Carcinoma dellEndometrio CronoprogrammaDiagnostico-Terapeutico.

Carcinoma dell’EndometrioCarcinoma dell’EndometrioCronoprogramma Cronoprogramma

Diagnostico-TerapeuticoDiagnostico-Terapeutico

CARCINOMA ENDOMETRIALE

Sensibile aumento di incidenza In Italia 5-6-% dei tumori femminili

4-5000/ casi anno e 1700 decessi/anno.

Diagnosticato in fase iniziale raggiunge tassi di sopravvivenza fino al 90%

CARCINOMA ENDOMETRIALE

Accuratezza stadiazione clinica

Chirurgia adeguata (isterectomia, linfoadenect., etc)

Terapie adiuvanti ( sovra-sottotrattamento)

Incremento sopravvivenzaRiduzione morbilità iatrogena

Migliore qualità della vita

da riferire urgentemente al Ginecologo

• Sanguinamento in post-menopausa (no TOS)

• Sanguinamento in post-menopausa (sospensione TOS >=6 sett.)

• Sanguinamento in post-menopausa (Tamoxifene)

Perdite Ematiche Atipiche

Eco Pelvi TV

Endometrio <4/5 mm Endometrio >4/5 mm

RassicuranteIsteroscopia + biopsia endometriale

Normale Pat. Ben Cancro

Rassicurante Terapia Riferimento

HRT/TAM Endometrio >8/10 mm

ENDOMETRIAL CARCINOMA

The management of patients with early stage EC is probably the least uniform when compared to that for

patients with other gynecological malignancies

!

EC - Scottish Pop-based StudyStaging Quality & Survival

(Crawford, 2002)

Surgeon Ctg No. Pts % FIGO doc. PWs

Non-specialist 616 88

Gynecol. Oncol. 87 12 p<.001 p<.0001

Hospital Caseload

(no. EC pts/year)

1-19 493 70

<=20 199 30 p<.0001 p<.002

79% of pts operated on by surgeons with <=5 EC pt caseload

Stadiazione FIGO (2009)Stadiazione FIGO (2009)

II Tumor confined to the corpus uteriTumor confined to the corpus uteri

IAIA No or less than half myometrial invasionNo or less than half myometrial invasion

IBIB Invasion equal to or more than half of the myometriumInvasion equal to or more than half of the myometrium

IIII Tumor invades cervical stroma, but does not extend beyond the uterusTumor invades cervical stroma, but does not extend beyond the uterus

IIIIII Local and/or regional spread of the tumorLocal and/or regional spread of the tumor

IIIAIIIA Tumor invades the serosa of the corpus uteri and/or adnexaeTumor invades the serosa of the corpus uteri and/or adnexae

IIIBIIIB Vaginal and/or parametrial involvementVaginal and/or parametrial involvement

IIICIIIC Metastases to pelvic and/or para-aortic LNMetastases to pelvic and/or para-aortic LN

IIIC1IIIC1 Positive pelvic LNPositive pelvic LN

IIIC2IIIC2 Positive para-aortic LN with or without positive pelvic LNPositive para-aortic LN with or without positive pelvic LN

IVIV Tumor invades bladder and/or bowel mucosa, and/or Tumor invades bladder and/or bowel mucosa, and/or distant metastasesdistant metastases

IVAIVA Tumor invasion of bladder and/or bowel mucosaTumor invasion of bladder and/or bowel mucosa

IVBIVB Distant metastases, including intra-abdominal metastases and/or inguinal LNDistant metastases, including intra-abdominal metastases and/or inguinal LN

Clinical assessment

Surgical Staging

Surgical Approach

Adjuvant TherapyFinal Pathology

ENDOMETRIAL CARCINOMA

Preoperative Assessment

Histotype

Grade

Myometrial infiltration

Risk ProfileRisk Profile

Extra-uterine spread

Lymphnode mets

CC inf.

Tumor diameter

Overview on spread pattern in different EC Overview on spread pattern in different EC subtypessubtypes

Amant et al. Gynecol Oncol, 2005Amant et al. Gynecol Oncol, 2005

N (%) Peritoneal cytology

Adnexa Omentum Pelvic LN

Grade 3 E 86/668 (13) 41/721 (6) 3/25 (12) 78/734 (11)

Ca.sarcoma

72/373 (19) 75/512 (15) 15/96 (16) 80/423 (19)

Serous pap.

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)

ENDOMETRIAL CARCINOMASerous Papillary/Clear Cell vs End G3

SP & CC G3

No Pts 63 76

IP mets (%) 28.6 7.9

N + (%) 28 19

M >50% (%) 58.3 64

Aneuploidia (%) 48.6 30.6

S.Greggi, Int J Gynecol Cancer (in press)

Endometrial CarcinomaLymph nodal Status by M & G

% G1-G2 G3

P A P A

M 0 5-11 2 12 n.a.

M < 50% 7-9 2-3 16 7

M > 50% 10-17

4-6 31 12

FIGO

EC – Upgrading on Final PathologyPreop. G1-2 Endometrioid

Author No. Pts % Upgraded

Daniel, 1988 205 14

Malviya, 1989 55 11

Stovall, 1991 39 13

Larson, 1995 145 27

Obermair, 1999 137 21

Frumovitz, 2004 153 24

Eltabbakh, 2005 182 29

Ben-Schacher, 2005 181 19

Case, 2006 43 44

Traen, 2007 64 3

Total 1204 21

Identification of High Grade EC(Preop. End. Samples vs Final Pathology)

% Missed

Reference centers 8-10

Overall 10-25

Literature Review

CARCINOMA ENDOMETRIALEDiagnostica per immagini - Accuratezza

Infiltrazione Miometrio

Sensibilità Specificità

US 69% 70.6%

TC 66-86% 66-75%

RM 78-100% 83-100%

Karen, Genit Imaging 1999Lara A, Genit Imaging 2000Hardesty ,AJR 2001Ruangvutilert, J Med Assoc Thai 2004Manfredi, Rad 2004

Clinical Stage I

Understaging

19-22 %

Endometrial Carcinoma

Literature review


Estensione alla Cervice


TC 20-70% 70-90%

RM 80-100% 96-100%

Karen, 1999Hardesty , 2001Manfredi, 2004Nagar, 2006

END CA – Involvement of CCHysteroscopy

Hysteroscopy

No Pts 200

Accuracy (%) 92.5

PPV (%) 93.3

NPV (%) 92.4

Lo, 2001

Analisys of EC Management North America & Western Europe

Pre-surgical North America Western EuropeStaging n° of center (%) n° of center (%)

Hysteroscopy

Routinely used 3 (6%)

27 (33%)

Usually omit 42 (87%)

47 (57%)

Maggino et al, 1995-98

SIOG – EC Management Survey(99 centers; 2008)

% yes

Histeroscopyroutine in preop staging 92.9

IRCCS/University 90.5

Hospital 93.6

Nord 88.5

Centro-sud 100.0

<20 EC/y 93.6

>=20 EC/y 86.4

EC - Parametrial Involvement (%)by FIGO Stage

Author Pts Clin

St. I St. II

Pathol

St. I St. II St. III St. IV

Total

Yura

1996

91Clin I-II

- - 0 11.5 52.9 - 13.2

Tamussino

2000

24Clin II

- 8.3 - 9

16*

- - 41.6

Sato

2003

269Clin I-III

1.5 9.8 0 63 16.9 100 5.9

Pts undergoing Rad. or Mod. Rad. Hysterectomy * trans. cervix/param. +

FIGO Stage II EC Outcome by Type of Hysterectomy

Author No. % 5y PFS

SH RH p

% 5y OS

SH RH p

Mariani, 2001 203 73 100 .01 80 100 .01

Cohn, 2007 160 76 94 .05 - - -

Cornelison,1999 932 - - - 84 93 .05

Sartori, 2001 203 - - - 79 94 .03

Ayhan, 2004 48 81 85 NS 83 90 NS


Metastasi linfonodali


TC 57% 92%

RM 50% 95%

Karen, Genit Imaging 1999Connor Obstet Gynecol 2000Manfredi, Rad 2004

Nodal Status Assessment?

<10 % of +ve N are grossly enlarged

(Creasman et al., Cancer 1987)

>50 % of +ve nodes < 1 cm (Girardi et al., Gynecol Oncol 1993)

(Benedetti et al., Int J Gynecol Cancer 1998)

537 patients randomly assigned

273 allocated

Lymphadenectomy

264 allocated

NO-Lymphadenectomy

9 patients not eligible intra-operatively

•Other histotype = 3

•Stage IA = 2

•Stage IB Grading 1 = 4

14 patients not eligible intra-operatively

•Other histotype = 5

•Stage IA = 3

•Stage IB Grading 1 = 6264 available for

Intention To Treat Analysis

250 available for

Intention To Treat Analysis

38 protocol violations

(< 20 nodes resected)

17 protocol violations

(≥20 nodes resected)

226 patients available for

Per-Protocol Analysis

233 patients available for

Per-Protocol Analysis

ILIADE-2 LIN.CE

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60

monthsmonths

%%

χ2=0.45; P=0.50

events total

---- Lymphadenectomy 30 264

___ No lymphadenectomy 23 250

Lymphad. 264 237 212 173 139 93

No lymph 250 226 193 160 125 93

Figure 3. Overall survival

90.0

85.9

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60

monthsmonths

%%

χ2=0.17; P=0.68

eventstotal

---- Lymphadenectomy 42 264

___ No lymphadenectomy 36 250

Lymphad. 264 225 196 159 131 89

No lymph 250 218 184 150 114 85

Figure 2. Disease free survival

81.7

81.0

ENDOMETRIAL CANCERINT-NAPLES Jan 2001-June 2005

(No.110 Clinical Stage I Endometrioid EC Pts op. on)

BMI >= 35: 43 (39%)

ASA >=3: 30 (27%)

Uterus sized >12wks (and/or stenotic/deep vagina):

15 (14%)

Potentially ineligible for LAVH:

50 (45%)

Variable No. %

Potentially eligible for LAVH LAVH performed Previous LPTM

34/612312

55.710052

Median Age (range)Median BMI (range)

63 (52-70)29 (26-30)

Pelvic LAAortic LANo. Pelvic N

7-

18 (12-28)

30-

Converted to LPTMMedian OR time (min)

2220 (160-330)

8.5

Lenght of Hospital stay (d)

3.5 (3-6)

LAVH in Clinical Stage I ECProspective Analysis – INT Naples (2005-07)(Endometrioid; Age<=70; BMI<35; ASA<3)

R

A

N

D

O

M

LAP-ASS VAGINAL SURGERY

ABDOMINAL SURGERY

GOG TRIAL LAP2

FIGO Stage I-IIa

Endometrial ca or Ut. Sarcoma

Planned sample size: 2000; date of activation 1996

Careful evaluation of general conditionsCo-pathology & ASA

Medical Operability

Selection forLAVH /TLH

S.I.O.G. - Indagine sulla Gestione Clinica del CE(99 centri; 2008)

Chirurgia elettiva St. I %Addominale 61.6

Vaginale 2.0

Totalmente lpsc 11.1

Vaginale lpsc-ass. 6.1

Add o Lpsc 17.2

Incl. Lpsc 34.4

Missing 2.0

END. CANCER IN YOUNG WOMEN

- is it possible to preserve fertility in

young patients?

- is it possible to achieve pregnancy

in patients conservatively treated ?

EC Pts Treated 1993-95.

Distribution of Pts by Age Group and Mode of Staging

0,4% 2.5%

EC < 40 year of Age

Multivariate Analysis

Factors Predicting Stage IA

OR 95% CI

Grade (1 vs 2-3) 16.8 (5.0 – 69)

Duska, 2001

Coexisting Ovarian Malignancies in EC Pts <45y-old

Author % <45y % >45y

Gitsch, 1995 29 5

Evans-Metcalf 1998

11 2

CaseAge

(years)BMI

(Kg/m2)

HistotypeGrade

HormoneTherapy

Relapse(months)

PregnancyFollow-up (months) /

Current Status

1 41 24 E-G1 Oral MA No No 79 / NED



4 36 27 E-G1 Oral MA No NFTD 62 / NED



7 37 23 E-G1 LNG-IUD No No 43 / NED






13 28 53 E-G1 LNG-IUD Yes No 17 / NED


G. Laurelli & S. Greggi, Gynecol Oncol (in press)

CA ENDOMETRIALE

RM addome-pelvi mdc

CA 125

Rx Torace (2 pr)

Val. Rischio Anestesiologico

ASA >=3

T scarsamente diff.

Istotipi Speciali

Sospetta infiltrazione CC

Sospetta/e metastasi LN

Val. terapia conservativa

Centro Riferimento Oncol

Ospedale di II Livello

Low-Intermediate Risk ECLow-Intermediate Risk EC

Mariani, 2000Mariani, 2000

No benefit from LND or adjuvant RTNo benefit from LND or adjuvant RT

Podratz, 1998; Keys, 2004 Podratz, 1998; Keys, 2004

Adjuvant RT reduces local relapses, no impact on survival Adjuvant RT reduces local relapses, no impact on survival

ESMO, 2009ESMO, 2009

IA, G1-2, <2cmIA, G1-2, <2cm

Intermediate & High Risk / Early StageIntermediate & High Risk / Early Stage

Stage I - Endometrioid Stage I - Endometrioid

G1-2, IA, <2cmG1-2, >2cm

G3IB

TH, BSO, Cyto TH, BSO, Cyto, pelvic LND

pelvic N- pelvic N+ Ut Serosa /Adnexa +

aortic N+ *

No adjuvant CT + pelvic RT CT + pelvic/aortic RT

aortic N-

aortic LND

Carcinoma dellEndometrio CronoprogrammaDiagnostico-Terapeutico.

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