Ovarian cancer nye tilfælde årligt i DK (incl Borderline) Livstidsrisiko - 2% Udgør 30 % af alle gynækologiske cancere

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1 Ovarian cancer nye tilfælde årligt i DK (incl 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

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

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

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

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

6 HNPCC Familiær kræft i tyktarm 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

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

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

9 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

10 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

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

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

13 Forbedre overlevelse Danmark..

14 Udredning Gynækologisk undersøgelse Ultralydscanning Blodprøver ~ CA-125

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

16 PET - CT

17 C PET-CT scanning diss sygdom hjertet nyre blæren Herlev Hospital, klinisk fysiologisk afd.

18 Behandling Operation Kemoterapi

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

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

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

22 RMI<200 laparoskopi med frys, hvis muligt.

23

24 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

25 Teknik i bækkenet - retroperotoneal en bloc resektion 25

26 Pelvis 26

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

28 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

29 Case 39-årig kvinde UL: bilat, multicyst ovarietumorer, hhv 6 og 4 cm CA-125 = 63 Hvad gør vi?

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

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

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

33 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?

34 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

35 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

36 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%).

37 Open Laparoscopy in stage III and IV ovarian carcinoma (n=228, ) Vergote et al Int J Gynecol Cancer : 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.

38 Laparoscopy for diagnosing resectability of disease in patients with advanced ovarian cancer (Review) Rutten MJ, Leeflang MMG, Kenter GG, Mol BWJ, Buist M Editorial group: Cochrane Gynaecological Cancer Group. Publication status and date: Edited (no change to conclusions), published in Issue 3, Review content assessed as up-to-date: 1 February Authors conclusions Laparoscopy is a promising test, but the low number of studies and the differences between the included studies do not allow firm conclusions to be drawn from these data. Due to a difference in prevalence, there is a wide range in negative predictive values between studies. Two studies verified all patients. These imply a high specificity of laparoscopy in diagnosing resectability and have a good sensitivity. Both studies show that the use of criteria for unresectable disease will result in no patients inappropriately unexplored. However, there will still be patients undergoing unsuccessful primary laparotomy. Using a prediction model does not increase the sensitivity and will result in more unnecessarily explored patients, due to a lower specificity

39 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

40 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

41 Abdominale metastaser: Kriterier for inoperabilitet Involvering af a. mesenterica superior, i et omfang, så denne ikke kan skånes. Dyb infiltration af tyndtarmskrøs (radix mesenterii) Diffus og confluerende carcinose på ventrikel og/ell tyndtarm, i en grad at resection vil medføre korttarmssyndrome (behov for mere end resektion af 1 m tyndtarm) og/ell en total gastrectomi. Multiple parenkymatøse levermetastaser i begge leverlapper Involvering af store dele af pancreas (ikke kun cauda pancreatis) og/ell duodenum Infiltrering i karrene i lig. Hepatoduodenale ell truncus coeliacus. Dyb infiltration i porta hepatis.

42 Kriterier for inoperabilitet Extraabdomonale metastaser: Alle ikke- komplet resectable metastaser, dvs multiple lungemetastaser, hjernemetastaser og ikke-resectable lymfeknudemetastaser Ingvinale, solitære retrocrurale ell paracardielle lymfeknudemetastaser, pleuravæske med pos cytologi er ikke i sig selv til hinder for operation. Ved st IV må man vurdere om makroradikal operation i abdomen kan opnås. Patientkarakteristika: Forringet performancestatus og co-morbiditet, der ikke tillader et maximal effort - indgreb. Hvis patienten ikke kan acceptere blodtransfusion ell stomi Alder i niveauet år og derover vil sjældent opfylde ovenstående krav, men man må vurdere individuelt.

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

44 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 trials Gordon Rustin (Mount Vernon Cancer Centre) and Maria van der Burg On behalf of all OV05 and Collaborators 31 st May 2009

45 Time from randomisation to second-line chemotherapy Proportion alive not started second-line chemotherapy Months since randomisation Median (months) Early 0.8 Delayed 5.6 HR=0.29 (95% CI 0.24, 0.35) p< Number at risk Early Delayed

46 Overall Survival HR=1.00 (95%CI ) p=0.98 Proportion surviving Abs diff at 2 years= 0.1% (95% CI diff= -6.8, 6.3%) Early Delayed Number at risk Early Delayed Months since randomisation

47 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 , p=0.98 Absolute difference at 2 years 0.1% (95%CI -6.8, 6.3%) Early chemotherapy does not improve Qol

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

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

50 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

51 Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, (the International Cancer Benchmarking Partnership): an analysis of population-based cancer registry data Lancet 2011; 377: 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.

52 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 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 %). International differences were widest for older women and for those with advanced stage or with no stage data

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

54 Type I og Type II Annu Rev Pathol. 2014;9: Origin and pathogenesis of pelvic (ovarian, tubal, and primary peritoneal) serous carcinoma. Nik NN 1, Vang R, Shih IeM, Kurman RJ.

55 Type I og Type II A new paradigm for the pathogenesis of ovarian cancer has recently been proposed which helps to explain persistent problems in describing the development and diverse morphology of these neoplasms. The paradigm incorporates recent advances in our understanding of the molecular pathogenesis of epithelial 'ovarian' cancer with new insights into the origin of these tumors. Correlated clinicopathologic and molecular genetic studies led to the development of a dualistic model that divides all the various histologic types of epithelial ovarian carcinomas into two broad categories designated 'type I' and 'type II'. The prototypic type I tumor is low-grade serous carcinoma and the prototypic type II tumor is high-grade serous carcinomas (HGSCs).

56 STIC (high- grade) serøs tubar intraepithelial carcinom Fimbriae Navnlig blandt BRCA I posiave, som Udgangspunktet for også primær peritoneal cancer og ovariecancer (type II) Genetisk instabilitet, mutationer i P53 KI67

57 STIC Ved salpingectomi af anden årsag en serøst carcinom i pelvis, findes hyppig forekomst af mutaaoner i p53 i fimbriae også hos kvinder uden BRCAI/II mutaaon eller anden ovariecancer i familien (19-33%) Shaw PA Candidate serous cancer precursors in fallopian tube epithelium of BRCA1/2 mutaaon carriers. Mod Pathol 2009;22: Lee Y A candidate precurser to serous carcinoma that originates in the distal fallopian tube. J Pathol 2007; 211:

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

59 Lymphadenectomy Prognostic impact Correct staging adjuvant therapy Therapeutic impact - micrometastases

60 The potential therapeutic role of lymph node resection in epithelial ovarian cancer: a study of patients British Journal of Cancer (2007) 96, 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).

61 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

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

63 Extensive Surgery - Retrospektive studies Aletti et al. Obstet Gynecol 2006;107:77-85 Chi et al Gyn Oncol 2006;103: Eisenhauer et al. Gyn Oncol 2006;103: Scholz et al. Gyn Oncol 2007;106: 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

64 Extensive Surgery Randomised, phase III trial +/- Maximal debulking - behind the times already a well established treatment

65 EORTC 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

66 Kritik af dette studie:

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

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

69 DESKTOP - studies The Descriptive Evaluation of preoperative Selection KriTeria for OPerability in recurrent OVARian cancer

70 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: AGO-OVAR OP.4 - Prospectively randomized trial to evaluate the impact on OS

71 AGO DESKTOP OVAR I survival probability 1 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0, DESKTOP OVAR I Recidual tumor 1-10 mm median OS 19.6 mos. months No residual tumor median OS 45.2 mos. Residual tumor > 10 mm median OS 19.7 mos. Harter P, du Bois A, Hahmann M, et al. Ann Surg Oncol 2006 DESKTOP v/ overlæge BJMosgaard

72 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

73 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

74 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

75 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

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

77 > 6000 patients Ovarian cancer Endometrial cancer Cervical cancer National based LPR CPR Cancerregister

78 TAK