High Risk disease is defined as “apparent localized cancer that has a high propensity of micro-metastatic disease” (cancer that is not visible on convention radiography, such as bone and CT scans). These cancers, once removed via radiation or surgery, are likely to "return," but in fact, they were never removed in the first place because the cancer cells were outside the treated region. Therefore, successful eradication of high risk disease requires both aggressive local control and systemic treatment with androgen deprivation therapy and extended field radiation. This lecture will review the most up-to-date data on dose-intensity radiation therapy, pelvic radiation, surgery with adjuvant radiation, and adjuvant hormone therapy. Finally, data on experimental chemotherapy and abiraterone (Zytiga) will be presented.

1. Richard Lam, MD
Prostate Oncology Specialists
September 8 2012

2. Definition: High-Risk
Localized cancer with a high likelihood of microscopic
spread and therefore relapse.
CT and bone scans are normal.
High-risk features (any one of the below)
 PSA > 20
 Gleason score = 8-10
 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 diagnosed at surgery

3. Examples of High Risk Prostate
Cancer
T1c, Gleason 4+5= 9, PSA=6.0
T3, Gleason 4+3=7, PSA=18.0
The differing profile of High Risk disease in research
studies is highly era-dependent 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 Cancer Demographics
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 aggressively
2. Radiation + Androgen Deprivation Therapy (ADT) is
generally better than Prostatectomy alone

5. Staging Studies: High Risk
Standard:
Bone Scan to look for possible bone metastasis
CT scan (or MRI ) of abdomen and pelvis to look for
possible abdominal and pelvic node metastases
New Methods (not approved):
Endorectal MRI to evaluate for possible seminal vesicle
invasion
C-11 PET scan
Na-Fluoride bone scan

6. Advanced Disease

7. Treatment for High Risk Disease:
Multi-pronged Attack
Surgery
Add Radiation?
Add Androgen Deprivation Therapy?
Lymph Node Dissection?
Add new drugs (abiraterone?)
External Beam Radiation Therapy
Add Androgen Deprivation Therapy?
Add Brachytherapy (Seeds)?
Add Chemotherapy?

8. Surgery or Radiation Head-to-Head
No good studies exist directly comparing the 2
treatments.
 Mostly retrospective single institution studies.
 Radiation patients are usually less healthy (ie not surgery
candidates).
 Surgery patients often get radiation after surgery.
 Radiation patients often get ADT.
 Surgical and radiation techniques constantly improving
(moving target phenomenon).

9. Surgery vs. Radiation for High-Risk
Arcangeli et al (RedJournal 75:975, 2009)
 162 men EBRT + ADT vs. 122 men treated with RP (+/-EBRT)
 3-year relapse rate was 13% for the radiation patients vs. 30%
for the RP patients.
Boojian et al (Cancer: 2883, 2011)
 609 men RP vs. 344 men EBRT+ADT
 88% of RP group received EBRT and/or ADT afterwards.
 Prostate cancer deaths were equivalent
Aizer er al (GreenJournal 93:185, 2009)
 204 men RP vs. 352 IMRT
 In the high risk subset, PSA relapse free survival was 38.4%
in RP group vs 62.2% in the IMRT +ADT group

10. Are You Ready for Your Prostatectomy?

11. 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

12. Surgery Outcomes for Gleason 8-10 Disease
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, especially when there is a
palpable abnormality on digital rectal examination

13. How to Improve Surgery Results?
Androgen Deprivation (ADT)
Radiation to the Prostate Bed
Radiation to the Pelvis
Lymph node dissection

16. Does ADT Improve Surgery
Outcomes?
 Retrospective review by the Mayo Clinic suggested
improved remission rates and survival (Zincke, JUrol 166:
2208, 2001)
 Two years of ADT 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 @ 5 years was only 7.5%
 However, there is no prospective data supporting the
routine use of ADT for all high risk patients after
prostatectomy.
Side Effects of ADT may negate the benefits.

17. ADT after Surgery Improves Outcomes in Men
with Lymph Node Metastasis
98 Men with Positive Nodes Detected at Surgery:
47 Men received Immediate ADT
51 Men received Delayed ADT at relapse
Deaths @ 7 years: 15% for ADT group vs 40%
(Messing, NEJM, 341:1781, 1999)

19. Radiation after Prostatectomy
EORTC 22911 Trial first reported an advantange to
immediate radiation vs wait-and-see approach (Bolla et al. Lancet
366: 572, 2005)
 74% vs 52.6% 5-year relapse free survival.
 Update in 2011 showed no survival benefit.
 Only treat younger patients?
 Treat immediately at PSA relapse (early salvage)?
ARO 96-02 Trial (Wiegel et al. JCO 27: 2924, 2009)
 72% vs 54% 5-year relapse free survival.
SWOG-8794 Trial (Thompson et al. JUrol 181: 956, 2009)
 72% vs 42% 10-yr relapse free survival.
 Less metastasis with adjuvant radiation
 Longer survival with adjuvant radiation: 15.2 vs. 13.3 years.

20. Adjuvant Radiation
Side Effects
EORTC 22911 Trial: used older radiation techniques
 Grade 3 Urinary and Bowel Toxicities:
 Radiation Grp: 4.2% vs. Observation Grp: 2.6%
SWOG-8794 Trial: used older radiation techniques
 Strictures:
 Radiation: 17.8% vs. Observation: 9.5%
 Rectal Complications:
 Radiation: 3.3% vs. Observation: 0.0%
ARO 96-02 Trial: used 3D conformal and IMRT radiation
 Grade 3 Urinary and Bowel Toxicities: 0.3%
Impotence>80%

22. Extensive Lymph Node Removal May Be
Curative for Small Volume Metastatic Disease
Bader (JUrol 2003; 169:849): If 1 lymph node
involved, 39% remained cancer free at 45 months.
Von Bodman (JUrol 2010; 184:143): If 1 lymph node
involved, 79% was relapse free at 24 months.
Side effects of extensive lymph node dissection
More bleeding
More scar tissue in the pelvis
More leg swelling
Longer operating time

24. Rationale for Pelvic Radiation
Lymph nodes are the first place of cancer metastasis
Historically, pelvic radiation is incorporated as
standard in all successful randomized prospective
trials of High-Risk disease
Still controversial
Mack Roach showed improved disease free survival at 5
years with pelvic radiation
Pascal Pommier showed no benefit
Modern IMRT radiation is far less toxic that older
radiation technology

25. Role of Pelvic Radiation after Surgery for
High Risk Disease (Spiotto, IJROBP 2007)
Retrospective Study at Stanford
114 men with high risk disease
72 men underwent whole pelvis + prostate bed
radiation
42 men underwent prostate bed radiation only
5 year PSA relapse free survival
47% in whole pelvis radiation group
21% in prostate bed radiation only group

26. Role of Pelvic Radiation after Surgery for
High Risk Disease (Briganti, Eur Urol 2011)
Retrospective study in Milan Italy
364 men node positive after surgery
117 men had ADT plus pelvic radiation vs.
247 men had ADT only
10-year cancer specific survival
86% pelvic radiation + ADT group
70% with ADT alone group

27. ADT Plus Pelvic Radiation
Roach, IJROBP 69:646, 2007
1500 patients randomized between pelvic radiation vs.
no radiation.
Also randomized between ADT for 4 months, starting
2 months before radiation vs. 4 months ADT starting
after radiation
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

28. Pelvic Radiation Ineffective?
Pommier, JCO 25:5366, 2007
444 patients
Pelvic node radiation 46 Gy (instead of 50Gy)
Smaller radiation field than the Roach study
Initial dose to prostate only 66 Gy
Many patients were NOT at high risk for relapse
Conclusion: No difference in cure rates at 5 years
but study was seriously underpowered to detect a
difference

29. 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

30. Is Surgery Appropriate for High Risk?
Consider the following:
If cure rates with surgery alone are poor…
If men need radiation after surgery anyway…
If men need ADT after surgery anyway…
Why not skip prostatectomy and proceed straight
to radiation?

32. How to Improve Radiation Results
for High Risk Disease?
Radiation to the pelvis
Increase the dosage directed to the prostate via:
Seeds
Image-guided technology
Androgen Deprivation Therapy (ADT) to treat
systemic disease
Chemotherapy (?)

34. Rationale for Seed Implant Boost
Higher dose, more conformal radiation treatment is
attained when seed implant are added to EBRT
Studies incorporating seed implant boost show
excellent relapse free survival rates

35. Sculpting Radiation Doses
with Seeds

36. Remission Rates with EBRT + HDR seeds
Mayo Clin Proc 83: 1364, 2008

37. Remission Rates with EBRT + Seeds vs RP
Oncology 22: 995, 2008

38. Remission Rates with EBRT + Seeds vs RP
Oncology 22: 995, 2008

39. Very High Risk Disease Treated with
Seeds + EBRT + ADT
 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

40. Relapse Rates: High-Risk
>40 months follow-up
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
09/14/12 40
Prostate Cancer Center of Seattle

42. ADT + Radiation Better than
Radiation Alone
EORTC 22863 (Bolla et al. Lancet 11: 1066,2010) showed
that adding 36 months of ADT to radiation resulted in:
Less likelihood of dying from cancer at 10 years: 10% vs
30%.
Improved overall survival: 58% vs 40%.
D’Amico study (JAMA 292: 821,2004) showed that adding
6 months of ADT to radiation resulted in:
Less likelihood of dying from cancer at 4 years: 0% vs
6%.
Improved overall survival: 88% vs 78%.
Intermediate risk

43. ADT + EBRT is than EBRT Alone
RTOG 94-08 (NEJM 365: 107,2011) showed that adding 4 months
of ADT resulted in:
 Less likelihood of dying from cancer at 9 years: 4% vs 8%.
 Improved overall survival: 62% vs 57%.
 Intermediate risk men.
Pilepich study (RTOG 86-10) showed that adding 4 months of
ADT resulted in:
 Less likelihood of dying from cancer at 10 years: 23% vs 36%.
 Bulky tumors.
RTOG 92-02 (JCO 26: 2497, 2008) showed that 28 months was
superior to 4 month for Gleason 8-10 cancers.
 10-year survival was 45 vs 32 months.

44. ADT Side Effects

45. Common Side Effects Associated with
Androgen Deprivation Therapy (ADT)
Osteoporosis Gynecomastia
Anemia Depression
Hot flashes Memory Loss
Loss of Libido Weakness/Fatigue
Penile Atrophy Gastrointestinal Toxicity
Muscle Wasting

47. Adjuvant Chemotherapy
Rationale: Treat hormone resistant micro-metastatic
cells while still vulnerable to eradication
Proven benefit in other tumor types such as breast,
colon and lung cancer
Early trials in the 1980-90’s for prostate cancer were
negative
Problems: inadequate trial participation, inadequate
medicines

48. Adjuvant Chemotherapy Studies
Mitoxantrone
Vinorelbine + Estramustine
Etoposide + Estramustine
Doxetaxel
Nab-Paclitaxel
Doxetaxel + Capecitabine

49. 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.
Study was too small.

50. Adjuvant Mitoxantrone
Mitoxantrone
No Mitoxantrone

51. 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)

52. 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

54. (Zelefsky et al, RedJournal 84: 125, 2012)

55. Abiraterone
Abiraterone is a potent, selective, and irreversible
inhibitor of CYP17A1
Blocking CYP17A1 further shuts down testosterone
production
“Super Lupron”

56. Abiraterone
6 2
Testosterone Androstenedione
5
4
nmol/l
ng/dl
Lower limit of
3 sensitivity 1
No rise at
2 progression No rise at
progression
1
0.07
0 0
1 Start of 10 20 60 70 At
Start of
28 56 At
treatment Days progression Days progression
treatment
12.5 12.5
DHEA Estradiol
10.0 10.0
ρmol/l
nmol/l
7.5 7.5
No rise at
5.0 progression 5.0
2.5 2.5
0 0
28 56 At 10 20 30 40 50 60
Start of
treatment Days progression Days post treatment

57. Abiraterone + ADT
Pre-Prostatectomy
29 men with high risk disease
 All received abiraterone and Lupron for 24 weeks
 All men then underwent prostatectomy
Before surgery, 26 men had a PSA < or =0.2
At surgery
 7 men (24%): <5mm of cancer in the removed prostate
 3 men (10%): no cancer seen.
This great response has never been reported.
Provocative, but more studies needed.
Taplin et al. JCO 30:2012 (abstr 4521)

58. The Best Treatment for High-Risk is
Multimodality Therapy
Local Therapy:
Prostatectomy + Radiation
Radiation + Seed Implant Boost
Regional Therapy:
Pelvic radiation
Systemic Therapy:
ADT for 2 years, to be started a couple months
before radiation
Chemotherapy in selected patients
(investigational)