Medical Treatment Of Uterine Sarcomas

Medical treatment of Medical treatment of uterine sarcomasuterine sarcomas

Amant Frederic MD PhDGynaecological Oncologist

UZ GasthuisbergKatholieke Universiteit Leuven

Belgium

March 23, 2007 Turku, Finland

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

ESS: Hormone sensitive diseaseESS: 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 adenosarcomaHormone receptors in endometrial adenosarcomaAmant et al., Gynecol Oncol 2004;93:680-5Amant et al., Gynecol Oncol 2004;93:680-5

N (%) ER epithelial

ER sarcoma

PR epithelial

PR sarcoma

UA (n=20) 17 (85) 16 (80) 13 (65) 12 (60)

UA + S (n=8)

4 (50) 0 (0) 2 (25) 1 (12)

Recurrent UA (n=2)

NA 2 (100) NA 0 (0)

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

ESS: hormone replacement?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?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)Amant et al, submittedAmant 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)

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)Amant et al, submittedAmant et al, submitted

Retrospective study in ESS (n= 31)Retrospective study in ESS (n= 31)Amant et al, submittedAmant et al, submitted

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 su

rviv

al

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

Indolent growth and hormone Indolent growth and hormone sensitivitysensitivity

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

ChemotherapyChemotherapyRadiotherapyRadiotherapy

ProgestinsProgestinsAIAIGnRHaGnRHa

36%36%

++

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)

Intraepithelial carcinoma

Endometrial carcinom

a

Carcinosarcoma

Monoclonal theory

Carcinosarcoma

Immunohistochemistry Clinicopathologic findingsIn vitro and in vivo studiesMolecular findings

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)

Serous EC: surgical stagingSerous EC: surgical stagingSlomovitz et al., Gynecol Oncol 2003;91:463-9Slomovitz 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 Surgical staging through midline incision performing hysterectomy, bilateral salpingo-oophorectomy, lymph node hysterectomy, bilateral salpingo-oophorectomy, lymph node dissection, omentectomy, biopsy of any abnormal peritoneal dissection, omentectomy, biopsy of any abnormal peritoneal

lesion lesion ((~ ovarian cancer)~ ovarian cancer)

Ovarian carcinosarcoma tumorigenesis: Ovarian carcinosarcoma tumorigenesis: composition of metastatic lesionscomposition of metastatic lesions

Amant et al., Amant et al., Gynecol Oncol 2003;90:372-7

N(%) C CS (>50% C) CS (>50% S) S Total

Primary 71(66) 21(20) 13(12) 2 (2) 107 (100)

Recurrent 0 (0) 1 (13) 4 (50) 3 (37) 8 (100)

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

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

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

Postoperative chemotherapy and radiotherapyPostoperative chemotherapy and radiotherapyProblem:Problem:

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

Adjuvant chemotherapyAdjuvant chemotherapyWong et al., Int J Gynecol Cancer 2006;16:1364-9Wong 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 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 trialRandomised trialHomesley 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

FEATURES OF VALUE IN DISTINGUISHING BENIGN FEATURES OF VALUE IN DISTINGUISHING BENIGN FROM MALIGNANT UTERINE SMOOTH MUSCLE FROM MALIGNANT UTERINE SMOOTH MUSCLE

TUMOURTUMOUR

ATYPIAMITOTIC ACTIVITY (INCLUDING ATYPICAL MITOSES)COAGULATIVE TUMOUR CELL NECROSIS (hypercellularity)(margin)vascular invasion)

Leiomyosarcoma: spread patternLeiomyosarcoma: spread patternSeries 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)

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)

Leiomyosarcoma: prognosisLeiomyosarcoma: prognosisGadducci et al., Gynecol Oncol 1996;62:25-32Gadducci et al., Gynecol Oncol 1996;62:25-32

N = 126N = 126

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

Bay et al., 2006 Gemcitabine

Docetaxel

900mg/m², d1&8

100mg/m², d8

18% RR

(34 % RR when PS 0)

Synergism of gemcitabine and docetaxel in Synergism of gemcitabine and docetaxel in leiomyosarcomaleiomyosarcoma

Leu et al., JCO 2004;22:1706-12Leu 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-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)

Imatinib mesylate no optionImatinib mesylate no option

Hormonal agents?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?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 Her2/Neu in pure mesenchymal uterine tumoursuterine 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/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

• Leuven– 1 LMS PD, 1 undiff uterine sarcoma PD; 2 LMS ongoing

ENDOMETRIAL STROMAL SARCOMAENDOMETRIAL STROMAL SARCOMAAdjuvant progestinsAdjuvant progestinsRepeat surgery Repeat surgery

ENDOMETRIAL CARCINOSARCOMAENDOMETRIAL CARCINOSARCOMA~ UPSC~ UPSCAdjuvant platin based chemotherapyAdjuvant platin based chemotherapyPaclitaxel-carboplatinPaclitaxel-carboplatin

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