Prostate cancer is a neoplasm involving the prostate. Various classifications have been developed to evaluate malignancy potential and prognosis.

• The degree of malignancy varies with the stage:
  1. Stage A: Confined to the prostate, no nodule palpable.
  2. Stage B: Palpable nodule confined to the gland.
  3. Stage C: Local extension.
  4. Stage D: Regional lymph nodes or distant metastases.
• In the Gleason classification (Box 1 and Fig. E1), two histologic patterns are independently assigned numbers 1 to 5 (best to least differentiated). These numbers are added to give a total tumor score between 2 and 10. Prognosis is best for highly differentiated tumors (e.g., Gleason score 2-6) compared with most poorly differentiated tumors (Gleason score 7-10).
• Another commonly used classification is the Tumor-Node-Metastasis (TNM) classification of prostate cancer (Table 1).
• Table 2 summarizes the definition of risk groups and biopsy criteria.

• Prostate cancer has surpassed lung cancer as the most common nonskin cancer in men.
• In the United States, more than 220,000 new cases are diagnosed yearly, and nearly 30,000 males die from prostate cancer each year (second leading cause of death from cancer in U.S. men).
• Incidence of prostate cancer increases with age: Uncommon <50 yr; 80% of new cases are diagnosed in patients aged ≥65 yr. Widespread prostate-specific antigen (PSA) testing has doubled the incidence of prostate cancer and the lifetime risk for prostate cancer to approximately 16%. Prostate cancer is also diagnosed earlier, and the incidence of clinically “silent” T₁ tumors has increased from 17% in 1989 to 48% in 2001 since the advent of PSA screening. Currently, approximately 80% of prostate cancer cases are diagnosed as localized disease and only 4% as metastatic disease. The incidence of metastatic prostate cancer for middle-aged men was stable from 2004 to 2010 and then increased from 12 to 17 cases/100,000 from 2010 to 2018.¹ It is unclear if this increase was due to U.S. Preventive Services Task Force (USPSTF) recommendations against PSA screening in 2008 and 2012 or to more aggressive diagnostic strategies.
• Prostate cancer is found at autopsy in more than half of U.S. men older than 50 yr but is the cause of death in only 3%.
• Average age at time of diagnosis is 72 yr.
• Blacks in the U.S. have the highest incidence of prostate cancer in the world (one in every nine males).
• Incidence is low in Asians.
• Approximately 9% of all prostate cancers may be familial. Obesity is a risk factor for prostate cancer. High-fat, low-fiber diet increases risk. High insulin levels may also increase the risk of prostate cancer. Dietary supplementation with vitamin E has been reported to significantly increase the risk of prostate cancer among healthy men. Linkage studies have implicated chromosome 17p21-22 as a possible location of a prostate-cancer susceptibility gene. Germline mutations in HOXB13 are associated with a significantly increased risk of hereditary prostate cancer.
• Mortality rates of prostate cancer have declined substantially in the past 15 yr from 34% in 1990 to <20% currently.

• Generally silent disease until it reaches advanced stages.
• Bone pain and pathologic fractures may be initial symptoms of prostate cancer.
• Local growth can cause symptoms of outflow obstruction.
• Digital rectal examination (DRE) may reveal an area of increased firmness; 10% of patients will have a negative DRE.
• Prostate may be hard, fixed, with extension of tumor to the seminal vesicles in advanced stages.

• Benign prostatic hypertrophy
• Prostatitis
• Prostate stones

• Measurement of PSA is controversial in early diagnosis of prostate cancer. PSA screening is associated with psychological harm, and its potential benefits remain uncertain. In asymptomatic men with no history of prostate cancer, screening using PSA does not reduce all-cause mortality or death from prostate cancer. Normal PSA is found in >20% of patients with prostate cancer, whereas only 20% of men with PSA levels between 4 ng/ml and 10 ng/ml have prostate cancer. Most guidelines encourage a shared decision-making approach between patient and physician regarding PSA testing. Available evidence favors clinician discussion of the pros and cons of PSA screening with average-risk men aged 65 to 69 yr. Only men who express a definite preference for screening should have PSA testing. Rather than widespread annual PSA screening, a reasonable approach may be to focus on high-risk men (those with PSA levels ≥2 ng/ml at age 60). The American Cancer Society recommends offering the PSA test and DRE yearly to men aged ≥50 yr who have a life expectancy of at least 10 yr. Earlier testing, starting at age 40 to 45 yr, is recommended for men at high risk (e.g., blacks, men with family history of prostate cancer). An isolated elevation in PSA level should be confirmed several weeks later before proceeding with further testing, including prostate biopsy. Screening for prostate cancer in men aged ≥75 yr is controversial and generally not recommended. The American College of Physicians (ACP) recommends that clinicians should not screen for prostate cancer using the PSA in average-risk men under age 50, men over age 69, or men with a life expectancy of <10 to 15 yr. The U.S. Preventive Services Task Force (USPSTF) recommends against PSA-based screening for prostate cancer in all age groups. According to the USPSTF:
  1. The magnitude of harms from screening (e.g., falsely high PSA levels, psychological effects, unnecessary biopsies, overdiagnosis of indolent tumors) is “at least small.”
  2. The magnitude of treatment-associated harms (i.e., adverse effects of surgery, radiation, and hormonal therapy) is “at least moderate.”
  3. The 10-yr mortality benefit of PSA-based prostate cancer screening is “small to none.”
  4. The overall balance of benefits and harms results in “moderate certainty that PSA-based screening has no net benefit.”
• The USPSTF currently recommends individualized screening decisions for men between ages 55 and 69 and advises against screening for older men.
• Free PSA: The use of serum free PSA for prostate screening has been proposed by some urologists as a means to decrease unwarranted biopsies without missing a significant number of prostate cancers. This approach is based on the higher free PSA in men with benign prostatic hyperplasia and the higher protein-bound PSA levels in men with prostate cancer. For example, in men with total PSA levels of 4 to 10 ng/ml, the cancer probability is 0.25, but if the percentage of free PSA is ≤17%, the probability of cancer increases to 0.45.
• PSA velocity: The rate of increase of serum PSA over time (PSA velocity) can aid in the diagnosis of prostate cancer. A yearly PSA velocity >0.75 ng/ml increases the likelihood of later malignancy when total PSA is still within normal range. Proper interpretation of PSA velocity requires at least three PSA measurements over an 18-mo period because most PSA variations are physiologic. Recent trials have cast a doubt on the value of PSA velocity by showing that adding PSA velocity as a trigger for biopsy did not improve predictive accuracy beyond that of using PSA threshold values alone. Retrospective studies² have also shown that PSA velocity threshold is different in black and non-Hispanic white men treated for low-risk prostate cancer with active surveillance. PSA velocity associated significantly with grade progression was 0.44 mg/ml/yr in black patients and 1.18 mg/ml/yr in non-Hispanic whites. The optimal PSA velocity threshold for development of metastases was 1.77 mg/ml/yr.
• Age-adjusted PSA: There is evidence that the current threshold of 4.0 ng/ml is inadequate for younger men, because in a recent study 22% of men with PSA levels between 2.6 and 4.0 were found to have prostate cancer. The concept of age-related cutoffs remains controversial. Lowering the upper limit of normal for PSA would improve sensitivity but decrease specificity.
• Prostatic acid phosphatase can be used for evaluation of nonlocalized disease.
• Prostate cancer gene 3 (PCA3) is overexpressed in prostate cancer cell, and high levels are suggestive of prostate cancer. Measurement of PCA3 in urine specimens collected after digital exams is helpful to make decisions about prostate biopsy in men with elevated PSA.
• Ultrasound-guided transrectal biopsy and fine-needle aspiration of prostate can confirm the diagnosis. Indications for biopsy include an abnormal PSA level, an abnormal DRE, or a previous biopsy specimen that showed prostatic intraepithelial neoplasia or prostatic atypia. The number of cores taken is patient specific, typically including a minimum of 10 cores. Prostate volume negatively affects cancer detection rate (23% in glands >50 cm³, 38% in glands <50 cm³). MRI-targeted biopsy identifies clinically significant prostate cancers more accurately than conventional systematic biopsy in men with suspected localized prostate cancer but misses one in five clinically significant cancers.^2b

• MRI can be used to guide decisions on whether to perform biopsies in men with elevated PSA levels on prostate cancer screening. MRI also facilitates targeted biopsy or suspicious areas.³ However the avoidance of systematic biopsy in favor of MRI-directed targeted biopsy for screening and early detection in persons with elevated PSA levels reduces the risk of over-diagnosis by half at the cost of delaying detection of intermediate-risk tumors in a small proportion of patients.^2b
• Bone scan is useful to evaluate bone metastasis (present or eventually develops in almost 80% of patients). However, according to the American Urological Association (AUA), the routine use of bone scanning is not required for staging of prostate cancer in asymptomatic men with clinically localized cancer if the PSA level is ≤20 ng/ml.
• CT scan, MRI, and transrectal ultrasonography may be useful in selected patients to assess extent of prostate cancer. High-resolution has been used for the detection of small and otherwise undetectable lymph node metastases in patients with prostate cancer. However, according to the AUA, transrectal ultrasonography adds little to the combination of PSA and DRE. Similarly, CT and MRI imaging are generally not indicated for cancer staging in men with clinically localized cancer and PSA <25 ng/ml. With regard to pelvic lymph node dissection in staging, the AUA states that it may not be required in patients with PSA levels <10 ng/ml and when PSA level is <20 ng/ml and the Gleason score is <6.

Watchful waiting is reasonable in selected patients with early-stage (T_1a) and projected life expectancy <10 yr or in patients with focal and moderately differentiated carcinoma.

• Therapeutic approach varies with the following:
  1. Stage of the tumor
  2. Patient’s life expectancy
  3. General medical condition
  4. Patient’s treatment preference (e.g., patient may be opposed to orchiectomy)
• The optimal treatment of clinically localized prostate cancer is unclear. It is important to remember that all forms of treatment have potential adverse effects. Management requires careful consideration of the potential benefits and harms of intervention and the patient’s age, health status, and individual preferences. A treatment algorithm for prostate cancer is described in Fig. 6. Table 3 summarizes recommended treatment based on risk group and life expectancy.
  1. Radical prostatectomy is generally performed in patients with localized prostate cancer and life expectancy >10 yr. Radical prostatectomy reduces disease-specific mortality, overall mortality, and the risks of metastasis and local progression. The absolute reduction in the risk of death after 10 yr is small, but the reductions in the risks of metastasis and local tumor progression are substantial. A 29-yr follow-up comparing radical prostatectomy with watchful waiting showed that men with clinically detected, localized prostate cancer and a long life expectancy benefited from radical prostatectomy with a mean 2.9 yr of life gained. A trial⁴ comparing surgery with radiation therapy for high-risk localized prostate cancer showed that prostate cancer-specific mortality at 5 yr was significantly lower with surgery than with external beam radiation therapy (2.3% vs 4.1% PS 0.001). Postoperative complications of radical prostatectomy include urinary incontinence (10%-20% depending on degree of neurovascular bundle and urethral preservation, patient age, and correct mucosal apposition) and erectile dysfunction (percentage >50% and varies with patient age, preoperative erectile dysfunction, stage of tumor at time of surgery, and preservation of neurovascular bundle). Lower complication rates occur in hospitals that perform a large number of prostatectomies. Fewer men will have postsurgical erectile dysfunction after unilateral or bilateral nerve-sparing surgery. In men undergoing prostatectomy, robotic-assisted laparoscopic surgery represents an alternative to open retropubic radical prostatectomy. Despite advertisements that suggest that there are fewer complications after robotic surgery, data show that sexual dysfunction occurs postoperatively in about 88% of patients who have undergone robotic-assisted or conventional prostatectomy and that incontinence problems are more prevalent (33%) with robotic surgery than with open retropubic radical prostatectomy (RPP) (27%). Trials have shown that prostatectomy is preferred over “watchful waiting” in patients with localized prostate cancer detected by PSA if the PSA level is >10 ng/ml. In this subgroup, the 10-yr mortality is 48.4% with prostatectomy versus 61.6% with watchful waiting. In men who have low-risk disease (PSA level <10 mcg/L, stage <T_2a, Gleason score ≤3 + 3), and <6% risk for prostate cancer-specific death at 15 yr, watchful waiting and active surveillance are reasonable and underutilized options.
  2. Radiation therapy (external-beam irradiation or brachytherapy with implantation of radioactive pellets [iodine-125 or palladium-103 seeds] into the prostate gland) represents an alternative in patients with localized prostate cancer, especially poor surgical candidates or patients with a high-grade malignancy. The efficacy of brachytherapy is comparable to external radiation and radical prostatectomy. In patients receiving external-beam radiation, a total dose of 79.2 Gy (high dose) compared with a total dose of 70.2 Gy (conventional dose) has been reported to lower the risk of recurrence without increased risk of morbidity and mortality. Newer radiation treatments such as intensity-modulated radiation therapy (IMRT) and proton therapy are becoming increasingly popular and replacing the older technique of conformal radiation therapy over the past 10 yr. Trials have shown that among patients with nonmetastatic prostate cancer, the use of IMRT compared with conformal therapy is associated with less GI morbidity and fewer hip fractures but more erectile dysfunction; IMRT compared with proton therapy is associated with less GI morbidity. Patients with localized prostate cancer and high risk for extraprostatic disease and disease recurrence (e.g., Gleason score ≤7 with multiple positive biopsy cores and clinical stage T_1b-T_2b) may benefit (increased overall survival) with the addition of 6 mo of androgen suppression therapy to radiation therapy. High-intensity focused ultrasound (HIFU) is a newer treatment option for patients with prostate cancer. It ablates localized areas of the prostate with the goal of sparing patients the morbidity of whole-gland therapy. Longer-term studies comparing HIFU with standard therapy are needed. Hemigland cryoablation is another newer treatment modality for intermediate-risk prostate cancer. Longer studies are needed before drawing conclusions.
  3. Watchful waiting is reasonable in patients who are too old or too ill to survive longer than 10 yr. If the cancer progresses to the point at which it becomes symptomatic, palliation can be attempted with several methods. Conservative management is also reasonable for patients with Gleason score of 2 to 4 because these patients do not have a shortened life expectancy and treatment is associated with long-term side effects. Watchful waiting also appears to be safe in older men with less-aggressive disease. Individual preferences play a central role in the decision whether to treat or to pursue active surveillance.
• Patients with advanced disease and projected life expectancy <10 yr are candidates for radiation therapy and hormonal therapy (diethylstilbestrol, luteinizing hormone-releasing hormone analogues, antiandrogens, bilateral orchiectomy).
• Recommended treatment of patients with regional metastatic prostate cancer with projected life expectancy ≥10 yr includes radiation therapy and hormonal therapy.
• Prostate cancer is an androgen receptor-dependent disease, and the blocking of androgen-receptor signaling is an effective treatment modality. Table 4 summarizes major circulating androgens. Androgen deprivation therapy (ADT) is the mainstay of treatment for metastatic prostate cancer. Adverse effects of ADT include decreased libido, impotence, hot flashes, osteopenia with increased fracture risk, metabolic alterations, and changes in mood and cognition. Adjuvant treatment with luteinizing hormone-releasing hormone (LHRH) agonists (goserelin, leuprolide, or triptorelin) plus antiandrogens (flutamide, bicalutamide, or nilutamide), when started simultaneously with external-beam radiation, improves local control and survival in patients with locally advanced prostate cancer. Pamidronate inhibits osteoclast-mediated bone resorption and prevents bone loss in the hip and lumbar spine in men receiving treatment for prostate cancer. Gonadotropin-releasing hormone (GnRH) receptor antagonists can be used for rapid medical castration of men with advanced prostate cancer. Degarelix is an injectable GnRH agonist useful to suppress testosterone in patients with prostate cancer who are not good candidates for LHRH agonists and refuse surgical castration. Assessment of bone density and treatment with once-weekly oral alendronate can prevent and improve the bone loss that occurs in men receiving ADT for prostate cancer.
• Docetaxel plus prednisone or docetaxel plus estramustine can be used in metastatic hormone-refractory prostate cancer. Newer treatments for hormone-refractory prostate cancer (castration-resistant cancer) include immunotherapy with sipuleucel and cabazitaxel, a microtubule inhibitor that interferes with cell mitosis and replication. Both agents can prolong survival but adverse effects can be severe, and both agents are very expensive. Abiraterone is an oral agent that blocks biosynthesis of androgens by inhibiting CYP17, an enzyme required for androgen biosynthesis. It has been FDA approved for oral treatment, in combination with prednisone, of metastatic castration-resistant prostate cancer in patients previously treated with docetaxel. Darolutamide is an androgen-receptor inhibitor approved for the treatment of nonmetastatic castration-resistant prostate cancer. The addition of darolutamide to androgen-deprivation therapy and docetaxel has also been shown to prolong survival in patients with metastatic, hormone-sensitive prostate cancer.⁵
• Enzalutamide is a newer nonsteroidal antiandrogen. Trials have shown it to be highly effective in extending survival in patients with metastatic castration-resistant prostate cancer. It can be used sequentially with other agents such as docetaxel, abiraterone, cabazitaxel, and immunotherapy.
• Radium-223, an alpha emitter, selectively targets bone metastases and has been found effective in improving survival in men with castration-resistant prostate cancer and bone metastases.
• The polyadenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor olaparib has shown a high response rate in trials in patients whose prostate cancers were no longer responding to standard treatments with enzalutamide or abiraterone and who had defects in DNA-repair genes.

Figure 6 Treatment algorithm.

²²³Ra, Radium-223.

From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

• Patients should be monitored at 3- to 6-mo intervals with clinical examination and PSA for the first year, then every 6 mo for the second year, then yearly if stable. For patients who have undergone radical prostatectomy, a rising PSA level suggests evidence of residual or recurrent prostate cancer. A recent study revealed that if the PSA level remains undetectable 3 to 5 yr after radical prostatectomy, the probability of biochemical recurrence is extremely low, and it is reasonable to stop PSA monitoring. Salvage radiotherapy may potentially cure patients with disease recurrence after radical prostatectomy. Recent trials have shown that addition of 24 mo of antiandrogen therapy with daily bicalutamide to salvage radiation therapy results in significantly higher rates of long-term overall survival and lower incidences of metastatic prostate cancer and death from prostate cancer than radiation therapy plus placebo.
• Chest radiography and bone scan should be performed yearly or sooner if patient develops symptoms.

• Prognosis varies with the stage of the disease and the Gleason classification (see “Definition”). For patients between ages 65 and 69 yr at diagnosis and a Gleason score of 2 to 4, the probability of dying from prostate cancer 15 yr after diagnosis is 0.06 and that of dying from other causes is 0.56. If the Gleason score is 7 to 10, the probability of dying from prostate cancer increases to 0.72 and from other causes varies from 0.25 to 0.36.
• The ploidy of the tumor also has prognostic value; prognosis is better with diploid tumor cells and worse with aneuploid tumor cells.
• For grade 1 tumors, the extended 10-yr, disease-specific survival is similar for patients with prostatectomy (94%), radiotherapy (90%), and conservative management (93%); survival rate is better with surgery than with radiotherapy or conservative management in patients with grade 2 or 3 localized prostate cancer.
• Expression of the gene EZH2 has been identified as an important factor in the determination of the aggressiveness of prostate cancer. A recent study revealed that expression of the EZH2 gene may be a better predictor of clinical failure than Gleason score, tumor stage, or surgical margin status. Testing for EZH2 protein in prostate cancer tissue may be useful to determine prognosis and direct treatment.
• Preoperative PSA level and PSA velocity have prognostic significance. Men whose PSA level increases by >2.0 mcg/ml during the year before the diagnosis of cancer may have a relatively high risk of death from prostate cancer despite undergoing radical prostatectomy.
• Extraprostatic disease is detected at radical prostatectomy in 38% to 52% of patients and is associated with a risk of disease recurrence, progression, and death. In these patients, adjuvant radiotherapy results in significantly reduced risk of PSA relapse and disease recurrence; however, the improvements in metastases-free survival and overall survival are not statistically significant. Table 5 summarizes common pain syndromes in metastatic castration-resistant prostate cancer.
• The Prostate Cancer Prevention trial revealed that the use of 5-alpha-reductase inhibitors lowers the incidence of prostate cancer but also increases the incidence of high-grade tumors (Gleason score >7). It is possible that these agents delay diagnosis of prostate cancer by lowering PSA levels and decreasing prostate size. The trade-off inherent in using 5-alpha-reductase inhibitors for prostate cancer prevention is risk of one additional high-grade cancer in order to avert three or four lower-grade cancers. Based on these results, the FDA’s Oncologic Drugs Advisory Committee concluded that finasteride and dutasteride do not have a favorable risk-benefit profile for chemoprevention of prostate cancer in healthy men.
• Patients undergoing prostatectomy are more likely to have urinary incontinence than those undergoing radiotherapy at 2 yr and 5 yr. However, at 15 yr there are no significant relative differences in disease-specific functional outcomes among men undergoing prostatectomy or radiotherapy.
• Bone health is a significant concern in men with prostate cancer. Trials involving bisphosphonates and denosumab reveal that both improve bone mineral density (BMD) in men with nonmetastatic prostate cancer receiving androgen deprivation therapy. Denosumab has also been shown to reduce the risk of vertebral fractures.

Prostate Cancer (Patient Information)