US Pharm. 2010;35(11)(Oncology suppl):9-16.
ABSTRACT: With the high costs of treatment and the large number of cases, prostate cancer places a great burden on the health care system. Therefore, it is essential to diagnose tumors at an early stage and begin therapy immediately. Various drugs are currently undergoing research and development to both treat and prevent prostate cancer. In this overview, we will discuss the risk factors for prostate cancer, current therapies, recommended treatments based upon the clinical stage of the disease, and new developments for this malignancy.
Prevalence and Economic Burden
Prostate cancer is the most common noncutaneous malignancy in males in the United States and the second leading cause of death from cancer among men, following lung cancer.1,2 Since most men die with the disease rather than from it, prostate cancer accounts for 10% of cancer-related deaths in men.1 Due to its high incidence of almost 200,000 cases per year and the substantial costs associated with treatment, approximately $7 billion is spent on prostate cancer annually.3
A study conducted in 2004 predicted that the number of men with prostate cancer is estimated to increase by more than 50% over the next 20 years.4 Furthermore, a recent global survey has shown that the incidence and mortality rates of cancers such as prostate cancer are on the rise in less developed countries and may soon surpass those of the U.S.2 With this in mind, pharmacists are very likely to encounter patients with prostate cancer and therefore should be aware of the disease path and its treatment.
Risk Factors
Apart from the well-established risk factors such as age, family history, and country of birth, evidence to support other risk factors is fairly recent.5 A number of modifiable and nonmodifiable factors, including hormonal, dietary, and environmental factors, are known to predispose men to prostate cancer. These are discussed in TABLE 1.6-26
Presentation, Diagnosis, and Staging
Prostate cancer commonly presents with dysuria combined with other obstructive symptoms and a palpable mass during a rectal examination or an elevated prostate-specific antigen (PSA) above 4 ng/mL.27 Early-stage disease is usually based upon an elevated serum PSA and/or digital rectal examination (DRE) abnormality. A patient presenting with clinical symptoms is usually an indication of more advanced disease. A biopsy gives a more confirmed diagnosis.28
The American Cancer Society (ACS) recommends that every man be given sufficient information to make an informed decision about the screening before any procedure is carried out.10 This should include information on the uncertainties, risks, and potential benefits of prostate cancer screening.29 This information should be provided to men at age 50 years if they do not have any risk factors. If patients are at an increased risk of developing prostate cancer and have a minimum 10-year life expectancy, they should be provided screening at the age of 45. This includes African American men and all men with a history of prostate cancer diagnosed in a first-degree relative younger than age 65. Patients who are at high risk and have multiple family members diagnosed with prostate cancer before the age of 65 should be given screening information at the age of 40.10 The ACS guidelines also recommend that screening should only be offered to those men who are considered to have a life expectancy of at least 10 years.10 Community-based screenings may not provide a practical means for follow-up for patients who require it; therefore, it is recommended that men who have access to regular medical care and/or health insurance should not rely solely on such events. While the ACS guidelines still recommend the PSA threshold level of 4 ng/mL, they go further to recommend screening tests, intervals for repeat testing, and follow-up of abnormal results for those who choose to be screened. These are summarized in TABLE 2.10
There are several diagnostic procedures available for prostate cancer screening. A DRE is a physical examination whereby a suitably qualified health care professional feels for lumps through the rectal area. The PSA test simply measures the amount of PSA in the blood. An elevated PSA is a useful marker of prostate cancer. The PSA is also high in men who have an infection or inflammation of the prostate or who suffer from benign prostatic hyperplasia (BPH).30 While the results of a PSA screening may be useful in reducing mortality, they are associated with a high rate of overdiagnosis and overtreatment. For this reason, complementary tests, including the PSA velocity, PSA density, and free or total PSA, should be performed. The gold standard for diagnosis of a prostate carcinoma is a transrectal ultrasound (TRUS) biopsy, which is useful in estimating the prostate volume and hence the PSA density.31
Magnetic resonance imaging (MRI) is becoming increasingly useful in diagnosing and staging prostate cancer.31 Computed tomography (CT) and positron emission tomography (PET) have little or no use in the early detection of prostate cancer. However, they may be helpful in the staging and detection of lymph nodes for distant metastases.31
The Gleason grading system scores the level of cancer based upon its microscopic appearance. The score is the sum of two figures--the most common tumor pattern and the next most common tumor pattern. It ranges from 2 to 10, with a score of 10 having the worst prognosis. The tumor, node, metastasis (TNM) system is used to stage cancers based upon the extent of the tumor (T), the extent of spread to the lymph nodes (N), and the presence of metastasis (M). A number follows each of these letters to indicate the size of the tumor and the extent of the spread. A “c” or “p” precedes this code to denote a tumor in the “clinical” or “pathological” stage. TABLE 3 summarizes the stages of cancer based upon their Gleason score and the various treatment options suggested for each.32,33
Treatment and Prevention
There are currently a number of possible management options for both low-risk and high-risk prostate cancer, and a management decision should ideally be made following input from a multidisciplinary team that includes urologists, oncologists, radiologists, pathologists, nurse specialists, and pharmacists.34 Medical therapy and prevention are primarily based upon the fact that prostate cancer is highly sensitive to hormones.35
Watchful Waiting and Active Surveillance
Watchful waiting and active surveillance are useful if the cancer is at a very early stage and expected to spread at a very slow pace. While both of these strategies do not involve active intervention and are commonly used interchangeably, there are distinct differences between the two. While watchful waiting defines the intent to treat only if metastases or a symptomatic progression appears, active surveillance aims to treat with curative intent those cancers that develop more aggressive features and are monitored more closely using follow-up examinations, PSA tests, and biopsies.33 In short, watchful waiting is a more passive approach as compared to the newer active surveillance.36
Androgen Deprivation Therapy
The normal growth and functioning of the prostate gland is primarily dependent upon androgens. Androgen deprivation therapy (ADT) targets the action of the androgen receptor by either reducing the level of circulating androgens or blocking androgen receptors. Androgen deprivation can be achieved in a number of ways, including bilateral surgical orchiectomy, medical castration, and blocking androgen receptors.34
Medical castration is achieved by the administration of a luteinizing hormone-releasing hormone (LHRH) such as leuprolide, goserelin, buserelin, or triptorelin.37 This has been common therapy for recurrent or metastatic resistant prostate cancer for many years.37 These agents stimulate the gonadotropin-releasing hormone (GnRH) levels, ultimately leading to their desensitization and hence reducing the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland.38 LHRH agonists are usually given as a monthly or trimonthly depot injection. Any initial flare of testosterone that may occur at the time of injection may be prevented using antiandrogen drugs. These drugs are associated with side effects such as erectile dysfunction, loss of libido, hot flashes, osteoporosis, weight gain, and breast swelling.34
Abarelix is a GnRH antagonist useful when rapid androgen suppression is required. It does not require coadministration with an antiandrogen since it does not cause tumor flare.38 It is available in the U.S. under the brand name of Plenaxis.
Bicalutamide is an orally administered androgen receptor blocker. In doses of 150 mg per day, it is useful as monotherapy, an alternative to surgical or medical castration, or as an adjuvant to primary radical prostatectomy or radiotherapy.39 While it helps maintain physical capacity and bone mineral density, it can cause gynecomastia and mastalgia.34 Bicalutamide should be stopped if the patient does not maintain satisfactory sexual dysfunction. Tamoxifen, anastrozole, and radiotherapy are useful in the management of gynecomastia.39 Other antiandrogens include flutamide and cyproterone. Both classes of ADT, GnRH antagonists and androgen receptor blockers, may be combined to achieve combined androgen blockade (CAB).
Although an effective measure of therapy, ADT is not without side effects. Since it reduces testosterone levels by about 95% and hence the levels of estrogen in the patient, it is accompanied by changes in body composition, increased risk of fractures, insulin resistance, and an unfavorable lipid profile. While metabolic syndrome is a risk factor for prostate cancer, hormone-modifying therapy has been linked to the development of metabolic syndrome.40,41 ADT has also been linked to the development of diabetes mellitus and cardiovascular mortality, although more research is required to validate this relationship.42 Health care providers should be aware of these long-term complications, so that early diagnosis and intervention can be achieved.41 The authors of one study recommend that baseline and serial screening tests be performed for fasting glucose, lipids, and other cardiovascular risk factors in men receiving ADT.40 In some patients, it might be advisable to perform glucose tolerance tests and cardiac evaluation tests. Both denosumab and toremifene citrate have been shown to reduce the fracture rates in men taking ADT.37
If used for prolonged periods of time, ADT can lead to the development of castration-resistant prostate cancer (CRPC), a lethal and incurable condition. Research is presently under way to combat this, and currently available effective strategies include methyl-seleninic acid (MSA), an agent the reduces the abundance of androgen receptors, and telomerase, an androgen receptor target.43
Radiotherapy
Radiotherapy has a role in different stages of prostate cancer. It may be used instead of surgical procedures, after surgery in early stage prostate cancer, in treatment of painful bone metastases in advanced metastatic prostate cancer, and combined with hormonal therapy in intermediate-risk patients. Side effects include diarrhea, mild rectal bleeding, and incontinence.
There are three types of radiotherapy: external beam radiotherapy (EBRT), intensity modulated radiation therapy, and brachytherapy. EBRT is commonly used for all stages of prostate cancer.34 Brachytherapy is well established as monotherapy in stage I and stage II or in combination with EBRT in stage II.32
Surgery and Radical Prostatectomy
The options for surgery depend upon the location of the malignancy. Bilateral surgical orchiectomy removes the testicles to decrease circulating androgens. Radical prostatectomy is the removal of the prostate gland through an incision in either the abdominal wall, known as retropubic prostatectomy, or the perineum, referred to as perineal prostatectomy. Surgical procedures are associated with loss of urinary control and sexual dysfunction.44
When compared to watchful waiting, radical prostatectomy has been associated with a lower risk of recurrence and improved survival.44 While radical retropubic prostatectomy was reserved for low-stage, low-risk prostate cancer, it is now considered first-line therapy for all strata.44
Chemotherapeutic Prevention
Considering the large burden of prostate cancer on the health care system, prevention strategies are highly valuable.
Chemotherapeutic prevention has focused on 5-alpha-reductase inhibitors, particularly finasteride and dutasteride, that block the conversion of testosterone to the more potent dihydrotestosterone (DHT).1 DHT is responsible for the enlargement of the prostate gland.1 Since prostate cancer is highly dependent upon androgens for growth, it is an excellent model for chemotherapeutic prevention. While these agents are primarily approved for the treatment of symptomatic BPH, they have shown promising results in the prevention of prostate cancer. The Prostate Cancer Prevention Trial (PCPT) showed that finasteride was effective in reducing the incidence of prostate cancer. However, the drug was associated with an increased risk of developing high-risk prostate cancer.1
The 4-year Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial showed that dutasteride shrank tumors and caused growth retardation. Furthermore, dutasteride did not reduce the incidence of high-grade cancers to a significant extent. The study concluded that dutasteride should be considered in men with both BPH and an increased risk of developing prostate cancer.45
5-alpha-reductase inhibitors are known to cause sexual dysfunction, postural hypotension, and weakness, and it is suggested that the potential benefits should be weighed against the risk of side effects before therapy is initiated.1,45
Other Prevention Strategies
The Selenium and Vitamin E Cancer Prevention Trial (SELECT) assessed the effectiveness of selenium and vitamin E in the prevention of prostate cancer in 35,533 healthy men aged 55 years or older. The results showed that when taken over a period of about 5 years, selenium (200 mcg/day) and vitamin E (400 IU/day) supplements, taken either alone or together, did not prevent prostate cancer.46
Angiogenesis Inhibitors
More recently, angiogenesis inhibitors (antiangiogenics) are being developed as chemotherapeutics available for CRPC. The formation of new blood vessels, known as angiogenesis, is essential for the growth of tumor cells. Antiangiogenics block the growth of tumors.47
Antiangiogenics may have a greater therapeutic index than chemotherapeutic agents because most mature tissues do not rely on angiogenesis and hence are not affected by angiogenesis inhibitors.47 Furthermore, antiangiogenics can arrest tumor growth without tumor regression because the tumor cells are not directly targeted. Since tumors in dormant state can rapidly grow once angiogenesis inhibitors are removed, it may be difficult to decide when to stop therapy, and patients may require higher doses of maintenance therapy.47
Contrary to initial assumptions, tumor cells can develop resistance to antiangiogenics. However, this is thought to occur through different mechanisms from that seen in chemotherapeutic drugs.47
The types of antiangiogenics available to date include vascular endothelial growth factor (VEGF)-targeted monoclonal antibodies (e.g., bevacizumab); VEGF-receptor (VEGFR) tyrosine kinase inhibitors (e.g., sorafenib, sunitinib); platelet-derived growth factor (PDGF)-targeted therapy (e.g., imatinib); thalidomide; and other agents (e.g., aflibercept, tasquinimod).47
New Therapies
Tumor flare as well as other complications caused by initial ADT drugs has led to the development of GnRH antagonists.48 Degarelix, a novel injectable GnRH-receptor antagonist, is one such drug that was recently approved by the FDA for patients with advanced prostate cancer. It does not cause tumor flare like the traditional ADT agents and has an acceptable safety profile.49 Degarelix has an immediate onset of action and causes a rapid decrease in LH and FSH. It is at least as effective as leuprolide at reducing testosterone levels to below 0.5 ng/mL.48
Additionally, several other drugs are currently undergoing clinical trials. Tremelimumab, a fully human IgG2 antibody targeted towards human cytotoxic T lymphocyte (CTLA)-associated antigen, is being developed by Pfizer for the treatment of various cancers.50 Ipilimumab is an anti-CTLA-4 monoclonal antibody undergoing phase III trials for melanoma and prostate cancer and phase II trials for lymphoma and non-small cell lung cancer (NSCLC) in the U.S.51
Lastly, drug companies are developing vaccines against prostate cancer, including a combination of granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF)-alpha vaccines.52 In 2010, Provenge (sipuleucel-T) became the first FDA-approved autologous cellular immunotherapy for the treatment of hormone-refractory prostate cancer.53 Unlike traditional prophylactic vaccines, it is a therapeutic vaccine designed to treat the disease itself.
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