EDITORIAL

Current Status of Enhancing the Detection ofProstate Cancer

The discovery of prostate-specific antigen (PSA)and its subsequent use as a tumor maker have revo-lutionized the detection of prostate cancer. This gly-coprotein, once thought to be exclusively secreted inthe prostate, is now known to be elaborated in severalother sites such as the kidney and breast, but only invery small amounts. The detectable levels of PSAfound in serum are thought to originate from the co-lumnar epithelial cells of the prostate. PSA is normallysecreted into the seminal fluid and is detected in theserum at concentrations of 2.5 ng/ml or less in 75% ofmen; a level >4.0 ng/ml is found in approximately10% of men. In order for PSA to be detected in serum,there must be some disruption of the normal internalarchitecture of the prostate gland that interferes withits normal pathway of secretion into the seminal fluid.In addition to cancer, any benign inflammatory pro-cess in the prostate can result in an elevation of serumlevel. Other benign conditions, such as atrophy or in-farction, can also be associated with abnormal PSAlevels. In fact, on a cell-for-cell basis, PSA is secreted ingreater amounts by benign cells than by cancer cells. Itis well-known that PSA is not detected in the serum of30% of patients who have prostate cancer, and isfound in increased concentrations in the serum of 20%of men who do not have prostate cancer [1,2,3]. Thereasons for these observations are only partly under-stood. This tumor marker is inversely related to dif-ferentiation in that as a cancer dedifferentiates, its abil-ity to produce PSA decreases. In fact, PSA is secretedin greater amounts by benign cells than by cancercells. Clearly, these factors underscore the limitationsof PSA as a prostate cancer-specific maker.

In 1989 and 1990, we were the first investigators toreport the association of gland volume and age withserum PSA level [5,6]. Since that time, several inves-tigators have sought to improve the utility of PSA indetecting prostate cancer in the hope of decreasingboth the false-positive and -negative rates of cancerdetection. The ultimate goal was to accomplish thistask and at the same time decrease the number ofunnecessary biopsies [7,8,9]. Thus was born the era ofPSA indices. In 1992, the concept of PSA density

(PSAD) was developed. This index is derived by di-viding the serum PSA level by the gland volume. Thefollowing year, age-specific reference ranges for PSAwere introduced and touted to improve the detectionof prostate cancer, particularly in men younger thanage 50 years [8]. In addition, it was reported that age-reference PSA could avoid the detection of insignifi-cant cancers and decrease unnecessary biopsies inmen older than age 70 years [7]. The reported resultswith either of these indices are controversial, stimu-lating considerable debate and the continued search toimprove upon the use of the total serum PSA value atthe 4.0 ng/ml threshold. Recent data regarding theincidence of significant disease in men who have aPSA level <4.0 ng/ml and who have undergone aradical prostatectomy (20–40%) have stimulated in-vestigators to search for ways to enhance the conven-tional PSA threshold [4,10].

Early experience with PSA clearly pointed to thesuperiority of the association of this marker withgland volume compared to that with age. In light ofthis fact, a new index, volume-referenced PSA, wasdeveloped and subjected to vigorous statistical analy-sis, comparing it to PSAD and age-specific referenceranges. In addition to overall analysis, PSA and itsdensity, age, and volume indices were evaluated byage and volume subcategories with receiver operatingcharacteristic (ROC) curves. Furthermore, a compara-tive analysis with respect to the number of cancersmissed and number of biopsies saved was under-taken.

In a retrospective review of 580 men who under-went a biopsy triggered by an abnormality in any oneof the components of the diagnostic triad (digital rectalexam [DRE], transrectal ultrasound [TRUS], or PSA[cutoff, 4 ng/ml]), a comparison of overall test perfor-mance by ROC curve analysis revealed that bothPSAD and volume-referenced PSA were superior toPSA, which was superior to age-referenced PSA. Simi-larly, volume-referenced PSA used alone would havemissed the fewest cancers (17/201, 8%) comparedwith, in increasing order, PSA (22/201, 11%), age-referenced PSA (33/201, 16%), and PSAD (38/201,

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19%). As anticipated, the increasing sensitivity wasinversely related to the number of biopsies saved(PSAD would have saved 48% of the biopsies com-pared with 31% for volume-referenced PSA).

With respect to the number of cancers missed,analysis by volume subsets in 10-cc increments from25 cc or less to >55 cc demonstrated that volume-referenced PSA, PSA, and PSAD were equivalent andthat they were all superior to age-referenced PSA ex-cept in the group of men whose gland was between25–35 cc, where volume-referenced PSA was signifi-cantly better than PSA, PSAD, or age-referenced PSA.This superiority was also applicable to age-referencedPSA except for men who had a gland between 45–55cc; in that group, volume-referenced PSA was equiva-lent to both age-referenced PSA and PSA alone. ROCcurve analysis revealed the equivalence of all param-eters except among men with glands between 25–35cc, in whom volume-referenced PSA and PSA weresignificantly better than age-referenced PSA. Analysisof numbers of cancers missed in decade incrementsfrom 50–>70 years revealed the equivalence of all pa-rameters for men age 50–59 years, and enhanced de-tection for volume-referenced PSA and PSA overPSAD and age-referenced PSA for men age 60 andolder. Area under the ROC curves for men age 60 orolder showed that volume-referenced PSA (V-PSA)and PSAD, which performed equally well, were bothsuperior to PSA and age-referenced PSA (A-PSA),which were equivalent.

Similar evaluations were also performed for sub-groups by PSA value, i.e., for men having a PSA in theintermediate (gray zone) range of 4–10 ng/ml and formen with a PSA of 2–7 ng/ml. In the gray zone, therewas no significant difference in a number of cancersmissed between V-PSA, A-PSA, and PSA alone; allthree indices missed fewer cancers than PSAD. ROCcurves demonstrated that V-PSA and PSAD per-formed better than PSA or A-PSA. In men with a se-rum PSA between 2–7 ng/ml, PSA and V-PSA de-tected more cancers than PSAD or A-PSA. As in menwith gray-zone PSA levels, the performance by ROCcurve analysis demonstrated that V-PSA and PSADwere equivalent and that they outperformed both PSAand A-PSA in men with PSA between 2–7 ng/ml.

It would appear that, statistically, volume-referenced PSA performs better than PSA, age-referenced PSA, and PSAD; however, scrutiny of clini-cal performance demonstrates only a marginal benefitof volume-referenced PSA over the conventional PSAthreshold of 4 ng/ml. A benefit to cancer detection ofusing density or age to enhance PSA alone has notbeen substantiated. In view of the potential for sub-jectivity associated with volume estimates and the cost

of determining volume, we conclude that PSA alone(threshold, 4 ng/ml) remains superior to volume, den-sity, and age indices from a clinical perspective in de-tecting cancer. The room for improvement is consid-erable, and time will allow us to evaluate the tools ofthe future, such as the ratio of the free to total PSA,prostate-specific membrane antigen ProstAsure index(Horus Therapeutics, Savannah, GA) human glandu-lar Kallikrein2, and complexed PSA, as well as toevaluate whether lowering the absolute PSA thresholdto 2.5 ng/ml will enhance detection.

Richard J. BabaianDepartment of Urology

University of Texas M.D. Anderson Cancer CenterHouston, Texas

REFERENCES

1. Kane RA, Littrup PJ, Babaian R, Drago JR, Lee F, Chesley A,Murphy GP, Mettlin C, and the Investigators of the AmericanCancer Society National Prostate Cancer Detection Project: Pros-tate-specific antigen levels in 1695 men without evidence ofprostate cancer: Findings of the American Cancer Society Na-tional Prostate Cancer Detection Project. Cancer 69:1201–1207,1992.

2. Babaian RJ, Mettlin C, Kane R, Murphy GP, Lee F, Drago JR,Chesley A, and the Investigators of the American Cancer SocietyNational Prostate Cancer Detection Project: The relationship ofprostate-specific antigen to digital rectal examination and tran-srectal ultrasonography: Findings of the American Cancer Soci-ety National Prostate Cancer Detection Project. Cancer 69:1195–1200, 1992.

3. Babaian RJ, Miyashita H, Evans RB, Ramirez EI: The distribu-tion of prostate specific antigen in men without clinical orpathological evidence of prostate cancer: Relationship to glandvolume and age. J Urol 147:837, 1992.

4. Babaian RJ, Troncoso P, Steelhammer LC, Lloreta-Trull J,Ramirez EI: Tumor volume and prostate specific antigen: Im-plications for early detection and defining a window of curabil-ity. J Urol 154:1808–1812, 1995.

5. Babaian RJ, Fritsche HA, Evans RB: Prostate-specific antigen:The relationship of serum concentration to age and prostategland volume. J Urol 141:183, 1989.

6. Babaian RJ, Fritsche HA, Evans RB: Prostate-specific antigenand the prostate gland volume: Correlation and clinical appli-cation. J Clin Lab Anal 4:135, 1990.

7. Benson MC, Whang IS, Olsson CA, McMahan DJ, Cooner WH:The use of prostate specific antigen density to enhance the pre-dictive value of intermediate levels of serum prostate specificantigen. J Urol 147:817, 1992.

8. Oesterling JE, Jacobsen SJ, Chute CG, Guess HA, Girman CJ,Panser LA, Lieber MM: Serum prostate-specific antigen in acommunity-based population of healthy men. Establishment ofage-specific reference ranges. JAMA 270:860, 1993.

9. Babaian RJ, Kojima M, Ramirez EI, Johnston D: Comparativeanalysis of prostate specific antigen and its indexes in the de-tection of prostate cancer. J Urol 156:432–437, 1996.

10. Partin AW, Pound CR, Clemens JQ, Epstein JI, Walsh PC: SerumPSA after anatomic radical prostatectomy. Urol Clinic N. Amer20(4):713−25, 1993.

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