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Course: Clinical Pharmacy II
Class: Pharm-D Final Year
Instructor
Dr. Muhammad Fawad Rasool
Associate Professor & Chairman
Department of Pharmacy Practice,
Bahauddin Zakariya University, Multan

Agenda
Introduction
Epidemology
Etiology
Pathophysiology
Clinical Presentation
Diagnosis and Staging
Treatment
© Muhammad Fawad Rasool

Participants
 Muhammad Saleem (65-E-17)
 Muhammad Irshad (81-E-17)
 Muhammad Asadullah (62-E-17)
 Muhammad Irfan (85-E-17)
 Hunain Ameen (83-E-17)

Prostate Cancer
 Prostate cancer is a malignant neoplasm that arises from the prostate
gland. Prostate cancer has an indolent course; localized prostate cancer is
curable by surgery or radiation therapy, but advanced prostate cancer is not
yet curable.
Prostate Gland:
 The prostate gland is a solid, rounded, heart-shaped organ positioned
between the neck of the bladder and the urogenital diaphragm. The normal
prostate is composed of acinar secretory cells arranged in a radial shape
and surrounded by a foundation of supporting tissue.

Epidemology
 Prostate cancer is the most frequent cancer among American men and
represents the second leading cause of cancer-related deaths in males.
 In the United States alone, it is estimated that 174,650 new cases of
prostate carcinoma were diagnosed and more than 31,620 men died from
this disease in 2019.
 Although the incidence of prostate cancer increased during the late 1980s
and early 1990s related to widespread PSA screening, deaths from prostate
cancer declined from 1993 to 2013.
 Prostate cancer mortality stabilized between 2013 and 2016 as a result of
the decrease in PSA(Prostate-specific antigen) screening and an increase in
advanced stage diagnoses.

Etiology
 Many risk factors are associated with prostate cancer. These factors are
age, race-ethnicity and family history of prostate cancer.
 The disease is rare in those younger than 40 years, but the incidence
sharply increases with each subsequent decade, most likely because of
increased lifetime exposure to testosterone, a known growth signal for the
prostate.
 Race and Ethnicity
 The incidence of clinical prostate cancer varies across geographic
regions. African American men have the highest rate of prostate cancer and
is more than twice that seen in white populations in the United States.

Etiology
 Testosterone, commonly implicated in the pathogenesis of prostate
cancer, is about 15% higher in African American men compared with white
males.
 Hormonal, dietary, and genetic differences, and differences in access to
healthcare may contribute to the altered susceptibility to prostate cancer in
these populations.
Family History
o Men with a brother or father with prostate cancer have twice the risk for
prostate cancer as compared with the rest of the population and 5% to 10%
of prostate cancers are thought to be inherited. . Carriers of germline
mutations in one of 16 DNA repair genes are known to have an increased
risk of developing prostate cancer

Diet
 The overall dietary factor associated with the lowest risk of developing
prostate cancer appears to be adherence to a Mediterranean diet. The
typical Mediterranean diet is high in fruits, vegetables, legumes, fish, olive oil
and red wine, with low-to-moderate amounts of red meat, poultry and dairy.
 About 1.5 million individuals have significantly reduced risk of prostate
cancer.

Other Factors
 Benign prostatic hyperplasia (BPH) is a common problem among elderly
men, affecting more than 40% of men older than 70 years and the presence
of BPH often complicates the diagnosis of prostat.
 Smoking and Alchol consumption was not associated with the
development of prostate cancer but smokers with prostate cancer have an
increased mortality resulting from the disease when compared with
nonsmokers with prostate cancer.

Risk factor associated with Prostate canceer

Pathophysiology
 The size, shape, or presence of acini is almost always altered in the gland
that has been invaded by prostatic carcinoma.
 Adenocarcinoma, the major pathologic cell type, accounts for more than
95% of prostate cancer cases.
 Normal growth and differentiation of the prostate depend on the presence
of androgens, specifically DHT.
 In early stage prostate cancer,tumor cell proliferation is promoted by
presence of androgens.
 The testes and the adrenal glands are the major sources of circulating
androgens.

Pathophysiology
 Hormonal regulation of androgen synthesis is mediated through a series
of biochemical interactions between the hypothalamus, pituitary, adrenal
glands, and testes.
 Luteinizing hormone-releasing hormone (LHRH) released from the
hypothalamus stimulates the release of luteinizing hormone (LH) and follicle-
stimulating hormone (FSH) from the anterior pituitary gland.
 FSH acts on the Sertoli cells within the testes to promote the maturation of
LH receptors and to produce an androgen-binding protein.

Pathophysiology
 Circulating testosterone and estradiol influence the synthesis of LHRH,
LH, and FSH by a negative feedback loop operating at the hypothalamic and
pituitary level.
 Prolactin , growth hormone and estradiol appear to be important
accessory regulators for prostatic tissue permeability, receptor binding, and
testosterone synthesis.
 Testosterone, the major androgenic hormone, accounts for 95% of the
androgen concentration.
 In advanced stage, prostate cell don’t respond to androgen signal and
proliferate independently. These tumors are often referred as hormone
refractory or androgen indepentent.

Hormonal regulation of the prostate gland

Clinical presentation

Diagnosis and staging
 Prostate cancer can be graded systematically according to the histologic
appearance of the malignant cell and then grouped into well, moderately, or
poorly differentiated grades.
 Gland architecture is examined and then rated on a scale of 1 (well
differentiated) to 5 (poorly differentiated).
 Two different specimens are examined, and the score for each specimen
is added. Groupings for total Gleason score are 2 to 4 for well differentiated,
5 or 6 for moderately differentiated, and 7 to 10 for poorly differentiated
tumors. Poorly differentiated tumors grow rapidly (poor prognosis), while
well-differentiated tumors grow slowly (better prognosis).

Diagnosis and staging
Diagnostic and staging workup for prostate cancer.

Initial Management of Prostate Cancer Based
on Expected Survival and Recurrence Risk

Treatment
 Desired outcome
 The desired outcome in early-stage prostate cancer is to minimize
morbidity and mortality caused by prostate cancer.
 Early-stage disease may be treated with surgery, radiation, or expectant
management.
 Advanced prostate cancer is not currently curable, and treatment should
provide symptom relief and maintain quality of life.
 The mainstay of treatment for advanced prostate cancer is ADT, with a
goal of reducing testosterone to castrate levels, with an orchiectomy.

Patient Care Process for Prostate Cancer

Non pharmacologic Therapy
Orchiectomy
 Bilateral orchiectomy, or removal of the testes, is a form of ADT that
rapidly reduces circulating androgens to castrate levels (less than 50 ng/dL
[1.7 nmol/L]).
 Many patient do not prefer orchiectomy due to advance age, but it is
preferred initial treatment in patient with impending spinal card compression
or ureteral obstruction.

Radiation
 Two methods are used for radiation therapy are external beam
radiotherapy and brachytherapy.
 In external beam radiotherapy, doses of 70 to 75 Gy (7,000-7,500 rad) are
delivered in 35 to 41 fractions in patients with lowgrade prostate cancer and
75 to 80 Gy (7,500-8,000 rad) for those with intermediate- or high-grade
prostate cancer.
 complications from radiation therapy include cystitis, proctitis, hematuria,
urinary retention, penoscrotal edema, and impotence.

Radical Prostatectomy
 It is surgery to remove prostate gland and seminal vesicle(and sometime
nearby lymph nodes) after a prostate cancer diagnosed. 50% to 80% regain
sexual potency within the first year.

Pharmacotherapy
Drug Treatments of First Choice
1. Luteinizing Hormone-Releasing Hormone Agonists (LHRH)
 These agonists are a reversible method of androgen ablation and are as
effective as orchiectomy in treating prostate cancer.
 Currently available LHRH agonists include leuprolide, leuprolide depot,
leuprolide implant, triptorelin depot, triptorelin implant, and goserelin
acetate implant.
 The leuprolide depot formulation is administered intramuscularly and
Goserelin acetate implant subcutaneously.
 They are alone used in advanced prostate cancer.

 LHRH agonist monotherapy can be used as initial therapy, with response
rates similar to those for orchiectomy.
 Appropriate pain and symptom management is required during this period,
and a short course of concomitant antiandrogen therapy may need to be
considered prior to initiating the LHRH agonist.
 The risk of cardiovascular-related adverse effects is lower with LHRH
therapy than with estrogen administration.

 2. Gonadotropin-Releasing Hormone Antagonists
 An alternative to LHRH agonists is the approved GnRH antagonist,
degarelix.
 Degarelix works by binding reversibly to GnRH receptors in the pituitary
gland, reducing the production of testosterone to castrate levels.
 The major advantage of degarelix over LHRH agonists is the rapidity at
which it reduces testosterone level.
 In a trial advanced prostate cancer degarelix was shown to be equivalent
to leuprolide in lowering testosterone levels for up to 1 year.

 3. Antiandrogens
 The first-generation antiandrogens include flutamide, bicalutamide, and
nilutamide.
 Three second-generation antiandrogens, apalutamide, enzalutamide, and
darolutamide, are currently available. Cyproterone is another agent with
antiandrogen activity.
 Antiandrogens have been used as monotherapy in previously untreated
patients, but a meta-analysis showed that monotherapy with antiandrogens
is less effective than LHRH agonists. Therefore, for advanced prostate
cancer, flutamide, bicalutamide, and nilutamide are indicated only in
combination with androgen-ablation therapy.

 4. Combined Androgen Blockade
 Although up to 80% of patients with advanced prostate cancer will
respond to initial hormonal manipulation, almost all patients will progress
within 2 to 4 years after initiating therapy.
 Two mechanisms have been proposed to explain this tumor resistance.
The tumor could be heterogeneously composed of cells that are hormone-
dependent and hormone independent, or the tumor could be stimulated by
extratesticular androgens that are converted intracellularly to DHT.
 The rationale for combination hormonal therapy is to interfere with multiple
hormonal pathways to completely eliminate androgen action.

 The combination of LHRH agonists or orchiectomy with antiandrogens is
the most extensively studied CAB approach.
 Although some clinicians consider CAB to be the initial hormonal therapy
of choice for newly diagnosed patients, the clinician must weigh the costs of
combined therapy against the modest survival benefit.
 It is appropriate to use either LHRH agonist monotherapy or CAB as initial
therapy for metastatic prostate cancer.
 CAB may be most beneficial in patients with minimal disease and prevents
tumor flare, particularly in those with advanced metastatic disease.

Alternative Drug Treatments
 1. Secondary Hormonal Manipulations
 This may include adding an antiandrogen to a patient with incomplete
suppression of testosterone secretion with an LHRH agonist.
 Androgen synthesis inhibitors, such as aminoglutethimide or
ketoconazole, can provide symptomatic relief for a short time in about 50%
of patients with progressive disease despite previous androgen-ablation
therapy.
 Central nervous system effects that include lethargy, ataxia, and dizziness
are the major adverse reactions.

 2. Chemotherapy
 Chemotherapy with docetaxel and prednisone improves survival in
patients with CRPC(castration resistan and is considered a first-line therapy
option. Docetaxel 75 mg/m2 every 3 weeks combined with prednisone 5 mg
twice a day improves survival in CRPC.
 Cabazitaxel 25 mg/m2 every 3 weeks with prednisone 10 mg daily.
 The most common adverse events with this regimen are nausea, alopecia,
and bone marrow suppression.
 Docetaxel and Cabazitaxel are not given to hepatic impaired patients.

 3. Immunotherapy
 Patients treated with sipuleucel-T undergo leukapheresis on day 1 to
collect peripheral blood mononuclear cells, the cellular fraction that includes
immune effector cells.
 These cells are incubated with specific tumor antigen and immune cell
activator. The cellular product is then infused IV into the patient on day 3 or
4.
 The disadvantage of therapy is high cost and Some insurers have
questioned the value of the therapy.

 4. Nuclear Medicine
 Radium-223, an alpha emitter, can be administered every 4 weeks to
target specific bone metastases with alpha particles in patients with
metastatic CRPC.
 . Improvements in skeletal pain, pain-related outcomes, and quality of life
were also significant.
 Radium-223 is a category 1 recommendation and may be used in first-,
second-, or third-line therapy in patients with metastatic castrate resistant
prostate cancer.
 . The most common adverse effects include nausea, diarrhea, vomiting,
peripheral edema, and bone marrow suppression.

EVALUATION OF THERAPEUTIC
OUTCOMES
 Monitoring of prostate cancer depends on the stage of the cancer.
 It include assessment of the primary tumor size, evaluation of involved
lymph nodes, and the response of tumor markers such as PSA to treatment.
Following definitive therapy, the PSA level is checked every 6 months for the
first 5 years, then annually.
 Local recurrence in the absence of a rising PSA may occur, so a DRE is
also performed.In the metastatic setting, chemotherapy and novel hormonal
manipulations have been shown to prolong overall survival.
 In addition, clinical benefit responses can be documented by evaluating
performance status, body weight, quality of life, and analgesic requirements,
in addition to the PSA or DRE at 3-month intervals.

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