Update on treatment Update on treatment modalities of uterine modalities of uterine

sarcomassarcomas

Amant Frederic MD PhDGynaecological Oncologist

UZ GasthuisbergKatholieke Universiteit Leuven

Belgium

Second Update in Gynaecological OncologyLeuven, 5th of may 2007

ENDOMETRIAL STROMAL SARCOMAENDOMETRIAL STROMAL SARCOMAENDOMETRIAL CARCINOSARCOMAENDOMETRIAL CARCINOSARCOMAUTERINE LEIOMYOSARCOMAUTERINE LEIOMYOSARCOMA

New classificationNew classification

Low-grade ESS

ESS

High-grade ESS

Undifferentiated or poorly differentiated

uterine sarcoma

Effective hormonal agents in Effective hormonal agents in recurrent settingrecurrent 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

14mm14mm 12mm12mm

28 mts MPA28 mts MPA

Role of BSO in ESS: Recurrence Role of BSO in ESS: Recurrence ratesrates

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?Adjuvant progestins?Chu et al., Gynecol Oncol 2003:90:170-6Chu 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)Retrospective study in ESS (n= 31)submittedsubmitted

• 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)

Condition: HT - No Adjuvant - Stage I -I I HT - No Adjuvant - Stage I I I -IVHT+BSO - No Adjuvant - Stage I -I I HT+BSO - No Adjuvant - Stage I I I -IV

HT+BSO - Adjuvant - Stage I -I I HT+BSO - Adjuvant - Stage I I I -IV

Est

imate

d p

robabili

ty o

f re

curr

ence

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time (years)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Retrospective study in ESS (n= 31)Retrospective study in ESS (n= 31)submittedsubmitted

Indolent growth and hormone Indolent growth and hormone sensitivity: proposal for treatmentsensitivity: proposal for treatment

HysterectomyHysterectomy Secondary and tertiarySecondary and tertiarydebulking includingdebulking includingorgan resectionorgan resectionand thoracotomy and thoracotomy

ChemotherapyChemotherapyRadiotherapyRadiotherapy

ProgestinsProgestinsAIAIGnRHaGnRHa

36%36%

++

Adj progestins?Adj progestins?

ENDOMETRIAL STROMAL SARCOMAENDOMETRIAL STROMAL SARCOMAENDOMETRIAL CARCINOSARCOMAENDOMETRIAL CARCINOSARCOMAUTERINE LEIOMYOSARCOMAUTERINE LEIOMYOSARCOMA

Adjuvant chemotherapyAdjuvant 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 treatmentBenefit for multimodality adjuvant treatmentof endometrial carcinosarcomaof endometrial carcinosarcoma

Authors:Authors:--Manolitsas et al., Cancer 2001;91:1437-43Manolitsas et al., Cancer 2001;91:1437-43-Peters et al., Gynecol Oncol 1989;34:323-7-Peters et al., Gynecol Oncol 1989;34:323-7-Menczer et al., Gynecol Oncol 2005;97:166-70-Menczer et al., Gynecol Oncol 2005;97:166-70-Wong et al., Int J Gynecol Ca 2006;16:1364-9-Wong et al., Int J Gynecol Ca 2006;16:1364-9

Postoperative chemotherapy and radiotherapyPostoperative chemotherapy and radiotherapyProblem:Problem:

-retrospective-retrospective-small series-small series-inadequate staging (!)-inadequate staging (!)

(years)

0 2 4 6 8 10 12 14 16

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk :

48 109 78 53 36 22 14 3 0

46 110 68 52 37 20 12 5 1

No treatment

Radiotherapy

Overall survival

by treatment

8 Nov 2002 11:43

Overall Logrank test: p=0.9231

EORTC 55874: RT vs observationEORTC 55874: RT vs observation

Overview on spread pattern in different subtypes of Overview on spread pattern in different subtypes of endometrial cancer as reported in literatureendometrial cancer as reported in literature

Amant et al. Gynecol Oncol 2005;98:274-80Amant 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)

Carcinosarcoma

72/373 (19) 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 Improved survival in surgical stage I UPSC treated with adjuvant platinum based chemotherapywith adjuvant platinum based chemotherapy

Kelly et al., Gynecol Oncol 2005;98:353-359Kelly et al., Gynecol Oncol 2005;98:353-359(Huh et al., Dietrich et al.)(Huh et al., Dietrich et al.)

No adjuvant R/

N (%)

Adj chemo

N (%)

Ia, no residual 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)

Recurrence rate: 20/43 (47%)Recurrence rate: 20/43 (47%) vs vs 1/33 (3%)1/33 (3%)5-year survival: 46 vs 100% (p<0.01)5-year survival: 46 vs 100% (p<0.01)

Adjuvant chemotherapy for surgical Adjuvant chemotherapy for surgical stage I CS in Leuvenstage 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 -

Randall, M. E. et al. J Clin Oncol; 24:36-44 2006Fig 4. Survival by treatment and stage

Randomized phase III trial of whole-abdominal irradiation versus doxorubicin Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinomaand cisplatin chemotherapy in advanced endometrial carcinoma

Randall et al., JCO 2006;24:36-44Randall et al., JCO 2006;24:36-44

Treatment of apparent early stage Treatment of apparent early stage endometrial carcinosarcomaendometrial 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 Single agent chemotherapy in carcinosarcomacarcinosarcoma

N Cytotoxic Dosage CR PR RR

Sutton et al., 1989

28 Ifosfamide 1,5mg/m²/5d 18% 14% 32%

Thierri et al., 1986

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 Combination chemotherapy in carcinosarcomacarcinosarcoma

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

Dacarbazine

Etoposide

2g

100mg/m²

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!Randomised trial!Homesley et al., J Clin Oncol 2007;25:526-31Homesley 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 Single agent or combination chemotherapy in carcinosarcoma?chemotherapy in carcinosarcoma?

N Cytotoxic Dosage RR

Sutton et al., 1989

28 Ifosfamide 1,5mg/m²/5d 32%

Gershenson et al., 1987

18 Cisplatin 75-100mg/m² 42%

Toyoshima, 2004

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 Trastuzumab in endometrial carcinosarcoma?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 SARCOMAENDOMETRIAL STROMAL SARCOMAENDOMETRIAL CARCINOSARCOMAENDOMETRIAL CARCINOSARCOMAUTERINE LEIOMYOSARCOMAUTERINE LEIOMYOSARCOMA

Leiomyosarcoma: spread patternLeiomyosarcoma: 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 leiomyosarcomaSingle 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%)

Anderson et al., (2005)

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

Combination chemotherapy in Combination chemotherapy in leiomyosarcomaleiomyosarcoma

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-tyrosine-C-kit as a target for anti-tyrosine-kinase in LMS?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; Serrano et al., Clin Cancer Res 2005;11:4977-8)

Imatinib mesylate no optionImatinib mesylate no option

Hormonal agents?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/YondelisET-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:Yondelis in Leuven: 2 US PD, 1/3 LMS responded 2 US PD, 1/3 LMS responded

3 cycli Yondelis°3 cycli Yondelis°

3 cycli Yondelis°3 cycli Yondelis°

15mm15mm

105mm105mm

11mm11mm

84mm84mm

11 mm11 mm15 mm15 mm

ENDOMETRIAL STROMAL SARCOMAENDOMETRIAL STROMAL SARCOMAHysterectomy only (no BSO)Hysterectomy only (no BSO)Adjuvant progestins?Adjuvant progestins?Repeat surgery Repeat surgery

ENDOMETRIAL CARCINOSARCOMAENDOMETRIAL CARCINOSARCOMAAdequate surgical stagingAdequate surgical stagingAdjuvant platin based chemotherapyAdjuvant platin based chemotherapyPaclitaxel-carboplatinPaclitaxel-carboplatin

UTERINE LEIOMYOSARCOMAUTERINE LEIOMYOSARCOMAHysterectomy onlyHysterectomy onlyDoxo, gemcitabine +/- docetaxelDoxo, gemcitabine +/- docetaxelLow grade: hormonal with resectionLow grade: hormonal with resectionYondelis/trabectedin/ET-743?Yondelis/trabectedin/ET-743?