Download 04-03-2013 referat - Valsgaard Skole

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
• HNPCC
prof lap BSO
•  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
St.II
Begrænset til
underlivet
St. I
Begrænset til
æggestokkene
Stage
St I
only the ovary (ies)
St II
pelvic involvement
St IIIa
IIIb
IIIc
Upper abdomen microscopic
Upper abdomen < 2 cm
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…..
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
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
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
Teknik i bækkenet - retroperotoneal en bloc resektion
25
Pelvis
26
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 ?
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.
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, 2014.
Review content assessed as up-to-date: 1 February 2013.
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
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
1.00
0.25
0.50
0.75
Early
Delayed
Median (months)
0.8
5.6
HR=0.29 (95% CI 0.24, 0.35) p<0.00001
0.00
Proportion alive not started
second-line chemotherapy
Time from randomisation to second-line chemotherapy
0
3
6
9
12
15
18
21
24
11
56
10
49
10
42
9
33
Months since randomisation
Number at risk
Early
Delayed
265
264
23
177
16
116
14
91
11
69
Overall Survival
0.75
Abs diff at 2 years= 0.1%
(95% CI diff= -6.8, 6.3%)
0.25
0.50
Early
Delayed
0.00
Proportion surviving
1.00
HR=1.00 (95%CI 0.82-1.22) p=0.98
0
6
12
247
236
211
203
Number at risk
Early 265
Delayed 264
18
24
30
36
42
Months since randomisation
48
54
60
165
167
38
38
31
31
22
19
131
129
94
103
72
69
51
53
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
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
HOT scientific topics
Ovarian cancer
• Difference among countries
• STIC
•  Lymphadenectomy
•  Extensive surgery
Neoadjuvant chemotharapy
• Recurrence – surgery
Type I og Type II
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
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.
HOT scientific topics
Ovarian cancer
• Difference among countries
•  Lymphadenectomy
•  Extensive surgery
Neoadjuvant chemotharapy
• Recurrence – surgery
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
HOT scientific topics
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
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:
HOT scientific topics
Ovarian cancer
• Difference among countries
•  Lymphadenectomy
•  Extensive surgery
Neoadjuvant chemotharapy
• Recurrence – surgery
Recurrence - surgery
Background
• 
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
Objectives of the AGO DESKTOP series
evaluating surgery in recurrent OC
DESKTOP I:
AGO-OVAR OP.1
- descriptive analysis in a multi
centre setting
- identify an appropriate endpoint
- creation of a model for a
predictive score for resectability
(allowing pts. selection for further studies)
DESKTOP II:
AGO-OVAR OP.2
- Validation of the predictive score
- 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
AGO DESKTOP OVAR I
1
0,9
survival probability
0,8
No residual tumor
median OS 45.2 mos.
0,7
0,6
0,5
0,4
0,3
Residual tumor > 10 mm
median OS 19.7 mos.
0,2
Recidual tumor 1 - 10 mm
median OS 19.6 mos.
0,1
0
0
12
24
DESKTOP OVAR I
Harter P, du Bois A, Hahmann M, et al. Ann Surg Oncol 2006
36
48
months
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
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
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
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