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ACOFP 53rd Annual Convention & Scientific Seminars
Prostate Cancer Update 2016
Ronnie Martin, DO, FACOFP dist.
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Name of CME Activity: ACOFP 53rd Annual Convention and Scientific Seminars
Dates and Location of CME Activity: April 6-9, 2016, The San Juan Puerto Rico Convention Center
Your presentation: Friday, Apri
2016 7:00am-8:00am; Men's Health: Prostate
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Ronnie Martin, DO, FACOFP, dist.
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Deadline: Friday, January 15. 2016
3/17/2016
Prostate Cancer Update 2016
Ronnie B. Martin, DO, FACOFP
Dean Liberty University College of
Osteopathic Medicine
Prostate cancer

33% of the none cutaneous malignancy’s in men in
USA.

2nd most common cause of cancer deaths in men.

In 2015 expected >220,000 newly diagnosed cases in
the U.S.

27,500 will die of P-Ca 2015, less than 2005 in spite of
increased diagnosis of disease.
Prostate cancer

Ethnic and genealogical propendency:
– African Americans having highest incidence in world (224 cases
per 100,000 vs. White Americans at 150/100,00, Japanese at
8.5/100,000 and Chinese at 1.1.
– Genetic link with familial pattern demonstrated
– Environmental link less clearly established
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Prostate cancer diagnosis peaked in
1993 at > 350,000 with advent of PSA
testing.
 Lifetime odds of developing P-Ca is 1:8
to 1:14.
 Mortality from prostate cancer declined
2.6% each year 1990 to 1998 but has
plateaued since then.

Prostate cancer

Identified risk factors include:
– Advancing Age



While q.s. 20% Men < 40 demonstrate
histological evidence of CA, clinical disease rare
20-30% of men > 50 have histological
evidence of disease
> 50% of men > than 80 years of age have
histological disease
Prostate cancer

Identified risk factors include:
– Family History


Men with first degree relatives with P-CA have
2 to 3 fold increase risk, men with two or more
first degree relatives have 5 fold increased risk.
Familial prostate cancer estimated 5 to 10% of
total cases and q.s. 50% of cases in men less
than 55 years old.
– Genetic Factors

Androgen receptor gene CAG sequence repeats
(AA have fewer repeats)
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General Information

Rarely found in men younger than 40

Vasectomy - recent studies have not found
increased risk

No correlation with BPH
Prostate cancer

Identified risk factors include:
– Diet


Red meat, animal fat and higher total fat, and
high calcium intake all increase risk.
Lycopene, selenium, fatty fish, Vitamin E, soy
and Vit. D may help decrease risk
– Hormone Levels

Androgen level elevation, especially free
testosterone, increases risk
Screening for Prostate Cancer

Goal is to detect organ confined prostate
cancer (potentially curable stage).

Digital Rectal Examination is foundation
of diagnosis but inadequate alone:
– Interpretation variable among physicians
– majority of cancers not palatable before
metastatic.
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Screening for Prostate Cancer

Prostate Specific Antigen:
– Produced by both normal and malignant prostate
epithelial cells (rate of release into serum in P-CA
is 30x higher)
– Also produced by seminal vesicles, breasts,
adrenals, parotid, etc.
– Elevated by inflammation, infection, ejaculation,
instrumentation, trauma, and increased gland
mass such as found with BPH

BPH is most common cause of elevated serum PSA.
PSA


Normal range 0 - 4 ng/ml ( Complexed measurement)
“gray zone” 4 - 10 ng/ml
– Chances of finding CA in this “gray zone” ranges from 25 to
30%
– Recommended that you perform free PSA when levels in gray
zone if no other findings.
Predictable CA (> 60%) when PSA > 10 ng/ml
Can obtain these levels from BPH, prostatitis,
orchitis, etc.
Can make more specific with calculations such as:
Free PSA
– PSA velocity
– PSA density
Screening for Prostate Cancer

Screening for prostate cancer combines
use of PSA and DRE
– Today, more cancers detected are organ
confided with use of combined diagnosis
techniques and more screening.
– PSA will detect CA an average of 5.5 years
before clinical detection alone.
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Screening for Prostate Cancer

American Urological Society recommends shared
decision between Doctor and patient about annual
DRE and PSA for men older than 55 who otherwise
have a life expectancy of >10 years.
– Epidemiological studies do not support implementation of
routine PSA screening of low risk asymptomatic men under
40-54.
– Screening is not indicated for men >69 or those with less
than 10 year life expectancy, recognizing that some men >
70 with projected life expectancy > 10 years may benefit.

If PSA is < 2.5 then screening if elected should be
done no more often then every two years.
Screening for Prostate Cancer

High Risk Patients: especially African American Males
and those with family history, screening may begin as
early as age 40 or < 54 years of age
– Annual screening being challenged, some recent megaanalysis show that screening at 40 and if normal again at 45
and then only every 2 years produce less morbidity and
similar mortality outcomes.
Problems with PSA and DRE
Combined Screenings

Lack of specificity between 4 and 10 leads to mix
results:
– Unnecessary treatment for insignificant cancers with
increased morbidity and cost.
– Most levels in this range are BPH on biopsy



morbidity and cost of biopsies is significant.
PSA > 10 generally CA but also most often organ
confined cancer.
10-15% of P-CA will have PSA level of < 4 and will
not be palpated by DRE.
– These malignancy’s tend to higher grade as well.
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Compensations for PSA

Age specific PSA:
– Especially important in younger men where
threshold of 2.6 ng/ml has been advocated for
men < 50.
– Less sensitivity in older men if raise level and may
miss non organ confined disease if > 4 ng/ml.

Race Specific PSA:
– AA males have base line levels higher than white
males.
Compensations for PSA

PSA Velocity:
– Measure rate of increase in PSA.
– Doubling time is correlated with mortality and morbidity as
well as response to therapy.
 Especially useful in younger men with normal or “grey
area” PSA readings.
 PSA increase of > 2.0 ng/ml in year prior to surgery was
significantly associated with lymph node metastases and
high grade disease and higher mortality, reoccurrence.
 PSA doubling time found to be independent predictor of
time to development of metastatic disease. < 3 month
doubling time was significantly associated with death
from prostrate cancer ( 20x the risk of other patients).
Compensations for PSA

PSA Density:
– Higher PSA/volume of gland with CA is supposed to reflect
more accurately elevations.


Problem is measurement of gland volume via TRUS and few
studies have documented value.
Free PSA:
– Percentage of PSA not bound to serum proteins.
– Normally 30-40% of total.
– Men with P-CA have less free PSA and higher levels of
complexed PSA.
– The lower the % of free PSA, the more likely malignancy.
– With threshold of 20-25% of Complexed PSA, accurate 90%
of time in predicting cancer.
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Partin Tables, Kattan Nomogram,
D’Amico’s Model
Prognostic models that combine 3 or more
independent variables, useful in predicting outcomes
and may direct management.

– Partin utilizes PSA, clinical stage and Gleason score to
predict organ confined disease vs. cancer spread to seminal
vesicles or lymph nodes.

Accurate in independent studies to stage tumor 70-80% of the
time.
– D”Amico uses preoperative PSA, Gleason, AJCC tumor stage
to predict 10 year PSA failure free survival post radical
prostatectomy.


10 year PSA free rate in those classified as low risk was 83%,
46% in those in intermediate risk and 29% in those in high risk
categories.
Patients may live years after reappearance of PSA.
Disease Markers Under
Investigation:
IGF-1--Insulin like growth factor,
increase associated with P-CA
 Prostate specific membrane antigen –
PSMA—Detected with ProstaScint, may
discriminate BPH, CA and no disease.
 Telomerase activity—present in majority
of CA patient but not in benign prostate
tissues.

Prevention of Prostate CA

Study using finasteride, a 5-alpha
reductase inhibitor that lower
testosterone conversion to DHEA
demonstrate ~25% reduction in
prostate CA after 7 year follow up.
– Those cancers that did develop were much
higher grade and aggressive
– Side effects were significant and often
precluded completion of study.
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Diagnosis of Prostate Cancer

Prostate Biopsy is cornerstone:
– Generally do a min. of 6 biopsies to cover all areas
of gland
– Indicated with elevated PSA, abnormal DRE or
both.

Biopsies are guided by Trans-Rectal U.S.
– TRUS by itself is not reliable screen or diagnostic of
P-CA.
– TRUS helpful in determining volume of gland and
calculating volume adjusted PSA.
Pathology
Overwhelming adenocarcinoma,
occasional small cell or sarcoma
 70% of prostate cancers arise in the
peripheral zone
 15 - 20% arise in the central zone
 10 - 15% arise in the transition zone

Pathology - Gleason Grading
System







Based on glandular disorganization in architecture on
examination of biopsy.
Tumors are graded 1 to 5 and total of the two most common
added together to get Gleason Score.
2 - 4 well-differentiated
5 - 7 moderately differentiated
8 - 10 poorly differentiated
Utilization limited by rarity to get score of less than 6.
Clinically differentiation is:
– Low grade< 6.
– Intermediate grades 6 to 8
– High grade > 8

For staging and prognosis charts.
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Staging of Prostate Cancer

Purpose is to determined if organ confined
(thus potentially curable) or not organ
confined.
– Local spread to capsule, seminal vesicles and local
lymph nodes
– Disease’s tendency is to metastasis to bone, lymph
nodes

Rare today to make diagnosis through evidence of boney
mets.
– Rarer to have metastasis to visceral organs such
as lung or liver
Staging of Prostate Cancer
Clinical Staging:
 Localized tumors are T1 and T2.

– Potentially curable with surgery or radiation.

Local advanced tumors are T3 and T4.

Today, with aggressive utilization of PSA,
most commonly cancers detected are non
palatable T1c cancers.
– Rarely curable by surgery or radiation alone
Multifactorial Staging of Prostate
Cancer

Combines use of clinical staging,
Gleason score and serum PSA level.
– Useful to determine if low, moderate or
high risk of relapse after therapy.

Prognosis worse if PSA increased by
more than 2 ng/ml in year preceding
diagnosis of P-CA
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Multifactorial Staging of Prostate
Cancer

Bone Scan, and MRI or CT useful in
patients with prostate CA and serum
PSA level > 10 ng/ml, Gleason score 7
to 10 or who have T3 or T4 tumors to
find regional lymph node and boney
spread.
Symptoms of Prostate CA

P-CA rarely causes local symptoms until
very large or advanced.
– S/S are more common with BPH.





urinary hesitancy
post void dribbling
urinary retention
hematuria
incontinence
Metastatic Prostate CA Symptoms
Bone pain
Neurological symptoms secondary to
cord compression
 Pathologic fractures


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Treatment for Prostate CA:
Observation Indications & Natural
Progression



In cases with high grade tumors (Gleason
score >/= 7) and patient < 74, the patient
should be treated.
All tumors with Gleason score of >/= 7
should be considered high grade tumors and
should be treated.
Patient’s age at diagnosis appears to have
little impact on 15 year mortality regardless
of low grade or high grade tumor.
Treatment for Prostate CA: Natural
Progression and Observation


Age at diagnosis can lead to determination of
treatment if locally confined.
10 year prognosis same with treatment or
without treatment is essentially the same in
the Connecticut Tumor Registry Study and the
SEER date bases (Surveillance, Epidemiology,
and End Results database):
– 70 year old man has 13.6 years of life expectancy.
– 75 year old man has 10.8 years of life remaining
– 80 year old man has 8.1 years of life remaining
Treatment for Localized
Prostate Cancer (T1 &T2)

Treatment decisions generally made by
patient based on physicians bias since
there is an absence of randomized
studies showing a therapeutic
superiority for surgery or radiation
therapy present in compatible
populations.
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Treatment for Localized
Prostate Cancer (T1 &T2)

Radical Prostatectomy
– Most common treatment in US for localized disease
– Retropubic approach most common since allows possibility
of lymph node dissection [extended pelvic
lymphadenectomy], preservation of nerves and wide
resection margins.
– Side effects and complications of urinary incontinence ( 535% of patients), sexual dysfunction (50-75% of men)
largely based on skill of surgeon
– Use of nerve sparing techniques, robotics et al have
improved co-morbidities, blood loss, side effect static's but
only a little.
Treatment for Localized
Prostate Cancer (T1 &T2)

Radiation Therapy
– Computer aided 3-D conformal treatment available
today allows higher doses than traditional 7000
rads, fewer side effects and better chance of cure
today.
– Side effects and efficiency both considerations
– Rectal injury’s seen more commonly than with
surgery with tenesmus, proctitis, colitis, bleeding
et al.
– Urinary incontinence (including urgency,
frequency, hematuria) and erectile dysfunction
less common than produced by surgery but still
present in majority of patients.
Treatment for Localized
Prostate Cancer (T1 &T2)


Observation:
Low risk patients, localized tumor, low
combined Gleason and PSA scores.
– Outcome at 10 years same with NO
treatment as with radiation or surgery in
meta analysis of studies.
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Treatment for Localized
Prostate Cancer (T1 &T2)

Brachytherapy:
– Implantation of I-125 (slower growing) or
Palladium 103 (higher grade tumors) seeds into
tumor.
– Advantage: Ease of treatment (one step),
favorable toxicity profile
– Concerns: May leave “cold spots” that allow
cancer persist or grow.
– Better static's in intermediate and high risk
patients if combined with external radiation and
hormone manipulation.
Treatment for Localized
Prostate Cancer (T1 &T2)

Cryotherapy
– Becoming utilized again with better probes and
less localized damage due to technique. Works by
local destruction and possibly activation of
immunological system

Hormonal therapy
– More commonly adjunctive therapy in early stages
because of anticipated loss of response and
chance of cure with other therapy.
– More common as palliative therapy in advanced
cases in USA.
Management of Intermediate Risk
Patients


Higher cancer volume, occult metastatic risk higher
or spread already apparent.
Surgery is still curative in locally spread cases about
50% of the time.
– Little benefit demonstrated by using androgen ablation
before surgery to reduce tumor size.


Combined external beam radiation and brachytherapy
used in some cases with mixed results.
Combined external bean radiation and androgen
ablation has been shown to provide survival benefit
in intermittent risk patients.
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Adjunctive Therapy and Relapse
Therapy:

Radiation after surgery is beneficial for:
– Adverse pathological finding such as not clean margins,
capsular penetration, seminal vesicle involvement.

Rising PSA post operatively is indication for radiation
adjunctive therapy &/or hormonal manipulation:
– Prognosis is predicted by several factors:


time to rise in PSA (> 2 years better)
Serum PSA < 1 ng/ml at time of salvage radiation therapy
Adjunctive Therapy and Relapse
Therapy:

Androgen ablation has been useful after
surgery or radiation.
– Three years of androgen deprivation
therapy demonstrated statically significant
improvement in outcome in men treated
with radiation in recent European study.
Management of Patients with
Advanced or Metastatic Cancer (T3
or T4)
Local therapy alone rarely curative,
therefore the morbidity of surgery
rarely justified.
Most treated with combined androgen
ablation followed by external beam
radiation therapy.
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ANDROGEN ABLATION THERAPY
Prostate cells require androgen for
growth and survival
 Two mechanism of therapy:

– Lower the production of testosterone
– Blockage of the binding to androgen
receptor
ANDROGEN ABLATION THERAPY



PSA drops rapidly
Symptoms from metastases lessen or disappear
rapidly
Androgen ablation is palliative rather than curative.
– Duration of response, dependent on androgen sensitivity of
the tumor, before first rise in PSA being noted is generally 12
to 18 months if patients had metastasis at initiation of
treatment, much longer if no metastasis present.
ANDROGEN ABLATION THERAPY


Castration: Surgical or chemical.
Orchiectomy
– Often not well received by many patients due to
emotional trauma, side effects, sexual deficits, hot
flashes, loss of muscle tone, weight gain etc.

LH-RH Agonists – block production at pituitary
of releasing hormones and thus decrease
production of testosterone at end organ.
– Leuprolide (Lupron) , Goserelin (Zoladex)
– Administered every 1 to 4 months
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Side Effects of LH - RH Agents








Hot flashes
Night Sweats
Testicular atrophy
Sexual dysfunction; decreased libido and impotency
Nausea
Gynecomastia
Weight Gain (adipose fat leads to risk of diabetes)
Loss of bone and muscle mass with resultant
osteoporosis, fractures, etc.
ANDROGEN ABLATION THERAPY
Antiandrogens – Flutamide (Eulexin),
Bicalutamide (Casodex) and Nilutamide
(Nilandron)
 Inhibits androgen uptake and binding to
androgen receptors.

Timing of Ablation Therapy

Early androgen suppression has been
shown to reduce disease progression
and related complications and slightly
improve 10 year survival rate in patient
who had either surgery or radiation for
locally advanced or metastatic prostate
cancer.
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Optimal Androgen Deprivation
Therapy


Antiandrogen monotherapy appears to be
inferior to LHRH agonist, orchiectomy or
estrogens alone in patients with know
advanced disease.
Recent study analysis have concluded that if
combined androgen blockade [use of
leuprolide plus flutamide] (CAB) does benefit
patients with established mets, the benefit is
“extremely modest”.
Adjunctive Prostate CA Therapy

Estrogen: Diethylstilbestrol lowers LH levels and may
have direct effect on cancer cells.
– Increased thromboembolic risk and cardiovascular effects
have caused loss of use in US.


Gn-RH – antagonist – Abarelix (Plenaxis) limited
availability in US
Zoledronic Acid (Zomeda) interferes with Ca
metabolism and interferes with boney reabsorption
due to orthoclastic activity.
Chemotherapy



Established role in hormone refractory prostate
cancer.
Mitoxantrone (Novantrone) approved by FDA for
treatment of hormone refractory prostate cancer.
[Use in conjunction with corticosteroids]
Taxanes: Docetaxel (Taxotene) and Paclitaxel (Taxol)
– Inhibit mitosis in prostate epithelial cells.
– Docetaxel plus prednisone in accepted as standard
chemotherapy for men with metastatic prostate cancer.
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Chemotherapy
Cyclophosphamide
methrotrexate
 5 - fluorouricil


Newer Therapies for Prostate
Cancer
Tyrosine kinase inhibitors and
proteasome inhibitors used in
combination with chemotherapy.
 Endothelin-1 inhibitor (Atrasentan)
 Angiogenesis inhibitors.
 Therapeutic vaccines and monoclonal
antibodies.

Palliative Therapy
Localized radiation for bone pain at
specific sites of mets.
 Radiopharmaceuticals such as
Strontium 89 or Samatium-153
concentrate in osseous tissue and are
used to treat multiple sites of pain.
 Analgesics-NSAID or Opioids
 TURP-for obstruction problems

18