Prostate Cancer

Background

• Prostate cancer is the second most common cancer in men worldwide (annual age-standardized incidence 29.3 per 100,000 men) and the most common cancer in men in the United States (annual age-adjusted incidence 109.8 per 100,000 men).
• Prostate cancer most commonly affects men ≥ 65 years old.
• Major risk factors are older age, African or Caribbean descent, and family history of prostate cancer.
• Localized and locoregional prostate cancer generally has good prognosis, with > 99% 5-year relative survival in United States.
• Most early prostate cancer may be asymptomatic. Symptoms associated with advanced disease may include lower urinary tract symptoms, hematuria, erectile dysfunction, and bone pain.

Evaluation

• Decision of initial assessment modality should involve shared decision making with patients.
• Suspect prostate cancer based on digital rectal exam (DRE) and/or prostate-specific antigen (PSA) levels (see Prostate Cancer Screening for additional information).
• Definitive diagnosis of prostate cancer requires histopathologic analysis of biopsy.
• To avoid unnecessary biopsy, further risk assessment is necessary. For asymptomatic men with normal DRE and PSA level 2-10 ng/mL, risk assessment includes risk calculators (Strong recommendation), imaging (Strong recommendation) and/or additional serum or urine testing (Weak recommendation).
• Prior to biopsy, perform multi-parametric magnetic resonance imaging (mpMRI) (Strong recommendation).
• Estimate life expectancy and evaluate health status and comorbidity to determine testing strategies (Strong recommendation).

Management

Management of Localized or Locally Advanced Prostate Cancer

• Risk stratification determines management strategies, and is based on a combination of clinical characteristics, biopsy results, and laboratory tests.

Table 1. Risk Stratification of Localized and Locally Advanced Prostate Cancer

	NCCN	EAU	AUA	NICE
Very low risk	All of the following Clinical stage T1c ISUP Grade Group 1 PSA < 10 ng/mL (10 mcg/L) PSA density < 0.15 ng/mL/g < 3 positive biopsy cores/fragments and ≤ 50% prostate cancer involvement in each core/fragment	NA	All of the following Clinical stage T1-T2a ISUP Grade Group 1 PSA < 10 ng/mL (10 mcg/L) PSA density < 0.15 ng/mL/g < 34% of positive biopsy cores and no core with > 50% involved	NA
Low risk	All of the following, but does not qualify for very low risk Clinical stage T1-T2a ISUP Grade Group 1 PSA < 10 ng/mL (10 mcg/L)	All of the following Clinical stage T1-T2a ISUP Grade Group 1 PSA < 10 ng/mL (10 mcg/L)	All of the following Clinical stage T1-T2a ISUP Grade Group 1 PSA < 10 ng/mL (10 mcg/L)	All of the following Clinical stage T1-T2a ISUP Grade Group 1 PSA < 10 ng/mL (10 mcg/L)
Intermediate risk	Has no high or very high risk features, and divided into favorable and unfavorable risk Favorable intermediate - has all the following Any 1 intermediate risk factor (clinical stage T2b-T2c, PSA 10-20 ng/mL [10-20 mcg/L], or ISUP Grade Group 2 or 3) ISUP Grade Group 1 or 2 < 50% positive biopsy cores Unfavorable intermediate - has ≥ 1 of the following 2-3 intermediate risk factors (clinical stage T2b-T2c, PSA 10-20 ng/mL [10-20 mcg/L], or ISUP Grade Group 2 or 3) ISUP Grade Group 3 ≥ 50% positive biopsy cores	One of the following Clinical stage T2b ISUP Grade Group 2 or 3 PSA 10-20 ng/mL (10-20 mcg/L)	One of the following: Clinical stage T2b-T2c, PSA 10-20 ng/mL [10-20 mcg/L] ISUP Grade Group 2 or 3 Further divided into favorable and unfavorable risk Favorable intermediate risk has ≥ 1 of the following ISUP Grade Group 1 with PSA 10-20 ng/mL ISUP Grade Group 2 with PSA < 10 ng/mL Unfavorable intermediate risk has ≥ 1 of the following ISUP Grade Group 2 with either PSA 10-20 ng/mL or clinical stage T2b-T2c ISUP Grade Group 3 with PSA < 20 ng/mL	One of the following Clinical stage T2b ISUP Grade Group 2 or 3 PSA 10-20 ng/mL (10-20 mcg/L)
High risk	≥ 1 of the following with no very high risk features Clinical stage T3a ISUP Grade Group 4 or 5 PSA > 20 ng/mL (20 mcg/L)	One of the following Localized Clinical stage T2c ISUP Grade Group 4 or 5 PSA > 20 ng/mL (20 mcg/L) Locally Advanced Clinical stage T3-T4 Any PSA or ISUP Grade Group Lymph node positive	One of the following Clinical stage ≥ T3 ISUP Grade Group 4 or 5 PSA > 20 ng/mL (20 mcg/L)	One of the following Clinical stage ≥ T2c ISUP Grade Group 4 or 5 PSA > 20 ng/mL (20 mcg/L)
Very high risk	≥ 1 of the following Clinical stage T3b-T4 Primary Gleason pattern 5 2-3 high risk features > 4 cores with ISUP Grade Group 4 or 5	NA	NA	NA
Abbreviations: AUA, American Urological Association; EAU, European Association of Urology; ISUP, International Society of Urological Pathology; NA, Not applicable; NCCN, National Comprehensive Cancer Network; NICE, National Institute for Health and Care Excellence; PSA, prostate-specific antigen. References - NCCN 2020 (free registration required), EAU 2020, AUA 2022, NICE 2019 May:NG131 (PDF)

• Decision between conservative management strategies and invasive definitive modalities should involve shared decision making, including discussion of complications and impact on quality of life related to each therapy (Strong recommendation).
• For men with very-low-risk disease:
  • If life expectancy is ≥ 20 years:
    • Offer active surveillance as the preferred option (Strong recommendation).
    • Other options include external beam radiation therapy (EBRT), brachytherapy, or radical prostatectomy (Weak recommendation).
  • If life expectancy is 10-20 years, offer active surveillance (Strong recommendation).
  • If life expectancy is ≤ 5-10 years, offer observation only (Strong recommendation).
• For men with low-risk disease:
  • If life expectancy is ≥ 10 years:
    • Offer active surveillance as the preferred option (Strong recommendation)
    • Other options include
      • EBRT or brachytherapy (Weak recommendation) without addition of androgen deprivation therapy (ADT) except for reducing size of prostate for brachytherapy (Strong recommendation);
      • radical prostatectomy (Weak recommendation), without pelvic lymph node dissection (Strong recommendation).
    • Only offer cryotherapy and high-intensity focused ultrasound in the setting of a clinical trial or well-designed cohort study (Strong recommendation).
  • If life expectancy is ≤ 5-10 years, offer watchful waiting only (Strong recommendation).
• For men with favorable intermediate-risk disease:
  • If life expectancy is ≥ 10 years:
    • Primary management options include
      • radical prostatectomy plus pelvic lymph node dissection if the probability of lymph node metastasis is ≥ 2%-5% (Strong recommendation);
      • EBRT and/or brachytherapy, with the addition of ADT (Strong recommendation).
    • Other management options include EBRT or brachytherapy monotherapy (Weak recommendation).
    • In select men, consider active surveillance (Weak recommendation).
    • Only offer cryotherapy or high-intensity focused ultrasound in the setting of a clinical trial or well-designed cohort study (Strong recommendation).
  • If life expectancy is ≤ 5-10 years:
    • Offer observation as the preferred option (Strong recommendation).
    • Other management options include EBRT or brachytherapy monotherapy (Weak recommendation).
• For men with unfavorable intermediate-risk disease:
  • If life expectancy is ≥ 10 years:
    • Primary management options include
      • radical prostatectomy plus pelvic lymph node dissection if the probability of lymph node metastasis is ≥ 2%-5% (Strong recommendation);
      • EBRT plus ADT for 4-6 months (Strong recommendation);
      • EBRT plus brachytherapy with or without the addition of ADT for 4-6 months (Weak recommendation).
    • Only offer cryotherapy or high-intensity focused ultrasound in the setting of a clinical trial or well-designed cohort study (Strong recommendation).
  • if life expectancy is ≤ 5-10 years:
    • Offer observation as the preferred option (Strong recommendation)
    • Other management options include
      • EBRT plus ADT for 4-6 months (Weak recommendation);
      • EBRT plus brachytherapy with or without the addition of ADT for 4-6 months (Weak recommendation).
• For men with high- or very-high-risk disease:
  • If the disease is symptomatic or if life expectancy is > 5 years, management options include
    • radical prostatectomy plus pelvic lymph node dissection as a part of multimodal therapy (Strong recommendation);
    • EBRT plus ADT for 1-3 years (with the optional addition of docetaxel for men with very high risk) (Strong recommendation);
    • EBRT plus brachytherapy (Weak recommendation) with the addition of ADT for 1-3 years (Strong recommendation).
  • If the disease is asymptomatic and life expectancy is ≤ 5-10 years:
    • Consider observation (Weak recommendation).
    • In select men with complications such as hydronephrosis or if metastasis is expected within 5 years, consider monotherapy with either ADT or EBRT (Weak recommendation).
• For men with locally advanced disease:
  • For men with nodal positive disease:
    • Primary management options:
      • Consider EBRT plus long-term ADT (Weak recommendation).
      • For highly selected men, offer radical prostatectomy plus extended pelvic lymph node dissection as a part of multimodal therapy (Strong recommendation), with the addition of long-term ADT (Weak recommendation).
    • Other options include
      • EBRT plus ADT with the addition of abiraterone or fine-particle abiraterone (Weak recommendation);
      • ADT with or without the addition of abiraterone or fine-particle abiraterone (Weak recommendation).
  • For men with nodal negative disease:
    • Offer EBRT with long-term ADT (Strong recommendation) for ≥ 2 years (Weak recommendation).
    • For highly selected men, offer radical prostatectomy plus extended pelvic lymph node dissection as a part of multimodal therapy (Strong recommendation).
  • For men who are unwilling or unable to accept local therapy or whose life expectancy is ≤ 5 years:
    • Offer ADT if prostate-specific antigen (PSA) doubling time is < 12 months and if they have any of the following characteristics: PSA > ng/mL, poorly differentiated tumors, troublesome local disease-related symptoms (Strong recommendation).
    • Consider observation with deferred ADT if they have asymptomatic disease, PSA doubling time > 12 months, PSA < 50 ng/mL and well-differentiated tumors (Weak recommendation).

Management of Biochemical Relapse of Localized Prostate Cancer

• Consider enrollment into a clinical trial (Weak recommendation).
• Management of prostate-specific antigen (PSA) recurrence/persistence after radical prostatectomy:
  • For men without distant metastases:
    • Management options include:
      • salvage radiation therapy alone (Strong recommendation);
      • salvage radiation therapy plus androgen deprivation therapy (ADT) (Weak recommendation for unselected men. Strong recommendation for men with postoperative PSA ≥ 0.2 ng/mL);
      • observation (Strong recommendation).
    • Do not offer ADT routinely, especially in men with low risk (PSA doubling time > 12 months) (Strong recommendation).
  • For men with positive for distant metastases, see the following topics for additional information
    • Management of Hormone-sensitive Metastatic Prostate Cancer;
    • Management of Castration-resistant Prostate Cancer.
• Management of PSA recurrence after radiation therapy:
  • For men without distant metastases and local therapy is appropriate:
    • If biopsy is negative for recurrence, primary management options include observation or ADT (Weak recommendation).
    • If biopsy is positive for recurrence, primary management options include observation or salvage prostatectomy with pelvic lymph node dissection (Weak recommendation).
  • For men without distant metastases and local therapy is not appropriate, management options include observation or intermittent ADT (Weak recommendation).
  • Consider not to use ADT routinely, especially in men with asymptomatic or low-risk disease (Weak recommendation).
  • For men with positive for distant metastases, see the following topics for additional information
    • Management of Hormone-sensitive Metastatic Prostate Cancer;
    • Management of Castration-resistant Prostate Cancer.

Management of Hormone-sensitive Prostate Cancer

• For men with symptomatic disease or life expectancy > 5 years who can tolerate combination therapy:
  • As preferred management option, offer androgen deprivation therapy (ADT) in combination with any one of the following options (Strong recommendation):
    • abiraterone acetate and prednisone (regardless of disease volume);
    • apalutamide (regardless of disease volume);
    • enzalutamide (regardless of disease volume);
    • docetaxel 75 mg/m² for 6 cycles (for high-volume disease only).
  • For men with low-volume disease, consider ADT in combination with external-beam radiation therapy to primary tumor (Weak recommendation).
• For men with asymptomatic disease and life expectancy ≤ 5 years, consider either immediate ADT or observation with deferred ADT (for men who are well-informed and can be closely monitored) (Weak recommendation).
• For men with evidence of impending spinal cord compression or fracture, offer surgery and/or local radiation therapy (Strong recommendation).
• Primary options for ADT include orchiectomy, luteinizing-hormone releasing hormone (LHRH) agonist, or LHRH antagonist (Strong recommendation).
• For men who are willing to accept worse overall survival and risk of gynecomastia, offer antiandrogen monotherapy with bicalutamide.
• Considerations for ADT:
  • For men initiating LHRH agonist, consider preceding with short-term first-generation antiandrogens to reduce risk of testosterone flare (Weak recommendation).
  • For men with impending spinal cord compression or bladder outlet obstruction, consider LHRH antagonists (Weak recommendation).
  • Consider intermittent ADT to improve quality of life (Weak recommendation).

Management of Castration-resistant Prostate Cancer

• For men with nonmetastatic castration-resistant prostate cancer:
  • Continue androgen deprivation therapy (ADT) to maintain castration level of testosterone, regardless of decisions on further therapies (Strong recommendation).
  • Initial treatment depends on prostate-specific antigen (PSA) doubling time
    • If PSA doubling time > 10 months, consider observation as the preferred option (Weak recommendation).
    • If PSA doubling time ≤ 10 months, offer one of the following preferred options: apalutamide, darolutamide, enzalutamide (Strong recommendation).
• Management of metastatic castration-resistant adenocarcinoma:
  • Continue ADT to maintain castration level of testosterone, regardless of decisions on further therapies (Strong recommendation).
  • When sequencing therapies, consider therapies with an alternative mechanism from prior therapies (Weak recommendation), with the possible exception of a docetaxel rechallenge.
  • Preferred first-line therapy options include
    • docetaxel (Strong recommendation);
    • enzalutamide (Strong recommendation);
    • abiraterone acetate plus prednisone (Strong recommendation);
    • radium-223 for patients with symptomatic bone metastases but no visceral metastases (Strong recommendation);
    • sipuleucel-T for asymptomatic or minimally symptomatic men with no visceral metastases only (Weak recommendation).
• Management of metastatic castration-resistant small cell or neuroendocrine tumor:
  • First and subsequent lines of chemotherapy include cisplatin plus etoposide, carboplatin plus etoposide, docetaxel plus carboplatin, or combination of atezolizumab, carboplatin, and etoposide (Weak recommendation)
  • Consider systemic therapy options similar to small cell lung cancer.
• For men with bone metastases:
  • Offer denosumab (Strong recommendation) or consider zoledronic acid (Weak recommendation) to prevent osseous complications. For men receiving either bone protective agents, monitor serum calcium level and provide supplemental calcium and vitamin D (Strong recommendation).
  • Offer palliative radiation therapy and analgesics for painful disease (Strong recommendation).

Screening

• The decision to offer testing for prostate cancer should be based on each individual’s estimated life expectancy as well as the probability that a clinically significant cancer may be present.
• Engage men in shared decision-making for an informed choice regarding prostate cancer screening based on benefits and harms of prostate-specific antigen (PSA) testing (Strong recommendation).
  • The potential benefits of screening include a small reduction in prostate cancer-specific mortality, but this effect is uncertain and inconsistent across trials.
  • The potential harms of screening include possible emotional distress with false positive results, the detection of clinically unimportant cancer and the risk for bleeding, infection, and urinary retention from a potentially unnecessary prostate biopsy, and a delayed diagnosis due to false negative results.
  • The potential harms of treatment for screen-detected prostate cancer are the same as for symptomatic patients diagnosed by workup and include urinary incontinence, erectile dysfunction, sarcopenia, osteoporosis, and bowel dysfunction, vs. risk of tumor growth and metastatic spread with watchful waiting.
• For men with average risk, age for prostate cancer screening based on shared decision-making differs among professional organizations:
  • age 45-75 years according to the National Comprehensive Cancer Network (NCCN)
  • age 50-69 years according to the American College of Physicians (ACP)
  • age 55-69 years according to the American Urological Association (AUA) and the United States Preventive Services Task Force (USPSTF)
  • age 50 years according to the American Cancer Society (ACS)
  • age 50 also for men at elevated risk not of African American ethnicity and without family history of prostate cancer according to the European Association of Urology (EAU)
• For men with high risk (including African American men, men with germline BRCA1 or BRCA2 mutation, or men with family history in first-degree relatives), start prostate cancer screening based on shared decision-making at age ≥ 40 years (Strong recommendation)
• For men ≥ 70 years old or with life expectancy < 10-15 years, prostate cancer screening is not recommended (Strong recommendation).
• For men < 40 years old, prostate cancer screening is not recommended (Strong recommendation).