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Is This Ovary Malignant? Separating the Olives from the Pits. Frederick R. Ueland, M.D. Associate Professor Gynecologic Oncology University of Kentucky Markey Cancer Center. Siena, Italy. Settled 900-400 BC Walled city by 12 th century 1 st Palio race in 1656. Il Palio di Siena.

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is this ovary malignant separating the olives from the pits

Is This Ovary Malignant?Separating the Olives from the Pits

Frederick R. Ueland, M.D.

Associate Professor Gynecologic Oncology

University of Kentucky Markey Cancer Center

slide2

Siena, Italy

Settled 900-400 BC

Walled city by 12th century

1stPalio race in 1656

outline
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
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
  • How common are ovarian tumors?
    • Premenopausal
      • 14% annual incidence (13 million), 30% prevalence (27 million)
    • Postmenopausal
      • 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
Ovarian Tumors

Premenopausal

Postmenopausal

  • Many tumors, few cancers
    • Low prevalence
  • 15% of ovarian neoplasms are malignant
    • Germ cell tumors
    • Borderline tumors
    • Epithelial cancers
  • Benign ovarian tumors
    • 70% functional cysts
    • 20% neoplastic
    • 10% endometriomas
  • Other
    • Inflammatory
  • Few tumors, many cancers
    • High prevalence
  • 50% of ovarian neoplasms are malignant
    • Epithelial ovarian cancer
    • Metastatic cancer
    • Granulosa cell tumors
  • Benign ovarian tumors
    • Cystadenoma
    • Fibroma
    • Thecoma
cancer mortality 1930 2003
Cancer Mortality1930-2003

Colon & rectum

Uterus

Stomach

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

nih consensus statement 1994
NIH Consensus Statement1994

“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
Value of Specialists
  • Meta-analysis of 18 studies concluded marked benefit with gynecologic oncologist (Giede 2005)
    • Complete surgical staging with early disease
    • Optimal cytoreductive surgery with advanced disease
    • Improved median and overall survival
  • Involvement of GO supported by:
    • NCCN guidelines
    • SGO, ACOG
    • SOGC clinical practice guidelines
    • NIH
    • London Medical Advisory statement
preoperative evaluation
Preoperative Evaluation
  • Physical examination
    • Pelvic, abdominal, and lymph node survey
  • Imaging study
    • Transvaginal ultrasonography
    • CT scan
  • Biomarkers
    • CA125
      • Not FDA-cleared as a diagnostic test
      • Low sensitivity and specificity
pelvic examination detecting ovarian tumors
Pelvic ExaminationDetecting ovarian tumors

Ovarian palpation is difficult in older women, obese women, and when the uterus is large

Ueland et al. Gyn Oncol, 2005

ultrasound ovarian tumors
UltrasoundOvarian 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

when cysts are not malignant
When Cysts are NOT Malignant
  • Unilocular cysts
  • Septated ovarian cysts

Modesitt et al. Risk of malignancy in unilocular ovarian cystic tumors. Gynecol Oncol 102:594-599, 2003

Saunders B. et al. Risk of Sonographically confirmed septated cystic ovarian tumors. Gynecol Oncol 118: 278-282, 2010.

ultrasound kentucky morphology index
UltrasoundKentucky Morphology Index

Ascites

Ueland et al. Gynecol Oncol, 2003

kentucky morphology index
Kentucky Morphology Index

Sensitivity 0.98

Specificity 0.81

PPV 0.41

NPV 0.99

83

92

77

38

32

20

Ueland et al. Gynecol Oncol, 2003

ovarian tumor ultrasound
Ovarian Tumor Ultrasound

Definition of (+) US varied with each author

slide23

Ovarian Biomarkers

  • CA125
  • HE4
  • CEA
  • CA19-9
  • LDH
  • β-hCG
  • AFP
  • OVA1
ca125
CA125
  • 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
  • Low sensitivity (false negatives)
    • 50% sensitivity in early stage ovarian cancers
    • 20-25% false negatives in advanced stage cancers
      • Mucinous, clear cell cancers, mixed mullerian tumors
  • FDA-cleared to monitor cancer treatment
  • Neither a screening nor a diagnostic test
ca125 non specific
CA125Non-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
slide26

HE4

  • Antigen derived from:
    • Human epididymis protein
  • Product of the WFDC2 (HE4) gene that is over-expressed in patients with ovarian carcinoma1
  • FDA-cleared to monitor cancer treatment with other clinical methods
    • HE4 not for monitoring mucinous or germ cell ovarian cancers 2
  • Neither a screening nor a diagnostic test
  • Quest Diagnostics Website www.questdiagnostics.com
  • He4 Product Insert, Fujirebio Diagnostics, Inc.
risk of malignancy algorithm
Risk of Malignancy Algorithm
  • CA125 and HE4
  • Accrual from tertiary centers

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.

slide28

Other Ovarian Biomarkers

  • CEA
    • Mucinous neoplasms
  • CA19-9
    • Gastrointestinal (pancreatic)
  • LDH*
    • Dysgerminoma
  • β-hCG*
    • Pregnancy
    • Trophoblastic disease
    • Choriocarcinoma
  • AFP*
    • Hepatic neoplasms
    • Endodermal sinus tumors

*Most beneficial in young women with solid tumors

slide34

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.

slide35
OVA1
  • Panel: CA125-II, transthyretin, apolipoprotein A1, beta 2 microglobulin, transferrin
  • 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
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

ACOG Committee Opinion: number 280, December 2002. Obstet Gynecol 2002;100:1413-6

acog validation
ACOG Validation
  • Im, 2005
    • 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
    • Prospective, single-institutional trial, 837 patients
    • Guidelines performed well in predicting advanced-stage 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
OVA1 Trial
  • 27 sites throughout United States
    • 516 patients,161 malignancies
    • 52% from primary care providers
  • Preoperative evaluation
    • 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
ACOG Performance

Presented at SGO Annual Meeting, San Francisco, CA March, 2010

acog performance premenopausal women
ACOG PerformancePremenopausal women

Presented at SGO Annual Meeting, San Francisco, CA March, 2010

acog revisited ova1 replacing ca125
ACOG Revisited OVA1 replacing CA125

Presented at SGO Annual Meeting, San Francisco, CA March, 2010

acog performance univariate comparison
ACOG PerformanceUnivariate comparison

Presented at SGO Annual Meeting, San Francisco, CA March, 2010

acog simplified
ACOG Simplified*
  • OVA1 (+)
  • Nodular or fixed mass
  • Ascites
  • Metastases

*presence of any criterion warrants referral to a gynecologic oncologist

Sensitivity 93%

Specificity 40%

PPV 41%

NPV 93%.

risk of malignancy index cutoff 200
Risk of Malignancy IndexCutoff = 200

Manjunath et al. Gynecol Oncol 81:225-229, 2001.

ultrasound with biomarker
Ultrasound with Biomarker

*US= solid, papillary projections, ascites only

Data from OVA1 trial presented at SGO, 2010

slide52

Evaluation of an ovarian tumor

Ovarian tumor

ultrasound*

Unilocular/septate

Complex morphology1

complex

US surveillance

every 3-4 months

CA125

(or OVA1; RMI; ACOG)

low risk

persistent

low risk

high risk2

US surveillance

every 6 months

Surgery with gynecologist

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
Patient Referrals
  • Specificity doesn’t correlate with referral decisions
  • Ovarian cancer prevalence for GYO
    • 20-40%
  • OVA1 trial
    • 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