1. Active surveillance in prostate cancer Dr John Yaxley Urological & robotic surgeon

2. Active Surveillance “I hate doctors – They find things wrong with you!!”

3. Disconnect between the histological phenotype and the historic clinical perception of a deadly disease

4. Active surveillance  Active surveillance is delayed curative treatment at the time of significant local progression  Limits adverse effects from treatment and maintains quality of life

6. Ongoing controversy....

8. PSA testing saves few lives and leads to risky and unnecessary treatments for large numbers of men. Healthy men don ’ t need PSA testing for prostate cancer, panel says Study: Surgery for early prostate cancer doesn't save lives

9. Eur Urol. 2013 ;63:428-35 15 Most men with curable disease who are untreated do not die within 10 years

10. PSA screening  Recent advances in prostate cancer detection, including PSA screening have diminished the incidence of high volume and aggressive tumours, with a stage shift to lower volume, lower stage cancer  PSA screening has been associated with a decrease in prostate cancer mortality  Many low grade cancers are unlikely progress to clinical symptoms and pose limited risk of death if left untreated

11. PSA screening  Despite its limitations, PSA has lead to a higher number of curable presentations  Randomised ERSPC study showed 21% reduction in PC deaths at 11 years and the randomised Swedish (Goteborg) trial showed a 44% reduction in PC death in the PSA screened arm at 14 years.  NNT to prevent 1 death is 12

12. Eur Urol. 2013 ;63:428-35 15 If prostate cancer mortality is used as the end-point, the follow- up must be ≥ 20 years. Most men with curable disease who are untreated do not die within 10 years

13. Cumulative risk of death from CaP Goetborg Study

14. Hitting the Target Unnecessary Surgery or radiotherapy Unnecessary side effects of impotence and incontinence Cure of Clinically Significant Prostate Cancer

15. Active surveillance  The long term outcome of active surveillance depends on the ability to initiate delayed intervention when required, but avoid overtreatment in those who do not require it  Prostate cancer kills over 3000 Australian men each year, more than women die from breast cancer

16. Active surveillance  Increasingly PSA screened tumours may resemble asymptomatic prostate cancer detected at autopsy who died from other causes  The high prevalence of prostate neoplasms compared to the low lifetime risk of PC death raises the concern about overtreatment of low volume, low grade prostate cancer

17. Prostate cancer Research International: Active Surveillance Criteria for inclusion 1. Histological proven adenocarcinoma of the prostate 2. Men should be fit for curative treatment 3. Clinical stage T1C or T2 4. Gleason score 3+3=6 5. One or 2 biopsy cores invaded with prostate cancer 6. PSA density less than 0.2 7. PSA ≤ 10 ng/mL 8. Participants must be willing to attend the follow-up visits 9. Adequate biopsy sampling

18. Active surveillance  Canadian study of 452 men by Klotz showed 10 y.r survival rate of low risk prostate cancer on active surveillance is 97.2% Klotz et el J Clin Oncol 2010;28:126-31  Randomised study in PSA era showed radical prostatectomy did not decrease death rate compared to observation over a median 10 yr. follow up period in men with low risk prostate cancer Wilt et el N Engl J Med 2102; 367: 203-13

19. Evidence for AS 450 men observed with active surveillance. Definitive treatment offered to those with PSA Doubling Time (DT) of <3 years, Gleason ≥ 4+3 or unequivocal clinical progression. 30% of patients were upstaged and offered definitive treatment * Klotz L et al. J Clin Onc. 2010 Jan 1;28(1):126-31. ParametersKlotz et al Age (median)70.3 years Length of Active Surveillance (median) 6.8 years [range 1 to 13] Pre-treatment PSA median level (ng/ml) 5 to 10 (48%) Gleason grade 5: 11% 6: 70% 7: 17%

20. Evidence for AS * Klotz L et al. J Clin Onc. 2010 Jan 1;28(1):126-31.

21. Active surveillance outcomes  Prospective active surveillance program of 1,298 men since 1995  Overall, cancer specific and metastasis specific survival at 15 years are 69%, 99.9% and 99.4% for Gleason 3+3 malignancy  Cumulative incidence of grade reclassification is 31% at 15 years  Cumulative incidence of curative intervention at 15 years is 57% Tosoian J, Epstein J, Carter H et el J Clin Oncol Oct 20;33(30)3379-3385

22. Defining active surveillance  Usually a PSA every 3-4 months for 2 years then every 6 months  Repeat biopsies, starting a 12 months post diagnosis then every 2-3 years thereafter  DRE on a yearly basis  MRI now being evaluated / incorporated into protocols

23. Courtesy Professor Barentsz

25. MRI in active surveillance  3T MRI can detect significant prostate cancer in 90% of cases Smaledone J Urol 2010;183:138-43  Decreases the risk of under grading by 20-30% compared to standard 12 core TRUS Hoeks et el 2012 Eur Urol 2012;62:902-9  Normal MRI may decrease the frequency of surveillance biopsies, especially if PSA stable

26. Why has prostate MRI improved ? 3T machine : Skyra at WMI Addition of functional techniques to T2 WI Improved sequencing protocols Post processing software PIRADS Urologist – Radiologist collaboration (> 7000 mpMRI at WMI – 200/month)

27. ADC Mapb1400

29. DWI Ca P → restricted water movement → Specificity → Indication of aggression Tightly packed cellular tissue Organized glandular tissue

30. Gleason 3+3 on TRUS Plan for Active Surveillance However lesion noted on MRITarget biopsy of lesion Gleason 4+5 Patient proceeded to Robot RRP

31. Active surveillance outcomes  Systematic review of AS trials shows that the prostate cancer mortality risk is <3%, but the median follow up period of the studies is only 7 years.  Approximately one third of patients will require curative treatment during the follow up period for local progression, usually by radical prostatectomy Dall’Era et el Europ Urol 2012;61:1079-92

32. Triggers for intervention  Progression to higher grade or higher volume tumour on surveillance biopsy  PSA doubling time of < 3 years  Change in patient preference  Identify a significant lesion on MRI Yaxley J et el Aus. Family Physician 42; Jan/Feb 2013, 74-76

33. 69y low volume Gleason 3+3=6 prostate cancer On active surveillance protocol MRI no significant tumour – ? avoid surveillance biopsies

34. 64y PSA 6.9 and rising Focus Gleason 3+3 cancer – on active surveillance Anterior tumour on MRI. - Gleason 3+4 on transperineal biopsy - proceeded to Robot prostatectomy

35. Novel biomarkers in active surveillance  PSA Isoforms  PCA 3  TMPRSS2:ERG  Oncotype DX prostate cancer assay  Others – kallikrein related peptidase 2, 4K score, CCP score (Polaris)

36. Conclusions  For patients with low risk prostate cancer, active surveillance is the preferred management stategy  For select patients, AS may be considered for low-volume Gleason 3+4 PC  Repeat biopsies showing higher grade or volume prostate cancer is a trigger for active treatment  More than half the patients remain on AS after >10 years follow up  Prostate cancer mortality risk at 10 years is <3%