Terni, 13 Novembre 2015

Conferenza Nazionale CIPOMO

Sergio BracardaDipartimento di Oncologia

Istituto Toscano Tumori (ITT)Ospedale San Donato

USL8, Arezzo

PSA Screening for Prostate Cancer ?

No, Thank You !!!

My Task:

Avoid Overtreatments !

1° Issue

Premessa:tre conditio sine qua non per

l’effettuazione di uno screening• Rilevante problema sociale:

– Sufficientemente serio (cioè clinicamente importante)

– e Frequente Si,

• Elevata sensibilità e specificità dei Tests di Screening impiegati:• PSA (organo specifico, non cancro specifico) …• DRE (operatore dipendente, limitata “geograficamente”) …• TRUS (secondo livello, invasiva, operatore dipendente …

?

• Evidenza che una diagnosi precoce riduca morbidita e mortalità della patologia oggetto di screening

Neoplasia prostatica ……

Neoplasia prostatica clinicamente importante ?

Why, not a Screening in PCa

• Da uno screening sul carcinoma prostatico possono infatti derivare due rischi maggiori :

OverTreatment

OverDiagnosis

• Perché non tutti i tre prerequisiti sono al momento soddisfatti, in particolare il terzo

• Ma anche un terzo parametro va accuratamente valutato: L’impatto sul Sistema sanitario:

Cost-Effectiveness

Screening and prostate-cancer mortality in a randomized European study (1).

ERSPC (European Randomized Study of Screening for P.Ca)

• Started in 90s to evaluate effect of PSA screening on P.Ca death rates.• 182,000 men (50–74 yrs) through registries in 7 EU Countries, 2 groups:

- PSA screening at an average of once every 4 years or

- Control group that did not receive such screening.

• Predefined core age group for this study: 162,243 men (ages 55-69 yrs). • Primary outcome: rate of death from P.Ca. Median follow-up: 9 years

• The cumulative incidence of P.Ca was:

- 8.2% In the screening group,

-- 4.8% in the control group.

Schroeder et Al. N Engl J Med. 2009 Mar 26;360(13):1320-8

The rate ratio for death from P.Ca in the screening group, vs the control group, was 0.80 (95% CI, 0.65 to 0.98; adjusted P=0.04). The absolute risk difference was 0.71 death per 1000 men.

This means that 1410 men would need to be screened and 48 additional cases of P.Ca would need to be treated to prevent one death from P.Ca.

The analysis of men screened during the 1st round (excluding subjects with noncompliance) provided a rate ratio for death from P.Ca of 0.73 (95% CI, 0.56 to 0.90).

• CONCLUSIONS:

• PSA-based screening reduced the rate of death from P.Ca by 20% but was associated with a high risk of overdiagnosis.

Screening and prostate-cancer mortality in a randomized European study (2).

ERSPC (European Randomized Study of Screening for P.Ca)

Schroeder et Al. N Engl J Med. 2009 Mar 26;360(13):1320-8

Results from a randomized Screening Trial. The PLCO (Prostate, Lung, Colorectal, and Ovarian)

Cancer Screening Trial (1). P.Ca Mortality.

Trial done from 1993 through 2001, to evaluate the effect of screening with PSA testing and DRE on the rate of death from P.Ca.

76,693 Men from 10 US Study Centers randomly assigned to receive either:

- Annual PSA testing for 6 yrs and DRE for 4 yrs (38,343 subjects) or

- Usual care (UC) as control (38,350 subjects); UC may include screening

Endpoint: numbers of all cancers and deaths and causes of death.

Andriole GL et Al .N Engl J Med. 2009 Apr 23;360(17):1797.

RESULTS after 7 years of follow-up,

Incidence of Prostate Cancer Cases per 10,000 person-years was:- Screening group: 116 (2.820 cases) and - Control group: 95 (2.322 cases) (rate ratio, 1.22; 95% CI, 1.16 to

1.29).

The incidence of death per 10,000 person-years was:- Screening group: 2.0 (50 deaths) and - Control group: 1.7 (44 deaths) (rate ratio, 1.13; 95% CI, 0.75 to 1.70).

CONCLUSIONS:

After 7 to 10 years of F.Up, the rate of death from P.Ca was very low and did not differ significantly between the two study groups.

Results from a randomized Screening Trial. The PLCO (Prostate, Lung, Colorectal, and Ovarian)

Cancer Screening Trial (2). P.Ca Mortality.

Andriole GL et Al .N Engl J Med. 2009 Apr 23;360(17):1797.

I due Studi a confronto

ERSPC (EU) PLCO (US)

73.000 (arm exp.) 38.343 (arm exp.)

Età 50-74 55-74

Tests utilizzati PSA (ogni 4 anni) PSA (annuale per 6 yrs),+ DRE (annuale ogni anno x 4

Indicazione alla biopsia PSA >3ng/ml PSA >4ng/ml and/or a suspicious DRE

Relative reduction in the risk of death from Prostate Cancer

20% (.04) Ns

Absolute reduction in death rate

7/10.000 Any

Principali criticità dei 2 Studi

• PSA Cut off: 3ng/ml (EU) vs 4ng/ml and/or suspicious DRE (US) Alto: minor sensibilità, maggior specificità. Basso: l’inverso

• Baselline PSA: rimozione preliminare di forme clinicamente importanti

• Elevata incidenza di Screening spontaneo nel braccio di controllo (40%)

• Miglioramento nel lungo termine delle tecniche terapeutiche come elemento confondente sulla OS (es. RT+HT)

• Follow up insufficiente ??

• Impatto su SS: 1410 uomini da screenare e 48 da trattare per prevenire una morte da cancro prostatico

2nd Issue: behind the Corner

• Which future Issues for a Prostate Cancer Screening Program ?

• Identify “real Killers”– How much they are ?

• Percentage (%) &• Absolute number (cost-effectiveness evaluation)

– How to identify this “real” Target ?• Multidisciplinar Strategy• New BioMarkers ?

– It’s possible to define a starting age for P.Ca risk, and why ?• Cohort evaluation, • eventual program planning

May Multiparametric MRI help in Detecting Significant Prostate Cancer ?

• Rationale: to evaluate the possibilities of multiparametric MRI (mpMRI) in increasing the accuracy of a significant P.Ca detection before diagnostic biopsy in men with abnormal PSA/DRE.

• Study Details: 388 men underwent mpMRI. Two radiologists allocated a score of 1-5 for suspicion of significant PC (Gleason 7 with >5% grade 4).

• Score 3-5 was considered positive. 18-region mapping biopsy, with more manually directed cores in MRI-positive regions. was performed,

• RESULTS: In men with abnormal PSA/DRE, mpMRI detected significant P.Ca with good sensitivity (96%) / specificity (36%) and excellent N.P.V (92%) and moderate PPV (52%).

Thompson JE, et Al. J Urol. Oct 31, 2015

A possible

Scenario ?

Original Article Prostate-Cancer Mortality at 11 Years of Follow-up

Fritz H. Schröder, M.D., Jonas Hugosson, M.D., Monique J. Roobol, Ph.D., Teuvo L.J. Tammela, M.D., Stefano Ciatto, M.D., Vera Nelen, M.D., Maciej Kwiatkowski, M.D.,

Marcos Lujan, M.D., Hans Lilja, M.D., Marco Zappa, Ph.D., Louis J. Denis, M.D., Franz Recker, M.D., Alvaro Páez, M.D., Liisa Määttänen, Ph.D., Chris H. Bangma, M.D.,

Gunnar Aus, M.D., Sigrid Carlsson, M.D., Arnauld Villers, M.D., Xavier Rebillard, M.D., Theodorus van der Kwast, M.D., Paula M. Kujala, M.D., Bert G. Blijenberg, Ph.D., Ulf-

Hakan Stenman, M.D., Andreas Huber, M.D., Kimmo Taari, M.D., Matti Hakama, Ph.D., Sue M. Moss, Ph.D., Harry J. de Koning, M.D., Anssi Auvinen, M.D.,

for the ERSPC Investigators

N Engl J MedVolume 366(11):981-990

March 15, 2012Updated

Results

Study Overview

• The European Randomized Study of Screening for Prostate Cancer continues to show a 21% reduction in prostate-cancer mortality in the screening group, after 11 years of follow-up.

• The number of cancers that would need to be detected to prevent one prostate-cancer death is 37.

• Screening does not affect all-cause mortality.

Enrollment and Outcomes.

Schröder FH et al. N Engl J Med 2012;366:981-990

Cumulative Hazard of Death from Prostate Cancer among Men 55 to 69 Years of Age.

Schröder FH et al. N Engl J Med 2012;366:981-990

Fritz H. Schröder et Al. Conclusions

• Analyses after 2 additional years of follow-up consolidated our previous finding that PSA-based screening significantly reduced mortality from prostate cancer but did not affect all-cause mortality.

• The European Randomized Study of Screening for Prostate Cancer continues to show a 21% reduction in prostate-cancer mortality in the screening group, after 11 years of follow-up.

• The number of cancers that would need to be detected to prevent one prostate-cancer death is 37.

• Screening does not affect all-cause mortality.

Reconciling the ERSPC results with those of the PLCO trial is difficult.

What the PLCO trial show is that adding an organized screening to opportunistic screening will result in no benefit and many adverse effects (false positive screening tests, unnecessary biopsies, overdiagnosis, and impaired quality of life.

In ERSPC, 13% of the screening tests were false positives (7% in PLCO).

In ERSPC, 76% of biopsies not resulted in a PCa diagnosis (PLCO: 62%) Rates of OverDiagnosis were approx. 50% in ERSPC, 17-30% in PLCO.

What’s about New Data on Prostate-Cancer Mortality after PSA Screening (1).

AB. Miller. N Engl J Med 2012; 366:1047-1048

In ERSPC, little change have been observed after 11 years of F-Up.

To prevent one death from PCa at 11 years of follow-up:

- 1055 men would need to be invited for screening and - 37 cancers would need to be detected.

No significant between-group difference in all-cause mortality was noted.

What’s about New Data on Prostate-Cancer Mortality after PSA Screening (2).

AB. Miller. N Engl J Med 2012; 366:1047-1048

In a similar update on prostate-cancer mortality in the PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening Trial, investigators reported no significant change from the earlier findings.

Thus, regarding PSA screening, the negative findings of the PLCO trial and the positive findings of the ERSPC are unchanged.

Both studies showed a relative reduction of 21% in the rate of death from PCa in the screening group, as compared with the control group

WhIch Factors could explain these contradictory results?

ERSPC is almost twice as large as the PLCO trial

In the PLCO trial, screening was annual, in ERSPC all Centers invited men for PSA testing every 4 years (except for Sweden, where invitations were sent every 2 years).

A lower cutoff for a positive PSA test was used in ERSPC than in PLCO (which led to a greater rate of positive screening tests in the ERSPC).

An increased rate of background screening in the US vs EU (many men not recruited in PLCO because of a previous PSA testing or a previously opportunistic screen-detected PCa. High incidence of opportunistic screening also in the Ccontrol group).

What’s about New Data on Prostate-Cancer Mortality after PSA Screening.

AB. Miller. N Engl J Med 2012; 366:1047-1048

What’s more ?

- Radical Prostatectomy vs Observation

Trial data for localized prostate cancer.

- The new Gleason Score System

Radical prostatectomy vs observation for localized prostate cancer.

731 men with localized P.Ca randomized to radical prostatectomy (RP) or observation (Obs) from Nov 1994 to Jan 2002.

Primary outcome: all-cause mortality. 2nd outcome: PCa mortality.median follow-up: 10.0 years171 of 364 men (47.0%) assigned to RP died, as compared with 183 of

367 (49.9%) assigned to Obs.(HR, 0.88; 95% CI, 0.71-1.08; p= 0.22; absolute risk reduction, 2.9%).

21 (5.8%) men assigned to RP died from prostate cancer or treatment, as compared with 31 (8.4%) assigned to Obs (HR, 0.63; 95% CI, 0.36-1.09; P=0.09; absolute risk reduction, 2.6%).

RP associated with reduced all-cause mortality among men with a PSA value >10 ng per milliliter (P=0.04 for interaction) and possibly among those with intermediate/high-risk tumors (P=0.07 for interaction).

Wilt TJ. N Engl J Med. 2012 Jul 19;367(3):203-13

American Journal of Surgical Pathology 2012

The new Gleason Score System

3rd Issue: Conclusions

The Actual Situation:

No sufficient data to support any kind of Screening Program in Prostate Cancer

Opportunistic Screening to be discouraged (NB: symptomatic pts derive this condition mainly from BPH and NOT P.Ca)