mati

Ovarian Cancer Screening Mati Zolti M.D. Department of Obstetrics & Gynaecology Sheba Medical Center Tel Hashomer, Israel

Ovarian Cancer: Burden of suffering
4 th leading cause of cancer death in women in the U.S. (after lung, breast and colon)
Overall 5-year survival rate is 35%
The “silent killer”: asymptomatic in early stages
75% diagnosed with advanced stage disease; 5-year survival only 10-28%
Woman’s lifetime risk of dying from ovarian cancer is 1.1%

Ovarian Cancer in Israel
New Cases : 220
Death : 95
Median age : 51
(2XXX)

Ovarian Cancer
Symptoms of ovarian cancer :
asymptomatic
Lower abdominal pain/pressure
mass
Abdominal enlargement
Vaginal bleeding
Urinary/bowel symptoms

Types of Ovarian Tumors
Functional
Follicle cyst
Corpus luteum cyst
Theca lutein cyst
Inflammatory
Tubo-ovarian abscess
Benign tumors/cysts *
Endometriotic cyst
Brenner tumor
Benign teratoma (dermoid cyst)
Fibroma
*Rare or very rare potential for malignancy
Malignant (or malignant potential)
Malignant teratoma
Endometrioid carcinoma
Dygerminoma
Secondary ovarian tumor
Cystadenoma, cystadenocarcinoma (>50% for serous, ~5% for mucinous)
Granulosa cell tumor (15-20%)
Arrhenoblastoma (<20%)
Theca cell tumor (<1%)

Epithelial Ovarian Cancer
Overall 5-year survival rate is 75-95% if cancer confined to ovaries; decreases to 10-17% if distant metastases
Survival improved when cancer detected in early stage
Only 25% diagnosed in Stage I

Early Detection and Mortality
No direct evidence that women with early stage cancer found on screening have lower mortality than women with more advanced disease
Indirect evidence supports benefits of early detection:
Most important prognostic factor in patients with advanced ovarian cancer is tumor burden after initial debulking
Surgical debulking and chemo more effective when cancer detected early

The challenge
Natural history of ovarian cancer not well understood
No well-defined precursor lesion
Length of time from localized tumor to dissemination is unknown
Multiple efforts underway to develop effective screening method for early detection

Risk factors
The majority of women with ovarian cancer have no known risk factors
Most significant risk factor is genetic predisposition

Risk factors: Heredity
Up to 10% of epithelial ovarian cancer cases are familial
3 familial syndromes
familial breast-ovarian cancer syndrome
site-specific ovarian cancer
cancer family syndrome (Lynch type II)
Familial breast-ovarian cancer and site-specific ovarian cancer syndromes both associated with mutations of the BRCA1 suppressor gene; account for 90% of familial ovarian cancers
Rollins,G. Ann Int Med 2000;133:1021-1024

Additional Risk Factors
Age
Women over age 50 account for ~80% of all cases (ave. age at dx is 61)
Reproductive history
early menarche, nulliparity or age >30 at first child-bearing, and late menopause
Fertility drugs
prolonged use of Clomid, especially without achieving pregnancy
Personal history of breast cancer
Hormone replacement therapy > 10 years
May be associated with 30% increased risk
Talcum powder
Some studies have shown slightly increased risk in women who use talc powder on genital area
American Cancer Society, 2001

Protective factors
Multiparity: First pregnancy before age 30
Oral contraceptives: 5 years of use cuts risk nearly in half
Tubal ligation
Hysterectomy
Lactation
Bilateral oopherectomy

Delays in Diagnosis
Lack of severity and specificity of early symptoms
Early signs/symptoms may include bloating, gas, indigestion, abdominal fullness or discomfort, constipation, pelvic pressure, urinary frequency, abnormal vaginal bleeding, fatigue, back pain, leg pain
Early stage tumors difficult to detect on pelvic exam

Diagnostic tools
History
Pelvic Exam (including rectal)
Transvaginal Ultrasound – detection of masses and mass characteristics
Tumor markers – CA-125, LPA (plasma lysophosphatidic acid)
CT – assess spread to LN, pelvic and abdominal structures
MRI – best for distinguishing malignant from benign tumors

Work-up of Adnexal Mass
Age
Size of mass
Unilateral vs. bilateral
CA-125 levels
Ultrasound configuration
Color-flow Doppler flow
Presence of symptoms
Must first categorize as functional, benign neoplastic or potentially malignant
Diagnostic approach depends on:

Diagnostic approach
If premenopausal and asymptomatic, with unilateral, mobile, simple cystic mass <8-10cm and no family history, can observe for 4-6 weeks and then repeat TVUS and pelvic exam.
If resolved, no further work-up necessary
If larger or unchanged, or if character of mass has changed on TVUS, surgical evaluation required

Diagnostic Approach
If postmenopausal and asymptomatic, with unilateral simple cyst <5cm AND normal CA-125, can follow closely with repeat TVUS
All other postmenopausal women with ovarian mass require surgical evaluation

Surgical Evaluation
Refer to Gyn-Onc specialist
Exploratory laparotomy has been the gold standard and includes:
Peritoneal washings for cytology
Evaluation of frozen section
Complete staging procedure if borderline or malignant tumor on frozen section

Surgical Evaluation
Laparoscopy can be considered in premenopausal woman with ovarian mass small enough to remove via laparoscopic approach; not recommended if high suspicion for malignancy

Stages Ia, Ib, Ic

Stages IIa, IIb, IIc

Stages IIIa, IIIb, IIIc

Stage IV

Treatment
Depends on staging, tumor type, age, desire for future fertility
Can include surgery, chemotherapy and/or radiation therapy
Clinical trials are ongoing

Surgical treatment
Primary debulking and cytoreduction; may include:
Bilateral salpingo-oopherectomy
Hysterectomy
Lymphadenectomy (para-aortic, inguinal)
Omentectomy
“brushing” of diaphragm, examination of liver

Chemotherapy and Radiation
Usually 6 cycles of chemotherapy
Cisplatin (or Carboplatin) plus Paclitaxel most commonly used combination therapy
XRT

Why screening for ovarian cancer is so difficult?
Anatomic location of the ovary, not easily accesible
Lack well defined precursor lesion and has poorly defined natural history
Low prevalence, need exquisite specificity to avoid unnecessary intervention
Lack of a good method

Screening Strategies
Ultrasound (transvaginal vs transabdominal)
Color-flow doppler
CA-125
Other tumor markers

Ultrasound
Both tranabdominal and transvaginal techniques identify enlarged ovaries or abnormal morphology; TVUS has better resolution
One large study of TVUS underway has reported sensivity of 81% and specificity of 98.9%
Major limitations are poor PPV in asymptomatic women and inability to detect malignances when ovaries are normal size
Allows earlier stage detection

Color-flow Doppler
Used in conjunction with TVUS
Measures resistance in blood vessels supplying the ovaries
May provide additional information to help distinguish malignant from benign masses

CA-125
Sustained elevation in 82% of women with advanced ovarian cancer, but fewer than 1% of healthy women
Poor sensitivity (elevated in only 50% of women with Stage I disease)
Poor specificity (elevated in many gynecologic and non-gynecologic malignancies as well as benign conditions)

CA-125
Malignant conditions
Cervical CA
Fallopian tube CA
Endometrial CA
Pancreatic CA
Colon CA
Breast CA
Lymphoma
Mesothelioma
Benign conditions
Endometriosis/Menses
Uterine fibroids
PID
Pregnancy
Diverticulitis
Pancreatitis
Liver disease
Renal failure
Appendicitis
IBD

Lysophosphatidic acid (LPA)
Tumor marker being investigated for screening
Phospholipid with mitogenic and growth factor-like actions
In 1 small study LPA was detected in 9 of 10 patients with Stage I ovarian CA, 24/24 with advanced cancer, and 14/14 with recurrent cancer. Only 28 of 47 pts had elevated CA-125, including 2 of 9 with Stage I disease

Current Screening Guidelines
“ Routine screening for ovarian cancer by ultrasound, the measurement of serum tumor markers, or pelvic examination is not recommended. There is insufficient evidence to recommend for or against the screening of asymptomatic women at increased risk of developing ovarian cancer.”

Screening Guidelines– cont’d
NIH Consensus Conference (1994)
women with presumed hereditary cancer syndrome should undergo annual pelvic exams, CA-125 measurements, and TVUS until childbearing is complete or at age 35, at which time prophylactic bilateral oopherectomy is recommended.
ACP
counsel high risk women about potential harms and benefits of screening

Screening, cont’d
American Cancer Society, AAFP and ACOG do not recommend screening for ovarian cancer in the general population
Canadian Task Force on Periodic Health Examination
“insufficient evidence to recommend for or against screening in high-risk women”

Where do we go from here?
Several strategies for screening currently under investigation
TVUS as primary screening method
Multimodal strategy using CA-125 as initial indicator and if elevated, TVUS used for secondary testing
LPA (phospholipid with mitogenic and GF-like actions) may be more sensitive than CA-125 in detecting early stage cancers

Ovarian Cancer Screening Trials
The United Kingdom Collaborative Trial of Ovarian Cancer Screening: will compare TVUS and multimodal screening to control
The European Study: RCT to screen women with TVUS at 18-month or 3-year intervals
The NIH Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: 10-year study using multimodal strategy

Take home points
Screening not indicated at this time
ASK about family history of cancers
LISTEN when women present with non-specific GI complaints; include OC in DDx
DO perform careful bimanual exam and rectal exam as part of pelvic exam
Refer women with + Family Hx to GynOnc

Marker Updates - Ca 125 • Approved marker to test for recurrence • Remains the single most sensitive and specific marker for ovarian cancer to date • Addition of other markers might improve sensitivity and specificity • Longitudinal assessment may also improve sensitivity and specificity

ROCA: Risk of Ovarian Cancer Algorithm

Marker Updates—OvaCheck
In 2002, a paper in Lancet described an approach to ovarian cancer screening using mass spectrometry to create protein patterns from blood and computer software to find patterns associated with disease.
In 2003, the software developer announced it would market a test called OvaCheck for screening high risk populations. The test would be offered as a “homebrew” diagnostic circumventing the need for premarket review.
In July 2004, the FDA ruled that the computer software was, in fact, a medical device and would require review.
In 2004 and 2005, the developer announces partnerships with several hospitals to further validate the assay and patents “A process for distinguishing between biological states based upon hidden patterns from biological data.”

Marker Updates—Ciphergen Panel
Collaborating with several academic centers, Ciphergen has sought to combine mass spectrometry with Protein Chip arrays including some antibody-based chips
In 2004, a paper in Cancer Research identified three biomarkers:Apoliporotein A1 and transthyretin (both downregulated), and a fragment of inter-α-trypsin (up-regulated) in ovarian cancer. The three markers plus CA 125 had a sensitivity of 74% for early stage disease and specificity of 97%. An update in 2006 CEBP, found somewhat lower sensitivity and specificity when benign disease included. Testing is underway on a panel of 7 markers.

Marker Updates - Yale’s Panel
In a paper in PNAS in 2004, a group led by Yale investigators used antibody microarrays to identify four proteins that distinguished ovarian cancer: leptin, prolactin, osteopontin, and insulin-like growth factor II.
The combination had a sensitivity of 95% and specificityof 95% for distinguishing ovarian cancer, all stages.
In 2006, Yale announced it would partner with a Chinese diagnostics company to develop this panel as a screening test for ovarian cancer.

Marker Updates - Luminex Panel
In an AACR abstract, Lokshin et al from the Univ. of Pittsburgh used the “bead-based” Luminex system for multiplexing many antibody-based assays to distinguish ovarian cancer cases from controls.
Eight biomarkers had the highest diagnostic power including: CA 125, CA 19-9, EGFR, G-CSF, Eotaxin, IL-2r, cVCAM, and MIF.
For postmenopausal ovarian cancer the sensitivity was 100% at a specificity of 98.6%.
Has partnered with Pittsburgh biostatisticians to develop an algorithm to combine the markers.

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by Flavio Guzmán on Dec 06, 2009

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