Salvage Cryotherapy. Bernard Malavaud MD, PhD, FEBU Institut Universitaire du Cancer Toulouse (France)

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Urethra protection Argon decompression -40 /-60 C 17G hollow needles Salvage Cryotherapy Ice all TRUS positioning & monitoring temperature monitoring of the rectal wall ernard Malavaud MD, PhD, FEU Institut Universitaire du Cancer Toulouse (France)

EUROPEAN UROLOGY 60 (2011) 411 412 available at www.sciencedirect.com journal homepage: www.europeanurology.com Platinum Priority Editorial Referring to the article published on pp. 405 410 of this issue Radiorecurrent Prostate Cancer: An Emerging and Largely Mismanaged Epidemic J. Stephen Jones * Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Department of Regional Urology, Glickman Urological and Kidney Institute, 9500 Euclid, Desk A100, Cleveland, OH 44120, USA 1990-2000: PSA recurrence in one patient out of three (Phoenix definition) 10% of good pronostic patients, up to 60% in the poor prognostic group etter results (DFSR) since IMRT and adjuvant ADT Grossfeld CAPSURE J.Urol 2002, olla Lancet 2002, Jones, Eur Urol 2011

EUROPEAN UROLOGY 65 (2014) 467 479 available at www.sciencedirect.com journal homepage: www.europeanurology.com PRad: PSA <10, PSAdT>12M, GS<7 and LDR brachytherapy failure Guidelines EAU Guidelines on Prostate Cancer. Part II: Treatment of Advanced, Relapsing, and Castration-Resistant Prostate Cancer Axel Heidenreich a, *,y, Patrick J. astian b, Joaquim ellmunt c, Michel olla d, Steven Joniau e, Theodor van der Kwast f, Malcolm Mason g, Vsevolod Matveev h, Thomas Wiegel i, Filiberto Zattoni j, Nicolas Mottet k,z Table 3 Guidelines on treatment options for prostate-specific antigen relapse following local treatment Recommendations Local recurrences are best treated by salvage RT with 64 66 Gy at a PSA serum level 0.5 ng/ml. Expectant management is an option for patients with presumed local recurrence who are too unfit or unwilling to undergo RT. PSA recurrence indicative of systemic relapse is best treated by early ADT, resulting in decreased frequency of clinical metastases if poor prognostic risk factors such as PSA DT <12 mo or Gleason score 8 10 are present. Luteinising hormone-releasing hormone analogues/antagonists/orchiectomy or bicalutamide 150 mg/d when hormonal therapy is indicated. Local recurrences can be treated with salvage RP in carefully selected patients, who presumably have organ-confined disease, that is, PSA <10 ng/ml, PSA DT >12 mo, low-dose brachytherapy, biopsy Gleason score <7. Cryosurgical ablation of the prostate and interstitial brachytherapy are alternative procedures in patients not suitable for surgery. HIFU may be an alternative option. However, patients must be informed about the experimental nature of this treatment modality due to the short follow-up periods reported. In patients with presumed systemic relapse, ADT may be offered. GR A C Salvage cryotherapy when not suitable for surgery experimental nature of salvage HIFU Heidenreich, Eur Urol 2014

Salvage Therapies for Radiorecurrent Prostate Cancer Kamran Zargar-Shoshtari, Pranav Sharma and Julio Pow-Sang* Radiation Therapy From the Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida Quite a few large series iochemical Recurrence PSA>2 ng/ml above Nadir Repeat Staging Histological Confirmation Local Recurrence and Candidate for Salvage Therapy Systemic Recurrence or Not candidate for Salvage Surgery rachytherapy Cryotherapy HIFU Androgen Deprivation Treatment for Oligometastatic disease Zargar, Urology Practice, 2015

EUROPEAN UROLOGY 60 (2011) 405 410 available at www.sciencedirect.com journal homepage: www.europeanurology.com Single institution London (Ontario) 2nd generation cryo. (1994-2004) 176 radio-recurrent PCa Platinum Priority Prostate Cancer Editorial by J. Stephen Jones on pp. 411 412 of this issue Disease-Free Survival Following Salvage Cryotherapy for iopsy-proven Radio-Recurrent Prostate Cancer Andrew K. Williams a, Carlos H. Martínez a, Chen Lu a, Chee Kwan Ng b, Stephen E. Pautler a, Joseph L. Chin a, * a Departments of Urology and Oncology, University of Western Ontario, London, Ontario, Canada b Department of Urology, Tan Tock Seng Hospital, Singapore EUROPEAN UROLOGY 60 (2011) 405 410 409 100 80 10 year Overall survival: 90% % Surviving 60 40 10 year Disease-free survival: 40% 20 Overall Survival Disease Free Survival 0 0 12 24 36 48 60 72 84 96 108 120 Time (Months) Mo 0 24 48 72 96 120 No. of patients 176 156 134 113 88 52 Fig. 4 Kaplan-Meier curve for overall and disease-free survival with corresponding n values. Williams, Eur Urol 2011

56 1 ]GIF$DT)([ rtile range; PSA = prostate-specific antigen; RT, radiation Two pre-salvage prognostic factors Fig. 2 Kaplan-Meier curve for prostate-specific antigen (PSA) nadir (nanograms per deciliter) with corresponding n v Pre-salvage PSA (5 or 10ng/mL) no analysis was shown using the Phoenix definition of PSA nadir plus 2 ng/ml, and they described recurrence rates that are significantly higher than our series. From our experience we have seen significantly higher biochemical recurrence rates in this cohort using the ASTRO definition [8] that do not seem to translate to an increased recurrence rate with time under the Phoenix definition. This highlights the fact that with a lack of a validated standard definition of failure, long-term follow-up is required. Compa treatment modalities can be heavily inf definitions used. Regardless, we have significant overall recurrence-free surviv optimized with appropriate stringent patie acknowledge that we have not proven any for this treatment given the absence of an trial of salvage versus observation, howev Pre Salvage x Gleason score 100 % Disease Free 80 60 40 < 7 7 > 7 20 0 0 12 24 36 48 60 72 84 96 108 120 Time (Months) Mo 0 24 48 72 96 120 It s therefore Gleason 7 50 47 39 33 28 18 _ important to refer patients early as possible 1 Kaplan-Meier curve for presalvage prostate-specific antigen (PSA; nanograms per deciliter) with corresponding n values. Gleason <7 38 36 34 30 18 8 Gleason >7 57 46 39 35 29 18 after failure (Phoenix) Fig. 3 Kaplan-Meier curve for presalvage Gleason scores with corresponding n values. Williams, Eur Urol 2011

PSA nadir <1ng/ml as post-salvage prognostic indicator EUROPEAN UROLOGY 60 (2011) 405 410

World J Urol (2013) 31:403 409 DOI 10.1007/s00345-012-0928-8 ORIGINAL ARTICLE The Dutch experience (4 centers) and review of the literature Patterns of outcome and toxicity after salvage prostatectomy, salvage cryosurgery and salvage brachytherapy for prostate cancer recurrences after radiation therapy: a multi-center experience and literature review Max Peters Maaike R. Moman Henk G. van der Poel Henk Vergunst Igle Jan de Jong Peter L. M. Vijverberg Jan J. attermann Simon Horenblas Marco van Vulpen Table 4 Comparison with results from previous literature toxicity Salvage procedure Radical prostatectomy 125-I implantation Cryosurgery GU genitourinary; GI gastrointestinal; NA not available a 44 % of patients had preexistent erectile dysfunction Literature No. studies [references] 5[9, 11, 20, 22, 27] 3 [9, 23, 24] 6 [9, 25, 28 31] N 308 66 707 % GU toxicity 20 68 % incontinence 12 % grade 1 2 4 83 % incontinence 22 41 % bladder neck stricture % GI toxicity 2 7 % rectal injury 0 12 % grade 1 2 38 % grade 3 4 7 55 % bladder neck stricture/ retention 0 2 % grade 3 4 6 37 % perineal pain 1 11 % fistula Erectile dysfunction 72 % Nearly uniform NA 72 86 % Present study % GU toxicity 23 % grade 3 23 % grade 3 22 % grade 3 % GI toxicity 9 % grade 3 6 % grade 3 7 % grade 3 Erectile dysfunction 86 % 45 % 93 % a A reputation of a somewhat morbid procedure driven by historical series Peters, World J Urol 213

Ramsay, Health Technology Assessment 2015 «There was no evidence that salvage ablative therapy was either better or worse than salvage RP following primary ERT for any outcomes» HEALTH TECHNOLOGY ASSESSMENT Ablative therapy for people with localised prostate cancer: a systematic review and economic evaluation VOLUME 19 ISSUE 49 JULY 2015 ISSN 1366-5278 Craig R Ramsay, Temitope E Adewuyi, Joanne Gray, Jenni Hislop, Mark DF Shirley, Shalmini Jayakody, Graeme MacLennan, Summary and conclusions from the evidence of the comparative effectiveness of salvage ablative therapy This review considered data from 400 participants treated with salvage therapy following primary ERT across nine studies, 120,208 215 all of which were single-arm case series. Six studies involved salvage RP, 209 211,213 215 two involved salvage cryotherapy 208,212 and one involved salvage HIFU. 120 All of the studies were considered as having a high risk of bias. Consequently, the findings should be interpreted cautiously to reflect the extremely poor quality of the evidence base and the heterogeneity of outcome definition, different time points of outcome measurement and different means of outcome reporting. Data on the long-term effectiveness of salvage therapy were limited, with the majority of studies reporting on short-term data only. In the short term, there was no robust evidence that mortality or other cancer-specific outcomes (biochemical disease-free survival or failure) differed between salvage cryotherapy and salvage RP. There were no data on cancer-specific outcomes for salvage HIFU. With regard to functional outcomes, including urinary and sexual dysfunction and quality of life outcomes, the limited data prevented any valid conclusions from being made. For adverse event outcomes, there was a general trend for salvage cryotherapy to have fewer procedure-related complications, especially for bladder neck stenosis (up to 2% at a median of 18.6 months), in comparison with salvage HIFU (up to 17% at a median of 15 months) and salvage RP (up to 25% at a median of 20 months). However, the data limitations render these findings uncertain at best. In conclusion, the results of this review on salvage therapies were associated with large uncertainty owing to the quality and quantity of the evidence base. There was a lack of long-term direct measures of effectiveness and a lack of prospective comparative studies. There was no evidence to suggest that salvage ablative therapy was either better or worse than salvage RP following primary ERT for any outcomes.

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