Comparison of Digital Rectal Examination and Serum Prostate Specific Antigen in the Early Detection of Prostate Cancer: Results of a Multicenter Clinical Trial of 6,630 Men

0022-5347 /94/1515-1283$03.00/0 Vol. 151,

THE JOURNAL OF UROLOGY Copyright© 1994 by AMERICAN UROLOGICAL ASSOCIATION, INC.

COMPARISON OF DIGITAL RECTAL EXAMINATION AND SERUM PROSTATE SPECIFIC ANTIGEN IN THE EARLY DETECTION OF PROSTATE CANCER: RESULTS OF A MULTICENTER CLINICAL TRIAL OF 6,630 MEN WILLIAM J. CATALONA,* JEROME P. RICHIE, FREDERICK R. AHMANN, M'LISS A. HUDSON, PETER T. SCARDINO, ROBERT C. FLANIGAN, ,JEAN B. DEKERNION, TIMOTHY L. RATLIFF, LOUIS R. KAVOUSSI, BRUCE L. DALKIN, W. BEDFORD WATERS, MICHAEL T. MACFARLANE AND PAULA C. SOUTHWICK From the Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri; Division of Urologic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Divisions of Urology and Hematology-Oncology, University of Arizona College of Medicine and Tucson Veterans Affairs Medical Center, Tucson, Arizona; Scott Department of Urology, Baylor College of Medicine, Houston, Texas; Department of Urology, Loyola University Medical Center, Chicago, Illinois; and Division of Urology, UCLA School of Medicine, Los Angeles and Department of Clinical Research, Hybritech Incorporated, San Diego, California

ABSTRACT To compare the efficacy of digital rectal examination and serum prostate specific antigen (PSA) in the early detection of prostate cancer, we conducted a prospective clinical trial at 6 university centers of 6,630 male volunteers 50 years old or older who underwent PSA determination (Hybritech Tandom-E or Tandem-R assays) and digital rectal examination. Quadrant biopsies were performed if the PSA level was greater than 4 µg,/L or digital rectal examination was suspicious, even if transrectal ultrasonography revealed no areas suspicious for cancer. The results showed that 15% of the men had a PSA level of greater than 4 µg./1., 15% had a suspicious digital rectal examination and 26% had suspicious findings on either or both tests. Of 1,167 biopsies performed cancer was detected in 264. PSA detected significantly more tumors (82%, 216 of 264 cancers) than digital rectal examination (55%, 146 of 264, p = 0.001). The cancer detection rate was 3.2% for digital rectal examination, 4.6% for PSA and 5.8% for the 2 methods combined. Positive predictive value was 32% for PSA and 21 % for digital rectal examination. Of 160 patients who underwent radical prostatectomy and pathological staging 114 (71 %) had organ confined cancer: PSA detected 85 (75%) and digital rectal examination detected 64 (56%, p = 0.003). Use of the 2 methods in combination increased detection of organ confined disease by 78% (50 of 64 cases) over digital rectal examination alone. If the performance of a biopsy would have required suspicious transrectal ultrasonography findings, nearly 40% of the tumors would have been missed. We conclude that the use of PSA in conjunction with digital rectal examination enhances early prostate cancer detection. Prostatic biopsy should be considered if either the PSA level is greater than 4 µg.jl. or digital rectal examination is suspicious for cancer, even in the absence of abnormal trans rectal ultrasonography findings. KEY WORDS:

antigens, neoplasm; prostatic neoplasms; ultrasonography; diagnosis

Prostate cancer is the most common visceral cancer in American men and the second leading cause of cancer deaths. 1 Unfortunately, the majority of prostate cancers have spread beyond the gland when first diagnosed using the conventional detection method, digital rectal examination. 2- 4 Prognosis is poor 5 and treatment options are limited to palliative therapy with late stage disease. 6 With no curative therapy for advanced prostate cancer available currently or in the foreseeable future, the most promising alternative for improving the prognosis of patients with prostate cancer is to enhance early detection. Recent reports show that prostate specific antigen (PSA) detects a significant number of tumors missed by the digital rectal examination. 4 • 7• 8 This multicenter, controlled clinical trial was conducted to compare the efficacy of digital rectal examination and PSA in the detection of prostate cancer, and to determine if PSA would significantly increase the detection rate of potentially curable, organ confined disease when added Accepted for publication October 15, 1993. Supported by a grant from Hybritech Incorporated and Grant P 20 CA 58193 from the National Cancer Institute. * Requests for reprints: 660 South Euclid, Box 8109, St. Louis, Missouri 63110.

to digital examinationo To our knowledge, this is the first large scale study in which PSA and digital rectal examination were evaluated as independent tests, and biopsy was based upon either a suspicious digital examination alone or elevated PSA levels (greater than 4 µg./1.) alone, without requiring a suspicious finding on transrectal ultrasonography. SUBJECTS AND METHODS

Subjects. Between May 1991 and September 1992, 6,630 male volunteers 50 years old or older were enrolled into this prospective study at 6 medical centers. Each center enrolled between 593 and 2,348 subjects, with 4 of the 6 centers enrolling more than 1,000 subjects each. Subjects were recruited from the community at large via advertisements in the lay media and they were excluded from enrollment if there was a history of prostate cancer, acute prostatitis or urinary tract infection. All study sites obtained Institutional Review Board approval of the study protocol and written informed consent was obtained from all study subjects. This planned multi-institutional cross-sectional study differs from the longitudinal PSA based screening protocol previously reported by Catalona et al. 4 Study design. All men underwent determination of serum

1283

1284

PROSTATE SPECIFIC ANTIGEN VERSUS RECTAL EXAMINATION

PSA concentration (Hybritech Tandem-E PSA immunoenzymetric assay or Tandem- R PSA immunoradiometric assay) and digital rectal examination. All digital examinations were performed by urological surgeons or medical oncologists who were experienced with examination of prostate cancer patients. Blood samples were obtained before or at least 1 week after digital rectal examination. All men were asked if they did or did not have the following signs or symptoms of prostate disease: hematuria, hematospermia, dysuria, frequency, urgency, weak urine stream or bone pain. Men with normal PSA levels (0 to 4 µg./1.) and normal digital rectal examination findings or digital findings that were abnormal but benign (including enlargement with a normal consistency) were not further evaluated. If the PSA concentration was elevated (greater than 4 µg./1.) and/or digital rectal examination was suspicious for cancer (including induration, asymmetry or irregularity suggesting cancer) the subjects underwent 4 (quadrant) transrectal ultrasound guided needle biopsies (2 apex and 2 base). Suspicious transrectal ultrasonography findings (including hypoechoic areas in the posterior peripheral zone) were recorded but ultrasound results were not used to determine whether a biopsy was performed. All 4 quadrants were biopsied even if no suspicious areas were present on transrectal ultrasonography or digital rectal examination. The men were given an enema containing sodium phosphate and sodium biphosphate, as well as antimicrobial prophylaxis. The prostate was scanned in the transverse and sagittal planes with the subject in the left lateral decubitus position. We used sonographic criteria for cancer as previously described4 in our evaluations. The ultrasound examinations and biopsies were performed by urological surgeons or radiologists who were experienced in prostatic sonography. A variety of different ultrasound equipment was used at the different sites. We used an automatic biopsy gun fitted with an 18 gauge biopsy needle, and a 4-core rather than a 6-core systematic biopsy technique to minimize the morbidity in patients with normal findings on digital rectal examination and ultrasonography. However, according to standard medical practice, we did perform additional biopsies directed at palpable abnormalities and hypoechoic areas. If cancer was detected, clinical tumor stage was recorded. For subjects treated with radical prostatectomy or lymphadenectomy, the pathological tumor stage was recorded. A summary flow chart of the study design is shown in figure 1. Staging. Clinical staging consisted of digital rectal examination, determination of serum acid phosphatase levels and radioisotope bone scanning with confirmatory radiography, if necessary. The same method of acid phosphatase determination was not used at all institutions. The tumor was categorized as organ confined if it was judged to be confined to the prostate and advanced if it extended through the capsule. Pathological staging was performed as described previously. 3 The staging system was similar to clinical staging, except that it was verified histologically. There was no central pathological analysis. However, staging was standardized to the extent that the protocol required all principal investigators to perform pathological staging to determine whether there was extracapsular tumor extension or cancerous surgical margins as described previously. 3 Briefly, bladder neck and urethral margins were removed from the prostate and sent as separate specimens. If the histological examination revealed cancer, these margins were considered positive. The prostate was fixed and painted with india ink. The specimen was "breadloafed" in 2 to 5 mm. segments and fixed overnight in formalin solution. Then, hematoxylin and eosin stained sections were examined for the peripheral surgical margins. In addition, longitudinal sections through the base of the seminal vesicles and the apex of the prostate were examined. If tumor extended to an inked margin, the margin was considered positive. Pa-

Male Voll.llteers

>

50 years

- (Both Tests) PSA and DRE +

Exit Study

(Either Test)

•

BX -

TRUS and Biopsy (BX)

Exit Study

BX+

•

•

Radical Prostatectomy

Alternative Treatment

Exit Study

• Pathologic Stage FIG. 1. Summary flow chart of study design. BX-, biopsy negative. BX+, biopsy positive. TRUS, transrectal ultrasound. DRE, digital rectal examination.

tients who had extracapsular extension of tumor or those in whom the resected prostatic tissue contained cancer at the margins were considered to have advanced disease. Statistical analysis. We used t tests for age comparisons and chi-square statistics for all other comparisons. Logistic regression analyses were performed, and odds ratios were calculated to determine the relative contributions of PSA, digital rectal examination, transrectal ultrasonography, symptoms and patient age to cancer prediction. Relative sensitivity analyses 9 were used to determine the comparative effectiveness of PSA and digital rectal examination if these tests had been used alone rather than in conjunction with each other. Positive predictive value, defined as the per cent of subjects with cancer when the detection method indicates a suspicious finding, was calculated for digital rectal examination, PSA, and combinations of digital rectal examination, PSA and transrectal ultrasonography findings. RESULTS

Subjects. The demographic and clinical characteristics of the subjects are shown in table 1. Mean patient age was 62.8 years (range 50 to 96, median 63). We included men in their eighties and nineties in the study population so as not to discriminate against elderly men who were concerned about prostate cancer and desired to be screened; however, these men comprised less than 2% of the study population and, overall, only 9 of 129 (7%) had cancer (9 of 28, or 32% of those biopsied). None was treated with radical prostatectomy. The majority of subjects were white (92%). At entry, approximately half of the men (53 %) had at least 1 symptom of prostatism (including frequency, urgency, weak urinary stream, dysuria, hematuria or hematospermia) or bone pain. Serum PSA levels and digital rectal examination results. The

1285

PROSTATE SPECIFIC ANTIGEN VERSUS RECTAL EXAMINATION TABLE

L Demographics and clinical characteristics

TABLE

4. Positive predictive value (per cent of subjects with cancer if

detection method is suspicious)

No.(%)

Results Category

Age distribution (yrs.): 50 to 59 60 to 69 70 to 79 80 or more Race distribution: White Black Hispanic Oriental/Asian Other Symptoms of prostatism: Absent Present

2,381 2,959 1,161 129

(35.9) (44.6) (17.5) (1.9)

6,098 194 164 121 53

(92.0) (2.9) (2.5) (1.8) (0.8)

Digital Rectal Examination

Pos.

3,130 (47.2) 3,500 (52.8)

2. PSA distribution and digital rectal examination results in 6,630 patients No.(%)

PSA (µg./1.): 0.0 to 4.0 4.1 to 9.9 10 or more Digital rectal examination: Not suspicious for Ca Suspicious for Ca Normal on both tests (PSA 0.0 to 4.0, digital rectal examination not suspicious) Suspicious on 1 or both tests (PSA more than 4.0 or digital rectal examination suspicious)

TABLE

5,647 (85.2) 809 (12.2) 174 (2.6) 5,648 (85.2) 982 (14.8) 4,920 (74.2) 1,710 (25.8)

3. Comparison of subjects with suspicious digital rectal

examination or PSA results No. PSA (%) Digital Rectal Examination

PSA (µg./ml.) More than 4.0 4.1 to 9.9 10.0 or more

The mean age ± standard deviation of the 6,630 patients enrolled was 62.8 ± 7.7 years.

TABLE

Transrectal Ultrasound

Pos. (more than 4.0 µg./1.)

Neg. (0 to 4.0 µg./1.)

Totals

Pos. (suspicious) Neg. (not suspicious)

255 (3.8) 728 (11.0)

727 (11.0) 4,920 (74.2)

982 5,648

Total No. subjects

983

5,647

6,630

distributions of PSA levels and digital rectal examination results are shown in table 2. Approximately 15% of the men had serum PSA levels of greater than 4.0 µg./1., 15% had suspicious findings on digital rectal examination and 26% had suspicious results on either or both tests (table 3). There was limited overlap in test results: only 255 men (4 %) tested suspicious with both methods, compared to 728 (11 %) with PSA alone and 727 (11 %) with digital rectal examination alone. Biopsy rate. Overall, 1,167 of 6,630 enrolled subjects (18%) underwent biopsy: 686 (10%) based on an elevated PSA level and 683 (10%) based on a suspicious digital rectal examination. Approximately 1,167 of the 1,710 subjects (68%) who had a suspicious PSA result or digital rectal examination underwent biopsy. Subjects who did not undergo biopsy chose to delay or refuse biopsy for health or personal reasons, or they were lost to followup. Mean subject ages for the biopsied versus not biopsied groups were 65.3 ± 7.3 years (standard deviation) versus 66.2 ± 7.8 years, respectively. Data on cases biopsied after a long delay are not included, since they may not be representative of the findings present at the time of this multicenter study. Biopsies were not performed in 261 of 809 men (32%) with a PSA level of 4.1 to 9.9 µg./1., 36 of 174 (21%) with levels of greater than 10 µg./1. and 299 of 982 (30%) with a suspicious digital rectal examination (table 4). Suspicious PSA or digital rectal examination results in the age groups of 50 to 59 years, 60 to 69 years, 70 to 79 years and 80 or more years were noted in 15%, 28%, 40% and 43% of men, respectively, and positive

Pos. Predictive No. Ca/No. Value(%) Biopsies 31.5 26.1 52.9

216/686 143/548 73/138

21.4

146/683

Pos. Pos. Pos. Pos.

4.0 or less More than 4.0 4.1 to 9.9 10.0 or more

10.0 48.5 40.8 69.1

48/481 98/202 60/147 38/55

Neg. Neg. Neg. Neg.

4.0 or less More than 4.0 4.1 to 9.9 10.0 or more

24.4 20.7 42.2

118/484 83/401 35/83

Pos. Pos. Pos. Pos.

Pos. Pos. Pos. Pos.

4.0 or less More than 4.0 4.1 to 9.9 10.0 or more

13.8 54.7 48.8 68.6

32/232 64/117 40/92 24/35

Pos. Pos. Pos. Pos.

Neg. Neg. Neg. Neg.

4.0 or less More than 4.0 4.1 to 9.9 10.0 or more

6.9 41.3 35.3 66.7

16/233 26/63 18/51 8/12

Neg. Neg. Neg. Neg.

Pos. Pos. Pos. Pos.

4.0 or less More than 4.0 4.1 to 9.9 10.0 or more

29.8 25.3 48.6

57/191 39/154 18/37

Neg. Neg. Neg. Neg.

Neg. Neg. Neg. Neg.

4.0 or less More than 4.0 4.1 to 9.9 10.0 or more

20.7 17.9 35.7

57/276 42/234 15/42

Pos.-suspicious for cancer. Neg.-not suspicious for cancer. * No biopsies in this category, in compliance with study protocol.

biopsies were noted in 19%, 22%, 27% and 32%, respectively. Biopsies were not performed in 30%, 31 %, 32% and 49% of men, respectively, and 71 %, 70%, 48% and 0%, respectively, were treated by surgery. In the event that a selection bias might have occurred, we compared the overall study positive predictive value for the 3 sites having the highest compliance rates (86%, 873 of 1,011 followup cases) to the positive predictive value for the 3 sites having low compliance rates (42%, 294 of 699 followup cases), and found that the positive predictive values were not significantly different (24% versus 20%, respectively, t test, p = 0.17). In addition, the overall calculated cancer detection rates are not significantly different when comparing the first 3 sites to the last 3 sites (6.0% versus 5.5%, respectively, t test, p = 0.37). Thus, any bias, if present, is not selective for the primary study end points. Cancer detection rate. We detected 264 cancers, and determined the calculated and the observed cancer detection rates for PSA, digital rectal examination and the 2 methods combined. We determined the calculated cancer detection rate by multiplying the number of subjects with suspicious results by the per cent of biopsied subjects with cancer, assuming that the rate would remain constant if all men with suspicious findings were biopsied. The overall calculated cancer detection rate was 5.8% for both tests, 4.6% for PSA alone and 3.2% for digital rectal examination alone. The observed cancer detection rate (that is the number of tumors detected divided by the number of subjects enrolled) was 4.0% for both tests, 3.3% for PSA alone and 2.2% for digital rectal examination alone. Comparison of PSA versus digital rectal examination for cancer detection. PSA detected significantly more tumors (82%, 216 of 264) than digital rectal examination (55%, 146 of 264, p <0.001). Of the cancers 118 (45%) were missed by digital rectal

1286

PROSTATE SPECIFIC ANTIGEN VERSUS RECTAL EXAMINATION

examination and detected solely by PSA, while 48 (18%) were missed by PSA and detected solely by digital examination. Thus, when the 2 methods were used in combination 118 additional cancers were detected, for an 81 % (118 of 146) increase over digital rectal examination alone (95% confidence interval 74 to 88%) and a 22% (48 of 216) increase over PSA alone (95 % confidence interval 17 to 28 %) . Logistic regression analysis showed that the following variables had a significant contribution in detecting prostate cancer: PSA (p = 0.0001), digital rectal examination (p = 0.0001), transrectal ultrasonography (p = 0.0004) and symptoms (p = 0.0378). The absence of symptoms was more predictive of cancer than the presence of symptoms. The contribution of patient age was not significant (p = 0.1687) due to the fact that once PSA, digital rectal examination, transrectal ultrasonography and symptom effects associated with age were eliminated, age alone was no longer a significant variable. The relative contribution of PSA was higher than that of any of the other variables. The odds ratios (and 95% confidence intervals) for PSA, digital rectal examination, transrectal ultrasonography, symptoms and patient age were 8.36 (5.38 to 12.98), 2.82 (1.93 to 4.13), 1.73 (1.26 to 2.36), 0.70 (0.51 to 0.96) and 1.02 (0.99 to 1.04), respectively. Per cent of total cancers detected by transrectal ultrasonography. Transrectal ultrasonography, when used to verify a suspicious digital rectal examination or PSA, missed 39% of the cancers. Positive predictive value. Table 4 and figure 2 show the positive predictive values for PSA, digital rectal examination, transrectal ultrasonography and suspicious or nonsuspicious combinations of these methods. The positive predictive value was significantly greater for a PSA level of greater than 4.0 ,ug./1. (32%) than for a suspicious digital rectal examination (21 %, p <0.0001). When PSA levels were greater than 4.0 µ,g./ 1. but digital rectal examination was not suspicious the positive predictive value was 24%. When digital rectal examination was suspicious but the PSA level was less than 4.0 µ,g./1. the positive

60

54.7

S5

50

45

40

Positive Predictive Value(%)

35

30

25

20

15

10

PSA>4

DRE(+)

PSA>4 DRE(-)

PSA<-4 DRE(+)

Method of Detect ion

PSA>4 DRE(+)

PSA>4 DRE(+) TRUS (+)

FIG. 2. Positive predictive value. DRE, digital rectal examination. TRUS, transrectal ultrasound. +,positive.-, negative.

predictive value was only 10%. When both were suspicious the positive predictive value was 49%. Addition of positive transrectal ultrasonography results slightly enhanced positive predictive value in most but not all situations (table 4). If digital rectal examination was suspicious but PSA and transrectal ultrasonography were not the positive predictive value was only 7%. In contrast, if the PSA was suspicious but digital rectal examination and transrectal ultrasonography were not the positive predictive value was 21 %. Differences in results were observed across centers, particularly in regard to the efficacy of digital rectal examination but the trends and conclusions regarding the relative predictive value of PSA and digital rectal examination for prostate cancer detection were the same at each site. PSA positive predictive values for prostate cancer detection were the same at each site, and ranged from 23 to 41 % across 6 sites, while digital rectal examination positive predictive values ranged from 12 to 27%. The PSA positive predictive value was always higher than that of the digital rectal examination by 7 to 22%. Transrectal ultrasonography and biopsy technique may contribute to variability. Symptoms and cancer. The presence of prostatic disease symptoms did not differentiate subjects with and without cancer. Cancer was noted in 144 of 667 biopsied men (22%) with versus 120 of 500 (24%) without symptoms. However, some symptoms were more predictive of cancer than others. The positive predictive value in men with hematuria (36%) or hematospermia (36%) was higher than that in men with dysuria (26%), frequency (22%), urgency (21%), weak urine stream (23%) or bone pain (21%) but these values were not significantly different (p = 0.745). Staging. Only 3 of the 264 patients (1 %) had clinical evidence of advanced disease. Of the 261 men with clinically localized cancer 162 (62%) selected radical prostatectomy (only 5 prostatectomy patients were older than 74 years). There were no significant differences between subjects who underwent surgery and those who did not in regard to PSA concentration (chisquare = 1.57, p = 0.46), digital rectal examination result (chisquare = 3.33, p = 0.19), number of positive biopsy quadrants (chi-square = 1.28, p = 0.73) or clinical stage (chi-square = 1.06, p = 0.79). However, patients who underwent surgery were significantly younger (median age 65 years) than those who did not (median age 70 years, t test, p <0.001). Overall, 114 of the 160 pathologically staged cancers (71 %) were organ confined. Of the 46 patients with advanced cancer 29 had microscopically positive margins, 13 had seminal vesicle invasion and 4 had pelvic lymph node metastases. The percentages of organ confined cancers detected by digital rectal examination at the 3 sites having the highest (86% followup) and lowest (42% followup) compliance rates were not significantly different: 57 of 100 (57%) versus 7 of 14 (50%), respectively (t test, p = 0.62). Also, the percentage of organ confined cancers detected by PSA at the first 3 sites was not significantly different from that detected at the latter 3 sites: 74 of 100 (74%) versus 11 of 14 (79%), respectively (t test, p = 0. 71). Thus, any bias, if present, is not selective for the detection of organ confined disease. Detection of organ confined cancers. PSA detected significantly more organ confined cancers (85 of 114, or 75%) than digital rectal examination (64 of 114, or 56%, p <0.003). Of the organ confined tumors 50 (44%) were missed by digital rectal examination and detected solely by PSA, and 29 (25%) were missed by PSA and detected solely by digital examination. Thus, when the 2 methods were combined, 50 additional organ confined tumors were detected, for a 78% (50 of 64 tumors) increase over digital rectal examination alone (95% confidence interval 67 to 89%) and a 34% (29 of 85) increase over PSA alone (95% confidence interval 24 to 44%). Logistic regression analysis showed that PSA (p = 0.0001), digital rectal examination (p = 0.0003) and transrectal ultra-

PROSTATE SPECIFIC ANTIGEN VERSUS RECTAL EXAl\UNATION

sonography (p = 0.004 7) had a significant contribution in detecting organ confined cancer. The contributions of symptoms (p = 0.0518) and patient age (p = 0.1764) were not significant. The relative contribution of PSA was higher than that of any of the other variables. The odds ratios (and 95% confidence intervals) for PSA, digital rectal examination, transrectal ultrasonography, symptoms and patient age, respectively, were 5.97 (3.37 to 10.57), 2.64 (1.57 to 4.42), 1.81 (1.18 to 2. 77), 0.70 (0.46 to 1.06) and 0.98 (0.95 to 1.01). The greater the PSA concentration, the less likely a cancer was to be organ confined (p <0.023). For PSA levels of Oto 4.0 µg./1., 4.1 to 9.9 µg./1., 10.0 to 19.9 µg./1. and 20.0 µg./1. or more, the percentage of men with organ confined cancer was 88%, 78%, 52% and 27%, respectively. However, 10 of the 19 subjects with advanced cancer in the 4.1 to 9.9 µg./1. range had relatively low PSA values of 4.1 to 6.0 µg./L Table 5 shows the per cent of subjects with pathologically organ confined cancer for PSA, digital rectal examination, transrectal ultrasonography and suspicious or nonsuspicious combinations of these methods. The cancers were organ confined in 78% of men with a PSA level of 4.1 to 9.9 µg./1. but only 45% in those with a PSA of 10 µg./1. or more. Of the men with a suspicious digital rectal examination 70% had organ confined cancer. The effect of transrectal ultrasonography results on stage prediction was inconsistent and did not have additive predictive value. Effects of patient age. A detailed analysis of the effects of patient age on the results of screening is beyond the scope of this report and has been described previously. 10 The older patients had up to a 4-fold higher rate of elevated serum PSA levels and nearly a 3-fold higher rate of suspicious digital rectal examination findings. The positive predictive values of PSA ranged from 30% in younger patients to 38% in older patients, TABLE 5.

Pathological stage (per cent of subjects with organ confined cancer) Results Category

No. Organ Confined Ca/No. Surgeries Confined Ca With Pathological Stage

% With Organ

Digital Rectal Transrectal Examination Ultrasound

PSA (µg./1.) More than 4.0 4.1 to 9.9 10.0 or more

Pos.

66.9 77.6 45.2

85/127 66/85 19/42

69.6

64/92

Pos. Pos. Pos. Pos.

4.0 or less More than 4.0 4.1 to 9.9 10.0 or more

87.9 59.3 67.6 45.5

29/3 35/59 25/37 10/22

Neg. Neg. Neg. Neg.

4.0 or less More than 4.0 4.1 to 9.9 10.0 or more

73.5 85.4 45.0

50/68 41/48 9/20

86.4

Pos. Pos. Pas. Pos.

Pos. Pos. Pos. Pos.

4.0 or less More than 4.0 4.1 to 9.9 10.0 or more

55.8 60.0 50.0

19/22 24/43 15/25 9/18

Pos. Pos. Pos. Pos.

Neg. Neg. Neg. Neg.

4.0 or less More than 4.0 4.1 to 9.9 10.0 or more

90.9 73.3 83.3 33.3

10/11 11/15 10/12 1/3

Neg. Neg. Neg. Neg.

Pos. Pos. Pos. Pos.

4.0 or less More than 4.0 4.1 to 9.9 10.0 or more

76.5 76.9 75.0

26/34 20/26 6/8

Neg. Neg. Neg. Neg.

Neg. Neg. Neg. Neg.

4.0 or less More than 4.0 4.1 to 9.9 10.0 or more

69.7 95.5 18.1

23/33 21/22 2/11

Pos.-suspicious for cancer. Neg.-not suspicious for cancer.

* No biopsies in this category, in compliance with study protocol.

1287

and the positive predictive values of digital rectal examination ranged from 17% in younger patients to 38% in older patients. Radical prostatectomy and serious tumors. The majority of cases (148 of 160 tumors, or 93%) exhibited the histological features frequently associated with serious disease, that is advanced stage or organ confined but moderately or poorly differentiated, or organ confined but involving 2 to 4 quadrants (multifocal or large volume). Only 12 of the 160 pathologically staged tumors (8%) were organ confined, well differentiated and involved only 1 quadrant. The pathological stage and histological tumor grade for PSA, digital rectal examination and transrectal ultrasonography result categories are shown in table 6. Only 3 patients had clinically advanced disease. The test results were stage C2, negative digital rectal examination, suspicious transrectal ultrasound and a PSA of 66 µg./1. in 1; stage DO, negative digital rectal examination, unknown ultrasound and a PSA of 20 µg./1. in 1, and stage D2, suspicious rectal examination and ultrasound, and a PSA of 66 µg./1. in 1. DISCUSSION

The primary objective of this multicenter, prospective, controlled clinical trial was to compare the efficacy of digital rectal examination and serum PSA in the detection of prostate cancer. The study results show that PSA detected significantly more of the total tumors (82%) than were detected by digital rectal examination (55%). Approximately 45% of the lesions were detected by PSA and not digital rectal examination, while 18% were detected by digital rectal examination and not PSA. When the 2 methods were combined an 81 % increase in cancer detection was noted over digital rectal examination alone. In addition to percentage of tumors detected, another important parameter in evaluating cancer detection methods is the positive predictive value, that is the per cent of patients actually having cancer when the detection method indicates a suspicious finding. The positive predictive value is particularly important because a higher value means that fewer biopsies would be performed needlessly. The results of this study show the positive predictive value for PSA (32%) to be significantly higher than that for digital rectal examination (21%). The positive predictive value was 24 % when PSA was suspicious but digital rectal examination was not, only 10% when digital rectal examination was suspicious but PSA was not and 49% when both tests were suspicious. An elevated PSA concentration provides cancer risk information that otherwise would not be available. For example, if a physician had no information about a patient, all that would be known is that the prostate cancer risk is 5.8%, which is the cancer incidence in elderly men. However, if the PSA level is known to be greater than 4.0 µg./1. the risk of cancer increases to 32%. If digital rectal examination is suspicious and the PSA level is greater than 10.0 µg./1. the cancer risk is nearly 70%. Cancer risk percentages obtained in this study for various combinations of PSA, digital rectal examination and transrectal ultrasonography results are shown in table 4 and figure 2. These percentages may be used as a guide in discussions with patients regarding the risk of cancer being present given certain detection test results. For ethical reasons, none of the men with normal digital rectal examination and PSA findings underwent biopsy. Therefore, we have no data concerning false-negative results. Previous studies suggest that the cancer detection rate would be low. For example, Vallancien et al biopsied 34 men with normal PSA and digital rectal examination findings and found no cancer. 11 Similarly, Colberg et al biopsied 111 men with PSA levels of 2.8 to 4.0 µg./1. and normal digital rectal examination findings, and found only 8 tumors. 12 We biopsied 68% of the men with a suspicious PSA or digital rectal examination result. Compliance is a problem with a protocol that calls for a transrectal needle biopsy. In a similar screening study only 56% of the men with suspicious PSA

1288

PROSTATE SPECIFIC ANTIGEN VERSUS RECTAL EXAMINATION TABLE 6.

Pathological staging and grading of cancer in 160 operations

Results Category Digital Rectal Examination

Transrectal Ultrasound

Pathological Stage

PSA (µg./1.)

No. Surgeries

Organ Confined

Grade* No. Serious Well Moderately Poorly Cat/Total(%) Differentiated Differentiated Differentiated

Advanced

Al A2 Bl B2 Cl C2 DO Dl D2 Pos.

or

More than 4.0 4.1 to 9.9 10.0 or more

Pos.

160

2

13 29 70 29 13

0

4

0

32

105

17

148/160 (92.5)

85 42

2 0

11 16 37 15 2 2 15 10

4 9

0 0

0 4

0 0

13 7

63 23

7 9

80/85 (94.1) 42/42 (100.0)

92

0

0 18 46 18

9

0

1

0

23

55

12

0 0 0

0 11 18 4 0 6 19 10 0 1 9 4

0 2 7

0 0 0

0 0 1

0 0 0

12 7 4

19 25 11

1 4 7

26/33 (78.8) 35/37 (94.6) 22/22 (100.0)

5 6

2 2

0 0

0 3

0 0

6 3

38 12

3 2

45/48 (93.8) 20/20 (100.0)

Pas. Pas. Pas.

4.0 or less 4.1 to 9.9 10.0 or more

33 37 22

Neg. Neg. Neg.

4.0 or less 4.1 to 9.9 10.0 or more

+ 48 20

2 0

11 10 18 2 1 6

83/92

(90.2)

Pos. Pos. Pas.

Pas. Pas. Pas.

4.0 or less 4.1 to 9.9 10.0 or more

22 25 18

0 0 0

0 0 0

7 12 4 11 1 8

3 9 3

0 1 5

0 0 0

0 0 1

0 0 0

5 6 3

16 16 8

0 2 7

18/22 (81.8) 23/25 (92.0) 18/18 (100.0)

Pas. Pas. Pas.

Neg. Neg. Neg.

4.0 or less 4.1 to 9.9 10.0 or more

11 12 4

0 0 0

0 0 0

4 2 0

6 8 1

1 1 1

0 1 2

0 0 0

0 0 0

0 0 0

7 1 1

3 9 3

1 2 0

8/11 (72.7) 12/12 (100.0) 4/4 (100.0)

Neg. Neg. Neg.

Pas. Pas. Pas.

4.0 or less 4.1 to 9.9 10.0 or more

+ 26

1 0

6 2

5 0

8 4

4 1

2 1

0 0

0 0

0 0

2 0

22 7

1 0

24/26 (92.3) 8/8 (100.0)

Neg. Neg. Neg.

Neg. Neg. Neg.

4.0 or less 4.1 to 9.9 10.0 or more

+ 22

1 0

5 0

5 10 1 2

1 5

0 1

0 0

0 3

0 0

4 3

16 5

2 2

21/22 (95.5) 12/12 (100.0)

8

12

Pos.-suspicious for cancer. Neg.-not suspicious for cancer. * Tumor grade not available on 6 patients. t Stages C and D or 2 to 4 quadrants, or moderately to poorly differentiated. No biopsies in this category, in compliance with study protocol.

+

levels underwent biopsy. 7 In our study 3 of the 6 sites had biopsy rates of approximately 75% or higher, and results were similar to those of the entire patient population. The distribution of men not undergoing biopsy was evenly represented across the subsets analyzed except for the small group of men 80 years old or older. Thus, we believe that any bias introduced by failure to biopsy was not selective for the parameters measured in our study. Whether to recommend biopsy in men with a PSA level of 4.1 to 9.9 µg./1. and a benign digital rectal examination has been a matter of controversy. Biopsy is routinely recommended for patients with a suspicious digital rectal examination and it is generally accepted that a biopsy is warranted if the PSA level is greater than 10 µg./1. However, the cancer risk in men with a PSA level of 4.1 to 9.9 µg./1. and benign findings on digital rectal examination has not been previously determined, since physicians have been reluctant to perform biopsy in such patients. Our study shows the cancer percentage in this group to be 21 %, which is equivalent to that noted for a suspicious digital rectal examination alone (21 %) and suggests that patients with a PSA level of 4.1 to 9.9 µg./1. should undergo biopsy regardless of digital examination results. In fact, men with a negative digital examination and a PSA level of 4.1 to 9.9 µg.j 1. have a better prognosis (85% organ confined cancer) than those with a suspicious digital rectal examination (70% organ confined cancer). Similarly, in men with a PSA level of 4.1 to 9.9 µg./1., a negative digital rectal examination and negative transrectal ultrasonography the proportion with cancer is 18%. Of these cancers 96% were organ confined, whereas only 5% were histologically well differentiated and microscopically focal (potentially latent cancers). These results suggest that this group would also benefit from biopsy. Some investigators have suggested that the PSA density should be calculated (serum PSA level divided by the prostate volume as determined by ultrasonography) and that only if the

density is greater than 0.15 should a biopsy be performed.13 We performed a detailed analysis of PSA density in the study population, which will be reported at a later date. The results show that PSA density was actually less accurate in predicting cancer than the PSA level in this group of patients, and that if only patients with a density of greater than 0.15 would have been biopsied approximately half of the tumors would have been missed. The overall percentage of tumors not detected by transrectal ultrasonography is an important finding. Many physicians recommend biopsy only if transrectal ultrasonography is also suspicious. Ultrasound used to verify a suspicious digital rectal examination or PSA level missed nearly 40% of the lesions. This reluctance to perform biopsy when there is a PSA elevation alone has lowered reported estimates of the sensitivity and positive predictive value of PSA, since PSA was not evaluated as an independent test. To our knowledge this is the first large scale trial in which patients underwent biopsy based on an elevated PSA concentration alone. In our study transrectal ultrasonography was performed only in men with a suspicious PSA level or digital rectal examination findings. In this subset, transrectal ultrasonography was less accurate than PSA or digital rectal examination in predicting prostate cancer, which is consistent with our previous findings. 4 We believe that transrectal ultrasonography is important to guide the biopsy needle into suspicious hypoechogenic regions so that systematic biopsies are not blind. The goal of active cancer detection efforts is to detect cancer at an earlier stage than it might otherwise be detected. Thus, the positive predictive value of a useful test may be considerably lower than 100% as long as sensitivity is high and a significant number of cancers are detected at an earlier stage. The positive predictive value of PSA is 32% but its "sensitivity" (the term is placed in quotes because not all men underwent biopsy) is 82%, and adding PSA to digital rectal examination nearly

PROSTATE SPECIFIC ANTIGEN VERSUS RECTAL EXAMINATION

doubles the detection of organ confined cancer, For comparison, the positive predictive value of PSA is higher than reported estimates of that for mammography in the detection of breast cancer (10 to 25 %) .14• 15 Our study produced an excellent cancer detection rate (4.0%) for a relatively low biopsy rate (18 %) . PSA has a higher detection rate (3.3%) than digital rectal examination (2.2%) but the 2 tests combined provided the highest detection rate (4.0%). A 1 to 2% detection rate is reported in the literature 16 but since the age distribution of the men screened may not be comparable to that in our study direct comparisons are not valid. Higher detection rates have been reported in referred, symptomatic patients (15%) but the biopsy rate was nearly 50%. 8

A remarkable finding observed at all centers was that overall only 1 % of the tumors detected through screening with PSA and digital rectal examination were clinically advanced, which is in marked contrast to the distribution of clinically advanced cancers observed in referred patient populations in which approximately 10 to 35% present with clinically advanced disease.2·4·8 Of the patients with clinically localized disease 61 % underwent pathological staging. However, the choice of treatment involved other considerations, including patient age, health, quality of life issues and so forth. Approximately 70% of men younger than 70 years elected to undergo radical prostatectomy compared to only approximately 45% older than 70 years. The overall percentage of pathologically staged, organ confined cancers obtained in this study (71 %) is nearly twice that reported in the literature. 8· 16 An important reason for this finding may be that literature estimates often reflect referred patients with symptoms rather than an early detection program comprised equally of symptomatic and asymptomatic men. It is also possible that the failure of previous studies to perform biopsy based upon PSA level alone has revealed a greater number of advanced cancers, since patients would not have undergone biopsy until at least 1 other detection test (digital rectal examination or transrectal ultrasonography) also had suspicious findings. Other important factors may be that in previous studies only 1 or 2 tissue cores were usually obtained from the area of the palpable abnormality. In our study we routinely obtained more tissue cores with sonographically guided systematic biopsies, making it more likely to detect early, nonpalpable cancer at other areas of the prostate. Moreover, the threshold for biopsy has changed recently as prostatic biopsy has moved from a procedure requiring hospitalization and anesthesia to a simple anesthesia-free office procedure. Also, physicians have become more aware that following subtle abnormalities until they become obvious can allow prostate cancer to become incurable before it is diagnosed. We believe that the PSA-based screening, rather than any vagaries in the pathological evaluation of the surgical specimens, accounts for this striking difference in the distribution of tumor stages. Another objective of this study was to determine if PSA would detect more organ confined tumors when added to digital rectal examination. Digital examination detected 64 (56%) and PSA detected 85 (75%) of the 114 total organ confined tumors. When the 2 methods were combined 50 additional organ confined lesions were detected, for a 78% increase over digital rectal examination alone. Pathological stage was related to the PSA concentration. The greater the PSA concentration, the less likely a cancer was to be organ confined. However, 10 of the 19 men with advanced disease and a PSA level of 4.1 to 9.9 µg./1. had relatively low PSA values of 4.1 to 6.0 µg./1. Thus, it may not be safe to assume that a slightly elevated PSA concentration does not require biopsy. Autopsy studies have shown that up to 30% of American men have prostate cancer. However, our study detected only 4%, which is due to the fact that many tumors seen at autopsy are

1289

microscopic and are not detectable by digital rectal examination, PSA or transrectal ultrasonography. The larger a tumor the more likely it is to be detected by biopsy. Recent studies have shown that the volume of a prostate cancer may be a major factor in predicting its biological behavior: as the volume increases, there is a greater likelihood that the disease has spread beyond the gland. 17 PSA is unlikely to detect smaller malignancies because they are usually not large enough to secrete sufficient PSA to cause an elevated serum level. PSA concentration increases as tumor volume increases. 18 Each gram of prostate cancer has been reported to increase serum PSA by an average of 2.3 µg./1. (Hybritech Tandem assay level) .19 · 20 Thus, if cancer cells, rather than benign hyperplastic cells, are responsible for the increase in PSA (greater than 4.0 µg./1.), a substantial volume of cancer cells would need to be present. Prostate cancers of less than 1 ml. usually do not elevate PSA levels, whereas tumors larger than 1 ml. usually do.21 Other studies have shown that more than 90% of PSA detected cancers have the histological features frequently associated with serious cancer (that is histologically defuse or moderate or high grade) 22 ·23 based upon the well established relationship between tumor volume and grade, and the likelihood for cancer progression.17· 24 Our results support this finding. Only 8% of the pathologically staged cancer cases had organ confined, well differentiated tumors involving only 1 quadrant. All other patients (92%) had histological evidence of a serious cancer in terms of tumor volume and/or grade. The majority of these latter cases were organ confined and, therefore, potentially curable but they are considered serious because moderately or poorly differentiated, or large volume tumors are more likely to progress beyond the prostatic capsule if left untreated. 17 We do not believe the high percentage of medically significant disease observed in our study was due to a selection bias. Statistical analysis revealed that patient age was the only clinical parameter that was significantly different between patients who did and did not undergo an operation. It is expected that with annual digital rectal examination and PSA evaluations, the percentage of organ confined, potentially curable cancers would continue to increase with time for 2 reasons: 1) most late stage tumors will have been detected and removed from the returning population and 2) if PSA levels that were normal in year 1 become elevated the following year, they are more likely to have moved into the 4.1 to 9.9 µg./1. range (as opposed to the greater than 10 range). Thus, the patient would be evaluated when PSA levels are still in the low range in which advanced disease is less likely to occur. The expected advantages of annual evaluations in increasing the number of early, potentially curable lesions have been demonstrated in studies showing that the proportion of organ confined tumors shifts from approximately 30% in nonscreened men to 70 to 85% in men screened with digital rectal examination and PSA. 22 Other studies also support the use of annual PSA determinations, reporting increased cancer detection and increased specificity with serial measurements. 25 · 26 All PSA testing in our study was performed with Hybritech PSA assays. Assays from various manufacturers appear to recognize different PSA isoforms in serum, 27 and recent studies have shown significant differences in the numerical value of the PSA concentration when assays from different manufacturers are used. 28 Therefore, it cannot be assumed that the positive predictive values and other findings will be replicated with assays from other manufacturers. PSA and digital rectal examination results may be used in combination with transrectal ultrasonography results and factors, such as patient age, race, family history, symptoms and general physical health, to help guide the physician in determining the management of individual patients. It may not be effective to measure PSA levels in men less than 50 years old unless there is a strong family history of prostate cancer or if

1290

PROSTATE SPECIFIC ANTIGEN VERSUS RECTAL EXAMINATION

symptoms are present. A history of prostate cancer in a firstdegree relative doubles the likelihood that a patient will have the disease. 29 It is also not expected that routine PSA testing would be desirable in men with a short life expectancy resulting from advanced age or poor health, since even if cancer were detected the patient may not benefit from treatment. A recent study using decision analysis suggested that only younger men with high grade tumors benefit from aggressive treatment. 30 However, in this study the cancer progression probabilities were based largely on patients with stage A disease, and the data used to predict treatment outcomes were not representative of those attainable with current methods of detection and treatment. Moreover, ideal candidates for early detection and treatment (men 50 to 60 years old) were not addressed in this study. For men 50 years old and older with a life expectancy of 10 years or more our findings suggest that routine testing with PSA and digital rectal examination may decrease the prostate cancer mortality rate, which can be determined by a prospective, randomized trial, such as that planned by the National Cancer Institute. A recent cost-effectiveness analysis projected that not only would a significant number of cancer deaths be avoided if men 50 years old and older were evaluated with PSA and digital rectal examination but that large savings to society in cancer treatment costs would accrue as well. 31 Our findings demonstrate that PSA is used most effectively in conjunction with digital rectal examination to define the population of men who are at risk for prostate cancer and, therefore, may require prostatic biopsy. However, PSA elevations greater than 4 µg./1. may warrant prostatic biopsy even if the digital rectal examination and transrectal ultrasonography findings are not suspicious. REFERENCES 1. Cancer Facts and Figures-1992. Atlanta: American Cancer Society, 1992. 2. Boring, C. C., Squires, T. S. and Tong, T.: Cancer statistics, 1993. CA, 43: 7, 1993. 3. Catalana, W. J. and Bigg, S. W.: Nerve-sparing radical prostatectomy: evaluation of results after 250 patients. J. Urol., 143: 538, 1990. 4. Catalana, W. J., Smith, D.S., Ratliff, T. L., Dodds, K. M., Coplen, D. E., Yuan, J. J. J., Petros, J. A. and Andriole, G. E.: Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. New Engl. J. Med., 324: 1156, 1991. 5. Murphy, G. P., Natarajan, N., Pontes, J.E., Schmitz, R. L., Smart, C. R., Schmidt, J. D. and Mettlin, C.: The national survey of prostate cancer in the United States by the American College of Surgeons. J. Urol., 127: 928, 1982. 6. Crawford, E. D., Eisenberger, M.A., McLeod, D. G., Spaulding, J. T., Benson, R., Dorr, F. A., Blumenstein, B. A., Davis, M. A. and Goodman, P. J.: A controlled trial of leuprolide with and without flutamide in prostate carcinoma. New Engl. J. Med., 321: 419, 1989. 7. Brawer, M. K., Chetner, M. P., Beatie, J., Buchner, D. M., Vessella, R. L. and Lange, P. H.: Screening for prostatic carcinoma with prostate specific antigen. J. Urol., part 2, 147: 841, 1992. 8. Cooner, W. H., Mosley, B. R., Rutherford, C. L., Jr., Beard, J. H., Pond, H. S., Terry, W. J., Igel, T. C. and Kidd, D. D.: Prostate cancer detection in a clinical urological practice by ultrasonography, digital rectal examination and prostate specific antigen. J. Urol., 143: 1146, 1990. 9. Coughlin, S. S., Trock, B., Criqui, M. H., Pickle, L. W., Browner, D. and Tefft, M. C.: The logistic modeling of sensitivity, specificity, and predictive value of a diagnostic test. J. Clin. Epidemiol., 45: 1, 1992. 10. Richie, J. P., Catalana, W. J., Ahmann, F. R., Hudson, M. A., Scardino, P. T., Flanigan, R. C., deKernion, J.B., Ratliff, T. L., Kavoussi, L. R., Daikin, B. L., Waters, W. B., MacFarlane, M. T. and Southwick, P. C.: Effect of patient age on early detection of prostate cancer through serum prostate specific antigen (PSA)

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