Prostate cancer smart screening, precision diagnosis, personalised treatment' Prof. Hashim Ahmed PhD, FRCS(Urol), BM, BCh (Oxon), BA(Hons) Consultant Urological Surgeon Bupa Cromwell Hospital Clinics: Tuesday & Wednesday AM
The Prostate Cancer Diagnostic & Therapy Pathway is CONTROVERSIAL and POLARISED
Total Number of Cases Diagnosed Prostate cancer is a growing 100,000 health burden 50,000 0 1984 2007 2030 2009 Time, years
The errors that result from the current pathway... Clinically indolent cancers are identified by chance Clinically significant lesions are missed Important cancers are incorrectly classified as unimportant Men undergo whole-gland treatment which carries harm
A strategy to overcome the errors in the current pathway Not all lesions have the potential to progress to invasive and metastatic cancer Novel imaging and precision biopsy can identify those lesions that are likely to progress Tissue preservation (active surveillance and focal therapy) can reduce treatment related harms
The impact of screening with PSA is small with significant over-diagnosis, over-detection and over-treatment and pathway-related harms
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` 5/1000 men over 14 years have PCa death averted 120/1000 men over 14 years have PCa diagnosis 8
Endorsed by the British Association of Urological Nurses (BAUN), the British Association of Urological Surgeons (BAUS) and the Primary Care Urology Society (PCUS)
Risk factors for referral 1. Elevated PSA >/=3ng/ml on two readings 2. Normal PSA but abnormal free/total PSA ratio (defined by each lab but usually <25%) 3. High PSA density >/=0.15ng/ml/ml if a transrectal ultrasound volume has been calculated 4. First degree relatives (>/=2) with prostate cancer 5. Ethnic risk e.g., African and African-Caribbean men
Can we diagnose prostate cancer better?
Template Mapping Biopsies Barzell and Melamed, 2007 Kepner and Kepner, 2010
Multi-parametric MRI: We can rule-out clinically significant disease accurately (but it s not 100%)
2 cores, Gleason 4+3, 2mm 1 core, Gleason 3+3,1mm
There was a palpable lack of level 1 evidence til now
PROMIS: Prostate MRI Imaging Study Presenter & Co-CI: Mr Hashim Ahmed Chief Investigator: Prof Mark Emberton Sponsored by University College London Managed by MRC Clinical Trials Unit Funded by UK NIHR HTA PROMIS is funded by the UK Government Department of Health, National Institute of Health Research Health Technology Assessment Programme, (Project number 09/22/67). UK Department of Health Disclaimer: The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the health technology assessment program, NIHR, NHS or the Department of Health.
Trial Design
Level 1b diagnostic study Validating paired-cohort confirmatory study Eligible, consenting patients with clinical suspicion of prostate cancer Visit 1: Registration Visit 2: MP-MRI (1.5 Tesla) Visit 3: Combined biopsy (under general anaesthetic) 1st: TPM-biopsy 2nd: TRUS-biopsy Visit 4: End of study Results given to patients El-Shater Bosaily A et al; PROMIS Group. Contemp Clin Trials. 2015;42:26-40.
Reference Test Template Prostate Mapping (TPM) Excellent diagnostic accuracy Prostate biopsies every 5mm Requires general anaesthetic Barzell WE, Melamed MR. Urology. 2007;70(6 Suppl) 27-35. Crawford ED et al. Prostate. 2013;73(7):778-87.
Blinding MP-MRI Report blinded to patients and physicians Radiologists not present at time of biopsy Biopsy Pathologists blinded to MP-MRI TPM-biopsy and TRUS-biopsy sent to different expert uropathologists
Results
MP-MRI compared to TRUS-biopsy Test attribute TRUSbiopsy MP-MRI Odds ratio* [95% CI] p-value Sensitivity 48% 93% 0.06 [0.02-0.12] Specificity 96% 41% 0.02 [0.003-0.05] PPV 90% 51% 8.2 [4.7-14.3] NPV 74% 89% 0.34 [0.21-0.55] p<0.0001 p<0.0001 p<0.0001 p<0.0001 McNemar test to compare sensitivity and specificity; GEE logistic regression model to compare PPV and NPV
If MP-MRI were used as a triage test, what types of clinically significant cancers would be missed?
% by status of disease MP-MRI scores and disease severity 100 90 80 70 60 50 40 30 20 10 Significant cancer Insignificant cancer No cancer 0 1 2 3 4 5 N=23 N=135 N=163 N=120 N=135 MP-MRI score
Clinically significant cancers missed by TRUS-biopsy and MP-MRI Number and cancer core length (mm) Gleason 3+3 Gleason 3+4 Gleason >/=4+3 TRUSbiopsy Total = 119 7 (6-11mm) 99 (6-14mm) 13 (3-16mm) MP-MRI Total = 17 1 (8mm) 16 (6-12mm) 0
Do we need systematic biopsies in addition to MR targeted biopsies? 32
Systematic TRUS biopsies detected 6.7% more tumours than targeted alone
MRI negative cases harboured only Gleason 6 cancer on systematic TRUS biopsy 34
If one is really serious about overcoming the 1 in 10 miss rate of MP-MRI for clinically significant prostate cancer, then you should not be applying a systematic TRUS biopsy that has a 1 in 3 miss rate You should do a template mapping biopsy 35
A recent update UCL series 18000 16000 14000 12000 10000 Total cores taken v Cores positive for any cancer 17113 400 men undergoing visual-estimated targeted transperineal biopsies and Template Mapping Biopsies 8000 6000 4000 2000 0 Template Biopsy 2517 1738 714 Targeted Biopsy
Balance between under-detection and overdiagnosis 450 400 350 300 250 200 150 Significant Cancer Insignificant Cancer No Cancer 100 50 0 Template Biopsy Biopsy Targeted Targeted Biopsy Biopsies
However, transperineal GA Mapping biopsies in all is an unsustainable strategy Would cost an additional 250M / year in the UK Impact on healthcare systems would be disastrous Such a strategy is clearly NOT the way forward 38
Can MRI targeted biopsies detect clinically significant cancer? 39
MRI-Targeted biopsy compared to TRUS Biopsy was better for clinically significant tumour SEN 0.91 vs. 0.76 MRI-targeted biopsy detected fewer insignificant prostate cancer SEN 0.44 vs. 0.83
Bupa London Prostate Diagnostic Pathway
The current pathway (predominantly private units South-East England) Elevated PSA or suspicious rectal exam First consultation Tests organised - Urine culture - Repeat PSA - Prostate volume ultrasound measurement Second consult MRI Third consult Prostate Biopsy Transperineal GA Biopsy or TRUS biopsy Results consult
The current pathway If 100 men were going through this typical pathway for private prostate cancer evaluation, there would be 400 face to face consultations, 100 MRI scans, and 100 biopsy procedures In London: Biopsies usually transperineal general anaesthetic with 10-20 histology pots OR Transrectal biopsies (sepsis risk of 2-4%).
The Bupa Prostate Pathway Streamlined, high quality, consultant-led, evidencebased.
Repeat PSA +/- MSU if dipstick positive Consult with urologist (teleconsult or face-to-face) Multi-parametric MRI (Cromwell Hospital) Consult with urologist (face-to-face) MRI not suspicious MRI suspicious PSA monitoring Transperineal sedation/la image-fusion biopsies (Cromwell)
The Bupa London Pathway If 100 men entered this pathway, there would be 100 teleconsults, 200 face-to-face consults, 100 MRI scans, and 75 biopsy procedures Biopsies under local anaesthetic/sedation with 2-3 histology pots and transperineal (sepsis 1 in 500)
So, we can detect prostate cancer better Can we reduce the harms of treatment once they are diagnosed?
Treatment options for localised prostate cancer Certainty of Cancer Control No to low risk of Side-effects Radical Treatments Prostate Cancer Active Surveillance Problems Incontinence (5-20%) Impotence (30-60%) Rectal toxicity (5-10%) Cost Over-treatment Problems Cancer Progression Psychological Burden Surveillance Burden Surveillance Cost
break our cultural addiction to immediate treatment for all and move toward discriminating, selective, and more socially responsible behavior in this challenging disease
Treatment of localised prostate cancer may have some survival benefit (if clinically significant)
Scandinavian Trial Watchful waiting vs. Surgery
USA Trial Watchful waiting vs. Surgery
UK PROTECT Trial
Treatment-related harms are significant Side-effects in the average centre
Treatment-related harms are significant Side-effects in the best centres
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Radical surgery Radical Radiotherapy Incontinence 10-20% 10-20% Impotence 30-60% 50-60% Rectal toxicity 1% 5% Failure at 5 years 5-10% 5-10%
Active surveillance
Active surveillance Low risk disease (Gleason 6, PSA <10, localised) Some intermediate risk cancers (Gleason 3+4) Other criteria - MRI shows no or small lesion - Biopsy low risk disease is concordant with MRI - Co-morbidity - Starting a family (short period of surveillance) - Patient choice
Life-style advice for prevention/reduced progression Aerobic exercise Foods to increase: - brassicas (cauliflower, broccoli, cabbage, Brussel sprouts) - cooked tomatoes - nuts - green tea - pomegranate juice Meds:?aspirin?5-alpha reductase inhibitors
Will imaging help me manage my patients on active surveillance? 68
71 years old Active surveillance for low risk prostate cancer Gleason 3+3 maximum core length 2mm confirmed on template guided prostate biopsies November 2010 2. Presenting PSA 2008 4.5 subsequently running between 8.5 2009 and 7 until February 2014 3. April 2014 PSA 9.6. Current PSA 11 69
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Scan two years later 71
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Repeat Targeted transperineal Local Anaesthetic Biopsies Gleason 3+4 2mm 75
64 years old Active surveillance for Gleason 3+3, 2mm on biopsy (49 cores) 2010 Presenting PSA around 7 rising to a peak of 12, sixmonth post-biopsy falling to 9 in May 2012 76
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Repeat scan every 2 years 4 years later 78
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Imaging can aid surgeons during radical prostatectomy
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Focal therapy in prostate cancer The male lumpectomy
Focal Therapy Treating the cancer not the whole organ
The question is not new in the cancer field Breast cancer Thyroid cancer Kidney Liver Lumpectomy Hemithyroidectomy Partial nephrectomy Partial resection In fact, almost all other nonhaemaotological cancers
Focal Cryotherapy
2008 2009 2013 56y PSA 8.9 DRE N PSA 16 PSA 18 PSA 25 Negative TRUS TRUS: Gl 3+3 1mm TRUS: Focal HPIN 86
DCE 87
3 weeks post 89
That which the scalpel fails to cure, heat can cure. If the heat cannot cure, it must be deemed incurable William Osler
Radical surgery Radical Radiotherapy Focal therapy Incontinence 10-20% 10-20% 1-2% Impotence 30-60% 50-60% 5-10% Rectal toxicity 1% 5% 0.1% Failure at 5 years 5-10% 5-10% 5-10%
Failure-free survival (need for radical and/or systemic therapy)
0 20 40 60 80 100 Metastases and/or cancer-specific survival At 5 years, - Metastasis-free survival 97% - Cancer-specific survival 100% - Overall survival 99% Number at risk 0 1 2 3 4 5 6 Time since Focal HIFU (years) 625 586 497 433 374 252 126
Conclusions
Prostate cancer is the last (solid organ) cancer in which imaging is not a key element of the diagnostic pathway Multi-parametric MRI is likely to become a key component of the prostate cancer diagnosis pathway
Prediction Two Prostate cancer is the last cancer in which the biopsy process is based on chance Targeted biopsies to an MRI lesion are improving detection of significant cancers and reducing over-diagnosis of low risk disease
Prediction Four Prostate cancer is the last cancer in which we insist upon treating the whole organ harbouring the cancer Tissue preservation, both active surveillance and focal therapy, will reduce the over-treatment burden of localised disease
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