Prostate Cancer

Course #63882 - $30 • 5 Hours/Credits


Study Points

  1. Review the epidemiology and demographics of prostate cancer.
  2. Discuss what is known about the pathophysiology of prostate cancer.
  3. Discuss the associated symptoms and diagnosis of prostate cancer.
  4. State the current recommendations regarding prostate cancer screening.
  5. Describe the potential role of diet in reducing prostate cancer risk.
  6. Discuss the role of surgery and radiotherapy as treatments for prostate cancer.
  7. Describe the role of androgen deprivation therapy for the treatment of prostate cancer.
  8. Discuss the role of chemotherapy as a treatment for prostate cancer.
  9. Analyze the research and use of 5-alpha reductase inhibitors as a treatment for prostate cancer.
  10. Recommend interventions for men who have experienced erectile dysfunction or depression as a result of prostate cancer, including considerations for non-English-proficient patients.

    1 . What percentage of men diagnosed with cancer will have prostate cancer?
    A) 1%
    B) 11%
    C) 21%
    D) 41%

    EPIDEMIOLOGY

    In the United States in 2016, new cases of prostate cancer (180,890) were projected to account for 21% of all cancers diagnosed in men [1]. Despite the advances in early detection and a decline in the death rate over the last decade, prostate cancer continues to cause substantial mortality in the United States. It ranked second among the 10 leading cancer-related causes of death for men in 2016; lung and bronchus cancer remained the number one cause [1]. The clinical incidence of prostate cancer in the United States has changed during the past several decades, increasing from less than 100 cases per age-adjusted 100,000 population in 1975 to a peak of 240 cases per 100,000 men in 1992, then fluctuating but declining (-4.0%) (averaging 155 cases per 100,000 men) between 2003 and 2012 [1,3].

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    2 . According to an analysis of incidence data in the United States (2009–2013),
    A) roughly 1% of cases were discovered in patients between 45 to 54 years of age.
    B) the smallest percentage group diagnosed with prostate cancer was 55 to 64 years of age.
    C) the largest percentage group diagnosed with prostate cancer was 65 to 74 years of age.
    D) roughly 10% of cases were discovered in patients older than 85 years of age.

    EPIDEMIOLOGY

    The incidence of prostate cancer generally increases with age. According to one report of prostate cancer cases in the United States between 2009 and 2013, approximately 57% of cases were diagnosed in men 65 years of age or older [3]. Nearly 9.5% of cases were diagnosed in men between the ages of 45 and 54 years, a drastic increase from almost no cases in younger age groups [3]. Men 65 to 74 years of age represented the largest percentage of diagnosed cases (37.6%). In addition, 15.5% of cases were diagnosed in men 75 to 84 years of age, and roughly 4% of cases were found in men 85 years of age or older [3].

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    3 . The increased risk of prostate cancer in African Americans is believed to be due to
    A) the environment.
    B) physiologic status.
    C) genetic background.
    D) All of the above

    EPIDEMIOLOGY

    In regards to race and ethnicity, African American men appear to be disproportionately affected [1,3]. An analysis of data from Surveillance, Epidemiology, and End Results (SEER) and from the North American Association of Central Cancer Registries found an age-adjusted incidence rate of prostate cancer nearly 70% higher for African Americans compared to white men. The highest prostate cancer incidence rates worldwide occur in black men and Jamaican men of African descent, suggesting a possible inherited genetic susceptibility [6]. African American men are also more likely to die of prostate cancer, with almost double the risk of white men the same age. The increased risk seen in the African American population is believed to be multifactorial, caused by alterations in an individual's environment (e.g., diet, exposure to toxins), participation in screening, genetic background, and physiologic status (e.g., sex steroid hormone levels) [5,8]. The SEER study's age-adjusted data confirmed the differences in race/ethnic populations. The incidence of prostate cancer is greatest in African Americans, lower in white and Hispanic/Latino populations, and least in Asian American/Pacific Islanders and Native American/Alaska Natives [1,3].

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    4 . Which of the following is TRUE regarding the different zones of the prostate?
    A) The ejaculatory ducts pass through the transitional zone before entering the urethra.
    B) The transition zone typically constitutes about 15% of the mass of the glandular prostate.
    C) The peripheral zone comprises about 50% of the normal glandular structure of the adult prostate.
    D) The central zone accounts for approximately 20% to 25% of the mass of the normal glandular prostate.

    PATHOPHYSIOLOGY

    The prostate gland consists of the prostate capsule and four zones. The transition zone typically constitutes about 5% to 10% of the glandular volume of the prostate and surrounds the urethra at the point that the ejaculatory ducts enter the gland [11,14]. The central zone surrounds the transition zone and accounts for approximately 20% to 25% of the mass of the normal glandular prostate [11,14]. The ejaculatory ducts pass through the central zone before entering the urethra [11]. The peripheral zone makes up about 75% of the prostatic volume in healthy adult males. It is a double row of duct buds that laterally surround the central zone, and it occupies the region of the prostate closest to the rectum [11,14]. The anterior zone is nonglandular (primarily made of fibromuscular tissue) and constitutes about one-third of the mass within the prostatic capsule. It is an intermingled region, with fibers descending from the bladder neck and urethral sphincter [11]. It is the portion of the prostate closest to the abdomen.

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    5 . Which zone of the prostate is the source of most cancers?
    A) Central
    B) Urethral
    C) Peripheral
    D) Transitional

    PATHOPHYSIOLOGY

    Most prostate cancer cases (about 70%) originate in the peripheral zone [11,13,14]. The rest develop in the transitional zone (10% to 15%) and in the central zone (15% to 20%) [13]. Most men have clinically localized disease at diagnosis. The majority of cases are multifocal (i.e., multiple separate malignant groups) [15]. These multicentric lesions are often present in different zones of the prostate and typically are of different grades.

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    6 . Which of the following is FALSE regarding prostate-specific antigen (PSA)?
    A) PSA levels can be elevated in BPH and prostatitis.
    B) Measuring PSA levels is considered a less invasive test for screening for prostate cancer than DRE.
    C) A PSA level >2.6 ng/mL has been advocated as an abnormal level for small, organ-confined tumors.
    D) A PSA level >4.0 ng/mL has been advocated as an abnormal level for small, organ-confined tumors.

    SYMPTOMS AND DIAGNOSIS

    Prostate-specific antigen (PSA) is a serine protease that liquefies the seminal fluid. Although it is found in a much greater concentration in seminal fluid, it can also be measured in serum. It is considered a more readily available and less invasive test for both screening and management of prostate cancer [22]. Unfortunately, PSA levels can also be elevated in benign prostatic conditions, such as BPH and prostatitis, leading to false-positive readings [22,24]. In fact, inflammation itself may play a role in the pathogenesis of prostate cancer, making it difficult to exclude any relationship between prostate cancer and a palpable abnormality in another neighboring area [25].

    Newer definitions of an abnormal PSA level have also been debated. Lower PSA thresholds are used now to recommend biopsy, with a corresponding increase in the number of men undergoing biopsy and the number of cancers found in men with low PSA levels [26]. A PSA level greater than 4.0 ng/mL is considered abnormal. However, a value of greater than 2.6 ng/mL has been advocated for the detection of small, organ-confined tumors [27].

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    7 . Which of the following American Urology Association (AUA) patient risk stratification schemes is correct?
    A) Low risk: PSA <10 ng/mL, a Gleason score of 6 or less, and clinical stage T1c to T2a
    B) Intermediate risk: PSA >30 ng/mL, or a Gleason score of 5, or clinical stage T2b
    C) High risk: PSA >50 ng/mL, or a Gleason score of 7, or clinical stage T2c
    D) None of the above

    SYMPTOMS AND DIAGNOSIS

    Patient risk stratification schemes have been developed by the American Urology Association (AUA) and the American Medical Association based on the PSA level, biopsy Gleason score, and American Journal of Cancer Care (AJCC) clinical T-category. The cancer is graded based on the risk of PSA failure and prostate-cancer-specific mortality following radical prostatectomy, external beam radiotherapy, or interstitial prostate brachytherapy [30]:

    • Very low risk: PSA <10 ng/mL, Gleason score 6 or less, clinical stage T1c, presence of disease in fewer than three biopsy cores, ≤50% prostate cancer involvement in any core, and PSA density ≤0.15 ng/mL/cm3

    • Low risk: PSA <10 ng/mL, Gleason score of 6 or less, and clinical stage T1c to T2a

    • Intermediate risk: PSA 10 to 20 ng/mL, or a Gleason score of 7, or clinical stage T2b to T2c (Note: Patients with multiple adverse factors may be shifted into the high-risk category.)

    • High risk: PSA >20 ng/mL, or Gleason score of 8 to 10, or clinical localized stage T3a

    • Very high risk: Clinical stage T3b to T4

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    8 . Which of the following is TRUE regarding the use of PSA and DRE?
    A) False-positive results are possible with PSA but not with DRE.
    B) Based on clinical evidence, PSA and DRE are best used in a complementary fashion.
    C) The use of DRE as a screening aid for diagnosing prostate cancer only came after the development of PSA.
    D) There is no evidence that prostate cancers detected by PSA alone or DRE alone have more favorable pathologic characteristics than those found due to abnormalities in both PSA and DRE.

    SCREENING

    Before the discovery of PSA, DRE was the primary tool used to screen for prostate cancer [22,25]. A positive DRE was followed by biopsy. Findings suggesting cancer or obstructive symptoms then led to transurethral resection of the prostate (TURP). However, a prostate tumor must reach a significant size to be palpable, and as with PSA, false-positive tests can also occur with DRE. Furthermore, prostate cancer is not always detected in the same area of the prostate with suspicious findings on DRE [32].

    Thus, other tests were needed to assist in prostate cancer diagnosis, and the PSA appeared to fill that need. As early as the late 1980s, physicians in the United States began to analyze PSA levels in men who did not have prostate cancer but were considered at high risk of having the disease (i.e., most men older than 50 years of age) [26]. In 1986, the U.S. Food and Drug Administration (FDA) approved the PSA test to monitor the disease status in prostate cancer patients [26]. In 1994, the FDA approved PSA for use as an aid in the early detection of prostate cancer. In the United States, the use of the PSA test in white men reached an annual rate of 38% in 1995 [33]. In 1996, a PSA test preceded 83% of the prostate cancer diagnoses in white patients and 77% in African American patients [33]. In 2005, nearly 50% of black and white men 50 to 79 years of age had undergone a PSA test in the past two years [173]. The literature has shown that PSA and DRE are best used in a complementary fashion [21]. Evidence has shown that prostate cancers detected either by PSA or DRE alone have more favorable pathologic characteristics than those found due to abnormalities in both PSA and DRE [21].

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    9 . There have been disagreements on prostate cancer screening guidelines between organizations. Which statement most correctly summarizes an organization's recommendation?
    A) The National Comprehensive Cancer Network does not recommend DRE screening.
    B) The American Cancer Society (ACS) and the AUA recommend screening for all age groups.
    C) The American College of Preventive Medicine reports insufficient evidence to recommend routine PSA- and DRE-based screening.
    D) The U.S. Preventive Services Task Force (USPSTF) has stated there is an urgent need for prostate cancer screening in men older than 75 years of age.

    SCREENING

    PROSTATE CANCER SCREENING RECOMMENDATIONS FROM VARIOUS ORGANIZATIONS

    OrganizationYear of PublicationRecommendationNotes
    U.S. Preventive Services Task Force2018Recommends against routine prostate cancer screening in men 70 years of age and older. For men 55 to 69 years of age, the decision should be an individual one made after discussion of benefits and risks.Clinicians should not screen men who do not express a preference for screening.
    National Comprehensive Cancer Network2014No consensus reached
    Primarily addresses process for men who choose to be screened.
    Consider obtaining a baseline PSA at 45 years of age. DRE should be used when indicated by PSA. Consider obtaining baseline DRE at 45 years of age.
    American Urological Association2013No routine screening
    Decisions should be individualized for men younger than 55 years who are at high risk.
    Shared decision-making should take place for men 55 to 69 years of age, for whom screening is of greatest benefit.
    American College of Physicians2013No routine screening with PSA for average-risk men younger than 50 years of age, men older than 69 years of age, or men with a life expectancy of less than 10 to 15 years
    American Society of Clinical Oncology2012Discourages general screening for men with a life expectancy of ≤10 years, as the harms outweigh the benefitsDiscuss the individual appropriateness of screening with men who have a life expectancy >10 years.
    American Cancer Society2010No routine screeningDiscuss potential benefits and limitations of prostate cancer early detection at specified ages. Men should choose to be screened only after they receive information about the uncertainties, risks, and potential benefits associated with prostate cancer screening.
    American College of Preventive Medicine2008Insufficient evidence to recommend routine population screening with DRE and PSA.Give men information about potential benefits and harms of screening, including limits of current evidence, and allow them to make their own decision. Discussion should be done annually. "Usual age" for screening is 50 to 70 years in average-risk men. Effectiveness is questionable in men with life expectancy <10 years. More information is needed regarding possible benefit of screening high-risk men at younger ages.
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    10 . Which of the following is TRUE regarding the role of diet in the prevention of prostate cancer?
    A) There is a clear positive relationship between diet and prostate cancer.
    B) There is no evidence that a diet high in cruciferous vegetables can prevent prostate cancer.
    C) It is generally believed that dietary associations are modified by genetic sensitivity.
    D) The Cancer Prevention Study II Nutrition Cohort showed increased prostate cancer rates correlating with increased red meat consumption in all groups studied.

    PROSTATE CANCER PREVENTION

    There have been studies indicating that diet may impact both the development of prostate cancer and the aggressiveness of tumors [25,54]. However, determining a causal relationship between individual foods and nutrients and prostate cancer is not simple. It is generally believed that dietary associations are modified by genetic sensitivity [55,56]. Chan and colleagues concluded that consuming a diet of a wide variety of plant-based foods (cruciferous vegetables) and fish may prevent prostate cancer; more controlled evidence is still needed regarding specific dietary components [54].

    Carmody and colleagues conducted a randomized trial of an intervention of men with recurrent prostate cancer changing to a primarily plant- and fish-based diet and assessed the affect of the change on their quality of life and rate of PSA increase [57]. The clinical trial faced multiple challenges, as only a minority of prostate cancer survivors adhered to the ACS recommended diet of five servings of fruit and vegetables daily [58]. This challenge in adherence was found to be a barrier to improved treatment outcomes.

    Crawford and colleagues also noted some correlation between diet and rates of prostate cancer [4]. This relationship was seen previously in studies showing prostate cancer incidence increased considerably in Japanese men who immigrated to the United States [59]. However, subsequent studies showed inconclusive results. For example, the Cancer Prevention Study II Nutrition Cohort found an association between higher total red meat intake and an increased risk of prostate cancer in African American men but not in white men [60]. However, these results were not duplicated by the Multiethnic Cohort Study, which failed to identify an association between fat/meat intake and prostate cancer risk in any of the four racial/ethnic groups studied (African Americans, Japanese Americans, Hispanics, and whites) [61].

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    11 . Regarding the SELECT study,
    A) there was a small decrease in the number of prostate cancer cases in men taking only selenium.
    B) there was a small decrease in the number of prostate cancer cases in men taking only vitamin E.
    C) supplemental selenium and vitamin E, taken either alone or together for 7 to 12 years, did not prevent prostate cancer.
    D) All of the above

    PROSTATE CANCER PREVENTION

    The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is the largest-ever prostate cancer prevention trial. Its focus is to determine the validity of previous studies suggesting that selenium and vitamin E (alone or in combination) might reduce the risk of developing prostate cancer by 60% and 30%, respectively [53,62]. However, study data from the SELECT trial (ongoing) are not promising; supplemental selenium (200 mcg/day) and vitamin E (400 IU/day), taken either alone or together for 7 to 12 years, did not decrease the risk of developing prostate cancer [63]. The data also show two concerning trends: a significant increase in the number of prostate cancer cases in men taking only vitamin E and slight increases in the number of cases in men taking only selenium and selenium/vitamin E combined [63]. The absolute increase in risk of prostate cancer per 1,000 person-years was 1.6 for vitamin E, 0.8 for selenium, and 0.4 for the combination.

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    12 . A recognized treatment option for early-stage/ low-grade prostate cancer is
    A) surgery.
    B) radiotherapy.
    C) watchful waiting.
    D) All of the above

    TREATMENTS FOR LOCAL AND ADVANCED PROSTATE CANCER

    The three options for early-stage/low-risk prostate cancer include surgery, radiation therapy (either external beam radiation or radioactive tumor seeding [brachytherapy]), and active surveillance, also known as expectant management or watchful waiting [77]. However, the last option is not treatment in itself; it is actually a form of close patient management. Presently, there is no effective systemic therapy for early-stage prostate cancer.

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    13 . Which of the following is TRUE regarding prostate cancer surgery?
    A) Cryosurgery is not associated with any serious adverse effects.
    B) A radical prostatectomy is more often performed in younger patients.
    C) A radical prostatectomy removes the prostate gland while retaining the seminal vesicles.
    D) Most surgeons will perform a radical prostatectomy even if cancer cells are detected in lymph nodes.

    TREATMENTS FOR LOCAL AND ADVANCED PROSTATE CANCER

    Before a radical prostatectomy is considered, physicians should ensure the disease is contained within the prostate gland. If so, there is a higher likelihood that surgery will be successful. A radical prostatectomy is a procedure whereby the prostate gland and the seminal vesicles are completely removed. Usually, this surgical procedure is performed in younger patients (40 to 60 years of age) with no metastases, as they have a greater chance of prostate-cancer-related death than older patients (70 to 90 years of age) [55]. Surgery has been widely documented to reduce mortality and rates of metastases in prostate cancer patients [55,75].

    There are several surgical options when completing a prostatectomy [76]. The first option is either retropubic or perineal prostatectomy. With the retropubic procedure, the surgeon makes an incision in the abdomen to reach the prostate and may also remove nearby lymph nodes as a precautionary measure to prevent spread of disease [75]. The second option is a perineal prostatectomy, in which the surgeon makes an incision in the perineum; another abdominal incision is needed to remove lymph nodes [76]. In some hospitals, surgeons may do a laparoscopic prostatectomy, whereby instruments are passed through a few small incisions. While the laparoscopic procedure is generally associated with fewer complications and faster recovery, it is technically challenging and not always appropriate for removing all prostate tumors [76].

    Cancer that has spread to lymph nodes signals the likelihood of more extensive disease that is less likely to be cured by surgery. This knowledge is vital when determining a treatment plan, so a pelvic lymphadenectomy is often completed prior to prostatectomy to check for prostate cancer spread [72]. The removed nodes are examined by a pathologist for evidence of cancer cells. If the nodes display evidence of cancer, radical prostatectomy would usually be excluded as a treatment option [72].

    Some treatment centers also perform cryosurgery. This is a technique whereby prostate tissue is ablated by alternate freezing and thawing. It can be an outpatient procedure. The experience with this type of surgery for prostate cancer is limited, as there has been little published data documenting the effect of cryosurgery on metastasis-free, prostate-cancer-specific, or overall survival [79]. The five-year biochemical disease-free survival rates have ranged from 48% to 92%, depending on the risk of recurrence, but long-term data on prostate cancer-specific survival are not yet available and there are no clearly defined guidelines for patient selection for cryosurgery as a salvage procedure [78]. However, the AUA notes that primary cryosurgery is an option for men with organ-specific disease without metastases [78]. Poorer outcomes after cryosurgery were noted for patients with larger prostates, as it is more difficult to uniformly freeze larger areas. A 2013 review of literature from 1980 to 2013 noted that this form of treatment has greatly improved over time, with biochemical disease-free survival rates now comparable to other treatment modalities [168]. Treatment-related morbidities have also decreased. Adjuvant ADT should be considered for men with clinical stage T3 prostate cancer [169].

    Cryotherapy is a good option for eligible patients who cannot undergo radical prostatectomy due to comorbidities, obesity, or history of pelvic surgery [78]. Salvage cryotherapy may be beneficial for men with locally recurrent disease, a PSA less than 4 ng/mL, and no metastases for whom radiotherapy was not effective [78]. It is important to note that serious toxic effects have been noted with cryosurgery, including bladder outlet injury, urinary incontinence, sexual impotence, and rectal injury [77].

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    14 . Which of the following is TRUE regarding radiotherapy for prostate cancer?
    A) Most investigators have advocated an optimal cumulative radiation dose of less than 40 Gy.
    B) Retrospective series have shown adjuvant radiotherapy to reduce the risk of biochemical failure while improving local and distant disease control.
    C) Studies of radiotherapy compared with observation have shown no significant improvement in biochemical-failure-free survival after adjuvant therapy.
    D) None of the above

    TREATMENTS FOR LOCAL AND ADVANCED PROSTATE CANCER

    In addition, published retrospective series have shown adjuvant radiotherapy to reduce the risk of biochemical failure while improving local and distant disease control [83,84,85]. Biochemical failure is defined as three consecutive measurements of an increase of PSA greater than 2 ng/mL compared to the lowest pretreatment level. Three randomized trials comparing treatment with adjuvant radiotherapy to observation (active surveillance) in men with pathologic stage T3 or margin-positive disease showed a significant improvement in biochemical-failure-free survival in the radiotherapy group [83,84,85]. In spite of these promising outcomes, no effect on overall survival has been reported [80].

    There has been no accepted optimal dose of radiotherapy as an adjuvant treatment for prostate cancer in spite of its use in the postoperative period. Reported doses have varied between 45 Gray (Gy) to 81 Gy, although most investigators have advocated a cumulative dose greater than 60 Gy [83,84,85]. According to the National Cancer Institute, greater improvements have been shown with higher doses of radiation (78–81 Gy) compared to conventional doses [77]. A treatment guideline published by the NCCN recommends the following dose schedule [30]:

    • 75.6–79.2 Gy in conventional fractions to the prostate (± seminal vesicles for part of the therapy) in patients with clinically localized prostate cancer at low risk

    • Up to 81 Gy in patients at intermediate or high risk

    Despite the lack of an identified optimal dose, radiotherapy has shown a significant benefit for prostate cancer therapy. Anscher and colleagues reported an improved rate of localized disease control with the addition of radiotherapy after prostatectomy; the 10-year local control rate was 92% with the addition of radiotherapy compared to 60% with observation alone [83]. In addition, Leibovich and colleagues reported that subjects who received adjuvant radiotherapy experienced no local or distance recurrence in men compared to a 16% rate of recurrence with observation alone [86]. Studies completed prior to the regular assessment of PSA levels have indicated significantly improved local disease control with adjuvant radiotherapy [87,88]. For example, a phase III study of adjuvant radiotherapy in men with stage T3 disease and a primary endpoint of metastasis-free survival found the 10-year rate favored adjuvant radiotherapy to observation alone; however, the difference was not significant [89]. Macdonald and colleagues noted their five-year rate of freedom from both local recurrence and distant metastasis with adjuvant radiotherapy treatment was significant, at respective rates of 95% and 97%, indicating that radiotherapy has a demonstrated benefit for many prostate cancer patients [80].

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    15 . Androgen deprivation therapy in prostate cancer treatment
    A) has hypergonadism as its main observed effect.
    B) has been shown to improve survival rates relative to observation.
    C) may cause physiologic changes in bone mineral density, body composition, lipid profiles, and insulin sensitivity.
    D) has not been shown to improve disease-free and overall survival in combination with radiation for locally advanced or high-risk nonmetastatic disease.

    TREATMENTS FOR LOCAL AND ADVANCED PROSTATE CANCER

    Most men are treated with a GnRH agonist rather than bilateral orchiectomies, as GnRH agonists are easily administered, reversible, and more acceptable to patients. GnRH agonist use has risen markedly over the last two decades across all ages, disease stages, and tumor grades [94]. More than one-third of the estimated 2 million prostate cancer survivors in the United States are treated with GnRH agonists [10]. GnRH agonists have been shown to improve disease-free and overall survival in combination with radiation for locally advanced or high-risk nonmetastatic disease [95]. Adjuvant therapy with a GnRH agonist also improves survival in men with node-positive disease after radical prostatectomy [96].

    ADT is also used in situations in which there are less clear benefits. PSA monitoring after primary therapy often detects recurrences long before they are revealed by either symptoms or imaging [97]. A rising PSA after primary surgery or radiation therapy commonly leads to long-term ADT, although the effects of early ADT on elevated PSA recurrences have not been adequately characterized. Additionally, some men with localized disease opt for long-term ADT instead of radiation or surgery, which has not been shown to improve survival rates relative to observation [98].

    It is important to note that ADT, and especially the use of GnRH agonists, leads to a significant reduction in serum testosterone and a number of physiologic changes in bone mineral density, body composition, lipid profiles, and insulin sensitivity [14]. Men receiving GnRH agonists are at an increased risk for bone fracture as well as diabetes and cardiovascular disease [14,99]. Treatment options to increase bone density, a surrogate for fracture risk in men without metastases, include denosumab (60 mg SQ every 6 months), zoledronic acid (5 mg IV annually), and alendronate (70 mg PO weekly) [176]. The increased risk of diabetes and cardiovascular disease may explain in part the excess number of noncancer deaths associated with ADT. GnRH agonists significantly increase fat mass and fasting insulin levels and decrease insulin sensitivity [100,101]. Treatment-related changes in serum lipoproteins and arterial stiffness, as well as possible QT interval prolongation, may also contribute to the association between GnRH agonists and adverse cardiovascular effects [14,102]. Although ADT has improved outcomes in metastatic prostatic cancer patients, research is needed to address the adverse effects often seen with this therapy.

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    16 . Which of the following statements is FALSE regarding prostate cancer chemotherapy?
    A) Docetaxel and prednisone have shown little efficacy in treating prostate cancer.
    B) Use of bevacizumab in the treatment of hormone-resistant prostate cancer is off-label.
    C) Angiogenesis treatments have been investigated related to the theory that prostate cancer tissue overexpresses several angiogenic proteins and leads to adverse outcomes.
    D) The Cancer and Leukemia Group B (CALGB) trial in the United States found that adding bevacizumab to docetaxel and prednisone did not improve overall prostate cancer survival.

    TREATMENTS FOR LOCAL AND ADVANCED PROSTATE CANCER

    Other therapies are being developed for patients who are docetaxel-resistant. Many of the newer chemotherapies have monoclonal antibodies for targeting angiogenesis. This treatment strategy relies on suppressing several angiogenic proteins, including those in the VEGF family and endothelin (ET)-A, that are expressed in prostatic tissue and may cause prostate cancer [103,104,105]. Preliminary research using a combination of the monoclonal antibody bevacizumab, which acts against VEGF-A, and docetaxel have shown some positive results in patients experiencing docetaxel failure [106]. The Cancer and Leukemia Group B (CALGB) phase III trial in the United States (CALGB 90401) was conducted to determine if adding the monoclonal antibody bevacizumab to docetaxel and prednisone would increase overall survival rates [105]. Despite an improvement in progression-free survival and objective response, the addition of bevacizumab to docetaxel and prednisone did not improve overall survival in men with metastatic castration-resistant prostate cancer and was associated with greater toxicity [171]. Bevacizumab was approved in 2014 for platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer; use of bevacizumab for hormone-resistant prostate cancer is off-label [166].

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    17 . Finasteride
    A) is primarily used as an agent for prostate cancer prevention.
    B) has been found to possibly decrease rates of high-grade cancers.
    C) inhibits the conversion of testosterone to the more potent androgen dihydrotestosterone.
    D) is an effective agent for prostate cancer prevention, although one with a high level of toxicity.

    TREATMENTS FOR LOCAL AND ADVANCED PROSTATE CANCER

    Finasteride is a low-toxicity chemopreventive agent that inhibits the conversion of testosterone to the more potent androgen DHT within the prostate. It originally became available for the treatment of BPH, and since then, it has been approved for the treatment of male pattern baldness. However, little was known about its long-term effects on the prostate. Thompson and colleagues undertook a study to determine whether finasteride can reduce the prevalence of prostate cancer among initially healthy men during a seven-year period [113]. Data from the PCPT showed a 24.8% overall reduction in prostate cancer prevalence with the use of finasteride (18.4%) compared to the placebo group (24.4%). However, there was a greater incidence of high-grade cancers (Gleason scores: 7–10) found in the finasteride arm (37%) versus placebo (22.2%) [43]. An 18-year follow-up study of the PCPT published in 2013 found that despite the increased incidence of high-grade cancers in the finasteride group compared to the placebo group, there was no significant between-group difference in the rates of overall survival or survival after the diagnosis of prostate cancer [41].

    The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial was a four-year, multicenter, randomized, double-blind, and placebo-controlled study evaluating the efficacy and safety of oral dutasteride (0.5 mg/day) in reducing the incidence of prostate cancer among men identified as being at increased risk for the disease (PSA between 2.5 and 10 ng/mL) [122]. Dutasteride differs from finasteride in that it inhibits both 5AR isoenzymes 1 and 2. The REDUCE trial also attempted to find the reason for an increased incidence of 5AR inhibitor-associated high-grade prostate cancer tumors [43]. Data from the REDUCE trials show a significant decrease in prostate cancer incidence in dutasteride-treated patients during the four years (relative risk reduction: 23%) [72]. In the dutasteride group, cancer was detected in 659 of the 3,305 men, compared with 858 of the 3,424 men in the placebo group. Whether dutasteride increases the incidence of high-grade tumors was somewhat unclear. In the dutasteride group, 29 men had tumors with a Gleason score of 8 to 10, compared with 19 in the placebo group. However, 141 men with tumors with a Gleason score of 5 to 7 were removed from the study during the first two years. It is speculated that the difference in number of high-grade tumors between groups would be statistically insignificant had these men not dropped out [146].

    Starting in 2011, the FDA required new labeling on 5AR inhibitors to include a warning for an increased risk of high-grade prostate cancer with their use based on the results of the PCPT and the REDUCE trials [121,165,170]. The results of the two trials indicated that the cancers prevented by 5AR inhibitors were Gleason ≤6 tumors, which would be expected to cause little-to-no morbidity in an individual's lifetime. Conversely, the increased number of high-grade cancers (Gleason ≥8 tumors) in the treatment groups was cause for serious concern. The FDA is unlikely to approve 5AR inhibitors for prostate cancer prevention (as manufacturers were requesting in 2011), and despite the agents' continued use for benign prostatic hyperplasia (BPH) and male pattern baldness, they are not recommended for prostate cancer chemoprevention and should not be used as such [121,165]. The FDA does recommend the continued use of finasteride/dutasteride for BPH, as the benefit outweighs the risk of prostate cancer, and is assessing the risk/benefit for male-pattern baldness [170]. Alpha-blockers have not been shown to reduce the risk of urinary retention or surgery related to BPH, and switching patients to one is not recommended. Men prescribed a 5AR inhibitor should be screened for prostate cancer using DRE in addition to PSA, and it should be remembered that PSA levels are 50% lower in men taking these drugs [170].

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    18 . The FDA recommends that 5AR inhibitors continue to be prescribed for
    A) prostate cancer treatment.
    B) prostate cancer prevention.
    C) benign prostatic hyperplasia.
    D) All of the above

    TREATMENTS FOR LOCAL AND ADVANCED PROSTATE CANCER

    Starting in 2011, the FDA required new labeling on 5AR inhibitors to include a warning for an increased risk of high-grade prostate cancer with their use based on the results of the PCPT and the REDUCE trials [121,165,170]. The results of the two trials indicated that the cancers prevented by 5AR inhibitors were Gleason ≤6 tumors, which would be expected to cause little-to-no morbidity in an individual's lifetime. Conversely, the increased number of high-grade cancers (Gleason ≥8 tumors) in the treatment groups was cause for serious concern. The FDA is unlikely to approve 5AR inhibitors for prostate cancer prevention (as manufacturers were requesting in 2011), and despite the agents' continued use for benign prostatic hyperplasia (BPH) and male pattern baldness, they are not recommended for prostate cancer chemoprevention and should not be used as such [121,165]. The FDA does recommend the continued use of finasteride/dutasteride for BPH, as the benefit outweighs the risk of prostate cancer, and is assessing the risk/benefit for male-pattern baldness [170]. Alpha-blockers have not been shown to reduce the risk of urinary retention or surgery related to BPH, and switching patients to one is not recommended. Men prescribed a 5AR inhibitor should be screened for prostate cancer using DRE in addition to PSA, and it should be remembered that PSA levels are 50% lower in men taking these drugs [170].

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    19 . Medication interventions for sexual dysfunction in men who have been treated for prostate cancer
    A) are usually effective.
    B) are not usually prescribed.
    C) are associated with no serious side effects.
    D) most commonly include a phosphodiesterase-5 inhibitor.

    CONSIDERATIONS FOR PROSTATE CANCER PATIENTS

    In the past, erectile dysfunction was often a silent condition, with many men being too embarrassed or ashamed to discuss the issue with their physicians. Today, there are many treatment options available to manage erectile dysfunction, including oral drug therapy, injection medications, suppositories or pellets that are deposited in the urethra of the penis, and surgery to insert penile implants or prostheses [126]. The most common approach is oral medication therapy with a phosphodiesterase-5 inhibitor (sildenafil, vardenafil, or tadalafil), with one guideline recommending initiation of therapy early in the course of recovering [125]. However, it is unclear how many post-treatment patients will benefit from the use of these medications [126]. In one study, only 38% of patients who had received either definitive radiotherapy or prostatectomy for localized prostate cancer reported improvements in sexual functions as the result of medication interventions [131]. If pharmacotherapy in unsuccessful, referral to a urologist or sexual health specialist warranted [125].

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    20 . Depression is underdiagnosed in men, including those with prostate cancer, due to
    A) the reluctance of men to seek help.
    B) a hesitancy of men to express emotion.
    C) a lack of men's recognition of the symptoms of depression.
    D) All of the above

    CONSIDERATIONS FOR PROSTATE CANCER PATIENTS

    A diagnosis of prostate cancer is often the cause of psychologic distress, and some men may become depressed as a result of the effect of the cancer or treatment. As discussed, the treatments available for prostate cancer patients can have significant effects on men's quality of life, negatively impacting self-esteem, relationships, and personal identity. Unfortunately, depression is underdiagnosed in men as the result of a divergence of factors, including clinicians' lack of appropriate training and discomfort with dealing with depression and issues related to male gender identity, such as:

    • Reluctance of men to seek help

    • Lack of men's recognition of the symptoms of depression

    • Hesitancy of men to express emotions

    • Inconsistency of men's symptoms with those in the Diagnostic and Statistical Manual of Mental Disorders

    • Tendency for men to see depression as a weakness

    • Men's misconceptions about mental illness and its treatment

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