The document discusses treatment considerations for low to intermediate risk prostate cancer, noting that men below the blue dotted line always require treatment while men above may or may not require treatment, and summarizes studies showing that modern seed implants result in cure rates that appear slightly better than surgery with less long-term side effects related to urinary and sexual function.

1. TREATMENT
CONSIDERATIONS FOR
LOW INTERMEDIATE RISK
/
PROSTATE CANCER
John Blasko MD

2. Diagnosing a Shade of Blue
* One core > 50% replaced with cancer bumps to Teal
** Two yellow boxes bumps Teal to Azure
*** Any rising PSA with a low testosterone bumps to Royal
ECE = Extra-capsular Extension, SV = Seminal Vesicle, PN = Pelvic
node

3. Shades: The Question of
Treatment
With occasional exceptions, men below the blue dotted
line always require treatment. Men above the blue
dotted line may or may not require treatment
Low Risk Sky Treatment vs.
Intermediat Teal no treatment?
e
High Azure
Relapsed Indigo Treatment
Advanced Royal

4. Treatments for Prostate Cancer
 Surgery- robotic or not (studies show no
difference)
 Radiation
 Seed implantation
 Permanent Seeds
 Iodine
 Palladium
 Cesium
 Temporary High Dose Rate (HDR) Seeds
 Beam Radiation
 IMRT (conventional, accelerated, hypofractionated)
 Proton

5. Surgery

6. The Prostate is “Built In”
Surgical Access is Difficult
Pubic
Bone
Urethra
Bladder
Intestines

7. Robotic Prostatectomy
 Computer enhanced
 Surgeon operates at the
console within a 3D view
 Bedside surgical
assistant is next to the
patient
 Instruments move like a
human wrist (↑ dexterity
and precision)

8. Surgeon Directs Instruments
 The surgeon’s
hands are placed in
special devices that
direct the instrument
movement

9. Bladder
Anatomy of the Neurovascular Bundles
To preserve sexual potency, the goal is to
avoid cutting the nerves

10. Surgery Pros and Cons
Pros
Learn more about cancer status
Some men feel better about “having it out”
Long experience
Cons
Major operation
Greater chance of incontinence and

11. Radiation
- Brachytherapy:
Permanent Seeds
High-Dose Rate Afterloading
- Beam Radiation:
IMRT (conventional and accelerated)
Hypofractionated (cyberknife)
- Protons

12. Seeds

13. Seed Implant
Procedure
Preloaded Needles
Mick Applicator

14. Implant Procedure

15. X-Ray of Patient after Completing a Seed
Implant

16. prostate
urethra
Peripheral Placement of Seeds to Avoid
Urethra

17. High-Dose-Rate Afterloading:
Temporary Iridium-192 Brachytherapy
1. HDR afterloader;
Ir-192 source on cable 2. Needle insertion by TRUS guidance
3. Implant completed; CT planning 4. Implant needles attached to HDR
afterloader

18. Catheters in place for hours to days

19. Brachytherapy Pros and
Cons
Pros
Delivers highest biologic dose of radiation
Most convenient and least disruptive
Less chance of long term complications
Cons
Requires expertise and experience
Short term urinary side effects

20. Linear
Accelerator
External Beam Radiation
(IMRT and Accelerated IMRT)

21. Intensity Modulated Radiation Therapy
(IMRT)

22. “Cut Away” View of IMRT Showing Dose
Distribution

23. External Beam Radiation Pros and
Cons
Pros
Widely available
Technical advances
Generally easy treatment
Cons
Radiation dose is limited
Standard treatment is time consuming
Risk of rectal injury

24. Goals of Treatment
- Cure the disease
- Prevent suffering
- Minimize impact on quality of life

25. Cure: What is its significance?
Cure does not necessarily mean longer
survival. The majority of men with prostate
cancer who have a relapse after treatment die
of causes unrelated to prostate cancer.

26. Summary of >100 Studies Looking at
5-year Cure Rates of Different Treatments
 18,000 prostate studies published between
2000 and 2010
 848 studies reported treatment results
 140 of those studies met the following criteria:
1. Reported on 100 or more patients
2. Results reported for Low, Intermediate and High-
Risk
3. Minimum of five years of follow up

27. Cure Rates with Seed Monotherapy
Intermediate Risk: Teal
100 33
33 23 13
14
14 23 13 37
37
90 44
44
16
16
39
39
6 12
6 12 42
42
80 17
17
BrachyAlone
Seeds
Surgery
70 29
29
EBRT
11
11 46 CRYO
60 46
HIFU
s ecc u St ne maer T
50
er gor P ASP %
← Years from Treatment →
t
40
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
•Numbers within symbols refer to references

28. Seed Monotherapy vs. Surgery*: Teal
(Intermediate Risk)
1
0.9 24
1540
8 Brachy
23
0.8 2
17 37
12 22 Brachy
4 40
Percentage 0.7 16
Relapse 3612
Surgery
0.6 34 32 Surg
Free 31
43 8
0.5
no ss er gor P %
0.4
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Years after Treatment
i
*Grimm, BJU Int, 2012, Vol. 109(Supp 1)

29. Cure Rates Intermediate Risk: Teal
14 33
14 33
13
13
EBRT + Seeds
37
37 Robot RP
31
31 35
35
34
34
90 1544
1544
+
+ Seeds + HT
38 40
Seeds Alone
3240
36 45
36 45 4
4 38 EBRT & Seeds
32
77 39
39
12 16
12 16 42
42
80 43
43 3
3 17
17
Hypo EBRT
18
18 28 Brachy
Seeds Alone
EBRT 6 5 28
6 5 9
9
70 7 25
7 4125 29
41
1
29
Surgery Surgery
1
2
2
10
10 11 46
11 46
60 EBRT
20 8
20 8
s ecc u St ne maer T
HDR
50
er gor P ASP %
← Years from Treatment →
t
21
21
40 22
22
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
29

30. 100
21
8
8 14 21
14
20
20
23
23
Brachy
4
4 17 10
17 10
90 19
19
16 5
EBRT &
16 5
26 12
26
24
12 Seeds
24
7
7 22
22 Robot RP
Surgery
3
3 9
9 18 Brachy
80 25
25
18
15 13
15 13 11
11
Surgery
13
13
EBRT
2
2 EBRT CRYO
70
HIFU
Protons
gor P ASP %
← Years → No TX
60
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
• Prostate Cancer Results Study Group 3/31/09
• Numbers within symbols refer to references
09/14/12 30

31. Conclusion on Cure Rates:
Modern seed implants result in
cure rates that appear slightly
better than surgery

32. Comparing Long-Term Side
Effects
What percentage of men recover
normal urinary and sexual function
(similar to before treatment) after
surgery or radiation?

33. Return to Baseline Urinary Function
Schellhammer, J Urol 183:1822, 2010
Brachytherapy or Cryotherapy
Robotic or Open Surgery
Months after Treatment

34. Return to Baseline Sexual Function
Schellhammer, J Urol 183:1822, 2010
Brachytherapy
Surgery or Cryotherapy

35. Return to Baseline Urinary Control
Gore , JNCI 101:888, 2009

36. Return to Baseline Sexual Function
Gore , JNCI 101:888, 2009

37. Sexual Distress of 625 Spouses
Sanda, NEJM 358:1250, 2008
Type of Median Age of % of Partners
Treatment Patient Distressed
Surgery 59 44%
Radiation 69 22%
Seed 65 13%
Implants

38. QOL after 5 years: Surgery vs. Seeds
Crook J Clin Onc 29:362, 2010
 Compared to surgery, seeds implants
showed significantly better:
 Urinary function
 Sexual function
 Overall patient satisfaction
 There was no difference in bowel function
between seeds and surgery

39. Study of Side Effects: IMRT vs.
Proton
Sheets, JAMA 307:1611, 2012
 Study evaluated the incidence of GI, urinary,
sexual function in 6600 men treated with IMRT
and 684 men with Proton between 2002 and
2007
 IMRT was associated with a lower incidence of
gastrointestinal morbidity compare to Proton
 There was no difference between the two
treatments in sexual or urinary function

40. Accelerated IMRT
 2.5 Gy in 5 weeks (Kupelian, IJROBP 68:1424,
2007)
 3.1% grade 2 rectal toxicity
 5.1% grade 2 urinary toxicity
 3.1 Gy in 4 weeks (Lock, IJROB 80:1306, 2011)
 25% grade 2 and 3% grade 3 rectal toxicity
 14% grade 2 and 5% grade 3 urinary toxicity

41. Conclusion: Quality of Life
 Chances for complete recovery of sexual
function are better after seed implantation than
they are after surgery
 Chances for complete recovery of urinary
function are better after seed implantation than
after surgery
 Chances for normal bowel function are better
after seeds than after external beam

42. Comparison of Treatments
“The Gold Standard”
 Surgery was the “Gold Standard” in the 1990s
when radiation was ineffective and toxic
 Surgical cure rates were better
 The side effects of surgery were less
 Seed implantation is the new “Gold Standard”
in the modern era. Compared to surgery:
 Cure rates from seeds are at least as good
 Side effects of seed implantation are less than
surgery

43. Cure Rates = Mortality Rates
Prostate cancer tends to be an indolent
disease, even if it isn’t cured. The majority
of men who develop a relapse after surgery
or radiation die of causes other than
prostate cancer (mainly heart disease).

44. Cancer Specific Survival after
Treatment
(I rm e d ia te -Ris k: Teal)
nte
 8 years: 1019 men (Zelefsky, JCO 28:1508, 2010)
 Surgery: 98.1%
 External beam 95.5%*
 10 years: 10,500 men (Kibel, J Urol 187:1259, 2012)
 Surgery: 98.2%
 External beam: 97.1%
 Seed implant: 97.7%
*In the Zelefsky study, patients initially treated with radiation
and who subsequently relapsed had delayed salvage
treatment compared to patients who relapsed after surgery

45. Dangerous Types of Prostate Cancer
Can be Indentified in Advance
Eggener, Journal of Urology 185:869, 2011
Different Types of PC 15-Yr.
Mortality
Gleason 6 0.2-1.2%
Gleason 8 - 10 26-37%
Seminal Vesicle Invasion 15-27%
Lymph Node Metastases 22-30%
Only 3 men of 10,000 who had Grade 6, organ-confined
disease died of prostate cancer

46. Predicting Prostate Cancer Mortality(PCSM)
Stephenson, Journal of Clinical Oncology 2009
“Only 4% (1 in 25) of contemporary patients have a PCSM risk greater than 5%”

47. To Treat or Not To Treat Low/Interm.
Risk
Whitmore’s Conundrum
“The quandary in prostate
cancer: is cure necessary in
those for whom it is possible,
and is cure possible in those
for whom it is necessary?”
1988 Willet Whitmore, Jr, MD
Father of Urologic Oncology

48. Management Choices for Low/
Interm
Risk
Monitoring
Observation Active Surveillance Definitive Treatment
Watchful Waiting
No testing. Periodic testing.
Treat to eradicate
Treat only when and Definitive treatment
the disease.
if symptoms develop. if progression.

49. “Watching” Palpable Disease
 Connecticut study: 20-year death rate of men
diagnosed in the 1970’s was 7%
 JA A2 0 0 5
M
 Swedish study: 15-year death rate of men with
well-differentiated prostate cancer was 2.5%
 JA A1 9 9 7
M

50. PIVOT Trial: Surgery vs. “Observation”
Wilt, NEJM 367:203, 2012
 731 men randomized between1994 to
2002
 Cancer detected by PSA testing
 Average age = 67, median PSA = 7.8
 Half the men had Gleason 7 or above
 Half the men had a palpable nodule
 Two-thirds were I
nte rm e d ia te -Ris k or
Hig h-Ris k

51. Outcome Ten Years Later
Wilt, NEJM 367:203, 2012
# Men Cancer Cancer Severe Potenc
Dead Death Death Loss y
from Rate Rate Urinary Gone
Cancer Overall (PSA>10 Control
)
Surgery 21 5.8% 5.6% 17% 81%
364 men
Observ. 31 8.4% 12.8% 6% 44%
367 men
Additional side effects of surgery: 1 death, 2 blood clots, 1 stroke,
2 lung emboli, 3 heart attacks, 1 on kidney dialysis, 10 required
additional surgery, 5 had serious infections, 17 had wound infections
or UTI, 6 had a urinary catheter for > 1 mo. and 6 blood transfusions.

52. Scandinavian Trial: Surgery vs. No Treatment
Bill-Axelson, NEJM 364:1708, 2011
 695 men randomized between1989 &
1999
 Cancer detected by rectal examination
(DRE)
 88% had a palpable abnormality on DRE
 Average age 65, average PSA was 13
 One-third of the men had Gleason 7 or
more
 Death rate @ 15 years 6% lower in men

53. Scandinavian Trial: Surgical Complications
Bill-Axelson, NEJM 364:1708, 2011
Complication in 289 Number Incidence 1 Year
Men of Events after Surgery
Urinary Leakage or 99 34.3%
Blockage
Impotence 168 58.1%
Leg or Lung Blood 7 2.4%
Clots
Death from Surgery 1 0.3%

54. “Observation” = Active Surveillance
Observation Active Surveillance
Aim Avoid treatment Individualize therapy
Monitoring Lax Aggressive
Indications for Cancer symptoms PSA increase,
treatment such as bone pain changes on ultrasound
or biopsy
Treatment timing Late Early
Treatment intent Symptom control Cure

55. The Advantage of Active Surveillance:
Accurate Selection of Men Who Need
Treatment
 At initial diagnosis, treatment decisions are
made by looking at a “single frame” from the
whole movie
 Changes in predictive factors such as
Gleason, PSA and imaging o ve r tim e enable
treatment decisions to be tailored to the tumor
biology in e a c h ind ivid ua l

56. Study of Active Surveillance
Klotz, JCO 28:126, 2010
 450 men monitored from 1 to 13 years
 Median age 70; Median PSA between 5 to10
 71% Lo w-Ris k; 29% I rm e d ia te -Ris k
nte
 10-year cancer survival was 97.2%--5 men
died of prostate cancer. Four of the five were
treated within 2 years of initial diagnosis
 117 patients had surgery or radiation and their
cure rate was 50%

57. Non–Prostate Cancer Mortality vs.
Prostate Cancer Mortality.
Ratio was 18.6 to 1
Klotz, JCO 28:126, 2010
X
X
X

58. X
X
Cure Rates with Surgery or Radiation
X after
X Active Surveillance
X
Xx
Klotz, JCO 28:126, 2010
X
#35
p = n.s.
#90

59. Study of Active Surveillance
Tosoian , JCO 29:2185, 2011
 769 men monitored from 1 to 15 years
 Median age 66; Median PSA was 5
 All Gleason six; most with 2 or fewer cores
positive
 No cancer deaths, no occurrence of
metastases
 192 had surgery or radiation of whom 18
(9.4%) have had a PSA relapse

60. Cure Rates with Surgery or
Radiation after Active Surveillance
Tosoian , JCO 29:2185, 2011

61. For Whom is Surveillance a Safe
Option?
Slide Provided by Laurence Klotz

62. National Comprehensive Cancer Network
(NCCN) Practice Guidelines
Mohler et al, J Natl Compr Canc Netw. 2010
ECURRENCE RISK EXPECTED INITIAL
RISK SURVIVAL THERAPY
Very Low Active
<20yr Surveillance
(Epstein Criteria) Preferred
Low Risk 1) Active
Surveillance
>10yr 2) Radiotherapy
(D’Amico Criteria)
3) Radical
Prostatectomy
Slide Provided by Laurence Klotz

63. Monitoring Protocols of Different
Centers
 Klotz
 DRE/PSA every 3 months for 2yrs, then every 6
months
 Biopsy 6-12 months after enrollment, then every
3-4yrs
 Multi-institutional (Univ Miami, Univ British Columbia; MSKCC;
Cleveland Clinic)
 DRE/PSA every 6-12 months
 Biopsy 18 months after enrollment, then every 1-
3yrs
 Johns Hopkins
Slide Provided by Laurence Klotz
 DRE/PSA at 6 month intervals

64. Surveillance vs. Surgery vs.
IMRT vs. Brachytherapy
Comparative Effectiveness and Value
Institute for Clinical and Economic Review
Massachusetts General Hospital

65. Results of Surgery after Active
Surveillance
Duffield, J Urol 182:2274, 2009
100% of men with tumor volume > 1.0 cm
were located in the anterior portion of the
prostate, “out of reach” to a standard 8-12 core
biopsy MRI directed
Standard or Color Doppler
Biopsy ultrasound directed
biopsy can
Prostate Prostate diagnose
anterior tumors
Rectum Rectum

66. Future Directions: Monitoring with Imaging
Instead of Repeated Biopsy?
AUA Abstracts 2012
 Abstract #2051: 179 men diagnosed with a 14-
core biopsy. Multi-parametric MRI prior to the
biopsy only missed one case of low volume
high grade disease (Case was low volume 4 +
4 = 8)
 Abstract #1444: 64 men evaluated with multi-
parametric MRI prior to a template mapping
biopsy. MRI predicted the absence of Gleason
above 3 + 4 = 7 with 95% accuracy

67. Individual Factors Affecting Treatment Choice,
But Not Addressed in this Talk
 Patient factors:
 Advanced age
 Comorbidity health issues
 Previous abdominal surgery
 Sexual factors:
 Baseline Potency
 Libido and sexual interest
 Partner’s sexual availability and libido
 Prostate factors:
 Prostate size
 Preexisting urinary symptoms
 Previous history of transurethral resection (TURP)

68. Conclusions Regarding
Treatment for Low/Intermediate
Risk
 Since mortality rates are low, treatment
selection should be influenced much more by
quality of life considerations than by survival
concerns
 The pros and cons of all the different
alternatives need to be evaluated in light of
each individual’s priorities and unique clinical
profile
 Delaying immediate treatment and taking time
to learn about all the various options is
usually a wise initial course of action.