Medco CE - Prostate Cancer

Men’s Health

Prostate Cancer: A Review and Therapy Updates

Joe Crea. D.O.Medco

Las Vegas12/12/10

Disclosure InformationI have the following financial relationships to disclose:

• Honoraria and expenses paid by:

Medco Health Solutions

through

Business Services International, Inc.

• I have no other financial relationships to disclose.

• I will discuss the following investigational use:

1. Finasteride (Proscar) as a combination therapy with flutamide.

2. Cabazitaxel (Jevtana) as a combination therapy with mitoxantrone.

• I will not discuss any off label uses.

Goals

A.Update the pharmacists' and technician's practical knowledge of prostate cancer and its pharmacotherapies.

B.Reinforce and encourage the pharmacists' and technician's use of patient assessment skills to identify at risk populations for prostate cancer.

C.Enhance the pharmacists' and technician's ability to monitor, identify, and intervene in issues related to the pharmacotherapy of prostate cancer.

OBJECTIVES (for pharmacists)

Upon completion, the successful pharmacist will be able to:

A1. Detail the pathophysiology of prostate cancer.

A2. Discuss in-depth the various pharmacotherapeutic strategies employed at the different stages of prostate cancer.

B1. Assess and counsel patients regarding the major risk factors, signs, and symptoms associated with prostate cancer.

C1. Incorporate into their practice the monitoring of patients at risk for adverse drug events related to the treatment of prostate cancer.

C2. Identify adverse events related to the pharmacotherapy of prostate cancer and recommend appropriate intervention strategies.

OBJECTIVES (for pharmacy technicians)

Upon completion, the successful technician will be able to:

A1. Detail the anatomy and physiology of the prostate and related structures.

B1. Incorporate into their practice the special issues associated with the compounding and dispensing of drug therapies

associated with the treatment of prostate cancer.

C1. Incorporate into their practice the ability to identify the at risk patient for adverse drug events, including interactions, related to the treatment of prostate cancer.

Anatomy

Anatomy

Anatomy

Anatomy

Anatomy

Anatomy

Physiology• The prostate gland makes ~25-30% of seminal fluid. Fluids

from the prostate, the seminal vesicles, and Cowper's glands make up the bulk of semen.

• During ejaculation millions of sperm arrive in the prostatic urethra and the prostate contracts to pinch a duct to the bladder so that the semen is kept urine-free and to secrete prostatic fluid containing prostate-specific antigen (PSA) into the ejaculate.

• Sperm are acid-sensitive so the semen is alkaline and the ejaculate neutralizes the protective acidity of the vagina (pH~4) for many hours after intercourse.

• There is a clotting enzyme derived from seminal vesicle fluid that makes the ejaculate gel and "glue" the semen next to the cervix. For a few minutes the sperm stay inside this gel. Within 15 to 30 min., PSA dissolves the clot liquefying the semen and frees the sperm to swim into the uterus.

Overview of Prostate CA• Prostate CA:

– Most commonly diagnosed non-skin cancer in American males. (Rare < age 50; increased risk after)

– 2nd leading cause of cancer-related death in the U.S. among men (Lung CA #1). However, most prostate cancer–related deaths are due to advanced disease.

– Found during autopsies performed following other causes of death. This latent or autopsy cancer is much greater than that of clinical cancer (as high as 80% by age 80 years).

• Prostate CA signs and symptoms are not evident in the early stages making regular screening vital for favorable prostate CA prognosis. Once they appear, the cancer has likely spread beyond the prostate.

• Radiation and prostate cancer surgery, or prostatectomy, are the 2 most common treatments for localized disease.

Epidemiology• 1 in 10 men will develop prostate CA.

• 2008: estimated 186,000 new cases and 26,000 deaths.

• Since the advent of prostate-specific antigen (PSA) screening in the 1980’s, the mortality rate has declined because it is being detected and treated earlier; still, 10%-20% of new cases involve locally advanced disease.

• Men with a family history of prostate cancer have a higher risk of developing prostate cancer and it presents 6-7 years earlier.

• A strong familial predisposition may be responsible for as many as 5-10% of prostate cancer cases.

• Higher incidence in Black men who tend to have higher-grade carcinoma at diagnosis; and, it tends to be more aggressive and progressive.

Diet• Diets high in animal fat increase risk of prostate CA.

– Rates of prostate CA are much greater in American men of Japanese descent than in native Japanese men , supporting the association of a high-fat diet with cancer.

– Cell culture studies have shown that omega-6 fatty acids are positive stimulants of prostate cancer cell growth, while omega-3 fatty acids are negative stimuli.

• A low-fat diet is recommended for patients at high risk of developing prostate cancer or undergoing treatment for advanced prostate cancer.

• The Physicians' Health Study II found that neither Vitamins E nor C supplementation reduced the risk of any cancer.

• The Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized placebo-controlled trial involving 35,533 relatively healthy study participants from 427 US sites, found that neither selenium nor vitamin E (alone or in combination) at the doses and formulations used prevented prostate cancer.

Genetics

• Gene alterations on chromosomes 1, 17, and X have been found in some patients with a family history of prostate cancer.

• Human prostate cancer gene is on the X chromosome.

• The hereditary prostate cancer 1 (HPC1) gene and the predisposing for cancer of the prostate (PCAP) gene are on chromosome 1.

Finger length linked to prostate cancer risk Wed Dec 1, 3:27 AM

PARIS (AFP) - Men whose index fingers are longer than their ring, or fourth, fingers run a significantly lower risk of prostate cancer, according to a study published Wednesday in the British Journal of Cancer. The chances of developing the disease drop by a third, and even more in younger men, the study found. "Our results show that relative finger length could be used as a simple test for prostate cancer risk, particularly in men aged under 60," said Ros Eeles, a professor at the Institute of Cancer Research in Britain and co-author of the study. Finger pattern could help identify which men should undergo regular screening, especially in combination with genetic testing or other risk factors such as a family history of the disease, she said.

From 1994 to 2009, Eeles and colleagues questioned more than 1,500 prostate cancer patients in Britain, along with 3,000 healthy control cases. For more than half the men, the index was shorter than the ring finger. Compared to this group, men whose index and ring fingers were the same length -- 19 percent of the cohort -- had a similar prostate cancer risk. But when the index finger was longer, the risk of developing the disease dropped by 33 percent. Men under 60 were 87 percent less likely to be in the cancer group. The relative length of the two fingers in question -- set before birth -- appears to be a marker of different levels of sex hormones to which a baby is exposed in the womb, with less testosterone correlating with a longer index finger.

Earlier research has shown that testosterone promotes the growth of prostate cancer.Underlying the unexpected connection between digits and cancer are two genes, HOXA and HOXD, that control both finger length and the development of sex organs. Other studies have found a link between exposure to hormones before birth and the development of other diseases, including breast cancer and osteoarthritis.

Copyright © 2010 Yahoo! Canada Co. All Rights Reserved. Copyright © 2010 Agence France Presse.

http://ca.news.yahoo.com/

Screening• Digital rectal exam (DRE) and PSA are the 2 components.

• A nodule felt on DRE is important, but findings such as asymmetry, difference in texture, and bogginess are important clues as well.

• A high index of suspicion for CA should be maintained if DRE results are abnormal. The DRE should be considered in conjunction with the PSA level.

• Controversial?!

– U.S. Preventive Services Task Force recommends against screening for prostate cancer at 75 yrs or older; Cost/Benefit in men younger than 75 years cannot be assessed because of insufficient evidence.

– American Cancer Society says screening should be offered (and documented) annually from age 50 if life expectancy at least 10 years; high-risk men (2 or more affected first-degree relatives, Blacks) should begin screening at 40-45.

Screening Controversy

• Advocates

Early detection is crucial to finding organ-confined disease and to reducing the likelihood of mortality. When symptoms develop or when DRE results become positive, most cases have already advanced beyond organ-confined disease.

• Non-advocates

Screening detects cancers that are not biologically significant (i.e. patients who will die with prostate cancer rather than from it).

Medicolegal Pitfalls

• The leading cause of malpractice claims against urologists is the failure to diagnose prostate cancer in a timely manner.

• Primary care physicians and internists also are increasingly being held liable for failure to obtain PSA testing for their patients and for failure to refer those with elevated PSA levels to a urologist.

Discussion

Pathophysiology• Prostate cancer develops when the rates of cell division and

cell death are no longer equal, leading to uncontrolled tumor growth. Following this event, mutations of a multitude of genes lead to tumor progression and metastasis.

• Most prostate cancers (95%) are adenocarcinomas.

• 70% arise in the peripheral zone, 15-20% arise in the central zone, and 10-15% arise in the transitional zone. Approximately 4% of cases arise from the urothelial lining of the prostatic urethra.

• Most prostate cancers are multifocal.

• The doubling time in early-stage disease is as slow as 2-4 years, but increases as tumors become more aggressive.

• Hormonal causes have also been postulated because androgen ablation causes a regression of prostate cancer, and eunuchs do not develop adenocarcinoma of the prostate.

Anatomy

Work-up• History

– Symptoms• Local

– Asymptomatic (47%)– Urinary frequency (38%)– Decreased urine stream (23%)– Urinary urgency (10%)

• Metastatic– Loss of appetite– Bone pain w/wo pathologic fracture (mets to bone)– Lower extremity pain– Uremic symptoms from obstruction

» Local (prostate growth)» Retroperitoneal (adenopathy d/t nodal metastasis)

– Signs• Hematuria (1.4%)• Weight loss• Lower extremity edema

Differential Diagnoses

• Prostate CA

• Benign Prostatic Hypertrophy (BPH)

• Prostatitis

• Prostatic calculi

• Prostatic cysts

• Prostatic tuberculosis

Work-up• Physical

– Complete exam• Distended bladder (d/t outlet obstruction) • Bone pain• Lower extremity lymphedema or DVT • Neurologic findings of cord compression • Cachexia

– Digital Rectal Exam (DRE)• Normal rectal examination findings:

– Strong sphincter tone, no rectal mass, prostate palpable» Symmetrically rounded, smooth, firm (not hard)

about the size of a walnut with a palpably discernible sulcus; non-tender.

» No nodules/masses– Heme (-) stool

• Abnormal prostate findings– Prostate enlarged, irregular or asymmetrical, nodule(s)– Probably not tender

– Many cancers are found in prostates that feel normal!

Anatomy

Work-up• Laboratory

– Prostate-Specific Antigen (PSA) w/ free-to-total PSA ratio - Most PSA is produced in the TZ; therefore, Cancers developing in the TZ tend to produce large amounts of PSA. Unfortunately, a relatively small amount is produced in the PZ, which is where 80% of prostate cancers originate.

– CBC

– Chemistry profile

– Liver function tests

– Urinalysis

– Urine culture if S/S of infection

Prostate-Specific Antigen (PSA)• Not cancer specific!• The upper limit of normal for PSA is 4 ng/mL; however, some

advocate age-related cutoffs:

– 2.5 ng/mL for the fifth decade of life;

– 3.5 ng/mL for the sixth decade of life;

– 4.5 ng/mL for the seventh decade of life; and

– 6.5 ng/mL for the eighth decade of life.

• The measurement of bound and free PSA is a recent development that can help to differentiate cancer from BPH. The lower the ratio of free-to-total PSA, the higher the likelihood of cancer because cancer cells tend to lose their ability to shed tumor markers as they increase in severity.

– > 25% free PSA, only 8% have cancer

– < 10% free PSA, > 25% have cancer

• Free PSA is most useful in patients who have a PSA level in the range of 4-10 ng/mL with enlarged prostate glands on exam.

• PSA > 10 ng/mL are more likely to progress to advanced cancer

Prostate-Specific Antigen (PSA)• Increased PSA

– Ejaculation• Returns to original levels within 48 hrs (t1/2 ~ 2.2-3.2 days). • Free PSA (fPSA) returns to baseline at 6 hours because of

its shorter half-life (t1/2 ~ 2 hrs). – Acute prostatitis, subclinical or chronic prostatitis, and urinary

retention – Prostate needle biopsy

• No significant change – DRE (w/o massage), – Cystoscopy, urethral catheterization, or TRUS

• Decreased PSA– 5-alpha reductase inhibitors [finasteride (Proscar), dutasteride

(Avodart)] decrease PSA levels by 50% (range: 20%-80%) in most men with BPH after a 6-month course of therapy, after which the level remains stable.

• The mean percent of free PSA is not affected significantly by 5-alpha reductase therapy.

– Return to the baseline level depends on the precipitating event (e.g. biopsy, D/C meds, or infection may take 2-8 wks).

Work-up• Imaging studies

– Transrectal ultrasonography (TRUS)• TRUS is used for guiding needle biopsy of prostate.• It is not specific enough for diagnostic purposes. • Hypoechoic areas are commonly associated with cancers. • At least 6-10 systematic biopsy specimens of peripheral and

(occasionally) transitional zones.• Samples should include most areas of the gland regardless

of ultrasonographic abnormalities.

Work-up• Imaging studies

– Others used for baseline or treatment response

• Abdominal/Pelvic CT or MRI may reveal extracapsular extension, seminal vesicle involvement, lymph node enlargement, liver metastases, or hydronephrosis due to ureteral obstruction.

• Bone scan

– Limited value in patients with a Gleason score < 6 and a PSA level of less than 20 ng/mL; but may be if > 6, regardless of PSA.

– Baseline for treatment response in patients with recurrent metastatic disease at high risk of having bone metastases.

– Indicated in patients with prostate cancer who have symptoms suggesting bone metastases.

• Chest X-ray used as a baseline or to help reveal rare pulmonary metastases in select cases.

Bone metastases on bone scan

Metastasis to the thoracic spine and 12th rib represented by the increased uptake of the isotope.

Histologic Grading System• The Gleason Score is the most common classification

used to determine the histological characteristics of prostate cancer.

• A grade of 1-5 is assigned to the glandular architecture of the tumor.

– Grade 1 indicates normal to Grade 5, which indicates the absence of any glandular pattern.

– The sum of the most predominant grade and the second most common histologic pattern determines the Gleason score.

• 2-4: low grade or well differentiated.

• 5-7: moderate grade or moderately differentiated.

• 8-10: high grade or poorly differentiated.

• Patients with a Gleason score of 6 or higher are likely to progress to advanced cancer (if they have not already done so).

TNM Staging System• T: Extent of local disease

– Stage T1-2c - Organ-confined disease – Stage T3a - Extracapsular extension of the tumor – Stage T3b - Invasion of the seminal vesicle(s) – Stage T4 - Tumor fixed or tumor invading adjacent structures

other than seminal vesicles

• N: Status of regional lymph nodes

– Stage NX - Regional lymph nodes cannot be assessed – Stage N0 - No regional lymph node metastasis – Stage N1 - Regional lymph node(s) metastasis

• M: Distant metastasis

– Stage MX - Distant metastasis cannot be assessed. – Stage M0 - No distant metastasis – Stage M1 - Distant metastasis – Stage M1a - Distant metastasis other than regional lymph nodes – Stage M1b - Metastasis to bone(s) – Stage M1c - Other site(s) – Stage pM1c - Metastasis to more than 1 site

Whitmore-Jewett System• The Whitmore-Jewett classification of stages A-D is no longer

widely used because prostate cancer does not necessarily progress in a sequential manner.

• However, Stage D has been further stratified by Crawford and Blumenstein to improve understanding of a subset of patients who have hormone-insensitive prostate cancer:

– Stage D1 - Involvement of pelvic lymph nodes

– Stage D1.5 - Rising PSA level after biochemical failure

– Stage D2 - Metastatic disease to bone and other organs

– Stage D2.5 - Rising PSA after nadir level

– Stage D3 - Hormone-refractory prostate cancer

– Stage D3.5 - Sensitive to hormones

– Stage D4 - Insensitive to hormones

Treatments• Medical

– Discerning whether the patient has widely vs. locally advanced disease (T3) determines treatment options.

• Surgical

– Radical prostatectomy of T3 or greater at initial presentation has not historically been considered beneficial because of the increased probability of incomplete resection and micrometastatic disease.

– Patients with widely advanced disease were previously treated with androgen deprivation (B/L orchiectomy); however, luteinizing hormone-releasing hormone (LHRH) agonist therapy has decreased the need except in cases of spinal cord compression.

• Consultations– Medical oncologist for chemotherapy. – Radiation oncologist for palliative therapy for bone metastases,

locally extensive tumors, and on an emergent basis for spinal cord compression.

– Neurosurgeon for spinal cord compression.– Orthopedic surgeon for pathologic fractures.

Radiation• For locally advanced prostate cancer (clinical stage T3), the

accepted treatment recommendation is external beam radiotherapy (EBRT).

• Studies have suggested that the addition of androgen deprivation therapy (ADT) yield improvement in progression-free survival in these patients.

• The standard treatment consists of 2 months of ADT prior to EBRT.

• Three-dimensional conformal radiation therapy is available to increase the radiation delivered to the prostate while minimizing the exposure to the rest of the pelvic structures.

• Also used in patients with metastatic prostate cancer, hormone-refractory disease, painful bone mets, or impending spinal cord compression.

• Adverse effects of EBRT include cystitis, proctitis, enteritis, impotence, urinary retention, and incontinence.

Biochemical Failure/Recurrence • The most common presentation of advanced prostate

cancer is a patient with a rising PSA level who has failed initial local therapy.

• Although the definition is not consistent in the literature, 2 consecutive PSA level elevations is generally considered biochemical failure.

• In general:– After radical prostatectomy, PSA should be < 0.2 ng/mL. – After radiation therapy, PSA should be < 0.5 ng/mL.

• Pretreatment Gleason score, clinical stage, PSA level, and percentage of positive core biopsy results were recently found to be reliable predictors of failure following local therapy.

• A Gleason grade of 7 or less is associated with a better prognosis than a grade of 8 or more if the PSA level rise occurs after 2 years than before 2 years.

• No means of identifying recurrences limited to the pelvis is reliable.

Biochemical Failure/Recurrence • The decision algorithm for initiation of treatment for biochemical

failure is controversial. No guidelines have been set for treating patients with advanced prostate cancer in whom local therapy has failed.

• Certain factors to consider include the type of local therapy previously instituted (if any), the patient's life expectancy, likelihood of cure, risk for increased morbidity, and patient's quality of life.

• A balance between disease control and minimization of the toxicity and intolerance of the treatment is difficult to maintain.

• Therapeutic options include the following:

– LHRH agonists - 1-month, 3-month, or once-yearly depots

– Complete Androgen Blockade (CAB)-LHRH agonist with an oral antiandrogen

– Monotherapy of nonsteroidal antiandrogens

– Gonadotropin-releasing hormone (GnRH) agonist

Androgen Deprivation Therapy (ADT)

• Considered to be the primary approach in the treatment of symptomatic metastatic prostate cancer.

• Palliative not curative.

• Although it can slightly improve the likelihood of survival, most men progress to hormone-refractory prostate cancer, also termed androgen-independent cancer. These patients have disease progression despite castration levels of ADT.

• CAB recognizes the 10% contribution of adrenal androgens to the total body testosterone. A GnRH antagonist with a nonsteroidal antiandrogen is used concurrently for what was thought to be complete ADT. However, multiple randomized trials have shown conflicting findings regarding significant improvement in survival.

Hormone feedback loops

Hormone feedback loops

Hormone-refractory Prostate CA • Hormone-refractory prostate cancer is defined as:

– 2-3 consecutive rises in PSA levels obtained at intervals of greater than 2 weeks in patients with castrate serum testosterone levels; and/or,

– Documented disease progression based on findings from CT and/or bone scan, bone pain, or obstructive voiding symptoms.

– In a subgroup of patients, the PSA level does not rise at diagnosis or throughout the entire course of the disease.

• If given enough time, all patients with metastatic disease become resistant to androgen ablation.

• The median time to symptomatic progression after a rise in PSA level of more than 4 ng/mL is approximately 6-8 months, with a median time to death of 12-18 months.

• Once the patient exhibits symptoms, the median survival is less than 1 year.

• Therapeutic options are limited. There is a lack of evidence for long-term survival; therefore, the best outcome may be to improve or at least maintain their quality of life.

Hormone-refractory Prostate CA Short-term palliative response and improved quality of life in these patients is achieved presently by single or multimodal therapies.

• Bisphosphonates– Stable analogs of Ca-pyrophosphate, which inhibit osteoclastic

activity to relieving bone pain. • Chemohormonal therapy

– Docetaxel is the drug of choice over mitoxantrone in patients with advanced prostate cancer that has become hormone refractory.

» A phase 3 trial demonstrated that docetaxel plus prednisone every 3 weeks improved patient survival by 3 months over mitoxantrone plus prednisone.

» Secondary endpoints found that patients also had an improved PSA response, decreased pain, and better quality of life.

• Suramin– Acts via growth factor inhibition and remains active in hormone-

refractory cancer. • Cabazitaxel

– A microtubular inhibitor indicated in combination with prednisone for hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen.

Drugs

Gonadotropin-releasing hormone (GnRH) analogs

These agents suppress ovarian and testicular steroidogenesis by decreasing LH and FSH levels.

Leuprolide (Lupron, Viadur, Eligard)

• Dosing:

– Injection: 3.75 mg/mo IM; 11.25 mg IM q3mos; 30 mg q4mos.

– Implant: 1 implant (65 mg or 72mg) q12mos. Implant is inserted SQ in the inner aspect of the upper arm under local anesthesia through a small incision. Must be removed after 12 mo, at which time another implant may be inserted.

• Interactions: None

• Contraindications: Documented hypersensitivity, spinal cord compression.

• Pregnancy: X; contraindicated, benefit does not outweigh risk.

• Precautions: Urinary tract obstruction, tumor flare, and bone pain may occur; monitor patients for weakness and paresthesias.

Goserelin (Zoladex)

• Dosing: Injection: 3.6 mg/mo. SC or 10.8 mg q3mos.


• Contraindications: Documented hypersensitivity


• Precautions: Urinary tract obstruction, tumor flare, hypercalcemia, and bone pain may occur; monitor patients for weakness and paresthesias.

GnRH antagonist

• Slows prostate cancer growth through potent antagonistic activity against naturally occurring GnRHs by competitively blocking GnRH receptors in pituitary, which lowers serum testosterone levels by suppressing LH and FSH.

• Indicated for advanced prostate cancer in men who cannot take other hormone therapies and who either refuse surgery or are not surgical candidates.

Abarelix (Plenaxis)• Dosing: 100 mg deep IM on days 1, 15, and 29, then q4wks

for total duration of 12 wks.

– Prescribing physicians must be certified following successful completion of a safety program.

• Interactions: Other drugs that prolong QT interval (e.g. quinidine, procainamide, amiodarone, sotalol, dofetilide) may increase risk of severe arrhythmia.

• Contraindications: Documented hypersensitivity; children, women, or breastfeeding mothers.


• Precautions: Life-threatening immediate-onset systemic allergic reactions may occur following any dose, observe patient in office for at least 30 min. following administration; following treatment on day 29, monitor serum testosterone level q8wks; increased treatment duration or body weight >225 lbs. (102 kg) may decrease overall effectiveness; extended treatment may decrease bone mineral density; hot flushes, sleep disturbance, breast enlargement, or breast/nipple pain.

Bisphosphonates

• These are analogs of pyrophosphate that act by binding to hydroxyapatite in bone matrix, thereby inhibiting the dissolution of crystals.

• They prevent osteoclast attachment to the bone matrix and osteoclast recruitment and viability.

Zoledronic acid (Zometa)• Dosing: 4-8 mg IV over at least 15 min. q3wk for 9-15

mos.

– Prescribing physicians must be certified following successful completion of a safety program.

• Interactions: Concurrent administration with loop diuretics may increase risk of hypocalcemia.

• Contraindications: Documented hypersensitivity.

• Pregnancy: B; fetal risk not confirmed in studies in humans, but has been shown in some studies in animals.

• Precautions: Caution in renal insufficiency; risk of renal deterioration increased with <15 min IV infusion; flu-like syndrome (e.g. fever, arthralgias, myalgias, skeletal pain), GI reactions, anemia, insomnia, dyspnea, and electrolyte and mineral disturbances (e.g. low serum phosphate, calcium, magnesium, potassium levels) may occur.

Antiandrogens

These agents are used as combination agents to treat prostate cancer.

Bicalutamide (Casodex)• Competitively inhibits androgen activity by cytosol

androgen receptor binding.

• Dosing: 50 mg PO daily as combination therapy.

– Monotherapy with 150 mg PO daily is presently being evaluated.

• Interactions: Concurrent therapy with warfarin increases anticoagulation effects (monitor PT/INR and adjust dose, if necessary).



• Precautions: Causes less loss of libido and diarrhea; monitor LFTs; adverse effects include hot flashes, gynecomastia, breast tenderness, and nausea.

Finasteride (Proscar)• Inhibits steroid 5-α-reductase, which converts

testosterone into 5-α-dihydrotestosterone (DHT).

• Dosing: 5 mg PO daily.

– Currently under investigation as combination therapy with flutamide.

• Interactions: PSA levels decrease as much as 50% in patients with BPH treated with finasteride.



• Precautions: Caution in liver function abnormalities; adverse effects include decreased volume of ejaculate (does not appear to interfere with sexual function), decreased libido, and impotence.

Flutamide (Eulexin)• Inhibits androgen uptake or binding of androgen to target

tissues.

• Dosing: 125 mg (2 caps) PO q8h; not to exceed 750 mg/day.



• Pregnancy: D; fetal risk shown in humans, use only if benefits outweigh risk to fetus.

• Precautions: Patient should not discontinue therapy without physician's advice; causes less loss of libido and diarrhea; monitor LFTs; adverse effects include hot flashes, gynecomastia, breast tenderness, and nausea; photosensitivity may occur with prolonged exposure to sunlight or tanning equipment.

Nilutamide (Nilandron)• Blocks testosterone effects at the androgen-receptor

level.

• Dosing: 150 mg PO daily.

• Interactions: May reduce clearance and increase half-life of vitamin K antagonists, theophylline, and phenytoin, which may increase risk of toxicity.


• Pregnancy: C; fetal risk revealed in studies in animals but not established or not studied in humans, may use if benefits outweigh risk to fetus.

• Precautions: Adverse effects include severe hepatic impairment, interstitial pneumonitis, visual disturbances, and inability to adapt to darkness.

Antifungal agents

• Produce a response similar to that of antiandrogens.

• Inhibit various Cytochrome P-450 enzymes, including 11-β-hydroxylase and 17-α-hydroxylase, which in turn inhibit steroid synthesis.

Ketoconazole (Nizoral)• Broad-spectrum antifungal agent that acts on several of the P-450 enzymes,

including the first step in cortisol synthesis, cholesterol side-chain cleavage, and conversion of 11-deoxycortisol to cortisol.

• May inhibit ACTH secretion when used at therapeutic doses; therefore, causes severe adrenal suppression; therefore, must be used in conjunction with supplementary hydrocortisone.

• Dosing: 400 mg PO tid on empty stomach in combination with supplementary hydrocortisone (20 mg in morning and 10 mg in evening).

• Interactions: Isoniazid may decrease bioavailability; coadministration decreases effects of either rifampin or ketoconazole; may increase effect of anticoagulants; may increase toxicity of corticosteroids and cyclosporine (cyclosporine dose can be adjusted); may decrease theophylline levels.

• Contraindications: Documented hypersensitivity; fungal meningitis.


• Precautions: Hepatotoxicity may occur; may reversibly decrease corticosteroid serum levels (adverse effects avoided with dose of 200-400 mg/day); administer antacids, anticholinergics, or H2-blockers at least 2 hrs. after taking ketoconazole; adverse effects include GI bloating, nausea, asthenia, and hepatotoxicity.

CorticosteroidsThese agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli. They are used in combination with other agents.

Hydrocortisone (Hydrocortone, Cortef)

• Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

• Dosing: 20 mg PO in am and 10 mg PO @ hs.

• Interactions: Clearance may decrease with estrogens; may increase digitalis toxicity secondary to hypokalemia.

• Contraindications: Documented hypersensitivity; viral, fungal, or tubercular skin infections; GI ulceration.


• Precautions: Caution in hyperthyroidism, osteoporosis, peptic ulcer, cirrhosis, nonspecific ulcerative colitis, diabetes, and myasthenia gravis.

Prednisone (Deltasone, Meticorten, Orasone)

• Provides significant subjective palliation and reduces PSA levels.

• Dosing: 5 mg PO bid. (Higher doses may be used in patients with spinal cord compression or cerebral edema.)

• Interactions: Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics.

• Contraindications: Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI ulceration.

• Pregnancy: B; fetal risk not confirmed in studies in humans but has been shown in some studies in animals.

• Precautions: Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur.

Chemotherapy agents• These agents inhibit cell growth and proliferation.

• Prostate cancer has been considered essentially a chemoresistant disease because of the poor survival outcomes reported in earlier series.

• No single agent has resulted in an objective response rate of greater than 30%.

• Because of the availability of PSA testing to monitor the disease, renewed interest has been generated in this regard, and clinical trials are being conducted.

Cabazitaxel (Jevtana)• Microtubule inhibitor; binds to tubulin and promotes its assembly into

microtubules while inhibiting disassembly; results in microtubule stabilization and the inhibition of mitotic and interphase cellular functions.

• Indicated for hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen.

– A trial with mitoxantrone decreased # of deaths from 74% to 62% (-16.2%), which translates to an increased median survival +2.4 mos. (12.7 mos. to 15.1 mos.).

• Dosing:

– 25 mg/m2 IV q3wk; infuse IV over 1 hr; use in-line filter (0.22 µm) during administration.

– Reduce dose to 20 mg/m2 with prolonged or febrile neutropenia, or persistent or severe diarrhea.

– Give with prednisone 10 mg PO daily.

– Premedicate with antihistamine, corticosteroid, H2-blocker, antiemetic.

Cabazitaxel (Jevtana)• Interactions: CYP3A substrate; coadministration with

strong CYP3A inhibitors (e.g. ketoconazole, clarithromycin, nefazodone, indinavir) may decrease elimination and result in increased toxicity; CYP3A inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifampin, rifabutin, rifapentine, St. John's wort) may increase elimination and decrease effectiveness.

• Contraindications: Documented hypersensitivity to cabazitaxel or drugs formulated with polysorbate 80; neutrophil count <1500/µl.


Cabazitaxel (Jevtana)• Precautions:

– Black box warning: Neutropenic deaths have been reported (requires frequent monitoring of blood cell counts); do not give if neutrophils <1500 cells/µl; severe hypersensitivity reactions can occur and may include generalized rash/erythema, hypotension, and bronchospasm (immediately discontinue and initiate treatment as indicated).

Cabazitaxel (Jevtana)• Precautions:

– Other precautions: Extensively metabolized in liver (hepatic impairment likely to increase serum concentrations); neutropenia and febrile neutropenia, including neutropenic deaths, have been reported; monitor blood cell counts frequently to determine if initiation of G-CSF and/or dosage modification is needed; GI symptoms (i.e. N/V, diarrhea), including mortality related to diarrhea, have been reported; rehydrate and treat with antiemetics and antidiarrheals as needed; renal failure, including cases with fatal outcomes, has been reported; elderly patients (> 65 y/o) were more likely to experience fatal outcomes not related to disease progression and certain adverse reactions, including neutropenia and febrile neutropenia.

Docetaxel (Taxotere)• Binds to tubulin and stabilizes the microtubular network, leading to arrest in the G2-M

phase of the cell cycle and subsequent programmed cell death. May promote apoptosis in prostate cancer cells, such as inducing Bcl-2 phosphorylation. 100x more potent than paclitaxel.

• Median reported survival in one series was 22.8 mos.

• Dosing: 75 mg/m2 IV q7-21 days.

• Interactions: Toxicity may increase when administered concurrently with ketoconazole, erythromycin, or cyclosporine.

• Contraindications: Documented hypersensitivity to docetaxel or polysorbate 80.


• Precautions: Premedicate with oral corticosteroids starting 1 day before docetaxel administration to reduce incidence of hypersensitivity reactions and fluid retention; during first dose of docetaxel, closely monitor patients with preexisting effusions for the possibility of exacerbation of the effusion; caution when administering to patients with abnormal liver function; blood counts should be monitored and docetaxel not administered if neutrophil count is <1500/µL; adverse effects include nausea, vomiting, granulocytopenia, GI tract toxicity, fluid retention, anemia, pleural effusions, fatigue, peripheral neuropathy, dyspnea, hyperglycemia, and hyperkalemia.

Estramustine (Emcyt)• Combines estradiol and nornitrogen mustard. Relatively weak

alkylating agent with weak estrogenic activity.

– Used in combination with vinblastine, etoposide, paclitaxel, docetaxel, mitoxantrone, or corticosteroids to achieve synergistic effects.

• Dosing: 280 mg PO tid.

• Interactions: Coadministration with milk products or calcium-rich products may impair absorption.

• Contraindications: Documented hypersensitivity; thrombophlebitis; thromboembolic disorders.


• Precautions: Adverse effects include, nausea, vomiting, edema, gynecomastia, thromboembolic episodes, thrombocytopenia, granulocytopenia, and esophagitis.

Mitoxantrone (Novantrone)• Inhibits cell proliferation by intercalating DNA and inhibiting

topoisomerase II.

– In combination with glucocorticoids, has been shown to induce statistically significant response in controlling pain and improving quality of life, time to treatment failure, and time to disease progression compared with glucocorticoids alone.

• Dosing: 12 mg/m2 IV with prednisone 5 mg PO.

• Interactions: None reported.

• Contraindications: Documented hypersensitivity


• Precautions: Caution in impaired hepatic function and preexisting cardiac disease (cardiotoxicity commonly observed after cumulative dose of 120-160 mg/m2); perform baseline and follow-up cardiac function tests (i.e. 2-dimensional echocardiogram with ejection fraction measurements).

Paclitaxel (Taxol)• Mechanisms of action are tubulin polymerization and microtubule

stabilization.

• Taxanes alone or in combination with other agents have demonstrated efficacy in the treatment of hormone-refractory prostate cancer.

• Dosing: 135 mg/m2 IV over 1 hr on day 2 of each 21-d treatment cycle.

– Max. of 6 cycles of therapy have been used in combination with estramustine 280 mg tid and oral etoposide 100 mg/day for 7 days.

– Alternatively, 120 mg/m2 by IV infusion over 96 hrs on days 1-4 of each 21-day cycle combined with oral EMP 600 mg/m2/day throughout.

• Interactions: Coadministration with cisplatin may further increase myelosuppression.

• Contraindications: Documented hypersensitivity to paclitaxel or polyoxyethylated castor oil; peripheral neuropathy; bone marrow suppression; liver failure; severe cardiac disease.


• Precautions: Premedicate with steroids and H1 and H2 blockers to decrease risk of hypersensitivity reactions; myelosuppression, alopecia, arthralgia/myalgias, and cardiac arrhythmia may occur.

Immunological Agent

Autologous cellular immunotherapy is designed to stimulate a patient’s own immune system to respond against the cancer.

Sipuleucel-T (Provenge)• A new therapeutic vaccine to treat advanced (hormone refractory)

prostate cancer that stimulates the body’s immune response to prostate cancer cells.

– Indicated for asymptomatic or minimally symptomatic prostate cancer with metastases that is resistant to standard hormone treatment.

– Customized immunotherapy

• Patient’s own white blood cells are harvested, sent to a lab, and combined with a prostate cancer cell antigen.

• Activated cells are then infused back into the patient.

Sipuleucel-T (Provenge)• Average life expectancy for advanced metastatic prostate cancer is

18-24 mos.

• 22.5% reduction in the risk of death, which translates to an increased survival of ~ 4 mos.

• Dosing: Each dose contains a minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF and suspended in 250 ml lactated Ringer solution. Product potency determined by measuring increased expression of CD54 molecules (ICAM-1) on surface of APCs.

– For autologous use only; therefore, confirm patient's identity matches patient identifiers on infusion bag.

– Do not use cell filter during IV infusion.

– Premedicate with acetaminophen PO and an antihistamine to minimize risk of infusion reaction.

– Administer 3 doses IV at approximately 2-wk intervals (range: 1-15 wks).

– IV infused over 60 min.

Sipuleucel-T (Provenge)• Interactions: None

• Contraindications: None known

• Pregnancy: N/A

• Precautions: Acute infusion reactions have been observed (decrease infusion rate or stop infusion if severe, and administer supportive therapy); monitor patient for 30 min. following infusion; closely monitor if cardiac or pulmonary conditions coexist; adhering to personalized leukapheresis and infusion schedules is important; common adverse reactions (≥15%) include chills, fatigue, fever, back pain, nausea, joint ache, and headache.

Goals

A.Update the pharmacists' and technician's practical knowledge of prostate cancer and its pharmacotherapies.

B.Reinforce and encourage the pharmacists' and technician's use of patient assessment skills to identify at risk populations for prostate cancer.

C.Enhance the pharmacists' and technician's ability to monitor, identify, and intervene in issues related to the pharmacotherapy of prostate cancer.

OBJECTIVES (for pharmacists)

Upon completion, the successful pharmacist will be able to:

A1. Detail the pathophysiology of prostate cancer. SLIDE 6-12, 23

A2. Discuss in-depth the various pharmacotherapeutic strategies employed at the different stages of prostate cancer. SLIDES

38- 44

B1. Assess and counsel patients regarding the major risk factors, signs, and symptoms associated with prostate cancer. SLIDES 13-18, 25

C1. Incorporate into their practice the monitoring of patients at risk for adverse drug events related to the treatment of prostate cancer. SLIDES 33, 34, Drugs (SLIDES 45-77)

C2. Identify adverse events related to the pharmacotherapy of prostate cancer and recommend appropriate intervention strategies. Drugs (SLIDES 45-77)

OBJECTIVES (for pharmacy technicians)

Upon completion, the successful technician will be able to:

A1. Detail the anatomy and physiology of the prostate and related structures. SLIDES 6-12

B1. Incorporate into their practice the special issues associated with the compounding and dispensing of drug therapies associated with the treatment of prostate cancer. Drugs (SLIDES 45-77)

C1. Incorporate into their practice the ability to identify the at risk patient for adverse drug events, including

interactions, related to the treatment of prostate cancer. Drugs (SLIDES 45-77)

Medco CE - Prostate Cancer

Health & Medicine

treatment of prostate

advanced prostate cancer

prostate cancer cases

prostate cancer surgery

prostate contracts

prostate gland

mens health prostate

prostate ca signs