Transcript Carcinoma of the Prostate Prevention, Screening, Diagnosis, and Treatment Roland T. Skeel, M.D.

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
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
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Gleason grading
DNA analysis by flow cytometry
PSA level
Predictive models for organ-confined versus
non-organ confined disease
Staging Prostate Cancer
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Abdominal and pelvic CT scans
Chest x-ray
Bone scan
LFT’s
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-α 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
T
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.
 1950’s – 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.
 1970’s – 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.