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 classification
Low-grade ESS

ESS

High-grade ESS

Undifferentiated or
poorly differentiated
uterine sarcoma

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

Role of BSO in ESS: Recurrence

rates
N (%)

BSO

No BSO

Gaducci, 1996

2/6 (33)

1/6 (17)

Chu, 2003

6/14 (43)

4/8 (50)

Li, 2005

10/24 (42)

4/12 (33)

Leuven, submitted

3/15 (20)

1/7 (14)

Adjuvant progestins?

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

Recurrence
Adjuvant Progestins

4/13 (31%)

No adjuvant progestins

6/9 (67%)

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)

Retrospective study in ESS (n= 31)

Estimated probability of recurrence

submitted
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0

10 11 12 13 14 15 16 17 18

Time (years)
Condition:

HT - No Adjuvant - Stage I-II

HT+BSO - No Adjuvant - Stage I-II
HT+BSO - Adjuvant - Stage I-II

HT - No Adjuvant - Stage III-IV

HT+BSO - No Adjuvant - Stage III-IV
HT+BSO - Adjuvant - Stage III-IV

Indolent growth and hormone

sensitivity: proposal for treatment
36%
Hysterectomy
Adj progestins?

Secondary and tertiary

debulking including
organ resection
and thoracotomy
+
Progestins
AI
GnRHa

Chemotherapy
Radiotherapy

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/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 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 (!)

EORTC 55874: RT vs observation

8 Nov 2002

Overall survival
by treatment
100

90

80

70

60

50

40

30

20
Overall Logrank test: p=0.9231

10

(years)
0

10

12

14

16

O
48

N
109

Number of patients at risk :

78
53

36

22

14

No treatment

46

110

68

37

20

12

Radiotherapy

52

11:43

Overview on spread pattern in different subtypes of

endometrial cancer as reported in literature
Amant et al. Gynecol Oncol 2005;98:274-80

N (%)

Peritoneal
cytology

Adnexal

Omental

Pelvic LN

Grade 3 E

86/668 (13)

41/721 (6)

3/25 (12)

78/734 (11)

Carcinosarc 72/373 (19)

oma

75/512 (15)

15/96 (16)

80/423 (19)

Serous

17/57 (13)

27/125 (22)

47/202 (23)

72/244 (30)

Clear cell

7/20 (35)

3/32 (9)

3/6 (50)

9/20 (45)

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.)

No adjuvant R/
N (%)

Adj chemo
N (%)

0/9 (0)

0/3 (0)

Ia, residual

6/14 (43)

0/7 (0)

Ib

10/12 (77)

0/15 (0)

Ic

4/5 (80)

1/7 (14)

Ia, no residual

Recurrence rate: 20/43 (47%) vs 1/33 (3%)

5-year survival: 46 vs 100% (p<0.01)

Adjuvant chemotherapy for surgical

stage I CS in Leuven
Drug

Surgery

Adequate staging

Status

BL

HAP

7-2004

NED

UM

none

10-2004

AWED

BB

3HAP, 1EpiC

11-2004

NED

LM

EpiC

1-2005

NED

BM

HAP

1-2005

NED

RA

EpiC

3-2005

NED

OJ

none

1-2006

DOD

EpiC

1-2006

No omentectomy

CR

BA

EpiC

2-2006

No omentectomy

CR

VM

EpiC

1-2007

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

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
N

Cytotoxic

Sutton et al.,
1989

28

Thierri et al.,
1986

Dosage

CR

PR

RR

Ifosfamide 1,5mg/m/5d

18%

14%

32%

28

Cisplatin

50mg/m

7%

11%

18%

Gershenson
et al., 1987

18

Cisplatin

75-100mg/m 8%

33%

42%

Thigpen et
al., 1991

63

Cisplatin

50mg/m

8%

11%

19%

Curtin et al.,
2001

44

Paclitaxel

175 mg/m

9%

9%

18%

Combination chemotherapy in
carcinosarcoma
N

Cytotoxic

Dosage

CR

PR

RR

Resnik, 1995

Etoposide
Cisplatin
adriamycin

2x100 mg/m
50 mg/m
50 mg/m

2/4

2/4

100%

Currie, 1996

32

Hydroxyurea 2g
Dacarbazine 100mg/m
Etoposide
2x100mg/m

2/32

3/32

16%

Ramondetta,
2003

16

Cisplatin
Ifosfamide

75mg/m
1,2mg/m
Too toxic

2/6

33%

Toyoshima,
2004

Paclitaxel
Carboplatin

175mg/m
AUC 6

4/5

80%

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 +
paclitaxel 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?
N

Cytotoxic

Dosage

RR

Sutton et al., 28
1989

Ifosfamide

1,5mg/m/5d

32%

Gershenson
et al., 1987

18

Cisplatin

75-100mg/m

42%

Toyoshima,
2004

Paclitaxel
Carboplatin

175mg/m
AUC 6

80%

Homesley,
2007

179

Ifosfamide
Paclitaxel

1.6 g/m x3
135 mg/m

45%

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

Leiomyosarcoma: spread
pattern
Series

Lymph node Meta

Ovarian Meta

Nr pos (%)

Nr pos (%)

Major et al.,
(1993)

57

2 (3.5)

59

2 (3.4)

Goff et al.,
(1993)

0 (0.0)

Chen et al.,
(1989)

3 (75.0)

Gadduci et
al., (1996)

0 (0.0)

Leitao et al,
(2003)

27

0 (0.0)

71

2 (2.8)

Total

101

5 (5.0)

130

4 (3.1)

Single agent activity in leiomyosarcoma

Series

Drug

Shedule

Response

Omura et al., (1983)

Doxorubicin

60mg/m

7/28 (25%)

Sutton et al., (1992)

Ifosfamide

1.5 mg/m, 5d

6 PR/35 (17%)

Sutton et al., (1999)

Paclitaxel

175mg/m

3 CR/33 (9%)

Gallup et al., 2003

Paclitaxel

175mg/m

4 CR, PR/48 (8%)

Look et al., (2004)

Gemcitabine

1000mg/m (1-8-15)

1 CR, 8 PR/ 42
(20%)

Temozolomide

variable

1CR/13 (8%)

Sutton et al., (2005)

Liposomal
doxorubicin

50mg/m

1 CR, 4 PR/35
(16%)

Tewari et al., (2006)

ET-743 (Yondelis)

1.2 mg/m

1 PR

Anderson et al.,
(2005)

Combination chemotherapy in
leiomyosarcoma
Series

Drug

Shedule

Response

Long et al.,
2005

Dacarbazine
Mitomycin
Doxorubicin
Cisplatin

Too toxic

28%

Hensley et al.,
2002

Gemcitabine
Docetaxel

900mg/m,
d1&8
100mg/m, d8

18/34 (53%) RR

Leu et al., 2004

Gemcitabine
Docetaxel

65mg/m, d1&8
100mg/m, d8

5 CR + 10 PR /
35 (43%) RR

Bay et al., 2006

Gemcitabine
Docetaxel

900mg/m,
d1&8
100mg/m, d8

18% RR
(34 % RR when
PS 0)

C-kit as a target for anti-tyrosinekinase 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

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)

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

11 mm
11mm

15 mm
15mm
3 cycli Yondelis

105mm

3 cycli Yondelis

84mm

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?