Cryotherapy in prostate cancer

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1 521806URO / Journal of Clinical UrologyPhillips et al. research-article2014 Review Cryotherapy in prostate cancer Jason M Phillips, Salvatore Catarinicchia, Kevin Krughoff and Al B Barqawi Journal of Clinical Urology 1 10 British Association of Urological Surgeons 2014 Reprints and permissions: sagepub.co.uk/journalspermissions.nav DOI: / uro.sagepub.com Abstract Review objectives: Cryotherapy use has increased due to technological advances. A review of the literature was performed to evaluate the efficacy and outcomes of whole gland, salvage and targeted focal cryotherapy in the management of prostate cancer. Review findings: Cryotherapy use has increased significantly over the last 10 years with a trend towards focal ablation. Whole gland cryotherapy, salvage cryotherapy and focal cryotherapy biochemical recurrence rates appear to be comparable to other treatment modalities for low risk disease, however biochemical failure remains difficult to compare across studies due to a lack of consensus regarding appropriate end points for evaluation of cryotherapy. Short-term focal cryotherapy outcomes are encouraging. Side effect profiles for cryotherapy have significantly improved with fourth generation systems while salvage cryotherapy continues to carry a slightly higher risk of incontinence than primary whole gland cryotherapy. The incidence of erectile dysfunction after focal cryotherapy is dramatically lower than that for whole gland ablation. Conclusions: Cryotherapy continues to have an active role in the primary and salvage treatment of prostate cancer. Targeted focal cryotherapy is a promising treatment with minimal morbidity. Further long-term data is needed to support targeted therapy in addition to direct comparison with other treatment modalities. Keywords Cryotherapy, cryosurgery, cryoablation, subtotal cryotherapy, targeted focal therapy, prostate cancer, prostate Introduction Prostate cancer continues to be the leading cause of newly diagnosed male cancers. In 2011, the American Cancer Society estimated 241,740 new cases and 28,170 deaths from prostate cancer leaving only lung cancer as the cause for more male cancer deaths. 1 However, prostate cancer related morbidity and mortality had decreased due to a combination of early detection and current treatment strategies. In fact, prostate cancer deaths have declined as incidence has increased. 2,3 As a direct result of improved early detection, prostate cancer is now often identified at an earlier stage and grade. 4 Newly diagnosed tumours are often organ confined and slow growing making them ideal targets for surveillance or for ablative therapies such as cryotherapy. However, few patients choose active surveillance and most will ultimately seek a definitive therapy for their prostate cancer. 5 It is well known that whole gland treatments such as radical prostatectomy or radiation have been shown to overtreat prostate cancer in as many as 30 50% of patients. 6 Morbidity, including incontinence and impotence can significantly affect a patient s quality of life. There is a need in these patients for ablative therapies that can destroy the underlying tumour while maintaining the trifecta of prostate treatment: tumour destruction, continence and potency. Division of Urology, University of Colorado, USA Corresponding author: Al B Barqawi, University of Colorado Denver School of Medicine, Division of Urology, MS C-319, Academic Office One Bldg, East 17th Ave, Room L , Aurora, CO 80045, USA. al.barqawi@ucdenver.edu

2 2 Journal of Clinical Urology Cryotherapy was recognised by the American Urological Association (AUA) as a treatment for prostate cancer in Since that time technological advances have led to better outcomes and consequently increased usage. In late 2008 the AUA released a consensus Best practice statement on prostate cryotherapy, stating that it is a treatment option for patients with clinically localised prostate cancer. 7 The consensus panel concluded that cryotherapy is an established treatment option for men with newly diagnosed, or radio-recurrent, organ-confined prostate cancer. Currently third and fourth-generation systems utilising an argon-based freezing system, urethral warming device, multisensory temperature probes, variable length cryoprobes and high quality ultrasound have led to acceptable results both in primary and salvage biochemical disease-free survival (bdfs) with decreasing adverse effects. The largest study to date reporting outcomes based on the COLD (Cryo On-Line Database) Registry reported primary five-year bdfs at 77% and salvage five-year bdfs at 58.9%. 8,9 Now that physicians are diagnosing prostate cancer earlier, treatment has shifted towards minimising the adverse effects of the therapy while maintaining cancer control. This ever changing delicate balance has yet to find the optimal position. For cryotherapy, however, the shift is towards minimising associated morbidity by decreasing the amount of gland ablated. Recent trends in cryotherapy include nerve sparing cryoablation and focal cryoablation. Impotence, which is almost universal for whole gland cryoablation is minimal for targeted therapy. 10 Our centre performs targeted focal therapy (TFT) using cryotherapy with promising results. Future validation of focal therapy is needed to find the sweet spot between cancer control and minimal adverse effects. The cryotherapy mechanism Cryotherapy causes coagulative necrosis at 40 C. To date, four distinct generations of cryotherapy for prostate cancer have been described. The first and second generations, developed in the 1960s 1990s, utilised liquid nitrogen but did not have urethral warmers, pinpoint thermocouples or small diameter probes. Disastrous complications including fistula and damage to adjacent organs occurred. The advent of transrectal ultrasound allowed visibility of the ice ball and fuelled the development of more precise systems. 11 Third and fourth generation cryotherapy systems entered the market in the last 13 years and were notable for their use of argon and helium, which caused coagulative necrosis through the Joule-Thompson principle. These systems used transrectal ultrasound (TRUS), a urethral warmer, pinpoint thermocouples and small diameter Figure 1. Transrectal ultrasound with brachytherapy template. Note the 5 mm increments. Also the transrectal ultrasound may by inserted at 5 mm increments to provide the opportunity to create a three-dimensional reconstruction. Figure 2. Three-dimensional reconstruction of the prostate with mapping of prostate cancer foci. probes. The transition to argon gas from liquid nitrogen allowed for smaller probes (1.47 mm) and transperineal placement. In 2007, Gowardhan and Greene assessed the benefits of a then novel advancement in cryosurgery: multipoint thermal sensors. 12 Multipoint thermal sensors marked the emergence of fourth generation systems and allowed for detailed assessment of temperature changes at the rectum, sphincter and neurovascular bundles. Indeed, improvements in freeze-thaw cycles definitions, standardised protocols, and more structured training programmes have all led to the increased use of cryoablation for localised prostate cancer treatment. 13 Figures 1 3 demonstrate the TRUS with brachytherapy template (Figure 1), a threedimensional reconstruction based off of mapping biopsies

3 Phillips et al. 3 Figure 3. Cryoablation of the prostate in the sagittal and transverse views. (a) Sagittal view of cryoablation of the prostate. Note the hypoechoic (black) iceball where the prostate should be. The warming catheter is easily seen superiorly and inferiorly to the prostate. Distal to the prostate the rhabdosphincer is visualised. (b) Transverse view of cryoablation of the prostate. Note the hypoechoic (black) iceball on the ultrasound image. Sound waves cannot penetrate the iceball. Thus care is taken to freeze anterior to posterior. Thermocouplers at Denonvilliers fascia and the neurovascular bundle help prevent rectourethral fistulae and impotence. (Figure 2), and cryoablation of the prostate in the sagittal and transverse views (Figure 3(a) and (b)). Evaluating outcomes Defining a standardised bdfs for newer treatments like cryotherapy is a major hurdle in evaluating outcomes, especially when considering the variability in outcomes measurements available for well established treatments. An analysis of bdfs criteria was performed by the AUA Prostate Guideline Update Panel in 2007 which found 53 different definitions of biochemical recurrence used in the evaluation of treatment with radical prostatectomy and 99 different definitions for those treated with radiation therapy. Most criteria used in the evaluation of radical prostatectomy utilised a variable threshold, typically >0.2 ng/ml. For radiation therapy, most criteria utilised the American Society for Therapeutic Radiology and Oncology (ASTRO) definition of bdfs or a variation of this definition. 14 The Panel was able to recommend the ASTRO criteria for radiation therapy and the AUA criteria for radical prostatectomy, however by 2008 there was still insufficient data for the AUA to make a statement on which endpoints to use for cryotherapy in their Best practice statement. 7 As of today, there is currently no established definition of biochemical failure after cryotherapy. The situation becomes even more complex when TFT removes only a small portion of the prostate gland and the prostate-specific antigen (PSA) remains elevated. For primary whole gland cryotherapy, surgeons have employed various static PSA cutoffs including 0.3, 0.4, 0.5, and 1 ng/ml However, these criteria are now rarely used. Instead, the most commonly used recurrence criteria are the ASTRO definitions for biochemical recurrence. Both the traditional ASTRO failure definition of three consecutive PSA rises after the post-treatment nadir and the more recent Phoenix criteria (nadir PSA+2) have been used to stratify recurrence Notably, a recent study comparing various biochemical failure criteria has shown the Phoenix criteria to be the most accurate in predicting local biopsy-proven cancer recurrence after cryoablation of the prostate, with a sensitivity and specificity of 68% and 59% respectively. 22 There is some speculation that ASTRO and Phoenix definitions may artificially inflate success rates due to delay in the identification of treatment failure relative to threshold definitions. 23,24 Some data exists to suggest that regardless of risk stratification, a reasonable threshold value of 0.5 ng/ml or less suggests treatment success, however the biopsy status and long-term disease outcomes have not been evaluated for this data. 25 Finally, some clinicians have used post-cryotherapy biopsies to stratify success. The variability in strict recurrence definitions makes it difficult to accurately evaluate different studies. Another limitation to evaluating outcomes has been duration of follow up time. Newer data

4 4 Journal of Clinical Urology studies have started exploring longer follow-up, including that of Cheetham et al. who evaluated prostate cancer specific survival after primary and postradiation salvage cryotherapy 10 years out. 26 Table 1 outlines the largest studies for whole gland, salvage and focal cryotherapy. Whole gland cryotherapy outcomes Primary cryotherapy is an acceptable treatment option for patients with clinical stage T1c T3 disease independent of tumour grade. A thorough metastatic workup should be negative and patients should expect to lose their potency. Randomised controlled trials for cryotherapy are rare and no randomised controlled trials exist comparing primary cryotherapy with surgery or active surveillance for localised disease. The results are also sometimes difficult to evaluate due to the heterogeneity of the equipment used, method of treatment and the variability in defining outcomes. 27 The Scandinavian Prostate Cancer Group Study Number 4 demonstrated a statistically significant reduction in death from prostate cancer and reduction in distant metastases for men undergoing surgery vs watchful waiting (10% vs 15%). 28 Extrapolating that cryotherapy has potentially excellent outcomes as compared to surgery for select low risk patients, cryotherapy should then be superior to watchful waiting in select patients. However, Wilt et al. in 2008 conducted a systematic review of peerreviewed publications and concluded that the level of evidence for the effectiveness of cryotherapy for localised prostate cancer was low. 29 Long-term data now support long-term outcomes. Cohen et al. reported 10-year bdfs of 56% according to the ASTRO criteria and 62% using the Phoenix criteria. 20 These patients were then stratified on the basis of risk (low, medium, high) resulting in improved 10-year survival according to the Phoenix criteria for the low risk (80%) and medium risk (74%) and worse 10-year survival for the high risk (45%) patients. Based on biopsy status post-cryotherapy, the 10-year survival rate for negative biopsies was 73%. The Cryotherapy Online Database (COLD) registry was created to address the limited data from individual institutions so that a pooled source could be better evaluated. Four academic medical centres and 34 community urologists reported data that was then evaluated by Jones et al. in The five-year biochemical disease-free survival based on the Phoenix criteria was evaluated in 1198 patients and demonstrated five-year survivals of 91% in low-risk, 78% in intermediate-risk, and 62% in high-risk patients. Utilising the ASTRO criteria, the five-year biochemical disease free survival was 84% in low-risk, 73% in intermediate-risk, and 75% in high-risk patients. 8 These biochemical results compare quite favourably to the results of radiation therapy as a monotherapy leading some authors to reflect that cryotherapy should be utilised more often. 30 Complication rates from primary cryosurgery have improved dramatically since the advent of the third generation systems. However, impotence is still common and expected in 86% or higher. 31 In a multicentre study of 106 patients only 5% of patients reported urethral sloughing, 5% perineal pain and 3% incontinence after a follow-up of one year. Importantly, none of the 106 patients experienced rectourethral fistula. 32 Other studies have supported these low complication rates, reporting urethral sloughing as low as 2%, incontinence as low as 2% and absent perineal pain. 16,33 In addition urinary function was improved as compared to brachytherapy patients at 18 and 24 months. 34 Rectourethral fistula was present in two of the four series. Taken together, three out of 300 patients had a fistula occurrence. 35 Salvage cryotherapy As expected due to patient presentation, salvage cryotherapy after radiation has a poorer outcome than primary cryotherapy. Approximately 83% of patients undergoing primary radiation treatment will have five-year biochemical free survival, but post-radiation biopsy rates test positive for prostate cancer 21 51% of the time. 36,37 The need for salvage therapy is great, especially in patients with localised recurrence, minimal clinical risk factors and a long life expectancy. For these patients, three possible therapies exist when salvage is indicated: surgery, cryoablation, and radiation. 38 Prostatectomy is associated with increased morbidity including 2% rectal injury, 23% incontinence rate and 30% anastomotic stricture rate due to unclear tissue planes and fibrosis to the sphincter. 39,40 For salvage cryotherapy, the five-year survival rate approaches 97% and the biochemical failure rate is reported 44 59%. 9,41 Pisters et al. reported 279 patients from the COLD database, the largest multi-institutional study on salvage cryotherapy outcomes to date. In his analysis their group reported a five-year bdfs of 59% using the ASTRO criteria and 54.5% using the Phoenix criteria. Other contemporary series include five-year biochemical free survival rates ranging from 56 72% based on different criteria. 17,42,43 Han et al. found 13 of 18 (72%) patients who had undergone salvage cryotherapy and were followed for at least 12 months remained with a PSA less than or equal to 0.4 ng/ml. Stephenson et al. stratified by low medium and high risk groups and found five-year bdfs to be 73%, 45% and 11% respectively. 44 Williams et al. also performed retrospective analyses on 187 patients who underwent salvage cryotherapy for biopsy-proven recurrences, 52 of which had >10 years of follow-up. They found the disease-free survival (DFS) rate at 10 years to be 39%, with DFS defined as time to recurrence after salvage treatment as per the Phoenix criteria. 45 It is important to

5 Phillips et al. 5 note that many patients undergoing salvage cryotherapy also receive androgen deprivation therapy (ADT). The administration of ADT confounds the use of biochemical recurrence criteria and the results stated by various studies should be evaluated carefully. Post-salvage cryoablation biopsies are positive roughly 15 35% of the time in contemporary series of patients treated for radio-recurrent disease. 9,43 In Pisters analysis of the COLD database, 46 of the 279 patients elected to undergo biopsy and 15 of 46 (32%) were found to have positive biopsies. 9 And among those patients who had biochemical recurrence (ASTRO or Phoenix criteria) 8 of 15 (53.3%) had a positive biopsy. Other studies have found lower positive biopsy reports including 16.6% for Ng et al. and 14% for Chin et al. 43,46 Ng et al. have also examined the prognostic value of post-salvage cryoablation biopsies and the location of persistent disease. Interestingly, they found the post-treatment presence of cancer at the base of the prostate to be a prognostic factor for biochemical failure, with a 0% five-year bdfs in their series of 122 salvage cryoablation patients. 47 A recent retrospective analysis was performed by Pisters et al. who compared salvage cryotherapy to salvage prostatectomy. 48 His group analysed patients with PSA less than 10 ng/ml, post-radiation therapy biopsy showing Gleason score 8 or less and prior radiation therapy alone without pre-salvage or post-salvage hormonal therapy. Biochemical free survival was assessed using prostate specific antigen greater than 0.4 ng/ml and the Phoenix criteria. Salvage prostatectomy was statistically superior to salvage cryotherapy using both definitions of bdfs. However, there was no significant difference in diseasespecific survival (at five years salvage cryotherapy 96% versus salvage radical prostatectomy 98%, p=0.283). The side effect profile was not evaluated. Multiple clinicians have attempted to qualify predictive factors for biochemical and biopsy proven recurrence. Izawa et al. analysed 131 patients who had received definielectron beam radiotherapy (EBRT) and subsequent salvage cryotherapy for locally recurrent prostate cancer and found that androgen-indelocal recurrences, Gleason score, and preradiation clinical stage were important determinants of disease-specific survival and disease-free survival. 49 In more contemporary studies, patients with a postradiation PSA greater than 10 ng/ml and/or a PSA doubling time of 16 months or less have been shown to be more likely to develop recurrent cancer following salvage cryotherapy. 7,43,50 Izawa et al. also reported on the determinants of a positive biopsy after salvage cryosurgery and found that patients with initial clinical stage T1 to T2 without lymph node involvment or metastases and PSA less than 10 ng/ml have a higher rate of negative biopsies after salvage cry. 41 In their 2011 retrospective analysis, Williams et al. also suggested that presalvage PSA as well as both preradiation and presalvage Gleason scores were predictive of recurrence, with PSA nadir >1.0 ng/dl being highly predictive of early recurrence. 45 Levy et al. showed the prostate gland disease burden, as indicated by the number of positive cores and the ratio of positive cores to gland volume (ml), as potential prognostic indicators of favourable biochemical outcomes following salvage cryotherapy. 51 In a study using serum PSA at diagnosis, initial clinical T-stage, and initial Gleason score as covariates in their logistic regression model, Spiess et al. retrospectively analysed 797 men at six tertiary-care referral centres who had salvage cryotherapy for local recurrence after primary radiotherapy. Based on their analysis, they were able to create their own pretreatment nomogram to be used when selecting appropriate salvage cryotherapy patients, which they internally validated using 500 patients. Still, with a concordance index of 0.70, there is much to be done before these types of nomograms can be optimally applied in selecting patients for salvage cryotherapy. 52 Side effects of salvage cryotherapy are slightly higher than primary cryotherapy but are significantly less than salvage radical prostatectomy. Rectourethral fistula rates are approximately 1% and incontinence has been reported at 4% for multi-institutional studies and as high as 16% for single institutional studies. 9,33 Incontinence rates continue to decrease as technology advances. Prior to thermocouple monitoring cryotherapy incontinence was over 80%. 54 Moreover, systematic evaluation methods utilizing validated instruments (i.e. International Prostate Symptom Score IPSS) and uroflowmetry have lead to better understanding of the effects of both primary and salvage cryoablation on urinary function. 54 Impotence continues to be high for salvage cryotherapy due to the inevitable damage of the neurovascular bundle. 55 Clearly, the morbidity benefits must be weighed against the biochemical recurrence risk for salvage cryotherapy. Recent data has shown the possibility of performing partial salvage cryoablation, thereby decreasing the morbidity that often precludes whole gland salvage therapy as an option. 56 Taken together, the data suggests both whole gland and partial/unilateral salvage cryotherapy remains a good option for properly selected patients. TFT with cryotherapy TFT with cryotherapy has gained traction as a method for targeting low-volume, less aggressive prostate cancer as these tumours become more prevalent in the era of PSA screening. Although radical prostatectomy or radiation is an effective approach to treating these patients, these treatments may lead to adverse complications. TFT seeks to ablate tumours while minimising complications so that the neurovascular bundles, sphincter and urethra are spared. Short-term efficacy appears promising with bdfs rate of 84% at three years of follow-up with improved preservation of erectile function in 68% of men. 10

6 6 Journal of Clinical Urology Other single institution studies have found bdfs as high as 94% at two years of follow-up with no positive post-treatment biopsies and a 90% potency rate. 58 Ellis et al. had one year of follow-up of 60 patients and found an 80% bdfs with 23% positive biopsy rate and a 70% potency rate. 58 The most definitive and longest study to date is a recent retrospective evaluation of the COLD database by Ward et al. in 2011, which found a statistically significant increase in the usage of focal cryotherapy for prostate cancer from A total of 1160 patients were evaluated resulting in the bdfs as per the ASTRO criteria to be 76% at 36 months. Prostate biopsy was performed in 14.1% of patients, was positive in 26.3% of those suspected of cancer recurrence and 3.7% of treated patients. The side effect profile included 98.4% continence rate (defined as use of 0 pads), 58.1% potency rate, 1.1% urinary retention rate and 0.1% rectourethral fistula rate. Three-dimensional (3D) prostate mapping biopsy has previously been shown to safely and accurately stage prostate cancer, and is especially useful in defining the area of cancer foci within the prostate gland when selecting patients for focal cryotherapy. 60,61 The value of it has also been seen when excluding patients from TFT by detecting clinically significant cancer outside the area that was to be focally ablated. 62 3D mapping is especially useful given the heterogeneity of prostate cancer even within a given prostate gland. 63 At our own institution we conducted the first Institutional Review Board (IRB) approved prospective study for focal treatment as guided by 3D mapping biopsy of the prostate (see Fig. 2). We treated more than 100 men with early prostate cancer. The initial short term results are encouraging and the findings are in process for publication in the near future. 64 TFT appears to have a similar efficacy as whole gland cryoablation but with minimal side effects, analogous to lumpectomy in breast cancer treatment. 65 The data presented above include a learning curve for the surgeon and future trends are likely to demonstrate an equal or better side effect profile. If it follows the previous trend in the last 10 years, the use of focal treatment is likely to increase. Local recurrence No cryotherapy specific algorithms for follow-up have been universally adopted. Residual tissue by definition remains, even in whole gland ablation where the periurethral tissue is saved by the urethral warmer. The ASTRO and Phoenix criteria are the most used criteria for determining bdfs. However, modifications have been proposed to help define the nadir, especially in TFT. Lambert et al. evaluated 25 TFT patients and used a definition of more than 50% reduction in PSA as the cutoff for recurrence based on the idea that half the prostate was ablated. 66 Post-treatment biopsy remains a useful marker for surveillance, however the triggers to obtain a biopsy are not clearly defined. Some clinicians use either of the radiation definitions. Biopsy results may be unclear, but must be done one year after the cryotherapy. 67 Patient selection may be one of the most important determinants for cryotherapy to be successful. Eggener et al. proposed that ideal patients for TFT have tumours that are low stage and low grade: clinical T1 T2a, PSA<10 ng/ml, PSA density less than 0.15 ng/ml, PSA velocity less than 2 ng/ml annually, and no evidence of Gleason 2 or 5 or extraprostatic extension. 68 Conclusion The best treatment for prostate cancer is a hotly debated topic that has showed a trend towards minimally invasive treatments with lower side effect profiles. Radical treatment has been challenged as overtreatment for low risk disease due to its higher side-effect profile with potentially no increase in survival. Consequently, active surveillance has gained popularity as treatment for low risk prostate cancer. Delayed intervention is not without its risks and retrospective studies have shown that patients who would have been active surveillance candidates at the time of radical prostatectomy have had upgrading and upstaging of their disease Recent studies have demonstrated that up to 26% of patients under active surveillance protocols who later selected radical treatment experienced a 50% rate of biochemical recurrence at a median 6.8 years of follow-up. 72 The short-term benefits of surveillance may not outweigh the long-term cancer outcomes of treatment. With the advent of ablative techniques, low-risk prostate cancer can now be treated with minimally invasive technologies that have a lower side effect profile. Despite the lack of identifiable risk factors for complications, modern cryotherapy is considered safe, and a majority of postoperative events tend to be short lived. 73 As such, cryotherapy utilisation has increased in the last decade with a paradigm shift mirroring current cancer treatment trends towards focal ablation. The oncologic outcomes for cryotherapy are promising, including the use of targeted focal cryotherapy. With proper patient selection, focal cryoablation s side effect profile on urinary, sexual and bowel function appears to be less than that of radical therapies. 74 Clinicians are still gaining an understanding of prostate cancer biology including the multifocality of prostate tumours. Focused ablation centres around the concept of destroying the index lesion and leaving the low-grade slow-growing small satellite lesions (<0.5 cm). 76 No long term comparisons have been studied to understand the true risk of remaining satellite lesions. 76,77 Future analyses of

7 Phillips et al. 7 whole gland, salvage and focal cryoablation are needed to evaluate the long term oncologic outcomes. Future directions If technical advances in tumour imaging, tumour targeting and cryotherapy technique continue to improve, TFT with cryotherapy should become even better at targeting prostate cancer. Additionally, a more thorough understanding of the molecular phenomena associated with cryosurgery will also increase the targeting potential of this treatment modality. To this end, Kimura et al. investigated the role and morphology of cryotherapy-induced tissue hypoxia, citing a positive correlation between hypoxia and tissue necrosis and apoptosis, especially in the peripheral zone of the impact area. 78 Evaluation of adjunctive therapies including chemotherapeutic agents and immunotherapy may improve the apoptosis and coagulative necrosis effects of cryotherapy. 79 Dendritic cells, in particular, may lead to an increase in tumour antigens and inflammatory signals. 80 Specific tumour antigens can then be presented to cytotoxic lymphocytes that initiate an antitumour response. Many institutions, including our own, are evaluating the role of immunotherapies in augmenting the effects of cryotherapy. In fact, a recent study utilizing pre-conditioning with tumor necrosis factor alpha (TNF-alpha) has been shown in mice to enhance cryosurgical lesions via an augmented immune response and increased tumor cell damage. 81 This study was based on earlier findings of decreased cell survival with in vitro usage of TNF-alpha on human prostate cancer cell lines undergoing simulated cryoablation. 82 Vitamin D3, or calcitriol, has also been implicated as a potential cryosensitising agent. Santucci et al. examined the peripheral area of the freeze zone in a murine model, and were able to show increases in cell death following dual freeze cycles from 65% with cryotherapy alone to 90% with the addition of calcitriol. Indeed, the future of adjunct therapies with cryotherapy proves promising and exciting. 83 A universal definition of treatment success will also be required as this focal technique continues to be implemented, with a great need for studies with long-term follow-up. Additionally, future comparisons of the data should utilise studies that implemented the same technology (i.e. same generation cryotherapy mechanism; same imaging modalities) so as to facilitate a more even comparison. 27 As of now, cryotherapy has a definitive role in low-risk prostate cancer. Targeted focal cryotherapy remains in its infancy and long-term success has yet to be proven. Additional studies are needed to determine methods of proper patient selection for this evolving and improving technology. Conflicts of interest None declared. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. References 1. Siegel R, Naishadham D and Jemal A. Cancer statistics, CA Cancer J Clin 2012;62: Jemal A, Siegel R, Xu J and Ward E. Cancer statistics, CA Cancer J Clin;60: Catalona WJ, Smith DS, Ratliff TL, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med 1991;324: Cooperberg MR, Lubeck DP, Meng MV, Mehta SS and Carroll PR. The changing face of low-risk prostate cancer: trends in clinical presentation and primary management. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2004;22: Koppie TM, Grossfeld GD, Miller D, et al. Patterns of treatment of patients with prostate cancer initially managed with surveillance: results from The CaPSURE database. Cancer of the Prostate Strategic Urological Research Endeavor. J Urol 2000;164: Etzioni R, Penson DF, Legler JM, et al. Overdiagnosis due to prostate-specific antigen screening: lessons from U.S. prostate cancer incidence trends. J Natl Cancer Inst 2002;94: Babaian RJ, Donnelly B, Bahn D, et al. Best practice statement on cryosurgery for the treatment of localized prostate cancer. J Urol 2008;180: Jones JS, Rewcastle JC, Donnelly BJ, Lugnani FM, Pisters LL and Katz AE. Whole gland primary prostate cryoablation: initial results from the cryo on-line data registry. J Urol 2008;180: Pisters LL, Rewcastle JC, Donnelly BJ, Lugnani FM, Katz AE and Jones JS. Salvage prostate cryoablation: initial results from the cryo on-line data registry. J Urol 2008;180:559 63; discussion Katz AE and Kacker R. Focal treatment for low-risk prostate cancer. BJU international 2008;102: David C Miller, Louis Leon Pisters and Arie S Belldegrun. Cryotherapy for Prostate Cancer. In: Campbell-Walsh Urology. 10 ed: Elsiever. Sanders.; Philadelphia PA; [accessed online] Gowardhan B and Greene D. Cryotherapy for the prostate: an in vitro and clinical study of two new developments; advanced cryoneedles and a temperature monitoring system. BJU Int 2007;100: Witzsch UK, Skriapas K and Becht E. [Cryoablation of prostate cancer]. Urologe A 2008;47: Cookson MS, Aus G, Burnett AL, Canby-Hagino ED, D Amico AV, Dmochowski RR, et al. Variation in the definition of biochemical recurrence in patients treated for localized prostate cancer: the American Urological Association Prostate Guidelines for Localized Prostate Cancer Update Panel report and recommendations for a standard in the reporting of surgical outcomes. J Urol 2007;177: Greene GF, Pisters LL, Scott SM and Von Eschenbach AC. Predictive value of prostate specific antigen nadir after salvage cryotherapy. J Urol 1998;160:86 90.

8 8 Journal of Clinical Urology 16. Polascik TJ, Nosnik I, Mayes JM and Mouraviev V. Shortterm cancer control after primary cryosurgical ablation for clinically localized prostate cancer using third-generation cryotechnology. Urology 2007;70: Donnelly BJ, Saliken JC, Ernst DS, et al. Role of transrectal ultrasound guided salvage cryosurgery for recurrent prostate carcinoma after radiotherapy. Prostate cancer and prostatic diseases 2005;8: Prepelica KL, Okeke Z, Murphy A and Katz AE. Cryosurgical ablation of the prostate: high risk patient outcomes. Cancer 2005;103: Long JP, Bahn D, Lee F, Shinohara K, Chinn DO and Macaluso JN, Jr. Five-year retrospective, multi-institutional pooled analysis of cancer-related outcomes after cryosurgical ablation of the prostate. Urology 2001;57: Cohen JK, Miller RJ, Jr., Ahmed S, Lotz MJ and Baust J. Ten-year biochemical disease control for patients with prostate cancer treated with cryosurgery as primary therapy. Urology 2008;71: Ritch CR and Katz AE. Update on cryotherapy for localized prostate cancer. Current urology reports 2009;10: Pitman M, Shapiro EY, Hruby GW, et al. Comparison of biochemical failure definitions for predicting local cancer recurrence following cryoablation of the prostate. Prostate 2012;72: Gretzer MB, Trock BJ, Han M and Walsh PC. A critical analysis of the interpretation of biochemical failure in surgically treated patients using the American Society for Therapeutic Radiation and Oncology criteria. J Urol 2002;168: Nielsen ME, Makarov DV, Humphreys E, Mangold L, Partin AW and Walsh PC. Is it possible to compare PSA recurrence-free survival after surgery and radiotherapy using revised ASTRO criterion XXX nadir + 2? Urology 2008;72: discussion Levy DA, Pisters LL and Jones JS. Primary cryoablation nadir prostate specific antigen and biochemical failure. J Urol 2009;182: Cheetham P, Truesdale M, Chaudhury S, Wenske S, Hruby GW and Katz A. Long-term cancer-specific and overall survival for men followed more than 10 years after primary and salvage cryoablation of the prostate. J Endourol 2010;24: Langenhuijsen JF, Broers EM and Vergunst H. Cryosurgery for prostate cancer: an update on clinical results of modern cryotechnology. Eur Urol 2009;55: Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2005;352: Wilt TJ, MacDonald R, Rutks I, Shamliyan TA, Taylor BC and Kane RL. Systematic review: comparative effectiveness and harms of treatments for clinically localized prostate cancer. Annals of internal medicine 2008; 148: Pisters LL. Cryotherapy for prostate cancer: ready for prime time? Curr Opin Urol 2010;20: Cresswell J, Asterling S, Chaudhary M, Sheikh N and Greene D. Third-generation cryotherapy for prostate cancer in the UK: a prospective study of the early outcomes in primary and recurrent disease. BJU Int 2006;97: Han KR, Cohen JK, Miller RJ, et al. Treatment of organ confined prostate cancer with third generation cryosurgery: preliminary multicenter experience. J Urol 2003;170: Ismail M, Ahmed S, Kastner C and Davies J. Salvage cryotherapy for recurrent prostate cancer after radiation failure: a prospective case series of the first 100 patients. BJU international 2007;100: Hubosky SG, Fabrizio MD, Schellhammer PF, Barone BB, Tepera CM and Given RW. Single center experience with third-generation cryosurgery for management of organconfined prostate cancer: critical evaluation of short-term outcomes, complications, and patient quality of life. Journal of endourology / Endourological Society 2007;21: Ritch CR and Katz AE. Prostate cryotherapy: current status. Curr Opin Urol 2009;19: De Meerleer GO, Fonteyne VH, Vakaet L, et al. Intensitymodulated radiation therapy for prostate cancer: late morbidity and results on biochemical control. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 2007;82: Zapatero A, Minguez R, Nieto S, Martin de Vidales C and Garcia-Vicente F. Post-treatment prostate biopsies in the era of three-dimensional conformal radiotherapy: what can they teach us? European urology 2009;55: Cox JM and Busby JE. Salvage therapy for prostate cancer recurrence after radiation therapy. Curr Urol Rep 2009;10: Stephenson AJ, Scardino PT, Bianco FJ, Jr., DiBlasio CJ, Fearn PA and Eastham JA. Morbidity and functional outcomes of salvage radical prostatectomy for locally recurrent prostate cancer after radiation therapy. J Urol 2004;172: Stephenson AJ, Scardino PT, Bianco FJ Jr. and Eastham JA. Salvage therapy for locally recurrent prostate cancer after external beam radiotherapy. Current treatment options in oncology 2004;5: Izawa JI, Perrotte P, Greene GF, et al. Local tumor control with salvage cryotherapy for locally recurrent prostate cancer after external beam radiotherapy. J Urol 2001;165: Han M, Partin AW, Zahurak M, Piantadosi S, Epstein JI and Walsh PC. Biochemical (prostate specific antigen) recurrence probability following radical prostatectomy for clinically localized prostate cancer. J Urol 2003;169: Ng CK, Moussa M, Downey DB and Chin JL. Salvage cryoablation of the prostate: followup and analysis of predictive factors for outcome. J Urol 2007;178:1253 7; discussion Stephenson AJ, Shariat SF, Zelefsky MJ, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA 2004;291: Williams AK, Martinez CH, Lu C, Ng CK, Pautler SE and Chin JL. Disease-free survival following salvage cryotherapy for biopsy-proven radio-recurrent prostate cancer. Eur Urol 2011;60: Chin JL, Touma N, Pautler SE, et al. Serial histopathology results of salvage cryoablation for prostate cancer after radiation failure. J Urol 2003;170: Ng CK, Touma NJ, Chalasani V, Moussa M, Downey DB and Chin JL. The pattern of prostate cancer local recurrence

9 Phillips et al. 9 after radiation and salvage cryoablation. Can Urol Assoc J 2011;5:E Pisters LL, Leibovici D, Blute M, et al. Locally recurrent prostate cancer after initial radiation therapy: a comparison of salvage radical prostatectomy versus cryotherapy. J Urol 2009;182:517 25; discussion Izawa JI, Madsen LT, Scott SM, et al. Salvage cryotherapy for recurrent prostate cancer after radiotherapy: variables affecting patient outcome. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2002;20: Spiess PE, Lee AK, Leibovici D, Wang X, Do KA and Pisters LL. Presalvage prostate-specific antigen (PSA) and PSA doubling time as predictors of biochemical failure of salvage cryotherapy in patients with locally recurrent prostate cancer after radiotherapy. Cancer 2006;107: Levy DA, Li J and Jones JS. Disease burden predicts for favorable post salvage cryoablation PSA. Urology 2010;76: Spiess PE, Katz AE, Chin JL, et al. A pretreatment nomogram predicting biochemical failure after salvage cryotherapy for locally recurrent prostate cancer. BJU Int 2010;106: Long JP, Fallick ML, LaRock DR and Rand W. Preliminary outcomes following cryosurgical ablation of the prostate in patients with clinically localized prostate carcinoma. J Urol 1998;159: Kimura M, Mouraviev V, Tsivian M, Moreira DM, Mayes JM and Polascik TJ. Analysis of urinary function using validated instruments and uroflowmetry after primary and salvage prostate cryoablation. Urology 2010;76: Anastasiadis AG, Sachdev R, Salomon L, et al. Comparison of health-related quality of life and prostate-associated symptoms after primary and salvage cryotherapy for prostate cancer. Journal of cancer research and clinical oncology 2003;129: Eisenberg ML and Shinohara K. Partial salvage cryoablation of the prostate for recurrent prostate cancer after radiotherapy failure. Urology 2008;72: Onik G, Vaughan D, Lotenfoe R, Dineen M and Brady J. The male lumpectomy : focal therapy for prostate cancer using cryoablation results in 48 patients with at least 2-year follow-up. Urologic oncology 2008;26: Ellis DS, Manny TB, Jr. and Rewcastle JC. Focal cryosurgery followed by penile rehabilitation as primary treatment for localized prostate cancer: initial results. Urology 2007;70: Ward JF and Jones JS. Focal cryotherapy for localized prostate cancer: a report from the national Cryo On-Line Database (COLD) Registry. BJU international 2011;11: Onik G, Miessau M and Bostwick DG. Three-dimensional prostate mapping biopsy has a potentially significant impact on prostate cancer management. J Clin Oncol 2009;27: Onik G and Barzell W. Transperineal 3D mapping biopsy of the prostate: an essential tool in selecting patients for focal prostate cancer therapy. Urol Oncol 2008;26: Barzell WE and Melamed MR. Appropriate patient selection in the focal treatment of prostate cancer: the role of transperineal 3-dimensional pathologic mapping of the prostate a 4-year experience. Urology 2007;70: Bostwick DG, Waters DJ, Farley ER, et al. Group consensus reports from the Consensus Conference on Focal Treatment of Prostatic Carcinoma, Celebration, Florida, February 24, Urology 2007;70: Barqawi AB and Crawford ED. The current use and future trends of focal surgical therapy in the management of localized prostate cancer. Cancer J 2007;13: Onik G, Vaughan D, Lotenfoe R, Dineen M and Brady J. Male lumpectomy : focal therapy for prostate cancer using cryoablation. Urology 2007;70: Lambert EH, Bolte K, Masson P and Katz AE. Focal cryosurgery: encouraging health outcomes for unifocal prostate cancer. Urology 2007;69: Izawa JI, Busby JE, Morganstern N, Vakar-Lopez F, Scott SM and Pisters LL. Histological changes in prostate biopsies after salvage cryotherapy: effect of chronology and the method of biopsy. BJU international 2006;98: Eggener SE, Scardino PT, Carroll PR, et al. Focal therapy for localized prostate cancer: a critical appraisal of rationale and modalities. J Urol 2007;178: Ploussard G, Salomon L, Xylinas E, et al. Pathological findings and prostate specific antigen outcomes after radical prostatectomy in men eligible for active surveillance does the risk of misclassification vary according to biopsy criteria? J Urol 2010;183: Smaldone MC, Cowan JE, Carroll PR and Davies BJ. Eligibility for active surveillance and pathological outcomes for men undergoing radical prostatectomy in a large, community based cohort. J Urol 2010;183: Thaxton CS, Loeb S, Roehl KA, Kan D and Catalona WJ. Treatment outcomes of radical prostatectomy in potential candidates for 3 published active surveillance protocols. Urology 2010;75: Klotz L, Zhang L, Lam A, Nam R, Mamedov A and Loblaw A. Clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010;28: Caso JR, Tsivian M, Mouraviev V, Kimura M and Polascik TJ. Complications and postoperative events after cryosurgery for prostate cancer. BJU Int 2012;109: Finley DS, Pouliot F, Miller DC and Belldegrun AS. Primary and salvage cryotherapy for prostate cancer. Urol Clin North Am 2010;37:67 82, Table of Contents. 75. Ahmed HU. The index lesion and the origin of prostate cancer. N Engl J Med 2009;361: Nelson BA, Shappell SB, Chang SS, et al. Tumour volume is an independent predictor of prostate-specific antigen recurrence in patients undergoing radical prostatectomy for clinically localized prostate cancer. BJU international 2006;97: Villers A, McNeal JE, Freiha FS and Stamey TA. Multiple cancers in the prostate. Morphologic features of clinically recognized versus incidental tumors. Cancer 1992;70: Kimura M, Rabbani Z, Mouraviev V, et al. Morphology of hypoxia following cryoablation in a prostate cancer murine model: its relationship to necrosis, apoptosis and, microvessel density. Cryobiology 2010;61:

10 10 Journal of Clinical Urology 79. Clarke DM, Baust JM, Van Buskirk RG and Baust JG. Addition of anticancer agents enhances freezing-induced prostate cancer cell death: implications of mitochondrial involvement. Cryobiology 2004;49: Machlenkin A, Goldberger O, Tirosh B, et al. Combined dendritic cell cryotherapy of tumor induces systemic antimetastatic immunity. Clin Cancer Res 2005;11: Jiang J, Goel R, Schmechel S, Vercellotti G, Forster C and Bischof J. Pre-conditioning cryosurgery: cellular and molecular mechanisms and dynamics of TNF-alpha enhanced cryotherapy in an in vivo prostate cancer model system. Cryobiology 2010;61: Geeslin MG, Swanlund DJ and Bischof JC. A parametric study of freezing injury in BPH1CAFTD-2 human prostate tumor cells. Cryo Letters 2007;28: Santucci KL, Snyder KK, Baust JM, et al. Use of 1,25alpha dihydroxyvitamin D3 as a cryosensitizing agent in a murine prostate cancer model. Prostate Cancer Prostatic Dis 2011; 14: