Early detection of high-grade prostate cancer using digital rectal examination (DRE) in men with a prostate-specific antigen level of <2.5 ng/mL and the risk of death

Authors


Jona Hattangadi, Brigham and Women's Hospital, Department of Radiation Oncology, 75 Francis St, L-2 Level, Boston, MA 02215, USA. e-mail: jhattangadi@partners.org

Abstract

Study Type – Prognosis (inception cohort)

Level of Evidence 2a

What's known on the subject? and What does the study add?

There is little data on the utility of digital rectal examination (DRE) as a diagnostic tool in the era of prostate-specific antigen (PSA) testing. Using a population-based database, we found that detection of prostate cancer while still localized among men with high-grade PSA-occult disease may result in survival benefit.

OBJECTIVE

  • • To determine whether detection of high-grade prostate cancer while still clinically localised on digital rectal examination (DRE) can improve survival in men with a normal prostate-specific antigen (PSA) level.

PATIENTS AND METHODS

  • • From the Surveillance, Epidemiology and End Results database, 166 104 men with prostate cancer diagnosed between 2004 and 2007 were identified.
  • • Logistic regression was used to identify factors associated with the occurrence of palpable, PSA-occult (PSA level of <2.5 ng/mL), Gleason score 8–10 prostate cancer.
  • • Fine and Gray's and Cox multivariable regressions were used to analyse whether demographic, treatment, and clinicopathological factors were associated with the risk of prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM), respectively.

RESULTS

  • • Both increasing age (adjusted odds ratio [aOR] 1.02, 95% confidence interval (CI) 1.01–1.03; P < 0.001) and White race (aOR 1.26, 95% CI 1.03–1.54; P= 0.027) were associated with palpable, Gleason 8–10 prostate cancer. Of 166 104 men, 685 (0.4%) had this subset of prostate cancer.
  • • Significant factors associated with risk of PCSM included PSA level (adjusted hazard ratio [aHR] 0.71, 95% CI 0.51–0.99; P= 0.04), higher Gleason score (aHR 2.20, 95% CI 1.25–3.87; P= 0.006), and T3–T4 vs T2 disease (aHR 3.11, 95% CI 1.79–5.41; P < 0.001).
  • • Significant factors associated with risk of ACM included age (aHR 1.03, 95% CI 1.01–1.06; P= 0.006), higher Gleason score (aHR 2.05, 95% CI 1.36–3.09; P < 0.001), and T3–T4 vs T2 disease (aHR 2.11, 95% CI 1.38–3.25, P < 0.001)

CONCLUSIONS

  • • Clinically localised disease on DRE among men with PSA-occult high-grade prostate cancer was associated with improved PCSM and ACM, suggesting that DRE in this cohort (older age and White race) may have the potential to improve survival.
Abbreviations
ACM

all-cause mortality

AJCC

American Joint Committee on Cancer

(a)HR

(adjusted) hazard ratio

IQR

interquartile range

(a)OR

(adjusted) odds ratio

PCSM

prostate cancer-specific mortality

RP

radical prostatectomy

SEER

Surveillance, Epidemiology, and End Results

INTRODUCTION

Before the use of PSA screening for prostate cancer, DRE was the most sensitive method of diagnosis [1]. Early prospective studies suggested that screening for prostate cancer with DRE was cost-effective and specific for detection of more aggressive tumour [1,2]. And contrary to the notion that DRE is highly subjective, studies have shown that there is little inter-observer variability when the prostate is examined in a systematic method [3,4]. More recent studies combining DRE and PSA levels for screening have shown that the sensitivity and accuracy of DRE are improved when PSA values are taken into account [5,6], and that DRE is particularly relevant in the detection of higher grade, clinically aggressive disease [7]. As a result, active surveillance protocols dictate that finding palpable disease on DRE during follow-up requires ceasing surveillance and initiation of treatment [8,9].

Other studies have questioned the role of DRE [10], or omitted DRE altogether in prostate cancer screening [11]. The recent American Cancer Society guidelines on prostate cancer screening recommended that DRE be considered an option rather than a necessary adjunct to PSA testing [12]. However, PSA testing as a screening tool has come under increased scrutiny recently, because of differing results from randomised trials [13,14], and the potential for unnecessary evaluation, detection and treatment [15]. Thus the role of DRE should be re-examined to determine if men can be identified in whom DRE can provide earlier detection and therefore be potentially lifesaving.

There is little data on the utility of DRE as a clinical diagnostic tool in the PSA era, particularly in cases of high grade disease where low PSA levels due to hypogonadism [16,17], dedifferentiation [18], or medications that lower PSA, e.g. 5α reductase inhibitors [19] make the PSA test unreliable. Therefore, we used a population-based database to examine whether detection of high-grade prostate cancer while still clinically localised on DRE can improve survival in men with a low PSA level.

PATIENTS AND METHODS

Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) database [20,21], which includes patients with cancer reported by 17 tumour registries since 2000. The SEER programme captures ≈97% of incident cancers and the 17 tumour registries cover ≈26% of the USA population [20,21]. Registries collect information on demographics, date of diagnosis, tumour characteristics, surgical treatment, radiation therapy, vital status, follow-up, and cause of death. Pre-treatment PSA levels (ng/mL) were collected from 2004 to 2007 in a recent release of SEER data [21].

We identified 166 104 men with non-metastatic prostate cancer who were diagnosed from 1 January 2004 to 31 December 2007 when PSA data was available. All patients had prostate cancer as their first and only cancer diagnosis, and cancer diagnosis not obtained through death certificate or autopsy. We next selected a subset of patients with PSA-occult (<2.5 ng/mL), clinically significant high-grade (Gleason score 8–10) and palpable (American Joint Committee on Cancer [AJCC] T2–T4) prostate cancer. A PSA value of <2.5 ng/mL was chosen, as it is below the standard threshold PSA level for further evaluation in prostate cancer screening [8,12]. Gleason score was obtained from the biopsy report if the patient did not undergo radical prostatectomy (RP), and was obtained from the surgical pathology report if the patient underwent RP.

Demographic, clinical and pathological factors, along with patient follow-up and determination of cause of death were extracted from the database. This study was determined to be exempt from review by the Institutional Review Board of the Dana-Farber Cancer Institute/Brigham and Women's Hospital.

COMPARISON OF BASELINE CLINICAL CHARACTERISTICS AMONG STUDY COHORT

Patient and clinical factors were compared stratified by DRE-based clinically localised (T2) or extraprostatic disease (T3, T4). Race was White, Black, or Other Race (including American Indian, Native Alaskan, East Asian, South Asian, Southeast Asian and Pacific Islander populations). Because of small numbers in the Other Race category, patients from Other and Black race were grouped for analyses. Curative treatment included RP and external beam radiation therapy approaches. Non curative approaches included active surveillance, and non-radiation, non-RP approaches, e.g. laser ablation, TURP, and primary hormonal therapy. The distribution of continuous variables including age, PSA level and follow-up were compared using the Wilcoxon two-sample test and categorical variables were compared using a chi-square metric.

PREDICTORS OF HIGH GRADE, PSA-OCCULT PROSTATE CANCER

Univariable and multivariable logistic regression analyses were used to identify predictors of high-grade, PSA-occult, clinically palpable disease. Covariates examined included age (continuous), race (Black and Other vs White), and year of diagnosis (continuous). Odds ratios (ORs) and associated 95% CIs were generated, with two-sided P values from the chi-square test.

PREDICTORS OF PROSTATE CANCER-SPECIFIC MORTALITY (PCSM) AND ALL-CAUSE MORTALITY (ACM)

Univariable and multivariable Fine and Gray's and Cox regression analyses were used to identify whether the risk of PCSM and ACM, respectively, were associated with clinical T-category (T2 vs T3,T4), adjusting for age at diagnosis (continuous), race (Black or Other vs White), year of diagnosis (continuous) and known prognostic factors including Gleason score (8 vs 9–10), PSA level (continuous), and treatment (curative vs non-curative). For these analyses, time to event was measured from date of diagnosis. PSA levels was log-transformed for all analyses to ensure normal distribution. Unadjusted and adjusted hazard ratios (aHR) for PCSM and ACM with associated 95% CIs were calculated for each covariate. This analysis was repeated for the subset of men who did not undergo RP (Gleason score was based on biopsy only).

ESTIMATES OF PCSM AND ACM

Estimates of PCSM and ACM stratified by T-category on DRE (T2 vs T3,4) were calculated using cumulative incidence and Kaplan–Meier methodology, respectively. These estimates were compared using a Gray's k-mean test and log-rank test, respectively. All statistical tests were two-sided and a two-sided P < 0.05 was considered to indicate statistical significance. R version 2.12.0 software (R Foundation for Statistical Computing, Vienna, Austria) was used for all calculations pertaining to Gray's k-mean P value and Fine and Gray's regression. SAS version 9.3 software (SAS Institute, Cary, NC) was used for all remaining calculations.

RESULTS

BASELINE CHARACTERISTICS OF THE STUDY COHORT AT DIAGNOSIS

Baseline characteristics of the study cohort (685 patients) are shown in Table 1, stratified by clinically localised (T2) vs extraprostatic (T3, T4) T stage. Patients with T2 tumours were significantly older than those with T3–T4 tumours (median age 69 vs 65 years, P < 0.001). Those presenting with more advanced T3–T4 stage had a significantly higher proportion of Gleason 9–10 prostate cancer (63.6 vs 35.7%, P < 0.001). Significantly more patients with T3–T4 tumours underwent curative treatment (definitive surgery or radiation) than men with T2 tumours (P < 0.001). There was no significant difference among the distribution of years of diagnosis (P= 0.14) or median follow-up (P= 0.94).

Table 1.  Baseline characteristics of the 685 men in the study cohort with PSA levels of <2.5 ng/mL, Gleason score 8–10 and AJCC T-category 2, 3, or 4 prostate cancer stratified by the AJCC Tumour-category
CharacteristicT2T3, T4 P
  1. RT, radiation therapy; percentages may not add up to 100 because of rounding. *Two-sided Wilcoxon two-sample test; †chi-square test; ‡log-rank test.

N 479206 
Median (IQR):   
 Age at diagnosis, years69 (62–76)65 (58–71)<0.001*
PSA, ng/mL1.5 (1–2)1.5 (1–2)0.92*
N (%):   
 Gleason score:  0.001
  8308 (64.3)75 (36.4)
  9–10171 (35.7)131 (63.6)
 Race  0.16
  White401 (83.7)170 (82.5)
  Black42 (8.8)26 (12.6)
  Other36 (7.5)10 (4.9)
 Treatment:  0.001
  Curative (surgery or RT)371 (77.5)182 (88.4)
  Non-curative108 (22.6)24 (11.7)
 Year of diagnosis:  0.14
  2004137 (28.6)62 (30.1)
  200599 (20.7)41 (19.9)
  2006106 (22.1)59 (28.6)
  2007137 (28.6)44 (21.4)
Median (IQR) follow-up, years2.83 (1.83–4.08)2.92 (2.08–4.08)0.94

FACTORS ASSOCIATED WITH AN INCREASED ODDS OF A PSA LEVEL OF <2.5 NG/ML AND PALPABLE GLEASON 8–10 PROSTATE CANCER

Of 166 104 men, 685 (0.4%) had a PSA level of <2.5 ng/mL, Gleason score 8–10, and AJCC T-stage T2–T4 prostate cancer. As shown in Table 2, increasing age was significantly associated with the occurrence of this cohort (adjusted OR [aOR] 1.02, 95% CI 1.01–1.03, P < 0.001) as was White race when compared with Black or Other Race (aOR 1.26, 95% CI 1.03–1.54, P= 0.027). The median (interquartile range [IQR]) age for White and Black or Other Race men were 68 (61–75) years and 66 (60–73) years, respectively.

Table 2.  Univariable and multivariable logistic regression analyses providing the odds for clinical factors of being diagnosed with a PSA level of <2.5 ng/mL, Gleason score 8–10 and AJCC T-category 2, 3, or 4 prostate cancer
Clinical factorUnivariable analysisMultivariable analysis
OR (95% CI) P aOR (95% CI) P
  1. Ref, reference.

Age at diagnosis, years (continuous)1.02 (1.01–1.03)<0.0011.02 (1.01–1.03)<0.001
Race:    
 Black or Other1.00 RefRef1.00 RefRef
 White1.28 (1.04–1.56)0.0181.26 (1.03–1.54)0.027
Year of diagnosis (continuous)0.93 (0.87–1.00)0.040.94 (0.88–1.00)0.06

FACTORS ASSOCIATED WITH INCREASED RISK OF PCSM AND ACM

After a median (IQR) follow-up period of 2.9 (1.9–4.1) years, 109 men (15.9%) died and 61 men (8.9%) died from prostate cancer. As shown in Table 3, increasing PSA level was associated with a lower risk of PCSM (aHR 0.71, 95% CI 0.51–0.99, P= 0.04). Gleason score 9–10 vs 8 (aHR 2.20, 95% CI 1.25–3.87, P= 0.006), T3–T4 vs T2 (aHR 3.11, 95% CI 1.79–5.41, P < 0.001) and non-curative compared with curative treatment (aHR 5.87, 95% CI 3.23–10.7, P < 0.001) were associated with a significantly higher risk of PCSM.

Table 3.  Univariable and multivariable Fine and Gray's regression analyses providing the risk of PCSM for each clinical factor
Clinical factorNumber of men (n= 685)Number of events (n= 61)Univariable analysisMultivariable analysis
HR (95% CI) P aHR (95% CI) P
  1. Ref, reference.

Age at diagnosis, years (continuous)685611.02 (0.98–1.06)0.271.00 (0.97–1.03)0.98
Log PSA, ng/mL (continuous)685610.68 (0.50–0.91)0.0090.71 (0.51–0.99)0.04
Gleason score:      
 8383171.00 RefRef1.00 RefRef
 9–10302443.38 (1.94–5.90)<0.0012.20 (1.25–3.87)0.006
Race:      
 Black or Other114121.00 RefRef1.00 RefRef
 White571490.83 (0.44–1.56)0.561.08 (0.54–2.17)0.82
AJCC T-stage:      
 T2479301.00 RefRef1.00 RefRef
 T3, T4206312.43 (1.48–4.01)<0.0013.11 (1.79–5.41)<0.001
Treatment:      
 Curative (surgery or RT)553291.00 RefRef1.00 RefRef
 Non-curative132325.26 (3.20–8.64)<0.0015.87 (3.23–10.7)<0.001
Year of diagnosis (continuous)685610.79 (0.61–1.02)0.070.87 (0.67–1.13)0.28

Increasing age (aHR 1.03, 95% CI 1.01–1.06, P= 0.006), Gleason score 9–10 vs 8 (aHR 2.05, 95% CI 1.36–3.09, P < 0.001), T3–T4 vs T2 (aHR 2.11, 95% CI 1.38–3.25, P < 0.001) and non-curative vs curative treatment (aHR 3.74, 95% CI 2.39–5.87, P < 0.001) were associated with an increased risk of ACM as shown in Table 4.

Table 4.  Univariable and multivariable Cox regression analyses of factors providing the risk of ACM for each clinical factor
Clinical factorNumber of men (n= 685)Number of events (n= 109)Univariable analysisMultivariable analysis
HR (95% CI) P aHR (95% CI) P
  1. Ref, reference.

Age at diagnosis, years (continuous)6851091.06 (1.03–1.08)<0.0011.03 (1.01–1.06)0.006
Log PSA, ng/mL (continuous)6851090.86 (0.67–1.10)0.220.90 (0.69–1.17)0.42
Gleason score:      
 8383361.00 RefRef1.00 RefRef
 9–10302732.73 (1.83–4.07)<0.0012.05 (1.36–3.09)<0.001
Race:      
 Black or Other114151.00 RefRef1.00 RefRef
 White571941.32 (0.76–2.27)0.321.41 (0.81–2.45)0.22
AJCC T-stage      
 T2479661.00 RefRef1.00 RefRef
 T3, T4206431.54 (1.05–2.25)0.0292.11 (1.38–3.25)<0.001
Treatment:      
 Curative (surgery or RT)553591.00 RefRef1.00 RefRef
 Non-curative132504.36 (2.99–6.36)<0.0013.74 (2.39–5.87)<0.001
Year of diagnosis (continuous)6851090.77 (0.63–0.95)0.010.84 (0.69–1.04)0.10

RISK OF PCSM AND ACM BY AJCC T-STAGE

Estimates of PCSM and ACM were significantly higher for men with clinical T3 or T4 vs T2 disease (P < 0.001 for PCSM and P= 0.027 for ACM) as shown in Figs 1 and 2, respectively. Estimates of PCSM at 3 years were 15.8% (95% CI 10.6–21.7) for men with T3–T4 disease, compared with 5.9% (95% CI 3.9–8.6) for men with T2 prostate cancer. These respective estimates were 21.5% (95% CI 15.9–28.7) and 14.5% (95% CI 11.2–18.7) for ACM.

Figure 1.

Cumulative incidence estimates of PCSM stratified by clinically localised (T2) or locally advanced (T3, T4) prostate cancer as per DRE (Gray's k-mean test, P < 0.001).

Figure 2.

Kaplan–Meier estimates of ACM stratified by clinically localised (T2) or locally advanced (T3, T4) prostate cancer as per DRE (log-rank test, P=0.027).

RISK OF PCSM AND ACM BY AJCC T-STAGE AMONG MEN WITH BIOPSY-ONLY GLEASON SCORES

Within the study cohort, 414 men did not undergo RP, and thus their Gleason score was based on biopsy findings only. Among these 414 men, there were 97 deaths, 53 (55%) from prostate cancer. Men with locally advanced compared with clinically localised disease on DRE (T3, T4 vs T2) had a statistically significant increased risk of PCSM (aHR 3.59, 95% CI 2.07–6.24, P < 0.001) and ACM (aHR 2.50, 95% CI 1.61–3.88, P < 0.001).

DISCUSSION

Whether DRE alone has the ability to decrease the risk of PCSM by providing earlier detection of high-grade prostate cancer, when the PSA level is <2.5 ng/mL, remains unknown. In the present study, using population-based data, we found that men most likely to be diagnosed with high-grade, PSA-occult, clinically palpable prostate cancer were older and of White race. We also found that the detection of prostate cancer while locally advanced as compared with clinically localised was associated with a three-fold increase in risk of PCSM and a two-fold increase in risk of ACM. The clinical significance of these findings are that DRE as a screening tool may have the ability to decrease both PCSM and ACM particularly in men of older age and White race, whom have a higher likelihood of harbouring high-grade prostate cancer despite a normal PSA level.

Several points require further consideration. First, it is well-established in the published literature that testosterone levels are lower among White than Black men, and that testosterone levels decline with advancing age for the vast majority of men [22,23]. In addition, basal testosterone levels and PSA levels are highly correlated [24–26]. Therefore, it is not unexpected that PSA-occult, high-grade, clinically palpable prostate cancers were most likely to be diagnosed in White, elderly men. Given that DRE results may affect survival in older Caucasian men with low PSA levels, this may support the idea of annual DRE in healthy men even beyond the age of 70 years, when screening for prostate cancer is more controversial [12].

Second, a declining PSA level was associated with a significantly increased risk of PCSM in the present cohort. This correlation between low serum PSA levels and high-grade prostate cancer has been shown in other studies [18,27,28], and may reflect the decrease in PSA production due to hypogonadism [29] or from dedifferentiated high-grade prostate cancer cells [30]. The biological mechanism to explain this later phenomenon remains unclear. As patients with high-grade tumours may produce less PSA per gram of tumour [18], this subset of men may benefit from earlier detection with a DRE than what PSA can afford.

There are several potential limitations to the present study. First, the study cohort comprised <1% of men with non-metastatic prostate cancer within the SEER database in the study period. So, while a survival benefit may be attained through the use of DRE in the present cohort, the absolute number of men is small. However, death rates from prostate cancer in the present cohort were substantial, particularly in men detected late with locally advanced (3-year PCSM 15.8%) as compared with localised prostate cancer (5.9%), respectively. Therefore, while the absolute numbers of men who may benefit are small, the potential impact of early detection is large. Second, the median follow-up was relatively short, at <3 years. But given the aggressive nature of disease in the subset of patients with PSA-occult, high-grade, clinically palpable prostate cancer, a survival benefit was seen in men diagnosed when their cancer was still clinically localised. Third, Gleason scores based on biopsies may differ from those after RP, with possible upgrading and downgrading. To address this, we additionally analysed the subset of men who did not undergo RP, thus their Gleason scores were based only on biopsy specimens. Among this subset of men, locally advanced compared with clinically localised prostate cancer on DRE (T3, T4 vs T2) was still associated with a significantly higher risk of PCSM and ACM. Finally, the present study is retrospective and does not systematically validate the use of DRE in the study cohort but provides evidence of a significant association between early detection based on the DRE and a reduction in risk of PCSM.

In conclusion, despite the potential limitations, it appears that the detection of prostate cancer when it is clinically localised as compared with locally advanced, among men with high-grade PSA-occult disease, may result in a survival benefit. These findings highlight the potential importance of DRE for the small but identifiable cohort of aging White men with declining testosterone levels where PSA lacks clinical utility.

ACKNOWLEDGMENTS

Dr Leon Sun, Surveillance Research Program, National Cancer Institute, Bethesda, MD, USA.

CONFLICT OF INTEREST

None declared.

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