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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 and Gynecology University of Kentucky Markey Cancer Center. Ovarian Cancer Epidemiology.

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identifying ovarian tumors at high risk for ovarian cancer

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 cancer epidemiology
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, 2007

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

cancer incidence rates 1975 2003
Cancer Incidence Rates 1975-2003

Colon and rectum


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

cancer mortality rates 1930 2003
Cancer Mortality Rates1930-2003

Colon & rectum




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

  • 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.

Hoskins WJ, Perez CA, Young RC, eds. Principles and practice of Gynecologic Oncology, 4th ed. Philadelphia: Lippincott Williams & Wilkins: 919-922, 2006

stage and outcome
Stage and Outcome

American Cancer Society

ovarian cancer symptoms
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, 2004

Olson S, et al. Obstet Gynecol. 98:212-7, 2001

challenge of ovarian tumors
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 (N=27,000)

ovarian tumors premenopausal women
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 tumors postmenopausal women
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
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
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, 2003

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

  • 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 examination detecting ovarian tumors
Pelvic ExaminationDetecting Ovarian Tumors
  • Ovarian detection on pelvic examination is infrequent in women ≥ 55 years old (30%)
  • Ovarian detection is exceedingly difficult in women weighing at least 200 lb (9%)
  • A large uterus (weight ≥ 200 g) makes ovarian palpation unlikely (16%)

Ueland et al. Gyn Oncol, 2005

pelvic exam vs ultrasound
Pelvic Exam vs. Ultrasound

Ueland et al. Gyn Oncol, 2005

sonographic characteristics ovarian tumors

Simple, unilocular

Septated (MI < 5)

No ascites



Complex (MI ≥ 5)

Solid wall abnormalities

Internal papillations


Persistence or growth

Sonographic CharacteristicsOvarian Tumors



ovarian tumor imaging
Ovarian Tumor Imaging

Spanos W. Am J Obstet Gynecol, 1973

ovarian tumor imaging1
Ovarian Tumor Imaging

Modesitt et al, Gyn Oncol, 2003

kentucky morphology index mi score 6
Kentucky Morphology IndexMI Score = 6


Ueland et al. Gyn Oncol, 2003

kentucky morphology index high risk score 5 10
Kentucky Morphology IndexHigh Risk Score (5-10)







Ueland et al. Gyn Oncol, 2003

morphology index predicting malignancy
Morphology IndexPredicting 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

ovarian tumor ultrasound
Ovarian Tumor Ultrasound

Definition of (+) US varied with each author

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 125 non specific
Benign ovarian cysts

Uterine leiomyomata

Pelvic inflammatory disease






Heart failure

Liver failure

Renal failure

Peritoneal tuberculosis



Recent abdominal or thoracic surgery

Other malignancies

role surgery
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
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 cytoreduction advanced stage ovarian cancer
Surgical CytoreductionAdvanced Stage Ovarian Cancer

Slide courtesy of Gynecologic Cancer Foundation

surgical cytoreduction advanced stage ovarian cancer1
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

Median Survival (months)

% Cytoreduction

Bristow, J Clin Oncol 20:1248, 2002

improved survival
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 survival1
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 98:3, 2006

value of specialists
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
nccn guidelines
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, 2008

Ozols et al. J Clin Oncol. 21: 3194-3200, 2003

ovarian cancer dilemma
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
ACOG Referral Guidelines

Premenopausal Women

Postmenopausal Women

  • 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
validation of guidelines
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
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



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
The OVA1 Test
  • Biomarker panel
    • CA125, transthyretin (prealbumin), apolipoprotein A1, beta 2 microglobulin, transferrin
  • OvaCalc software algorithm
  • OVA1 risk index, range 0-10
ova1 indications
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
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

  • 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
ova1 sensitivity
OVA1 Sensitivity

Tumor subtype

Cancer stage

ova1 clinical utility
OVA1 Clinical Utility
  • The OVA1 test successfully classifies patients into high or low probability of malignancy.
  • OVA1 has high sensitivity in pre- and postmenopausal women, all stages of EOC.
  • OVA1 outperforms the ACOG criteria and physician assessment.
  • 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
Simplified Algorithm

Ovarian Tumor

Physician Assessment

OVA1 Blood Test

Low Risk

High Risk

Local surgery

Referral to GYO for Surgery

  • 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
  • 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