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Keywords:

  • prostate cancer;
  • PSA;
  • screening;
  • guidelines

Abstract

  1. Top of page
  2. Abstract
  3. Policy statement of the Japanese Urological Association on screening for prostate cancer
  4. Theoretical background of the policy statement
  5. Review of the literature on PSA screening
  6. Well balanced informed consent in screening for prostate cancer
  7. Ideal screening system in Japan
  8. Benefits and drawbacks of screening for prostate cancer
  9. Baseline consensus on screening for prostate cancer in the post-ERSPC era
  10. References
  11. Appendix

The exposure rate of screening for prostate cancer using prostate-specific antigen (PSA) in Japan is still very low compared with that in the USA or western Europe. The mortality rate of prostate cancer will increase in the future and in 2020 it will be 2.8-fold higher than in 2000. Therefore, there is an urgent need to determine the best available countermeasures to decrease the rate of prostate cancer death. PSA screening, which can reduce the risk of death as a result of prostate cancer, should be offered to all men at risk of developing prostate cancer with fact sheets showing updated benefits and drawbacks of screening for prostate cancer.


Policy statement of the Japanese Urological Association on screening for prostate cancer

  1. Top of page
  2. Abstract
  3. Policy statement of the Japanese Urological Association on screening for prostate cancer
  4. Theoretical background of the policy statement
  5. Review of the literature on PSA screening
  6. Well balanced informed consent in screening for prostate cancer
  7. Ideal screening system in Japan
  8. Benefits and drawbacks of screening for prostate cancer
  9. Baseline consensus on screening for prostate cancer in the post-ERSPC era
  10. References
  11. Appendix

The Japanese Urological Association (JUA) recommends prostate-specific antigen (PSA) screening, which can reduce the risk of death as a result of prostate cancer,1 for men at risk of prostate cancer. The recommendation is based on fact sheets showing the benefits and drawbacks of screening for prostate cancer. The JUA provides the best available screening system for men who want to be screened.

Theoretical background of the policy statement

  1. Top of page
  2. Abstract
  3. Policy statement of the Japanese Urological Association on screening for prostate cancer
  4. Theoretical background of the policy statement
  5. Review of the literature on PSA screening
  6. Well balanced informed consent in screening for prostate cancer
  7. Ideal screening system in Japan
  8. Benefits and drawbacks of screening for prostate cancer
  9. Baseline consensus on screening for prostate cancer in the post-ERSPC era
  10. References
  11. Appendix
  • 1
    The exposure rate of screening for prostate cancer using PSA in Japan is still very low compared with that in the USA or western Europe. Therefore, many clinically significant cancer cases in Japan might be undetected and missed until they develop into clinically advanced disease.2 At present, approximately 30% of newly detected prostate cancer cases have bone metastases in municipalities where the exposure rates of population-based PSA screening have been lower than 5%.3 In the mean time, mortality rates as a result of prostate cancer have increased and were estimated to be 9985 in 2008.4 The number of deaths as a result of prostate cancer will reach 21 062 in 2020.5 Therefore, there is an urgent need to determine the best available countermeasures to decrease the rate of prostate cancer death.
  • 2
    The Cancer Countermeasure Fundamental Law, which is an important national policy in Japan declared in 2007, stated the goal of a 20% decrease in the mortality rates as a result of cancer in people aged below 75 years within 10 years. The JUA recommends PSA screening, which can lead to a decrease in the mortality rate of prostate cancer, based on well-balanced fact sheets in human dry-dock (Ningen dock) and also population-based screening for prostate cancer to contribute to achieving the goal in terms of reducing the mortality rate of prostate cancer in all age ranges.
  • 3
    The latest results from the European Randomized Study of Screening for Prostate Cancer (ERSPC) showed that the mortality rate of prostate cancer showed a 20% and 31% decrease in the screening group compared with the control group during 9 years of observation on average by intention-to-screen (ITS) analysis1 and a second analysis adjusted by compliance and contamination for the PSA test,6 respectively. This study clearly showed the effectiveness of PSA screening in terms of reducing the mortality rate of prostate cancer.
  • 4
    The screening rate in the USA is approximately 75% among men aged 50 years or older.7 According to the latest cancer registry in the USA, the mortality rate of prostate cancer has decreased since 1992, and in 2005 showed a 36% decrease compared with 1990.8 Because there was no effective prevention of clinically manifested prostate cancer at that time, the decreasing prostate cancer mortality shown in the USA could be a result of PSA-based screening and subsequent appropriate treatments for screen-detected prostate cancer.
  • 5
    The latest results in the Tyrol screening project showed a 70% decrease in metastatic prostate cancer in the area after the introduction of free PSA tests for inhabitants.9 The exposure rate for the PSA test between 1988 and 2005 was high at 86.6%. As a result, the mortality rate from prostate cancer in 2005 showed a 54% decrease compared with that expected. These results might be a result of the high exposure to PSA screening and subsequent appropriate treatment.
  • 6
    The most important benefit of the routine use of PSA screening for asymptomatic males is mortality reduction. Alternatively, screened men might still have risks of overdetection, overtreatment and a decrease in quality of life (QOL) after treatment. However, these problems will be solved in the future with progress being made in active surveillance protocols and minimally invasive prostate cancer treatment.
  • 7
    There are both benefits and drawbacks of any screening system for cancer. Therefore, a man at risk of prostate cancer should decide whether or not to be screened based on the latest reliable information provided by a national scientific organization. Even in PSA screening for prostate cancer, which can lead to a decrease in the mortality rate, screening can lead to problems during screening itself (e.g., false positive and false negative PSA tests), prostate biopsy and treatment procedure. Therefore, the JUA provides an optimized screening system with a fact sheet, which shows the benefits and drawbacks of the screening system, for men who want to be screened for prostate cancer in the two main screening systems in Japan – the population-based screening and human dry-dock (Ningen dock).

Review of the literature on PSA screening

  1. Top of page
  2. Abstract
  3. Policy statement of the Japanese Urological Association on screening for prostate cancer
  4. Theoretical background of the policy statement
  5. Review of the literature on PSA screening
  6. Well balanced informed consent in screening for prostate cancer
  7. Ideal screening system in Japan
  8. Benefits and drawbacks of screening for prostate cancer
  9. Baseline consensus on screening for prostate cancer in the post-ERSPC era
  10. References
  11. Appendix

The latest results from the European Randomized Study of Screening for Prostate Cancer (ERSPC) clearly showed that expanding PSA screening to the public could lead to a decrease in mortality from prostate cancer.1,6 The risk of death as a result of prostate cancer in the screening arm showed a 20% decrease compared with the control arm according to the intention-to-screen analysis,1 and a 31% decrease after controlling for compliance and contamination for the PSA test6 over only 8.8 years of follow up, on average. However, what we really want to know is the lifetime-risk reduction as a result of PSA screening. The results from the first analysis of the ERSPC might underestimate the risk reduction throughout a lifetime, because they simply observed the short-term effect of PSA screening. Further follow-up can provide an appropriate answer to the previous question.

In terms of the drawbacks of screening for prostate cancer, the ERSPC showed an increased risk of overdetection and overtreatment as a result of screening. They estimated the number of need for treatment to prevent one prostate cancer death (NNT) and the number of need for screening to prevent one prostate cancer death (NNS).1 The NNT was 48 and NNS was 1410 according to the estimate in the manuscript. However, the drawbacks of the PSA screening might be overestimated, because of the short follow-up duration. Furthermore, NNT cannot estimate how large the drawbacks of the screening would be, because it is simply an estimate of the assumption that any stage of prostate cancer is equal. The treatment duration and quality adjusted life years of metastatic prostate cancer patients are different from those of localized prostate cancer. Increasing the number of metastatic prostate cancer might cause a lot of socioeconomic damage, not only to the individuals, but also to the community because of loss of QOL, high treatment cost, loss of activity as a result of long-term treatment and also suffering severe adverse effects as a result of the treatments. Therefore, from a clinical point of view, one treatment for metastatic prostate cancer and one treatment for localized prostate cancer should not be handled as the same entity. In fact, the number of patients with metastatic prostate cancer in the control arm of the ERSPC was almost twice as high as that in the screening arm.

The Prostate, Lung, Colorectal, and Ovarian (PLCO) screening study10 failed as a randomized controlled trial as a result of serious and uncontrollable contamination of the control cohort. Nearly half of the participants were pre-screened using the PSA test at least once within 3 years before entry into the trial. The estimated contamination in the first year was very high, at 40%, and this increased to 52% in the 6 years after trial entry. The lead-time in the screening cohort was just 1.5 years compared with the control cohort. The stage distributions between the screening and control cohorts were almost the same. Therefore, the percentage of patients with stage IV and stage III disease was very low, at 2.7% and 1.9%, respectively, even in the control cohort, and the crude number of patients with stage IV disease did not differ between the screening and control cohorts. The percentages of patients with distant metastases and locally advanced disease were 21% and 19%, respectively, in Japan,2 where the rate of PSA screening is very low at between 5 and 10%. The control cohort in the PLCO study should not be handled as a non-screening cohort. Therefore, intention-to-screen analysis does not make sense.

In the pre-ERSPC era, there were some reasonable data and research, which suggested or showed positive effects of PSA screening in terms of decreasing deaths as a result of prostate cancer and decreasing the risk of developing metastatic prostate cancer. In the USA, the exposure rate of PSA screening is estimated to be very high at about 75% of men aged 50 years or over.7 According to research on the trend in the mortality rate of prostate cancer based on the cancer registry in USA, the mortality rates of prostate cancer have continued to decrease since 1992 and showed a 36% decrease between 1990 and 2005.8 Because there is no effective primary prophylaxis to prevent the development of prostate cancer, the drastic decrease in the prostate cancer mortality rate might be a result of the high exposure rate of PSA screening and subsequent appropriate treatment strategies in the USA. In the USA, Colloi et al.11 also carried out an ecological study to investigate the relationship among the age-adjusted mortality rate 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 inverse correlation between PSA test frequency and the age-adjusted mortality rate of prostate cancer, and also between the population density of urologists and mortality rate of prostate cancer. Therefore, the mortality rate of prostate cancer might decrease with PSA testing and easy access to urologists who can provide appropriate treatment.

Mortality as a result of prostate cancer in Japan has increased and was estimated to be 9985 in 2008,4 which ranked seventh overall and was approximately 5% of all causes of death in males. Furthermore, the number of deaths from prostate cancer is estimated to increase to 21 062 in 2020, which is 2.8-fold higher than that in 2000.5 However, mortality as a result of prostate cancer in the USA has decreased and was estimated to be approximately 28 905 in 2005.8 The difference in the population between the USA and Japan is approximately 2.5-fold; therefore, the mortality rate as a result of prostate cancer in the USA and Japan might be converging. Furthermore, there are opposing recent trends in the mortality rate as result of prostate cancer between the two countries, so the future mortality rate in Japan will catch up with that in the USA, and might surpass it. The low exposure rate of PSA screening in Japan and the high exposure rate in the USA might result in completely different trends in the mortality rate as a result of prostate cancer, because although the treatment level provided in each nation might be the same, genetic and dietary factors related to the risk of developing lethal prostate cancer might be more favorable in Japanese than in Americans.12

The publication of the ERSPC section in Sweden showed 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 arm13. The prognosis of advanced prostate cancer is worse than that of cancer detected at earlier stages. Therefore, the results can be evaluated as a high priority study in the field of screening for prostate cancer in the pre-ERSPC era.

According to the latest results in the Tyrol study,9 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. In the meantime, the mortality rate of prostate cancer showed a drastic decrease of 54% compared with the expected mortality rate in the area. These results were important in the field of screening for prostate cancer in the pre-ERSPC era.

Alternatively, the reliability of ecological studies that denied or did not show a positive relationship between PSA screening and a decrease in the mortality rate of prostate cancer included 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.12

Well balanced informed consent in screening for prostate cancer

  1. Top of page
  2. Abstract
  3. Policy statement of the Japanese Urological Association on screening for prostate cancer
  4. Theoretical background of the policy statement
  5. Review of the literature on PSA screening
  6. Well balanced informed consent in screening for prostate cancer
  7. Ideal screening system in Japan
  8. Benefits and drawbacks of screening for prostate cancer
  9. Baseline consensus on screening for prostate cancer in the post-ERSPC era
  10. References
  11. Appendix

In the post-ERSPC era, the informed consent for screening for prostate cancer using the PSA test for asymptomatic men has dramatically changed. The debatable points have already shifted from whether the PSA test decreases the mortality rate to the issue of overdiagnosis, overdetection and influence on QOL after various treatments for screen-detected prostate cancer. In the meantime, advances in minimally-invasive treatment to maintain QOL for patients and the development of active surveillance protocols might solve uncertainties and controversies regarding the negative effect of PSA screening. The present baseline recommendation on PSA screening is to carry out PSA-screening after shared-informed decision-making based on fact sheets showing updated information on epidemiological features, and the benefits and drawbacks of screening and treatment. The JUA recommends providing updated fact sheets, including all important issues regarding prostate cancer, to men who want to be screened. Fact sheets should be divided into two stages, one for men before undergoing screening (Appendix 1) and the other one is for men after undergoing the PSA test (Appendix 2). The guidelines on screening for prostate cancer edited by the JUA clearly shows expected outcomes, including both positive and negative effects, on men undergoing PSA screening and also those on men not undergoing PSA screening.

Ideal screening system in Japan

  1. Top of page
  2. Abstract
  3. Policy statement of the Japanese Urological Association on screening for prostate cancer
  4. Theoretical background of the policy statement
  5. Review of the literature on PSA screening
  6. Well balanced informed consent in screening for prostate cancer
  7. Ideal screening system in Japan
  8. Benefits and drawbacks of screening for prostate cancer
  9. Baseline consensus on screening for prostate cancer in the post-ERSPC era
  10. References
  11. Appendix

Candidates for PSA screening are men aged 50 years or older in general, and 40 years or older in men with a family history, in the population-based screening for prostate cancer. In individual-based screening for prostate cancer, such as the human dry-dock (Ningen dock) in Japan, the JUA recommends checking baseline PSA at the age of 40 years. To check baseline PSA at the age of 40 years would not contribute to cancer detection at the time of the measurement, but might be valuable in terms of minimizing the likelihood of missing clinically important prostate cancer in patients in their early 50s, for which the detection rate of prostate cancer is approximately 0.1% in Japan. Furthermore, if a man diagnosed with prostate cancer had his PSA measured from the age of 40 years, his individual PSA kinetics might be very helpful to predict the aggressiveness of the prostate cancer and select the appropriate treatment.14,15

The screening modality should be the PSA test for population-based screening for prostate cancer mainly concomitant with the basic health check-up system in Japan and PSA with or without DRE in the human dry-dock (Ningen dock). Fact sheets including the benefits and drawbacks of PSA screening should be provided to candidates before carrying out the screening test. The cut-off of PSA test level for the biopsy indication is recommended at 4.0 ng/mL. Alternative cut-offs for the biopsy indications are age-specific reference ranges of PSA, which are set at 3.0, 3.5 and 4.0 ng/mL in the age ranges of 50 to 64 years, 65 to 69 years and 70 years or older, respectively.16 The optimal screening interval cannot be stated at present, but it is well known that the risk of developing prostate cancer might be closely related to baseline PSA levels. Therefore, it is reasonable to set the screening interval according to baseline PSA levels. One recommendation is to set the screening interval at once every 3 years for men with baseline PSA levels lower than 1.0 ng/mL and annually for men with baseline PSA levels between 1.0 ng/mL and the cut-offs.17–19

Systematic prostate biopsy must be carried out by transrectal ultrasonography guidance. The optimal number of biopsy cores is uncertain at present, but should be at least six cores. Recently, the usefulness of multiple-core biopsy has been shown in many studies around the world. Therefore, a multiple-core biopsy, which takes around 12 cores, is an alternative option for prostate biopsy.

In Japan, the exposure rate of the PSA test before an age where the life expectancy is approximately another 10 years, which is about 78 years-of-age in Japan, might be very low at approximately 10%. Therefore, we do not recommend an upper age limit for PSA screening at present. Alternatively, men who have been screened often until they are of an age where their life expectancy is approximately another 10 years and have also shown low PSA levels might have less need to continue PSA screening.

Benefits and drawbacks of screening for prostate cancer

  1. Top of page
  2. Abstract
  3. Policy statement of the Japanese Urological Association on screening for prostate cancer
  4. Theoretical background of the policy statement
  5. Review of the literature on PSA screening
  6. Well balanced informed consent in screening for prostate cancer
  7. Ideal screening system in Japan
  8. Benefits and drawbacks of screening for prostate cancer
  9. Baseline consensus on screening for prostate cancer in the post-ERSPC era
  10. References
  11. Appendix

Benefits for men who undergo screening for prostate cancer

  • 1
    Decrease in the incidence of metastatic prostate cancer.
  • 2
    Definite decrease in the mortality of prostate cancer according to the latest results from the ERSPC study.
  • 3
    The probability of men being diagnosed with prostate cancer in the early stage increases if they decide to be screened. If men are diagnosed with prostate cancer in the early stage, they can be recommended various treatment strategies including radical prostatectomy, external beam radiation therapy, brachytherapy, hormonal therapy and active surveillance according to age, tumor grade, PSA level, clinical stage, social activity, economic issues, patient's preference and so on.
  • 4
    Decrease in the risk of underdetection of clinically significant prostate cancer.

Drawbacks for men who undergo screening for prostate cancer

  • 1
    Increase in the risk of detecting clinically insignificant cancer. The percentage of insignificant prostate cancer in screen-detected prostate cancer was estimated at approximately 10% in Japanese men who participated in a prospective study on active surveillance.
  • 2
    Likelihood of overtreatment. Risk of overtreatment might not decrease until establishment of a reliable active surveillance protocol.
  • 3
    Rare, but very high-grade prostate cancer that does not secrete PSA might be missed in PSA screening.
  • 4
    Approximately 60–80% of men with PSA above the cut-offs might undergo unnecessary biopsy, but the likelihood of undergoing unnecessary biopsy might decrease as PSA levels increase.
  • 5
    According to the survey carried out by the JUA20, approximately 15% of men biopsied might have complications including fever, rectal bleeding, hematuria, hemospermia and so on. The percentage of men with high fever above 38°C was rare at 1.1%, and those having severe complications, such as septic shock, were very rare at 0.07%. The most severe complication, death as a result of prostate biopsy, was extremely rare at 0.0005%.
  • 6
    Likelihood of reduced QOL (e.g., urinary incontinence, erectile dysfunction, rectal bleeding, loss of libido, anemia, etc.) as a result of surgery, radiation therapy, androgen deprivation therapy and so on.

How to reduce the drawbacks of screening for prostate cancer

  • 1
    To reduce the chance of missing clinically significant prostate cancer, which shows poorly differentiated features and also less PSA production in the tissues, digital rectal examination and transrectal ultrasonography should be offered to men who visit physicians with any specific urinary symptoms.
  • 2
    To decrease the risk of having severe complications as a result of prostate biopsy, men with acute or complicated urinary infection should not be considered candidates for undergoing prostate biopsy until being cured.
  • 3
    To reduce the risk of developing advanced stage prostate cancer in men with missed small prostate cancer at initial prostate biopsy, men with negative findings on previous prostate biopsies should be followed by serial PSA measurements. If men are diagnosed with prostate cancer during the appropriate follow-up by PSA test, most cases would be diagnosed with prostate cancer within a curative stage.
  • 4
    To decrease the likelihood of unnecessary prostate biopsies, especially for men with PSA below 10 ng/mL, which shows a relatively low probability of cancer between 20 and 40%, nomogram, PSA-related marker, magnetic resonance imaging and so on would be useful to select more appropriate candidates for biopsy.
  • 5
    To provide an ideal screening system to men who want to be screened, avoiding underdetection of clinically important cancer, overdetection of clinically insignificant cancer, overtreatment, loss of QOL as a result of diagnostic procedures and treatments are desirable. Research on progress on a screening system that includes offering screening to appropriate candidates, setting life-expectancy oriented PSA cut-offs, selecting candidates for prostate biopsy by available PSA-related markers or nomogram to estimate the probability of detecting prostate cancer, individually optimized prostate biopsy, and providing tailor-made treatment strategies have been investigated and studies are now on-going around the world
  • 6
    Appropriate candidates and follow-up schedules for an active surveillance strategy are now being investigated21–24 and have not been established. Therefore, the possibility of missing appropriate timing for curative intent exists. However, some pilot studies on the acceptability of active surveillance showed successful results.25,26 In the mean time, a nomogram that estimates the probability of having clinically insignificant prostate cancer is being investigated by several clinical researchers. In the near future, clinically acceptable treatment strategies on active surveillance will be available.
  • 7
    Even if a man is offered appropriate treatment in terms of cancer control, he might have a risk of a lower QOL after or during treatment. Progress in minimally invasive and effective treatments might decrease the drawbacks of the screening itself.

Benefits for men who do not undergo screening

  • 1
    Significantly decreased risk of overdetection and overtreatment of men with insignificant prostate cancer, which was estimated at 10% of all screen-detected prostate cancer in Japan.
  • 2
    Reduced risk of undergoing unnecessary biopsy.
  • 3
    Reduced risk of having anxiety about having prostate cancer, especially for men with false-positive PSA results.

Drawbacks for men who do not undergo screening

  • 1
    Missed chance of reducing mortality as a result of prostate cancer, as already shown in the ERSPC study.
  • 2
    Increased risk of underdetection of clinically significant prostate cancer still in the early stage. Significant increase in the risk of detecting metastatic prostate cancer or advanced prostate cancer. If men are detected with prostate cancer in the advanced stage, the prognosis might be limited.

Baseline consensus on screening for prostate cancer in the post-ERSPC era

  1. Top of page
  2. Abstract
  3. Policy statement of the Japanese Urological Association on screening for prostate cancer
  4. Theoretical background of the policy statement
  5. Review of the literature on PSA screening
  6. Well balanced informed consent in screening for prostate cancer
  7. Ideal screening system in Japan
  8. Benefits and drawbacks of screening for prostate cancer
  9. Baseline consensus on screening for prostate cancer in the post-ERSPC era
  10. References
  11. Appendix

The American Urological Association (AUA) recommends PSA-based screening (with DRE) for prostate cancer for men aged 40 years or older and those who have a life-expectancy of at least another 10 years.27 Information should be provided to recipients about the benefits and limitations of PSA screening. The AUA and the JUA have already agreed on a joint statement on screening for prostate cancer, which has stated the aforementioned policy since 2008.28,29

Overall, almost all medical organizations have a policy that information on screening for prostate cancer, including the benefits and limitations of PSA screening, complications of biopsy and treatment, and so on 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 that informed decision making is not necessary (i.e. D recommendation in the ranking provided by the US Preventive Services Task Force) is outdated in both individual-based and population-based screening for prostate cancer.

Some scientific organizations overestimated the risk of overtreatment based on the NNT data shown in the ERSPC paper1 and underestimated the risk of reduction of death as a result of prostate cancer by PSA screening based on ITS analysis data from the PLCO screening trial9 and showed risk reduction of 20% by ITS analysis of the ERSPC obtained after a very short follow-up duration of 9 years on average.1 As mentioned earlier regarding issues, PSA screening, which can reduce the risk of death as a result of prostate cancer, should be offered to all men at risk for developing prostate cancer with fact sheets showing the updated benefits and drawbacks of screening for prostate cancer.

References

  1. Top of page
  2. Abstract
  3. Policy statement of the Japanese Urological Association on screening for prostate cancer
  4. Theoretical background of the policy statement
  5. Review of the literature on PSA screening
  6. Well balanced informed consent in screening for prostate cancer
  7. Ideal screening system in Japan
  8. Benefits and drawbacks of screening for prostate cancer
  9. Baseline consensus on screening for prostate cancer in the post-ERSPC era
  10. References
  11. Appendix

Appendix

  1. Top of page
  2. Abstract
  3. Policy statement of the Japanese Urological Association on screening for prostate cancer
  4. Theoretical background of the policy statement
  5. Review of the literature on PSA screening
  6. Well balanced informed consent in screening for prostate cancer
  7. Ideal screening system in Japan
  8. Benefits and drawbacks of screening for prostate cancer
  9. Baseline consensus on screening for prostate cancer in the post-ERSPC era
  10. References
  11. Appendix
Table Appendix1.  Fact sheet on screening for prostate cancer for men before undergoing the prostate-specific antigen test
For men before deciding whether or not to take the test for screening
About prostate cancer and the diagnostic modality/procedureBenefits and limitations of screening for prostate cancer
  1. DRE, digital rectal examination; PSA, prostate-specific antigen.

• The number of men who died from prostate cancer in 2007 is estimated to be around 10 000, making it the eighth most lethal cancer in Japanese men. • It is estimated that the number of men with detected prostate cancer will increase and it will be the second highest male cancer following lung cancer in 2020. The number of deaths from prostate cancer in 2020 is estimated to be three times higher than that in 2000. • In Japan, men can undergo screening for prostate cancer in population-based screening carried out by local governments or a human dry-dock carried out mainly by screening centers in public or private hospitals. • The risk of developing prostate cancer increases from the age of 50 years. Therefore, in population-based screening provided by local governments, men aged 50 years or older are recommended to begin PSA screening. Men with a family history of prostate cancer might have a higher risk of developing cancer than those without; therefore, they are recommended to begin PSA testing from 40 years-of-age. • The risk of detecting prostate cancer is low for men in their 40s. However, it is reasonable to begin PSA testing from the age of 40 year in individual-based screening for the following reasons: baseline PSA is a reliable and objective risk factor, which can predict the future risk of developing prostate cancer. If a man begins PSA screening from the age of 40 years and has serial PSA measurements maintaining an appropriate screening interval, the risk of developing life- threatening prostate cancer might decrease. Furthermore, if a man begins PSA screening from the age of 40 years and prostate cancer is detected thereafter, he will have his own PSA kinetics, which might help estimate the aggressiveness of prostate cancer. Individual PSA kinetics are important for offering appropriate treatment strategies to patients. • The screening modality for PSA in both screening system and occasional DRE in a human dry-dock. • In general, there are no specific symptoms in early stage prostate cancer. Therefore, it might be difficult to detect it without screening using the PSA test and/or DRE. • PSA is the best screening tool in terms of detecting prostate cancer in the early stage, with a high sensitivity at 80–90%. The probability of prostate cancer increases with increasing PSA levels in serum. • Approximately 8% of men screened might have PSA levels above the cut-offs and might require a prostate biopsy. Men with abnormal findings on a PSA test and DRE are recommended to undergo a transrectal ultrasonography-guided prostate biopsy, which takes cores of prostate tissue using a fine needle. The number of biopsy cores is set between 6 and 12 on average at institutions in Japan, but some institutions occasionally take more than 12 cores. • Prostate biopsy is carried out under local or lumbar anesthesia in outpatient or inpatient clinics. • If a man undergoes a prostate biopsy, prostate cancer is detected at approximately 40%. The detection rate is approximately 20% in men with a slight increase in PSA level, but that increases with higher PSA levels.• If a man at risk for prostate cancer undergoes PSA screening, the risk of dying as a result of prostate cancer is decreased significantly. • If screening for prostate cancer is not provided to the public, approximately 30% of men diagnosed with prostate cancer will have metastases. If a man undergoes screening for prostate cancer, the risk of detecting it in the metastatic stage decreases. • Although rare, 2–3% of prostate cancer cases cannot be detected by PSA screening, because very poorly differentiated or undifferentiated prostate cancer cells do not secrete PSA. • Some biopsied men might have complications, such as fever, rectal bleeding, hematuria, hemospermia and so on. However, severe complications, such as high fever that needs hospitalization and septic shock, are rare at 1.1% and 0.07%, respectively. • If a man undergoes a standard prostate biopsy, approximately 20–30% of prostate cancer is missed. Therefore, men with suspicious findings on PSA and/or DRE, but without prostate cancer on biopsy, should be followed carefully. • If men with PSA levels below 10 ng/mL underwent prostate biopsy, prostate cancer would be detected in 20–40% of them and 60–80% would undergo unnecessary biopsy without detecting prostate cancer. However, the likelihood of unnecessary biopsy might decrease with higher PSA levels. • Approximately 30–50% of men have latent insignificant prostate cancer throughout their lives. There is little possibility of detecting such insignificant prostate cancer within a screening system using PSA with or without DRE. • Screening for prostate cancer can detect many clinically significant prostate cancer cases within the curative stage. However, approximately 10% of screen-detected prostate cancer might be clinically insignificant, which is known as overdetection. However, the risk of overdetection decreases with higher PSA levels. • An appropriate diagnosis of clinically insignificant prostate cancer before the treatment might be difficult in general. The risk of overdetection and overtreatment increases with age. Alternatively, a man diagnosed with prostate cancer with a slight PSA increase, and small, well-differentiated tumors might be overdetected and overtreated by intensive treatment.
Table Appendix2.  Fact sheet on screening for prostate cancer for men after receiving their prostate-specific antigen test results
For men after undergoing PSA screening
Correspondence according to individual PSA resultsBenefits, drawbacks and uncertainties regarding biopsy and treatment
  1. DRE, digital rectal examination; LHRH, luteinizing hormone-releasing hormone; PSA, prostate-specific antigen, QOL, quality of life; TRUS, transrectal ultrasound.

• Men with PSA levels of 1.0 ng/mL or lower might have a low risk of increased PSA above 4.0 ng/mL at 1.3% over 5 years of follow-up and should be screened every 3 years. • Men with PSA levels between 1.1 and 2.0 ng/mL might have a risk of increased PSA above 4.0 ng/mL at 7.5% over 5 years of follow-up and should be screened annually. • Men with PSA levels between 2.1 and 3.0 ng/mL might have a high risk of increased PSA above 4.0 ng/mL at 30% over 5 years of follow-up and are highly recommended to undergo annual screening. • Men with PSA levels between 3.1 and 4.0 ng/mL have a very high risk of increased PSA above 4.0 ng/mL at 62% over 5 years of follow-up and are highly recommended to undergo annual screening. • The cut-off of PSA for biopsy indication is set at 4.0 ng/mL in general. Alternative cut-offs are set in an age-specific manner (50–64 years; 3.0 ng/mL, 65–69 years; 3.5 ng/mL, 70 years or older; 4.0 ng/mL). • Men with abnormal findings on a PSA test and DRE are recommended to undergo TRUS-guided prostate biopsy, which takes cores of prostate tissue using a fine needle. The number of biopsy cores is set between 6 and 12 on average at institutions in Japan. Occasionally more than 12 cores are taken in some institutions. • Men diagnosed with prostate cancer are recommended to check disease status by computed tomography, magnetic resonance imaging, bone scan, DRE and TRUS. • Primary treatments for prostate cancer are active surveillance, radical prostatectomy, radiation therapy and hormonal therapy. • Patients with prostate cancer decide their treatment strategy after getting enough information on available treatments in terms of benefits and adverse effects. It is also important to select the treatment according not only to their own disease status, but also to socioeconomic status, individual tolerability and future perspectives. • If men with abnormal PSA results are investigated further and undergo appropriate treatment, the risk of developing metastatic prostate cancer and dying from prostate cancer is decreased significantly.• Some biopsied men might have complications, such as fever, rectal bleeding, hematuria, hematospermia and so on. However, severe complications are rare. • If a man underwent standard prostate biopsy, prostate cancer would be missed in approximately 20–30% of cases. Therefore, men with suspicious findings on PSA and/or DRE, but without prostate cancer on biopsy should be followed carefully. • If men with PSA levels below 10 ng/mL undergo prostate biopsy, prostate cancer is detected in 20–40% of them and 60–80% of them undergo unnecessary biopsy without detecting prostate cancer. However, the likelihood of unnecessary biopsy decreases with higher PSA levels. • Approximately 30–50% of men have latent insignificant prostate cancer throughout their lives. There might be little possibility of detecting such an insignificant prostate cancer within a screening system using PSA with or without DRE. • Screening for prostate cancer can detect many clinically significant prostate cancer cases within the curative stage. Alternatively, approximately 10% of screen-detected prostate cancer might be clinically insignificant, which is known as overdetection. However, the risk of overdetection decreases with higher PSA levels. • Radical prostatectomy might give high curability if cancer is limited to the prostate. However, the likelihood of residual cancer is possible, because there is a limitation of clinical staging before surgery. Major complications are erectile dysfunction and urinary incontinence, but the frequency of urinary incontinence is not so high at around 10%. If patients want to preserve sexual function, nerve-sparing radical prostatectomy is one option. Mortality from the operation itself is very rare. • Treatment modalities for radiation therapy are varied, including external beam radiation therapy and brachytherapy. Recently, intensity modulated radiation therapy, which improves the treatment efficacy and reduces adverse effects, has been made available in Japan. Another option is carbon ion beam and proton beam therapy, but there are only a few institutions offering the treatment. Indications for primary radiation therapy are localized and locally advanced prostate cancer. There might be a high curability, even for patients with locally advanced prostate cancer in combination with radiation therapy and hormonal therapy. Major complications are radiation proctitis, prostatitis and urethritis. The risk of erectile dysfunction is approximately 20–40% of treated cases, but this might be lower than radical prostatectomy. • Hormonal therapy can be effective, even for patients with metastatic disease. Treatment agents are monthly or 3-monthly LHRH agonist injection, anti-androgen drugs and castration. LHRH agonists and castration might have equal efficacy. An LHRH agonist in combination with an anti-androgen might be an important treatment option. Estrogen agents are also used, especially for patients with disease recurrence after treatment with primary androgen deprivation therapy, such as an LHRH agonist and surgical castration. Alternative treatment options for hormonal therapy are combination therapy with surgery and radiation in neoadjuvant, adjuvant or salvage settings. Major complications of primary hormonal therapy are erectile dysfunction, loss of bone mineral density, hot flushes, sweating and reduced muscle power. • Active surveillance might be an important treatment option, especially for older men with small and low-grade cancer. • There might be many men who survive prostate cancer without lowering their QOL after receiving appropriate treatment. However, some patients survive prostate cancer but have a resultant loss of QOL. Also, some patients might be overtreated without benefits in terms of prolonging their lives.