OVARIAN CANCERS: NO LONGER SILENT KILLERS

DR. ASHUTOSH MUKHERJI,ASSOCIATE PROFESSOR,

DEPARTMENT OF RADIOTHERAPY,REGIONAL CANCER CENTRE, JIPMER

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.

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

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

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

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:

1. Abdominal fullness or bloating not responding to medication2. Lump or tenderness in the abdomen3. Increased frequency of urination with feeling of lump in abdomen4. Increasing feeling of lack of appetite

should be investigated further (imaging, clinical examination, biomarkers).

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.

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 (beta-hCG) as well as serum CA125, to identify women who may not have epithelial ovarian cancer.

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.

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:

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%.

Simple ovarian cyst

Complex ovarian cyst suspicious for malignancy

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.

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

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.

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.

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.

WHY SCREEN?

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).

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.

………… and finally a point to remember

THANK YOUFROM THE DEPARTMENT OF

RADIOTHERAPY, REGIONAL CANCER CENTRE, JIPMER