Guidelines On Prostate Cancer - Uroweb

20.1.2 Androgen-receptor-dependent mechanisms20.2Definition of relapsing prostate cancer after castration20.3Assessing treatment outcome in CRPC20.3.1 PSA level as marker of response20.3.2 Other parameters20.4Androgen deprivation in castration-resistant PCa20.5Secondary hormonal therapy20.6Classical hormonal treatment alternatives after CRPC occurrence20.6.1 Bicalutamide20.6.2 Anti-androgen withdrawal20.6.3 Oestrogens20.7Novel hormonal drugs targeting the endocrine pathways20.8Non-hormonal therapy20.8.1 Docetaxel regimen20.8.2 Other classical regimen20.8.2.1 Mitoxantrone combined with corticosteroids20.8.2.2 Other chemotherapy regimen20.8.3 Vaccine20.9How to choose the first “second-line” treatment in CRPC20.10 Salvage treatment after first-line docetaxel20.10.1 Cabazitaxel20.10.2 Enzalutamide20.10.3 Abiraterone acetate20.11 Conclusion and recommendations for salvage treatment after docetaxel20.12 Bone targeted therapies in mCRPC20.12.1 Common complications due to bone metastases20.12.2 Painful bone metastases20.12.2.1 Ra 223 and other radiopharmaceuticals20.12.3 Bisphosphonates20.12.4 RANK ligand inhibitors20.13 Recommendations for treatment after hormonal therapy (first second-line modality) inmetastatic CRPC20.14 Recommendations for cytotoxic treatment and pre/post-docetaxel therapy in mCRPC20.15 Recommendations for “non-specific” management of mCRPC20.16 References16316316416421.1708ABBREVIATIONS USED IN THE TE CANCER - UPDATE APRIL 2014

1.INTRODUCTION1.1IntroductionThe European Association of Urology (EAU) Guidelines Group for Prostate Cancer have prepared thisguidelines document to assist medical professionals assess the evidence-based management of prostatecancer (PCa). The multidisciplinary guidelines panel includes urologists, radiation oncologists, a medicaloncologist, a radiologist and a pathologist.It must be emphasised that clinical guidelines present the best evidence available but followingthe recommendations will not necessarily result in the best outcome. Guidelines can never replace clinicalexpertise when making treatment decisions for individual patients, also taking individual circumstances andpatient preferences into account.1.2Data identification and evidence sourcesThe recommendations provided in the current guidelines are based on literature searches performed bythe panel members. A systemic literature search was performed to assess the evidence for the medicalmanagement of men with CRPC (Chapter 20 - Castration-resistant PCa). Key findings are presented in the text.For this review, Embase, Medline on the Ovid platform and the Cochrane Central Register of Controlled Trialswere searched without time limitations. Search cut-off date was October 2013. A total of 1158 records wereidentified and after deduplication and a structured data selection, nine studies were included in the review.Standard procedure for EAU publications includes an annual assessment of newly published literaturein this field, guiding future updates.1.3Level of evidence and grade of recommendationReferences in the text have been assessed according to their level of scientific evidence (Table 1.1), andguideline recommendations have been graded (Table 1.2) according to the Oxford Centre for Evidence-basedMedicine Levels of Evidence (1). Grading aims to provide transparency between the underlying evidence andthe recommendation given.Table 1.1: Level of evidence*Level1a1b2a2b3Type of evidenceEvidence obtained from meta-analysis of randomised trialsEvidence obtained from at least one randomised trialEvidence obtained from one well-designed controlled study without randomisationEvidence obtained from at least one other type of well-designed quasi-experimental studyEvidence obtained from well-designed non-experimental studies, such as comparative studies,correlation studies and case reports4Evidence obtained from expert committee reports or opinions or clinical experience of respectedauthorities*Modified from (1).When recommendations are graded, the link between the level of evidence and grade of recommendationis not directly linear. Availability of RCTs may not translate into a grade A recommendation when there aremethodological limitations or disparity in published results.Absence of high-level evidence does not necessarily preclude a grade A recommendation, if thereis overwhelming clinical experience and consensus. There may be exceptions where corroborating studiescannot be performed, perhaps for ethical or other reasons, and unequivocal recommendations are consideredhelpful. Whenever this occurs, it is indicated in the text as “upgraded based on panel consensus”. The qualityof the underlying scientific evidence must be balanced against benefits and burdens, values and preferencesand cost when a grade is assigned (2-4).The EAU Guidelines Office does not perform cost assessments, nor can it address local/national preferencessystematically. The expert panels include this information whenever it is available.PROSTATE CANCER - UPDATE APRIL 20149

Table 1.2: Grade of recommendation*GradeANature of recommendationsBased on clinical studies of good quality and consistency addressing the specific recommendationsand including at least one randomised trialBBased on well-conducted clinical studies, but without randomised clinical trialsCMade despite the absence of directly applicable clinical studies of good quality*Modified from (1).1.4Publication historyThe Prostate Cancer Guidelines were first published in 2001, with partial updates achieved in 2003 and 2007,followed by a full text update in 2009. Also in 2011, 2012 and 2013 a considerable number of sections of thePCa guidelines were revised. For this 2014 publication all chapters have been re-assessed, as detailed below.A quick reference document presenting the main findings of the PCa guidelines is also available,alongside several scientific publications in European Urology (5,6).All documents are available with free access through the EAU website Uroweb: /.For the 2015 PCa Guidelines publication a complete restructuring of the document is envisaged as well asinclusion of data from additional systematic reviews.1.5Summary of updated information1.5.1AcknowledgementThe EAU Prostate Cancer guidelines panel are most grateful for the support and considerable expertiseprovided by Prof.Dr. J-P. Droz, Emeritus Professor of Medical Oncology (Lyon, France) for the topic of‘Management of PCa in senior adults’ (Chapter 14). As a leading expert in this field, and prominent member ofthe International Society of Geriatric Oncology, his contribution has been invaluable.For this 2014 update, the following changes should be noted:Chapter 2: BackgroundThe literature has been revised.Chapter 3: ClassificationThe literature has been updated and the text has been expanded (definitions and d’Amico classification).Chapter 4: Risk factors and chemopreventionThe literature has been revised and additional information included on 5-alpha-reductase inhibitors (5-ARIs).Chapter 5: Screening and early detectionThe literature has been revised.Chapter 6: DiagnosisThe literature has been revised and information on the role of imaging as a diagnostic tool has been added. Anumber of recommendations have been included.Chapter 7: StagingThis chapter has been restructured, and additional information on the use the use of MRI as a diagnostic toolhas been added.Chapter 8: Treatment: deferred treatment (active surveillance/watchful waiting)The literature has been revised and the text has been restructured.Chapter 9: Treatment Radical ProstatectomyNew information has been included, in particular in sections 9.4.1 - 9.4.3.Chapter 10: Treatment: definitive radiotherapyThe literature has been revised and an overview table listing the three randomized trials for adjuvant radiationtherapy after radical prostatectomy has been added.Chapter 11: Options other than surgery and radiotherapy for the primary treatment of localised PCaThe literature has been revisited and the text was restructured. A number of new recommendations wereadded.Chapter 12: Hormonal therapy; rationale and available drugsThe literature has been revised.Chapter 13: Metastatic PCa - Hormonal therapyThe literature has been revised.10PROSTATE CANCER - UPDATE APRIL 2014

Chapter 14: Management of PCa in senior adultsThis section was completely revised.Chapter 15: Quality of life of patients with localised PCaThe literature has been revised and the text has been condensed. A number of new recommendations wereadded.Chapter 17: Follow-up after treatment with curative intentThe literature has been revised and the text was condensed.Chapter 18: Follow-up after hormonal treatmentThe literature has been revised and the text was condensed.Chapter 19: Treatment of biochemical failure after curative intentThe literature has been revised and the text has been restructured. A number of new recommendations wereadded.Chapter 20: Castration-resistant PCa (CRPC)The literature has been updated and the text has been completely restructured. Table 20.3 presents anoverview of the review done to assess the medical management of men with CRPC. A treatment flowchart isprovided and a number of new recommendations were added.1.6Potential conflict of interest statementThe expert panel have submitted potential conflict of interest statements which can be viewed on the EAUwebsite: /.1.7References1.Oxford Centre for Evidence-Based Medicine Levels of Evidence (May 2009). Produced by BobPhillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes sinceNovember 1998. Updated by Jeremy Howick March 2009.http://www.cebm.net/index.aspx?o 1025 [Access date February 2014]Atkins D, Best D, Briss PA, et al. GRADE Working Group. Grading quality of evidence and strength ofrecommendations.BMJ 2004 med/15205295Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidenceand strength of recommendations. BMJ 2008 bmed/18436948Guyatt GH, Oxman AD, Kunz R, et al. GRADE Working Group. Going from evidence torecommendations. BMJ 2008 36/7652/1049.longHeidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. part 1: screening,diagnosis, and local treatment with curative intent-update 2013. Eur Urol 2014 d/24207135Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU Guidelines on Prostate Cancer. Part II: Treatment ofAdvanced, Relapsing, and Castration-Resistant Prostate Cancer. Eur Urol 2014 d/243215022.3.4.5.6.2.BACKGROUNDProstate cancer is the most common cancer in elderly males in Europe. It is a major health concern, especiallyin developed countries with their greater proportion of elderly men in the general population. The incidence ishighest in Northern and Western Europe ( 200 per 100,000), while rates in Eastern and Southern Europe haveshowed a continuous increase (1). There is still a survival difference between men diagnosed in Eastern Europeand those in the rest of Europe (2). Overall, during the last decade, the 5-year relative survival percentages forprostate cancer steadily increased from 73.4% in 1999-2001 to 83.4% in 2005-2007 (2).With the expected increases in the life expectancy of men and in the incidence of prostate cancer, thedisease’s economic burden in Europe is also expected to increase substantially. It is estimated that the totaleconomic costs of prostate cancer in Europe exceed 8.43 billion (3), with a high proportion of the costs ofprostate cancer care occurring in the first year after diagnosis. In European countries with available data (UK,Germany, France, Italy, Spain, the Netherlands), this amounted to 106.7-179.0 million for all prostate cancerpatients diagnosed in 2006.PROSTATE CANCER - UPDATE APRIL 201411

2.1References1.Arnold M, Karim-Kos HE, Coebergh JW, et al. Recent trends in incidence of five common cancers in26 European countries since 1988: Analysis of the European Cancer Observatory. Eur J Cancer. 2013Oct 8. pii: S0959-8049(13)00842-3. doi: 10.1016/j.ejca.2013.09.002. [Epub ahead of e Angelis R, Sant M, Coleman MP, et al; EUROCARE-5 Working Group. Cancer survival in Europe1999-2007 by country and age: results of EUROCARE--5-a population-based study. Lancet Oncol2014 Luengo-Fernandez R, Leal J, Gray A, et al. Economic burden of cancer across the European Union: apopulation-based cost analysis. Lancet Oncol 2013 med/241316142.3.3.CLASSIFICATIONThe 2009 TNM (Tumour Node Metastasis) classification for PCa is shown in Table 3.1 (1).Table 3.1: Tumour Node Metastasis (TNM) classification of PCaT - Primary tumourTXPrimary tumour cannot be assessedT0No evidence of primary tumourT1Clinically inapparent tumour not palpable or visible by imagingT1aTumour incidental histological finding in 5% or less of tissue resectedT1bTumour incidental histological finding in more than 5% of tissue resectedT1c umour identified by needle biopsy (e.g. because of elevated prostate-specific antigen [PSA]Tlevel)Tumour confined within the prostate1T2T2aTumour involves one half of one lobe or lessT2bTumour involves more than half of one lobe, but not both lobesT2cTumour involves both lobesTumour extends through the prostatic capsule2T3T4T3a xtracapsular extension (unilateral or bilateral) including microscopic bladder neckEinvolvementT3bTumour invades seminal vesicle(s) umour is fixed or invades adjacent structures other than seminal vesicles: external sphincter,Trectum, levator muscles, and/or pelvic wallN - Regional lymph nodes3NXRegional lymph nodes cannot be assessedN0No regional lymph node metastasisN1Regional lymph node metastasisM - Distant metastasis4MXDistant metastasis cannot be assessedM0No distant metastasis12PROSTATE CANCER - UPDATE APRIL 2014

M1Distant metastasisM1aNon-regional lymph node(s)M1bBone(s)M1cOther site(s)1 umour found in one or both lobes by needle biopsy, but not palpable or visible by imaging, is classified asTT1c.2 Invasion into the prostatic apex, or into (but not beyond) the prostate capsule, is not classified as pT3, but aspT2.3 Metastasis no larger than 0.2 cm can be designated pN1 mi.4 When more than one site of metastasis is present, the most advanced category should be used.Table 3.2: Defined risk groups of localized prostate cancerVery low-riskD’Amico (2)NCCN (3)CAPRAscore (4)EAU (5)Low-riskPSA 10 ng/mLand GS 7 andcT1-2acT1c, GS 7, PSA PSA 10 ng/mL, 10 ng/mL, PSAD GS 7, cT1-2a 0.15, 3 positivebiopsies 3PSA 10 ng/mL,GS 7, cT1cIntermediate-riskHigh-riskLocallyadvancedPSA 10-20 ng/mL PSA 20 ng/or GS 7, or cT2b mL, or GS 7, orcT2c-3acT3b-4PSA 10-20 ng/mL, PSA 20 ng/mL,or GS 7, or cT3aor GS 7, orcT2b-2c3-56-10PSA 10-20 ng/mL, PSA 20 ng/mL, GS 8-10 or or GS 7, or cT3acT2b-2cIn these guidelines, the D’Amico risk-group classification is used to define high-risk PCa (high-risk or locallyadvanced PCa comprise stages T3 and T4). Low-risk, versus high-risk PCa is based on PSA findings only, or onGleason score only.3.1References1.Sobin LH, Gospodariwicz M, Wittekind C (eds). TNM classification of malignant tumors. UICCInternational Union Against Cancer. 7th edn. Wiley-Blackwell, 2009 Dec; pp. 243-248.http://www.uicc.org/tnm/Boorjian SA, Karnes RJ, Rangel LJ, et al. Mayo Clinic validation of the D’amico risk groupclassification for predicting survival following radical prostatectomy. J Urol 2008 med/18289596National Comprehensive Cancer Network (NCCN) clinical practice guidelines in Oncology.Prostate Cancer, version I.2014. NCCN.org [Access date March 2014].Cooperberg MR, Pasta DJ, Elkin EP, et al. The University of California, San Francisco Cancer of theProstate Risk Assessment score: a straightforward and reliable preoperative predictor of diseaserecurrence after radical prostatectomy. J Urol 2005 Jun;173(6):1938-42. Erratum in: J Urol bmed/15879786Heidenreich A1, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. part 1: screening,diagnosis, and local treatment with curative intent-update 2013. Eur Urol 2014 /242071352.3.4.5.PROSTATE CANCER - UPDATE APRIL 201413

4.RISK FACTORS AND CHEMOPREVENTIONThe factors that determine the risk of developing clinical prostate cancer (PCa) are not well known, although afew have been identified. There are three well-established risk factors for PCa: increasing age; ethnic origin; heredity.If one first-line relative has PCa, the r

7.1.3 Multiparametric MRI 32 7.2 N-staging 35 7.2.1 PSA level and biopsy findings 35 7.2.2 Nodal staging using CT and MRI 35 7.2.3 Lymphadenectomy 36 7.3 M-staging 36 7.3.1 Alkaline phosphatase 36 7.3.2 Bone scan 36 7.3.3 New imaging modalities 37 7.4 Guidelines for the diagnosis and staging of PCa 38 7.5 References 39 8.