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

Ovarian CancerEpidemiology

● 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, 2007Surveillance, Epidemiology, and End Results (SEER) Program: National Cancer Institute, 2008

Cancer Incidence Rates 1975-2003

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 andPopulation Sciences, National Cancer Institute, 2006

0

25

50

1975 1978 1981 1984 1987 1990 1993 1996 1999 2002

Colon and rectum

Rate Per 100,000

Uterine Corpus

Ovary

Cancer Mortality Rates1930-2003

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

0

10

20

30

4019

30

1935

1940

1945

1950

1955

1960

1965

1970

1975

1980

1985

1990

1995

2000

Colon & rectum

UterusStomach

Ovary

Rate Per 100,000

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.orgHoskins WJ, Perez CA, Young RC, eds. Principles and practice of Gynecologic Oncology, 4 th ed.

Philadelphia: Lippincott Williams & Wilkins: 919-922, 2006

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

Ovarian Cancer Symptoms• Symptom awareness

– 95% report symptoms prior to diagnosis– > 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 > 50yo• 86% for premenopausal women

Goff B, et al. JAMA. 291:2705-12:2068-75, 2004Olson S, et al. Obstet Gynecol. 98:212-7, 2001Goff B, et al. JAMA. 291:2705-12:2068-75, 2004Olson S, et al. Obstet Gynecol. 98:212-7, 2001

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, 2008Data from University of Kentucky Ovarian Cancer Screening Program, 2009 (N=27,000)

Ovarian TumorsPremenopausal 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

Ovarian TumorsPostmenopausal Women

• 50% of ovarian neoplasms in postmenopausal women are malignant

• Benign epithelial tumor • Stromal tumor

– Granulosa cell – Fibroma– Thecoma

• Epithelial ovarian cancer• Metastatic cancer

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

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. 65:29, 2003Sainz de la Cuesta R, et al. Obstet Gyn. 84:1, 1994

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

Pelvic ExaminationDetecting 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

Pelvic Exam vs. Ultrasound

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

Sonographic CharacteristicsOvarian Tumors

• Unilateral• Simple, unilocular• Septated (MI < 5)• No ascites• Resolution

• Bilateral• Complex (MI ≥ 5)

– Solid wall abnormalities– Internal papillations

• Ascites• Persistence or growth

Benign Malignant

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

Ovarian Tumor Imaging

Modesitt et al, Gyn Oncol, 2003

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%

Kentucky Morphology IndexMI Score = 6

Ueland et al. Gyn Oncol, 2003Ascites

Kentucky Morphology IndexHigh Risk Score (5-10)

20

3238

92

7783

Ueland et al. Gyn Oncol, 2003

Morphology IndexPredicting Malignancy

• Sensitivity 0.98

• Specificity 0.81

• Positive predictive value 0.41

• Negative predictive value0.99

• Accuracy 0.83

Ueland et al. Gyn Oncol, 2003

Ovarian Tumor Ultrasound

Definition of (+) US varied with each author

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

CA-125• Antigen derived from:

– coelomic epithelium (pericardium, pleura, peritoneum)– mullerian epithelium (tubal, endometrial, endocervical)

• Two different assays– Assay I < 35 U/ml– Assay II < 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

CA-125Non-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

Role Surgery

• Proper staging for early disease– Determine adjuvant therapy

• Cytoreduction for advanced disease– Radical surgery as indicated– “Optimal” ≤ 1cm

• Reassessment laparotomy

• Secondary debulking

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 Gynecol;65:568-72, 1985

Surgical CytoreductionAdvanced Stage Ovarian Cancer

Slide courtesy of Gynecologic Cancer Foundation

Surgical CytoreductionAdvanced 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

20

22

24

26

28

30

32

34

36

38

40

0 10 20 30 40 50 60 70 80 90 100

% Cytoreduction

Med

ian

Sur

viva

l (m

onth

s)

Bristow, J Clin Oncol 20:1248, 2002

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 < 0.01

Carney ME, et al. Gynecol Oncol;84:36-42, 2002

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 oncologistEarle C.C, et al. JNCI 98:3, 2006

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 > 1 cm)

●Gynecologic oncologist ●perform the initial surgical procedure●Improved overall survival●Category I recommendation

●Combination adjuvant chemotherapy●Most patients (>70%) relapse after 1st line therapy●Clinical trials

NCCN Clinical Practice Guidelines in Oncology, 2008Ozols 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

ACOG Referral Guidelines

• CA125 >200 U/mL• Ascites• Evidence of abdominal or

distant metastases• Family history one or

more first-degree relatives with ovarian or breast cancer

• 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

Premenopausal Women Postmenopausal Women

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 <67 U/mL (pre), exclude FH of breast, ovarian cancer

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, 2010Presented at the Society of Gynecologic Oncology Annual Meeting, 2010

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

ACOG Results

Premenopausal (N= 235)

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

ACOG Results

ACOG CriteriaPremenopausal women

Cancer Stage

Early Late

Sensitivity, % 47 10095% CI 26 to 69 72 to 100

Specificity, % 77 7795% CI 71 to 83 71 to 83

PPV, % 16 1995% CI 8 to 28 11 to 31

NPV, % 94 10095% CI 89 to 97 98 to 100

FDA NEWS RELEASE

For Immediate Release: Sept. 11, 2009

Media Inquiries: Peper Long, 301-796-4671, mary.long@fda.hhs.govConsumer Inquiries: 888-INFO-FDA

FDA Clears a Test for Ovarian CancerTest 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.

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 < 5.0 < 4.4

High Risk ≥ 5.0 ≥ 4.4

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

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, 2010Presented at the Society of Gynecologic Oncology Annual Meeting, 2010

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

Study Population All Subjects

Non-GO Physicians

GO Physicians

Patients 516 269 247Mean age, yr (sd) 52 (14) 50 (14) 55 (14)Median age, yr 52 48 54Range (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%)

OVA1 Trial

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

Tru

e p

osi

tive

rate

(S

en

siti

vit

y)

False positive rate (1-Specificity)

Premenopausal, AUC= 0.80 (95% CI: 0.73-0.88)Postmenopausal, AUC=0.82 (95% CI: 0.77-0.87)

OVA1 Test Alone

Sensitivity 92%

Specificity 43%

PPV 42%

NPV 93%

OVA1 Sensitivity

Tumor subtype Cancer stage

I 90%

II 100%

III 100%

IV 100%

Epithelial OC 99%

Non EOC 78%

LMP 75%

Metastases 94%

Premenopausal Postmenopausal

PerformancePreoperativ

e 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) 41% (116/281)

OVA1 Results

non-GO physicians GO physicians

PerformancePreoperativ

e 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) 36% (89/247)

OVA1 Results

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.

Simplified Algorithm

Ovarian Tumor

Physician Assessment

Local surgery

High RiskLow Risk

Referral to GYO for Surgery

OVA1 Blood Test

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

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