Endometriumkarzinom - Diagnose und Therapie C Tempfer

Allgemeines Häufigstes Malignom - Genitaltrakt 31 000 neue Fälle/5400 Todesfälle pro Jahr hohe Prävalenz – westl. Industriestaaten geringe Prävalenz - Entwicklungsländer, Südasien, Indien Östrogen-abhängig ERT, BMI, Ernährung, anovulatorische Zyklen Alter/Postmenopause, ger. Parität, hoher Sozialstatus

PAP Test Kein Screening-Test für Endometriumkarzinom Sensitivität 50% (rp/k) 50% aller Frauen mit EK zeigen abnormale Endometriumzellen im Abstrich Spezifität 25% (rp/pt) 75% falsch positiv

TVS – N. endometrii n=5013; TVS-Doppler N. endometrii stage I: 6 (Kurjak 1994) n=1000; TVS 4mm cut-off; N. endometrii stage I: 1 (Karlsson 1996) n=1074; TVS+Doppler 4mm cut-off/PI; N. endometrii stage I: 3 (Vuento 1999) n=2025; TVS N. endometrii: 3 (Ciatto 1995) Summe: 9112/13; NNS 701 The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about 120-200 cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

Screening Kein etabliertes Massenscreening Hochrisikopopulationen Kein adäquater Bluttest, kein Tumormarker Keine ideale sampling-Methode Hochrisikopopulationen Tamoxifen Lynch II/HNPCC

Gerber 2000; n=247; 10mm cut-off; 5a; 1 asymptomatic cancer; 52 D&Cs; 4 perfor. Love 1999; n=487; 5mm cut-off; 0 cancers; 134 D&Cs Fung 2003; 9mm cut-off; 304 D&Cs - 6 cancers-all with bleeding 1/525 D&C TVS und TAM The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about 120-200 cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

HNPCC TVS TVS + CA 125 - keine Daten TVS + endometrial sampling 2 Studien (Rijcken 2003; Dove 2002) n=41; 5 yrs; 17/179 TVS positive: 3 atyp. Hyperpl.; 1 Ca nicht entdeckt n=269; 3 yrs; 2 Endometrium-Ca; 0/2 durch TVS TVS + CA 125 - keine Daten TVS + endometrial sampling 1 Studie (Renkonen 2006) n=175; 5 yrs; 11/14 entdeckt (8 durch Biopsie) + 14 atypische Hyperplasien; 0/4 N. ovarii entdeckt

Empfehlung Empfehlung American Cancer Society, US Preventive Task Force ‚…annual screening with endometrial biopsy beginning at age 35‘ Smith et al. ACS guidelines for the early detection of cancer, 2006. CA Cancer J Clin. 2006;56:11-25

Klinik Persist. perimenopausale Blutung Hämatometra/Pyometra in Postm. PMB endometrial cancer: 15% of PMB - specificity 15% 90% of women with endometrial cancer - sensitivity 90% (Hacker et al. 1986)

Diagnose Histologie 1) Endometrium-Biopsie (Pipelle®, Kevorkian-Curette) 2) D&C 3) advanced stage disease – LAP/LSK

Hysteroskopie 65 Studien, n=26 346 (Clark et al. 2002) Sensitivität 86.4% Spezifität 99.2% 13.7% of cancers will be missed post-test LR 0.15 not low enough to negate need for further testing ERSETZT NICHT ABRASIO zusätzlich zu Abrasio? - keine Daten

Hysteroskopie Upstaging? Prognose? 10/113 (9%) pos. periton. Zytologie (Obermair et al. 2000) – FIGO IIIa n=262, Ia, Ib +/- HSK assoziiert mit HSK (p=0.04), nicht Stadium, Grading, Histologie n=123; CO2 1.4% vs. saline 14%; p=0.0009 (Lo et al. 2002) 5-yr DFS, n=135+HSK; 127-HSK: 92.4% vs. 84.7% (p=0.5) (Obermair et al. 2000)

Endometriumhyperplasie 2 unterschiedliche Entitäten +/- Atypien (Kurman 1985) Risiko Progression 1.6% vs. 23% (Kurman 1985; n=170) Ansprechen auf MPA 94% vs. 50% (Ferenczy 1989; n=85) 1) Die meisten Frauen mit EMH ohne Atypien sprechen auf MPA an 2) Hysterektomie: Atypien, non-Responder MPA

Endometriumhyperplasie Konkomitantes Karzinom n=54; EMH+Atypien, HE (Hunter 1994) Karzinom 19/54 (35%) n=46; EMH+Atypien, HE (Bilgin 2004) Karzinom 11/46 (24%) n=289; EMH+Atypien, HE (Trimble 2006) Karzinom 123/289 (43%)

Biologie Ausbreitungsrouten Direkte Extension - häufigste lymphatisch - pelvin/paraaortal hämatogen - Lunge Tube - Hysteroskopie

Staging Surgically staged disease (FIGO 1988) Unterschied? replaced clinical staging system (1971) Unterschied? significant understaging (Tiitinen 1986)

Staging (FIGO 1988) I - corpus II - cervix III - extrauterine spread Ia - endometrium; Ib/Ic - </>50% myometrium II - cervix III - extrauterine spread IIIa - serosa/adnexae/pos. washing, IIIb - vagina, IIIc -nodes IV - bladder or distant

Verteilung nach Stadium Tumor Stage Number (n) Percent (%) I 5730 74.8 II 871 11.4 III 818 10.7 IV 227 2.9 No Stage 17 0.2 Total 7663 100.0

Pelvine Lymphknotenmetastasen Depth of Inv. G1 (n=180) G2 (n=288) G3 (n=153) Endometrium 0 (0%) 1 (3%) 0 (0%) Inner Third 3 (3%) 7 (5%) 5 (9%) Middle Third 0 (0%) 6 (9%) 1 (4%) Outer Third 2 (11%) 11 (19%) 22 (34%) Creasman et al. 1987

Lnn-Metastasen - Tumorgrösse Depth of Inv. <2cm (%) >2cm (%) Surf. (%) None 0/17 (0) 0/8 (0) 0/0 (0) <50% 0/27 (0) 5/41 (12) 2/9 (22) >50% 2/9 (22) 6/23 (26) 4/8 (50) Schink et al. 1987

Paraaortale Lnn-Metastasen Depth of Inv. G1 (n=180) G2 (n=288) G3 (n=153) Endometrium 0 (0%) 1 (3%) 0 (0%) Inner Third 1 (1%) 5 (4%) 2 (4%) Middle Third 1 (5%) 0 (0%) 0 (0%) Outer Third 1 (6%) 8 (14%) 15 (23%) Creasman et al. 1987

Prognosefaktoren Alter young women better prognosis (stage, grading) Histo 52/388 (13%) (Wilson 1990) adenosquamous, clear cell, USPC, undifferentiated 33% vs. 92% 5-yr OS Stadium, Grading, LVSI Spülzytologie+: 10.8%-22% (7 studies, n=1541) ER+, PR+ better prognosis (Palmer et al. 1988) DNA-Ploidie aneuploid worse prognosis

Treatment Stage I Abdominal washing Total abdominal hysterectomy and bilateral oophorectomy (TAH-BSO) full pelvic lymphadenectomy >50% (Ic), poor histology, G3, G2>2cm, stage II paraaortic lymphadenectomy? G2/3 outer third invasion, grossly positive pelvic nodes or adnexae, palp. paraaortic nodes (GOG-study, Morrow 1991)

Therapie I Adjuvant irradiation does not improve OS Adjuvant irradiation improves local control vault irrad. recurrences: 14%-1.7% (Lotocki 1983) pelvic irrad. G3, Ic, II, pN+ extended field irrad. G2/3+outer third, aN+, multiple pN+ whole adominal irrad. perit., oment. metast., +cytology?

PORTEC n=715; Stadium I (G1 Ic, G2, G3 Ib) adjuvant pelvic irradiation vs. no therapy no lymphadenectomy; 46 Gray Lokalrezidive 4 vs. 14% (p<0.001) 5-YOS: 81 vs. 85% (p=n.s.) complications: 25 vs. 6% keine adjuvante Bestrahlung Prädiktiver Faktor: Alter >60yrs

PORTEC G1 Ia,b.........................keine Irrad G1 Ic, G2 Ib..................Irrad >60 yrs G2 Ic, G3………….………..Irrad pelvic irradiation G1 Ia, Ib, G1 Ic <60 yrs, G2 Ib <60 yrs vaginal vault irradiation

Therapie II Stage II: surgery, combined radiation/surgery, Wertheim-procedure Stage III: surgical removal of all macroscopic tumor Stage IV: combination surgery: local control - palliation, bowel; exenteration (sole bladder or rectum involvement) irradiation, progestins: 10% CR, 28% PR (Thigpen 1986; n=331) chemotherapy: Carbo/Taxol

Prognose 5-Jahres Überleben Grade Stage (%) Ia Ib Ic IIa IIb 1 92.3 94.1 83.2 86.1 72.7 2 89.7 84.9 79.8 71.8 71.1 3 81.5 76.3 68.3 65.9 49.0 Stage III-IV: 5-Year OS rates 0%-16% (Aalders 1984) Stage III ovary/tube only: 80% 5-Year OS (Bruckman 1980)

UPSC/CCC/recurrent

UPSC/CCC/recurrent

Serös-papillär Prognosis, treatment 50% of all relapses caused by UPSC & CC subsequent breast cancer: 3.2% vs. 25% (Geisler et al. 2001) paclitaxel - III, IV, recurrent; n=20 (Ramondetta et al. 2001) OR rate 77%; med. time to progess. 7.3 mos treat equivalent to ovarian cancer (Carbo/Taxol)