Il PSA nello screening del carcinoma della prostata PRO Franco Gaboardi Urologia Ospedale San Raffaele Turro Milano

Epidemiology In Europe, PCa is the most common solid neoplasm, with an incidence rate of 214 cases per 1000 men, outnumbering lung and colorectal cancer PCa affects elderly men more often and therefore is a bigger health concern in developed countries Approximately 15% of male cancers are PCa in developed countries, compared with 4% of male cancers in developing countries There are large regional differences in incidence rates of PCa, with a range from 68.8 per 1000 in Malta to 182 per 1000 in Belgium EAU Guidelines 2015

Epidemiology: incidence Siegel et al. CA Cancer J Clin 2013

Epidemiology: incidence Center et al. Eur Urol 2012(61):

Epidemiology: incidence Siegel et al. CA Cancer J Clin 2013

Epidemiology Mortality rates tend to be higher in less developed regions of the world including parts of South America, the Caribbean, and sub-Saharan Africa PCa mortality rates decreased in 27 of the 53 countries under study, whereas rates increased in 16 and remained stable in 10 countries The increase in PCa mortality rates mainly occurred in lower resource settings, with declines largely confined to high- resource countries EAU Guidelines 2013

Epidemiology: mortality Siegel et al. CA Cancer J Clin 2013

Epidemiology: mortality Center et al. Eur Urol 2012(61):

Mass screening requires: a frequent disease a lethal disease an effective (i.e. discriminant) screening test an acceptable (i.e.: low false negative) non toxic diagnostic tool the proof of a survival benefit in screen detected patients Mass screening: asymptomatic patients The aim of screening is to reduce the risk of dying from the disease and from overall mortality Screening

PSA is not a unique indicator of PCa, but may also detect prostatitis or benign prostatic hyperplasia Prostate-Specific Antigen (PSA)

Hayes et al. JAMA 2014;311(11): The evidence addressing the effectiveness of PSA screening is dominated by 2 trials: the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer screening trial from the United States and the European Randomized Study of Screening for Prostate Cancer (ERSPC) Three smaller trials do not contribute appreciably to the evidence base because they assessed 1-time screening and did not use intention-to- treat methods

Screening and early detection: guidelines recommendations Hayes et al. JAMA 2014;311(11):1143-9

Heidenreich et al. Eur Urol 2013 PSA screening might reduce PCa-related mortality by 21–44% Any reduction in PCa-related mortality might take up to 10 yr, so screening in men with a life expectancy of at least 10 yr might be beneficial STATEMENT 1: EARLY DETECTION REDUCES PCA-SPECIFIC MORTALITY

Schroder F.H. et al, N Engl J Med 2009

Main end-point: prostate cancer mortality Screen interval 4 years (87%) or 2 years (13%) Sextant (lateral) biopsy recommended for PSA ≥ 3 (vast majority) or ≥ 4 ng/ml With ancillary tests (DRE, F/T ratio for PSA ng/ml) EUROPEAN RANDOMIZED STUDY OF SCREENING FOR PROSTATE CANCER Schroder et al, NEJM 2009, 360:1320-8

Cumulative incidence of PCa: 8.2 vs 4.8% in the screening and control group, respectively Median follow-up: 9 yrs EUROPEAN RANDOMIZED STUDY OF SCREENING FOR PROSTATE CANCER Schroder et al, NEJM 2009, 360:1320-8

EUROPEAN RANDOMIZED STUDY OF SCREENING FOR PROSTATE CANCER  Relative risk of PCa related death 0.80 (95% CI: , p=0.04), a 20% relative reduction  After adjustment for non-compliance: a relative risk reduction of 27% results  Absolute risk reduction: 7.1 per screened men  NNS: in order to prevent one PCa death we have to screen 1410 (95% CI: ) men Schroder et al, NEJM 2009, 360:1320-8

EUROPEAN RANDOMIZED STUDY OF SCREENING FOR PROSTATE CANCER The additional PCa diagnosed by screening resulted in an increase in cumulative incidence of 34 per 1000 men, as compared with the control group. In other words, 48 additional subjects (1410 ÷ 1000 × 34) would need to be treated to prevent one death from PCa. NUMBER NEEDED TO TREAT: 48 (IN EXCESS OF CONTROL GROUP) Schroder et al, NEJM 2009, 360:1320-8

ERSCP: CONCLUSIONS  Increased diagnosis of PCa in the screened group  Higher rates of well differentiated PCa in the screened group  ERSPC shows a significant reduction in the relative risk in Pca death in men aged 55 – 69 of 20% relative risk reduction of 27%  After adjustment for non-compliance: relative risk reduction of 27%  No heterogeneity between centers  The trend seen in the mortality curves suggests larger effect with longer follow-up

The aim of this study was update PCa mortality in ERSPC with 2 additional years of follow-up Schroder F.H. et al, N Engl J Med 366;11: , 2012

ERSCP: RESULTS Median follow-up: 11 years Incidence of PCa was: 9.66 cases per 1000 person-years in the screening group 5.95 cases per 1000 person-years in the control group 299 deaths from PCa in the screening group and 462 in the control group

Schroder F.H. et al, N Engl J Med 366;11: , 2012 ERSCP: RESULTS

After a median follow-up of 11 years, the relative reduction in the risk of death from PCa in the screening group was 21% (p = 0.001) After correction for selection bias and noncompliance, a relative risk reduction of 29% (p = 0.001) was obtained for screened men Overall mortality was similar in the two study groups To prevent one death from PCa at 11 years of follow-up, 936 men would need to be screened and 33 cancers would need to be detected (vs. 48 in the 2009 study) Schroder F.H. et al, N Engl J Med 366;11: , 2012 ERSCP: RESULTS

Updated results of mortality from prostate cancer with follow-up to 2010, with analyses truncated at 9, 11, and 13 years Schroder F.H. et al, The Lancet 2014

With data truncated at 13 years of follow-up, 7408 prostate cancer cases were diagnosed in the intervention group and 6107 cases in the control group Pca incidence

Schroder F.H. et al, The Lancet 2014, in press Pca mortality

Schroder F.H. et al, The Lancet 2014 The rate ratio of Pca incidence between the intervention and control groups was 1·91 (95% CI 1·83–1·99) after 9 years (1·64 [1·58–1·69]), 1·66 (1·60–1·73) after 11 years, and 1·57 (1·51–1·62) after 13 years The rate ratio of mortality was 0·85 (0·70–1·03) after 9 years, 0·78 (0·66– 0·91) after 11 years, and 0·79 (0·69–0·91) at 13 years The absolute risk reduction of death at 13 years was 0·11 per 1000 person- years or 1·28 per 1000 men randomised, which is equivalent to one Pca death averted per 781 (95% CI 490–1929) men invited for screening or one per 27 (17–66) additional prostate cancer detected

Schroder F.H. et al, The Lancet 2014 In this update the ERSPC confirms a substantial reduction in mortality attributable to testing of PSA, with a substantially increased absolute effect at 13 years compared with findings after 9 and 11 years Despite these findings, further quantification of harms and their reduction are still considered a prerequisite for the introduction of populated-based screening

Hugosson et al. The Lancet 2010;11:725 In December, 1994, 20,000 men born between 1930 and 1944, randomly sampled from the population register, were randomised by computer in a 1:1 ratio to either a screening group invited for PSA testing every 2 years (n=10,000) or to a control group not invited (n=10,000) Men in the screening group were invited up to the upper age limit (median 69, range 67–71 years) and only men with raised PSA concentrations were offered additional tests such as digital rectal examination and prostate biopsies The primary endpoint was prostate-cancer specific mortality, analysed according to the intention-to-screen principle

Hugosson et al. The Lancet 2010;11:725 Pca mortality

Andriole et al NEJM 360; ,2009

PLCO TRIAL From 1993 through 2001, we randomly assigned 76,693 men at 10 U.S. study centers to receive: annual screening (38,343 subjects) or usual care as the control (38,350 subjects) Men in the screening group were offered annual PSA testing for 6 years and digital rectal examination for 4 years. The subjects and health care providers received the results and decided on the type of follow-up evaluation (Bx cut-off 4 ng/ml) Usual care sometimes included screening, as some organizations have recommended. Andriole et al NEJM 360; ,2009

(RELATIVE INCREASE: 22%) After 7 years of follow-up, the incidence of PCa per 10,000 person-years was 116 (2820 cancers) in the screening group and 95 (2322 cancers) in the control group (RELATIVE INCREASE: 22%) The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate ratio, 1.13; 95% CI, 0.75 to 1.70). The median duration of follow-up was 11.5 years PLCO TRIAL

At 13 years, a total of 158 deaths occurred in the intervention arm, compared with 145 deaths in the control arm The cumulative mortality rates from PCa were 3.7 and 3.4 deaths per person-years in the intervention and control arm No statistically significant difference was recorded between the two arms Screening and early detection Andriole G.L. J Natl Canc Inst 104 (2): 125 – 32, 2012

After 13 years of follow-up, there was no evidence of a mortality benefit for annual screening compared to opportunistic screening A statistically significant 12% relative increase in the incidence of PCa was observed in the intervention arm There was no apparent PCa mortality interaction of trial arm with age, baseline comorbidity and pretrial PSA testing Screening and early detection Andriole G.L. J Natl Canc Inst 104 (2): 125 – 32, 2012

Heidenreich et al. Eur Urol 2013 The risk of being diagnosed with metastatic PCa was reduced by 30% and 48.9% in the ERSPC and the Goteborg branch of ERSPC, respectively The absolute risk reduction was 3.1 cases per 1000 men randomized. It became evident that the risk of developing metastatic disease started to diverge at years 4 and 5 after initiation of screening The number needed to invite (NNI) and the number needed to diagnose to avoid 1 case of metastatic disease were 328 and 12, respectively STATEMENT 2: EARLY DETECTION OF PROSTATE CANCER REDUCES THE RISK OF BEING DIAGNOSED AND DEVELOPING ADVANCED AND METASTATIC PROSTATE CANCER

Schroder et al. Eur Urol 2012;62: Risk of metastases OR: 0.6

Schroder et al. Eur Urol 2012;62: Risk of metastases at presentation OR: 0.5

Incidence of Cancer That Was Metastatic at First Presentation, United States, 1975–2012. N Engl J Med 2015, 373 SEER DATABASE

Heidenreich et al. Eur Urol 2013 A baseline serum PSA level >1.0 ng/ml at 45 yr of age and a baseline serum PSA level >2.0 ng/ml at 60 yr of age are associated with a significantly increased risk of PCa- related mortality and diagnosis of advanced or metastatic disease even 25 years after the initial PSA was obtained STATEMENT 3: A BASELINE SERUM PROSTATE-SPECIFIC ANTIGEN LEVEL SHOULD BE OBTAINED AT 40–45 YR OF AGE

Vickers et al. BMJ 2013;15:346;f2023 Population: Swedish men aged (74% of the eligible population) who provided blood at baseline in , and 4922 men invited to provide a second sample six years later Rates of PSA testing remained extremely low during median follow-up of 27 years Main outcome measures: Metastasis or death from prostate cancer ascertained by review of case notes

Vickers et al. BMJ 2013;15:346 Cumulative incidence of metastases according to baseline PSA

Vickers et al. BMJ 2013;15:346;f2023 PSA concentrations can indicate not only the current risk of cancer— and hence the need for prostate biopsy—but are also predictive of the future risk of prostate cancer metastasis and cancer specific death Screening programmes can be designed to focus on men at highest risk, with three lifetime PSA tests between the ages of 45 and 60 sufficient for at least half of the male population This is likely to reduce the risk of overdiagnosis while still enabling early cancer detection among those most likely to gain from early diagnosis As such, a risk stratified approach to PSA screening will improve the ratio of its benefits and harms

Heidenreich et al. Eur Urol 2013 Screening intervals should be 2–4 yr for men with PSA serum concentrations >1.0 mg/l at 45–59 yr of age, whereas it could be up to 8 yr in men with PSA serum concentrations below this threshold value Using this approach, it will be possible to reduce the potential harms of screening by targeting a high-risk group of men Longer intervals might be preferable to reduce the substantial risk of overdiagnosis and reduce costs associated with frequent screening STATEMENT 4: INTERVALS FOR EARLY DETECTION OF PROSTATE CANCER SHOULD BE ADAPTED TO THE BASELINE PROSTATE-SPECIFIC ANTIGEN SERUM CONCENTRATION

Heidenreich et al. Eur Urol 2013 The current EAU guidelines on the diagnosis and treatment of PCa recommend screening in men who have a life expectancy >=10 yr There is limited evidence of the effect of screening for PCa in elderly men Early detection of cancer in men >70 yr of age might not be cost- effective STATEMENT 5: PROSTATE-SPECIFIC ANTIGEN SCREENING SHOULD BE OFFERED TO MEN WITH A LIFE EXPECTANCY OF >=10 YR

Urine biomarkers DNA-based urine test GSTP1 expression Combination of GSTP1, RARB and APC RNA-based urine PCA3 test TMPRSS2 – ERG gene fusion transcript expression levels of GOLPH2, SPINK1 Are there new markers?

New perspectives ? -MRI and Fusion biopsies -Prolaris

New surgical perspectives Open Laparoscopica/Robotica Robotica single-port

PSA screening Conclusions PSA screening reduces Pca-specific mortality PSA screening reduces the rate of metastatic disease at diagnosis and at follow-up Overdiagnosis remains a major issue Individual based screening????