1. John Blasko MD
Seattle, WA

2. Definition: High-Risk
Standard definition of High-Risk (any one of the
below)
PSA > 20
Gleason > 7
Stage > T2b
Two or three Intermediate-Risk Factors
An even more serious form of High-Risk:
Any Gleason grade 5 (Gleason score 9 or 10)
Seminal vesicle invasion
Pelvic lymph node metastases

3. High Risk Group is Heterogeneous
Big difference between a T1c, Gleason 8, PSA 6
and a T3, Gleason 7, PSA 40.
The differing profile of High Risk disease in
research studies is highly era dependant and
continues to be a problem in comparing
treatment outcomes today.
Trend for High Risk category today is lower
volume disease but high grade

4. High Risk
Approximately 15% of the 220,000 men who are
diagnosed annually (33,000 men) are High-Risk
Cancer specific mortality at 10 years for High-Risk
disease averages between 5% and 15%
There is some consensus among experts about
treatment:
1. Treat, don’t observe (except the very elderly or infirm)
2. Radiation plus testosterone inactivating
pharmaceuticals (TIP) is generally a better treatment
than surgery (except perhaps in men who have a high
Gleason but very low volume disease)

5. Staging Studies: High Risk
Considered standard:
Bone Scan to evaluate for possible bone metastasis
CT scan (or MRI ) of abdomen and pelvis to evaluate for
possible pelvic node metastases
Logical but still not considered standard: Endorectal
MRI to evaluate for possible seminal vesicle invasion
(scan quality varies depending on equipment and
physician experience )

6. What to Do with Scan Results that
Are Considered Ambiguous?
Suspicious bone scan findings can be further
evaluated with MRI or with CT directed biopsy
Suspicious pelvic node findings can be evaluated
with ProstaScint, experimental PET scans, CT
directed needle biopsy or laparoscopic surgery
Suspicious endorectal MRI findings suggesting
seminal vesicle invasion can be evaluated with
color doppler or endorectal MRI directed biopsy

7. Surgery for Gleason 8-10?
Epstein, Urology 76:715, 2010
9300 men with median:
PSA of 7.5 and stage T2
80% recurrence rate at 15 years
70% had extra capsular disease
An even worse outcome was associated with any:
Gleason grade 5
Seminal vesicle invasion
Positive lymph nodes
Take home message: Surgical cure rates are low with
high Gleason score when there is a palpable
abnormality on digital rectal examination

8. 5-Year Surgery Relapse Rates for High-Risk
# Patients % Relapsed Reference
110 55% Nguyen, J Urol 181:75, 2009
206 48% Yossepowitch, J Urol 178:493, 2007
957 32% Spahn, EurUrol 58:1 2010
712 35% Ward, BJU 95:751, 2005
1179 53% Matti, Eur Urol 53:118, 2008
188 29% Zwergel, Eur Urol 52: 1058, 2007
42% Average Relapse Rate @ 5 years

9. Outcome after Surgery in Men
with
High-Risk is Improved with TIP
Men with High-Risk:
Two years of TIP consisting of Zoladex plus Casodex
resulted in surprisingly low relapse rate in 481 men with
High-Risk disease (Dorff, JCO 29:2040, 2011)
Relapse rate @ five years was only 7.5%
Men with Positive Nodes:
Immediate TIP was better than TIP started at relapse in
men with positive nodes at surgery (Messing, NEJM, 341:1781,
1999)
Mortality @ 7 years: 15% vs. 40%

10. Pelvic XRT after Surgery in Men
Found Node Positive from Surgery
Briganti, Eur Urol 2011
364 men node positive after surgery
117 men had TIP plus pelvic radiation vs.
247 men had TIP without radiation
10-year cancer specific survival
86% with TIP plus XRT to pelvic nodes
70% with TIP alone

11. Is Surgery Appropriate for High Risk?
Please consider the following:
If cure rates with surgery alone are poor…
If men do better after surgery with the addition
of TIP….
If men do better after surgery with pelvic node
radiation…..
Why not proceed straight to radiation and skip
the surgery ?

12. Surgery Vs. Radiation for High-Risk
Arcangeli, IJROBP 75:975, 2009
162 men treated with EBRT plus TIP
9 months of testosterone deprivation started 2 months
before xrt
80 gy without node treatment
122 men treated with radical prostatectomy
Radiation patients had higher Gleason scores and
clinical stage that surgery patients
3-year relapse rate was 13% for the radiation patients
and 30% for the surgery patients

13. Rationale for seed implant boost
Higher dose, more conformal radiation treatment is
attained with seed implant compared to external
beam radiation alone
Studies incorporating seed implant boost show
excellent relapse free survival rates

14. Sculpting Radiation Doses
with Seeds

15. Radiation Dose From Seeds in EBRT
Equivalent Doses
Prostate
Typical IMRT ≈ 100 Gy EBRT
high dose equivalent
78 – 81 Gy
Area of
Prostate
Receiving
150+ Gy
EBRT
equivalent

16. Seeds + EBRT
Dose vs. Risk Grouping
Low Risk Disease High Risk Disease
(standard)
(seeds + EBRT)
(inadequate)
(standard for
seeds alone)
552 patients
2,188 patients
p < 0.0001
(inadequate)
Achieving high dose more important for *Stone NN et al, IJROBP
High Risk disease than for Low risk Vol. 69, #5, 1472, 2007

17. Cure Rates: Seeds for High-Risk
# TIP Cure Follow Reference
Pts. Rate Up
190 6 mo. 95% 8 yr. Merrick, IJROBP 61:32, 2005
243 ½ 6 m0. 88% 10 yr. Bittner, IJROBP 72:433, 2008
107 no 63% 10 yr Demanes, AJCO 32:342, 2009

18. Very High Risk Treated with
Seeds + EBRT + TIP*
131 patients, median age 68 yr.
 T3
 PSA > 40
 Gleason 10
 Gleason 8-9 with >50% + bx cores,
 Gleason 8-9 with PSA > 20
12 year results
 Overall survival 61%
 Cause-specific survival 88%
 PSA progression free 71%
Cause of death
 Prostate cancer 8.3%
 Heart disease 22.2%
*Bittner N, Merrick GS, Butler WM, et al.
Brachytherapy 11(2012) 250-255

19. Relapse Rates: High-Risk
EBRT, Seeds & ADT
20
20 16
16 45
45
109
109
Brachy
19 18
19 18 4
4
38 22
22
108
108 EBRT & ADT
17
EBRT & Seeds
Treatment Success
43 32
43 32 37
37
34
34
44
47
47 Hypo EBRT
44
9 41
9 41 22 104
48 104
36
36 48 10
10 42
11 12 42 24
12 8 24
25
25 8
101
101
106
106 33 21
33 21 5
5
39
39
EBRT
103
103
35
35
11
11
7 6 26
7 6 26 Surgery
31 30
Protons
46 31 30
46 107
107
102 15
102 15 HDR
105
105
EBRT Seeds +
r g or P AS P %
23 29
29
← Years from 23
Treatment 49
49 ADT
→ Robot RP
• Prostate Cancer Results Study Group
• Numbers within symbols refer to references
19
Prostate Cancer Center of Seattle

20. Relapse Rates: High-Risk
>40 months follow-up or less than 100 patients
65
81 20
20 16
16 45 109
109
Brachy
19 18 45
80 19 18 4
74 4 108
108 EBRT & ADT
78 38 22
22
67
67 17
55 75 EBRT & Seeds
72 54 85 43 76
43 37
37
72 54 34
34 44 32
32
47
47 Hypo EBRT
66 9 41
66 9 41 68 44
2 57 104
71 6436 68
71 6436
79 48 59
48 59
2
10
104
10 42
42
50
50 56 11
56 12
12 24
24
53 25 8 61
8 61
25 89
89
101
101
EBRT 62 106
62 106
70
70
33 21
33 21 5
39
5
39
11
11 60
60
103
103 83 7 82 26
83 7 82 26
35
35 63 66
Protons
ss ecc uS t ne maer T
52 63
52 84
84
73 31 30 58
77 46 73
46
31 30 58
88
88
86 87
86 87
107
107
102 15
102 15
HDR
t
51
51 105
105
EBRT Seeds +
r g or P AS P %
23 29
Surgery
29
← Years from 23 Treatment
69
69 49
49
ADT
→ Robot RP
• Prostate Cancer Results Study Group HIFU
• Numbers within symbols refer to references
02/23/13 20
Prostate Cancer Center of Seattle

22. Rationale for Pelvic Radiation
Metastatic disease represents the most dangerous
component of the cancer
Historically, pelvic radiation is incorporated as standard in
all randomized prospective trials of High-Risk disease
One randomized study by Mack Roach showed improved
disease free survival at 5 years with pelvic xrt
Another randomized study by Pascal Pommier showed no
benefit
Modern IMRT radiation is far less toxic that older
radiation technology

23. Hormones Plus Node Radiation
Roach, IJROBP 69:646, 2007
1500 patients randomized between no node radiation
and 50 Gy of node radiation. Dose to prostate was 70
Gy. Men were also randomized between TIP starting
two months before radiation and continuing for four
months vs. starting TIP at the end of radiation (also
for four months)
Patients: Median PSA was 22, 73% of men had
Gleason 7 or more, 2/3 of men were stage T2c, T3 or
T4
Conclusion: Node radiation improved cure rates.
However, the improvement was only seen when TIP
was started 2 months before radiation

24. Pelvic Node Radiation Ineffective?
Pommier, JCO 25:5366, 2007
444 patients
Pelvic node radiation 46 Gy (instead of 50Gy)
Small radiation field than the Roach study
Initial dose to prostate only 66 Gy
50% of study participants had calculated risk of node
metastases of less than 15%
Patients: Median PSA 16, 50% Gleason 6 or less, 25% stage
T3 (the rest were T1 or T2)
Conclusion: No difference in cure rates at 5 years but
study was seriously underpowered to detect a difference

25. Toxicity from Node Radiation?
Deville, IJROBP 78:763, 2010
30 patients treated with IMRT 79 Gy
30 patient treated IMRT 79 Gy and 45 Gy to pelvis
At 24 months no “late” GI or GU toxicity
Deville, IJROBP 82:1389, 2012
31 patients IMRT 70.2 Gy (to fossa after surgery)
36 patients IMRT 70.2 to fossa & 45 Gy to pelvis
No significant difference in “late” toxicity at 25 months

26. Calculating Risk of Nodes
Yu, IJROBP 80:69, 2011
Mack Roach has proposed that only men with more
than a 15% risk of node metastases should be
considered candidates for node radiation
The % risk of nodes involvement can be calculated as:
(Gleason score minus 5) x (PSA/3 +1.5 x T stage)
where T = 0, 1 or 2 for T1c, T2a, and T2b or T2c.
This is the so called Yale formula which has
supplanted the Roach formula and the Nguyen
formula due to enhanced accuracy
Note: Formula does not incorporate other important
prognostic info such as % biopsy or imaging results

27. Not All Node Radiation Equal
Lawton, IJROBP 74:377, 2009
Two different clinical cases distributed to 14 radiation
oncologists with expertise in genitourinary oncology
Conclusion, “Significant disagreement exists in the
definition of…. pelvic nodal radiation therapy among
GU radiation oncology specialists”
Consensus meeting October 2007 to develop a
clinical target volume (CTV) for node radiation by 10
GU radiation specialists.
Access to their conclusions was published in the same
journal (Lawton, IJROB 74:383, 2009)

29. Longer Duration of TIP is Clearly Better
1. 4 months Zoladex/Flutamide vs. none (Pilepich, IJROBP 50:1243, 2001)
 Cancer death @ 8 years: 23% vs. 31%
2. 36 months of Zoladex vs. none (Bolla, Lancet 2010)
 Cancer death @ 10 years: 10% vs. 30%
3. 24 months of Zoladex vs. 4 months of Zoladex plus
Flutamide: (Horwitz, JCO 26:2497, 2008)
 Cancer death @ 10 years: 11% vs. 16%

30. Rationale for Casodex or Flutamide
Nanda, IJROBP 76: 1439,2010
628 High-Risk men treated with:
 Beam radiation
 Brachytherapy boost
 Average of 4 months hormone blockade
401 men received Lupron alone whereas 227 men were
treated with a combination of Lupron plus antiandrogen
Outcome at 5 years: Men receiving Lupron plus
antiandrogen had a significantly lower rate of prostate
cancer mortality

31. Adjuvant Chemotherapy
Rationale: Treat micro-metastatic disease while still
vulnerable to eradication
Proven benefit in other tumor types such as breast,
colon and lung cancer
Chemotherapy options limited to two drugs: Taxotere
or Mitoxantrone
Preliminary trials in prostate cancer suggest a
possible benefit

32. Adjuvant Mitoxantrone
Wang, BJU 86:675, 2000
38 men with locally advanced disease
All given with Lupron / Flutamide indefinitely
19 men randomly allocated to 4 cycles of
mitoxantrone (this is the only randomized trial of
adjuvant chemotherapy in existance)
Kaplan-Meier survival curve shows significantly
prolonged survival in the men administered
mitoxantrone (next slide)

33. Mitoxantrone
No Mitoxantrone

34. Adjuvant Taxotere
Kibel, J Urol 177:1777, 2007
77 men treated with surgery most who had seminal vesicle
invasion and high Gleason scores
The median time to relapse for this group of patients based
on their stage, Gleason score and PSA was predicted to be
10 months by a Kattan Nomogram
All 77 men were administered weekly Taxotere for 6 mo.
Actual median time to relapse was improved by 50% (to
15.7 months)

35. Radiation + Hormones + Taxotere
DiBiase IJROP 81:732,2011
42 patients
75 % grade 4 + 3 or higher
Median PSA 17.8
Treatment
Pelvic radiation
Brachytherapy boost
Lupron for two years
Weekly Taxotere for 3 months
Outcome: 70% disease free after 7 years

36. Conclusion: The Best Treatment
for High-Risk is Multimodality
Therapy
TIP for two years, to be started a couple
months before XRT
IMRT to prostate and pelvic nodes when
calculated risk of nodes is > 15%
Seed implant boost to prostate
Palladium or Iodine permanent seeds
HDR temporary seeds (for SV invasion?)
Adjuvant chemotherapy is still considered
investigational