Medical treatment of uterine sarcomas

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
3
New classification

• Low-grade ESS
• ESS

• High-grade ESS
• Undifferentiated or poorly differentiated uterine
  sarcoma

4
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

5
Hormone receptors in endometrial
adenosarcomaAmant et al., Gynecol Oncol
200493680-5
6
Effective hormonal agents in recurrent setting

• Progestins
• Aromatase inhibitor
• Maluf et al., Gynecol Oncol 200182384-8
• Leunen et al., Gynecol Oncol 200495769-71
• GnRH analogue
• Burke et al., Obstet Gynecol 20041041182-4

7
ESS hormone replacement? Chu et al., Gynecol
Oncol 200390170-6

• 10/22 (45) women recurred
• 4/5 women who used HRT recurred
• 4/8 (50) with retained ovaries recurred

8
Adjuvant progestins?Chu et al., Gynecol Oncol
200390170-6
9
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)

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
36
Secondary and tertiary debulking including organ
resection and thoracotomy
Chemotherapy Radiotherapy
Hysterectomy

Progestins AI GnRHa
13
ENDOMETRIAL STROMAL SARCOMA ENDOMETRIAL
CARCINOSARCOMA UTERINE LEIOMYOSARCOMA
14
Adjuvant chemotherapy Omura et al., J Clin Oncol
198531240-5

• 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)

15
(No Transcript)
16
Immunohistochemistry Clinicopathologic
findings In vitro and in vivo studies Molecular
findings
Monoclonal theory
Carcinosarcoma
Carcinosarcoma
Endometrial carcinoma
Intraepithelial carcinoma
17
Overview on spread pattern in different subtypes
of endometrial cancer as reported in
literatureAmant et al. Gynecol Oncol
200598274-80
18
Serous EC surgical stagingSlomovitz et al.,
Gynecol Oncol 200391463-9

• 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)
19
Ovarian carcinosarcoma tumorigenesis composition
of metastatic lesions Amant et al., Gynecol
Oncol 200390372-7
20
Improved survival in surgical stage I UPSC
treated with adjuvant platinum based
chemotherapyKelly et al., Gynecol Oncol
200598353-359
Recurrence rate 1/33 (3) vs 20/43 (47) 5-year
survival 46 vs 100 (plt0.01)
21
Benefit for multimodality adjuvant treatmentof
endometrial carcinosarcoma

• Authors
• -Manolitsas et al., Cancer 2001911437-43-Peter
  s et al., Gynecol Oncol 198934323-7-Menczer et
  al., Gynecol Oncol 200597166-70
• Postoperative chemotherapy and radiotherapy
• Problem
• -retrospective
• -small series
• -inadequate staging (!)

22
Adjuvant chemotherapyWong et al., Int J Gynecol
Cancer 2006161364-9

• N43
• 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

23
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

24
Single agent chemotherapy in carcinosarcoma
25
Combination chemotherapy in carcinosarcoma
26
Randomised trialHomesley et al., J Clin Oncol
200725526-31

• 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

27
Single agent or combination chemotherapy in
carcinosarcoma?
28
Trastuzumab in endometrial carcinosarcoma?

• Amant et al., Gynecol Oncol 200495583-7
• 7/22 CS ERBB-2 or 3/7 FISH, 3/22 (14)
• Sarcoma component negative
• Raspollini et al., Int J Gynecol Ca
  200616416-22
• 9/22 (32) CS ERBB-2 all four / FISH
• Endometrial cancer
• Jewell et al., Int J Gynecol Ca 2006161370-3
• 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 -

29
ENDOMETRIAL STROMAL SARCOMA ENDOMETRIAL
CARCINOSARCOMA UTERINE LEIOMYOSARCOMA
30
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)

31
Leiomyosarcoma spread pattern
32
Adjuvant chemotherapy Omura et al., J Clin Oncol
198531240-5

• 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)

33
Leiomyosarcoma prognosisGadducci et al.,
Gynecol Oncol 19966225-32
N 126
34
Single agent activity in leiomyosarcoma
35
Combination chemotherapy in leiomyosarcoma
36
Synergism of gemcitabine and docetaxel in
leiomyosarcoma Leu et al., JCO 2004221706-12

• Sarcomas of various types, n 35
• Gemcitabine 675mg/m² over 90 min, day 18
  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

37
C-kit as a target for anti-tyrosine-kinase in LMS?

• 17/32 (53) c-KIT expression (Raspollini et al.,
  Clin Ca Res 2004103500-3) 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
  2005114977-8)
• But tumors with mutations in exon 11 are likely
  to respond
• Lack of mutations in uterine sarcomas (Rushing et
  al., Gynecol Oncol 2003919-14)

Imatinib mesylate no option
38
Hormonal agents?

• Mifeprostone
• 1/3 3y stabilisation (2 PD)
• (Koivisto-Korander et al., Obstet Gynecol
  2007109512-4)
• Progestins
• USMN-LMP, recurrence after 4y as LMS, PR 250
  mg MPA
• (Amant et al., Int J Gyn Cancer 2005151210-12)

39
Isolated metastatic disease?

• Lack of response to other modalities
• Improved outcome after
• Resection of lung metastasis (Berchuck et al.,
  198871845-50)
• Resection of liver metastasis (Lang et al.,
  2000231500-5)
• Advantage of a biopsy
• Assessment tumor biology (Lo et al., J Obstet
  Gynaecol Res 200531394-8)
• Reclassification of tubal LMS as an eGist
  (Imatinib) (Foster et al., Gynecol Oncol
  2006101363-6)

40
Her2/Neu in pure mesenchymal uterine tumours

• Foster et al., Am J Clin Oncol 200326188-91
• Soft tissue LMS no positivity
• Amant et al., Gynecol Oncol 200495583-7
• All negative in primary and recurrent setting
• 10 adenosarcoma
• 21 ESS
• 10 LMS
• 1 /4 undifferentiated sarcomas FISH

41
ET-743/ecteinascidin/Yondelis

• Le Cesne et al., J Clin Oncol 200523576-84
• 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 2006102421-4
• 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

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?
43
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)

44
(No Transcript)
45
Multimodality treatment for carcinosarcomas
pilot study Manolitsas et al., Cancer
2001911437

• 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

46
Aggressive treatmentRosenberg et al., Gynecol
Oncol 19934832-7

• Serous endometrial cancer n 10
• Treatment
• HT, BSO, pelvic node sampling
• external radiotherapy
• -gt Local control !!
• Cisplatin-epirubicin x 4
• 100 survival

47
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

48
KIT receptor
Exon 11 activating mutation
Exon 17 activating mutation
Imatinib
Imatinib
Signal transduction continues
Signal transduction blocked
Rushing et al., Gynecol Oncol 2003919-14 Raspoll
ini et al., Clin Cancer Res 2004103500-3
49
C-erbB-2 in uterine sarcomas

• 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)?

Gynecol Oncol 2004, in press
50
ImmunohistochemistryMeis Lawrence Am J Clin
Pathol 1990941-7George et al., Hum Pathol
199122215-223
51
Clinicopathologic findings Silverberg et al.,
Int J Gynecol Pathol 199091-19(Bitterman et
al., Am J Surg Pathol 199014317-328)(Sreenan
et al., Am J Surg Pathol 199519666-7)

• 203 uterine carcinosarcomas
• Metastases were studied in 40 cases
• None with pure sarcoma
• Majority pure carcinoma (n30)
• Predominant (34/40) pelvic and para-aortic lymph
  nodes

Epithelial component is the driving force
52
Molecular genetic evidence
N T
Identical alleles were lost in the epithelial and
mesenchymal component Abeln et al., J Pathol
1997183424-31
Identical TP53 point mutational genotype in the
epithelial and mesenchymal component Kouneli
s et al., Hum Pathol 19982982-87
53
USPC a single institution review of 129
casesSlomovitz et al., Gynecol Oncol 2003463-9
54
Implications of histogenesis on treatment

• Carcinoma directed cytotoxic treatment in primary
  setting
• After surgery
• Disseminated at presentation
• Sarcoma directed cytotoxic treatment in recurrent
  setting

55
USPC Outcomes in 60 surgical stage I patients
with and without adjuvant treatmentHuh et al.,
Gynecol Oncol 200391470-5
Differences are not statistically significant
56
Improved survival in surgical stage I UPSC
treated with adjuvant platinum based
chemotherapyKelly et al., Gynecol Oncol
200598353-359

• 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

57
Efficacy of adjuvant chemotherapy in 29 stage I
UPSCDietrich et al., Gynecol Oncol 200599557-63
58
Fig 1. Progression-free (PF) survival by two
randomized treatment groups
Homesley, H. D. et al. J Clin Oncol 25526-531
2007
59
Clinicopathologic data of women in whom the
diagnosis of endometrial stromal sarcoma was
initially missed Amant et al., Gynecol Oncol
20039037-43