The goal of screening for any malignancy is early detection with the hopes of intervening with treatment at an earlier time period in order to reduce cancer-specific mortality. Screening for prostate cancer involves a digital rectal examination (DRE) and a serum PSA blood test. Screening in certain instances may lead to over treatment of clinically insignificant disease, for which urologists have been criticized with regards to prostate cancer over treatment.1, 2 Notwithstanding, during the PSA screening era for prostate cancer, disease mortality has declined by ~40% with a substantial decrease in men presenting with advanced malignancy.3
Two randomized control trials (RCTs) were initiated in 1993 to compare prostate cancer-specific mortality between prostate cancer screened and unscreened men.4, 5 The European Randomized Study of Screening for Prostate Cancer (ERSPC) trial identified 182,000 men (ages 50-74 years) who were randomly assigned to a group that was offered PSA screening once every four years or to a control group that did not receive screening4. During a median follow-up of 9 years, the cumulative incidence of prostate cancer was 8.2% in the screening group and 4.8% in the control group. The rate ratio (RR) for death from prostate cancer in the screening vs control group, was 0.80 (95%CI 0.65-0.98). This correlated to 1410 men needing to be screened and 48 additional cases of prostate cancer treated to prevent one death from prostate cancer. The Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial randomly assigned men in the US to receive either annual screening (n=38,343) or usual care (n=38,350).5 Importantly, in this trial “usual care” occasionally included screening; rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing. After seven years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 in the screening group and 95 in the control group (RR 1.22; 95CI 1.16-1.29). The incidence of death per 10,000 person-years was 2.0 in the screening group and 1.7 in the control group (RR 1.13; 95%CI 0.75-1.70), thus the results of the study suggested that prostate cancer screening did not reduce cancer-specific mortality.
Since the initial reporting of these two RCTs nearly a decade ago, several follow-up iterations have been published for the ERSPC6, 7 and PLCO8, 9 trials, confirming initial results: a screening benefit in the ERSPC trial and no benefit in the PLCO trial. These trials have been thoroughly analyzed as to potential reasons for differing results. The PLCO trial had (i) a shorter screening interval, (ii) higher threshold for prostate biopsy, (iii) halted regular screening after six rounds, and had (iv) “contamination” in the control group, considering that these men often received screening. As such, the PLCO has been described as organized screening vs opportunistic screening, rather than screening vs no screening.8, 9
Recommendations for Screening
The United States Preventative Services Task Force (USPSTF) has been highly critical of PSA screening and relied heavily on results of the PLCO trial for their recommendations against routine screening for prostate cancer.2, 10 The American Urological Association (AUA) guidelines for prostate cancer screening were most recently released in 2013 and revalidated in 2018,11 suggesting shared decision making for men 55-69 years of age who are considering PSA-based screening. These recommendations were based on the benefits outweighing the harms of screening in this age group. Other organizations, such as the European Association of Urology (EAU), recommend a baseline PSA test at age 40-45, which is then used to guide a subsequent screening interval.12 Most recently, the USPSTF changed their recommendation against PSA screening for men aged 55-69 (Grade D) to a Grade C recommendation for prostate cancer screening: clinicians should not screen men who do not express a preference for screening.13
Triggers for Biopsy
Various “triggers” for prostate biopsy have been proposed with no consensus agreement. Generally, urologists agree that a positive DRE finding should be followed by a prostate biopsy. When the DRE is unremarkable, PSA thresholds are primarily used to guide recommendations for consideration of a prostate biopsy. The upper limit of a normal PSA has historically been set at 4 ng/mL, however the ERSPC has suggested this level should be lowered to 2.5-3.0 ng/mL. A recent study suggested that men <50 years of age with a PSA >1.5 ng/mL should consider a prostate biopsy, as more than half of these patients diagnosed with prostate cancer exceed the Epstein criteria for active surveillance.14 Furthermore, in an ad hoc analysis of the placebo arm of the Prostate Cancer Prevention Trial (PCPT), Thompson et al.15 showed a continuum of prostate cancer risk at all PSA values: PSA cutoff values of 1.1, 2.1, 3.1, and 4.1 ng/mL yielded sensitivities of 83.4%, 52.6%, 32.2%, and 20.5%, and specificities of 38.9%, 72.5%, 86.7%, and 93.8%, respectively, for detecting any prostate cancer. Undoubtedly, there is no perfect trigger for deciding whether to perform a prostate biopsy, as all factors must be taken into account, including age, race, family history, PSA trend, etc.
The clinical staging of prostate cancer relies on factors prior to treatment, such as PSA, DRE, prostate biopsy results, and imaging findings. Pathologic staging of prostate cancer relies on the stage of disease after surgical extirpation of the prostate. The following discussion will primarily focus on clinical staging.
Prostate Biopsy and Gleason Classification
At the time of prostate biopsy, a “systematic sampling” of the prostate is undertaken, typically consisting of 10-12 biopsy cores of tissue. Positive samples are then scored a primary and secondary Gleason score: 3+3, 3+4, 4+3, 4+4, 4+5, 5+4, or 5+5. Over the last 20 years, the D’Amico risk stratification has been commonly used to guide treatment16 Low-risk disease (cT1-2a, PSA ≤10 ng/mL, and Gleason ≤6), intermediate-risk disease (T2b or PSA >10 ng/ml but <20 ng/ML, or Gleason score 7), and high-risk disease (T2c, or PSA >20 ng/mL or Gleason 8-10), conferred freedom of disease 10-years after radical prostatectomy rates of 83%, 46%, and 29%, respectively.16
Several years ago, the Gleason Grade Group (GGG) was proposed to better reflect the true cancer biologic aggressiveness and better guide treatment: GGG 1 is Gleason 6, GGG 2 is 3+4=7, GGG 3 is Gleason 4+3=7, GGG 4 is Gleason 8, GGG 5 is Gleason 9-10.17 In a Swedish population-level database of 5,880 men diagnosed with prostate cancer, using the GGG schema demonstrated four-year biochemical recurrence-free survival rates of 89% (GGG 1), 82% (GGG 2), 74% (GGG 3), 77% (GGG 4), and 49% (GGG 5) on biopsy, and 92% (GGG 1), 85% (GGG 2), 73% (GGG 3), 63% (GGG 4), and 51% (GGG 5) based on prostatectomy data18 Generally, the GGG classification offers a simplified nomenclature with predictive accuracy comparable to previously used classification schemes.
Several imaging modalities have been used to radiographically stage prostate patients. Generally, staging studies have included a radionuclide bone scan (to assess for skeletal metastases) and a computed tomography (CT) scan of the abdomen and pelvis (to assess for lymphadenopathy). Selecting appropriate patients for imaging is a point of much debate. The general consensus is that there is no role for imaging patients with low-risk disease, whereas imaging is appropriate for patients with either PSA >20 ng/mL, GGG 4-5, cT3-T4 or clinical symptoms of bone metastases.11
The improvement in multi-parametric MRI (mpMRI) technology has allowed, not only the ability to perform targeted prostate biopsies but also to stage patients for locoregional extent of disease. mpMRI comprises anatomic sequences (T1/T2) supplemented by functional imaging techniques such as diffusion-weighted and dynamic contrast-enhanced (DCE) imaging. When performed at high resolution, DCE facilitates detection of disease, as well as an assessment of extracapsular extension, urethral sphincter, and seminal vesicles involvement.20 Furthermore, mpMRI may provide accurate information for planning robotic prostatectomy. In a study assessing the ability of mpMRI to assist with planning neurovascular bundle preservation, mpMRI results changed preoperatively planning in 26% of cases based on the extent of disease.21