Commentary: The ubiquity of prostate cancer: echoes of the past, implications for the present: "What has been will be again, what has been done will be done again,; there is nothing new under the sun." ECCLESIASTES 1:9
It was over 70 years ago that Rich made a simple observation: prostate cancer can be found surprisingly often in asymptomatic men who succumb to other diseases. The prostate cancer student of today is humbled by the prescience of Rich. The context is important: Rich was a member of the faculty of the home of the discipline of Urology in the USA at Johns Hopkins. Hugh Hampton Young, MD, the ‘father of American Urology’, was the Chair and had previously described treatments for the cure of prostate cancer. Young was the first to suggest that early detection (at the time, with digital rectal examination) could identify the disease prior to metastasis, allowing surgical intervention for cure. Rich’s observation was startlingly simple: upon pathological examination of a very small sample of the prostate from men who had expired, most without a previous diagnosis of prostate cancer, the disease was commonly encountered. He observed as well that the disease developed on the periphery of the prostate and often invaded the prostate capsule; he furthermore implied that the disease might even be more common if it was sought more assiduously. Since Rich’s landmark observation, others have looked carefully at the autopsy risk of prostate cancer. Prevalence rates of prostate cancer have been found to range from 31% for men aged 31–40, 44–46% for men aged 51–60, to over 80% for men aged 71–80. Despite the observations of Rich and subsequent authors, it has been generally felt that if a small sample of the prostate is obtained at biopsy and then examined pathologically, the disease found must be significant in size and clinically consequential. Bolstering this impression was the observation that even among men with a small focus of cancer in one biopsy core, over 90% were found to have what was called ‘significant’ disease at radical prostatectomy. As a result, when prostate cancer is detected, fearing it represents large-volume and potentially lethal disease, over 92% of men found with low-risk disease in the United States receive active treatment; of men over age 75, three-quarters are treated. Said the sage: ‘things change’. In the time of Rich as well as until the early 1980s, using digital rectal examination, if men were screened with the only available test—a rectal examination of the prostate, between 0.8% and 1.4% were found to have prostate cancer. Diagnosis of prostate cancer was established at that time by what might be considered a poorly representative sample of the gland: as few as two to four 18-gauge needle biopsies of the gland with the biopsy needle directed by the physician’s finger either through the rectum or perineum. Using this technique, it was not possible to ensure that the needle sampled the peripheral zone of the gland where most tumours develop. What has changed? Regarding diagnosis, prostate specific antigen (PSA) is now the most common cause of biopsy. With its introduction for screening in the late 1980s, the rate of diagnosis of prostate cancer in the general population increased dramatically. Instead of 2–4 biopsy cores, the average number of cores obtained initially increased to six and currently is most commonly 10–12. If biopsy is negative, it is not unusual for a physician to recommend a ‘saturation’ biopsy with as many as 24 cores. Ultrasound is now used to ensure that the peripheral zone of the prostate is targeted with the biopsy needle. The result of these changes has been dramatic: an 8% lifetime risk of diagnosis in 1985 is now 17%. This rate reflects the prevalence rate of screening with PSA: about 75% of men over 50 have had at least one PSA test and about 50% have the test regularly. A variety of factors may further increase the lifetime risk of diagnosis including, (i) lower PSA thresholds below the traditional 4.0 ng/ml cutoff for biopsy, (ii) an increasing fraction of the population screened, (iii) further aging of the population, (iv) new biomarkers for prostate cancer to increase screening sensitivity and (v) increases in the number of biopsy cores obtained. The implications of these changes are enormous and were, to an extent, foretold by Rich. The first regards early detection of prostate cancer based on any ‘marker’ of the disease and biopsy sampling of the prostate. PSA as a biomarker actually has reasonable performance characteristics with an area under the receiver operating characteristic curve (AUC or C-statistic) of 0.68. The ‘problem’ with PSA is actually the disease prevalence. If only six biopsy samples are obtained, the most common cutpoint of PSA, 4.0 ng/ml, has only 20.5% sensitivity. To achieve an 83.4% sensitivity, a threshold value of PSA of 1.1 ng/ml must be used. With this recognition and the patient’s and physician’s desires to not ‘miss’ prostate cancers, lower levels of PSA are increasingly used, increasing the likelihood that smaller tumours will be detected. Additionally, as a prostate biopsy * Corresponding author. Department of Urology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. E-mail: thompsoni@uthscsa.edu 1 Department of Urology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. 2 Department of Pathology, University of Colorado Health Science Center, Denver, Colorado. 3 Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Published by Oxford University Press on behalf of the International Epidemiological Association The Author 2007; all rights reserved. International Journal of Epidemiology doi:10.1093/ije/dym056
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