Ovarian cancer - gynobsguideline.dkgynobsguideline.dk/wp/wp-content/uploads/2013/02/Ovariecancer.pdf · Treatment – ovarian cancer • Surgery (RMI< 200: laparoscopy frozen section)

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

•  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

St. I Begrænset til æggestokkene

St.II Begrænset til underlivet

St III Også i øvre del af bughulen

St IV Yderligere spredning

STADIER

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

St. I - 15 % Begrænset til æggestokkene

St.II - 15 % Begrænset til underlivet

St III - 70% Også i øvre del af bughulen

St IV - 70 % Yderligere spredning

Stadier

St. I - 85 % Begrænset til æggestokkene

St.II - 65 % Begrænset til underlivet

St III - 40 % Også i øvre del af bughulen

St IV – 10-20 % Yderligere spredning

Stadier 5-års overlevelse

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…..

Udredning

• Gynækologisk undersøgelse

• Ultralydscanning

• Blodprøver ~ CA-125

Udredning RMI (Risk of Malignancy Index)

Menopause x UL-score x CA-125 > 200 PAKKEFORLØB

PET - CT

Herlev Hospital, klinisk fysiologisk afd.

C PET-CT scanning diss sygdom

blæren

nyre

hjertet

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

RMI<200 – laparoskopi med frys, hvis muligt……….

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

26

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 •  CA-125 = 63

•  Hvad gør vi ?


Menopause x UL-score x CA-125 UL malignitetskriterier : > Bilokulær , Solide områder,

Bilateral ,Excrescenser , Ascites, + Extra-ovariel sygdom


Menopause x UL-score x CA-125 1 x 3 x 63= 189 dvs < 200


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%).

•  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.

Open Laparoscopy in stage III and IV ovarian carcinoma (n=228, 1995 - 2002)

Vergote et al Int J Gynecol Cancer 2005 15:776-9

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

Laparoscopy for diagnosing resectability of disease in patientswith 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, 2014. Review content assessed as up-to-date: 1 February 2013.

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

Kriterier for inoperabilitet

Abdominale metastaser: • 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.

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 75-80 år og derover vil sjældent opfylde ovenstående krav, men man må vurdere individuelt.

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

0.00

0.

25

0.50

0.

75

1.00

Prop

ortio

n al

ive

not s

tart

ed

seco

nd-li

ne c

hem

othe

rapy

264 177 116 91 69 56 49 42 33 Delayed 265 23 16 14 11 11 10 10 9 Early Number at risk

0 3 6 9 12 15 18 21 24 Months since randomisation

Time from randomisation to second-line chemotherapy

Median (months) Early 0.8 Delayed 5.6 HR=0.29 (95% CI 0.24, 0.35) p<0.00001

0.00

0.

25

0.50

0.

75

1.00

Prop

ortio

n su

rviv

ing

264 236 203 167 129 103 69 53 38 31 19 Delayed 265 247 211 165 131 94 72 51 38 31 22 Early

Number at risk

0 6 12 18 24 30 36 42 48 54 60 Months since randomisation

Overall Survival HR=1.00 (95%CI 0.82-1.22) p=0.98

Early Delayed

Abs diff at 2 years= 0.1% (95% CI diff= -6.8, 6.3%)

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 Ovarian cancer

• Difference among countries

• STIC

•  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



• STIC




Annu Rev Pathol. 2014;9:27-45. Origin and pathogenesis of pelvic (ovarian, tubal, and primary peritoneal) serous carcinoma. Nik NN1, Vang R, Shih IeM, Kurman RJ.

Type I og Type II

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).

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

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;22:1133-‐1138. 5 Lee Y A candidate precurser to serous carcinoma that originates in the distal fallopian tube. J Pathol 2007; 211: 26-‐35.






Lymphadenectomy

Prognostic impact

•  Correct staging – adjuvant therapy •  Therapeutic impact - micrometastases

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






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

Extensive Surgery

Randomised, phase III trial

+/- Maximal debulking

- behind the times already a well established treatment

EORTC 55971

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:






•  The primary treatment of ovarian cancer is surgery

•  80-90 % have effect of adjuvant chemotherapyeffekt (Carboplatin og Paclitaxel) •  Neoadjuvant chemotherapy

Recurrence rate 85%

Recurrence - surgery Background

DESKTOP v/ overlæge BJMosgaard

DESKTOP - studies

The Descriptive Evaluation of preoperative Selection KriTeria

for OPerability in recurrent OVARian cancer

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

AGO DESKTOP OVAR I

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 12 24 36 48

months

surv

ival

pro

babi

lity

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)


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


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


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)


DANSK GYNÆKOLOGISK CANCER

DGC

Dansk Selskab for Gynækologi og Obstetrik

Dansk Selskab for Onkologi Dansk Selskab for Patologisk Anatomi og Cyt.

2005-12

•  > 6000 patients –  Ovarian cancer –  Endometrial cancer –  Cervical cancer

•  National based –  LPR –  CPR –  Cancerregister

TAK

Documents

Ovarian cancer - gynobsguideline.dkgynobsguideline.dk/wp/wp-content/uploads/2013/02/Ovariecancer.pdf · Treatment – ovarian cancer • Surgery (RMI< 200: laparoscopy frozen section)