Prostate‐specific antigen testing testing in the modern era

Prostate cancer (PCa) continues to be one of the most commonly diagnosed cancers, particularly in Australia where incidence rates of PCa are amongst the highest in the world. More concerning is that PCa contributes to the second-highest number of cancer-related deaths in men in Australia, and despite widely held perceptions to the contrary, has been shown to have a five-year survival rate of 31–36% when diagnosed at an advanced stage. The introduction of serum prostate-specific antigen (PSA) testing in the 1990s aimed to detect PCa earlier at a stage amenable to curative treatment. Evolving evidence since then shows that PSA testing leads to an increase in PCa diagnosis and a slight reduction of disease-specific mortality over 10 years but may not improve overall mortality. Initially, many men were diagnosed and treated for low grade and clinically non-significant cancers, and the most common treatments for PCa come with a risk of urinary, sexual and bowel-related dysfunction. For this reason, PSA testing needs to be weighed against potential harms of over-diagnosis(lifetime risk of PCa diagnosis that would never have been clinically detected before death) and over-treatment (intervention for indolent disease with limited clinical benefit and associated morbidity). PSA testing should also be balanced with patients health-related quality of life, family history and pre-existent anxiety. Hence, PSA testing is not routinely performed and remains controversial. The last decade, however, has seen significant improvements in PCa diagnosis and management. The introduction of new imaging modalities such as multiparametric magnetic resonance imaging (mpMRI) allows for more accurate characterization of the disease leading to decreased rates of over-diagnosis. Sepsis is the most serious complication related to prostate biopsies, and investigation of false-positive PSA testing subjects patients to unwarranted morbidity. The significant improvement in sepsis rates with transperineal prostate biopsies (TPB) as compared with TRUS can reduce the harm from biopsies. Furthermore, the implementation of active surveillance for low-risk men has decreased rates of morbidity due to over-treatment. Consequently, it appears timely re-evaluating the effectiveness of serum PSA screening for the early detection of PCa in Australia, with a view to broader promotion of this investigation. Current guidelines recommend informed decision making regarding PSA testing, taking into consideration specific risk factors (i.e., family history), age, life expectancy and the need to balance benefit vs. harm of further investigations. However, recently published data demonstrate that PSA screening is more effective than initially thought. While the Prostate Lung Colorectal and Ovarian (PLCO) cancer screening trial found no significant difference in prostate cancer-specific deaths. The European Randomized Study of Screening for Prostate Cancer (ERSPC) trial randomized patients to PSA screening or no PSA screening. The control group of this study had significantly less crossover compared to the PLCO trial. The most recent update of this data found the number needed to invite (NNI) for men (aged 55–69 years) was 570; meaning 570 men were needed to be invited to screening to prevent one death from PCa. This number is less than that noted in a metaanalysis of eight trials for breast cancer screening (currently recommended in guidelines) where the number needed to screen was 838 for women over 50 years of age at 14 years follow up. These earlier studies were performed in the era before multiparametric prostate MRI (mpMRI) and TPB. MpMRI allows the selection of men with a high probability of clinically significant disease for biopsy (PIRADS score 4–5), thereby minimizing the potential for harm associated with a PCa diagnosis. Comparative analysis has shown TPB to have a lower rate of readmission due to sepsis as compared with transrectal prostate biopsies and thus reduced harm associated with biopsy and PSA screening. Prostate mpMRI now acts as the initial evaluation of a persistently elevated PSA and has significantly decreased the rates of overdiagnosis of clinically insignificant (low volume Gleason score 3 + 3/ISUP Grade 1) Pca. The diagnostic accuracy of mpMRI was confirmed in the PROMIS and PRECISION trials. The PROMIS group found that mpMRI had a higher sensitivity and negative predictive value (sensitivity 87%, NPV 72%) than transrectal ultrasound-guided (TRUS) biopsy (sensitivity 60%, NPV 65%). They estimated that mpMRI could save 27% of men from an unnecessary prostate biopsy and increase detection of clinically significant cancers by 18%. The PRECISION group found that mpMRI targeted biopsies detected 12% more clinically significant cancers and 13% fewer clinically insignificant cancers. Combined, these practice-changing studies revealed that the rate of overdiagnosis of clinically insignificant prostate cancer decreased when using mpMRI in the diagnostic pathway. Due to these studies, guidelines and clinical practice have changed to include the use of mpMRI. In Australia, this culminated in a world-first government-funded mpMRI for men with suspected PCa. The effect of this can be seen, with health systems reporting a decrease in the number of prostate biopsies and a reduction in the detection of clinically insignificant prostate cancer (Gleason 3 + 3/ ISUP 1). Like mpMRI, active surveillance has progressed to become the standard of care approach for men diagnosed with low-risk prostate cancer to delay or even mitigate the need for radical treatment. Before active surveillance, most men diagnosed with prostate cancer were initiated on ‘curative’ treatment with inherent risks of