WRITE UPS - MISCELLANEOUS: (GYN) - Current Concepts In Screening For Ovarian Cancer

 

INTRODUCTION:


Ovarian cancer is a major killer and every year more and more cases are being diagnosed with ovarian cancer. The lifetime risk of dying from ovarian cancer is 1.1%.1,2 The overall 5-year survival rate is at least 75% if the cancer is confined to the ovaries and decreases to 17% in women diagnosed with distant metastases. Symptoms usually do not become apparent until the tumor compresses or invades adjacent structures, ascites develops, or metastases become clinically evident. As a result, in India, approximately 80% of the patients are diagnosed in advanced stages of disease and hence the morbidity and mortality is very high.


We know that carcinoma of the ovary is most common in women over age 60. 3 Other important risk factors are low parity and a family history of ovarian cancer. Less than 0.1% of women are affected by hereditary ovarian cancer syndrome, but these women may face a 40% lifetime risk of developing ovarian cancer.11 Ovarian cancers are often observed within hereditary breast cancer families.


 Like in all malignancies survival from ovarian cancer is related to stage at diagnosis. The 5-year survival rate is 89% for localized disease, 36% for women with regional metastases, and 17% for women with distant metastases. Studies have shown that the most important prognostic factor in patients with advanced ovarian cancer is the size of residual tumor after treatment.2 Surgical debulking and chemotherapy for ovarian cancer appear to be more effective in reducing the size of residual tumor when ovarian cancer is detected early. Thus, screening for ovarian cancer is of paramount importance.


 Screening tests


Potential screening tests for ovarian cancer include the bimanual pelvic examination, the Papanicolaou (Pap) smear, tumor markers, and ultrasound imaging.


ANNUAL PELVIC EXAMINATION


The pelvic examination, which can detect a variety of gynecologic disorders, is of unknown sensitivity in detecting ovarian cancer. Although pelvic examinations can occasionally detect ovarian cancer, small, early-stage ovarian tumors are often not detected by palpation, due to the deep anatomic location of the ovary. Thus, ovarian cancers detected by pelvic examination are generally advanced and associated with poor survival. The pelvic examination may also produce false positives when benign adnexal masses (e.g., functional cysts) are found.2 Palpable ovary in a postmenopausal women should definitely raise suspicion of ovarian cancer.


A large clinical trial has recently been launched by the National Cancer Institute 4 to determine if annual pelvic examination can have a role in screening. Under the most optimistic assumptions (100% sensitivity, 30% reduction in 5-year mortality with screening, no lead-time bias), annual pelvic examinations of 40-year-old women could reduce 5-year mortality from ovarian cancer in the population by less than 0.0001%.


PAP SMEAR


Pap smear is extensively used in screening for cervical disease in most countries. The Pap smear may occasionally reveal malignant ovarian cells, but it is not considered a valid screening test for ovarian carcinoma.2,3 Studies indicate that the Pap smear has a sensitivity for ovarian cancer of only 10-30%.


SERUM TUMOR MARKERS


Serum tumor markers are often elevated in women with ovarian cancer. Examples of these markers include carcinoembryonic antigen, ovarian cystadenocarcinoma antigen, lipid-associated sialic acid, NB/70K, TAG 72.3, CA15-3, and CA-125. 5 Of these the CA 125 ovarian cancer-associated antigen is present at elevated levels in the serum of up to 90% of all ovarian cancer patients, including approximately 50% of patients with early-stage disease, suggesting its potential utility in the early detection of ovarian cancer. However, it has been reported that CA- 125 is elevated in 1% of healthy women, 6-40% of women with benign masses (e.g., uterine fibroids, endometriosis, pancreatic pseudocyst, pulmonary hamartoma), and 29% of women with non-gynecologic cancers (e.g., pancreas, stomach, colon, breast) and so false-positive results are common.6, 7 This high false-positive rate relative to the low incidence of ovarian cancer has led to the general consensus that a single CA 125 assessment is not useful in detecting early-stage ovarian cancer. So serial measurements may be required.


Also evidence is limited on whether tumor markers become elevated early enough in the natural history of occult ovarian cancer to provide adequate sensitivity for screening in asymptomatic women. Studies of stored sera have found that about one half of women who developed ovarian cancer had elevated CA-125 levels (>35 U/mL) 18 months to 3 years 8 before their diagnosis. Further research is needed, however, to provide more reliable data on the sensitivity of this and other tumor markers in detecting early-stage ovarian cancer in asymptomatic women.
It may be possible to improve the specificity of CA-125 measurement by selective screening of postmenopausal women, modifying the assay technique, adding other tumor markers to CA-125, requiring a higher concentration or persistent elevation of CA-125 levels over time, or combining CA-125 measurement with ultrasound. 5


ULTRASOUND
Ultrasound imaging is able to estimate ovarian size, detect masses as small as 1 cm, and distinguish solid lesions from cysts. Transvaginal color-flow Doppler ultrasound 9,10 can also identify vascular patterns associated with tumors. In screening studies, the reported sensitivity and specificity of transabdominal or transvaginal ultrasound are 50-100% and 76-97%, respectively, but small sample sizes, limited follow-up, and outdated techniques may limit the validity of the data.9, 10,11


14,356 ultrasound examinations performed over 3 years on 5,489 asymptomatic women over age 45 detected five ovarian cancers.10 Although the sensitivity and specificity of the test were excellent (100% and 94.6%, respectively), the positive predictive value in this low-risk study population was only 2.6% and follow-up was of short duration.
Another study using transvaginal sonography (TVS) for the detection of ovarian cancer consisted of 14,469 asymptomatic women, all of whom were either >/= 50 years of age or >/= 30 years of age with a family history of ovarian cancer, followed between 1987 and 1999 at the University of Kentucky.9, 10,11 An abnormal sonogram was defined as one in which the ovarian volume was greater than 10 cm3 in postmenopausal women, and greater than 20 cm3 in premenopausal women, or one in which a papillary or complex tissue projection into a cystic ovarian tumor was evident. All women with an abnormal TVS underwent a repeat sonogram after 4-6 weeks, and if abnormal scans persisted, surgery was recommended.


Of the 180 patients with persistent TVS abnormalities that underwent exploratory laparoscopy or laparotomy, 17 ovarian cancers were detected, 14 of which were stage I or II at diagnosis. With a mean follow-up of 4.6 years (range, 0.8 — 9.6 years), all of the patients with early-stage disease were still alive without recurrence, whereas 2 of the 3 patients with advanced-stage disease had died. Of the group without evidence of TVS abnormality, 4 patients developed ovarian or primary peritoneal cancers within 1 year of a negative scan, 2 of which were early stage and 2 of which were advanced stage.


In this study, TVS was associated with a sensitivity of 81%, a specificity of 98.9%, a positive predictive value of 9.4%, and a negative predictive value of 99.9%. After a total of 46,113 screening years, there have been 3 ovarian cancer deaths in the annually screened population and a 5-year survival of 88% for the ovarian cancer patients in the study population.
These studies show that TVS screening for ovarian cancer in the general population may be effective at detecting disease at an earlier, more curable stage, thus improving long-term survival from this malignancy but it has relatively low positive predictive value of only 9%, which is probably not acceptable from the standpoint of cost-effectiveness and patient acceptance. It should also be noted that this methodology does not appear to be effective at detecting primary peritoneal cancer, which is perhaps not surprising, given the frequent absence of enlarged ovaries associated with this malignancy. Clearly, further studies of the utility of TVS in detecting early-stage ovarian cancer are warranted.


COMBINED MODALITIES


It may be possible to improve accuracy by combining ultrasound with other screening tests, such as the measurement of CA-125.12 One prospective study screened 1,010 asymptomatic postmenopausal women over age 45 with pelvic examination and CA-125 measurement; those with abnormal results received an ultrasound examination. Although one ovarian cancer was detected (all three screening tests were positive in this woman), the study demonstrated poor positive predictive value with each of the three screening tests. No abnormality was discovered in 28 of the 31 women with elevated CA-125. Fibroids and benign cysts were responsible for over half of the 28 abnormal pelvic examinations. Various studies reported that the combination of abdominal ultrasound and sequential CA-125 measurements had a sensitivity of 58-79%, a specificity of about 100%, and a positive predictive value of 27%. 12,13,14


In our own study we have found that pelvic examination gave a sensitivity of 82.1% and specificity of 73.07%. trans vaginal ultrasound gave a sensitivity and specificity of 75% and 76.9% while CA 125 levels had a sensitivity and specificity of 92.8% and 75% respectively. When a combined modality was used the sensivity and specificity improved to 95.2% and 94.2%.


GENETIC SCREENING


Women with germline BRCA1 or BRCA2 mutations are at substantially increased risk for breast and ovarian cancer, although the risks may not be as high as originally reported. It appears that both breast and ovarian cancer risk may be lower among BRCA2 carriers than among BRCA1 carriers, these cancers may occur at later ages, on average, in BRCA2 carriers, and risk may also vary with the location of the mutation within the gene. The choice of whether to undergo genetic testing is a difficult one as it is expensive, there are several variants to the gene and once detected there are no definitive prophylactic methods to prevent the occurrence of the disease. It has also proved to be very psychologically disturbing to the women.15, 16


Several very large, prospective trials designed to test the efficacy of this type of multimodality screening in both the general and high-risk populations are currently under way.


SUMMARY


There is no direct evidence from prospective studies till date that women with early-stage ovarian cancer detected through screening have lower mortality from ovarian cancer than do women with more advanced disease. A large body of indirect evidence, however, suggests that this is the case. Conclusive proof will require properly conducted prospective studies comparing long-term mortality from ovarian cancer between screened and nonscreened cohorts.


The sensitivity and specificity of available screening tests for ovarian cancer in asymptomatic women are uncertain and require further study. Although various tests can detect occasional asymptomatic tumors, there is currently no evidence that a particular test or combined approach is definitely effective for routine screening. The large majority of women with abnormal screening test results does not have cancer, yet will require invasive procedures (laparoscopy or laparotomy) to rule out malignancy. Given the risks, inconvenience, and substantial costs of follow-up testing, and the current lack of evidence that screening reduces morbidity or mortality from ovarian cancer, routine screening cannot be recommended.


Recommendations of Other Groups


There are no official recommendations to screen routinely for ovarian cancer in asymptomatic women by performing ultrasound or serum tumor marker measurements. The American College of Physicians (ACP), the Canadian Task Force on the Periodic Health Examination, and the American College of Obstetricians and Gynecologists recommend against such screening.


Current recommendations


The current recommendations made are pelvic examination to be performed with the Pap test every 1-3 years in women aged 18-40 years and annually thereafter. Identified high risk women or women with presumed hereditary cancer syndrome should undergo annual pelvic examinations, CA-125 measurements and transvaginal ultrasound.


REFERENCES


1. Wingo PA, Tong T, Bolden S. Cancer statistics, 1995. CA Cancer J Clin 1995;45:8-30.


2. Goswamy RK, Campbell S, Whitehead MI. Screening for ovarian cancer. Clin Obstet Gynecol 1983;10:621-643.


3. Carlson KJ, Skates SJ, Singer DE. Screening for ovarian cancer. Ann Intern Med 1994;121:124-132


4. Kramer BS, Gohagan J, Prorok PC, Smart C. A National Cancer Institute sponsored screening trial for prostatic, lung, colorectal, and ovarian cancers. Cancer 1993;71:589-593.


5. Jacobs IJ, Oram DH, Bast RC. Strategies for improving the specificity of screening for ovarian cancer with tumor-associated antigens CA125, CA15-3, and TAG 72.3. Obstet Gynecol 1992;80:396-399.


6. Einhorn N, Sjovall K, Knapp RC, Hall P, Scully RE, Bast RC, Zurawski VR. Prospective evaluation of serum CA 125 levels for the early detection of ovarian cancer. Obstet Gynecol 1992;80:14-18.


7. Zurawski VR Jr, Orjaseter H, Andersen A, et al. Elevated serum CA 125 levels prior to diagnosis of ovarian cancer neoplasia: relevance for early detection of ovarian cancer. Int J Cancer 1988;42:677-680.


8. Helzllsouer KJ, Bush TL, Alberg AJ, Bass KM, Zacer H, Comstock GW. Prospective study of serum CA125 levels as markers of ovarian cancer. JAMA 1993;269:1123-1126.


9. Van Nagell JR, DePriest PD, Puls NE, Donaldson ES, Gallion HH, Pavlik EJ, et al. Ovarian cancer screening in asymptomatic postmenopausal women by transvaginal sonography. Cancer 1991;68:458-462.
10. Andolf E, Jorgensen C, Astedt B. Ultrasound examination for detection of ovarian carcinoma in risk groups. Obstet Gynecol 1990;75:106-109.


11. Bourne T, Campbell S, Steer C, Whitehead MI, Collins WP. Transvaginal colour flow imaging: a possible new screening technique for ovarian cancer. BMJ 1989;299:1367-1370.


12. Campbell S, Royston P, Bhan V, Whitehead MI, Collins WP. Novel screening strategies for early ovarian cancer by transabdominal ultrasonography. Br J Obstet Gynaecol 1990;97:304-311.


13. Jacobs I, Davies AP, Bridges J, et al. Prevalence screening for ovarian cancer in postmenopausal women by CA 125 measurement and ultrasonography. BMJ 1993;306:1030-1034.


14. Jacobs I, Stabile I, Bridges J, et al. Multimodal approach to screening for ovarian cancer. Lancet 1988;1:268-271.


15. Finkler NJ, Benacerraf B, Lavin PT, et al. Comparison of serum CA 125, clinical impression, and ultrasound in the preoperative evaluation of ovarian masses. Obstet Gynecol 1988;72:659-664.


16. Karlan BY, Raffel LJ, Crvenkovic G, et al. A multidisciplinary approach to the early detection of ovarian carcinoma: rationale, protocol design, and early results. Am J Obstet Gynecol 1993;169:494-501.


17. Amos CI, Struewing JP. Genetic epidemiology of epithelial ovarian cancer. Cancer 1993;71:566-572.


18. Biesecker B, Boehnke M, Calzone K. Genetic counseling for families with inherited susceptibility to breast and ovarian cancer. JAMA 1993;269:1970-1974.

 
     

 
         
     

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