Salvage Cryoablation for Locally Recurrent Prostate Cancer Following Primary Radiotherapy

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1 EUROPEAN UROLOGY 61 (2012) available at journal homepage: Review Prostate Cancer Salvage Cryoablation for Locally Recurrent Prostate Cancer Following Primary Radiotherapy Vladimir Mouraviev a, *, Philippe E. Spiess b, J. Stephen Jones c a Division of Urology, Department of Surgery, Medical College of Cincinnati, Cincinnati, OH, USA; b Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, FL, USA; c Cleveland Clinic Department of Regional Urology, Glickman Urological and Kidney Institute, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA Article info Article history: Accepted February 29, 2012 Published online ahead of print on March 8, 2012 Keywords: Radiorecurrent prostate cancer Focal salvage treatment Salvage whole-gland cryoablation Abstract Context: The purpose of this paper is to review current salvage cryoablation (SCA) outcomes in patients with locally recurrent prostate cancer (PCa) following primary radiation therapy. Objective: The objectives of this review are (1) to analyze the eligibility criteria for careful patient selection for these salvage modalities and (2) to evaluate the oncologic results and reported complication rates for these respective modalities. Evidence acquisition: A Medline/PubMed literature search was performed of peerreviewed scientific articles published from 1991 to 2012 regarding salvage therapy for radiorecurrent PCa. The following search terms and various permutations were used: radiorecurrent prostate cancer, local salvage treatment, salvage radical prostatectomy, salvage cryoablation, salvage brachytherapy, and salvage high-intensity focused ultrasound. Only articles written in English were included. Evidence synthesis: SCA is a feasible and efficacious treatment modality, especially using third-generation technology, whereby the biochemical disease-free survival is estimated to be between 50% and 70% at 5-yr follow-up in properly selected patients. Severe complications such as rectourethral fistulas are significantly less common over the last decade than was reported in the past. Because there are no prospective, randomized studies and the definitions of PSA failure vary among many studies, comparisons between these different salvage modalities are limited in terms of cancerspecific outcomes. Nevertheless, in recent years, tertiary care referral centers for prostate cryotherapy have reported their treatment outcomes using rigorous treatment end points and morbidity grading systems, dramatically improving the quality of reported clinical data. Consequently, favorable predictors of treatment outcomes have been identified. Conclusions: The inability to effectively salvage patients with locally recurrent PCa following radiation therapy has in large part resulted from the lack of sufficiently sensitive and specific diagnostic tools to detect local recurrences at an early, potentially curable stage. Consequently, a more stringent definition of biochemical failure, improved imaging techniques, and accurate PCa mapping imaging technology is greatly needed within our diagnostic armamentarium. Additional research and randomized clinical trials are required to determine which salvage modality is superior in terms of oncologic efficacy and reduced morbidity. # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. 231 Albert Sabin Way, ML 0589, Cincinnati, OH 45267, USA. Tel ; Fax: address: mouravvr@ucmail.uc.edu (V. Mouraviev) /$ see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 EUROPEAN UROLOGY 61 (2012) Introduction Despite continuous implementation of novel radiotherapy (RT) techniques such as three-dimensional (3D) conventional RT and intensity-modulated conformal RT, providing more targeted and higher doses of radiation to the prostate as a definitive primary treatment, the risk of local recurrence after RT has not been obviated. Kuban et al, for instance, have shown that of 4839 patients, 1582 (33%) had biochemical failure by prostate-specific antigen (PSA) criteria, 416 (9%) had clinical local failure, and 329 (7%) had distant failure after external beam RT (EBRT) for clinically localized prostate cancer (PCa) [1]. Other, more optimistic, large systematic reviews of >3000 patients treated between 1990 and 2003 showed improvement in 5-yr survival from 82% to 92% with increase of radiation doses from 70 Gy to 80 Gy [2]. However, this rise in treatment dose led to increased acute and chronic gastrointestinal and genitourinary morbidity and toxicity. Among the treatment choices for recurrent PCa, salvage surgery and cryoablation are the most reliable treatment options [3 7]. In general, salvage radical prostatectomy (RP) has been more technically challenging than primary RP [8 11]. Radiation-induced vasculitis, fibrosis, and tissueplane obliteration have been factors leading to significant complications, such as rectal injuries, anastomotic strictures, and urinary incontinence [8,12]. Taking into consideration the technical challenge and the reported surgical morbidity of salvage RP, salvage cryoablation (SCA) has rapidly found a niche as an alternative salvage local treatment modality with the added benefit of being minimally invasive. Langerhuijsen et al. reported data on third-generation SCA that suggested better cancer control and safety profile compared with first- and secondgeneration SCA [7]. Miller et al. just recently welcomed an introduction of fourth-generation cryotherapy. This approach includes the latest development of multipoint thermal sensors (MTS) with precise temperature monitoring along an entire tissue plane to the third-generation technique with transrectal ultrasound (TRUS) guidance, a brachytherapy-like template for needle insertion, and use of argon gas (freeze) and helium gas (thaw) [13]. Although the new technique is not without complications and inherent challenges, modern targeted SCA has been performed safely across a host of international academic and community facilities [4,7,14 16]. 2. Evidence acquisition The aims of this review are (1) to define selection criteria for appropriate candidates and (2) to evaluate the cancer control results and complications of SCA. A Medline/PubMed literature search for articles from 1991 to 2012 regarding SCA of radiorecurrent PCa was conducted, and 139 articles were identified. The following search terms were used: radiorecurrent PCa, focal salvage cryoablation, salvage whole gland cryoablation, salvage brachytherapy,andsalvage highintensity focused ultrasound. In this paper, we review the current status of SCA as an effective salvage modality following RT as a primary treatment for localized PCa. We also provide a critical appraisal of the scientific literature with regard to the treatment-specific outcomes and reported morbidity of SCA in contrast to other minimally invasive salvage therapies. The following criteria were used in selecting clinically relevant and robust scientific literature on this subject matter: English language Original and review papers Reports from tertiary cryocenters with a large sample size in a contemporary cohort of patients Reports on only third- and fourth-generation cryotherapy devices Some of the larger series on older cryotherapy devices (second generation) with a follow-up of at least 12 mo. 3. Evidence synthesis 3.1. Diagnosis of locally recurrent prostate cancer after primary radiation therapy According to American Urological Association (AUA) panel recommendations on best practices pertaining to SCA, an elevation of PSA after primary radiation of PCa does not necessarily imply local recurrence because this clinical scenario can result with local, regional, and micro- or macrometastatic disease [17]. Furthermore, rising PSA can result from a benign etiology such benign prostatic hyperplasia or a PSA bounce phenomenon following ERBT [18]. Ultimately, all of these potential confounders add to the significant diagnostic challenge of detecting early local recurrence at a time where it is at greater likelihood of being cured. The cryosurgical community still commonly uses a definition of biochemical failure borrowed from one of two sources. The American Society for Therapeutic Radiology and Oncology (ASTRO) definition consists of three consecutive rises in serum PSA separated by at least 3 mo, backdated to the midpoint between the first two values, following establishment of a nadir post-treatment PSA level [19]. Alternatively, the new Phoenix criteria consists of a rise by 2 ng/ml above the nadir PSA after EBRT [20]. In contrast, the 2007 European Association of Urology guidelines panel considered a PSA rising >2 ng/ml above a nadir of 0.5 ng/ml as the current definition of biochemical failure following RT [7]. The scientific literature suggests that the rate of organconfined disease among patients with a rising PSA level and biopsy-proven local recurrence following EBRT is only between 20% and 39.5% [12,14,18]. Several salvage RP series in the clinical context of radiorecurrent PCa reported that approximately 80% of patients have extraprostatic extension and an overall 5-yr biochemical disease-free survival (bdfs) of 30 40% following salvage surgery [4,8,21]. These results reflect a high proportion of patients harboring locally advanced disease at the time of salvage therapy. Therefore, the major problem with any salvage procedure

3 1206 EUROPEAN UROLOGY 61 (2012) currently performed for locally recurrent PCa is that the cancer may already be locally advanced and/or micrometastatic at the time of treatment. In the absence of valid biochemical and molecular markers of systemic disease, we emphasize the merit of a salvage procedure as a potentially curative treatment modality based on established selection criteria. SCA can potentially cure versus palliative androgen deprivation therapy, which can result in potential widespread systemic side effects [4,15]. Only salvage RP series can validate clinical, biopsy, and pathology characteristics by assessment of pathologic surgical specimens, whereas ablative treatments leave the prostate in situ. Even at tertiary care referral cancer centers such as Memorial Sloan-Kettering Cancer Center (MSKCC), 54% of salvage prostatectomy patients had an advanced pathologic stage (ie, seminal vesicle invasion and/or lymph node metastases) [8]. Although many of these patients were not cured, an additional proportion of patients achieved local cancer control. A few tertiary centers reported 10-yr cancer-specific survival rates after salvage RP between 30% and 77% [4,8,21,22]. Sanderson et al. reported a 47% bdfs at 5 yr with a median follow-up of 86 mo and concluded that early salvage surgery for a biopsy-proven local treatment failure led to a more favorable outcome often not necessitating adjuvant hormonal therapy [23]. In another study from MSKCC, bdfs at 5 yr was 86%, 55%, and 37% for patients with a preoperative PSA of <4 ng/ml, 4 10 ng/ml, and >10 ng/ml, respectively [8]. Hence salvage surgery has a role in providing cancer control and delaying disease progression in highly motivated patients with favorable clinical parameters, which to date translate to having a low PSA value Specifics of prostate biopsy after radiation therapy failure A tissue diagnosis of PCa on biopsy core is a current requirement to identify locally recurrent PCa following primary RT. Most urologists obtain a biopsy only after mo following primary RT treatment to decrease falsepositive rates [24,25]. Crook et al. demonstrated in a univariate analysis that the biopsy status between 24 and 36 mo was highly predictive of ultimate outcome [26]. One of the crucial factors is the request of an experienced uropathologist to review tissue slides to distinguish radiation effects from early recurrence features, significantly decreasing false-negative results (on average up to 20%) as well as false-positive results. In case of a rising PSA and a negative first set of extended biopsies, the second set should be performed to sample suspicious areas as well as the whole prostate with an increased number of cores (saturation or multicore protocol), potentially using 3D pathology mapping or novel fusion magnetic resonance imaging (MRI) TRUS imaging navigation systems [27 29]. Under these circumstances, the likelihood of missing a tumor focus of clinical significance can be diminished. Another direction is to sample every 0.5 cm 3 of prostate, called transperineal template 3D pathology mapping biopsy, with a total of approximately 80 to 120 cores taken [28,30]. Finally, to date, there is still no available universal protocol or approach (transrectal vs transperineal). Some authors recommended a biopsy of both seminal vesicles (SVs) in addition to prostate biopsy after radiation failure [25,31,32]. The AUA best statement also suggested a biopsy of both SVs, even with an absence of robust supportive data [17]. Although it is technically possible to freeze the SVs, most authors realized that SCA cannot cure most patients with SV involvement as a sign of systemic tumor spread [32] Selection of appropriate candidates From the above data, it becomes clear that potential salvage surgery may be curing treatment for almost one-third of patients who still harbor organ-confined recurrent PCa, and the main purpose of selection is to precisely define this subset of patients. From this body of literature, ideal candidates for local salvage therapy at a greater likelihood of favorable bdfs can be identified [14,33 40]: Low-risk patients with a pre-rt serum PSA level <10 ng/ml, Gleason score <8, and clinical stage T1c or T2 before RT A low presalvage PSA level (4 to 5 ng/ml) A long PSA doubling time (16 mo) PSA velocity before initial RT <2 ng/ml per year Negative metastatic workup (bone scan and pelvic imaging) at the time of diagnosis and management of local recurrence No evidence of intensive SV invasion Life expectancy >10 yr can be promising as a surrogate marker of the risk of locally treatable disease, although this statement needs to be proved with a collection of longer follow-up data. Ismail et al. showed in their prospective case series of their first 100 patients undergoing SCA for recurrent PCa after radiation failure that stratification into three risk categories according to the Blasko definition [41] before radiation treatment (PSA level, Gleason score, and clinical stage) was a very useful prognosticator for final outcome [42]. In terms of PSA levels at the time of salvage therapy, many studies have demonstrated that men with a serum PSA level 10 ng/ml had a worse outcome compared to those with a PSA level <10 ng/ml. In the MD Anderson Cancer Center reported series, investigators reported 5-yr bdfs of 57% and 23% for patients with presalvage PSA levels <10 ng/ml and 10 ng/ml, respectively [43]. Ng et al. reported clinical variables that predict an unfavorable outcome among patients undergoing SCA including a PSA level >10 ng/ml before cryoablation, a Gleason score 8 before radiation, clinical stage T3/T4 disease, and an increasing PSA level despite initiation of hormone ablative therapy [36]. Recent updates of this group, including data of 187 patients with a longer follow-up of 7.46 yr, suggested that pre-sca PSA (especially >10 ng/ml), preradiation, and presalvage Gleason score were predictors

4 EUROPEAN UROLOGY 61 (2012) Table 1 Oncologic results of salvage cryoablation based on different generations of cryotechnology References Cryodevice No. of patients Median follow-up Adjuvant hormonal manipulation, % BDFS, % Definition of failure Pisters et al. [45] Cryocare mo (SF) Nadir (DF) Bahn et al. [46] Cryocare mo NA 59 (7 yr) PSA >0.5 Han et al. [47] Seednet mo NA 72.2 (1 yr) PSA >0.4 Ismail et al. [42] Seednet mo (5 yr; low risk) ASTRO Ghafar et al. [25] Seednet mo (2 yr) Nadir +0.3 Pisters et al. [48] Cryocare mo (5 yr) ASTRO and Phoenix 55 (5 yr) Williams et al. [44] Candela yr (8 yr), 39 (10 yr) Nadir +2 Cryocare Spiess et al. [39] Multiple mo PSA >0.5 Cheetham et al. [35] Cryocare yr NR 52.2 Phoenix Seednet Gowardhan [49] CryoCare mo NR 61 PSA >0.5 BDFS = biochemical disease-free survival; SF = single freeze-thaw cycle; DF = double freeze-thaw cycle; NA = not available; NR = not reported. of SCA failure. A particularly strong prognosticator of early recurrence was PSA nadir >1.0 ng/dl [44] Oncologic efficacy of salvage cryoablation A summary of contemporary oncologic outcomes of SCA is reported in Table 1 including cases using second- and third-generation cryotherapy devices [25,35,39,42,45 48]. Currently, SCA is a feasible option due to more precise prostate ice ball formation and the flexibility to place additional cryoneedles where needed to selectively target a site of tumor recurrence. Gowardhan et al. reported data on 91 consecutive patients treated with third-generation cryosurgery including 42 with SCA for radiation failure. At 1 yr, PSA level <0.5 ng/ml was found in 61% of SCA group [49]. The oncologic outcomes from the largest database (963 patients including primary ablation and SCA) with a 10-yr undetectable PSA response following SCA were achieved in approximately 60% of patients (ie, comparable to the results of salvage RP) [50]. Katz et al. recently presented their 10-yr experience with SCA in 157 patients, demonstrating that 83.4% of patients achieved a PSA nadir <1.0 ng/ml with significantly fewer complications than after salvage RP [51]. The 50 most recently treated patients had an 83.3% biochemical recurrence free survival using the ASTRO definition, and 6.4% reported post-treatment urinary incontinence. Ng et al. reported a 5-yr bdfs rate of 56% and 1% in patients with serum PSA <4 ng/ml and 10 ng/ml, respectively, prior to SCA [24]. Recently, in a large study from the Cryo Online Data (COLD) Registry, 5-yr bdfs was reported to be 58.9% using the ASTRO definition and 54.5% using the Phoenix definition [48]. It needs to be acknowledged that no established definition of failure has been agreed on, thus biochemical survival rates vary widely based on the definition of failure used. Whereas an undetectable PSA would be the optimal benchmark if one assumes that the prostate is completely ablated and no metastasis are present, it has been demonstrated that complete ablation is not usually attained, especially around the urethral warmer that intentionally preserves the structure and a margin of adjacent prostatic tissue. As another feasible option, Eisenberg et al. recently reported on 19 radiorecurrent PCa patients treated with focal SCA, with a 3-yr bdfs rate of 50% using the ASTRO definition [52]. In carefully selected patients in which the surgeon suspects the patient may in fact harbor a focal recurrence after radiation failure based on biopsy data, focal SCA offers the potential for favorable short-term oncologic outcomes with a lower complication rate compared to whole-gland SCA Prediction and challenges of salvage cryoablation success or failure Spiess et al. recently reported the largest multi-institutional trial (among tertiary cryocenters across the United States) including a subset of 450 SCAs from which a pretreatment nomogram predictive of bdfs was developed (Fig. 1) [39]. BDFS was defined as a serum PSA level 0.5 ng/ml, and SCA biochemical failure was defined as a total serum PSA >0.5 ng/ml. At a median follow-up of 3.4 yr, the overall bdfs rate was 66%. Potential predictors of failure on multivariate analysis included initial serum PSA and biopsy Gleason score at time of diagnosis. Serum PSA was found to be a strong predictor of biochemical failure with 1 unit increases in the log-log of serum PSA associated with an odds ratio (OR) of 3.8 and a biopsy Gleason score 8 at time of diagnosis (OR: 2.9). Levy et al. analyzed the data of 455 hormone-naïve patients from the COLD Registry assessing the prognostic value of nadir serum PSA level after SCA [53]. In the cohort that had an initial PSA level of <0.6 ng/ml after the procedure, biochemical progression free survival rates of 80%, 73.6%, and 67% were reached at 12, 24, and 36 mo, respectively. In 60% of patients with an initial PSA level 0.6 ng/ml after SCA, patients remained at risk of developing biochemical disease progression at 12 mo. Based on the medical records of 58 patients with SCA, the same investigators demonstrated that tumor burden as measured by the number of positive biopsy cores and the ratio of

5 1208 [(Fig._1)TD$FIG] EUROPEAN UROLOGY 61 (2012) Fig. 1 Pretreatment nomogram to predict biochemical failure after salvage cryoablation (adopted from Spiess et al. [39]). PSA = prostate-specific antigen. positive cores to prostate volume were significant prognostic factors of favorable biochemical outcomes [54]. Ng et al. [31] reported the pattern of local recurrence after SCA in 122 patients. At a mean follow-up of 56 mo, 23% of patients were diagnosed with locally recurrent PCa based on the presence of positive post-treatment prostate biopsy. Interestingly, most recurrences were located in the apex (51.5%), in the base (21.2%), and in the SVs (18.2%). The authors postulated that it was truly the location of less aggressive freezing (ie, cryoablation) used in close proximity to vital structures such external sphincter and rectum that was predictive of treatment failure. The presence of cancer at the base of the prostate was a significant prognostic factor ( p = 0.014) of SCA success, probably due to more extensive disease among patients with SV involvement. Reiterating the concept of incomplete ablation of radiorecurrent PCa, Huang et al. demonstrated the distribution of tumor lesions on whole-mount sections at final pathology assessment after salvage RP for failed primary RT [55]. The authors found periurethral tumors in 67% cases, with 7% located in direct contact with the urethra (Fig. 2). In an additional 17.4%, tumors were revealed within 2 mm of the urethra. This is the exact area where cryosurgeons attempt to protect the urethral wall from deep freezing (and hence avoid sloughing) using the urethral warmer with 43 8C irrigation throughout the procedure. Extracapsular extension was noted in 43% of cases and SV involvement in 28%. Lastly, the apex contained cancer foci in 93% of cases. These data may initially appear worrisome regarding the ability to achieve a complete ablation of tumor with SCA, but the bdfs rate of SCA is significantly more encouraging. Nevertheless, one of the possible directions for increasing the killing effect (ie, efficacy of the freezing) is the local use of cryosensitizers (eg, peritumoral injection of vitamin D3 before cryoablation) that significantly enhance the tissue destruction in vitro and in vivo with more soft freezing while preserving vital surrounding structures [56] Complications of salvage cryoablation Unfortunately, there is still negative sentiment among many urologic oncologists that SCA causes serious side effects such as post-treatment urinary incontinence, rectal fistula formation, and impotence in most cases. This perception largely results from the early results of rudimentary first- and second-generation cryotherapy devices from which a substantial proportion of patients experienced voiding and bowel difficulties, perineal pain, and urethral sloughing. In one early study, the incontinence rate following SCA was reportedly as high as 73% [45]. [(Fig._2)TD$FIG] Urethra < 2 mm 2 5 mm 5 10 mm > 10 mm No. of Specimens (%) 3 (6.5%) 8 (17.4%) 20 (43.5%) 14 (30.4%) 1 (2.2%) Fig. 2 Minimal distance from radiorecurrent cancer and urethra in millimeters (adopted from Huang et al. [55]).

6 EUROPEAN UROLOGY 61 (2012) Table 2 Complications of salvage cryoablation References No. of patients Cryodevice Incontinence, % Obstruction/ retention, % Perineal pain, % Rectourethral fistula, % LUTS, % UTI, % ED, % Pisters et al. [45] 150 Cryocare NA NA 72 Chin et al. [36] 118 Candela NA 3.3 NA NA NA Cryocare Bahn et al. [46] 59 Cryocare 8 NA NA 3.4 NA NA NA Han et al. [47] 18 Seednet NA 86 Cresswell et al. [34] 20 Seednet 4 4 NA 0 0 NA 86 Ismail et al. [42] 100 Seednet 13 4 NA 1 16 NA NA Ghafar et al. [25] 38 Cryocare NA Seednet Pisters et al. [48] 279 Cryocare NA 1.2 NA NA NA Ng et al. [24] 187 Candela Cryocare NA LUTS = lower urinary tract symptoms; UTI = urinary tract infection; ED = erectile dysfunction; NA = not available. The third-generation SCA dramatically decreased the reported incidence of major complications. Ghafar et al. presented a relatively low rate of complications including incontinence (9.7%), voiding complications (5.8%), rectal pain (12.8%), and urinary retention (1.9%) [25]. Noone case from this series with rectal fistula formation was reported. The reported rates of acute and late complications associated with SCA are presented in Table 2 [24,25,34,36, 42,45 48]. In general, recent studies would suggest a lower incidence of previous commonly occurring complications after SCA such as perineal pain (range: 4 14%), mild-moderate incontinence (6 13%), severe incontinence (2 4%), urinary retention (2 21%), and rectourethral fistula formation (1 2%). The incontinence rates decreased to <5% in recently reported SCA series, especially with the use of MTS, allowing precise thermal control of the freezing process around the external sphincter and hence optimizing the likelihood of preserving urinary continence following treatment. The major risk of SCA, even with contemporary fourth-generation cryotherapy devices, remains incontinence, but this risk remains significantly lower than with salvage RP. Recent studies, however, report a much lower incidence of incontinence (8 9%), and total urinary incontinence now constitutes a rare event (<1%) when SCA is performed by an experienced cryosurgeon (Table 2). Cohen compared the complications of SCA between first-, second-, and third-generation devices and showed tremendous improvements, with a substantial decrease in serious side effects such as incontinence and rectourethral fistulas in a large, single-institution patient cohort [50]. Furthermore, he demonstrated that the rate of certain complications has dramatically decreased with time due to improvements in technology and techniques when comparing first- and second-generation to third-generation cryotherapy devices, most notably in terms of urethral sloughing (from 14% to 2%), incontinence (from 3.2% to 0%), and prostatic stone formation (from 4% to 0%). Of all possible complications, the incidence of erectile dysfunction (ED) remains exceedingly high (69 86%) after SCA (Table 2). The rate of ED is exceedingly high, and patients should be counseled that ED is a likely sequela of SCA. It should be noted that most studies have shown that that many patients considering salvage procedures already exhibit significant ED following RT. Recently, a study of focal SCA demonstrated a potential benefit of such an approach over whole-gland SCA; however, focal SCA may be a therapeutic consideration for a highly selected subset of patients [52]. According to this preliminary report, of the five patients with available follow-up potency data in the form of Sexual Health Inventory for Men questionnaires, two men preserved potency and three were rendered impotent following focal SCA. Pelvic, rectal, or perineal pain was a relatively frequent complication, and it appeared to significantly hinder quality of life and to interfere with normal activity in up to 39.5% of patients in one series [25]. Tissue sloughing was once a frequent complication in earlier SCA studies, when the use of a urethral warming device was not standardized. The rates of bladder outlet obstruction, retention, and urethral stricture have greatly improved with time. The proportion of bladder outlet obstruction necessitating surgical intervention has similarly declined with use of the current generation of cryotherapy devices and technical expertise. A serious potential complication of salvage cryosurgery is rectourethral fistula, with a reported incidence between 0% and 3% (Table 2). This underscores the importance of accurate probe placement and real-time treatment monitoring. Two factors may have accounted for this poor historical outcome: lack of sufficiently precise ultrasound equipment and inadequate experience with prostate ultrasonography. Most fistulas have been reported to occur within the first 25 patients treated by a cryosurgeon [50]. Following this initial learning curve, the occurrence of rectourethral fistulas typically becomes very infrequent and, in fact, is much lower than for salvage RP [4,12,31,35, 50,57 59]. 4. Conclusions Local recurrence of PCa after RT is typically associated with an adverse prognosis. At the time of salvage treatment, two-thirds of patients have an advanced pathologic stage. Stringent definition of biochemical failure, use of new

7 1210 EUROPEAN UROLOGY 61 (2012) prognostic molecular markers, and improved imaging as well as mapping of the prostate by extended biopsy templates are needed to detect local recurrences PCa following RT at an early stage of progression during which it is likely curable and associated with a more favorable therapeutic outcome. Several prognostic factors help define patients who are ideally suited for SCA: serum PSA level <10 ng/ml, Gleason score 8, and clinical stage T1c or T2 before salvage therapy. Furthermore, a recently developed nomogram developed by Spiess et al. based on the largest multi-institutional pooled analysis can be used to improve patient selection and to provide some insight for patients in terms of their expected oncologic outcomes. Although the most established salvage modality with long-term survival benefit is salvage RP, this surgical procedure remains very challenging and should be performed only by select genitourinary surgeons at tertiary care referral centers. Patients must be informed of the high complication rate, which far surpasses those of other local salvage therapies. Compared to salvage RP, less invasive modalities such as SCA or high-intensity focused ultrasound appear to constitute promising alternative treatment options for RT-failure patients, although we await the long-term outcome of these salvage modalities in comparison to salvage RP. Among those minimally invasive modalities, recent SCA series have reported comparable and acceptable intermediate-term oncologic efficacy and morbidity when compared to salvage RP. Consequently, SCA should be recognized as an established salvage therapeutic option. Author contributions: Vladimir Mouraviev had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Mouraviev, Spiess, Jones. Acquisition of data: Mouraviev, Spiess. Analysis and interpretation of data: Mouraviev, Spiess, Jones. Drafting of the manuscript: Mouraviev. Critical revision of the manuscript for important intellectual content: Spiess, Jones, Mouraviev. Statistical analysis: Mouraviev, Spiess. Obtaining funding: Mouraviev, Spiess. Administrative, technical, or material support: Mouraviev, Spiess. Supervision: Jones. Other (specify): None. Financial disclosures: Vladimir Mouraviev certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: V. Mouraviev is a research advisor for thecold Registrysponsored byendocare. P. Spiess is a research advisor for the COLD Registry sponsored by Endocare. J.Stephen Jones is a lecturer and teacher for Endocare. Funding/Support and role of the sponsor: None. References [1] Kuban DA, Thames HD, Levy LB, et al. Long-term multi-institutional analysis of stage T1-T2 prostate cancer treated with radiotherapy in the PSA era. Int J Radiat Oncol Biol Phys 2003;57: [2] van Tol-Geerdink JJ, Stalmeier PF, Pasker-de Jong PC, et al. 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