ECCLU 2011 - B. Tombal - Prostate cancer: From biology to live expectancy - Screening and active surveillance

Screening and active surveillance Bertrand TOMBAL Division of Urology Cliniques universitaires Saint Luc Brussels, Belgium

Introduction Natural History of Prostate Cancer

The pathways to death by cancer… Localized PIN 1 Malignant transformation Death Locally advanced 2 Local progression Metastatic 3 Generalization

Malignant transformation occurs frequently in the adult prostate Autopsies studies Sanchez-Chapado, Prostate 2003, 54, 238-247 Holund, Scand J Urol Nephrol 1980, 14, 29-35 Kabalin, J.Urol 1989, 141, 1091-4 Ward, Urol.Oncol., 2004, 22; 40-7 Localized PIN 1 Malignant transformation Sanchez-Chapado Holund Kabalin Ward Age 36-94 20-80 31-82 44-92 PSA range 0-2 ng/ml PCa Prevalence (%) 22 18.5 38 23

Transformation into lethal phenotype can be anticipated 767 patients with clinically localized PCa followed up for a median of 24 Years, 71 % being diagnose by BPH surgery. 222 deaths from PCa 470 deaths from other causes Albertsen PC et al, 20-Year Outcomes Following Conservative Management of Clinically Localized Prostate Cancer JAMA 293(17):2095-101, 2005. Death Localized Locally advanced 2 Local progression Metastatic 3 Generalization

Lethal phenotype is predictable Albertsen PC et al, J AMA 293(17):2095-101, 2005. Gleason rate correlates with mortality rates It significantly increases for Gleason 7 and higher But Gleason 7 and higher represent only 30% of the tumors Gleason score % of patient Mortality rate death/1000 person years 2 - 4 24% 6 5 20% 12 6 37% 30 7 13% 65 8 – 10 6% 121 Overall 31

Prostate cancer distribution A 3 compartments model Normal / BPH Prostate cancer Potentially Lethal prostate cancer Ideal diagnostic Test

PCa diagnostic strategy DRE PSA Prostate Biopsy

When to diagnose Prostate Cancer ? Symptomatic Patients Asymptomatic Patients LUTS General Symptoms In every men (Mass screening) In men who are visiting a doctor for a non urological reasons (Opportunistic Screening) In category at higher risk In men who are willing to

Database analysis Baade PD et al., International trends in prostate-cancer mortality: the decrease is continuing and spreading. Cancer Causes Control 15:237–41, 2004. Year of Onset Period (years) Reduction Year (%) Total reduction USA 1994 8 5.1 40.8 Germany 1994 8 3.6 28.8 Australia 1994 8 4.9 39.2 Canada 1991 11 2.9 31.9 Austria 1991 11 2.1 23.1 Italy 1988 14 2.1 29.4 UK 1991 11 2.0 22.0 France 1988 14 1.9 24.7 Spain 1994 11 1.8 14.4

Database analysis Baade PD et al., International trends in prostate-cancer mortality: the decrease is continuing and spreading. Cancer Causes Control 15:237–41, 2004. Oliver SE, et al. International trends in prostate-cancer mortality in the "PSA ERA". Int J Cancer. 92(6):893-8, 2001 There Non-significant downward trends in PCa mortality in The Netherlands, Ireland, Portugal and Sweden. BUT

Non-randomized trials The Tyrol screening project. Non randomized trial 33% reduction in mortality 6 years after introduction of screening. Bartsch G et al. Urology 58: 417-24, 2001 The Quebec screening trial. Death rate reduced from 48.7 vs. 15/100.000 man-years in favor of screening after 8 years. Labrie F et al. Prostate 38: 83-9, 1999

Randomized control trials. Screening and Prostate-Cancer Mortality in a Randomized European Study FH Schröder et al. N Engl J Med 2009;360:1320-8. Mortality Results from a Randomized Prostate-Cancer Screening Trial GL Andriole et al. N Engl J Med 2009;360:1310-9 .

Screening and prostate cancer mortality in a randomised European study (ERSPC) Initiated in the early 1990s to evaluate the effect of screening by PSA testing on death rates from prostate cancer Schröder FH, et al. N Engl J Med 2009;360:1320–8 Offered PSA screening at an average of once every 4 years R Control group – Did not receive screening 82,000 men aged 50–74 years from seven European countries were invited to participate

ERSPC – Cumulative risk of death from prostate cancer PSA-based screening reduced the rate of death from prostate cancer by 20%

What does this result mean? Objective benefit for 1000 men Reduce individual chance of dying from PCa by 0,07% You need to screen 1410 men to save one death. PSA/DRE screening No screening Prostate cancer death 2.9 3.6

After 14 years of follow-up, Pca mortality was reduced from 0,9% in control group to 0,4% in screened group Mortality results from the Göteborg randomised population-based prostate-cancer screening trial. J. Hugosson et al. Lancet Oncol. 2010, 11(8):725-32.

The question The benefits and consequences

Distribution of PSA value in a given population aged 50 to 75 years old. Postma R, Schröder FH. Eur J Cancer 2005;41:825-33 From the 1 st Screening Round of the ERSPC (n=19970) 1/3 of healthy men will become patients

Incidence of PSA if only men with a + DRE below 3 ng/ml of PSA are receiving a biopsy From the 1 st Screening Round of the ERSPC (n=19970) Postma R, Schröder FH. Eur J Cancer 2005;41:825-33

PSA in middle age predicts PCa development in the following 25 years Lilja H, et al. J Clin Oncol 2007;25:431-6 Predicted probability of a prostate cancer diagnosis before age 75 years by total prostate-specific antigen (PSA) measured at age 44 to 50 years, with 95% Cls Probability of prostate cancer (%) 10 20 30 40 50 60 70 80 0 0 2 3 4 PSA at baseline venipuncture (ng/mL) ~38% 1 ~20%

Prostate specific antigen concentration at age 60 and death or metastasis from prostate cancer: case-control study A. Vickers et al. BMJ 2010;341:c4521

On average 4 biopsies are required to diagnose one PCa Postma R, Schröder FH. Eur J Cancer 2005;41:825-33 First round ERSPC n Biopsies Cancer Excess biopsy PSA 19970 n % n % < 2 ng/ml 13344 695 5% 49 7% 93% 2-4 ng/ml 3934 1013 25% 209 20% 80% > 4 ng/ml 2692 2409 89% 756 31% 69% 4117 1014 75%

PSA as a screening tool. Prostate cancer detection . Postma et al., European urology 50 ( 2 0 0 6 ) 70–75 Screened Control Arm N° 1596 464 Age at diagnosis 66.5 67.9 PSA mean 8,6 57.2 % % Stage localized 83,1 49,3 Locally advanced 12.3 15.3 Advanced 2.3 10.1 Gleason < 7 69.6 41 7 23.7 33.8 7 6.4 5.2

For 1000 patients in the study PSA as a screening tool. Prostate cancer detection . Adapted from addendum to Schröder FH, et al. N Engl J Med 2009;360:1320–8 PSA/DRE Screening No screening Prostate cancer 82 48 T1 54 23 Gleason score <7 59 26

The surgical imperative Prostate cancer screening: accepting the consequences of PSA testing. Chisholm GD. Br J Urol 1993;71:375–7 ‘ There is now the prospect of a prostatectomy holocaust, unless acceptable data can resolve this debate …’

Increased detection of indolent PCa and overtreatment 293 /1014 (29%) of patients with Gleason ≤ score 6 (3 + 3) Maximum 2 biopsies (+) m Stage T1c or T2 PSA density <0.2 ng/ml/cc, PSA ≤15 ng/ml. Roemeling St, European Urology 50, 475–482, 2006

For 1000 patients in the study PSA as a screening tool. Prostate cancer detection . Adapted from addendum to Schröder FH, et al. N Engl J Med 2009;360:1320–8 80% of patients receive aggressive treatment, although more than 50% of cancers are low stage and low grade … PSA/DRE Screening No screening Prostate cancer 82 48 T1 54 23 Gleason score <7 59 26 Surveillance 15 5 +10 Treatment 56 30 +26

For 1000 patients in the study PSA as a screening tool. Prostate cancer detection . Adapted from addendum to Schröder FH, et al. N Engl J Med 2009;360:1320–8 *± hormone therapy PSA/DRE Screening No screening Prostate cancer 82 48 T1 54 23 Gleason score <7 59 26 Radical prostatectomy 29 11 +18 Radiation therapy* 22 12 +10 Hormone therapy 11 14 -2

Risk Profiles and Treatment Patterns Among Men Diagnosed as Having Prostate Cancer and a Prostate-Specific Antigen Level Below 4.0 ng/mL YH Shao, Arch Intern Med. 2010;170(14):1256-1261 Data from SEER, 123 934 men with newly diagnosed PCa from 2004 to 2006.

Selectively eradicate cancers needing treatment avoiding collateral damages

“ Active Surveillance ” Is not a “ treatment option ” Consists of deferring treatment in patients with low risk cancers that are candidate for immediate radical treatment Implies revisiting periodically the status of the patient and treating upon progression. ≠ from Watchful Waiting that implies delaying treatment until symptoms occurs in patients that are not candidate or refuse radical treatment

Active surveillance Criteria Gleason PSA Clinical stage Number of positive biopsy ’ s cores number Amount of cancer per core

Insignificant Prostate Cancer and Active Surveillance: From Definition to Clinical Implications PJ. Bastian et al. European urology 55 ( 2009) 1321–1332 Author cT PSA (ng/ml) Gleason PSA density Pos. cores Max % per core Epstein, 1994 T1c Gr. < 3 < 0,15 <3 <50 Dall’Era, 2008 ≤ T2a ≤ 10 Gr. < 3 < 0,15 <33% Soloway, 2008 ≤ T2 <15 Gr. < 3 <2 <50 PRIAS, 2007 ≤ T2b <10 Gr. < 3 < 0,20 <3 Van Ass, 2008 ≤ T2a <15 Sc < 7(3+4) <50% Klotz, 2010 < 10 <15 (>70 y.o) Sc < 7 Sc ≤ 3+4 Stattin, 2010 ≤ T2 < 20 ≤ 7

Active surveillance Gleason ≤ 6 (grade < 4) PSA < 11-15 ng/ml T1c –T2a 1 or 2 biopsies; max 30-50% cancer PSA density < 0,20 ng/ml Does it identify precisely indolent PCa ?

1565 RRP from 2000 to 02/2008 Group I ( N= 205) cT1c, PSAd < 0.15 ng/mL/cc, Gleason sc. 6, max 2 positive biopsy cores, and no single core with 50% involvement. Group II ( N=771) cT1c-cT2a, PSA < 10 ng/dL, and Gleason sc. 6 (no gr. 4-5) Pathologic Outcomes of Candidates for Active Surveillance Undergoing Radical Prostatectomy. P. Mufarrij et al., UROLOGY 76: 689–694, 2010

SEARCH database of 2062 RRP (1988 to) and 2007, 398 (19%) met criteria for active surveillance cT1c or cT2a, PSA < 10 ng/mL, Gleason sum 6, no more than 1 or 2 positive cores on at least a sextant biopsy. Outcomes After Radical Prostatectomy Among Men Who Are Candidates for Active Surveillance: Results From the SEARCH Database CJ. Kane et al., UROLOGY 76: 695–702, 2010.

Active surveillance Gleason ≤ 6 (grade < 4) PSA < 11-15 ng/ml T1c –T2a 1 or 2 biopsies; max 30-50% cancer PSA density < 0,20 ng/ml Does it identify precisely indolent PCa ? With current accepted criteria, there is a 25 to 50% upgrading to Gleason 7 < 10% upgrading to Gleason ≥ 8 10-25% upstaging to extra-capsular disease < 3% positive lymph nodes But, this is extremely dependant on the biopsy regimen

Active surveillance Gleason ≤ 6 (grade < 4) PSA < 11-15 ng/ml T1c –T2a 1 or 2 biopsies; max 30-50% cancer PSA density < 0,20 ng/ml How to define progression ?

Insignificant Prostate Cancer and Active Surveillance: From Definition to Clinical Implications PJ. Bastian et al. European urology 55 ( 2009) 1321–1332 Study DRE PSA Rebiopsy TRUS Van As et al., 2008 Every 3 mo for 2 yr, then every 6 mo Year 1: monthly Year 2: every 3 mo Afterwards: every 6 m At 18–24 mo, then biannually No mention Dall’Era et al., 2008 Every 3 mo Every 3 mo Every 12–24 mo 6–12-mo interval Carter et al., 2006 Every 6 mo Every 6 mo Yearly No mention Klotz et al., 2005 Every 3 mo for 2 yr, then every 6 mo if PSA level is stable Every 3 mo for 2 yr, then every 6 mo if PSA level is stable At 12–18 mo Optional Patel et al., 2004 Every 3 mo for 1 yr, then every 6 mo Every 3 mo for 1 yr, then every 6 mo At 6 mo At 6 mo Soloway et al., 2008 Every 3 mo Every 3 mo for 2 yr At 6–12 mo, afterwards when indicated No mention Hardie et al., 2005 Every 3–6 mo for 2 yr, then every 6 mo Every 3–6 mo for 2 yr, then every 6 mo if PSA is stable Not routine Not routine

Insignificant Prostate Cancer and Active Surveillance: From Definition to Clinical Implications PJ. Bastian et al. European urology 55 ( 2009) 1321–1332 Study Median age yr (range) Median Fup mo Treatment criteria Van As et al., 2008 67 (50–79) 22 PSAV >1 ng/ml per year; Gleason score ≥4 + 3; >50% cancer per core Dall’Era et al, 2008 63.4 (40–86) 24 Gleason score ≥7 on rebiopsy, rising PSA, increase in volume by biopsy parameters Carter et al., 2006 65.7 (45.8–81.5) 23 Gleason score ≥7; any pattern 4, 5; >2 cores involved; >50% any single core involved. Klotz et al., 2005 NA 64 PSA DT <2 yr; Gleason score ≥8; Gleason score ≥7 (4 + 3) Patel et al., 2004 Mean: 65.3 (44–79) 44 Gleason score increase, PSAV >0.75/yr, increase DRE/TRUS detected lesion, increase biopsy volume Hardie et al., 2005 70.5 (59–81) 42 Rising PSA, clinical judgment Roemeling et al., 2007 69.8 (25–75) 40 PSA DT Ercole et al., 2008 68 (52–75) 48 Increase in tumour volume, Gleason score progression, urinary symptoms, change of DRE, patient preference Soloway et al., 2008 67 (mean: 66.02) 45.3 (mean) Gleason score increase, PSA and PSA DT increase, stage progression, increase biopsy volume, patient preference

Prostate-Specific Antigen Kinetics During Follow-Up Are an Unreliable Trigger for Intervention in a Prostate Cancer Surveillance Program A .Ross. J Clin Oncol 28:2810-2816. 2010 290 men with PSA density ≤ 0.15 ng/mL/cm 3; Gleason score 6 with no pattern 4, ≤ 2 (+) cores, ≤ 50% involvement 188 (65%) remained on AS, 102 (35%) developed unfavorable findings on surveillance biopsy and were recommended to undergo treatment (including 45 RRP (44%))

Role of Prostate Specific Antigen and Immediate Confirmatory Biopsy in Predicting Progression During Active Surveillance for Low Risk Prostate Cancer A. Adamy, J Urol. 185, 477-482, 2011 238 men with indolent Pca (PSA < 10 ng/ml, no Gleason gr. 4-5, cT1T2a, ≤ 3/10 (+) cores, ≤ 50% cancer. Biopsy 12 - 18 months, then every 2 - 3 years Progression = no more indolent (Full criteria), without PSA > 10 ng/ml = modified criteria .

Active surveillance Gleason ≤ 6 (grade < 4) PSA < 11-15 ng/ml T1c –T2a 1 or 2 biopsies; max 30-50% cancer PSA density < 0,20 ng/ml How to define progression ? A biopsy is required to define progression

Active surveillance Gleason ≤ 6 (grade < 4) PSA < 11-15 ng/ml T1c –T2a 1 or 2 biopsies; max 30-50% cancer PSA density < 0,20 ng/ml What are the results ?

Careful Selection and Close Monitoring of Low-Risk Prostate Cancer Patients on Active Surveillance Minimizes the Need for Treatment M. Soloway European urology 58 (2010) 831 – 835 230 men, Gleason ≤ 6, PSA ≤ 10, ≤ 2 (+) cores with ≤ 20% tumor in each core. Progression : increase in tumor volume, Gleason grade >3, or more than 2(+) cores on re-biopsy Biopsy : “dramatic” increase in PSA or after 2000 after 9-12 months

Clinical Results of Long-Term Follow-Up of a Large, Active Surveillance Cohort With Localized Prostate Cancer L.Klotz J Clin Oncol 28:126-131. 450 men, Gleason ≤ 6, PSA ≤ 10 ng/mL (patients > 70 y.O. PSA ≤ 15 ng/mL or Gleason ≤ 3 + 4) Progression PSA doubling time (DT) of less than 3 y.; histologic upgrade; clinical progression Biopsy : 6 to 12 months and then every 3 to 4 years until 80 years old 30% of patients have been reclassified as higher risk and have been offered definitive therapy.

Active surveillance Gleason ≤ 6 (grade < 4) PSA < 11-15 ng/ml T1c –T2a 1 or 2 biopsies; max 30-50% cancer PSA density < 0,20 ng/ml Is there a “loss of chance” differing treatment ?

Outcome of Primary Versus Deferred Radical Prostatectomy in the National Prostate Cancer Register of Sweden Follow-up Study B. Holmström, J.Urol Vol. 184, 1322-1327, 2010 2,344 men who underwent primary RP and 222 who underwent deferred radical prostatectomy after an initial period of surveillance. ≤ Gleason 6, cT1-2, N0M0, PSA ≤ 20 ng/ml at the date of diagnosis. Indication for deferred RP in AS men : PSA progression 50%; other progression 9%, patient decision 39%. Immediate RP (%) Delayed RP (%) OR p Age mean (%<65 y.) 61.1 (70) 61.9 (70) <0,05 EPE 27 25 1.1 0.56 Pos Margin 33 24 0.8 0.10 ≥ Gleason 7 25 38 2.4 <0.001 Any out of 3 55 56 1.3 0.09

Outcome of Primary Versus Deferred Radical Prostatectomy in the National Prostate Cancer Register of Sweden Follow-up Study B. Holmström, J.Urol Vol. 184, 1322-1327, 2010

Conclusions : screening and active surveillance PSA and DRE based screening reduce mortality in one large randomized trial There is a very high risk of unveiling indolent disease and over-treating patients Addressing individual patient risk and incorporating patients in active surveillance protocol is a mandatory companion to screening policies.

‘… an encounter with a urologist and, subsequently, his biopsy gun is the most powerful risk factor for its [prostate cancer] diagnosis.’ Rebalancing ratios and improving impressions: later thoughts From the prostate cancer prevention trial investigators J Clin Oncol 2005;23:7388–90 Talcott JA, et al. J Clin Oncol 2005;23:7388–90

ECCLU 2011 - B. Tombal - Prostate cancer: From biology to live expectancy - Screening and active surveillance

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