British Journal of Medical and Surgical Urology (2012) 5S, S35S38

Current status of cryotherapy in prostate cancer

A.S.M. Ali a,b , H. Smith a , D. Greene a, *
a b

Department of Urology, Sunderland Royal Hospital, Sunderland, UK Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK

Introduction
In recent years there has been growing interest in development of alternative ablative therapies that attempt to avoid the morbidity, sideeffects and expense of conventional radical therapies whilst retaining cancer control and avoiding the psychological morbidity associated with surveillance. Cryotherapy of the prostate was first described 45-years ago [1] and has been used clinically for over two decades and currently represents the most studied and utilised ablative technique for prostate cancer treatment. It is considered to be a relatively inexpensive, effective treatment for prostate cancer that can be applied in a focal or whole gland pattern. The complications of cryotherapy have also been greatly reduced as a result of technical improvements. This review will assess the potential and current status of cryotherapy in the management of prostate cancer.

Technology
When first introduced 2030 years ago, much like radiotherapy and surgery in their infancy, prostate Cryotherapy had an unacceptably high complication rate but since then it has undergone considerable

* Corresponding author. Prof. Damian Greene, Department of Urology, Sunderland Royal Hospital, Kayll Road, Sunderland, Tyne and Wear, SR4 7TP, UK. Tel.: +44 (0) 191 565 6256. E-mail address: Damien.Greene@chsft.nhs.uk (D. Greene).

technical improvements that have significantly reduced the complication rate to a much lower and acceptable rate. The first-generation of cryosurgery ablation for prostate cancer was carried out without transrectal ultrasound guidance and urethral warmers which resulted in a high incidence of complications (urinary incontinence, urethral sloughing, and recto-urethral fistulae). The use of transrectal ultrasound by the 1990s in second generation devices enabled accurate percutaneous needle placement and monitoring of the prostatic iceball, improving the precision of tissue ablation and minimising the risk of injury to adjacent structures such as the rectum, bladder, and urethra [2]. These devices were also used with urethral warming catheters which helped reduce the risk of urethral sloughing and incontinence [3]. By the early 2000s, pinpoint needle thermocouples were also included and these could be placed transperineally to give accurate temperature readings originally at the tip then later along the entire shaft of the needle [4]. Thermocouples are able to ensure that lethal temperatures are achieved in the prostate (40C) while the temperature is kept warmer temperatures at critical points outside of the prostate such as at Denonvillier' s fascia and the external sphincter. The latest third-generation devices have also seen a transition from liquid nitrogen as the cryogen to argon gas [5]. Pressurized argon gas is used to freeze and then helium gas to actively thaw. Thus facilitating the development of much thinner probes that can be inserted percutaneously through a brachytherapytype template which coupled with computer software enables more precise treatment and optimal

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S36 targeting of the prostate while avoiding damage to important structures.

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Focal therapy
Analysis of radical prostatectomy specimens has revealed that a significant percentage of patients diagnosed with the disease have single focus prostate cancer and many additional patients have secondary foci that may not be clinically significant [10,11]. The concept of focal cryotherapy is therefore based upon the premise that with accurate identification of the extent of disease, ablative therapy could be restricted to the diseased portion (or half) of the gland. Due to the limitations of current imaging techniques however, focal therapy is increasingly guided by a large number of transperineal template mapping biopsies which allow accurate targeting of the tumour. Preliminary data is now available from a number of studies in relation to cancer control following focal Cryotherapy. One of the first reports showing favourable results was produced by Bahn et al. in 2006 and showed 93% bDFS (as per ASTRO criteria) over an average follow-up of 70 months [12]. In one patient with biochemical recurrence, PCa was detected on subsequent biopsy in the apex of the untreated side. On average, patients had two or more biopsies after treatment with no evidence of new cancer. Subsequently in 2007, a series by Onik et al. reported that after a minimum of 1-year followup in 55 treated patients, 95% had stable PSA levels [13]. Furthermore, none of the patients had histological evidence of cancer on their routine repeat biopsy 1-year after therapy (including those with a biochemical recurrence). In a later analysis of 48 patients with at least 2-years follow-up, the same group demonstrated that the effectiveness of focal cryotherapy was maintained at longer followup [14]. Also in 2007, Ellis et al., published their slightly larger series of 60 patients from all risk groups in which they reported a somewhat lower 80.4% bDFS with an average follow-up of 15 months [15]. However, post-treatment biopsies were carried out in 35 patients and of the 14 that had cancer detected, 13 had it on the untreated side of the prostate. Lambert et al. reported on 25 patients treated for unifocal prostate cancer with a median follow-up of 28 months where bDFS was observed in 88% of patients [16]. The latest data again comes from the American led national Cryo On-Line Database (COLD) Registry. Ward and Jones analysed the registry from 1997 to 2007 to identify patients treated with partial gland cryoablation. Records of 1160 patients were examined and a biochemical recurrence-free rate of 75.7% for all risk groups at 36 months was calculated [17]. In summary, taken as a whole the reported series to date have shown very encouraging short-term

Primary treatment for prostate cancer

In the National Institute for Clinical Excellence (NICE) prostate cancer guidelines of 2008, cryotherapy was not recommended for men with localised prostate cancer other than in the context of controlled clinical trials comparing their use with established interventions. In contrast, also in 2008, the American Urological Association Best Practice Statement panel gave the consensus opinion that primary cryotherapy is an option for men who have clinically organ-confined prostate cancer of any grade without evidence of metastasis [6]. However the panel noted that there was no data the panel could use to make a statement about end points to measure success of cryosurgical treatment. While there are defined biochemical standards of treatment success for both radiation therapy and surgery, no such criteria exist for cryosurgery [7,8]. However, both of these guidelines were developed prior to the first randomised trial published Donnelly et al. in 2010 [9]. The Canadian group published the results of a randomized, unblinded, noninferiority trial to compare cryoablation with external beam radiotherapy in these patients. The trial randomized 244 men with clinical stage T2 or T3 prostate cancer with all patients initially given neoadjuvant antiandrogen treatment after which half were treated with whole-gland cryotherapy and the other half with external beam radiotherapy. Biochemical disease-free survival (bDFS) was assessed at 3-years using two definitions (two consecutive PSA rises with a value above 1 ng/ml and nadir plus 2ng/ml). Noninferiority was defined at the outset as a 10% or less difference in biochemical outcome between the two arms. Unfortunately, although the bDFS in both arms was similar, there were large confidence intervals and the study was slightly underpowered to confirm noninferiority. However, the longer term trend for bDFS favoured the cryotherapy arm. More recently, Dhar et al. reported on primary full-gland prostate cryoablation in older men (over the age of 75) from the American Cryo OnLine Database (COLD) Registry. Again, two definitions were used (American Society for Therapeutic Radiation and Oncology [ASTRO] criterion 3 PSA rises and Phoenix criterion nadir +2), resulting in a 5-year bDFS for the entire population of 79% (ASTRO) and 62.6% (Phoenix). When stratified by risk group, 5-year bDFS under ASTRO criterion was 82.4%, 78.3%, and 77.6% for low, moderate and high risk disease, respectively.

Current status of cryotherapy in prostate cancer cancer control outcomes for focal cryotherapy. Although, there is variability in the rate of biochemical recurrence in the different reports, direct comparisons remain difficult as at least some of the difference is due to patient selection.

S37 For primary cryotherapy, rectal fistula, which was an important complication in early studies is now very rare, with quoted incidences of between 0 and 0.5% [2426]. Incontinence (requiring pads) has also become much less common since the switch to Argon gas as the cryogen, with reported incidences ranging from less than 1 to 8% [16]. In contrast the risk of erectile dysfunction in the first year is relatively high with a range from 49 to 93% reported [24,27]. However, this ice-injury is less severe than surgical injury as the nerve sheath often remains intact enhancing the potential for recovery of erectile function as demonstrated by penile rehabilitation regimes where rates of potency were reported by Ellis et al. as 51.3% at 4 years [28]. Nonetheless, whole-gland cryotherapy is still probably best reserved for patients in whom erectile function is not a major concern. The functional outcomes for focal therapy are better as one might expect. There are no reports of bowel-related morbidity in contemporary series and the majority of series report that continence is preserved in patients with no-one requiring pads [13,14,16], only one study reported 3.6% of incontinence [15]. In terms of potency, the reported rates range from 90% to 71% [13,14,16] With their rehabilitation programme, Ellis et al. reported 70% potency within 12 months from the treatment [15]. Measuring functional outcomes for salvage cryotherapy is more complex due to the effects of prior treatment and different levels of disease progression. An in depth discussion is beyond the scope of this review but it should be noted that the complications reported in the 2008 COLD Registry report on salvage cryotherapy compared favourably with salvage prostatectomy [29,30]. The incontinence rate was 4.4%, rectal fistula rate was 1.2% and 3.2% underwent TURP to remove sloughed tissue [30].

Salvage therapy
The early use of cryosurgery from the late 1990s was primarily as a salvage procedure in cases of recurrent disease following radiotherapy based on threshold PSA levels [18,19]. These were initially defined by ASTRO criterion and then later by the Phoenix criterion [20]. There have been numerous studies reporting outcomes after salvage therapy but due to changing definitions, variable pre-treatment PSA, staging, follow-up, etc. make comparisons between series very difficult. One of the largest single-centre studies is published by Izawa et al. from MD Anderson in Texas and includes 131 patients with a median follow-up of 4.8 years. Using criterion that were the same as later agreed in Phoenix, they reported 5-year bDFS rates of 57% and 23% for patients with pretreatment PSA levels of 10 ng/mL and 10 ng/mL, respectively. They also stratified according to preradiotherapy clinical stage, bDFS rates for T1/T2 and T3/T4 disease were 90% and 69% respectively [21]. More recently, a large multi-institutional study by Spiess et al. pooled 450 salvage patients to create a pre-treatment nomogram [22]. At a median follow-up of 3.4 years, the rate of biochemical failure was 66%, predictors of biochemical failure included serum PSA and Gleason score at diagnosis. The most contemporary data comes from the COLD registry. At the 2012 annual meeting of the AUA an update was provided of outcome from salvage cryotherapy for locally recurrent prostate cancer. Long-term results were available for 132 patients who underwent salvage cryotherapy with curative intent, without hormonal therapy and with serial PSA measuerments [23]. With a mean follow-up of 4.3 years, the 1, 2, and 5 year actuarial biochemical disease-free survival rates using the Phoenix definition were 87.8%, 72.4%, and 45.5%, respectively.

Conclusion
Recent technological advances have significantly reduced the morbidity of cryotherapy to a low and acceptable level. While still a relatively new therapeutic approach, available data indicates similar efficacy to alternative approaches. Whole-gland cryotherapy may be considered as an alternative treatment in men with localised disease or as a salvage treatment following radiotherapy. Focal cryotherapy also shows promising early results with the potential for preserving potency in up to 90% of men. Nonetheless, it is paramount for future studies that a definition is created for treatment success until then it will remain difficult to delineate the true efficacy of this treatment.

Functional outcomes
As for other treatment modalities for prostate cancer, functional outcomes in cryotherapy are frequently of equal importance to patients as cancer outcomes. Not surprisingly however, the functional outcomes will vary according to the indication for cryotherapy.

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