• Clinical science

Prostate cancer

Abstract

Prostate cancer is the second most common cancer in men after skin cancer 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.

Epidemiology

  • Second most common cancer in men following skin cancer
    • Mostly affects elderly men
  • Second leading cause of cancer deaths in American men (after lung cancer)

References:[1][2][3][4]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Risk factors

  • Advanced age (> 50 years)
  • Family history
  • African-American race
  • Genetic disposition (BRCA-2, Lynch syndrome)
  • Obesity and diet high in animal fat

Advanced age is the main risk factor for developing prostate cancer! Sexual activity and benign prostatic hypertrophy (BPH) are not associated with developing prostate cancer !; ; ;
References:[1][5][2][3]

Classification

TNM classification for prostate cancer

TNM Extension
T1

Clinically inapparent tumor; neither palpable nor visible by imaging

  • T1a: tumor incidental histologic finding in ≤ 5% of tissue resected (e.g., after TUR-P)
  • T1b: tumor incidental histologic finding in ≤ 5% of tissue resected
  • T1c: tumor identified by needle biopsy, tumor not palpable
T2

Tumor confined within prostate

  • T2a: tumor involves one-half of one lobe or less
  • T2b: tumor involves more than one-half of one lobe but not both lobes
  • T2c: tumor involves both lobes
T3

Tumor has spread beyond the prostatic capsule

T4 Tumor has become attached to or invades adjacent structures other than seminal vesicle(s) (e.g., bladder, rectum, levator muscles, and/or pelvic wall)
N1 Metastases in regional lymph node(s)
M1

Distant metastases

  • M1a: nonregional lymph nodes(s)
  • M1b: bone(s)
  • M1c: other site(s) with or without bone disease

UICC classification

UICC staging TNM
Stage I T1, T2a
Stage II T2b or T2c
Stage III T3
Stage IV T4 or N1 or M1

Clinical features

Early-stage prostate cancer

Advanced-stage prostate cancer

References:[2][6]

Diagnostics

Approach

  • Physical examination and a digital rectal examination (DRE) are performed to screen for prostate cancer.
  • Measurement of prostate-specific antigen levels for screening is controversial because of the risk of overdiagnosis and overtreatment.
  • An irregular and nodular prostate in DRE is suspicious for malignancy.
  • Since DRE or PSA irregularities are not specific to prostate cancer, multiple ultrasound-guided biopsies are collected to confirm the diagnosis.
  • In cases of confirmed prostate cancer, staging is used to assess the extent of disease and plan adequate treatment.

Screening and basic diagnostics

  • Digital rectal examination (DRE)
    • Indication
    • Findings upon palpation
      • Physiological findings: smooth, non-firm, symmetric, roughly heart-shaped, painless prostate with a palpable sulcus between right and left lobes
      • Early stage: localized indurated nodules, otherwise smooth, non-firm, painless prostate
      • Advanced stage: asymmetric areas or frank nodules, painless prostate
  • Blood
    • Measure prostate-specific antigen levels : indications
      • If prostate cancer is suspected
      • Marker to monitor metastasis or cancer recurrence following treatment of PSA-positive prostate cancer
      • For potential screening
        • Benefit is controversial
        • Usefulness should be evaluated on a case-by-case basis by the physician and patient.
          • Current guidelines of the American Urological Association:
          • Greatest benefit in men aged 55–69 years with an interval of two years after shared decision-making based on a man's preferences
          • PSA test considered on a case-by-case basis in men above age 40 years with risk factors (e.g., family history, African-American race, gene changes (BRCA-1/ 2, Lynch syndrome)
          • PSA test not recommended in men < 40 years of age or men between 40–54 years who are at average risk
          • The US Preventive Services Task Force (USPSTF) recommends against any routine PSA-based screening for prostate cancer.
      • Interpretation: a total PSA > 4 ng/mL suggests malignancy
        • PSA levels may be elevated for a variety of reasons including cancer, benign prostate hyperplasia, urinary tract infection, prostatitis, trauma, and following manipulation of the prostate gland.
        • Following factors suggest malignancy
          • Total PSA > 4 ng/mL (or > 2,5 ng/mL)
          • Increase in PSA levels > 0.35–0.75 ng/mL per year
          • A free total PSA ratio < 0.2 is associated with a higher risk of developing cancer (free PSA = PSA that is not complexed with alpha-1 anti-chymotrypsin; total PSA = free PSA + PSA bound to protease inhibitors)
        • Future handling depends upon baseline PSA levels:
          • PSA < 1 ng/mL: repeat PSA testing at 4-year intervals
          • PSA 1–2 ng/mL: repeat PSA testing at 2-year intervals
          • PSA > 2 ng/mL: repeat PSA testing on a yearly basis
    • ↑ Alkaline phosphatase in bone metastases
    • ↑ Prostatic acid phosphatase (PAP)
  • Urine: urinalysis and urine culture to rule out hematuria or urinary tract infection

Normal PSA values do not exclude the presence 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.

Confirmatory test

  • Prostate biopsy
  • Experimental methods
    • Adapted MRI pulse sequence (assessment of density differences and using comparison algorithms)
    • PCA 3 (prostate cancer antigen 3) testing: detecting prostate cancer by collecting post-prostatic massage urine samples

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.-
  • Imaging
  • Laparoscopic pelvic lymphadenectomy is performed prior to performing elective prostatectomy in T3 stage cancers if lymph node metastasis is suspected.
    • Technique: usually, at least 10 pelvic lymph nodes are removed
  • Pelvis MRI scan: to assess the operability in cT3/4 stage cancers, or, if invasion of the prostate capsule cannot be excluded by other diagnostic procedures An MRI scan is of great utility in the planning of surgery especially for identifying and preserving cavernous nerves intraoperatively. In addition, an MRI scan can help determining the volume of radiation to be delivered .

References:[5][2][7][8][9][10][11]

Pathology

  • Most common type: adenocarcinoma expressing PSA
  • Most common localization: peripheral zone (posterior lobe) of prostate

Types of prostate cancer

  • Adenocarcinoma is characterized by a microglandular growth pattern with a highly prismatic epithelium. It is the most common type of prostate cancer.
  • Rare prostate cancers
    • Small cell prostate cancer
    • Mucinous adenocarcinoma
    • Ductal carcinoma
    • Transitional cell (or urothelial) cancer
    • Squamous cell carcinoma
    • Rhabdomyosarcoma
    • Leiomyosarcoma

Localization of the tumor

  • Prostate cancer most commonly occurs in; the peripheral zone → approx. 85% of all cancers.
  • Prostate cancer in the transition zone is less common → approx. 15% of all cancers.
  • Prostate cancer in the inner gland is very rare.

References:[12][2]

Differential diagnoses

Histological differential diagnosis: Prostatic intraepithelial neoplasia (PIN)

The differential diagnoses listed here are not exhaustive.

Treatment

Approach

The treatment plan is based upon the patient's age, life expectancy, medical condition, and 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: regular follow-ups with cancer restaging instead of treating
    • Preferred option for most early-stage cancers )
    • Treatment is only started if the tumor progresses.
  • Watchful waiting: less intensive type of follow-up than active surveillance
    • Best approach in elderly patients with slow-growing tumors, a life-limiting comorbidity, or a life expectancy < 10 years who are more likely to die from other causes.
    • Systemic or local treatment to relieve symptoms is initiated if symptomatic progression of the tumor occurs.
  • Definitive treatment: radiation therapy and/or prostatectomy

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

Management of disseminated disease

Management of castration-resistant prostate cancer (CRPC)

CRPC is characterized by disease progression (elevated serum PSA levels, progression of pre-existing metastasis, or new metastases) despite ADT (surgical or medical castration).

References:[2][11][13][14][15][16][17][18][19][20][21][22][23]

Detailed explanation of treatment

According to risk of tumor progression

Tumor expansion according to TNM Risk of tumor progression according to D'Amico Classification criteria Treatment options
Curative treatment options

Localized prostate cancer

T1 and T2, N0, M0

Low risk

The doctor will need to discuss the following treatment options with the patient, tailoring an appropriate personal treatment plan based on patient preference.

  • Active surveillance
  • Radical prostatectomy
  • External radiotherapy (with approx. 74 up to < 80 Gy)
  • Low dose rate (LDR) brachytherapy using afterloading technique with radioactive iodine-125 seeds
Intermediate risk

A choice for or against the following approaches depends upon an informed patient decision incorporating knowledge about the treatment's associated potential benefits and side effects along with personal preference:

  • Radical prostatectomy
    • In patients with an estimated high risk (> 5%) of N1, in T3/4 stage, or in patients with high risk of tumor progression: + lymphadenectomy
    • In R1 resection : adjuvant radiotherapy of the tumor bed with 66 Gy
    • In N1: adjuvant hormone therapy
  • External radiotherapy (with approx. 74 up to < 80 Gy) +/- hormone therapy for 3–6 months or (in T3/4 or N1) for 2–3 years or HDR brachytherapy in addition (up to stage cT3)
  • External radiotherapy (with approx. 74 up to < 80 Gy) + hormone therapy for 6 months or (in T3/4 or always in N1) for 2–3 years or + high dose rate (HDR) brachytherapy (only in cT3, N0, M0 or lower stages)

Prostate cancer without distant metastasis

All T stages, All N stages, M0

High risk

Recurrence of prostate cancer
  • E.g., if PSA increases or
  • PSA persists
  • Following radical prostatectomy: radiatiotherapy of the previous tumor lesions with 66 Gy
  • Following primary radiatiotherapy: salvage prostatectomy
Palliative treatment options

Localized prostate cancer

T1–T2, N0, M0

  • Life expectancy < 10 years
  • Curative treatment is not possible or patient refuses treatment

A choice for or against the following approaches depends upon an informed patient decision incorporating knowledge about the treatment's associated potential benefits and side effects along with personal preference:

Locally advanced or metastatic disease
  • T3T4
  • N1 and/or
  • M1

Explanation of further treatment options in detail

Active Surveillance

  • Concept: Initially, a wait-and-see approach is taken. Patients are closely monitored over time to ensure that the cancer is caught early in case it progresses; curative treatment can be promptly initiated. Advantage: potential adverse effects of therapy may be avoided. Disadvantage: risk of not commencing treatment in a timely manner.
  • Indications (all four must be fulfilled)
    • Patient's wish after being informed about advantages and disadvantages of all potential treatment options
    • Low risk of tumor progression: PSA ≤ 10 ng/mL and Gleason score ≤ 6
    • Localized cancer: cT1 and cT2a stages
    • Small amount of cancer found on biopsy: ≤ 2 cancerous samples (out of 10–12 samples) found on biopsy with the tumor mass in each sample not exceeding 50%
  • Technique
    • Patients will have regular follow-ups, which includes cancer restaging.
      • DRE and PSA levels are repeated every 3 months for 2 years (if PSA levels are stable, PSA testing every 3 months)
      • First, repeat biopsy after 6 months following initial biopsy to assess for upgrading. Thereafter, 12–18-monthly repeat biopsy for 3 years. If there are no significant findings, 3-yearly repeat biopsy is taken.
      • Curative (rarely palliative) treatment is only commenced if the tumor has progressed
        • PSA doubling times < 3 years
        • Indication criteria are no longer met.

Complications

References:[24][25][2][26][27][20]

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

Prognosis

  • Established prognostic indicators include:
  • With early treatment, prognosis is good in men with local or regional prostate cancer.
  • If metastasis is present, survival rates are much lower.
Tumor-specific mortality in patients receiving palliative treatment
Gleason score Mortality
≤ 6 < 25%
7 50%
≥ 8 > 75%