Transcript Screening in Gynaecological Cancers

Ovarian Cancer Screening
Mati Zolti M.D.
Department of Obstetrics & Gynaecology
Sheba Medical Center
Tel Hashomer, Israel
Ovarian Cancer: Burden of suffering
• 4th 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
Death
Median age
:
:
:
220
95
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 (1520%)
Arrhenoblastoma (<20%)
Theca cell tumor (<1%)
Epithelial Ovarian Cancer
•
Overall 5-year survival rate is 75-95% if
cancer confined to ovaries; decreases to 1017% 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
• Must first categorize as functional, benign neoplastic
or potentially malignant
• Diagnostic approach depends on:
•
•
•
•
Age
Size of mass
Unilateral vs. bilateral
CA-125 levels
• Ultrasound configuration
• Color-flow Doppler flow
• Presence of symptoms
Diagnostic approach
• If premenopausal and asymptomatic, with
unilateral, mobile, simple cystic mass <810cm 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 CA125, 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
1.
2.
3.
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 nonspecific 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, GCSF, 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.