current status of cryotherapy in prostate cancer - ali

7/28/2019 Current Status of Cryotherapy in Prostate Cancer - Ali

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

Introduction

In recent years there has been growing inter-est in development of alternative ablative ther-apies that attempt to avoid the morbidity, side-effects and expense of conventional radical ther-apies whilst retaining cancer control and avoidingthe psychological morbidity associated with surveil-lance. Cryotherapy of the prostate was first de-scribed 45-years ago [1] and has been used clini-cally for over two decades and currently representsthe most studied and utilised ablative techniquefor prostate cancer treatment. It is considered tobe a relatively inexpensive, effective treatment forprostate cancer that can be applied in a focal orwhole gland pattern. The complications of cryother-apy have also been greatly reduced as a result oftechnical improvements. This review will assess thepotential and current status of cryotherapy in themanagement of prostate cancer.

Technology

When first introduced 20

30 years ago, much likeradiotherapy and surgery in their infancy, prostateCryotherapy had an unacceptably high complicationrate but since then it has undergone considerable

* Corresponding author. Prof. Damian Greene, Department ofUrology, Sunderland Royal Hospital, Kayll Road, Sunderland,Tyne and Wear, SR4 7TP, UK. Tel.: +44 (0) 191 565 6256.

E-mail address: [email protected] (D. Greene).

1875-9742/$ see front matter 2012 British Association of Urological Surgeons. Published by Elsevier Ltd. All rights reserved.

technical improvements that have significantly re-duced the complication rate to a much lower andacceptable rate. The first-generation of cryosurgeryablation for prostate cancer was carried out withouttransrectal ultrasound guidance and urethral warm-ers which resulted in a high incidence of complica-tions (urinary incontinence, urethral sloughing, andrecto-urethral fistulae). The use of transrectal ul-trasound by the 1990s in second generation devicesenabled accurate percutaneous needle placementand monitoring of the prostatic iceball, improvingthe precision of tissue ablation and minimising therisk of injury to adjacent structures such as the rec-tum, bladder, and urethra [2]. These devices werealso used with urethral warming catheters whichhelped reduce the risk of urethral sloughing and in-continence [3]. By the early 2000s, pinpoint needlethermocouples were also included and these couldbe placed transperineally to give accurate temper-ature readings originally at the tip then later alongthe entire shaft of the needle [4]. Thermocouplesare able to ensure that lethal temperatures areachieved in the prostate (40C) while the tem-perature is kept warmer temperatures at critical

points outside of the prostate such as at Denonvil-lier's fascia and the external sphincter. The latestthird-generation devices have also seen a transitionfrom liquid nitrogen as the cryogen to argon gas [5].Pressurized argon gas is used to freeze and thenhelium gas to actively thaw. Thus facilitating thedevelopment of much thinner probes that can beinserted percutaneously through a brachytherapy-type template which coupled with computer soft-ware enables more precise treatment and optimal


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targeting of the prostate while avoiding damage toimportant structures.

Primary treatment for prostate cancer

In the National Institute for Clinical Excellence

(NICE) prostate cancer guidelines of 2008, cryother-apy was not recommended for men with localisedprostate cancer other than in the context of con-trolled clinical trials comparing their use with estab-lished interventions. In contrast, also in 2008, theAmerican Urological Association Best Practice State-ment panel gave the consensus opinion that primarycryotherapy is an option for men who have clinicallyorgan-confined prostate cancer of any grade with-out evidence of metastasis [6]. However the panelnoted that there was no data the panel could useto make a statement about end points to measure

success of cryosurgical treatment. While there aredefined biochemical standards of treatment successfor both radiation therapy and surgery, no such cri-teria exist for cryosurgery [7,8].

However, both of these guidelines were devel-oped prior to the first randomised trial publishedDonnelly et al. in 2010 [9]. The Canadian grouppublished the results of a randomized, unblinded,noninferiority trial to compare cryoablation withexternal beam radiotherapy in these patients. Thetrial randomized 244 men with clinical stage T2 orT3 prostate cancer with all patients initially givenneoadjuvant antiandrogen treatment after whichhalf were treated with whole-gland cryotherapy andthe other half with external beam radiotherapy. Bio-chemical disease-free survival (bDFS) was assessedat 3-years using two definitions (two consecutivePSA rises with a value above 1 ng/ml and nadir plus2ng/ml). Noninferiority was defined at the outsetas a 10% or less difference in biochemical outcomebetween the two arms. Unfortunately, although thebDFS in both arms was similar, there were largeconfidence intervals and the study was slightly un-derpowered to confirm noninferiority. However, thelonger term trend for bDFS favoured the cryother-

apy arm. More recently, Dhar et al. reported on pri-mary full-gland prostate cryoablation in older men(over the age of 75) from the American Cryo On-Line Database (COLD) Registry. Again, two defini-tions were used (American Society for Therapeu-tic Radiation and Oncology [ASTRO] criterion 3PSA rises and Phoenix criterion nadir +2), result-ing in a 5-year bDFS for the entire population of79% (ASTRO) and 62.6% (Phoenix). When stratifiedby risk group, 5-year bDFS under ASTRO criterionwas 82.4%, 78.3%, and 77.6% for low, moderate andhigh risk disease, respectively.

Focal therapy

Analysis of radical prostatectomy specimens has re-vealed that a significant percentage of patients di-agnosed with the disease have single focus prostatecancer and many additional patients have secondaryfoci that may not be clinically significant [10,11].

The concept of focal cryotherapy is therefore basedupon the premise that with accurate identificationof the extent of disease, ablative therapy could berestricted to the diseased portion (or half) of thegland. Due to the limitations of current imagingtechniques however, focal therapy is increasinglyguided by a large number of transperineal templatemapping biopsies which allow accurate targeting ofthe tumour.

Preliminary data is now available from a numberof studies in relation to cancer control following fo-cal Cryotherapy. One of the first reports showing

favourable results was produced by Bahn et al. in2006 and showed 93% bDFS (as per ASTRO criteria)over an average follow-up of 70 months [12]. In onepatient with biochemical recurrence, PCa was de-tected on subsequent biopsy in the apex of the un-treated side. On average, patients had two or morebiopsies after treatment with no evidence of newcancer. Subsequently in 2007, a series by Onik etal. reported that after a minimum of 1-year follow-up in 55 treated patients, 95% had stable PSA levels[13]. Furthermore, none of the patients had histo-logical evidence of cancer on their routine repeatbiopsy 1-year after therapy (including those with abiochemical recurrence). In a later analysis of 48patients with at least 2-years follow-up, the samegroup demonstrated that the effectiveness of fo-cal cryotherapy was maintained at longer follow-up [14]. Also in 2007, Ellis et al., published theirslightly larger series of 60 patients from all riskgroups in which they reported a somewhat lower80.4% bDFS with an average follow-up of 15 months[15]. However, post-treatment biopsies were carriedout in 35 patients and of the 14 that had cancerdetected, 13 had it on the untreated side of theprostate. Lambert et al. reported on 25 patients

treated for unifocal prostate cancer with a medianfollow-up of 28 months where bDFS was observed in88% of patients [16].

The latest data again comes from the Americanled national Cryo On-Line Database (COLD) Registry.Ward and Jones analysed the registry from 1997to 2007 to identify patients treated with partialgland cryoablation. Records of 1160 patients wereexamined and a biochemical recurrence-free rate of75.7% for all risk groups at 36 months was calculated[17]. In summary, taken as a whole the reported se-ries to date have shown very encouraging short-term


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Current status of cryotherapy in prostate cancer S37

cancer control outcomes for focal cryotherapy. Al-though, there is variability in the rate of biochemi-cal recurrence in the different reports, direct com-parisons remain difficult as at least some of the dif-ference is due to patient selection.

Salvage therapy

The early use of cryosurgery from the late 1990s wasprimarily as a salvage procedure in cases of recur-rent disease following radiotherapy based on thresh-old PSA levels [18,19]. These were initially definedby ASTRO criterion and then later by the Phoenixcriterion [20]. There have been numerous studiesreporting outcomes after salvage therapy but dueto changing definitions, variable pre-treatment PSA,staging, follow-up, etc. make comparisons betweenseries very difficult.

One of the largest single-centre studies is pub-lished by Izawa et al. from MD Anderson in Texasand includes 131 patients with a median follow-upof 4.8 years. Using criterion that were the sameas later agreed in Phoenix, they reported 5-yearbDFS rates of 57% and 23% for patients with pre-treatment PSA levels of10 ng/mL and 10 ng/mL,respectively. They also stratified according to pre-radiotherapy clinical stage, bDFS rates for T1/T2and T3/T4 disease were 90% and 69% respectively[21]. More recently, a large multi-institutional studyby Spiess et al. pooled 450 salvage patients to cre-ate a pre-treatment nomogram [22]. At a median

follow-up of 3.4 years, the rate of biochemical fail-ure was 66%, predictors of biochemical failure in-cluded serum PSA and Gleason score at diagnosis.The most contemporary data comes from the COLDregistry. At the 2012 annual meeting of the AUAan update was provided of outcome from salvagecryotherapy for locally recurrent prostate cancer.Long-term results were available for 132 patientswho underwent salvage cryotherapy with curativeintent, without hormonal therapy and with serialPSA measuerments [23]. With a mean follow-up of4.3 years, the 1, 2, and 5 year actuarial biochemical

disease-free survival rates using the Phoenix defini-tion were 87.8%, 72.4%, and 45.5%, respectively.

Functional outcomes

As for other treatment modalities for prostate can-cer, functional outcomes in cryotherapy are fre-quently of equal importance to patients as canceroutcomes. Not surprisingly however, the functionaloutcomes will vary according to the indication forcryotherapy.

For primary cryotherapy, rectal fistula, which wasan important complication in early studies is nowvery rare, with quoted incidences of between 0 and0.5% [2426]. Incontinence (requiring pads) has alsobecome much less common since the switch to Ar-gon gas as the cryogen, with reported incidencesranging from less than 1 to 8% [16]. In contrast the

risk of erectile dysfunction in the first year is rel-atively high with a range from 49 to 93% reported[24,27]. However, this ice-injury is less severethan surgical injury as the nerve sheath often re-mains intact enhancing the potential for recoveryof erectile function as demonstrated by penile re-habilitation regimes where rates of potency werereported by Ellis et al. as 51.3% at 4 years [28].Nonetheless, whole-gland cryotherapy is still proba-bly best reserved for patients in whom erectile func-tion is not a major concern.

The functional outcomes for focal therapy are

better as one might expect. There are no reportsof bowel-related morbidity in contemporary seriesand the majority of series report that continenceis preserved in patients with no-one requiring pads[13,14,16], only one study reported 3.6% of inconti-nence [15]. In terms of potency, the reported ratesrange from 90% to 71% [13,14,16] With their rehabil-itation programme, Ellis et al. reported 70% potencywithin 12 months from the treatment [15].

Measuring functional outcomes for salvagecryotherapy is more complex due to the effects ofprior treatment and different levels of disease pro-gression. An in depth discussion is beyond the scopeof this review but it should be noted that the com-plications reported in the 2008 COLD Registry reporton salvage cryotherapy compared favourably withsalvage prostatectomy [29,30]. The incontinencerate was 4.4%, rectal fistula rate was 1.2% and 3.2%underwent TURP to remove sloughed tissue [30].

Conclusion

Recent technological advances have significantly re-duced the morbidity of cryotherapy to a low and

acceptable level. While still a relatively new ther-apeutic approach, available data indicates simi-lar efficacy to alternative approaches. Whole-glandcryotherapy may be considered as an alternativetreatment in men with localised disease or asa salvage treatment following radiotherapy. Focalcryotherapy also shows promising early results withthe potential for preserving potency in up to 90% ofmen. Nonetheless, it is paramount for future stud-ies that a definition is created for treatment successuntil then it will remain difficult to delineate thetrue efficacy of this treatment.


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current status of cryotherapy in prostate cancer - ali

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