This presentation was the prostate cancer lecture for the oncology therapeutics course (31:725:560) that was presented to the class of 2014 PharmD students at the Ernest Mario School of Pharmacy.
I really enjoyed researching and preparing this lecture for the students, and hope you also will find at least something useful in this presentation.
2. Objectives
Define prostate cancer
Discuss potential etiology, risk factors, signs
and symptoms for prostate cancer
Identify diagnosis and screening guidelines,
and possible prevention of prostate cancer
Recommend appropriate treatments based on
the characteristics of the tumor and
information specific to the patient
2
3. Epidemiology
Prostate cancer is the most common cancer in
men in the United States
In 2012, 241,740 new cases and 28,170
deaths are predicted
American Cancer Society. Prostate cancer. American Cancer Society Web site. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003134
pdf.pdf. Accessed November 25, 2012.
3
4. Normal Prostate
Prostate is a gland
About the size of a walnut
Divided into lobes: base, apex, and left and right lateral
Gland cells produce prostate-specific antigen (PSA)
Wikipedia Commons. Prostatelead. Wikipedia Web site. Available at: http://en.wikipedia.org/wiki/File:Prostatelead.jpg. Accessed November 25, 2012.
American Cancer Society. Prostate cancer. American Cancer Society Web site. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003134-pdf.pdf.
Accessed November 25, 2012.
Anatomy of the prostate. National Cancer Institute Web site. Available at: http://training.seer.cancer.gov/prostate/anatomy/. Accessed November 25, 2012.
4
5. Where It All Goes Wrong…
Etiology: unknown; may involve several factors…
Most (~95%) cases of prostate cancer are
adenocarcinomas, or arise from gland cells
Inflammation
Unknown cause; may include infection or trauma
Sexually transmitted infections
Physical/chemical trauma
De Marzo AM, Platz EA, Sutcliffe S, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007;7:256-269.
College of American Pathologists. Prostate cancer. College of American Pathologists Web site. Available at::
http://www.cap.org/apps/docs/reference/myBiopsy/ProstateAdenocarcinoma.pdf. Accessed November 25, 2012.
5
6. Gene Mutations in Prostate Cancer
Gene mutations that have been associated:
Bcl-2: encodes proteins that suppress apoptosis
May be overexpressed
Androgen receptor (AR): encodes androgen receptor,
which binds testosterone and dihydrotestosterone
(DHT)
Testosterone and DHT promote cell growth; DHT is primarily
responsible in prostate
Mutations have been found
SRD5A2: encodes 5-alpha reductase, the enzyme that
converts testosterone dihydrotestosterone (DHT)
Polymorphisms have been found; may raise enzyme activity
Steers. Urology. 2001;58:17-24.
6
7. Progression to Prostate Cancer
Supposed, precancerous lesions develop from injury:
Proliferative inflammatory atrophy (PIA): increased
proliferation of gland cells in areas of atrophy
Prostatic intraepithelial neoplasia (PIN): presence
of abnormal, high grade gland cells
Unreversed damage leads to prostate cancer
Process: inflammation (?) gene mutations
cancer
American Cancer Society. Prostate cancer. American Cancer Society Web site. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003134
pdf.pdf. Accessed November 25, 2012.
7
8. Risk Factors
The following increase risk of prostate cancer:
Family history
1st degree relative (father or brother)
Age: rarely occurs before age 40
Median age at diagnosis: ~67 years old
Median age at death: ~80 years old
~2 of 3 prostate cancers are in men > 65 years old
Race: more common in African Americans
Not known why; historically, proposed to have higher
testosterone levels, but evidence is lacking
1. American Cancer Society. Prostate cancer. American Cancer Society Web site. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003134
pdf.pdf. Accessed November 25, 2012.
1. Rohrmann S, Nelson WG, Rifai N, et al. J Clin Endocrinol Metab. 2007;92:2519-25.
SEER stat fact sheets: prostate. National Cancer Institute Web site. Available at: http://seer.cancer.gov/statfacts/html/prost.html. Accessed November 25, 2012.
8
9. Possible Risk Factors
Indefinite risk factors: diet, obesity, gene
mutations, smoking, inflammation of prostate,
sexually transmitted infections
Definite correlation has not been established
9
10. Signs/Symptoms of Prostate Cancer
May be asymptomatic, especially in early stages
Otherwise, symptoms include:
Difficult/painful/frequent urination
Blood in urine/semen
And also…
Pain in back, hips, or upper thighs
Weakness/numbness in legs and feet, incontinence
Fractures
Why these?
10
11. Metastatic Prostate Cancer
Prostate cancer (and others) commonly
metastasizes to bone
Higher mortality and morbidities associated with
bone metastasis in prostate cancer
Sathiakumar N, Delzell E, Morrisey MA, et al. Mortality following bone metastasis and skeletal-related events among men with prostate cancer: a population-
based analysis of US Medicare beneficiaries, 1999-2006. Prostate Cancer Prostatic Dis. 2011;14:177-183.
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
11
12. The Vicious Cycle of Bone Metastasis
Tumor releases:
Parathyroid hormone-
related peptide
(PTHrP)
Osteoblasts release:
Transforming growth factor (TGF)
Insulin-like growth factor (IGF)
13. Janssens K, ten Dijke P, Janssens S, et al. Transforming growth factor-β1 to the bone. Endocr Rev. 2005;26:743-774.
14. Ara T, DeClerck YA. Interleukin-6 in bone metastasis and cancer progression. Eur J Cancer. 2010;46:1223-1231.
…Hence, the pain, weakness, and fractures
Osteoclasts cause bone resorption:
PTHrP binds to osteoblasts,
increasing expression of RANKL
RANKL binds to RANK, leading
to excess osteoclast activation
12
13. There are several methods to diagnosis:
Prostate-specific antigen (PSA) blood test:
Not specific for prostate cancer; surgery, urinary tract
infection and benign prostatic hyperplasia (BPH) can
also raise PSA levels
No consensus on “normal” levels, but generally, < 4.0
ng/mL
PSA velocity: measurement of change in PSA levels
over time
Digital rectal exam (DRE):
Not specific for prostate cancer (may indicate BPH)
Normal prostate is hard (like the tip of your nose);
prostate cancer is soft (like your chin)
Diagnosis of Prostate Cancer
Prostate-Specific Antigen (PSA) test. National Cancer Institute Web site. Available at: http://www.cancer.gov/cancertopics/factsheet/Detection/PSA. Accessed
November 25, 2012.
13
14. Diagnosis of Prostate Cancer
Diagnostic methods continued:
Transrectal ultrasound (TRUS)
Done as follow up after PSA and DRE
Probe inserted into rectum
Biopsy: the only definitive method
Prostate tissue is removed with needles and examined
For metastasis/lymph node involvement:
Bone scan/CT scan/MRI
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
14
15. Screening for Prostate Cancer
When should men be screened?
Remains controversial and without consensus
Should be ongoing discussion between patient and
physician
Know the NCCN recommendations:
Obtain initial screening (PSA level and DRE) at age 40
Individualize screening for men over 75 years old
Get baseline evaluation
Family history, race, history of prostate disease and screening
(previous biopsies, PSA tests, etc.), medication use
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
15
16. Adapted from NCCN:
Prostate Cancer Screening Guidelines
Initial
PSA and
DRE
Men at least 40
years old
• Not at risk
• At risk:
- African American
- Family history
- PSA ≥ 1.0 ng/mL
- Taking 5-alpha-
reductase
inhibitors
Repeat
annually
Repeat at
age 45
Repeat at
age 50, then
annually
PSA > 1
ng/mL
DRE negative
PSA ≤ 1
ng/mL
DRE negative
PSA ≤ 1
ng/mL
DRE negative
If PSA > 2.6 ng/mL or
DRE is positive at any
exam, obtain biopsy
PSA > 1
ng/mL
DRE negative
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
16
17. Prostate Cancer Screening Guidelines
Summary of NCCN recommendations:
Start screening with PSA and DRE at age 40
If PSA ≤ 1 ng/mL, screen at age 45 and 50, then
annually thereafter
If PSA > 1 ng/mL at any point, screen annually
If PSA > 2.6 ng/mL or DRE positive at any point,
obtain a biopsy
Just know the above (if you want more details,
read NCCN guidelines)
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
17
18. Why 5-alpha reductase inhibitors?
5-alpha reductase inhibitors (dutasteride and
finasteride) reduce prostate size
Mechanism of action:
They also lower PSA Levels
Therefore, may cause false-negative due to lowered
PSA level when there is cancer
Hence, screening evaluation includes medication use
5-alpha reductase inhibitor
Testosterone Dihydrotestosterone (DHT)
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
18
19. Prevention of Prostate Cancer
5-alpha reductase inhibitors were studied in
two major trials: PCPT and REDUCE
Objective: Determine if 5-alpha reductase
inhibitors reduce risk of prostate cancer
Rationale for studies: mechanism of action
Trial results: fewer cases of cancer, but a larger
rate of cancers were higher grade (more
aggressive) compared to those in placebo group
Not truly prophylactic
Selenium and vitamin E were also studied
They don’t work
Dutasteride decreases prostate cancer risk. National Cancer Institute Web site. Available at: http://www.cancer.gov/clinicaltrials/results/summary/2010/prostate-
chemoprevention0410. Accessed November 25, 2012.
19
20. Determining Treatment
Treatment depends on “recurrence risk” of cancer
Recurrence risk = life expectancy + prognostic group
Life expectancy is estimated using period life table from
US Social Security Administration (SSA)
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
20
21. Grouping of Prostate Cancer
Prognostic group is determined from TNM
classification, Gleason score, and PSA levels:
PSA levels:
Not specific to prostate cancer, but generally < 4 ng/mL
TNM classification:
T: size of primary tumor
N: metastasis to regional lymph nodes
M: metastasis to distant organs/lymph nodes
Gleason score:
Histologic grade (from 1 to 5) is assigned to two areas that
comprise majority of tumor for score between 2 and 10
Higher score = worse prognosis
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
21
22. TNM Staging
T1: Tumor is not palpable with DRE or visible
with imaging
T2: Tumor is palpable with DRE or visible with
imaging, and still confined to prostate
T3: Tumor has spread beyond prostate up to
seminal vesicles
T4: Tumor has spread beyond seminal
vesicles to nearby organs
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
22
23. T1
T1: Tumor is not palpable with DRE or visible
with imaging
Found through needle biopsy or tissue removal for
other reasons (like benign prostatic hypertrophy)
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
23
24. T2
T2: Tumor is palpable with DRE or visible with
imaging, and still confined to prostate
T2a: Tumor is on at most, one half of one side
T2b: Tumor is on more than one half of one side
T2c: Tumor is on both sides of prostate
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
24
25. T3
T3: Tumor has spread beyond prostate up to
seminal vesicles
T3a: Extends beyond prostate but not seminal vesicles
T3b: Spreads to seminal vesicles
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
25
26. T4
T4: Tumor has spread beyond seminal
vesicles to adjacent structures like bladder,
levator muscles, or pelvic wall
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
26
27. Gleason Score
Two grades are assigned from 1 – 5, to total a
score between 2 and 10
Figure: Gleason score
for prostate
adenocarcinoma
(majority of cancers
arise from glands)
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
27
28. Recurrence Risk Determines Treatment
Appropriate treatment is based on patient’s
health and tumor characteristics
Recurrence risk = life expectancy + prognostic group
Divided into three main categories:
Life expectancy is only used if clinically localized
Recurrence Risk Life
Expectancy
Primary Tumor Gleason Score PSA Level
Clinically
Localized
< or ≥
10 or 20 years
T1 – T3a Up to 10 Up to 20
ng/mL or
greater
Locally Advanced Any T3b – T4 Any Any
Metastatic Any Any T, N1, M0
Any T, Any N, M1
Any Any
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
28
29. Tips for Studying
For your exam, know the treatments given:
The type of recurrence risk (clinically localized,
locally advanced, or metastatic)
Life expectancy
Still need to understand T stage, Gleason score, and
PSA levels, but not for identifying risk
Recurrence Risk Life
Expectancy
Primary Tumor Gleason Score PSA Level
Clinically
Localized
< or ≥
10 or 20 years
T1 – T3a Up to 10 Up to 20
ng/mL or
greater
Locally Advanced Any T3b – T4 Any Any
Metastatic Any Any T, N1, M0
Any T, Any N, M1
Any Any
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
29
30. Prostate Cancer Treatment Guidelines
Treatment by Recurrence Risk
Clinically Localized Expected Survival Therapy
Very Low - T1c
- Gleason score ≤ 6
- PSA < 10 ng/mL
- Fewer than 3
prostate biopsy cores
positive
- PSA density < 0.15
ng/mL/g
< 20 years
≥ 20 years
• Active surveillance
• Refer to therapy for “Low” recurrence risk
Low - T1 – T2a
- Gleason score ≤ 6
- PSA < 10 ng/mL
< 10 years
≥ 10 years
• Active surveillance
• Active surveillance
• Radiation therapy
• Radical prostatectomy +/- Pelvic lymph node dissection
Intermediate - T2b-T2c
- Gleason score = 7
- PSA = 10 – 20 ng/mL
< 10 years
≥ 10 years
• Active surveillance
• Radiation therapy +/- Androgen deprivation therapy (4 to
6 months) +/- Brachytherapy
• Radical Prostatectomy +/- Pelvic lymph node dissection
• Radiation therapy +/- Androgen deprivation therapy (4 to
6 months) or Brachytherapy
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
30
31. Prostate Cancer Treatment Guidelines
Treatment by Recurrence Risk
Clinically Localized Therapy
High - T3a
- Gleason score 8 - 10
- PSA > 20 ng/mL
• Radiation therapy + Androgen deprivation therapy (2 – 3 years)
• Radiation therapy + Brachytherapy +/- Androgen deprivation therapy (4 to
6 months)
• Radical prostatectomy + Pelvic lymph node dissection (in select patients)
Treatment by Recurrence Risk
Locally Advanced Therapy
T3b – T4 with any Gleason
score or PSA level
• Radiation therapy + Androgen deprivation therapy (2 – 3 years)
• Radiation therapy + Brachytherapy +/- Androgen deprivation therapy (4 to 6
months)
• Radical prostatectomy + Pelvic lymph node dissection (in select patients)
• Androgen deprivation therapy (in select patients)
Metastatic Therapy
Any T, N1, M0
Any T, N, M1
• Androgen deprivation therapy
• Radiation therapy + Androgen deprivation therapy (2 – 3 years)
• Androgen deprivation therapy
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
31
32. Treatments for Prostate Cancer
Active Surveillance
Radiation Therapy
Radical Prostatectomy
Androgen Deprivation Therapy
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
32
33. How to Monitor Treatments
33
Once therapy is initiated, monitor for
progression/relapse:
For non-metastatic cases: obtain PSA every 6 –
12 months and DRE every year (optional if PSA
levels are undetectable)
For metastatic cases (N1 or M1): get physical
exam, PSA, and DRE every 3 – 6 months
Definition of relapse is specific to each
treatment
34. Overview: Active Surveillance
Active Surveillance (also called “observation”)
Active monitoring of disease with expectation to
intervene if the cancer progresses
What “active” means: periodic PSA, DRE, and/or
biopsy tests:
PSA at least every 6 months
DRE and/or biopsy at least every 12 months
Disadvantages/Adverse effects:
Anxiety (I’m just watching a tumor inside me…)
Cancer may progress/metastasize, cost more to treat
later, and cause more side effects
May miss a chance to cure
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
34
35. Active Surveillance Indications
Very low
< 20 years
≥ 20 years
Low
Active surveillance
Active surveillance
(or Radiation therapy, Radical prostatectomy
+/- Pelvic lymph node dissection
< 10 years
≥ 10 years
Active surveillance
Intermediate
< 10 years
Active surveillance
(or Radiation therapy +/- short-term Androgen
deprivation therapy (4 – 6 months) +/-
Brachytherapy
Clinically Localized Expected Survival Therapy
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
35
36. Active Surveillance
Only for clinically localized recurrence risk
Not done beyond intermediate risk and ≥ 10 years
life expectancy
Discontinue active surveillance when:
Patient experiences:
- Symptoms
- Increase In PSA
- Positive DRE
- Suspicious biopsy
Repeat clinical assessment
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
36
37. Overview: Radiation Therapy
Active Surveillance
Radiation Therapy (RT)
External beam radiation therapy: ionizing radiation
using X-ray beams of protons22,23
Radionuclide therapy: beta particles
Brachytherapy: Radiation is injected directly into tumor site
External beam radiation therapy Radionuclide therapy
Disadvantages Time-consuming Beta particles have a wide range
of effect (hence the side effects)
Adverse
effects
Sexual dysfunction, proctitis,
urinary and bowel problems24
Myelosuppression
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
37
38. Clinically Localized Expected Survival Therapy
Low
≥ 10 years Radiation therapy
(or Active surveillance, Radical prostatectomy +/-
Pelvic lymph node dissection
Intermediate
Radiation therapy +/- short-term Androgen
deprivation therapy (4 – 6 months) or +/-
Brachytherapy
High Radiation therapy + long-term Androgen deprivation
therapy (2 – 3 years)
OR
Radiation therapy + Brachytherapy +/- short-term
Androgen deprivation therapy (4 – 6 months)
(regardless of
expected survival)
Radiation Therapy Indications
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
38
39. Indications beyond clinically localized risk:
Locally advanced:
Used with either: long-term Androgen deprivation
therapy (2 – 3 years) or Brachytherapy +/- short-term
Androgen deprivation therapy (4 – 6 months)
Metastatic (to lymph nodes [N1]):
Used with long-term Androgen deprivation therapy (2
– 3 years)
Summary: indicated for all cases except very
low risk, and distant metastasis
Radiation Therapy Indications
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
39
40. Relapse in Radiation Therapy
Next treatment after relapse depends on metastasis
Relapse = increase in PSA ≥ 2 ng/mL or positive DRE
Relapse
Distant metastasis
No distant metastasis
Radiation therapy Androgen deprivation therapy
OR
Observation
OR
Clinical trial
Radical prostatectomy
OR
Observation
OR
Cryosurgery
OR
Brachytherapy
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
Androgen deprivation therapy
OR
Observation
Biopsy +
for cancer
Get biopsy
Biopsy -
for cancer
40
41. Overview: Radical Prostatectomy
Active Surveillance
Radiation Therapy (RT)
Radical Prostatectomy
Surgical removal of prostate
Done with pelvic lymph node dissection for certain
risks, or if predicted probability of lymph node
metastasis > 2 %
Adverse effects: Sexual dysfunction, proctitis,
urinary and bowel problems24
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
41
42. Radical Prostatectomy Indications
Indications are similar to those for Radiation therapy,
But not used in metastasis, or with Androgen deprivation
therapy
Recurrence Risk Expected Survival Therapy
Low
≥ 10 years
Radical Prostatectomy
(or Active surveillance, Radiation therapy)
Intermediate
Radical Prostatectomy +/- Pelvic lymph node
dissection
High /
Locally
Advanced
Radical Prostatectomy + Pelvic lymph node
dissection (in select patients with no fixation)
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
42
≥ 10 years
43. Relapse in Radical Prostatectomy
Next treatment after relapse depends on metastasis
Relapse = failure of PSA to reach undetectable
levels or detectable PSA that increases on two
subsequent measurements
Relapse
Distant metastasis
No distant metastasis
Androgen deprivation therapy
+/- Radiation therapy (to site of
metastasis/weight-bearing
bones/or symptomatic)
OR
Observation
Radical prostatectomy
Radiation therapy +/- Androgen
deprivation therapy
OR
Observation
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
43
44. Overview: Androgen Deprivation Therapy
Active Surveillance
Radiation Therapy
Radical Prostatectomy
Androgen Deprivation Therapy (ADT)
Bilateral orchiectomy (surgical castration of
testes)
Luteinizing-hormone releasing hormone (LHRH)
agonist or antagonist (medical castration)
It helps to review the hypothalamic-pituitary-adrenal
(HPA) axis to understand the rationale for ADT
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
44
45. Hypothalamic-Pituitary-Adrenal Axis
45
Hypothalamus secretes
LHRH
LHRH binds to receptors on
anterior pituitary
Anterior pituitary secretes LH and
Follicle Stimulating Hormone
(FSH), and adrenalcorticotropic
hormone (ACTH)
LH and FSH bind to receptors in
testes to produce androgens
ACTH binds to receptors in adrenal
glands to produce androgens
46. LHRH Agonists/Antagonists in Detail
Drug class Drugs in
class
Mechanism of Action Adverse Effects
LHRH agonist Leuprolide
Goserelin
Triptorelin
Gonadotropin releasing
hormone (GnRH aka LHRH)
competitively binds to
pituitary receptors, releasing
FSH and LH
Hot flashes, impotence,
reduced libido,
gynecomastia, tumor flare
LHRH
antagonist
Degarelix Gonadotropin releasing
hormone (GnRH aka LHRH)
competitively binds to
pituitary receptors,
preventing release of FSH
and LH
Hot flashes, impotence,
reduced libido, gynecomastia
Antiandrogen Flutamide
Bicalutamide
Nilutamide
Competitively binds to
androgen receptors
Hot flashes, impotence,
reduced libido,
gynecomastia, hepatotoxicity
- Specific for nilutamide:
night blindness, pneumonitis
46
47. Optimal ADT
Bilateral orchiectomy, LHRH agonist or antagonist?
Pick any one; all are equally effective
LHRH agonist should be used with antiandrogen
for at least one week
LHRH agonist initially increases production of
testosterone before achieving castrate levels
Initial increase is “tumor flare” and lasts ~1 week
Antiandrogen blocks AR receptor, preventing surge
47
48. ADT Indications
The only option for metastatic cases
Use with Radiation therapy when possible (category 1)
Short-term ADT (4 – 6 months), used optionally
with Radiation therapy
Intermediate
(regardless of
expected survival)
Long-term ADT (2 – 3 years) + Radiation
therapy
OR
Short-term ADT (4 – 6 months), used optionally
with Radiation therapy + Brachytherapy
OR (for locally advanced only)
ADT alone (in select patients)
High
Metastasis
Long-term ADT (2 – 3 years) + Radiation
therapy
OR
ADT
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
Locally
Advanced
48
49. “Castration-Resistant” Prostate Cancer
ADT is eventually used for prostate cancer
(whether due to relapse or recurrence risk)
Prostate cancer becomes refractory to ADT
Called “castration-resistant prostate cancer”
(CRPC)
Occurs within 12 - 18 months; mechanisms
include:16
Increased expression of AR
Increased expression of enzymes that synthesize
androgens
Utilization of other pathways to activate AR
Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65:1180-92.
16. Amaral TMS, Macedo D, Fernandes I, et al. Castration-resistant prostate cancer: mechanisms, targets, and treatment. Prostate. 2012;2012:1-11.
49
50. Treatments for CRPC
Determine whether CRPC has metastasized:
CRPC
Chemotherapy
Distant metastasis
No distant metastasis
Secondary hormone therapy
OR
Observation
OR
Clinical trial
PSA relapse
OR
Distant metastasis
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
50
51. First, maintain castrate levels of testosterone
Continue using LHRH agonist/antagonist
Secondary hormone therapy is an option; others
include observation and enrollment in a clinical trial
CRPC: Without Distant Metastasis
CRPC
Chemotherapy
Distant metastasis
No distant metastasis
Secondary hormone therapy
OR
Observation
OR
Clinical trial
PSA relapse
OR
Distant metastasis
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
51
52. CRPC: Secondary Hormone Therapy
52
None have shown improvement in overall survival
Decrease and maintain PSA response for a few months
Therapies Mechanism Adverse Effects
Antiandrogen Competitively binds to androgen
receptors
Hot flashes, impotence, reduced libido,
gynecomastia, hepatotoxicity (nilutamide;
night blindness, pneumonitis)
Antiandrogen
withdrawal
Unknown; may involve androgen
receptor mutation that uses
antiandrogen as an agonist
Withdrawal may allow some patients to
improve quality of life, and avoid adverse
effects of treatment
Ketoconazole Non-selective CYP17 inhibitor;
prevents androgen synthesis
Nausea, vomiting, hepatotoxicity, impotence,
reduced libido
Estrogen Prevents androgen synthesis by
inhibiting release of LHRH
Gynecomastia, weight gain, edema,
myocardial infarction, stroke
53. CRPC: Secondary Hormone Therapy
Secondary hormone therapies continued:
Therapies Mechanism Adverse Effects
Corticosteroids
(prednisone,
dexamethasone)
Prevents androgen synthesis in
adrenal glands
Edema, hyperglycemia, mood/appetite
changes, hypertension, osteoporosis
Aminoglutethamide Non-selective aromatase
inhibitor, and prevents androgen
synthesis by inhibiting conversion
of cholesterol to pregnenolone
Drowsiness, skin rash, hepatotoxicity,
fever, adrenal insufficiency
Megestrol acetate Progesterone receptor agonist,
and prevents androgen synthesis
by inhibiting release of LHRH
Weight gain, insomnia, impotence,
reduced libido
53
54. Treatments for CRPC
For metastatic or relapsing CRPC:
Chemotherapy is used once PSA relapse or
metastasis occurs
CRPC
Chemotherapy
Distant metastasis
No distant metastasis
Secondary hormone therapy
OR
Observation
OR
Clinical trial
PSA relapse
OR
Distant metastasis
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
54
55. First, maintain castrate levels of testosterone
Continue using LHRH agonist/antagonist
If bone metastasis, add denosumab or zoledronic
acid (recall the cycle of bone metastasis)
Both inhibit osteoclasts to delay bone resorption
CRPC: With Distant Metastasis
55
Yes
Metastasis
to bone?
CRPC
with distant
metastasis
No
Add denosumab or
zoledronic acid
Maintain castrate
levels of
testosterone
Determine if patient
has symptoms
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
56. CRPC: With Distant Metastasis
Then, pick a therapy based on whether patient
is symptomatic/asymptomatic:
Chemotherapy for CRPC with Distant Metastasis
Symptomatic Asymptomatic
Docetaxel (category 1) Sipuleucel-T (category 1)
Cabazitaxel Secondary hormone therapy
Abiraterone acetate Docetaxel
Mitoxanthrone Clinical trial
Radiation Therapy (palliative)
Clinical trial
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
56
57. Chemotherapy for Symptomatic CRPC
Docetaxel is first line
Demonstrated longest survival vs. others
Drug name Mechanism Adverse Effects Regimens
Docetaxel18,19
(category 1)
Antimitotic; binds to
tubulin, prevents
microtubule disassembly
Neutropenia, peripheral
neuropathy, edema,
alopecia, hepatotoxicity
75 mg/m2 IV over 1 hr
every 3 weeks with 5
mg prednisone BID
Cabazitaxel Similar to docetaxel Neutropenia, nausea,
vomiting, diarrhea
25 mg/m2 IV over 1 hr
every 3 weeks with 10
mg prednisone qd
Abiraterone21 Selective CYP17 inhibitor;
prevents androgen
synthesis
Hypertension, edema,
electrolyte disturbances,
hepatotoxicity
1000 mg orally QD with
5 mg prednisone BID
Mitoxanthrone20 Type II topoisomerase
inhibitor; prevents DNA
synthesis
Nausea, vomiting,
alopecia,
myelosuppression
12 mg/m2 IV over 30
minutes on day 1 with 5
mg prednisone BID
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
57
58. Chemotherapy for Asymptomatic CRPC
If asymptomatic cases, sipuleucel-T is first line
Class: autologous immunotherapy
Mechanism of action:
Uses patient’s own immune cells; white blood cells are
exposed to PAP – GM-CSF fusion protein (PAP is an
antigen expressed in prostate cancers; granulocyte-
macrophage colony-stimulating factor [GM-CSF] is a
growth factor)
Primed immune cells are injected back into patient
Adverse effects: chills, fatigue, fever, acute infusion
reactions
Administration: three doses, every two weeks
Give acetaminophen and diphenhydramine 30 minutes prior
National Comprehensive Cancer Network. Prostate Cancer (Version 3.2012). Available at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Accessed November 25, 2012.
58
59. Review
Be able to describe the pathogenesis and risk
factors, signs and symptoms for prostate cancer
Know how it is diagnosed, and when to screen
Choose treatment options for each recurrence
risk and what to do for relapses
Know the drugs
59
Maybe add a picture of 300 to illustrate testosterone
RANKL and OPG (OPG is decoy ligand that competes with RANKL) on osteoblasts binds to RANK found on osteoclasts. RANK binds and activates NF-Kb (found on most cells; normally chills in cytoplasm, then activated by things like IKK, then moves to nucleus and binds to genes)
Cite NCCN and NCI fact sheet.
from ACS detailed guide: If PSA is 4 - 10, then 25% of having cancer
We know how to diagnose, but when? Prostate cancer grows relatively slowly, and occurs in elderly men, who usually die from other causes and may not experience symptoms from cancer
PCPT trial (using finasteride): lasted 7 years, http://www.cancer.gov/newscenter/qa/2008/PCPTQandA
REDUCE trial (using dutasteride): lasted 4 years, http://www.cancer.gov/ncicancerbulletin/040610/page2
Vitamin E actually increased risk of cancer; selenium was not significant
http://www.ssa.gov/OACT/STATS/table4c6.html
Descriptions of stages: http://www.cancer.gov/cancertopics/pdq/treatment/prostate/HealthProfessional/page3
Staging is based on risk: MS-16
PSA levels can be BPH: http://www.cancer.gov/cancertopics/screening/understanding-prostate-changes/page1/AllPages#b2
Gleason score measures primary and secondary pattern. Each pattern can be 1-5 and there are two so hence, ranges from 2 - 10
Pelvic lymph node dissection if predicted probabiltiy of lymph node metastasis > 2 %
PROS-1 is summary of treatments
Now keep in mind that once you start therapy you don’t just leave the patient alone, you monitor for progression and relapse…
PROS-1 is summary of treatments
Pelvic lymph node dissection if predicted probabiltiy of lymph node metastasis > 2 %
PROS-1 is summary of treatments
PROS-1 is summary of treatments
Radical prostatectomy is not used with ADT because it was not shown to improve Overall Survival; radiation therapy has
PROS-1 is summary of treatments
LH and FSH Leydig cells make testosterone
Adrenal glands produce 5~10% of testosterone
ADT alone in select patients…when? For high/locally advanced
Why isn’t duration specified for ADT alone?
NCCN says maintain castrate level of testosterone after relapsing with CRPC after ADT
Info from Kirby et al.:
Prevalence: ~90% of men with CRPC have bone metastasis at diagnosis
Incidence: ~33% of men with CRPC develop metastasis within two years of diagnosis
Steroids as in dexamethasone, prednisone, etc…
Steroids as in dexamethasone, prednisone, etc…
Can give acetaminophen with aminogluthethamide to reduce fever
Steroids as in dexamethasone, prednisone, etc…
Mitoxanthrone demonstrated shorter survival compared to docetaxel
Abiraterone and cabazitaxel only studied in patients already treated with docetaxel, hence, they are not first line
Give with acetaminophen, diphenhydramine 30 min before injection to avoid infusion reactions and fever