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Identifying Ovarian Tumors at High Risk for Ovarian Cancer

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Identifying Ovarian Tumors at High Risk for Ovarian Cancer Frederick R. Ueland, M.D. Associate Professor Gynecologic Oncology Vice Chairman, Department of Obstetrics ... – PowerPoint PPT presentation

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Title: Identifying Ovarian Tumors at High Risk for Ovarian Cancer


1
Identifying Ovarian Tumors at High Risk for
Ovarian Cancer
  • Frederick R. Ueland, M.D.
  • Associate Professor Gynecologic Oncology
  • Vice Chairman, Department of Obstetrics and
    Gynecology
  • University of Kentucky Markey Cancer Center

2
Ovarian Cancer Epidemiology
  • Fifth leading cause of female cancer death in the
    United States
  • Approximately 21,500 new cases of ovarian cancer
    and 14,600 deaths in 2009
  • Median age at diagnosis 63 years
  • Incidence 13.1 per 100,000 women
  • Prevalence 176,000 women alive with a history of
    ovarian cancer (2006)
  • Lifetime risk 1/71 (1.4)

American Cancer Society, 2007 Surveillance,
Epidemiology, and End Results (SEER) Program
National Cancer Institute, 2008
3
Cancer Incidence Rates 1975-2003
Colon and rectum
Ovary
Uterine Corpus
Rate Per 100,000
Age-adjusted to the 2000 US standard population
and adjusted for delays in reporting. Source
Surveillance, Epidemiology, and End Results
Program, 1975-2003, Division of Cancer Control
and Population Sciences, National Cancer
Institute, 2006
4
Cancer Mortality Rates 1930-2003
Colon rectum
Stomach
Uterus
Ovary
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
5
Background
  • Advanced stage presentation common (70)
  • Poor prognosis (50 5-year survival)
  • Slowly improving outcomes
  • Annual mortality change 1.4 (2002-2006)
  • Treatment
  • Comprehensive surgical staging for early disease
  • Cytoreduction for advanced disease
  • Combination chemotherapy
  • Clinical trials
  • American Cancer Society Facts Figures, 2009.
    Atlanta. www. Cancer.org
  • Hoskins WJ, Perez CA, Young RC, eds. Principles
    and practice of Gynecologic Oncology, 4th ed.
    Philadelphia Lippincott Williams Wilkins
    919-922, 2006

6
Stage and Outcome
Stage Percent Survival
I 24 95
II 6 65
III 55 15-30
IV 15 0-20
Overall 50
American Cancer Society
7
Ovarian Cancer Symptoms
  • Symptom awareness
  • 95 report symptoms prior to diagnosis
  • gt 12 times monthly
  • Pelvic and abdominal pain (77)
  • Bloating, early satiety, GI symptoms (70)
  • Pelvic (26) and urinary symptoms (34)
  • Physician evaluation
  • Avoid diagnostic delay
  • Examination, imaging, laboratory testing as
    indicated
  • Sensitivity
  • 57 for early stage
  • 80 for advanced stage
  • Specificity
  • 90 if gt 50yo
  • 86 for premenopausal women

Goff B, et al. JAMA. 2912705-122068-75,
2004 Olson S, et al. Obstet Gynecol. 98212-7,
2001
8
Challenge of Ovarian Tumors
  • There are 155 million women in United States
  • 125 million women 13 years of age or older
  • 90 million are between 13 and 50 years of age
  • 30 million are over age 50
  • 40 million women are Baby Boomers (age 41-59)
  • How common are ovarian tumors?
  • Premenopausal women
  • 14 annual incidence (13 million)
  • 30 prevalence (27 million)
  • Postmenopausal women
  • 5 annual incidence (1.5 million)
  • 16 prevalence (5 million)
  • 30 of unilocular and 45 of complex tumors
    typically persist
  • Annually, there are tens of millions of ovarian
    cystic tumors, but only 22,000 ovarian cancers
    diagnosed
  • United States Census Bureau, 2008
  • Data from University of Kentucky Ovarian Cancer
    Screening Program, 2009 (N27,000)

9
Ovarian Tumors Premenopausal Women
  • 15 of ovarian neoplasms in premenopausal women
    are malignant
  • Non-inflammatory ovarian tumors
  • 70 functional cysts
  • 20 neoplastic
  • 10 endometriomas
  • Other
  • Inflammatory process, bowel

10
Ovarian Tumors Postmenopausal Women
  • 50 of ovarian neoplasms in postmenopausal women
    are malignant
  • Benign epithelial tumor
  • Stromal tumor
  • Granulosa cell
  • Fibroma
  • Thecoma
  • Epithelial ovarian cancer
  • Metastatic cancer

11
Guidelines and Algorithms
  • NIH Consensus Statement, 1994
  • Women with ovarian masses identified
    preoperatively having a significant risk of
    cancer should be given the option of surgery
    performed by a gynecologic oncologist
  • Clinical algorithms
  • Examination, imaging, patient history, and
    laboratory tests
  • Infrequently utilized, not standardized
  • Challenging to evaluate

12
Biopsy of Ovarian Tumors
  • Percutaneous FNA cytology of cystic ovarian
    tumors has low cancer sensitivity, ranging from
    25 to 82
  • Approximately 25-50 of ovarian cystic tumors
    aspirated in perimenopausal women will recur
    within 1 year
  • Aspiration of a malignant cystic tumor may
    disseminate the cancer, increase the stage and
    worsen the prognosis

ACOG Practice Bulletin no 83, 2006. Mizuno M,
et al. Oncology. 6529, 2003 Sainz de la Cuesta
R, et al. Obstet Gyn. 841, 1994
13
Evaluation
  • Physical examination
  • Pelvic, abdominal, and lymph node survey
  • Imaging study
  • Transvaginal ultrasonography
  • CT scan
  • CA-125
  • Not FDA-approved as a diagnostic test
  • Low sensitivity and specificity

14
Pelvic Examination Detecting Ovarian Tumors
  1. Ovarian detection on pelvic examination is
    infrequent in women 55 years old (30)
  2. Ovarian detection is exceedingly difficult in
    women weighing at least 200 lb (9)
  3. A large uterus (weight 200 g) makes ovarian
    palpation unlikely (16)

Ueland et al. Gyn Oncol, 2005
15
Pelvic Exam vs. Ultrasound
Pelvic Exam Ultrasound P value
Age 55 0.30 0.74 lt 0.001
Patient wt 200 lb 0.09 0.73 lt 0.001
Uterine wt 200 g 0.16 0.80 lt 0.001
Ueland et al. Gyn Oncol, 2005
16
Sonographic Characteristics Ovarian Tumors
Benign
Malignant
  • Unilateral
  • Simple, unilocular
  • Septated (MI lt 5)
  • No ascites
  • Resolution
  • Bilateral
  • Complex (MI 5)
  • Solid wall abnormalities
  • Internal papillations
  • Ascites
  • Persistence or growth

17
Ovarian Tumor Imaging
Type of Cyst Patients
Regressed under observation 205 72
Required exploratory laparotomy 81 28
Ovarian neoplasms 46 16
Benign epithelial 32 11
Benign teratoma 9 3
Malignant epithelial 4 1.4
Dysgerminoma 1 0.3
Endometriosis 28 10
Para-ovarian cyst 4 1.4
Hydrosalpinx 3 1
Functional cysts 0 0
Spanos W. Am J Obstet Gynecol, 1973
18
Ovarian Tumor Imaging
Type of Cyst Patients
Resolution 2261 69
Cyst septum 537 17
Persistent cyst 220 7
Cyst solid area 180 5
Solid mass 21 0.7
Removed by surgery 40 1.3
Total 3259 100
Modesitt et al, Gyn Oncol, 2003
19
Kentucky Morphology Index MI Score 6
Ascites ?
Ueland et al. Gyn Oncol, 2003
20
Kentucky Morphology Index High Risk Score (5-10)
92
83
77
38
32
20
Ueland et al. Gyn Oncol, 2003
21
Morphology Index Predicting Malignancy
  • Sensitivity 0.98
  • Specificity 0.81
  • Positive predictive value 0.41
  • Negative predictive value 0.99
  • Accuracy 0.83

Ueland et al. Gyn Oncol, 2003
22
Ovarian Tumor Ultrasound
Author Number Prevalence Sens() Spec () PPV() PPV (at 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

23
CA-125
  • Antigen derived from
  • coelomic epithelium (pericardium, pleura,
    peritoneum)
  • mullerian epithelium (tubal, endometrial,
    endocervical)
  • Two different assays
  • Assay I lt 35 U/ml
  • Assay II lt 20 U/ml
  • Expressed by 80 non-mucinous EOC
  • FDA-approved to monitor cancer treatment
  • Neither a screening nor a diagnostic test
  • False negative CA-125 values (low sensitivity)
  • 50 of early stage ovarian cancers
  • 20-25 of advanced stage ovarian cancers
  • Mixed mullerian tumors, clear cell cancers

24
CA-125 Non-specific
  • Benign ovarian cysts
  • Uterine leiomyomata
  • Pelvic inflammatory disease
  • Endometriosis
  • Adenomyosis
  • Pregnancy
  • Menstruation
  • Ascites
  • Heart failure
  • Liver failure
  • Renal failure
  • Peritoneal tuberculosis
  • Diverticulitis
  • Pancreatitis
  • Recent abdominal or thoracic surgery
  • Other malignancies

25
Role Surgery
  • Proper staging for early disease
  • Determine adjuvant therapy
  • Cytoreduction for advanced disease
  • Radical surgery as indicated
  • Optimal 1cm
  • Reassessment laparotomy
  • Secondary debulking

26
Staging by Specialty
  • Women with early stage ovarian cancer
  • 291 subjects
  • Complete surgical staging performed
  • 97 gynecologic oncologists
  • 52 general obstetrician/gynecologists
  • 35 general surgeons

McGowan L, et al. Obstet Gynecol65568-72, 1985
27
Surgical Cytoreduction Advanced Stage Ovarian
Cancer
Slide courtesy of Gynecologic Cancer Foundation
28
Surgical Cytoreduction Advanced Stage Ovarian
Cancer
  • Meta-analysis of 53 studies
  • 6,885 stage III/IV patients
  • Cytoreduction
  • High volume centers have higher rates of
    optimal surgery
  • Optimal improved survival by 11 months (50
    increase)
  • Each 10 increment in cytoreduction 5.5
    improvement in survival

Median Survival (months)
Cytoreduction
Bristow, J Clin Oncol 201248, 2002
29
Improved Survival
  • Utah Cancer Registry
  • 848 new ovarian cancers, 1992-1998
  • Only 39 were ever seen by a gyn onc
  • Patients with advanced disease had significant
    survival advantage when managed by gynecologic
    oncologist
  • median survival 26 mo vs. 15 mo, p lt 0.01

Carney ME, et al. Gynecol Oncol8436-42, 2002
30
Improved Survival
  • Medicare claims by physician specialty
  • SEER database
  • 65 years or older
  • 3067 surgeries for ovarian cancer
  • Only 33 of patients with ovarian cancer were
    treated by gynecologic oncologist
  • Improved outcomes and overall survival when
    managed by gynecologic oncologist

Earle C.C, et al. JNCI 983, 2006
31
(No Transcript)
32
Value of Specialists
  • Meta-analysis (18 studies) concluded marked
    benefit with gynecologic oncologist (Giede 2005)
  • Complete surgical staging with early stage
    disease
  • Optimal cytoreductive surgery with advanced
    disease
  • Improved median and overall survival
  • Others supporting GO involvement
  • NCCN guidelines
  • SGO, ACOG
  • SOGC clinical practice guidelines
  • NIH consensus statement
  • London Medical Advisory statement

33
NCCN Guidelines
  • Cytoreductive surgery
  • all patients with stage II, III or IV ovarian
    cancer
  • optimal cytoreduction (no residual disease gt 1
    cm)
  • Gynecologic oncologist
  • perform the initial surgical procedure
  • Improved overall survival
  • Category I recommendation
  • Combination adjuvant chemotherapy
  • Most patients (gt70) relapse after 1st line
    therapy
  • Clinical trials

NCCN Clinical Practice Guidelines in Oncology,
2008 Ozols et al. J Clin Oncol. 21 3194-3200,
2003
34
Ovarian Cancer Dilemma
  • Ovarian tumors are very common, particularly in
    young women
  • Women with benign tumors prefer to have their
    surgery close to home with their established
    gynecologist
  • Women with ovarian cancer are best managed by a
    gynecologic oncologist
  • Current methods are unreliable in differentiating
    benign from malignant ovarian tumors,
    particularly in young women and early stage
    disease

35
ACOG Referral Guidelines
Premenopausal Women
Postmenopausal Women
  • CA125 gt200 U/mL
  • Ascites
  • Evidence of abdominal or distant metastases
  • Family history one or more first-degree relatives
    with ovarian or breast cancer
  • CA125 gt35 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

36
Validation of Guidelines
  • Im, 2005
  • Chart review with 7 tertiary centers 1035
    patients
  • 95 had imaging, 68 had preop CA-125, 24 had
    both
  • SGO and ACOG referral guidelines effectively
    separate women with pelvic masses into two risk
    categories for malignancy
  • Dearking, 2007
  • Prospective, single-institutional trial 837
    patients
  • Guidelines performed well in predicting
    advanced-stage disease, but poorly in
    early-stage disease, and premenopausal women
  • Recommended modifications
  • CA-125 lt67 U/mL (pre), exclude FH of breast,
    ovarian cancer

37
A Multi-institutional Evaluation of ACOG and SGO
Referral Guidelines for an Ovarian Mass
  • Rachel Ware, Alan Smith, Chris Desimone, Leigh
    Seamon, Scott Goodrich, Iwona Podzielinski, Lori
    Sokoll, Joseph Santoso, J.R. van Nagell Jr., Zhen
    Zhang,
  • Frederick Ueland.

Presented at the Society of Gynecologic Oncology
Annual Meeting, 2010
38
Results
ACOG Criteria Modified ACOG Criteria
Sensitivity, 77 80
95 CI 70 to 83 73 to 85
Specificity, 68 71
95 CI 63 to 72 66 to 75
PPV, 52 55
95 CI 46 to 58 49 to 61
NPV, 87 88
95 CI 82 to 90 84 to 92
39
ACOG Results
Premenopausal (N 235) Premenopausal (N 235) Postmenopausal (N 281) Postmenopausal (N 281)
ACOG Criteria ACOG Criteria Modified ACOG Criteria ACOG Criteria Modified ACOG Criteria
Sensitivity, 58 76 84 81
95 CI 43 to 71 61 to 86 77 to 90 73 to 87
Specificity, 77 70 56 71
95 CI 71 to 83 64 to 77 49 to 64 64 to 77
PPV, 38 38 58 66
95 CI 27 to 50 28 to 48 50 to 65 58 to 74
NPV, 89 92 84 84
95 CI 83 to 92 87 to 96 76 to 90 77 to 89
40
ACOG Results
ACOG Criteria Premenopausal women Cancer Stage Cancer Stage
ACOG Criteria Premenopausal women 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
41
  • FDA NEWS RELEASE
  • For Immediate Release Sept. 11, 2009
  • Media Inquiries Peper Long, 301-796-4671,
    mary.long_at_fda.hhs.gov 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.

42
The OVA1 Test
  • Biomarker panel
  • CA125, transthyretin (prealbumin), apolipoprotein
    A1, beta 2 microglobulin, transferrin
  • OvaCalc software algorithm
  • OVA1 risk index, range 0-10

Premenopausal Postmenopausal
Low Risk lt 5.0 lt 4.4
High Risk 5.0 4.4
43
OVA1 Indications
  • Known pelvic mass or ovarian tumor
  • Complete physician assessment
  • Examination, imaging, history, labs
  • Decision for surgery
  • OVA1
  • Low risk OVA1 reassuring
  • High risk OVA1 referred to gyn oncologist

44
The OVA1 Test Improves the Preoperative
Assessment of Ovarian Tumors
  • Frederick Ueland, Chris Desimone, Leigh Seamon,
    Rachel Ware, Scott Goodrich, Iwona Podzielinski,
    Lori Sokoll, Alan Smith, Joseph Santoso, J.R. van
    Nagell Jr., Zhen Zhang.

Presented at the Society of Gynecologic Oncology
Annual Meeting, 2010
45
Methods
  • 27 primary care, specialty sites throughout U.S.
  • Preoperative evaluation
  • imaging to confirm ovarian tumor
  • serum collection for CA125
  • physician assessment (Is it malignant? yes or
    no)
  • Centralized assay at Quest Diagnostics
  • Validation assays
  • Johns Hopkins Biomarker Discovery Center
  • Specialty Laboratories
  • Independent data analysis
  • Applied Clinical Intelligence

46
OVA1 Trial
Study Population All Subjects Non-GO Physicians GO Physicians
Patients 516 269 247
Mean age, yr (sd) 52 (14) 50 (14) 55 (14)
Median age, yr 52 48 54
Range (min, max) 18 to 92 19 to 90 18 to 92
Menopausal Status, n ()
Pre 235 (46) 144 (54) 91 (37)
Post 281 (54) 125 (46) 156 (63)
Pathology Diagnosis, n ()
Benign ovarian condition 355 (69) 197 (73) 158 (64)
Epithelial ovarian cancer (EOC) 96 (19) 45 (17) 51 (21)
Other primary ovarian malignancy 9 (2) 5 (2) 4 (2)
Low malignant potential (borderline) 28 (5) 12 (4) 16 (6)
Non-primary ovarian malignancy with involvement of the ovaries 18 (4) 5 (2) 13 (5)
Non-primary ovarian malignancies with no involvement of ovaries 10 (2) 5 (2) 5 (2)
47
OVA1 Test Alone
Sensitivity 92
Specificity 43
PPV 42
NPV 93
48
OVA1 Sensitivity
  • Tumor subtype
  • Cancer stage

Epithelial OC 99
Non EOC 78
LMP 75
Metastases 94
I 90
II 100
III 100
IV 100
49
OVA1 Results
Premenopausal Premenopausal Postmenopausal Postmenopausal
Performance Preoperative assessment Preoperative assessment plus OVA1 Preoperative assessment Preoperative assessment plus OVA1
Sensitivity, 60 89 81 98
95 CI 46 to 73 76 to 95 73 to 87 94 to 100
Specificity, 83 40 74 28
95 CI 77 to 88 34 to 48 67 to 81 22 to 35
PPV, 46 26 69 49
95 CI 34 to 58 20 to 34 61 to 76 43 to 55
NPV, 90 94 85 96
95 CI 84 to 93 86 to 97 78 to 90 86 to 99
Negative Likelihood Ratio 0.48 0.27 0.25 0.06
95 CI 0.33 to 0.69 0.12 to 0.64 0.17 to 0.37 0.02 to 0.25
Prevalence 19 (45/235) 19 (45/235) 41 (116/281) 41 (116/281)
50
OVA1 Results
non-GO physicians non-GO physicians GO physicians GO physicians
Performance Preoperative assessment Preoperative assessment plus OVA1 Preoperative assessment Preoperative assessment plus OVA1
Sensitivity, 72 92 78 99
95 CI 61 to 81 83 to 96 68 to 85 94 to 100
Specificity, 83 42 75 26
95 CI 77 to 87 35 to 49 67 to 81 20 to 33
PPV, 60 36 63 43
95 CI 50 to 70 30 to 44 54 to 72 36 to 50
NPV, 89 93 86 98
95 CI 84 to 93 86 to 97 79 to 90 88 to 100
Negative Likelihood Ratio 0.34 0.20 0.30 0.04
95 CI 0.23 to 0.49 0.09 to 0.44 0.20 to 0.45 0.01 to 0.31
Prevalence 27 (72/269) 27 (72/269) 36 (89/247) 36 (89/247)
51
OVA1 Clinical Utility
  1. The OVA1 test successfully classifies patients
    into high or low probability of malignancy.
  2. OVA1 has high sensitivity in pre- and
    postmenopausal women, all stages of EOC.
  3. OVA1 outperforms the ACOG criteria and physician
    assessment.
  4. When combined with other clinical information,
    the OVA1 test can help determine the risk of
    malignancy for an ovarian tumor before surgery,
    and facilitate decisions about referral to a
    gynecologic oncologist.

52
Simplified Algorithm
Ovarian Tumor
Physician Assessment
OVA1 Blood Test
High Risk
Low Risk
Local surgery
Referral to GYO for Surgery
53
Summary
  • Ovarian tumors are exceedingly common,
    particularly in premenopausal women
  • 5-10 of American women will undergo surgery to
    evaluate ovarian mass in their life-time
  • Ovarian cancer is infrequent but often fatal in
    advanced stages
  • Current algorithms (which combine symptoms,
    imaging, physical examination, and CA-125) are
    useful for identifying advanced stage cancer but
    of limited utility in detecting early stage
    disease

54
Summary
  • OVA1 is the only FDA-approved blood test for
    ovarian tumors to assist physicians in making
    preoperative referral decisions
  • Appropriate referral to a gynecologic oncologist
    for women at high risk for ovarian cancer may
    lead to improved survival
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