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Original Contribution |

Variation of Serum Prostate-Specific Antigen Levels:  An Evaluation of Year-to-Year Fluctuations FREE

James A. Eastham, MD; Elyn Riedel, MA; Peter T. Scardino, MD; Moshe Shike, MD; Martin Fleisher, PhD; Arthur Schatzkin, MD, DrPh; Elaine Lanza, PhD; Lianne Latkany, MS; Colin B. Begg, PhD; for the Polyp Prevention Trial Study Group
[+] Author Affiliations

Author Affiliations: Memorial Sloan-Kettering Cancer Center, New York, NY (Drs Eastham, Scardino, Shike, Fleisher, and Begg, and Mss Riedel and Latkany); and Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Md (Drs Schatzkin and Lanza).


JAMA. 2003;289(20):2695-2700. doi:10.1001/jama.289.20.2695.
Text Size: A A A
Published online

Context Serum prostate-specific antigen (PSA) testing is frequently used in early detection programs for prostate cancer. While PSA testing has resulted in an increase in prostate cancer detection, its routine use has been questioned because of a lack of specificity.

Objective To determine whether year-to-year fluctuations in PSA levels are due to natural variation and render a single PSA test result unreliable.

Design, Setting, and Participants Retrospective analysis of an unscreened population of 972 men (median age, 62 years) participating in the Polyp Prevention Trial (1991-1998). Five consecutive blood samples were obtained during a 4-year period and were assessed for total and free PSA levels.

Main Outcome Measure Abnormal PSA test result based on a PSA level higher than 4 ng/mL; a PSA level higher than 2.5 ng/mL; a PSA level above the age-specific cutoff; a PSA level in the range of 4 to 10 ng/mL and a free-to-total ratio of less than 0.25 ng/mL; or a PSA velocity higher than 0.75 ng/mL per year.

Results Prostate biopsy would have been recommended in 207 participants (21%) with a PSA level higher than 4 ng/mL; in 358 (37%) with a level higher than 2.5 ng/mL; in 172 (18%) with a level above the age-specific cutoff; in 190 (20%) with a level between 4 and 10 ng/mL and a free-to-total ratio of less than 0.25 ng/mL; and in 145 (15%) with a velocity higher than 0.75 ng/mL per year. Among men with an abnormal PSA finding, a high proportion had a normal PSA finding at 1 or more subsequent visits during 4-year follow-up: 68 (44%) of 154 participants with a PSA level higher than 4 ng/mL; 116 (40%) of 291 had a level higher than 2.5 ng/mL; 64 (55%) of 117 had an elevated level above the age-specific cutoff; and 76 (53%) of 143 had a level between 4 and 10 ng/mL and a free-to-total ratio of less than 0.25 ng/mL.

Conclusion An isolated elevation in PSA level should be confirmed several weeks later before proceeding with further testing, including prostate biopsy.

Figures in this Article

Measurements of serum prostate-specific antigen (PSA) levels in combination with digital rectal examination have long been recommended as part of an early detection program for prostate cancer.1,2 Epidemiological data demonstrate a marked increase in the number of men diagnosed as having prostate cancer and a shift toward earlier-stage disease.35 While many of these men are diagnosed as having localized and therefore potentially curable tumors, there has also been a substantial increase in the number of men undergoing radical prostatectomy for small cancers that may be clinically insignificant. Epstein et al6 reviewed 157 men undergoing radical prostatectomy for clinical stage Tlc prostate cancer. Using a definition of insignificant cancer as a pathologically confined tumor with no Gleason component of 4 or 5, and a total tumor volume of less than 0.5 cm3, these investigators found that 26% of their study population had insignificant disease. Similarly, Ohori et al7 reported that 17% of men undergoing radical prostatectomy met the above definition for an insignificant tumor. These data suggest that while widespread use of PSA testing has resulted in the detection of earlier-stage cancers, many of these tumors were unlikely to be a threat to the overall health of the individual.

While PSA testing has resulted in an increase in prostate cancer detection, its routine use as a screening tool has been questioned because of a lack of specificity when levels are moderately elevated (4 to 10 ng/mL). Twenty-five percent of men with PSA levels in this range do have biopsy-proven prostate cancer, but 75% have negative biopsy results.2 A variety of methods have been suggested to improve the specificity of PSA testing, including age-specific PSA reference ranges,8 which normalize levels to a particular decade of life in an attempt to account for normal prostatic enlargement with age; PSA velocity,9 which correlates change in PSA over time with the likelihood that this change may be associated with benign prostatic growth; and percentage-free PSA,10,11 which accounts for the observation that men with benign prostatic hyperplasia are more likely to have PSA in an unbound state in the serum compared with men diagnosed as having prostate cancer. However, regardless of which serum PSA derivative is used, natural variations in PSA level may confound our ability to use PSA testing as a successful screening tool.

Natural biological variations in PSA levels have been previously studied. Nixon et al12 evaluated daily biological variations of PSA levels by obtaining 10 serum samples from 24 patients during a 2-week period to determine the difference required between 2 consecutive PSA measurements that would indicate a significant elevation. These investigators concluded that the degree of biological variation differs among patients, such that an increase between 2 consecutive PSA levels that is less than 20% to 46% may be due to biological and analytical variation alone. Furthermore, they estimated that 3 consecutive PSA measurements would be needed to achieve an estimate of the mean concentration within 10% of the actual mean for half the patients, whereas 15 measurements would be needed to ensure that 95% of the population had estimated mean concentrations of PSA at the same level of accuracy. Similarly, Ornstein et al13 examined the biological variation of total, free, and percentage-free PSA in 92 men who are older than 50 years. All men underwent PSA testing on 3 occasions, each 2 weeks apart. The study showed a mean variation of approximately 15% in measurements of total, free, and percentage-free PSA. These studies suggest that natural biological variation occurs in PSA testing in the short term.

In this investigation, we have taken advantage of a population of male participants in a colon polyp prevention trial who had blood drawn annually during a 4-year period. These samples were later analyzed to study natural variation in PSA levels. These men can be considered representative of the healthy population of men at risk for prostate cancer, who would be candidates for population-based screening. Our analysis focuses on the effect of PSA screening strategies for this population.

We used data and blood samples from the Polyp Prevention Trial, a multicenter randomized trial designed to evaluate the effect of a diet low in fat and high in fiber, fruits, and vegetables on the recurrence of colorectal adenomas.1416 Participants were men and women aged 35 years or older with 1 or more adenomas. Recruitment was from 1991 through 1994. Participants were followed up from their baseline recruitment date for 4 years. The study was completed in 1998. At baseline and at each subsequent year of follow-up, participants completed food records, questionnaires, and health and lifestyle forms, and provided 3 fasting blood samples. Data and blood samples for each participant were labeled with a new record number by the central data center to ensure anonymity of the results. The protocol was approved by the institutional review boards of Memorial Sloan-Kettering Cancer Center (New York, NY) and the National Cancer Institute (Bethesda, Md). For this PSA analysis of the serum samples taken from the main trial, informed consent was waived. This was approved as exempt by the office of human subjects research of the National Cancer Institute with the stipulation that all specimens and data be made completely anonymous. It was approved by the institutional review board of Memorial Sloan-Kettering Cancer Center in 1998 with the understanding that the specimens and data be made completely anonymous. This was followed exactly as all serum samples and data provided by the National Cancer Institute were made completely anonymous and any links to the original data were broken.

For each sample, serum was separated from the clot, aliquotted, and frozen at −70°C in a central repository within 4 hours of the blood draw. Serum PSA testing was performed from mid-1999 through the beginning of 2000. Therefore, samples were stored between 1 and 9 years prior to their analysis. The stability of total PSA levels over this time frame has been previously documented.17 The long-term stability of free PSA levels is unknown, although these levels are apparently stable for at least 39 months when stored under the conditions used in our study.18 Samples were not thawed from the time of the initial freezing until PSA determinations were made. Coded specimen inventory listings were organized by subject, so that all specimens from a particular subject could be identified and assayed at the same time, thus eliminating the possibility of between-assay variability. Serum PSA concentration was measured by a heterogeneous sandwich magnetic separation assay using the Immuno 1 PSA assay (Bayer Diagnostics, Leverkusen, Germany). The PSA assay has a detection limit of 0.05 ng/mL. The coefficients of variation for the assay at concentrations of 0.7 ng/mL were 3.1%; 2.8 ng/mL, 2.9%; and 17.9 ng/mL, 0.6%. Samples with PSA levels between 4 and 10 ng/mL were also analyzed for free PSA by a 2-site immunoradiometric assay using monoclonal antibodies directed against distinct antigen sites on the free-PSA molecule (Hybritech Tandem R, Hybritech, San Diego, Calif).

The Polyp Prevention Trial randomized 2079 men and women. The study design and results are described elsewhere.1416 There were 1351 male participants. We excluded participants with a prior history of prostate cancer (n = 36). Cancer diagnoses were obtained from the health and lifestyle forms and from hospital records. Initially, we also excluded men with fewer than 2 serum samples (n = 85), leaving 1230 male participants. However, since most of these participants (n = 972; 79%) had PSA measurements at each of the 5 time points, we further restricted our cohort to these 972 participants. Results were not substantially different if all 1230 participants were included (data not shown). Stored blood from these participants was analyzed for PSA levels under the supervision of a single clinical chemist (M.F.), and for free PSA in samples for which the total PSA was between 4 and 10 ng/mL. Further details are available in an earlier report of the effect of dietary intervention on changes in PSA.19

Because there is no consensus as to what a healthy PSA level should be, we used a variety of PSA cutoffs to estimate the frequency of an abnormal result in our study population. These cutoffs included (1) any PSA level higher than 4 ng/mL,1 (2) any PSA level higher than 2.5 ng/mL,20 (3) age-specific PSA levels8 (age <50 years: >2.5 ng/mL; age 50-59 years: >3.5 ng/mL; age 60-69 years: >4.5 ng/mL; age >70 years: >6.5 ng/mL), (4) free-to-total PSA ratio lower than 0.25 ng/mL among men with PSA levels between 4 and 10 ng/mL (as suggested in the Guidelines for Interpretation of Results for the Hybritech Tandem R assay),11 and (5) PSA velocity higher than 0.75 ng/mL per year.9

A total of 972 men between the ages of 35 and 89 years (median age, 62 years) were included in this study. Baseline PSA levels by age group are presented in Table 1. A variety of PSA cutoffs were used to determine the number of men who met the criteria for prostate biopsy during the 4-year study period (Table 2). Using any of these PSA thresholds, 361 (37%) of the participants would have met at least 1 of the criteria for an abnormal PSA test result. This result is driven by the 2.5-ng/mL cutoff, which is the least restrictive criterion for prompting a biopsy. The other 4 criteria for prompting a biopsy would identify between 15% and 21% of the participants. If the 2.5-ng/mL criterion were excluded, 245 (25%) men would have been recommended for biopsy by exceeding 1 of the 4 remaining criteria. Of the men whose baseline PSA level was in the normal range, 12% experienced a subsequent PSA level higher than 4 ng/mL; 17% had a PSA level higher than 2.5 ng/mL; 9% and 10%, respectively, had age-specific and free-PSA ratio criteria.

Table Graphic Jump LocationTable 1. Baseline PSA Levels by Age Group
Table Graphic Jump LocationTable 2. Participants With PSA Levels Meeting Standard Criteria for Prostate Biopsy

We next sought to determine how often a participant's PSA level would return to normal the year after the level had been elevated. We considered 4 of 5 criteria in this analysis: PSA level higher than 4 ng/mL; PSA level higher than 2.5 ng/mL; age-specific PSA levels; and free-PSA ratio. Men who were documented as developing prostate cancer during the study period (n = 37) were excluded. Although we cannot be sure that all diagnosed cases were reported, the expected number of incident cases in a population of this size and age distribution during the 4-year follow-up was 26. It is likely that few diagnosed cases were included erroneously. In any event, we further excluded 3 participants whose PSA profiles strongly indicated a diagnosis and treatment of prostate cancer. These individuals had an initial PSA level that was high and all subsequent levels were close to zero. For each remaining participant, we identified the first visit in which an abnormal PSA level was recorded. The PSA level at the subsequent visit (if available) was checked to see if it reverted to a result in the normal range (Table 3). There were 172 men in whom the PSA level was above the 4-ng/mL threshold at 1 or more visits. Of the 154 men for whom the first elevated PSA level did not occur at the final visit, 30% had a PSA level below 4 ng/mL at the next visit. The corresponding percentages of participants whose PSA levels returned to the normal range at the next visit were 26% for the PSA level higher than 2.5-ng/mL criterion; 37% for the age-specific criterion; and 35% for the free-PSA criterion. When we considered the number of men whose PSA level returned to the normal range at any subsequent visit, these percentages increase to 44% with a PSA level higher than 4 ng/mL; 40% with a PSA level higher than 2.5 ng/mL; 55% for the age-specific level; and 53% for the free-PSA level. The average number of patient visits (number of PSA levels) following the abnormal PSA level were 2.9, 3.0, 2.7, and 2.9, respectively, depending on the criterion (Table 4).

Table Graphic Jump LocationTable 3. Initial Abnormal PSA Level Returned to Normal on Next PSA Test
Table Graphic Jump LocationTable 4. Initial Abnormal PSA Level Returned to Normal at Any Subsequent Visit

For those men whose PSA levels returned to the normal range, we also determined if the decline in PSA level remained within the normal range on the subsequent PSA evaluation (Table 5). For the criteria used in our study, between 65% and 83% of participants maintained a normal PSA level on the next annual evaluation. To illustrate spontaneous variations in PSA levels over time, Figure 1 shows a random sample of participants with PSA levels greater than 4 ng/mL. Ten participants had an elevated PSA level that did not return to normal range (Figure 1, A) and 10 participants had an elevated PSA level that subsequently returned to normal (Figure 1, B).

Table Graphic Jump LocationTable 5. Participants With Abnormal and Subsequent Normal PSA Levels
Figure. Random Sample of Participants
Graphic Jump Location
Participants had prostate-specific antigen (PSA) levels of greater than 4 ng/mL.

The use of PSA testing as a screening tool for prostate cancer became widespread after its introduction more than a decade ago. This led to a rapid increase in prostate cancer incidence, but the impact on prostate cancer mortality is unclear. Two recent ecological studies show divergent results. In one study in a region of Austria in which PSA testing was made freely available to men aged 45 to 75 years, the region experienced a significant reduction in mortality compared with other regions of Austria.21 However, in a similar comparison in the United States, 2 regions with different, although low, rates of PSA testing exhibited equivalent prostate cancer mortality.22 More definitive randomized trials on this issue are in progress. At present, PSA testing is not recommended as a screening tool by the US Preventive Services Task Force23 or by the Canadian Task Force on Preventive Health Care.24 The National Cancer Institute defines PSA testing as a strategy that is still under investigation.25

Despite this, a PSA test is often used as part of an early detection program for prostate cancer, in part in response to public demand.26 In a population-based study in New York State conducted during 1994 and 1995, 37% of white men aged 50 years or older and 26% of black men reported knowledge of having received a PSA test.27 In addition, results from large-scale prostate cancer screening, such as Prostate Cancer Awareness Week28 and a prospective trial of prostate cancer screening from 6 university centers,1 demonstrated that approximately 10% to 15% of men in their initial year of screening will have a PSA level greater than 4 ng/mL and will be recommended to undergo a prostate biopsy. These results are similar to what was found in our study, in which 21% of men had a PSA level greater than 4 ng/mL over a 4-year period. Importantly, our results show that nearly half of men who had 1 abnormal PSA level subsequently had a normal level, suggesting that PSA level fluctuations may result in many false-positive elevations. While PSA testing does lead to the early detection of prostate cancer, a single abnormal PSA level should be viewed with caution. A newly elevated level should be confirmed before expensive or invasive tests, such as a prostate biopsy, are recommended.

Currently, there is no standardized policy for the examination of an elevated PSA level. Actual practice includes 3 likely scenarios. The first is immediate referral for prostate biopsy. This discounts any potential role for random fluctuations in PSA levels, or the possibility of laboratory error. The second is immediate repeat of the PSA test. This decision assumes a potential laboratory error. If the repeat test result is another elevated PSA level, a biopsy is usually recommended. However, if the repeat PSA test result is a normal level, the participant is not referred for further testing, but has continued PSA testing on an annual or semiannual basis. The third is to wait 4 to 6 weeks, usually requesting that the participant take antibiotics with or without an anti-inflammatory agent, and then have a repeat PSA test. This assumes an infection and/or inflammation as the cause of the elevated PSA level, which will resolve with time and/or treatment. We found a substantial percentage of elevated PSA levels that spontaneously returned to normal. In our study, PSA levels were assessed annually, so we have no data on the amount of time required for a newly elevated PSA level to return to baseline. Other studies report 4 to 6 weeks for the PSA level to return to baseline after a prostate biopsy or transurethral resection of prostate.29 It seems reasonable to wait at least this long before repeating a PSA test.

A policy of confirming an abnormal PSA result certainly has important public health considerations. If a significant proportion of participants have a normal PSA level on subsequent testing, the cost-savings would be substantial because these men would not be referred for prostate biopsy. Prostate biopsy is generally safe, but infections have been reported in 1% to 7%,30 and hematuria in 2% to 4%.31 A policy of confirming newly elevated PSA levels several weeks later may reduce the number of unnecessary procedures markedly. The most important benefit, however, could be a reduction in the diagnosis of cancer in men with small incidental tumors, who would be subjected to the morbidity of definitive treatment for what could be a pseudodisease that presents no threat to their life or health.

Of course, a policy of confirmation after 4 to 6 weeks could, theoretically, allow growth and spread of a malignant tumor. This concern seems unfounded in regard to prostate cancer. Cancer progression in "watchful waiting" trials support the concept that prostate cancer has a prolonged natural history. Epstein et al32 studied 70 men with clinical stage T1c prostate cancer who underwent watchful waiting with repeat needle sampling to assess progression. Of 70 cases, 9 (12.9%) showed an increase in Gleason grade from 6 or less to 7 or greater. They concluded that a delay of several months between biopsy and surgical therapy was no cause for concern. Lastly, Stamey and Kabalin33 examined serial PSA levels in men with untreated prostate cancer. These investigators concluded that the rate of increase of PSA levels in men with clinical stage T1 or T2 prostate cancer suggested a doubling time of at least 2 years. Furthermore, data in the recent Swedish randomized trial of radical prostatectomy vs watchful waiting showed no difference in time to metastases for the first 5 years after treatment, suggesting that delay in diagnosis of a few weeks or months is unlikely to alter treatment efficacy.34 One can extrapolate these results to suggest that men should not be concerned about waiting several weeks to confirm an elevated PSA level before proceeding to prostate biopsy.

A potential limitation of our study is that we cannot be certain that men have not been diagnosed as having prostate cancer without our knowledge during the study period. This seems unlikely, however. Each participant completed an annual health summary that requested information regarding new medical problems, including a new diagnosis of malignancy. Men diagnosed as having prostate cancer usually undergo treatment. Men treated with radical prostatectomy or hormonal therapy would have had a marked decline in PSA level that would have been noted during annual testing.

Another limitation is the lack of biopsy data in men who developed an elevated PSA level during this trial. Some of these men may have had prostate cancer. Nevertheless, there is little risk in waiting to confirm a sustained increase in PSA level before proceeding with a diagnostic biopsy. Because of the apparent fluctuations in PSA levels over time, this policy would decrease the number of unnecessary biopsies, but still diagnose men within a reasonably safe time frame.

Catalona WJ, Richie JP, Ahmann FR.  et al.  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.  J Urol.1994;151:1283-1290.
Catalona WJ, Smith DS, Ratliff TL.  et al.  Measurement of prostate-specific antigen in serum as a screening test for prostate cancer.  N Engl J Med.1991;324:1156-1161.
Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002.  CA Cancer J Clin.2002;52:23-47.
Gann PH, Hennekens CH, Stampfer MJ. A prospective evaluation of plasma prostate-specific antigen for detection of prostate cancer.  JAMA.1995;273:289-294.
Carter HB, Epstein JJ, Partin AW. Influence of age and prostate-specific antigen on the chance of curable prostate cancer among men with nonpalpable disease.  Urology.1999;53:126-130.
Epstein JJ, Walsh PC, Brendler CB. Radical prostatectomy for impalpable prostate cancer: the Johns Hopkins experience with tumors found on transurethral resection (stages T1a and T1b) and on needle biopsy (stage T1c).  J Urol.1994;152:1721-1729.
Ohori M, Wheeler TM, Dunn JK, Stamey TA, Scardino PT. The pathological features and prognosis of prostate cancer detectable with current diagnostic tests.  J Urol.1994;152:1714-1720.
Oesterling JE, Jacobsen SJ, Chute CG.  et al.  Serum prostate-specific antigen in a community-based population of healthy men: establishment of age-specific reference ranges.  JAMA.1993;270:860-864.
Carter HB, Morrel CH, Pearson JD.  et al.  Estimation of prostatic growth using serial prostate-specific antigen measurements in men with and without prostate disease.  Cancer Res.1992;52:3323-3328.
Stenman UH, Leinonen J, Alfthan H, Rannikko S, Tuhkanen K, Alfthan O. A complex between prostate-specific antigen and alpha-1-chymo-trypsin is the major form of prostate-specific antigen in serum of patients with prostatic cancer: assay of the complex improves clinical sensitivity for cancer.  Cancer Res.1991;51:222-226.
Catalona WJ, Partin AW, Slawin KM.  et al.  Use of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trail.  JAMA.1998;279:1542-1547.
Nixon RG, Wener MH, Smith KM, Parson RE, Strobel SA, Brower MK. Biological variation of prostate specific antigen levels in serum: an evaluation of day-to-day physiological fluctuations in a well-defined cohort of 24 patients.  J Urol.1997;157:2183-2190.
Ornstein DK, Smith DS, Rao GS, Basler JW, Ratliff TL, Catalona WJ. Biological variation of total, free and percent free serum prostate specific antigen levels in screening volunteers.  J Urol.1997;157:2179-2182.
Schatzkin A, Lanza E, Freedman LS.  et al.  The Polyp prevention trial, I: rationale, design, recruitment, and baseline participant characteristics.  Cancer Epidemiol Biomarkers Prev.1996;5:375-383.
Lanza E, Schatzkin A, Ballard-Barbash R.  et al.  The polyp prevention trial II: dietary intervention and baseline participant dietary characteristics.  Cancer Epidemiol Biomarkers Prev.1996;5:385-392.
Schatzkin A, Lanza E, Corle D.  et al.  Lack of effect of a low-fat high-fiber, fruit- and vegetable-enriched diet on the recurrence of colorectal adenomas.  N Engl J Med.2000;342:1149-1155.
Hakama M, Stenman U-H, Aromaa A, Leinonen J, Hakulinen T, Knekt P. Validity of the prostate-specific antigen test for prostate cancer screening: follow-up study with a bank of 21,000 sera in Finland.  J Urol.2001;166:2189-2192.
Jacobsen SJ, Klee GG, Lilja H, Wright Jr GL, Oesterling JE. Stability of serum prostate-specific antigen determinations across laboratory, assay, and storage time.  Urology.1995;45:447-453.
Shike M, Latkany L, Riedel E.  et al.  Lack of effect of a low-fat, high-fruit and -vegetables and -fiber diet on serum prostate-specific antigen (PSA) of men without prostate cancer: results from a randomized trial.  J Clin Oncol.2002;20:3592-3598.
Catalona WJ, Ramos CG, Carvalhal GF, Yan Y. Lowering PSA cutoffs to enhance detection of curable prostate cancer.  Urology.2000;55:791-795.
Bartsch G, Horninger W, Klocker H.  et al.  Prostate cancer mortality after introduction of prostate-specific antigen mass screening in the federal state of Tyrol, Austria.  Urology.2001;58:417-424.
Lu-Yao G, Albertsen PC, Stanford JL, Stukel TA, Walker-Corkery ES, Barry MJ. Natural experiment examining impact of aggressive screening and treatment on prostate cancer mortality in two fixed cohorts from Seattle area and Connecticut.  BMJ.2002;325:740-743.
US Preventive Services Task Force.  Recommendation on prostate cancer screening. Available at: http://www.ahrq.gov/clinic/uspstf/uspsprca.htm. Accessed November 15, 2002.
Feightner JW. Screening for prostate cancer. In: Canadian Task Force on the Periodic Health Examination: Canadian Guide to Clinical Preventive Health Care. Ottawa, Ontario: Health Canada; 1994:812-823.
US Preventive Services Task Force.  Recommendations and rationale: screening for prostate cancer. Available at: http://www.ahrq.gov/clinic/3rduspstf/prostatescr/prostaterr.htm. Accessed April 10, 2003.
Chapple A, Ziebland S, Sheppard S, Miller R, Herxheimer A, McPherson A. Why men with prostate cancer want wider access to prostate-specific antigen testing.  BMJ.2002;325:737-739.
Steele CB, Miller DS, Maylahn C, Uhler RJ, Baker CT. Knowledge, attitudes, and screening practices among older men regarding prostate cancer.  Am J Public Health.2000;90:1595-1600.
Crawford ED, Leewansangtong S, Goktas S, Holthaus K, Bair M. Efficiency of prostate-specific antigen and digital rectal examination in screening, using 4.0 ng/mL and age-specific reference range as a cutoff for abnormal values.  Prostate.1999;38:296-302.
Tchetgen MB, Oesterling JE. The effect of prostatitis, urinary retention, ejaculation, and ambulation on the serum prostate-specific antigen concentration.  Urol Clin North Am.1997;24:283-291.
Coplen DE, Andriole GL, Yuan JJ, Catalona WJ. The ability of systematic transrectal ultrasound guided biopsy to detect prostate cancer in men with the clinical diagnosis of benign prostatic hyperplasia.  J Urol.1991;146:75-77.
Hammer P, Huland H. Systematic sextant biopsies in 651 patients referred for prostate evaluation.  J Urol.1994;151:99-102.
Epstein JI, Walsh PC, Carter HB. Differentiation of prostate cancer grade with time in men followed expectantly for stage T1c disease.  J Urol.2001;166:1688-1691.
Stamey TA, Kabalin JN. Prostate-specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate, I: untreated patients.  J Urol.1989;141:1070-1075.
Holmberg L, Bill-Axelson A, Helgeson F.  et al.  A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer.  N Engl J Med.2002;347:781-789.

Figures

Figure. Random Sample of Participants
Graphic Jump Location
Participants had prostate-specific antigen (PSA) levels of greater than 4 ng/mL.

Tables

Table Graphic Jump LocationTable 1. Baseline PSA Levels by Age Group
Table Graphic Jump LocationTable 2. Participants With PSA Levels Meeting Standard Criteria for Prostate Biopsy
Table Graphic Jump LocationTable 3. Initial Abnormal PSA Level Returned to Normal on Next PSA Test
Table Graphic Jump LocationTable 4. Initial Abnormal PSA Level Returned to Normal at Any Subsequent Visit
Table Graphic Jump LocationTable 5. Participants With Abnormal and Subsequent Normal PSA Levels

References

Catalona WJ, Richie JP, Ahmann FR.  et al.  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.  J Urol.1994;151:1283-1290.
Catalona WJ, Smith DS, Ratliff TL.  et al.  Measurement of prostate-specific antigen in serum as a screening test for prostate cancer.  N Engl J Med.1991;324:1156-1161.
Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002.  CA Cancer J Clin.2002;52:23-47.
Gann PH, Hennekens CH, Stampfer MJ. A prospective evaluation of plasma prostate-specific antigen for detection of prostate cancer.  JAMA.1995;273:289-294.
Carter HB, Epstein JJ, Partin AW. Influence of age and prostate-specific antigen on the chance of curable prostate cancer among men with nonpalpable disease.  Urology.1999;53:126-130.
Epstein JJ, Walsh PC, Brendler CB. Radical prostatectomy for impalpable prostate cancer: the Johns Hopkins experience with tumors found on transurethral resection (stages T1a and T1b) and on needle biopsy (stage T1c).  J Urol.1994;152:1721-1729.
Ohori M, Wheeler TM, Dunn JK, Stamey TA, Scardino PT. The pathological features and prognosis of prostate cancer detectable with current diagnostic tests.  J Urol.1994;152:1714-1720.
Oesterling JE, Jacobsen SJ, Chute CG.  et al.  Serum prostate-specific antigen in a community-based population of healthy men: establishment of age-specific reference ranges.  JAMA.1993;270:860-864.
Carter HB, Morrel CH, Pearson JD.  et al.  Estimation of prostatic growth using serial prostate-specific antigen measurements in men with and without prostate disease.  Cancer Res.1992;52:3323-3328.
Stenman UH, Leinonen J, Alfthan H, Rannikko S, Tuhkanen K, Alfthan O. A complex between prostate-specific antigen and alpha-1-chymo-trypsin is the major form of prostate-specific antigen in serum of patients with prostatic cancer: assay of the complex improves clinical sensitivity for cancer.  Cancer Res.1991;51:222-226.
Catalona WJ, Partin AW, Slawin KM.  et al.  Use of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trail.  JAMA.1998;279:1542-1547.
Nixon RG, Wener MH, Smith KM, Parson RE, Strobel SA, Brower MK. Biological variation of prostate specific antigen levels in serum: an evaluation of day-to-day physiological fluctuations in a well-defined cohort of 24 patients.  J Urol.1997;157:2183-2190.
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