Prostate cancer

Prostate cancer is the second most common cancer in men after skin cancer (malignant and nonmalignant melanoma) and the second leading cause of cancer death in men after lung cancer. The risk of developing prostate cancer increases with age. It is more common in African Americans. In early stages, prostate cancer generally causes no symptoms and is typically detected by screening. The preferred diagnostic procedures are digital rectal examination (DRE), PSA testing, and ultrasound-guided transrectal prostate biopsy. Bone metastases are common in advanced prostate cancer and can be diagnosed using a bone scan. Because most patients with prostate cancer are of advanced age, life expectancy and the histological evaluation of a tumor biopsy should be taken into account when planning treatment. Radical prostatectomy and radiotherapy are indicated in young patients. In older patients, “watchful waiting” (i.e., purely symptomatic treatment) and “active surveillance” (i.e., continuous restaging and initiation of curative measures if tumor progresses) are also a treatment option since localized prostate cancer typically has a slower growth rate and a better prognosis compared to other malignancies.

• 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.

Risk factors ^[2][3]

• Advanced age (> 50 years) ^[1][4]
• 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.

Early-stage prostate cancer

• Typically asymptomatic
  • Early prostate cancers are found during screening tests.
  • Some prostate cancers are found incidentally (incidental prostate cancer, e.g., in patients that require a transurethral resection due to BPH)

Advanced-stage prostate cancer

Constitutional symptoms

• Fatigue
• Loss of appetite
• Weight loss

Urinary symptoms ^[5]

• Urinary retention
• Hematuria
• Incontinence
• Hydronephrosis (associated with flank pain and renal failure)

Metastatic disease

• Bone pain (due to bone metastasis, especially in the lumbosacral spine)
• Neurological deficits (due to spinal cord compression)
• Lymphedema (caused by obstructing metastases in the lymph nodes) leading to:
  • Swelling
  • Pain
  • Redness

Approach to suspected prostate cancer

• Physical examination, including digital rectal examination (DRE)
• Measurement of prostate-specific antigen (PSA) levels
• In case of suspicious findings/elevated PSA levels: multiple ultrasound-guided biopsies to confirm the diagnosis.
• Staging in case of confirmed prostate cancer to assess disease extent and plan adequate treatment.

Screening and basic diagnostics ^[6]

Digital rectal examination (DRE) ^[7]

• Low sensitivity (approx. 30%)
  • Not an accurate screening test for prostate cancer
  • A gland that feels normal does not rule out prostate cancer.
• Good specificity (approx. 90%) : Irregular and nodular prostate is suspicious for malignancy, but not specific for cancer.
• Indications
  • If prostate cancer is suspected
  • Screening test ^[8]
• Physiological DRE findings
  • Smooth
  • Nonfirm
  • Symmetric
  • Roughly heart-shaped
  • Painless
• Early stage prostate cancer DRE findings
  • Localized indurated nodules
  • Otherwise smooth
  • Nonfirm
  • Painless
• Advanced stage prostate cancer DRE findings
  • Asymmetric areas
  • Frank nodules
  • Painless

Blood tests

Prostate-specific antigen (PSA) levels

• Overview
  • Serine protease that splits the semenogelin-1 protein and thereby liquefies semen.
  • Only produced by the prostate gland: organ-specific marker
• Indication
  • Suspected prostate cancer
  • Screening
    • Benefit is controversial
    • Usefulness should be evaluated on a case-by-case basis by the physician and patient.
  • Monitoring of metastasis or detection of cancer recurrence following treatment of PSA-positive prostate cancer
• Interpretation
  • Total PSA > 4 ng/mL suggests malignancy, but can be elevated for a variety of reasons, including: ^[9]
    • BPH
    • Urinary tract infection
    • Prostatitis
    • Trauma
    • Manipulation of the prostate gland
  • Significantly ↓ free PSA levels are found in prostate cancer.

Normal PSA values do not exclude the diagnosis of prostate cancer.

Inflammation, manipulation of the prostate, and other malignant or benign prostate disease causing elevated enzyme levels may lead to false-positive PSA results.

Other blood tests

• Alkaline phosphatase: ↑ in bone metastases
• ↑ Prostatic acid phosphatase (PAP)

Urine

• Urinalysis and urine culture to rule out hematuria or urinary tract infection

Confirmatory testing

Prostate biopsy

• Indication
  • Histological confirmation of suspicious findings on DRE
  • Suspicious PSA levels or velocities
  • Clinically suspicious prostate cancer
• Technique: ∼ 12 prostate samples are taken from different areas of the prostate guided by transrectal ultrasonography (TRUS) under local anesthesia and prophylactic antibiotics.
• Interpretation: : When prostate cancer is present in the biopsy, the tumor is graded using the Gleason score.
  • Calculated based on the microscopic appearance of prostate cancer
  • Higher score indicates a worse prognosis (ranges from 2 to 10)
  • Score is established by adding the Gleason grades of the most prevalent and the second most prevalent differentiation pattern within the biopsy
  • Grade ranges from 1 to 5
    • Grade 1: well-differentiated, microscopically uniform glands without invasion into adjacent healthy prostate tissue
    • Grade 5: undifferentiated cancer cells with no glandular differentiation
• Complications
  • UTI
  • Prostatitis
  • Hematuria
  • Hematospermia
  • Acute urinary retention
  • Psychological effects

Staging

Indication

• In confirmed prostate cancer to assess the extent of the disease
• Should be performed, if advanced cancer is suspected by either PSA levels > 10 ng/mL or a Gleason score ≥ 7

Modalities

• Abdominal ultrasound and CT/MRI
  • Extraprostatic invasion
  • Liver metastasis
  • Urinary obstruction
• Spinal x-ray: detection of bone metastases (hyperdense osteoblastic lesions in vertebral bodies)
• Bone scintigraphy (technetium-99m): detection of bone metastases

• Most common type: adenocarcinoma expressing PSA ^[10]
• Most common localization: peripheral zone (posterior lobe) of prostate ^[11]

Prostate cancer is commonly localized in the Peripheral zone (Posterior lobe).

Approach

• The treatment plan is based upon:
  • Patient's age
  • Life expectancy
  • Medical condition
  • Preferences
• Results of imaging studies, PSA levels, and the Gleason score are taken into consideration when evaluating the different treatment options.

Management of localized disease

Active surveillance ^[12]

• Regular follow-ups with cancer restaging instead of treatment
• Preferred option for most early-stage cancers)
• Treatment is only started if the tumor progresses.

Watchful waiting ^[12]

• Less intensive type of follow-up than active surveillance
• Best approach in a number of different cases, including:
  • Elderly patients with slow-growing tumors
  • Life-limiting comorbidity
  • Life expectancy < 10 years due to other causes
• Systemic or local treatment to relieve symptoms is initiated if symptomatic progression of the tumor occurs.

Radiation therapy ^[13]

• Indication: localized disease
• Technique
  • External beam radiation therapy (EBRT)
  • Brachytherapy
  • Androgen deprivation therapy (ADT) may be combined with radiotherapy if the chance of cancer recurrence based on PSA level and/or Gleason score is high.

Radical prostatectomy ^[13]

• Indication: localized disease
• Technique
  • Removal of the entire prostate gland, including the prostatic capsule, the seminal vesicles, and the vas deferens
  • In addition, lymphadenectomy of pelvic lymph nodes, and adjuvant radiotherapy may be performed.
  • Postoperative monitoring of PSA levels: PSA level should drop to undetectable levels.
• Variant: salvage prostatectomy ^[14]
  • Radical prostatectomy after unsuccessful primary radiation therapy
  • Challenging procedure with slightly higher risk of complications due to scarred and damaged tissue caused by prior radiation.

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

Antiandrogen therapy ^[13]

• Indication: androgen sensitive localized high-grade or metastatic prostate cancer
• Methods
  • Medical castration: gonadotropin-releasing hormone (GnRH) agonists (e.g., leuprolide) or antagonist (e.g., degarelix)
    • May be combined with an antiandrogen (e.g., flutamide, bicalutamide) for complete androgen blockade.
    • Continuous administration of GnRH receptor agonists causes a transient increase in androgen levels during the first few weeks of therapy, followed by a sustained decrease.
  • Surgical castration
    • Bilateral orchiectomy: in case of situations in which testosterone levels should be decreased immediately.
      • Impending spinal cord compression or urinary retention
      • Costs or compliance to medical treatment are an issue
    • Prosthetic testicles may be implanted to regain a normal appearance.

Management of disseminated disease

• Antiandrogen therapy
• Chemotherapy with docetaxel
• Osteoclast inhibitors (e.g., bisphosphonates, denosumab) in bone metastases

Management of castration-resistant prostate cancer (CRPC)

• Overview: CRPC is characterized by disease progression (elevated serum PSA levels, progression of pre-existing metastasis, or new metastases) despite ADT (surgical or medical castration).
• General approach
  • Continue ADT
  • Additional systemic therapy, including:
    • Chemotherapy with docetaxel
    • Immunotherapy with sipuleucel-T
• CRPC with asymptomatic bone metastases
  • IV zoledronic acid every 3 to 4 weeks or denosumab: to prevent/delay complications like pathological fracture and spinal cord compression
  • Good oral hygiene should be maintained to prevent osteonecrosis of the jaw, a complication of both zoledronic acid and denosumab.
• CRPC with symptomatic bone metastases
  • Single or few focal symptomatic metastases: palliative external beam radiotherapy
  • Multifocal symptomatic metastases: IV radiopharmaceuticals (radium-223)

Metastasis

• Regional metastasis: pelvic lymph nodes
• Distant metastasis: most commonly bone metastases (less common: lungs, liver, and adrenal glands)
  • Prostate cancer spreads to the bones early.
  • Spinal metastasis are common and occur because of spread through the Batson vertebral venous system.
  • Metastases from prostate cancer are predominantly osteoblastic. Also, osteolytic metastases can be found, causing pathologic fractures.
  • Occult prostate cancer: prostate cancer that is not detected by symptoms caused by the primary cancer but by cancer metastasis (e.g., back pain caused by bone metastases)

Complications following surgery or radiotherapy

• Erectile dysfunction
• Urinary incontinence
• Infertility

Radiotherapy-specific risks

• Radiation proctitis
• Enteritis (e.g., diarrhea)
• Cystitis and urethritis

We list the most important complications. The selection is not exhaustive.