28 Million £ Down The Drain
Muhieddine Seoud, MD, FACOG, FACS
American University of Beirut Medical Center
Department of Obstetrics and Gynecology
Kuwait City, Lebanon February 7 2017
Screening For Ovarian Cancer In Low Risk Women:
Re-assessing The UKTOCS After The Latest FDA Warning
Muhieddine Seoud, MD, FACOG, FACS
American University of Beirut Medical Center
Department of Obstetrics and Gynecology
Kuwait City, Lebanon February 7 2017
Ovarian Cancer screening: Dust in the wind
Objectives
• Review the latest USA SEER’s data on ovarian cancer
• Define the different populations to screen:
1. Asymptomatic women with low Genetic Risk for ovarian cancer
2. Asymptomatic women with high Genetic Risk for ovarian cancer
3. Women presenting with a pelvic mass
• Analyze the available data on the various screening modalities
• Learn about : UKOPS, OVA1, Ova Check, UKOCSP, ROCA Algorithm, PLCO,
UKCTOCS, UKFOCSS, ROMA Algorithm, RMI, OTI, etc..
• Present the September 2016 FDA announcement and its repercussions
• Take home message
Ovarian Cancer: SEER’s Facts, USA
•
Average age: 63, 10% diagnosed in women < 45
•
USA 2016 data: ~ 22 200 new patients, ~ 14 200 deaths
•
Age Specific Incidence Rate (ASIR): ~ 12.5/100,000
•
The life time risk: 1.8% 1 in 72
•
Prevalence: ~ 1/2000-2500
•
~ 20 % are detected at an early stage
– Stages 1 and 2:
< 35%
– Stages 3 and 4:
> 65%
•
Overall 5 YSR 2015:
– Confined:
– Metastatic:
~ 45%
90%
25%
1. Ohio Cancer Incidence Surveillance System, Ohio Department of Health, 2011 2. Anderson MR et al. Cancer 2008;113:484-489. 3. Myers ER et al. Evidence Report Technology Assessment 2006 full report 1-145. 4.
Cancer Research UK. http://info.cancerresearchuk.org/cancerstats/types/ovary/survival/index.htm#Five-year.
Presenting symptoms of ovarian cancer
• Lack of specific symptoms- Early stages EOC:
– Usually portrayed as asymptomatic
– Only < 11% are truly asymptomatic
– Mostly vague pain or discomfort
• Lack of screening for early diagnosis:
– By the time they reach 3cm, >50 are stage III/ IV
• Advanced stages EOC:
–
–
–
–
Early satiety and vague GI or GU
Abdominal swelling, feeling full (tight closing)
Rare vaginal bleeding
General cancer symptoms: malaise, anorexia,
weight loss and, orthopnea, SOB, dyspnoea
– Rarely present as pelvic mass
– Pap smear sensitivity: 10-30%
Goff et al 2000- Clin Obstet Gynecol. 2012 Mar;55(1):36-42. doi: 10.1097/GRF.0b013e3182480523. “Symptoms associated with ovarian cancer.”
Screening Basics
A screening program
for
all women > 50
Condition (or
Disease)
with a sensitivityTrueof 80 %
would
require
False
Positive
True Positive
False Positive
 Positive
Predictive Value
Negative
False
Negative
True
Negative
 Negative
Predictive Value
test with a specificity of at least 99.6 %
Test
outcome
to achieve a PPV of 10 %Accuracy
Sensitivity
Specificity
The Quest for Ovarian Cancer Screening markers:
Are We on the Right Road?
• PPV of a test can differ enormously due to:
1. Different prevalence even with same SN and SP (Cervical Vs
Ovarian Vs Breast ca)
2. Prevalence of pre-invasive disease and early Vs late stages
3. The time it takes to go from normal to pre-invasive to cancer
• Clinically meaningful OVCA screening tools must meet 2 major conditions:
1. Should recognize cancers with high SN and SP
1. Should recognize these cancers early enough, permitting interventions that
can alter the natural history of the disease (especially mortality)
1.
Anna E. Lokshin (Int J Gynecol Cancer 2012;22: S35YS40 2 . Brown PO, Palmer C. PLoS Med. 2009;6:e1000114. 3. Mongia SK et. Am J Clin Pathol. 2006;125:921Y927.
Mathematical modeling from the pathology RR prophylactic BSO:
• OVCAs spend > 4.3 years as in-situ or stage I-II disease
• Serous OVCAs have progressed to a late stage ~ 1 year before their discovery
• Changes in CA 125 are detectable within 3-12 months before clinical diagnosis
• Early-stage serous OCs have a median diameter of < 0.3 cm
• Modeling: annual screen needs to detect tumors before they advance to stage III:
– < 1.3 cm to achieve 50% SN
- < 0.4 cm to achieve 80% SN
• No imaging modality could presently detect such small lesions
1.
Anna E. Lokshin (Int J Gynecol Cancer 2012;22: S35YS40 2 . Brown PO, Palmer C. PLoS Med. 2009;6:e1000114. 3. Mongia SK et. Am J Clin Pathol. 2006;125:921Y927.
The Quest for Ovarian Cancer Screening markers:
Available screening modalities
•
•
Imaging:
– Ultrasonography:
• TV: “extension of the fingers”
• Trans-abdominal
• Trans-rectal
• +/- Doppler
• 3 D rendering
– Advanced: MRI??
•
Proteomics
– OVA1
– OVA Check
•
Genomic profiling: the 100 K project
(similar to the human genome
project)- trying to identify genomic
alteration prior to the phenotypic
transformation- “Systems Biology”
Founder at ASCO
Biomarkers:
– CA125
– HE4
– Lysophosphatidic Acid (LPA)
1.
Anna E. Lokshin (Int J Gynecol Cancer 2012;22: S35YS40 2 . Brown PO, Palmer C. PLoS Med. 2009;6:e1000114. 3. Mongia SK et. Am J Clin Pathol. 2006;125:921Y927.
Ovarian Cancer Screening: Serum Markers: CA-125
• A high MW mucin-type GP surface Ag
• CA125 > 35 units/ml in:
– 60% of women with ovarian cancer
• > 80% of patients with disseminated ovarian cancer
– 1% of normal healthy women
– 3% of normal healthy women with benign ovarian diseases
– 20% of benign ovarian tumors
– 6% of patients with non-neoplastic conditions
• Limited SN for early stage disease (high in only 20%)
• Limited SP: Benign conditions, Other malignancies
Sonographic Predictors of Ovarian Malignancy
• TVUS +/- Doppler:
– SN: 80-100%
– PPV: Limited
-Specificity: 94-99%
Poor at Dx early stages
• 249 women had a TVUS for a pelvic mass at BWH, 2005-2010, and surgery
• Images reviewed retrospectively by one sonologist blinded to diagnosis &
clinical information:
– 12 U/S features were scored into high, intermediate and low risk
• Low risk lesions: Invasive tumors: 2/49
(4.0%)
Barroilhet, Lisa et al Journal of Clinical Ultrasound. 41(5):269-274, June 2013
Sonographic Predictors of Ovarian Malignancy
• Intermediate risk lesions: thick wall or thick septa without internal blood flow:
– Borderline tumors: 5/6
(83.3%)
– Invasive tumors: one additional patient
•
High risk lesions: all masses with internal vascularity:
– Benign tumors:
9/82
(11%)
– Borderline tumors: 1/6
(16.7%)
– Invasive tumors:
9/12
(75%)
•
Conclusion:
– In the absence of high or intermediate risk U/S
features, the risk of malignancy is low
Barroilhet, Lisa et al Journal of Clinical Ultrasound. 41(5):269-274, June 2013
Major Ovarian Cancer Screening Studies
in Asymptomatic low risk Women
Screening Trial
Japan Screening
Study
UKOCSP
PLCO Study
UKCTOCS
Type of
Study
RCT
Single–arm
study
RCT
RCT
Population
Screening
Modality
82,487
Annual CA 125
and TVUS
No SS #
1985–2002 in ovarian cancer
incidence
39,337
Annual
TVUS
Describes
1987–2011 ovarian cancer
incidence and FU
78,216
Annual CA 125 for
6 yrs and
Annual TVUS for 4
yrs
No SS #
1993–2010 in ovarian cancer
mortality
202,638
ROCAAnd CA 125–
based-algorithms
Ovarian cancer
mortality,
To be discussed
Dates
2001–2014
Results
Angela Chan, et al Obstet Gynecol 2012;120:935–40
Ovarian Cancer Screening:
Development of the Risk of Ovarian Cancer Algorithm
(ROCA)
Development of the Risk of Ovarian Cancer Algorithm (ROCA)
• 2 screening trials of CA125 for early detection of ovarian cancer were initiated:
1. UK:
22,000 women > 45 yrs had a prevalence screen2:
SN: 40%
2. Sweden: 5,550 women > 40 yrs had two annual screens3:
SN: 50%
• Concern: small # of cases and the still low sensitivity
• Statistical analysis: data from the trials were pulled and analyzed
– longitudinal features of CA125
– A computer algorithm determined ‘‘change-point’’ CA-125 levels
1. Karen H. Lu et al. Cancer 2013;119:3454-3461
2. Jacobs I et al. BMJ. 1993;306(6884):1030–4 3. Einhorn N et al. Obstet Gynecol. 1992 ;80(1):14–8.
Development of the Risk of Ovarian Cancer Algorithm (ROCA)
• 2 statistical models:
1. One estimated from the ovarian cancer cases
2. One from all other women
• To calculate the risk for a new woman with a series of CA125
values:
1. Average distance between her CA125 profile and the changepoint profiles is calculated
2. And compared to the average distance between her CA125
profile and the flat profiles
1. Karen H. Lu et al. Cancer 2013;119:3454-3461
2. Jacobs I et al. BMJ. 1993;306(6884):1030–4 3. Einhorn N et al. Obstet Gynecol. 1992 ;80(1):14–8.
Ovarian Cancer Screening: Serum Markers
CA-125
change-point profiles
Flat profiles
Development of the Risk of Ovarian Cancer Algorithm (ROCA)
• The initial OR for having ovarian cancer is:
1. Based on the age as derived from population tumor registries:
• At 50 yrs her risk is:
1/2,000
• At 75 yrs her risk is:
1/1,000
2. This risk is Xed by 2 yrs (estimated average duration of preclinical OVCA)
1. Karen H. Lu et al. Cancer 2013;119:3454-3461
2. Jacobs I et al. BMJ. 1993;306(6884):1030–4 3. Einhorn N et al. Obstet Gynecol. 1992 ;80(1):14–8.
Development of the Risk of Ovarian Cancer Algorithm (ROCA)
• The final OR is:
– The initial OR Xed OR calculated from her serial CA125
(converted to a risk of having a change-point, interpreted as the
risk of having undetected ovarian cancer)
• If a 50 yrs has a sequence of CA125 10 X as close to a change-point
profile as to a flat profile:
– Initial OR:
1/2000
– Final OR:
10 times 1/2,000 = 1 in 200
•
ROCA was intended for average-risk patients
1. Karen H. Lu et al. Cancer 2013;119:3454-3461
2. Jacobs I et al. BMJ. 1993;306(6884):1030–4 3. Einhorn N et al. Obstet Gynecol. 1992 ;80(1):14–8.
Development of the Risk of Ovarian Cancer Algorithm (ROCA)
The clinical recommendations for FU are based on the ROCA risk score
Annual CA 125
screening
ROCA
Calculation
Low Risk:
< 1/2000
Intermediate Risk:
1/2000- 1/500
High Risk:
1/500
Resume Annual
CA125 Screening
Repeat CA 125
In 3 months
Repeat CA 125
And do TVUS
After each additional CA125 , ROCA is recalculated and a new recommendation is made
Lu et al Cancer 2013“A 2-stage ovarian cancer screening strategy using the Risk of Ovarian Cancer Algorithm (ROCA) identifies early-stage incident cancers and demonstrates high positive predictive value”
Risks and Benefits of Screening Asymptomatic Women for OVCA
Systematic Review and Meta-Analysis 2013: 1975-2012
• In 8/10 trials:
– FP results in 10.6% of the controls led to additional testing, including surgery
• 9 surgeries (95% CI, 5.5-17.0) were performed to diagnose one case of OVCA:
– TVUS:
38 surgeries per OVCA detected (95% CI, 15.7-178.1)
– CA-125: 4 surgeries per OVCA detected (95% CI, 2.7-4.5)
• Unnecessary surgeries increase morbidity (surgical complications, pain and
recovery time, and increased anxiety)
• Conclusions: Screening asymptomatic women for ovarian cancer
=> Does not reduce mortality
=> Results in unnecessary surgery
=> Does not result in diagnosis at an earlier stage
Gynecologic Oncology 2013;130:674-681, PMID: 23822892
Ovarian cancer screening and mortality in the
United Kingdom Collaborative Trial of Ovarian Cancer Screening
(UKCTOCS)- Lancet December 17 2015
Jacobs IJ, Menon U, Ryan A, et al. The Lancet: December 17, 2015 DOI: 10.1016/S0140-6736(15)01224-6
Jacobs I et al, Lancet Dec 17 2015 http://dx.doi.org/10.1016/ S0140-6736(15)01224-6
28 million pounds funding
• 1ry endpoint:
– To establish the impact of ovarian cancer screening on ovarian
cancer mortality 7 yrs after randomization (by December 2014)
• 2ry endpoints:
1. Morbidity of ovarian cancer screening
2. Resource implications of screening
3. Feasibility of population screening as reflected by:
• Uptake of invitations
• Compliance rates with annual screening
4. Compare the performance of two screening strategies
• 3ry endpoint:
– Establish a serum bank for future novel tumor markers
Jacobs I et al, Lancet Dec 17 2015 http://dx.doi.org/10.1016/ S0140-6736(15)01224-6
•
Size of study population: 1 243 282 women invited
– 202,638 recruited over 4 years ( June 2001 and October 2005)- FU till Dec 2014
– 13 regional centers in the NHS
•
Inclusion criteria
– Age 50-74 years
– Postmenopausal:
• > 12 months amenorrhea following a natural menopause or hysterectomy OR
• > 12 months of HRT commenced for menopausal symptoms
•
Exclusion criteria:
– Bilateral oophorectomy or ovarian cancer
– Currently active non-ovarian malignancy (excluding skin cancer)
– Women who have had an ovarian malignancy in the past
– Women at high risk of ovarian cancer due to a familial predisposition
– Woman participating in other ovarian ca
Jacobs I et al, Lancet Dec 17 2015 http://dx.doi.org/10.1016/ S0140-6736(15)01224-6
202 638 out of 1243 282 PM women
PM women: randomized 1:1:2
Multimodal group:
Annual CA 125: 50 640
TVUS group:
Annual: 50 639
Normal
Control group:
101 359
Abnormal
Normal
Level II Screen
Normal
Level II screen:
Detail TVUS in both groups + repeat CA 125 in multimodal group
Abnormal
Normal
Refer to
Gyn Oncol
All women FU in NHS cancer registry and by postal questionnaire
Jacobs I et al, Lancet Dec 17 2015 http://dx.doi.org/10.1016/ S0140-6736(15)01224-6
202 638: randomized 1:1:2
Multimodal group:
Annual CA 125: 50 640
Normal
Intermediate
Repeat CA 125 in 3 months
TVUS group:
Annual: 50 639
Control group:
101 359
Abnormal
Repeat CA 125 in 6 weeks and Level II Screen
Normal
Abnormal
Refer to
Gyn Oncol
Jacobs I et al, Lancet Dec 17 2015 http://dx.doi.org/10.1016/ S0140-6736(15)01224-6
Level II screen-TVUS
Complex morphology
Simple cyst
Volume > 60 ml
Normal morphology
Volume < 60 ml
Level II Screen-TVUS in 6-8 wks
Complex morphology OR
Simple cyst > 60 ml
Refer to Gyn Oncol
Normal
morphology
Normal
Jacobs I et al, Lancet Dec 17 2015 http://dx.doi.org/10.1016/ S0140-6736(15)01224-6
• Average age is 60 yrs
• Average FU duration 11 years
• Parity ~ 2, OCP 5 years, 59% ever used OCP
• 6% family hx of OVCA
• Take into consideration:
– lead time for ovarian cancer between prevalent Vs.
developing case in the intervention Vs. the no screen groups
Jacobs I et al, Lancet Dec 17 2015 http://dx.doi.org/10.1016/ S0140-6736(15)01224-6
Screening Basics
A screening program for all women > 50
with a sensitivity of 80 % would require
test with a specificity of at least 99.6 %
to achieve a PPV of 10 %
• The overall SN for detection of OVCA (within a year of a screening):
– MMS:
84% (95% CI 79–88; 199 of 237)
– USS:
73% (95% CI 66–79; 161 of 221)
• Proportion of “ early stages OVCA: I, II, and IIIa”:
– MMS:
40% (119 of 299; p<0·0001)
– USS:
24% (62 of 259; p=0·57)
– No screening: 26% (149 of 574)
• The mortality reduction over years 0–14 with the Cox model:
– MMS:
15% (95% CI: –3 to 30 ; p=0·10)
– USS:
11% (95% CI: –7 to 27 ; p=0·21)
– Not SS
Jacobs I et al, Lancet Dec 17 2015 http://dx.doi.org/10.1016/ S0140-6736(15)01224-6
UKCTOCS: the Kaplan-Meier cumulative death rates
The no screening group HR continues to rise
The MMS HR starts levelling off, becoming substantially
lower than that of the no screening group at about 7 years
The USS HR levelling off at about 9 years
Potential delayed effect of screening
Jacobs I et al, Lancet Dec 17 2015 http://dx.doi.org/10.1016/ S0140-6736(15)01224-6
The Kaplan-Meier cumulative death rates
• The mortality:
• HRs was lower in the MMS Vs. no screening (20% [95% CI: –2 to 40],p=0·021)
• SS higher for:
– years 0–7:
– years 7–14:
(8% [95% CI: –27 to 43])
(28% [95% CI: –3 to 49])
• For each OCA or PPC detected by screening additional FP surgeries in:
– MMS:
2 (< 0.1%) (211 annual screens)
– USS:
10 (< 0.1%) (164 annual screens)
• Complication rate
– MMS:
– USS:
3.1% or 15/488 (95% CI 1·7–5·0)
3.5% or 57/1634 (95% CI 2·7–4.7)
Jacobs I et al, Lancet Dec 17 2015 http://dx.doi.org/10.1016/ S0140-6736(15)01224-6
Performance characteristics of Invasive EOC/FT/PPC
Screen positive surgery and Histological finding
Slide 6
True Positives :
MSS 180
Presented By Usha Menon at 2016 ASCO Annual Meeting
USS 105
Performance characteristics of Invasive EOC/FT/PPC
Screen positive surgery and Histological finding
Slide 7
False Positives:
MSS 556
Presented By Usha Menon at 2016 ASCO Annual Meeting
USS 1719
Performance characteristics of Invasive EOC/FT/Peritoneal cancer
diagnosed within one year of diagnosis
Slide 8
Presented By Usha Menon at 2016 ASCO Annual Meeting
Invasive EOC/FT/Peritoneal ca diagnosed after randomization: 2001-2005
Screening till Dec 31 2011- FU till Dec 31 2014.
Mean FU 11.1 years
Proportion of all invasive Ca that were screen detected: MSS 60.2% USS 40.5%
Presented By Usha Menon at 2016 ASCO Annual Meeting
Stage Distribution of invasive EOC/FT/Peritoneal cancers
ITT population
Slide 10
SS higher % of earlier stages ca Vs
control arm
SS lower % of stages
I/II/IIIA Vs. control arm
P=0.002 as SS due to multiple comparisons
Presented By Usha Menon at 2016 ASCO Annual Meeting
Invasive EOC/FT/Peritoneal cancers:
Histological types
All are likely to be HGSOC
Presented By Usha Menon at 2016 ASCO Annual Meeting
Most are probably HGSOC
Stage Distribution of Type I cancers
Slide 12
No Stage shift in type I cancer in
MMS Vs. Controls, USS Vs. Controls
Presented By Usha Menon at 2016 ASCO Annual Meeting
Stage Distribution of Type II HGSOC cancers
Slide 13
SS Stage shift in type II cancer in
MMS Vs. Controls
P=0.002 as SS due to multiple comparisons
Presented By Usha Menon at 2016 ASCO Annual Meeting
Invasive EOC/FT/Peritoneal ca
Summary
• MMS: SN of 86%, SP of 99.8% PPV of 24.5% with 4 surgeries/Invasive ca
• USS: SN of was 63% with 17 surgeries/Invasive ca
• Screen detected ca: SS stage shift for MMS: 44% and USS: 43% Vs control 26%
• All Cancers (ITT): SS Stage shift only with MMS 40% Vs control 26%
• Type I detected ca: No SS stage shift for MMS or USS% Vs control 83%
• Type II detected ca: SS stage shift for MMS both screen detected (37%) and ITT
33% Vs control (17%)
• Overall SS stage shift in MMS arm is a reflection of both higher sensitivity and
better ability to detect Type II cancers earlier
Presented By Usha Menon at 2016 ASCO Annual Meeting
The FDA recommends against using screening tests for ovarian cancer screening:
September 7, 2016
•
Based on currently available information, the FDA recommends against using currently offered tests to
screen for ovarian cancer (false-positives and false-negatives)
•
For women: (including those at increased risk)
1. Currently, there is no safe and effective screening test
2. Do not rely on screening test results to make health or treatment decisions
3. Talk to your doctor about ways to reduce your risk (esp. with a family history) or are BRCA1 or
BRCA2 muted
•
For physicians:
1. Do not recommend or use tests that claim to screen for ovarian cancer in the general population.
2. Testing higher risk asymptomatic patients has no proven benefit and is not a substitute for
preventive actions that may reduce their risk.
http://www.fda.gov/medicaldevices/safety/alertsandnotices/ucm519413.htm
28 Million £ Down
The Drain
Abcodia Statement on the ROCA® Test for Ovarian Cancer Screening
October 2016
1. Abcodia acknowledges the recent statement issued by the U.S.
FDA regarding the use of blood tests for ovarian cancer screening.
2. Notwithstanding our confidence in the clinical utility of the ROCA®
Test, we are voluntarily choosing to temporarily suspend its
commercial availability in the US and the UK.
http://www.abcodia.com/index.php
If you look like some of them: I am in trouble
Part II
Screening for Ovarian Cancer in Women
with High Genetic Risk for Ovarian Cancer
Screening for Ovarian Cancer
U.S. Preventive Services Task Force Recommendation (USPSTF): September 2012
Population
Asymptomatic women with known genetic mutations that increase
risk for ovarian cancer
Women are at increased risk if they have:
1. BRCA1 and BRCA2 genetic mutations
2. Lynch syndrome
3. Family history of OVCA
Risk Assessment
Women with an increased-risk family history should be considered for
genetic counseling:
1. Having > 2 1rst- or 2nd-degree relatives with a history of OVCA or
a combination of BCA and OVCA
2. Of Ashkenazi Jewish descent: having a 1rst-degree relative (or 2
2nd-degree relatives on the same side of the family) with BCA &
OVCA
Screening Tests
TVUS and CA–125 testing are the suggested screening modalities.
Relevant
USPSTF
Recommendations
http://www.uspreventiveservicestaskforce.org/
http://www.uspreventiveservicestaskforce.org.
Ovarian Cancer Screening in High Risk women
3 Pending Trials
1. ROCA trial in High Risk women (NCI’s Cancer Genetics Network, the Early
Detection Research Network, Ovarian Specialized Program on Research
Excellence):
– Single-arm trial of 2400 High Risk women > 30 yrs, initiated in 2001
– CA125 tests are scheduled every 3 months (results pending)
2. GOC 0199:
– 2-arm prospective study begun in 2003 of women at High Risk women
– Chose between RR-BSO and screening with ROCA
– ~ 1600 women chose ROCA
– During the course of the study, ~ 400 screening patients switched to RR BSO
– Data pending
3. UKFOCSS in 2 phases:
Steven J. Skates. Int J Gynecol Cancer 2012;22: S24YS26
United Kingdome Familial Ovarian Cancer Screening Study
(UKFOCSS)- 42 centers
Adam N. Rosenthal et al ESGO 2013
Ovarian Cancer Screening in the High-Risk Population
United Kingdome Familial Ovarian Cancer Screening Study
(UKFOCSS)
•
UKFOCSS in 2 phases:
1. 1rst : initiated in 2002 on 4,531 high-risk women, screened with an annual CA125 >35 U/mL
2. 2nd: 4531 women at an estimated ≥10% lifetime risk of OC/FTC begun in 2007:
3. At baseline, their mean age was 44.6 years
4. All women were counseled that RR BSO was recommended
UKFOCSS Phase II Study design
High Risk women > 35 yrs
Assess menopausal status
CA 125 every 4 months
15% every 4 months
ROCA
Return to Annual screening if ROCA OK
Refer to Gynecologic Oncologist if TVUS abnormal or ROCA is high
Adam N. Rosenthal et al ESGO 2013
Ovarian Cancer Screening in the High-Risk Population
United Kingdome Familial Ovarian Cancer Screening Study
(UKFOCSS)
•
18 incident OVCA/FTCA:
– 6/18 were occult discovered at RR BSO
•
No symptomatic cancers
•
Sensitivity:
– 100% (74- 100%) if occult cancers are counted as TP
– 67% (41%-87%) if classified as FN
•
PPV: 13% (7-22%) NPV: 100% (99-100%)
•
Cancers detected:
– 26% incident screen-detected OC/FTC were stage IIIC vs. 85.7% on annual screening
(UK FOCSS Phase 1) (p=0.009)
– 92% were completely cyto-reduced on Phase 2 vs. 62% on Phase 1 (p=0.16)
Adam N. Rosenthal et al ESGO 2013
Ovarian Cancer Screening in the High-Risk Population
United Kingdome Familial Ovarian Cancer Screening Study
(UKFOCSS)
Conclusions:
• 4-monthly ROCA-based screening:
– had high sensitivity for OC/FTC
– was associated with high complete cytoreduction rates
– failed to detect the majority of OC/FTC at early stage
• These results are encouraging but screening cannot currently be considered a
safe alternative to RRSO
Adam N. Rosenthal et al. 18th ESGO Oct 2013
Part III
Estimating the Risk of epithelial ovarian cancer
in women presenting with a pelvic mass
Diagnostic Value of Serum Human Epididymis Protein 4 (HE4) in OVCA
A Systematic Review and Meta-Analysis
•
(HE4), a precursor of human epididymis protein. Recently identified as a new promising serum
biomarker for ovarian carcinoma.
•
A systematic review of a total of 9 studies involving 1807 women
•
When the control group was composed of healthy women for diagnosing ovarian cancer:
– pooled sensitivity:
83% (95% CI, 77%Y88%)
– specificity :
90% (95% CI, 87%Y92%) . The area under the SROC curve was 0.9271
•
When the control group was composed of women with benign disease
– pooled sensitivity:
74% (95% CI, 69%Y78%)
– Specificity:
90% (95% CI, 87%Y92%). The area under the SROC curve was 0.8853
•
Conclusions:
1. HE4 may be a valuable marker in the diagnosis of ovarian carcinoma: useful preoperative test
for predicting the benign or malignant nature of pelvic masses
2. Has a potential to be used as an initial step in ovarian cancer screening strategy
Li Wu et al Int J Gynecol Cancer 2012;22: 1106Y1112
Risk of Ovarian Malignancy Algorithm (ROMA)
Classifies patients as being low or high risk for malignant disease
Uses the ratio of CA125 and HE4 to calculate the ROMA depending on the menopausal
status
Premenopausal
Postmenopausal
≥ 7.4% High risk of finding EOC
≥ 25.3% High risk of finding EOC
< 7.4% Low risk of finding EOC
< 25.3% Low risk of finding EOC
Menopausal Status
Disease
Sensitivity
Specificity
PPV
NPV
Combined
Benign + Cancer Total
87.3%
75.3%
60.6%
93.2%
Premenopausal
Benign + Cancer Total
79.4%
75.4%
36.0%
95.5%
Postmenopausal
Benign + Cancer Total
89.7%
75.2%
73.8%
90.3%
Li Wu et al Int J Gynecol Cancer 2012;22: 1106Y1112
Risk of Malignancy Index (RMI)
Classifies patients as being low or high risk for malignant disease
•
RMI is a product of U/S score (U), menopausal status (M) and CA125 level (IU/ml):
RMI = U x M x CA125
•
The U/S is scored 1 point for each of the following characteristics:
– multilocular cysts, solid areas
– metastases, ascites
– bilateral lesions
– U = 0 (for U/S score of 0), U = 1 (for U/S score of 1), U = 3 (for U/S score of 2–5)
•
The menopausal status is scored as:
– 1 = pre-menopausal and 3 = post-menopausal (no period for more than 1 year or
a woman over 50 who has had a hysterectomy)
•
Serum CA125 is measured in IU/ml
Ovarian Tumor Index (OTI)
Classifies patients as being low or high risk for malignant disease
• Combines
1. Patient’s age
2. Specific TVUS markers
3. Doppler velocimetry
4. Color-flow mapping
• Continuous US variables included:
1. Ovarian volume
2. Sassone morphology scale
3. Doppler determination of angle-corrected systole, diastole, and timeaveraged velocity
4. Patient’s age
5. The Doppler pulsatility index (PI), vessel location, presence of a diastolic
notch, and echogenic predominance of the lesion, suggestive of
dermoid, also were assessed
Ovarian Tumor Index (OTI)
Classifies patients as being low or high risk for malignant disease
•
Of 244 women
– 214 had nonmalignant findings (85 of which were benign neoplasm)
– 30 had malignant neoplasms
•
Age and all U/S continuous variables except systole were found to be statistically
significant (P < 0.05) between:
–
–
Malignant (N = 30) Vs nonmalignant masses (N = 214)
Malignant (N = 30) Vs benign neoplasms( N = 85)
•
A ROC (area under the curve = 0.91) :
– was generated by adding the continuous measures (age [in years], ovarian volume
[mL], and Sassone morphology scale [1–15]) and weighting other variables ([−10] ×
PI, central or septal location [+10], peripheral location [−10], and echogenic [−10])
– was found to be discriminating, predictive, and able to replicate the more complex
logistic regression model
•
Prediction of malignancy was generated from the population-based data of the current
study.
Comparison of ROMA, RMI, & OTI in patients with adnexal mass
•
Objectives: To compare of ROMA, RMI, OTI indexes in patients with adnexal mass
•
Methods: 51 patients with adnexal mass: surgery done when suspicious for malignancy
– Demographic and clinical characteristics of the patients were identified
– Morphological scores calculated via gray-scale and Doppler ultrasonography
– Pre-operatively blood samples were taken to assess CA 125 and HE4 levels
– Scores of ROMA, RMI and OTI were calculated of all the cases
– Compared each other to SN, SP, PPV and NPV to detect the malignancy
•
Results:
– 43 of the adnexal mass were benign, 2 were borderline and 6 were malignant
– The mean of age of patients with:
• Benign mass:
44.27±14,9 yrs
• Malignant mass:
55.25±17,16 yrs (p=0,029)
Tevfik Guvenal et al. ESGO 2013
Comparison of ROMA, RMI, & OTI in patients with adnexal mass
Pre-menopausal patients
ROMA
score
•
Post-menopausal patients
SN
SP
PPV
NPV
SN
SP
PPV
NPV
50%
100%
96.5
92.8%
50%
85.7%
96.5%
100%
sensitivity
specificity
PPV
NPV
RMI score
87.5%
100%
100%
97.6%
OTI Score
100%
79%
57.1%
100%
Conclusions:
1. ROMA index was more sensitive and specific in postmenopausal patient group
rather than other tests
2. ROMA index is better on detecting malignant masses at postmenopausal patients
and benign masses on premenopausal patients
3. OTI is also has a remarkable sensitivity though the specificity is not enough at all
Tevfik Guvenal et al. ESGO 2013
Ovarian Cancer: To Screen or not to screen?
Conclusions
• Need to identify specific symptoms for OVCa
(UKOPS)
• Need to control for systemic therapy and
type of surgery
(PLCO)
• CA 125 and ROCA: high specificity and PPV
decreasing unnecessary procedures
Early stage detection is cost effective
(ROCA)
• Waiting on UKCTOCS for its main outcome
(UKCTOCS)
Ovarian Malignancy Risk Stratification of the Adnexal Mass Using a Multivariate Index Assay
•
Several prediction models and referral guidelines have been investigated to assist in the diagnostic triage of women with an adnexal
mass and determine the need for gynecologic oncology referral, but none has received widespread acceptance.
•
a diagnostic multiple biomarker test, the multivariate index assay (OVA1) marketed by Vermillion, was developed to assist in the
diagnostic triage of women with an adnexal mass
•
In 2011, a pivotal trial examined the predictive value of OVA1 for ovarian malignancy; it contained a mix of subjects enrolled by both
gynecologists and gynecologic-oncologists
– the overall prevalence of ovarian malignancy was 29%.
Robert E. Bristow et al Gynecol Oncol 2013;128:252Y259
Ovarian Malignancy Risk Stratification of the Adnexal Mass Using a Multivariate Index Assay
•
A multi-institutional trial was to investigate the effectiveness of OVA1 for identifying ovarian malignancy among an
intended-use cohort of women undergoing surgery for an adnexal mass after enrollment by non-gyn oncologists
1.
The predictive performance of OVA1 was compared with that of clinical assessment and serum CA125-II.
2.
The comparative sensitivity of each method for detecting malignancy was stratified according to histology, stage of
disease, and menopausal status.
3.
494 patients were evaluable for OVA1 and CA125-II and clinical impression
4.
A pelvic malignancy was found in 92 (18.6%): Ovarian cancer in 65 (13.2%), with 43.1% having stage I
5.
Combined with clinical impression, the sensitivity of OVA1 in detecting OVCA was 95.7% (95% CI, 89.3%Y98.3%)
6.
OVA1 had higher sensitivity than CA125-II in detecting OVCA among women with early-stage disease
1. 91.4% [95% CI, 77.6%Y97.0%] vs CA125-II, 65.7% [95% CI, 49.2%Y79.2%]
2. OVA1 correctly identified 83.3% of malignancies missed by clinical impression and 70.8% of cases missed by
CA125-II
3. Both clinical impression and CA125-II were more accurate than OVA1 for identifying benign disease:
1. When combined with clinical impression, OVA1 correctly identified benign pathology in 204 of 402
patients (specificity, 50.7%; 95% CI, 45.9%Y55.6%)
Robert E. Bristow et al Gynecol Oncol 2013;128:252Y259