Prostate cancer screening: promise and peril--a review.

This review summarizes the current status of and recommendations for prostate cancer screening with prostate-specific antigen in light of recent reductions in prostate cancer incidence and mortality. It describes how the uncertain effectiveness of aggressive treatment for prostate cancer and a reservoir of unsuspected indolent cancers make prostate cancer fit poorly into conventional screening models. The large proportion of men with unsuspected prostate cancers that may not cause morbidity or mortality and are unlikely to benefit from aggressive treatment decrease the effectiveness of a screening program. In addition, indolent, unsuspected prostate cancers in the screening population accentuate the detrimental effects of length bias on studies evaluating the effectiveness of prostate cancer screening. Screening tests for prostate cancer will continue to improve, but chemoprevention or nutritional prevention with vitamins and micronutrients such as tocopherols or selenium may prove to be effective methods of reducing prostate cancer incidence and should be aggressively investigated.     

Epilogue: Different approaches for prostate cancer screening in the EU?

Individual approaches to prostate cancer screening in European countries could occur as a result of individual decision taking, public health policies or the relevance of the prostate cancer problem determined by incidence and mortality in individual countries.MethodsAn attempt is made to analyse current literature with respect to factors that could influence the individual or country-wide preference for or against the use of PSA driven screening.To obtain background information the incidence and mortality of prostate cancer in the EU countries participating in the ERSPC study, as well as the results of a recent join-point analysis of prostate cancer mortality for the same countries are reviewed. In addition, the question whether geographic differences in incidence and mortality could influence the value of screening tests in the different countries is evaluated.ResultsOur literature review shows large regional differences in incidence and mortality of prostate. Proportions of men testing positive with PSA values ?4.0 ng/ml and PPVs do not reflect these regional differences. Also, regional differences are not in line with negative outcomes for any ERSPC center in an exploratory analysis of prostate cancer mortality. In all centers a decrease of prostate cancer mortality at various degrees was seen. Differences in attitude may be visible in the join-point regression analysis which shows differences in mortality trends for some countries. Detection of T1c cancers in the control group is a measure of opportunistic screening (limitations addressed in the text). The differences reported may best reflect regional decision patterns. As far as the validity of PSA driven testing in countries with a different incidence and mortality is concerned, it seems that neither the levels nor the predictive value of PSA is influenced by such differences.ConclusionsA number of factors are identified which may explain the different individual decisions and different levels of use of opportunistic screening in the different EU countries.     

Risk for incident and fatal prostate cancer in men with a family history of any incident and fatal cancer

BackgroundFamilial clustering of incident prostate cancer and some cancers at other discordant sites has been reported. Less is known about familial clustering of fatal prostate cancer with any fatal discordant cancers. Estimates on familial aggregation based on mortality are free from bias of overdiagnosis.Patients and methodsWe used the nationwide Swedish Family-Cancer Database to calculate standardized incidence ratios (SIRs) for incident prostate cancer for relatives of patients with any common cancer and standardized mortality ratios (SMRs) for death in prostate cancer for relatives of individuals who died from cancer. Similar risks were determined for any common cancer when relatives were affected by prostate cancer.ResultsWe observed familial aggregation of incident and fatal prostate cancers. Familial clustering (SIRs increased) of prostate cancer and of cancers at discordant sites was found for breast, ovarian, and kidney cancers and melanoma. Also, fatal prostate cancer clustered with these and cervical cancers (SMRs increased).ConclusionsOur findings demonstrate that familial aggregation of prostate and breast cancers are not due to shared screening habits. The data on the association of cancers at discordant sites might be useful for clinical counseling and for mechanistic studies searching explanations to the familial clustering between discordant cancers.     

Prostate Cancer Screening

Prostate cancer is the most common cancer and the second leading cause of cancer-related deaths in American men. Although the use of the prostate-specific antigen (PSA) test for prostate cancer screening since the 1990s has led to increased early diagnoses, the most recent studies are in conflict about the risks and benefits of routine prostate cancer screening. Recently, evidence has emerged to support the use of the PSA test to lower mortality, but there is still concern that over-diagnosis may lead to over-treatment of cancers that would not significantly affect patients’ health for several years. This article describes the results of important recent prostate cancer screening trials, the National Comprehensive Cancer Network and American Cancer Society screening guidelines, and discusses the implications for clinical practice.     

Prostate cancer specific mortality in the Florence screening pilot study cohort 1992-1993

The impact of screening on prostate cancer mortality is still unknown. A favourable impact is suggested by uncontrolled and possibly biased studies. Mortality from all causes and from prostate cancer was assessed in a cohort of 6,861 males aged 60-74 years, participants to a pilot screening study during 1991-1994. Observed/expected mortality was determined by linkage with cancer and mortality registries. Prostate cancer standardised mortality rate (SMR) in the overall series (751 subjects excluded by GPs for disabling illness or prostate cancer; 3,448 refusers, 2,662 attenders; 67,321.2 men-year) was 0.96 (95% confidence interval (CI)=0.74-1.22) when deaths from prevalent cancers diagnosed before screening were considered. Reduced prostate cancer mortality (SMR=0.48; 95% CI=0.26-0.83), persisting beyond five years after study entry (SMR=0.48; 95% CI=0.22-0.90), was observed in attenders and not in refusers (SMR=0.99; 95% CI=0.69-1.37). This finding might suggest a screening effect, but might also be ascribed to an healthy screening effect, and cannot be assumed as a reliable evidence of screening efficacy.     

Screening for prostate cancer

Epidemiologically, prostate cancer is the most common cancer in the Western world after skin cancer. To date, it is still unknown whether screening for prostate cancer is justified, because results of randomised clinical trials are not yet available. The available screening tests (i.e. prostate-specific antigen (PSA) test) do not always detect cancers that otherwise would have resulted in prostate cancer mortality. Favourable results from prostate cancer screening include an increasing number of men with localised disease and an increase in the number of well-differentiated tumours. However, the risk of overdiagnosis and subsequent over-treatment (due to the diagnosis of localised disease), using aggressive therapies fuels arguments against screening. Therefore, until more evidence is available proving otherwise, prostate cancer screening can only be justified in the context of clinical trials.     

Characteristics of prostate cancers found in specimens removed by radical cystoprostatectomy for bladder cancer and their relationship with serum prostate-specific antigen level

Prostate cancer mass screening using serum prostate-specific antigen (PSA) has been conducted widely in the world. However, little is known about the true prevalence of prostate cancer in the 'normal' PSA range (4.0 ng/mL or less). The aim of the present study was to elucidate the clinicopathological features of prostate cancer occurring in men with a wide range of PSA levels. The study comprised 349 male patients who underwent radical cystoprostatectomy for bladder cancer. Patients who had had treatment for known prostate cancer were excluded. Tissue specimens were reviewed microscopically. Ninety-one patients (26.1%) were found to have prostate cancer, and 68 (74.7%) of these 91 cancers were considered to be clinically significant. Both increasing patient age and PSA level were significantly correlated with an increased incidence of both all and significant prostate cancers. Sixty-five (21.9%) among 297 patients with PSA < 4.0 ng/mL had prostate cancer, and 45 (69.2%) of the 65 cancers were significant cancers. Eighteen patients had prostate cancers 0.5 mL or more in volume. Among the 18 patients, the PSA level was 4 ng/mL or more in 11, and 3 ng/mL or more in 15. Our study shows that prostate cancer is a common finding in radical cystoprostatectomy specimens excised because of bladder cancers, and a significant proportion of these cancers are clinically significant. PSA still appears to be a useful screening tool for detecting prostate cancers with significant volume. ( Cancer Sci  2009; 100: 1880–1884)     

Prostate and breast cancer in four Nordic countries: A comparison of incidence and mortality trends across countries and age groups 1975–2013

In recent decades, management of prostate and breast cancer patients has changed considerably. The purpose of our study is to interpret patterns of prostate and breast cancer incidence and mortality in four Nordic countries across age groups and time periods. Prostate and breast cancer incidence and mortality data (1975–2013) were obtained from the NORDCAN database. Joinpoint regression models were used to identify changes in the trends. A more prominent increase in prostate than breast cancer incidence was observed. From the mid‐1990s, mortality rates in patients below 75 years of age have decreased for both cancers in all four countries. The relative decline in breast cancer mortality from 1985–1989 to 2009–2013 were largest in women under 50 years of age, with reductions in mortality rates ranging from 38% in Finland to 55% in Denmark. In the age group 55–74 years, mortality rates for prostate cancer declined more than for breast cancer in all countries except Denmark, ranging from 14% in Denmark to 39% in Norway. The substantial decrease in breast cancer mortality in women below regular screening age and the reductions in mortality from both cancers in Denmark from the mid‐1990s are consistent with beneficial contributions from improved treatment besides mammography screening and increased PSA testing. Alongside similar mortality decreases, the larger increases in prostate cancer incidence as compared to breast cancer indicate that a higher proportion of prostate cancer cases are overdiagnosed.     

Lower urinary tract symptoms and risk of prostate cancer: the HUNT 2 Cohort, Norway

Screening for early prostate cancer is frequently employed in the routine management of men with lower urinary tract symptoms (LUTS), but the evidence‐base linking LUTS with prostate cancer is limited. We assessed the association of LUTS with a subsequent prostate cancer diagnosis in a prospective cohort study based on 21,159 Norwegian men who completed baseline questionnaires, including the International Prostate Symptom Score (IPSS) questionnaire, between 1995 and 2007 as part of the second Nord‐Trøndelag Health Study (HUNT 2). Men were followed‐up for prostate cancer incidence and mortality from the date of clinical examination to end 2005. During a mean of 9 years follow‐up, 518 incident prostate cancers were diagnosed and 74 men died from prostate cancer. Men with severe LUTS (IPSS 20–35) had a 2.26‐fold (95% CI: 1.49–3.42) increased risk of prostate cancer compared to men reporting no symptoms. A positive association was observed for localized (hazard ratio, HR: 4.61; 2.23–9.54), but not advanced (HR: 0.51; 0.15–1.75), cancers (p for heterogeneity <0.001). There was no evidence that moderate/severe symptoms (IPSS 8–35) were associated with prostate cancer mortality (HR: 0.83; 0.42–1.64) vs. no symptoms. Amongst 518 men with prostate cancer, there was a 46% lower (10–68%) risk of death with moderate/severe symptoms vs. no symptoms. We conclude that LUTS are positively associated with localized, but not advanced or fatal, prostate cancer, suggesting that urinary symptoms are not caused by prostate cancer. Thus, screening for early cancers on the basis of LUTS may not be justified. © 2008 Wiley‐Liss, Inc.     

Variation in general practice prostate‐specific antigen testing and prostate cancer outcomes: An ecological study

Knowledge is sparse about the consequences of variation in prostate‐specific antigen (PSA) testing rates in general practice. This study investigated associations between PSA testing and prostate cancer‐ related outcomes in Danish general practice, where screening for prostate cancer is not recommended. National registers were used to divide general practices into four groups based on their adjusted PSA test rate 2004–2009. We analysed associations between PSA test rate and prostate cancer‐related outcomes using Poisson regression adjusted for potential confounders. We included 368 general practices, 303,098 men and 4,199 incident prostate cancers. Men in the highest testing quartile of practices compared to men in the lowest quartile had increased risk of trans‐rectal ultrasound (incidence rate ratio (IRR): 1.20, 95% CI, 0.95–1.51), biopsy (IRR: 1.76, 95% CI, 1.54–2.02), and getting a prostate cancer diagnosis (IRR: 1.37, 95% CI, 1.23–1.52). More were diagnosed with local stage disease (IRR: 1.61, 95% CI, 1.37–1.89) with no differences regarding regional or distant stage. The IRR for prostatectomy was 2.25 (95% CI, 1.72–2.94) and 1.28 (95% CI, 1.02–1.62) for radiotherapy. No differences in prostate cancer or overall mortality were found between the groups. These results show that the highest PSA testing general practices may not reduce prostate cancer mortality but increase the downstream use of diagnostic and surgical procedures with potentially harmful side effects.     

Unanswered questions in screening for prostate cancer

Prostate cancer fulfils some of the conditions required of a disease that might be managed by population screening. In a cohort of 50- to 60-year-old men, carrying out a rectal examination and prostate specific antigen (PSA) test will detect clinically suspicious areas within the prostate in approximately 5%, and approximately 10% will have a raised PSA. We are however unsure which of the prostate cancers that are known to be present in approximately 30-40% of men aged over 60 years will be detected. Eventually after such screening, around 4% of men with an otherwise normal prostate will be found to have prostate cancers. The use of rectal examination may increase the number of tumours found, but will reduce compliance. The use of free/total PSA ratios will reduce the number of unnecessary biopsies at the expense of missing some tumours. Of more concern, we remain uncertain how effective aggressive local treatment is in altering the natural history of the disease. The risk of a 50-year-old man with a 25 year life expectancy of having microscopic cancer is 42%, of having clinically evident cancer is 9.5%, and of dying of prostate cancer 2.9%. Only a small proportion of cancers known to be present become clinically evident: more men die with prostate cancer than of it. Screening will identify some men with cancer who will not benefit from treatment. It is unclear whether screening would be followed by a reduction in morbidity and mortality. Recent data suggest a screening effect has been observed in the USA with: an increase in incidence, a decrease in men with distant metastases. The small decrease in mortality recently observed (many times smaller than the increase in incidence) may be confounded by inappropriate 'attribution' of cause of death, the detection of men with better prognosis distant metastatic disease responsive to hormonal ablation and changes in social factors such as diet. Future changes may incorporate molecular markers that might aid identification of men best treated aggressively because of a risk of progression. Tests to identify genetic pre-disposition may also allow targeted screening. New treatments and early chemoprevention or dietary strategies will again shift the ground on which these arguments are being rehearsed. The most urgent evidence required concerns the effectiveness of treatment strategies.     

Screening for cancer: future potential

Much progress has been made in cancer screening over the past decade, but a great deal more needs to be done if screening is to make a major impact on worldwide cancer mortality. Where fully implemented, cytological screening for cervical precursor lesions has had a major impact on mortality. However, the cost and required infrastructure levels are high, and new approaches are needed if screening is to be effective in the developing world. Testing for the human papillomavirus and automated liquid based cytology offer great promise to improve quality, reduce overall cost and make screening more viable generally. Breast screening has been less successful, although useful mortality benefits have been achieved in women aged over 50 years. Full implementation in countries that can afford it will save lives, but radical new approaches will be needed to conquer breast cancer. Colorectal cancer screening offers the best hope of a major reduction in cancer mortality over the next decade. Less certainty exists about screening for other major cancers such as lung, prostate and ovary, but a range of potential approaches merit investigation.     

Baseline prostate-specific antigen level and risk of prostate cancer and prostate-specific mortality: diagnosis is dependent on the intensity of investigation

BACKGROUND: When considering prostate biopsy, men and their physicians must balance the potential benefits of early diagnosis of localized cancer with the implications of overdiagnosis of clinically insignificant cancers. We investigated the risk of prostate cancer and prostate cancer-specific and all-cause mortality by baseline prostate-specific antigen (PSA) level in a population-based cohort study in Northern Ireland, where PSA screening is not recommended and where low to moderately raised (<10.0 ng/mL) PSA levels were not routinely investigated. METHODS: From a regional electronic database of PSA results, men who had their initial PSA between January 1, 1994 and December 31, 1998 were identified and followed for diagnosis of prostate cancer and prostate cancer-specific and all-cause mortality until December 31, 2003. RESULTS: 68,354 men (mean age, 65.2 years) were included, with 50,676 (74.1%) having a baseline PSA of <4.0 ng/mL; 402 (0.8%) of these were subsequently diagnosed with prostate cancer. PSA level was positively associated with risk of prostate cancer and prostate-specific mortality. In men with baseline PSA <4.0 ng/mL, the rate of prostate cancer and high-grade cancer diagnosis was <2 and <1 cases per 1,000 person-years, respectively, whereas prostate-specific mortality was very low (0.18 cases per 1,000 person-years) compared with overall mortality (28.71 cases per 1,000 person-years). CONCLUSION: Following a PSA result, men need to be aware not only of the risk of prostate cancer but also of having cancer that may cause them harm during their lifetime or, more importantly, kill them. These data should inform and reassure men of their risk of clinically significant prostate cancer.     

Smoking and aggressive prostate cancer: a review of the epidemiologic evidence

Although tobacco use has been recognized as one of the leading causes of cancer morbidity and mortality, a role of smoking in the occurrence of prostate cancer has not been established. However, evidence indicates that factors that influence the incidence of prostate cancer may differ from those that influence progression and fatality from the disease. Thus, we reviewed and summarized results from prospective cohort studies that assessed the relation between smoking and fatal prostate cancer risk, as well as epidemiological and clinical studies that focused on aggressive behavior in prostate cancer, such as poorer survival, advanced stage, or poorer differentiation at diagnosis. The majority of the prospective cohort studies showed that current smoking is associated with a moderate increase of ~30% in fatal prostate cancer risk compared to never/non-smokers. This association is likely to be an underestimate of the effect of smoking because most studies had a single assessment of smoking at baseline and long follow-up times, and the association was considerably stronger in some sub-groups of heaviest smokers, or when smoking was assessed in a relatively short period (within 10 years) prior to cancer mortality. Using aggressive behavior of prostate cancer as outcome, current smoking was associated with significantly elevated risk, ranging from around twofold to threefold or higher. Although alternative explanations, such as publication bias, residual confounding, screening bias, and the influence of smoking-related comorbidities cannot be ruled out entirely, these findings suggest that smoking is associated with aggressive behavior of prostate cancers or with a sub-group of rapidly progressing prostate cancer. Based on evidence presented in this review, cigarette smoking is likely to be a risk factor for prostate cancer progression and should be considered as a relevant exposure in prostate cancer research and prevention of mortality from this cancer.     

Screening for cancer: future potential

Much progress has been made in cancer screening over the past decade, but a great deal more needs to be done if screening is to make a major impact on worldwide cancer mortality. Where fully implemented, cytological screening for cervical precursor lesions has had a major impact on mortality. However, the cost and required infrastructure levels are high, and new approaches are needed if screening is to be effective in the developing world. Testing for the human papillomavirus and automated liquid based cytology offer great promise to improve quality, reduce overall cost and make screening more viable generally. Breast screening has been less successful, although useful mortality benefits have been achieved in women aged over 50 years. Full implementation in countries that can afford it will save lives, but radical new approaches will be needed to conquer breast cancer. Colorectal cancer screening offers the best hope of a major reduction in cancer mortality over the next decade. Less certainty exists about screening for other major cancers such as lung, prostate and ovary, but a range of potential approaches merit investigation. ©     

Risk factors for prostate cancer incidence and progression in the health professionals follow-up study

Risk factors for prostate cancer could differ for various sub-groups, such as for "aggressive" and "non-aggressive" cancers or by grade or stage. Determinants of mortality could differ from those for incidence. Using data from the Health Professionals Follow-Up Study, we re-examined 10 factors (cigarette smoking history, physical activity, BMI, family history of prostate cancer, race, height, total energy consumption, and intakes of calcium, tomato sauce and alpha-linolenic acid) using multivariable Cox regression in relation to multiple subcategories for prostate cancer risk. These were factors that we previously found to be predictors of prostate cancer incidence or advanced prostate cancer in this cohort, and that have some support in the literature. In this analysis, only 4 factors had a clear statistically significant association with overall incident prostate cancer: African-American race, positive family history, higher tomato sauce intake (inversely) and alpha-linolenic acid intake. In contrast, for fatal prostate cancer, recent smoking history, taller height, higher BMI, family history, and high intakes of total energy, calcium and alpha-linolenic acid were associated with a statistically significant increased risk. Higher vigorous physical activity level was associated with lower risk. In relation to these risk factors, advanced stage at diagnosis was a good surrogate for fatal prostate cancer, but high-grade (Gleason >/= 7 or Gleason >/= 8) was not. Only for high calcium intake was there a close correspondence for associations among high-grade cancer, advanced and fatal prostate cancer. Tomato sauce (inversely) and alpha-linolenic acid (positively) intakes were strong predictors of advanced cancer among those with low-grade cancers at diagnosis. Although the proportion of advanced stage cancers was much lower after PSA screening began, risk factors for advanced stage prostate cancers were similar in the pre-PSA and PSA era. The complexity of the clinical and pathologic manifestations of prostate cancer must be considered in the design and interpretation of studies.     

The high prevalence of undiagnosed prostate cancer at autopsy: implications for epidemiology and treatment of prostate cancer in the Prostate‐specific Antigen‐era

Widespread prostate‐specific antigen (PSA) screening detects many cancers that would have otherwise gone undiagnosed. To estimate the prevalence of unsuspected prostate cancer, we reviewed 19 studies of prostate cancer discovered at autopsy among 6,024 men. Among men aged 70–79, tumor was found in 36% of Caucasians and 51% of African‐Americans. This enormous prevalence, coupled with the high sensitivity of PSA screening, has led to the marked increase in the apparent incidence of prostate cancer. The impact of PSA screening on clinical practice is well‐recognized, but its effect on epidemiologic research is less appreciated. Before screening, a larger proportion of incident prostate cancers had lethal potential and were diagnosed at advanced stage. However, in the PSA era, overall incident prostate cancer mainly is indolent disease, and often reflects the propensity to be screened and biopsied. Studies must therefore focus on cancers with lethal potential, and include long follow‐up to accommodate the lead time induced by screening. Moreover, risk factor patterns differ markedly for potentially lethal and indolent disease, suggesting separate etiologies and distinct disease entities. Studies of total incident or indolent prostate cancer are of limited clinical utility, and the main focus of research should be on prostate cancers of lethal potential.     

The role of prevalence in the diagnosis of prostate cancer.

BACKGROUND: The worldwide incidence of prostate cancer has been rising rapidly, likely due to intensified effort in early detection and screening. Intense effort is also directed at novel schemas of chemoprevention and therapy. Incidence data are insufficient to identify the true magnitude of prostate cancer in a given population. The true prevalence of prostate cancer must be identified. METHODS: We reviewed the latest worldwide epidemiologic data and clinical studies on prostate cancer studying the true prevalence of this disease. RESULTS: The incidence of prostate cancer is increasing worldwide, with strong variation among regions. Prevalence studies based on autopsy data have confirmed a high frequency of latent prostate cancer in men of all ages. More aggressive screening measures using a lower prostate-specific antigen (PSA) threshold, together with an increasing number of biopsies, have escalated the detection of these latent cancers. CONCLUSIONS: Recent improvements in prostate cancer detection narrow the gap between the incidence and true prevalence of prostate cancer. This, however, raises concerns about the risk of over detection of latent cancers and thus identifying a need for improvement in screening strategies to better identify clinically significant disease.     

Prostate-Specific Antigen Testing: Good or Bad?

Prostate-specific antigen (PSA) screening is not the panacea that enthusiasts hoped for, but it is not worthless. Men who have elevated PSA need to be aware that a prostate biopsy can identify both clinically significant and insignificant cancers and that intervention can affect quality of life. The oncologist can provide expert guidance, but once a patient understands the risks and benefits, only he can make the choice to be screened or not.The authors of the recent 13-year update of the European Randomised Study of Screening for Prostate Cancer (ERSPC) claim that testing for prostate-specific antigen (PSA) at least once every 4 years reduces prostate cancer mortality by as much as 27% among men aged 55–70 years [1]. This interpretation of the data is probably the most optimistic but is often quoted by the media or prostate cancer screening enthusiasts. The recent statement by the U.S. Preventive Services Task Force (USPSTF) takes the opposite position [2]. The USPSTF stated that the harms associated with PSA testing far outweigh the benefits and argued that PSA screening should not be done. What should patients be told regarding these seemingly contradictory statements concerning PSA screening? Several factors affect PSA testing outcomes including how the data are accrued and analyzed, the prevalence of prostate cancer among the men being tested, the natural history of prostate cancer progression, and the impact of treatment interventions. This commentary will review these factors with the goal of assisting the practicing oncologist in counseling patients appropriately.A careful review of the abstract of the ERSPC 13-year update reveals several numbers summarizing the trial results [1]. What do they all mean? The “rate ratio of prostate cancer incidence” between the intervention and control groups was 1.57 after 13 years. This means that one and a half times as many cancers were identified in the screening arm as in the control arm. Many people assume that it is good to find more cancers, but unfortunately, with prostate cancer, this may not be so. In the screening arm, more than half of the cancers identified were categorized as Gleason 6 tumors. In the control arm, less than one-third of the tumors were classified this way. Gleason 6 tumors are usually associated with an excellent prognosis; therefore, many men tested for PSA now carry the burden of a prostate cancer diagnosis without obvious benefit. Epidemiologists describe this problem as overdiagnosis. The ERSPC investigators estimate that almost half of the men diagnosed with screen-detected cancers have disease that will probably never cause morbidity.The abstract states that the “rate ratio of prostate cancer mortality” was 0.79 at 13 years [1]. What does this mean? This means that 21% fewer men died in the screening arm than in the control arm. Although this number may sound impressive, it is actually difficult to interpret in isolation because it is a relative rate. The percentage depends not on the number of men who died but simply on the ratio of deaths in the two arms of the trial. The next sentence states that the “absolute risk reduction” was 0.11 per 1,000 person-years or 1.28 per 1,000 men randomized. This means that the difference in prostate cancer deaths between the screening arm and the control arm was fairly modest. The authors note that for every 781 men invited for PSA testing, 1 prostate cancer death is averted. More important, for every 27 prostate cancers diagnosed by screening, 1 prostate cancer death is averted. Presenting the outcomes in relative terms versus absolute terms can influence how PSA testing is perceived. The editorial that accompanied the publication of the ERSPC update suggests that the absolute risk reduction will increase with longer follow-up [3]. This may or may not be true. The absolute risk reduction did not change when follow-up was extended from 11 to 13 years.The authors of the update end the abstract by stating that “after adjustment for nonparticipation,” the rate ratio of prostate cancer mortality in men screened was 0.73 [1]. What does this mean? This is an attempt to estimate the maximum possible impact of screening. Men participating in the screening arm of the ERSPC study, for example, were supposed to be screened every 4 years, to undergo a prostate biopsy if PSA was elevated, and to undergo treatment if they were found to have cancer. Conversely, men participating in the control arm should not have had any PSA screening. Unfortunately, in the real world, not every man actually does what he is supposed to do. To avoid selection biases that might occur by reclassifying men, researchers conducting a randomized trial usually perform an “intent-to-screen” analysis. Patients who do not complete their assigned intervention are considered not to have participated. By adjusting for nonparticipation, the authors are trying to calculate the maximum possible impact of PSA testing in a perfect world. As noted in the editorial, “such adjustments are not a precise science” [3]. Most epidemiologists usually quote the more conservative rate ratio derived from the unbiased intent-to-screen approach.A review of the entire paper reveals other important factors that have affected outcomes. Table 1 [1] lists all of the centers participating in the ERSPC trial. On quick inspection, one would assume that the trial was conducted in a similar fashion at each site, but this is not actually the case. Many epidemiologists look at this study as a series of seven separate screening trials, of which two are positive and the rest are negative. Each site had somewhat different accrual methods and used different screening criteria and different screening intervals. From an absolute perspective, the number of cases randomized differs significantly by center. Finland enrolled >80,000 men; the Netherlands enrolled 35,000; Italy enrolled almost 15,000; and Sweden enrolled almost 12,000. I mention these four sites because the trial showed no advantage for PSA testing in Finland or Italy but showed a statistically significant decline in prostate cancer mortality in the Netherlands and Sweden. Finland had the largest number of men randomized but did not show a positive outcome, whereas Sweden had the smallest number of men among these four centers but showed the most dramatic outcome. Why were findings so different among these sites? This question raises concerns about whether the results can be generalized to other nations and other populations. Sweden is unusual in that it has much higher mortality from clinically significant prostate cancer than the other participating European centers. Prostate cancer mortality among men aged 65–74 years is twice as high in Sweden compared with the U.S. Consequently, screening is likely to be much more effective in identifying clinically significant disease in Sweden and less effective in the U.S.A review of Table 4 [1] also raises concerns. This table lists prostate cancer mortality by age groups at the time of randomization. The results are statistically significant for the core age group of 55–69 years and for all ages from 54 to ≥70 years. A review by each age group, however, shows a more complex story. The results were dramatically positive for men aged 65–69 years at randomization but were not statistically significant for men aged 55–59 and 60–64 years despite comparable sample sizes and the fact that the men in the younger age groups were screened for a longer period of time. The positive findings of the entire trial are driven primarily by the older cohort of patients. Most screening advocates recommend that PSA testing start at age 50, but no evidence shows that more clinically significant cancers are found at this age.The paper does not address two other issues that affect the screening debate and that led the U.S. Preventive Services Task Force to recommend against PSA testing: treatment efficacy and associated treatment complications. Screening works only if there is an effective treatment that alters the outcome of the disease. Fortunately, two randomized trials address these issues. The Prostate Cancer Intervention Versus Observation Trial (PIVOT) trial was conducted by the U.S. Veterans Administration and enrolled 731 men with localized prostate cancer between 1994 and 2002 [4]. Men were randomly assigned to observation or radical prostatectomy and followed through January 2010. After a median follow-up of 10.0 years, 171 of 364 men assigned to radical prostatectomy died compared with 183 of 367 assigned to observation. Among men undergoing radical prostatectomy, 21 died of prostate cancer or treatment compared with 31 men assigned to observation. The authors concluded that radical prostatectomy did not provide a survival advantage for men identified with localized prostate cancer by PSA testing through 12 years of follow-up. Analysis by prostate cancer risk showed that observation was the preferred strategy for men with low-grade disease. There was a suggestion that surgery benefitted men with intermediate- or high-grade disease, but the sample size was too small to achieve statistical significance.The other key trial, the Scandinavian Prostate Cancer Group 4 study, was recently updated in March 2014 [5]. This trial was conducted in Sweden and accrued patients between 1989 and 1999 and followed them until December 31, 2012. Although most of the patients were not identified by PSA testing, this trial provides important data concerning the efficacy of surgery to treat prostate cancer. After a median follow-up of 13.4 years, 200 of 347 men assigned to radical prostatectomy had died compared with 247 of 348 men assigned to observation. Among men undergoing radical prostatectomy, 63 had died of prostate cancer or treatment compared with 99 men assigned to observation. In this case, radical prostatectomy provided a survival advantage, but the primary beneficiaries were men aged <65 years with intermediate-grade disease. Relatively few men with low-grade disease succumbed to prostate cancer (11 and 20, respectively, in the surgery and observation arms), and surgery appeared to have no impact among men with high-grade disease (28 and 29 prostate cancer deaths, respectively, in the surgery and observation arms). The data surrounding the efficacy of radiation therapy is much less robust.Unfortunately, whether effective or not, treatment can be associated with morbidity. This has been well documented for both surgery and radiation [6]. The USPSTF estimated that PSA testing will prevent 1 prostate cancer death for every 1,000 men tested [2]; however, to achieve this outcome, approximately 100–120 men will undergo a prostate biopsy, with the associated risks of bleeding and infection. Approximately 110 men will be diagnosed with prostate cancer. A majority of these men will undergo treatment. Treatment is associated with at least 2 serious cardiovascular events, 1 serious deep vein thrombosis, 29 cases of erectile dysfunction, and 18 cases of incontinence. From the USPSTF’s perspective, the ability to spare 1 prostate cancer death for every 1,000 men screened is not justified by the associated morbidity experienced by the 110 men undergoing treatment.Is PSA testing good or bad? It clearly is not the panacea that PSA screening enthusiasts hoped for, but it is not worthless. The significant overdiagnosis and the modest number of deaths prevented over 13 years of follow-up raise major concerns from a public health perspective. Many patients, however, still want to be tested. They believe that early diagnosis can protect them from prostate cancer progression, and in some cases, it can. From a practical standpoint, screening makes the most sense for men in their 50s and 60s. Obtaining a series of PSA levels drawn annually or biannually allows a physician to monitor the growth of the prostate over time. PSA levels often rise with age as a consequence of benign hypertrophy. Elevated PSA values should always be repeated after a few weeks before proposing a biopsy. Many will return to baseline within 1 month. An increase of up to 0.75 ng/mL over a 3-year period is normal.Those men who have elevated PSA need to be aware that a prostate biopsy can identify both clinically significant and insignificant cancers. Men found to have high-grade cancers will receive treatment, but this may improve outcomes for only a subset of patients. Men found to have low-grade cancers have a more difficult decision. Should they undergo treatment or active surveillance? Low-grade tumors usually do not progress for 10–20 years or longer. Patients must also recognize that intervention can have a serious impact on their quality of life, although not always. The oncologist can provide expert guidance, but once a patient understands the risks and benefits, only he can make the choice to be screened or not.