Detection

Early prostate cancer is nearly invariably asymptomatic. Classic clinical symptoms of prostate cancer are due to urinary obstruction and resemble those of benign prostate hyperplasia (BPH). The most common symptoms are frequent urination, difficulties in maintaining adequate urine flow, urinary obstruction, nocturia, dysuria and hematuria. Advanced prostate cancer can give systemic symptoms, such as unintentional weight loss, fever, anemia, fatigue and bone pain (typically in spine) or fractures (Taari et al. 2013).

The first clinical exam is the digital rectal examination (DRE). Typical findings in prostate cancer include abnormally hard or irregular prostate. It is important to consider that stage tumor might not be palpable and therefore to detect early-stage cancers further examination is required (Duodecim 2014).

PSA concentration helps clinicians to decide which patients might benefit from additional urological examination. Patients with evidently high PSA levels should be

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referred to a urologist, but often PSA level is only marginally over the reference levels (Taari et al. 2013). If total PSA is 2.5 - 10 ug/l, it is useful to determine the proportion of free PSA. Low free PSA concentration indicates an increased prostate cancer risk and 15 % is considered as a cut-point to decide whether a patient needs further examination (Duodecim 2014). Probability of prostate cancer at certain levels of PSA and free PSA percentages are presented in Table 1. It is essential to comprehend that poor sensitivity is the most relevant disadvantage of PSA testing. There is a lot of variation in sensitivity and specificity of PSA depending on a study population and a method used to confirm the prostate cancer diagnosis. The American Cancer Society concluded that baseline PSA of 4.0 ug/l or more has a sensitivity of 21% and specificity of 91% (Wolf et al. 2010).

In suspicious but unclear cases it is important to monitor PSA concentration since with prostate cancer PSA level usually rises over time. PSA velocity over 0.75 ug per year is an indication for further examination. In addition, if 5-ARI has been prescribed for the patient, PSA level should decrease 50% during the treatment and if this does not occur, the possibility of prostate cancer should be excluded.

Urologist’s basic exams to patient with suspected prostate cancer are transrectal ultrasound (TRUS) and prostate biopsy. TRUS is useful to evaluate the size and consistency of the prostate, but malignancy cannot be excluded by TRUS. Prostate biopsy is conveniently taken after ultrasound. It is recommended to take 12 tissue samples at different parts of the prostate. Negative biopsy results do not definitively exclude a prostate cancer, so examination should be repeated if malignancy is clinically probable. (Duodecim 2014).

Magnetic resonance imaging (MRI) provides additional information besides classic diagnostic methods. The primary indication for MRI is a situation, in which prostate biopsy is negative but PSA increases during a follow-up. If a suspicious area is found, MRI-targeted prostate biopsies are taken. The cancer detection percentage among men with previous negative biopsies was found to be higher with MRI-targeted biopsy compared to TRUS-guided biopsy (46% vs. 23%, p<0.05) and cancers diagnosed with MRI-targeted biopsy showed more features of clinical significance (biopsy Gleason pattern ≥ 4 or tertiary pattern 5, serum PSA >10 ug/l and PSA density >0.15 ug/l/cm3) (Kaufmann et al. 2015). In the PRECISION trial, among the MRI-targeted biopsy group Gleason score 3+4 or greater cancer was detected in 95 men (38%) whereas among men in the standard-biopsy group clinically significant cancer was detected in 64 men (26%) (p = 0.005) (Kasivisvanathan et al. 2018). However, conflicting results have been published (Arsov et al. 2015). In the future, it might be possible to perform MRI and take

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targeted biopsies before or instead random prostate biopsies. Studies have observed that the method mentioned above reduces the detection of low-grade prostate cancers and the number of biopsies whereas the detection of clinically significant prostate cancer is improved (Delongchamps et al. 2013; Garcia Bennett et al. 2017;

Pokorny et al. 2014).

Due to poor sensitivity of PSA, several new prostate cancer detectors are being researched. A four-kalligrein panel called 4Kscore includes total PSA, free PSA, intact PSA and kallikrein-related peptidase 2. Combining markers mentioned above can reduce unnecessary prostate biopsies. Data from ERSPC shows that four-kallikrein panel had better predictive accuracy compared to PSA and age alone (the area under the curve (AUC) of 0.711 vs 0.585, p<0.001) (Vickers et al. 2010). The Stockholm 3 model is a combination of plasma protein biomarkers (PSA, free PSA, intact PSA, hK2, MSMB, MIC1), gene polymorphisms (232 Single nucleotide polymorphisms (SNPs)), and clinical variables (age, family history, previous prostate biopsy). When the Stockholm 3 model was compared to PSA testing only, the Stockholm 3 was significantly better for detection of prostate cancers with a Gleason score 7 or more (the AUC 0.74, 95% CI 0.72-0.75 vs 0.56, 95% CI 0.55-0.60, p<0.0001) (Scott et al. 2017).

The Prostate Health Index (phi) is a combination of three different isoforms of PSA: total PSA, free PSA, and [−2]proPSA. An Italian study of 268 men with PSA levels of 2-10 ng/ml and negative DRE evaluated phi. Men were referred to extended prostate biopsy with the primary objective to compare phi with commonly used tests, total PSA, free PSA percentage and PSA density. Diagnosed prostate cancer cases (39.9%) had a higher phi (median 44.3 compared to 33.1, p < 0.001).

Phi had superior sensitivity (42.9%) than free PSA percentage (20.0%) or PSA density (26.5%) and predictive accuracy (AUC 0.76 for phi) than PSA density (AUC 0.61), free PSA percentage (AUC 0.58) or total PSA (AUC 0.53) (Guazzoni et al.

2011). A similar observation was made in a US study (Catalona et al. 2011).

In addition, biomarkers can be used to distinguish prostate cancer from BPH even though they are not commonly used. The Prolaris cell cycle progression (CCP) test is a gene test evaluating how quickly neoplastic cells proliferate. It has been suggested to be potentially used to advance the accuracy of individual risk evaluation.

However, a review evaluating two before-after studies observed that even though CCP test may change the treatment for some low- and intermediate-risk patients it would result in a major increase in cost to the health care budget (Health Quality Ontario 2017).

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Table 1. Likelihood of prostate cancer at certain PSA (prostate specific antigen) concentrations (Jousimaa et al. 2017).

Total PSA Probability of prostate cancer

0-2 ug/l 1%

2-4 ug/l 15%

4-10 ug/l 25%

>10 ug/l >50%

Free PSA percentage when total PSA between 4-10 ug/l

0-10% 56%

10-15% 28%

15-20% 20%

20-25% 16%

>25% 8%