ORIGINAL ARTICLE. Department of Urology, Sacro Cuore Catholic University, A. Gemelli University Hospital, Rome, Italy

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1 0 EDIZIONI MINERVA MEDICA Online version at Prostate cancer (PCa) is the most commonly diagnosed malignancy in men and the second leading cause of cancer death in developed countries. With the introduction of PSA as a marker of tumor screening the majority of PCa was detected at an early stage, before the onset of clinical disease, which is usually represented by locally advanced or metastatic cancer. ORIGINAL ARTICLE Minerva Urologica e Nefrologica 0 February;9():9-0 Doi:./S High intensity focused ultrasound as first line salvage therapy in prostate cancer local relapse after radical prostatectomy: -year follow-up outcomes Giuseppe *, Angelo TOTARO, Emilio SACCO, Nazario FOSCHI, Gaetano GULINO, Marco RACIOPPI, Pierfrancesco BASSI, Francesco PINTO Department of Urology, Sacro Cuore Catholic University, A. Gemelli University Hospital, Rome, Italy *Corresponding author: Giuseppe Palermo, Catholic University of Sacred Heart, Department of Urology, Largo F. Vito, 008 Rome, Italy. gpalerm@libero.it ABSTRACT BACKGROUND: Prostate cancer (PCa) is the most commonly diagnosed malignancy in men and the second leading cause of cancer death in developed countries. Despite the primary treatments, 0-0% of patients experience a recurrence. The main objective of this study was to evaluate the clinical efficacy of salvage high intensity focused ultrasound (HIFU) after radical prostatectomy in terms of biochemical free survival rate (BFSR) and PSA nadir. METHODS: Twenty two patients with local recurrence of Pca after radical prostatectomy underwent HIFU as first-line salvage therapy. Considering that in all HIFU experiences, PSA nadir and PSA failure are different and PSA definition of BFSR is unknown, we defined treatment success as a PSA nadir 0. ng/ml months after treatment. All early and late medical and surgical complications were recorded. RESULTS: Ten of the patients (.%) were classified as success three months after HIFU, showing a nadir PSA 0. ng/ml; / patients (.%) were classified as failure during follow-up (median follow-up: 8 months). Seventeen of (%) patients were continent (no-pad) before HIFU. A new diagnosis of stress urinary incontinence was made in cases (early onset) after treatment. A case of vesicoureteral anastomotic stenosis was treated, endoscopically through cold urethrotomy. We did not observe cases of recto-urinary fistula or persistent lower urinary tract symptoms. Two sevenths of the patients complained about de novo erectile dysfunction after HIFU. CONCLUSIONS: The positive oncologic outcomes in the short term anyway obtained in selected patients, associated with documented mild side effects, represent the basis to start more organic, prospective, randomized and multicenter study protocols, that with a long term follow-up could confirm these promising preliminary results. (Cite this article as: Palermo G, Totaro A, Sacco E, Foschi N, Gulino G, Racioppi M, et al. High intensity focused ultrasound as first line salvage therapy in prostate cancer local relapse after radical prostatectomy: -year follow-up outcomes. Minerva Urol Nefrol 0;9:9-0. Doi:./S ) Key words: Prostatic neoplasms - Recurrence - Ultrasound, high-intensity focused, transrectal. Current guidelines for the management of localized prostate cancer leave much action s margin to the clinician. For example, in the context of low-risk disease active surveillance, radiation therapy (RT) and radical prostatectomy (RP) are potential treatment options for patients with reasonable ( years) life expectancy. Despite progress over the years in both Vol. 9 - No. Minerva Urologica e Nefrologica 9

2 The HIFU exploits the coagulative necrosis that occurs at temperatures above 0 C. The ultrasonic energy is highly focused, absorbed and converted to heat, resulting in a clear demarcation between treated tissue and intact tissue. 9 Hundreds of cycles are often necessary for the complete treatment of a lesion that leads to a rapid drying and coagulation necrosis. The size and position of the area to be treated are modifiable through a focusing system, ultrasonic frequency, and the duration coefficient and absorption of the tissue. The limitations include the difficulty in treating the anterior region of the prostate or very large prostates. Usually, the treatment is performed in general or spinal anesthesia with a catheter in the bladder and the patient lying on the right side and fixed with a transrectal probe inserted in the rectum with a device cooling; the real-time vifields, there is still a significant risk of relapse after therapy, and up to -% of all patients undergoing RT or RP develop local recurrences or distant metastasis within years after initial therapy, and -% of patients receive a second-line treatment within five years after initial therapy. The recurrence of prostate cancer after RP is defined as biochemical recurrence (BCR) only if a detectable increase in serum PSA value is found, in the absence of clinical evidence of local recurrence or metastatic disease. The local recurrence is defined as the occurrence of an abnormal digital exploration of the prostate, (asymmetries, the presence of newly formed tissue in the prostate bed, when peri-anastomotic, and/or abnormalities documented by ultrasound) in the presence of a detectable PSA value, regardless by the results of the biopsy of the prostate. For patients with local recurrence after radical prostatectomy and in the absence of documented metastatic disease, salvage radiotherapy (SRT) is the standard treatment. However, therapy is long (it takes several weeks to complete one cycle) and the potential gastrointestinal and genitourinary toxicity may themselves be a contraindication to perform the treatment in older patients with multiple comorbidities and/or poor performance status. Moreover, it has been documented as the salvage RT has less success in local, palpable recurrence than on the non-palpable (overall survival rate at years significantly better for those patients underwent salvage RT, for the only PSA level rising than those with rising PSA and palpable local recurrence (9% vs. 8%, P=0.0). Treatment options for local recurrence after radical prostatectomy The natural history of clinical progression after BCR is variable, and the majority of men lives a long period of time after relapse. Therefore, life expectancy and comorbidities should be considered when deciding on the best therapeutic management of relapse. Currently, several clinical and pathological variables are used to estimate the progression of the disease and thus the most appropriate treatment. For ex- ample, the low-risk patients could be managed conservatively and wait, while in patients with intermediate and high risk, it is very important to establish early a more aggressive salvage therapy. 8 However, the variable clinical course of these patients leaves a lot of uncertainty about how and when to actively manage these men. While the SRT represents the gold standard of care in the local recurrence after radical prostatectomy, has been described in the literature the use of focal therapy as salvage high intensity focused ultrasound (HIFU), cryotherapy, brachytherapy, Ciberknyfe. These studies are mostly experimental, single-center, nonrandomized and with short/medium periods of follow-up, therefore only after further extensive, randomized and prospective studies, with a detailed evaluation of outcomes these cancer treatment options may be routinely used in the clinical practice. Our scientific work reinforces the findings of other previous works (with less case series), that in selected patients HIFU may represent a viable alternative, in the local relapse of PCa after RP, to salvage RT. HIFU Technical characteristics and clinical applications 9 Minerva Urologica e Nefrologica February 0

3 sualization of ultrasound allows to control the effect of the treatment. Treatment planning begins marking the prostatic apex on transverse and longitudinal line by transrectal ultrasound. The treatment begins at mm away from the apex. Usually, three areas overlapping target (two lateral and one central) are defined and treated from the apex to the bladder neck to treat the entire prostate and the seminal vesicles near the prostate device. The distance between the rectal mucosa and the prostate capsule backbone can be defined between and mm. One of the piezoceramic applicator works as a continue control unit of the distance from the rectal wall to prevent accidental injuries of the rectum. In the treatment of a gland already radiated, care must be taken that the dissipation of energy is lower, due to decreased blood flow in the prostate, which as a result of radiation damage to the blood supply of the prostate. This is important because if there is not enough time for the dissipation of energy, it may accumulate and cause rectal lesions and other complications. The same is true, although to varying degrees, for a prostate that has already undergone a previous HIFU session. It has to be underlined that in our study salvage-hifu after radical prostatectomy was performed in the standard modality as before described, unlike other authors who used the re-treatment mode with smaller quantity of focused energy applied for less time. The main objective of the study was to evaluate the clinical efficacy of HIFU as first line salvage therapy in prostate cancer local relapse after radical prostatectomy in terms of biochemical free survival rate (BFSR) and PSA nadir. Secondary objectives of the study were to evaluate the tolerability of the procedure in terms of side effects in the short and long-term and the evaluation of the overall survival and cancer specific survival rate. Materials and methods enrollment and ethical considerations From March 00 to January 0, patients with local recurrence of Pca after radical prostatectomy (RP) sonographically and PET- TAC evident, and in most cases also confirmed by a biopsy postprostatectomy (/), were enrolled and underwent HIFU as first-line salvage therapy. enrolled were made aware of all existing treatment options for Pca local recurrence after RP, including experimental treatments, and side effects of the different treatment options. All the patients were enrolled in the study after obtaining written informed consent of patients. The study was conducted in accordance with the ethical principles contained in the Declaration of Helsinki and with the Good Clinical Practice rules. The clinical and pathological characteristics of patients at baseline are summarized in Table I. Inclusion criteria Peri-anastomotic recurrence of disease evident at transrectal ultrasonography, in most cases confirmed by the trans-perineal biopsy Table I. Clinical and pathologic baseline characteristics of enrolled patients. Number of patients Mean age before HIFU (years) 0. (9-8) Median interval from RP to HIFU (-) (months) RP pathological stage (number of patients) pta ptb ptc 8 pta ptb Gleason score RP (N.) 8 Median PSA before HIFU (ng/ml). (0.-8) Continent patients before HIFU (%) / (%) with IIEF->0 before HIFU / (.8%) (%) Average size of local recurrence (cm ).0 (.-9.) Biopsy Gleason score of local recurrence (N.) 8 Gleason score not specified biopsy not performed Median follow-up (months) 8 (8-) RP: radical prostatectomy; IIEF: International Index of Erectile Function; HIFU: high intensity focus ultrasound. Vol. 9 - No. Minerva Urologica e Nefrologica 9

4 of the suspicious areas and/or by a positive PET/CT; no evidence of distant metastases assessed by bone scan and total body CT scan with contrast medium or choline PET/CT. The sonographic findings were considered suggestive of local recurrence in the case of a suspected lesion identified inside or around the area of the anastomosis, at the level of the bladder neck, the presence of any obvious distortion or asymmetry of the urethrovesical anastomosis. The size of the local recurrence was determined by its entire volume. Exclusion criteria Evidence of distant metastases, lesions not evident with ultrasound, adjuvant radiotherapy after radical prostatectomy, vesico-urethral anastomotic stricture, or any other condition that would not permit the introduction of the HIFU probe in the rectum (anal stenosis, ulcerative colitis, hemorrhoids, previous colorectal surgery). Endpoints and study methodology The primary endpoint is the evaluation of the oncologic efficacy of salvage HIFU in terms of PSA nadir and biochemical disease free survival (BDFS). Treatment success was defined as a PSA nadir 0. ng/ml. Biochemical disease free survival was defined as PSA 0. ng/ ml three months after HIFU. The secondary endpoint is that all medical and surgical complications that occurred both during hospitalization and after discharge were recorded. They were registered as early (onset <0 days after surgery) and late (>0 Table II. Post-HIFU complications and their treatment. days) complications according to the revised Clavien classification system. The surgical time, intra and postoperative complications, and hospital stay were recorded. Overall survival and cancer-specific survival were evaluated. All patients underwent HIFU with the standard protocol of Ablatherm device. HIFU treatment was performed under spinal anesthesia, except in cases where it was not technically feasible or because the patient refused. The bladder catheter was placed after the induction of the anesthesia, removed during the procedure to allow the treatment of periurethral tissue, and replaced at the end of the treatment. The patients were all discharged with the bladder catheter still in place which was then removed days after surgery on an outpatient basis. The follow-up visits were scheduled every months during the first year and every months thereafter. Each follow-up control included: digital rectal examination, evaluation of total serum PSA, (uroflowmetry and urine sampling were also checked at the first follow-up visit at months), evaluation of the state of continence (number of diapers/ day), and erectile function by administering the questionnaire IIEF-. The baseline characteristics and the data of follow-up of patients who responded and those who did not respond to therapy were compared using t-test (parametric) or the Fisher exact test (nonparametric data). P-values <0.0 were considered significant. on which the HIFU treatment was not considered a success were treated with total androgen blockade or with salvage RT if no radiological signs of distant metastasis. Complications N. of patients (%) Treatment Uretral stricture/anastomotic-stricture / (.%) Endoscopic urethrotomy sec. Sachse Urinary incontinence (de novo) Mild/moderate Severe / (%) / / Pelvic floor FKT (Waiting) Acute urinary retention / (.%) Prolonged catheterization for days Persistent LUTS - - Erectile dysfunction (de novo) months after HIFU / (8.%) - FKT: fisiokinesis therapy; LUTS: lower urinary tract symptoms. 9 Minerva Urologica e Nefrologica February 0

5 Results Ten of the patients (.%) were classified as successful three months after HIFU, showing a nadir PSA 0. ng/ml; a patient of the success group presented an increase in PSA during follow-up and further local recurrence (PET/CT capturing only in the prostate) was subjected to a second HIFU treatment with an actual PSA values of ng/ml; / patients (.%) were classified as failure during follow-up (median follow-up: 8 months). These, in which an increase of PSA was observed, after staging exams (PET/CT with choline or Bone scintigraphy + body CT with contrast medium) were treated with radio/ hormone therapy. At a median follow-up of 8 months, / (.%) patients continue to be PSA before RP (ng/ml) Age (years) Lesion dimensions (cm ) PSA before RP (ng/ml) Age (years) 8 9 Lesion dimensions (cm ) 8 9 P value=0.0* P value=0. P value=0. Figure. Clinic-pathologic features of success and failure groups. considered as a success, as defined above. During follow-up none of the patients died of prostate cancer. One patient died of aortic dissection. Currently, / patients classified as failure have a PSA level <0. ng/ml after radio and/or hormone therapy, while / have a PSA>0. ng/ml (from. to. ng/ ml, and are being treated with total androgen blockade). The comparisons between success and failure clinic-pathological groups are shown in Figure and Table III. The age, the size of the lesion, the histological Gleason Score of the prostate examined postradical prostatectomy, the relapse volume, the bioptic histology of the local recurrence (pre- HIFU), and the average time from radical prostatectomy to HIFU did not differ significantly between the success group and the failure 8 9 P value=0. Vol. 9 - No. Minerva Urologica e Nefrologica 9 Time from RP to HIFU (years) PSA before HIFU (ng/ml) Gleason score RP Time from RP to HIFU PSA before HIFU 8 9 Gleason score RP 8 9 P value=0.0* P value=0.8

6 one. A statistically significant difference was observed between the two groups for the average pre-radical prostatectomy PSA (.8 vs..8 ng/ml; P=0.0) and the average pre-hifu PSA (. vs. : ng/ml; P=0.0). The procedure was safe and feasible in all cases and took place within an average time of 0 minutes (range from to 0 minutes). There were no major intra or immediate postoperative complications. All patients were discharged after hours with the bladder catheter in place that was then regularly removed after days with ultrasound evaluation of residual urine. A case of acute urinary retention after catheter removal required prolonged catheterization for weeks. Seventeen of (%) patients were continent (no-pad) before HIFU. A new diagnosis of stress urinary incontinence was made in cases (early onset) after treatment; four of the five patients had a mild to moderate incontinence (grade I), which resolved after physiokinesistherapy of the pelvic floor muscles, and in any case within six months from HIFU procedure; one case of severe incontinence, requiring surgery, has not yet been treated. Regarding the five patients incontinent before HIFU none reported worsening of the degree of incontinence. A case of vesico-urethral anastomotic stenosis was successfully treated with endoscopic urethrotomy by Sachse s ure- Table III. Clinic-pathologic features of success and failure groups. throtome. We did not observe cases of rectourinary fistula or persistent bladder filling and/ or emptying phase disorders. Two sevenths of the patients, who had an IIEF- Score 0 pretreatment, complained about de novo erectile dysfunction. Table II summarizes the early and late complications. Discussion Few papers have been published on the use of HIFU as salvage therapy in the local recurrence of Pca after RP. Our study is novel compared to prior small series because it has the largest number of enrolled patients, longest follow- up and introduces new parameters associated with the success of the therapy not found in the other studies. Tasso et al. treated with HIFU patients with local recurrence after radical prostatectomy declaring a disease-free survival rate of % (/ patients) at twenty months follow-up period and considering a cut-off of PSA of 0. ng / ml; Asimakopoulos et al. more recently enrolled 9 patients with locally recurrent PCA after RP, palpable, visible at transrectal ultrasound and biopsy-proven and treated with salvage HIFU. At the median follow-up of 8 months.% of patients (/9) were considered disease-free with success defined by a PSA nadir (N. of patients=) (N. of patients=) P value Age (years) 9.8 (9-) 0. (-8) 0. PSA before RP (ng/ml). (.-).9 (.8-) 0.0* PSA before HIFU (ng/ml). (0.-.). (0.-8) 0.0* Lesion Dimensions (cm ). (.-9.) 9.9 (.-.8) 0. Gleason score RP (+) 8 Gleason score of the local relapse 8 Not specified/biopsy not done Negative biopsy Median Follow-up (months).8 (0-) 0. (-) Time from RP to HIFU (years). (-). (-) 0. *P<0.0: statistical significance; RP: radical prostatectomy; HIFU: High Intensity Focused Ultrasound. 98 Minerva Urologica e Nefrologica February

7 0. ng/ml. Murota-Kawano et al. published their preliminary experience on the role of salvage HIFU after RP. In their small series of only patients, / patients enrolled had initially been treated with salvage radio-hormone therapy after RP and the persistence of local recurrence treated subsequently with HIFU. At months follow-up, / patients (0%) were free of biochemical recurrence (defined as an increase in the level of PSA>0. ng/ml). In our study, however, according to the above methods, / patients (.%) were classified as successful at the median follow-up of 8 months in line with other studies. We considered an arbitrary cut-off of PSA of 0. ng/ ml at months from HIFU as a parameter to evaluate the success (PSA 0. ng/ml) or failure (PSA>0.) of the procedure, following the guidelines of the NCCN - which do not set a limit, (unlike AUA and EAU suggesting a cut-off of PSA of 0. ng/ml post RP) to define disease recurrence but consider any increase in PSA, the nadir of the RP, in two or more consecutive doses as an indicator of relapse in the absence of suspect distant metastases. This choice in our view, according to other scientists, is also justified by the fact that often the patients in the face of very small rises in PSA (e.g. of ng/ml - stable values over time) undergo an over treatment with associated side effects for a disease that probably would have remained stable for several years. Regarding the factors that potentially affect the oncologic efficacy of the procedure in line with what was observed by Asimakopoulos, in our series a higher value of total PSA pre-hifu is statistically associated with a higher failure rate, some news coming from our study include the direct correlation between lower PSA values pre-rp and HIFU success (P=0.0, Table III) which has not been found in other series. RP Gleason Score and/or biopsy on local recurrence Gleason Score did not statistically influence the success or failure of the procedure in our study, unlike the results of other authors in which a statistically significant correlation (P=0.0) was observed between the histological Gleason Score of the RP (Gleason Score +) and the group of patients in which the treatment was a success. In our series this figure is probably not statistically significant (we got a P>0.0) given the small population studied even if also in the present work can be seen a trend whereby the majority of patients who responded to the HIFU procedure (Table III) had a RP histologic Gleason Score. As for the side effects in the short and medium term in all published works major complications were not recorded. Side effects we recorded were mild and transient, despite the HIFU procedure was performed according to the Standard mode (with the use of higher energies), unlike for example Tasso and Asimakopoulos, who used the re-treatment mode of the Ablatherm device consequently applying lower energies for the shortest time to neoplastic lesions. Although our results seem promising, the low number of patients and the absence of a control arm make it difficult to draw definitive conclusions on oncologic efficacy of the procedure. Moreover, the absence of an extended follow-up is a further limitation since a recurrence of the disease can occur with a more extensive follow-up. As already observed in previous studies for SRT, our study seems to confirm that low values of serum PSA before HIFU salvage represent a predictor of favorable response. In our study, salvage first-line HIFU for palpable and radiologically proven local recurrence after RP failure presented better results if compared with the gold standard treatment of salvage RT in the same setting. For example MacDonald et al. 8 reported poor results of SRT in the treatment of locally palpable recurrence after RP ( patients) with a -year bdfs of % at -year follow-up. Choo et al. reported a bdfs of % at -year follow-up 9 in patients with palpable recurrence after RP. It should be noticed that the failure rate of any salvage treatment may be affected by the difficulty to distinguish between local recurrence and distant one due to low sensitivity of the methods used to. In fact, MRI, bone scan, CT, SPECT TRUS, have their limited intrinsic sensitivity, as well as the clinical parameters used, as the interval from RP and upward PSA, postoperative PSA velocity, 0 or postoperative PSA dou- Vol. 9 - No. Minerva Urologica e Nefrologica 99

8 bling time. So the final oncological outcomes may be hampered because many patients who receive definitive local salvage therapies may already have micrometastasis, suggesting the need for a more accurate selection of patients in order to achieve better results. Conclusions There is little experience on the use of HIFU as salvage therapy after failure of radiation therapy and/or radical prostatectomy and the data are mostly single-center and with small populations. The positive oncologic results in the short term anyway obtained in selected patients, associated with documented mild side effects, represent the basis on which to start more organic, prospective, randomized and multicenter study protocols, that with a long term follow-up could confirm the preliminary results of this promising new minimally invasive technology. References. landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics. Cancer J Clin 999;9:8-.. Catalona WJ, Smith DS, Ratliff TL, Basler JW. Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 99;0:98-.. National Comprehensive Cancer Network Clinical Practice Guidelines: Prostate Cancer; [Internet]. Available from: [cited 0, Nov ].. Blana A, Walter B, Rogenhofer S, Wieland WF. Highintensity focused ultrasound for the treatment of localized prostate cancer: -Year experience. Urology 00;: Pound CR, Partin AW, Epstein JI, Walsh PC. Prostatespecific antigen after anatomic radical retropubic prostatectomy: Patterns of recurrence and cancer control. Urol Clin North Am 99;:9-0.. Murota-Kawano A, Nakano M, Hongo S, Shoji S, Nagata Y, Uchida T. Salvage high-intensity focused ultrasound for biopsy-confirmed local recurrence of prostate cancer after radical prostatectomy. BJU Int 0;:-.. MacDonald OK, Schild SE, Vora S, Andrews PE, Ferrigni RG, Novicki DE, et al. Salvage radiotherapy for men with isolated rising PSA or local palpable recurrence after radical prostatectomy: Do outcomes differ? Urology 00;: Abdollah F, Boorjian S, Cozzarini C, Suardi N, Sun M, Fiorino C, et al. Survival following biochemical recurrence after radical prostatectomy and adjuvant radiotherapy in patients with prostate cancer: the impact of competing causes of mortality and patient stratification. Eur Urol 0;:-. 9. Kennedy JE, Ter Haar GR, Cranston D. High intensity focused ultrasound: surgery of the future? Br J Radiol 00;: Leventis AK, Shariat AF, Slawin KM. Local recurrence after radical prostatectomy: Correlation of US features with prostatic fossa biopsy findings. Radiology 00;9:-9.. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: A new proposal with evaluation in a cohort of, patients and results of a survey. Ann Surg 00;0:0-.. Tasso M, Varvello F, Ferrando U. Prostate cancer: transrectal high-intensity focused ultrasound for the treatment of local recurrence after radical prostatectomy or radiotherapy. Urologia 009;:-.. asimakopoulos AD, Miano R, Virgili G, Vespasiani G, Finazzi Agrò E. HIFU as salvage first-line treatment for palpable, TRUS- evidenced, biopsy-proven locally recurrent prostate cancer after radical prostatectomy: A pilot study. Urol Oncol 0;0:-8.. Mohler J, Bahnson RR, Boston B, Busby JE, D Amico A, Eastham JA, et al. NCCN clinical practice guidelines in oncology: prostate cancer. J Natl Compr Canc Netw 0;8:-00.. Stephenson AJ, Kattan MW, Eastham JA, Dotan ZA, Bianco FJ Jr, Lilja H, et al. Defining biochemical recurrence of prostate cancer after radical prostatectomy: a proposal for a standardized definition. J Clin Oncol 00;:9-8.. Stephenson AJ, Klein EA, Simmons MN. Natural history of biochemical recurrence after radical prostatectomy: risk assessment for secondary therapy. Eur Urol 00;:-8.. Stephenson AJ, Scardino PT, Kattan MW, Pisansky TM, Slawin KM, Klein EA, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 00;: MacDonald OK, Schild SE, Vora S, Andrews PE, Ferrigni RG, Novicki DE, et al. Salvage radiotherapy for men with isolated rising PSA or local palpable recurrence after radical prostatectomy: Do outcomes differ? Urology 00;: choo R, Morton G, Danjoux C, Hong E, Szumacher E, DeBoer Get al. Limited efficacy of salvage radiotherapy for biopsy confirmed or clinically palpable local recurrence of prostate carcinoma after surgery. Radiother Oncol 00;: - 0. Partin AW, Pearson JD, Landis PK, Carter HB, Pound CR, Clemens JQ, et al. Evaluation of serum prostatespecific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases. Urology 99;:9-9.. Patel A, Dorey F, Franklin J, dekernion JB. Recurrence patterns after radical retropubic prostatectomy: Clinical usefulness of prostate specific antigen doubling times and log slope prostate specific antigen. J Urol 99;8:-. Conflicts of interest. The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript. Article first published online: September 9, 0. - Manuscript accepted: September, 0. - Manuscript revised: September, 0. - Manuscript received: March 0, 0. 0 Minerva Urologica e Nefrologica February 0