Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Abstract

The age-standardised incidence of prostate cancer in the European Union (EU) was 65/100 000 men in 2008, ranging in different member states from 18 per 100 000 in Greece to 126 per 100 000 in Ireland depending predominantly on the prevalence of prostate-specific antigen (PSA) screening [1.OECD/European Union Cancer Incidence’, in Health at a Glance: Europe 2010. OECD Publishing, 2010http://dx.doi.org/10.1787/9789264090316–18-enGoogle Scholar]. Age-standardised mortality rates are predominantly between 15 and 37 per 100 000 [2.Bray F. Lortet-Tieulent J. Ferlay J. et al.Prostate cancer incidence and mortality trends in 37 European countries: an overview.Eur J Cancer. 2010; 46: 3040-3052doi:10.1016/j.ejca.2010.09.013Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar]. It is the most common cancer in men with an estimated 382 000 cases occurring during 2008 in Europe. The mortality in the EU is 30.6/100 000 men/year and almost 90 000 deaths from prostate cancer occurred in Europe in 2008, making it the third most common cancer death in men [2.Bray F. Lortet-Tieulent J. Ferlay J. et al.Prostate cancer incidence and mortality trends in 37 European countries: an overview.Eur J Cancer. 2010; 46: 3040-3052doi:10.1016/j.ejca.2010.09.013Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar]. Subclinical prostate cancer is common in men >50 years. Population-based screening of healthy men between 55 and 69 years old using PSA testing reduces prostate cancer mortality by an estimated 20%. Six trials and a meta-analysis have been published evaluating the role of screening, of which three were originally designed to evaluate prostate cancer mortality [3.Schroder F.H. Hugosson J. Roobol M.J. et al.Prostate-cancer mortality at 11 years of follow-up.N Engl J Med. 2012; 366: 981-990doi:10.1056/NEJMoa1113135Crossref PubMed Scopus (1018) Google Scholar, 4.Andriole G.L. Crawford E.D. Grubb III, R.L. et al.Prostate cancer screening in the randomized prostate, lung, colorectal and ovarian cancer screening trial: mortality results after 13 years of follow-up.J Natl Cancer Inst. 2012; 104: 125-132doi:10.1093/jnci/djr500Crossref PubMed Scopus (833) Google Scholar]. After a median follow-up of 11 years the European screening trial demonstrated a relative reduction in the risk of prostate cancer mortality of 21% for the screened population (29% if adjusted for non-compliance). However, 1055 men needed to be invited for screening and 37 patients needed to be treated to prevent one patient from dying from prostate cancer. At 11 years follow-up, there was no reduction in overall mortality between the screened and non-screened population. In a further evaluation of the European screening study, it was shown that the benefit of screening was diminished by loss of quality-adjusted life years [5.Heijnsdijk E.A. Wever E.M. Auvinen A. et al.Quality-of-life effects of prostate-specific antigen screening.N Engl J Med. 2012; 367: 595-605doi:10.1056/NEJMoa1201637Crossref PubMed Scopus (311) Google Scholar]. Recommendation: population-based screening for prostate cancer reduces prostate cancer mortality at the expense of a high over-treatment rate [I, B]. Based on the digital rectal examination (DRE), 23%–45% of prostate cancers are missed and if prostate cancer is diagnosed on the basis of DRE ∼50% are locally advanced tumours. A DRE is not a very sensitive and reproducible investigation and has a low positive predictive value (PPV), but DRE in combination with serum PSA should be done in an appropriately counselled patient in whom there is clinical suspicion of prostate cancer or in those who wish further investigation for the presence of prostate cancer. A number of factors improve the predictive power of PSA level in identifying cancer [6.Thompson I.M. Ankerst D.P. Chi C. et al.Assessing prostate cancer risk: results from the prostate cancer prevention trial.J Natl Cancer Inst. 2006; 98: 529-534doi:10.1093/jnci/djj131Crossref PubMed Scopus (754) Google Scholar]. A new biomarker for prostate cancer has recently been introduced, the urinary PCA3 test. Some studies have shown that this test was superior to total PSA [7.Hessels D. van Gils M.P. van Hooij O. et al.Predictive value of PCA3 in urinary sediments in determining clinic-pathologic characteristics of prostate cancer.Prostate. 2010; 70: 10-16doi:10.1002/pros.21032Crossref PubMed Scopus (142) Google Scholar], and the PCA3 test is now registered for the indication to perform a re-biopsy. Recommendation: the decision whether or not to have a prostate biopsy should be made in the light of DRE findings, prostate size, ethnicity, age, comorbidities, family history, patient values and history of previous biopsy, as well as on the PSA level. In case of an elevated PSA and negative initial biopsies, a PCA3 test can be carried out to determine whether re-biopsies are indicated [II, B]. Sampling error is inherent in the process of prostate biopsies. Most of the aggressive tumours are located in the peripheral zone and therefore, at least six biopsies (three from each lobe) should be taken from this zone. However, 20%–35% of the tumours will be missed if only these areas are sampled; therefore, the anterolateral area of the prostate should be sampled as well. A recent meta-analysis demonstrated an improvement in the prostate cancer detection rate of 25% if 12 biopsies were taken instead of six, especially if the prostate volume exceeded 40 cc [8.Scattoni V. Zlotta A. Montironi R. et al.Extended and saturation prostatic biopsy in the diagnosis and characterisation of prostate cancer: a critical analysis of the literature.Eur Urol. 2007; 52: 1309-1322doi:10.1016/j.eururo.2007.08.006Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar]. Initial saturation biopsies were not of any advantage. Recommendation: a prostate biopsy should be carried out under antibiotic cover with transrectal ultrasound (TRUS) guidance, and a minimum of eight cores obtained [II, A]. The most dominant Gleason pattern and the pattern with the highest Gleason grade determine the Gleason score [9.Epstein J.I. Allsbrook Jr, W.C. Amin M.B. et al.The 2005 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma.Am J Surg Pathol. 2005; 29: 1228-1242doi:10.1097/01.pas.0000173646.99337.b1Crossref PubMed Scopus (2160) Google Scholar] because tumours with a tertiary Gleason grade 4 or 5 behave more like a Gleason score 3+4 or 3+5 than the sum of the two most dominant patterns. Reporting of Gleason grades 1 and 2 should be avoided on biopsies. The extent of tumour in biopsies correlates with the pathological stage, tumour volume in the prostate and chance of positive margins. Recommendation: the maximum length of cancer involvement of each core and the commonest and the worst Gleason grades should be reported in the biopsies, as they help predict pathological stage and progression-free survival [III, A]. General health and co-morbidities should be assessed. Patients who are not considered suitable for treatment with curative intent due to poor general health do not normally require staging investigations. Clinical T stage (Table 1) should be evaluated by DRE supplemented, when clinically relevant, with magnetic resonance imaging (MRI). Experience in the interpretation of the MRI is essential, and contrast-enhanced MRI and 3 Tesla MRI can improve sensitivity of local staging of the prostate cancer. Preoperative MRI can help to identify those patients in whom a nerve-sparing radical prostatectomy can be carried out. Clinically localised prostate cancer should be categorised as low-, intermediate- or high-risk and a widely used classification (Table 2) identifies those with respectively a 90%, 60% and 30% probability of biochemical control at 5 years [10.D'Amico A.V. Whittington R. Malkowicz S.B. et al.Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer.JAMA. 1998; 280: 969-974doi:10.1001/jama.280.11.969Crossref PubMed Scopus (3686) Google Scholar]. Other prognostic nomograms may help to inform patient choice [11.Shariat S.F. Karakiewicz P.I. Roehrborn C.G. et al.An updated catalog of prostate cancer predictive tools.Cancer. 2008; 113 (Review): 3075-3099doi:10.1002/cncr.23908Crossref PubMed Scopus (226) Google Scholar].Table 1Prostate cancer staging summary (Seventh Edition of the AJCC/UICC Cancer Staging Manual)T1Not palpable or visible T1a≤5% T1b>5% T1cNeedle biopsyT2Confined within prostate T2a≤half of 1 lobe T2b>half of 1 lobe T2cBoth lobesT3aThrough prostatic capsuleT3bInvading seminal vesicleT4Fixed or invading adjacent structureN1Regional nodesM1aNon-regional nodesM1bBoneM1cOther sitesEdge SB, Byrd DR, Compton CC, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY.: Springer, 2010.Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springer.com. Open table in a new tab Table 2Localised prostate cancer: risk groups (NCCN) [3.Schroder F.H. Hugosson J. Roobol M.J. et al.Prostate-cancer mortality at 11 years of follow-up.N Engl J Med. 2012; 366: 981-990doi:10.1056/NEJMoa1113135Crossref PubMed Scopus (1018) Google Scholar]1. Low-risk: all of T1 or T2a, Gleason <7 PSA <102. Intermediate-risk: between low and high3. High-risk: any of T3 or T4, Gleason >7 PSA >20 Open table in a new tab Edge SB, Byrd DR, Compton CC, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY.: Springer, 2010. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springer.com. Recommendation: localised disease should be classified as low-, intermediate- or high-risk as a guide to staging and therapy [III, A]. Low-risk: within the low-risk category, higher percent positive cores, maximum length of cancer involvement, PSA density and lower free/total PSA ratio are associated with the risk of understaging compared with findings after prostatectomy [12.Suardi N. Capitanio U. Chun F.K. et al.Currently used criteria for active surveillance in men with low-risk prostate cancer. An analysis of pathologic features.Cancer. 2008; 113: 2068-2072doi:10.1002/cncr.23827Crossref PubMed Scopus (93) Google Scholar]. Recommendation: bone imaging is not routinely recommended for men with low-risk disease [II, B]. Intermediate-risk: a study of criteria for staging with isotope bone scan [13.O'Sullivan J. Norman A.R. Cook G.J. et al.Broadening the criteria for avoiding staging bone scans in prostate cancer: a retrospective study of patients at the Royal Marsden Hospital.BJU Int. 2003; 92: 685-689doi:10.1046/j.1464-410X.2003.04480.xCrossref PubMed Scopus (50) Google Scholar] found that unless the primary Gleason grade was at least 4, of men with Gleason <8, PSA <20 and stage <T4 the bone scans were positive in only 1% (95% CI 0.3% to 4%). The general guidelines suggest that bone scintigraphy should be considered if bone metastases are suspected clinically, if the Gleason score is 4+3 or serum PSA is >10 ng/ml [13.O'Sullivan J. Norman A.R. Cook G.J. et al.Broadening the criteria for avoiding staging bone scans in prostate cancer: a retrospective study of patients at the Royal Marsden Hospital.BJU Int. 2003; 92: 685-689doi:10.1046/j.1464-410X.2003.04480.xCrossref PubMed Scopus (50) Google Scholar]. Recommendation: the sensitivity of pelvic imaging is lower than surgical lymph node staging, but those patients with intermediate-risk disease to be treated with radical radiotherapy (RT) should ideally have pelvic MRI. Intermediate-risk patients having a radical prostatectomy should have discussion about risk/benefit of lymph node dissection based on nomogram estimates [III, B]. Recommendation: For high-risk disease, bone scintigraphy should be carried out and an MRI of the pelvis should be considered [IV, B]. There is no consensus regarding optimum management of localised disease. Options include watchful waiting, active surveillance, open, laparoscopic or robotic-assisted radical prostatectomy, external beam RT, and brachytherapy. Cryotherapy, high-intensity focused ultrasound (HIFU) and focal therapy are not recommended as standard initial treatment, but rather are regarded as options in development. Patients should be informed of the potential benefits and harms of the different options. Given the range of treatment options and their side-effects, men should have the opportunity to consult with both the urologist and the radiation oncologist. Men should be warned that treatment for prostate cancer may cause sexual dysfunction, infertility, rectal/voiding problems and incontinence. One randomised, controlled trial, PIVOT, has compared radical prostatectomy and watchful waiting in men with PSA-detected cancers [14.Wilt T.J. Brawer M.K. Jones K.M. et al.Radical prostatectomy versus observation for localized prostate cancer.N Engl J Med. 2012; 367: 203-213doi:10.1056/NEJMoa1113162Crossref PubMed Scopus (1467) Google Scholar]. In the low-risk subgroup of 296 men, the risk of death from prostate cancer was <3% at 12 years, with no significant benefit of surgery. Indeed, the trend both in terms of prostate cancer-specific mortality [hazard ratio (HR) 1.48; 95% confidence interval (CI): 0.42–5.24)] and overall mortality (HR 1.15; 95% CI: 0.80–1.66), favoured watchful waiting rather than surgery. The Scandinavian Prostate Cancer Group Study 4 was the first randomised, controlled trial comparing radical prostatectomy versus watchful waiting [15.Bill-Axelson A. Holmberg L. Filén F. et al.Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial.J Natl Cancer Inst. 2008; 100: 1144-1154doi:10.1093/jnci/djn255Crossref PubMed Scopus (489) Google Scholar]. Eligible patients were <75 years and had newly diagnosed clinically localised prostate cancer with a negative bone scan, a PSA of <50 ng/ml and a life expectancy of ≥10 years. They were recruited in Scandinavia during the early 1990s, at a time when PSA testing was not routinely carried out, and the results may not be applicable to screen-detected cancers. Many of the 695 patients had high-risk disease, with 18% having a PSA >20 ng/ml and 13% a Gleason score of 8–10. With 11 years median follow-up, 137 men in the surgery group and 156 in the watchful waiting group had died (P = 0.09). The actuarial risk of death from prostate cancer at 12 years was 12.5% for surgery compared with 17.9% for watchful waiting (P = 0.03). Put another way, the number needed to treat (NNT) to avoid one death from prostate cancer was 18.5. This beneficial impact of surgery on prostate cancer mortality was restricted to men aged ≤65 years. Radical prostatectomy increased the rate of erectile dysfunction by 35% (80% versus 45%), and urinary leakage by 28% (49% versus 21%), in comparison with watchful waiting [16.Steineck G. Helgesen F. Adolfsson J. et al.Quality of life after radical prostatectomy or watchful waiting.N Engl J Med. 2002; 347: 790-796doi:10.1056/NEJMoa021483Crossref PubMed Scopus (617) Google Scholar] but these toxicity rates may not be generalisable to high-volume surgical centres and did not appear to lead to a worse overall quality of life compared with the watchful waiting group [17.Johansson E. Bill-Axelson A. Holmberg L. et al.Time, symptom burden, androgen deprivation, and self-assessed quality of life after radical prostatectomy or watchful waiting: the randomized Scandinavian prostate cancer group study number 4 (SPCG-4) clinical trial.Eur Urol. 2009; 55: 422-430doi:10.1016/j.eururo.2008.08.054Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar]. Recommendation: in men with low-risk disease, no benefit for active treatment has been demonstrated in overall survival (OS). Observation should be discussed and should be an option for these patients. Options for patients with intermediate-risk prostate cancer include radical prostatectomy, external beam RT plus androgen deprivation therapy (ADT) or high-dose rate brachytherapy. Watchful waiting with delayed hormone therapy is an option for men who are not suitable for radical treatment [I, A]. The standard radical approach is based on RT, though prostatectomy with extended lymphadenectomy can be an option in highly selected cases. For high-risk cancers there is abundant level I evidence that the combination of RT and ADT leads to significantly higher OS rates when compared with RT alone [18.Bolla M. Van Tienhoven G. Warde P. et al.External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study.Lancet Oncol. 2010; 11: 1066-1073doi:10.1016/S1470-2045(10)70223-0Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar] and to ADT alone [19.Widmark A. Klepp O. Solberg A. et al.Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer: an open randomised phase III trial.Lancet. 2009; 373: 301-308doi:10.1016/S0140-6736(08)61815-2Abstract Full Text Full Text PDF PubMed Scopus (691) Google Scholar, 20.Warde P. Mason M. Ding K. et al.Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial.Lancet. 2011; 378: 2104-2111doi:10.1016/S0140-6736(11)61095-7Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar]. Hormone therapy alone is not recommended and the case for adding radical local treatment for men with locally advanced disease is based on two randomised, controlled trials. The SPCG-7 trial, in which 875 men (T2–3; PSA <70 ng/ml; N0; M0) received 3 months of combined androgen blockade (CAB) followed by flutamide monotherapy, and were randomised whether or not to receive radical RT to the prostate [19.Widmark A. Klepp O. Solberg A. et al.Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer: an open randomised phase III trial.Lancet. 2009; 373: 301-308doi:10.1016/S0140-6736(08)61815-2Abstract Full Text Full Text PDF PubMed Scopus (691) Google Scholar], showed a beneficial impact of radical RT in terms of cause-specific (11.9% versus 23.9%, P < 0.001), and overall mortality (29.6% versus 39.4%, P = 0.004). The NCIC/MRC trial randomised high-risk patients to either lifelong ADT alone or to ADT plus RT. The addition of RT improved the 7-year survival probability from 66% to 74% (P = 0.003) [20.Warde P. Mason M. Ding K. et al.Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial.Lancet. 2011; 378: 2104-2111doi:10.1016/S0140-6736(11)61095-7Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar]. Watchful waiting with delayed hormone therapy is an option for asymptomatic men who are not suitable for or are unwilling to have radical treatment. Recommendation: high-risk or locally advanced prostate cancer patients should be offered external beam RT plus hormone treatment for at least 2 years. Radical prostatectomy plus extended lymphadenectomy can be considered in highly selected cases [I, B]. In TROG 96–01 [21.Denham J.W. Steigler A. Lamb D.S. et al.Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised controlled trial.Lancet Oncol. 2011; 12: 451-459doi:10.1016/S1470-2045(11)70063-8Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar] 818 men with locally advanced prostate cancer were randomly assigned to RT alone, RT plus 3 months neo-adjuvant and concurrent CAB or RT plus 6 months CAB. Compared with RT alone, the use of 6 months of hormone therapy significantly improved PSA progression (HR 0.57 [0.46–0.72]), prostate-cancer-specific survival (HR 0.49 [0.32–0.74], P = 0.04) and all-cause mortality (HR 0.63 [0.48–0.83]). This result is supported by an American study [22.D'Amico A.V. Manola J. Loffredo M. et al.6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial.JAMA. 2004; 292: 821-827doi:10.1001/jama.292.7.821Crossref PubMed Scopus (717) Google Scholar]. In the RTOG trial 86–10, 456 patients with T2–4 disease received CAB for 2 months before and during RT, or RT alone [23.Roach 3rd, M. Bae K. Speight J. et al.Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610.JCO. 2008; 26: 585-591doi:10.1200/JCO.2007.13.9881Crossref PubMed Scopus (526) Google Scholar]. There was a statistically significant improvement in 10-year prostate cancer-specific mortality (23% versus 36%; P = 0.01) with the addition of hormone therapy. In RTOG 9202 [24.Hanks G.E. Pajak T.F. Porter A. et al.Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92–02.J Clin Oncol. 2003; 21: 3972-3978doi:10.1200/JCO.2003.11.023Crossref PubMed Scopus (656) Google Scholar] 1554 patients received 4 months of neo-adjuvant and concurrent CAB plus radical RT and were randomised to receive an additional 2 years of adjuvant androgen deprivation or not. In an unplanned subgroup analysis, the addition of adjuvant therapy improved OS in those with Gleason score 8–10 (81.0% versus 70.7%, P = 0.044). The EORTC 22961 [25.Bolla M. de Reijke T.M. Van Tienhoven G. et al.Duration of androgen suppression in the treatment of prostate cancer.N Engl J Med. 2009; 360: 2516-2527doi:10.1056/NEJMoa0810095Crossref PubMed Scopus (758) Google Scholar] trial randomised 970 men between 6 months and 36 months of androgen deprivation in addition to radical RT. The 5-year overall mortality for short-term and long-term suppression was 19.0% and 15.2%, respectively. Men starting luteinizing hormone-releasing hormone (LHRH) agonist therapy should be informed that regular exercise may be helpful to reduce fatigue and improve quality of life [26.Galvao D.A. Taaffe D.R. Spry N. et al.Combined resistance and aerobic exercise program reverses muscle loss in men undergoing androgen suppression therapy for prostate cancer without bone metastases: a randomized controlled trial.J Clin Oncol. 2010; 28: 340-347doi:10.1200/JCO.2009.23.2488Crossref PubMed Scopus (474) Google Scholar]. Recommendation: neoadjuvant LHRH agonist therapy for 4–6 months is recommended for men receiving radical RT for high-risk disease, and this should be considered also for men with intermediate-risk disease. Adjuvant hormonal therapy for 2 to 3 years is recommended for men receiving neo-adjuvant hormonal therapy and radical RT who are at high risk of prostate cancer mortality [I, A]. Bicalutamide 150 mg daily was evaluated for locally advanced disease in a subgroup analysis of one trial but was compared with placebo rather than an LHRH agonist. It can be considered as an alternative adjuvant to LHRH agonist therapy in men who place a high value on retaining sexual function during treatment [27.McLeod D.G. Iversen P. See W.A. et al.Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer.BJU Int. 2006; 97: 247-254doi:10.1111/j.1464-410X.2005.06051.xCrossref PubMed Scopus (246) Google Scholar]. Men starting long-term (>6 months) bicalutamide should consider prophylactic RT to both breast buds within the first month of treatment or use of tamoxifen [28.Kunath F. Keck B. Antes G. et al.Tamoxifen for the management of breast events induced by non-steroidal antiandrogens in patients with prostate cancer: a systematic review.BMC Med. 2012; 10: 96doi:10.1186/1741-7015-10-96Crossref Scopus (23) Google Scholar]. Recommendation: adjuvant hormone therapy can be based on bicalutamide 150 mg daily rather than an LHRH agonist in men who prefer its toxicity profile and understand that the data on outcomes are limited [II, C]. Three randomised trials, EORTC 22911, SWOG 8794 and ARO 96–02, have compared post-op RT versus observation after radical prostatectomy in patients with locally advanced disease, but they did not have sensitive PSA monitoring and early RT salvage in the control arms, and current trials are addressing this. Each trial has shown an advantage to postoperative RT in terms of PSA failure, but the impact on OS is less clear. SWOG 8794 included 425 men and reported that OS was improved with adjuvant radiation (HR 0.72; 95% CI: 0.55, 0.96; P = 0.023). However, EORTC 22911, which included 1005 men [29.Bolla M. van Poppel H. Tombal B. et al.Postoperative radiotherapy after radical prostatectomy for high risk prostate cancer: long term results of a randomized controlled trial (EORTC trial 22911).Lancet. 2012; 380: 2018-2027doi:10.1016/S0140-6736(12)61253-7Abstract Full Text Full Text PDF PubMed Scopus (644) Google Scholar] found no OS benefit (10-year OS 76.9% for adjuvant radiation versus 80.7% for observation). Radiotherapy to the prostate bed has a risk of adverse effects on urinary, bowel and sexual function. For example, the SWOG 8794 trial [30.Thompson I.M. Tangen C.M. Paradelo J. et al.Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term follow up of a randomized clinical trial.J Urol. 2009; 181: 956-962doi:10.1016/j.juro.2008.11.032Crossref PubMed Scopus (1029) Google Scholar] reported urethral strictures in 17.8% of men randomised to adjuvant RT versus 9.5% in those randomised to observation [relative risk (RR) 1.9; 95% CI: 1.1–3.1; P = 0.02]. Total urinary incontinence was seen in 6.5% versus 2.8% (RR 2.3; 95% CI: 0.9–5.9; P = 0.11), and rectal complications in 3.3% versus 0% (P = 0.02). Recommendation: immediate postoperative RT after radical prostatectomy can be considered but is not routinely recommended. Adjuvant hormone therapy after radical prostatectomy is not recommended. Patients with positive surgical margins or extracapsular extension after radical prostatectomy should be informed about the pros and cons of adjuvant RT [I, C]. In patients with a biochemical relapse following radical prostatectomy, biopsy of the prostatic bed should not be carried out. There are no randomised trials comparing salvage RT versus observation in men with PSA failure after radical prostatectomy. A retrospective analysis of men with PSA failure after surgery compared the long-term outcome of those managed by observation (n = 397) with that of those managed by salvage RT (n = 160) [31.Trock B.J. Han M. Freedland S.J. et al.Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy.JAMA. 2008; 299: 2760-2769doi:10.1001/jama.299.23.2760Crossref PubMed Scopus (543) Google Scholar]. A pooled analysis of trials of intermittent androgen deprivation (IAD) published up till September 2012 was based on a total of 5508 patients and did not reveal any significant differences in time-to-event outcomes [HR for PFS 0.96 (95% CI: 0.76–1.20), HR for OS 1.02 (95% CI: 0.94–1.11)] [32.Niraula S. Le L.W. Tannock I.F. et al.Treatment of prostate cancer with intermittent versus continuous androgen deprivation: a systematic review of randomized trials.J Clin Oncol. 2013; 31: 2029-2036Crossref PubMed Scopus (89) Google Scholar]. There were 116 deaths from prostate cancer for analysis. Salvage RT was associated with a significant reduction in prostate cancer mortality (HR 0.32; 95% CI: 0.19–0.54; P < 0.001). The reduction in prostate cancer mortality associated with salvage RT was greatest in men with a PSA doubling time of <6 months. Recommendation: following radical prostatectomy patients should have their serum PSA levels monitored with salvage RT to the prostate bed recommended in the event of PSA failure, assuming that there are no metastases. Salvage RT should start early [III, B]. ADT for relapse following radical prostatectomy or RT has been evaluated in retrospective series. For example, Moul et al. [33.Moul J.W. Wu H. Sun L. et al.Early versus delayed hormonal therapy for prostate antigen only recurrence of prostate cancer after radical prostatectomy.J Urol. 2004; 171: 1141-1147doi:10.1097/01.ju.0000113794.34810.d0Crossref PubMed Scopus (224) Google Scholar] observed no survival benefit, although time to clinical metastases was delayed by early androgen treatment. IAD was studied in a randomised trial which included 1386 patients with a PSA at relapse of >3.0 ng/ml more than 1 year after radical or salvage RT with or without neo/adjuvant hormonal therapy (≤1-year duration) for localised prostate cancer. Several quality of life domains were improved. Median OS was 8.8 and 9.1 years for the IAD and continuous androgen deprivation arm, respectively [34.Crook J.M. O'Callaghan C.J. Duncan G. et al.Intermittent androgen suppression for rising PSA level after radiotherapy.N Engl J Med. 2012; 367: 895-903doi:10.1056/NEJMoa1201546Crossref PubMed Scopus (364) Google Scholar]. Recommendation: hormonal therapy is not routinely recommended for men with prostate cancer who have a biochemical relapse unless they have symptomatic local disease progression or proven metastases, or PSA doubling time <3 months. IAD is not inferior to continuous androgen deprivation and has quality-of-life benefits [I, C]. Androgen suppre