Early detection of prostate cancer in men with prostatism and intermediate prostate-specific antigen levels

ADULT UROLOGY

ELSEVIER

EARLY DETECTION OF PROSTATE CANCER IN MEN WITH PROSTATISM AND INTERMEDIATE PROSTATE-SPECIFIC ANTIGEN LEVELS H.-P. SCHMID, V. RAVERY, T. BILLEBAUD, M. TOUBLANC, L.A. BOCCON-GIBOD, J.F. HERMIEU, V. DELMAS, AND L. BOCCON-GIBOD

ABSTRACT Objectives. To determine the prevalence of prostate cancer and the diagnostic ability of prostate-specific antigen density (PSAD) in men with lower urinary tract symptoms and intermediate prostate-specific antigen (PSA) levels of 4 to 10 ng/mL (Hybritech assay) and to assess the clinical significance of prostate cancers in men who subsequently underwent radical prostatectomy. Methods. Six systematic transrectal ultrasonography (TRUS)-guided biopsies were performed in 153 symptomatic men (mean age, 66 years) with PSA levels between 4 and 10 ng/mL, irrespective of digital rectal examination (DRE) findings. Prostate volume was also determined by TRUS and PSAD was calculated (serum PSA divided by volume of entire prostate). The rate of positive biopsies was compared with PSAD (more than 0.2 versus less than 0.2), DRE (positive versus negative), and patient's age (more than 70 years versus 61 to 70 versus 60 or less). Eligible patients with cancer underwent radical prostatectomy, and specimens were analyzed with regard to clinical significance of tumors. Results. The overall cancer detection rate was 29.4%. PSAD and DRE, but not age, were both statistically significant in differentiating negative from positive biopsies. Independent of DRE findings, mean PSAD was significantly lower in biopsy-negative cases (0.29 _+0.17 and 0.25 _+0.16) than it was in positive cases (0.34 _+0.17 and 0.35 ___0.15). Half of the patients who underwent radical prostatectomy had pathologically nonorgan-confined disease (more than pT3), 34% had positive margins, and 47% had a Gleason score of 8 to 10. PSAD, DRE, and age could not predict outcome, probably owing to the small number of patients. However, the number of positive biopsies ( 1 or 2 versus 3 to 6) was able to predict pathologic stage. Conclusions. In men with lower urinary tract symptoms and intermediate PSA levels of 4 to 10 ng/mL, PSAD may be useful in the selection of patients for prostate biopsy. Carcinomas found using these criteria are of clinical importance. UROLOGY® 47: 699-703, 1996.

creening for and early detection of prostate cancer are primarily based on digital rectal exSamination (DRE) and prostate-specific antigen (PSA), of which the serum marker has proved to be superior to the physical examination. ~ Transrectal ultrasonography (TRUS) is not a first-time diagnostic tool; rather, it is used to guide the needle for prostate biopsies if one of the just-mentioned procedures raises the suspicion of cancer.

From the Departments of Urology and Pathology, CHU Bichat, and the Department of Pathology, Hopital Trousseau, Paris, France Reprint requests: Hans-Peter Schmid, M.D., Service d'Urologie, CHU Bichat, 46 rue Henri Huchard, 75018 Paris, France Submitted: October 19, 1995, accepted (with revisions): December 22, 1995 COPYRIGHT 1996 BY ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED

In general, there is consensus that a positive DRE or a PSA level above 10 ng/mL (Hybritech assay) needs further evaluation by TRUS. However, a considerable diagnostic dilemma exists when a patient has a negative DRE and a PSA value between 4 and 10 ng/mL. Whereas the diagnostic ability of DRE cannot be improved, novel approaches to the use of PSA for prostate cancer detection have been introduced recently. In a community-based population, Oesterling et al. 2 found that serum PSA levels were directly correlated with patient age and volume of the prostate, the latter being also directly related to age. They, therefore, established age-specific reference ranges for PSA in healthy individuals. Compared with the currently recommended reference range of 0.0 to 4.0 ng/mL, these age-spe0090-4295/96/$15.00 PII S 0 0 9 0 - 4 2 9 5 ( 9 6 ) 0 0 0 1 8 - 0

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cific reference ranges s h o u l d lead to an increased sensitivity for p r o s t a t e cancer in y o u n g e r m e n a n d to a better specificity in older m e n . Benson a n d colleagues 3 i n t r o d u c e d the c o n c e p t of PSA d e n s i t y ( P S A D ) . This p a r a m e t e r is determ i n e d b y dividing the c o n c e n t r a t i o n of s e r u m PSA ( n g / m L ) b y the v o l u m e of the entire p r o s t a t e as m e a s u r e d b y TRUS. Since cancer p r o d u c e s m o r e s e r u m PSA per v o l u m e o f tissue t h a n benign p r o static h y p e r p l a s i a ( B P H ) , PSAD s h o u l d be higher in cancer patients a n d s h o u l d e n h a n c e the specificity of PSA alone. Nevertheless, the clinical value of PSAD r e m a i n s a m a t t e r of c o n t r o v e r s y . Serial PSA m e a s u r e m e n t s over time have b e e n p r o p o s e d for the d e t e r m i n a t i o n of PSA velocity ( i n c r e a s e of PSA levels per y e a r ) 4 or PSA d o u b l i n g t i m e P Both c o n c e p t s m i g h t be able to distinguish BPH f r o m cancer, since, in addition to p r o d u c i n g less s e r u m PSA per v o l u m e of tissue, BPH has a slower g r o w t h rate t h a n cancer. H o w e v e r , m o n i toring of velocity a n d d o u b l i n g time d e p e n d o n patient's f o l l o w - u p a n d are n o t applicable at o n e given p o i n t in time. In s e r u m , PSA is f o u n d either in the free f o r m or, m o r e c o m m o n l y , c o m p l e x e d to the serine p r o tease i n h i b i t o r a l p h a l - a n t i c h y m o t r y p s i n . 6'7 It has b e e n s h o w n that the p r o p o r t i o n of PSA existing as a P S A - a l p h a l - a n t i c h y m o t r y p s i n c o m p l e x is h i g h e r in patients w i t h p r o s t a t e cancer t h a n in those w i t h BPH. Research assays have b e e n d e v e l o p e d that can specifically m e a s u r e these c o m p l e x e s , w h i c h m a y i m p r o v e the specificity of PSA as a m a r k e r for early d e t e c t i o n of p r o s t a t e cancer. T h e a i m s of this s t u d y w e r e to estimate the rate of p r o s t a t e cancer in patients w i t h a critical PSA r a n g e of 4 to 10 n g / m L a n d to evaluate the clinical significance of PSAD for the d e t e c t i o n of p r o s t a t e c a r c i n o m a in this group. In addition, it was int e n d e d to c o m p a r e the p a t h o l o g i c features of positive p r o s t a t e biopsies a n d radical p r o s t a t e c t o m y s p e c i m e n s in patients s u b m i t t e d to radical surgery. MATERIAL AND METHODS For the period April 1988 to February 1995, 153 unselected patients with serum PSA values of 4.0 to 10.0 ng/mL (Hybritech assay), evaluation by DRE, and six systematic TRUSguided prostate biopsies were identified retrospectively from our database. These patients did not represent a screening population but were seen at our outpatient clinic for various lower urinary tract symptoms. The mean age of the 153 men was 66 years (range, 43 to 91 ). Blood samples were drawn on an ambulatory basis and prior to any prostate manipulation. Serum PSA determination was performed using a polyclonal radioimmunoassay (modified Yang Proscheck) in 129 patients and a monoclonal immunoradiometric assay (Hybritech) in the other 24 patients. For the purpose of this report, all polyclonal values were converted to the corresponding values of the monoclonal Hybritech assay. DRE was done with the patient in the dorsal lithotomy position and was considered to be either pos700

itive (nodularity, induration, asymmetrical firmness ) or negative for cancer. TRUS was performed by two urologists (V.R., T.B.) with the patient in the left lateral decubitus position. The Bruel and Kjaer 1846 console equiped with a 7 MHz transducer was used. Prostate gland volume was determined automatically by measuring the circumference and the diameter of the prostate at its greatest width in the transverse plane using the ellipse method. Volumes ranged from 13 to 171 cc (mean, 52.1 _+ 29.6; median, 38). PSAD was calculated by dividing serum PSA value by the entire ultrasound prostate volume. Six systematic TRUS-guided biopsies were performed with the automatic Biopty system and an 18 gauge needle? Whenever a hypoechoic lesion was detected, the needle was directly guided to sample this area, in addition to the six systematic biopsies. The Gleason grading system was used for histologic assessment. The sum of the primary and secondary Gleason grades (Gleason score) was calculated. In this group of patients with intermediate PSA values we compared, according to DRE findings, the rate of positive biopsies, the Gleason score, the number of positive biopsies, PSAD, and the age of the patients. All mean and median values were determined and the differences were compared for their statistical significance using the chi-square test, the Student's t test, and the Wilcoxon test. Of the 45 patients in whom prostate cancer was detected, 32 subsequently underwent radical prostatectomy (RP) by either the retropubic or the perineal approach. Thirteen patients received androgenic blockage therapy because of their ages. For those patients, we assessed postoperatively the Gleason score, the rate of capsule perforations (defined as the presence of tumor beyond the prostate capsule of the specimen), and the rate of positive surgical margins (defined as the presence of tumor at the inked limits of the gland, suggesting that the removal was incomplete). Postoperative biologic progression, defined as a postoperative PSA level greater than 0.1 ng/mL (hypersensitive assay), could not be assessed owing to the limited mean follow-up of these patients.

RESULTS T h e overall cancer d e t e c t i o n rate in 153 m e n w i t h s e r u m PSA levels b e t w e e n 4.0 a n d 10.0 n g / m L was 29.4%. T h e rate was i n d e p e n d e n t of patient's age, a l t h o u g h there was a slight t e n d e n c y t o w a r d increasing c a n c e r p r e v a l e n c e w i t h increasing age. DRE a n d PSAD w e r e b o t h statistically significant in differentiating negative f r o m positive biopsies ( T a b l e I ) . Table II s h o w s PSAD values in DRE-negative a n d DRE-positive patients. All the differences w e r e statistically significant ( P ~ 0 . 0 1 ) . A PSAD of 0.2 app e a r e d to be the t h r e s h o l d level for o p t i m a l differentiation b e t w e e n cancer a n d b e n i g n disease. This o p t i m a l PSAD t h r e s h o l d of 0.2 was validated in an i n d e p e n d e n t g r o u p of 317 s y m p t o m a t i c m e n . 9 Table III s h o w s m e a n values of age, PSA, a n d PSAD a c c o r d i n g to DRE a n d p r e s e n c e of c a n c e r at biopsy. Irrespective of DRE findings, m e a n PSAD was l o w e r in b i o p s y - n e g a t i v e cases (0.29 and 0.25 ) t h a n it was in positive cases (0.34 a n d 0.35 ) w i t h a statistical significance (P ~ 0 . 0 5 , W i l c o x o n test). UROLOGY® 47 (5), 1996

Presence of cancer at biopsy according to age, digital rectal examination (DRE), and PSA density TABLE

I.

Patient Characteristics

No. Men (n = 153)

Age (yr) >70 61-70 -<60 DRE Positive Negative PSA density* ->0.2 <0.2

No. Cancer (%) (n = 45)

35 86 32

1 1 (31.4%)* 25 (29.1%)* 9 (28.1%)*

46 107

22 (47.8%)* 23 (21.5%)*

99 48

33 (33.3%) § 8 (16.7%) §

P not significant. t P <0.01. $ Six patients without determination of PSA density of whom 4 had cancer. § P <0.05. *

II. Ability of PSA density to detect the presence of cancer, according to digital rectal examination

TABLE

Digital Rectal Examination

PSA Density

Negative (n = 107)

Positive (n = 46)

No. Men

No. Cancer (%)

->0.2 <0.2

71 33 104"

18 (25.4%) 4 (12.1%) 22*

->0.2 <0.2

28 15 43 t

15 (53.6%) 4 (26.7%) 19*

Three patients without determination of PSA density, of whom 1 had cancer. t Three patients without determination of PSA density, of whom all 3 had cancer.

*

Table IV shows pathologic features of radical prostatectomy specimens for the 32 patients submitted to surgery. Two patients were Stage pT1 (6%), 14 were Stage pT2 (44%), and 16 were

TABLE

III.

Biopsy I

Positive n = 46 (30.1%)

COMMENT The rate of detection of prostate cancer depends on several factors. First, it increases with the age of the patient. 1° In one study, 100 men who presented with minor disturbances of micturition and a negative DRE underwent six systematic TRUS biopsiesll: in patients more than 70 years old, the prevalence was 24.0%; for men between 60 and 70 years, it was 11.0%; and for men less than 60 years old, it was 8.5%. Lepor et al. 12 reported on a cohort of males who presented with clinically significant prostatism following exclusion of carcinoma of the prostate. The overall cancer detection rate in this particular population was 6.7%, but only 26.7% of the prostate cancers were diagnosed in men less than 70 years of age. In the present series, however, there was no significant increase of positive biopsies with age (Table I), probably owing to the fact that the range of PSA (4 to 10 ng/mL) was predetermined. 9 Second, the detection rate may depend on the population studied. In men with prostatism, cancer prevalence would be greater than in randomly chosen males, that is, a screening population, despite conflicting data. 1°'13 Finally, it is conceivable that the detection rate is related to the number of biopsies performed. Six systematic biopsies might provide optimal histologic information. 14'15

Mean value of age, PSA, and PSA density according to digital rectal examination and presence of cancer at biopsy

Digital Rectal Examination Negative n = 107 (69.9%)

Stage pT3 (50%). Positive margins were present in 11 cases (34%). Seminal vesicle invasion was found in 3 patients (9%). The Gleason score of the radical prostatectomy specimen was 5 in i case (3%), 6 in 1 case (3%), 7 in 15 cases (47%), 8 in 8 cases (25%), and 9 in 7 cases (22%). No statistically relevant statement can be made with regard to PSAD, owing to the low numbers of patients with a PSAD less than 0.2 who underwent surgery. The number of positive biopsies is statistically discriminant (0.02 < P < 0.05) for pT stage.

Negative n = 84 (54.9%) Positive n = 23 (15%) Negative n = 25 (15.7%) Positive n = 22 (14.4%)

Age* (yr)

PSA* (ng/mL)

PSA Density*

64.9 _+ 7.9

6.5 ~ 1.8

0.29 _ 0.17

66.5 ± 9.0

7.0 ± 1.9

0.34 ± 0.17

69.5 ± 7.8

6.3 _ 2.0

0.25 _~ 0.16

66.2 _+ 5.6

6.4 _ 2.1

0.35 ± 0.15

* Values are means +. SD.

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TABLE IV.

Features of radical prostatectomy specimens according to digital rectal examination, PSA density, and number of positive biopsies

Test Results PSA density <0.2 _>0.2 ND Digital rectal examination Negative Positive No. of positive biopsies

Features of Radical Prostatectomy Specimen Pathologic Stage Margins Gleason Score -~pT2 _>pT3 Negative Positive -<7 _>8 (n= 16) (n= 16) (n= 21) (n= 11) (n= 17) (n= 15) 2 (100%) 13 (48%) 1

0 (0%) 14 (52%) 2

2 (100%) 17 (63%) 2

0 (0%) 10 (37%) 1

1 (50%) 15 (56%) 1

1 (50%) 12 (44%) 2

9 (56%) 7 (44%)

7 (44%) 9 (56%)

11 (69%) 10 (62%)

5 (31%) 6 (38%)

11 (69%) 6 (38%)

5 (31%) 10 (62%)

1-2

10 (71%)

4 (29%)

10 (71%)

4 (29%)

8 (57%)

6 (43%)

3-6

6 (33%)

12 (67%)

11 (61%)

7 (39%)

9 (50%)

9 (50%)

KeY: N D = not d e t e r m i n e d .

In the present study, we performed six systematic sextant biopsies in men with prostatism and PSA values in the critical range of 4 to 10 ng/mL, irrespective of age, DRE findings, and PSAD. The overall cancer detection rate was 29.4%. Both DRE and PSAD were useful in enhancing the positive predictive value (PPV) of a serum PSA in the intermediate range (Table I). Cancer detection rates in men with prostatism and PSA levels between 4 and 10 ng/mL range from 11% to 34%. 10"12'16-18 Data, from the literature and from the present series, indicate that cancer detection rates in patients with a PSA of 4 to 10 ng/mL and a positive DRE are important (38% to 40%) and, therefore, justify the performance of biopsies. However, there is a diagnostic dilemma in men with a negative DRE, for w h o m detection rates range from 14% to 21.5%, lO.12,16,19,2obearing in mind the high number of patients and the specific costs of the TRUS diagnostic biopsy. In other words, 5 to 7 patients have to undergo biopsies so that 1 case of cancer can be detected. Although the morbidity (infection, bleeding) of six systematic TRUS biopsies is as low as 0.5% to 2% 20 and does not represent a limiting factor, the question of cost-effectiveness has yet to he answered. To optimize the PPV of PSA, several authors have suggested the use of the PSAD. Our own resuits demonstrate that the PPV for a PSAD of 0.2 or greater is twice as high as the PPV for a PSAD below 0.2 (Table I), irrespective of the DRE findings (Table II). Benson et al., 3 in men with a normal DRE, reported that the mean PSAD was 0.279 +_ 0.13 in positive biopsies and 0.204 ___ 0.10 in negative biopsies, this difference being statistically significant. Our mean PSAD values were somewhat higher, but the difference was also significant (Table III ). 702

W h e n there is a normal DRE and a PSA between 4 and 10 ng/mL, Babaian et al. 17 recommend determination of PSAD in all patients and performance of biopsies in those for w h o m the PSAD is 0.16 or greater. In our study, PPV was 25% for a PSAD of 0.2 or more and 12.1% for a PSAD less than 0.2 in this critical group of DRE-negative patients (Table II). These findings suggest that PSAD is useful for better selection of patients with a normal DRE for biopsies. However, one has to bear in mind that determination of prostate volume by TRUS is very operator dependent 18 and entails additional expense. Analysis of the radical prostatectomy specimens revealed that only 50% of tumors were still organ confined (Table IV); these results are in keeping with those in the literature. However, at this point the results from screening studies show that in the intermediate PSA range of 4 to 10 ng/mL, 53% to 70% of tumors are organ confined. 1°'16m'22 The rate of pT2 tumors in patients with prostatism is about in the same range. A close analysis of the age-specific rates of pT2 may reveal whether pT2 tumors are more frequent in the younger men (50 to 60 years old). DRE was not helpful in predicting pathologic stage, but the number of positive biopsies ( 1 or 2 versus 3 to 6) could distinguish between organconfined and locally advanced tumors (Table IV) ; this has been assumed previously, j4 In conclusion, determination of PSAD is useful in symptomatic men who present with intermediate PSA values of 4 to 10 ng/mL and a negative DRE. The prostate cancers that were detected in this setting and were removed by radical prostatectomy are of clinical importance. It will be interesting to learn whether the determination of free PSA, which is less expensive and less time UROLOGY® 47 (5), 1996

consuming than TRUS, will further enhance the P P V o f PSA a l o n e .

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