Serum PSA is Strong Predictor of Future Prostate Growth in Men With BPH

Original Articles

SERUM PROSTATE SPECIFIC ANTIGEN IS A STRONG PREDICTOR OFFUTURE PROSTATE GROWTH IN MEN WITH BENIGN PROSTATIC

HYPERPLASIACLAUS G. ROEHRBORN,*,† JOHN MCCONNELL, JAIME BONILLA,* SIDNEY ROSENBLATT,

PERRY B. HUDSON,* GHOLEM H. MALEK, PAUL F. SCHELLHAMMER, REGINALD BRUSKEWITZ,ALVIN M. MATSUMOTO,*,‡ LLOYD H. HARRISON,* HAROLD A. FUSELIER, PATRICK WALSH,*JOHNNY ROY,* GERALD ANDRIOLE,* MARTIN RESNICK AND JOANNE WALDSTREICHER* FOR

THE PROSCAR§ LONG-TERM EFFICACY AND SAFETY STUDYFrom the University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, Department of Veterans Affairs, VA Medical Center, Bay Pines,

Florida, Irvine Clinical Research Center, Irvine, California, Jackson Foundation, Madison, Wisconsin, Eastern Virginia Medical School, Norfolk,Virginia, University of Wisconsin, Madison, Wisconsin, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, Wake ForestUniversity School of Medicine, Winston-Salem, North Carolina, Ochsner Clinic, New Orleans, Louisiana, Johns Hopkins Hospital, Baltimore,Maryland, University of Oklahoma, Oklahoma City, Oklahoma, Washington University, St. Louis, Missouri, University Hospital of Cleveland,

Cleveland, Ohio and Department of Clinical Research Endocrinology and Metabolism, Merck Research Laboratories, Rahway, New Jersey

ABSTRACT

Purpose: We analyze patterns of prostate growth in men diagnosed with benign prostatichyperplasia (BPH) and treated with placebo during 4 years, and determine which baselineparameters were the strongest predictors of growth.

Materials and Methods: A total of 3,040 men were enrolled in the 4-year randomized, placebocontrolled Proscar Long-Term Efficacy and Safety study. Of these men a subgroup of 10%underwent pelvic magnetic resonance imaging prostate volume measurement at baseline andyearly thereafter. Absolute and percent volume changes during 4 years were calculated in the 164placebo treated men in the subgroup. The ability of age, baseline prostate volume and prostatespecific antigen (PSA) to predict prostate growth in placebo treated patients was assessed bymultiple linear regression analyses, receiver operator characteristics curves, and evaluations ofgrowth stratified by tertiles of baseline serum PSA and decades of life.

Results: In placebo treated patients a steady increase in mean plus or minus standard deviationprostate volume from year to year was noted (2.5 6 6.1, 4.9 6 6.8, 6.4 6 8.5 and 7.2 6 8.8 ml. at years 1,2, 3 and 4, respectively). Mean volume changes at 4 years ranged from 29 to 130 ml. Mean percentchange from baseline ranged from 12.5% to 16.6% for men 50 to 59 years old to those 70 to 79 years old.Baseline serum PSA was a strong predictor of growth with 7.4% to 22.0% change at 4 years from thelowest to highest PSA tertiles. Annualized growth rates from baseline were 0.7 ml. per year for PSA 0.2to 1.3, 2.1 for PSA 1.4 to 3.2 and 3.3 for PSA 3.3 to 9.9 ng./ml. Multiple linear regression analysis showedthat serum PSA was a stronger predictor of prostate growth than age or baseline prostate volume. All but1 man with baseline serum PSA greater than 2.0 ng./ml. had prostate growth during 4 years, and 32.6%of men with serum PSA less than 2.0 exhibited a decrease in volume.

Conclusions: Serum PSA is a stronger predictor of growth of the prostate in placebo treated patientsthan age or baseline prostate volume. Since prostate volume is a risk factor for acute urinary retentionand the need for BPH related surgery, the ability of PSA to predict prostate growth may be an importantfactor when considering individual treatment options for BPH. Such use of PSA represents a shift inparadigm away from focusing solely on symptoms of BPH toward a more comprehensive approach withconsideration of predicting and preventing risk factors of BPH related outcomes.

KEY WORDS: prostatic hyperplasia, prostate-specific antigen, magnetic resonance imaging, prostate

Benign prostatic hyperplasia (BPH) is a common disorderin aging men.1 Histological evidence of BPH is found in 60%

of men 60 to 69 years old, the majority of whom will eventu-ally have lower urinary tract symptoms. Disease severity iscommonly measured with quantitative symptom frequencyand severity assessments,2, 3 which measure the impact ofdisease and symptoms on activities of daily living,4 and dis-

Accepted for publication July 30, 1999.Presented at annual meeting of American Urological Association,

San Diego, California, May 30–June 4, 1998.* Financial interest and/or other relationship with Merck.† Financial interest and/or other relationship with Glaxo, Syn-

thelabo, Abbott, U.S. Surgical, Vida Med, Dornier, Urologix and Pfizer.‡ Financial interest and/or other relationship with Serono,

Unimed, Biotek, Wyeth Ayerst, Organon and Smith Kline.§ Merck, West Point, Pennsylvania.

Editor’s Note: This article is the first of 5 published in thisissue for which category 1 CME credits can be earned. In-structions for obtaining credits are given with the questionson pages 288 and 289.

0022-5347/00/1631-0013/0THE JOURNAL OF UROLOGY® Vol. 163, 13–20, January 2000Copyright © 2000 by AMERICAN UROLOGICAL ASSOCIATION, INC.® Printed in U.S.A.

13

ease specific quality of life assessment tools.5 An indirectmeasure of disease severity is peak urinary flow rate which isuseful to assess the degree of bladder outlet obstruction,although not specific enough to differentiate a weakeningdetrusor muscle and outlet obstruction.6–10 Although theterm BPH suggests that the prostate is at the heart of thepathophysiological condition, it has long been believed thatprostate volume alone is not useful to assess disease severity,determine the need for treatment and/or help choose amongtherapeutic interventions.11 The Agency for Health Care Pol-icy and Research Guidelines for the diagnosis and treatmentof BPH and the International Consultation on BPH did notrecommend prostate volume assessment.5, 12 Nonetheless, ithas been shown that prostate volume increases with advanc-ing age,13 and prostate size and shape often dictate treat-ment. For example, open prostatectomy is the surgical pro-cedure of choice when the prostate gland is enlarged, whiletransurethral resection of the prostate is the preferred sur-gical alternative in most other cases.

Recently it was recognized that baseline prostate volumeassessed during the initial evaluation of patients presentingwith lower urinary tract symptoms may have important ram-ifications. A meta-analysis of all available data from placebocontrolled, randomized finasteride trials of 1-year durationdemonstrated that therapeutic response to treatment withthe 5a-reductase inhibitor finasteride is volume dependent,with larger prostates exhibiting better response.14 In addi-tion, recent longitudinal community based studies have in-dicated that prostate volume is a strong predictor of episodesof acute urinary retention. Men with a baseline prostatevolume of greater than 30 ml. are 3 times as likely to haveacute urinary retention compared to those with a volume ofless than 30 ml.15 In the 4-year placebo controlled ProscarLong-Term Efficacy and Safety (PLESS) trial prostate vol-ume and PSA were strong predictors of future episodes ofacute urinary retention as well as the need for BPH relatedsurgery in placebo treated patients with BPH.16

Because of the increasing risk of acute urinary retentionand need for surgery with increasing baseline prostate vol-ume, knowing whether an individual presenting with symp-toms of BPH has a lesser or greater tendency for furtherprostate growth with time is of interest to clinicians andpatients. Such information would help decide whether toinitiate treatment or continue watchful waiting, and alsochoose among therapeutic interventions. Baseline PSA, pros-tate volume and age were evaluated as risk factors for futureprostate growth in placebo treated patients from the PLESStrial.

MATERIALS AND METHODS

Details of the overall study design, and the primary effi-cacy and safety results have been previously published.17, 18

A total of 3,040 men with clinical BPH diagnosed on the basisof moderate to severe symptoms, a peak urinary flow rate ofless than 15 ml. per second with a voided volume of at least150 ml. and an enlarged prostate gland on digital rectalexamination were enrolled in a 4-year study of finasterideversus placebo. Men receiving a-blockers or antiandrogensand those with a history of chronic prostatitis, recurrenturinary tract infections, prostate or bladder cancer or sur-gery, or serum PSA greater than 10 ng./ml. were excludedfrom study. Men with serum PSA between 4.0 and 9.9 ng./ml.

had to have a negative prostate biopsy before enrollment.The present analysis is based only on placebo treated pa-tients.

The study was approved by the Institutional Review Boardat all 95 participating centers and all men gave writteninformed consent. After a 1-month, single-blind placebolead-in men were randomly assigned to receive placebo or 5mg. finasteride daily. Symptoms, bothersomeness, adverseevents and flow rates were assessed every 4 months. SerumPSA was measured every 4 months in year 1 and every 8months during subsequent years at a central laboratory us-ing the Hybritech* assay. Physical examinations, and rou-tine hematological and serum chemistry studies were per-formed yearly. In a 10% subset of all patients at 13 centersmagnetic resonance imaging (MRI) and measurement ofprostate volume were performed at baseline and annuallythereafter. MRI was reviewed for quality assurance purposesduring the trial, and then read at the end of the study by thecentral radiologist (J. B.) who was blinded to treatment allo-cation and time of imaging (that is baseline or followup).17

All statistical and receiver operating characteristics (ROC)curve analyses were performed using computer software.Simple linear and multiple linear regression analyses wereperformed, with p ,0.05 considered significant.

RESULTS

A total of 164 patients were available at baseline with amean age of 63 6 6.1 years (range 50 to 77) and a meanbaseline prostate volume of 54.6 6 25.9 gm. (range 14 to 222)on MRI (table 1). Mean baseline serum PSA was 2.7 6 2.1ng./ml. (range 0.2 to 9.4). Of the patients 50 were 50 to 59years old, 92 were 60 to 69 years old and 22 were older than70 years (table 1). Patients dropped out of the study toundergo BPH related surgery, to receive other active medicaltherapy (for example finasteride or a-blockers), or because ofworsening symptoms, lack of improvement, adverse events,logistical reasons or lost to followup.18 Baseline and followupdata for all parameters were available for 145 men at 1, 125at 2, 107 at 3 and 91 at 4-year followup. A total of 83 men hadcomplete sets of prostate volume and serum PSA at baselineand all followup times. A steady increase in prostate volumewas noted from a mean baseline of 54.6 6 25.9 gm. (fig. 1).Mean increase in absolute volume was 2.5 6 6.1 ml. at 1,4.9 6 6.8 at 2, 6.4 6 8.5 at 3 and 7.2 6 8.8 at 4 years, whichrepresent a percent increase of 5.2 6 11.8%, 9.0 6 11.1%,11.8 6 14.5% and 14.1 6 17.5%, respectively.

Absolute and percent prostate volume changes were strat-ified by baseline PSA (tertiles) and age (decade of life) (table1). Volume changes from baseline at the 4 followup times byPSA (tertile) and decade of life are listed in table 2. Volumechanges ranged from 2.8% for men 50 to 59 years old to 6.4%for those 70 to 79 years old at year 1 and from 12.0% for those50 to 59 years old to 16.6% for those 70 to 79 years old at year4. Absolute volume changes ranged from 1.1 ml. for men 50 to59 years old to 3.1 for those 70 to 79 years old at year 1, andfrom 5.8 to 9.6 at year 4 for these age groups (fig. 2, A). Theannualized growth rate was 1.45 ml. per year for men 50 to59 years old and 2.4 for those 70 to 79 years old. Absolutevolume changes stratified by PSA ranged from 4.2% (1.1 ml.)to 6.5% (3.9) for the lowest to the highest PSA tertile at year

* Hybritech, Inc., San Diego, California.

TABLE 1. Baseline data on all patients and stratified by decade of life

All Pts. Age 50–50 Yrs. Age 60–69 Yrs. Age Older Than 70 Yrs

No. pts. 164 50 92 22Mean baseline age 6 SD (range) 63 6 6.1 (50 to 77) 55.7 6 2.8 64.9 6 2.8 72.1 6 2.1Mean baseline (ml.) prostate vol. 6 SD (range) 54.6 6 25.9 (14 to 222) 50.0 6 22.2 (23 to 146) 56.2 6 28.1 (14 to 222) 58.9 6 24.6 (30 to 117)Mean baseline (ng./ml.) PSA 6 SD (range) 2.7 6 2.1 (0.2 to 9.4) 2.2 6 1.8 (0.2 to 7.6) 2.9 6 2.1 (0.3 to 9.4) 3.1 6 2.3 (1.0 to 9.4)

SERUM PROSTATE SPECIFIC ANTIGEN PREDICTS PROSTATE GROWTH14

1 but from 7.4% (2.8 ml. per year to 22.0% (13.3), respec-tively, at year 4 (fig. 2, B). Mean percent growth at 4 yearsvaried little among age groups compared to differences ingrowth rates among patients when stratified by PSA tertiles.

The relationships among baseline age, prostate volumeand baseline serum PSA are shown in figure 3. The estimatedcorrelation between age and baseline prostate volume wasmodest (correlation coefficient r 5 0.17, r2 5 0.027, p 5 0.04,fig. 3, A), and the typical modest increase of serum PSA withadvancing age, which led to the development of age specificreference ranges for PSA, was apparent (r 5 0.19, r2 5 0.037,p 5 0.01, fig. 3, B). By far the strongest relationship wasbetween baseline prostate volume and PSA (r 5 0.53, r2 50.28, p ,0.001, fig. 3, C). This relationship is best expressedas a double logarithmic presentation (fig. 3, D). Similarly, weevaluated the relationship between baseline parameters and

percent volume change with time (fig. 4). There was littlerelationship between age and percent volume change (r 50.09, r2 5 0.007, p 5 0.42, fig. 4, A). The relationship betweenbaseline prostate volume and percent volume change waspoor (r 5 0.014, r2 5 0.0002, p 5 0.9, fig. 4, B). The relation-ship between baseline prostate volume and absolute volumechange at year 3 was stronger (r 5 0.32, r2 5 0.1, p 5 0.003),which is a reflection of the impact of baseline volume on thepotential absolute changes in volume. However, the stron-gest relationship existed between baseline serum PSA, andabsolute (r 5 0.35, p 5 0.001) and percent prostate volumechange (r 5 0.31, p 5 0.004, fig. 4, C).

Of 46 patients 15 (32.6%) who had baseline PSA less than2.0 ng./ml. had a net decrease in prostate volume during 4years. In contrast, only 1 patient who had baseline PSAgreater than 2.0 ng./ml. had a decrease while all others hadan increase in prostate volume. Using a cutoff of 5 ml. ormore to represent significant growth during 4 years, a ROCcurve analysis was performed to determine which of thebaseline parameters of age, prostate volume and serum PSAbest identified men destined to experience such growth. Thearea under the curve representing the probability of correctlydistinguishing men with and without significant prostatevolume growth was 0.584 for age, 0.719 for baseline pros-tate volume and 0.787 for baseline serum PSA (fig. 5).

Multiple linear regression was performed using absolute orpercent volume change at 4 years as the dependent variable,and age, baseline volume and baseline PSA as independentvariables. PSA was the strongest predictor of absolute changesin prostate volume (age p 5 0.88, volume p 5 0.54, PSA p,0.001) and percent changes in prostate volume (age p 5 0.58,volume p 5 0.1, PSA p 5 0.001) with time. In contrast, age andbaseline volume contributed only marginally to the model. Datawere also analyzed by serum PSA tertiles at baseline (fig. 6).While patients in the second (PSA 1.4 to 3.2 ng./ml.) and third(3.3 to 12) tertiles had substantial volume increases during the4-year followup, those with baseline PSA from 0 to 1.3 (lowesttertile) had small volume increases.

FIG. 1. Absolute volume changes during 4 years of followup with mean (thick line), median (thin line), 25th to 75th percentile (box), 10thto 90th percentile (whiskers) and individual outliers.

TABLE 2. Absolute and percentage changes from baseline inprostate volume stratified by PSA tertiles and decade of life at 12

to 48 months of followup

VariableMean 6 95% CI

12 Mos. 24 Mos. 36 Mos. 48 Mos.

Absolute changes by PSA:0.2–1.3 1.1 6 1.6 2.5 6 1.2 1.6 6 1.6 2.8 6 1.81.4–3.2 2.5 6 1.8 5.5 6 2.3 8.7 6 3.0 8.3 6 3.53.3–9.4 3.9 6 2.1 7.0 6 2.7 10.6 6 3.7 13.3 6 4.2

% Changes by PSA:0.2–1.3 4.2 6 3.7 6.8 6 3.3 4.8 6 4.3 7.4 6 4.81.4–3.2 5.1 6 3.3 9.4 6 3.4 15.7 6 4.6 16.2 6 7.43.3–9.4 6.5 6 3.7 11.3 6 4.0 16.7 6 5.7 22.0 6 6.9

Absolute changes by age:50–59 Yrs. 1.1 6 2.1 4.5 6 2.7 4.4 6 3.6 5.8 6 2.660–69 Yrs. 3.0 6 1.4 5.5 6 1.6 6.8 6 2.1 7.5 6 3.170–77 Yrs. 3.1 6 2.8 3.7 6 2.9 9.8 6 4.1 9.6 6 4.9

% Changes by age:50–59 Yrs. 2.8 6 3.9 7.9 6 3.4 8.1 6 5.3 12.0 6 5.060–69 Yrs. 6.2 6 2.7 10.1 6 3.0 12.8 6 4.0 14.8 6 6.470–77 Yrs. 6.4 6 5.1 7.8 6 4.4 16.3 6 7.2 16.6 6 9.1

SERUM PROSTATE SPECIFIC ANTIGEN PREDICTS PROSTATE GROWTH 15

DISCUSSION

To our knowledge this study is the longest randomizedclinical trial in men with BPH to date which documentslongitudinal changes in prostate volume growth with time inplacebo treated patients. The trial was designed using mod-ern MRI and quality controls with a central reviewer blindedto time and treatment assignment to provide for a high

degree of reproducibility and confidence in the data.17 The164 placebo treated patients followed for up to 4 years dem-onstrated an overall annualized prostate growth rate of 1.8ml. per year, ranging from 1.45, 1.88 and 2.40 for men 50 to59, 60 to 69 and 70 to 79 years old, respectively. These growthrates are higher than those described in the Olmsted Countystudy in randomly selected community dwelling men (0.4 ml.

FIG. 2. Mean percent prostate growth from baseline by year and decade of life (A), and PSA tertile (B)


per year in men 40 to 60 years old and 1.2 in men 60 to 80years old).19 This difference is most likely due to the fact thatall men in the present study had clinically diagnosed BPH,while the Olmsted County study is based on a communitypopulation sample, suggesting that growth in those alreadydiagnosed with BPH is greater than in unselected commu-nity dwelling men. Interestingly, prostate growth in thepresent cohort of men with BPH occurred steadily, with anincrease of 5.2% at 1, 9.0% at 2, 11.8% at 3 and 14.1% at 4years.

Although they were almost eliminated from the routineevaluation of BPH,12 prostate size assessment and consider-ation of future prostate growth have recently generated re-newed interest for several reasons. Prostate size as well asurinary flow rates, symptoms and age have been found topredict health care seeking behavior for urinary symptoms inmen.20 In addition, a stronger correlation between the vol-ume of the transition zone of the prostate, and symptomseverity, peak urinary flow rate and invasive pressure flowstudies has been described.21 A most important contributionto our understanding of the importance of prostate size wasthe Olmsted County study by Jacobsen et al which demon-strated a 3-fold increase in the risk of acute urinary retentionin men with prostate volume greater than 30 ml. at base-line.15 While data from the Olmsted County study are basedon community dwelling men randomly selected without re-gard to symptoms of BPH, results from the PLESS study alsoindicated a strong association between prostate volume orPSA, and the risk of acute urinary retention and a need forBPH related surgery.16 The risk of either of these 2 compli-cations occurring during 4 years in placebo treated patientsranged from 8.9% to 22.0% when stratified by increasing

prostate volume (by tertiles in our MRI subset) and from7.8% to 19.9% when stratified by increasing serum PSA (bytertiles of the entire study population). Compared to all otherurological measures and assessment tools, such as symptomscores, flow rate, residual urine volume and so forth, serumPSA and prostate volume were the most powerful predictorsof spontaneous acute urinary retention in placebo treatedpatients with an area under the curve of 0.70 and 0.81,respectively.16 These observations refocused attention onprostate size as an important predictor of BPH related out-comes and stressed the need for understanding which pa-tients with BPH are at high risk for future increasing pros-tate volume growth and, by inference, future BPH relatedoutcomes.

Previous placebo controlled trials have provided limiteddata on prostate volume growth due to shorter followup,more variable ultrasound measurements and less rigorousstandardization than used in our study. The 2-year transrec-tal ultrasound prostate volume data are available on 197 of707 patients with moderate symptoms of BPH in the 2-yearrandomized, controlled trial at 59 centers in 5 Scandinaviancountries.22 Prostate volume increased from a baseline of41.7 by 11.5 ml. for an annualized growth rate of 5.75 ml. inthese patients. Similar growth patterns have also been re-ported from the 2-year placebo controlled, randomized finas-teride trials conducted in Canada.23 However, except forthese trials few data are available on prostate growth withtime in patients treated with watchful waiting or placebo. Inplacebo controlled a-blocker trials prostate volume assess-ment was not typically done as no effect on prostate size isexpected from this therapy.24 When assessing all of theseother data sets the sample sizes and variability associated

FIG. 3. Relationships at baseline between age and baseline prostate volume (A, r 5 0.17, p 5 0.04), age and baseline serum PSA (B, r 50.193, p 5 0.01), baseline prostate volume and baseline PSA (C, r 5 0.534, p ,0.001), and baseline prostate volume versus baseline serumPSA expressed as double logarithmic linear relationship (D). r2 Values derived from regression analyses.


with transrectal ultrasonography at multiple centers withouta central reviewer must be considered.25

Our objective was to identify the key predictors of prostategrowth with time since they would likely be key predictors ofBPH related outcomes as well. Thus, we performed regres-sion analyses between various baseline parameters and thepercent changes at 4 years. The relationships between base-line prostate volume or age and percent changes at 4 yearswere weak, while those of absolute change and baseline pros-tate volume were stronger. In contrast, annualized percentincreases in prostate volume in randomly selected commu-nity men followed for 5 years were highly dependent onbaseline prostate volume (r 5 0.75, unpublished data). In thecurrent 4-year controlled clinical trial prostatic enlargementon digital rectal examination and symptoms of BPH wereentry criteria, whereas distribution of prostate volumes atbaseline in the Olmsted County community based study wasbroader.

The strongest relationship was identified between baselinePSA and percent volume changes with time. Observed aver-age percent growth from baseline ranged from 7.4% to 22%when stratified by PSA tertile but only from 12.5% to 16.6%by decade of life. Similar relationships held true at 36 monthsbut differences at 12 and 24 months were less evident. Av-erage annualized growth rate was 0.7 ml. per year in menwith the lowest PSA tertile (0.2 to 1.3 ng./ml.), which issimilar to that seen in randomly selected community dwell-ing men, compared to 2.1 ml. in those with the second PSAtertile (1.4 to 3.2) and 3.3 ml. in those with the highestPSA tertile (3.3 to 9.4). Figure 6 suggests that lower urinarytract symptoms have been similar between men with thelowest and highest PSA tertiles but the underlying disease

FIG. 5. ROC curve for baseline PSA and prostate volume to pre-dict growth defined as net increase of 5 ml. from baseline during 4years. Areas under curve for prostate volume (0.719) and PSA (0.787)are not significantly different (p 5 0.270).

FIG. 4. Relationship between age and percent volume change (A, r 5 0.09, p 5 0.42), baseline prostate volume and percent volume change(B, r 5 0.014, p 5 0.9) and baseline serum PSA versus percent volume changes (C, r 5 0.31, p 5 0.004) at 4 years. Additional lines in Cindicate zero growth line (horizontal) and 2.0 ng./ml. PSA baseline (vertical). All but 1 patient with PSA greater than 2.0 ng./ml. had growthduring 4 years. r2 Values derived from regression analyses.


process in the prostate may have been considerably different.Differences regarding histological composition (stromal ver-sus PSA producing glandular epithelial tissue) may be sus-pected of being at the core of such differences.

There are multiple important implications of these find-ings for the clinical practice of urology. The relationshipbetween serum PSA, and baseline symptom severity andpeak urinary flow rate in men with BPH has been shown tobe weak. Prostate volume has been shown to be a predictor ofBPH related outcomes, such as risk of retention and sur-gery,15, 16 and rates of prostatic growth (unpublished data).Due largely to its relationship with prostate volume, serumPSA in the PLESS trial was strongly predictive of acuteurinary retention and the need for BPH related surgery16 aswell as prostatic growth. With its greater accuracy it may bean even stronger predictor. It is recommended that men olderthan 50 years have annual physical examinations, whichoften include serum PSA for prostate cancer screening. Thus,consideration should be given to the use of PSA, alreadyreadily available and routinely obtained, to predict futureprostatic growth and risk for long-term negative BPH relatedoutcomes.

Despite the strong correlation between serum PSA andprostate size, the estimate of prostate size for any given PSAvalue still retains some variability. For example, if a patientpresents at age 60 years with a PSA of 1.0, a prostate volumeof 33 ml. and a symptom severity score of 10 points, watchfulwaiting may be considered a reasonable alternative. Basedon PSA and prostate volume, the risk of disease progressionwith the possibility of retention or need for surgery is likelyto be extremely small. However, if the same patient has ahigh symptom score, one might consider treatment witha-blockers to be a reasonable option with a high probability ofreducing symptom severity quickly. On the other hand, if apatient presents at age 60 years with a PSA of 3.3, a prostatevolume of 45 or 50 ml. and a moderate to severe AmericanUrological Association symptom severity score, one mightconsider treatment with finasteride for several reasons. The5a-reductase inhibition has been shown to be most effectiveto improve symptoms compared to placebo in men with largerprostate glands.14 Additionally, prostate shrinkage is in-duced with finasteride, thereby reducing the risk of retentionand need for surgery.

Clinical decision making becomes more interesting whenan otherwise healthy man presents at age 65 years with aPSA of 6.0 and a prostate of about 60 ml. on transrectalultrasonography but a sextant biopsy is negative for cancer.The patient has a depressed urinary flow rate but only mod-est symptoms. Assuming an annualized prostatic growth ratein patients with a PSA in the range of 5.5 ng./ml., he mighthave a 55% increase in volume during the next 10 years,resulting in a volume of approximately 90 ml. By recognizingwhich patients are at risk for significant prostate growthwith time (for example those with PSA greater than 1.3

ng./ml.), one may be able to assess better which symptomaticpatients may be best treated with finasteride to arrest pros-tate growth, and reduce the risk of surgery and reten-tion.16, 18 In these patients it is unknown whether a-blockerswill affect the future risk of surgery or retention. On theother hand, in symptomatic men with low PSA who are likelyto have little prostate growth with time and are at low riskfor retention or needing surgery, finasteride may not be ben-eficial as the risk of complications is low, and an a-blockermight be considered more appropriate for symptomatic im-provement.24, 26

The limitations of this study are noteworthy. Of the 3,040patients originally enrolled in the PLESS trial only 10% hadprostate volume assessed by MRI and only 164 in the placeboarm had prostate volume assessed. Of those patients only 83had complete data sets at each time in the study. Fortu-nately, however, these patients were reasonably well strati-fied from a low value to a PSA of 10 ng./ml., and equally wellstratified by decade of life, thus allowing conclusions to bedrawn. In addition, the average growth rate when calculatedbased on an intention to treat last value carried forwardapproach, including data on patients who dropped out of thestudy, was similar to the analysis of those who completedthe study (data not shown). Another limitation is that pa-tients were selected based on moderate to severe symptomsof BPH as well as an enlarged prostate on digital rectalexamination. Therefore, these data may not be applicable tomen without symptoms or enlarged glands.

The translation of clinical research results into daily clinicalpractice is often difficult to achieve. Even more difficult is trans-lating what amounts to a paradigm shift in the assessment andtreatment of men with lower urinary tract symptoms and BPH.While in the past prostate volume was considered unimportantand the only goal of therapy was to improve BPH symptoms,recent data have demonstrated that prostate volume and serumPSA are strong predictors of adverse outcomes, such as urinaryretention and the need for surgery.15,16 We demonstrated thatserum PSA is an even better key to understanding future pros-tate growth potential. By reviewing serum PSA, which is usu-ally obtained routinely, physicians can evaluate future poten-tial for development of detrimental BPH related outcomes.Using PSA beyond the current use as a screening tool for pros-tate cancer, physicians now have the opportunity to counselpatients regarding future risk of BPH related outcomes and toincorporate preventive medicine into the therapeutic paradigm.A simple PSA can provide the key information on future risk ofprostate volume growth, and risk factors of retention and sur-gery in individual patients, and can help therapeutic manage-ment of BPH.

CONCLUSIONS

The 164 placebo treated patients of the 4-year randomizedPLESS trial who underwent baseline and yearly MRI pros-

FIG. 6. Mean percent changes in prostate volume during 4 years stratified by serum PSA tertile. Numbers below panels represent numberof patients available for followup at each time. Vertical bars represent standard error.


tate volume measurement had continual increases in volumewith time. Prostate volume is an important predictor of fu-ture development of acute urinary retention and the need forBPH related surgery. Although prostatic growth was relatedto baseline prostate volume, the strongest predictor of futureprostate growth was baseline serum PSA. Thus, serum PSAis a useful predictor to assess future prostate growth and therisk of future BPH related outcomes, and to help make ther-apeutic decisions for individuals with BPH. Such thinkingreflects a shift from focusing solely on symptoms and flowrate changes toward a more comprehensive approach withpreventative considerations of care of patients with BPH.

REFERENCES

1. Guess, H. A., Arrighi, H. M., Metter, E. J. et al: Cumulativeprevalence of prostatism matches the autopsy prevalence ofbenign prostatic hyperplasia. Prostate, 17: 241, 1990.

2. Barry, M. J., Fowler, F. J., O’Leary, M. P. et al: The AmericanUrological Association symptom index for benign prostatichyperplasia. J Urol 148: 1549, 1992.

3. Barry, M. J. and O’Leary, M. P.: Advances in benign prostatichyperplasia. The developmental and clinical utility of symp-tom scores. Urol Clin North Am, 22: 299, 1995.

4. Barry, M. J., Fowler, F. J., Jr., O’Leary, M. P. et al: Measuringdisease-specific health status in men with benign prostatichyperplasia. Med Care, 33: AS145, 1995.

5. Cockett, A. T. K., Khoury, S., Aso, Y. et al: The 3rd InternationalConsultation on Benign Prostatic Hyperplasia (BPH). ChannelIslands: Scientific Communication International Ltd., 1996.

6. Abrams, P. H.: Prostatism and prostatectomy: the value of urineflow rate measurement in the preoperative assessment foroperation. J Urol 117: 70, 1977.

7. Jensen, K. M., Jorgensen, J. B. and Mogensen, P.: Urodynamicsin prostatism. I. Prognostic value of uroflowmetry. ScandJ Urol Nephrol, 22: 109, 1988.

8. Jensen, K. M., Jorgensen, J. B. and Mogensen, P.: Urodynamicsin prostatism. IV. Search for prognostic patterns as evaluatedby linear discriminant analysis. Scand J Urol Nephrol, suppl,114: 84, 1988.

9. Jensen, K. M., Jorgensen, J. B. and Mogensen, P.: Urodynamicsin prostatism. II. Prognostic value of pressure-flow study com-bined with stop-flow test. Scand J Urol Nephrol, suppl, 114:72, 1988.

10. Chancellor, M. B., Blaivas, J. G., Kaplan, S. A. et al: Bladderoutlet obstruction versus impaired detrusor contractility: therole of uroflow. J Urol, 145: 810, 1991.

11. Barry, M. J., Cockett, A. T., Holtgrewe, H. L. et al: Relationshipof symptoms of prostatism to commonly used physiological andanatomical measures of the severity of benign prostatic hyper-plasia. J Urol, 150: 351, 1993.

12. McConnell, J. D., Barry, M. J., Bruskewitz, R. C. et al: Benignprostatic hyperplasia: diagnosis and treatment. Clinical Prac-tice Guideline, In: No. 8. Rockville, MD: Agency for Health

Care Policy and Research, Public Health Service, U.S. Depart-ment of Health and Human Services, 1994.

13. Oesterling, J. E., Jacobsen, S. J., Chute, C. G., et al: The estab-lishment of age specific reference ranges for prostate specificantigen. J Urol, 149: 510A, abstract 1188, 1993.

14. Boyle, P., Gould, A. L. and Roehrborn, C. G.: Prostate volumepredicts outcome of treatment of benign prostatic hyperplasiawith finasteride: meta-analysis of randomized clinical trials.Urology, 48: 398, 1996.

15. Jacobsen, S. J., Jacobson, D. J., Girman, C. J. et al: Naturalhistory of prostatism: risk factors for acute urinary retention.J Urol, 158: 481, 1997.

16. Roehrborn, C. G., McConnell, J. D., Lieber, M. et al: Serumprostate specific antigen concentration is a powerful predictorof acute urinary retention and need for surgery in men withclinical benign prostatic hyperplasia. Urology, 53: 473, 1999.

17. Bonilla, J., Stoner, E., Grino, P. et al: Intra- and interobservervariability of MRI prostate volume measurements. Prostate,31: 98, 1997.

18. McConnell, J. D., Bruskewitz, R., Walsh, P. et al: The effect offinasteride on the risk of acute urinary retention and the needfor surgical treatment among men with benign prostatic hy-perplasia. N Engl J Med, 338: 557, 1998.

19. Rhodes, T., Girman, C. J., Jacobsen, S. J., et al: Longitudinalmeasures of prostate volume in a community-based sample:3.5 year followup in the Olmsted County study of health statusand Urinary symptoms among men. J Urol, 153: 301A, ab-stract 291, 1995.

20. Jacobsen, S. J., Girman, C. J., Guess, H. A. et al: Do prostate sizeand urinary flow rates predict health care-seeking behavior forurinary symptoms in men? Urology, 45: 64, 1995.

21. Kaplan, S. A., Te, A. E., Pressler, L. B. et al: Transition zoneindex (TZI) as a method of assessing benign prostatic hyper-plasia: correlation with symptoms, uroflow and detrusor pres-sure. J Urol, 154: 1764, 1995.

22. Andersen, J. T., Ekman, P., Wolf, H. et al: Can finasteridereverse the progress of benign prostatic hyperplasia? A two-year placebo-controlled study. The Scandinavian BPH StudyGroup. Urology, 46: 631, 1995.

23. Nickel, J. C., Fradet, Y., Boake, R. C. et al: Efficacy and safety offinasteride therapy for benign prostatic hyperplasia: results ofa 2-year randomized controlled trial (the PROSPECT Study).Can Med Assoc J, 155: 1251, 1996.

24. Roehrborn, C. G., Oesterling, J. E., Auerbach, S. et al: Effective-ness and safety of terazosin versus placebo in the treatment ofmen with symptomatic benign prostatic hyperplasia in theHYCAT study. Urology, 47: 159, 1996.

25. Collins, G. N., Raab, G. M., Hehir, M. et al: Observer variabilityand reproducibility of transrectal ultrasound in the meas-urement of prostate volume. Ultrasound Med Biol 21: 1101,1995.

26. Lepor, H., Williford, W. O., Barry, M. J. et al: A randomizedplacebo controlled clinical trial of the safety and efficacy oftherapies in men with clinical benign prostatic hyperplasia.N Engl J Med, 335: 533, 1996.


Serum PSA is Strong Predictor of Future Prostate Growth in Men With BPH

Documents

Transcript of Serum PSA is Strong Predictor of Future Prostate Growth in Men With BPH