Routine screening for ovarian cancer harms more than it helps, says US authorityBMJ 2012; 345 doi: https://doi.org/10.1136/bmj.e6203 (Published 13 September 2012) Cite this as: BMJ 2012;345:e6203
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We read with interest the article on Ovarian Cancer screening published recently.
Guidance from the National Institute of Clinical Excellence (NICE) published in April 2011 relates to the use of serum levels of CA125 in the investigation of lower urinary tract symptoms. This amounts only to a form of ‘targeted’ screening with the intention to use this biomarker for prompt and early diagnosis of ovarian cancer and hence to improve survival in such women. From the Urologists perspective, this includes post-menopausal women with symptoms suggestive of the overactive bladder syndrome (OAB) over the age of 50 years.
Serum markers are essential tools in the investigation and diagnosis of malignant disease but have limitations in their disease specificity exemplified by the ongoing debate with Prostate Specific Antigen (PSA) in relation to prostate cancer screening (Schroeder et al 2009).
Sturgeon et al (2011) stressed that successful implementation of screening relied on both patient and clinician awareness of the causes of a false positive result, as well as the possibility of false negative. Rightly, a process of audit and re-analysis was suggested to determine effectiveness of this guidance. It is unclear how many departments or hospital trusts within the United Kingdom National Heath Service have so far followed this guidance from NICE.
Symptoms of an overactive bladder (OAB syndrome) are common in both sexes. The Olmstead study (Yawn et al 2004) reported all primary, secondary and tertiary care provided to a population-based cohort of women with the diagnosis of primary ovarian cancer. Of those women with a diagnosis of ovarian cancer, the most commonly documented presenting symptom was abdominal pain. Urinary symptoms were present in just over 10% of all cancers at diagnosis. Fewer than 25% of presenting symptoms related directly to the pelvis.
CA125 itself is a high molecular weight glycoprotein, normally expressed by a variety of epithelial cell types. These include adult tissues derived from Mullerian (endocervical, endometrial, tubal) and Coloemic (peritoneum, pericardium, mesothelium) epithelial cells. As with PSA in Prostate Cancer, the predictive value of the test in determining if the patient is likely to have disease is dependent on the serum CA125 level.
The potential pitfalls in setting a threshold are two-fold.
Firstly, as is the case in Prostate Cancer, benign disease may be the cause for CA125 levels above this threshold, resulting in an over-investigation and over-treatment. Such non-ovarian disorders, affecting breast, lung, pancreas and the endometrium (Givens et al 2009) have been shown also to elevate serum levels of CA125, as well as non-malignant processes such as cirrhosis, endometriosis, pelvic inflammatory disease and uterine leiomyoma. This will have the potential effect of reducing the predictive value of CA125 and increasing the false positive rate.
Secondly, the use of a single threshold may affect the effectiveness of CA125 testing. Again using the experience with Prostate Cancer and PSA, there is not a ‘normal’ cut off level that is associated with no cancer being present. There are various thresholds below which the incidence of cancer was not shown to be statistically significant, but disease is potentially present in very low PSA values. Setting serum CA 125 levels under 35 iU/ml as a ‘normal’ reference range (Bast et al 1983) runs the gauntlet of missing the steady increase in disease incidence observed with rising marker levels, as has been described in Prostate Cancer (Catalona 1991).
We would agree therefore that screening for Ovarian Cancer may be harmful by virtue of over-reliance on a serum marker with relatively poor levels of statistical sensitivity and specificity. We would suggest that clinicians understand this before following guidance from NICE on ovarian cancer screening.
1.NICE Guidance 122 - Ovarian Cancer - The recognition and initial management of ovarian cancer. The National Institute of clinical Excellence (2011).
2.Schröder F.H., Hugosson J., Roobol M.J., Tammela T.L.J., Ciatto S., Nelen V.,Kwiatkowski M, Luja M., Lilja H., Zappa M., Denis L.J., Recker, F., Berengue A., Määttänen L., Bangma, C.H., Aus G., Viller A, Rebillard X.,Van der Kwast T., Blijenberg, B.G., Moss S.M.M., Harry De Koning, H.J., Auvinen A. Screening and Prostate-Cancer Mortality in a Randomized European Study N Engl J Med 2009;360:1320-8.
3.Sturgeon CM, Duffy MJ, Walker G. The National Institute for Health and Clinical Excellence (NICE) guidelines for early detection of ovarian cancer: the pivotal role of the clinical laboratory. Ann Clin Biochem. 2011 Jul;48(Pt 4) 295-9
4.Yawn A.P., Barrette B.A., Wollan P.C. Ovarian Cancer: The neglected diagnosis. Mayo Clin Proc. 2004;79(10):1277-1282
5.Givens V., Mitchell G., Harraway-Smith C., Reddy A., Maness D.L. Am Fam Physician Volume 80, No 8, Oct 15, 2009
6.Bast R.C. Jr., Klug T.L., St John E., Jenison E., Niloff J.M., Lazarus H., Berkowitz R.S., Leavitt T., Griffiths C.T., Parker L., Zurawski V.R. Jr., Knapp R.C. A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med 1983, 309:883-887.
7.Catalona W.J., Smith D.S., Ratliff T.L., Measurement of prostate-specific antigenin serum as a screening test for prostate cancer N Engl J Med 1991;324:1156-61.September 12, 2002
Competing interests: No competing interests