1. OVARIAN CANCERS: NO
LONGER SILENT KILLERS
DR. ASHUTOSH MUKHERJI,
ASSOCIATE PROFESSOR,
DEPARTMENT OF RADIOTHERAPY,
REGIONAL CANCER CENTRE, JIPMER

2. 
Malignant epithelial ovarian tumors account for 90% of all malignancies of the
ovary and are the fourth most common cause of tumor-related death in women.

During the year 2002, it ranked third worldwide in frequency (4.1%) among all
cancers in women.

The overall lifetime risk of developing ovarian cancer for women in the US is 1.4%
to 1.8%. This risk varies from 0.6% for women with no family history, at least three
term pregnancies, and four or more years of oral contraceptive use, to 3.4% for
nulliparous women with no oral contraceptive use. For women with a family
history, the lifetime risk for ovarian cancer is estimated at 9.4%.

Worldwide highest rates observed in Northern and Western Europe, notably
Scandinavia, and in North America.

3. 
1 in 12 women in urban India develop cancer in their lifetime (WHO study).
About 40% of new cases of cancer in India afflict women.

In the past decade, breast cancer has overtaken cervical cancer as the most
common cancer among women in Indian cities such as Mumbai and Delhi.

While cancer of the cervix is still a major killer of Indian women (accounting
for about 73000 deaths per year); it has shown significant decline in some
urban cancer registries and a modest decline in the rural registries.

On the other hand ovarian cancers have shown a steady increase in numbers
in data compiled from 1968 to 2005

4. Trends in ovarian cancer crude incidence rates in India
1980-2000

6. 
In India, cancer of the ovary is one of the most common cancers in
females and occupied third / fourth rank among cancers occurring in
women during the year 2004-05 in various Indian registries.

Epithelial ovarian cancers have been called “Silent Killers” as they rarely
give rise to symptoms in the early stages and by the time a patient
presents with large abdominal growth or other signs, the disease has
grown considerably or even spread to other organs.

Only 25% of cancers are detected as stage I disease. When diagnosed in
Stage I, however, the cure rate can approach 90% with modern
cytoreductive surgery and combination chemotherapy

7. 
Once stage III and IV ovarian cancer, (peritoneal and extra peritoneal
metastatic spread), is diagnosed, the survival decreases to approximately
20-25% five-year survival despite appropriate treatment.

According to NCCN guidelines, patients who are suspected of having
ovarian malignancy; presenting with symptoms like:
Abdominal fullness or bloating not responding to medication
Lump or tenderness in the abdomen
Increased frequency of urination with feeling of lump in abdomen
Increasing feeling of lack of appetite
1.
2.
3.
4.
should be investigated further (imaging, clinical examination, biomarkers).

9. NICE guidelines recommend:
To investigate if a woman (especially if 50 or over) reports having any of the
following symptoms on a persistent or frequent basis – particularly more than 12
times per month:
– persistent abdominal distension
– feeling full (early satiety) and/or loss of appetite
– pelvic or abdominal pain
- increased urinary urgency and/or frequency.


Carry out appropriate tests for ovarian cancer in any woman of 50 or over who
has experienced symptoms within the last 12 months that suggest irritable bowel
syndrome (IBS), because IBS rarely presents for the first time in women of this
age.
Measure serum CA125 in primary care in women with symptoms that suggest
ovarian cancer.
1.
If serum CA125 is 35 IU/ml or greater, ultrasound scan of the abdomen and
pelvis to be done.
2.
Any woman with normal serum CA125 (less than 35 IU/ml), or CA125 ≥ 35
IU/ml but a normal ultrasound to be assessed carefully for other clinical causes
of symptoms.


10. Tumour markers: which to use?

Measure serum CA125 in all women with suspected ovarian cancer.

In women under 40 with suspected ovarian cancer, measure levels of
alpha fetoprotein (AFP) and beta human chorionic gonadotrophin (betahCG) as well as serum CA125, to identify women who may not have
epithelial ovarian cancer.

11. 
Based on screening patterns, 2 distinct populations are at increased risk
for ovarian cancer:
1.
Women with hereditary risk factors for disease, comprise 10% of all
cases.
2.
Much larger group includes postmenopausal women who are over 50
years of age, in whom 90% of ovarian cancer occurs sporadically.

12. Role of Trans vaginal USG:

From 1987 to 1999, 14,469 women were enrolled onto the University of
Kentucky Ovarian Cancer Screening Program and underwent TVS
screening on an annual basis.

Abnormality criteria were simplistic and included an ovarian volume of
more than 10 cm3 in a postmenopausal woman, an ovarian volume of
more than 20 cm3 in a premenopausal woman, and any cystic ovarian
lesion with an internal or papillary projection.

180 women with persistent ovarian masses underwent surgery to remove
the lesion. 17 were found to have ovarian cancers. The effectiveness of
TVS as a screening tool was:

15. 
Trans-vaginal or pelvic ultrasonography is used to visualize the adnexae.

Benign and malignant tumours are distinguished from one another on the
basis of morphology.

Complex ovarian cysts with wall abnormalities or solid areas are associated
with significant risk for malignant disease whereas unilocular ovarian cysts are
associated with a less than 1% risk for ovarian cancer in asymptomatic
premenopausal women.

Second-line studies, such as morphologic tumor indexing or Doppler
sonography, may prove beneficial in differentiating benign from malignant
masses and increasing the positive predictive value of a screening algorithm
while maintaining a high sensitivity.

Application of morphologic scoring systems to sonographic screening
protocols could allow the maintenance of a high sensitivity, approaching 80%
to 90%, and improve the positive predictive value to greater than 20%.

16. Simple ovarian cyst

17. Complex ovarian cyst suspicious
for malignancy

18. CA-125 SCREENING: WHAT DOES IT MEAN?
 Bast and colleagues in 1981 first described CA-125, a 200 kd glycoprotein
recognized by the murine monoclonal antibody OC 125 as a marker for
epithelial malignancies. They demonstrated that a raised level of antigen
was detectable in the serum of 82% of women with epithelial ovarian
cancer but in only 1% of healthy blood donors.

Serum tumour markers for ovarian cancer like CA-125 is expressed by
about 80% of epithelial cancers (the most common type of malignant
tumour) but has limited specificity when used alone.

However it may also be increased in the presence of other cancers
(pancreatic, breast, bladder, liver, lung) as well as benign disease
(diverticulitis, leiomyoma, endometriosis). Specificity of CA-125 screening
is improved by the addition of pelvic ultrasonography as a second-line test
to assess ovarian lesions.

19. 
Stratified by disease stage, elevated levels were found in more than 90%
of patients with advanced stage ovarian cancer but in only 50% of
patients with stage I disease.

In addition, elevated levels of CA125 are more strongly associated with
serous, rather than mucinous tumors

Numerous studies have confirmed the usefulness of CA125 levels in
monitoring the progress of patients with epithelial ovarian cancer. Most
reports indicate that a rise in CA125 levels precedes clinical detection by
about 3 months

20. 
Commonly accepted definitions of disease recurrence based on serum
CA125 levels alone specify a doubling of this tumor marker level, either
from the upper limit of normal (35 U/mL) in patients with normalization
of this marker after primary treatment or from the nadir levels in patients
with an elevated serum marker value that never normalizes after primary
treatment.

Marksman (2006) suggested that reduction in serum CA-125
concentration over the initial 2 cycles of chemotherapy was an
independent predictor of survival.

Ron (1991) suggested early response (CA125 normalcy by the end of the
second chemotherapeutic course) was a highly significant predictor of
disease-free survival at 12 months.

21. 
The postoperative serum CA125 level is an independent prognostic factor
in patients with invasive ovarian cancer and CA125 tumor marker half-life
(t1/2) and tumor marker doubling time (DT) often used as kinetic
parameters for the evaluation of clinical response and follow-up of
patients with ovarian cancer

Serum CA125 half-life during early chemotherapy is an independent
prognostic factor for both the achievement of a pathologically complete
response.

22. 
Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, to
evaluate the efficacy of transvaginal ultrasound and serum cancer antigen
125 (CA-125) as screening tools to reduce ovarian cancer mortality
evaluated nearly 40,000 women.

These women underwent screening with a CA-125 blood test and
transvaginal ultrasound at baseline, an annual transvaginal ultrasound for
an additional 3 years, and an annual CA-125 for an additional 5 years.

There was no statistically significant reduction in mortality from ovarian
cancer in a cohort of women derived from the general population who
were screened for ovarian cancer with 6 annual CA-125 tests and 4
annual transvaginal ultrasound examinations even though more cases
were detected. However compliance with screening was high in the
intervention group.

24. WHY SCREEN?

25. 
Ovarian cancer screening recommended for women over age of 50.

Those willing to pursue further work up and investigation if screening is
positive.

Estimated to have a 7 – 9 year benefit from screening.

Patients with BRCA 1 or BRCA 2 mutations.

Those with strong family history of ovarian cancers.

Ovarian cancer screening is not recommended for women with no risk
factors (RR≤3).

26. 
For women with increase risk (RR=3-6 times), after evaluating risks and
benefits, ovarian cancer screening with CA-125 and/or transvaginal
ultrasonography can be done.

In women at inherited risk (RR>6 times), usually with mutations in ovarian
cancer susceptibility genes, should receive screening by a combination of
transvaginal ultrasonography and CA-125.

For patients with mutations in BRCA1 or the mismatch repair genes,
MLH1, MSH2, and MSH6, screening should begin around 30-35 years of
age.

27. ………… and finally a point to
remember