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Improving the surgical treatment of high-risk localised or locally advanced

ROGER KIRBY, HEATHER PAYNE, VINCENT KHOO, NOEL CLARKE, MARK BERESFORD, CAROLINE MOORE, PHILIPPA ASLETT, AMIT BAHL, RUPESH BHATT, GREG BOUSTEAD AND SIMON BREWSTER Radiologists, oncologists, urologists and clinical nurse specialists met to evaluate how patients with high-risk localised or locally advanced prostate cancer might be better diagnosed and managed. In the first article in this series, the authors reviewed diagnosis and hormonal and radiotherapy. 1 In this second paper, they Figure 1. 3T MRI showing a tumour (arrowed), which has invaded and evaluate findings from penetrated the capsule of the prostate the meeting relating to provided that the tumour is not fixed to the pelvic wall, or that there is no invasion the surgical management of the urethral sphincter (Figure 1). 2 of the disease and how this The use of neoadjuvant hormones in might be optimised. this setting is uncertain: the majority of studies have shown a reduction in positive margins but no survival advantage, and he management of patients with research is ongoing in this area. 3 Thigh-risk localised or locally advanced disease (stage T3-T4, Nx-N0, M0) is Roger Kirby, Medical Director, The Prostate Centre, ; Heather Payne, Consultant in considered one of the most perplexing areas Clinical Oncology, University College London Hospitals Trust; Vincent Khoo, Consultant in of prostate cancer. Issues relate to the Clinical Oncology, Royal Marsden Hospital, London; Noel Clarke, Consultant Urologist, The classification of the disease and the optimal Christie and Salford Royal Hospitals, Manchester; Mark Beresford, Consultant Oncologist, treatment decisions for these patients. Royal United Hospital, Bath; Caroline Moore, Consultant Urological Surgeon, University Current guidelines do not provide a College London Hospitals Trust; Philippa Aslett, Nurse Specialist, Basingstoke and treatment strategy, which is clearly needed. North Hampshire Hospital; Amit Bahl, Consultant Oncologist, University Hospitals Bristol, Bristol Haematology and Oncology Centre; Rupesh Bhatt, Consultant Urological Surgeon, RADICAL University Hospitals Birmingham, New Queen Elizabeth Hospital, Birmingham; Greg Boustead, There is no consensus on the optimal Consultant Urological Surgeon, Lister Hospital, Stevenage; Simon Brewster, Consultant treatment of men with high-risk prostate Urological Surgeon, Oxford University Hospitals cancer; radical prostatectomy is an option

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Ghavamian et al . reported the combined % (95% CI) approach of orchiectomy (within 3 months 5 years 10 years 15 years of radical prostatectomy) plus or minus radical prostatectomy/pelvic Death from any cause 4.9 (4.2–5.7) 15.4 (13.2–17.7) 33 (17.3–48.8) lymphadenectomy in a series of patients Low risk 2.8 (1.6–4) 8.4 (4.9–11.9) 19 (4.2–33.7) with pTxN+ treated between 1966 and 1995. 4 Intermediate risk 5.4 (4.3–6.5) 12.6 (9.9–15.3) 18.1 (12.4–23.7) This matched-pair study reported an overall High risk 6 (4.5–7.5) 21.6 (16.2–27.1) 41.9 (21.2–62.6) survival advantage at 10 years for the Death from prostate 1.3 (0.9–1.9) 6.6 (4.9–8.2) 20 (4.5–35.4) combined treatment approach (66% versus cancer 28%; p<0.001) as well as for cause-specific Low risk 0.4 (0–0.8) 2.2 (0–4.8) 8.9 (0–22.2) survival (79% versus 39%). However, it is Intermediate risk 0.8 (0.4–1.3) 3.6 (2.1–5.2) 5.1 (1.8–8.4) important to be cautious in interpreting non- High risk 2.7 (1.6–4.3) 15.4 (10.2–20.6) 29 (9.6–48.4) randomised case series data of this type. Table 1. Cumulative incidence of death in men treated with radical prostatectomy. Radical prostatectomy has been compared to Reproduced with permission from Røder et al. BJU Int 2014;113:541–7 9 observation in a randomised study of men with early prostate cancer (predominantly T2) Additional support for the use of radical prostate cancer death at 8 years for and shown to reduce disease-specific prostatectomy in high-risk prostate cancer low-, intermediate- and high-risk patients mortality, overall mortality and the risk of patients comes from the Cancer of the was 0, 4.5 and 9.5%, respectively, for metastases and local progression for up to Prostate Strategic Urologic Research radiotherapy patients, and 0, 1.9 and 3.8%, 10 years. 5 This contrasts with the lack of Endeavor (CAPSURE) registry of 7538 respectively, for surgery patients. Multivariate benefit at 12 years reported by Wilt et al., men. 10 Results from the study indicated Cox regression analysis showed that the most where a reduction in all-cause mortality was that radical prostatectomy was associated significant variable associated with metastatic reported only for men with a PSA >10ng/ml with a significant and substantial reduction progression was risk group (high versus lower and possibly for those with low- or high-risk in mortality relative to radiation therapy risk group; p<0.0005) followed by treatment prostate cancer. 6 and to androgen deprivation therapy as (surgery versus radiotherapy; p<0.001). monotherapy. The absolute differences Again, the difference in case mix needs to be between prostatectomy and radiation Spahn et al. examined pre-treatment recognised in the two randomised studies: therapy were small for men at low risk outcome predictors in men with PSA cases in the first report were largely clinically but increased substantially for men at >20ng/ml treated with radical prostatectomy detected with proportionally higher stage intermediate and high risk. in a European multi-institute study of 712 disease, while those in the Wilt study were men. 14 The strongest predictor of progression mainly screen detected with a high proportion There have been no randomised studies of and mortality was biopsy Gleason score; a of men with low-risk characteristics. the relative effectiveness of radiotherapy Gleason score ≤7 resulted in a 10-year and surgery in this setting but there prostate-cancer-specific mortality rate The majority of the evidence currently are an increasing number of case series of 5% compared with 35% in men with a available is from published case series, with reports suggesting that surgery can be Gleason score ≥8. Lymph node positivity in all the caveats associated with data of this advantageous. 11,12 Interpretation of these patients with a Gleason score >7 was high type. Single-institute 10-year studies have must be with caution because of the at around 30%. been reported for radical prostatectomy in inevitable problems of case selection men with locally advanced prostate cancer, and stage/grade migration. An example Adjuvant treatment: lymphadenectomy showing that surgery for T3 disease can of such series is the report of the effect Extended lymphadenectomy is being achieve good cancer-specific survival with of radical prostatectomy compared with advocated more widely on the basis of morbidities similar to those reported for cT2 external beam radiotherapy (EBRT) on the increased node-positive detection, although prostate cancer. 7,8 rate of distant metastases in 2380 men the effect in relation to curative benefit with localised disease, in a single-centre remains to be determined. A limited pelvic A large-scale Danish study of radical study by Zelefsky et al .13 The 8-year lymph node dissection (PLND) has a lower prostatectomy conducted in 6489 men probability of freedom from metastatic positive node detection rate than extended with localised prostate cancer, including progression was 97% for radical lymphadenectomy (eLND). A number of 1818 men with high-risk disease, reported prostatectomy patients and 93% for EBRT studies have reported the lymph node good outcomes at 15 years (Table 1). 9 patients. The Kaplan-Meier probability of invasion (LNI) according to the type

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of dissection conducted. Large-scale population-based cohort study that Declaration of interests studies on limited LND report LNI rates examined the benefits of LND in 281 patients All authors received an honorarium from of 2–3.7%, 15–17 which compares with the and matched these against 41 case controls Ipsen for attendance at the advisory board rate of 11–26% in ePLND studies. 18–20 It is who died of their prostate cancer within meeting. H. Payne and G. Boustead act as generally accepted that the eLND provides 10 years. 28 A therapeutic benefit of LND consultants for Ipsen. important staging information, but there was reported in node-negative patients. is no consensus regarding the absolute However, this study exemplifies the problem REFERENCES indications for eLND. 2 of interpreting data of this type because of 1. Payne H, Khoo V, Clarke N, et al . 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