How to make treatment decisions about prostate cancer, When is watchful waiting appropriate and how to chose between radiation or surgery.

1. Some questions
about Prostate
Cancer
Part 2 2021
Robert Miller MD

2. Deciding on Treatment
for Prostate Cancer in 2021
You need to find current, accurate and trustworthy sources of information. The most comprehensive, reliable site that is
updated continuously is hosted by the National Comprehensive Cancer Network or NCCN and I encourage everyone to
start there first (https://www.nccn.org/ or https://www.nccn.org/patientresources/patient-resources)

3. NCCN.org

4. https://www.nccn.org

5. www.aboutcancer.com
tinyurl.com/robertmillermd
www.youtube.com/c/RobertMillerMD

6. Bladder
Prostate
Urethra
Cancer
Prostate View
from the
front, notice
the overlap
with the
bladder and
urethra

7. Prostate View
from the side
Close proximity to
major structures
makes surgery or
radiation risky
sphincter

8. Why is the management of prostate cancer still
controversial?
Because many cases grow too slowly to affect the patient
so there is no justification to risk the possible side effects
of treatment in every case.
Need to understand the biology of the cancer to predict its
behavior and balance that with the man’s health, longevity
and interest in considering therapy.

9. https://gis.cdc.gov/Cancer/USCS/DataViz.html
At 5 Years almost
everyone with
prostate cancer is still
alive
So no value in using 5
years stats to
compare treatments

10. Prostate
Stage Distribution of SEER Incidence Cases, 2009-
2018
Stage at Diagnosis Percent of cases
Localized 73.3
Regional 12.4
Distant 6.3
Prostate
Recent Trends in SEER Relative Survival Rates, 2000-
2018
All 96.5%
Localized 100%
Regional 99.6%
Distant 39.8%
https://seer.cancer.gov/explorer
Male By Race/Ethnicity, All Ages, 5 years
85% of cases are
diagnosed at local or
regional stage and
their relative 5-year
survival is close to
100%

11. Prostate
Stage Distribution of SEER Incidence Cases, 2009-
2018
Stage at Diagnosis Percent of cases
Localized 73.3
Regional 12.4
Distant 6.3
Prostate
Recent Trends in SEER Relative Survival Rates, 2000-
2018
All 96.5%
Localized 100%
Regional 99.6%
Distant 39.8%
https://seer.cancer.gov/explorer
Male By Race/Ethnicity, All Ages, 5 years
6% present with
metastases but even
in this group 40% are
alive at 5 years
New and improved
hormone therapy drugs
are extending survival
from three years out to 4
or 5 years in this group

12. 12.5%
2.4%
6.1%
4.5%
https://seer.cancer.gov/explorer

13. 39%
19%

14. https://seer.cancer.gov/explorer/
12.5%
2.4%
60-70’s
80-90’s

15. Cancer Median Age at Diagnosis Median Age at Death
All 66 (M) 65 (F) 72 (M) 73 (F)
Breast 68 (M) 63 (F) 70 (M) 69 (F)
Colon 67 (M) 70 (F) 70 (M) 75 (F)
Lung 70 (M) 71 (F) 71 (M) 73 (F)
Prostate 67 (W) 64 (B) 81 (W) 76 (B)
SEER Median Age of Cancer Patients at Diagnosisa,
2014-2018
By Primary Cancer Site, Race and Sex
https://seer.cancer.gov/csr/1975_2018/browse_csr.php?sectionSEL=1&pageSEL=sect_01_table.11
Median Age of Cancer Patients at Deatha,
2014-2018
6 – 8 years
2 – 6 years
3 -5 years
1 – 2 years
12 – 14 years

16. Final Guidance on Metastasis-Free Survival in nmCRPC (non-metastatic castrate
resistant prostate cancer)
Released by the FDA / August 9, 2021
Because overall survival comparisons may take
years to show a benefit, they may be willing to
approve a new drug if the study shows that it
prevents or delays the development of metastases.

17. Things that might affect the decision to treat
one you’ve made the diagnosis of cancer
• Biology and extent of the cancer (how
aggressive and how advanced)
• Health status of the patient (general state of
health, other disease problems, life
expectancy, personal goals)

18. 19.4
15.3
11.5
8.3
5.8
4
13.9
10.4
7.4
5
3.3
2.2
8
5.6
3.8
2.4 1.5 1
0
5
10
15
20
25
70 75 80 85 90 95
Life Expectancy in Years for Men
Top 25th Percentile
Median
Bottom 25th Percentile

19. https://www.ssa.gov/oact/STATS/table4c6_2016.html
+ or –
by 50%
based
on
health
status

25. FDA Approves First PSMA-Targeted PET Imaging Drug
for Men with Prostate Cancer
For Immediate Release:
December 01, 2020

26. PSMA is better than Fluciclovine (Axumin) PET
Scans

29. Biology: The more mutated the cancer cells the lower the cure rate
88% if well differentiated cells
70% if moderate differentiated cells
50% if poorly differentiated cells

30. Cancer Grade or Gleason Score, the more poorly
differentiated (mutated) the worse the outcome

31. Risk of Relapse Based on Gleason Grade Group
Grade Group Relapse at 5 Years
1 4%
2 12%
3 37%
4 52%
5 74%
Relapse may just mean that the PSA blood test which went back to normal
after treatment, starts rising again.

33. Extra Biomarkers May Help Better Predict Low Risk or High-Risk Behavior
Would it be safe to hold off on any initial treatments and just monitor the
cancer for months (or even years)?

34. In 2018 the NCCN Included Genomics in the
Decision Process

35. Genomic test evaluates the activity of genes in
the tumor that are shown to be involved in the
development and progression of prostate cancer.

38. Risk of Metastases using Combined System
Spratt Journal of Clinical
Oncology 36, no. 6, 2018
Clear separation
between risk groups
and outcome
Intermediate
High
Low

39. Risk of Metastases using Combined System
10 Year Risk of Mets
Very-low 3.1%
Low 3.7%
Favor Intermed 25.9%
Unfav Intermed 31.7%
High 49.7%
Very High 61.9%
Spratt Journal of Clinical
Oncology 36, no. 6, 2018

40. 10 Year Risk of Metastases
Very-low 3.1%
Low 3.7%
Favor Intermed 25.9%
Unfav Intermed 31.7%
High 49.7%
Very High 61.9%
How is this Helpful?
Do Less Therapy
Do More Therapy
Do A lot More Therapy
Bone mets

41. Low Risk: observation (short life expectancy) or active surveillance (long life
expectancy) e.g. Gleason 6 and PSA below 10
Intermediate Risk: active surveillance (short life expectancy) or curative local
therapy (surgery or radiation) e.g Gleason 6 or 7 and PSA 10 - 20
High Risk: surgery or radiation possibly combined with hormone therapy or
chemotherapy. e.g. Gleason 8 or higher or PSA > 20
Metastatic: hormone therapy but also other options (including chemotherapy,
immunotherapy, isotope therapy)

42. Should I hold off on initial treatment?

43. If you decide to Treat, which is
better, surgery or radiation?
For surgery: “high volume surgeons in high volume centers generally provide
better outcomes” For radiation “highly conformal techniques with daily
prostate localization” is optimal

45. External Beam Radiation Therapy
Usually daily (M:F) for 4 to 8 weeks (photons or protons)
but newer techniques can complete in just 5 treatments

46. Brachytherapy (seeds or wires)
One or two treatments, sometimes combined with external in high-
risk patients

47. Trends in Diagnosis and Disparities in Initial Management of High-Risk Prostate Cancer in the US
JAMA Netw Open. 2020;3(8):e2014674 The NCDB was queried to identify men with high-risk prostate cancer
from 2004 to 2016.
Radiation
Surgery
IMRT (radiation) or Robotic Laparoscopic
(surgery) now about equal choices

48. Are there studies comparing men who proceed directly to
treatment (surgery or radiation) versus men who hold off
and just do surveillance?
Are we sure it is safe to wait and hold off initially or is
there a big chance that the cancer will progress and
become incurable during the watchful waiting period?
Prostate Cancer Intervention versus Observation Trial
(PIVOT)

49. 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 at
Department of Veterans Affairs and National Cancer Institute medical
centers
localized prostate cancer (stage T1-T2NxM0 of any grade diagnosed
within the previous 12 months. Patients had to have a PSA value of less
than 50 ng per milliliter, an age of 75 years or younger, negative results
on a bone scan for metastatic disease, and a life expectancy of at least
10 years.
N Engl J Med 2017; 377:132-142

50. Follow-up of Prostatectomy versus
Observation for Early Prostate Cancer / N
Engl J Med 2017; 377:132-142
Long term survival not affected by
delaying or avoiding treatment
Even just looking at deaths from
prostate cancer there was very little
harm due to delaying or avoiding
treatment

51. Follow-up of Prostatectomy versus Observation for Early Prostate Cancer / N Engl
J Med 2017; 377:132-142
Cumulative Incidence of Death
from Prostate Cancer through 19.5
Years.
Group Prostatectomy Observation
Low risk 0.9% 6.6%
Intermediate 9.0% 8.6%
High Risk 12.8% 23.5%
Only high-risk patients need to start
treatment immediately

52. 24% eventually treated
So, 76% avoided ever getting treated
Radical prostatectomy
Observation

53. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate
Cancer . Hamdy NEJM 2016;375:1415
Prostate Testing for Cancer and Treatment (ProtecT)
Between 1999 and 2009, a total of 82,429 men 50 to 69 years of age received a PSA
test; 2664 received a diagnosis of localized prostate cancer, and 1643 agreed to
undergo randomization to active monitoring (545 men), surgery (553), or
radiotherapy (545) The median age of the participants was 62 years (range, 50 to 69), the median PSA level at the
prostate-check clinic was 4.6 ng per milliliter (range, 3.0 to 19.9), 77% had tumors with a Gleason score of 6
Triggers to reassess patients and consider a change in clinical management were
based largely on changes in PSA levels
Randomized Trial between Surgery or Radiation or
Monitoring

54. 54% of monitoring group
were eventually treated

55. Results at 10 Years
Variable Monitoring Surgery Radiation
Prostate Survival 98.8% 99.0% 99.6%
Survival Great in all
three groups
More likely to
progress in the
monitor arm

56. Randomized Trial between Surgery or Radiation…Surgery
and Radiation same cure rate
ProtecT Trial, NEJM 2016;375:1415
Even at 10 years
the results with
surgery or radiation
were the same

57. Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer/ProtecT Study Group
N Engl J Med 2016; 375:1425-1437
Patient-Reported Outcomes after Monitoring, Surgery, or
Radiotherapy for Prostate Cancer | NEJM
Surgery worst
Surgery worst

58. 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
Cleveland Clinic Study out to 8 Years
and basically same outcome between
radiation or surgery

59. Same 10 Year Survival with very high Gleason
(score of 9 – 10)
Kishan JAMA 2018;319:895
Even with High Gleason
Score (high-risk cancer) the
10-year results were the
same

60. 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 plus Hormones 344 92%
Radiation alone 265 88%
Mayo Clinic Study (Boorjian Cancer 117;2883, 2011)
Same results in Mayo Clinic study but the radiation patients generally require
hormone therapy which has its own side effects which many men object to

61. Patient-Reported Outcomes Through 5 Years for Active Surveillance, Surgery, Brachytherapy, or
External Beam Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer
January 14, 2020
JAMA. 2020;323(2):149-163
prospective, population-based study of 1386 men with favorable-risk prostate
cancer and 619 men with unfavorable-risk prostate cancer, age, 64 [59-70]
treatments (favorable-risk disease: active surveillance, nerve-sparing
prostatectomy, external beam radiation therapy, or low-dose-rate brachytherapy;
unfavorable-risk disease: prostatectomy or external beam radiation therapy with
androgen deprivation therapy
measured with Expanded Prostate Cancer Index Composite scores, attenuated
over time with no clinically meaningful bowel or hormonal functional differences at 5
years.
However, prostatectomy was associated with worse incontinence over 5 years
(adjusted mean difference of –10.9 for favorable-risk disease and −23.2 for

62. Side Effects
Initially surgery
worse
By 5 years radiation was worst
(many also had hormone therapy)

63. surgery worse

64. Initially seeds
worst

65. Initially seeds
worst

66. Charles B Huggins
Awarded the 1966 Nobel Prize for
Physiology or Medicine for discovering in
1941 that hormones could be used to
control the spread of prostate cancer.
This was the first discovery that showed
that cancer could be controlled by
chemicals.
DES (diethylstilbestrol) a synthetic form of
estrogen discovered in 1938

67. Strategies of Hormone
Therapy for Prostate Cancer
Interfere at the pituitary level
Interfere at the adrenal gland level
Interfere at the testicle level
Interfere at the cell receptor level

68. Androgens include androstenediol (A5),
androstenedione (A4), dehydroepiandrosterone
(DHEA), dihydrotestosterone (DHT),
androsterone, and testosterone.
These androgens become activated when
bound to androgen receptors. In
males, androgens are produced in the testes
(95%) and the adrenal glands.

69. • 5 Types of Endocrine therapy (LHRH agonists, LHRH antagonists,
1st gen antiandrogen, 2nd gen antiandrogen, androgen biosynthesis
inhibitors)
• Multiple chemotherapy drugs (cabazitaxel and docetaxel)
• Two types of immunotherapy (sipuleucel-T or pembrolizumab)
• PARP inhibitors (olaparib)
• Isotope Therapy (Ra 223 Xofigo)
Any new drugs since DES? ….2021 List

70. LHRH agonists
Goserelin (Zoladex)
Histrelin (Supprelin)
Leuprolide (Lupron)
Triptorelin (Trelstar)
LHRH antagonists
Degarelix (Firmagon)
First generation antiandrogens
Nilutamide (Nilandron)
Flutamide (Eulexin)
Bicalutamide (Casodex)
Second generation antiandrogens
Enzalutamide (Xtandi)
Apalutamide (Erleada)
Darolutamide (Nubeqa)
Androgen biosynthesis inhibitor
Abiraterone (Zytiga)
Endocrine Therapy for Prostate Cancer

73. Multiple Sites of Action for Apalutamide (second generation androgen receptor
blocker)

74. Spartan Trial / failed surgery or radiation and now had rising PSA despite Lupron, if they
then added in Apalutamide, marked delay in progression. NEJM 2018 / Feb 8
Metastasis-Free Survival

75. Study adding Nubeqa to hormone therapy in men whose PSA was rising again despite
remaning on hormone therapy (castrate resistant, non-metastatic)

77. Overall Survival in
LATITUDE Updated
Analysis

78. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. James.
NEJM 2017;377. STAMPEDE Trial

79. Other Options to Endocrine Therapy
with a microsatellite instability-high (also known as MSI-H) or a
mismatch repair deficient (dMMR) biomarker

80. Isotope Therapy Against Prostate Cancer

81. Radioactive
isotope attached
to the peptide,
releases gamma
ray for SPECT
imaging and beta
particles that will
kill the cancer
Peptide
designed to
attach to the
target receptors
on the cancer
cells

82. Attach to the
receptors on the
surface of the
cell
Gets inside Beta radiation
kills the cancer

83. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer
NEJM /June 23, 2021
https://www.nejm.org/doi/full/10.1056/NEJMoa2107322
Prostate-specific membrane antigen (PSMA) is highly expressed in metastatic
castration-resistant prostate cancer.
Lutetium-177 (177Lu)–PSMA-617 is a radioligand therapy that delivers beta-particle
radiation to PSMA-expressing cells and the surrounding microenvironment.
phase 3 trial evaluating 177Lu-PSMA-617 in patients who had metastatic
castration-resistant prostate cancer previously treated with at least one androgen-
receptor–pathway inhibitor and one or two taxane regimens and who had PSMA-
positive gallium-68 (68Ga)–labeled PSMA-11 positron-emission tomographic–
computed tomographic scans.
Radioligand therapy with 177Lu-PSMA-617 prolonged imaging-based progression-
free survival and overall survival

84. FDA Approves First PSMA-Targeted PET Imaging Drug
for Men with Prostate Cancer
For Immediate Release:
December 01, 2020

85. Progression-free survival
Overall Survival

86. Lutetium-177–PSMA-617
PET Scan results
before and after
treatments

88. Treatment
Algorithm
Initial
approach to
treatment of
metastatic and
nonmetastatic
castration-
resistant
prostate
These need to be
computerized
and driven by AI
(though Watson
was considered a
failure)
Its failed partnership with MD
Anderson Cancer Center in 2017
brought a fresh wave of criticism to
the business, and in April 2019,
IBM announced it was winding
down Watson's work on AI-
enabled drug discovery due to
poor financial returns.

89. https://www.nccn.org

90. www.youtube.com/c/RobertMillerMD

91. https://www.mskcc.org/nomograms/prostate
Calculate the outcome from a radical prostatectomy for 75 yo man with Gleason 7 / T1c / PSA 6 / 4 + core biopsies
By 10 years after surgery 41% had a recurrence by at 15 years the chance
of dying of prostate cancer was only 1%
Using Nomograms

92. https://www.mskcc.org/nomograms/prostate
Calculate the outcome from a radical prostatectomy for 60 yo man with Gleason 8 / T2b / PSA 20 / 6 + core
biopsies
By 10 years after surgery 88% had a recurrence by at 15 years the chance
of dying of prostate cancer was only 4%

93. https://prostate.predict.nhs.uk/tool

94. https://umich-biostatistics.shinyapps.io/star-cap/
STAR CAP Prostate Cancer Staging System
Our staging model is for patients diagnosed with prostate cancer who have not yet begun treatment. We predict
the long-term chances of dying from prostate cancer with standard curative treatments including surgical
removal of the prostate gland or curative radiation therapy with or without hormonal therapy.
Metric Prediction
Stage IIB
5-Year Prostate Cancer
Specific Mortality
1.1%
10-Year Prostate Cancer
Specific Mortality
4.4%
This patient is 65 years old with clinical T1c N0 M0 prostate adenocarcinoma, Gleason 4+3 with
6/12 (50%) core biopsies positive, and a PSA of 12 ng/mL. This patient is NCCN risk group
Unfavorable Intermediate. This patient is grouped in STAR CAP Stage IIB.

95. How to think about prostate cancer treatment in 2021
1. May want to review the current NCCN guidelines (ideally with
your doctor) to feel confident in understanding the biology of
your specific cancer
2. Meet with both a surgeon (Urologist) and a Radiation Oncologist
to hear their recommendations and to get a better understanding
of the risks and side effects associated with the various treatment
options
3. For high risk or metastatic cancers, you may want to also meet
with a Medical Oncologist to get an opinion about the place of
chemotherapy, hormone therapy or other options (e.g.
immunotherapy) or to consider whether a clinical research trial
would be an option.
Both modern radiation and robotic surgery are highly technical, and the best outcome and lowest risk of complications
accrue from being treated by a doctor or center that has the most modern equipment (image guided IMRT) and expertise
(how many robotic cases has he/she performed) in treating prostate cancer, so spend the time to do some research on the
qualifications of your doctors….(you may need a couple of ‘second’ opinions)
Or…you may trust your doctor and let him tell you what to do and just stay out of it.

96. Or…you may trust your doctor and let him/her
tell you what to do and just stay out of it.

97. www.youtube.com/c/RobertMillerMD
tinyurl.com/robertmillermd