One in every nine American men will be diagnosed with prostate cancer at some point during his lifetime [1]. In 2022, the estimated projected number of new prostate cancer diagnoses is 268,490, and the projected number of deaths related to prostate cancer is 34,500 [1]. Prostate cancer accounts for 27.3% of all new cancer diagnoses among men [1]. The majority of newly diagnosed prostate cancers have localized disease and a good prognosis. Ninety percent of men are diagnosed with local (77%) or regional (13%) disease, and the five-year survival rate for localized or regional prostate cancer is 100% [3]. However, metastatic prostate cancer at the time of diagnosis has shown a five-year survival rate as low as 30.5% [1,3].

The incidence of prostate cancer increases with age. According to one report of prostate cancer cases in the United States between 2012 and 2016, approximately 58% of cases were diagnosed in men 65 years of age or older [3]. Nearly 8.7% 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 (39.2%). In addition, 14.9% 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].

In regard to race and ethnicity, Black 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 73% 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]. The increased risk seen in the Black 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. In the United States, the incidence of prostate cancer is highest among Black men (172.6 cases per 100,000), lower among White and Hispanic/Latino men (99.9 and 85.3 per 100,000), and lowest among Asian American/Pacific Islander men (55.0 per 100,000) [1].

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.

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.

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].

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]:

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 patients with prostate cancer [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].

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 effect 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 White men) [61].

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.

The three primary management options for localized/low-risk prostate cancer are active surveillance (also known as expectant management or watchful waiting), surgery (prostatectomy), and radiation therapy (external beam radiation or radioactive tumor seeding [brachytherapy]) [77]. Clinicians should inform patients that all prostate treatments carry risk. In discussing management choices, the risks of treatment to urinary, sexual, and bowel function should be incorporated with risks posed by the cancer, patient life expectancy, co-morbidities, and patient preferences to facilitate a shared decision-making approach to management [179].

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 patients with prostate cancer [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].

Cryosurgery

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].

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]:

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 where the potential benefit of primary therapeutic options is less clear. 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) [30]. 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 patients with metastatic prostatic cancer, research is needed to address the adverse effects often seen with this therapy.

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].

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].

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].

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].

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 patients with prostate cancer 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: