Screening for prostate cancer: an updated review

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tion methods for prostate cancer, as well as the recent recommendations for screening. Prostate-specific antigen. PSA is an enzyme that belongs to the human.
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Screening for prostate cancer: an updated review Expert Rev. Anticancer Ther. 13(1), 101–108 (2013)

Gustavo Nader Marta*1, Samir Abdallah Hanna1, João Luis Fernandes da Silva1 and Heloisa de Andrade Carvalho1 Radiation Oncology Department Hospital Sírio-Libanês, Rua Dona Adma Jafet 91, Sao Paulo-SP, Brazil * Author for correspondence: Tel.: +51 113 155 0558 Fax: +51 113 155 0983 [email protected] 1

Prostate cancer is the most frequently diagnosed malignancy in men and its incidence has been increasing in the last decades. Diagnosis and treatment of prostate cancer were radically improved after the discovery of prostatic-specific antigen. Early detection rates increased, especially in asymptomatic individuals, confirmed by recent published randomized trials. The impact of screening in overdiagnosis and overtreatments is discussed, since benefits in overall mortality rates were not clearly demonstrated. Perhaps younger patients with a longer life expectancy would be the ones with the most benefits from screening. This study presents an update of the most important screening methods for prostate cancer as well as the recent recommendations for screening. Keywords: cancer screening • diagnoses • examinations • mass screening • neoplasms • prostate • prostate cancer • prostatic-specific antigen

Prostate cancer is the most frequently diagnosed malignancy in men (except for skin cancer) and its incidence has been increasing over the past decades. In 2008, it was estimated that 903,000 new cases would be diagnosed worldwide, with 258,000 cancer-related deaths [1] . Global incidence rates represent 9.7% of the malignancies in men; however, the distribution varies from 15.3% in developed countries to only 4.3% in developing countries [2] . In 2011, the USA estimated a diagnosis of 241,000 new cases, with approximately 34,000 cancer-related deaths [3] . This corresponds to a lifetime risk of 16% of being diagnosed with prostate cancer and a lifetime risk of 2.9% of dying from the disease [101] . In Brazil, the National Cancer Institute estimated 60,180 new cases for 2012, corresponding to a risk of 62:100,000 men [102] . Allied to the development of improved diagnostic methods, longer life expectancy and the Occidental lifestyle (sedentary and high calorie diets) are among the factors that may contribute to the increasing incidence of prostate cancer. Migration of individuals from low- to high-risk countries substantially increases the incidence of the cancer, demonstrating that the environment and lifestyle may influence tumoral genesis [4–6] . Nevertheless, besides the differences in the incidence of prostate cancer among populations, the findings of latent tumors in autopsy studies are similar worldwide [6] . www.expert-reviews.com

10.1586/ERA.12.154

Discovery of prostate-specific antigen (PSA) three decades ago was revolutionary for both the diagnosis and treatment of prostate cancer. An increase in early detection was observed, mainly in asymptomatic individuals with a significantly increased proportion of organ-confined tumors compared with those detected through evaluation for an abnormal digital rectal examination (DRE) alone [7] . Considering PSA screening, a third of the cases are diagnosed in men less than 80 years of age and two-thirds in older ones, in an era where screening was opportunistic [8] . This characterizes the slow-growing nature of the disease and most of these patients will die from causes other than cancer. However, since the influence in mortality was not well established, the value of screening remained highly debated mainly for the elderly population. These controversies have recently been acknowledged and strategies to reduce the detection of clinically insignificant cancers could result in cost savings by reducing the number of men needing radical treatment. This study presents an update on the most important screening and early detection methods for prostate cancer, as well as the recent recommendations for screening. Prostate-specific antigen

PSA is an enzyme that belongs to the human calicrein family (hK3) and is synthesized in the prostatic epithelium. It has the function of promoting seminal protein lysis. This protease

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has a half-life of 2.2 days and is under the control of androgens and progestins [9] . PSA is an organ-specific rather than a diseasespecific marker. The concept that cancer cells produce more PSA is misguided, since the physiologic mechanism of the serum concentration increase of PSA is related to the cellular lyses. However, PSA may also be produced by paraurethral glands, normal or neoplastic mammary tissue, amniotic fluid and rarely some ovarian neoplasms, but the amount synthesized can not significantly affect plasma concentrations. Serum PSA exists in several molecular forms that can be measured by immunoassays: free PSA (fPSA), complexed PSA bound to α1-antichymotrypsin (cPSA) and total PSA (tPSA; which represents the sum of free and complexed form). There are several situations that can interfere in the normal range of PSA. Among those that may present an increase of this marker, we can mention [10–17] : DRE, ejaculation, bacterial prostatitis, asymptomatic prostatic inflammation, prostate biopsy, trans­urethral resection of the prostate, urinary retention, transrectal ultrasonography, benign prostatic hyperplasia and prostate cancer. Factors, in turn, that can reduce the plasma concentration of PSA are related to the intake of substances such as 5-α reductase inhibitors (5ARI [18–27]) responsible for inhibition of the production of the androgen dihydrotestosterone (DHT) from its precursor testosterone. DHT is responsible for the normal development and maintenance of the prostate gland, but also contributes to the growth of benign prostatic hyperplasia and may influence the development of prostate cancer. In addition, DHT is one of the main regulators of PSA secretion [28] . Finasteride (at 5 mg or 1 mg per day) reduces prostate volume and the PSA value by approximately 50% during the first year of use [22] , while dutasteride may further inhibit DHT production and decrease prostate volume and PSA more than finasteride. A 59.5% decrease at 2 years and a 66.1% decrease at 4 years is reported for patients taking dutasteride, with the decrease starting at 6 months [18,19,28] . Thus, it is essential to consider duration of therapy when evaluating the risk of prostate cancer in patients on 5ARI treatment. A doubling factor was proposed to compensate for the reduction in PSA, with its value confirmed by two large, double-blind, placebo-controlled trials [25] . Despite this validation, it is important for clinicians to remain aware of potential confounding effects when using the doubling rule to estimate prostate cancer risk. A correction factor of 2 should be used to interpret the value of PSA in patients taking finasteride for 2 years; the factor should be increased to 2.5 when the medication is being used for a longer period [20] . On the other hand, applying the doubling rule too early can overestimate risk. As the initial 50% decrease in PSA takes place over the course of a year of therapy, applying the doubling rule within the first year of finasteride treatment can result in an overestimation of prostate cancer risk [29] . Nevertheless, the REDUCE trial suggests that any increase in the PSA levels in patients taking dutasteride should be investigated [18,19] . Furthermore, in men not taking 5ARI, a rise in PSA does not always lead to a recommendation to undergo biopsy, which is usually based on multiple factors, including absolute PSA level and the magnitude of PSA velocity. 102

Other drugs such as NSAIDs and acetaminophen (­paracetamol), statin and hydrochlorothiazide, can cause moderate reductions in serum PSA levels [30–33] . In addition, substances that promote chemical castration, such as analogues of LH-RH, cause drastic reductions (to normal values) in serum PSA levels, in approximately 90 days [34] . Variables such as age, BMI and ethnicity can also influence the serum levels of total PSA. In general, Caucasians have lower PSA levels when compared with black individuals; obesity sufferers have lower plasma concentrations, which can be explained by the influence of estrogen. The tPSA also varies regarding age, being higher in older age [35–41] : 40–49 years to 0–2.5 ng/ml, 50–59 years to 0–3.5 ng/ml, 60–69 years to 0–4.5 ng/ml and 70–79 years to 0–6.5 ng/ml. Therefore, the PSA value above which a biopsy should be indicated for confirmation of malignancy is still controversial. Based on key studies, a value of 4.0 ng/ml has been widely accepted as a cutoff for biopsy indication [7,42–44] . The American Cancer Society (ACS) demonstrated, in a joint analysis of a systematic literature review [45] , a 21% estimated sensitivity for the detection of prostate cancer using 4.0 ng/ml as the cutoff value PSA and 51% for tumors with high histological grade (Gleason ≥8). However, using a cutoff of 3.0 ng/ml, the sensitivity increased to 32 and 68%, respectively. Specificity was estimated as 91% for 4.0 ng/ml and 85% for 3.0 ng/ml, respectively. These values were derived from different study populations and it has become increasingly clear that there is no PSA threshold that effectively discriminates between the presence and absence of prostate cancer. However, the authors comment that the higher prostate cancer detection rate, together with the reduced specificity, that would occur if the threshold were lowered uniformly from 4.0 ng/ml would translate into an increase in overdiagnosis and overtreatments. They recommend that in patients with PSA levels between 2.5 and 4 ng/ml, risk assessment and decision‑making should be individualized. Despite the attempt to establish a cutoff value for investigation, there is a risk of prostate cancer even in patients with PSA values ≤4.0 ng/ml that can vary from 6.6 (PSA between 0 and 0.5 ng/ml) to 26.9% (PSA between 3.1 and 4 ng/ml [46,47]). Patients with PSA between 4 and 10 ng/ml and above 10 ng/ml have a 30 and 62% probability of developing prostate cancer, respectively [48] . Thus, there is no reliable PSA cutoff value for the diagnosis of prostate cancer. Due to this limitation, there is a continuous effort to improve the diagnostic tools for the detection of prostate cancer. The most promising approach to improve the specificity of PSA, particularly in the range of 10 ng/ml or lower, is the measurement of molecular isoforms of PSA. These are the disengaged fPSA and the cPSA bound to α1-antichymotrypsin, already cited above. Several studies have shown an increase in sensitivities and specificities, primarily in the PSA range of 10 ng/ml or lower, for the ratio of free to total PSA (f/tPSA). This ratio can better distinguish between patients with prostate cancer from patients with a benign hyperplasia of the prostate [49–51] . For cPSA, the data in the current literature are inconsistent. Some demonstrate an improvement in the early detection of prostate cancer, while others do not [52–55] . Expert Rev. Anticancer Ther. 13(1), (2013)

Screening for prostate cancer

Other markers were also developed in an attempt to improve the s­creening efficacy for prostate cancer. PSA velocity or PSA doubling time (‘PSA kinetics’)

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underwent prostate biopsy showed that the PSA conjugate was more specific than the tPSA. For patients with tPSA between 4 and 10 ng/ml, when a cPSA cutoff was chosen to obtain 90% sensitivity, cPSA had a higher specificity than the tPSA (13.3 vs 8.6%). For males with tPSA between 2 and 6 ng/ml, cPSA was more specific than other methods. However, the marginal benefit of measuring cPSA compared with tPSA remains uncertain [64] .

The PSA velocity is defined as the variation of serum PSA levels in a given time interval. Usually, the individual without prostate cancer has an increase of less than 0.1 ng/ml per year. Carter et al. have shown that individuals with a PSA rise greater than 0.75 ng/ml per year are at an increased risk of being diagnosed with prostate cancer and that this parameter is more specific than the use of the cutoff value of 4.0 ng/ml of tPSA (90 vs 60% specificity) [56] . Moreover, according to a systematic review of the literature, the rate of rise of PSA as a predictor of prostate cancer presents several methodological limitations and essentially there is no evidence to support its use for clinical decision‑making [57] . Thus, even if the PSA velocity can be independently correlated with a diagnosis of cancer, it adds little to the diagnostic accuracy of the tPSA alone [58–60] .

The DRE is a practice widely used to diagnose prostate cancer. The main abnormal findings on clinical examination are nodules, gland asymmetry and hardening. No controlled studies have demonstrated a reduction in the morbidity and mortality rates of prostate cancer when detected by digital examination at any age [65] . The digital examination has 59% sensitivity and 94% specificity to detect prostate cancer [66] . The positive predictive value of an abnormal DRE for prostate cancer ranges from 5 to 30% [67–69] .

PSA density

Combination PSA & DRE

PSA density is defined by the relationship between the value of serum PSA and prostate volume assessed by ultrasound or MRI. Individuals with PSA values between 4.0 and 10.0 ng/ml and PSA density greater than 0.15 were more likely to develop prostate tumor [61] . However, measurements of PSA density require imaging methods to assess the prostate volume which restricts its applicability and reproducibility, and is not routinely used.

The PSA and DRE are complementary and their combined use may increase the overall rate of detection of prostate cancer [70–72] . The screening of more than 6000 individuals showed a tumor detection rate of 3.2% for digital rectal examination, 4.6% for PSA and to 5.8% for both methods combined [73,74] . PSA alone detected 45% of cancer cases and DRE, 18%. A positive predictive value of 10% was found in the presence of a suspected DRE with normal PSA levels. The positive predictive value was 24% with a high PSA and normal DRE. Based on this rationale and in order to verify whether screening with DRE and PSA is effective in reducing the mortality rate from prostate cancer, two major ­studies were conducted. The first study, performed by a European group, aimed to evaluate the effect of screening, with serial PSA measurements, in the death rate from prostate cancer [75] . The study included 182,000 men from 50 to 74 years of age registered in seven European countries. Patients were randomized into two groups: screening group – 82,816 men who had PSA control in an average of at least one examination every 4 years and control group – 89,353 men with no screening. The mean follow-up was 9 years and the cumulative incidence of prostate cancer was 8.2% in the screening group versus 4.8% in the control group. The hazard ratio (HR) for mortality was 0.80 (95% CI: 0.67–0.95) in favor of the screening group. The absolute risk of death was 0.71 per 1000 men in the screening group. The authors concluded that screening with PSA has led to a 20% reduction in mortality from prostate cancer in 9 years for patients with 55–69 years of age. An update of this study, with 11 years of follow-up, confirms that screening with PSA significantly reduces mortality from prostate cancer [76] . The second study with similar design was developed by the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial [77] . The study aimed to evaluate the effectiveness of screening with PSA and DRE and its impact on the mortality rates from prostate cancer. This was a prospective randomized study with 76,693 men between 55 and 74 years of ten US centers. The cases

PSA isoforms Free PSA

The PSA, entering the bloodstream, can be added to plasma proteins or remain in free form. The fPSA represents 5–40% of the total detectable PSA and does not have proteolytic characteristics; it is inactivated in the prostate epithelium before reaching the bloodstream. Cancer cells cannot synthesize larger amounts of PSA than benign cells. However, the PSA originating from the tumor tissue is not inactivated before entering the bloodstream and can fuse with plasma proteins and thus be measured. This is why patients with prostate cancer have lower PSA fractions. The percentage of fPSA can be used to select patients who will undergo prostate biopsy when the value of tPSA is between 4.0 and 10.0 ng/ml. Employing the tPSA/fPSA ratio with the cutoff value set at 25%, 95% of the tumors were diagnosed and 20% of unnecessary biopsies were avoided [62] . The role of fPSA as a predictor of tumor was evaluated in a meta-analysis [63] . Considerable variability in the analysis of PSA, in the form of samples preparation, in the definitions of cutoff points and in studied populations was found. The conclusion was that more research is needed to determine the ideal cutoff value and to accurately assess the diagnostic performance and utility of screening in populations. Complexed PSA

Approximately 70–90% of the serum PSA is combined with the α-1 antichymotrypsin. A prospective study of patients who www.expert-reviews.com

Digital rectal examination

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were selected in the period from 1993 to 2000 and divided into two groups: men who had annual screening (n = 38,343) – annual PSA for 6 years and DRE for 4 years – and men who received only routine care (n = 38,350) – control group. Of the screening group, 85% of men were included in the analysis and 52% of the control group. After 7 years of follow-up, the number of diagnoses of prostate cancer was higher in the screening group: 2820 versus 2322 in the control group (HR 1.22, 95% CI: 1.16–1.29), keeping the same profile after 10 years: 3452 diagnoses for the screening group versus 2974 for the control group (HR: 1.17; 95% CI: 1.11–1.22). However, regarding the deaths, there were 50 events in the screening group and 44 in the controls (HR: 1.13; 95% CI: 0.75–1.70) in 7 years of follow-up, keeping a similar proportion in 10 years (92 screening group vs 82 control group, HR: 1.11; 95% CI: 0.83–1.50). They concluded that after 7 and 10 years of follow-up, the death rate from prostate cancer is small and no statistically significant difference between the two groups related to mortality was found. An update of this study, with 13 years of follow-up, shows that there was no influence in mortality rates when comparing annual with opportunistic screening, which forms part of usual care, and there was no apparent interaction with age, baseline comorbidity or pretrial PSA testing [78] . The findings of these two studies were conflicting, and some comments should be made. In the American study, the minimum follow-up time was 7 years, with a median of 11.5 years (7.2–14.8), while in the European group it was 9 years. It is well known that for prostate cancer such periods are not enough to delineate the actual mortality rates profile (the number of events ‘death’ is small). Thus, a longer follow-up would be necessary to achieve a more definitive conclusion. In addition, the European study showed a benefit for patients younger than 70 years, who naturally have a longer life expectancy. The control group was ‘contaminated’ in the US study, since over 40% of patients ended up screening, reducing the statistical power of the study. In the European study, no mention of the contamination of the c­ontrol group is made. Despite these results, the ACS emphasizes the need to involve men in deciding whether or not to undergo screening for prostate cancer, reporting on the risks and benefits of the screening. For those who choose screening, the ACS recommends performing a PSA test with or without DRE from the age of 50 years. Screening should not be offered to men with a life expectancy below 10 years. Men with baseline PSA greater than or equal to 2.5 ng/ml should undergo annual tests, and the others can be evaluated every 2 years. The guidelines also recommend to start screening at 40 or 45 years in patients at high risk of developing prostate cancer (e.g., black men and men with a first‑degree relative with prostate cancer diagnosed before the age of 65 years) and keep the reference threshold for biopsy in 4.0 ng/ml. However, for men with PSA levels from 2.5 to 4.0 ng/ml, the decision must be individualized by assessing factors such as age, race, family history, DRE, previous biopsy results and use of drugs such as inhibitors of 5α-redutase [50] . In the randomized European study already mentioned, after 9 years of follow-up, the screened group showed cancer-specific 104

survival rates 20% higher than those not screened, with a tendency to a separation of the curves at long-term follow-up. Although these data have been criticized, it generated an undesirable side effect: risk of overdiagnosis and overtreatments accompanied by their potential side effects. The study showed that, to save one life from prostate cancer it would be necessary to treat 48 men and perform screening of 1410 individuals, which is considered a small gain to recommend routine screening by public health authorities. One must therefore wait for more mature results and future studies with larger samples to determine the best ­recommendation to be followed. The 2008 recommendations from the US Preventive Services Task Force [103] concluded that there was no evidence to support PSA testing for men over the age of 75 years. An update of these recommendations, published in 2012 [79] , considered those two major trials of PSA testing in asymptomatic men to assess the lifesaving benefits and risks of treatment of localized prostate cancer. The Task Force now recommends against PSA-based screening for all men, regardless of age. This recommendation does not include the use of the PSA test for surveillance after diagnosis or treatment of prostate cancer; the use of the PSA test for this indication is outside the scope of the US Preventive Services Task Force. These recommendations were intensively debated with the arguments that the Task Force considers health benefits and risks, but not costs, when developing recommendations, in addition to a panel that did not include a urologist or cancer specialists. The primary goal of prostate cancer screening programs is to save lives and prevent symptomatic disease. The Task Force recommendation has underestimated the benefits and over­estimated the risks of prostate cancer screening and largely bases its recommendations on flawed studies with inadequate follow-up time. The Task Force recommendations focus on mortality and do not take into consideration the substantial illness related to living with advanced cancer [80] . On the other hand, conflicting recommendations were stated by the American Society of Clinical Oncology [81] based on the strength of evidence: in men with a life expectancy ≤10 years, it is recommended that general screening for prostate cancer with total PSA be discouraged, because risks seem to outweigh potential benefits (evidence based: strong); in men with a life expectancy >10 years, it is recommended that physicians discuss with their patients whether PSA testing for prostate cancer screening is appropriate for them. PSA testing may save lives, but is associated with risks, including complications from unnecessary biopsy, surgery or radiation treatment (evidence based: moderate). It is recommended that information written in lay language should be available to clinicians and their patients to facilitate the discussion of the benefits and potential risks associated with PSA testing before the routine ordering of a PSA test. To stimulate this discussion, the extent to which PSA screening affects quality of life resulting from overdiagnosis and treatment was recently addressed. Various screening strategies, efficacies and quality-of-life-year (QALY) assumptions were modeled and applied in the patients of the European Randomized Study of Screening for Prostate Cancer. The authors reported that screening of all men between the ages of 55 and 74 years would result in Expert Rev. Anticancer Ther. 13(1), (2013)

Screening for prostate cancer

more life years gained (82 years), but the same number of QALYs (56 years). However, the benefit of PSA screening was diminished by loss of QALYs owing to postdiagnosis long-term effects [82] . At this point, we agree that men concerned about prostate cancer should talk with their healthcare providers to make a decision based on their individual risk factors and personal preference. Expert commentary

The use of population screening for early detection of prostate cancer is still a controversial issue. Although it is a very common disease, evidence of improved survival with screening and their economic benefits are still uncertain. Due to the lack of categorical evidence of population benefits, the decision should be discussed individually between doctor and patient. PSA and DRE are still the best tools for screening.

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New tumor markers have been studied to better define the appropriate approach in this context [83] , such as the prostate cancer antigen 3 gene (PCA3). PCA3 is overexpressed in most of all prostate cancer tissue, but not in hyperplastic or normal tissue. After a robust digital rectal examination, the PCA3 score is analyzed from a urine specimen collected. It has also been used for guiding biopsy decisions when PSA levels are in indeterminate levels and for patients with negative biopsies with persistently elevated PSA [84] . Despite the fact that genetic markers have the potential to add to tumor screening, they have not been prospectively validated to give useful predictive information or improve the clinicopathologic parameters already in use. New methods that would allow for the distinction between indolent disease and disease that is likely to clinically progress are critically needed, in order to lower the risk of overdiagnosis and subsequent overtreatment.

Five-year view

Screening for prostate cancer can reduce mortality from disease, but the absolute risk reduction is very small. Based on the recent randomized trials, it is unclear whether the benefits of screening outweigh the potential risks for overdiagnosis and treatment complications. Longer-term follow-up is important to assess the potential effects of PSA-based screening on prostate cancer ­mortality beyond 10 years.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Prostate cancer is the most frequently diagnosed malignancy in men. • Prostate-specific antigen (PSA) is an enzyme that belongs to the human calicrein family (hK3) and is synthesized in the prostatic epithelium. • There are several situations that can interfere in the normal range of PSA. • PSA velocity or PSA doubling time, PSA density and PSA isoforms can be used, but they do not add important screening information. • PSA and digital rectal exam are complementary and their use together may increase the overall rate of detection of prostate cancer. • The evidence of improved survival with screening and their economic benefits are still uncertain. • The genetic markers are promising but they have not been prospectively validated. 4

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