1. Disease Outcome of Surgical Treatment for Localized and High Risk Prostate Cancer
Dr Tak-Hing Bill WONG
Consultant Urologist & Head
Division of Urology, Department of Surgery
Queen Elizabeth Hospital
HONG KONG

4. Queen Elizabeth Hospital

5. Prostate Cancer Natural History
> 50 % of men of age > 80 yr will have histological evidence of prostate cancer
Hirst AE, Bergman RT Cancer 7:136,1954
Rich AR J Urol 33:215,1935
1 in 6 (about 16 %) of all men will develop clinically evident prostate cancer
Bostwick DG Eur Urol 32(Suppl 3):2-14,1997

6. Prostate Cancer Incidence in Hong Kong
Hong Kong Cancer Registry

7. Prostate Cancer Incidence
Incidence Cancer Mort : Incid
Mortality Ratio
U S A (1999) 1 180,000 37,
England & 17,000 9,
Wales (1997) 2
H K (1999)
1 Landis SH, et al CA Cancer J Clin 49:8-31,1999
2 Chamberlain J, et al Health Technol Assess 1:1-53,1997
3 Hong Kong Cancer Registry

8. E737757A LiMY M / 46. A9360460 WongHS M / 56. 20-9-2001 PSA = 171. 3
E737757A LiMY M / 46 A WongHS M / PSA = PSA = Bone scan Bone scan
Hormone refractory in 11/2 yr Hormone refractory in 1/2 yr

9. Does Prostate Cancer need to be Treated ?

10. Localized Prostate Cancer Conservative Tx
‘At first sight, it seems illogical to consider deferred treatment in any condition whether malignant or not ….. Further thought suggests that particularly in the elderly, conditions may be monitored rather than treated if the risk of treatment is high, the toxicity considerable, or the likely benefit small.’
Philip Smith Urol Clin N Am 17: ,1990

11. Prostate Cancer: Natural History
Retrospective analysis
M0 at diagnosis
Survive > 10 yr  63 % died from CaP
Age < 65 yr at dx  75 % died from CaP
Aus G Scand J Urol Nephrol 167(Suppl):1-41,1994

12. Localised Prostate Ca Watchful Waiting
N = 828 (untreated cases pooled from 6 studies)
Metastasis-free survival Cancer-specific survival
13 %
66 % 
Mortality
19 %
42 %
74 % 
Metastases
Chodak, et al NEJM 330:242, 1994

13. Albertsen PC, et al JAMA 280:975-980, 1998 *
Risk Analysis of Men Aged Yrs at Dx Managed Conservatively for Localized CaP
15-yr risk of dying from CaP
in relation to Gleason score:
Gleason score Risk of cancer Cancer-specific
death mortality
% 8 %
% 14 %
% 44 %
% 76 %
% 93 %
Albertsen PC, et al JAMA 280: , 1998 *
Risk of CaP death:
Very high in Gleason
Intermediate in Gleason 6
Low in Gleason 2 - 5

14. Does Prostate Cancer need to have Curative Treatment ?

15. Localised Prostate Cancer Curative Treatment
Radical prostatectomy
Radical radiotherapy
Hormonal therapy

16. Long-Term Survival & Mortality in Prostate Ca Treated with Non-curative Intent (HT) Cancer-specific Survival
M0 at diagnosis (n = 301)
Ca deaths 149 (50 %)
Deaths of other causes 152 (50 %)
Years
% Risk of Ca Death
0 – 5 39
5 – 10 54
10 – 15 57
15 – 20 71
20 + M0
514 prostate cancer patients, who died in Goteborg, Sweden, between 1988 & 1991
Treated with non-curative intent – either deferred or immediate hormonal treatment
Retrospectively analysed from initial diagnosis until death
Aus G, et al J Urol 154:460, 1995 *

17. Localised Prostate Cancer Curative Treatment
Radical prostatectomy
Radical radiotherapy
Hormonal therapy
TURP

18. Localised Prostate Cancer T1a / b
(Stage A1)
T1b
(Stage A2)
Cantrell, et al (1981) 1 John Hopkins
No progression
32 % progression
Epstein, et al (1986) 2 John Hopkins
8 / 50 (16 %) progression after 3.5 – 8 yr
6 / 8 died of cancer
Blute, et al (1986) 3 Mayo Clinic
4 / 15 progression after average 10.2 yr
2 / 8 progression
1 / 8 died of mets
1 J Urol 125:516, J Urol 136:840, 1986
2 J Urol 136:837, 1986

19. Early Prostate Ca: RP vs WW Scandinavian Randomized Trial
Distant metastases Cancer-specific mortality
WW 27.3 %
WW 13.6 %
RP 13.4 %
RP 7.1 %
Surgical removal of primary tumour reduces distant metastases & cancer-specific mortality by ~ 50 % at 8 years
Holmberg, et al NEJM 347:781, 2002

20. Prostate Cancer Progression to Advanced Disease
Disease Progression
Local
Bladder outflow obstruction
Ureteric obstruction
Metastatic
M0  M1
Symptomatic metastases
Catastrophic complications - Spinal cord compression
- Pathological fracture
Mortality
Reduced survival

21. So C & Wong BTH Proc HKUA 6th ASM, 2001
Hormonal Therapy for Metastatic Prostate Ca Orchiectomy vs LHRH Agonist
Orchiectomy
n = 34
LHRH Agonist
n = 11
P value
Disease progression
44 %
(15)
45 %
(5)
0.604
Time to disease progression
16.1 mth
(9 – 42)
17.4 mth
(12 – 24)
0.755
Progression free survival
28.1 mth
(6 – 81)
15.5 mth
(8 – 21)
0.127
So C & Wong BTH Proc HKUA 6th ASM, 2001

22. Clinically Localized Prostate Ca Deferred Definitive Therapy
Highly selected men w/ low risk cancers
Choose to delay tx, until evidence that cancer is biologically active
Actuarial progression-free probability
At 5 years 67 %
At 10 years 55 % ~ ½ had progression
Actuarial treatment-free probability
At 5 years 58 %
At 10 years 41 % *
Repeat biopsy
Objective measure
Most significant prognostic factor for progression
Repeat within 1st year
Patel, Scardino, et al J Urol 171:1520,2004
Fewer than half had progression
Some patients with no evidence of progression were treated because they had significant anxiety
All 31/88 except 1 underwent RP or RT

23. Prostate Cancer Deferred Therapy - Disadvantages
Sampling error / underdiagnosis at initial biopsy
Cancer growth / progression
Might miss the chance of treating a low risk CaP
Might need additional treatment for a high risk CaP
Tx for high risk CaP might have more complications
Repeat biopsies & follow-up mandatory
Anxiety of harboring untreated cancer  adversely affects QoL

24. What is the Disease Outcome following Curative Treatment ?

25. Prostate Cancer Staging of Disease
Clinical stage (TNM)
Gleason score
Preoperative PSA level
Goals:
To predict prognosis
To rationally select therapy based on predicted extent of disease

26. Prostate Cancer: TNM T Stage
T1 – Tumour non-palpable, not evident by imaging
T1a Tumour found in tissue removed at TUR
=/< 5 % cancerous, histological grade =/< 7
T1b Tumour found in tissue removed at TUR
> 5 % cancerous, histological grade > 7
T1c Tumour identified by prostate needle biopsy
due to elevated PSA
T2 – Palpable tumour confined to prostate
T2a Tumour involves < ½ lobe
T2b Tumour involves > ½ lobe
T2c Tumour involves both lobes

27. Prostate Cancer: TNM T Stage
T3 – Tumour palpable, beyond prostate
T3a Unilateral extracapsular extension
T3b Bilateral extracapsular extension
T3c Tumour invades seminal vesicle(s)
T4 – Tumour invades adjacent structures, or fixed
T4a Tumour invades bladder neck, external sphincter,
&/or rectum
T4b Tumour invades levator muscle, &/or fixed to
pelvic wall

28. Prostate Cancer Gleason Grade

29. Prostate Cancer Gleason Score

30. Definitive Tx for Prostate Ca Outcome Criteria
Radical Prostatectomy
Radiotherapy
PSA nadir
Definition
Time to nadir
< 0.1
3 – 6 wk
? < 0.5, 1, 1.5, 2,
or stable
17 mth
PSA recurrence
> 0.4 1
3 consecutive rises
1 Amling, et al J Urol 165:1146, 2001

31. Radical Prostatectomy PSA RecurrenceFU
PSA recurrence
Catalona, et al (1993) Washington University
925
22 %
Zincke, et al (1994) Mayo Clinic
3170
15 yr
48 %
van den Ouden, et al (1997) 3 Rotterdam
273
38 %
Pound, et al (1999) John Hopkins
1997
15 %
1 JAMA 270:948, BJU 79:203,1997
2 J Urol 152:1850, JAMA 281:1591, 1999

32. Long-Term Survival following Radical Retropubic Prostatectomy
Urol Clin N Am 28(3):555, 2001

33. Radical Prostatectomy vs Radiotherapy PSA Recurrence
Clinical stage T1-2,
PSA < 10, GS < 7
 RP, margin –ve
 RT
 RP, margin +ve
5-year biochemical recurrence-free survival:
RT & RP – difference not significant
Margin-negative & margin-positive disease after RP – difference significant
Kupelian, et al Cancer J Sci Am 3:78, 1997 *

34. Radiotherapy for Localised Prostate Ca PSA Recurrence
PSA levels pre-tx
(ng/mL)
 > 20
 10 – 20
 4 – 10
 < 4
Zagars, et al Int J Radiat Oncol Biol Phys 32:293, 1995

36. Han,Partin,Pound,Epstein,Walsh Urol Clin N Am 28(3):555, 2001
Long-Term Biochemical Disease-Free Survival following Radical Retropubic Prostatectomy PSA Progression-Free vs Clinical Stage
Han,Partin,Pound,Epstein,Walsh Urol Clin N Am 28(3):555, 2001

37. Han,Partin,Pound,Epstein,Walsh Urol Clin N Am 28(3):555, 2001
Long-Term Biochemical Disease-Free Survival following Radical Retropubic Prostatectomy PSA Progression-Free vs Gleason Score
Han,Partin,Pound,Epstein,Walsh Urol Clin N Am 28(3):555, 2001

38. Han,Partin,Pound,Epstein,Walsh Urol Clin N Am 28(3):555, 2001
Long-Term Biochemical Disease-Free Survival following Radical Retropubic Prostatectomy PSA Progression-Free vs Pre-op PSA
Han,Partin,Pound,Epstein,Walsh Urol Clin N Am 28(3):555, 2001

39. Radical Retropubic Prostatectomy Queen Elizabeth Hospital, Hong Kong
Mar 1993 – Dec 2004
N = 108
114 cases, 6 excluded
Age = 49 – 75 (median 68.5) years
Follow-up = 3 – 132 (median 36) months
Clinical (pre-op) categories:
75 Low risk (GS </= 7, PSA </= 20)
33 High risk (GS =/> 8, PSA > 20)

40. Radical Retropubic Prostatectomy Disease Outcome
Low Risk
n = 75
High Risk
n = 33
Pre-op PSA
Median
Range
7.5
0.4 – 19.2
31.2
5.9 – 122.8
Pathological stage
T2a,b,c
T3a
T3b N+
67 %
24 %
9 % -
36 %
27 %
21 %

41. Radical Retropubic Prostatectomy Disease Outcome
Low Risk
n = 75
High Risk
n = 33
PSA nadir
(PSA < 0.1 ng/mL)
Overall
78 %
Indiv risk groups
93 %
42 %
Rising PSA
(PSA > 0.4 ng/mL)
8 % (6 / 75)
61 % (20 / 33)

42. Radical Retropubic Prostatectomy PSA Recurrence Free

43. Radical Retropubic Prostatectomy Biochemical Recurrence-Free Survival
Kaplan-Meier survival rates
1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1
Cum
bRFS
(%)
–– Low risk (n = 75)
GS =/< 7, PSA =/< 20
–– High risk (n = 33)
GS =/> 8, PSA > 20
Months following surgery

44. Han,Partin,Pound,Epstein,Walsh Urol Clin N Am 28(3):555, 2001
Long-Term Biochemical Disease-Free Survival following Radical Retropubic Prostatectomy PSA Recurrence-Free in High Risk Cases
Han,Partin,Pound,Epstein,Walsh Urol Clin N Am 28(3):555, 2001

45. Pound, Partin, Walsh, et al JAMA 281:1591, 1999
Natural History of Progression after PSA Elevation following Radical Prostatectomy PSA Recurrences RP
32 %
4 %    1 2 3 4 5 6 7 8 9 10
>10 years  
45 %
19 %
Pound, Partin, Walsh, et al JAMA 281:1591, 1999

46. Pound, Partin, Walsh, et al JAMA 281:1591, 1999
Natural History of Progression after PSA Elevation following Radical Prostatectomy
1997 men, 15 years after surgery
Cancer-specific survival = 91 %
Biochemical disease-free survival = 85 %
Pound, Partin, Walsh, et al JAMA 281:1591, 1999
PSA elevation = 15 %
Of these, developed metastases = 34 %
Median actuarial time to metastases
= 8 years from time of PSA elevation
Median actuarial time to death
= 5 years from developing metastases
Placebo controlled - pooled data from 18 placebo-controlled studies
Open label extension - pooled data from 10 open-label extension studies

47. Pound, Partin, Walsh, et al JAMA 281:1591, 1999
Natural History of Progression after PSA Elevation following Radical Prostatectomy Median Actuarial Times RP
PSA elevation
Metastasis   
8 yr
5 yr 
Death
Pound, Partin, Walsh, et al JAMA 281:1591, 1999

48. Post Radical Prostatectomy Rising PSA
Clinical variable
Local recurrence
Distant recurrence
Onset of PSA rise
> 2 years
< 2 years
PSA doubling time
> 1 year
< 6 months
PSA velocity
(ng/mL/year)
< 0.75
> 0.75

49. Radical Retropubic Prostatectomy Disease Outcome
Low Risk
n = 75
High Risk
n = 33
Rising PSA
8 % (6 / 75)
61 % (20 / 33)
Adjuvant hormonal tx
For rapid PSA rise
Post-op (median)
1 / 6
12 mth
6 / 20
18 mth
(9,12,12,24,36,48)
Mortality
(2 due to medical co-morbidities)

50. Radical Retropubic Prostatectomy PSA Recurrence
High risk cases
(GS =/> 8, PSA > 20)
n = 33
20 had ‘PSA recurrence’
(PSA > 0.4 ng/mL)
6 started on adjuvant HT

51. High Risk Prostate Cancer Treatment Options
Radical prostatectomy alone
Hormonal therapy alone
Neoadj HT RP
RP Adj HT
RP Adj EXR
NeoAdj HT RP Adj HT
EXR Neoadj HT / Adj HT
Investigational strategies :
RP or EXR Chemo-hormonal therapy

52. High Risk Prostate Cancer Treatment Options
Radical prostatectomy alone
Hormonal therapy alone
Neoadj HT RP
RP Adj HT
RP Adj EXR
NeoAdj HT RP Adj HT
EXR Neoadj HT / Adj HT
Investigational strategies :
RP or EXR Chemo-hormonal therapy

53. Prostate Cancer: pT3 RRP + Adjuvant Tx
Retrospective study
Immediate postoperative (planned, within 3 mths) adjuvant treatment:
Orchiectomy
Radiotherapy
Significantly  progression
(local, systemic, or overall)
No improvement in survival
(cause-specific, or crude)
Cheng, Zincke, et al Urol 42:283, 1993 *
Mayo Clinic
Of 2,838 pts undergone RRP, 1,035 (36.5 %) found to have pathologic Stage C (or pT3)
Among them orchiectomy 103 (10 %)
radiotherapy 131 (13 %)
none (64 %)

54. Radical Prostatectomy Neoadjuvant Hormonal Therapy
3-month [leuprolide + flutamide]
cT2b
(+) margin rate =  ~50 %
5-year biochemical recurrence rate = no difference
Soloway, et al J Urol 167:112, 2002 *
3-month [goserelin + flutamide]
T3N0M0
4-year biochemical recurrence rate = no difference
Schulman, et al Eur Urol 38:706, 2000
* Longest follow-up of any neoadjuvant trial
3-month vs 8-month [leuprolide + flutamide]
pT2-3, equally stratified risk groups
3-year biochemical recurrence rate = no difference
Gleave, et al J Urol 169(4,supp):179, 2003

55. Radical Prostatectomy Adjuvant Radiotherapy
EORTC randomised control trial
Wait-&-see until failure vs Immediate postop RT
pT2-3 N0 M0
with (+) surgical margin / capsule perforation / invasion of SV RT
Wait RT
Wait
Wait RT
Bolla, et al Lancet 366:572, 2005

56. Radical Prostatectomy Adjuvant Radiotherapy
EORTC randomised control trial
Wait-&-see until failure vs Immediate postop RT RT
Wait
Bolla, et al Lancet 366:572, 2005

57. Locally Advanced Prostate Ca Radiotherapy +/- Hormonal Therapy
Radiotherapy vs Radiotherapy + Goserelin for 3 years
Disease-free interval
Overall survival
Bolla, et al NEJM 337:295, 1997

58. Node +ve Prostate Ca: Rad Prostatectomy & Pelvic Lymphadenectomy plus Immediate Hormonal Therapy vs Observation
Median follow-up = 7.1 years
Immediate (within 3 months of surgery) & continuous androgen ablative monotherapy – Goserelin or B orchiectomy vs
Treatment withheld until distant metastases were identified
Early antiandrogen therapy significantly improved survival
Messing, et al NEJM 341:1781, 1999 *

59. Node +ve Prostate Ca: Rad Prostatectomy & Pelvic Lymphadenectomy plus Immediate Hormonal Therapy vs Observation
Median follow-up = 10 years
Survival
Immediate hormonal therapy
Observation & Deferred hormonal therapy P
Disease specific
87.2 %
56.9 %
.001
Overall
72.4 %
49.0 %
.025
Toxicities of tx were tolerable
No immediately treated men had experienced an osteoporotic fracture or had discontinued hormonal therapy
Messing, et al J Urol 169(4,supp):396, 2003 *

60. High Risk Localized CaP Radical Prostatectomy
Columbia Univ Comprehensive Urologic Oncology Database
N = 2, radical prostatectomy (1988 – 2005)
n = 190 high risk localized CaP
(Kattan Normogram 5-yr progression free probability </= 60 %)
After
Biochemical failure (PSA =/> 0.2ng/ml)
Kaplan-Meier survival analysis
Biochemical disease free (PSA < 0.2 ng/ml)
Cancer specific survival rate
5 years 33
52.0 %
99.4 %
10 years
33 + 2
30.4 %
High risk patients undergoing RP are not at high risk for disease specific death
McCann, et al J Urol 175(4,supp):171, 2006

61. Advanced Prostate Ca: Immediate vs Deferred Hormonal Therapy MRC Trial
Major complications
Immediate (n = 469)
Deferred (n = 465) 2P
Underwent TURP 65
141
< 0.001
Ureteric obstruction 33 55
< 0.025
Pathological fracture 11 21
Cord compression 9 23
Extra skeletal metastases 37
< 0.05
BJU 79:235, 1997

62. Localized CaP: Radical Prostatectomy EAU Guidelines 2001
With a life expectancy =/> 10 years, the goal of management must be the eradication of the disease.
Huland In Proc 1st Int Consult’n on Prostate Ca,1997
There is no age limit for radical prostatectomy, and a patient should not be denied this procedure on the grounds of age alone.
Corral, Bahnson J Urol 151: ,1994

63. 22 – 26 August 2006