Prostate Cancer: Emerging Concepts: Part I

Glossary Androgen deprivation therapy: The elimination, by either medical or surgical means, of male androgens, used to treat prostate cancer. Clinical and pathologic staging of cancer (cT1, cT2a, cT2b, cT3, pT1, pT2, pT3): A description of prostate cancer tumor size and degree of extension using clinical criteria, such as results of digital rectal examination. The letter c denotes staging using clinical criteria; p denotes pathologic staging, usually determined by the pathologist examining the radical prostatectomy specimen. T1, tumor not palpable; T2a, tumor limited to one lobe; T2b, tumor limited to both lobes; T3, tumor with regional extension. Gleason pattern score: A pathologic grading system to describe the pathologic characteristics of prostate cancer on biopsy and surgical specimens. In general, pattern scores of 2 to 4 represent well-differentiated cancer; scores of 5 to 7 indicate moderately differentiated cancer; and scores of 8 to 10 suggest poorly differentiated cancer. Stage T1c cancer: Nonpalpable prostate cancer that is diagnosed by examination of biopsy specimens. The biopsy is prompted by an abnormal prostate-specific antigen blood test result. In 1993, Annals published a review article describing clinical aspects of prostate cancer [1]. An accompanying article [2] reported risk factors for prostate cancer, and subsequent articles discussed in detail the status of prostate-specific antigen (PSA) screening [3, 4]. In 1993, the annual incidence of prostate cancer was estimated to be 165 000 newly diagnosed cases. In 1996, an estimated 318 000 new cases will be diagnosed in the United States alone [5]. Thus, largely on the basis of the widespread use of PSA-based screening, many more patients are receiving a diagnosis and are being offered treatment at earlier stages of disease. In August 1994, the Food and Drug Administration approved the use of PSA testing in association with digital rectal examination for early detection of prostate cancer. This approval has created a new spectrum of management decisions for a broad range of physicians, including many internists [6]. In the first part of this review, we assess these challenges; screening for the early detection of prostate cancer is covered in a separate articles by the Clinical Evaluation Task Force of the American College of Physicians (American College of Physicians. Clinical practice guidelines on the early detection of prostate cancer. Unpublished report). New Concepts in Interpretation of Prostate-specific Antigen Values Most of the initial screening studies that assessed an abnormal PSA value used 4.0 ng/mL as the upper limit of normal. Several investigations have challenged this normal value and have suggested refinements in the interpretation of PSA test results. Emerging concepts that may help interpret the significance of elevated PSA levels include density, velocity, age-specific reference ranges, and free values compared with bound values. Prostate-specific Antigen Density The PSA density refers to a numerical ratio determined by dividing the PSA serum value by the volume of the prostate gland, as determined by transrectal ultrasonography. Because prostate cancer tissue produces more PSA per gram of tissue than does normal prostate tissue or benign prostatic hyperplasia, elevated PSA densities (usually more than 0.15) may more strongly indicate the presence of prostate cancer. One study [7] generated a probability curve that predicts the likelihood of prostate cancer on the basis of the PSA density. Another study [8] indicated that in the presence of a persistently elevated PSA value and negative biopsy results, a PSA density greater than 0.15 could be used to predict that examination of a subsequent biopsy specimen would have a greater than 80% likelihood of detecting prostate cancer. Inherent difficulties surround PSA density, including errors in measuring the prostate volume with transrectal ultrasonography and a variation as great as 15% in repeated examinations in the same patient [9]. Thus, despite the suggestion that PSA density can differentiate between large groups of patients with benign prostatic hyperplasia and patients with prostate cancer, the sensitivity in extrapolation of these data to the individual patient varies considerably. Additional data are needed. Prostate-specific Antigen Velocity (Rate of Change of the Antigen with Time) Prostate-specific antigen velocity refers to the rate of change in the PSA value over time. Patients with an elevated PSA value that continues to increase with time are more likely to have prostate cancer than are patients with stable PSA elevations. Thus, patients whose PSA value changes by more than 0.8 ng/mL per year are more likely to have prostate cancer. This rate of change in the PSA value may help identify patients who should have biopsy even if the results of the digital rectal examination and transrectal ultrasonographic examination are normal. These data are largely based on longitudinal studies done in Baltimore [10], in which men had serum samples stored for decades and were then followed before various disorders, including benign prostatic hyperplasia and prostate cancer, began to develop. In this study, the rate of change in the PSA value with time could be distinguished among cohorts of patients who never developed cancer, who had benign prostatic hyperplasia, and who had both localized and metastatic disease. Subsequent studies have confirmed these velocity changes, indicating that levels that change by more than 0.75 ng/mL per year should be regarded with a high degree of suspicion. Although additional data are needed, the rate of change of the PSA value with time may be the most notable indicator of a malignant or premalignant change in the histologic characteristics of the prostate. Careful follow-up of the rate of change may be an early indication of low-volume (that is, curable) prostate cancer or may provide an opportunity for the implementation of preventive strategies. Prostate-specific Antigen Reference Ranges Specific to Patient Age In the past, one normal range of values of PSA was used, regardless of the patient's age. Recent data have shown that the upper-limit normal PSA value of a man who is in the fourth decade of life and has no known prostate disorders is less than the normal value of a man in his sixth or seventh decade [11, 12]. Benign prostatic hyperplasia causes an increased prostatic volume, which in turn leads to an increased serum PSA level even without a malignant change. Thus, refining the previously accepted normal values of 0 to 4 ng/mL for all men may improve the specificity, sensitivity, and positive predictive value of the PSA test in diagnosing prostate cancer. Table 1 shows one recent recommendation for age-specific reference ranges. The ultimate value of this approach is that it decreases the number of biopsies in older patients with PSA values greater than 4 ng/mL and that it may increase the rate of cancer detection in younger men with PSA values less than 4 ng/mL. Preliminary data suggest that such goals can be reached when these new reference ranges are used. Table 1. Prostate-specific Antigen Age-specific Reference Ranges* Serum Free and Bound Prostate-specific Antigen Levels In a more recent refinement of the test for serum PSA values, the relative percentage of free PSA and PSA that binds to serum proteins (bound PSA) is determined. Several reports [13, 14] indicate that men with a higher ratio of bound to free PSA are more likely to have prostate cancer seen on examination of biopsy specimens regardless of the total serum PSA level. Although no confirmatory studies have been done, the serum bound to free ratio may be an important factor in determining which patients should have prostate biopsy regardless of the total PSA value. A recent study [15] established more definitive reference ranges. Correlation of Prostate-specific Antigen Value, Clinical Stage, Gleason Pattern Score, and Prediction of the Pathologic Extent of Disease One of the major clinical challenges in the management of clinically localized prostate cancer (for example, cT1, cT2a, cT2b, and certain cT3 Figure 1 is to provide appropriate, curative treatment of cancer that appears to be confined to the prostate gland. Although this seems straightforward, nearly half of patients who are originally considered to have organ-confined prostate cancer develop cancer that spreads beyond the prostate gland when radical prostatectomy is done (Table 2). In pathologic terms, this may be cancer that has spread into the regional lymph nodes or the seminal vesicles, cancer that has perforated or penetrated the prostate capsule, or cancer that has reached the inked margin. In this process, the pathologist, after receiving the prostatectomy specimen from the operating room, inks the outside surface of the gland and marks the left and right sides of the gland. If cancer is present at this margin, it is presumed that the in situ portion of the resected margin contains cancer that has exceeded the margins of surgical resection. Figure 1. Comparison of the older Whitmore-Jewett classification system for prostate cancer with the tumor, node, metastases (TNM) system. Table 2. Understaging in Patients with Clinical Stage B (T1/T2) Cancer Who Had Radical Prostatectomy Prostate cancer that is not confined to an organ is associated with an alarmingly high incidence of recurrence. Table 3 shows the clinical and total recurrence rates after radical prostatectomy according to the pathologic state of the resected gland (the total recurrence rate is the clinical recurrence rate plus the recurrence rate for patients with detectable serum PSA values). The rates shown in Table 3 raise the question of whether radical surgery was appropriate, because these patients are often not cured by surgery alone. Table 3. Clinical and Biological Failure as a Function of Prostatectomy Pathology* By using the