Transcript Slide 1

A New Test for Assessing
the Risk of Ovarian Cancer
in Women with Adnexal Mass
Presenter
Place
Date
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Ovarian Cancer is a Major
Women's Health Problem
• High morbidity and mortality
• Appropriate treatment improves survival1
– Oncology specialists
– High volume centers
• Need better risk assessment tools
1ACOG
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Practice Bulletin. Obstet Gynecol. 2007;110:201-213.
ROMA™: A Novel Ovarian
Cancer Risk Assessment Tool
• Evaluated 15 biomarkers including HE4, which is:
– Putative protease inhibitor
– CE-Marked and available for clinical use
• Assess Risk of ovarian cancer in patients with Pelvic Mass
• Monitor patients with ovarian cancer
– Expressed in reproductive, respiratory tissues
– Complementary to CA 125
• Developed ROMA™
– 89% sensitive1
– 75% specific1
1FDI-03
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Clinical Study Report.
ROMA™: A Novel Ovarian
Cancer Risk Assessment Tool
• Stratify risk of ovarian cancer
• Ensure treatment by right surgeon/right facility
• Used in conjunction with other Dx methods
• Not intended for detection or screening
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ROMA™ Will Improve
Treatment of Women
with Adnexal Mass
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Agenda
• Ovarian Cancer Risk Assessment
• ROMA™ Development
• Multicenter Validation Trial
• Conclusion and Summary
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Ovarian Cancer Risk Assessment
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Need New Tools to Better
Assess Ovarian Cancer Risk
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Ovarian Cancer is a
Deadly Disease
• 204,499 new cases in 2008
• 124,860 deaths
• Leading cause of gynecologic cancer deaths
• 5th leading cause of cancer deaths in women
International Agency for Research on Cancer. Globocan 2002. http://www-dep.iarc.fr/
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1 in 5 Women will have
a Pelvic Mass
• 20% of women will be diagnosed with an
adnexal mass1
• 5 - 10% of women will have surgery for an
ovarian neoplasm (100,000 to 200,000)2
• 13 - 21% of these masses will be malignant2
1Curtin
2NIH
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JP. Gynecol Oncol. 1994;55:S42-S46.
Consensus Development Conference Statement. Gynecol Oncol. 1994;55:S4-S14.
Survival Rates for Ovarian
Cancer Need to be Improved
Ovarian Cancer 5-yr Survival Rate by Stage
Stage Distribution
at Diagnosis
Survival Rate
Stage I
20-27%
73-93%
Stage II
5-10%
45-70%
Stage III
52-58%
21-37%
Stage IV
11-17%
11-25%
Heintz APM, et al. FIGO Annual Report on the Results of Treatment in Gynecologic Cancers. 2000; 24 :107-138.
Holschneider CH, Berek JS. Semin Surg Oncol. 2000;19:3-10.
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How can we Affect Ovarian
Cancer Survival?
• Prevention
• Screening
• Early detection
• Surgery
• Chemotherapeutic agents
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Surgery can Impact Survival
• Cytoxan to Paclitaxel
– 14 month survival advantage1
• Intravenous to Intraperitoneal
– 16 month survival advantage2
• Surgery by gynecologic oncologist
– 12 month survival advantage3,4
1McGuire
WP et al. NEJM. 1996;334(1):1-6.
DK et al. NEJM. 2006;354(1):34-43.
3Engelen MJA et al. Cancer. 2006;106(3):589-598.
4Bristow RE et al. J Clin Oncol. 2002;20(5):1248-1259
2Armstrong
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The Optimal Care
for Ovarian Cancer
• Cytoreductive surgery with complete
surgical staging
• Rationale for surgical staging:
– Define the extent of disease
– Determine the need for adjuvant treatment
– Provide prognosis
– Outline a plan of care
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Surgical Debulking Increases
Survival for Ovarian Cancer
Optimal surgical debulking can include:
• Hysterectomy
• Removal of ovaries
• Bowel resection
• Peritoneal stripping
• Diaphragmatic stripping
• Lymph node debulking
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Gynecologic Oncologists are
Ovarian Cancer Specialists
• Gynecologic oncologist
– Recognized sub-specialty in US
• Residency in Obstetrics and Gynecology (4 yrs)
• Fellowship in Gynecologic Oncology (3-4 yrs)
– Outside US Gynecologists with high oncology surgical
volume
• Experienced in:
– Surgical care
– Medical management
– Chemotherapy
– Natural history
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Oncology Specialist Most Likely to
Perform Comprehensive Surgery
*Ovarian Cancer Surgery by: Surgeon
Surgeon Specialty
Gynecologic oncologist
75.7%
Obstetrician gynecologist
37.3%
General surgeon
38.5%
* South Carolina admissions
Goff BA et al. Cancer. 2007;109(10):2031-2042.
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Rate of Comprehensive
Surgery
High Volume Surgeons Most Likely to
Perform Comprehensive Surgery
Ovarian Cancer Surgery by: Surgeon
Surgery Volume
Very Low
1 case/year
Low / Medium
2-9 cases/year
High
≥ 10 cases/year
Goff BA et al. Cancer. 2007;109(10):2031-2042.
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Percentage
of Cases
Rate of
Comprehensive
Surgery
25.2%
55.2%
22.7%
65.1%
52.1%
75.2%
Less than Half of Ovarian Cancer
Surgery is at High Volume Hospital
Ovarian Cancer Surgery by: Hospital
Surgery Volume
Low
1-9 cases/year
Medium
10-19 cases/year
High
≥ 20 cases/year
Goff BA et al. Cancer. 2007;109(10):2031-2042.
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Percentage
of Cases
Rate of
Comprehensive
Surgery
33.3%
57.4%
18.1%
69.5%
48.6%
73.7%
Significantly Higher Survival
Rates with Oncology Specialists
Type of Hospital
Impacts Survival Rates
1.0
1.0
0.8
0.8
Cumulative Survival
Cumulative Survival
Type of Surgeon
Impacts Survival Rates
0.6
0.4
0.2
0.4
0.2
0.0
TH: Teaching hospital
NTH: Nonteaching hospital
0.0
0
200
400
600
800
Survival in days
Paulsen T et al. Int J Gynecol Cancer. 2006;16(Suppl 1):11-17.
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0.6
1000
0
200
400
600
Survival in days
800
1000
Significantly Higher Survival
Rates with Oncology Specialists
Gynecologic
Oncologists
Gynecologists/
General
Surgeons
p value
Eisenkop 1992
35 months
17 months
<0.001
Junor 1999
18 months
13 months
<0.005
Carney 2002
26 months
15 months
<0.01
Tingulstad 2003
21 months
12 months
0.01
Study
Eisenkop SM et al. Gynecol Oncol. 1992;47(2):203-209.
Junor EJ et al. Br J Obstet Gynaecol. 1999;106(11):1130-1136.
Carney ME et al. Gynecol Oncol. 2002;84:36-42.
Tingulstad S et al. Obstet Gynecol. 2003;102(3):499-505.
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Cytoreductive Surgery Increases
Survival for Ovarian Cancer Patients
Multiple studies and large meta-analyses have
shown residual disease following surgery is the
most significant prognostic factor:
53 studies, 6,885 patients
Optimal cytoreduction  survival
from 22.7 to 33.9 months (50% )
Bristow RE et al. J Clin Oncol. 2002;20(5):1248-1259.
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Current Practice is Sub-Optimal
for Ovarian Cancer Patients
• In the US only 50% of women with ovarian
cancer are operated on by high volume
surgeons or at high volume centers1
• Studies around the world show that
survival rates are improved when patients
have surgery by surgeons and at centers
experienced in the management of
ovarian cancer2
1Goff
BA et al. Cancer. 2007;109(10):2031-2042.
Practice Bulletin. Obstet Gynecol. 2007;110:201-213.
2ACOG
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Current Clinical Tools to
Assess Risk of Ovarian Cancer
• History
• Physical exam
• Imaging (US, CT and MRI)
• Tumor markers (CA 125)
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We can Improve the Care for
Ovarian Cancer Patients
• Better risk assessment
• Improved patient care and management
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Validation of ROMA™ as a
Risk Assessment Tool and
Patient Benefit
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Development and Validation
of ROMA™
• Two pilot studies combined to generate ROMA™
– Patients enrolled from:
• Women and Infants’ Hospital, Providence RI
• Massachusetts General Hospital, Boston MA
• Pivotal trial (FDI-03) to validate ROMA™
– National trial
– New patient cohort for validation
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Primary Objective of
Pivotal Trial
• To validate a predictive model utilizing a dual
marker assay of HE4 and CA 125 to assess the
risk for epithelial ovarian cancer including
borderline/low malignant potential tumors in
women with a pelvic mass
FDI-03 Clinical Study Report.
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Pivotal Trial Study Sites Chosen to
Enrich Ovarian Cancer Population
• 14 geographically dispersed sites across the US
• Divisions of Gynecologic Oncology, within
Departments of Obstetrics and Gynecology
• Sites chosen to enrich study population
FDI-03 Clinical Study Report.
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Pivotal Trial Methods
• Prospective double-blind multicenter trial
• Eligibility criteria:
– ≥18 years of age
– Ovarian cyst or a pelvic mass
– Planned surgical intervention
• All EOC patients to be surgically staged
• All blood samples obtained preoperatively
• Central pathology review
FDI-03 Clinical Study Report.
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Pivotal Trial Enrollment
• 566 patients enrolled
• 530 evaluable patients
– 246 premenopausal
– 284 postmenopausal
• 94% of patients were evaluable
FDI-03 Clinical Study Report.
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Study Cohort Disease
Distribution: Enriched for EOC
Pivotal Trial:
Pathology Distribution for All Cases
Pathology
Benign
All Patients
(N)
200
151
351 (66%)
Invasive EOC
18
111
129 (24%)
LMP Tumors
16
6
22 (4%)
Non EOC
6
0
6 (1%)
Metastatic
5
9
14 (3%)
Other Gyn
1
7
8 (2%)
246
284
530
Total
FDI-03 Clinical Study Report.
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Premenopausal Postmenopausal
(N)
(N)
Spectrum of Benign Disease
as Expected
Pathology
Pre
Post
All
%
Serous cystadenoma/Cystadenoma
25
53
78
22.2
Endometriosis
42
2
44
12.5
Simple/Paratubal
34
21
55
15.7
Teratoma
18
11
29
8.3
Adenofibroma/Cystadenofibroma
6
16
22
6.3
Mucinous Cystadenoma
9
13
22
6.3
16
3
19
5.4
Fibroma/Fibrothecoma
3
15
18
5.1
Tubo-ovarian abscess/Hydrosalpinx
8
6
14
4.0
14
0
14
4.0
3
2
5
1.4
Other
22
9
31
8.8
Total
200
151
351
100
Leiomyoma
Functional cyst/Hemorrhagic cyst
Normal
Data on file, FDI.
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Stage Distribution for
EOC as Expected
Invasive
EOC
Premenopausal
(N)
Postmenopausal
(N)
All Patients
(N)
Stage I
4
13
17 (13%)
Stage II
3
15
18 (14%)
Stage III
8
76
84 (65%)
Stage IV
1
5
6 (5%)
Unstaged
2
2
4 (3%)
Total
18
111
129
Data on file, FDI.
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Most Ovarian Cancers
Correctly Classified
All Patients: Distribution of Benign vs EOC + LMP Tumors
Low
Risk
High
Risk
(N)
(N)
Benign
262
89
351
EOC +
LMP
17
134
151
Total
279
223
502
Disease
FDI-03 Clinical Study Report.
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All
(N)
Sensitivity
Specificity
89%
75%
PPV
NPV
60% 94%
Most Ovarian Cancers
Correctly Classified
EOC Stage
Age Groups
I
II
III
&
IV
Not
Staged
% EOC
correctly
classified
Postmenopausal
(n=111)
3
1
3
1
1
5%
95%
Premenopausal
(n=18)
6
1
-
-
1
11%
89%
All Ages
(n=129)
9
2
3
1
2
6%
94%
FDI-03 Clinical Study Report.
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LMP
% EOC
incorrectly
classified
Most Early Stage
EOC Correctly Classified
Correctly
Identified
Total
Cases
Percentage
correctly
Identified
Stage I & II
30
35
86%
Stage III & IV
89
90
99%
All Invasive
EOC*
121
129
94%
*All EOC including unstaged EOC
FDI-03 Clinical Study Report.
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ROMA™ vs RMI
Risk of Malignancy Index (RMI)
RMI = U x M x serum CA 125 level
U = 0 for imaging score of 0
= 1 for imaging score of 1
= 3 for imaging score of 2-5
M = 1 if premenopausal
= 3 if postmenopausal
Jacobs I et al. Br J Obstet Gynecol.1990; 97:992-929.
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Secondary Analysis of
ROMA™ vs RMI
• Able to calculate an RMI for 80% of patients
• Utilized US, CT scans and MRI results for RMI
imaging scores
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ROMA™ has Increased Sensitivity
Compared with RMI
Benign and EOC: All Stages
Benign (n=315) vs EOC (n=124)
Pre & Post
Menopausal
Sensitivity*
(95% CI)
(95% CI)
RMI
85%
(77% to 90%)
75%
(70% to 80%)
ROMA™
94%
(89% to 98%)
75%
(70% to 80%)
*Two Sample Test of Equality of Proportions p=0.0129
CI: Confidence Interval
Data on file, FDI.
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Specificity
ROMA™ has Increased Sensitivity
vs RMI for Early Stage Cancer
Benign and EOC: Stage I & II
Benign (n=315) vs Stage I-II EOC (n=35)
Pre & Post
Menopausal
Sensitivity*
(95% CI)
(95% CI)
RMI
66%
(48% to 81%)
75%
(70% to 80%)
ROMA™
86%
(70% to 95%)
75%
(70% to 80%)
*Two Sample Test of Equality of Proportions p=0.0510
CI: Confidence Interval
Data on file, FDI.
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Specificity
ROMA™ Demonstrates
Superior Performance
• Correctly identifies 94% of EOC1
• Performs better than RMI
• Simple and easy to use
• Quantitative test
• No subjective data
• Assigns a risk for malignancy
Data on file, FDI.
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Additional Slides
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Ovarian Cancer Epidemiology
• Age adjusted
incidence is 2 to
15 cases per
100,000 women
• Incidence rates
are stable or
slowly increasing
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Surgical Staging
• The current standard of care for ovarian cancer is cytoreductive
surgery with complete surgical staging.
• Complete surgical staging includes:
–
–
–
–
–
–
–
–
–
Laparotomy
Hysterectomy
Bilateral salpingo-oophorectomy
Careful evaluation of all peritoneal surfaces
Multiple washings for cytology
Multiple peritoneal biopsies
Hepatic and diaphragmatic cytology
Omentectomy
Pelvic and periaortic lymphadenectomy
• Less than 50% of women undergoing surgery for an ovarian
cancer
will have an adequate staging or cytoreductive surgery1,2.
Gynecologic Oncologists are trained in staging of ovarian cancer.
1Carney
2McGowan
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ME et al. Gynecol Oncol. 2002;84:36-42.
L et al. Obstet Gynecol. 1985;65(4):568-572.
Ovarian Cancer
• Age at presentation is bimodal with
peaks at age 40 and 60 years old
• Symptoms often are nonspecific:
–
–
–
–
–
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Abdominal bloating
Pelvic pressure
GI symptoms
Respiratory
Constitutional
EDRN “Top Ten” Biomarkers for
Detection of Ovarian Cancer
• CA 125
• HE4
• CA 15-3
• CA 72-4
• B7-H4 (Ov110)
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• Transthyretin
• IGFBP-2
• SMRP
(Mesomark™)
• HK6
• Cytokeratin 19
(CYFRA 21-1)
Biomarkers for Ovarian
Cancer
CA 125
• “Gold Standard” biomarker in ovarian cancer
• Elevated CA 125 in 50% of Stage I disease and 80% of epithelial
ovarian cancers1
• Elevated in the pre-clinical asymptomatic phase of the disease
Limitations
– Elevated levels in benign gynecological disease1,2
– Low sensitivity in Stage I ovarian cancer
– CA 125 alone is not a sensitive marker
HE4
• A commonly up-regulated biomarker in ovarian cancer
• Serum HE4 is a useful biomarker in the early diagnosis of ovarian
cancer
1NIH
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Consensus Development Conference Statement. Gynecol Oncol. 1994;55:S4-S14.
2ACOG Practice Bulletin. Obstet Gynecol. 2007;110:201-213.
Genetic Risk Factors for
Ovarian Cancer
Only 10% of ovarian cancers are inherited
• BRCA 1 (17q21)
• BRCA 2 (13q12)
• P53 (17q13)
• PTEN (10q24)
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• HNPCC
– MLH 1 (3p21)
– MSH 2 (2p16)
– PMS 1 (2q31)
– PMS 2 (7p22)
Ultrasound Assessment of Pelvic Mass
• Limitations of Ultrasound
– Not all morphologic variables are commonly
reported or measured
– User variability (tertiary care vs community)
– Ultrasound reporting is not standardized
– Quality and complexity of machine (e.g.
Doppler)
– Complex algorithms
Moore RG et al. J Clin Oncol. 2007;25:4159-4161.
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Preoperative Differentiation of Benign and Malignant
Pelvic Masses
•
•
•
•
To evaluate the risk of a malignancy
To determine the need for surgery
To triage patients
To Improve the quality of care for
patients
– Allow patients to stay in their community
– Appropriate patients referred to specialists
• Medical-legal implications
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Epidemiologic Risk Factors for Ovarian Cancer
• Age
• Early age at menarche
• Late age at menopause
• Nulliparity
• Infertility
• Caucasian race
• History of endometriosis
ACOG Practice Bulletin. Obstet Gynecol. 2007;110:201-213.
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Surgical Staging
Surgical Staging by Specialty
Study
Earle 2006
Engelen 2006
Grossi 2002
Gynecologic
Oncologist
Gynecologist
General surgeon
60% (nodes)
36% (nodes)
16% (nodes)
118/198
146/409
23/144
61% (nodes)
30% (nodes)
40/65
41/135
47%
15%
0%
(ext staging)
(ext staging)
(ext staging)
-
Earle CC et al. J Ntl Cancer Inst. 2006;25:172-180.
Engelen MJA et al. Cancer. 2006;106:589-598.
Grossi M et al. MJA..2002;177:11-16.
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Ultrasound and CA125
Likelihood ratio for
malignancy
if result is:
Positive
Negative
RMI
Score
Sensitivity
(%)
Specificity
(%)
25
100
62.2
2.7
0.00
50
95.1
76.5
4.1
0.06
75
92.7
84.7
6.1
0.09
100
85.4
87.8
7.0
0.17
150
85.4
93.9
14.0
0.16
200
85.4
96.9
42.1
0.15
250
78.0
99.0
76.9
0.22
Jacobs I et al. Br J Obstet Gynecol.1990; 97:992-929.
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Adequacy of Surgical Staging
Results of repeat staging in apparent early stage ovarian cancers
Initial Stage
# of Patients
% Upstaged
IA
37
16
IB
10
30
IC
2
0
IIA
4
100
IIB
38
39
IIC
9
33
Total
100
31
Young RC et al. JAMA.1983;250(22):3072-3076.
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Ultrasound Evaluation of a Pelvic Mass
Study
Score
Sensitivity
(%)
Specificity
(%)
PPV
(%)
NPV
(%)
Ferrazzi 1997
9
87
67
41
95
Granberg 1990
2
87
49
31
93
Sassone 1991
9
74
65
36
90
DePriest 1993
5
88
40
28
93
Lerner 1994
4
87
59
36
95
Ferrazzi E et al. Ultrasound Obstet Gynecol.1997;10:192-197.
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Pivotal Trial Referral Patterns
Gastroenterologist
0%
Self-referred
1%
Other
Surgeon
10%
2%
Family Practitioner
9%
Internist
9%
Gynecologist
69%
N=524 of the 566 trial population
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Data on File, FDI.
ACOG Referral Guidelines
• Premenopausal
– CA125 > 200
– Ascites
– Evidence of
metastasis
– Family history of
breast or ovarian
cancer
• Postmenopausal
– CA125 >35
– Ascites
– Fixed or nodular
mass
– Evidence of
metastasis
– Family history of
breast or ovarian
cancer
ACOG Practice Bulletin. Obstet Gynecol. 2007;110:201-213.
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