Understanding Prostate Cancer

Pharmacists can and should play a vital role in educating patients about prostate specific antigen testing and current knowledge about prostate cancer.

Diagnosis, Treatment Options and Guidelines

Prostate cancer (PCa) is the secondmost common type of cancer in men in the United States. It accounts for approximately 25% of cancers and is the second-leading cause of cancer death in American men.¹ As the population ages, the number of men with PCa is expected to increase. With the current controversy over prostate specific antigen (PSA) testing, more men are likely to seek advice from health care providers when deciding to undergo prostate evaluation.

Epidemiology and Risk

The American Cancer Society’s 2012 estimates for PCa in the United States include: 241,740 new cases will be diagnosed; 28,170 men will die; and 1 man in 6 will be diagnosed with PCa during his lifetime.² PCa occurs mainly in older men with nearly two-thirds diagnosed at 65 years or older; it is rare before age 40 years.² About 1 in 36 men will die of PCa, but most men diagnosed do not die from it. In fact, more than 2.5 million men in the United States who were diagnosed with PCa are still alive today.³

The exact cause of PCa is unknown.^4-6 People with 1 or more risk factors may never get PCa, whereas others who get this cancer may have had few or no known risk factors.

Causes of PCa are not well defined, but researchers have identified the following factors^4-6:

Age. The risk of having PCa increases rapidly after age 50 years. Almost 2 of 3 prostate cancers are found in men older than 65 years.

Race/ethnicity. It occurs more often in African American men than men of other races. African American men are also more likely to be diagnosed at an advanced stage, and are more than twice as likely to die as white men.

Family history. PCa seems to run in families, suggesting that there is an inherited or genetic factor. Having a father or brother with prostate cancer more than doubles the risk of developing this disease.

Obesity. Obese men with PCa may be more likely to have advanced disease that is more difficult to treat.

Most PCas begin developing from prostate gland cells and are termed “adenocarcinoma.”^4,5 Some PCas can grow and spread quickly, but most grow slowly. In fact, autopsy studies show that many older men who died from other diseases also had prostate cancer that never affected them during their lives.

Prostate Anatomy and PSA

The prostate is a gland located in front of the rectum and below the urinary bladder.^4,7 The prostate in younger men is about the size of a walnut, but it can be much larger in older men. The prostate starts to develop before birth and grows rapidly during puberty. The main androgen, testosterone, is made in the testicles. The enzyme 5-alpha reductase converts testosterone into dihydrotestosterone (DHT).⁸ DHT is the main hormone that signals the prostate to grow.

The prostate usually grows slowly in adults. It produces fluids that protect and nourish sperm cells in semen. The inner portion of the prostate often keeps growing as men get older, which can lead to a common condition called benign prostatic hyperplasia (BPH). In BPH, the prostate tissue can press on the urethra, leading to problems passing urine. BPH is not cancer, however, and it does not develop into cancer.

PSA is a serine protease produced by the prostate and a component of seminal fluid.⁹ PSA is a substance made by both normal and cancerous cells in the prostate gland. PSA is mostly found in semen, but a small amount is also found in the blood. Since 1980, the PSA test has had a significant impact on the management of prostate cancer by allowing detection of asymptomatic disease. Conditions that may elevate PSA levels include prostate cancer, BPH, infections, trauma, ejaculation within 48 hours of serum evaluation, and age.

Normal PSA values range from 0 to 4.0 ng/mL but may be further characterized based on age and ethnicity.⁹ Men who have a PSA value lower than 2.5 ng/ mL may only need to be retested every 2 years.^10-12 Screening should be done annually for men whose PSA level is 2.5 ng/ mL or higher.

Most PCas are first found during screenings, either by PSA or digital rectal exam (DRE). The risk of having PCa goes up as the PSA level increases. When prostate cancer develops, the PSA level usually goes above 4. Approximately 15% of men with a PSA below 4 will have PCa on biopsy. Men with a PSA level between 4 and 10 have about a 1 in 4 chance of having PCa. If the PSA is greater than 10, the chance of having PCa is greater than 50%. At this level, a core needle prostate biopsy may be needed.

American Cancer Society Recommendations for Early Detection

The current recommendation is that men have a discussion with their health care provider about when to be screened for PCa. Screening usually includes a blood test for PSA and/or a DRE. This discussion should take place between 40 and 45 years of age for men at higher risk (African American men) or at age 50 years for men who are at average risk of PCa.^13,14

Diagnosis

Cancer that originates in glandular epithelial cells is called adenocarcinoma.⁵ Adenocarcinoma accounts for more than 95% of PCas. The diagnosis is accomplished by a histologic evaluation of prostate tissue sampled from a prostate needle biopsy.⁵ Transrectal ultrasoundguided needle biopsy is the most widely used method for obtaining prostatic tissue. Prostate biopsy is recommended for men with a PSA value less than or equal to 4.0 ng/mL, regardless of DRE findings. Whether PCa is suspected based on screening tests or symptoms, the actual diagnosis can only be made with a prostate biopsy.

Signs and Symptoms

Early PCas usually cause no symptoms.⁵ Some advanced PCas can slow or weaken the urinary stream or cause urination more often, especially at night. But noncancerous diseases of the prostate, such as BPH, cause these symptoms more often. Common signs and symptoms of PCa include impotence, trouble urinating, decreased force in the stream of urine, blood in the urine, blood in the semen, swelling in the legs, discomfort in the pelvic area, and bone pain.^10,15 Advanced PCa commonly spreads to the bones, which can cause pain in the hips, back (spine), chest (ribs), or other areas. Cancer that has spread to the spine can also press on the spinal nerves, causing weakness or numbness in the legs or feet, or even loss of bladder or bowel control.

Complications of PCa and/or its treatments include metastasis to nearby organs and bones. Advanced PCa can cause fatigue, weakness, weight loss, blockade of ureters, bone pain and broken bones, urinary incontinence that will likely improve over time, and erectile dysfunction (ED).⁴

PCa Grading and Gleason Score

Pathologists frequently categorize prostate biopsy results using a grading system known as the Gleason Scoring system.⁴ This system assigns a grade to the 2 largest areas in each biopsy. Grades range from 1 to 5 based on how much the cells in the cancerous tissue look like normal prostate tissue, 1 being the least aggressive and 5 being the most aggressive. The 2 numbers are added together to equal the total Gleason Score. Cancers with a Gleason Score of 6 or less are often termed well differentiated or low grade. Cancers with a score of 7 may be called moderately differentiated or intermediate grade. Cancers with scores of 8 to 10 may be called poorly differentiated or high grade. The higher the Gleason Score, the more likely it is that cancer will grow and spread quickly.

Treatment of PCa

Treatment approaches vary based on staging. Patient factors often considered include overall health status, risk benefit, extent of disease, age, competing co-modalities, and adverse reactions of therapy. The National Comprehensive Cancer Network has published the following evidence-based guidelines to aid clinicians in the decision-making process.¹⁶

Options for Localized PCa

Active surveillance.¹⁷ Active surveillance has become more common since the diagnosis of early stage PCa has increased with the advent of PSA testing. Active surveillance, formerly called “watchful waiting,” may be an appropriate alternative to definitive therapy for men with a 10-year life expectancy, low-volume PCa, low PSA, and early-stage disease. Active surveillance protocols include periodic PSA assessments, DRE, prostate biopsies, and assessments of the patient’s psychosocial, adaptive, and supportive resources. Definitive therapy should be offered to patients whose cancer is found to progress or become aggressive.

Radical prostatectomy.¹⁸ Surgical intervention for definitive treatment of PCa includes open radical prostatectomy, laparoscopic radical prostatectomy, and robot-assisted laparoscopic radical prostatectomy. Radical prostatectomy removes the entire prostate gland and seminal vesicles. A nerve-sparing approach may be used if the resection of cancer is not compromised that is nerve-sparing and the neurovascular bundles that induce erections are preserved.¹⁹ Salvage radical prostatectomy may be considered after radiation failure. Men who have ED before radical prostatectomy are more likely to have ED postoperatively and may have a longer time regaining erectile function. The rate of ED following prostatectomy is as high as 80%.²⁰

External beam radiation therapy (XRT). The goal of radiation therapy is to deliver a curative dose of radiation to the prostate without damaging surrounding tissues such as the bladder, rectum, and bowel.

Intensity modulated radiation therapy (IMRT) achieves higher prostate radiation dose and less radiation to surrounding tissue because it offers more precise control over the radiation field. Radiation regimens are formulated based on PCa risk level. XRT for the treatment of prostate cancer usually occurs 5 days a week for 4 to 6 consecutive weeks. Depending on risk, men may receive radiation to the prostate with or without treatment to the seminal vesicles and with or without androgen deprivation therapy (ADT).¹⁶ Radiation combined with ADT has improved outcomes in men with highrisk PCa compared with men undergoing radiation alone.²¹ All radiation options may also have 3 to 6 months of hormone therapy.

Radiation is contraindicated in patients who have had prior pelvic radiation or certain bowel diseases. Side effects of radiation include urinary urgency and frequency, dysuria, diarrhea, and proctitis.¹⁵ Delayed side effects include ED and change in bowel habits.¹⁵ ED can occur 6 to 8 months after completion of treatment. Onset of symptoms can occur as late as 15 years.¹⁵ The most common late genitourinary effects include dysuria and incontinence thought to be caused by edema, irritation, and inflammation to the urothelial lining.²²

Brachytherapy. Brachytherapy involves placing low-dose radioactive sources into the prostatic tissues via needles, rice-sized seeds, or wires under transrectal ultrasound guidance.⁴ Brachytherapy may be used alone or in combination with XRT. There are 2 techniques for delivering brachytherapy: low-dose rate and high-dose rate. Low-dose rate brachytherapy is a permanent implantation of “seeds,” whereas highdose-rate brachytherapy is temporary and combined with XRT.

Cryotherapy. Cryotherapy is a type of surgical intervention that involves freezing and reheating the prostate gland to kill cancer cells. Cryotherapy may be a treatment of choice for men with localized high-risk disease if radiation therapy or radical prostatectomy are contraindicated.²³ During cryotherapy, a cryoprobe is inserted into the prostate under ultrasound guidance and the prostate is frozen to a temperature of -100Ëš F to -200Ëš F for approximately 10 minutes.²³ Complications resulting from cryotherapy include ED, urinary incontinence and retention, rectal pain, and fistula.

Treatment for Advanced PCa

Advanced PCa refers to recurrent PCa following definitive therapy, locally recurrent disease, systemic recurrence, or clinical recurrence. Treatment for these conditions includes hormone therapy, chemotherapy, and newer therapies.

Hormone Therapy

The goal of ADT is to reduce the levels of male hormones, especially testosterone, and includes therapy that prevents androgens from activating the androgen receptor.²⁴ Cutting off the supply of hormones may cause cancer cells to die or to grow more slowly. Castration may be accomplished surgically with orchiectomy or chemically with luteinizing hormone-releasing hormone (LHRH) agonists. Commonly used LHRH agonist drugs include leuprolide, goserelin, buserelin, triptorelin, and histrelin. LHRH agonists may be used as monotherapy or in combination with a nonsteroidal antiandrogen for combined androgen blockage.

Data suggest antiandrogens decrease the “flare” effect associated with LHRH agonists in patients with bone metastases.²⁴ Examples include flutamide, bicalutamide, and nilutamide. LHRH antagonists block gonadotropin-releasing hormone receptors in the pituitary, which decreases the luteinizing hormone, follicle stimulating hormone, and testosterone. Degarelix is the available agent in this category. Symptomatic men with advanced disease without metastasis should be started on ADT.²⁵

PCa responds well to chemical castration for an average of 2 to 3 years before PSA levels increase.²⁵ Once this occurs, patients are considered to have hormone refractory disease. In these patients, some cancer cells continue to respond to LHRH agonists, so primary ADT should be continued. Treatment options for men with hormone refractory disease include secondary hormone therapy with a different antiandrogen such as aminogluthimide or a combination of ketoconazole and steroids. Depending on patient symptoms, PSA velocity, and PSA doubling time, clinicians should evaluate for metastatic disease with a bone scan and CT scan. ADT is accompanied with acute and long-term side effects that may significantly impact quality of life. Acute toxicities include fatigue, hot flashes, ED, loss of bone mass, weight gain, and flare effect. Long-term consequences of ADT include hyperlipidemia, insulin resistance, cardiovascular disease, anemia, osteoporosis, sexual dysfunction, and cognitive deficits.²⁵

Chemotherapy

Chemotherapy is used to treat men with hormone refractory metastatic PCa, with docetaxel-based regimens as standard of care.²⁶ Docetaxel every 3 weeks plus prednisone was found to be superior to weekly docetaxel and mitoxantrone in a clinical trial comparing the 3 regimens. Improvements were reported in quality of life and overall survival.²⁶ Adverse effects associated with docetaxel, such as bone loss, should be considered for bisphosphonate therapy with zoledronic acid.²⁷

Emerging Therapies

High-intensity focused ultrasound (HIFU) is a transrectal procedure that ablates prostate tissue using heat and cavitation and is an option for men with low-risk PCa. In a recent study, patients were treated with HIFU for PCa; 5-year follow-up showed an 81% negative biopsy rate.²¹ The authors concluded that, based on their data, outcomes of transrectal HIFU are similar to other nonsurgical options for the treatment of PCa.^28,29 Adverse effects of HIFU include urinary retention, bladder outlet obstruction, urinary incontinence, and ED. HIFU use has been limited.²⁹

Cabazetaxel. In 2010, cabazetaxel was approved in the United States for secondline use in the treatment of advanced hormone-refractory prostate cancer in men who have already been treated with docetaxel.³⁰ Adverse effects of cabazetaxel include neutropenia, gastrointestinal disturbance, and renal insufficiency.

Abiraterone. Abiraterone acetate is an oral androgen biosynthesis inhibitor for the treatment of advanced metastatic castrate-resistant PCa that has failed conventional hormonal therapy. It is believed that abiraterone acetate inhibits cytochrome P450 17, an enzyme needed for androgen synthesis in the testes, adrenals, and tumor.³¹

Denosumab. Denosumab is a monoclonal antibody that targets a protein involved in cancer-related bone destruction called human receptor activator of nuclear factor kappa-B ligand. Denosumab is approved by the FDA to prevent skeletal related events in prostate cancer patients with bone metastases. Serious adverse effects associated with denosumab include hypocalcemia and osteonecrosis of the jaw.³²

Sipuleucel-T. Sipuleucel-T is a vaccine recently approved by the FDA for the treatment of metastatic castrationresistant PCa. The vaccine is designed to boost the patient’s immune system to target and destroy PCa cells and is administered intravenously in 3 doses over a 1-month period.³³ The side effect profile is considered favorable in comparison with chemotherapeutics such as docetaxel. Researchers reported that the vaccine increases median survival in this population by 4.1 months when compared with men in a placebo control group.³³

The Pharmacist’s Role

Pharmacist can play a vital role in educating patients on PCa and different treatment options and answering related questions. Men should be educated regarding the need for routine PSA and/or DRE screening. Men treated for prostate cancer should be counseled about potential complications and frequently assessed for possible side effects of therapies that may impact quality of life, including urinary incontinence, erectile disjunction, compromised bone health, and the inherent uncertainty of active surveillance. Clinicians should consider obtaining a baseline and periodic bone density scan to evaluate for treatment-related osteoporosis.

Mr. Brown is professor emeritus of clinical pharmacy and a clinical pharmacist at Purdue University College of Pharmacy, Nursing, and Health Sciences, Department of Pharmacy Practice, in West Lafayette, Indiana.

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