Current Pharmacological Treatment Options for Prostate Cancer ABSTRACT

Current Pharmacological Treatment Options
for Prostate Cancer
Kirsten D. Fanning, PharmD, CGP, and Kimberly Braxton Lloyd, PharmD
Prostate cancer is the most prevalent male cancer and is the
second leading cause of cancer-related death in men. Advances
in screening through digital rectal examinations and prostatespecific antigen have led to earlier diagnosis and, presumably,
to more effective management. This article reviews the current
pharmacological treatment options in the management of
prostate cancer.
According to American Cancer Society statistics in 2002,
prostate cancer is the most common cause of cancer in men, with
an estimated 189,000 new cases identified each year. It is the second leading cause of cancer death in men, following lung cancer.1 Relative survival after a diagnosis of
prostate cancer has improved over the
years, and currently the estimated 10-year
survival rate is 75%. The earlier the cancer
is detected, the more favorable the survival
rate; the 5-year survival rate in patients
whose prostate cancer is discovered early,
while it is still in the local and regional
state, is 100%.1
Kirsten Fanning,
PharmD, CGP
Regular screening with the prostate-specific antigen (PSA) test and the digital rectal examination (DRE)
can result in early detection and treatment. Normal PSA levels
range from 0 to 4 ng/ml. The use of PSA as a screening test is
highly controversial because of the relatively high prevalence of
prostate cancer at autopsy compared to the relatively low mortality rate from the disease. PSA values can be elevated not only
due to prostate carcinoma but also by benign prostatic hypertrophy (BPH), prostatitis, recent ejaculation, or recent biopsy.2
Despite the possibility of false-positive results, both the American Cancer Society and the American Urological Society recommend that the PSA, along with a DRE, be offered annually to men
ages 50 and older with a life expectancy of at least another 10 years.
These screenings are recommended earlier in men of AfricanAmerican descent, who have a 50% higher risk of developing the
disease, and in individuals with a family history of the disorder.1
The probability of prostate cancer also increases with age, from one
in 48 for men ages 40 to 59 to one in eight for men ages 60 to 79.1
Dr. Fanning is Clinical Assistant Professor in the Department of Pharmacy Practice, Harrison School of Pharmacy at Auburn University in
Auburn, Alabama, and a Geriatric Clinical Pharmacist at East Alabama Medical Center in Opelika, Alabama. Dr. Braxton Lloyd is Assistant Professor in the Department of Pharmacy Practice, Harrison
School of Pharmacy at Auburn University, and Director of the Pharmaceutical Care Center at Auburn University in Auburn, Alabama.
500 P&T®
• October 2002 • Vol. 27 No. 10
Early signs and symptoms can also serve as an indicator to recommend screening, but localized disease is commonly asymptomatic.1 Symptoms may include weak or interrupted urine
flow, inability to urinate, difficulty controlling urine flow, urinary
frequency, nocturia, hematuria, and dysuria.
Most diagnoses of prostate cancer are made following an abnormal PSA result and transrectal ultrasonography (TRUS).
The pathological stage can be assessed after the surgical removal and examination of the prostate gland, seminal vesicles,
and local lymph nodes. The tumor-node-metastasis (TNM) staging classification system includes categories for prostate cancer
with no palpable abnormality (T1), palpable tumor but confined
to the prostate gland (T2), and cancer that
has extended outside the gland (T3 and
T4). Nodal (N) involvement and distant
metastases (M) are also incorporated into
the staging system.3,4 Other systems for
staging have also been developed combining information from the DRE, biopsy,
a PSA test, TRUS, and a Gleason score
(histological grade).3–5 Staging and treatKimberly Braxton
ment of localized disease are also disLloyd, PharmD
cussed by Roth.5 These systems are used
to direct treatment and to assess the probability of cure.
Prostate cancer treatment is dependent on patient age, staging, and comorbid conditions. The American Cancer Society and
the National Comprehensive Cancer Network (NCCN) have
developed guidelines for the treatment of prostate cancer based
on risk for recurrence and expected survival.6 In the earliest
stages of clinically localized prostate cancer (T1-2, N0, M0) or
in patients with a life expectancy of less than 10 years from the
time of diagnosis, conservative management or “watchful waiting” without active treatment, localized therapy, or combined
systemic and local therapy might be appropriate.
Surgery and Radiotherapy
For patients with disease confined to the prostate gland, the
most common treatment option is surgery along with a radical
perineal prostatectomy or prostatoseminovesiculectomy, including removal of all prostatic tissue. In a recent randomized
trial conducted by the Scandinavian Prostatic Cancer Group,
men with localized prostate cancer who underwent a radical
prostectomy, compared with watchful waiting, experienced a reduction in prostate cancer–specific mortality (4.6% versus 8.9%,
P = .02) and a decrease in frequency of distant metastases (10.1%
versus 15.5%, P = .03). No difference was found between the
groups in overall mortality.7 In addition, men who underwent
Current Pharmacological Treatment Options for Prostate Cancer
surgery had a higher incidence of erectile dysfunction and urinary incontinence; however, nerve-sparing surgery was not routinely performed in this trial.8 The external validity of this trial
is unclear because the study population primarily included men
who had palpable disease, with a diagnosis established in only
10% of cases as a result of elevated PSA levels.
External beam radiotherapy is another option for men with localized disease and can be an alternative to surgery in men with
a comorbid condition, such as cardiovascular disease. For men
with small tumors confined to the prostate gland (stage T1 or
T2), brachytherapy, the interstitial implantation of radioactive
seeds directly into prostatic tissue is a one-time treatment alternative to external beam radiotherapy.
Complications of surgery, radiation, and brachytherapy can
include urinary incontinence, impotence, and rectal bleeding, all
of which may limit the usefulness of these treatments. Newer irradiation techniques and nerve-sparing surgical techniques can
decrease the incidence of treatment-related adverse effects.
Postoperatively, erectile dysfunction can be treated with sildenafil citrate (Viagra®, Pfizer), the intraoperative use of cavernous nerve stimulation, and grafting of peripheral nerves to restore innervation of the corpora cavernosa.9
Hormone Therapy
Prostate cancer cell growth is hormone-dependent and can become hormone-independent later in the course of the disease.1
In metastatic disease, bilateral orchiectomy (surgical removal of
the testes) is the preferred method of treatment because of the
complete blockade of androgens; however, as a result of the psychological trauma associated with this method, many patients
consider this procedure unacceptable.
Hormonal therapy can decrease androgen production and is
considered when initial curative therapy with radical prostatectomy or radiation therapy has failed or when the cancer is advanced. Hormonal therapy is not curative but can provide prolonged remission by shrinking tumor size and by decreasing
symptoms such as pain and incontinence.
Pharmacological treatment options consist of agents that
lower serum testosterone levels and agents that interfere locally
with the binding of testosterone and dihydrotestosterone to the
androgen receptor (Figure 1).
Luteinizing Hormone–Releasing Hormone Analogues
Luteinizing hormone-releasing hormone (LHRH) analogues,
or LHRH agonists, include goserelin acetate and leuprolide acetate. These agents bring about a biphasic response by initially
causing elevations of luteinizing hormone (LH) and folliclestimulating hormone (FSH), followed by down-regulation of the
release of gonadotropic hormone–releasing hormone (GnRH)
in the hypothalamus and gonadotropins in the anterior pituitary gland. This down-regulation reduces androgen synthesis
in the testes, causing a chemical castration. The initial rise in
testosterone may result in a clinical flare of the disease with a
transient increase in tumor growth and an increase in other
symptoms, such as urinary obstruction and bone pain in men
with metastatic disease.
Goserelin (Zoladex®, AstraZeneca) is available as a monthly
and as a 3-month implant that is administered subcutaneously.
A clinical trial of 401 patients with localized advanced prostate
cancer compared irradiation alone versus goserelin plus irradiation. The results showed a five-year survival rate of 79% in the
combined treatment group and 62% in the irradiation-only group
(95% confidence interval [CI]: 72–86 and 52–72, P = .001).10
Leuprolide acetate is available as an injectable suspension (Eligard®, Atrix Laboratories), given subcutaneously monthly or
every 3 three months; as a long-acting depot formulation (Lupron
Depot®, TAP Holdings), given intramuscularly, also monthly or
every three months; or as a subcutaneous implant (Viadur®,
Alza Corporation), given every 12 months.
The efficacy of goserelin and leuprolide appears similar, but
a large-scale comparative trial has not been conducted. Another
LHRH analogue, triptorelin (Trelstar®, Debio Recherche), has
a twofold greater potency than leuprolide and was approved for
use in prostate cancer in 2000. In a randomized trial, triptorelin
suppressed testosterone to castration levels in 91% of patients
with advanced prostate cancer during the first month of treatment, with levels maintained through day 253 in 96% of patients.11
The individual selection of an LHRH analogue depends on cost
and on the desired administration schedule. Whether any possible differences in morbidity and mortality exist has not yet been
established. Timing of hormonal therapy for prostate cancer has
been a point of controversy in the literature. Early treatment with
hormonal therapy can be expensive and can cause a rise in anxiety as a result of frequent follow-up testing with PSA tests and
an increased incidence of adverse effects caused by long-term
use. All of the LHRH analogues can cause hot flushes, decreased
libido, impotence, gynecomastia, fluid retention, anemia, fatigue, cognitive impairment, and bone demineralization, sequelae that affect a patient’s quality of life. Using hormonal therapy intermittently may decrease some of these acute toxicities.
Mounting evidence supports initiating treatment once the disease is locally advanced or once recurrent or metastatic disease
is diagnosed.12
In a follow-up phase III trial of the previously mentioned study
of patients with locally advanced disease, it was shown that patients randomly assigned to radiation therapy plus three years
of adjuvant hormonal therapy with goserelin had a significantly
better five-year survival over patients receiving radiation therapy
initially plus hormonal therapy only at disease recurrence. The
five-year clinical disease-free survival rates were 74% (95% CI:
67–81) in the combined treatment group and 40% (95% CI: 32–
48) in radiation alone.13
Because hormone suppression causes systemic castration,
long-term therapy with LHRH analogues can result in a severe
decline in bone density. Prevention of osteoporosis in these patients is imperative in order to decrease fracture risk. Bisphosphonates, such as pamidronate (Aredia®, Novartis) and zoledronic acid (Zometa®, Novartis), have been evaluated in
protecting the bone mineral density during treatment with
LHRH analogues. It has been suggested that bisphosphonates
not only might protect bone density but also might have antimetastatic potential.14
Abarelix, an agent similar to an LHRH analogue, is currently
under review by the U.S. Food and Drug Administration (FDA).
Abarelix is a modified GnRH antagonist and offers an advantage
over LHRH agonists through its direct antagonist action, which
avoids the initial flare phenomenon.15 This agent has not yet un-
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Current Pharmacological Treatment Options for Prostate Cancer
dergone long-term studies, and clinical data are too limited to assess its role in therapy. It is possible that GnRH antagonists
might be an alternative treatment option to LHRH agonists in
prostate cancer if their efficacy proves similar and if the reduced adverse effects linked to the testosterone surge can be
Because androgens are also produced outside the testes in the
adrenal glands, antiandrogens such as bicalutamide (Casodex®,
AstraZeneca), flutamide (Eulexin®, Schering-Plough), and nilutamide (Nilandron®, GH Besselaar Associates) are used to block
the action of testosterone at the cellular level.16 In contrast to the
injectable LHRH analogues, these agents are given orally one to
three times per day. Because monotherapy with an antiandrogen
can induce a compensatory rise in LH release from the pituitary
gland and a subsequent rise in testosterone levels, combination
therapy with an LHRH analogue is usually recommended.
To provide adequate androgen deprivation, physicians com-
monly use the combination therapy of an antiandrogen with an
LHRH analogue, orchiectomy, or radiotherapy. This combination may be referred to as “chemical castration,” “maximal androgen deprivation,” or “combined androgen blockade.” The antiandrogens can also be used to block the flare response from
the initial rise in testosterone from LHRH analogues.
Toxicities differ among the agents, but all include gynecomastia, fatigue, elevation in serum transaminases, and diarrhea (Table
1). Flutamide is more frequently associated with diarrhea and gynecomastia and, rarely, with liver toxicity. Bicalutamide and nilutamide offer an advantage over flutamide because they can be given
as a once-daily formulation, whereas flutamide administration is required three times daily. Nilutamide is associated with visual impairment, causing a decrease in adaptation to darkness and interstitial pneumonitis. It is recommended that visual examinations be
conducted periodically and that a chest radiograph be obtained before initiation of nilutamide and then repeated periodically. These
unique adverse effects have not been reported with bicalutamide.
Controversy exists as to whether a combined regimen that in-
Table 1 Pharmacological Treatment Options for Prostate Cancer
Generic/Brand Name
LHRH Analogues
Side Effects/Comments
All: hot flushes, skeletal pain, impotence, gynecomastia, osteopenia
(Lupron Depot®,
TAP Holdings)
(Zoladex®, AstraZeneca)
(Trelstar®, Debio Recherche)
7.5 mg IM q mo
22.5 mg IM q 3 mo
30 mg IM q 4 mo
1 mg SQ q.d.
Keep vials refrigerated; fractional dose is not equivalent
to monthly formulation
3.6 mg SQ q 28 days
10.8 mg SQ q 3 mo
Implant system
3.75 mg IM q mo
Monitor BP for first 4–8 wk
All: hot flushes, fatigue, increase in liver function tests, gynecomastia
(Casodex®, AstraZeneca)
50 mg PO q.d.
Long terminal half-life
(Eulexin®, Schering-Plough)
250 mg PO q 8 hr
Nausea, vomiting, diarrhea
Nilutamide (Nilandron ,
GH Besselaar Associates)
300 mg PO q.d.
Long terminal half-life, decreased night vision, rare pulmonary toxicity
Megestrol Acetate
(Megace®, Bristol-Myers Squibb)
80–160 mg/day
Edema, increased appetite, myelosuppression
(Cytadren®, Novartis)
125 mg PO q.i.d
Sedation, skin rash, weakness
(Nizoral®, Janssen)
600–1200 mg/day
GI upset, hepatotoxicity
(Provera®, Pharmacia & Upjohn)
1 g IM 3x/wk x 5 wk,
then 1 g IM weekly
Gynecomastia, loss of libido, venous thrombosis
Other Hormonal Agents
BP, blood pressure; g, gram; GI, gastrointestinal; IM, intramuscularly; LHRH, luteinizing hormone-releasing hormone; PO, by mouth; q.d., every day; q.i.d, four times a day;
SQ, subcutaneously.
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Current Pharmacological Treatment Options for Prostate Cancer
cludes androgen blockade with LHRH analogues and an antiandrogen is superior to chemical castration without an antiandrogen. Randomized trials have reported both positive and
negative results, with the majority showing no difference.
The National Cancer Institute sponsored a randomized trial
of 603 men with previously untreated metastatic disease. It was
found that the combination of leuprolide plus flutamide versus
leuprolide plus placebo resulted in a longer progression-free survival (16.5 vs. 13.9 months, P = .039) and a longer median overall survival than treatment with leuprolide plus placebo (35.6 vs.
28.3 months, P = .035).17 Other studies, including a meta-analysis of 27 randomized trials involving maximum androgen blockade using flutamide, nilutamide, or cyproterone acetate, did not
show this survival advantage for combined androgen blockade.
Cyproterone acetate has progestational properties that may be
associated with an excess of nonprostate cancer deaths. When
the data from the trials of cyproterone acetate were excluded,
the survival difference in the trials with flutamide or nilutamide
was 3% (95% CI: 0.4–5.4).18 Direct comparisons between bicalutamide, flutamide, and nilutamide have not been conducted.
Antiandrogen withdrawal may also be considered if disease
recurs during combination androgen blockade therapy. It is hypothesized that a mutation in the androgen receptor can result
in stimulation of tumor growth by antiandrogens acting as an agHypothalamus
LHRH agonists
Pituitary Gland
DHT Receptor
Prostate Cell
Figure 1. Hormonal therapy for prostate cancer. ACTH = adrenocorticotropic
hormone; DES = diethylstilbestrol; DHT = dihydrotestosterone; FSH = follicle-stimulating hormone; LH = luteinizing hormone; LHRH = luteinizing hormone–
releasing hormone.
onist instead of an antagonist.19 The decline and rise in PSA levels guide this intermittent treatment, with cycling continuing until
androgen-independent cancer develops. A rising PSA level is a possible sign of progression and sometimes indicates cancer recurrence. In patients who have undergone a prostatectomy, the PSA
should be undetectable. Investigators do not yet agree on what constitutes an acceptable serum PSA level after radiotherapy and
cryotherapy. PSA levels decline slowly after radiation, and it appears that men with very low (e.g., <0.5 ng/ml) or undetectable
PSA levels are not likely to demonstrate clinical or biochemical relapse following treatment.20 Other important outcome indicators
include control of pain and maintenance of quality of life.
Other Hormonal Therapies
Progestational agents, such as medroxyprogesterone acetate
(Provera®, Pharmacia & Upjohn) and megestrol acetate
(Megace, Bristol-Myers Squibb), are not commonly used as
first-line treatment options for prostate cancer. Megestrol has
limited activity in advanced prostate cancer. In a trial comparing high doses (640 mg/day) and standard doses (160 mg/day)
of megestrol, no apparent dose-response could be demonstrated
in the palliative response rate.21 The use of megestrol is also limited by its potential for pain flare, thrombosis, hypertension,
and hyperglycemia.
Although diethylstilbestrol (DES), a semisynthetic estrogen
analogue, had been used frequently in the past to decrease
testosterone levels, its use is limited because of its significant
cardiovascular complications, including edema, congestive heart
failure, myocardial infarction, cerebrovascular accidents,
phlebitis, and pulmonary embolism.22 Similar survival rates and
quality-of-life benefits have been demonstrated by LHRH analogues without the excess cardiovascular mortality.23
Aminoglutethimide (Cytadren®, Novartis) is also a rarely
used second-line hormonal agent that inhibits the synthesis of
androgens, glucocorticoids, and mineralocorticoids. Therapy
is usually initiated with 250 mg twice daily and gradually increased to four times a day based on tolerance.14 Given the prevention of synthesis of all adrenally derived steroids, concurrent
replacement of glucocorticoids is necessary.
High-dose ketoconazole (Nizoral®, Janssen), an antifungal
agent (400 mg three times a day), can also produce a rapid
chemical castration through inhibition of adrenal steroid synthesis.16 Because kenazole requires an acidic environment for
absorption, it is usually given with citrus juices; coadministration
with antacids, histamine (H2) antagonists, and proton pump inhibitors should be avoided. Long-term use is limited by hepatotoxicity.
Finasteride (Proscar®, Merck), a 5α-reductase inhibitor, can
be used symptomatically for the management of BPH. It works
by blocking the conversion of testosterone to dihydrotestosterone. It has been demonstrated to have minimal effects on PSA
levels but continues to have a limited role in the treatment of
prostate cancer. Clinically, it has been incorporated as part of an
intermittent androgen blockade regimen during the “off” period.14 This treatment approach has not been compared with
more established regimens, and mortality data are unknown.
The role of finasteride in the prevention of prostate cancer is
being evaluated in the ongoing Prostate Cancer Prevention Trial
(PCPT), a randomized, double-blinded, placebo-controlled study,
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Current Pharmacological Treatment Options for Prostate Cancer
sponsored by the National Cancer Institute. This trial represents
a shift from secondary prevention efforts, such as early detection
and treatment of prostate cancer, to primary prevention.24
Chemotherapy may be considered in patients who have hormone-refractory or androgen-independent prostate cancer; however, no current treatment regimen has been shown to improve
survival in a prospective, randomized clinical trial.25 Chemotherapy can be used to delay progression, and it can palliate symptoms of the disease, including pain. Single agents have shown
relatively low response rates. One small trial of 25 patients with
endocrine-refractory prostate cancer receiving weekly infusions
of doxorubicin (Adriamycin®, Pharmacia) showed an overall response rate of 84%.26 The NCCN Practice Guidelines also recognize combinations of ketoconazole and doxorubicin, mitoxantrone and prednisone, and estramustine combined with one
of the following: vinblastine, etoposide, paclitaxel, or docetaxel.6
One combination that has been shown to improve pain and quality of life is mitoxantrone with prednisone.27
Mitoxantrone (Novantrone®, Wyeth), an anthracenedione
similar to doxorubicin, inhibits topo-isomerase II, the enzyme responsible for DNA helix supercoiling, thus resulting in decreased replication. When mitoxantrone was combined with
prednisone in men with metastatic disease, it was fairly well tolerated and effective in achieving a “palliative response,” or a significant reduction in pain when compared to prednisone alone.27
Estramustine (Emcyt®, Pharmacia and Upjohn), a synthetic
combination of estrogen and nitrogen mustard, affects microtubule assembly and disassembly and thus prevents cell division.
After undergoing extensive first-pass metabolism, it is converted
to an estrone analogue that exerts an antigonadotropin effect. Its
adverse effects include fatigue, nausea, vomiting, edema, and venous thromboembolism. Estramustine is both an oral and a recent intravenous treatment option in patients whose hormone
therapy has failed, and it can also be used in combination with
other agents, including taxanes and etoposide.28 Randomized trials are currently under way to evaluate other chemotherapeutic regimens and, it is hoped, to address the question of whether
this agent should be used earlier in the course of the disease.
Dietary Supplements
Dietary supplements, such as saw palmetto, soy, citrus pectin,
and PC-SPES, have also been touted for use in the treatment of
prostate cancer. PC-SPES is a combination of eight herbs and
phytoestrogens, including chrysanthemum, reishi mushroom,
licorice, sanchi ginseng, and saw palmetto. Its action is similar
to that of DES, and therefore it is contraindicated in patients with
a history of thromboembolic or significant cardiovascular disease because of the risk of thromboembolic side effects. The
FDA recently warned consumers to stop using PC-SPES because the California Department of Health Services found it to
be adulterated with traces of prescription medications, including DES, alprazolam, and warfarin.29 The manufacturer has
since voluntarily recalled this product.
Saw palmetto is a dietary supplement similar in action to the 5αreductase inhibitor finasteride. It can falsely lower the PSA value,
which may rebound to its true level once it has been discontinued.
Saw palmetto is not recommended for the treatment of prostate
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• October 2002 • Vol. 27 No. 4
cancer.30 As with all dietary supplements, caution must be used
until quality standards for formulations are in place.
A number of studies have questioned the possibility of preventing prostate cancer. In a study sponsored by the National
Cancer Institute, healthy men aged 55 and older are being recruited to test whether selenium and vitamin E can reduce the
incidence of prostate cancer.31 This trial is based on evidence
that these antioxidants play a role in the prevention of head and
neck cancer. Final results are anticipated in 2013.
Until treatment options are clearly identified to significantly
affect survival , the treatment of prostate cancer will continue to
focus on improving quality of life. Although hormonal therapy
is effective in controlling localized disease, the expense and adverse effects limit its use.
The treatment options for prostate cancer are quite expensive.
Even though the lifetime cost of an antiandrogen or an LHRH
analogue is substantially higher than the one-time cost of orchiectomy, some patients might not consider this surgical procedure acceptable. Improvement in the prostatectomy surgical
technique, particularly for the retropubic procedure, can protect
the neurovascular supply to the corpora cavernosa and therefore
preserve potency in most patients younger than age 60 without
compromising the completeness of the operation.
At this time, the optimal regimen and timing of administration
of hormonal agents in the treatment of prostate cancer are still
a matter of debate. Trials comparing combined androgen blockade regimens with monotherapy, followed by institution of a
combined regimen at the time of recurrence, have not been
completed. Treatment remains patient-specific and should be
based on the extent of tumor, PSA level, Gleason score, quality
of life, and life expectancy. Future agents being studied for the
treatment of prostate cancer include angiogenesis inhibitors, signaling inhibitors, vaccines, and oncolytic viruses, all of which
offer some promise.
American Cancer Society. Cancer Facts and Figures 2002. Available
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Holmberg L, Bill-Axelson A, Helgesen F, et al. A randomized trial
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of Total Amount of Bonds, Mortgages, or Other Securities: None;
12) Tax Status: Not applicable; 13) Publication Name: P&T: A
Peer-Reviewed Journal for Managed Care and Hospital Formulary
Management; 14) Issue date for circulation data below: September 2002; 15) Circulation:
No. Copies
No. Copies
Of Single
Each Issue
Issue Published
During Preceding
Nearest to
12 Months
Filing Date
Extent and Nature
Of Circulation
a. Total no. of copies
(net press run)
b. Paid and/or requested
1. Paid/requested
mail subscriptions
2. Paid in-county
3. Sales through
dealers and carriers,
street vendors, counter
sales and other non-USPS
paid distribution
4. Other classes mailed
through the USPS
c. Total paid and/or requested
d. Free distribution by mail
1. Outside-county
2. In-county
3. Other classes mailed
through the USPS
e. Free distribution
outside the mail
f. Total free distribution
g. Total distribution
h. Copies not distributed
I. Total
j. Percent paid and/
or requested circulation
I certify that all the above information is true and complete.
Timothy P. Search, R.Ph.
Vol. 27 No. 10 • October 2002 •
P&T® 505