patiënte Kan het zonder echografie Dirk Timmerman VVOG Genk 11 oktober 2013 CME This presentation is free from any commercial bias and or promotional intent ID: 779282
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Slide1
De asymptomatische screenings patiënte. Kan het zonder echografie?
Dirk Timmerman
VVOG Genk, 11
oktober
2013
CME:
This
presentation
is free
from
any
commercial bias and /
or
promotional
intent
Slide2Endometrial CarcinomaPremenopausal:1) Endometrial thickness varies in relation to menstrual cycle (Day 4-8!)2) Benign endometrial pathology will be more common3) Endometrial cancer would be expected to be lower
Pos. predictive value will be lower
Cutt
-off 5 mm
Postmenopausal
Premenopausal
Sensitivity
95 %
80 %
Specificity
55 %
34 %
Slide3Prognosis of Endometrial Cancer Screen detected vs Symptomatic Lesions: No prognostic
advantage
Gerber et al. EJC 2001
16 screen detected vs
190 symptomatic endo ca 5-year DFS OS
No Bleeding: 77% 86%
< 8 Weeks Bleeding 83% 98%
8-16 Weeks Bleeding 74% 90%
>16 Weeks Bleeding 62% 69%
Slide4Screening (WHO criteria)High prevalence
and serious
Spectrum of symptoms
is
known Screening should be
easy
few FP
Few FN Methods for further confirmation exist Diagnosis will lead to improved therapy Cost
Slide5ConclusionNot any trial of screening for endometrial cancer has shown a positive effect on mortality
Many false positive results lead to a large number of interventions and create much morbidityRoutine screening of all (postmenopausal) women would be very costful
Patients at higher risk avoid screening
Slide6Ovarian cysts and tumors
Slide7Pre- vs. postmenopausal womenInvasive
ovarian cancer
Invasive
ovarian
cancer
Slide8Ovarian cancerLeading cause of death from gynecological cancers> 50% mortality rate“Silent killer”: early disease is asymptomatic or non-specific nature of symptoms and signs10% diagnosed at localized stage I – 90% 5Y survival rateMost women are diagnosed with advanced disease1/70 life-time risk60.000 new patients per year in Europe; 22,220 new cases in US
Slide9Ovarian Cancer
ScreeningDiagnosis
Risk assessment
Monitoring
FDA approvedOVA1CA125
HE4
On
market
OvPlex
Ultrasound
ROMA
Clinical practice(CA 125Ultrasound)CA 125UltrasoundRMI / CT / MRIIOTA simple US rulesCA 125(ultrasound)CT/ MRIIn develop-mentROCA (MMS)Ultrasound ++OvaSure
OvaDxOvaCheck
IOTA multi-class
models (US)
Slide10Ovarian Cancer
ScreeningDiagnosis
Risk assessment
Monitoring
FDA approvedOVA1CA125
HE4
On
market
OvPlex
Ultrasound
ROMA
Clinical practice(CA 125Ultrasound)CA 125UltrasoundRMI / CT / MRIIOTA simple US rulesCA 125(ultrasound)CT/ MRIIn develop-mentROCA (MMS)
Ultrasound ++OvaSureOvaDx
OvaCheck
IOTA multi-class
models (US)
Slide11Rationale for screening for ovarian cancerIII
III
IV
STAGE
%% EACH STAGE
% 5 YR SURVIVAL
Slide12BIOPHYSICAL MARKERSBIOCHEMICAL MARKERSScreening tests
TUMOUR MARKERSCA 125HE4
OVA1
Imaging
TV ultrasoundColor Doppler
3D
Slide13Screening: 1 ovarian cancer/1000
Normal
/
benign
999
Slide14Screening: 1 ovarian cancer/1000
Normal
/
benign
999
Ovarian
cancer
1
Slide15Screening. Test performance?
Sensitivity
100%
Specificity
95%
50
operations
/1cancer
Slide16Screening. Test performance?
Sensitivity
100%
Specificity
99%
10
operations
/1cancer
Slide17IOTA: preoperative assessment of postmenopausal patientsInvasive 367
Benign
515
Borderline
66
Metastatic
53
Slide18IOTA: Benign vs not benign Invasive 367
Benign
515
Borderline
66
Metastatic
53
Laparoscopy
Oncology
treatment
Slide19Screening: detection of invasive cancerInvasive 367
Benign
515
Borderline
66
Metastatic
53
False
positives
True
positives
Slide20Screening vs. Preoperative diagnosisUKCTOCSIOTA 1, 1b, 2, 3
Slide21Screening vs. Preoperative diagnosisUKCTOCS
IOTA 1, 1b, 2, 3
Slide22Screening studies in general populationCA 125 +/- USSEinhorn et alJacobs et al
Grover et alAdonakis et al
49,590 women
28 ovarian cancers detected
USS +/- CDIVan
Nagell
/
DePriest
et al
Sato et al
Hayashi et al
Campbell et al
Schingalia et alParkes et alVuento et al Goswamy et al110,322 women 47 ovarian cancers detected
Slide23Ultrasound criteria in screening studiesOvarian volumePLCO : CA-125 ≥35 U/mL: abnormal(1) ovarian volume greater than 10 cm3, (2) cyst volume greater than 10 cm3, (3) any solid area or papillary projection extending into the cavity of a cystic ovarian tumor of any size; (4) any mixed (solid and cystic) component within a cystic ovarian tumorUKCTOCS: abnormal scan: one or both ovaries had complex morphology or simple cysts greater than 60 cm³, or ascites
Slide24Is surgical resection of benign ovarian tumors useful to prevent ovarian cancer? 9 women treated with ovarian cancer
202 bilateral oophorectomies for benign lesions Follow-up for 15.5 years
Ovarian cancer mortality
Predicted Observed 25 22
(Crayford et al 2000)
(Courtesy Prof Lil Valentin)
Slide25Bart’s / Royal London Study
22,000postmenopausal
womenprevalencescreen
Study
Group10,958Annualscreening 3yControl
Group
10,977
No
screening
Follow up - Mean 8y
Questionnaire & Cancer Registry
Slide26Bart’s / Royal London trial
9
6
8
4
7
2
6
0
4
8
3
6
2
4
1
2
0
1
.
0
.
8
.
6
.
4
.
2
0
.
0
Cumulative Survival
Months post randomisation
p=0.011
Control
Group
(n=20)
Screened
Group
(n=16)
Median Survival 73mths vs 42mths
(Jacobs et al, Lancet 1999;
353:1207
)
Slide27Is ovarian cancer a suitable disease for screening?
NORMAL
OVARY
PRE-
MALIGNANT CHANGES
PRE-
CLINICAL DISEASE
Does early detection improves prognosis?
Lead time
bias
Length time bias
No
recognised premalignant stageDuration unknown
(Courtesy U
Menon)
CLINICAL DISEASE
Slide28Ovarian cancerLead time bias Length time bias
…earlier detection …slow growing cancers with good not altering the time of death prognosis are detected at screening
Screen
Death
Stage
I
II
III
IV
45
52
65
61
Symptoms
Screen
Screen
Death
Stage
IV
III
II
I
45
(Courtesy Prof Lil Valentin)
Slide29TrialMethodN of screensAgeCompletedERTOCSUS
2 or 350-64StoppedPLCO
Phys exam, US + CA125
460-74
2011UKCTOCSUS or CA125650-742015
Randomised trials on ovarian cancer screening
Slide30Slide31Cumulative deaths
Slide32Conclusions from PLCO trialAmong women in the general US population, simultaneous screening with CA-125 and transvaginal ultrasound compared with usual care did not reduce ovarian cancer mortality. Diagnostic evaluation following a false-positive screening test result was associated with complications.
Slide33Retrospectively evaluated serial preclinical serum CA125 values measured annually in 44 incident ovarian cancer cases identified from participants in the PLCO trialLongitudinal algorithm identified ovarian cancer 10 months earlier and at lower CA125 concentrations (20 U/mL) than a single-threshold screening algorithm (≥35 U/mL)
Slide34Slide35Screening for ovarian cancerVan Nagell2007Kobayashi2008PLCO2005
UKCTOCSUS groupUKCTOCSMMS groupStudy design
Single armRCTRCT
RCTRCT
StrategyUltrasoundPhys. exam, US + CA125US + CA125USCA125 (ROCA)N of
women
25327
41688
28816
48227
50078
N of
screens4.85.41 (first)1 (first)1 (first)N mal (border)39 (10)27 (-)27 (9)45 (20)42 (8)N surgeries36490357084597Sensitivity76%(77%)-75%89%Specificity98.7-98.4%98.3%
99.9%N oper/
cancer933
21353
% stage I/II ca82%-
22%50%47%
(Lancet
Oncol
2009)
Slide36Impact on mortality is not known yetTotal cost cannot be calculated (MMS: patented)No clear guidelines given for USUS is very sensitive for benign tumours (no benefit in removing benign tumours)Bias in favour of MMS? Changing of cut offs in MMS group DURING the study
Slide37Screening (WHO criteria)High prevalence
and serious
Spectrum of symptoms
is
known Screening should be
easy
few FP
Few FN Methods for further confirmation exist Diagnosis will lead to improved therapy Cost
Slide38Screening for ovarian cancer:conclusionsAt present screening of the general population cannot be recommendedNeed to prove decrease of mortality from ovarian cancer in the screened groupFurther studies are needed to improve screening algorithms: better diagnostic tests?
Slide39Ovarian cancer: the silent killer?JournalYearStudy
TypeN casesN
controls
Symptoms ov
caSymptoms controlGynecol Oncol
1999
Retrospect
Early
stI-II
50
ov
ca22BOT82% (3.4mths)Pain, bloating, vaginal bleedingBOT: 68% (8mths)Pain, bloating,vaginal bleedingJAMA2004Prospect44Ov ca1709controlsIncreased abdominal size (OR 7.4), bloating (OR 3.6), urinary urgency(OR 2.5), pelvic pain (OR 2.2)Healthy: Back pain, fatigue, bloating , abdom pain, constipGynecolOncol2004Prospect665Ov ca
146BOT96%
of stage III-IV93% of stage I-II
Abdominal pain (44%), bloating (39%), mass (12%)
84% of BOTLess general malaise
Cancer 2005
Retrospect19856024 br
ca10941 nl30% abdom
pain (OR 6),
16%
abdom
swelling
(OR 31),
8%
gastrointest
sympt
(OR 2),
5%
pelvic
pain (OR 4)
Symptoms
more
than
6
months
before
diagnosis
J
Womens
Health
2007
Retrospect
920
2760
36%
abdominal
symptoms
10%
genital
symptoms
13% urethra/
urinary
symptoms
7%
3%
6%
Eur
J
Gynaecol
Oncol
2007
Prospect
244
151
benign
92%
:
weight
loss/
gain
,
general
malaise,
chest
pain,
abd
swelling
,
bowel symptoms
GynecolOncol2008
Prospect4459 benign21 normal
Persistent abdom distention (OR 5)PMB (OR9), appetite loss (OR 3)
Slide40Symptoms of ovarian cancerAbdominal pain (persistent) Abdominal swellingBloating, loss of appetiteWeight reduction or increaseMalaiseUrinary symptoms (urgency, urethra)Pelvic painVaginal bleedingThoracic painNot: back pain, constipation, fatigue…
Slide41Preoperative assessment of ovarian tumors
Slide42Slide43LR2 prediction model
Blood flow in a papillary structure
Max size of solid component
Irregular internal cyst walls
Ascites
Acoustic shadows
z
= −5.3718 + 0.0354(1) + 1.6159(2) + 1.1768(3) + 0.0697(4) + 0.9586(5) −2.9486 (6)
AGE
Cut off ≥ 10%
Not: color score, max diameter of lesion, purely solid lesion...
Slide44Role of CA 125 ?
Slide45Slide46Histological diagnosisCA-125 related to tumour stageAbscess, fibromas,
endometriomas have higher CA-125; comparable to borderline tumours
Slide47Conclusions of serum CA 125 for preoperative classificationCA 125 has no added value to predict malignancy in adnexal massesIn multivariate modelsIn comparison to subjective impressionAs a second stage test (subjective assessment)In specific cases (borderline, stage I, difficult)
Slide48Prospective study on 389 patients with a pelvic mass, who were scheduled to have surgery. The performance of each of HE4 and CA125 as well as that of ROMA, was analysed.
Slide49Slide50Slide51these 10 rules were applicable to 1501/1938 (77.0%) tumorssensitivity 92% (pattern recognition 91%)specificity 96% (pattern recognition 96%)LR+ 21.29LR- 0.08
Slide52Green-top Guideline November 2011
Slide53User-friendly IOTA apps
Slide54Multiclass model as reliable as IOTA LR
(Van
Calster B et al,
BMC Medical Res Methodol, 2010
)DataAll IOTA data
3511 patients
21 centers
Slide55Conclusies screening naar
ovariumcarcinoom
Nut van screening
is nog
niet bewezenHet is wel zeer
belangrijk
om
klachten
ernstig
te
nemen
en gyn echo uit te voerenNieuwe studies verdienen betere technieken:simple ultrasound-based rules subjectieve beoordelingMulti-class modellenDank u!