Prostate cancer

Prostate cancer is one of the most common cancers that affect men, especially those > 50 years of age. Typically, prostate cancer has an indolent course and is usually discovered while still localized in the prostate. This allows many patients to undergo monitoring for progression rather than active treatment, preventing unnecessary treatment-related adverse effects. Prostate cancer is typically diagnosed and monitored using prostate-specific antigen (PSA) testing, multiparametric MRI (mpMRI), and guided biopsy. Once the decision to treat has been made, therapeutic options include radical prostatectomy, radiation therapy, androgen deprivation therapy (ADT), and chemotherapy. Since all treatment options may adversely affect the patient's quality of life, shared decision-making with the patient is strongly encouraged in all current guidelines. Symptomatic management may be preferable in patients with significant comorbidities or limited life expectancy, as further treatment is unlikely to be life-prolonging.

• Incidence: following skin cancer (i.e., melanoma and nonmelanoma combined) most common cancer in men in the US ^[1]
• Mortality: in 2020, second leading cause of cancer deaths in men in the US (after lung cancer)

Epidemiological data refers to the US, unless otherwise specified.

• Advanced age (> 50 years) ^[1][2]
• Family history
• African-American descent
• Genetic disposition (e.g., BRCA2, Lynch syndrome)

Advanced age is the main risk factor for prostate cancer. Sexual activity and benign prostatic hyperplasia (BPH) are not associated with prostate cancer.

References: ^[3][4]

Symptoms

• Typically asymptomatic
  • Early prostate cancers are typically detected during screening tests.
  • Some prostate cancers are found incidentally (incidental prostate cancer).
• Patients may present with features of complicated lower urinary tract symptoms (LUTS), including: ^[5]
  • Urinary retention
  • Hematuria
  • Incontinence
  • Flank pain (due to hydronephrosis)
• Advanced prostate cancer can manifest with:
  • Constitutional symptoms: fatigue, loss of appetite, clinically significant unintentional weight loss
  • Features of metastatic disease; examples include:
    • Bone pain (due to bone metastasis, especially in the lumbosacral spine)
    • Neurological deficits (e.g., due to vertebral fracture causing spinal cord compression)
    • Lymphedema (caused by obstructing metastases in the lymph nodes)

Digital rectal examination (DRE) ^[6][7][8]

A DRE should be performed in individuals with elevated serum PSA levels; and as part of the comprehensive evaluation of male LUTS. DRE has a low positive predictive value for detecting prostate cancer and should not be performed as the sole screening modality.

• May be normal; in early disease or if the cancer is located in areas of the gland that are not palpable on DRE ^[9]
• Features suggestive of prostate cancer include:
  • Localized indurated nodules on an otherwise smooth surface
  • Prostatomegaly, lobar asymmetry, obliteration of the sulcus
  • Hard nontender nodules

Most prostate cancers are located in the peripheral zone (posterior lobe) of the prostate. In contrast, BPH occurs in the transitional zone of the prostate.

Even patients with advanced prostate cancer may have a normal DRE; if clinical suspicion is high, continue diagnostic evaluation for prostate cancer!

Approach

The following content is related to diagnosing prostate cancer in symptomatic patients or those with a positive screening test. Screening for prostate cancer in asymptomatic individuals is detailed separately.

• Suspect prostate cancer in patients with elevated PSA levels detected on routine screening and/or abnormal findings on DRE.
• Consider adjunctive PSA testing (e.g., free PSA:total PSA ratio, PSA density, urinary prostate cancer antigen 3 levels) before performing a biopsy.
• Confirm the diagnosis on image-guided prostate biopsy.
• Stage prostate cancer to determine the appropriate management and prognosis.

Prostate-specific antigen (PSA) levels

PSA is a serine protease produced only in the prostate gland and, therefore, is an organ-specific marker. It is not cancer-specific however, as levels may also be elevated in benign conditions. ^[10]

• Indications
  • Suspected prostate cancer
  • Monitoring for recurrence following treatment of prostate cancer
  • Screening for prostate cancer (controversial).
• Interpretation ^[11][12]
  • Total PSA levels
    • PSA < 2.5 ng/mL: Prostate cancer is unlikely.
    • PSA 2.5–4 ng/mL: Prostate cancer is possible in symptomatic patients. ^[13]
    • PSA > 4 ng/mL: Prostate cancer is likely. ^[12]
      • PSA 4–10 ng/mL (moderately elevated PSA): ∼ 25% chance of prostate cancer
      • PSA > 10 ng/mL: > 50% chance of prostate cancer
  • Free PSA (unbound) : Free PSA levels are lower in prostate cancer than in normal prostate tissue or benign disease.
• Other causes of elevated total PSA: BPH, UTI, prostatitis, prostatic trauma or manipulation (including DRE) ^[14]

A PSA level ≤ 4 ng/mL does not exclude prostate cancer!

5-alpha reductase inhibitors (5-ARIs) can suppress PSA production, resulting in spuriously low PSA levels. This should be taken into consideration in patients on long-term 5-ARIs (e.g., for BPH). ^[15][16]

Inflammation, manipulation of the prostate, and other malignant and benign prostate diseases may lead to a false-positive PSA result!

Urinalysis ^[17][18]

• Should be performed as part of the initial workup of LUTS and to rule out differential causes of elevated PSA
• Urinalysis is typically normal in patients with prostate cancer.
• Pyuria and/or bacteriuria in a patient with LUTS indicate a UTI or prostatitis.

Initial imaging

• mpMRI of the prostate ^[19][20]
  • Becoming the preferred imaging modality for suspected prostate cancer ^[19][21]
  • Additional indications include:
    • Guidance of prostate biopsy
    • Clinical suspicion of prostate cancer despite negative transrectal ultrasound (TRUS) or TRUS-guided biopsy
    • Initial staging of confirmed prostate cancer
    • Active surveillance and follow-up
• Transrectal ultrasound of the prostate: predominantly used to guide prostate biopsy if there is clinical suspicion of prostate cancer ^[22][23]

Prostate biopsy

• Indication: clinical suspicion of prostate cancer after shared decision-making with a patient whose life expectancy is ≥ 10 years ^[8][24]
• Important considerations: Consider the following to minimize unnecessary biopsies. ^[8]
  • Adjunctive PSA tests
    • Free PSA:total PSA ratio of < 10–20% suggests a high probability of prostate cancer. ^[25]
    • PSA density ^[26]
      • Calculated by dividing total PSA by prostate volume (as determined on imaging)
      • A low PSA density (< 0.8 ng/mL/cc) suggests that clinically significant cancer is unlikely.
  • mpMRI of the prostate (if not already performed)
  • Presence of risk factors for prostate cancer
  • Prostate cancer antigen 3 gene (PCA3) levels in urine ^[27]
    • The PCA3 gene is expressed more frequently in cancerous tissue than in normal prostate tissue.
    • Increased PCA3 expression in a urine sample taken after DRE suggests a high probability of prostate cancer. ^[7]
• Technique
  • Prophylactic antibiotics to prevent prostatitis: recommended for transrectal biopsy; consider before transperitoneal biopsy
  • Anesthesia: local anesthesia, nerve blocks, procedural sedation, or general anesthesia
  • Under image guidance (TRUS-guided or MRI-guided), several biopsy cores are obtained from the prostate via the transperineal or transrectal approach. ^[28][29]
• Findings: adenocarcinoma ; ^[30][31]
  • Gleason grade (Gleason pattern): depending on the degree of differentiation of tumor cells and stromal invasion, tumors are graded from 1 (well-differentiated) to 5 (poorly differentiated)
  • Gleason score (ranges from 2 to 10): the sum of the two most prevalent Gleason grades ^[32]
  • Grade groups: prognostic categories based on the Gleason score that are used to guide management ^[31]

Gleason score and grade groups are used to grade the metastatic potential of prostate adenocarcinoma based on gland-forming differentiation.

Evaluation of tumor extent ^[21][22][33]

• mpMRI provides information on local tumor extent (e.g., tumor size and volume).
• Additional imaging to assess for local tumor extent and metastasis to guide management: ^[21]
  • Recommended in patients with intermediate or high-risk prostate cancer (i.e., patients with PSA > 10 ng/mL and an unfavorable grade group
  • Not routinely recommended for patients with low or very low-risk prostate cancer (i.e., patients with PSA < 10 ng/mL, a favorable grade group, and low tumor burden in biopsy cores)
• Cross-sectional imaging (CT, MRI, or PET-CT scan) is recommended to identify: ; ^[34][35]
  • The spread of cancer beyond the prostatic capsule
  • Pelvic and distal lymph node involvement
  • Hepatic and osseous metastasis
• Assessment of bone metastases
  • Serum alkaline phosphatase may be elevated bone metastases.
  • Bone scintigraphy (technetium-99m) is the standard study for detecting bone metastases. ^[22]
  • PET scan is more sensitive than bone scintigraphy and may become the new standard. ^[22][36]
  • X-rays (e.g., spinal x-ray) may be appropriate to evaluate undifferentiated bone pain or if pathological fractures are suspected.

mpMRI is the preferred method for detecting local tumor extent (including recurrent prostate cancer) and PET-CT is preferred to evaluate for metastatic disease. ^[34][35]Skeletal metastases are the most common nonnodal sites of metastasis in prostate cancer. Vertebral metastases commonly occur due to the spread of malignant cells through the Batson vertebral venous system. Skeletal metastases are predominantly osteoblastic but osteolytic metastases can also occur.

The TNM staging system is based on American Joint Committee on Cancer recommendations (see “Grading and staging” in “General oncology”). Broadly, prostate cancer is divided into the following clinical stages. ^[21][37][38]

• Localized prostate cancer
  • Tumor confined to the prostate (T1–T2) or tumor with extracapsular extension (T3a)
  • And no evidence of lymph node involvement or metastasis (i.e., N0, M0)
• Locally advanced prostate cancer ^[39]
  • Extension to the seminal vesicles (T3b) or adjacent periprostatic tissue (T4)
  • Or regional lymph node involvement (N1) ^[38]
  • And no evidence of distant metastases (M0)
• Metastatic prostate cancer
  • Involvement of lymph nodes outside the true pelvis (M1a)
  • Or spread to nonnodal regions (M1b–c)
    • Most common site: bone (M1b), especially the vertebrae
    • Less common sites: lungs, liver, and adrenal glands (M1c)

Approach ^[21][33]

Management options for prostate cancer depend on the cancer stage, presence of high-risk features, and the patient's life expectancy. The impact of potential adverse effects of treatment on quality of life should be discussed with the patient prior to treatment initiation.

• Estimate the patient's life expectancy.
  • Limited life expectancy (≤ 5 years): Consider watchful waiting (asymptomatic patients) or palliative ADT (symptomatic patients). ^[21]
  • Life expectancy > 5 years: Manage according to cancer stage.
• Stage prostate cancer to determine if it is localized, locally advanced, or metastatic.
  • Localized prostate cancer: Stratify risk based on the histological grade group and pretreatment PSA levels.
    • Low or very low-risk prostate cancer: Consider active surveillance.
    • Intermediate or high-risk prostate cancer: radical prostatectomy OR radiotherapy in combination with ADT
  • Locally advanced prostate cancer: ADT PLUS androgen synthesis inhibitor PLUS radiation therapy
  • Metastatic prostate cancer
    • Management is similar to that of locally advanced prostate cancer.
    • Antiandrogens or chemotherapy can be considered instead of androgen synthesis inhibitors.
• Anticipate and manage treatment-related complications (e.g., osteoporosis, pathological fractures, erectile dysfunction).
• Schedule follow-ups to assess response to therapy.

Watchful waiting ^[21]

• Indications: recommended approach if all of the following apply
  • Limited life expectancy (≤ 5 years)
  • Slow-growing tumor (i.e., low-risk or intermediate-risk localized tumors)
  • Asymptomatic or minimal symptoms
• Method
  • Regular monitoring with scheduled DRE and serum PSA levels (less intensive follow-up than active surveillance).
  • Initiate definitive management according to cancer stage only when symptoms occur.

Active surveillance ^[21][40]

• Indications ^[21]
  • Very low-risk and low-risk localized prostate cancers in patients with a life expectancy > 5 years
  • May be considered in favorable intermediate-risk localized prostate cancer
• Method
  • Regular monitoring with scheduled DRE, PSA, prostate biopsies, and mpMRI
  • Initiate definitive management according to cancer stage if disease progression is demonstrated.

Androgen deprivation ^[33][41]

Androgen deprivation therapy (ADT)

• Definition: therapy designed to decrease testosterone production by the testes
• Indications
  • Locally advanced and metastatic prostate cancer: primary treatment modality
  • High-risk localized prostate cancer: alternative to radical prostatectomy
• Options
  • Medical castration: decreases pituitary stimulation of androgen production by the testes
    • Gonadotropin-releasing hormone (GnRH) agonists (e.g., leuprolide)
    • Gonadotropin-releasing antagonist (e.g., degarelix)
    • GnRH receptor antagonist (e.g., relugolix)
  • Surgical castration: bilateral orchiectomy
• Adverse effects: increased risk of osteoporosis and fractures

Androgen synthesis inhibitors and androgen receptor antagonists ^[42]

• Indication: adjunct to ADT in locally advanced and metastatic prostate cancer
• Androgen synthesis inhibitors
  • Mechanism of action: inhibition of CYP17 gene products (including 17α-hydroxylase and 17,20-lyase) → inhibits androgen synthesis in the adrenal glands, testis, and tumor tissue
  • Commonly used agent: abiraterone
  • Specific adverse effects:
    • Increased production of mineralocorticoids: hypertension, hypokalemia, cardiac arrhythmias
    • Inhibition of glucocorticoid production: adrenal insufficiency
  • Important consideration
    • Glucocorticoids should be coadministered to avoid adrenal insufficiency.
    • Glucocorticoids further increase bone fragility associated with androgen deprivation and aging.
• Androgen receptor antagonists (antiandrogen therapy)
  • Mechanism of action: displaces androgens from androgen receptors
  • Commonly used agents: apalutamide and enzalutamide (second-generation antiandrogens) ^[43]

Initiate prophylaxis against treatment-induced osteoporosis and fractures in all patients on androgen deprivation and/or glucocorticoids.

First-generation antiandrogens (flutamide and bicalutamide) are used only for the short-term management of a testosterone flare. ^[43]

Radiation therapy ^[21][44]

• Indications
  • Localized prostate cancer: primary treatment option
  • Metastatic prostate cancer, high-risk localized prostate cancer, local recurrence following prostatectomy: as an adjunct to androgen deprivation
  • After prostatectomy: adjuvant therapy if adverse features are detected
• Options: brachytherapy; and/or external beam radiation therapy (EBRT)
• Complications
  • Radiation proctitis, enteritis (e.g., diarrhea),
  • Cystitis, urethritis, and urinary incontinence
  • Erectile dysfunction ^[45]
  • Increased risk of rectal cancer ^[46]

Radical prostatectomy ^[21]

• Indications
  • Localized prostate cancer in patients who are not candidates for active surveillance
  • Following unsuccessful primary radiation therapy (salvage prostatectomy) ^[47]
• Technique
  • Removal of the entire prostate gland, including the prostatic capsule, the seminal vesicles, and the vas deferens ^[21]
  • Pelvic lymph node dissection may be performed during prostatectomy.
• Important consideration: PSA levels should drop to undetectable levels after a successful prostatectomy.
• Complications: erectile dysfunction; , urinary incontinence; , infertility ^[45]

Radical prostatectomy involves the removal of the vas deferens, resulting in infertility.

Chemotherapy ^[33]

• Indication: Consider as an adjunct to ADT in patients with metastatic prostate cancer.
• Commonly used agent: docetaxel (a cytotoxic agent)

Management of bone health ^[48][49][50]

Prostate cancer patients are at an increased risk of skeletal features due to osteoporosis (treatment-induced and age-related) and bone metastases. ^[33]

Prophylaxis against treatment-induced osteoporosis and fractures

• Indications: patients on ADT, antiandrogens, and/or glucocorticoids
• Method
  • Optimize bone health (see “Treatment of osteoporosis” for details).
  • Assess fracture risk
    • Assess bone mineral density (e.g., DEXA scan)
    • Assess of 10-year fracture risk (e.g., using tools such as FRAX^®)
  • Consider osteoclast inhibitors (e.g., bisphosphonates, denosumab) in patients at high risk of a skeletal-related event.
  • See “Pharmacotherapy for osteoporosis” for details and dosages.

Management of skeletal events ^[51]

• Pain due to skeletal metastases: Consider EBRT.
• Acute skeletal pain: urgent x-rays to assess for pathological fractures
• New neurological symptoms: urgent MRI spine to identify spinal cord compression (see “Acute back pain” for details)

Patients with known vertebral metastatic disease and new neurological symptoms must have an urgent MRI to rule out spinal cord compression.

• Monitor serum total PSA levels. ^[52]
  • Every 6 months for the first 5 years, then annually for patients who have had definitive local therapy
  • Every 3–6 months for patients on ADT
• Consider assessing PSA velocity (PSA doubling time); a significant rise or short doubling time suggests a recurrence. ^[11]
• Arrange further studies for patients with abnormal PSA values.
  • After radical prostatectomy: Any measurable PSA value should prompt evaluation for recurrence.
  • After radiation therapy: Any rise in PSA from nadir should prompt evaluation for recurrence. ^[52]
• Annual DRE: to monitor for prostate cancer recurrence and rectal cancer ^[46]

General principles ^[53]

Given the indolent nature of prostate cancer and the significant potential for treatment-related decline in quality of life, patients should be educated on the risks and benefits of participating in screening and undergoing treatment if cancer is detected. For patients with a limited life expectancy, neither screening nor treatment may be appropriate. ^[21][54]

• PSA screening is controversial as it has:
  • A high false-positive rate ^[53]
  • A high detection rate of clinically insignificant cancers (leading to overdiagnosis) ^[53]
  • Minimal or no effect on prostate cancer-related mortality. ^[55][56][57]
• Patient harm may occur as a result of testing and/or treatment initiated by a positive PSA screening test.

Because of the low benefit and potential risk associated with PSA screening, patients should be involved in the decision to screen for prostate cancer. ^[6]

Screening recommendations ^[58]

Recommendations for screening are based on age and life expectancy. Screening is not recommended for patients with a life expectancy < 10 years.

Screening for prostate cancer is not recommended in patients with a life expectancy < 10 years. ^[54]

Screening modalities ^{[58] [6]}

• PSA level remains the standard screening tool.
  • A PSA of ≥ 4 ng/mL is the most common threshold used to prompt referral to urology and possible biopsy.
  • Lower thresholds are used in:
    • Patients receiving a 5-ARI ^[59]
    • Patients receiving gender-affirming hormone therapy (see “Preventive health care of transgender individuals”)
• DRE is not recommended as the sole screening tool for prostate cancer. ^[60]
• A screening interval of 2 years (or more) is recommended.

• The most important prognostic indicator for prostate cancer is the histological grade (i.e., grade group or Gleason score). ^[38]
• Broadly, patients with cancer confined to the prostate and pretreatment PSA levels < 10 ng/mL have a favorable prognosis. ^[21][61]

• Benign prostatic hyperplasia
• Prostatitis
• Other tumors of the prostate

The differential diagnoses listed here are not exhaustive.