Trevor McKibbin and Jill M. Kolesar
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. List the risk factors associated with the development of prostate cancer.
2. Compare placebo versus finasteride for the prevention of prostate cancer.
3. Recommend a prostate cancer screening program for a man on the basis of his age and risk factors.
4. Recommend a treatment for initial treatment of prostate cancer on the basis of stage, Gleason score, age, and symptoms.
5. Understand the role of chemotherapy in the treatment of metastatic hormone-refractory prostate cancer.
KEY CONCEPTS
Prostate cancer is the most frequent cancer in U.S. men. African American ancestry, family history, and increased age are the primary risk factors for prostate cancer.
Prostate-specific antigen (PSA) is a useful marker for detecting prostate cancer at early stages, predicting outcome for localized disease, defining disease-free status, and monitoring response to androgen-deprivation therapy or chemotherapy for advanced-stage disease.
The prognosis for prostate cancer patients depends on the histologic grade, the tumor size, and disease stage. More than 85% of patients with stage A1 disease but less than 1% of those with stage D2 can be cured.
Androgen ablation with a luteinizing hormone–releasing hormone (LHRH) agonist plus an antiandrogen should be used prior to radiation therapy for patients with locally advanced prostate cancer to improve outcomes over radiation therapy alone.
Androgen ablation therapy, with orchiectomy, an LHRH agonist alone or an LHRH agonist plus an antiandrogen (combined hormonal blockade), can be used to provide palliation for patients with advanced (stage D2) prostate cancer. The effects of androgen deprivation seem most pronounced in patients with minimal disease at diagnosis.
Antiandrogen withdrawal, for patients having progressive disease while receiving combined hormonal blockade with an LHRH agonist plus an antiandrogen, can provide additional symptomatic relief. Mutations in the androgen receptor have been documented that cause antiandrogen compounds to act like receptor agonists.
Chemotherapy with docetaxel and prednisone improves survival in patients with hormone-refractory prostate cancer.
INTRODUCTION
Prostate cancer is the most commonly diagnosed cancer in U.S. men.1 For most men, prostate cancer has an indolent course, and treatment options for early disease include expectant management, surgery, or radiation. With expectant management, patients are monitored for disease progression or development of symptoms. Localized prostate cancer can be cured by surgery or radiation therapy; advanced prostate cancer is not yet curable. Treatment for advanced prostate cancer can provide significant disease palliation for many patients for several years after diagnosis. The endocrine dependence of this tumor is well documented, and hormonal manipulation to decrease circulating androgens remains the basis for the initial treatment of advanced disease.
EPIDEMIOLOGY AND ETIOLOGY
Prostate cancer is the most frequent cancer among U.S. men and represents the second leading cause of cancer-related deaths in all males.1 In the United States alone, it is estimated that 192,280 new cases of prostatic carcinoma will be diagnosed and more than 27,360 men will die from this disease in 2009.1 Although prostate cancer incidence increased during the late 1980s and early 1990s owing to widespread prostate-specific antigen (PSA) screening, deaths from prostate cancer have been declining since 1995.1
Table 92–1 summarizes the possible factors associated with prostate cancer.2,3 The widely accepted risk factors for prostate cancer are age, race ethnicity, and family history of prostate cancer.2,3 The disease is rare under the age of 40, but the incidence sharply increases with each subsequent decade, most likely because the individual has had a lifetime exposure to testosterone, a known growth signal for the prostate.3
Race and Ethnicity
The incidence of clinical prostate cancer varies across geographic regions. Scandinavian countries and the United States report the highest incidence of prostate cancer, while the disease is relatively rare in Japan and other Asian countries.4 African American men have the highest rate of prostate cancer in the world, and in the United States, prostate cancer mortality in African Americans is more than twice that seen in Caucasian populations.1 Hormonal, dietary, and genetic differences, as well as differences in access to health care, may contribute to the altered susceptibility to prostate cancer in these populations.2,3Testosterone, commonly implicated in the pathogenesis of prostate cancer, is 15% higher in African American men compared with Caucasian males. Activity of 5-α-reductase, the enzyme that converts testosterone to its more active form, dihydrotestosterone (DHT), in the prostate, is decreased in Japanese men compared with African Americans and Caucasian.2,3 In addition, genetic variations in the androgen receptor exist. Activation of the androgen receptor is inversely correlated with trinucleotide (CAG) repeat length. Shorter CAG repeat sequences have been found in African Americans. Therefore, the combination of increased testosterone and increased androgen receptor activation may account for the increased risk of prostate cancer in African American men.2,3 The Asian diet generally is considered to be low in fat and high in fiber with a high concentration of phytoestrogens, potentially explaining their decreased risk.4,5
Table 92–1 Risk Factors Associated With Prostate Cancer
Family History
Men with a brother or father with prostate cancer have twice the risk for prostate cancer compared to the rest of the population.5 There appears to be a familial clustering of a prostate cancer syndrome and genome-wide scans have identified potential prostate cancer susceptibility candidate genes. Male carriers of germline mutations of BRCA1 and BRCA2 are known to have an increased risk for developing prostate cancer.6 Common exposure to environmental and other risk factors may also contribute to increased risk among patients with first degree relatives with prostate cancer.5,7
An alternative explanation for the familial clustering may be polymorphisms in genes important for prostate cancer function and development.5,7 Candidate polymorphisms include a polymorphism in the androgen receptor, which has two different nucleotide repeat variants, the CAG or the GCC. The CAG repeat varies in repeat number from 11 to 31 repeats in healthy individuals, and the number of repeats is inversely proportional to the activity of the androgen receptor. Some studies have demonstrated that shorter CAG repeats are associated with increased prostate cancer risk. Another candidate polymorphism is SRD5A2, which is the gene that codes for 5-α-reductase, the enzyme that converts testosterone to the more active DHT. A variant in SRD5A2, the Ala49Thr, increases the activity and may increase prostate cancer risk.5,7
Diet
A number of epidemiologic studies support an association between high-fat intake and risk of prostate cancer. A strong correlation between national per capita fat consumption and national prostate cancer mortality has been reported, and prospective case-control studies suggest that a high-fat diet doubles the risk of prostate cancer.5,8 This relationship between high-fat intake and prostate cancer may explain differences in insulin-like growth factor-1 (IGF-1). High-calorie and high-fat diets stimulate production of IGF-1 by the liver. This factor is involved in the regulation of proliferation of cancer cells and may also prevent them from undergoing apoptosis.5,8 High levels of IGF-1 are associated with an increased risk for prostate cancer.5
Other dietary factors implicated in prostate cancer include retinol, carotenoids, lycopene, and vitamin D consumption.5,7,9 Retinol, or vitamin A, intake, especially in men older than 70, is correlated with an increased risk of prostate cancer, whereas intake of its precursor, β-carotene, has a protective or neutral effect. Lycopene, obtained primarily from tomatoes, decreases the risk of prostate cancer in small cohort studies. Men who developed prostate cancer in one cohort study had lower levels of 1,25(OH)2-vitamin D than matched controls, although a prospective study did not support this. Clearly, dietary risk factors require further evaluation, but because fat and vitamins are modifiable risk factors, dietary intervention may be promising in prostate cancer prevention. Investigations of selenium and vitamin E supplementation are discussed further in the chemoprevention section.
Other Factors
Benign prostatic hyperplasia (BPH) is a common problem among elderly men, affecting more than 40% of men over the age of 70. BPH results in the urinary symptoms of hesitancy and frequency. Since prostate cancer affects a similar age group and often has similar presenting symptoms, the presence of BPH often complicates the diagnosis of prostate cancer, although it does not appear to increase the risk of developing prostate cancer.2,7
Smoking has not been associated with an increased risk of prostate cancer, but smokers with prostate cancer have an increased mortality resulting from the disease when compared with nonsmokers with prostate cancer (relative risk 1.5–2).2,7 In addition, in a prospective cohort analysis, alcohol consumption was not associated with the development of prostate cancer.
Chemoprevention
Currently, the most promising agents for the prevention of prostate cancer are the 5-α-reductase inhibitors, finasteride and dutasteride.7,10,11 These medications work by inhibiting 5-α-reductase, an enzyme that converts testosterone to its more active form, DHT, which is involved in prostate epithelial proliferation. There are two types of 5-α-reductase, type I and type II; both are implicated in the development of prostate cancer. Finasteride selectively inhibits the 5-α-reductase type-II isoenzyme, whereas dutasteride inhibits both isoenzymes.11 Both finasteride and dutasteride falsely lower the PSA in patients and this needs to be adjusted for when measuring the PSA in patients on these medications.7,11
The Prostate Cancer Prevention Trial (PCPT) compared finasteride 5 mg daily for 7 years to placebo for the prevention of prostate cancer.7 When compared to placebo, the point prevalence of prostate cancer was reduced for those on finasteride by 24.8% (95% confidence interval [CI] 18.6–30.6%) (hazard ratio 0.75). However, in those that did develop prostate cancer, there was an increase in the number of high-grade (Gleason grade 7–10) tumors detected at biopsy in the finasteride group. Overall, finasteride did reduce the frequency of prostate cancer; however, the prostate cancers that were diagnosed in the finasteride group were more aggressive.
The use of finasteride to prevent prostate cancer is the subject of a recent joint consensus statement. The American Society of Clinical Oncology (ASCO) and the American Urological Association (AUA) used the results from a systematic review of the literature to develop evidence-based recommendations for the use of 5-α-reductase inhibitors for prostate cancer chemoprevention. 5-α-reductase inhibitors decrease the period prevalence of for-cause prostate cancer by approximately 26% (relative risk 0.74; 95% CI, 0.67–0.83). The absolute risk reduction is about 1.4% (4.9% in controls versus 3.5% in the treatment arms), although this may vary with the age of the treated population. On the basis of these outcomes, ASCO and AUA recommend that asymptomatic men with a PSA less than or equal to 3 ng/mL, who are regularly screened with PSA, may benefit from a discussion of both the benefits of 5-α-reductase inhibitors for 7 years for the prevention of prostate cancer and the potential risks (including the possibility of high-grade prostate cancer). Men who are taking 5-α-reductase inhibitors for benign conditions such as lower urinary tract symptoms may benefit from a similar discussion, understanding that the improvement of symptoms should be weighed with the potential risks of high-grade prostate cancer.
Selenium and vitamin E alone or in combination were evaluated in the Selenium and Vitamin E C ancer Prevention Trial (SELECT), a clinical trial investigating their effects on the incidence of prostate cancer. The data and safety monitoring committee found that after 5 years selenium and vitamin E taken alone or together did not prevent prostate cancer. On the basis of these data and safety concerns, the trial was halted.12 Other agents, including vitamin D, lycopene, green tea, nonsteroidal anti-inflammatory agents, isoflavones, and statins, are under investigation for prostate cancer and show promise; however, none are currently recommended for routine use outside of a clinical trial.13
Screening
Early detection of potentially curable prostate cancers is the goal of prostate cancer screening. For cancer screening to be beneficial, it must reliably detect cancer at an early stage, when intervention would decrease mortality. Whether prostate cancer screening fits these criteria has generated considerable controversy.14 Digital rectal examination (DRE) has been recommended since the early 1900s for the detection of prostate cancer. The primary advantage of DRE is its specificity, reported at greater than 85%, for prostate cancer. Other advantages of DRE include low cost, safety, and ease of performance. However, DRE is relatively insensitive and is subject to interobserver variability. DRE as a single screening method has poor compliance and had little effect on preventing metastatic prostate cancer in one large case-control study.15
Prostate-specific antigen is a useful marker for detecting prostate cancer at early stages, predicting outcome for localized disease, defining disease-free status, and monitoring response to androgen-deprivation therapy or chemotherapy for advanced-stage disease. PSA is used widely for prostate cancer screening in the United States, with simplicity as its major advantage and low specificity as its primary limitation.16 PSA may be elevated in men with acute urinary retention, acute prostatitis, and prostatic ischemia or infarction, as well as BPH, a nearly universal condition in men at risk for prostate cancer. PSA elevations between 4.1 ng/mL (4.1 mcg/L) and 10 ng/mL (10 mcg/L) cannot distinguish between BPH and prostate cancer, limiting the utility of PSA alone for the early detection of prostate cancer. Additionally, only 38% to 48% of men with clinically significant prostate cancer have a serum PSA outside the reference range.17
Neither DRE nor PSA is sensitive or specific enough to be used alone as a screening test. Although the relative predictability of DRE and PSA is similar, the tumors identified by each method are different. Catalona and associates18 confirmed that the combination of a DRE plus PSA determination is a better method of detecting prostate cancer than DRE alone.
The common approach to prostate cancer screening today involves offering a baseline PSA and DRE at the age of 40 with annual evaluations beginning at the age of 50 to all men of normal risk with a 10-year or greater life expectancy. Men with an increased risk of prostate cancer, including men of African American ancestry and men with a family history of prostate cancer, may begin screening earlier, at age 40 to 45.
Despite this common practice, the benefits of prostate cancer screening are unproven.19 PSA measurements can identify small, subclinical prostate cancers, where no intervention may be required. Detecting prostate cancer in those not needing therapy not only increases the cost of care through unnecessary screening and workups but also increases the toxicity of therapy, by subjecting some patients to unnecessary therapy.20,21 Currently, the American College of Physicians recommends that rather than screening all men for prostate cancer as a matter of routine, physicians should describe the potential benefits and known risks of screening, diagnosis, and treatment, listen to the patient’s concerns, and then decide on an individual’s screening method.
Patient Encounter 1: Prevention and Screening
OC is a 66-year-old Caucasian male who comes into the pharmacy requesting some “vitamins” for prostate health. He is interested in lycopene, zinc, selenium, and finasteride.
OC does not have a family history of prostate cancer and no symptoms suggestive of BPH. He has never been screened for prostate cancer.
What do you recommend for prostate cancer screening?
What do you recommend for prostate cancer chemoprevention?
PATHOPHYSIOLOGY
The prostate gland is a solid, rounded, heart-shaped organ positioned between the neck of the bladder and the urogenital diaphragm (Fig. 92–1). The normal prostate is composed of acinar secretory cells arranged in a radial shape and surrounded by a foundation of supporting tissue. 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.22,23 Much rarer tumor types include small-cell neuroendocrine cancers, sarcomas, and transitional cell carcinomas.
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.23,24 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).
FIGURE 92–1. The prostate gland. (From DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach, 6th ed. New York: McGraw-Hill, 2005: 1856.)
Metastatic spread can occur by local extension, lymphatic drainage, or hematogenous dissemination.24,25 Lymph node metastases are more common in patients with large, undifferentiated tumors that invade the seminal vesicles. The pelvic and abdominal lymph node groups are the most common sites of lymph node involvement (Fig. 92–1). Skeletal metastases from hematogenous spread are the most common sites of distant spread. Typically, the bone lesions are osteoblastic or a combination of osteoblastic and osteolytic. The most common site of bone involvement is the lumbar spine. Other sites of bone involvement include the proximal femurs, pelvis, thoracic spine, ribs, sternum, skull, and humerus. The lung, liver, brain, and adrenal glands are the most common sites of visceral involvement, although these organs usually are not involved initially. About 25% to 35% of patients will have evidence of lymphangitic or nodular pulmonary infiltrates at autopsy. The prostate is rarely a site for metastatic involvement from other solid tumors.
Normal growth and differentiation of the prostate depends on the presence of androgens, specifically DHT.25,26 The testes and the adrenal glands are the major sources of circulating androgens. Hormonal regulation of androgen synthesis is mediated through a series of biochemical interactions between the hypothalamus, pituitary, adrenal glands, and testes (Fig. 92–2). 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. LH complexes with receptors on the Leydig cell testicular membrane and stimulates the production of testosterone and small amounts of estrogen. FSH acts on the Sertoli cells within the testes to promote the maturation of LH receptors and to produce an androgen-binding protein. Circulating testosterone and estradiol influence the synthesis of LHRH, LH, and FSH by a negative feedback loop operating at the hypothalamic and pituitary level.27Prolactin, growth hormone, and estradiol appear to be important accessory regulators for prostatic tissue permeability, receptor binding, and testosterone synthesis.
FIGURE 92–2. Hormonal regulation of the prostate gland. ACTH, adrenocorticotropic hormone; DHT, dihydrotestosterone; FSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; LHRH, luteinizing hormone–releasing hormone; PROL, prolactin; R, receptor. (From DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach, 6th ed. New York: McGraw-Hill, 2005: 1856.)
Testosterone, the major androgenic hormone, accounts for 95% of the androgen concentration. The primary source of testosterone is the testes; however, 3% to 5% of the testosterone concentration is derived from direct adrenal cortical secretion of testosterone or C19 steroids such as androstenedione.24–26
In early stage prostate cancers, aberrant tumor cell proliferation is promoted by the presence of androgens. For these tumors, blockade of androgens induces tumor regression in most patients. Hormonal manipulations to ablate or reduce circulating androgens can occur through several mechanisms25,26 (Table 92–2). The organs responsible for androgen production can be removed surgically (orchiectomy, hypophysectomy, or adrenalectomy). Hormonal pathways that modulate prostatic growth can be interrupted at several steps (see Fig. 92–2). Interference with LHRH or LH (by estrogens, LHRH agonists, progesterones, and cyproterone acetate) can reduce testosterone secretion by the testes. Estrogen administration reduces androgens by directly inhibiting LH release, by acting directly on the prostate cell, or by decreasing free androgens by increasing steroid-binding globulin levels.24–26
Table 92–2 Hormonal Manipulations in Prostate Cancer
Isolation of the naturally occurring hypothalamic decapeptide hormone LHRH has provided another group of effective agents for advanced prostate cancer treatment. The physiologic response to LHRH depends on both the dose and the mode of administration. Intermittent pulsed LHRH administration, which mimics the endogenous release pattern, causes sustained release of both LH and FSH, whereas high dose or continuous IV administration of LHRH inhibits gonadotropin release due to receptor downregulation.19 Structural modification of the naturally occurring LHRH and innovative delivery have produced a series of LHRH agonists that cause a similar downregulation of pituitary receptors and a decrease in testosterone production.27
Androgen synthesis can also be inhibited in the testes or adrenal gland. Aminoglutethimide inhibits the desmolase-enzyme complex in the adrenal gland, thereby preventing the conversion of cholesterol to pregnenolone. Pregnenolone is the precursor substrate for all adrenal-derived steroids, including androgens, glucocorticoids, and mineralo corticoids. Ketoconazole, an imidazole antifungal agent, causes a dose-related reversible reduction in serum cortisol and testosterone concentration by inhibiting both adrenal andtesticular steroidogenesis.28 Megestrol is a synthetic derivative of progesterone that exhibits a secondary mechanism of action by inhibiting the synthesis of androgens. This inhibition appears to occur at the adrenal level, but circulating levels of testosterone also are reduced, suggesting that inhibition at the testicular level also may occur.28
Antiandrogens inhibit the formation of the DHT-receptor complex and thereby interfere with androgen-mediated action at the cellular level.28 Megestrol acetate, a progestational agent, also is available and has antiandrogen actions.28 Finally, the conversion of testosterone to DHT may be inhibited by 5-α-reductase inhibitors.7
In advanced stages of the disease, prostate cancer cells may be able to survive and proliferate without the signals normally provided by circulating androgens.29 When this occurs, the tumors are no longer sensitive to therapies that are dependent on androgen blockade. These tumors are often referred to as hormone refractory or androgen independent.
CLINICAL PRESENTATION AND DIAGNOSIS
Prior to the implementation of routine screening, prostate cancers were frequently identified on the investigation of symptoms including urinary hesitancy, retention, painful urination, hematuria, and erectile dysfunction. With the introduction of screening techniques, most prostate cancers are now identified prior to the development of symptoms.30
The information obtained from the diagnostic tests is used to stage the patient. There are two commonly recognized staging classification systems (Table 92–3). The formal international classification system (tumor, node, metastases; TNM), adopted by the International Union Against Cancer in 1974, was last updated in 2002. The AUA classification is the most commonly used staging system in the United States (Table 92–4). Patients are assigned to stages A through D and corresponding subcategories based on the size of the tumor (T), local or regional extension, presence of involved lymph node groups (N), and presence of metastases (M). Some studies classify patients who have progressed after hormonal therapy as stage D3.31 On the basis of men diagnosed with prostate cancer at Walter Reed Army Medical Center from 1988 to 1998, including over 2,042 prostate cancer diagnoses, localized prostate cancer (stage T1 and T2) was diagnosed more frequently (89% versus 68%), and advanced disease (stages T3, T4, and D) was diagnosed less frequently (11% versus 32%) when comparing the incidence rates in 1998 to the 1988 rates31.
Clinical Presentation of Prostate Cancer
Localized Disease
Asymptomatic
Locally Invasive Disease
Ureteral dysfunction, frequency, hesitancy, and dribbling Impotence
Advanced Disease
Back pain
Cord compression
Lower extremity edema
Pathologic fractures
Anemia
Weight loss
Table 92–3 Diagnostic and Staging and Classification Systems Workup for Prostate Cancer
The prognosis for patients with prostate cancer depends on the histologic grade, tumor size, and local extent of the primary tumor.23 The most important prognostic criterion appears to be the histologic grade because the degree of differentiation ultimately determines the stage of disease. Poorly differentiated tumors are highly associated with both regional lymph node involvement and distant metastases.23
Table 92–4 Staging and Classification Systems for Prostate Cancer
During 1996 to 2003, 5-year overall survival rates were estimated at 99% for whites and 95% for African Americans.1 For this same period, the survival rates for localized or regional disease (100%) and distant disease (31%) in white males were about the same as the survival rates for localized or regional disease (100%) and distant disease (26%) in African American males.1 A 4.1% decline in age-adjusted mortality has been documented for the period 1994 to 2004. 10-year cancer-specific survival is estimated as 95% for stage A1, 80% for stages A2 to B2, 60% for stage C, 40% for stage D1, and 10% for stage D2.32 It is estimated that more than 85% of patients with stage A1 can be cured, whereas fewer than 1% of patients with stage D2 will be cured.
TREATMENT
Desired Outcome
The desired outcome in early stage prostate cancer is to minimize morbidity and mortality due to prostate cancer.33 The most appropriate therapy of early stage prostate cancer is a matter of debate. Early stage disease may be treated with surgery, radiation, or watchful waiting. While surgery and radiation are curative, they are associated with significant morbidity and mortality. Since the overall goal is to minimize morbidity and mortality associated with the disease, watchful waiting is appropriate in selected individuals. Advanced prostate cancer (stage D) is not currently curable, and treatment should focus on providing symptom relief and maintaining quality of life.34
General Approach to Treatment
The initial treatment for prostate cancer depends primarily on the disease stage, Gleason score, presence of symptoms, and life expectancy of the patient.33 Prostate cancer is usually initially diagnosed by PSA and DRE and confirmed by a biopsy, where the Gleason score is assigned. Asymptomatic patients with a low risk of recurrence, those with a T1 or T2a, with a Gleason score of 2 through 6, and a PSA of less than 10 ng/mL (10 mcg/L) may be managed by expectant management, radiation, or radical prostatectomy (Table 92–5). As patients with asymptomatic early stage disease generally have an excellent 10-year survival, immediate morbidities of treatment must be balanced with the lower likelihood of dying from prostate cancer. In general, more aggressive treatments of early stage prostate cancer are reserved for younger men, although patient preference is a major consideration in all treatment decisions. In a patient with a normal life expectancy of less than 10 years, expectant management or radiation therapy may be offered. In those with a normal life expectancy of equal to or greater than 10 years, either expectant management, radiation (external beam or brachytherapy), or radical prostatectomy with a pelvic lymph node dissection may be offered. Radical prostatectomy and radiation therapy generally are considered therapeutically equivalent for localized prostate cancer, although neither has been proven to be better than observation alone.34,35 Complications from radical prostatectomy include blood loss, stricture formation, incontinence, lymphocele, fistula formation, anesthetic risk, and impotence. Nerve-sparing radical prostatectomy can be performed in many patients; 50% to 80% regain sexual potency within the first year. Acute complications from radiation therapy include cystitis, proctitis, hematuria, urinary retention, penoscrotal edema, and impotence (30% incidence).23 Chronic complications include proctitis, diarrhea, cystitis, enteritis, impotence, urethral stricture, and incontinence.23 Since radiation and prostatectomy have significant and immediate mortality when compared with expectant management alone, many patients may elect to postpone therapy until symptoms develop.
Table 92–5 Management of Prostate Cancer With Low and Intermediate Recurrence Risk
Individuals with T2b and T2c disease or a Gleason score of 7 or a PSA ranging from 10 to 20 ng/mL (10–20 mcg/L) are considered at intermediate risk for prostate cancer recurrence.33 Individuals with less than a 10-year expected survival may be offered expectant management, radiation therapy, or radical prostatectomy with or without a pelvic lymph node dissection, and those with a greater than or equal to 10-year life expectancy may be offered either radical prostatectomy with or without a pelvic lymph node dissection or radiation therapy (see Table 92–5).
The treatment of patients at high risk of recurrence (stages T3, a Gleason score ranging from 8 to 10, or a PSA value greater than 20 ng/mL [20 mcg/L]) should be treated with androgen ablation for 2 to 3 years combined with radiation therapy (Table 92–6). Selected individuals with a low tumor volume may receive a radical prostatectomy with or without a pelvic lymph node dissection.
Table 92–6 Management of Prostate Cancer With High and Very High Recurrence Risk
Patients with T3b and T4 disease have a very high risk of recurrence and are not candidates for radical prostatectomy because of extensive local spread of the disease.33
Androgen ablation with a luteinizing hormone–releasing hormone (LHRH) agonist plus an antiandrogen should be used prior to radiation therapy for patients with locally advanced prostate cancer to improve outcomes over radiation therapy alone. Recent evidence suggests that androgen ablation should be instituted at diagnosis rather than waiting for symptomatic disease or progression to occur. In a randomized clinical trial enrolling 500 men with locally advanced prostate cancer, who were randomized to either immediate initiation of androgen ablation with either orchiectomy or androgen ablation, or deferred hormonal therapy, individuals with immediate therapy had a median actuarial cause-specific survival duration of 7.5 years for immediate treatment and 5.8 years for deferred treatment.36
Patient Encounter 2: Initial Presentation and Treatment
FF is a 66-year-old male who presents to the clinic complaining of impotence for the last 1 to 2 months and requesting a prescription for Cialis. Upon questioning, he gives a history of fatigue, gradual weight loss of 10 lb, and difficulty with urination that began about 6 months ago.
Physical exam is positive for a 1-cm nodule in the prostate and his laboratories reveal the following: PSA 12 ng/dL (12 mcg/L); PSA from 1 year ago was 2 ng/dL (2 mcg/L).
A prostate biopsy by transrectal ultrasound (TRUS) reveals adenocarcinoma of the prostate, with a Gleason score of 8. CT scanning and bone scan reveal disease that is metastatic to the bone, and a final stage of T4 (metastatic) prostate cancer is determined.
What is the pathophysiology underlying his clinical presentation?
Based on his stage, what are treatment options for this patient?
Androgen ablation therapy, with either orchiectomy, an LHRH agonist alone or an LHRH agonist plus an antiandrogen (combined androgen blockade), can be used to provide palliation for patients with advanced (stage D2) prostate cancer. Estrogens were once widely used; however, the primary estrogen, diethylstilbestrol (DES), was withdrawn from the U.S. market in 1997 due to the increased cardiovascular risk. Secondary hormonal manipulations, cytotoxic chemotherapy, or supportive care is used for the patient who progresses after initial therapy.37
Nonpharmacologic Therapy
Expectant Management
Expectant management, also known as observation or watchful waiting, involves monitoring the course of disease and initiating treatment if the cancer progresses or the patient becomes symptomatic. A PSA and DRE are performed every 6 months with a repeat biopsy at any sign of disease progression. The advantages of expectant management are avoiding the adverse effects associated with definitive therapies such as radiation and radical prostatectomy and minimizing the risk of unnecessary therapies. The major disadvantage of expectant management is the risk that the cancer progresses and requires a more intensive therapy.33
Orchiectomy
Bilateral orchiectomy, or removal of the testes, rapidly reduces circulating androgens to castrate levels (i.e., serum testosterone levels less than 50 ng/dL [1.74 nmol/L]).22 However, many patients are not surgical candidates owing to their advanced age, and other patients find this procedure psychologically unacceptable.22 Orchiectomy is the preferred initial treatment in patients with impending spinal cord compression or ureteral obstruction.
Radiation
The two commonly used methods for radiation therapy are external beam radiotherapy and brachytherapy.33 In external beam radiotherapy, doses of 70 to 75 Gy are delivered in 35 to 41 fractions in patient with low grade prostate cancer and 75 to 80 Gy for those with intermediate or high-grade prostate cancer. Brachytherapy involves the permanent implantation of radioactive beads of 145 Gy 125-Iodine or 124 Gy of 103-Palladium and is generally reserved for individuals with low-risk cancers.
Radical Prostatectomy
Complications from radical prostatectomy include blood loss, stricture formation, incontinence, lymphocele, fistula formation, anesthetic risk, and impotence. Nerve-sparing radical prostatectomy can be performed in many patients; 50% to 80% regain sexual potency within the first year. Acute complications from radical prostatectomy and radiation therapy include cystitis, proctitis, hematuria, urinary retention, penoscrotal edema, and impotence (30% incidence).15 Chronic complications include proctitis, diarrhea, cystitis, enteritis, impotence, urethral stricture, and incontinence.22 Since radiation and prostatectomy have significant and immediate mortality when compared with observation alone, many patients may elect to postpone therapy until symptoms develop.
Pharmacologic Therapy
LHRH Agonists
LHRH agonists are a reversible method of androgen ablation and are as effective as orchiectomy in treating prostate cancer38 (Table 92–7). Currently available LHRH agonists include leuprolide, leuprolide depot, leuprolide implant, triptorelin depot, triptorelin implant, and goserelin acetate implant. Leuprolide acetate is administered once daily, whereas leuprolide depot and goserelin acetate implant can be administered either once monthly, once every 12 weeks, or once every 16 weeks (leuprolide depot, every 4 months). The leuprolide depot formulation contains leuprolide acetate in coated pellets. The dose is administered intramuscularly, and the coating dissolves at different rates to allow sustained leuprolide levels throughout the dosing interval. Goserelin acetate implant contains goserelin acetate dispersed in a plastic matrix of d,l-lactic and glycolic acid copolymer and is administered subcutaneously. Hydrolysis of the copolymer material provides continuous release of goserelin over the dosing period. A recently approved leuprolide implant is a mini-osmotic pump that delivers 120 mcg of leuprolide daily for 12 months. After 12 months, the implant is removed and a different implant can be placed. Triptorelin LA is administered as an intramuscular (IM) injection of 11.25 mg every 84 days. Triptorelin depot is administered 3.75 mg once every 28 days.
Table 92–7 LHRH Agonist
Several randomized trials have demonstrated that leuprolide, goserelin, and triptorelin are effective agents when used alone in patients with advanced prostate cancer.26 Response rates around 80% have been reported, with a lower incidence of adverse effects compared with estrogens.26 There are no direct comparative trials of the currently available LHRH agonists or the dosage formulations, but a recent metaanalysis reported that there is no difference in efficacy or toxicity between leuprolide and goserelin. Triptorelin is a more recent addition but is generally considered equally effective. Therefore, the choice between the three agents is usually made on the basis of cost and patient and physician preference for a dosing schedule.
The most common adverse effects reported with LHRH agonist therapy include a disease flare-up during the first week of therapy, hot flashes, erectile impotence, decreased libido, and injection-site reactions.26 The disease flare-up is caused by an initial induction of LH and FSH by the LHRH agonist, leading to an initial phase of increased testosterone production, and manifests clinically as either increased bone pain or increased urinary symptoms.26 This flare reaction usually resolves after 2 weeks and has a similar onset and duration pattern for the depot LHRH products.39,40 Initiating an antiandrogen prior to the administration of the LHRH agonist and continuing for 2 to 4 weeks is a frequently employed strategy to minimize this initial tumor flare.27
LHRH agonist monotherapy can be used as initial therapy, with response rates similar to orchiectomy. There is a lower incidence of cardiovascular-related adverse effects associated with LHRH therapy than with estrogen administration. Patients should be counseled to expect worsening symptoms during the first week of therapy, 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. Caution should be exercised if initiating LHRH agonist therapy in patients with widely metastatic disease involving the spinal cord or having the potential for ureteral obstruction because irreversible complications may occur.
Another potentially serious complication of androgen deprivation therapy is a resultant decrease in bone-mineral density, leading to an increased risk for osteoporosis, osteopenia, and an increased risk for skeletal fractures. Most clinicians recommend that men starting long-term androgen deprivation therapy should have a base-line bone-mineral density and be initiated on a calcium and vitamin D supplement.27
Gonadotropin-Releasing Hormone (GnRH) Antagonists
An alternative to LHRH agonists is the recently approved GnRH antagonist, degralix. Degralix works by binding reversibly to GnRH receptors on cells in the pituitary gland, reducing the production of testosterone to castrate levels. The major advantage of degralix over LHRH agonists is the speed at which it can achieve the drop in testosterone levels; castrate levels are achieved in 7 days or less with degralix, compared to 28 days with leuprolide, eliminating the tumor flare seen and need for antiandrogens, with LHRH agonists.
In a trial of 610 men with advanced prostate cancer, degralix was shown to be equivalent to leuprolide in lowering testosterone levels for up to 1 year and is approved by the FDA for the treatment of advanced prostate cancer. Degralix is available as a 40 mg/mL and a 20 mg/mL vial for SC injection and the starting dose is 240 mg followed by 80 mg every 28 days. The starting dose should be split into two injections of 120 mg.
The most frequently reported adverse reactions were injection-site reactions, including pain (28%), erythema (17%), swelling (6%), induration (4%), and nodule (3%). Most were transient and mild to moderate, leading to discontinuation in less than 1% of study subjects. Other adverse effects included elevations in lever function tests, which occurred in approximately 10% of study subjects. Like other methods of androgen deprivation therapy, osteoporosis may develop and calcium and vitamin D supplementation should be considered.
Degralix has not been studied in combination with antiandrogens and routine use of the combination cannot be recommended.
Like degralix, abarelix is a GnRH antagonist, with the same advantage of reducing testosterone to castrate levels rapidly and avoiding the tumor flare associated with LHRH agonists. Unfortunately, abarelix is also associated with severe allergic reactions, including syncope and hypotension, which occur in approximately 1% of initial doses and an increased frequency with repeat doses, for an incidence approaching 5% overall. Therefore, abarelix is available only through a restricted distribution program (Plenaxis PLUS Program) and is only indicated for men with advanced prostate cancer who cannot tolerate LHRH agonist therapy and who refuse surgical castration, and have one or more of the following: (a) risk of neurologic compromise due to metastases; (b) ureteral or bladder outlet obstruction due to local encroachment or metastatic disease; or (c) severe bone pain from skeletal metastases persisting on narcotic analgesia. The recommended dose of abarelix is 100 mg administered intramuscularly to the buttock on days 1, 15, 29 (week 4), and every 4 weeks thereafter.
Table 92–8 Antiandrogens
Antiandrogens
Three antiandrogens, flutamide, bicalutamide,39 and nilutamide,38 are currently available (Table 92–8). Cyproterone is another agent with antiandrogen activity but is not available in the United States. Antiandrogens have been used as monotherapy in previously untreated patients, but a recent metaanalysis determined that monotherapy with antiandrogens is less effective than LHRH agonist therapy.40Therefore, for advanced prostate cancer, all currently available antiandrogens are indicated only in combination with androgen-ablation therapy; flutamide and bicalutamide are indicated in combination with an LHRH agonist; and nilutamide is indicated in combination with orchiectomy.37
The most common antiandrogen-related adverse effects are listed in Table 92–7. In the only randomized comparison of bicalutamide plus an LHRH agonist versus flutamide plus an LHRH agonist, diarrhea was more common in flutamide-treated patients. Antiandrogens can reduce the symptoms from the flare phenomenon associated with LHRH agonist therapy.27
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.22 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. In clinical trials, combination hormonal therapy, sometimes also referred to as maximal androgen deprivation or total androgen blockade, or combined androgen blockade (CAB), has been used. The combination of LHRH agonists or orchiectomy with antiandrogens is the most extensively studied CAB approach.
Many studies comparing CAB with conventional medical or surgical castration have been performed.31,41,42 In studies with LHRH agonists, the results have varied, with no consistent benefit demonstrated for CAB. A recently completed National Cancer Institute (NCI) intergroup trial involving 1,387 evaluable stage D2 prostate cancer patients failed to show any significant survival benefits for the combination of orchiectomy plus flutamide over orchiectomy alone.43 Like other studies of CAB, overall survival was longest in patients with minimal disease. Diarrhea, elevated liver function tests, and anemia were more common in those patients who received flutamide.
A metaanalysis of 27 randomized trials in 8,275 patients (4,803 treated with flutamide, 1,683 treated with nilutamide, and 1,784 treated with cyproterone) comparing CAB with conventional medical or surgical castration showed a small survival benefit at 5 years for those treated with flutamide or nilutamide (27.6%) compared to those with castration alone (24.7%; P = 0.0005).41
In one of the few combination androgen-deprivation studies comparing two different antiandrogens (bicalutamide versus flutamide), the time to treatment failure (the main study end point), time to progression (as defined by appearance of new or worsening bone or extraskeletal lesions), and time to death were equivalent, suggesting that the two treatments are equally effective.44
Although some investigators now consider CAB to be the initial hormonal therapy of choice for newly diagnosed advanced prostate cancer patients, the clinician is left to weigh the costs of combined therapy against potential benefits in light of conflicting results in the randomized trials37 and the modest benefit seen in the metaanalysis.41 For those trials that did show an advantage for CAB, whether these effects are specific to the testosterone-deprivation method (orchiectomy vs leuprolide vs goserelin), the antiandrogen, the duration of therapy, or patient selection is not clear. Until further carefully designed studies that use survival, time to progression, quality of life, patient preference, and cost as end points are conducted, it is appropriate to use either LHRH agonist monotherapy or CAB as initial therapy for metastatic prostate cancer. CAB may be most beneficial for improving survival in patients with minimal disease and for preventing tumor flare, particularly in those with advanced metastatic disease. All other patients may be started on LHRH monotherapy, and an antiandrogen may be added after several months if androgen ablation is incomplete.
There is considerable debate concerning when to start hormonal-deprivation therapy in patients with advanced prostate cancer.26 The original recommendation to start therapy when symptoms appeared was based on the Veterans Administration Cooperative Urologic Research Group (VACURG) trials, in which no overall survival difference was demonstrated in patients who either started DES initially or crossed over to active treatment when symptoms appeared; the excess mortality was attributed to estrogen administration.44 Because LHRH agonists and antiandrogens are viable therapies with less cardiovascular toxicity, it is not clear whether delaying therapy is justified with these agents. Reanalysis of the original VACURG data45 and recent combined androgen-deprivation trials demonstrate a survival advantage for young, good-performance status, minimal-disease patients treated initially with hormonal therapy, suggesting that early intervention before symptoms appear may be appropriate.45 The issue of when best to start hormonal therapy is the subject of several ongoing clinical trials.45
Secondary Therapies
Secondary or salvage therapies for patients who progress after their initial therapy depend on what was used for initial management.33 For patients initially diagnosed with localized prostate cancer, radiotherapy can be used in the case of failed radical prostatectomy. Alternatively, androgen ablation can be used in patients who progress after either radiation therapy or radical prostatectomy.
In patients treated initially with one hormonal modality, secondary hormonal manipulations may be attempted. This may include adding an antiandrogen to a patient who incompletely suppresses testosterone secretion with an LHRH agonist. In patients that have progression while receiving CAB, withdrawing antiandrogens, or using agents that inhibit androgen synthesis may be attempted. Supportive care, chemotherapy, or local radiotherapy can be used in patients who have failed all forms of androgen-ablation manipulations because these patients are considered to have hormone-refractory prostate cancer.
For patients who initially received an LHRH agonist alone, castration testosterone levels should be documented. Patients with inadequate testosterone suppression (greater than 20 ng/dL, 0.7 nmol/L) can be treated by adding an anti-androgen or performing an orchiectomy. If castration testosterone levels have been achieved, the patient is considered to have androgen-independent disease, and palliative androgen-independent salvage therapy can be used.
Antiandrogen withdrawal, for patients having progressive disease while receiving combined hormonal blockade with an LHRH agonist plus an antiandrogen, can provide additional symptomatic relief. Mutations in the androgen receptor have been documented that cause antiandrogen compounds to act like receptor agonists.
If the patient initially received CAB with an LHRH agonist with an antiandrogen, then androgen withdrawal is the first salvage manipulation.33 Objective and subjective responses have been noted following the discontinuation of flutamide, bicalutamide, or nilutamide in patients receiving these agents as part of combined androgen ablation with an LHRH agonist. Mutations in the androgen receptor have been demonstrated that allow antiandrogens such as flutamide, bicalutamide, and nilutamide (or their metabolites) to become agonists and activate the androgen receptor. Patient responses to androgen withdrawal manifest as significant PSA reductions and improved clinical symptoms. Androgen withdrawal responses lasting 3 to 14 months have been noted in up to 35% of patients, and predicting response seems to be most closely related to longer androgen exposure times.44 Incomplete cross-resistance has been noted in some patients who received bicalutamide after they had progressed while receiving flutamide, suggesting that patients who fail one antiandrogen may still respond to another agent. Adding an agent that blocks adrenal androgen synthesis, such as amino-glutethimide, at the time that androgens are withdrawn may produce a better response than androgen withdrawal alone. Because of the potential for response immediately after antiandrogen withdrawal, a sufficient observation and assessment period (usually 4–6 weeks) is usually required before a patient can be enrolled on a clinical trial evaluating a new agent or therapy for advanced prostate cancer.
Androgen synthesis inhibitors, such as aminoglutethimide 250 mg orally every 6 hours or ketoconazole 400 mg orally three times a day, can provide symptomatic relief for a short time in approximately 50% of patients with progressive disease despite previous androgen-ablation therapy.37 Adverse effects during aminoglutethimide therapy occur in approximately 50% of patients.37 CNS effects that include lethargy, ataxia, and dizziness are the major adverse reactions. A generalized morbilliform, pruritic rash has been reported in up to 30% of patients treated. The rash is usually self-limiting and resolves within 5 to 8 days with continued therapy. Adverse effects from ketoconazole include GI intolerance, transient rises in liver and renal function tests, and hypoadrenalism. Additionally, ketoconazole is a strong inhibitor of CYP1A2 and CYP3A4 and is contraindicated in combination with a number of medications that are commonly used in men with prostate cancer, including cisapride, lovastatin, midazolam, and triazolam because ketoconazole inhibits their metabolism and leads to increased toxicity. Arrhythmias often fatal have been reported with the combination of cisapride and ketoconazole. Absorption of ketoconazole requires gastric acidity; therefore, ketoconazole should not be administered with H2-blockers, proton pump inhibitors, or antacids. Additionally, ketoconazole should not be administered with strong CYP3A4 inducers, such as rifampin, as this may reduce the effectiveness of ketoconazole because it is also a substrate for CYP3A4. Ketoconazole is combined with replacement doses of hydrocortisone to prevent symptomatic hypoadrenalism.37
Table 92–9 First-Line Chemotherapy for Metastatic Hormone-Independent Prostate Cancer
After all hormonal manipulations are exhausted, the patient is considered to have androgen-independent disease, also known as hormone-refractory prostate cancer. At this point, either chemotherapy or palliative supportive therapy is appropriate. Palliation can be achieved by pain management, using radioisotopes such as strontium-89 or samarium-153 lexidronam for bone-related pain, analgesics, corticosteroids, bisphosphonates, or local radiotherapy.33,45,46
Skeletal metastases from hematogenous spread are the most common sites of distant spread of prostate cancer. Typically, the bone lesions are osteoblastic or a combination of osteoblastic and osteolytic. Bisphosphonates may prevent skeletal related events and improve bone-mineral density. A randomized, controlled trial of zoledronic acid at a dose of 4 mg every 3 weeks reduced the incidence of skeletal-related events by 25% (P = 0.021) compared to placebo.47 The usual dose of pamidronate is 90 mg every month and the usual dose of zoledronic acid is 4 mg every 3 to 4 weeks. A trial of pamidronate or zoledronic acid can be initiated in prostate cancer patients with bone pain; if no benefit is observed, the drug may be discontinued.48
Chemotherapy with docetaxel and prednisone improves survival in patients with hormone-refractory prostate cancer.
Docetaxel 75 mg/m2 every 3 weeks combined with prednisone 5 mg twice a day improve survival in hormone-refractory metastatic prostate cancer.49 The most common adverse events reported with this regimen are nausea, alopecia, and bone marrow suppression. In addition, fluid retention and peripheral neuropathy, known effects of docetaxel, are observed. Docetaxel is hepatically eliminated; patients with hepatic impairment may not be eligible for treatment with docetaxel because of an increased risk for toxicity.
Patient Encounter 3: Progressive Disease
AX is a 62-year-old male who was initially diagnosed with metastatic prostate cancer 5 years ago. He was initially started on leuprolide and has progressed through treatment as described in the treatment summary below.
Treatment Summary
Why was bicalutamide discontinued on 10/2/07?
How would you characterize the patient’s disease?
What treatment is an option for him?
What long-term complications would you expect from his chronic androgen suppression?
The combination of estramustine (280 mg three times a day, days 1–5) and docetaxel 60 mg/m2 on day 2 every 3 weeks also improves survival in hormone-refractory metastatic prostate cancer.50 Estramustine causes a decrease in testosterone and a corresponding increase in estrogen; therefore, the adverse effects of estramustine include an increase in thromboembolic events, gynecomastia, and decreased libido (Table 92–9). Estramustine is an oral capsule and should be refrigerated. Calcium inhibits the absorption of estramustine. While both the docetaxel/prednisone and the docetaxel/estramustine regimens are effective in hormone-refractory prostate cancer, most clinicians prefer the docetaxel/prednisone regimen because of the cardiovascular adverse effects associated with estramustine and the improved survival seen with docetaxel/prednisone. In addition, androgen ablation is usually continued when chemotherapy is initiated.33
Patient Care and Monitoring
1. Obtain complete past medical history, family history, and social history.
2. Obtain complete list of any concomitant prescription and over-the-counter medications, be sure to include herbal, vitamin, and mineral supplements.
3. Verify completion of prostate-cancer workup and staging.
4. Using information obtained, identify appropriate treatment options.
5. Discuss the benefits and risks of appropriate treatment options with health care team and patient.
6. If drug therapy is selected, review patient medical history for drug–drug, drug–herbal interactions.
7. Initiate therapy, if patient was asymptomatic, monitor PSA and circulating androgens for castration level of testosterone. If patient was symptomatic, monitor symptoms for improvement or worsening.
8. Monitor for any new symptoms and adverse events from therapy.
The regimen of mitoxantrone plus prednisone has been shown to be effective in reducing pain from bone metastasis and was a standard therapy prior to the development of docetaxel and prednisone. The effectiveness of mitoxantrone after failure of docetaxel-based therapy has not been scientifically evaluated. Many clinicians will treat patients with radiation therapy for palliation of symptoms after failure of docetaxel-based chemotherapy.33
OUTCOME EVALUATION
Monitoring of prostate cancer depends on the stage of the cancer.33 When definitive, curative therapy is attempted, objective parameters to assess tumor response include assessment of the primary tumor size, evaluation of involved lymph nodes, and the response of tumor markers such as PSA to the 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 the DRE is also performed. In the metastatic setting, clinical benefit responses can be documented by evaluating performance status changes, weight changes, quality of life, and analgesic requirements, in addition to the PSA or DRE at 3-month intervals.
Abbreviations Introduced in This Chapter
|
ASCO |
American Society of Clinical Oncology |
|
AUA |
American Urological Association |
|
BPH |
Benign prostatic hyperplasia |
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
REFERENCES
1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin 2009;59:225–249.
2. Hsieh K, Albertsen PC. Populations at high risk for prostate cancer. Urol Clin North Am 2003;30:669–676.
3. Odedina FT, Ogunbiyi JO, Ukoli FA. Roots of prostate cancer in African-American men. J Natl Med Assoc 2006;98:539–543.
4. Denis L, Morton MS, Griffiths K. Diet and its preventive role in prostatic disease. Eur Urol 1999;35:377–387.
5. Crawford ED. Epidemiology of prostate cancer. Urology 2003;62:3–12.
6. Liede A, Karlan BY, Narod SA. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: A review of the literature. J Clin Oncol 2004;22:735–742.
7. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:215–224.
8. Gurel B, Iwata T, Koh CM, et al. Molecular alterations in prostate cancer as diagnostic, prognostic, and therapeutic targets. Adv Anat Pathol 2008;15:319–331.
9. Marberger M, Adolfsson J, Borkowski A, et al. The clinical implications of the prostate cancer prevention trial. BJU Int 2003;92:667–671.
10. Musquera M, Fleshner NE, Finelli A, et al. The REDUCE trial: Chemoprevention in prostate cancer using a dual 5alpha-reductase inhibitor, dutasteride. Expert Rev Anticancer Ther 2008;8: 1073–1079.
11. Kramer BS, Haggerty KL, Justman S, et al. Use of 5-alpha-Reductase Inhibitors for Prostate Cancer Chemoprevention: American Society of Clinical Oncology/American Urological Association 2008 Clinical Practice Guideline Published Ahead of Print on February 24, 2009 as 10.1200/JCO.2008.16.9599.
12. Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2009;301: 39–51.
13. Neill MG, Fleshner NE. An update on chemoprevention strategies in prostate cancer for 2006. Curr Opin Urol 2006;16:132–137.
14. Schmid HP, Prikler L, Semjonow A. Problems with prostate-specific antigen screening: A critical review. Recent Results Cancer Res 2003;163:226–231.
15. Galic J, Karner I, Cenan L, et al. Role of screening in detection of clinically localized prostate cancer. Coll Antropol 2003;27(Suppl 1): 49–54.
16. Wilson SS, Crawford ED. Screening for prostate cancer: Current recommendations. Urol Clin North Am 2004;31:219–226.
17. Gohagan JK, Prorok PC, Kramer BS, et al. The prostate, lung, colorectal, and ovarian-cancer screening trial of the National-Cancer-Institute. Cancer 1995;75:1869–1873.
18. Catalona WJ, Smith DS, Ratliff TL, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med 1991;324:1156–1161.
19. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2008;149:185–191.
20. Harris R, Lohr KN. Screening for prostate cancer: An update of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2002;137:917–929.
21. Ross KS, Carter HB, Pearson JD, et al. Comparative efficiency of prostate-specific antigen screening strategies for prostate cancer detection. JAMA 2000;284:1399–1405.
22. Khauli RB. Prostate cancer: Diagnostic and therapeutic strategies with emphasis on the role of PSA. J Med Liban 2005;53:95–102.
23. Iczkowski KA. Current prostate biopsy interpretation: Criteria for cancer, atypical small acinar proliferation, high-grade prostatic intraepithelial neoplasia, and use of immunostains. Arch Pathol Lab Med 2006;130:835–843.
24. De Marzo AM, Meeker AK, Zha S, et al. Human prostate cancer precursors and pathobiology. Urology 2003;62:55–62.
25. Culig Z. Role of the androgen receptor axis in prostate cancer. Urology 2003;62:21–26.
26. Marks LS. Luteinizing hormone-releasing hormone agonists in the treatment of men with prostate cancer: Timing, alternatives, and the 1-year implant. Urology 2003;62:36–42.
27. Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer. JAMA 2005;294:238–244.
28. Anderson J. The role of antiandrogen monotherapy in the treatment of prostate cancer. BJU Int 2003;91:455–461.
29. Nieto M, Finn S, Loda M, et al. Prostate cancer: Refocusing on androgen receptor signaling. Int J Biochem Cell Biol 2007;39:1562–1568.
30. Cooperberg MR, Moul JW, Carroll PR. The changing face of prostate cancer. J Clin Oncol 2005;23:8146–8151.
31. Labrie F, Dupont A, Cusan L, et al. Combination therapy with flutamide and medical (LHRH agonist) or surgical castration in advanced prostate cancer: 7-year clinical experience. J Steroid Biochem Mol Biol 1990;37:943–950.
32. Leach FS, Koh MS, Chan YW, et al. Prostate specific antigen as a clinical biomarker for prostate cancer: What’s the take home message? Cancer Biol Ther 2005;4:371–375.
33. National Comprehensive Cancer Network. National Comprehensive Cancer Network guidelines for the management of prostate cancer. Prostate Cancer v.1. 2009, www.nccn.org.
34. Schroder FH, de Vries SH, Bangma CH. Watchful waiting in prostate cancer: review and policy proposals. BJU Int 2003;92:851–859.
35. Scher HI. Prostate carcinoma: Defining therapeutic objectives and improving overall outcomes. Cancer 2003;97:758–771.
36. The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: Initial results of the Medical Research Council Trial. Br J Urol 1997;79:235–246.
37. Oh WK. Secondary hormonal therapies in the treatment of prostate cancer. Urology 2002;60:87–92.
38. Prostate Cancer Trialists’ Collaborative Group. Maximum androgen blockade in advanced prostate cancer: An overview of the randomised trials. Lancet 2000;355:1491–1498.
39. Hedlund PO, Henriksson P. Parenteral estrogen versus total androgen ablation in the treatment of advanced prostate carcinoma: Effects on overall survival and cardiovascular mortality. The Scandinavian Prostatic Cancer Group (SPCG)-5 Trial Study. Urology 2000;55:328–333.
40. Seidenfeld J, Samson DJ, Hasselblad V, et al. Single-therapy androgen suppression in men with advanced prostate cancer: A systematic review and meta-analysis. Ann Intern Med 2000;132:566–577.
41. Moul JW, Fowler JE, Jr. Evolution of therapeutic approaches with luteinizing hormone-releasing hormone agonists in 2003. Urology 2003;62:20–28.
42. Tyrrell CJ, Altwein JE, Klippel F, et al. Comparison of an LH-RH analogue (Goeserelin acetate, “Zoladex”) with combined androgen blockade in advanced prostate cancer: Final survival results of an international multicentre randomized-trial. International Prostate Cancer Study Group. Eur Urol 2000;37:205–211.
43. Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 1998;339:1036–1042.
44. Carcinoma of the prostate: Treatment comparisons. J Urol 1967;98: 516–522.
45. Crawford ED, Kozlowski JM, Debruyne FM, et al. The use of strontium 89 for palliation of pain from bone metastases associated with hormone-refractory prostate cancer. Urology 1994;44:481–485.
46. Resche I, Chatal JF, Pecking A, et al. A dose-controlled study of 153Sm-ethylene diaminetetra methylene phosphonate (EDTMP) in the treatment of patients with painful bone metastases. Eur J Cancer 1997;33:1583–1591.
47. Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96:879–882.
48. Posadas EM, Dahut WL, Gulley J. The emerging role of bisphosphonates in prostate cancer. Am J Ther 2004;11:60–73.
49. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502–1512.
50. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513–1520.