an update on prostate

1. Prostate Cancer 2013
Still an

2. Cancer Cases in 2013

3. Cancer Deaths in 2013

4. Life time risk of developing cancer
2007 - 2009
Site Men Women
All sites 44% 38%
Breast 12.4%
Colorectal 5.17% 4.78%
Lung 7.8% 6.4%
Melanoma 2.9% 1.9%
Prostate 16.2%

5. Life time risk of dying of
cancer
Site Men Women
All sites 23.5% 19.9%
Breast 2.9%
Colorectal 2.3% 2.2%
Lung 7.8% 4.9%
Melanoma 0.35% 0.20%
Prostate 2.97%

6. Prostate Cancer
Incidence Peaked
During the Clinton
Years

7. Male Cancer
Incidence Rates 1975
to 2009
Prostate
Peak year 1992

8. Male Cancer Mortality Rates 1930 to 2009
lung
stomach
prostate
colorectal

9. Median Age at Diagnosis and Death

10. Median Age at Diagnosis and Death
80
Diagnosis
78
Death
76 13
74 year
72 age
70 gap
68
66
64
62
60
Lung Colon All Breast Prostate

11. Leading Cause of Cancer
Death in 2009

12. Trends in Relative 5 Year
Survival Rate
Time Period Survival Rate
1975-1977 68%
1987-1989 83%
2002-2008 100%

13. Prostate Cancer…more
men die with it than of it
 80% found at autopsy
 16% diagnosed during their
lifetime
 3% will die of it

14. Risk Factors for Prostate Cancer
Age
Family History
Hormones
Race
Dietary Fat
Multivitamin use
Dairy and Calcium Intake
Cadmium Exposure (-)
Dioxin Exposure (-)

15. Can you Prevent
Prostate Cancer?
Based on solid evidence, chemoprevention with
finasteride and dutasteride reduces the incidence
of prostate cancer, but the evidence is inadequate
to determine whether chemoprevention with
reduces mortality from prostate cancer.

16. Prostate Cancer
Prevention
Trials
•(PCPT) Prostate Cancer Prevention Trial the 24.8% reduction of
prostate cancer prevalence over a 7-year period in those men
taking the 5alpha-reductase inhibitor, finasteride (Proscar 5mg per
day)
•REDUCE study using dutasteride (Avodart) (-23%)
•CombAT Trial (Avodart + Tamsulosin (Flomax) (-40% and no
increase in high grade cancers)
•SELECT study using vitamin E and selenium (worse, Viy E
increased prostate cancer by 17%)
•Physicians Health Study (PHSII) beta-carotene, Vit E, C or
multivitamins (no benefit)

17. Vitamins E and C in the Prevention of
Prostate and Total Cancer in Men The
Physicians' Health Study II Randomized
Controlled Trial
JAMA. 2009;301(1):52-62

18. Should you screen for
prostate cancer?

19. Age Distribution of Men Diagnosed with
Prostate Cancer 2000-2010
39%
40%
35%
28%
30%
22%
25%
20%
15%
7%
10%
3%
5% 1%
0%
30 40 50 60 70 80 90
Age

20. The evidence is insufficient to determine
whether screening for prostate cancer
with prostate-specific antigen (PSA) or
digital rectal exam (DRE) reduces
mortality from prostate cancer.

21. Men who have at least a 10-y life expectancy
should have an opportunity to make an
informed decision with their health care
provider about whether to be screened for
prostate cancer. Asymptomatic men who
have less than a 10-year life expectancy
based on age and health status should not be
offered prostate cancer screening.

22. Median Life Expectancy in Men by Health
(poor, average or excellent)

24. ? Proven Benefit from
PSA Screening ERSPC
European Randomized Screening for Prostate Cancer (ERSPC)
Trial, 182,000 men age 50-74y, PSA yearly for 4 years
Median follow up of 11 years
Screen No Screen
Diagnosis of prostate cancer 7.4% 5.1%
Deaths from prostate cancer 299 462
Death risk prostate cancer 0.79 1.00
Conclusion: screen lowers the death rate by 21%, but
you would need to screen 1,055 men and treat 37 to
prevent one death

25. Mortality results from the Göteborg
randomized population-based
prostate-cancer screening trial.
University of Göteborg, Sweden.
Lancet Oncol. 2010 Aug;11(8):725-32. Epub 2010 Jul 2.
 20,000 men, age 50 to 64, half PSA every 2
years
 14 year follow up
Screen Control
prostate cancer 12.7% (1.64)
8.2%
Screening had 44% lower 0.5% (0.56X) rate so had
prostate death prostate death 0.9%
to screen 293 and treat an additional 12 to save 1

26. ? Proven Benefit from PSA
Screening PLCO Study
Prostate, Lung, Colorectal, Ovary US Study, n =
76,693 , annual PSA for 6 years and DRE 4
years, with 13 years follow up
Screen No Screen
Incidence cancer 1.22 1
prostate cancer death 50 44
mortality rate/100,000 2 1.7

27. Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer
Screening Trial on prostate-cancer mortality. NEJM.org March 18, 2009
76,693 men at 10 U.S. study centers, Men in the screening group were
offered annual PSA testing for 6 years and digital rectal examination for 4
years.
Incidence 22% higher Mortality was 13% higher (not
lower)

28. Long Term PLCO Trial
• Those who had 2 or more early PSA screenings had 25% lower
prostate cancer mortality
• Those with minimal comorbidities had a 44% reduction in prostate
cancer mortality. Treat an additional 5 to save 1
Prostate Cancer
Mortality
No screen
screen
JCO February 1, 2011 vol. 29no. 4 355-361

29. Prostate Cancer Screening
Mata-analysis of 6 trials ( n = 387,286)
• Odds of diagnosing prostate cancer
= increased by 46%
• Odds of being in stage I = increased
by 95%
• Impact on prostate cancer mortality
= none
• Impact on overall survival = none
BMJ. 2010 Sep 14;341:c4543

30. Prostate Cancer Screening
Mata-analysis of 6 trials ( n = 387,286)
Favor Screening Favor Control
BMJ. 2010 Sep 14;341:c4543

31. Check for a baseline PSA at age 40 and if 1 or
over go to annual (if less than 1 start screening
at 50)
Median PSA for Men age 40 – 49
median 0.5 to 0.7
75th percentile is 0.7 to 0.9

32. • If PSA is > 2.5 or higher or velocity is 0.35/y
consider biopsy or check Free-PSA
• If PSA 4-10 get biopsy or at least free-PSA
• If over 10 get biopsy

33. Probability of finding cancer in men with
clinically normal prostate glands but PSA
between 4 – 10 using Free PSA
PSA Cancer
% Free PSA Age 50 - 64y Age 65 - 75y
0.5 6.60%
0 - 10% 56% 55%
.6-1 10%
10.1 - 15% 24% 35%
1.1-2 17%
15.1 - 20% 17% 23%
2.1-3 24% 20.1 - 25% 10% 20%
3.1-4 27% > 25% 5% 9%
4-10 25-30%
>10 42-64%

34. Prostate Cancer Biopsy Predictor
http://www.aboutcancer.com/prostate_calc_main_page.htm

35. Prostate Cancer Biopsy Predictor

36. Prostate Cancer Biopsy Predictor

37. Positive Biopsy based on PSA and
Family History

38. Positive Biopsy by Age, Race and
PSA
80%
70%
60%
50% W55
40% W70
30% B55
B70
20%
10%
0%
2.5 4 10 20 50

39. Positive High Grade Biopsy by Age, Race
and PSA
80%
70%
60%
50% W55
40% W70
30% B55
B70
20%
10%
0%
2.5 4 10 20 50

40. Radical Prostatectomy versus
Observation for Localized Prostate
Cancer
Prostate Cancer Intervention versus Observation Trial (PIVOT).
From November 1994 through January 2002, we randomly assigned 731
men with localized prostate cancer (mean age, 67 years; median PSA
value, 7.8 ng per milliliter) to radical prostatectomy or observation and
followed them through January 2010.
Patients had to be medically fit for radical prostatectomy and to have
histologically confirmed, clinically localized prostate cancer (stage T1-
T2NxM0) of any grade diagnosed within the previous 12 months.
Patients also had to have a PSA value of less than 50 ng per milliliter, an
age of 75 years or less, negative results on a bone scan for metastatic
disease, and a life expectancy of at least 10 years from the time of
randomization.
NEJM 2012; 367:203

41. Death from Any Cause During the median follow-
up of 10.0 years, 47.0%
assigned to radical
prostatectomy died, as
compared with 49.9%
assigned to observation
absolute risk reduction,
2.9 percentage points).
Among men assigned to
Death from Prostate Cancer radical prostatectomy,
5.8% died from prostate
cancer or treatment, as
compared with 8.4%
assigned to observation
absolute risk reduction,
2.6 percentage points
NEJM 2012; 367:203

42. NEJM 2012; 367:203

43. Incidence of death from prostate cancer in a randomized trial that
compared radical prostatectomy with watchful waiting.
Only the young men (< 65 years) did poorly without active
treatment
Death from Prostate Cancer

44. Patient Reported Dysfunction
at 2 Years
Dysfunction Surgery Observation
Urinary 17.1% 6.3%
Incontinence
Erectile 81.1% 44.1%
Dysfunction
Bowel 12.2% 11.3%
Dysfunction
NEJM 2012; 367:203

45. Treating prostate cancer
Surgery?
Radiation?
Or Watchful Waiting?

46. Prostate Cancer Treatment
120
in 2008 from NCDB
100
80
Surgery
60
Radiation
Watchful Waiting
40
20
0
18-64 65-74 75-85

47. Choices with Prostate Cancer
1. Depending on the man’s life expectancy
and the nature of the specific cancer
(Gleason score) is treatment necessary?
2. If treatment is appropriate how to
choose between surgery or radiation?

48. Watchful Waiting or Active Surveillance
NCCN appropriate for:
1. Very low risk cancers
and life expectancy < 20 y
2. Low Risk and life
expectancy < 10 y

49. Very Low Recurrence Risk
1. Stage T1c
2. Gleason 6 or lower
3. Less than 3 cores positive and
none over 50%
4. PSA density < 0.15 (so PSA was
5 and volume 35g then density
would be 0.14 or 5/35)

50. Low Recurrence Risk
1. Stage T1 – T2a
2. Gleason 6 or lower
3. PSA < 10

51. Median Life Expectancy in Men by Health
(poor, average or excellent)

52. Life Tables for Men in the US (2007 data)
Age Expectancy
50 29
55 25
60 21
65 17
70 14
75 11
80 7.9
85 5.7

53. Watchful Waiting?
Mortality if Untreated
Gleason Score Death by 15 Years
2–4 4 – 7%
5 6 – 11%
6 18 – 30%
7 42 – 70%
8 – 10 60 – 87%

54. Mortality with No Active Therapy

56. Watchful Waiting, the odds that untreated prostate
cancer would cause death related to the age and the Gleason
Score

57. Active Surveillance
• Limited to men with low risk cancer and shorter life
expectancy
• PSA every 3 to 6 months
• DRE every 6 to12 months
• Repeat biopsy may be considered every 12 months up
to the age of 75
• Repeat biopsy if increased PSA or PSA velocity
Considered Disease Progression and Reason to
Initiate Therapy
• If Gleason Grade 4 or 5 is found on repeat biopsy
• If prostate volume increase (number of + biopsies or
the extent of the cancer)

59. Partin Tables: calculate the risk that the
cancer is already outside the capsule
prior to therapy

60. Laparoscopic Prostate Surgery
The surgeon
tries to dissect
the prostate
away from the
rectum, bladde
r, the
neurovascular
bundle (nerves)
and penile
urethra

61. Radiation Fields with Prostate Cancer
A Low Dose Large Area (Phase 1)
With radiation it is
possible to include
a wider area
around the
prostate to cover
any cells that may
have escaped
After the highest
safe dose is
reached, the
radiation target
will be made
smaller

62. Radiation Fields with Prostate Cancer
A High Dose Large Area (Phase 2)
The final, high
dose radiation
target will be
focused very
precisely only
on the prostate
gland

63. NCCN.org

66. Prostate Cancer Risk Groups
combine all 3 things, the
stage, the PSA level and the
Gleason score
•Low risk: (T1c, T2a Gleason 6, PSA <10)
•Intermediate risk: (T2b, T2c, Gleason 7, PSA 10-20)
•High risk: (T3, Gleason 8-10 or PSA > 20)

72. Cure Rates with Radiation versus Surgery for
Early Stage Prostate Cancer are the same
from the Cleveland Clinic.
Kupelian. JCO Aug 15 2002: 3376-3385

73. 10 Year Cure Rates for Patients with High Risk
Prostate Cancer
(PSA >20 or Gleason 8-10 or T3)
Treatment Number Cure Rate
Radical Prostatectomy 1,238 92%
Radiation/Hormones 344 92%
Radiation 265 88%
Mayo Clinic Study (Cancer Jan 10, 2011)

74. Long-Term Functional Outcomes after
Treatment for Localized Prostate Cancer
The Prostate Cancer Outcomes Study (PCOS), comprised 1655
men in whom localized prostate cancer had been diagnosed
between the ages of 55 and 74 years and who had undergone
either surgery (1164 men) or radiotherapy (491 men).
Functional status was assessed at baseline and at 2, 5, and 15
years after diagnosis
• Urinary Incontinence: worse with surgery at 2 and 5
years but the same by 15 years
• Erectile Dysfunction: worse with surgery at 2 and 5
years but the same by 15 years
• Bowel Urgency: worse with radiation at 2 and 5 years'
but by 15 years' the same
N Engl J Med 2013; 368:436-445

75. Sexual Function after
Radiotherapy or
Surgery
N Engl J Med 2013; 368:436-445

76. Quality of Life / Medicare Survey
Prostate Cancer Patients
Symptom Surgery Radiation
Wear Pads 30% 7%
Potent (< 70y) 11% 33%
Potent (>70y) 12% 27%
More frequent bowel 3% 10%
movements
J Clin Oncol 14 (8): 2258-65, 1996

77. Potency Rates after Prostate
Cancer Treatment
Treatment Probability Range
Seeds 80% 64 – 96%
Seeds + External 69% 51 – 86%
External 68% 51 – 95%
Radical Prostatectomy
Nerve Sparing 22% 0 – 53%
Standard 16% 0 – 37%
Cryotherapy 11% 0 - 53%
IJROBP 2002:54:1063

78. Potency Rates after Surgery
can range from 2% to
70%)
 Did they have a ‘nerve sparing’
prostatectomy?
 Hold old is the man?
 How high was the PSA?
 How good was their sexual function
before?
JAMA. 2011;306(11):1205-1214

79. Potency Results after External
Radiation can range from 16% to 92%
 Did they get hormone therapy along
with the radiation?
 How high was the PSA prior to
radiation?
 How good was their sexual function
before?

80. Responded to
Viagra
Surgery: 43%
Radiation: 70 – 91%
General Population: 80%
from other studies in the literature

81. Choosing Treatment Prostate Cancer
Urologist with
experience and a good
outcome with the
procedure
Experienced Radiation
Oncologist with
Modern Technology
(IGIMRT) and good
outcome data

82. The experience of the surgeon is a critical
factor associated with a successful outcome
Open prostatectomy the learning curve did not
plateau until a surgeon had performed at least
250 retropubic radical prostatectomies The
probability of biochemical recurrence at five
years was significantly lower (10.7 versus 17.9
percent)

83. Minimally invasive prostatectomy – In a
series of 4,702 men who were managed with
laparoscopic prostatectomy by one of 29
surgeons at seven centers,
the five-year risk of recurrence progressively
decreased with increasing experience (17, 16,
and 9 percent with 10, 250, and 750 prior
laparoscopic procedures)

84. Evolving
Radiation
Technology

85. Using the proper dose of
radiation
“It may be a bit over-exposed”

86. Prostate Cures Rates by Treatment,
The Radiation Dose is Critical
External beam > 72Gy
Surgery or Seeds
External beam < 72Gy
IJROBP 2004; 58:25
Months

87. Cure Rate (PSA cure) in 2991
Men By Therapy
Best results with
high dose external

88. Prostate Cancer Relapse Rate by
Radiation Dose
< 72Gy
72 - 82Gy
82Gy
Years
Kupelian. IJROBP 2008:71:16

89. Goal = radiation zone precisely around
the prostate cancer with small margin
bladder prostate
Radiation zone
rectum

90. IMRT (intensity
modulated
radiation therapy)
using 7 different beams
to target the prostate
The computer can
determine the optimal
number of beams to
deliver the radiation
dose to hit the target and
avoid other structures

91. After IMRT was established then IGRT
(image guided) was introduced

92. Lower Risk of Side Effects with Image
Guided IMRT compared to IMRT

93. Better Cure Rates with Image Guided IMRT
compared to IMRT for Prostate
Intermediate Risk High Risk

94. The most sophisticated technique for
image guided IMRT is Tomotherapy.
Combine a CT scan and linear accelerator to ultimate in
targeting (IGRT) and ultimate in delivery (dynamic, helical
IMRT) ability to daily adjust the beam (ART or adaptive
radiotherapy)

95. There is significant movement of the
prostate gland based on daily gas in rectum
Planned
target
No Rectal
gas
Planned target,
missed badly if
rectal gas pushes
the prostate Rectal gas
forward

96. Cyberknife Radiosurgery

97. Non Isocentric Delivery with CK
Beams

98. SBRT Prostate Cancer / Naples-Tampa
Experience
 Feb 2005 – Apr 2008 (Naples, FL)
• 164 monotherapy, 35 Gy
• 168 monotherapy, 36.25 Gy
• 59 EBRT + CK boost
 Jul 2008 – Dec 2011 (Tampa, FL)
• 121 monotherapy, 36.25 Gy
• 10 monotherapy, 38 GY
• 12 EBRT + CK boost

99. PSA Response to CyberKnife
Mean PSAi 6.8ng/ml
Mean PSAp 0.78ng/ml
97% biochemical control at 30 months median follow-up

100. Cure Rate after Cyberknife
N = 515, Alan Katz in New York

101. PSA Response after Cyberknife
 Follow-up median 54 months (range, 7 -
78)
 Median PSA 7
35 Gy
◦ 36 m 0.20 ng/ml 6
36.25 Gy
5
◦ 60 m 0.10 ng/ml PSA ng/ml 4
 By 48 months 3
◦ 290 of 329 pts 2
1
PSA < 0.5
0
0 12 24 36 48 60 72
Months

102. New Medical
Treatments
for Prostate
Cancer

103. Clinical development of novel therapeutics
for castration‐resistant prostate cancer

104. New Drugs for Prostate
Cancer

105. New Drugs for Advanced
Prostate Cancer
Drug FDA Approval Cost
Provenge (sipuleucal) immunoRx 4/2010
$93,000
Jevtana(cabazitaxel) chemoRx 6/2010
$8.000 q3w
Xgeva (denosumab) skeletal 11/201
$1,600 dose
Zytiga (abiraterone) hormone
Lupron (1985) LHRH agonist 4/2011
$5,000/mos
Bicalutamide (Casodex, 1995) anti-androgen
Xtandi (enzalutamide) hormone 8/2012
Degarelix/ Firmagon(2008) GnRH antagonist
$7,450/mos
Abiraterone androgen synthesis inhibitor
Enzalutamide androgen receptor blocker

107. Expose the patient’s
activated T cells to
cancer antigen
targets
Then re-infuse the
patient’s activated cells
(atc’s) back into them
which will attack prostate
cancer cells

108. FDA Approval 4.29.10
median OS of 25.8 months compared to 21.7
months for patients who received the control
treatment There was no difference in time-to-
progression.
The total cost for three courses of treatment
with Sipuleucel-T is $93,297.60

109. Phase 3 TROPIC clinical study involving 755
patients with mHRPC previously treated with a
docetaxel-containing
Median overall survival in the patients receiving
JEVANA + prednisone was 15.1 months
compared to 12.7 months
tumor response rates were 14.4% and 4.4% for
cabazitaxel-treated and mitoxantrone-treated
patients respectively,
FDA Approval 6.18.10

110. Xgeva the first and only RANK Ligand inhibitor to
prevent SRE (skeletal related events in cancer)
FDA Approval 11.19.10

111. Xgeva RANK Ligand inhibitor

112. Recent advances have demonstrated that
androgen-based pathways continue to have a
clinically significant role in the progression of
castrate-resistant prostate cancer.
In addition to androgen production by the
adrenal gland and testis, several of the enzymes
involved in the synthesis of testosterone and
dihydrotestosterone, including CYP17, are highly
expressed in tumor tissue

113. ZYTIGA is an oral androgen
biosynthesis inhibitor that works
by inhibiting the CYP17 enzyme
complex, which is required for
the production of androgens at
these three sources.
FDA Approval 4.28.11

114. Zytiga and prednisone combination had
a median overall survival of 14.8
months compared to 10.9 months for
patients receiving the placebo and
prednisone combination.

116. August 2012
In clinical trials, men who received the drug, which was
previously known as MDV3100, lived a median of 18.4
months, nearly five months longer than the median of
13.6 months for those who received a placebo. Before
2004, the only drug shown to prolong the survival of men
with advanced prostate cancer was
the chemotherapy drug docetaxel. Now there are four
others on the market — Jevtana, Provenge, Zytiga and

117. Enzalutamide (marketed as Xtandi and formerly known as MDV3100) is a
second generation androgen receptor antagonist drug for the treatment of
metastatic castration-resistant prostate cancer.
Enzalutamide has approximately fivefold higher binding affinity for the
androgen receptor (AR) compared to the antiandrogen bicalutamide
(Casodex)

118. www.aboutcancer.com
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