Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

108. Prostate Cancer

LeAnn B. Norris and Jill M. Kolesar


KEY CONCEPTS

 Images Prostate cancer is the most frequent cancer in men in the United States. African American ancestry, family history, and increased age are the primary risk factors for prostate cancer.

 Images Prostate-specific antigen is a useful marker to detect prostate cancer at early stages, predict outcome for localized disease, define disease-free status, and monitor response to androgen-deprivation therapy or chemotherapy for advanced-stage disease.

 Images The prognosis for prostate cancer patients depends on the histologic grade, the tumor size, and the disease stage. More than 85% of patients with stage A1 disease but less than 1% of those with stage D2can be cured.

 Images Androgen deprivation therapy 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.

 Images Androgen deprivation therapy, with either 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.

 Images 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.

 Images Chemotherapy, with docetaxel and prednisone improves survival in patients with castrate-refractory prostate cancer and is considered first-line therapy for these patients. Additional effective agents include cabazitaxel, enzalutamide, and abiraterone.


Prostate cancer is the most commonly diagnosed cancer in American 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 treatment of advanced disease.

EPIDEMIOLOGY

Images Prostate cancer is the most frequent cancer among American men and represents the second leading cause of cancer-related deaths in all males.1 In the United States alone, it is estimated that 238,590 new cases of prostatic carcinoma were diagnosed and more than 29,720 men died from this disease in 2013.1 Although prostate cancer incidence increased during the late 1980s and early 1990s related to widespread prostate-specific antigen (PSA) screening, deaths from prostate cancer have been declining since 1995.1

ETIOLOGY

Table 108-1 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 in those younger than 40 years of age, 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

TABLE 108-1 Risk Factors Associated with Prostate Cancer

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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, whereas 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 white populations.1 Hormonal, dietary, and genetic differences, and differences in access to healthcare may contribute to the altered susceptibility to prostate cancer in these populations.2,3Testosterone, commonly implicated in the pathogenesis of prostate cancer, is approximately 15% higher in African American men compared with white 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 whites.2,3 In addition, genetic variations in the androgen receptor exist. Activation of the androgen receptor is inversely correlated with 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 for African American men.2,3The Asian diet is generally considered to be low in fat and high in fiber with a high concentration of phytoestrogens, potentially explaining their decreased risk.4,5

Family History

Men with a brother or father with prostate cancer have twice the risk for prostate cancer as compared with the rest of the population.5 Familial clustering of a prostate cancer syndrome has been reported, 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

Diet

Several 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 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 hepatic production of IGF-1, which is involved in the regulation of proliferation and apoptosis of cancer cells.5 High levels of IGF-1 are associated with an increased risk for prostate cancer.5

Other dietary factors implicated in the development or prevention of prostate cancer include retinol, carotenoids, lycopene, and vitamin D consumption.5,7 Retinol, or vitamin A, intake, especially in men older than 70 years, 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, and since 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 section titled chemoprevention.

Other Factors

Benign prostatic hyperplasia (BPH) is a common problem among elderly men, affecting more than 40% of men older than 70 years of age (see Chap. 67). BPH results in the urinary symptoms of hesitancy and frequency. Because 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 to 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.811 These drugs inhibit 5-α-reductase, an enzyme that converts testosterone to its more active form, DHT, which is involved in prostate epithelial proliferation. 5-α-reductase exists as two types, type I and type II, and both are implicated in the development of prostate cancer. Finasteride selectively inhibits the 5-α-reductase type II isoenzyme, whereas dutasteride inhibits both isoenzymes.9 Both finasteride and dutasteride falsely lower the PSA by approximately 50% in patients, and this must be considered when one interprets PSA in patients on these medications.12

The efficacy of 5-α-reductase inhibitors in reducing the risk of prostate cancer was recently evaluated in a Cochrane review.8 Eight randomized studies involving 41,638 men were included. Both the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study, which compared dutasteride to placebo and included more than 8000 subjects and the Prostate Cancer Prevention Trial (PCPT), which compared finasteride to placebo and enrolled more than 18,000 subjects in the analysis. The mean subject age in the analysis was 64 years; 92% of subjects were white and 15% had a family history of prostate cancer. The mean (range) baseline PSA level was 3.1 (1.2 to 9.8 ng/mL [1.2 to 9.8 mcg/L]). Compared with placebo, 5-α-reductase inhibitors reduced the risk of prostate cancers detected by 25% (relative risk 0.75, 95% confidence interval [CI] 0.67–0.83; 1.4% absolute risk reduction [3.5% vs. 4.9%]). Studies were not designed to evaluate prostate cancer mortality, and in the combined analysis, 5-α-reductase inhibitors did not improve mortality.

Subjects who discontinued therapy or were lost to follow-up were not different between the placebo and treatment arms, but adverse effects, including gynecomastia, decreased libido, and erectile dysfunction, were more common in patients treated with 5-α-reductase inhibitors than in placebo. In the REDUCE trial, the incidence of “cardiac failure,” defined as congestive heart failure, cardiac failure, acute cardiac failure, ventricular failure, cardiopulmonary failure, or congestive cardiomyopathy, was greater in the dutasteride group (0.7%, n = 30) compared with the placebo group (0.4%, n = 16; P = 0.03), but deaths from cardiovascular events were not significantly different between groups.

The American Society of Clinical Oncology and the American Urological Association published a joint practice guideline for prostate cancer chemoprevention.13 The guideline recommends that asymptomatic men with a PSA ≤3.0 ng/mL (3.0 mcg/L) who are regularly screened with PSA for early detection of prostate cancer may benefit from a discussion of both the benefits of dutasteride or finasteride for 7 years for the prevention of prostate cancer and the potential risks.13

The guideline does not recommend the use of finasteride or dutasteride for prostate cancer chemoprevention and noted that, while most panel members believed the higher risk of high-grade cancer in the finasteride group observed in the PCPT is most likely related to biases, cancer induction or promotion by finasteride cannot be excluded with certainty. In addition, while finasteride and dutasteride reduce the prevalence of prostate cancer, the impact of 5-α-reductase inhibitors on prostate cancer morbidity and mortality has not been demonstrated. Patients considering finasteride or dutasteride for prostate cancer chemoprevention or taking it for benign conditions such as BPH must weigh the risks and benefits of treatment. The primary benefit is that these agents reduce the incidence of prostate cancer by about 25%, and improve lower urinary tract symptoms of BPH, but the risks include the potential for more high-grade prostate cancers; the long-term benefit of these agents is not known; and reversible sexual adverse effects can occur.13

Selenium and vitamin E alone or in combination were evaluated in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a clinical trial investigating their effects on the incidence of prostate cancer in healthy men. The data and safety monitoring committee found that after 5 years selenium or vitamin E taken alone or together did not prevent prostate cancer. Based on these data and safety concerns, the trial was halted. With longer follow-up of that trial, dietary supplementation with vitamin E significantly increased the risk of prostate cancer by 17% (P = 0.008).14 Other agents, including vitamin D, lycopene, green tea, nonsteroidal antiinflammatory 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.15

SCREENING

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 showed little effect in preventing metastatic prostate cancer in one large observational study.16

Images 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. PSA is used widely for prostate cancer screening in the United States, with simplicity its major advantage and low specificity its primary limitation.17 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 and 10 ng/mL (4.1 and 10 mcg/L) cannot distinguish between BPH and prostate cancer, limiting the utility of PSA alone for the early detection of prostate cancer. Additionally, many men with clinically significant prostate cancer do not have a serum PSA outside the reference range.18

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, with PSA, DRE or a combination fits these criteria has generated considerable controversy, and two recent studies have done little to resolve the controversy.1922 The European Randomized Study of Screening for Prostate Cancer (ERSPC) evaluated the effect of PSA screening on prostate cancer mortality. More than 182,000 men from seven different European countries were randomized between being offered screening with PSA to no screening. The frequency of screening and PSA threshold for a biopsy varied by country. Most centers used a PSA cutoff of 3 ng/mL (3 mcg/L), but Belgium allowed up to 10 ng/mL (10 mcg/L). Most centers screened every 4 years, although Sweden screened every 2 years. Eighty-two percent of men in the screening group had at least one PSA performed. With a median follow-up of 11 years, the cumulative incidence of prostate cancer was 9.6% in the screening group and 6.0% in the control group.23 The rate ratio for death from prostate cancer in the screening group, compared with the control group, was 0.79 (95% CI, 0.68 to 0.91; adjusted P = 0.001), which corresponds to about one less death from prostate cancer per 1000 men (at a median follow-up of 11 years) in the screened group compared with the unscreened group. Of the 136,689 PSA tests performed, 16.6% of the tests were positive; biopsies were performed for 86% of men with elevated PSAs. Overall mortality was similar in the two study groups (rate ratio 0.99, 95% CI, 0.97 to 1.01).23

In the United States, the Prostate, Lung, Colon and Ovarian Screening (PLCO) study randomized 76,693 men to receive either annual screening (38,343 subjects) or usual care as the control (38,350 subjects). In the screening group, men were offered annual PSA testing for 6 years and DRE for 4 years. Compliance with screening was 85%. Men in the usual care group were able to receive screening, with the rate of PSA testing ranging from 40% to 52% and DRE from 41% to 46%. After 13 years of follow-up, the incidence of death per 10,000 person-years was not significantly different between the two groups with 3.7 (158 deaths total) in the screening group and 3.4 (145 deaths total) in the control group (relative risk, 1.09; 95% CI, 0.87 to 1.36).24

In the United States, clinicians believe that 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. The common approach to prostate cancer screening today involves offering a baseline PSA and DRE at age 40 years with annual evaluations beginning at age 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 years.

Despite this common practice, the benefits of prostate cancer screening remain controversial.19,20,22 The ERSPC demonstrated that PSA testing every 4 years was better than no PSA testing, decreasing prostate cancer deaths in the screened group by about 1 per 1,000 men screened compared with the unscreened group, but the false-positive rate was 76%, resulting in more than 13,000 unnecessary biopsies. The PLCO screening study showed no reduction in prostate cancer death between the annual (PSA and DRE) screening group and the usual care group, which is not surprising given the small reduction in death expected and that about one-half of the patients in the usual screening groups had PSA and DRE screening performed. Both studies demonstrated that screening identifies more prostate cancers than not screening.21,23,24 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 harm by subjecting some patients to unnecessary therapy. Based on this evidence, the United States Preventative Services Task Force (USPSTF) recommends against screening for prostate cancer (grade D recommendation), based on moderate or high certainty that screening has no net benefit or that the harms outweigh the benefits.21,22 The American Cancer Society recommends that asymptomatic men who have at least a 10-year life expectancy have an opportunity to make to make an informed decision about prostate cancer screening, including discussion of the uncertainties, risks, and potential benefits associated with screening.20


Clinical Controversy…

Prostate cancer screening with prostate-specific antigen (PSA) tests is controversial. Recently completed trials of screening show no overall survival benefit in screened patients. However, usual clinical practice was allowed in the control arm, and control patients received PSA screening nearly as frequently as those in the screening arm. Overall, the trial compared screening annually to screening every 2 to 3 years, not to no screening.

Based on the available evidence, Gulati et al. recently evaluated the comparative effectiveness of alternative PSA screening strategies.25 Examples of alternative screening strategies include the use of higher PSA thresholds for biopsy referral or longer screening intervals. Several of the screening scenarios were predicted to produce similar reductions in prostate cancer mortality and reduce harms.

PATHOPHYSIOLOGY

The prostate gland is a solid, rounded, heart-shaped organ positioned between the neck of the bladder and the urogenital diaphragm (Fig. 108-1). 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.26,27 Much rarer tumor types include small cell neuroendocrine cancers, sarcomas, and transitional cell carcinomas.

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FIGURE 108-1 The prostate gland.

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.27,28 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).

Metastatic spread can occur by local extension, lymphatic drainage, or hematogenous dissemination.28,29 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 (see Fig. 108-1). 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 are not usually initially involved. 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 depend on the presence of androgens, specifically DHT.29,30 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. 108-2). 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.31Prolactin, growth hormone, and estradiol appear to be important accessory regulators for prostatic tissue permeability, receptor binding, and testosterone synthesis.

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FIGURE 108-2 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).

Testosterone, the major androgenic hormone, accounts for 95% of the androgen concentration. The primary source of testosterone is the testes, but 3% to 5% of the testosterone concentration is derived from direct adrenal cortical secretion of testosterone or C19 steroids such as androstenedione.2830

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 mechanisms29,30 (Table 108-2). 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. 108-2). Interference with LHRH or LH can reduce testosterone secretion by the testes (estrogens, LHRH agonists, progestogens, and cyproterone acetate). 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.2830

TABLE 108-2 Hormonal Manipulations in Prostate Cancer

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Isolation of the naturally occurring hypothalamic decapeptide hormone luteinizing hormone-releasing hormone or 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.23 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.31

Androgen synthesis can also be inhibited in the testes or in the 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 mineralocorticoids. Ketoconazole, an imidazole antifungal agent, causes a dose-related reversible reduction in serum cortisol and testosterone concentration by inhibiting both adrenal and testicular steroidogenesis.31 Megestrol is a synthetic derivative of progesterone that exhibits a secondary mechanism of action by inhibiting androgen synthesis. This inhibition appears to occur at the adrenal level, but circulating levels of testosterone are also reduced, suggesting that inhibition at the testicular level may also occur.31

Antiandrogens inhibit the formation of the DHT-receptor complex and therefore interfere with androgen activity at the cellular level.31 The conversion of testosterone to DHT may be inhibited by 5-α-reductase inhibitors.7

In advanced stages of disease, prostate cancer cells may be able to survive and proliferate without the signals normally provided by circulating androgens.31 When this occurs, the tumor is no longer sensitive to therapies that depend on androgen blockade. These tumors are often referred to as hormone refractory or androgen independent.

CLINICAL PRESENTATION

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.


CLINICAL PRESENTATION

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

The information obtained from the diagnostic tests is used to stage the patient (Table 108-3). There are two commonly recognized staging classification systems (Table 108-4). The formal international classification system (tumor, node, metastases [TNM]), adopted by the International Union Against Cancer in 1974, was last updated in 2002. The AUS classification is the most commonly used staging system in the United States. Patients are assigned to stages A through D and corresponding subcategories based on size of the tumor (T), local or regional extension, presence of involved lymph node groups (N), and presence of metastases (M). Based on men diagnosed with prostate cancer at Walter Reed Army Medical Center from 1988 to 1998, including more than 2,042 prostate cancer diagnoses, localized prostate cancer (stage T1 and T2) was diagnosed more frequently (89% vs. 68%), and advanced disease (stages T3, T4, and D) was diagnosed less frequently (11% vs. 32%) in 1998 as compared to 1988.

TABLE 108-3 Diagnostic and Staging Workup for Prostate Cancer

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TABLE 108-4 Staging and Classification Systems for Prostate Cancer

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Images The prognosis for patients with prostate cancer depends on the histologic grade, the tumor size, and the local extent of the primary tumor.27 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.27

From 1999 to 2005, 5-year overall survival rates were estimated at 100% for whites and 97% for African Americans.1 For this same period, the survival rates for localized or regional disease (100%), and distant disease (30%) in white males were about the same as the survival rates for localized or regional disease (100%), and distant disease (29%) in African American males.1 A 4.1% decline in age-adjusted mortality has been observed for the period 1994 to 2006. Ten-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. It is estimated that more than 85% of patients with stage A1 can be cured, whereas less than 1% of patients with stage D2 will be cured.

TREATMENT

Prostate Cancer

Desired Outcomes

The desired outcome in early-stage prostate cancer is to minimize morbidity and mortality caused by prostate cancer.32,33 The most appropriate therapy of early-stage prostate cancer is a matter of debate. Early-stage disease may be treated with surgery, radiation, or expectant management. While surgery and radiation are curative, they are associated with significant morbidity and mortality. Because 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 provide symptom relief and maintain quality of life. The mainstay of treatment for advanced prostate cancer is androgen deprivation therapy, with a goal of reducing testosterone to castrate levels, with either an orchiectomy or an LHRH agonist.

General Approach To Treatment

The initial treatment for prostate cancer depends primarily on the disease stage, the Gleason score, the presence of symptoms, and the life expectancy of the patient.32 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 observation, radiation, or radical prostatectomy (Table 108-5). 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 treatment of early-stage prostate cancer is 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, observation or radiation therapy may be offered. In those with a normal life expectancy of equal to or greater than 10 years, either observation, radiation (external beam or brachytherapy), or radical prostatectomy with a pelvic lymph node dissection may be offered. Radiation and radical prostatectomy therapy are generally considered therapeutically equivalent for localized prostate cancer, although neither has been proven to be better than observation alone.34

TABLE 108-5 Initial Management of Prostate Cancer Based on Expected Survival and Recurrence Risk

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Wilt and colleagues conducted a systematic review of 18 randomized trials and 473 observational studies to compare the effectiveness and potential complications from treatment options from prostate cancer. This study showed that the effectiveness of radiation, radical prostatectomy, and androgen deprivation therapy could not be compared because of the paucity of high-quality evidence available for analysis. Adverse effect profiles were similar, although severity varied among the treatments.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. Although a recently published prospective study showed that even in patients with good preoperative sexual health, many do not return to baseline after surgery even with the assistance of erectile dysfunction treatments.36 Acute complications from radiation therapy include cystitis, proctitis, hematuria, urinary retention, penoscrotal edema, and impotence (30% incidence).27 Chronic complications include proctitis, diarrhea, cystitis, enteritis, impotence, urethral stricture, and incontinence.27 In addition, androgen deprivation can also cause cognitive impairment, mood disturbances, and lack of initiative.35 Because radiation and prostatectomy have significant and immediate mortality when compared with expectant management alone, many patients may elect to postpone therapy until symptoms develop.

Individuals with T2b and T2c disease or a Gleason score of 7 or a PSA ranging from 10 to 20 ng/mL (10 to 20 mcg/L) are considered at intermediate risk for prostate cancer recurrence.32 Individuals with less than a 10-year expected survival may be offered observation or radical prostatectomy with pelvic lymph node dissection or radiation therapy with or without 4 to 6 months of neoadjuvant androgen deprivation therapy with or without brachytherapy, 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 with or without 4 to 6 months of neoadjuvant androgen deprivation therapy with or without brachytherapy (see Table 108-5).

The treatment of patients at high risk of recurrence (stage 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 with or without brachytherapy (see Table 108-5). Selected individuals with a low tumor volume may receive a radical prostatectomy with or without a pelvic lymph node dissection.

Patients with T3b and T4 disease have a very high risk of recurrence and are usually not candidates for radical prostatectomy because of extensive local spread of disease, although it may be possible for some individuals.32 ImagesAndrogen deprivation therapy with a 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 of 500 men with locally advanced prostate cancer who were randomized to either immediate initiation of androgen ablation (either orchiectomy or androgen ablation) or deferred hormonal therapy, patients who received immediate therapy had a median actuarial cause-specific survival duration of 7.5 years for immediate treatment as compared with 5.8 years for deferred treatment.37

Images Androgen deprivation therapy, with 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.

Patients who develop metastatic disease often have tumor progression and develop castration resistant prostate cancer.32 This may be described clinically by a rising PSA while on optimal androgen deprivation therapy, or the development of symptoms, typically related to bone metastases, including bone pain and fractures. Patients with metastatic disease may be continued on androgen deprivation therapy and denosumab (receptor activator of nuclear factor κ B [RANK] ligand inhibitor) or an IV bisphosphonate is added in patients with bone metastases. Importantly, further therapy is determined by the presence of symptomatic disease or whether the metastatic progression is manifested as only a rising PSA.

For clinically asymptomatic patients with a rising PSA, the recently approved sipuleucel-T is recommended as first-line treatment. Prior to the introduction of sipuleucel-T, standard therapy was a secondary hormonal manipulation, including the addition or withdrawal of antiandrogen therapy.

For those with symptomatic or disease involving internal organs, such as the liver, treatment with docetaxel is recommended as first-line therapy. For patients with symptomatic visceral disease who have a rising PSA following docetaxel chemotherapy, abiraterone acetate is recommended as first-line treatment. Other first-line treatment options following docetaxel chemotherapy include cabazitaxel, a microtubule inhibitor, in combination with prednisone, or the antiandrogen enzalutamide (Fig. 108-3).

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FIGURE 108-3 Treatment of castrate-resistant prostate cancer.

Nonpharmacologic Therapy

Observation

Observation is often referred to as expectant management, and active surveillance or watchful waiting. Observation involves monitoring the course of disease and initiating treatment if the cancer progresses. It is estimated that only about 10% of men who are eligible for observation choose this option.34 A PSA and DRE are performed every 6 months, with a repeat biopsy at any sign of disease progression. The advantages of observation 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 observation is the risk that the cancer progresses and requires a more intensive therapy.

Orchiectomy

Bilateral orchiectomy, or removal of the testes, is a form of androgen deprivation therapy that rapidly reduces circulating androgens to castrate levels (less than 50 ng/dL [1.7 nmol/L]).22 However, many patients are not surgical candidates because of advanced age, and other patients find this procedure psychologically unacceptable.26 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.32 In external beam radiotherapy, doses of 70 to 75 Gy (7000 to 7500 rad) are delivered in 35 to 41 fractions in patients with low-grade prostate cancer and 75 to 80 Gy (7500 to 8000 rad) for those with intermediate- or high-grade prostate cancer. Brachytherapy involves the permanent implantation of radioactive beads of 145 Gy (14500 rad)125iodine or 124 Gy (12400 rad) of 103palladium and is generally reserved for individuals with low-risk cancers. Radiation therapy may also be given after surgery in patients with localized disease. Acute complications from radiation therapy include cystitis, proctitis, hematuria, urinary retention, penoscrotal edema, and impotence (30% incidence).16 Chronic complications include proctitis, diarrhea, cystitis, enteritis, impotence, urethral stricture, and incontinence.26Because radiation and prostatectomy have significant and immediate mortality when compared with observation alone, many patients may elect to postpone therapy until symptoms develop.

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.

Pharmacologic Therapy

Drug Treatments of First Choice

Luteinizing Hormone-Releasing Hormone Agonists LHRH agonists are a reversible method of androgen ablation and are as effective as orchiectomy in treating prostate cancer.38 Currently available LHRH agonists include leuprolide, leuprolide depot, leuprolide implant, triptorelin depot, triptorelin implant, and goserelin acetate implant. Leuprolide acetate is administered once daily, while 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) (Table 108-7). 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 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 injection of 11.25 mg every 84 days. Triptorelin depot is 3.75 mg once every 28 days.

Several randomized trials have demonstrated that leuprolide, goserelin, and triptorelin are effective agents when used alone in patients with advanced prostate cancer.30 Response rates around 80% have been reported, with a lower incidence of adverse effects as compared with estrogens.30 The currently available LHRH agonists or the dosage formulations have not been directly compared in clinical trials, but a meta-analysis showed no significant differences in efficacy or toxicity between leuprolide, goserelin, and orchiectomy.39 Triptorelin is a more recent addition but is generally considered equally effective. Therefore the choice between the three agents is usually made based on cost and patient and physician preference for a dosing schedule.

The most common adverse effects reported with LHRH agonist therapy include a disease flareup during the first week of therapy, hot flashes, erectile impotence, decreased libido, and injection-site reactions.30 The disease flareup 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.30 This flare reaction usually resolves after 2 weeks and has a similar onset and duration pattern for the depot LHRH products.40,41 Tumor flare can be minimized by initiating an antiandrogen prior to the administration of the LHRH agonist and continuing for 2 to 4 weeks.31

LHRH agonist monotherapy can be used as initial therapy, with response rates similar to those for orchiectomy. The incidence of cardiovascular-related adverse effects is lower 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 (ADT) is a resultant decrease in bone mineral density leading to an increased risk for osteoporosis, osteopenia, and an increased risk for skeletal fractures. During initial therapy, bone mineral density of the hip and spine decreases by 2% to 3%.42 Additionally, ADT has been associated with a 21% to 45% relative increase in fracture risk.4345 Therefore, most clinicians recommend that men starting long-term ADT should have a baseline bone mineral density and be initiated on a calcium and vitamin D supplement.31,32

In addition, an antiresorptive agent, either zoledronic acid or denosumab should be considered. A recent meta-analysis combined data from three identically designed double-blind randomized controlled trials that compared the efficacy and safety of denosumab at a dose of 120 mg with that of zoledronic acid at a dose of 4 mg administered IV.46 Almost 6,000 patients with breast and prostate cancer and multiple myeloma were included in the meta-analysis. Denosumab reduced the risk of first skeletal-related event (SRE) by 17% (hazard ratio, 0.83 [95% CI: 0.76 to 0.90]; P < 0.001 for both noninferiority and superiority tests) as compared with zoledronic acid and the median time to first SRE was 27.66 (24.21 to not estimable) months for denosumab versus 19.45 (18.53 to 21.42) months for zoledronic acid. The benefits were consistent across tumor types evaluated and the incidence of adverse effects was not significantly different between the denosumab and zoledronic acid groups.

ADT has also been associated with a higher incidence of metabolic effects. In a landmark population-based trial, patients treated with an ADT and a gonadotropin-releasing hormone (GnRH) agonist had a greater risk of new-onset diabetes, coronary artery disease, and myocardial infarctions.47 However, it is not clear whether ADT increases the risk of cardiovascular death. A recently published meta-analysis of eight trials with 4,141 patients treated with ADT evaluated prostate cancer specific mortality and all-cause mortality.48 The trials included patients with nonmetastatic disease who were treated with immediate predominantly GnRH-agonist–based ADT versus no immediate ADT (control group). The incidence of cardiovascular deaths was 11.0% (95% CI, 8.3% to 14.5%) in the ADT group versus 11.2% (95% CI, 8.3% to 15.0%) in the control group. The risk of cardiovascular death for ADT versus control was not significantly different (relative risk 0.93; 95% CI, 0.79 to 1.10; P = 0.41) and these results suggest that ADT does not lead to increased cardiovascular mortality.32 Patients receiving ADT should be screened for cardiovascular disease and diabetes and appropriate interventions to prevent and treat these complications should be initiated.32

Gonadotropin-Releasing Hormone Antagonists An alternative to LHRH agonists is the recently approved GnRH antagonist, degarelix. Degarelix works by binding reversibly to GnRH receptors in the pituitary gland, reducing the production of testosterone to castrate levels. The major advantage of degarelix over LHRH agonists is the rapidity at which it reduces testosterone levels. Castration levels are achieved in 7 days or less with degarelix, as compared with 28 days with leuprolide; tumor flare does not occur and antiandrogens are not required.

In a trial of 610 men with advanced prostate cancer, degarelix was shown to be equivalent to leuprolide in lowering testosterone levels for up to 1 year. Degarelix is available as a 40 mg/mL and a 20 mg/mL vial for subcutaneous injection, and the starting dose is 240 mg followed by 80 mg every 28 days. The starting dose should be divided into two 120 mg injections.49 Degarelix has not been studied in combination with antiandrogens, and routine use of the combination cannot be recommended.

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 liver function tests, which occurred in about 10% of study subjects. Osteoporosis may develop, and calcium and vitamin D supplementation should be considered.49

Antiandrogens Four antiandrogens, flutamide, bicalutamide, nilutamide, and enzalutamide, are currently available (Table 108-6). Cyproterone is another agent with antiandrogen activity, but it is not available in the United States. Antiandrogens have been used as monotherapy in previously untreated patients, but a recent meta-analysis determined that monotherapy with antiandrogens is less effective than LHRH agonist therapy.41 Therefore, for advanced prostate cancer, flutamide, bicalutamide, and nilutamide 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.50 Antiandrogens can reduce the symptoms from the flare phenomenon associated with LHRH agonist therapy.31 Recently, the FDA approved the newest androgen receptor inhibitor, enzalutamide. Enzalutamide, also known as MDV3100, is currently approved as a single agent for patients with metastatic hormone-resistant prostate cancer who have previously received docetaxel.51 As with the other antiandrogens, enzalutamide does not lower androgen levels but inhibits androgen-receptor signaling by competitively inhibiting the binding of androgens without stimulation of the androgen receptor. Enzalutamide may have an advantage over the currently available antiandrogen agents in that it inhibits nuclear translocation of the androgen receptor, DNA binding, and coactivator recruitment. It also has a greater affinity for the androgen receptor and has shown activity in patients resistant to other antiandrogens. There is also an ongoing trial in patients with advanced prostate cancer with enzalutamide prior to docetaxel.52

TABLE 108-6 Hormonal Therapies for Prostate Cancer65–-72

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The most common antiandrogen-related adverse effects are listed in Table 108-7. 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. The adverse effects of enzalutamide are similar to those of the other antiandrogens, but enzalutamide does have an increased risk of seizures.

TABLE 108-7 Chemotherapy and Immunotherapy for Prostate Cancer7376

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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.26 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 combined androgen blockade approach.

A systematic review of six meta-analyses concluded that the best evidence for CAB came from the largest meta-analysis, conducted by the Prostate Cancer Trialists Collaborative Group including 8725 patients from 27 trials.53That analysis found no difference in overall survival between CAB and castration alone at 2 or 5 years, but a subgroup analysis showed that CAB with nonsteroidal antiandrogens, including flutamide, bicalutamide or nilutamide was associated with a statistically significant improvement in 5-year survival over castration alone (27.6% vs. 24.7%; P = 0.005). As expected, antiandrogens increased toxicity over placebo.

Although some clinicians consider CAB to be the initial hormonal therapy of choice for newly diagnosed patients, the clinician must weigh the costs of combined therapy against the modest survival benefit.53It 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.

It is not clear when to start hormonal-deprivation therapy in patients with advanced prostate cancer.30 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 diethylstilbestrol (DES) initially or crossed over to active treatment when symptoms appeared; the excess mortality was attributed to estrogen administration.54 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 data55 and recent combined androgen-deprivation trials54 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.55

Alternative Drug Treatments

Secondary or salvage therapies for patients who progress after their initial therapy depend on what was used for initial management.32 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.

Secondary Hormonal Manipulations In patients treated initially with one hormonal modality, secondary hormonal manipulations may be attempted. This may include adding an antiandrogen to a patient with incompletely supressed 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. 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 antiandrogen 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.

Images 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 antiandrogens to act like receptor agonists.

If the patient initially received combined androgen blockade with an LHRH agonist and an antiandrogen, then androgen withdrawal is the first salvage manipulation.32 Objective and subjective responses have been noted following the discontinuation of flutamide,56 bicalutamide,57 or nilutamide58 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.59 Patient responses to androgen withdrawal manifest as significant PSA reductions and improved clinical symptoms. Androgen withdrawal responses lasting 3 to 14 months have been observed in up to 35% of patients, and predicting response seems to be most closely related to longer androgen exposure times. Incomplete cross-resistance has been noted in some patients who received bicalutamide after they had progressed while receiving flutamide.60 The addition of an agent that blocks adrenal androgen synthesis, such as aminoglutethimide, at the time that androgens are withdrawn may produce a better response than androgen withdrawal alone.59 Because of the potential for response immediately after antiandrogen withdrawal, a sufficient observation and assessment period (usually 4 to 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 or ketoconazole, can provide symptomatic relief for a short time in approximately 50% of patients with progressive disease despite previous androgen-ablation therapy.32Adverse effects during aminoglutethimide therapy occur in about 50% of patients.32 Central nervous system 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 gastrointestinal intolerance, transient rises in liver and renal function tests, and hypoadrenalism. Ketoconazole is combined with replacement doses of hydrocortisone to prevent symptomatic hypoadrenalism.32

Abiraterone is the newest androgen synthesis inhibitor that targets cytochrome P450 (CYP)17A1, which results in a decrease in circulating levels of testosterone.61 Abiraterone is indicated in patients with metastatic castration-resistant prostate cancer, either before or after docetaxel-based chemotherapy. The initial approval was based on the results of a phase III study of patients previously treated with a docetaxel-containing regimen. The combination of abiraterone and prednisone increased median overall survival by 3.9 months in comparison to placebo. Hypertension, hypokalemia, and edema may occur due to hypoadrenalism. Abiraterone is available as the prodrug, abiraterone acetate, and should be taken on an empty stomach as food increases bioavailability by up to 10-fold. Monitoring of liver function tests is recommended at baseline, every 2 weeks for the first 3 months, and then monthly thereafter. Since abiraterone is an inhibitor of CYP2D6, medication profiles should be reviewed for potential drug interactions prior to initiation of abiraterone therapy.

Images Chemotherapy Chemotherapy with docetaxel and prednisone improves survival in patients with castrate-refractory prostate cancer and is considered first-line therapy for these patients. Docetaxel 75 mg/m2 every 3 weeks combined with prednisone 5 mg twice a day improves survival in hormone-refractory metastatic prostate cancer.62 The most common adverse events with this regimen are nausea, alopecia, and bone marrow suppression. Other adverse effects of docetaxel include fluid retention and peripheral neuropathy. Docetaxel is metabolized in the liver; patients with hepatic impairment may not be eligible for treatment with docetaxel because of an increased risk for toxicity (Table 108-7).

Cabazitaxel is a taxane with demonstrated activity in docetaxel resistant cell lines and animal models of human cancer.63 Cabazitaxel has lower affinity for P-glycoprotein multidrug resistance transporter than docetaxel, which may explain why cabazitaxel is active in the setting of docetaxel resistance. In patients previously treated with docetaxel and prednisone, treatment with cabazitaxel 25 mg/m2 every 3 weeks with prednisone 10 mg daily significantly improved progression-free survival and overall survival as compared to mitoxantrone and prednisone. Neutropenia, febrile neutropenia, neuropathy, and diarrhea are the most significant toxicities. Hypersensitivity reactions may occur and premedication with an antihistamine, a corticosteroid and an H2 antagonist is recommended. Cabazitaxel is extensively metabolized in the liver and should be avoided in patients with hepatic dysfunction (see Table 108-7).

Immunotherapy Sipuleucel-T is a novel autologous cellular immunotherapy that was FDA-approved in April 2010 for the treatment of asymptomatic or minimally symptomatic metastatic hormone-refractory prostate cancer.64Alternative treatment options for this patient population are secondary hormonal therapy, including antiandrogen therapy, withdrawal of antiandrogen therapy, ketoconazole, abiraterone acetate, steroids, estrogen, or enrollment on a clinical trial, although none of these options has been shown to improve overall survival. No clinical trials have compared sipuleucel-T to secondary hormonal therapies. Patients treated with sipuleucel-T undergo leukapheresis on day 1 to collect peripheral blood mononuclear cells, the cellular fraction that includes immune effector cells. These cells are incubated with a prostatic acid phosphatase (PAP)–granulocyte-macrophage colony-stimulating factor (GM-CSF) fusion protein; PAP is the specific tumor antigen, and GM-CSF is the immune cell activator. The cellular product is then infused IV into the patient on day 3 or 4, providing an autologous infusion of activated cells. Each course of sipuleucel-T consists of three infusions of activated cells, given every 2 weeks. In the pivotal trial, sipuleucel-T prolonged median survival by 4.1 months and reduced the risk of death by 22% (hazard ratio = 0.78, 95% CI, 0.61 to 0.98; P = 0.03).64 Adverse effects related to sipuleucel-T were generally mild and nearly all patients were able to receive the entire course (i.e., 3 infusions). A course of sipuleucel-T costs about $93,000, and some insurers have questioned the value of the therapy.


Clinical Controversy…

The use of sipuleucel-T is controversial. The treatment is indicated for minimally symptomatic prostate cancer and has not been compared to standard second-line hormonal interventions.

PERSONALIZED PHARMACOTHERAPY

Prevention strategies for prostate cancer, specifically whether to undergo PSA screening for early detection or whether to start chemoprevention with finasteride or dutasteride in an effort to prevent prostate cancer, are highly personalized decisions and depend on an individual patient weighing the risks and benefits of either strategy. This is a major change from previous recommendations, which uniformly recommended screening regardless of age, health status or patient preference.

Prostate cancer therapy is personalized based on clinical factors, including stage of cancer, life expectancy of the patient, and a patient’s fitness for surgical interventions (see Table 108-5). Agents used in the treatment of prostate cancer are often personalized with dose adjustments for organ dysfunction of other clinical characteristics (see Table 108-7). Although there are no current selection strategies, where individuals with a specific mutation receive a specific therapy, this remains an important area of research.

EVALUATION OF THERAPEUTIC OUTCOMES

Monitoring of prostate cancer depends on the stage of the cancer.32 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 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, chemotherapy and novel hormonal manipulations have been shown to prolong overall survival. In addition, 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

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