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Carcinoma of the Prostate

Prevention, Screening, Diagnosis, and


Treatment
Roland T. Skeel, M.D.

Conflict of Interest Disclosure


Neither I nor my immediate family members
have any Financial Interests or Significant
Relationships that might affect or reasonably
appear to affect this presentation on
Prostate Cancer

Objectives
List risk factors for prostate cancer, and
discuss relative strength
Discuss potential prevention strategies
Discuss benefits and risks of prostate cancer
screening, including expected survival rates
Counsel patients about primary treatment
options for local disease
Recommend systemic therapy for advanced
cancer.

Carcinoma of Prostate
Most common cancer in United States with
exception of skin cancer
Increases in new cases by 50% between 1980
and 1990
New cases in 2009 192,280 (Est.), 80 % early
disease
Deaths 27,360 (Est.)
Increasing number of non-lethal tumors being
diagnosed
1 in 6 will be diagnosed, 1 in 35 will die from it.
(10% of cancer related deaths in men.)

Survival Rates Prostate Cancer


5-year relative survival rate nearly 100%
10-year relative survival rate is 91%
15 year relative survival rate is 76%

Risk Factors for Prostate Cancer


Age Rare before 40; 65% over the age of 65
Race - More common in African-American men; more likely
diagnosed at advanced stage; 2x more likely to die of the
disease; less common in Asian-American and Hispanic-American
men than non-Hispanic whites.
Family History - 1st degree relatives, father, brother
Nationality - North America and NW Europe vs Asia, Africa,
Central and South America
Genetics BRCA1 and BRCA2 increase risk, but account for
very small percentage of prostate cancer
Obesity, Diet, Exercise, prostatitis, STDs, Vasectomy not much
effect, BUT.

Risk Factors for Prostate Cancer


Claimed by some studies
Diet
Red meat, high fat dairy products
Fruits, vegetables, grains

Exercise and maintaining healthy weight


may decrease the risk

Finasteride Chemoprevention for


Prostate Cancer
Finasteride = 5-alpha reductase inhibitor, blocks
intracellular conversion of testosterone to
dihydrotestosterone
Based on solid evidence, chemoprevention with
finasteride reduces the incidence of prostate cancer
(6% absolute; 25% relative risk reduction), but the
evidence is inadequate to determine whether
chemoprevention with finasteride reduces mortality
from prostate cancer.
Harms: erectile dysfunction, loss of libido,
gynecomastia, higher grade cancers.
Thompson IM, Goodman PJ, Tangen CM, et al.: The influence of finasteride on the development of
prostate cancer. N Engl J Med 349 (3): 215-24, 2003

Chemoprevention - Other
The Selenium and Vitamin E cancer
Prevention Trial was a large randomized
placebo-controlled trial of Vitamin E and
selenium, alone or in combination. It failed
to demonstrate that these drugs reduce
prostate cancer in relatively healthy men.
Lippman SM, Klein EA, Goodman PJ, et al.: Effect of selenium and vitamin E on risk of prostate
cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT).
JAMA 301 (1): 39-51, 2009

Early detection and screening


Digital rectal exam Feel for nodules
PSA How high?
Transrectal ultrasound not for screening
First two tests are convenient and
inexpensive, but consequences may not be

ACS, AUA, ACR, NCI Screening


Recommendations
No major scientific or medical organizations, including the
American Cancer Society (ACS), American Urological
Association (AUA), US Preventive Services Task Force
(USPSTF), American College of Physicians (ACP), National
Cancer Institute (NCI), American Academy of Family Physicians
(AAFP), and American College of Preventive Medicine (ACPM)
support routine testing for prostate cancer at this time.
In 2008 the USPSTF concluded that the risks of screening for
prostate cancer outweigh the benefits for men age 75 years or
older.
The ACS and AUA recommend that health care professionals
offer the option of testing for early detection of prostate cancer to
all men who are at least 50 years old (or younger if at higher
risk).

PSA and Prostate Cancer Risk


When prostate cancer develops, the PSA level usually
goes above 4. Still, a level below 4 does not mean
that cancer isn't present -- about 15% of men with a
PSA below 4 will have prostate cancer on biopsy. Men
with a PSA level in the borderline range between 4
and 10, have about a 1 in 4 chance of having prostate
cancer. If the PSA is more than 10, the chance of
having prostate cancer is over 50%

Confounding Factors for PSA


Increase

BPH
Age
Prostatitis
Ejaculation

Decrease
Finasteride, dutasteride
Some herbal mixtures
Obesity

Under investigation: PSA Density,


PSA Velocity, % free PSA
PSA Density - Normalized to prostate
volume
PSA Velocity - Change in PSA over time
(e.g., more than 15% per year)
Free PSA/Total PSA - lower ratio suggests
cancer, since more free PSA from normal
prostate is degradated (< 10% - biopsy)

Presenting Symptoms of Prostate


Cancer
Decreased urinary stream
Urinary frequency
Hematuria
Bone pain
LE numbness or weakness
Badder/bowel incontinence

Prostate Cancer: Remarkably Common With Many


Unanswered Questions
Understood:
Natural history
Prevalence
Patterns of spread
Questions:
Universal use of screening tests
Choices of therapy
Contributing factors

???

Sources: Nelson WG, DeMarzo AM, Isaacs WB. Prostate cancer. NEJM. 2003;349:366-381.

Aging and
Prostate Cancer
As men age, prostate cells
are increasingly likely to turn
cancerous
Autopsies reveal:
- Age 30-40: 29% prevalence
- Age 60-70: 64% prevalence
Bad News: American male has a 16.7% risk of being
diagnosed with prostate cancer
Good News: In most cases, the cancer cells are slow
growing and occur late in life only 3.5% of U.S males die
from prostate cancer
Sources: Nelson WG, DeMarzo AM, Isaacs WB. Prostate cancer. NEJM. 2003;349:366-381.
Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, et al. Prevalence of prostate cancer among men with a prostate-specific antigen
level 4.0 ng per milliliter. NEJM. 2004;350:2239-2245.

Why Has Diagnostic Progress Not Resulted


In Greater Long-Term Survival Rates?
Death rate is comparatively low considering prevalence
Lifetime risk of diagnosis: 1 in 6
Lifetime risk of death: 1 in 33
5-year survival rate: 98%
Diagnostic and therapeutic advances have improved quality of life, but not
necessarily the years of life
Risk is tied to age
- All ages: 17.7 cases per 100,000
- Age 75 to 84: 248 cases per 100,000
- Over 85: 591 cases per 100,000
Prostate cancer cells are generally less aggressive with increasing age,
suggesting many prostate cancers detected in routine practice may be
clinically unimportant
Sources: Mayo Clinic.com. Prostate Cancer Guide. Available at: http://www.mayoclinic.com/health/prostate-cancer/PC99999.
Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, et al. Prevalence of prostate cancer among men with a prostate-specific antigen
level 4.0 ng per milliliter. NEJM. 2004;350:2239-2245.

Use of PSA Testing is a Double-Edged Sword


Illustrates challenges of using imperfect markers/surrogates
to indicate disease.
Although the use of PSA testing in the United States has led to earlier
diagnosis and a marked shift in the stage at which prostate cancer is
identified, it is unclear whether PSA testing reduces the rate of death from
prostate cancer.

Clinical experts

Unresolved dilemma:
Over-treating clinically unimportant disease revealed by PSA testing

vs.
Under-treating clinically important disease that goes undetected
without extensive use of PSA testing

Sources: Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, et al. Prevalence of prostate cancer among men with a prostate-specific
antigen level 4.0 ng per milliliter. NEJM. 2004;350:2239-2245.

PSA Levels and Their Predictive Value for Diagnosis

Other conditions besides prostate cancer can increase PSA levels


infection
inflammation
benign growths
2004 Study of men: PSA never above 4ng/ml; no abnormal rectal exam

Percent with prostate cancer


26%
24%
17%
10%
7%

PSA level (ng/ml)


3.1 to 4.0
2.1 to 3.0
1.1 to 2.0
.6 to 1.0
less than .5

In those with cancer and low PSA levels, 12.5% had aggressive, rapidly multiplying
high-grade tumors likely to spread.
Sources: Cooner WH, Mosley BR, Rutherford CL Dr. et al. Prostate cancer detection in a clinical urological practice by ultrasonography, digital rectal
examination and prostate specific antigen. J Urol. 1990;143:1146-52. Cited in Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, et al.
Krumholtz JS, Carvalhal GF, Ramos CG, et al. Prostate-specific antigen cutoff of 2.6 ng/mL for prostate cancer screening is associated with
favorable pathologic tumor features. Urology. 2002;60:469-473.

Economics of Treating and Screening For the


Disease
Cost of treating prostate cancer in California
$360 million per year
Cost of universal screening (as previously recommended by ACS)
approximately $12.7 billion per year
Savings from increased diagnosis at earlier stages, minus increased costs from
pursuing false positives or occasional high-grade tumors
with false negative PSAs remains to be explored.
Against PSA Screening (all men 50+)
American Urological Association
American Cancer Society

National Cancer Institute


U.S. Preventive Services Taskforce

Sources: Max W, et al. The economic burden of prostate cancer in California. Cancer. June 2002;94:2906-13.

What Can We Learn?

1. Markers are imperfect predictors requiring a strong


understanding of the upsides and downsides when used
2. Prevention requires screening screening often
relies on markers
3. Answer is not to throw away markers, but learn from
and improve them

Effect of Early Diagnosis


Unknown: In areas where there is aggressive screening, the
incidence in higher than where there is not; the death rate
from prostate cancer is similar
Randomized trials to test screening underway
Conclusion:
Do not screen over age 70, or if life expectancy < 10 years
Do not screen under age 60, unless strong family history
Recognize limitations age 60-70

Prostate Cancer Survival


Related to
Stage
Grade
Extent of tumor at diagnosis

Local disease - Median Survival > 5 years


Metastatic disease Median Survival 1-3 years, but
individuals may survive 10 or more years

Establishing a Diagnosis of
Prostate Cancer

DRE
PSA/PSA velocity/percent-free PSA
Transrectal U/S
U/S- guided biopsy

Evaluation of Abnormal PSA or


Prostate Mass
Ultrasound guided needle biopsies (6-12)
If positive, Gleeson score (2 predominant
histologies). Range - 2 (1+1) to 10 (5+5)
2-4 - Best
5,6 - Intermediate
7-10 - Worse

PSA < 10, rarely have detectable metastatic


disease

What Does the Grade


of the Tumor Mean?
Grade of a tumor is predictive
of its likelihood to spread
beyond confines of the prostate,
affecting curability.
12% of low-grade tumors (2-4)
spread beyond prostate in 10 years
33% of medium-grade tumors (5,6)
spread beyond prostate in10 years
61% of high-grade tumors (7-10)
spread beyond prostate in 10 years

Sources: Mayo Clinic.com. Prostate Cancer Guide. Available at: http://www.mayoclinic.com/health/prostate-cancer/PC99999.


Prostate Cancer in California. Ed. Mill PK. Public Health Institute. 2000.

Staging and Prognostic Factors


TNM staging system
Prognostic Factors

Gleason grading
DNA analysis by flow cytometry
PSA level
Predictive models for organ-confined versus
non-organ confined disease

Staging Prostate Cancer

Abdominal and pelvic CT scans


Chest x-ray
Bone scan
LFTs
Serum PSA and acid phosphatase

Staging Prostate Cancer


Stage I - T1a and grade 1 (Incidental, early)
Stage II T1a and Grade 2-4; T1b,c (By biopsy only)
T2 (Confined to Prostate)

Stage III - T3 (Through prostate capsule)


Stage IV - T4 (Invades adjacent structures), N1-3,
M1

Recurrence Risk for Clinically


Localized Prostate Cancer
Low Risk:
T1-T2a and Gleason score 2-6 and
ng/ml

PSA < 10

Intermediate Risk:
T2b-T2c or Gleason score 7 or PSA 10-20

High Risk:
T3a or Gleason score 8-10 or PSA > 20

Very High Risk:


T3b-T4(locally advanced)

Treatment Decisions for Clinically


Localized Prostate Cancer
Based on recurrence risk (Low,
intermediate, or high) and
Life expectancy (<10 years vs > 10 years).

Prostate - Goals of Therapy


Primary Therapy
T1a - Except in very young (< 60), follow with no therapy
T1b, T1c, T2 - radical prostatectomy or high dose
radiation therapy. (May also observe if low-grade)
T3 (Stage III) - Usually treated with radiation therapy
Metastatic - Treat when symptoms.
In high risk disease, may add hormonal therapy

Radical Retropubic Prostatectomy (RRP)


Nerve Sparing procedure developed by Walsh
consisted of modified surgical technique to control
blood and enhance visibility within surgical site.
Allowed for the identification and potential
preservation of the nerves that control erectile
function (potency).
Two neurovascular bundles on either side of the
prostate that control erectile function.

The Da Vinci Robot


Surgeon operates from a
console with a 3-D screen.
Grasp controls to manipulate
surgical tools within the patient.
Robotic arms translate finger,
hand, and wrist movements.
Very High-Precision

http://www.intuitivesurgical.com

Radiation Therapy (RT)


High-Powered X-Rays that damage DNA
and kill prostate cancer cells.
1. External Beam Radiation Therapy (EBRT):
X-rays aimed at prostate.
2. Brachytherapy: Radioactive seed implants
into prostate.

External Beam Radiation


Goal: Maximize damage to the prostate
and minimize damage to surrounding
tissues (i.e. bladder and rectum)
Seminal
Vesicles

Prostate

Brachytherapy: Distribution
Cross-Section of Prostate
Urethra

Uneven
Distribution

Ultrasound-guided
bead placement for
even distribution

Image of Prostate With Radioactive


Bead Implants

RT: Complications
EBRT
Most symptoms occur during treatments and
subside after completion.
Diarrhea, rectal irritation, fatigue, frequent and
painful urination, blood in the urine.
Erectile dysfunction: less common than radical
prostatectomy following treatment but slower
recovery.

RT: Complications
Brachytherapy
High initial dose of radiation that slowly fades over
1 year.
Prostate inflammation and swelling, sometimes
with severe urinary symptoms.
Other, more rare symptoms include persistent
urinary and bowel frequency and urgency.
Erectile dysfunction: similar to EBRT.

Watchful Waiting
A.K.A. observation, expectant therapy or
deferred therapy.
Diagnosis of an early-stage (T1-T2), lowgrade tumor.
No medical treatment is provided.
Patient receives regular follow-up to
monitor tumor.

Why Wait?
PSA and DRE can detect prostate cancer at a very early
stage.
Average doubling time of a prostate tumor is quite slow (2-4
years).
Immediate radical therapy may constitute over-treatment and
an introduce unnecessary urinary and potency risks.
May be appropriate if the patient is elderly and/or in poor
health, and will live out their life spans without the cancer
causing problems.
May also be appropriate for a younger patient who is willing to
be vigilant and accept the risk of the cancer spreading.

Treatment of Symptomatic
Metastatic Disease
1. Hormonal Therapy - initial therapy for
locally advanced or metastatic disease

Orchiectomy
Estrogens (No longer used)
LHRH analogs (+/- anti-androgens)
Antiandrogens + finasteride
Second line therapies consist of one of
therapies not used before, e.g., anti-androgens
if used only LHRH analogs

Hormone Therapy
Prostate cells and prostate cancer cells are dependant upon
androgens (male sex hormones) for survival and growth.
Removal of androgens kills a majority of prostate cancer cells.

Testosterone

95%

Testes

Prostate
Growth and
Function

Adrenal
Androgen
5
%

Adjuvant Hormone Therapy


Hormone therapy (androgen ablation) is a
standard method of treating advanced and
metastatic prostate cancer.
However, for newly-diagnosed advanced cancers,
androgen ablation may be performed prior to
prostatectomy or radiation in order to shrink the
tumor.
The effectiveness of this technique is still under
debate.

Removing Androgens
1.
2.
3.
4.
5.

Orchiectomy (castration): surgical removal of the


testicles.
Oral drug which has the same effect as castration.
Blocks testosterone production. Include LHRH
agonists and (oral estrogens).
Anti-androgens which block the effects of
testosterone. (Blocks binding of DHT to androgen
receptors.)
5- reductase inhibitor (enhances intracellular
androgen blockade)
Combination therapies.

LHRH Analogs
Goserelin (Zolodex)
Leuprolide (Lupron)
Available as every 1, 3, or 4 month
injections
Castrate levels of testosterone attainable in
a few weeks

Antiandrogens
Flutamide
Bicalutamide
Nilutamide
Combined androgen blockade not superior to
LHRH therapy alone
Higher cost and more side effects than LHRH
therapy alone
Primary value when starting LHRH to limit the
flare reaction

Finasteride and bicalutamide as primary hormonal


therapy in advanced adenocarcinoma of the prostate

Duration of control comparable to


castration, with preserved sexual function
in some patients
With recurrence, some patients may still
respond to LHRH agonists

Tay, MH et al. Annals of Oncology 15:974, 2004

Results of Androgen Removal


Impotence
Loss of sexual desire (libido)
Hot flashes
Weight gain
Fatigue
Reduced brain function
Loss of muscle and bone mass
Some cardiovascular risks

Hormone-Refractory Prostate Cancer


(HRPC)
Despite initial response rates of 80-90%, nearly all
men with advanced prostate cancer develop
hormone-resistant prostate cancer after 18-36
months.
These hormone-refractory (HR) prostate cancer
cells can grow in the absence of androgens.
The behavior of HR prostate cancers differ widely
between patients.

Treatment of Symptomatic, Hormone


Refractory Metastatic Disease
1. Cytotoxic chemotherapy
Docetaxel (every three weeks) and prednisone
improves pain and reduces need for analgesic agents
Mitoxantrone
Other agents have had limited effectiveness
Continue hormone therapy to prevent flare with rising
testosterone levels.
2. Bisphosphonates - decreases skeletal complications

Treatment of Symptomatic
Metastatic Disease
3. Radiation therapy
External beam radiotherapy
Radioisotopes, such as Strontium 89

Evaluation of Response
PSA and Acid Phosphatase are useful in
selected circumstances
Bone scans are difficult, because increase
can be seen in healing as well as
worsening

Complications of Systemic Prostate


Cancer Therapy
All hormonal therapies can cause sexual
dysfunction and decreased libido; less with
finasteride and anti-androgen
Orchiectomy - rarely local infection or hematoma
Anti-androgen - diarrhea, hepatic dysfunction
Estrogen - thromboembolic disease, fluid retention,
cardiac disease
Chemotherapy - nausea, vomiting, mucositis,
marrow suppression, and alopecia

Management of Prostate Cancer Bone


Metastases
Goal: prevent pain, improve mobility,
prevent complications such as fractures or
compression.
Goal: Maintain acceptable quality of life.
Methods: bis-phosphonates, radiation of
detected metastatic lesions, surgery.

Conclusions
Risk factors are age, family history, race, and possibly diet
and exercise
Overall survival excellent (many years)
Early detection can find localized cancer, but survival
benefits still uncertain
Treatment depends on grade, extent and location of disease
Surgery and radiation are equivalent therapeutic tools for
localized prostate cancer
Hormonal therapy is effective for metastatic prostate cancer
Hormone refractory prostate cancer responds to
chemotherapy, with occasional long term improvement.

History of the Prostatectomy


Hugh Hampton Young (Johns Hopkins)
pioneered a systematic technique and
performed the first radical perineal
prostatectomy in 1904.
1943 - Theodore Millin introduced the
retropubic prostatectomy approach.
1983 Patrick Walsh described a
modified nerve-sparing retropubic
approach to preserve potency.

The Nerve Bundles


Cross-Section
of Prostate
Urethra
Prostate

Rectum

Neurovascular
Bundles of
Walsh

RRP: The Surgical Surgical


Approach

1.5-4 hours, usually


epidural anesthesia.
Incision:
Begins just below
navel and extends to
pubic bone.

Remaining Urethra
is sewn to bladder
neck over a catheter.

Approach

Pelvic
Bone
(Pubis)

Bladder
Rectum

Urethra

Prostate

RRP: Complications
Severe or life-threatening complications are
rare.
Incontinence (Urinary Control): complete
incontinence is uncommon, although a
significant number of patients experience some
stress-incontinence. Usually improves with
time.
Impotence (Erectile Dysfunction): if both
neurovascular bundles were spared, potency
rates range from 30-86%, depending on
institution. Usually improves over time, and
other ED treatments can work.

RRP: Advantages
Whole prostate - and thus the entire tumor can be examined histologically.
Surgeon has access to regional lymph nodes to
test if prostate cancer cells have left the
tumor.
Surgical margin can be examined.
T

Negative
Surgical
Margin

OR

Positive
Surgical
Margin

Not all
of tumor
removed

Radical Perineal Prostatectomy


Very similar to
Retropubic protocol
Pelvic
(nerve sparing, sewing
Bone
of urethra, etc.)

Prostate
Bladder

(Pubis)

Rectum

Incision:
Between Anus and base
of Scrotum.

Urethra

Surgical
Approach

Perineal Prostatectomy
Comparison with RRP: Comparable cure
rates as well as similar urinary and
potency complications.
Disadvantages:
Cannot access regional lymph nodes
Slight increase in risk of rectal injury and
associated complications.

Emerging Therapy: Laparoscopic


Radical Prostatectomy
Eliminates the need for a
large incision by using a
telescopic instruments
called a laparoscopes.
Small camera attached to
the laparoscope allows the
surgeon to view inside the
abdomen.

Laparoscopic Prostatectomy
Advantages:
Less blood loss.
No large incision.
Shorter hospital stay and earlier return to activities.

Disadvantages:
Longer procedure
Variable surgical margins rates.
Slower return of urinary continence.
Variable potency rates.

General Procedure:
EBRT and Brachytherapy

EBRT:

1.
2.

Map precise area that will receive radiation.


Multiple treatments ~5 days/week for ~8 weeks.
Each treatment takes about 10 minutes and no
anesthesia is required.

Brachytherapy

1.

2.

40-100 rice-sized radioactive seeds are implanted


into the prostate via ultrasound-guided needles.
Anesthesia is required.
All radiation inside the pellets is generally
exhausted within a year.

History of Radiation Therapy


1898 The first use of newly discovered Xrays was to alleviate the pain of pelvic bone
metastases.
Early use of external beam radiation therapy
was limited because of power necessary to
reach deep-seated cancers such as prostate
cancer.
1950s New and more powerful isotopes and
machines were discovered and built.
Today Computers and improved radiation
technologies allow high-dose and high-precision
treatment of prostate tumors.

History of Brachytherapy
1909 Minet first placed a radium tube in a
catheter to irradiate prostate cancer.
1970s Real interest occurred when Whitmore
described an implant technique using I-125.
Inconsistent dose distribution was a problem.
1985 Holm and Ragde used TransRectal
UltraSound (TRUS) to position Pd-103 implants
and established a national brachytherapy
implant course.

Cryotherapy
Destroys prostate cells by freezing tissue.
Old idea that is making a comeback due to greater
precision and better methods of imaging and
temperature monitoring.
Method: insertion of sub-zero cryoprobes into
prostate perineally (between scrotum and anus).
As yet unresolved how effective cryotherapy is
compared to surgery or radiation.