Transcript Background - University of Kentucky

Frederick R. Ueland, M.D.
Associate Professor Gynecologic Oncology
University of Kentucky Markey Cancer Center
Siena, Italy
Settled 900-400 BC
Walled city by 12th century
1st Palio race in 1656
Il Palio di Siena
Outline
■ The challenge of ovarian tumors
■ Value of specialists in ovarian cancer
■ Essentials in preoperative evaluation



Examination
Imaging
Biomarkers
■ Algorithms


ACOG
RMI
■ Summary
Challenge of Ovarian Tumors

There are 155 million women in United States

~125 million women 13 years of age or older



How common are ovarian tumors?

Premenopausal




14% annual incidence (13 million), 30% prevalence (27 million)
Postmenopausal


90 million are between 13 and 50 years of age
30 million are over age 50
5% annual incidence (1.5 million), 16% prevalence (5 million)
Resolution: 70% of unilocular, 55% of complex tumors
Millions of ovarian tumors, 22,000 cancers annually
Which tumors need removal and by whom?
United States Census Bureau, 2008; Data from University of Kentucky Ovarian Cancer
Screening Program, 2009 (N=27,000)
Ovarian Tumors
Premenopausal

Many tumors, few cancers


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
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70% functional cysts
20% neoplastic
10% endometriomas
Other

Inflammatory
Few tumors, many cancers


Germ cell tumors
Borderline tumors
Epithelial cancers
Benign ovarian tumors


Low prevalence
15% of ovarian neoplasms are
malignant

Postmenopausal
50% of ovarian neoplasms are
malignant




High prevalence
Epithelial ovarian cancer
Metastatic cancer
Granulosa cell tumors
Benign ovarian tumors



Cystadenoma
Fibroma
Thecoma
Cancer Mortality
1930-2003
40
Colon & rectum
30
Uterus
20
Stomach
10
Rate Per 100,000
Age-adjusted to the 2000 US standard population. Source: US Mortality Public Use Data Tapes 1960-2003, US
Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006
2000
1995
1990
1985
1980
1975
1970
1965
1960
1955
1950
1945
1940
1935
0
1930
Ovary
NIH Consensus Statement
1994
“Women with ovarian masses identified
preoperatively as having a significant risk of
cancer should be given the option of surgery
performed by a gynecologic oncologist”
Value of Specialists

Meta-analysis of 18 studies concluded marked
benefit with gynecologic oncologist (Giede 2005)


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Complete surgical staging with early disease
Optimal cytoreductive surgery with advanced disease
Improved median and overall survival
Involvement of GO supported by:
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
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NCCN guidelines
SGO, ACOG
SOGC clinical practice guidelines
NIH
London Medical Advisory statement
Preoperative Evaluation

Physical examination
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Imaging study
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Pelvic, abdominal, and lymph node survey
Transvaginal ultrasonography
CT scan
Biomarkers

CA125


Not FDA-cleared as a diagnostic test
Low sensitivity and specificity
Pelvic Examination
Detecting ovarian tumors
Ovarian palpation is difficult in older women, obese women, and
when the uterus is large
Pelvic
Exam
Ultrasound
P-value
Age ≥ 55
0.30
0.74
< 0.001
Patient wt ≥ 200 lb
0.09
0.73
< 0.001
Uterine wt ≥ 200 g
0.16
0.80
< 0.001
Ueland et al. Gyn Oncol, 2005
Ultrasound
Ovarian tumors
Benign
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Unilateral
Simple, unilocular
Septated (MI < 5)
No ascites
Resolution
Malignant
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Bilateral
Complex (MI ≥ 5)
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Solid wall abnormalities
Internal papillations
Ascites
Persistence or growth
When Cysts are NOT Malignant

Unilocular cysts
Modesitt et al. Risk of malignancy in unilocular ovarian cystic tumors. Gynecol Oncol 102:594-599, 2003

Septated ovarian cysts
Saunders B. et al. Risk of Sonographically confirmed septated cystic ovarian tumors. Gynecol Oncol 118: 278-282,
2010.
Ultrasound
Kentucky Morphology Index
Ascites
Ueland et al. Gynecol Oncol, 2003

Kentucky Morphology Index
High Risk 5-10
100
90
80
70
92
60
83
77
50
40
38
30
32
20
20
10
0
5
6
7
% Benign
Ueland et al. Gynecol Oncol, 2003
8
% Cancer
9
10
Sensitivity
Specificity
PPV
NPV
0.98
0.81
0.41
0.99
Ovarian Tumor Ultrasound
Author
N
Prevalence
Sens (%)
Spec (%)
PPV (%)
PPV (20%)
Kobayashi, 1976
406
15
70
73
31
39
Hermann, 1987
241
21
82
93
75
73
Finkler, 1988
102
36
62
95
88
75
Benacerraf, 1990
100
30
80
87
72
62
Granberg, 1990
180
22
82
92
74
73
Sassone, 1991
143
10
100
83
37
59
Ueland, 2003
442
12
98
81
41
56
Definition of (+) US varied with each author
Ovarian Biomarkers
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CA125
HE4
CEA
CA19-9
■
■
■
■
LDH
β-hCG
AFP
OVA1
CA125

Antigen derived from:
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

Two different assays
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Coelomic epithelium (pericardium, pleura, peritoneum)
Mullerian epithelium (tubal, endometrial, endocervical)
Assay I < 35 U/ml; Assay II < 20 U/ml
Expressed by 80% non-mucinous EOC
Low sensitivity (false negatives)


50% sensitivity in early stage ovarian cancers
20-25% false negatives in advanced stage cancers
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Mucinous, clear cell cancers, mixed mullerian tumors
FDA-cleared to monitor cancer treatment
Neither a screening nor a diagnostic test
CA125
Non-specific
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Benign ovarian cysts
Uterine leiomyomata
Pelvic inflammatory
disease
Endometriosis
Adenomyosis
Pregnancy
Menstruation
Ascites
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Heart failure
Liver failure
Renal failure
Peritoneal tuberculosis
Diverticulitis
Pancreatitis
Recent abdominal or
thoracic surgery
Other malignancies
HE4

Antigen derived from:
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Product of the WFDC2 (HE4) gene that is overexpressed in patients with ovarian carcinoma1
FDA-cleared to monitor cancer treatment with other
clinical methods
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■
Human epididymis protein
HE4 not for monitoring mucinous or germ cell ovarian cancers 2
Neither a screening nor a diagnostic test
1. Quest Diagnostics Website www.questdiagnostics.com
2. He4 Product Insert, Fujirebio Diagnostics, Inc.
Risk of Malignancy Algorithm
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CA125 and HE4
Accrual from tertiary centers
All Subjects
(N= 503)
Premenopausal Postmenopausal
(N= 236)
(N= 267)
Sensitivity
89
76
92
Specificity
75
75
75
PPV
60
34
74
NPV
94
95
93
Prevalence= 34%
Moore R, et al. A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in
patients with a pelvic mass. Gynecol Oncol 2009;112:40-46.
Other Ovarian Biomarkers
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CEA
■
β-hCG*
 Mucinous neoplasms
■
CA19-9
■
 Gastrointestinal (pancreatic)
■
LDH*
 Dysgerminoma
■
AFP*
■
■
*Most beneficial in young women with solid tumors
Pregnancy
Trophoblastic disease
Choriocarcinoma
Hepatic neoplasms
Endodermal sinus tumors
FDA NEWS RELEASE
For Immediate Release: Sept. 11, 2009
Media Inquiries: Peper Long, 301-796-4671, [email protected]
Consumer Inquiries: 888-INFO-FDA
FDA Clears a Test for Ovarian Cancer
Test can help identify potential malignancies, guide surgical
decisions
The U.S. Food and Drug Administration today cleared a test that can
help detect ovarian cancer in a pelvic mass that is already known to
require surgery. The test, called OVA1, helps patients and health
care professionals decide what type of surgery should be done and
by whom.
OVA1


Panel: CA125-II, transthyretin, apolipoprotein
A1, beta 2 microglobulin, transferrin
Range 0-10
Premenopausal
Postmenopausal
Low Risk
< 5.0
< 4.4
High Risk
≥ 5.0
≥ 4.4
Sensitivity


EOC 99%, nonEOC 78%, borderline 75%,
metastases 94%
Stage I 90%, stage II-IV 100%
Presented at SGO Annual Meeting, San Francisco, CA March, 2010
ACOG Referral Guidelines
Premenopausal Women

CA125 >200 U/mL
Postmenopausal Women
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Ascites
Evidence of abdominal or
distant metastases
Family history one or
more first-degree
relatives with ovarian or
breast cancer
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
CA125 >35 U/mL
Nodular or fixed mass
Ascites
Evidence of abdominal or
distant metastases
Family history one or
more first-degree
relatives with ovarian or
breast cancer
ACOG Committee Opinion: number 280, December 2002. Obstet Gynecol 2002;100:1413-6
ACOG Validation

Im, 2005
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Chart review 1035 patients, 7 tertiary centers
95%- imaging, 68%- CA125, 24%- both
“SGO and ACOG referral guidelines effectively
separate women with pelvic masses into two risk
categories for malignancy”
Dearking, 2007
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Prospective, single-institutional trial, 837 patients
Guidelines performed well in predicting advancedstage disease, but “poorly” in early-stage disease,
and premenopausal women
“Need a more sensitive biomarker”
Recommended modifications:

CA-125 >67 U/mL (pre); exclude FH of breast, ovarian
cancer
OVA1 Trial

27 sites throughout United States
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516 patients,161 malignancies
52% from primary care providers
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Preoperative evaluation
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Physician assessment
 Imaging, serum
Biomarker assays- Quest laboratories
 Johns Hopkins Biomarker Discovery Center
 Specialty Laboratories

Independent data analysis


Applied Clinical Intelligence
Presented at SGO Annual Meeting, San Francisco, CA March, 2010
ACOG Performance
All Subjects
(N= 516)
ACOG
Premenopausal Postmenopausal
(N= 235)
(N= 281)
Modified
Modified
Modified
ACOG
ACOG
ACOG
ACOG
ACOG
Sensitivity
77
80
58
76
84
81
95% CI
70 to 83
73 to 85
43 to 71
61 to 86
77 to 90
73 to 87
Specificity
68
71
77
70
56
71
95% CI
63 to 72
66 to 75
71 to 83
64 to 77
49 to 64
64 to 77
PPV
52
55
38
38
58
66
95% CI
46 to 58
49 to 61
27 to 50
28 to 48
50 to 65
58 to 74
NPV
87
88
89
92
84
84
95% CI
82 to 90
84 to 92
83 to 92
87 to 96
76 to 90
77 to 89
Presented at SGO Annual Meeting, San Francisco, CA March, 2010
ACOG Performance
Premenopausal women
Cancer Stage
Early
Late
Sensitivity
47
100
95% CI
26 to 69
72 to 100
Specificity
77
77
95% CI
71 to 83
71 to 83
PPV
16
19
95% CI
8 to 28
11 to 31
NPV
94
100
95% CI
89 to 97
98 to 100
Presented at SGO Annual Meeting, San Francisco, CA March, 2010
ACOG Revisited
OVA1 replacing CA125
All subjects
N=516
Premenopausal
N= 235
Postmenopausal
N= 281
Sensitivity
94
91
95
95% CI
89 to 97
79 to 97
89 to 98
Specificity
35
43
26
95% CI
30 to 40
36 to 50
19 to 33
PPV
40
28
47
95% CI
35 to 45
21 to 35
41 to 54
NPV
93
95
88
95% CI
87 to 96
89 to 98
75 to 94
Presented at SGO Annual Meeting, San Francisco, CA March, 2010
ACOG Performance
Univariate comparison
ACOG Criteria
Odds Ratio P Value
(95% CI)
Modified ACOG Criteria
Odds Ratio
P Value
(95% CI)
Menopausal status
3.0
<.001
3.0
<.001
CA125-II level
11.6
<.001
9.3
<.001
Ascites
7.8
<.001
7.8
<.001
Evidence of metastasis
Nodular or fixed mass
FH of breast cancer
11.7
3.3
1.9
<.001
<.001
0.036
11.7
---
<.001
---
FH of ovarian cancer
1.5
0.332
--
--
Presented at SGO Annual Meeting, San Francisco, CA March, 2010
ACOG Simplified*
1.
2.
3.
4.
OVA1 (+)
Nodular or fixed mass
Ascites
Metastases
Sensitivity
Specificity
PPV
NPV
93%
40%
41%
93%.
*presence of any criterion warrants referral to a gynecologic
oncologist
Risk of Malignancy Index
U x M x CA125
US
Meno
Size
CA125
HR
Score
0, 1, 3
1, 3
NA
U/mL
>200
RMI 2 Tingulstad 1996
1, 4
1, 4
NA
U/mL
>125
RMI 3 Tingulstad 1999
1, 3
1, 3
NA
U/mL
>200
RMI 4 Yamamoto 2006
1, 4
1, 4
1, 2*
U/mL
>450
?
?
NA
U/mL
?
RMI 1 Jacobs 1990
RMI 5 Lee 2010
*<7 cm or ≥7 cm
Risk of Malignancy Index
Cutoff = 200
100
91
93
90
80
73
67
70
60
RMI 1
RMI 2
RMI 3
50
40
30
20
10
0
Sens
Spec
Manjunath et al. Gynecol Oncol 81:225-229, 2001.
PPV
NPV
Ultrasound with Biomarker
US* with OVA1
US* with CA125
n/N
Sensitivity
95% CI
n/N
Sensitivity
95% CI
All stages3
102/105
97
92 to 99
82/105
78
69 to 85
Stage I
28/31
90
75 to 97
16/31
52
35 to 68
Stage II
18/18
100
82 to 100
14/18
78
55 to 91
Early stage (I & II)
46/49
94
84 to 98
30/49
61
47 to 74
Late stage (III & IV)
54/54
100
93.4 to 100
52/54
96
88 to 99
Early stage (I & II)
14/17
82
59 to 94
5/17
29
13 to 53
Late stage (III & IV)
10/10
100
72 to 100
9/10
90
60 to 98
Early stage (I & II)
32/32
100
89 to 100
25/32
78
61 to 89
Late stage (III & IV)
44/44
100
92 to 100
43/44
98
88 to 100
Premenopausal women
Postmenopausal women
*US= solid, papillary projections, ascites only
Data from OVA1 trial presented at SGO, 2010
Correlation of OVA1 and Cancer
High risk imaging
Low risk imaging
OVA1 score
% Malignant
Odds Ratio
% Malignant
Odds Ratio
4.4 as cut-off
50.5
8.8
16.7
5.2
5.0 as cut-off
51.7
4.9
16.3
3.3
6.0 as cut-off
66.1
8.4
24.4
4.9
7.0 as cut-off
79.5
13.4
31.6
5.4
8.0 as cut-off
82.5
12.0
50.0
10.6
9.0 as cut-off
84.8
10.9
100.0
NC
Evaluation of an ovarian tumor
Ovarian tumor
ultrasound*
Complex morphology1
Unilocular/septate
complex
US surveillance
every 3-4 months
persistent
US surveillance
every 6 months
low risk
CA125
(or OVA1; RMI; ACOG)
low risk
Surgery with
gynecologist
high risk2
Surgery with
gynecologic oncologist
*Perform tumor morphology indexing (MI)
1Complex morphology: solid or papillary areas, ascites, metastases, or MI ≥ 5
2High risk: CA125 > 200 U/mL (pre), >35 U/mL (post), OVA1 (+), RMI > 200, or per ACOG guidelines
Patient Referrals


Specificity doesn’t correlate with referral
decisions
Ovarian cancer prevalence for GYO


20-40%
OVA1 trial



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72% of all benign tumors referred to GYO for surgery
45% referred despite a NEGATIVE physician
assessment
Physicians lack confidence in impression
Non-medical factors