Active Surveillance or Watchful Waiting – How do They Apply to Your Patients? 蒲永孝 臺大醫院泌尿部主任 臺大醫學院泌尿科教授 臺灣楓城泌尿學會理事長 台灣泌尿科醫學會常務理事 臺大醫學院臨床醫學研究所博士

大部分 攝護腺癌病人 死於其他疾病 Lifetime risk of PC for western men is 15-20%, but the lifetime risk of PC death is only 3% CA Cancer J Clin 2006; 56: % of men with a PSA-detected PCa are candidates for conservative management Eur Urol 2013; 63:101-7

Radical Prostatectomy vs Observation for Localized Prostate Cancer (PIVOT study) 731 men eligible for surgery (median follow-up 10 yrs) No differences in overall or PC mortality RP: better CSS if PSA > 10 (p=0.04) and if intermediate or high-risk tumors (p=0.07). But no differences at all for men > 65 years. More urinary incontinence and erectile dysfunction in men with RP Observation: watchful waiting, not active surveillance !! NEJM 2012; 367: Overall mortalityPC mortality P=0.22 P=0.09

N=695 Median FU: 13.4 yrs Better survival with RP than with WW No survival benefit for men > 65 yrs NEJM 2011; 364: 1708 NEJM 2014; 370: 932 Radical Prostatectomy vs WW for Localized Prostate Cancer (SPCG-4)  65 <65 PC mortality All-cause mortality

Are Results of PIVOT contradictory to SPCG-4? PIVOTSPCG-4 * EraPSAPre-PSA Mean age (year)6765 PSA > 1034%47% Gleason  7 26%32% Stage  T2 45%69% %High-risk22%24% Enrollment Period 1994~ ~1999 *Only 5% of subjects were diagnosed by screening.  More younger age in SPCG-4  More advanced tumors in SPCG-4  More prominent survival benefit from surgery in SPCG-4 > < < < <  Surgery may confer survival benefit in younger men or men with more advanced or high-risk tumors.  Men > 65 years may not benefit from surgery.

National Taiwan Cancer Registry (2008~2010) 12,894 cases of incident prostate cancer Median age at diagnosis: 74 years Median age at death: 80 years Age distribution 63%

Watchful Waiting vs Active Surveillance WW (Obs)AS IntentionPalliativeCurative Potential subjectsShort life expectancyLong life expectancy Follow-upNo agreed protocolRe-Biopsy, PSA kinetics, DRE, (MRI) Timing to initiate treatment Mets or local progressionProgression criteria* Treatment to be initiated ADT, TUR-P, Urinary diversion, pall- RT Definitive treatments (Surgery, RT, etc.) IntroducedBefore PSA eraIn past decade *Progression in tumor grade, tumor size, cancer percentage or PSA kinetics 積極監控追蹤觀察

Clinical Case 1 75-year-old man (life expectancy: 10  15 years) Low-risk (PSA 8, Gleason 3+3=6, cT1cN0M0) Average health Treatment plan? 1. Active surveillance 2. Watchful waiting (observation) 3. Definitive treatment (prostatectomy, radiotherapy, etc.) 4. Primary ADT √ √ √

Clinical Case 1 Low Risk

Clinical Case 1 Very Low Risk

Clinical Case 1 European Association of Urology 2014 EAU Guideline: Patients with low-risk PCa should be informed about the results of two randomized trials comparing RP vs WW in localized PCa. In the SPCG-4 study, the survival benefit associated with RP was observed in men with low-risk PCa, but only in men < 65 years. In the PIVOT trial, a subgroup analysis of men with low-risk tumors showed that RP did NOT reduce all-cause mortality, even in men < 65 years. (not to mention men ≥ 65 years)

Active Surveillance Introduced in the past 15 years Active decision NOT to treat patients immediately Instead, patients are followed under surveillance and actively treated at pre-defined thresholds of progression Short PSA doubling time (unreliable) Deteriorating histopathological factors on repeat biopsy (size or grade progression) EAU 2014 Prostate Cancer Guidelines

Watchful Waiting or Observation ‘deferred treatment’ or ‘symptom-guided treatment’ Pre-PSA screening era (before 1990) Palliative Tx until local or systemic progression Palliative treatments include TURP, urinary diversion, ADT, and/or palliative RT for metastatic lesions EAU 2014 Prostate Cancer Guideline

Active Surveillance: Advantages vs Disadvantages Advantages: Reducing risk of unnecessary treatment of small, indolent cancers Avoiding side effects of definitive therapy that may be unnecessary Quality of life/normal activities potentially less affected Disadvantages: Chance of missed opportunity for cure Subsequent treatment may be complex with more side effects Nerve sparing may be more difficult, which may reduce chance of potency preservation after surgery Increased anxiety Needs frequent tests and re-biopsies, which may have complications Long-term natural history of prostate cancer—unpredictable 2015 NCCN Prostate Cancer Guideline (Ver 1)

Observation (Watchful Waiting): Advantages vs Disadvantages Advantage: Avoiding side effects of unnecessary definitive therapy and early initiation and/or continuous ADT Disadvantage: Risk of urinary retention or pathologic fracture without prior symptoms or concerning PSA level 2015 NCCN Prostate Cancer Guideline (Ver 1)

Selection Criteria for Active Surveillance EAU Prostate Cancer Guideline, 2014  Gleason  3+3 or 3+4  PSA  or PSAD  15%  Clinical T  T1/T2  Bx Pos cores  2 cores or 33%  %cancer in core  20%~50%

Follow-up Protocol for AS PSA  every 6 mo DRE  every 12 mo Repeat prostate biopsy to be repeated within 6 mo of diagnosis if initial biopsy was <10 cores if prostate exam changes or PSA increases, but neither is very reliable for detecting progression as often as annually to assess progression not indicated when life expectancy < 10 y PSADT: unreliable for assessing progression Multi-parametric MRI: not recommended for routine use, unless to exclude possible anterior cancer NCCN PC guideline 2015

Progression Criteria Gleason Gr 4 or 5 cancer is found upon repeat prostate Bx Prostate cancer is found in: a greater number of biopsy cores a greater extent in biopsy cores Tumor grade criteria Tumor size criteria NCCN PC guideline 2015

Clinical Series with Active Surveillance EAU Guideline 2014 J Clin Oncol 2010; 28:126

Long-Term Follow-Up of an Active Surveillance Cohort Klotz, et. J Clin Oncol 2015; 33: 272 OS CSS Mortality N=993 (median FU: 6.4 years, 0.2 ~19.8 years) Only 1.5% died of PC The 10 &15-yr actuarial CSS: 98% and 94%, respectively. At 5, 10, and 15 years, 76%, 64%, and 55% of pts remained untreated. Non-PC to PC death: 9.2 : 1

Stage IV Stage I 5-year survival Stage I: 90% Stage II: 92% Stage III: 86% Stage IV: 49% Stage III Unknown Stage II Taiwan Prostate Cancer Database Consortium Overall Survival by Stage 10-year survival Stage I: 83% Stage II: 77% Stage III: 71% Stage IV: 28%

Stage IV Stage I, II, III 5-year survival Stage I: 100% Stage II: 98% Stage III: 98% Stage IV: 64% Taiwan Prostate Cancer Database Consortium Cancer-Specific Survival by Stage 10-year survival Stage I: 100% Stage II: 94% Stage III: 96% Stage IV: 48% 98% 96% Men with localized PC have a good survival.

RP RT Cryo ADT Active Surveillance or WW Nil Taiwan Prostate Cancer Database Consortium Treatments (Localized, T1-3N0M0) US: 7% US: 50% US: 25% US: 4% US: 14% Up to 30% of new patients at NTUH are now managed with AS/Obs.

Conclusions Men with localized prostate cancer have a good cancer- specific survival AS/Obs is a viable option for patients with localized PC Men eligible for AS or WW:  Older age: > 65 for AS or <10 years of life expectancy for WW  Low risk for AS  More co-morbidities for WW