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Recommendations nationales de bonne pratique pour la prise en charge du cancer localisé de la prostate: première partiePublished by: KCELast published: 2014Nationale praktijkrichtlijn voor de aanpak van gelokaliseerde prostaatkanker: deel 1Published by: KCELast published: 2014

Treatment may consist of observation, active surveillance (also known as expectant management), androgen deprivation therapy (ADT), external beam radiotherapy (EBRT), brachytherapy, radical prostatectomy, or a combination of two or more of these modalities.

EBRT, brachytherapy, and radical prostatectomy are definitive treatments. If they are used in patients with non-metastatic disease, the treatment goal is cure. ADT alone is not curative, but it may slow progression and help control symptoms.

Additional treatment options are available for metastatic disease, including anti-androgen therapy, chemotherapy, immunotherapies, and targeted therapies.

The treatment decision depends on:

  • The patient's risk group assigned at diagnosis.[3][5]​​​​​​​​[139]​​ Risk stratification groups defined by the National Comprehensive Cancer Network (NCCN) are employed in the treatment sections of this topic. Other risk groups may be used depending on region; therefore, local guidance should be consulted when assigning risk groups to patients with prostate cancer.[140] See Classification.

  • The patient's life expectancy (i.e., >10 years or <10 years) based on age, comorbidities, and health status. The International Society of Geriatric Oncology (SIOG) recommends that treatment should be based on health status rather than age.[141] Older patients (aged >70 years) are assigned a health status group (healthy, vulnerable, frail) premised upon assessment of dependence, comorbidities, and nutritional status. SIOG recommends screening for frailty with the G8 tool and for cognitive impairment with the Mini-COG instrument.[141]

  • Patient preferences (e.g., adverse effects of treatment versus living with cancer) and shared decision-making with the patient.[142]

Nomograms (e.g., the Partin nomogram and the Memorial-Sloan-Kettering Cancer Center nomogram) provide individualised disease-related risk estimations that facilitate management-related decisions.[3][111] Brady Urological Institute: the Partin tables Opens in new window Memorial-Sloan-Kettering Cancer Center: prostate cancer nomograms Opens in new window

Additional tools (e.g., Decipher 22-gene genomic classifier, somatic and germline genetic testing, imaging) may provide information to refine risk management and inform treatment decisions in selected patients.[3][102][108]​​​​

Observation

Observation involves monitoring the course of the disease with a view to delivering treatment or palliative therapy when symptoms arise or when there is a change in clinical findings that suggest symptoms are imminent.[3]

Observation should include a history and physical examination no more often than every 12 months (without prostate biopsies).[143]​ If patients become symptomatic, assessment should be performed (including prostate specific antigen [PSA] and PSA doubling time [PSADT], life expectancy estimate, and quality-of-life measures) to determine need for, and consideration of, treatment or palliation.[3]

Active surveillance

Involves monitoring the course of the disease (with additional use of prostate biopsies) until symptoms or signs of disease become clinically evident, with the expectation to treat with definitive treatment (e.g., radiotherapy or radical prostatectomy, with or without ADT) if there is disease progression.

For active surveillance, PSA levels and digital rectal examination (DRE) are checked no more than every 6 and 12 months, respectively, unless clinically indicated.[3][143] Repeat prostate biopsy and repeat multiparametric magnetic resonance imaging (MRI) are carried out no more often than every 12 months, unless clinically indicated.[3] ​Intensity of active surveillance may be individualised based on patient and tumour factors, risk of progression, and life expectancy. However, most patients should have repeat biopsies every 2-5 years.

Determining patient suitability for active surveillance

Confirmatory testing is recommended before starting active surveillance (within 6-12 months of diagnosis) if multiparametric MRI was not performed prior to diagnostic biopsy.[144] The role of confirmatory testing is to identify those at high risk for future disease upgrading or progression, and to ensure appropriate patients are selected for active surveillance.[144] 

Confirmatory testing for active surveillance involves performing a multiparametric MRI (with PSA density calculation), if available, and/or repeat biopsy (systematic and targeted), and/or molecular tumour analysis.[3][90][145]​​ All patients should have a confirmatory prostate biopsy within 1-2 years of initial diagnostic biopsy.[3]

Androgen deprivation therapy (ADT)

Early-stage prostate cancer is almost always androgen-dependent. Androgen deprivation (to slow or reduce prostate cancer growth) may be achieved medically, with:

  • a luteinising hormone-releasing hormone (LHRH) agonist (e.g., goserelin, leuprorelin, triptorelin), or

  • an LHRH antagonist (e.g., degarelix, relugolix), or

  • by surgical castration (bilateral orchiectomy).[146]

Surgical castration is rarely used.

Addition of a first-generation antiandrogen (e.g., nilutamide, flutamide, bicalutamide) to an LHRH agonist may be considered to achieve adequate testosterone suppression in unfavourable intermediate-risk disease (life expectancy >5 years).[3] Abiraterone, a second-generation antiandrogen, can be used in combination with ADT in high-risk and very high-risk disease, and metastatic disease.[3] 

Advise patients about the risk of adverse effects with ADT, including rapid loss of bone mineral density, which increases the risk of osteoporosis and fractures.[147]​ Risk assessment for treatment-related bone loss is recommended for all patients starting ADT.[3][148]​​​ ​University of Sheffield: FRAX tool Opens in new window See Complications.

LHRH agonists may cause an increase in testosterone levels during the first week of treatment (testosterone flare), which can exacerbate symptoms in patients with metastatic disease.[149][150][151] If an LHRH agonist is used in the metastatic setting, it should be combined with a first-generation antiandrogen for ≥7 days to avoid testosterone flare or, alternatively, an LHRH antagonist can be used before transitioning to an LHRH agonist.[3][152]

External beam radiotherapy (EBRT)

EBRT precisely delivers radiation to cancerous tissue. Intensity-modulated radiotherapy and image-guided radiotherapy are the standard EBRT techniques because they allow for a highly conformal delivery of radiation that minimises dose to normal tissues (bladder, rectum, and small bowel), thereby potentially decreasing toxicity to these structures. Stereotactic body radiotherapy (SBRT) is the technique used to deliver ultra-hypofractionated radiotherapy.

Biocompatible and biodegradable perirectal spacer materials can be implanted between the prostate and rectum in patients with organ-confined disease to reduce toxicity to the rectum.[3][153][154]

Patients with significant baseline urinary symptoms may not be good candidates for EBRT due to increased risk of urinary obstruction.

EBRT fractionation regimens

Several EBRT regimens have acceptable efficacy and toxicity, including moderate hypofractionation, conventional fractionation, and ultra-hypofractionation.[26][155][156][157]​​ [ Cochrane Clinical Answers logo ] ​

Moderate hypofractionation is the preferred approach.[158]​ Although it shortens treatment duration, it may slightly increase the risk of acute gastrointestinal adverse effects compared with conventional fractionation.[155] Comparable biochemical control and toxicity have been reported with ultra-hypofractionation versus more protracted fractionation schedules, but higher total doses are associated with a greater risk of severe late genitourinary complications.[157] Moderate hypofractionation or ultra-hypofractionation may be options across all risk groups; conventional fractionation is not recommended for low-risk or favourable intermediate-risk disease.[3]

Brachytherapy

Brachytherapy (low-dose rate or high-dose rate) can be given as monotherapy or as a brachytherapy boost with EBRT, depending on risk.[3][159]

Low-dose rate brachytherapy involves the permanent transperineal implantation of radioactive sources into the prostate without any incision. The highest radiation dose is confined to the prostate and a small volume of surrounding tissue. The strength of radiation decreases over time, but low levels of radioactivity in the prostate will persist for 4-6 months depending on the half-life of the isotope used. Precautions should be taken in the short term to minimise close contact with pregnant women and small children.

High-dose rate brachytherapy involves the transperineal placement of treatment catheters through which an individual radioactive source is robotically placed temporarily at various dwell positions to achieve a conformal dose of radiation to the prostate. At the end of treatment, the catheters are removed. Treatment is repeated up to five times to achieve a curative dose to the prostate.

Radical prostatectomy

Radical prostatectomy is a treatment option (depending on patient preference and suitability for surgery) when the tumour is confined to the prostate in a patient with life expectancy ≥10 years; pelvic lymph nodes may be dissected depending on the nomogram predicted risk of lymph node metastases.[3]​​

Classically, the prostate and prostatic capsule are removed by excision of the urethra at the prostatomembranous junction. The seminal vesicles, ampulla, and vas deferens are also removed. Of the two classic open surgical approaches (retropubic/suprapubic and perineal), the retropubic/suprapubic approach is preferred by many urologists, as this approach facilitates access for pelvic lymph node dissection.

Laparoscopic and robotic-assisted radical prostatectomy are alternative approaches that typically involve five or six small incisions in the abdomen from which the entire prostate is removed, theoretically sparing nerves more easily damaged by a retropubic/suprapubic approach.[160][161] One Cochrane review found that laparoscopic or robotic-assisted radical prostatectomy may result in shorter hospital stays and fewer blood transfusions compared with open surgical radical prostatectomy, but improvements in oncological outcomes (e.g., recurrence or survival) were inconclusive.[162] Complications (e.g., sexual and urinary dysfunction) appear to be similar between these alternative approaches and the open surgical approach.[162][163]

Radical prostatectomy in men with clinically localised prostate cancer that was not detected through PSA screening improves prostate cancer-specific mortality, overall survival, and risk of local disease progression and metastasis, compared with active surveillance.[164][165] These benefits have been shown to continue over the long-term, particularly in those aged ≤65 years.[166][167]

Radical prostatectomy in men with PSA-detected localised prostate cancer does not significantly reduce all-cause mortality or prostate cancer-specific mortality compared with active surveillance or observation.[168][169][170][171] Furthermore, radical prostatectomy is associated with a higher frequency of adverse events than active surveillance and observation.[168][169][170][171][172] [ Cochrane Clinical Answers logo ]

Very low-risk disease

For very low-risk disease, the following criteria must be met:[3]

  • cT1c tumour

  • Grade Group 1

  • PSA <10 micrograms/L (<10 nanograms/mL)

  • <3 prostate biopsy fragments/cores positive, ≤50% cancer in each fragment/core

  • PSA density <0.15 micrograms/L/g (<0.15 nanograms/mL/g).

Observation is recommended for patients with very low-risk disease with life expectancy <10 years. Patients with life expectancy ≤5 years who become symptomatic during observation can receive ADT alone (LHRH agonist or antagonist, or orchiectomy) for palliation.[3]

If life expectancy is ≥10 years, active surveillance is recommended.[3] Patients can move to observation if their life expectancy decreases to <10 years.

Low-risk disease

For low-risk disease, patients have all of the following and do not qualify for very low-risk disease:[3]

  • cT1-cT2a tumour

  • Grade Group 1

  • PSA <10 micrograms/L (<10 nanograms/mL)

Observation is recommended for patients with low-risk disease with life expectancy <10 years. Patients with life expectancy ≤5 years who become symptomatic during observation can receive ADT alone for palliation.[3]

If life expectancy is ≥10 years, treatment options include:[3][173][174][175]

  • Active surveillance

  • Brachytherapy

  • EBRT

  • Radical prostatectomy (depending on patient preference and suitability for surgery).

Active surveillance is the preferred approach for most patients with low-risk disease if life expectancy is ≥10 years, but is often under-utilised due to patient preference and lack of adherence.[176][177]​​ Use of standardised patient information, clinician education, and guidelines may improve uptake of and adherence to active surveillance.[176]​ Factors that may increase the likelihood of regrading, and initiation of treatment, include high PSA density, ≥3 positive cores, high genomic risk, and/or a known BRCA2 germline mutation.[3]

Favourable or unfavourable intermediate-risk disease

For favourable intermediate-risk disease, patients have no high-risk or very high-risk features and all of the following:[3]

  • One intermediate risk factor (cT2b-c tumour; Grade Group 2; or PSA 10-20 micrograms/L [10-20 nanograms/mL])

  • Grade Group 1 (if not Grade Group 2)

  • Percentage of positive biopsy cores <50%.

The treatment options for patients with favourable intermediate-risk disease are generally the same as for patients with low-risk disease, except that EBRT or brachytherapy may be offered if life expectancy is 5-10 years (although observation is preferred).[173][174][175]​​ Patients with life expectancy ≥10 years who are treated with radical prostatectomy may undergo pelvic lymph node dissection (depending on nomogram assessment).[3]

For unfavourable intermediate-risk disease, patients have no high-risk or very high-risk features and one or more of the following:[3]

  • Two or three intermediate risk factors (cT2b-c tumour; Grade Group 2 or 3; and/or PSA 10-20 micrograms/L [10-20 nanograms/mL])

  • Grade Group 3 alone

  • Percentage of positive biopsy cores ≥50%

The treatment option for patients with unfavourable intermediate-risk disease and life expectancy ≤5 years is observation. ADT alone can be used for palliation if patients become symptomatic during observation.[3]

If life expectancy is >5 years, treatment options for unfavourable intermediate-risk disease are:[3] 

  • Observation (if life expectancy is 5-10 years)

  • EBRT (with or without brachytherapy boost), or brachytherapy alone, plus ADT for 4-6 months (if life expectancy >5 years)

  • Radical prostatectomy with pelvic lymph node dissection, depending on patient preference and suitability for surgery (if life expectancy is >10 years)

There is no standard approach to managing patients with intermediate-risk disease. Assessment of the comparative effectiveness and harms of localised prostate cancer treatments is difficult because of limitations in the evidence.[178][179]

Adverse effects of treatments may influence treatment choice.[180][181][182][183]​​​​​​ Worse urinary incontinence and sexual/erectile dysfunction have been reported in patients who had radical prostatectomy compared with other treatments.[184][185][186][187]​​ Brachytherapy may be associated with worse short-term urinary obstruction and irritation, and EBRT with worse bowel function and short-term bowel symptoms.[185][187][188]

ADT (e.g., an LHRH agonist or antagonist) may be given before, during, and/or after radiotherapy, for a total of 4-6 months, in patients with unfavourable intermediate-risk disease.[3] ADT greater than 6 months duration is not recommended in patients with intermediate-risk disease.[189][190]​ ADT may have multiple synergistic effects when combined with radiotherapy, and is associated with significant clinical benefit.[191][192][193][194][195][196][197][198]

High-dose radiation to the prostate and periprostatic tissue is recommended for patients who are candidates for radiotherapy plus ADT.[199][200][201][202][203]​​​​​​ Dose escalation with EBRT alone or with the addition of brachytherapy boost to EBRT improves biochemical control, but increases toxicity.[204][205]​​​​​​​​[206]​​​​​ Brachytherapy alone may achieve similar control (5-year freedom from progression) to EBRT plus brachytherapy boost in patients with intermediate-risk disease, but with lower toxicity.[207]​ Targeted dose escalation techniques, using EBRT plus a micro-boost to the MRI-dominant lesion or an SBRT (stereotactic body radiotherapy) boost, may be a further option for select patients to improve biochemical control without increased toxicity.[3]​​​​​[208][209][210]​​[211]​ 

​Prophylactic pelvic nodal irradiation may be considered in highly selected patients with intermediate-risk disease who are undergoing radiotherapy, but only if further risk assessment (e.g., nomograms, biomarker testing) indicates aggressive disease.[3][212]

High-risk or very high-risk disease

For high-risk disease, patients have one or more of the following high-risk features, but do not meet the criteria for very high-risk:[3] 

  • cT3-cT4 tumour

  • Grade Group 4 or 5

  • PSA >20 micrograms/L (>20 nanograms/mL)

For very high-risk (locally advanced) disease, patients have at least two of the following:

  • cT3-cT4 tumour

  • Grade group 4 or 5

  • PSA >40 micrograms/L (>40 nanograms/mL)

The treatment options for patients with high-risk or very high-risk disease who are asymptomatic and have a life expectancy ≤5 years include:[3]

  • Observation

  • ADT (with or without EBRT)

  • EBRT

Observation is the usual approach. However, ADT and/or EBRT may be considered if symptoms or complications (e.g., hydronephrosis) of untreated disease or metastases are expected within 5 years.

The treatment options for patients with high-risk or very high-risk disease who are symptomatic or have a life expectancy >5 years include:[3]

  • EBRT (with or without brachytherapy boost) plus ADT

  • EBRT (with or without brachytherapy boost) plus ADT (2 years) plus abiraterone (for selected very high-risk disease)

  • Radical prostatectomy (with pelvic lymph node dissection for fit patients without tumour fixation to the pelvic musculature or skeleton), depending on patient preference and suitability for surgery

  • ADT alone (for patients unsuitable for surgery or radiotherapy due to comorbidities).

ADT may be given before, during, and/or after EBRT, for a total of 1.5 to 3 years.[213][214][215][216][217][218][219][220]​ A shortened duration of 1 year can be considered for patients having EBRT plus brachytherapy boost.[3][221] However, the optimal duration of ADT for these patients remains controversial.[222] A significant improvement in disease-free survival is demonstrated for a longer duration of ADT in patients with high-risk disease.[215][222][223][224]​ Use of combined radiotherapy with ADT significantly increases some treatment-related symptoms (e.g., pain with urination and overall urinary and bowel bother), although none are serious. However, given the substantial survival benefit of combined treatment, the increased risk of symptoms seems acceptable and has little extra effect on quality of life after 4 years compared with ADT alone.[225][226][227][228][229][230]

The addition of brachytherapy boost to EBRT (with or without ADT) may provide superior disease control compared with EBRT plus ADT for patients with high-risk or very high-risk disease.[204][231][232]​​ In a randomised study, EBRT plus brachytherapy plus ADT improved biochemical disease-free survival compared with EBRT plus ADT. No benefit in overall survival was demonstrated.[204]

High-dose radiation to the prostate and periprostatic tissue is recommended for patients who are candidates for radiotherapy plus ADT.[199][200][201][202][203]​​ Dose escalation with EBRT alone or with the addition of brachytherapy boost to EBRT improves biochemical control, but increases toxicity.[204][205][206]​ Targeted dose escalation techniques, using EBRT plus a micro-boost to the MRI-dominant lesion or an SBRT boost, may be a further option for select patients to improve biochemical control without increased toxicity.[3]​​​​[208][209][210][211]

Prophylactic pelvic nodal irradiation should also be considered in patients with high-risk or very high-risk disease who are undergoing radiotherapy.[3][212]

ADT alone can be used for patients who are unsuitable for surgery or definitive radiotherapy due to medical comorbidities. Exclusionary medical comorbidities may include inflammatory bowel disease or prior pelvic irradiation.[229] ADT on an intermittent rather than a continuous basis may be considered, although whether this approach improves quality of life is controversial.[233][234][235]

Abiraterone (a second-generation anti-androgen) is approved for use in metastatic disease. However, off-label use in combination with ADT (e.g., an LHRH agonist or antagonist) for 2 years, plus EBRT, is recommended for selected patients with very high-risk (non-metastatic) disease.[3][236][237]​​​​ Abiraterone should not be used concurrently with another anti-androgen (e.g., nilutamide, bicalutamide, flutamide), and it should always be given with prednisolone or methylprednisolone (depending on the formulation of abiraterone). The addition of abiraterone to primary ADT has been shown to improve overall and failure-free survival in a randomised study of men with locally advanced prostate cancer (radiotherapy was required if node negative, and encouraged if node positive) or metastatic disease.[236] Overall survival data for the subgroup of patients with non-metastatic disease at randomisation are immature.[236] However, there are data showing improved metastasis-free survival in this subgroup.[238]

Adjuvant and salvage therapy

Adjuvant or salvage therapy may be required following definitive treatment in patients with localised or locally advanced disease. The goal of adjuvant and salvage therapy is cure.

Salvage therapy after radical prostatectomy

Risk assessment (including use of nomograms) should be carried out to inform decision-making after radical prostatectomy. The Decipher (22-gene genomic classifier) molecular assay may be considered to aid decision-making discussions, along with clinical and pathological information, PSA level, and PSADT.[3]​​[103][239]​​[240][241]

Post-operative salvage therapy is indicated for patients with life expectancy >5 years if there is PSA persistence (PSA does not fall to undetectable levels) or recurrence (increase of previously undetectable PSA on two or more measurements or to PSA >0.1 nanograms/mL).[3][242]​​ Evaluation for distant metastases should be carried out (e.g., if the patient develops symptoms or PSA is increasing rapidly), which may include bone and soft-tissue imaging, and prostate bed biopsy. For patients with life expectancy ≤5 years, observation is recommended.[3]

Options for salvage treatment include:[3][242]​​​​​

  • EBRT with or without ADT if negative for pelvic nodal recurrence and distant metastases

  • EBRT with ADT with or without abiraterone (plus prednisolone or methylprednisolone) if positive for pelvic nodal recurrence

EBRT (with or without ADT) is the preferred treatment option for post-operative salvage therapy.[3][243][244][245]​​​ Combining ADT with salvage EBRT reduces the likelihood of progression and may improve survival outcomes compared with salvage EBRT alone, but decisions (including duration of ADT) should be individualised.[243][244][245][246]

Adjuvant therapy and monitoring for progression after radical prostatectomy

​Decisions about adjuvant treatment for patients with adverse pathological features or detectable PSA, but without PSA persistence or recurrence, should be individualised based on risk assessment and patient preferences.

Adjuvant radiation therapy may be considered for patients with positive margins, extracapsular extension [pT3 disease], seminal vesicle invasion, or a detectable PSA, and with no lymph node metastases.[3][247][248][249][250]​​​​​​​

Patients with multiple adverse features (regardless of PSA levels) may be offered salvage EBRT (with or without ADT) as for patients with post-operative PSA persistence or recurrence.[3] 

Randomised controlled trials have shown that early salvage EBRT results in similar biochemical control and event-free survival rates, and lower genitourinary toxicity, compared with immediate adjuvant EBRT.[251][252][253][254]​ Monitoring, with salvage treatment for PSA persistence or recurrence, may reduce overtreatment compared with immediate adjuvant EBRT.[3][254]​​

​​​Following a careful review of the balance of risks and benefits, monitoring for progression (physical examination and PSA every 3-6 months, and imaging for symptoms or increasing PSA) may be an alternative to salvage therapy in patients with PSA persistence or recurrence after radical prostatectomy (and in whom post-operative imaging studies for pelvic nodal recurrence and distant metastases were negative).[3][241]​​ However, salvage therapy is more effective when given at lower levels of PSA (≥0.1 to 0.2 nanograms/mL), and should be considered for patients with a detectable, rising PSA, and before PSA levels reach 0.5 nanograms/mL.[242][255]​​ 

Salvage therapy after primary radiotherapy

Salvage therapy is indicated for patients with life expectancy >5 years if there is PSA recurrence or positive DRE after primary radiotherapy.[3] PSA recurrence after radiotherapy is defined as PSA increase of ≥2 micrograms/L (≥2 nanograms/mL) above the nadir PSA.[256] ​Evaluation for salvage therapy can also be considered if the PSA is increasing but has not reached 2 micrograms/L (2 nanograms/mL) above nadir. 

Treatment decisions should be individualised, guided by risk stratification; PSA density, and bone and soft-tissue imaging should be performed.[3][257]

If negative for regional lymph nodes and distant metastases, consider prostate/seminal vesicle biopsy and:[3][257][258][259][260]

  • Monitoring for progression, or

  • ADT (based on PSA density), or

  • Local secondary therapy alone, which may include:

    • Salvage prostatectomy plus pelvic lymph node dissection

    • Salvage cryotherapy

    • Re-irradiation (low- or high-dose rate brachytherapy, or SBRT)

    • High-intensity focused ultrasound

If positive for regional lymph nodes and negative for distant metastases, consider prostate/seminal vesicle biopsy and:[3]

  • Monitoring, or

  • ADT with or without abiraterone (plus prednisolone or methylprednisolone), or

  • Local secondary therapy (e.g., pelvic lymph node dissection, pelvic lymph node radiation or re-irradiation [low- or high-dose rate brachytherapy, or SBRT]) with or without ADT

Observation is recommended for patients with life expectancy ≤5 years.[3]

Salvage brachytherapy provides precise treatment for pathologically confirmed (e.g., using MRI-guided biopsy) locally recurrent disease, therefore minimising toxicity to adjacent organs. Use of salvage prostatectomy and salvage cryotherapy is limited by treatment-related adverse effects (e.g., erectile dysfunction).[260][261][262][263][264][265][266]

Non-metastatic castration-resistant disease

Patients with non-metastatic castration-resistant prostate cancer are those with clinical, radiographic, or biochemical (PSA) progression despite treatment with ADT, but who do not have metastases. These patients are at high risk for developing metastases, particularly if PSADT is short (e.g., ≤10 months). ADT with an LHRH agonist or antagonist should continue in these patients to maintain castrate serum levels of testosterone, but further hormonal treatment may be added depending on the PSADT.[3]

If PSADT is >10 months, monitoring with continued ADT is the preferred option. A secondary hormone therapy can be added to ADT (if not previously used), although evidence of survival benefit is lacking. Secondary hormone therapy may include:[3]

  • Ketoconazole plus hydrocortisone

  • First-generation anti-androgen (e.g., nilutamide, bicalutamide, flutamide)

  • Corticosteroid (e.g., hydrocortisone, prednisolone, dexamethasone)

Anti-androgen withdrawal (i.e., to exclude an anti-androgen withdrawal effect) may be an option for non-metastatic castration-resistant disease.[267][268][269]

Ketoconazole may cause severe liver injury and adrenal insufficiency. It is contraindicated in patients with liver disease and expert guidance should be sought if used. Liver and adrenal function should be monitored before and during treatment.[270]

If PSADT is ≤10 months, the following second-generation anti-androgens can be added to ADT.[3]

  • Apalutamide

  • Darolutamide

  • Enzalutamide

Randomised studies of second-generation anti-androgens in patients with non-metastatic castration-resistant prostate cancer and PSADT ≤10 months have demonstrated improved overall survival, metastasis-free survival, and time to progression compared with placebo, without compromising quality of life.[271][272][273][274][275][276][277][278][279] It is not known if similar benefit would be achieved in men with a PSADT >10 months.

Alternative options for patients with non-metastatic castration-resistant disease and PSADT ≤10 months include other secondary hormone options or anti-androgen withdrawal (as described for PSADT >10 months).[3][267][268]​​[269]

ADT alone or observation are recommended for asymptomatic non-metastatic castration-resistant prostate cancer patients with life expectancy ≤5 years.[3]

Metastatic disease: castration-sensitive

The main treatment goals for metastatic disease are prolongation of survival while maintaining quality of life, and palliation of symptoms that may arise from metastatic tumour deposits.

Patients with castration-sensitive metastatic disease include those with metastatic disease at presentation, and those who are not receiving ADT when metastatic disease develops (i.e., castration-naive).

Genetic testing (germline and somatic) should be carried out in all patients with metastatic disease (if not done previously) to inform prognosis and guide treatment decisions, including eligibility for clinical trials and suitability for novel targeted therapies.[280][281]​​​​​ See Diagnosis approach.

Therapeutic approaches to castration-sensitive metastatic disease

Combination therapy with ADT (e.g., an LHRH agonist or antagonist) plus a second-generation anti-androgen with or without docetaxel is recommended.[236][281]​​​​​[282][283][284][285][286][287][288][289][290][291][292][293]​​​​​​​ EBRT to the primary tumour may be an option for some patients.[3][294][295] Decisions about treatment should take into account toxicity, disease volume, and timing of metastases.​

Specific treatment options include:[3][237][293][296]

  • ADT plus docetaxel and one of: abiraterone, apalutamide, darolutamide, or enzalutamide

  • ADT plus one of: abiraterone, apalutamide, darolutamide, or enzalutamide

  • ADT plus EBRT to the primary tumour alone or with one of: abiraterone, apalutamide, docetaxel, or enzalutamide

Abiraterone should always be given with prednisolone or methylprednisolone (depending on the formulation of abiraterone).

For patients with high-volume disease (i.e., visceral metastases and/or ≥4 bone metastases with ≥1 beyond the vertebral bodies and pelvis) or low-volume disease (i.e., non-regional lymph-node-only disease, or presence of <4 bone metastases without visceral/other metastasis) with synchronous metastases, ADT plus a second-generation anti-androgen with docetaxel should be considered.[3] Triplet combination therapy may improve survival compared with ADT plus docetaxel alone, particularly in those with high-volume castration-sensitive disease.[297][298][299][300][301]

For low-volume disease (i.e., non-regional lymph-node-only disease, or presence of <4 bone metastases without visceral/other metastasis) with metachronous metastases, ADT plus abiraterone, apalutamide, or enzalutamide is preferred.[3][302]​​​

Improved survival has been demonstrated with EBRT plus ADT versus ADT alone in patients with low-volume castration-sensitive disease.​[294][301]​​[303][304][305] Moderate hypofractionation and ultra-hypofractionation are the preferred approaches for EBRT.[3][303]​ 

ADT is usually given continuously, but intermittent ADT may be considered if adverse effects occur with continuous ADT.[72][306][307][308][309][310]

ADT alone is not recommended for patients with castration-sensitive metastatic disease unless combination treatment is clearly contraindicated.[3]​ Bilateral orchiectomy is an option for patients with castration-sensitive metastatic disease, but is rarely used. 

A PSA level ≤0.2 micrograms/L (≤0.2 nanograms/mL) after 7 months of ADT is a strong predictor for longer overall survival in patients with castration-sensitive metastatic disease.[311] 

Oligometastatic disease

Patients with 1-5 metastatic lesions are generally considered to have oligometastatic disease, although there is no agreed definition for this disease state.[312] The standard treatment for oligometastatic disease is similar to that for low metastatic burden disease.

Focal therapy with SBRT may be an option for patients with oligometastatic disease (when the goal is metastasis-directed ablation) or for patients with oligometastatic progression (when the goal is progression-free survival).[3][313][314]

One randomised study of SBRT in oligometastatic cancers reported improved overall survival and progression-free survival in patients receiving SBRT compared with standard palliative care.[315][316]​​​​ The optimal treatment approach for managing oligometastatic disease is unclear.

Metastatic disease: castration-resistant

The main treatment goals for metastatic disease are prolongation of survival while maintaining quality of life, and palliation of symptoms that may arise from metastatic tumour deposits.

Patients with castration-resistant metastatic disease are those who develop metastatic disease despite achieving castrate levels of testosterone with primary ADT.

Tumour testing for somatic homologous recombination repair (HRR) mutations, microsatellite instability (MSI)/mismatch repair (MMR) deficiency, and tumour mutational burden (TMB) should be carried out in patients with castration-resistant metastatic disease (if not done previously) to inform prognosis and guide treatment decisions, including eligibility for clinical trials and suitability for novel targeted therapies.[280][281] Re-evaluation of somatic testing may be considered if done previously.[3] Germline testing for HRR mutations is recommended if not done previously.​​​​​ See Diagnosis approach.

Treatment options for patients with castration-resistant metastatic disease have expanded rapidly. Optimal sequencing of therapies following docetaxel or cabazitaxel and/or second-generation anti-androgen therapy is unclear. Studies may help guide decisions.[317][318][319]​​​​

Initial treatment options for castration-resistant metastatic disease

Treatment decisions should take into account patient goals and preferences, prior treatment exposures, the presence or absence of symptoms, performance status, the location and number of metastases, potential adverse effects, and the presence of certain biomarkers.[3] ADT should be continued to maintain castrate levels of testosterone in patients with castration-resistant metastatic disease. Patients should be closely monitored for progression, and treatments added sequentially.[3]

For patients with no prior treatment with second-generation anti-androgen therapy (abiraterone, enzalutamide, darolutamide, or apalutamide), ADT can be combined with one of the following options:[320][321][322][323]​​​​​​[324][325][326][327][328]​​​​​​[329]​​[330][331]

  • Abiraterone (with prednisolone or methylprednisolone)

  • Enzalutamide

  • Docetaxel plus prednisolone (if no prior docetaxel use)

  • Cabazitaxel plus prednisolone (if prior docetaxel use)

For patients with progression following treatment with second-generation anti-androgen therapy, with no prior docetaxel treatment, docetaxel plus prednisolone can be added to ADT.[3] If the patient has a BRCA1 or BRCA2 mutation, either of the poly (ADP-ribose) polymerase (PARP) inhibitors olaparib or rucaparib may be considered as alternative options in this setting.​[332][333][334][335]

For patients with progression following treatment with second-generation anti-androgen therapy and prior docetaxel treatment, cabazitaxel plus prednisolone can be added to ADT.[328][329]​​​​​​​​[330][336]​​​​​ Docetaxel rechallenge is a further option for patients with castration-sensitive disease who progressed on prior docetaxel and second-generation anti-androgen therapy.[3]

Patients who show signs of progression while tak​​​ing abiraterone plus prednisolone may benefit from switching from prednisolone to dexamethasone.[337][338]

Further treatment options for castration-resistant metastatic disease

The following treatments may be considered for selected patients with castration-resistant metastatic disease. Optimal sequencing is unknown; patients can try any of these options, if indicated.

  • Sipuleucel-T:

    • An autologous active cellular immunotherapy, sipuleucel-T may be an option for asymptomatic or minimally symptomatic patients with good functional status (e.g., an Eastern Cooperative Oncology Group performance status of 0 to 1).[3][339][340]​​​​

    • Sipuleucel-T is not recommended for patients with visceral disease and a life expectancy of less than 6 months, or patients with hepatic metastases.[3][339]

  • PARP inhibitors:

    • Recommended for patients with HRR gene alterations; response may be greatest for BRCA1 and BRCA2 variants.[3]

    • Olaparib can be considered for patients with a homologous recombination repair (HRR) gene mutation who have had prior second-generation anti-androgen therapy.[3][237][332][333][334]​​​​ Efficacy may vary depending on the genes involved; in one study of patients with an alteration in one of 15 prespecified HRR genes, those with a BRCA1 or BRCA2 mutation appeared to derive the greatest survival benefit.[334]​​​​ 

    • Rucaparib can be considered for patients with a BRCA1 or BRCA2 mutation who have had prior second-generation anti-androgen therapy.[3][335][341][342]​​​​ Rucaparib is not recommended for patients without a BRCA1 or BRCA2 mutation.[3][343]

    • Olaparib or niraparib may be used in combination with abiraterone (plus prednisolone or methylprednisolone) for patients with a BRCA1 or BRCA2 mutation who have not received prior second-generation anti-androgen therapy.[3][344][345]​​​[346] 

    • Talazoparib plus enzalutamide may be an option for patients with an HRR mutation who have not been treated in the castration-resistant setting, depending on treatments received before progression.[3][347][348]

    • Anaemia, fatigue, and nausea are commonly reported with PARP inhibitors. Careful monitoring for anaemia and renal and hepatic function is required.[3]

  • Pembrolizumab:

    • A programmed death receptor-1 (PD-1)-blocking monoclonal antibody, pembrolizumab may be considered for patients with MMR deficient, MSI-high, or TMB-high metastatic castration-resistant prostate cancer.[3][281]

    • Much of the evidence for this treatment is based on different tumour types; however, early phase trials report antitumour activity among specific subsets of patients with metastatic castration-resistant prostate cancer.[349][350][351][352]

    • Pembrolizumab may cause severe, life-threatening immune-mediated adverse reactions.[353]

  • Lutetium (Lu-177) vipivotide tetraxetan:

    • A radioligand therapeutic agent that delivers beta-radiation to prostate-specific membrane antigen (PSMA)-expressing cells and the surrounding microenvironment. Can be considered for patients with progression after second-generation anti-androgen therapy who have PSMA-positive castration-resistant metastatic disease.[3][237][281][354][355][356]​​​ 

    • PSMA-PET imaging is required for patient selection. Gallium (Ga-68) PSMA-11, piflufolastat F-18, or flotufolastat F-18 may be used as radiotracers to detect PSMA expression and determine eligibility.[3][354]​​​[357]

  • Carbazitaxel plus carboplatin:

    • May be considered in combination with prednisolone for patients with aggressive disease or unfavourable genomics (two or more defects in PTEN, TP53, and RB1)[358]

    • Adverse events may include fatigue, anaemia, neutropenia, and thrombocytopenia

  • Mitoxantrone:

    • May be considered in combination with prednisolone for palliative treatment of symptomatic patients who have progressed on prior docetaxel and cannot tolerate other therapies. It has not been shown to improve survival.[3][359][360]

  • Radium-223:

    • A calcium mimetic that localises to the bone and delivers radiation directly to bone metastases, radium-223 can be considered for patients with castration-resistant metastatic disease who have symptomatic bone metastases without visceral metastases.[3][361] 

    • Radium-223 is associated with adverse effects including anaemia, neutropenia, thrombocytopenia, bone pain, and gastrointestinal disorders. There have also been reports of increased risk of fracture and deaths when used in combination with abiraterone plus prednisolone.[362][363]

    • The European Medicines Agency has restricted the use of radium-223 to symptomatic patients who have received two prior treatments for metastatic prostate cancer, or who cannot receive other treatments. It should not be used with abiraterone and prednisolone or with other systemic cancer therapies (except hormone therapy).[363]

    • A careful assessment of risk of fractures should be carried out before, during, and after treatment with radium-223. Concomitant bisphosphonate or denosumab is recommended when radium-223 is prescribed.[3][363]​See Complications.

Supportive care

Supportive care should be considered to manage complications and symptoms related to metastatic disease.

Patients with castration-resistant disease who have bone metastases should be offered treatment to prevent skeletal-related events. See Complications.

Systemic radiotherapy with the beta-particle emitters strontium-89 or samarium-153 can be considered for palliation in patients with symptomatic bone metastases without visceral metastases. Their use is purely palliative and has largely been superseded by radium-223, which confers a survival advantage.

Radiotherapy in palliative doses can be given to sites of painful bony metastasis. Radiation may include a single treatment or a 1- or 2-week course depending on normal tissue toxicity and patient convenience.[364] Studies do not show a consistent difference between regimens for pain control, but some have reported higher rates of reirradiation in patients receiving single-fraction regimens (although the reason for this is unclear).[364][365][366][367]​​​ SBRT may be considered instead of conventional palliative radiotherapy for some patients with painful bony metastases (e.g., with an Eastern Cooperative Oncology Group performance status 0 to 2, without neurological symptoms, and not receiving surgery).[364][368] Radiation may also be given to the pelvis, if previously untreated, in palliative doses to relieve obstructive symptoms or bleeding.

Evidence is lacking to guide the use of SBRT combined with targeted therapy and immunotherapy.[369]

Male urethral catheterisation animated demonstration
Male urethral catheterisation animated demonstration

How to insert a urethral catheter in a male patient using sterile technique.

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