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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; 56:106-30

45% 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 !!
Overall mortality
P=0.22
PC mortality
P=0.09
NEJM 2012; 367: 203-213
Radical Prostatectomy vs WW
for Localized Prostate Cancer (SPCG-4)




N=695
Median FU: 13.4 yrs
Better survival with RP than
with WW
No survival benefit for men
> 65 yrs
PC mortality
All-cause mortality
65
<65
NEJM 2011; 364: 1708
NEJM 2014; 370: 932
65
<65
Are Results of PIVOT contradictory to SPCG-4?
PIVOT
SPCG-4*
Era
PSA
Pre-PSA
Mean age (year)
67
PSA > 10
34%
Gleason  7
26%
Stage  T2
45%
%High-risk
22%
Enrollment Period
1994~2002
>
<
<
<
<
65
47%
32%
69%
24%
1989 ~1999
 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.
*Only 5% of subjects were diagnosed by screening.
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
63%
600
Age distribution
500
400
300
200
100
2
10
98
94
90
86
82
78
74
70
66
62
58
54
50
46
42
24
0
Watchful Waiting vs Active Surveillance
追蹤觀察
積極監控
WW (Obs)
AS
Intention
Palliative
Curative
Potential subjects
Short life expectancy
Long life expectancy
Follow-up
No agreed protocol
Re-Biopsy, PSA kinetics,
DRE, (MRI)
Timing to initiate
treatment
Mets or local progression
Progression criteria*
Treatment to be
initiated
ADT, TUR-P,
Urinary diversion, pallRT
Definitive treatments
(Surgery, RT, etc.)
Introduced
Before PSA era
In past decade
*Progression in tumor grade, tumor size, cancer percentage or PSA kinetics
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
 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)
European Association of Urology 2014
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





Gleason  3+3 or 3+4
PSA  10-15 or PSAD  15%
Clinical T  T1/T2
Bx Pos cores  2 cores or 33%
%cancer in core  20%~50%
EAU Prostate Cancer Guideline, 2014
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
Tumor grade criteria

Prostate cancer is found in:
a greater number of biopsy cores
a greater extent in biopsy cores
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
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
OS
Mortality
CSS
Mortality
Klotz, et. J Clin Oncol 2015; 33: 272
Taiwan Prostate Cancer Database Consortium
Overall Survival by Stage
Stage I
Stage II
Unknown
5-year survival
Stage I:
90%
Stage II: 92%
Stage III
Stage III: 86%
Stage IV: 49%
10-year survival
Stage IV
Stage I:
83%
Stage II: 77%
Stage III: 71%
Stage IV: 28%
Taiwan Prostate Cancer Database Consortium
Cancer-Specific Survival by Stage
5-year survival
Stage I, II, III
Stage I: 100%
Stage II: 98%
Men with localized PC have a good survival.
98%
Stage III: 98%
Stage IV: 64%
Stage IV
10-year survival
Stage I: 100%
Stage II: 94%
Stage III: 96%
Stage IV: 48%
96%
Taiwan Prostate Cancer Database Consortium
Treatments (Localized, T1-3N0M0)
Up to 30% of new patients at NTUH are now managed with AS/Obs.
Nil
US: 14%
ADT
Cryo
US: 4%
Active Surveillance
or WW
US: 7%
RP
US: 50%
RT
US: 25%
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