Ovarian cancer 650-700 nye tilfælde årligt i DK (incl. 150-200 Borderline) Livstidsrisiko - 2% Udgør 30 % af alle gynækologiske cancere Udgør 3,8% af kræft hos kvinder Stiger med alderen 1/3 er yngre end 60 år 90 % epithelial carcinoma

Hyppigere i Danmark end i resten af Europa....

Årsager til kræft i æggestokken Hypoteser Celleskade ved ægløsningen Påvirkning fra hormoner i kroppen Udefra kommende carcinogener

Etiology Risk factors BRCA I & II prof lap BSO HNPCC Hereditary – 10 % BRCA I & II prof lap BSO HNPCC Reproductive factors Nulliparity Infertility Contraceptive pill Tidlig menarch – sen menopause Exogene factors Talcum Tubal ligation / hysterectomi

Familiær mamma / ovarie cancer HBOC Kromosom 17q og 13q BRCA1 og BRCA2 Defekt evne til at reparere DNA

Familiær kræft i tyktarm HNPCC Kromosom 2 og 7 Mismatch repair (MMR) system hMLH1, hMSH2, hMSH6, and hPMS2 45% risiko for kræft i livmoderen 10 % risiko for kræft i æggestok

Symptomer ved kræft i æggestokken er oftest svage.... Øget omfang af maven Tyngdefornemmelse Forstoppelse - diarré Hyppig vandladning Træthed Almen sygdomsfølelse

STADIER St IV Yderligere spredning St III Også i øvre del af bughulen Begrænset til underlivet St. I Begrænset til æggestokkene

Stage St I only the ovary (ies) St II pelvic involvement St IIIa Upper abdomen microscopic IIIb Upper abdomen < 2 cm IIIc Upper abdomen > 2 cm or node pos. St IV levermetastases, above diagphragm, groins, bowel

Stadier St IV - 70 % Yderligere spredning St III - 70% Også i øvre del af bughulen St.II - 15 % Begrænset til underlivet St. I - 15 % Begrænset til æggestokkene

Stadier 5-års overlevelse St IV – 10-20 % Yderligere spredning St III - 40 % Også i øvre del af bughulen St.II - 65 % Begrænset til underlivet St. I - 85 % Begrænset til æggestokkene

Prognosis 5 year suvival St I 85% St II 65% St III 40 % = 70 % of all o.c. St IV 10-20 %

Forbedre overlevelse… Danmark….. Baggrund for dette indlæg om åben laparoskopi ved avanceret ovariecancer, er de erfaringer jeg fik under mit ophold på gynækologisk afdeling i Leuven, Belgien i febr i år, hvor flere af os jo har været mhp at føre den kirurgiske behandling af ovariecacner på højde med Leuven, som et måske dét mest radikalt opererende sted i Europa

Udredning Gynækologisk undersøgelse Ultralydscanning Blodprøver ~ CA-125

Udredning RMI (Risk of Malignancy Index) Menopause x UL-score x CA-125 > 200 PAKKEFORLØB

PET - CT

C PET-CT scanning diss sygdom hjertet nyre Gammeltoft, Gerd Willemoes 061250-0762 Dato: 12.02.09 Beskrivelse (PET): Der ses øget aktivitetsoptagelse i flere delvist konfluerende foci i såvel venstre som højre halsrod, i højresidigt paratrachealt focus, i flere højresidige parasternale foci, i store delvist konfluerende foci beliggende i relation til abdominalkarrene fra diaphragma og videre ned langs iliacakarrene bilateralt samt i focus i højre lyske. Endelig bemærkes let øget aktivitetsoptagelse i randområder af overvejende aktivitetstom proces i det lille bækken. Delkonklusion (PET): Talrige patologiske foci – primært i relation til lymfeknuder i halsrod, i mediastinum, parasternalt, udtalt ned langs abdominalkarrene og i højre. Desuden let øget FDG-optagelse i randområde af aktivitetstom proces i det lille bækken. Susanne B. Søndergaard Beskrivelse (CT): CT-skanning af thorax og abdomen med peroral og i.v. kontrast viser flere små lymfeknuder svarende til halsroden og bilateralt omkring halskarrene. Ingen lymfeadenopati i mediastinum og ingen lungeinfiltrater. Under diafragma ses flere lymfeknudekonglomerater, som ligger omkring leverhilus samt i retroperitoneum mellem aorta og cava og i relation til nyrevenen på venstre side. Der er hydronefrose på venstre side. Der er en del vækst af lymfeknuderne i relation til bækkenkarrene bilateralt, og i det lille bækken findes cystiske forandringer med solid komponent anteriort for livmoderen (IMA 330). Derudover findes ødematøst udseende af den nedre abdominalvæg og bilaterale, forstørrede lymfeknuder i lyskerne. Forsinket kontrastopladning i venstre nyre i forhold til højre nyre. I leveren ses enkelte cystiske forandringer. Med henblik på monitorering vælges følgende parametre: TumorIMA nr.OrganDagens måling / cmA189Lymfeknudekonglomerat i leverhilus5,2B216Til venstre for aorta2,4C223Retroperitonealt4,5D343I relation til højre iliaca externa2,4E341I relation til venstre iliaca externa2,5SUM17,00 Den solide/cystiske proces anteriort for livmoderen måler 7,6 cm og har en tyk kapsel. Delkonklusion (CT): Formentlig ovarietumor/gynækologisk tumor med cystisk/solid komponent – udmålt Udtalt lymfeknudesvulst i retroperitoneum og venstresidige leverhilus Nedsat nyrefunktion på venstre side med nedsat udskillelse og hydronefrose/hydroureteres Talrige små lymfeknuder i relation til halskarrene bilateralt Ingen metastasering til knogler eller lunger Gina Al-Farra/bs Samlet konklusion: Ovarietumor/gynækologisk tumor med cystisk/solid komponent o.p. – let PET-positive randområder Udtalt PET-positiv lymfeknudesvulst i retroperitoneum og venstresidige leverhilus Talrige små PET-positive lymfeknuder i relation til halskarrene bilateralt PET-positive målemæssigt ikke forstørrede lymkfenuder parasternalt og i mediastinum Patientens sygdomsudbredning er ikke typist for spredning af ovariecancer, alternativ diagnose: lymfom o.p. Gina Al-Farra og Susanne B. Søndergaard Billeddokumentation vedlagt separat. blæren Herlev Hospital, klinisk fysiologisk afd.

Behandling • Operation • Kemoterapi

Treatment – ovarian cancer Surgery (RMI< 200: laparoscopy frozen section) Bilat salpingooopherectomy Hysterectomy Omentectomy Lymphadenectomy (Appendectomy) NO RECIDUAL TUMOR Maximal debulking bowel, spleen, diagphragm

Kemoterapi To-tre-stof-behandling Carboplatin og taxol, bevazicumab 6/3uger

Neoadjuverende kemoterapi - 3 serier efterfulgt af operation Dissimineret sygdom - inoperabel Høj alder Comorbiditet

Teknik – lille bækken Adgang til retroperitoneum Ureteres frilægges Uterus fjernes extraperitonealt, idet vagina åbnes 3-9, ned under peritoneum sv.t fossa Douglasi, så højt på rectum som nødvendigt

Pelvis

Teknik – øvre abdomen Incisionen forlænges Ligamentum falciforme deles Leveren mobiliseres Peritoneum på diagphragma reseceres skarpt Omentectomi Colonresektion, splenectomi, ect

Extensivt kirurgisk indgreb omfattende Lille bækken: En bloc resektion af genitalia interna, peritoneum og tarmsegment, med primær tarmanastomose eller stomi, blære- og ureterresektion. Øvre abdomen: Omentectomi, operation på diaphragma (peritoneal resektion eller argon beaming), splenectomi, resektion cauda pancreatis, yderligere tarmresektion Operationsvarighed 4-8 timer

Case 39-årig kvinde UL: bilat , multicyst ovarietumorer, hhv 6 og 4 cm Hvad gør vi ?

Udredning RMI (Risk of Malignancy Index) Menopause x UL-score x CA-125 UL malignitetskriterier : > Bilokulær , Solide områder, Bilateral ,Excrescenser , Ascites, + Extra-ovariel sygdom

Udredning RMI (Risk of Malignancy Index) Menopause x UL-score x CA-125 1 x 3 x 63= 189 dvs < 200

Udredning RMI (Risk of Malignancy Index) Menopause x UL-score x CA-125 < 200 Laparoskopi USO til frys

Case 46 årig præmenopausal kvinde UL: multilokulær tumor, ve adnex PET-CT: mulig carcinose i lille bækken + øvre abd CA-125 = 841 Hvad gør vi ?

Åben laparoskopi ved avanceret ovariecancer Be-/afkræfte diagnosen – 2/3 vs 1/3 Vurdere operabilitet – 90 %, Tilrettelægge/udnytte operationstid mere rationelt Planlægge evt gastrokirurgisk assistence Ingen neg effekt på prognosen

Open laparoscopy in advanced ovarian cancer Open laparoscopy - the best technique to evaluate operability, plan operating time of debulking surgery make a histological diagnosis, exclude other primary tumors (or benign disease) refer patients to a tertiary center

Other studies on laparoscopy to judge operability Fagotti et al (Gyn Oncol 2005): Optimal reduction in 90% of the patients jugded to be operable. Deffieux et al (Int J Gyn Cancer 2006). 10/11 patients thought to be resectable were resected to no residual tumor. Angioli et al (Gyn Oncol 2006): Optimal reduction (R0) in 96% of the patients jugded to be operable (i.e. n = 53/87 or 61%).

Open Laparoscopy in stage III and IV ovarian carcinoma (n=228, 1995 - 2002) Vergote et al Int J Gynecol Cancer 2005 15:776-9 55 patients (32%) with suspect ovarian mass in combination with omental cake and/or ascites have no ovarian carcinoma stage III or IV (metastases from other primaries, stage I-II, benign, ..) 90% of the patients with advanced ovarian carcinoma (n = 173) judged to be operable were optimally debulked. In 71 patients the port sites were completely excised at the time of debulking.

Åben laparoskopi ved advanceret ovariecancer Længdeincision (3 cm) under umbilicus Fascie og peritoneum åbnes Sikre sig fri adgang Trokar med stump spids, ballon på peritonealsiden, skumkrave på hudsiden

Laparoscopy to judge operability Definitions for inoperability: Extended visceral peritoneal disease Extended small bowel involvement Large involvement of upper abdomen (diaphragm, liver, porta) Heavily bleeding tumors Sammenholdes med PET-CT

Indications for neoadjuvant chemotherapy 1. Tumors larger than 2 cm around the superior mesenteric artery or around the porta hepatis, or 2. Intrahepatic (multiple) metastases or several extraabdominal metastases (excluding resectable inguinal or supraclavicular lymph nodes) larger than 2 cm , or 3. Poor general condition (e.g. > 80 years) making a “maximal surgical effort” to no residual tumor impossible, or 4. Extensive serosal invasion (e.g. plaques) of the intestines necesitating bowel resections of > 1.5 m

Case C ovarii st IIIC, makroradikal operation 2012 Adjuv kemoterapi (carbo/tax) 9 mdr kontrol: velbefindende CA-125= 86 Hvad gør vi ?

Early treatment of relapsed ovarian cancer based on CA125 level alone versus delayed treatment based on conventional clinical indicators Results of the randomized MRC OV05 and EORTC 55955 trials Gordon Rustin (Mount Vernon Cancer Centre) and Maria van der Burg On behalf of all OV05 and 55955 Collaborators 31st May 2009

Time from randomisation to second-line chemotherapy 0.00 0.25 0.50 0.75 1.00 Proportion alive not started second-line chemotherapy 264 177 116 91 69 56 49 42 33 Delayed 265 23 16 14 11 10 9 Early Number at risk 3 6 12 15 18 21 24 Months since randomisation Median (months) Early 0.8 Delayed 5.6 HR=0.29 (95% CI 0.24, 0.35) p<0.00001

Overall Survival HR=1.00 (95%CI 0.82-1.22) p=0.98 0.00 0.25 0.50 0.75 Proportion surviving 264 236 203 167 129 103 69 53 38 31 19 Delayed 265 247 211 165 131 94 72 51 22 Early Number at risk 6 12 18 24 30 36 42 48 54 60 Months since randomisation Abs diff at 2 years= 0.1% (95% CI diff= -6.8, 6.3%) Early Delayed

Conclusions In early treatment arm based on rise in CA125 Second-line chemotherapy started a median of 4.8 months earlier Third-line chemotherapy started a median of 4.6 months earlier This early treatment did not improve overall survival HR=1.00, 95% CI 0.82-1.22, p=0.98 Absolute difference at 2 years 0.1% (95%CI -6.8, 6.3%) Early chemotherapy does not improve Qol

HOT scientific topics Difference among countries Lymphadenectomy Ovarian cancer Difference among countries Lymphadenectomy Extensive surgery Neoadjuvant chemotharapy Recurrence – surgery

Difference among countries HOT scientific topics Ovarian cancer Difference among countries Lymphadenectomy Extensive surgery Neoadjuvant chemotharapy Recurrence – surgery

Benchmarking study Modul 1: Basis-benchmarking på grundlag af eksisterende data Modul 2: Patienters opmærksomhed på egen sundhedstilstand, herunder patienters kultur og opfattelser Modul 3: Almen praksis’ kultur, opfattelser og ageren Modul 4: Årsager til forsinkelser i diagnosticeringen Modul 5: Behandlingskvalitet

Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995–2007 (the International Cancer Benchmarking Partnership): an analysis of population-based cancer registry data Lancet 2011; 377: 127–38 Interpretation Up-to-date survival trends show increases but persistent differences between countries. Trends in cancer incidence and mortality are broadly consistent with these trends in survival. Data quality and changes in classification are not likely explanations. The patterns are consistent with later diagnosis or differences in treatment, particularly in Denmark and the UK, and in patients aged 65 years and older.

Stage at diagnosis and ovarian cancer survival: Evidence from the International Cancer Benchmarking Partnership, Gynecologic Oncology Data from population-based cancer registries in Australia, Canada, Denmark, Norway, and the UK were analysed for 20,073 women diagnosed with ovarian cancer during 2004–07. Results. One-year survival was 69% in the UK, 72% in Denmark and 74–75% elsewhere. In Denmark, 74% of patients were diagnosed with FIGO stages III–IV disease, compared to 60–70% elsewhere. International differences in survival were evident at each stage of disease; women in the UK had lower survival than in the other four countries for patients with FIGO stages III–IV disease (61.4% vs. 65.8–74.4%). International differences were widest for older women and for those with advanced stage or with no stage data

DGCG

HOT scientific topics Difference among countries Lymphadenectomy Ovarian cancer Difference among countries Lymphadenectomy Extensive surgery Neoadjuvant chemotharapy Recurrence – surgery

Lymphadenectomy Prognostic impact Correct staging – adjuvant therapy Therapeutic impact - micrometastases Kan du finde flere ref , vi skal have med ?

The potential therapeutic role of lymph node resection in epithelial ovarian cancer: a study of 13 918 patients British Journal of Cancer (2007) 96, 1817–1822 For all patients, a more extensive lymph node dissection (0, 1, 2–5, 6–10, 11–20, >20 nodes) was associated with an improved 5-year disease-specific survival of 26.1, 35.2, 42.6, 48.4, 47.5, and 47.8%, respectively (P<0.001) Of the stage IIIC patients with nodal metastases, the extent of nodal resection (1, 2–5, 6–10, 11–20, >20 nodes) was associated with improved survivals of 36.9, 45.0, 47.8, 48.7, and 51.1%, respectively (P<0.023).

Venter på det randomiserede studie du Bois A multicenter, prospective randomised study of advanced ovarian cancer by the AGO Ovarian Cancer Study Group is planned to analyse the therapeutic impact of systematic lymphadenectomy in ovarian cancer

HOT scientific topics Difference among countries Lymphadenectomy Ovarian cancer Difference among countries Lymphadenectomy Extensive surgery Neoadjuvant chemotharapy Recurrence – surgery

Extensive Surgery - Retrospektive studies Aletti et al. Obstet Gynecol 2006;107:77-85 Chi et al Gyn Oncol 2006;103:559-564 Eisenhauer et al. Gyn Oncol 2006;103:1083-1090 Scholz et al. Gyn Oncol 2007;106:591-595. Winter III WE et al. J Clin Oncol 2008;26:83-89 Conclusion: Increased PFS and OS among ptt with extensive surgery, with no residual tumor in selected patients with ovarian cancer stage IIIC Billeder hv. 2. minut foretages , start 15 min efter inj. Slutbillede efter 2 h.

Randomised, phase III trial +/- Maximal debulking - behind the times Extensive Surgery Randomised, phase III trial +/- Maximal debulking - behind the times already a well established treatment Kan du finde flere ref , vi skal have med ?

EORTC 55971 CONCLUSION: No difference in OS Randomized Phase III study comparing upfront debulking surgery versus neo-adjuvant chemotherapy in patients with Stage IIIc or IV epithelial ovarian carcinoma. CONCLUSION: No difference in OS

Kritik af dette studie:

EORTC 55971

HOT scientific topics Difference among countries Lymphadenectomy Ovarian cancer Difference among countries Lymphadenectomy Extensive surgery Neoadjuvant chemotharapy Recurrence – surgery

Recurrence - surgery Background Recurrence rate 85% The primary treatment of ovarian cancer is surgery 80-90 % have effect of adjuvant chemotherapyeffekt (Carboplatin og Paclitaxel) Neoadjuvant chemotherapy Recurrence rate 85% DESKTOP v/ overlæge BJMosgaard

DESKTOP - studies The Descriptive Evaluation of preoperative Selection KriTeria for OPerability in recurrent OVARian cancer Tilfreds med præ-el.peroperativt

Objectives of the AGO DESKTOP series evaluating surgery in recurrent OC DESKTOP I: - descriptive analysis in a multi AGO-OVAR OP.1 centre setting - identify an appropriate endpoint - creation of a model for a predictive score for resectability (allowing pts. selection for further studies) DESKTOP II: - Validation of the predictive score AGO-OVAR OP.2 - descriptive analysis of the selection bias for offering surgery to ROC pts. DESKTOP III: - Prospectively randomized trial to AGO-OVAR OP.4 evaluate the impact on OS

Harter P, du Bois A, Hahmann M, et al. Ann Surg Oncol 2006 AGO DESKTOP OVAR I No residual tumor median OS 45.2 mos. Residual tumor > 10 mm median OS 19.7 mos. Recidual tumor 1 - 10 mm median OS 19.6 mos. DESKTOP OVAR I Harter P, du Bois A, Hahmann M, et al. Ann Surg Oncol 2006 DESKTOP v/ overlæge BJMosgaard

AGO-score AGO-score positivt (All three factors) Good performance status (ECOG 0) No redidual tumor after primary surgery No ascites at recurrence (< 500 ml) DESKTOP v/ overlæge BJMosgaard

Acceptabel komplikationsrate AGO DESKTOP OVAR II Operation af kvinder med de gunstige egenskaber (God almen tilstand, positiv primær kirurgi, væske i bughulen < 500ml) KONKLUSION AGO- score kan forudsige sandsynligheden for at man ved operationen for tilbagefald, kunne fjernet alt synligt kræftvæv hos 76% Acceptabel komplikationsrate DESKTOP v/ overlæge BJMosgaard

SAMLET KONKLUSION AGO DESKTOP OVAR I-II Kun patienter med makroradikal operation havde gavn af kirurgi AGO-scoren kan pålideligt selektere patienter med favorabelt kirurgisk resultat Patienterne tålte operationen for tilbagefaldet lige så godt, som de tålte den primære operation ved udbredt sygdom DESKTOP v/ overlæge BJMosgaard

Prospectively randomized evaluation of AGO-OVAR OP.4 (AGO DESKTOP OVAR III) Prospectively randomized evaluation of cytoreductive surgery as adjunct preceding standardplatinum-based chemotherapy in platinum-sensitiverecurrent cancer of the ovary, fallopian tube, or peritoneum AGO Study Group Ovarian Cancer (AGO-OVAR) DESKTOP v/ overlæge BJMosgaard

DANSK GYNÆKOLOGISK CANCER Dansk Selskab for Onkologi DGC Dansk Selskab for Gynækologi og Obstetrik Dansk Selskab for Onkologi Dansk Selskab for Patologisk Anatomi og Cyt.

2005-12 > 6000 patients National based Ovarian cancer Endometrial cancer Cervical cancer National based LPR CPR Cancerregister

TAK