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Publication Date: October 2002
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AN UPDATE ON THE SCREEN-
ING INFORMATION AND THE
USE OF LEUPROLIDE IN PROS-
TATE CANCER

Robert Lehmann, Pharm.D. Candidate


Introduction
Prostate cancer (PCA) is a major public
health problem in this country. It is second to lung
cancer as the leading cause of death in men. Ap-
proximately 189,000 new cases of PCA are ex-
pected in 2002 and about 30,200 men will die this
year from PCA.
Some of the major risk factors for develop-
ing PCA include: a positive family history (first de-
gree relative), race (African Americans are twice as
likely as Caucasians to have the disease) and age
(patients older than 65 years of age account for
70% of patients with PCA). Also, at a higher risk of
developing PCA are people who smoke, have a
high fat diet, have high circulating androgens and
those who have high insulin-like growth factors.
PCA is less prevalent in Asia, Africa, and South
America but more prevalent in North America and
northwestern Europe. The American Cancer Soci-
ety suggests vitamin E 50 mg per day, foods high in
lycopene (tomato, grapefruit, watermelon) and
regular physical activity as means to help decrease
the risk of developing PCA.1
The main objective of this article is to edu-
cate clinicians on the new screening tools used for
PCA. It also discusses the role of leuprolide as a
treatment option for patients with moderate to se-
vere PCA.


Screening Tests
The initial screening test is usually the digi-
tal rectal exam (DRE). It is recommended annually
starting at age 50. However, if risk factors are pre-
sent, it is recommended to start at age 45.1
Another screening tool is the Prostate Spe-
cific Antigen (PSA). Like the DRE, it should be of-
fered annually beginning at age 50 (45 if a risk fac-
tor is present). The normal range is < 4 ng/ml; be-
tween 4 and 10 ng/ml is the intermediate range and
PSAs > 10 ng/ml are considered high. Unfortu-
nately, there are some limitations to the utility of
PSA. It is not specific for PCA and some benign
conditions can cause it to be elevated. Also, PCA
can exist even when a patients' PSA is within the
normal range. Nevertheless, the PSA may help de-
tect PCA at an earlier and potentially more treatable
stage and thus improve the chances for survival.8
There are two distinct forms of PSA: free
PSA and a completed form that is attached to the
serum protease inhibitor alpha 1-antichymotrypsin
(ACT). The completed PSA does not appear to be
correlated with cancer at least at the tissue level.
Antibodies have been identified so the assay can
specifically measure the free form and the total
PSA completedd plus free).13 A higher ratio of free
to total PSA correlates with a lower risk of PCA.
The free type of PSA has three different forms of
inactive PSA. The free/total PSA increases the
specificity of PSA for PCA without compromising
its sensitivity. A threshold of 0.20 free/total de-
tected 91% of cancers and relieved 48% of men
with BPH from progressing to biopsy.3
The first type of free PSA is a proenzyme,
or precursor, called pPSA and is associated with
PCA. It is difficult to know if pPSA is present in
PSA levels less than 10 ng/ml. The pPSA is only
found in the blood.


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A second type of free PSA, BPSA, is a de-
graded form of PSA that is more correlated with
benign prostatic hypertrophy (BPH). BPSA seems
to be elevated in the serum of biopsy negative men
with elevated PSA levels. It appears to be corre-
lated with higher prostate volume, regardless of
whether cancer is present. BPSA can be detected in
the seminal plasma. The BPSA level also can
change if the patient is using 5-alpha-reductase in-
hibitors like finasteride (Proscar).
The third type is similar to active PSA,
however there is some conformational changes that
renders it enzymatically inactive. There is a posi-
tive correlation between benign disease and in-
creased percentage of free PSA. Measuring the
pPSA may be helpful to increase the specificity for
cancer diagnosis.13
Another advance in testing is the measure-
ment of serum total sialic acid (TSA) to distinguish
patients with Benign Prostatic Hypertrophy (BPH)
from patients with PCA. TSA has been found to be
elevated in patients with prostate cancer. Further-
more, the TSA is elevated during the final four
months of terminal care for those patients with
PCA compared to patients earlier in the disease
process. The TSA alone is not helpful, but when
combined with the DRE, PSA, free/total PSA ratio,
it can be helpful in distinguishing patients with
cancer form those with BPH, even if their PSA is in
the intermediate zone between 4-10 ng/ml.16
A retrospective analysis was done to distin-
guish BPH from PCA when the PSA was less than
10 ng/ml. MRI-based PSA density (PSAD) and
prostatic transitional zone (PSAT) were measured.
The optimal cutoff point for PSAD was 0.07 ng/ml/
cc and 0.15 ng/ml/cc for the PSAT. The authors
concluded that the use of PSA with PSAD and
PSAT can help avoid unnecessary biopsies in pa-
tients with PSA less than 10 ng/ml. It requires a
single, axial, T2 weighted prostate scan and takes
about 2-6 minutes.14
PSA velocity (PSAV) was evaluated in pa-
tients with a PSA of 2-4 ng/ml. The sensitivity and
specificity of a PSAV of 0.1 ng/ml/year was 81%
and 50% respectively. The 10 year cumulative
freedom from PCA was 97.1% and 35.2% when
the PSAV was less than 0.1 ng/ml/yr respectively
(p<0.05). The PSAV may be helpful in the risk as-
sessment of patients with low PSA values.5


A separate study demonstrated that African
American men tended to have higher PSA levels
and more variable carcinomas compared with white
American men. In this study, Gleason and PSA
scores were better at detecting the disease in Afri-
can Americans versus Caucasians. Therefore, it
raised the question that African Americans less
than 70 years of age may need to have a lower cut-
off PSA value than the usual <4.0 ng/ml due to
their high PSA level; and concluded that having a
uniform range may lead to an under diagnosis of
early stage prostate carcinomas in African Ameri-
cans.6
On the other hand, Britain has chosen not to
screen using the PSA test. Observational studies
have demonstrated that PSA levels >4 ng/ml have a
sensitivity and positive predictive value (PPV) of
79-82% and 32-40% respectively. The Finnish
community-based trial demonstrated similar results
with 92% sensitivity and a 29% PPV. Therefore,
they concluded that due to the inaccuracy of the test
and the morbidity from the biopsy and treatment,
that population-based screening would not be intro-
duced.15
Finally, core needle biopsy is an option for
evaluation of the patient suspected of having PCA.
A needle is guided by Transrectal Ultrasound
(TRUS) and a 1/2" to 3/4" core is removed.1
Samples from two different areas in the prostate
can be used to develop the Gleason score. Each
sample is graded 1-5 and the sum is used to de-
velop the Gleason score. This is a grading system
on a scale of 1-10. A score of 2-4 is considered
low, 5-6 intermediate and 7-10 is considered high.1
The prognostic value of the Gleason Score was
evaluated in 305 patients documenting their dis-
ease-specific mean survival (DSMS). Patients with
scores of 4-5, 6, 7 and 8-10 had DSMS of 20, 16,
10 and 5 years respectively (p<.001). This Gleason
score breakdown was also predictive of those who
died from prostate cancer. A total of 4.5%, 23.6%,
41.8% and 70.2 % died based on their Gleason
scores of 4-5, 6, 7, 8-10 respectively. The DSMS
did not significantly differ between 4-5 and 8-10.
The authors concluded that Gleason scores are
good indicators of long-term prognosis and suggest
four categories (4-5, 6, 7, 8-10).4
All of the previous testing information is
combined to determine the stage of the disease.


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Table 1. Decrease in serum PSA from baseline in response to leuprolide implantation 7
Group 1 (27 patients) Group 2 (24 patients)
Months Post Implantation .
Months Post Implant(% mean +/- SD, median) (% mean +/- SD, median)
Month 1 65.5 +/-18.8 67.0 68.5 +/- 17.9 66.0
Month 3 86.1 +/-15.2 91.0 87.8 +/-11.7 92.0
Month 6 88.3 +/- 14.0 94.0 89.7 +/- 10.1 92.5
Month 12 84.2 +/- 26.5 95.0 90.7 +/- 10.2 95.5
Month 14 79.3 +/- 44.5 95.0 91.2 +/- 10.6 96.0


Staging is from I-IV with stage IV being the most
severe form of the disease. Stage I is low grade
and localized. It can not be felt during DRE. Stage
II is an intermediate grade, localized and present in
more than 5% of the prostate tissue. Stage III has
spread outside the prostate to the seminal vesicle,
but not to any other organs and can be any grade or
score. Stage IV has spread to organs or lymph
nodes and can be any grade or score.

Treatment
Treatment options for PCA include orchiec-
tomy (surgical castration), androgen ablation
through the use of leutinizing hormone releasing
hormone (LHRH) agonists or antagonists, gonad-
otropin-releasing hormone antagonists (Gn-RH),
non-steroidal anti-androgens, combined androgen
blockade with a leutinizing hormone releasing hor-
mone agonist or orchiectomy and non-steroidal
anti-androgen, radiation, prostatectomy or watchful
waiting. If a patient has undergone surgery or ra-
diation and their PSA starts to rise, this is often in-
dicative of recurrent cancer. Studies have evaluated
watchful waiting as well as short term and long
term androgen ablation on survival. A recent study,
showed no difference between radical prostatec-
tomy and watchful waiting in terms of overall sur-
vival after 6 years of follow-up.17 Additional stud-
ies evaluated survival when combined androgen
blockade was compared to single androgen abla-
tion. However, there are no clear-cut guidelines in
place to help practitioners decide whether or not to
treat these patients. Nevertheless, it is generally
recommended to treat patients with recurrent pros-
tate cancer with androgen deprivation while the
PSA is rising and before symptoms develop. This
is especially true for patients with aggressive dis-
ease (Gleason scores >8).10


Androgen Ablation with Leuprolide

Pharmacology/Pharmacokinetics
Leuprolide (Leupron or Viadur") is a
newly modified Gn-RH antagonist that directly an-
tagonizes LHRH. Leutinizing hormone releasing
hormone is normally released from the hypothala-
mus in a pulse-like manor. This causes a release of
LH and follicle-stimulating hormone (FSH). Leu-
tenizing hormone attaches to the leydig cells in the
testes and is responsible for promoting testosterone
production. Constant exposure to a leutinizing
hormone releasing hormone agonist can cause
down-regulation of the receptors in the pituitary
gland and thus can decrease the release of LH and
FSH. This in turn causes a decline in the testoster-
one level.10
Leuprolide is given either intramuscularly
or subcutaneously. It has a bioavailability of 94%
and peak levels are achieved within 4 hours of the
intramuscular injection. Approximately 20-25% of
the drug is absorbed into the circulation each week.
Once the drug is absorbed, high concentrations can
be found in liver, pineal, pituitary and kidney tis-
sues. The plasma half-life is 3 hours.
Viadur is a subcutaneous formulation that
provides continuous, osmotically driven delivery of
the medication for up to one year. The patient re-
quires an implant placed in their upper arm. Water
from the tissue enters one end of the cylinder
through a semi-permeable membrane. This causes
the osmotic engine to swell, which then pushes the
piston toward the drug compartment, causing a
drug-release rate equal to the influx of water. The
drug is delivered from an exit port opposite the
semi-permeable membrane. The intramuscular for-
mulations that are available include: 1, 3 and 4-
month formulations.2


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Dosing
Leuprolide dosing is dependent on the for-
mulation used. The SC injection can be dosed
daily as a 1mg injection and monthly (Eligard) as
a 7.5 mg depot injection. Viadur contains 72 mg
of leuprolide acetate which delivers 120 mcg of le-
uprolide a day for 12 months. The intramuscular
injection can be given as a 7.5 mg dose once
monthly, 22.5 mg every 3 months or 30 mg every 4
months.

Clinical Trials
The safety and efficacy of the Viadur de-
livery system for patients with advanced PCA was
evaluated. The primary endpoint was testosterone
suppression at 12 months, but PSA and LH were
also evaluated. Fifty-one patients entered the study
and 27 received one (group 1) and 24 received two
(group 2) implants. Forty-nine patients completed
the trial. After initial exposure to leuprolide, an ini-
tial LH and testosterone surge occurred during the
first week, subsequently castration levels (below 50
ng/dl) were maintained through week 60 of the
study. There was no transient increase in testoster-
one after the implants were removed and a new one
was inserted. Testosterone suppression was 100%
in both groups. The authors concluded that leu-
prolide was effective at causing androgen ablation
and offered the patient convenience of yearly dos-
ing as opposed to the intramuscular injections.7
A separate study evaluated the benefit of 3
to 8 months of neo-adjuvant hormonal therapy with
leuprolide 7.5 mg IM monthly and 250 mg of flu-
tamide PO tid before radical prostatectomy. Ini-
tially, PSA was less than 10 ng/ml in 63%, 10-20
ng/ml in 27% and greater than 20 ng/ml in 10% of
patients in the study. After treatment, PSA values
were less than 0.1 ng/ml in 43.3% versus 75%
(p<0.0001) of patients and 0.3 ng/ml or larger in
21% versus 9.2% (p<0.0006) of patients after 3
versus 8 months of treatment respectively. Prostatic
volume decreased by 37% after the third month
(p=0.0001) and an additional 13% in the 8-month
group (p=0.03). This study suggested that optimal
duration of neoadjuvant hormonal therapy may be
longer than 3 months. However, the authors con-
cluded that more data was needed to determine
whether this longer treatment altered the PSA re-


currency rate.9
A separate study evaluated the benefit of
androgen ablation in reducing the prostate volume
so brachytherapy could be initiated. The goal was
a prostate volume less than 50 ml. Other reasons
for reducing the prostate include a prostate length
exceeding 5.5 cm or having some pubic arch bone
interference. This retrospective study included 107
patients who were on one of the following proto-
cols for androgen ablation: leuprolide alone
(37.4%), leuprolide and bicalutamide (46.8%), leu-
prolide plus nilutamide (7.5%) or some other com-
bination of LHRH agonist and a non-steroidal anti-
androgen combination. The mean percentage in re-
duction of prostate volume was 33% after 3.7
months of treatment. Among those who had a vol-
ume greater than 50 ml at the beginning of the
study, 82% had a volume of less than 50 ml after
the androgen ablation treatment was completed.11
Lee, et al. evaluated the benefit of hormonal
therapy in intermediate to high risk PCA patients
with radioactive seed implantation. Two hundred
and one patients with stage Tlb-3b PCA, Gleason
scores >7 or PSA >10 ng/ml were treated with per-
manent seed implantation either with or without
hormonal therapy. Sixty-six percent of patients
were treated with hormonal therapy (leuprolide or
goserelin) and anti-androgen (flutamide or bicalu-
tamide) for 3 months before brachytherapy and 2-3
months afterward. Patients on hormonal treatment
had lower PSA values as evidenced by the 66%
(hormone) versus 87% (non-hormone) of patients
having PSAs >10 ng/ml (p=0.02). However, Glea-
son scores were higher for the hormone treatment
group. Forty-nine percent of patients in the hor-
mone group had a Gleason score higher than 7
compared to only 30% in the non-hormone group.
The five-year freedom from biochemical failure
(FFBF) was evaluated and those with the hormonal
therapy faired better (79%) versus the non-hormone
group (54%) (p=0.0001). This retrospective study
showed some beneficial effects of hormonal ther-
apy for patients with intermediate PCA.12

Adverse effects
The most common side effects (occur in
greater than 2% patients) are listed in Table 2. They
are usually a result of testosterone suppression.


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Volume 18, Issue 1 October 2002







Table 2. Adverse events documented during clinical trials 7

Adverse Event No. Pts (%)
Asthenia 4 (7.8)
Headache 3 (5.9)
Extremity pain 2 (4.9)
Vasodilatation (hot flashes) 38 (74.5)
Diarrhea 2 (3.9)
Anemia 2 (3.9)
Peripheral edema 4 (7.8)
Bone pain 2(3.9)
Depression 5 (9.8)
Impotence 3 (5.9)
Testicular atrophy/pain 3 (5.9)
Gynecomastia 2 (3.9)


It is recommended to monitor FSH, LH and
testosterone levels during treatment. Bone pain,
weakness, urinary tract obstructions and paresthe-
sias can also occur during the first few weeks of
treatment. Contraindications include spinal cord
compression and hypersensitivity to benzyl alcohol.
There are no reported drug-drug interactions
with leuprolide. However, androgens and estro-
gens can counteract the effects of leuprolide and
would therefore not be recommended. Dehydroepi-
andosterone is a weak androgen and thus may an-
tagonize leuprolide's effect and is not recom-
mended. Agents that can cause hyperprolactinemia
(anti-psychotics, metoclopramide, reserpine, and
methyldopa) can cause a down regulation of Gn-
RH receptors and should not be used concomi-
tantly.

Cost of therapy
See retail costs of treatment in Table 3.

Summary
Leuprolide is a Gn-RH antagonist that is
used in advanced PCA to decrease circulating tes-


Table 3. Retail price for a month supply of leuprolide

Dose Price
Img SC QD $300 $600
$300- $400 (3.75mg)
3.75mg IM every month $300 $400 (.75mg)
$600 $800 (7.5mg) usually needed


tosterone. It is useful to halt the tumor size and
metastases. The main marker for PCA is the PSA.
Multiple trials have demonstrated leuprolide to be
helpful in decreasing the PSA. It can be used alone
or in combination with an anti-androgen or orchiec-
tomy. It usually will increase testosterone for 2-4
weeks after initiating therapy, then decrease testos-
terone levels to castration levels. Clinical trials for
up to 18 months have demonstrated no rebound in-
creases in PSA. It has multiple dosage forms and
can be given in a once a year implant in the arm.

References
1. American Cancer Society. www.cancer.org.
2. Clinical Pharmacology online. www.cp.gsm
3. Do V, Choo R, De Boer G, Danjoux C, Morton
G, Szumacher E, et al. The role of serial free/
total prostate-specific antigen ratios in a watch-
ful observation protocol for men with localized
prostate cancer. Br J Urol Int 2002;89:703-9.
4. Egevad L, Granfors T, Bergh A, et al. Prognos-
tic Value of the Gleason Score in prostate can-
cer. Br J Urol Int 2002;89(6):538-542.
5. 5. Fang, J, Metter EJ, Landis P, Carter HB.
PSA Velocity For Assessing Prostate Cancer
Risk In Men With PSA Levels Between 2.0 and
4.0 ng/ml. Urology 2002;59(6):889-94.
6. Fowler JE, Bigler SA, Farabaugh PB. Prospec-
tive study of cancer detection in black and
white men with normal DRE but prostate spe-
cific antigen equal or greater than 4.0 ng/ml.
Cancer 2002;94(6): 1661-6.
7. Fowler, JE, Gottesman JE, et al. Safety And Ef-
ficacy Of An Implantable Leuprolide Delivery
System In Patients With Advanced Prostate
Cancer. J Urol 2000;164:730-4.
8. Foxhall LE, Von Eschenbach AC. Counseling
Patients about Prostate Cancer Screening. Am
Fam Physician. 2002;65(9):1752, 54, 57.
9. Gleave ME, Goldenberg SL, et al. Randomized
Comparative Study Of 3 Versus 8 Month
Neoadjuvant Hormonal Therapy Before Radical
Prostatectomy: Biochemical And Pathological
Effects. J Urol 2001;166:500-7.
10. Hellerstedt BA, Pienta KJ. The Current State of
Hormonal therapy for Prostate Cancer. CA
Cancer J Clin. 2002;52(3):154-79.
11. Kucway R, Vicini F, Huang R, Stromberg J, et
al. Prostate Volume Reduction With Androgen
Deprivation Therapy Before Interstitial Brachy-


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Volume 18, Issue 1 October 2002







therapy. J Urol 2002 167:2443-7.
12. Lee LN, Stock RG, Stone NN. Role of Hormo-
nal therapy in the Management of Intermediate
to High-risk Prostate Cancer Treated with Per-
manent Radioactive Seed Implantation. Interna-
tional Journal of Radiation Oncology and Bio-
logical Physiology 2002;52(2):444-52.
13. Mikolajczyk SD, Marks LS, Partin AW, Ritten-
house HG. Free Prostate-Specific Antigen In
Serum Is Becoming More Complex. Urology
2002;59(6):797-802.
14. Mueller-Lisse UG, Mueller-Lisse UL, Haller S,
Schneede P, et al. Likelihood of Prostate Can-
cer Based on Prostate-Specific Antigen Density
by MRI: Retrospective Analysis. J Comput As-
sist Tomogr 2002;26(3):432-7.
15. Parkinson MC, Bott SRJ, Montironi R, Melia J.
Screening for the Prostatic cancer and its evolu-
tion within Britain. J Path 2002; 197:139-42.
16. Romppanen J, Haapalainen T, Punnonen K,
Penttila I. Serum Sialic Acid and Prostate-
Specific Antigen in Differential Diagnosis of
Benign Prostate Hyperplasia and Prostate Can-
cer. Anticancer Research 2002;22:415-20.
17.Holmberg L, Bill-Axelson A, et al. A Random-
ized Trial Comparing Radical Prostatectomy
with Watchful Waiting in early Prostate Cancer.
N Engl J Med 2002;347(11):781-9.


Topic


Issue (Page)


A
Accutane
AdN icor'
Almotriptan Malate
Alzheimer's Disease
Aranesp
Axert


B-C
Colesevelam
Community Acquired Pneumonia

D
Darbepoetin Alfa
Drotrecogin Alfa
Dyslipidemia
ATP III Guidelines to Specific
Patient Populations

E-F
Ethinyl Estradiol/Norelgestronim
Foradil AerolizerTM
Formoterol Fumarate

G-H-I-J
Hormone Replacement Therapy
Insulin: New Products
Isotretinoin

K-L-M-N
Niacin/Lovastatin

O-P-Q-R
Ortho EvraT
Protopic

S-T-U-V
Tacrolimus (topical)

W-X-Y-Z
Welchol
XigrisTM


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Pha rma Note Volume 18, Issue 1 October 2002


Index for Volume 17
October 2001 September 2002


The PharmaNote is Published by:
The Department of Pharmacy Services,
UF Family Practice Medical Group,
Departments of Community Health
and Family Medicine and Pharmacy
Practice
University of Florida


John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

John M. Tovar Assistant Editor
Pharm.D.

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