Prostate Cancer

Full Text Guidelines Summary of Changes Scientific Publications & Appendices Pocket Guidelines Archive Panel


N. Mottet (Chair), P. Cornford (Vice-chair), R.C.N. van den Bergh, E. Briers, Expert Patient Advocate (European Prostate Cancer Coalition/Europa UOMO), M. De Santis, S. Gillessen, J. Grummet, A.M. Henry, T.H. van der Kwast, T.B. Lam, M.D. Mason, S. O‘Hanlon, D.E. Oprea-Lager, G. Ploussard, H.G. van der Poel, O. Rouvière, I.G. Schoots, D. Tilki, T. Wiegel
Guidelines Associates: T. Van den Broeck, M. Cumberbatch, A. Farolfi, N. Fossati, G. Gandaglia, N. Grivas, M. Lardas, M. Liew, L. Moris, P-P.M. Willemse

1.INTRODUCTION

1.1.Aims and scope

The Prostate Cancer (PCa) Guidelines Panel have prepared this guidelines document to assist medical professionals in the evidence-based management of PCa.

It must be emphasised that clinical guidelines present the best evidence available to the experts but following guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions - also taking personal values and preferences/individual circumstances of patients into account. Guidelines are not mandates and do not purport to be a legal standard of care.

1.2.Panel composition

The PCa Guidelines Panel consists of an international multidisciplinary group of urologists, radiation oncologists, medical oncologists, radiologists, a pathologist, a geriatrician and a patient representative.

All imaging sections in the text have been developed jointly with the European Society of Urogenital Radiology (ESUR) and the European Association of Nuclear Medicine (EANM). Representatives of the ESUR and the EANM in the PCa Guidelines Panel are (in alphabetical order): Dr. D. Oprea-Lager, Prof.Dr. O Rouvière and Dr. I.G. Schoots.

All radiotherapy sections have been developed jointly with the European Society for Radiotherapy & Oncology (ESTRO). Representatives of ESTRO in the PCa Guidelines Panel are (in alphabetical order): Prof.Dr. A.M. Henry, Prof.Dr. M.D. Mason and Prof.Dr. T. Wiegel.

The International Society of Urological Pathology is represented by Prof.Dr. T. van der Kwast.

Dr. S. O’Hanlon, consultant geriatrician, representing the International Society of Geriatric Oncology (SOIG) contributed to the sections addressing life expectancy, health status and quality of life in particular.

Dr. E. Briers, expert Patient Advocate Hasselt-Belgium representing the patient voice as delegated by the European Prostate Cancer Coalition/Europa UOMO.

All experts involved in the production of this document have submitted potential conflict of interest statements which can be viewed on the EAU website Uroweb: https://uroweb.org/guideline/prostate-cancer/.

1.2.1.Acknowledgement

The PCa Guidelines Panel gratefully acknowledges the assistance and general guidance provided by Prof.Dr. M. Bolla, honorary member of the PCa Guidelines Panel.

1.3.Available publications

A quick reference document (Pocket guidelines) is available, both in print and as an app for iOS and Android devices. These are abridged versions which may require consultation together with the full text version. Several scientific publications are available [1,2] as are a number of translations of all versions of the PCa Guidelines.

All documents can be accessed on the EAU website: http://uroweb.org/guideline/prostate-cancer/.

1.4.Publication history and summary of changes

1.4.1.Publication history

The EAU PCa Guidelines were first published in 2001. This 2021 document presents an update of the 2020 PCa Guidelines publication.

1.4.2.Summary of changes

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

*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.

Figure 5.1: Prostate biopsy workflow to reduce infectious complications*

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-risk 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

A negative PET/CT scan should not delay salvage radiotherapy (SRT), if otherwise indicated.

Strong

Do not wait for a PSA threshold before starting treatment. Once the decision for 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 Low-Risk BCR 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

6.4.9 Guidelines for the first-line treatment of metastatic disease

Recommendations

Strength rating

Discuss combination therapy including ADT plus systemic 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

6.5.14 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, co-morbidities, 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

Recommendations for BCR after radiotherapy

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