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Overdetection of prostate cancer ESMO Brussel 2007 Chris H.Bangma Erasmus University Medical Centre Rotterdam, The Netherlands Increasing Pca incidence with age 225.000 in Europe annually PSA and cancer incidence in men aged 50-75 40 36 30 31 Proportion Prostate Cancer 20 13 10 11 % 7 2 0 < 1.0 >= 2.0 - < 3.0 >= 1.0 - < 2.0 PSA (ng/ml) >= 4.0 - < 10.0 >= 3.0 - < 4.0 >= 10.0 Clinical incidence over time increases (Netherlands) 10000 9000 8000 7000 6000 5000 4000 3000 2000 1000 0 2000 2001 2002 2003 2004 2005 new Pca The diagnosis of low risk prostate cancer is increasing 100 80 % of patients 60 40 20 0 ‘90 Cooperberg et al, J Urol 2003 ‘92 ‘94 ‘96 Year ‘98 ‘00 Natural course of Pca Albertsen tables JAMA ‘97 N=767 Clinical stage ≤ T2 Palliative treatment Dark grey = PCa † Light grey = nonPCa † White = survival There is more cancer than we can detect currently Autopsy data (Gosselaer 2005) Cystoprostatectomy data (Damiano R, Eur Urol 2007) 70 60 50 40 30 20 10 0 Sakr 1993 autopsy incidence screening incidence 30- 40- 50- 60- 7039 49 59 69 79 Pca detection frequency in screening ERSPC first round 2.6 2.4 5.1 2.5 3.2 1.1 1.7 1.6 260.000 participants aged 50-75 in 8 EC countries Tumor volumes in 550 radical prostatectomy specimens per PSA range detected in round 1 and 2 (ERSPC Rotterdam) minimal tumours: <0.5 ml, Gleason <7 Median, mean tumor volume in ml (range) % minimal tumor Median, mean tumor volume in ml (range) % minimal tumor PSA range (ng/mL)** < 3.0 Round 1 (n=386) Round 2 (n=164) 0.28, 0.32 (0.00-1.09) 67 0.28, 0.38 (0.00-1.80) 56 3.0 – 3.9 0.58, 0.72 (0.00-3.10) 45 0.43, 0.63 (0.00-2.17) 31 4.0 – 9.9 0.77, 1.08 (0.00-13.48) 27 0.63, 1.06 (0.01-7.93) 46 > 10 1.82, 2.16 (0.00-7.99) 13 1.33, 2.04 (0.00-8.94) 36 Total 0.65, 1.06 (0.00-13.48)* 33 0.45, 0.86 (0.00-8.94)* 43 * Significant, p=0.001 2 2= ** Correlation tumor volume/PSA level. round 1: R = 0.15, round 2: R 0.12 (p=0.0001) Overdiagnosis estimated to be 54 % in screening (Draisma 2003) Conclusion 1: Big wave of small cancers…big threat of overdiagnosis (and subsequent overtreatment!) Hokusai 1830 Can we recognise indolent tumours upfront? (Steyerberg, Kattan, Roobol, et al. J Urol 2007) 247 patients Pca T1-2 >> radical prostatectomy>> step section histology 121 (48 % !) indolent disease (<0.5 ml, no Gleason 4) Statistic analysis identifies relevant prognostic factors Age PSA Prostate volume Micturition complaints Stage Grade Cancer volume in biopsies Number of positive cancer biopsies Score chart for the prediction of indolent prostate cancer (Steyerberg et al 2007) Variable Serum PSA (ng/mL) Ultrasound volume (cc) Values 20 13 9.0 6.0 5.0 4.0 3.3 2.2 1.0 20 Score 0 2 4 6 7 8 9 11 15 0 Variable Biopsy Gleason Scores 1 and 2 Values 3+3 2+3 2+2 Score 0 1 4 mm cancerous tissue (total over biopsy cores) 20 10 8 4 2 1 0 2 3 5 7 9 40 60 80 2 4 6 mm non-cancerous tissue (total over biopsy cores) Score (sum all scores) 40 60 80 0 2 4 Sum 24 Predicted probability of indolent cancer according to sum of scores 100% Probability of indolent cancer 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 11 8 12 13 16 24 27 27 28 28 21 16 15 7 7 9 9 13% 16% 19% 23% 28% 33% 39% 45% 52% 58% 64% 69% 74% 79% 83% 86% 89% N Prediction <= 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 >= Score Active surveillance: strategy to deminish overtreatment of minimal cancers Active surveillance: regular monitoring, and delayed invasive treatment on signs of tumour progression Watchful Waiting Active Surveillance PRIAS: free access www.prias-project.org PRIAS means Prostate cancer Research International: Active Surveillance It is a web-based tool used to include and follow-up patients considered to have indolent disease International observational study based on experience in watchful waiting and guided by experts to optimise active surveillance http://www.urosource.com/congress-television/berlin-2007/ PRIAS inclusion: conservative approach Criteria for inclusion in PRIAS: 1. Histologically proven adenocarcinoma of the prostate 2. Men should be fit for curative treatment 3. PSA-level at diagnosis ≤ 10 ng/mL 4. PSA density (PSA D) less than 0,2 5. Clinical stage T1C or T2 6. Adequate biopsy sampling (see 'biopsy protocol') 7. Gleason score 3+3=6 8. One or 2 biopsy cores invaded with prostate cancer 9. Participants must be willing to attend the follow-up visits Exclusion-criteria: 1. Men who can not or do not want to be irradiated or operated 2. A former therapy for prostate cancer Schedule active surveillance study Analysing biologic tumour behavior Year 1 Year 2 Year 3 - ~ PSA 4 times 4 times 2 times a year DRE 2 times 1 time 1 time a year Repeat biopsy 1 time Visit At 4, 7 and 10 years, thereafter every 5 years Correcting for sampling 2 times 1 time errors 1 time PSA kinetics can indicate a biopsy or treatment shift Flowchart for follow-up Active Surveillance Yes PSA < 20 ng/ml Yes Yes No End of Study Metastases on bone scan? No Clinical stage < cT 3 No Yes Definitive therapy PSA DT > 3 years No Yes Repeat biopsy indicated by time path? Yes No PSA DT > 10 years No Yes Continue Active Surveillance Repeat biopsy: Maximal 2 cores with PC AND Gleason score 3+3 Yes No Unique protected individualised entry Modification of followup data feasible: curves Is active surveillance safe? Natural course of disease of Gleason 6 cancer after 20 years 85-96 % Lead time of 12 years in screening setting D’Amico: low risk population (PSA<10, Bx Gleason <7 and T1-2): 5 year cancer specific survival after therapy of 98% Klotz 2005: PSADT< 2 years as an indication for active therapy after active surveillance misses few progressive tumours over 8 years (1 % metas) ERSPC: 100% tumour specific survival in 61 patients over 4 years of active surveillance (Roemeling 2006) Delayed radical prostatectomy does not increase tumor stages (Carter 2003, Roemeling 2007) Overall and cancer specific survival minimal (cGleason 6, PSA 10, T1c) versus relevant cancers (> Gleason 6, cT2) Survival Functions Overall survival Survival Functions Pca specific survival Indolent 1,0 Ja Nee Onbekend Ja-censored 0,8 Nee-censored Onbekendcensored 1,0 Cum Survival Cum Survival 0,8 0,6 0,4 0,2 Indolent Ja Nee Onbekend Ja-censored Nee-censored Onbekendcensored 0,6 0,4 0,2 10 year 10 year 0,0 0,0 0 50 100 150 200 250 LastFUMnthSinceRP months 300 350 0 50 100 150 200 250 LastFUMnthSinceRP months 300 350 What can we offer European men? Men want to know their risks….how can we reduce overdiagnosis? Level 1: Man age 55 – 74: do I need to screen? Level 2: PSA known: shall I visit a urologist? Level 3: Levels 1+2, DRE, TRUS, and prostate volume known: do I need a biopsy? Level 4: Biopsy result known: do I need a therapy? PRIAS? Level 5: first biopsy shows no cancer: do I need a second screen? Level 6: in case of cancer: what is my risk to get metastases? Future: reducing overdiagnosis will reduce overtreatment. Risk calculators We may offer risk analysis to decrease wild screening / rescreening in low-risk groups Avoid screening of asymptomatic cancers in the elderly: only 0.09% of men aged 70-75 in ERSPC died in six years of Pca (Roobol 2007) Avoid rescreen within 5 years in men with PSA< 1.0 (Roobol, Prostate. 2006 , Crawford, J Urol. 2006) Conclusion 2: overdiagnosis in Europe Can men be protected? Overtreatment of indolent tumours can be avoided with active surveillance (www.prias-project.org) Introduction of step-wise risc-calculation will likely reduce overdiagnosis in men aware of prostate cancer (EAUwebsite:www.urolog.org) Active Surveillance policies should be improved with respect to patient inclusion and monitoring by validated markers Europe as a scaffold to integrate research for prostate cancer patients Biomarker research: P-MARK, PROCABIO Patient organisations: Europa Uomo Research programs: ERSPC , EORTC Industry Health care professionals: EAU Tailored treatment (Active Surveillance) by PROstate CAncer BIOmarkers: PROCABIO year 1 years 2-4 outcome WP1: Biorepository management Management serum and tissue validation set Management prospective biomaterials from active surveillance study Active surveillance biorepository WP2: Proteomics biomarkers & WP3: Genomics biomarkers Marker validation for discrimination indolent and progressive PCa Clinical implementation selected markers in active surveillance study Marker format optimisation Marker implementation in treatment policies WP4: Clinical study Preparatory phase participating clinical centres European multi-centre active surveillance study Cohort A: entry by set parameters Cohort B: entry by risk calculator Evaluation intermediate endpoints WP5: Public relations Informing stakeholders on active surveillance Informing stakeholders on progress and outcome active surveillance study and marker implementation Guidelines on active surveillance Detection of indolent cancers PSAirways …risk of flying…