Focal Therapy in the Management of Localized Prostate Cancer BJUIBJU INTERNATIONAL Carvell T

2010 THE AUTHORS; BJU INTERNATIONAL 2010 BJU INTERNATIONAL Mini Reviews FOCAL THERAPY IN LOCALIZED PROSTATE CANCER NGUYEN and JONES

Focal therapy in the management of localized prostate cancer BJUIBJU INTERNATIONAL Carvell T. Nguyen and J. Stephen Jones Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA Accepted for publication 1 October 2010

OBJECTIVES What’s known on the subject? and What does the study add? Focal therapy, which includes cryotherapy and high-intensity focused ultrasound,is a • To assess the rationale, efficacy, and nascent and somewhat controversial field in the management of prostate cancer. The morbidity of various methods of achieving current review presents the rationale, indications and potential role for focal therapy in focal prostatic ablation. patients withlocalized prostate cancer. • To determine the current role of focal therapy in the management of localized prostate cancer. RESULTS AND CONCLUSIONS • Until we have the ability to identify patients reliably with truly focal disease and METHODS • Focal ablative methods allow targeted predict their natural history, focal therapy destruction of prostatic tissue while limiting cannot be considered to be the definitive • We performed a literature review of focal the morbidity associated with whole-gland therapy for localized prostate cancer. therapy in prostate cancer, with an emphasis therapy. on more established methods such as • Local cancer control after focal therapy KEYWORDS cryoablation and high-intensity focused appears promising but does not approach ultrasound. that of established whole-gland therapies. focal therapy, cryoablation, prostate cancer

INTRODUCTION Investigators of the Prostate, Lung, As such, there has been recent interest in Colorectal and Ovarian screening trial found organ-sparing therapy for controlling local The advent of PSA testing more than two no significant difference in prostate cancer cancer that eschews the invasiveness, decades ago has improved the early death rates between men who were screened morbidity and costs of traditional detection of prostate cancer, leading to and those who were not [2], while the intervention with RP or RT. Limiting treatment more men being diagnosed and treated. A European Randomized Study of Screening effect to only the portion of the gland with stage migration has also been observed, for Prostate Cancer reported a 20% disease is a capability unique to thermal such that the majority of men are now reduction in the mortality rate of screened ablative technologies such as cryoablation diagnosed with organ-confined disease [1]. men [3]. Indeed, given that the majority of and high-intensity focused ultrasound (HIFU). Such patients can be managed with men diagnosed with prostate cancer will not These therapies are still novel (and even definitive therapy, in the form of whole- die of their disease [4], there is concern that considered experimental by some) when gland treatment represented by radical screening has led to overdetection and compared with RP and RT in the management prostatectomy (RP) and radiation therapy overtreatment. According to recent estimates of prostate cancer. This review will assess (RT), or active surveillance (with deferred in the literature, approximately 1 million the potential of focal cryotherapy and HIFU treatment). However, defining the optimal men have been subjected to overdiagnosis in the management of clinically localized management of this patient population and overtreatment during the PSA era, prostate cancer by offering a critical review of remains difficult, largely because of the lack unnecessarily exposing them to treatment- the indications, efficacy and limitations of of randomized trials directly comparing the related side effects and financial costs [5]. each. efficacy and morbidity of the various Unfortunately, current screening methods treatment options. lack the ability to predict tumour biology and the natural history of a given patient’s DEFINING FOCAL THERAPY Interestingly, there is some controversy cancer. Because we cannot distinguish the regarding whether the increased detection tumours that will progress and cause Interestingly, current modes of delivering and treatment of prostate cancer have mortality from those that will likely not energy-based focal therapy have up until now translated into a definitive survival or cause any harm (i.e. clinically insignificant), been used as minimally invasive ways of mortality benefit for men with screen- rational application of treatment or treating the whole gland in prostate cancer. detected cancer. Interim data from two long- surveillance can be quite difficult, often Only in the last several years has the term screening studies were published in leading to an all-or-nothing approach that is technology of thermal ablation been applied 2009 and revealed conflicting results. not suited to every patient. in a focal or subtotal manner in an attempt to

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control localized disease and limit morbidity. spurred increased interest in organ-sparing IDENTIFYING PATIENTS WITH Based on the current literature, there is no approaches to treating prostate cancer, which FOCAL DISEASE consensus on what ‘focal’ means. Some are particularly suited to cases of unifocal advocates have attempted to treat only areas or unilateral disease. Advocacy of focal The multifocal nature of prostate cancer was of known cancer. Others have administered therapy in prostate cancer is attributable known even before the PSA era, with hemispheric treatment of the involved side, to its lower morbidity and more rapid approximately 80% of prostate cancer while others have treated the entire gland convalescence compared with RP or RT and to showing multiple lesions and/or bilateral with the exception of the contralateral the fact that it still offers a proactive cancer [11,12]. Because it remains difficult to neurovascular bundle. Because of the approach for patients and clinicians who do discern cases of clinically insignificant relatively novel status of focal therapy in not favour the inaction of surveillance. multifocal disease, appropriate use of focal prostate cancer, data on these options However, in order for focal therapy to be therapy requires the ability to identify those are limited but will be considered in this accepted as a viable treatment alternative, it men with unifocal or unilateral disease. review. should not compromise local cancer control Contemporary data from modern biopsy and by failing to eradicate secondary lesions of imaging techniques are analysed in the Techniques of focal therapy in prostate cancer unknown malignant potential elsewhere in present paper to see if any of these generally involve thermal ablation of the the gland. techniques can facilitate this task. tumour. Established ablative technologies include cryoablation and HIFU and achieve Predicting preoperatively whether a patient Tumours are more likely to be multifocal when tumour destruction by inducing extremes of has unifocal cancer, unilateral cancer or biopsies are diagonally positive or horizontally temperature within the targeted tissue. clinically insignificant multifocal prostate positive than in those that are vertically Cryoablation supercools lesions to cancer remains a challenge, even with positive (relative to the transverse plane), temperatures <−40 °C using liquid nitrogen- today’s improved imaging and biopsy which is logical because such findings based probes (generally applied techniques. Indeed, a critical point in indicate cancer in disparate portions of the percutaneously via a perineal approach), assessing the potential efficacy of focal gland [13]. However, the false-negative rate inducing intracellular ice formation and therapy is the determination of the clinical for prostate biopsy is substantial and may be microvascular damage, and eventually significance (e.g. biological aggressiveness) as high as 50% [14]. The traditional sextant leading to tissue ischaemia and necrosis. A of synchronous multifocal tumours. Hall prostate biopsy is unlikely to identify satellite significant advantage of cryosurgery is the et al. [6] reported that pathological lesions in multifocal prostate cancer. ability to visualize the ice ball in real time evaluation of the index tumour accurately Unfortunately, the sampling error associated using ultrasonography, allowing the surgeon predicted the clinical behaviour of the entire with prostate biopsy is not fully corrected to assess the adequacy of the ‘kill’ zone as gland, regardless of synchronous tumours in even with the use of extended biopsy well as to minimize injury to adjacent >90% of patients, suggesting that secondary schemes. Additional sampling of the lateral structures (e.g. the rectum or external urinary tumours in the majority of contemporary and apical peripheral zone increases accuracy, sphincter). patients may indeed be clinically [15] but still misses many tumours with insignificant. Furthermore, it has been extended 10–12 core biopsy schemes [13]. High-intensity focused ultrasound uses demonstrated that 80% of secondary Using office-based saturation biopsy, Walz intersecting, precision-focused ultrasound tumours are <0.5 mL, a common criterion for et al. [16] identified cancer in 41% of 161 waves to induce hyperthermia (up to 90 °C) the determination of clinical insignificance. patients who had previously undergone of the targeted tissues, leading to rapid [7] Similarly, Rukstalis et al. [8] reported that at least two negative biopsies. Moreover, desiccation and coagulative necrosis. Unlike the median size of secondary lesions was 61% of men with known prostate cancer, cryoablation, HIFU is delivered noninvasively, only 0.3 mL, concluding that nearly 80% of characterized by low-risk tumours, have a and its ability to deliver precisely its patients would achieve local tumour control, negative repeat sextant biopsy when destructive energies with no effect on tissues if the index cancer only was targeted. evaluated on an active surveillance protocol surrounding the target zone is another [17]. Thus, there is little evidence to support advantage. In contrast to cryoablation, it can Despite these encouraging data, it must be the use of biopsy, even if performed with be difficult to monitor the destructive effect reiterated that current screening tests still extended or saturation schemes, as a reliable and ‘kill’ zone with HIFU as there is no true ice lack the ability to predict accurately which means of ruling out multifocal and/or ball equivalent. tumours are destined to progress and which bilateral disease. will remain organ-confined. Indeed, the natural history of a given patient’s disease Imaging techniques, such as MRI, have RATIONALE FOR FOCAL THERAPY OF may not even be governed by the major been evaluated as tools for identifying PROSTATE CANCER component of a tumour. There are data intraprostatic cancer but suffer from an suggesting that tertiary Gleason grade 5 inherent drawback. Their accuracy in Because of the downward stage migration cancer more strongly predicts the stage and predicting cancer can be difficult to assess attributable to PSA screening, contemporary the risk of biochemical recurrence than do the because the true likelihood of tumour at any prostate cancers tend to be smaller and are primary/secondary grades of a tumour [9,10]. site in the prostate is unknown, unless the more likely to be localized within the prostate. As such, the most prudent application of focal imaging findings are compared directly to Combined with improved biopsy and imaging therapy is probably in cases of unifocal or whole-mount prostatectomy specimens. techniques, these epidemiological trends have unilateral prostate cancer. In addition, the MRI technique is not

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standardized regarding lesion size criteria, indications or preferences. For example, RP of patients and a 96.0% negative-biopsy rate imaging source, magnet strength or use of an may not be suitable for patients who are (24/25) after a mean follow-up of 70 months. endorectal coil [18]. Finally, prior therapy or high-risk surgical candidates, e.g. those of The one biopsy-positive patient was even prior biopsy can complicate the advanced age or with multiple medical subsequently treated with full-gland interpretation of imaging results. comorbidities. RT can be contraindicated in cryoablation and reported to be disease-free, men with pre-existing bowel or urinary suggesting that salvage cryotherapy is The detection rate of standard unenhanced dysfunction because such symptoms can be feasible in cases of local recurrence. In T2-weighted MRI for prostate cancer ranges severely exacerbated after RT [22]. For such addition, 88.9% of the men maintained from 37 to 96% [18]. This wide range is at cases, focal therapy of the prostate provides potency, with or without the aid of oral least partially explained by the disparate an appealing alternative that avoids many of phosphodiesterase (PDE)-5 inhibitors [36]. criteria used for determining the presence or these risks, while still allowing a proactive absence of cancer; some studies only defined approach to controlling focal cancer. The The largest published experience with focal tumours over a certain size as being truly thermal ablative techniques of cryoablation cryotherapy thus far is represented by Onik malignant, which is in contrast to convention. and HIFU are applied via minimally invasive et al. [37] with their series of 48 patients who T2-weighted MRI detects only 5% of tumours techniques, avoiding damage to adjacent underwent focal cryoablation. After a mean <5 mm, whereas 89% of those >10 mm are tissues and potentially limiting morbidity, follow-up period of 4.5 years, 94% of patients identified [19]. Dynamic MRI using contrast such as impotence or incontinence. demonstrated stable PSAs with no evidence of agents has shown improved accuracy in the recurrent disease. No patient who underwent detection of tumours. Jager et al. [20] surveillance biopsy had any local recurrence reported an increase in sensitivity from 57 to OUTCOMES FOR CRYOABLATION in previously ablated zones, and potency and 73% when dynamic contrast-enhanced continence rates were 90 and 100%, sequences were used, maintaining 80% Because of its relatively recent application in respectively [37]. The authors have dubbed specificity. Likewise, a study by Schlemmer prostate cancer, there are limited data in the this focal therapy the ‘male lumpectomy’, et al. [21] reported increased sensitivity from current literature regarding focal therapy. comparing its implications with that of the 79 to 89% for peripheral zone lesions. Thus, the long-term oncological efficacy of female corollary, breast cancer. either cryoablation or HIFU in this setting has In summary, neither biopsy nor emerging not been established to the same degree as Other reports of subtotal or focal cryotherapy imaging methods have been able to reliably that of RP or RT. In the USA, there is greater have been in unpublished abstract form. The confirm unifocal disease or rule out experience with cryoablation (as HIFU is not largest is from the CryoOnline Database multifocal cancer, particularly for lesions yet FDA-appoved for the treatment of registry study, which includes data on 795 <1 cm in size. However, using aggressive prostate cancer), but much of the data patients treated with less than total biopsy schemes, possibly in combination with concerning the use of cryotherapy in prostate cryotherapy [38]. Kaplan–Meier analysis MRI, the likelihood of overlooking a large cancer are derived from studies of whole- showed 3-year actuarial biochemical disease- tumour can be reduced. gland treatment. free survival of 80% for focal cryotherapy patients. On surveillance biopsy, 36 patients Though more prevalent than the focal (4.5% of the cohort and 25% of those PATIENT SELECTION FOR FOCAL THERAPY approach, whole-gland primary cryotherapy undergoing biopsy) showed residual or itself has only seen limited use, probably recurrent disease after focal therapy. The goal In our practice, observation of prostatic because of reports of an 80–100% risk of of preserving erections was achieved with intraepithelial neoplasia, atypical findings, or impotence [23–25]. Review of the current notable success; of those patients who were cancer on contralateral biopsy cores literature on prostatic cryoablation shows potent before cryotherapy, 65% retained effectively excludes patients from widely disparate biochemical disease-free potency sufficient for intercourse, although consideration for subtotal therapy. In our rates ranging from 56 to 90% after median half required oral PDE-5 inhibitors. Taken experience, younger men paradoxically seem follow-ups of 9 months to 12.6 years [23,25– together, these short-term data suggest that to have greater interest in focal therapy, while 32]. The wide variation in biochemical control focal cryotherapy may indeed fulfill the having a theoretically higher risk of future after cryoablation may be attributable to promise of organ-sparing therapy by limiting malignancy in the untreated areas based on several confounding factors, including complications without substantially years of potential risk. However, there is no different generations of cryotechnology, compromising local cancer control. established age cut-off. varying definitions of treatment failure, small patient numbers, and short follow-up periods. There are other clinical situations in which Rates of recurrence based on positive biopsy MORBIDITY OF CRYOTHERAPY focal therapy for prostate cancer might be after primary whole-gland cryoablation range appropriate, and might at least be considered, from 8 to 25% [32–35]. Known complications of prostatic as long as patients are effectively counselled cryoablation include erectile dysfunction, regarding the limitations of this approach (to Preliminary data on focal cryotherapy appears incontinence, urethral sloughing, rectal injury be reviewed below). Conventional therapy to show at least comparable oncological and fistula formation. The risks of such with either surgical excision or radiation efficacy. Bahn et al. [36], in their series of 31 complications have decreased with advances might not be ideal for all cases of localized men treated with less than whole gland in technology, such as urethral warming prostate cancer because of individual patient cryotherapy, reported PSA stability in 92.8% techniques, and improved patient selection. In

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general, contemporary data show relatively help reduce the incidence of impotence after field of prostate cancer. However, neither low rates of incontinence (2–4.3%), urethral HIFU. Poissonnier et al. [50] reported a cryoablation nor HIFU can be currently sloughing (0–6%) and fistula formation (0– maintained potency rate of 61% in men who considered viable alternatives to the 1%), while the risk of erectile dysfunction underwent whole-gland HIFU , which standards of RP or RT as both treatment tends to be much higher (45–100%) increased to 69% among patients treated methods have several potential limitations [30,31,39]. When compared with RP or RT, the with HIFU that spared the neurovascular that must be carefully considered during incidence of most complications and quality- bundles. patient counselling and clinical decision- of-life outcomes after whole-gland making. cryoablation appear to be comparable, but the higher rate of impotence is concerning OTHER METHODS OF FOCAL THERAPY The current literature contains only short- [30,31,39,40]. Indeed, this shortcoming of term follow-up data based on small patient whole-gland cryotherapy may encourage Laser as an energy source for focal ablation of cohorts for focal therapy, and even whole- increased use of focal/nerve-sparing localized prostate cancer has been evaluated gland thermal ablation has not had its long- cryotherapy. in phase I trials, demonstrating limited term efficacy established. Preliminary data on morbidity, particularly with regards to oncological outcomes are encouraging but potency and urinary control [56,57]. Tissue durable cancer control can only be OUTCOMES OF HIFU destruction can be monitored using demonstrated with extended follow-up of real-time MRI guidance and temperature larger patient cohorts. In addition, assessing Because it is not yet FDA-approved for the measurements. However, short-term cancer-specific mortality as a measure of treatment of prostate cancer in the USA, the oncological efficacy appears to be suboptimal, cancer control is difficult given the lack of majority of outcomes data regarding HIFU with up to a third of patients showing long-term data. PSA level is used instead as a come from Canada and Europe, where, for the residual disease at the ablated zone upon surrogate marker of disease control and last decade, it has been primarily used as post-procedure biopsy [56]. Phase II trials will treatment effect but, as demonstrated by the whole-gland therapy for localized prostate be needed to validate the ability of this literature on RP and RT, there is uncertainty cancer. A review of the available literature on technique to achieve adequate tumour regarding whether or not biochemical HIFU reveals biochemical disease-free rates destruction and durable cancer control. recurrence is actually predictive of overall or from 56.3 to 92% after mean follow-ups of cancer-specific mortality [61]. 12–76.8 months [41–51]. Given the modern ability to precisely image and target the prostate, brachytherapy may Moreover, biochemical standards for defining As with cryoablation, there are only limited be suited to subtotal or focal applications. treatment success or failure have not been data regarding the application of focal HIFU However, to date, all reports have involved established for either cryoablation or HIFU of in prostate cancer. An early report involved 10 whole-gland seed placement with the prostate, with criteria varying significantly patients, believed to have low-risk focal concentration of additional seeds in areas between different studies and institutions. For tumours, treated with HIFU [52]. Pathological believed to involve tumour [58]. MRI example, a number of different values for PSA examination following subsequent RP found spectroscopy has been advocated to offer the nadir have been used to report treatment residual tumour in 70% of the patients, ability to focus treatment on malignant sites, success, including <0.2 ng/mL, <0.4 ng/mL, although the results were more favourable but no centre has published data on truly <0.5 ng/mL or <1 ng/mL, none of which have when the entire gland was treated. Although focal therapy [59]. been validated prognostically. Using PSA nadir the technology of HIFU has significantly can be particularly problematic as focal improved since this initial report, Focal delivery of external beam radiation has therapy spares at least half of the prostate, contemporary studies of focal HIFU are also been suggested as a potential treatment thereby leaving PSA production intact. distinctly lacking, and represent future of small, localized prostate cancer. The Another related disadvantage of focal therapy avenues of investigation. Cyberknife system has achieved more focused is the inability to confirm complete tumour delivery of radiation energy than traditional destruction because of the lack of tissue to externally applied energy sources. This has provide a pathological diagnosis following MORBIDITY OF HIFU become standard treatment for certain brain treatment. tumours, but data on its use for focal Data on complications have been treatment of prostate cancer remain almost Another confounding factor in determining inconsistently reported in most of the studies nonexistent. With further development, the true efficacy of focal ablation for localized on HIFU, but morbidity associated with this however, it is feasible that this or some other prostate cancer is the question of what treatment method appears to be low overall. energy source can be delivered externally for constitutes treatment failure. Lack of disease Complications of HIFU include urinary focal therapy [60]. recurrence is often based on PSA stability, but retention (1–9%), urethral stricture (4–14%), there is currently no standard definition of incontinence (1–15%), erectile dysfunction biochemical recurrence. Both the ASTRO (13–53%) and rectourethral fistulae (0–3%) LIMITATIONS OF FOCAL THERAPY (three consecutive rises in PSA after [53–55]. The risk of complications increases backdating to halfway between nadir and the with repeated treatments [54,55]. The use of Because it is less invasive and presumably first rise) and Phoenix (nadir + 2) definitions MRI or duplex ultrasound to visualize, and associated with reduced morbidity, focal have been used to define treatment failure thus spare the neurovascular bundles, might therapy is beginning to be favoured in the after ablation, but these criteria have only

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been validated for external beam radiation. patient selection for focal therapy remains of Morphologic features of clinically Furthermore, neither surveillance biopsy nor paramount importance. Based on current recognized versus incidental tumors. any current imaging method offer a reliable data, focal therapy should be reserved for Cancer 1992; 70: 2313–8 means of determining recurrent or residual patients with focal cancer. It may also be 8 Rukstalis DB, Goldknopf JL, Crowley disease, given their high false-negative rates. reasonable to recommend primary focal EM, Garcia FU. Prostate cryoablation: therapy for the treatment of low-risk, low- a scientific rationale for future There are also certain disadvantages of focal volume disease in patients who are poor modifications. Urology 2002; 60: 19–25 therapy, based on limitations of the surgical candidates or in those who wish to 9 Patel AA, Chen MH, Renshaw AA, technology itself. For both cryoablation and avoid urinary or sexual dysfunction. D’Amico AV. PSA failure following HIFU, tissue damage can extend beyond the definitive treatment of prostate cancer intended zone of destruction, probably Currently, the role of focal ablation in the having biopsy Gleason score 7 with explaining the high rates of erectile management of localized prostate cancer tertiary grade 5. JAMA 2007; 298: 1533–8 dysfunction after whole-gland thermal remains controversial, and much work will be 10 Sim HG, Telesca D, Culp SH et al. Tertiary ablation. Indeed, this particular shortcoming required to put this field on more solid Gleason pattern 5 in Gleason 7 prostate is an argument for a subtotal delivery of ground. Until further studies, preferably cancer predicts pathological stage and ablative energy, which would reduce the risk randomized controlled trials, demonstrate biochemical recurrence. J Urol 2008; 179: of such collateral injury. Focal therapy may long-term oncological efficacy that is 1775–9 also be ill-suited to anterior tumours, as both equivalent to whole-gland treatment, 11 Byar DP, Mostofi FK. Carcinoma of the cryoablation and HIFU have difficulty advocacy of focal therapy in prostate cancer prostate: prognostic evaluation of certain reaching the anterior prostate [54]. Finally, will be based mainly on its minimally invasive pathologic features in 208 radical although local recurrences after primary nature and reduced potential for morbidity. prostatectomies. Examined by the step- focal ablation presumably can be managed section technique. Cancer 1972; 30: 5–13 with repeat ablation, indiscriminate use 12 Mouraviev V, Mayes JM, Madden JF, of such treatment methods could hamper CONFLICT OF INTEREST Sun L, Polascik TJ. Analysis of laterality subsequent salvage attempts because of and percentage of tumor involvement in histopathological changes (e.g. fibrosis) that J. Stephen Jones is an Employee of Endocare. 1386 prostatectomized specimens for could complicate surgical excision [62]. selection of unilateral focal cryotherapy. Technol Cancer Res Treat 2007; 6: 91–5 In conclusion, many treatment options are REFERENCES 13 Epstein JI, Walsh PC, Akingba G, Carter available to a patient with clinically localized HB. The significance of prior benign prostate cancer, including RP, RT and active 1 Catalona WJ, Smith DS, Ratliff TL, needle biopsies in men subsequently surveillance. Currently, there is no consensus Basler JW. Detection of organ-confined diagnosed with prostate cancer. J Urol on what constitutes optimal management of prostate cancer is increased through 1999; 162: 1649–52 localized prostate cancer. RP and RT have prostate-specific antigen-based 14 Applewhite JC, Matlaga BR, shown comparable long-term survival and screening. JAMA 1993; 270: 948–54 McCullough DL. Results of the 5 region mortality outcomes and are both associated 2 Andriole GL, Crawford ED, Grubb RL prostate biopsy method: the repeat biopsy with significant morbidity that adversely 3rd et al. Mortality results from a population. J Urol 2002; 168: 500–3 affect quality of life. Active surveillance randomized prostate-cancer screening 15 Keetch DW, Catalona WJ, Smith DS. protocols have failed to gain widespread trial. N Engl J Med 2009; 360: 1310–9 Serial prostatic biopsies in men with adoption despite evidence of overdiagnosis 3 Schroder FH, Hugosson J, Roobol MJ persistently elevated serum prostate and overtreatment of prostate cancer from et al. Screening and prostate-cancer specific antigen values. J Urol 1994; 151: screening efforts during the last two decades. mortality in a randomized European 1571–4 Focal therapy offers an appealing compromise study. N Engl J Med 2009; 360: 1320–8 16 Walz J, Graefen M, Chun FK et al. High between these two approaches that has 4 Bill-Axelson A, Holmberg L, Ruutu M incidence of prostate cancer detected by shown encouraging short-term cancer et al. Radical prostatectomy versus saturation biopsy after previous negative control as well as reduced morbidity watchful waiting in early prostate cancer. biopsy series. Eur Urol 2006; 50: 498–505 compared with whole-gland therapies. N Engl J Med 2005; 352: 1977–84 17 Patel MI, DeConcini DT, Lopez-Corona 5 Welch HG, Albertsen PC. Prostate cancer E, Ohori M, Wheeler T, Scardino PT. An The overall data concerning focal cryotherapy diagnosis and treatment after the analysis of men with clinically localized and HIFU, however, are inadequate compared introduction of prostate-specific antigen prostate cancer who deferred definitive with data for the established therapies of RP screening: 1986–2005. J Natl Cancer Inst therapy. J Urol 2004; 171: 1520–4 and RT. Because of the high rate of false- 2009; 101: 1325–9 18 Kirkham AP, Emberton M, Allen C. negative results with biopsy or current 6 Hall GS, Kramer CE, Epstein JI. How good is MRI at detecting and imaging methods, focal therapy has the Evaluation of radical prostatectomy characterising cancer within the prostate. inherent risk of leaving viable cancer outside specimens. A comparative analysis of Eur Urol 2006; 50: 1163–74 the treatment zone. The benefits of minimally sampling methods. Am J Surg Pathol 19 Ikonen S, Karkkainen P, Kivisaari L et al. invasive focal therapy for prostate cancer 1992; 16: 315–24 Magnetic resonance imaging of clinically must therefore be weighed against the 7 Villers A, McNeal JE, Freiha FS, Stamey localized prostatic cancer. J Urol 1998; increased risk of local failure, and careful TA. Multiple cancers in the prostate. 159: 915–9

FOCAL THERAPY IN LOCALIZED PROSTATE CANCER

20 Jager GJ, Ruijter ET, van de Kaa CA et al. after primary cryosurgical ablation for in the treatment of primary prostate Dynamic TurboFLASH subtraction clinically localized prostate cancer using cancer: the first UK series. Br J Cancer technique for contrast-enhanced MR third-generation cryotechnology. Urology 2009; 101: 19–26 imaging of the prostate: correlation with 2007; 70: 117–21 42 Blana A, Murat FJ, Walter B et al. First histopathologic results. Radiology 1997; 32 Prepelica KL, Okeke Z, Murphy A, Katz analysis of the long-term results with 203: 645–52 AE. Cryosurgical ablation of the prostate: transrectal HIFU in patients with localised 21 Schlemmer HP, Merkle J, Grobholz R high risk patient outcomes. Cancer 2005; prostate cancer. Eur Urol 2008; 53: 1194– et al. Can pre-operative contrast- 103: 1625–30 201 enhanced dynamic MR imaging for 33 Koppie TM, Shinohara K, Grossfeld GD, 43 Blana A, Rogenhofer S, Ganzer R et al. prostate cancer predict microvessel Presti JC Jr, Carroll PR. The efficacy of Eight years’ experience with high- density in prostatectomy specimens? Eur cryosurgical ablation of prostate cancer: intensity focused ultrasonography for Urol 2004; 14: 309–17 the University of California, San Francisco treatment of localized prostate cancer. 22 Chen RC, Clark JA, Manola J, Talcott JA. experience. J Urol 1999; 162: 427– Urology 2008; 72: 1329–33 Treatment ‘mismatch’ in early prostate 32 44 Blana A, Walter B, Rogenhofer S, cancer: do treatment choices take patient 34 Long JP, Bahn D, Lee F, Shinohara K, Wieland WF. High-intensity focused quality of life into account? Cancer 2008; Chinn DO, Macaluso JN Jr. Five-year ultrasound for the treatment of localized 112: 61–8 retrospective, multi-institutional pooled prostate cancer: 5-year experience. 23 Bahn DK, Lee F, Badalament R, Kumar analysis of cancer-related outcomes after Urology 2004; 63: 297–300 A, Greski J, Chernick M. Targeted cryosurgical ablation of the prostate. 45 Chaussy CG, Thuroff S. High-intensive cryoablation of the prostate: 7-year Urology 2001; 57: 518–23 focused ultrasound in localized prostate outcomes in the primary treatment of 35 Shinohara K, Rhee B, Presti JC Jr, cancer. J Endourol 2000; 14: 293–9 prostate cancer. Urology 2002; 60: 3– Carroll PR. Cryosurgical ablation of 46 Ficarra V, Antoniolli SZ, Novara G et al. 11 prostate cancer: patterns of cancer Short-term outcome after high-intensity 24 Donnelly BJ, Saliken JC, Ernst DS et al. recurrence. J Urol 1997; 158: 2206–9 focused ultrasound in the treatment of Prospective trial of cryosurgical ablation 36 Bahn DK, Silverman P, Lee F Sr, patients with high-risk prostate cancer. of the prostate: five-year results. Urology Badalament R, Bahn ED, Rewcastle JC. BJU Int 2006; 98: 1193–8 2002; 60: 645–9 Focal prostate cryoablation: initial results 47 Mearini L, D’Urso L, Collura D et al. 25 Ellis DS. Cryosurgery as primary show cancer control and potency Visually directed transrectal high intensity treatment for localized prostate cancer: a preservation. J Endourol 2006; 20: 688– focused ultrasound for the treatment of community hospital experience. Urology 92 prostate cancer: a preliminary report on 2002; 60 (Suppl. 1): 34–9 37 Onik G, Vaughan D, Lotenfoe R, Dineen the Italian experience. J Urol 2009; 181: 26 Aus G, Pileblad E, Hugosson J. M, Brady J. The ‘male lumpectomy’: focal 105–11 Cryosurgical ablation of the prostate: 5- therapy for prostate cancer using 48 Misrai V, Roupret M, Chartier-Kastler E year follow-up of a prospective study. Eur cryoablation results in 48 patients with at et al. Oncologic control provided by HIFU Urol 2002; 42: 133–8 least 2-year follow-up. Urol Oncol 2008; therapy as single treatment in men with 27 Cohen JK, Miller RJ Jr, Ahmed S, Lotz 26: 500–5 clinically localized prostate cancer. World MJ, Baust J. Ten-year biochemical 38 Dhar N, Cher ML, Scionti SM, Lugnani J Urol 2008; 26: 481–5 disease control for patients with prostate FM, Jones JS. Focal/partial gland 49 Murat FJ, Poissonnier L, Rabilloud M cancer treated with cryosurgery as prostate cryoablation: results of 795 et al. Mid-term results demonstrate primary therapy. Urology 2008; 71: 515–8 patients from multiple centers tracked salvage high-intensity focused 28 Cresswell J, Asterling S, Chaudhary M, with the COLD registry. J Urol 2009; 181 ultrasound (HIFU) as an effective and Sheikh N, Greene D. Third-generation (Suppl.): 715 acceptably morbid salvage treatment cryotherapy for prostate cancer in the UK: 39 Hubosky SG, Fabrizio MD, option for locally radiorecurrent prostate a prospective study of the early outcomes Schellhammer PF, Barone BB, Tepera cancer. Eur Urol 2009; 55: 640–7 in primary and recurrent disease. BJU Int CM, Given RW. Single center experience 50 Poissonnier L, Chapelon JY, Rouviere O 2006; 97: 969–74 with third-generation cryosurgery for et al. Control of prostate cancer by 29 Cytron S, Paz A, Kravchick S, management of organ-confined prostate transrectal HIFU in 227 patients. Eur Urol Shumalinski D, Moore J. Active rectal cancer: critical evaluation of short-term 2007; 51: 381–7 wall protection using direct transperineal outcomes, complications, and patient 51 Uchida T. [High-intensity focused cryo-needles for histologically proven quality of life. J Endourol 2007; 21: 1521– ultrasound for localized prostate cancer]. prostate adenocarcinomas. Eur Urol 2003; 31 Nippon Rinsho 2005; 63: 345–9. [Article 44: 315–20 40 Robinson JW, Donnelly BJ, Siever JE in Japanese] 30 Han KR, Cohen JK, Miller RJ et al. et al. A randomized trial of external beam 52 Madersbacher S, Pedevilla M, Vingers L, Treatment of organ confined prostate radiotherapy versus cryoablation in Susani M, Marberger M. Effect of high- cancer with third generation cryosurgery: patients with localized prostate cancer: intensity focused ultrasound on human preliminary multicenter experience. J Urol quality of life outcomes. Cancer 2009; prostate cancer in vivo. Cancer Res 1995; 2003; 170: 1126–30 115: 4695–704 55: 3346–51 31 Polascik TJ, Nosnik I, Mayes JM, 41 Ahmed HU, Zacharakis E, Dudderidge T 53 Ahmed HU, Moore C, Emberton M. Mouraviev V. Short-term cancer control et al. High-intensity-focused ultrasound Minimally-invasive technologies in uro-

oncology: the role of cryotherapy, HIFU guided focal laser therapy in patients with 61 D’Amico AV, Moul J, Carroll PR, Sun L, and photodynamic therapy in whole low-risk prostate cancer. Eur Urol 2010; Lubeck D. Vital statistics following gland and focal therapy of localised 58: 173–7 surgery or radiation for patients with prostate cancer. Surg Oncol 2009; 18: 58 DiBiase SJ, Hosseinzadeh K, Gullapalli clinically localized prostate cancer 219–32 RP et al. Magnetic resonance managed during the PSA era [abstract 54 Marberger M, Carroll PR, Zelefsky MJ spectroscopic imaging-guided 1528]. Proc Am Soc Clin Oncol 2003; 22: et al. New treatments for localized brachytherapy for localized prostate 381 prostate cancer. Urology 2008; 72: S36– cancer. Int J Radiat Oncol Biol Phys 2002; 62 Schmidt JD, Doyle J, Larison S. Prostate 43 52: 429–38 cryoablation: update 1998. CA Cancer J 55 Thuroff S, Chaussy C, Vallancien G 59 Ellis RJ, Zhou H, Kim EY et al. Clin 1998; 48: 239–53 et al. High-intensity focused ultrasound Biochemical disease-free survival rates and localized prostate cancer: efficacy following definitive low-dose-rate Correspondence: J. Stephen Jones, Chairman, results from the European multicentric prostate brachytherapy with dose Department of Regional Urology, Glickman study. J Endourol 2003; 17: 673–7 escalation to biologic target volumes Urological & Kidney Institute, Cleveland Clinic, 56 Lindner U, Weersink RA, Haider MA identified with SPECT/CT capromab 9500 Euclid Avenue, Q10-1, Cleveland, OH et al. Image guided photothermal focal pendetide. Brachytherapy 2007; 6: 16– 44195, USA. therapy for localized prostate cancer: 25 e-mail: [email protected] phase I trial. J Urol 2009; 182: 1371– 60 Pawlicki T, Kim GY, Hsu A et al. 7 Investigation of linac-based image- Abbreviations: RP, radical prostatectomy; RT, 57 Raz O, Haider MA, Davidson SR et al. guided hypofractionated prostate radiation therapy; HIFU, high-intensity Real-time magnetic resonance imaging- radiotherapy. Med Dosim 2007; 32: 71–9 focused ultrasound; PDE, phosphodiesterase.