The literature for the complete document has been assessed and updated based upon a review of all recommendations and creation of appropriate GRADE forms. Evidence summaries and recommendations have been amended throughout the current document and several new sections have been added. All chapters of the 2021 PCa Guidelines have been updated. New data have been included in the following sections, resulting in new sections and added and revised recommendations in:
5.1.4 Guidelines for germline testing*
| Recommendations | Strength rating |
| Consider germline testing in men with metastatic PCa. | weak |
| Consider germline testing in men with high-risk PCa who have a family member diagnosed with PCa at age < 60 years. | weak |
| Consider germline testing in men with multiple family members diagnosed with PCa at age < 60 years or a family member who died from PCa. | weak |
| Consider germline testing in men with a family history of high-risk germline mutations or a family history of multiple cancers on the same side of the family. | weak |
* Genetic counseling is required prior to germline testing.
5.2.7.3 Summary of evidence and recommendations for performing prostate biopsy
(in line with the Urological Infections Guidelines Panel)
| Summary of evidence | LE |
| A meta-analysis of seven studies including 1,330 patients showed significantly reduced infectious complications in patients undergoing transperineal biopsy as compared to transrectal biopsy. | 1a |
| Meta-analysis of eight RCTs including 1,786 men showed that use of a rectal povidone-iodine preparation before transrectal biopsy, in addition to antimicrobial prophylaxis, resulted in a significantly lower rate of infectious complications. | 1a |
| A meta-analysis on eleven studies with 1,753 patients showed significantly reduced infections after transrectal biopsy when using antimicrobial prophylaxis as compared to placebo/control. | 1a |
| Recommendations | Strength rating* |
| Perform prostate biopsy using the transperineal approach due to the lower risk of infectious complications. | Strong |
| Use routine surgical disinfection of the perineal skin for transperineal biopsy. | Strong |
| Use rectal cleansing with povidone-iodine in men prior to transrectal prostate biopsy. | Strong |
| Do not use fluoroquinolones for prostate biopsy in line with the European Commission final decision on EMEA/H/A-31/1452. | Strong |
| Use either target prophylaxis based on rectal swab or stool culture; augmented prophylaxis (two or more different classes of antibiotics); or alternative antibiotics (e.g., fosfomycin trometamol, cephalosporin, aminoglycoside) for antibiotic prophylaxis for transrectal biopsy. | Weak |
| Use a single oral dose of either cefuroxime or cephalexin or cephazolin as antibiotic prophylaxis for transperineal biopsy. Patients with severe penicillin allergy may be given sulphamethoxazole. | Weak |
| Ensure that prostate core biopsies from different sites are submitted separately for processing and pathology reporting. | Strong |
Figure 5.1: Prostate biopsy workflow to reduce infectious complications
*Note on strength ratings:
The above strength ratings are explained here due to the major clinical implications of these new recommendations. Although data showing the lower risk of infection via the transperineal approach is low in certainty, its statistical and clinical significance warrants its Strong rating. Strong ratings are also given for routine surgical disinfection of skin in transperineal biopsy and povidone-iodine rectal cleansing in transrectal biopsy as, although quality of data is low, the clinical benefit is high and practical application simple. A Strong rating is given for avoiding fluoroquinolones in prostate biopsy due to its legal implications in Europe.
6.1.6 General guidelines for the treatment of prostate cancer
| Recommendations | Strength rating |
| Radiotherapeutic treatment | |
| Offer low-dose rate (LDR) brachytherapy monotherapy to patients with good urinary function and low- or good prognosis intermediate-risk localised disease. | Strong |
| Offer LDR or high-dose rate brachytherapy boost combined with IMRT including IGRT to patients with good urinary function and intermediate disease with adverse features or high risk disease. | Strong |
6.2.1.3 Summary of evidence and guidelines for the treatment of low-risk disease
| Summary of evidence |
| Systematic biopsies have been scheduled in AS protocols, the number and frequency of biopsies varied, there is no approved standard. |
| Although per-protocol MR scans are increasingly used in AS follow up no conclusive evidence exist in terms of their benefit/and whether biopsy may be ommitted based on the imaging findings. |
| Personalised risk-based approaches will ultimately replace protocol-based management of patients on AS. |
| Recommendations | Strength rating |
| Active surveillance (AS) | |
| Selection of patients | |
| Perform a mpMRI before a confirmatory biopsy if no MRI has been performed before the initial biopsy. | Strong |
| Radiotherapeutic treatment | |
| Offer low-dose rate brachytherapy to patients with low-risk PCa, without a recent transurethral resection of the prostate and a good International Prostatic Symptom Score. | Strong
|
| Other therapeutic options | |
| Do not offer ADT monotherapy to asymptomatic men not able to receive any local treatment. | Strong |
6.2.2.5 Guidelines for the treatment of intermediate-risk disease
| Recommendations | Strength rating |
| Active surveillance (AS) | |
| Offer AS to highly selected patients with ISUP grade group 2 disease (i.e. < 10% pattern 4, PSA < 10 ng/mL, ≤ cT2a, low disease extent on imaging and biopsy) accepting the potential increased risk of metastatic progression. | Weak |
| Radiotherapeutic treatment | |
| Offer low-dose rate brachytherapy to intermediate-risk patients with ISUP grade 2 with ≤ 33% of biopsy cores involved, without a recent transurethral resection of the prostate and with a good International Prostatic Symptom Score. | Strong
|
| For intensity-modulated radiotherapy (IMRT) plus image-guided radiotherapy (IGRT), use a total dose of 76─78 Gy or moderate hypofractionation (60 Gy/20 fx in 4 weeks or 70 Gy/28 fx in 6 weeks), in combination with short-term androgen deprivation therapy (ADT) (4 to 6 months). | Strong
|
| In patients not willing to undergo ADT, use a total dose of IMRT plus IGRT (76─78 Gy) or moderate hypofractionation (60 Gy/20 fx in 4 weeks or 70 Gy/28 fx in 6 weeks) or a combination with brachytherapy. | Weak
|
6.2.3.4 Guidelines for radical treatment of high-risk localised disease
| Recommendation | Strength rating |
| Therapeutic options outside surgery and radiotherapy | |
| Only offer ADT monotherapy to those patients unwilling or unable to receive any form of local treatment if they have a prostate-specific antigen (PSA)-doubling time < 12 months, and either a PSA > 50 ng/mL or a poorly-differentiated tumour. | Strong |
6.2.5.7 Guidelines for adjuvant treatment in pN0 and pN1 disease after radical prostatectomy
| Recommendation | Strength rating |
| Offer adjuvant intensity-modulated radiation therapy (IMRT) plus image-guided radiation therapy (IGRT) to high-risk patients (pN0) with ISUP grade group 4─5 and pT3 ± positive margins. | Strong |
6.2.6.5 Recommendations for the management of persistent PSA after radical prostatectomy
| Recommendation | Strength rating |
| Offer a prostate-specific membrane antigen positron emission tomography (PSMA PET) scan to men with a persistent PSA > 0.2 ng/mL if the results will influence subsequent treatment decisions. | Weak |
6.3.14 Guidelines for second-line therapy after treatment with curative intent
| Local salvage treatment | Strength rating |
| Recommendations for biochemical recurrence (BCR) after radical prostatectomy | |
| Offer monitoring, including prostate-specific antigen (PSA), to EAU BCR low-risk patients. | Weak |
| Offer early salvage intensity-modulated radiotherapy plus image-guided radiotherapy to men with two consecutive PSA rises. | Strong |
| In case of a negative PET/CT start salvage radiotherapy immediately. | Strong |
| Do not wait for a threshold before starting treatment. Once the decision for salvage radiotherapy (SRT) has been made, SRT (at least 66 Gy) should be given as soon as possible. | Strong |
| Recommendations for BCR after radiotherapy | |
| Offer monitoring, including prostate-specific antigen (PSA), to EAU BCR low-risk patients. | Weak |
6.4.9 Guidelines for the first-line treatment of metastatic disease
| Recommendations | Strength rating |
| Discuss combination therapy with all M1 patients. | Strong |
| Do not offer ADT monotherapy to patients whose first presentation is M1 disease if they have no contraindications for combination therapy and have a sufficient life expectancy to benefit from combination therapy and are willing to accept the increased risk of side effects. | Strong |
| Do not offer ADT combined with surgery to M1 patients outside of clinical trials. | Strong |
| Only offer metastasis-directed therapy to M1 patients within a clinical trial setting or well-designed prospective cohort study. | Strong |
6.3.14 Guidelines for second-line therapy after treatment with curative intent
| Local salvage treatment | Strength rating |
| Recommendations for biochemical recurrence (BCR) after radical prostatectomy | |
| Offer monitoring, including prostate-specific antigen (PSA), to EAU BCR low-risk patients. | Weak |
| Offer early salvage intensity-modulated radiotherapy plus image-guided radiotherapy to men with two consecutive PSA rises. | Strong |
| In case of a negative PET/CT start salvage radiotherapy immediately. | Strong |
| Do not wait for a threshold before starting treatment. Once the decision for salvage radiotherapy (SRT) has been made, SRT (at least 66 Gy) should be given as soon as possible. | Strong |
| Recommendations for BCR after radiotherapy | |
| Offer monitoring, including prostate-specific antigen (PSA), to EAU BCR low-risk patients. | Weak |
| Only offer salvage radical prostatectomy (RP), brachytherapy, high intensity focused ultrasound, or cryosurgical ablation to highly selected patients with biopsy proven local recurrence within a clinical trial setting or well-designed prospective cohort study undertaken in experienced centres. | Strong
|
6.5.14 Summary of evidence and guidelines for life-prolonging treatments of castrate-resistant disease
| Recommendations | Strength rating |
| Treat patients with mCRPC with life-prolonging agents. | Strong |
| Offer mCRPC patients somatic and/or germline molecular testing as well as testing for mismatch repair deficiencies or microsatellite instability. | Strong |
6.5.15 Guidelines for systematic treatments of castrate-resistant disease
| Recommendations | Strength rating |
| Base the choice of treatment on the performance status, symptoms, comorbidities, location and extent of disease, genomic profile, patient preference, and on the previous treatment for hormone-sensitive metastatic PCa (mHSPC) (alphabetical order: abiraterone, cabazitaxel, docetaxel, enzalutamide, olaparib, radium-223, sipuleucel-T). | Strong |
| Offer patients with mCRPC who are candidates for cytotoxic therapy and are chemotherapy naïve docetaxel with 75 mg/m2 every 3 weeks. | Strong |
| Offer patients with mCRPC and progression following docetaxel chemotherapy further life-prolonging treatment options, which include abiraterone, cabazitaxel, enzalutamide, radium-223 and olaparib in case of DNA homologous recombination repair (HRR) alterations. | Strong |
| Base further treatment decisions of mCRPC on performance status, previous treatments, symptoms, co-morbidities, genomic profile, extent of disease and patient preference. | Strong |
| Offer abiraterone or enzalutamide to patients previously treated with one or two lines of chemotherapy. | Strong |
| Avoid sequencing of androgen receptor targeted agents, | Weak |
| Offer chemotherapy to patients previously treated with abiraterone or enzalutamide. | Strong |
| Offer cabazitaxel to patients previously treated with docetaxel. | Strong |
| Novel agents | |
| Offer poly(ADP-ribose) polymerase (PARP) inhibitors to pretreated mCRPC patients with relevant DNA repair gene mutations. | Strong |
7.2.6 Guidelines for follow-up during hormonal treatment
| Recommendations | Strength rating |
| In M1 patients, schedule follow-up at least every 3 to 6 months. | Strong |
| In patients on long-term androgen deprivation therapy (ADT), measure initial bone mineral density to assess fracture risk. | Strong |
During follow-up of patients receiving ADT, check PSA and testosterone levels and monitor patients for symptoms associated with metabolic syndrome as a side effect of ADT. As a minimum requirement, include a disease-specific history, haemoglobin, serum creatinine, alkaline phosphatase, lipid profiles and HbA1c level measurements. | Strong |
| When disease progression is suspected, restaging is needed and the subsequent follow up adapted/individualised. | Strong |
| In M1 patients perform regular imaging (CT and bone scan) even without PSA progression. | Weak |
| In patients with suspected progression, assess the testosterone level. By definition, castration- resistant PCa requires a testosterone level < 50 ng/dL (< 1.7 nM/L). | Strong |
8.3.2.5 Guidelines for quality of life in men undergoing systemic treatments
| Recommendations | Strength rating |
| Advise men on ADT to maintain a healthy weight and diet, to stop smoking, reduce alcohol to ≤ 2 units daily and have yearly screening for diabetes and hypercholesterolemia. Ensure that calcium and vitamin D meet recommended levels. | Strong |
| Offer anti-resorptive therapy to men on long term ADT with either a BMD T score of <-2.5 or with an additional clinical risk factor for fracture or annual bone loss on ADT is confirmed to exceed 5%. | Strong |