1. Prostate Cancer: Overview
Alan J. Wein, MD, PhD (hon)
Professor and Chair, Urology
University of Pennsylvania School of Medicine
Chief of Urology
University of Pennsylvania Health System

2. The Future
• “It’s hard to make predictions, especially
about the future.”
-Yogi Berra
• “For every problem there is a solution that
is simple, neat and wrong.”
-H L Mencken

3. Who Gets Prostate Cancer and Why (1)
• Man, Dog: only species
• Both possess genes for PSA and hKZ (?related)

4. Who Gets Prostate Cancer and Why (2)
• Hormones
• Age
• Genetic component
• Race
• Ethnicity
• Diet (nutrition)
• Geography (?climate, soil)
• Inflammation (at molecular level)
• Toxins

5. New Cancer Cases
CA Cancer J Clin 2007;57:43-66.

6. Cancer Deaths
CA Cancer J Clin 2007;57:43-66.

7. Lifetime Risk of Developing or Dying of
Prostate Cancer for a 50-Year-Old Man
in the United States
Lifetime Risk of Risk (%) Risk Ratio Proportional
Developing Risk
Developing 42 11.7 100
Incidental Cancer
Developing 16.7 4.4 38
Clinical Cancer
Dying of Prostate 3.6 1 8.6
Cancer
For every 100 men who develop cancer cells in their prostate during their lifetime,
For every 100 men who develop cancer cells in their prostate during their lifetime,
only 38 of them will ever be diagnosed with prostate cancer by biopsy, and only
only 38 of them will ever be diagnosed with prostate cancer by biopsy, and only
8.6 are at risk of dying of prostate cancer.
8.6 are at risk of dying of prostate cancer.

8. Incidental vs. Clinical Cancer
• 8-10 % grow, develop capacity to turn lethal
and spread
Scardino, PT. The Prostate Book, Penguin Group, NYC, 2005

9. Probability of Developing Significant
Prostate Cancer, US, 2000
0-39 yr 40-59 yr 60-69 yr ≥70 yr 0-?
1/10149 1/38 1/14 1/7 1/6
National Cancer Institute, 2005

11. Genetics
• 1 First Degree Relative 2.5X
• 2 First Degree Relatives 5-10X
• 3 First Degree Relatives 11X

12. Genetics
• 9 separate genes that appear to have some
correlation with PCa but only ~4-5% have
an inherited form of the disease

13. Toxins
• Dioxin (Agent Orange byproduct)

14. Diet (Nutrition)
• Fat (↑)
• Red Meat (↑)
• Soy (↓)
• Cruciferous Greens (broccoli, cabbage) (↓) (?)
• Native Japanese vs 3rd Generation in US

15. Additives
• Selenium
• Lycopene
• Vitamin E
• Green tea

16. The PCPT
• Long term finasteride ↓ incidence 25%
(24.4 to 18%) compared with placebo
• Control incidence in the study 24.4%, much
higher than expected (6%)
• Those with tumor had higher grade/score,
but… in play now

17. Prostate Cancer: Factoids
• 75% of all and 90% of serious cases arise in
PZ
• 20 % eventual mortality

18. Doubling Time
• Early: 2-4 yr
• Later: Growth rate ↑, DT ↓

19. Untreated: Factoids
• 10-12 yr to metastases
• 15-17 yr to death
• Large, locally advanced 8-12 yr to death
• Gross LN involvement 6-8 yr to death
• Bone metastases 5-6 yr to death

20. Detection, Diagnosis

21. Digital Rectal Exam

22. PSA
• A glycoprotein enzyme found in ejaculate

23. Normal Range of PSA Levels for
Men in Each Age Group
Age Range (Yr) PSA Normal Range (mg/ml)
40-49 0-2.5
50-59 2.6-3.5
60-69 3.6-4.5
70-79 4.6-6.5

24. Probability of Finding Cancer on
Biopsy According to a Man’s DRE
Result and PSA Level
PSA 2-4 PSA 4-10 PSA >10
Normal DRE 15% 25% 50%
Abnormal DRE 20% 45% >75%

25. PSA: Factors
• Absolute number
• Age
• Density <0.07; 0.07-0.15; >0.15
• Velocity 0.75 units or 20% per year
• Free % (from BPH) <10-13; >25
• Complexed (~bound) (?)

26. PSA Screening

27. Screening
PRO CON
↓ Death rate • # of unnecessary
•
↑ Lower Stage Disease biopsies
•
• Incidental Ca
• Diagnosis at younger age
detected –
• Less Progression to
unnecessary to treat
Metastases

28. Prostate Needle Biopsies

29. Treatment
Algorithm

30. Factors in Choosing Treatment
• Gleason Score and Stage
• Life-expectancy without prostate
cancer: overall medical health
• Knowledge and acceptance of risks for
selected treatment

31. Gleason Score

32. TNM Staging System for Prostate Cancer

33. Staging
Metastatic Disease: lymphatic and venous

34. Staging Simplified
• Confined, clinically localized
• Locally extensive
– Minimal
– Gross
• Widespread, metastatic

35. Treatment
Algorithm

36. Treatment Options
• Active Surveillance (watchful waiting)
• Surgery
– Retropubic
– Retropubic
– Perineal
– Perineal
– Laparoscopic
– Laparoscopic
– Robotic Assisted Laparoscopic
– Robotic Assisted Laparoscopic
• Radiotherapy
– External Beam
– External Beam
– IMRT
– IMRT
– Brachytherapy
– Brachytherapy
– Brachytherapy + External Beam/IMRT
– Brachytherapy + External Beam/IMRT
• Cryotherapy
• High Intensity Focused Ultrasound

37. Relative 5 Yr Survival Rate (%), US,
Prostate Cancer: Adjusted for
Normal Life Expectancy
1974-1976 1983-1985 1995-2001
Prostate 67% 75% 100%
Lung 12% 14% 15%
Pancreas 3% 3% 5%
Colon 50% 58% 64%
Breast 75% 78% 88%
Ries, Lag, et al., Seer Cancer Statistics Review, 1975-2002, 2005

38. Surgery for Prostate Cancer Cure

39. Radical Retropubic Prostatectomy

40. Perineal Prostatectomy

41. Laparoscopic Prostatectomy

42. Robotic Prostatectomy

43. External Beam Radiation

44. External Beam Radiotherapy

45. Radiation Therapy

46. Brachytherapy

47. Brachytherapy

48. Surgery
• PSA goes to zero
– easy to follow
• Recurrence detected early
– curative treatment possible (XRT)
• Psychological
• Lower longer term biochemical recurrence rate
• Longer survival

49. Surgery
• Time from work
• Hospitalization
• Anesthesia
• General risks
• Specific risks

50. Factors in Choosing Treatment
• Gleason Score and Stage
• Life-expectancy without prostate
cancer: overall medical health
• Knowledge and acceptance of risks for
selected treatment

51. Risks of All Types of Surgery
Must be individualized for each patient

52. Risks of All Types of Surgery
• Incontinence 2-15%
• Erectile Dysfunction 25-90%
• Rectal Injury 1%
• Temporary Colostomy 0.1%
• Bladder Neck Contracture (requiring treatment) 3%
• Ureteral Injury 0.2%
• Lymphocele (requiring treatment) 0.4%

53. Surgery Outcomes

54. Surgery Outcomes -Stratified

55. EBRT Outcomes for T1-2 Disease
Institution No. FU Gy Prog Group 5yr BRFS
Harvard 1765 4.1 69.4 I 81
II 69
III 47
MSKCC 743 3 75.4 Fav. 85
Inter 65
Unfav 35
Cleveland Clin 628 4.3 70.2 Fav 90
Unfav 59

56. XRT value of dose escalation
• Doses above 70 Gy may
benefit patients
• Data from MD Anderson
70% vs 60% BRFS
p=0.03
• Rectal complications
higher (26 v. 12 percent)
• IMRT provides improved
conformality with lower
symptoms

57. Brachytherapy Outcomes
Author No. PSA FU BRFS
Grado 392 7.3 30 76
Blasko 230 7.3 41.5 83.5
Ragde 147 8.8 93 66
Zelefsky 248 7.0 48 71
Brachmn 695 ---- 51 64

58. Biochemical Failure -
Treatment Options
Observation
•
Androgen Blockade
•
Radiation Therapy
•
Cytoreductive Chemotherapy
•
Immunomodulation (Vaccines)
•

59. Salvage XRT for Post Prostatectomy
PSA Elevation
• Review of 501 patients at 5 academic centers [median FU
45 months]
– Stephenson et al JAMA 291:1325, 2004
– Stephenson et al JAMA 291:1325, 2004
• Overall 50% disease progression
If no adverse features 77% bNED at 4 years
•
• Adverse features include
– Gleason 8-10
– Gleason 8-10
– SV involvement
– SV involvement
– Negative surgical margins
– Negative surgical margins
– PSADT of < 10 months
– PSADT of < 10 months
– Treatment after PSA >2.0
– Treatment after PSA >2.0

60. Post RRP Radiation
• General take home
message:
– Delay in therapy until
recurrence biopsy
proven is deleterious
– Multiple series suggest
that treating before the
PSA is greater than 1
or 2 has the best impact

61. PSA Failure - Salvage
Prostatectomy
Study Pts FU Organ Confined% DFS%
Link 14 9 35 33
Pontes 43 12-120 30 28
Rogers 40 39 20 47
Lerner 132* 64 30 52
Moul 12* 49 25 33
Garzotto 29 65 28 79

62. PSA Failure - Salvage
Prostatectomy
Study Pts Rectal BNC Incont
Link 16 0 7 55
Ahlering 11 0 64 64
Pontes 35 6 11 30
Lerner 79 6 27 41
Garzotto 97 0 22 67
Gheirler 30 3 16 50*

63. Salvage Cryosurgery- Response
Study # FU mo Pos Bx
mo
Pisters 150 13.5 (1.2-32.2) 23%
Lee 43 3 mo 15%
12mo 35%
Miller 33 17.1 (4.1-34.3) 27.3%
Katz 43 21.9 (1.2-54) 37%
6 mo 79%
12mo 66%

64. Androgen Blockade
• Finasteride alone
• Oral Antiandrogen Alone (Casodex)
• Finasteride plus oral antiandrogen
• LHRH agonist
• Total Androgen Blockade
• Tertiary Androgen Blockade

65. Androgen Blockade
• Can androgen blockade improve survival in
recurrent/ advanced prostate cancer?
• Arguments for early vs. late hormonal
therapy mixed
• Medical Research Council study was
positive but flawed.
• ECOG [Messing] trial in D1 patients
positive, but can it be applied to PSA only
failures?

66. Androgen Blockade - Side
Effects
• Vasomotor hot flashes
• Loss of libido
• Loss of lean muscle mass
• Anemia
• Osteopenia - Osteoporosis
• Fatigue
• Memory Loss

67. PSA Failure -Summary
• One of the largest and fastest growing group of prostate
cancer patients
• Diagnosis of PSA failure has heterogeneous outcomes
• No consensus on BEST treatment for post surgery or
post radiation patients
• Radiation or androgen blockade are the principle
treatments
• Adjuvant therapy for intermediate and high risk patients?
• Novel therapies on the horizon

68. Newer Developments
• Vaccine Therapies
– Dendritic Cells
– Viral Vector antigens and costimulants
– DNA vaccines
• Chemotherapy
– Taxanes and Estramustine
• Photodynamic Therapy
– Phase One investigations