Prostate-Specific Antigen Screening and 15-Year Prostate Cancer Mortality: A Secondary Analysis of the CAP Randomized Clinical Trial.

Importance: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) reported no effect of prostate-specific antigen (PSA) screening on prostate cancer mortality at a median 10-year follow-up (primary outcome), but the long-term effects of PSA screening on prostate cancer mortality remain unclear. Objective: To evaluate the effect of a single invitation for PSA screening on prostate cancer-specific mortality at a median 15-year follow-up compared with no invitation for screening. Design, Setting, and Participants: This secondary analysis of the CAP randomized clinical trial included men aged 50 to 69 years identified at 573 primary care practices in England and Wales. Primary care practices were randomized between September 25, 2001, and August 24, 2007, and men were enrolled between January 8, 2002, and January 20, 2009. Follow-up was completed on March 31, 2021. Intervention: Men received a single invitation for a PSA screening test with subsequent diagnostic tests if the PSA level was 3.0 ng/mL or higher. The control group received standard practice (no invitation). Main Outcomes and Measures: The primary outcome was reported previously. Of 8 prespecified secondary outcomes, results of 4 were reported previously. The 4 remaining prespecified secondary outcomes at 15-year follow-up were prostate cancer-specific mortality, all-cause mortality, and prostate cancer stage and Gleason grade at diagnosis. Results: Of 415 357 eligible men (mean [SD] age, 59.0 [5.6] years), 98% were included in these analyses. Overall, 12 013 and 12 958 men with a prostate cancer diagnosis were in the intervention and control groups, respectively (15-year cumulative risk, 7.08% [95% CI, 6.95%-7.21%] and 6.94% [95% CI, 6.82%-7.06%], respectively). At a median 15-year follow-up, 1199 men in the intervention group (0.69% [95% CI, 0.65%-0.73%]) and 1451 men in the control group (0.78% [95% CI, 0.73%-0.82%]) died of prostate cancer (rate ratio [RR], 0.92 [95% CI, 0.85-0.99]; P = .03). Compared with the control, the PSA screening intervention increased detection of low-grade (Gleason score [GS] ≤6: 2.2% vs 1.6%; P < .001) and localized (T1/T2: 3.6% vs 3.1%; P < .001) disease but not intermediate (GS of 7), high-grade (GS ≥8), locally advanced (T3), or distally advanced (T4/N1/M1) tumors. There were 45 084 all-cause deaths in the intervention group (23.2% [95% CI, 23.0%-23.4%]) and 50 336 deaths in the control group (23.3% [95% CI, 23.1%-23.5%]) (RR, 0.97 [95% CI, 0.94-1.01]; P = .11). Eight of the prostate cancer deaths in the intervention group (0.7%) and 7 deaths in the control group (0.5%) were related to a diagnostic biopsy or prostate cancer treatment. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, a single invitation for PSA screening compared with standard practice without routine screening reduced prostate cancer deaths at a median follow-up of 15 years. However, the absolute reduction in deaths was small. Trial Registration: isrctn.org Identifier: ISRCTN92187251.

Opportunistic prostate-specific antigen testing in Norwegian men: a public health challenge.

OBJECTIVE: To describe age-specific prostate-specific antigen (PSA) distributions and resulting prostate cancer diagnoses that arise from population-wide opportunistic PSA testing. PATIENTS AND METHODS: Over 8 million PSA tests were performed on >1.4 million Norwegian men from 2000 to 2020. During this period 43 486 men were diagnosed with localised prostate cancer. Most of the PSA testing reflected opportunistic testing. Age-specific PSA value distributions were constructed for men aged 45-75 years with and without prostate cancer. RESULTS: The distributions of PSA values in men with and without prostate cancer widened with age and overlapped extensively from 3 to 7 ng/mL. Localised prostate cancer diagnoses increased 10-fold from the age of 45 to 75 years. PSA testing identified intermediate- or high-grade cancers in 21% (95% confidence interval [CI] 19-23%) of men aged 50-54 years and 42% (95% CI 41-43%) of men aged 70-74 years. Grade group (GG)1, GG2, GG3 and ≥GG4 constituted 49%, 31%, 10% and 10% of cancers identified at age 50-54 years and 26%, 26%, 18%, and 30% of cancers identified at age 70-74 years. CONCLUSION: Opportunistic PSA testing increases with ageing and often generates values that cannot discriminate benign prostate enlargement from prostate cancer. A clinical cascade using additional imaging or serum tests is necessary to avoid negative biopsies and the overdiagnosis of indolent disease. The declining specificity of PSA testing with ageing poses a significant public health challenge especially among older men aged ≥70 years.

Baseline Serum Prostate-specific Antigen Value Predicts the Risk of Subsequent Prostate Cancer Death-Results from the Norwegian Prostate Cancer Consortium.

BACKGROUND: Prostate-specific antigen (PSA) levels in midlife are strongly associated with the long-term risk of lethal prostate cancer in cohorts not subject to screening. This is the first study evaluating the association between PSA levels drawn as part of routine medical care in the Norwegian population and prostate cancer incidence and mortality. OBJECTIVE: To determine the association between midlife PSA levels <4.0 ng/ml, drawn as part of routine medical care, and long-term risk of prostate cancer death. DESIGN, SETTING, AND PARTICIPANTS: The Norwegian Prostate Cancer Consortium collected >8 million PSA results from >1 million Norwegian males ≥40 yr of age. We studied 176 099 men (predefined age strata: 40-54 and 55-69 yr) without a prior prostate cancer diagnosis who had a nonelevated baseline PSA level (<4.0 ng/ml) between January 1, 1995 and December 31, 2005. INTERVENTION: Baseline PSA. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We assessed the 16-yr risk of prostate cancer mortality. We calculated the discrimination (C-index) between predefined PSA strata (<0.5, 0.5-0.9, 1.0-1.9, 2.0-2.9, and 3.0-3.9 ng/ml) and subsequent prostate cancer death. Survival curves were plotted using the Kaplan-Meier method. RESULTS AND LIMITATIONS: The median follow-up time of men who did not get prostate cancer was 17.9 yr. Overall, 84% of men had a baseline PSA level of <2.0 ng/ml and 1346 men died from prostate cancer, with 712 deaths (53%) occurring in the 16% of men with the highest baseline PSA of 2.0-3.9 ng/ml. Baseline PSA levels were associated with prostate cancer mortality (C-index 0.72 for both age groups, 40-54 and 55-69 yr). The fact that the reason for any given PSA measurement remains unknown represents a limitation. CONCLUSIONS: We replicated prior studies that baseline PSA at age 40-69 yr can be used to stratify a man's risk of dying from prostate cancer within the next 15-20 yr. PATIENT SUMMARY: A prostate-specific antigen level obtained as part of routine medical care is strongly associated with a man's risk of dying from prostate cancer in the next two decades.

PSA testing, cancer treatment, and prostate cancer mortality reduction: What is the mechanism?

Any effective screening program must satisfy 2 criteria: 1) the test must identify clinically significant disease earlier than its clinical presentation, and 2) a treatment must be available that will alter the natural history of the disease. The controversy surrounding PSA testing that has raged since 1991 centers on these 2 points. Screening and treatment trials published during the past 3 decades have provided critical insights into our understanding of the natural history of PSA identified cancers and the impact of treatment. This in turn raises questions concerning the mechanism of prostate cancer mortality reduction. This essay reflects on the mechanisms of disease progression and the implications for future screening and treatment efforts.

How many cores are enough? Optimizing the transperineal prostate biopsy template.

INTRODUCTION AND OBJECTIVE: Most urologists use a 10-12 core template during transrectal ultrasound guided prostate biopsy (TRUS-B). A similar consensus template does not exist for transperineal prostate biopsy (TP-B) including the optimal number and location of biopsy cores. We examined our institutional cohort to develop an optimal systematic template for TP-B. METHODS: We prospectively monitored our first 200 consecutive free-hand TP-B. These included men who were biopsy naïve (n = 117), had elevated PSA with prior negative biopsy (n = 18), and men on active surveillance (n = 65). All men underwent a 20 core TP-B with each core placed in a separate specimen container. This allowed the 20-core TP-B to be easily broken down as though fewer cores had been taken in each patient. Ten, 12, and 16 core templates were designed a priori and compared within each patient to the 20 core template. The highest Grade Group (GG) at pathologic analysis was assigned to each biopsy. Primary outcome was detection of clinically significant prostate cancer, defined as ≥GG2. Secondary outcome was detection of GG1 prostate cancer. We performed sub-group analyses of biopsy naïve men and biopsy naïve men stratified by PSA density (<0.15 vs. ≥0.15 ng/mL/cc). An historic institutional cohort of 10-12 core TRUS-B (n = 170) was used to compare prostate cancer detection between techniques. P value of ≤0.05 was considered statistically significant. RESULTS: Clinically significant cancers were detected in 98 men (49%) using a 20 core TP-B technique. Had we sampled fewer cores we would have identified clinically significant cancers in 93 (47%, 16 core), 91 (46%, 12 core), and 82 (41%, 10 core) men. More clinically significant cancers were detected by the 20 core template compared to the 10 core template for both the whole cohort (49% vs. 41%, P = 0.02) and the biopsy naïve subset (48% vs. 40%, P = 0.05). Additional cores did not result in an increased detection of GG1 cancers (20-core: 35% vs. 10-core: 44%, P = 0.09). Less than one quarter of biopsy naïve men with a PSA density <0.15 were found to have clinically significant cancers. More clinically significant cancers were detected in the 12-core TP-B cohort compared to the 12-core TRUS-B series (46% vs. 38%, P < 0.001). CONCLUSIONS: A 20 core TP-B systematic biopsy template detected a greater number of clinically significant prostate cancers compared to a 10 core TP template. Cancer detection was similar for 12, 16, and 20 core templates. Higher core numbers did not result in greater detection of GG1 tumors reflecting increased detection of concomitant ≥GG2 with greater sampling. We propose a minimum 12 core systematic biopsy template for men undergoing TP-B.

Prostate-specific Antigen Screening Using the Traditional Cut Point of 3 ng/ml: Con.

The prostate-specific antigen (PSA) threshold of 3.0 ng/ml is obsolete because it yields a test that is too sensitive. Urologists should adopt a more nuanced approach that accounts for benign prostate hypertrophy. This includes the use of magnetic resonance imaging, PSA density, and age-specific PSA reference ranges.

Prostate cancer screening and treatment: where have we come from and where are we going?

OBJECTIVE: To evaluate the current prostate cancer screening and treatment paradigm in light of recently published long-term results of major screening and treatment trials. METHODS: Historical review of the evolution of the diagnosis and treatment of prostate cancer followed by a detailed summary of the findings and differences among the three major screening trials and the three major treatment trials. RESULTS: Prostate-specific antigen (PSA) testing can identify clinically significant prostate cancer and has produced a significant stage shift and is the likely explanation for the decline in prostate cancer mortality. Unfortunately, PSA testing predominantly identifies low-grade disease that is unlikely to progress during a patient's lifetime leading to substantial diagnosis of indolent disease. Treatment with radical prostatectomy (RP) appears to benefit primarily younger men (aged <65 years) with intermediate-grade disease. Too few men with low-grade disease benefit from RP to justify intervening in all. Unfortunately, high-grade prostate cancer often progresses despite surgery and radiation. CONCLUSION: The primary PSA testing paradigm is wrong. Rather than attempting to identify all prostate cancers as early as possible, testing objectives should shift towards identifying men likely to harbour clinically significant disease. These are the men who appear to benefit from early diagnosis and intervention, including the earlier use of antiandrogen therapy prior to widespread metastases.