Hormone sensitive disease
      • Biochemical
      • Baker et al., 1984
      • Sabini et al., 1992
      • Immunohistochemistry
      • Tosi et al., 1989
      • Sabini et al., 1992
      • Reich et al., 2000
      • N = 21
      • 71% ER +, 95% PR +
      • 100% hormonal sensitive
    • 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)
    • 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
    • ESS: hormone replacement? Chu et al., Gynecol Oncol 2003;90:170-6
      • 10/22 (45%) women recurred
      • 4/5 women who used HRT recurred
      • 4/8 (50%) with retained ovaries recurred
    • Adjuvant progestins? Chu et al., Gynecol Oncol 2003:90:170-6 No adjuvant progestins Adjuvant Progestins 6/9 (67%) 4/13 (31%) Recurrence
    • Retrospective study in ESS (n= 31) Amant et al, 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)
    • Retrospective study in ESS (n= 31) Amant et al, submitted
    • Retrospective study in ESS (n= 31) Amant et al, submitted
    • Indolent growth and hormone sensitivity Hysterectomy Secondary and tertiary debulking including organ resection and thoracotomy Chemotherapy Radiotherapy Progestins AI GnRHa 36% +
    • ENDOMETRIAL STROMAL SARCOMA ENDOMETRIAL CARCINOSARCOMA UTERINE LEIOMYOSARCOMA
    • 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)
    •  
    • Intraepithelial carcinoma Endometrial carcinoma Carcinosarcoma Monoclonal theory Carcinosarcoma Immunohistochemistry Clinicopathologic findings In vitro and in vivo studies Molecular findings
    • 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 (%)
    • Serous EC: surgical staging Slomovitz et al., Gynecol Oncol 2003;91:463-9
      • Single institution review of 129 cases: no
      • myometrial invasion (n = 32):
          • 19% lymph node metastasis
          • 37% stage III or IV disease
      Surgical staging through midline incision performing hysterectomy, bilateral salpingo-oophorectomy, lymph node dissection, omentectomy, biopsy of any abnormal peritoneal lesion ( ~ ovarian cancer)
    • 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(%)
    • 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 (%)
    • 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
      • Postoperative chemotherapy and radiotherapy
      • Problem:
      • -retrospective
      • -small series
      • -inadequate staging (!)
    • Adjuvant chemotherapy Wong et al., Int J Gynecol Cancer 2006;16:1364-9
      • N=43
      • Surgical staging:
        • HT and BSO in 100%
        • Pelvic lymphadenectomy in 79%
        • Pelvic and paraAO lymphadenectomy in 26%
        • Omentectomy in 72%
      • Six cycles cisplatin (20mg/m²) and ifosfamide (1.5 g/m² d1-5)
      • Stage I-II: 2 and 5 year survival was 95%
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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 -
    • ENDOMETRIAL STROMAL SARCOMA ENDOMETRIAL CARCINOSARCOMA UTERINE LEIOMYOSARCOMA
    • FEATURES OF VALUE IN DISTINGUISHING BENIGN FROM MALIGNANT UTERINE SMOOTH MUSCLE TUMOUR
      • ATYPIA
      • MITOTIC ACTIVITY (INCLUDING ATYPICAL MITOSES)
      • COAGULATIVE TUMOUR CELL NECROSIS
      • (hypercellularity)
      • (margin)
      • vascular invasion)
    • 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
    • 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)
    • Leiomyosarcoma: prognosis Gadducci et al., Gynecol Oncol 1996;62:25-32 N = 126
    • 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
    • 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
    • Synergism of gemcitabine and docetaxel in leiomyosarcoma Leu et al., JCO 2004;22:1706-12
      • Sarcomas of various types, n = 35
      • Gemcitabine 675mg/m² over 90 min, day 1&8 + Docetaxel 100mg/m² day 8
      • 5 CR + 10 PR / 35 (43% RR)
      • Gemcitabine: 90-minute vs standard 30-minute inf
      • In vitro:
        • Simultaneous: inhibition
        • Docetaxel -> gemcitabine: inhibition
        • Gemcitabine -> docetaxel: synergism
    • 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)
      Imatinib mesylate no option
    • Hormonal agents?
      • Mifeprostone
        • 1/3 3y stabilisation (2 PD)
          • (Koivisto-Korander et al., Obstet Gynecol 2007;109:512-4)
      • Progestins
        • USMN-LMP, recurrence after 4y as LMS, PR +++: 250 mg MPA
        • (Amant et al., Int J Gyn Cancer 2005;15:1210-12)
    • Isolated metastatic disease?
      • Lack of response to other modalities
      • Improved outcome after:
        • Resection of lung metastasis (Berchuck et al., 1988;71:845-50)
        • Resection of liver metastasis (Lang et al., 2000;231:500-5)
      • Advantage of a biopsy:
        • Assessment tumor biology (Lo et al., J Obstet Gynaecol Res 2005;31:394-8)
        • Reclassification of tubal LMS as an eGist (Imatinib) (Foster et al., Gynecol Oncol 2006;101:363-6)
    • Her2/Neu in pure mesenchymal uterine tumours
      • Foster et al., Am J Clin Oncol 2003;26:188-91
        • Soft tissue LMS: no positivity
      • Amant et al., Gynecol Oncol 2004;95:583-7
        • All negative in primary and recurrent setting
          • 10 adenosarcoma
          • 21 ESS
          • 10 LMS
        • 1 /4 undifferentiated sarcomas FISH +
    • 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
      • Leuven
        • 1 LMS PD, 1 undiff uterine sarcoma PD; 2 LMS ongoing
    • 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?
    • Rapid growth of a uterine leiomyoma
      • Increase by 6 weeks’ gestational size over 1 year (Butram & Reiter, 1981)
      • 1/371 (0.27%) (Parker et al., 1994)
      • 15/580 (2.6%) (meta-analysis of 26 studies between 1962-1993)
    • 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
    • Multimodality treatment for carcinosarcomas: pilot study Manolitsas et al., Cancer 2001;91:1437
      • ‘ Sandwich’
      • 19/21 (90%) disease free
          • 16 stage I ->1 DOD
          • 2 stage II
          • 3 stage III->1 AWED
      • No combined R/
      • 8/17 (47%) disease free
          • 11 stage I ->5 DOD
          • 2 stage III ->1 DOD
          • 4 stage IV->3DOD
    • Aggressive treatment Rosenberg et al., Gynecol Oncol 1993;48:32-7
      • Serous endometrial cancer: n = 10
      • Treatment:
        • HT, BSO, pelvic node sampling
        • external radiotherapy
        • -> Local control !!
        • Cisplatin-epirubicin x 4
      • 100% survival
    • NSGO/EORTC Trial 55991: RT vs RT + CT
      • ‘ High risk’: clear cell, serous, gr 3 Ic endometrioid
      • FIGO surgical stage I or occult II
      • Results at ASCO 2007
    • 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
      • Absence of c-erbB-2 expression in AS, ESS and LMS.
      • 1/4 of primary undifferentiated sarcomas is c-erbB-2 positive.
      • 3/22 (14%) amplification of c-erbB-2 in primary CS
      • 3/3 recurrent tumours (2 CS and 1 undiff) were positive.
      • Trastuzumab (Herceptin°)?
      C-erbB-2 in uterine sarcomas Gynecol Oncol 2004, in press
    • 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 %
    • Clinicopathologic findings Silverberg et al., Int J Gynecol Pathol 1990;9:1-19 (Bitterman et al., Am J Surg Pathol 1990;14:317-328) (Sreenan et al., Am J Surg Pathol 1995;19:666-7)
      • 203 uterine carcinosarcomas
      • Metastases were studied in 40 cases
      • None with pure sarcoma
      • Majority pure carcinoma (n=30)
      • Predominant (34/40) pelvic and para-aortic lymph nodes
      Epithelial component is the driving force
    • 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
    • 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
    • Implications of histogenesis on treatment
      • Carcinoma directed cytotoxic treatment in primary setting
        • After surgery
        • Disseminated at presentation
      • Sarcoma directed cytotoxic treatment in recurrent setting
    • 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
    • Improved survival in surgical stage I UPSC treated with adjuvant platinum based chemotherapy Kelly et al., Gynecol Oncol 2005;98:353-359
      • Retrospective study (1987-2004)
      • N = 74
      • Comprehensive surgical staging including
          • Pelvic lymph node dissection
          • Paraortic lymph node sampling
          • omentectomy
      • Cytotoxic drugs
        • Doxo-cis
        • Doxo
        • Cyclophosphamide-cisplatin
        • Doxo-Cyclophosphamide-intraperitoneal cisplatin
        • Etoposide-cisplatin-doxo
        • Carboplatin-paclitaxel
    • 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
    • Homesley, H. D. et al. J Clin Oncol; 25:526-531 2007 Fig 1. Progression-free (PF) survival by two randomized treatment groups
    • Clinicopathologic data of women in whom the diagnosis of endometrial stromal sarcoma was initially missed Amant et al., Gynecol Oncol 2003;90:37-43