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Keywords:

  • prostate cancer;
  • prostate-specific antigen;
  • screening

Abstract

  1. Top of page
  2. Abstract
  3. Recent trends and future perspectives on the incidence and mortality of prostate cancer in Japan and USA
  4. Guidelines on PSA screening in Japan and other developed countries
  5. Positive evidence regarding PSA-based screening for prostate cancer
  6. Critical review of research that could not demonstrate a positive correlation between PSA-based screening and mortality reduction
  7. Ongoing global prospective study
  8. Step by step distress points in a screening system for prostate cancer
  9. Future perspectives on screening for prostate cancer
  10. References

The most recent epidemiological survey revealed that the mortality rate for prostate cancer in Japan has increased and has been getting very close to that in the USA, where it has decreased since 1992. The low exposure rate of prostate-specific antigen (PSA) screening in Japan and the high exposure rate of PSA screening in the USA may result in completely deferent trends in the mortality rate of prostate cancer between the two countries. The Japanese Urological Association recommends PSA-based screening for men at risk of prostate cancer at age 50 years or older in general and 45 years or older in men with a family history of prostate cancer within first generation relatives. The fact sheet on screening for prostate cancer should indicate the most recent reliable clinical research on screening for prostate cancer and its demerits including false-negative and false-positive PSA test results and prostate biopsy, overdetection and overtreatment. However, it should be explained to the public that the demerits for PSA screening will be clarified step by step during screening, and in general, men having more information on screening results (PSA level, pathological findings of biopsy specimens, clinical stage, etc.) can understand their current situation better than those having no information on screening results, including PSA levels.


Recent trends and future perspectives on the incidence and mortality of prostate cancer in Japan and USA

  1. Top of page
  2. Abstract
  3. Recent trends and future perspectives on the incidence and mortality of prostate cancer in Japan and USA
  4. Guidelines on PSA screening in Japan and other developed countries
  5. Positive evidence regarding PSA-based screening for prostate cancer
  6. Critical review of research that could not demonstrate a positive correlation between PSA-based screening and mortality reduction
  7. Ongoing global prospective study
  8. Step by step distress points in a screening system for prostate cancer
  9. Future perspectives on screening for prostate cancer
  10. References

In the USA, prostate cancer has caused social problems because it has the highest incidence of all malignant tumors and the second highest mortality rate.1 The insurance system provided by the US Government, Medicare, supports annual PSA check-ups for asymptomatic men.2 In terms of the exposure rate of PSA screening, about 75% of men aged 50 years or older have their PSA levels measured at least once and about 50% of men have annual PSA check-ups.3 The high exposure rate of PSA screening and subsequent appropriate treatment strategy may have led to a significant decrease in the prostate cancer mortality rate in the USA. The prostate cancer mortality rate has decreased since 1992, and that in 2004 showed a 34% reduction compared with that in 1990.1

The age-adjusted incidence rate of prostate cancer in Japan is extremely low at 9.9 per 100 000 (world population) compared with 112.3 in the USA, according to a survey of the International Agency for Research on Cancer (IARC) between 1993 and 1996.4 Therefore, one opinion is that PSA screening should not be recommended for Japanese men. However, it is quite difficult to do an international comparison of prostate cancer incidence because it may be strongly influenced by differences in the cancer registration system and penetration of PSA screening in each country. The most recent report demonstrated that the actual difference in the incidence rate of prostate cancer between the Netherlands and Japan, which was estimated by comparing the risk of PSA increase above 4 ng/mL in men without any suspicious prostate cancer finding within the screening studies, may be two times or lower.5 Mortality due to prostate cancer in Japan has increased and was estimated to be 9265 in 2005 and 9786 in 2007, which ranked seventh overall and was about 5% of all causes of death in males.6 Furthermore, the number of deaths from prostate cancer is estimated to increase to 21 062 in 2020, which is 2.8 times higher than 2000.7 However, mortality due to prostate cancer in the USA has decreased and was estimated to be about 28 905 in 2005.1 The difference in population between the USA and Japan is about 2.5-fold; therefore, the mortality rate due to prostate cancer between the USA and Japan may be converging (Fig. 1). Furthermore, recent trends in the prostate cancer mortality rate are opposite between the two countries, so the future mortality rate in Japan will catch-up with that in the USA, and may even surpass it. The low exposure rate of PSA screening in Japan and the high exposure rate in the USA may result in completely different trends in the prostate cancer mortality rate because the treatment level provided in each nation may be the same, genetic factors regarding the risk of developing lethal prostate cancer may be more favorable in Japanese than in Americans, and diet factors in terms of developing prostate cancer may be more favorable in Japanese than in Americans.

image

Figure 1. Changes in the number of deaths due to prostate cancer in the USA and Japan.

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There is speculation that wide or intelligent use of hormonal therapy for localized to metastatic prostate cancer may have led to the recent decrease in the prostate cancer mortality rate in a specific area.8 Early hormonal therapy intervention for asymptomatic metastatic prostate cancer or intelligent use of hormonal therapy in adjuvant or salvage settings for patients with high risk features or biochemical recurrence after definitive treatment may improve cancer-specific death.9–11 However, wide and intelligent use of hormonal therapy without PSA screening may not cause a decrease in prostate cancer mortality because the mortality rate due to prostate cancer has increased in Japan, where the exposure rate of PSA screening is very low and the percentage of cases mainly treated with hormonal therapy is very high at about 57% of all patients registered with the Japanese Urological Association.12

Guidelines on PSA screening in Japan and other developed countries

  1. Top of page
  2. Abstract
  3. Recent trends and future perspectives on the incidence and mortality of prostate cancer in Japan and USA
  4. Guidelines on PSA screening in Japan and other developed countries
  5. Positive evidence regarding PSA-based screening for prostate cancer
  6. Critical review of research that could not demonstrate a positive correlation between PSA-based screening and mortality reduction
  7. Ongoing global prospective study
  8. Step by step distress points in a screening system for prostate cancer
  9. Future perspectives on screening for prostate cancer
  10. References

The Japanese Urological Association published guidelines for PSA screening written in English in September 2008.13 It recommends PSA screening for men aged 50 years or older after shared-informed decision-making using the fact sheet on present status and future perspectives of prostate cancer, merits and demerits of screening for prostate cancer for the public.

Guidelines from the American Cancer Society14 and the American Urological Association15 also recommend PSA and digital rectal examination (DRE) screening for prostate cancer from 50 years of age through to those with a life-expectancy of over 10 years in the general population and from 40- or 45-year-old men with prostate cancer patients among their first generation relatives and also in black males after obtaining informed consent in terms of the merits and demerits of screening for prostate cancer. Recently, the American Urological Association and the Japanese Urological Association made a joint statement on screening for prostate cancer, which stated the above-mentioned policy.16

The US Preventive Services Task Force does not recommend routine PSA screening for men without any urinary symptoms because large-scale randomized controlled trials (RCTs) investigating the effectiveness of screening for prostate cancer in the USA and Europe have not demonstrated any significant reduction in prostate cancer mortality.17 They point out that issues such as overdetection, overtreatment, quality of life (QOL), adverse effects of biopsies and treatment are still unclear at present. They recommend neither routine use of PSA screening nor stopping PSA screening. They suggest that a well-balanced fact sheet should be provided for men aged younger than 75 years old who want to have some information on screening for prostate cancer. Then, each individual should decide whether to be screened or not.

Almost all medical organizations have a policy that information on screening for prostate cancer, including the benefits and limitations of PSA screening, complications for biopsy and treatment, etc., should be provided to recipients before taking the test. If a man wants to undergo the test, physicians should provide the best available screening system. A policy statement that PSA screening should be omitted and informed decision-making is not necessary is no longer acceptable in either individual-based or population-based screening for prostate cancer at present.

Positive evidence regarding PSA-based screening for prostate cancer

  1. Top of page
  2. Abstract
  3. Recent trends and future perspectives on the incidence and mortality of prostate cancer in Japan and USA
  4. Guidelines on PSA screening in Japan and other developed countries
  5. Positive evidence regarding PSA-based screening for prostate cancer
  6. Critical review of research that could not demonstrate a positive correlation between PSA-based screening and mortality reduction
  7. Ongoing global prospective study
  8. Step by step distress points in a screening system for prostate cancer
  9. Future perspectives on screening for prostate cancer
  10. References

The exposure rate of PSA screening in the USA is very high at about 75% of men over the age of 50 years.3 According to the cancer registry in the USA, the mortality rates of prostate cancer have continued to decrease since 1992 and showed a 34% decrease between 1990 and 2004.1 Because there is no effective primary prophylaxis to prevent development of prostate cancer, the drastic decrease in the mortality rate of prostate cancer in the USA may be due to the high exposure rate of PSA screening and subsequent appropriate treatment strategies.

Two large prospective randomized controlled trials investigating the effect of PSA screening on mortality from prostate cancer are now ongoing in the USA and eight countries in Europe. The most recent publication from the European Randomized Study of Screening for Prostate Cancer (ERSPC) section in Sweden demonstrated that the incidence of advanced prostate cancer cases, defined as metastatic prostate cancer and cancer with pretreatment PSA levels above 100 ng/mL, significantly decreased (49%) in the screening arm compared with the control arm over about 10 years of follow-up.18 There could be a limitation in the study because they only showed a reduction in the incidence of advanced prostate cancer, but not in mortality due to prostate cancer. However, a prognosis of advanced prostate cancer is worse than that of cancer detected at earlier stages. About half of patients with metastatic prostate cancer die due to the disease within 5 years and about 80% of patients with PSA levels over 100 ng/mL may progress to hormone refractory prostate cancer (HRPC), which is difficult to manage and maintain patient QOL, within 5 years (unpublished clinical data from Gunma University). Therefore, the results can be evaluated as a high priority in the field of screening for prostate cancer.

According to the latest results from the Tyrol study, the exposure rate of screening was extremely high at 86.6% in 2005, and the incidence rate of metastatic prostate cancer showed a 70% decrease.19 In the mean time, the mortality rate of prostate cancer showed a drastic decrease of 54% compared with the expected mortality rate in the area. Because all analyses were done by the IARC, the reliability of the results is likely very high.

The first RCT using modern techniques in the screening test and biopsy method was conducted in Quebec, Canada.20,21 Participants were 46 486 men living in Quebec province and aged between 45 and 80 years. They were divided into an intervention arm and a control arm at a ratio of 2:1, respectively. The participants in the intervention arm received an invitation letter for a PSA test and DRE in the first year of the study and for an annual PSA test thereafter. The intention-to-screen analysis could not show a reduction in mortality rate (per 100 000 men/year) in the intervention arm because of very low compliance at 23%. Therefore, the second analysis, a prospective cohort study, was done using the data from the Quebec study. They investigated changes in the mortality rate between men who were actually screened by PSA test and those who were not. The mortality rates (per 100 000 person/year) were 19.0 and 53.4 in men screened and those not screened, respectively. There was a 64% reduction in the mortality rate in men screened by PSA test compared with those who were not. They investigated the difference in mortality rate among men who were screened in the intervention arm, those screened in the control arm, those not screened in the intervention arm and those not screened in the control arm, then demonstrated that the only factor that led to a difference in mortality rate of prostate cancer was whether men were screened by PSA test or not. The main flaw in the study was the difference in age distribution between men screened and those not screened. However, they investigated the mortality rate of prostate cancer stratified by age range, then showed the difference in mortality reduction in men screened in each age range. The second flaw in such a cohort study was a health screening bias. However, there is no effective primary preventive method such as diet for developing lethal prostate cancer. At any rate, they demonstrated mortality reduction by PSA testing in their prospective cohort study.

Another prospective cohort study was conducted in Florence, Italy.22 They prospectively followed men who were screened by PSA test, those not screened and those not invited for PSA screening because of severe complications for 9.8 years on average. They investigated the standardized mortality rate (SMR) for cause specific death and also all causes of death among the three groups. It was clear that the SMR (95% confidence interval; 95% CI) for all causes of death in men who were not invited was the worst at 1.80 (1.64–1.99), followed by those not screened, which was 1.04 (0.98–1.10), and those screened, which was 0.73 (0.67–0.79), because of severe complications in the former group and existing health screening bias among all three groups. The huge discrepancy in the SMR on prostate cancer death, which was 0.48 (0.26–0.83) in men screened and 0.99 (0.69–1.37) in men not screened, may be mainly due to the screening test, but less due to any health screening effect because there is no known effective primary preventive method against developing lethal prostate cancer.

There are reliable ecological studies, which showed a positive effect of screening for prostate cancer in terms of mortality reduction or a reduction in incidence of metastatic prostate cancer. Jemal et al.23 investigated the relationship of incidence of metastatic prostate cancer with frequency of PSA testing and mortality rate of prostate cancer among states using the Behavior Risk Factor Surveillance System for frequency of PSA tests in 2001, the National Cancer Registry for incidence of all prostate cancer and also incidence of metastatic prostate cancer between 1995 and 2000, and the National Health Statistics for mortality of prostate cancer between 1996 and 2000. They demonstrated a positive correlation between frequency of incidence of metastatic prostate cancer and mortality rate of prostate cancer. They also showed a negative correlation between frequency of PSA test and incidence of metastatic prostate cancer. Their study showed that screening for prostate cancer could decrease the incidence rate of metastatic prostate cancer, possibly leading to a reduction in the mortality rate due to prostate cancer. Colloi et al.24 also conducted an ecological study to investigate the relationship among age-adjusted mortality rates for prostate cancer, population density of urologists, frequency of PSA tests, income, urbanization and insurance coverage stratified by state. Multivariate analysis clearly showed an independent negative relationship between frequency of PSA test and the age-adjusted mortality rate of prostate cancer, and also between population density of urologists and mortality rate of prostate cancer. Therefore, the mortality rate of prostate cancer may decrease with PSA testing and easy access to urologists who can provide appropriate treatment.

An observational study in Japan demonstrated the effect of PSA- based screening on mortality reduction.25 Cause-specific survival in prostate cancer cases detected in PSA-based screening was significantly higher than that in those detected in the screen system before introducing the PSA test. The 10-year relative survival rate in screen-detected prostate cancer cases was close to 100%, but that in non-screen detected prostate cancer cases was significantly lower at around 40% (P < 0.05). Although lead-time bias should be taken into account for such an observational study, the most recent study demonstrated that the impact of lead-time bias on survival in screen-detected cancer was not so large in that cohort.26 Self-selection bias could not be eliminated from such an observational study. However, screening and subsequent appropriate treatment may be effective to improve cause-specific and relative survival. According to another observational study in Japan, the proportion of metastatic prostate cancer cases in a specific area, where the exposure rate of screening between 1995 and 2004 was estimated to be high at 65%, was low at 8% between 1995 and 1999 and decreased to 3% between 2000 and 2004.27

Critical review of research that could not demonstrate a positive correlation between PSA-based screening and mortality reduction

  1. Top of page
  2. Abstract
  3. Recent trends and future perspectives on the incidence and mortality of prostate cancer in Japan and USA
  4. Guidelines on PSA screening in Japan and other developed countries
  5. Positive evidence regarding PSA-based screening for prostate cancer
  6. Critical review of research that could not demonstrate a positive correlation between PSA-based screening and mortality reduction
  7. Ongoing global prospective study
  8. Step by step distress points in a screening system for prostate cancer
  9. Future perspectives on screening for prostate cancer
  10. References

The reliability of time series research and ecological studies that rejected, or did not show, a positive relationship between PSA screening and a decrease in the mortality rate due to prostate cancer is doubtful. There were serious flaws in their study protocols in terms of insufficient duration of follow-up and a small difference in the exposure rates of PSA screening among comparable regions.28–38

The two papers that have been frequently selected as negative findings on the effectiveness of PSA screening are here reviewed critically. The ecological study conducted by Lu-Yao et al. did not show a positive correlation between PSA screening followed by aggressive treatment and mortality reduction between Seattle and Connecticut.28,29 They asserted that aggressive screening by PSA test followed by radical prostatectomy did not result in a decreased prostate cancer mortality because the trend in the mortality rates was the same between the two states; there was discrepancy in the exposure rate of screening and the number of operated cases between them. However, there are many uncertainties and flaws in the study. First, the exposure rate of PSA screening in Connecticut between 1988 and 1993 was high at 44% and PSA spread rapidly in only 1.5 years compared with the Seattle area. It is better to compare the trends in the mortality rate between countries or regions where the difference in the exposure rate of screening is large in order to achieve statistical power. Second, the frequency of radiation therapy, which may result in almost the same outcomes in terms of biochemical recurrence, between the two states was almost same. Furthermore, there were no data on the frequency of prostate brachytherapy. Third, there were no data on stage distribution. Fourth, to clarify effective compliance with screening, the frequency of biopsies undergone may be very informative. The latest paper in this study showed that the frequency of prostate biopsies undergone was almost the same between the two states. Therefore, the selection of provinces compared was not appropriate because there was little difference in the number of men who were screened and no difference in the effective compliance of screening (i.e. number of biopsies undergone) between the two states.

Recently, a nested case control study conducted by Concato et al. was published, which did not show a positive effect of PSA screening.30 The case group was 501 patients who saw doctors at the Veterans Affairs (VA) Medical Center and were diagnosed with prostate cancer between 1991 and 1995, then died of any cause between 1991 and 1999. All participants’ clinical records were checked for screening for prostate cancer using PSA and DRE between 6 months and 5 years before the diagnosis. The control group was age-adjusted men who also saw doctors at the VA Medical Center and who were alive at the same time each correspondence case died. Screening histories using PSA and DRE were also investigated. They concluded that exposure rates of screening by DRE or PSA were not significantly different between the case and control groups; therefore, screening for prostate cancer could not lead to a decrease in all causes of death or cause-specific death. However, there were many serious flaws in their study. First, the exposure rate of screening was extremely low at around 13%. Second, to adjust for all risk factors that may influence all causes of death is impossible. Third, subgroup analysis concerned with cancer-specific death also showed no difference in the exposure rate of screening between the case and control groups. The exposure rates of both groups were relatively high at around 45%. The distribution of PSA both in the case and control groups should be clarified because it may be important to judge whether screening for prostate cancer was effectively provided to the public at the time of the survey or not. Patients in the case group died due to prostate cancer between 0 and 8 years after the diagnosis, so the screening system may not have been effectively provided. This study may not be of value for developing a modern PSA screening system.

Ongoing global prospective study

  1. Top of page
  2. Abstract
  3. Recent trends and future perspectives on the incidence and mortality of prostate cancer in Japan and USA
  4. Guidelines on PSA screening in Japan and other developed countries
  5. Positive evidence regarding PSA-based screening for prostate cancer
  6. Critical review of research that could not demonstrate a positive correlation between PSA-based screening and mortality reduction
  7. Ongoing global prospective study
  8. Step by step distress points in a screening system for prostate cancer
  9. Future perspectives on screening for prostate cancer
  10. References

Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial

The PLCO Cancer Screening Trial is a RCT which has been ongoing at 11 screening centers in the USA since 1993.39 Participants in the screening for prostate cancer were men aged between 55 and 74 years in good general health. The number of participants was 76 705 with 38 350 in the screening group and 38 355 in the control group. The primary endpoint of the study was comparing cause-specific death between the case and control groups. Participants in the screening group were invited to screening using both modalities (PSA and DRE) in the first 3 years, then using only the PSA test in the following 2 years. Participants in the control group were followed with routine medical care. Updated results showed that the compliance of both screening tests was high at around 90%, while 7.9% and 7.5% of all participants had abnormal findings on PSA and DRE, respectively. About 75% of men with abnormal findings on PSA or DRE saw urologists for further examinations, and 31.5% of those underwent prostate biopsy.40 The detection rate of prostate cancer was 1.4% and clinical stage was I/II in 83%, III in 6% and IV in 4% of all detected prostate cancer cases. The main problem in the PLCO study may have been contamination in the control cohort because the exposure rate of PSA screening in men aged 50 years or older was estimated to be 75%.3

European Randomized Study of Screening for Prostate Cancer

The ERSPC was conducted to clarify the impact of population-based screening for prostate cancer mainly using PSA on mortality from prostate cancer. ERSPC has been ongoing in Belgium, the Netherlands, Sweden, Finland, Italy, Spain, Switzerland and France.41 The screening interval was set at 4 years in most countries, except for Belgium (7 years) and Sweden (2 years).

Although the final analysis is not planned until 2010 or 2011, the results of a pilot study in Rotterdam were published.42 A total of 2367 men aged between 55 and 75 years were randomly divided into a screening arm and control arm. The screening arm was offered PSA, DRE and transrectal ultrasonography (TRUS) at initial screening, followed by PSA at 4 and 8 years after the initial screening. During 11 years’ median follow-up, 111 and 71 prostate cancer cases were diagnosed in the screening and control arms, respectively. The number of deaths from all causes was almost the same between the two arms. There was no significant difference in prostate cancer death between the two arms because of a lack of statistical power. However, the number of deaths from prostate cancer in the control arm was fourfold that in the screening arm.

Clinical dilemma of RCT in screening for prostate cancer and feasibility of secondary analysis

Intent-to-screen analysis must be the gold standard in any randomized controlled study. However, the PSA test can be accessed very easily by many men aged 50 years or older, so the likelihood of contamination in the control arm in ERSPC and also PLCO may increase with time. Otto et al. demonstrated that effective contamination (rate of men with abnormal PSA test followed by biopsy) was relatively small at 10% over a 4-year rescreening interval in the control arm.43 However, men who had a rapid PSA increase tended to undergo biopsy and those who had a stable PSA velocity tended not to undergo prostate biopsy. Therefore, the statistical power of the screening study may have been underestimated with the compliance of the screening arm being lower and the contamination of the control arm being higher. Therefore, the second analysis using the Cuzick model, which adjusts for contamination and non-compliance for the PSA test, may be very important.44 Within the ERSPC Rotterdam, contamination of the PSA test in the control arm was 30.7% and non-compliance in the screening arm was 27.1%. They proposed three different scenarios according to the effects of screening: (i) no effect; (ii) small effect with a reduction in mortality of 7% in the screening arm; and (iii) a large effect with a reduction in mortality rate of 33% in the screening arm. If a reduction in mortality in the screening arm is very small at 7% by intention-to treat analysis, a reduction in death from prostate cancer in the screening arm would be estimated to have a 16% reduction according to the second analysis using the Cuzick model. Adjustment for non-compliance and contamination may be feasible in the ERSPC, Rotterdam. The second analysis may be valuable for men who are screened.

Japanese Prospective Cohort Study of Screening for Prostate Cancer

The low exposure rate of screening in Japan may be an advantage for a screening study in terms of lowering contamination in the control cohort. A cluster prospective cohort study, the Japanese Prospective Cohort Study of Screening for Prostate Cancer (JPSPC), was conducted in order to evaluate the effectiveness of screening for prostate cancer in 2001 and has been ongoing since 2002.13 The primary endpoint of JPSPC is comparing changes in the mortality rate of prostate cancer between a screening cohort and a control cohort. JPSPC is a prospective cluster cohort study. The screening cohort includes municipalities in Hokkaido, Gunma, Hiroshima and Nagasaki prefectures, which have about 100 000 men in an age range between 50 and 79. Within the screening cohort, a campaign about screening for prostate cancer has been conducted and it is expected to lead to a high exposure rate of screening of over 60% over 5 years. The control cohort includes municipalities in the same prefectures which have almost the same male populations. Aggressive promotion of screening for prostate cancer has not been done in the control cohorts.

The exposure rate of screening in Isesaki city (screening cohort in Gunma Prefecture) between 2002 and 2007 was 85.5%, while the level of contamination of PSA screening in Kiryu city (control cohort in Gunma Prefecture) was extremely low at 12.5% between 1992 and 2006. The age-adjusted mortality rates have decreased since 2004 in the screening cohort and increased in the control cohort.

JPSPC has been successfully carried out in terms of compliance and contamination for the PSA test in the screening and control cohorts, respectively. The first analysis on the changes in the mortality rate due to prostate cancer will be carried out around 2012.

Step by step distress points in a screening system for prostate cancer

  1. Top of page
  2. Abstract
  3. Recent trends and future perspectives on the incidence and mortality of prostate cancer in Japan and USA
  4. Guidelines on PSA screening in Japan and other developed countries
  5. Positive evidence regarding PSA-based screening for prostate cancer
  6. Critical review of research that could not demonstrate a positive correlation between PSA-based screening and mortality reduction
  7. Ongoing global prospective study
  8. Step by step distress points in a screening system for prostate cancer
  9. Future perspectives on screening for prostate cancer
  10. References

What distresses men who are at risk of prostate cancer before undergoing PSA-based screening?

Fundamentally, a man at risk of prostate cancer is totally free to choose whether or not to undergo a PSA test. Distress points throughout the screening system for prostate cancer, which includes the PSA test, DRE, prostate biopsy, computed tomography (CT), magnetic resonance imaging (MRI), bone scan and treatment choice, may be different among individuals. For a man with urinary symptoms, a policy statement on the PSA test may be very simple. According to the Japanese guidelines on male lower urinary tract symptoms (LUTS),45 all men with urinary symptoms should be screened by PSA test before starting follow-up or having any treatment for LUTS. The policy statement on the PSA test for men with some urinary symptoms is acceptable for almost all men, physicians and urologists worldwide.

Men without any urinary symptoms will have step by step distress during screening for prostate cancer. What are distressed points for men before undergoing a PSA test? An asymptomatic man waiting for the results of ongoing RCT conducted in the USA and Europe cannot be a candidate for PSA screening. However, it should also be made known that the most recent reliable research on screening for prostate cancer, excluding RCT, revealed a possible mortality reduction.19–23 Furthermore, it should also be announced that the most resent RCT demonstrated that the incidence of advanced prostate cancer decreased about 50% in the screening arm compared with the control arm over 10 years of observations.18

An asymptomatic man with a negative impression of the PSA screening system (e.g. biopsy complications, overdetection, overtreatment, likelihood of erectile dysfunction, decrease in QOL, etc.) after understanding a fact sheet on screening for prostate cancer may not be a candidate for PSA screening. However, for example, the anxiety of detecting indolent prostate cancer can be reduced after checking PSA levels. Although about 30–50% of men have latent insignificant prostate cancer throughout their lives, there may be little possibility of detecting such insignificant prostate cancer within a screening system using PSA and DRE. It should also be demonstrated in the fact sheet that screening for prostate cancer can detect many clinically significant prostate cancer cases in a curative stage. Furthermore, it should also be indicated that the risk of overdetection decreases with higher PSA levels. The likelihood of detecting insignificant cancer is zero for about 90% of screened men who have PSA levels lower than the biopsy threshold. Therefore, it is important to provide information that overdetection is one of the demerits of screening for prostate cancer, but it is more important to provide information that the likelihood of having insignificant prostate cancer could be a problem mainly for men with PSA levels above the cut-offs and below 10 ng/mL before undergoing prostate biopsy. The likelihood of having insignificant prostate cancer can be clarified after undergoing a prostate biopsy. The risk of overtreatment is a problem mainly for men with low volume and low grade prostate cancer with PSA below 10 ng/mL.

To show a diagnostic flowchart of the screening system including prostate biopsy, CT, bone scan, treatment options is very important for men who want to be screened. However, it may not be easy to decide one's own risk from a prostate biopsy or treatment for prostate cancer before having a PSA test or detecting prostate cancer, respectively. A man who does not want to proceed with a prostate biopsy because of side effects and the likelihood of undergoing unnecessary biopsy following abnormal findings on PSA test/DRE, may not be a candidate for PSA-based screening. However, in general, a man usually decides whether or not to undergo prostate biopsy according to the balance between the probability of detecting prostate cancer and the demerits of prostate biopsy. Therefore, a man who has some anxiety about the prostate biopsy itself should decide whether to undergo prostate biopsy or not after finding out his PSA level. Alternatively, anxiety about side effects of treatment should be faced after detecting prostate cancer because the level of anxiety about treatment side effects may be strongly related to individual risk of progressing to metastatic prostate cancer and/or dying of prostate cancer. Treatments for prostate cancer are varied, especially in the early stage. Therefore, it is important to show a summary of the treatment and likelihood of side effects, but it is more important to indicate that patients at an earlier stage of prostate cancer can select a treatment according to their wishes and a specialist's recommendation. Alternatively, it should be demonstrated that risk of detecting advanced stage prostate cancer increases in men who have not undergone screening for prostate cancer compared with men who have been screened. It should also be indicated in the fact sheet that metastatic prostate cancer is very hard to treat curatively.

What distresses men who have an abnormal finding on PSA/DRE?

If men with PSA levels below 10 ng/mL undergo prostate biopsy, 20–40% will have prostate cancer detected and 60–80% will undergo unnecessary biopsy without detecting prostate cancer. A man who thinks that a risk for having an unnecessary biopsy is not acceptable cannot be a candidate for prostate biopsy. However, the likelihood of unnecessary biopsy decreases with higher PSA levels. Therefore, the number of men who refuse to undergo prostate biopsy may decrease with higher PSA levels. A reliable nomogram to estimate the probability of detecting prostate cancer using available clinical parameters is desirable.

Anxiety about detecting indolent prostate cancer may be a problem mainly for men with PSA levels below 10 ng/mL. It may be impossible to show a probability of detecting indolent prostate cancer in men with PSA below 10 ng/mL before undergoing prostate biopsy. However, it is very difficult to judge the individual risk of detecting indolent prostate cancer without any information on pathology in biopsy specimens. Therefore, men should be informed before undergoing prostate biopsy that it is still difficult to judge the probability of having indolent cancer after undergoing prostate biopsy, but it may be better clarified after obtaining pathological findings on biopsy specimens. It should also be indicated in the fact sheet that if a man has low volume and low grade prostate cancer, he is a candidate for an active surveillance protocol. The criteria for acceptability of active surveillance have not been decided, but an ongoing study showed acceptable positive intermediate results and research will continue.46

Anxiety about missing clinically significant prostate cancer in men with negative results on a first set of prostate biopsies may be one of the problems of PSA screening. However, the risk of missing clinically significant prostate cancer has decreased with the introduction of multiple-core biopsy. The risk of false negative results on multiple-core biopsy series is uncertain, but it can be said that serial PSA checking is very important for those men. It is also uncertain when would be the best time to undergo the second set of prostate biopsies. However, it may be informative for men with negative biopsy results that early stage prostate cancer with a pretreatment PSA velocity of lower than 2 ng/mL has an excellent outcome in terms of cause-specific survival and overall survival after radical prostatectomy or external beam radiation therapy.47,48

What distresses men who are diagnosed with prostate cancer?

Overtreatment may be the most serious anxiety, especially for older men with PSA levels below 10 ng/mL and also with low grade and low volume cancer in biopsy specimens. There is an opinion that the risk of overdetection and overtreatment is a serious problem for all men who want to be screened, but this is unfounded. Anxiety about the likelihood of overdetection and overtreatment may be a problem mainly for prostate cancer patients with specific clinicopathologic features, who are suitable for active surveillance. Active surveillance may be an important treatment option, especially for older men, with small and low grade cancer.

Alternatively, many men have survived prostate cancer without lowering the quality of life after receiving appropriate treatment. However, some patients survived prostate cancer but had side effects, which lowered QOL. Also, the inclusion criteria and follow-up strategy for active surveillance have not been established, so some patients may be overtreated by following definitive therapies and some may be undertreated at present. Investigating a reliable nomogram to estimate the probability of indolent cancer and establishing a well-validated treatment strategy are essential to optimize the screening system for prostate cancer.

Future perspectives on screening for prostate cancer

  1. Top of page
  2. Abstract
  3. Recent trends and future perspectives on the incidence and mortality of prostate cancer in Japan and USA
  4. Guidelines on PSA screening in Japan and other developed countries
  5. Positive evidence regarding PSA-based screening for prostate cancer
  6. Critical review of research that could not demonstrate a positive correlation between PSA-based screening and mortality reduction
  7. Ongoing global prospective study
  8. Step by step distress points in a screening system for prostate cancer
  9. Future perspectives on screening for prostate cancer
  10. References

Establishing an optimal screening system, which minimizes overdetection, overtreatment, loss of QOL due to treatment and maximizes the decrease in mortality rate due to prostate cancer and development of metastatic prostate cancer, must be the focus, because many men at risk of prostate cancer already think that intelligent use of PSA screening may be of some value. Recent reliable research including RCT revealed a significant decrease in metastatic and advanced prostate cancer, and some reliable ecological and cohort studies demonstrated a decrease in mortality rate due to prostate cancer. Also, some research that did not show a positive effect on screening for prostate cancer may have included serious flaws in the study design. Therefore, it is natural that the number of men who want to be screened has increased in developed countries. It could be a problem that there are still many patients with lower QOL due to treatment without prolonging their lives (overtreatment), deaths due to insufficient or inappropriate treatment (undertreatment), while many patients have had their lives saved due to screening and subsequent appropriate treatment. In the future, even if ongoing RCTs and a cluster cohort trials show a positive effect in terms of decreasing the mortality rate due to prostate cancer and even if epoch-making tumor markers for detecting clinically significant prostate cancer are discovered, screening for prostate cancer, and all other effective cancer screening, should be provided after shared-informed decision-making using a fact sheet including the best available evidence.

References

  1. Top of page
  2. Abstract
  3. Recent trends and future perspectives on the incidence and mortality of prostate cancer in Japan and USA
  4. Guidelines on PSA screening in Japan and other developed countries
  5. Positive evidence regarding PSA-based screening for prostate cancer
  6. Critical review of research that could not demonstrate a positive correlation between PSA-based screening and mortality reduction
  7. Ongoing global prospective study
  8. Step by step distress points in a screening system for prostate cancer
  9. Future perspectives on screening for prostate cancer
  10. References