Download LEIOMYOSARCOMA

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
1
2
3
4
5
6
7
8
9
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/m², 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
0
(years)
0
2
4
6
8
10
12
14
16
O
48
N
109
Number of patients at risk :
78
53
36
22
14
3
0
No treatment
46
110
68
37
20
12
5
1
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 (%)
Adnexal
Omental
Pelvic LN
41/721 (6)
3/25 (12)
78/734 (11)
Carcinosarc 72/373 (19)
oma
Serous
17/57 (13)
75/512 (15)
15/96 (16)
80/423 (19)
27/125 (22)
47/202 (23)
72/244 (30)
Clear cell
3/32 (9)
3/6 (50)
9/20 (45)
Grade 3 E
Peritoneal
cytology
86/668 (13)
7/20 (35)
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 (%)
0/9 (0)
Adj chemo
N (%)
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
H
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/m²/5d
18%
14%
32%
28
Cisplatin
50mg/m²
7%
11%
18%
Gershenson
et al., 1987
18
Cisplatin
75-100mg/m² 8%
33%
42%
Thigpen et
al., 1991
63
Cisplatin
50mg/m²
8%
11%
19%
Curtin et al.,
2001
44
Paclitaxel
175 mg/m²
9%
9%
18%
Combination chemotherapy in
carcinosarcoma
N
Cytotoxic
Dosage
CR
PR
RR
Resnik, 1995
4
Etoposide
Cisplatin
adriamycin
2x100 mg/m²
50 mg/m²
50 mg/m²
2/4
2/4
100%
Currie, 1996
32
Hydroxyurea 2g
Dacarbazine 100mg/m²
Etoposide
2x100mg/m²
2/32
3/32
16%
Ramondetta,
2003
16
Cisplatin
Ifosfamide
75mg/m²
1,2mg/m²
Too toxic
0
2/6
33%
Toyoshima,
2004
6
Paclitaxel
Carboplatin
175mg/m²
AUC 6
4/5
0
80%
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?
N
Cytotoxic
Dosage
RR
Sutton et al., 28
1989
Ifosfamide
1,5mg/m²/5d
32%
Gershenson
et al., 1987
Toyoshima,
2004
18
Cisplatin
75-100mg/m²
42%
6
Paclitaxel
Carboplatin
175mg/m²
AUC 6
80%
Homesley,
2007
179
Ifosfamide
Paclitaxel
1.6 g/m² x3
135 mg/m²
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
N
Nr pos (%)
N
Nr pos (%)
Major et al.,
(1993)
57
2 (3.5)
59
2 (3.4)
Goff et al.,
(1993)
9
0 (0.0)
-
-
Chen et al.,
(1989)
4
3 (75.0)
-
-
Gadduci et
al., (1996)
4
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/m²
7/28 (25%)
Sutton et al., (1992)
Ifosfamide
1.5 mg/m², 5d
6 PR/35 (17%)
Sutton et al., (1999)
Paclitaxel
175mg/m²
3 CR/33 (9%)
Gallup et al., 2003
Paclitaxel
175mg/m²
4 CR, PR/48 (8%)
Look et al., (2004)
Gemcitabine
1000mg/m² (1-8-15)
1 CR, 8 PR/ 42
(20%)
Temozolomide
variable
1CR/13 (8%)
Sutton et al., (2005)
Liposomal
doxorubicin
50mg/m²
1 CR, 4 PR/35
(16%)
Tewari et al., (2006)
ET-743 (Yondelis)
1.2 mg/m²
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/m²,
d1&8
100mg/m², d8
18/34 (53%) RR
Leu et al., 2004
Gemcitabine
Docetaxel
65mg/m², d1&8
100mg/m², d8
5 CR + 10 PR /
35 (43%) RR
Bay et al., 2006
Gemcitabine
Docetaxel
900mg/m²,
d1&8
100mg/m², 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/m², 3-weekly
Yondelis in Leuven: 2 US PD, 1/3 LMS responded
11mm
11
mm
15 mm
15mm
3 cycli Yondelis°
105mm
84mm
3 cycli Yondelis°
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?