Focal Cryotherapy for Localized Prostate Cancer: a Report from the National Cryo On-Line Database (COLD) Registry BJUIBJU INTERNATIONAL John F

Focal cryotherapy for localized prostate cancer: a report from the national Cryo On-Line Database (COLD) Registry BJUIBJU INTERNATIONAL John F. Ward and J. Stephen Jones * Department of Urology, University of Texas, M.D. Anderson Cancer Center, Houston, TX, and * Department of Regional Urology, Glickman Urological and Kidney Institute at Cleveland Clinic, Cleveland, OH, USA Accepted for publication 13 June 2011

Study Type – Therapy (cohort) What ’s known on the subject? and What does the study add? Level of Evidence 2b Selective destruction of targeted prostate tissue is now technically feasible. Much has been theorized but little is known about the proper patient selection or treatment outcomes to determine if this organ preserving approach to prostate cancer has merit OBJECTIVES for further study and diffusion into wider practice. Herein we present the largest retrospective registry report of men treated with • To identify recent trends in focal sub-total prostate cryotherapy in order to begin to understand how this treatment is cryotherapy from a prospectively being applied despite the paucity of data. maintained treatment registry. • To describe treatment outcomes after uncontrolled application of focally ablative was the codifi ed procedure in 1160 patients CONCLUSIONS techniques within community practice. (19.8%). • A dramatic increase in focal treatments • Focal cryoablation is increasingly was observed, from 46 in 1999 to 567 in used for selected patients with prostate MATERIALS AND METHODS 2005 (P < 0.01). cancer. • The biochemical recurrence-free rate • Oncological effi cacy in the present series • We conducted an analysis of the COLD (ASTRO defi nition) at 36 months was appears similar to that of whole-gland Registry to identify patients treated with 75.7%. cryoablation. partial gland prostate cryoablation between • Prostate biopsy, performed in 164/1160 • The impact of focal cryoablation 1997 and 2007. of patients (14.1%), was positive in 43 on urinary, sexual and bowel function • Preoperative characteristics and (26.3%) of those suspected of cancer appears to be less than that of radical postoperative cancer-specifi c and recurrence, but in only 3.7% (43/1160) of therapies, although preservation of sexual functional outcomes were assembled for treated patients. function is not as high as might be analysis. • Urinary continence (defi ned as use of 0 expected. pads) was 98.4%. Maintenance of spontaneous erections was 58.1%. RESULTS Prolonged urinary retention (> 30 days) KEYWORDS occurred in six (1.1%) patients. • The COLD Registry contained information Rectourethral fi stula was observed in one focal therapy , prostate cancer , cryotherapy , for 5853 patients and focal cryotherapy (0.1%) patient. outcomes , registry

INTRODUCTION both frequency and personal impact. notion that many patients diagnosed Methods of avoiding or correcting iatrogenic with PCa may not need any treatment Whole-gland prostate cancer (PCa) dysfunction have not progressed at all (active surveillance), patients are treatments can damage the anatomical signifi cantly in the last 20 years, making this often reluctant to forgo treatment for any structures (bladder, erectile nerves, dysfunction a lifelong debilitation for many cancer diagnosis, and the use of active rhabdosphincter and rectum) that contribute men treated for PCa. These morbidities, surveillance remains limited in current to a high health-related quality of life. While although tenable if required to avoid practice. the incidence of such damage has decreased disease-specifi c mortality, are more as techniques to deliver both radiation objectionable if the costs are not justifi ed Organ-sparing therapy, most commonly and surgical extirpation have improved, by the disease risk. Although medical termed ‘ focal therapy ’ , has been suggested morbidity remains signifi cant in terms of professionals continue to embrace the as a way to eliminate small-volume PCa,

this being the largest growing group of Pharmaceuticals. The database is maintained for the focal cryoablation cohort are patients with newly diagnosed PCa. The by an independent research company, compared with men from the same database hypothetical premise of focal therapy is that Watermark Research Partners, Inc. who underwent primary whole-gland although clinically insignifi cant smaller (Watermark, Indianapolis, IN, USA) and an cryoablation or salvage therapy after tumours may coexist elsewhere in the independent physician board oversees the primary radiation therapy. For this cohort prostate gland, a dominant tumour drives database and takes all publication decisions. analysis, age, Gleason grade, clinical stage the biology of the disease; destroying the Physician participation in the COLD Registry (according to the American Joint Committee dominant tumour may, therefore, alter the is voluntary and uncompensated. The entire on Cancer Staging Manual, 5th edition) and natural history of the disease for the registry is approved by Liberty Institutional baseline PSA were assessed in relation to individual patient [ 1,2 ] . If focal therapy can Review Board (IRB), and individually outcomes. Patients were risk stratifi ed destroy the dominant tumour in a way that approved by local IRBs, based on according to the defi nitions of D ’ Amico limits the collateral damage to urinary, participating institutional policies. et al . [ 3 ] Patients who had received bowel and erectile functions associated with preoperative hormone therapy or TURP were other PCa therapies, this form of therapy Watermark and the COLD Registry advisory excluded from the analysis. may be desirable for well selected patients board created standard clinical review who may be willing to accept potential forms that are completed by a physician Biochemical recurrence was defi ned, oncological concessions in order to limit or physician ’s employee for each patient according to the ASTRO defi nition [ 4 ] , as these risks. treated with prostate cryoablation. three consecutive increases in serum PSA Watermark completes random audits of level > 6 months after focal cryoablation. The The concept of focal therapy for PCa follows 10% of participating sites annually to date of recurrence was considered to be the the same treatment paradigm used for ensure that all data are as accurate and midpoint between the PSA nadir and the almost all other solid tumours, where careful complete as possible. The data are wholly fi rst PSA increase. This defi nition was used study has shown that functional outcomes analysed by Watermark and presented because it is commonly used to report are improved by minimizing the excised or independently of review or input from results in which the prostate gland is left destroyed tissue with no resulting loss of industry interests. in situ which would allow simplifi ed oncological effi cacy. The use of focal therapy interpretation of the present results to treat kidney and bladder malignancies is Patient data are entered into the COLD compared with those of the other therapies. well established in the literature; however, Registry under ‘ primary ’ or ‘ salvage ’ therapy Data were summarized using descriptive additional research is needed to determine and are further classifi ed as ‘ whole-gland ’ or statistics. Comparisons between categorical the clinical outcomes of focal therapy in the ‘ partial-gland ’ cryoablation. The COLD variables were performed using the management of PCa, even though the Registry advisory board does not provide chi-squared test and Fisher exact test, when multifocal nature of PCa is known to be participating physicians with standard appropriate. The 5-year, biochemical similar to that of urothelial cancer. While selection criteria regarding the appropriate recurrence-free survival rates were the concept of organ preservation in PCa candidates for focal cryotherapy, therefore, estimated using the Kaplan – Meier method. treatment is attractive to many patients, the available data represent current All statistical tests were two-sided, and a P published data supporting such a hypothesis community practice and prevailing selection value of 0.05 was considered to indicate are sparse and almost completely anecdotal. criteria. The COLD Registry advisory board statistical signifi cance. All statistical analyses To identify both recent trends in the does not identify a standard volume of were performed independently at Watermark treatment of PCa and clinical outcomes in tissue for targeted destruction (treatment using commercial statistical software patients with PCa treated with focal template), therefore, this dataset also (MedCalc, Mariakerke, Belgium). cryoablation, we retrospectively reviewed represents the current state and data from the COLD Registry. heterogeneity of community organ-sparing techniques. RESULTS

MATERIALS AND METHODS STATISTICS Our search of the COLD Registry identifi ed 1160 patients for the focal cryoablation We queried the COLD Registry ( http://www. On June 13, 2010 we searched the treatment cohort. This subset represents 19.8% of the coldregistry.com ) to identify men who had records of 5853 patients with PCa treated entire database and 22.1% of all primary undergone prostate cryoablation between with cryoablation between 1999 and 2007 cryotherapy procedures performed. Table 1 1999 and 2007 as a primary therapy for (the last year for which verifi able data shows the clinical characteristics of the localized, histologically identifi ed were available at that time). Our focal patients by type of cryotherapy received adenocarcinoma of the prostate. cryoablation cohort comprised men with (focal, whole-gland, salvage). Patients who localized PCa (cT1-T2) receiving primary had undergone focal cryoablation were The COLD Registry is a web-based database cryotherapy that was categorized as younger (mean age 67.8 years), had a lower designed to address the specialized clinical ‘ partial-gland ’ ablation by the surgeon. Men clinical grade (74% with Gleason sum ≤ 6) data associated with prostate cryoablation. receiving whole-gland cryoablation with and stage (87% ≤ cT2b), and were stratifi ed It is fi nancially supported by Endocare Corp., ‘ nerve warming ’ were evaluated separately to a lower risk group (12% high risk) than a manufacturer of cryotherapy technology, and are not included in the study cohort patients undergoing either whole-gland or which was recently acquired by Endo presented as ‘ focal cryoablation ’. Outcomes salvage prostate cryoablation.

TABLE 1 Clinical characteristics of men within the COLD Registry undergoing focal, whole-gland and salvage prostate cryoablation during the same time period

Focal cryoablation Whole-gland cryoablation Salvage cryoablation No. of patients 1160 4099 594 Mean (SD ) age , years 67.8 (7.80) 70.4 (21.8) 70.2 (6.8) Mean (SD ) follow-up , months 21.1 (19.7) 31.8 (30.5) 38.5 (39.5) Gleason sum Data available, n (%) 1148 (99) 3982 (97) 564 (95) ≤ 6, n (%) 844 (74) 2383 (60) 249 (44) 7, n (%) 240 (21) 1046 (26) 168 (30) ≥ 8, n (%) 64 (6) 5531 (4) 147 (26) Clinical stage Data available, n (%) 1160 (100) 4099 (100) 594 (100) < T2b, n (%) 1013 (87) 2863 (70) 458 (77) ≥ T2b 147 (13) 1236 (30) 136 (23) PSA (ng/mL) at baseline Data available, n (%) 1149 (99) 4011 (98) 590 (99) < 4, n (%) 211 (18) 618 (15) 187 (32) 4< 10, n (%) 782 (68) 2374 (59) 254 (43) 1 0< 20, n (%) 126 (11) 707 (18) 94 (16) 20+ , n (%) 30 (3) 312 (8) 55 (9) Risk category * Data available, n (%) 1157 (100) 4067 (99) 592 (100) Low risk, n (%) 541 (47) 934 (23) 57 (10) Intermediate risk, n (%) 473 (41) 1885 (46) 294 (50) High risk, n (%) 143 (12) 1248 (31) 241 (41)

* Patients ’ risk is assigned to one of three categories using D’ Amico risk deﬁ nitions (low risk: Gleason score ≤ 6 AND ≤ clinical stage T2a AND PSA < 10 ng/mL; high risk: Gleason score 8 or higher and/or PSA > 20 ng/mL and/or > T2b; intermediate risk anything else).

We observed a signiﬁ cant increase (Fisher ’ s FIG. 1. Changes in total number of focal and FIG. 2. Variation over time in risk group exact test, P < 0.001) in the number of whole-gland prostate cryoablation procedures per categorization at time of prostate cryoablation. patients undergoing focal cryoablation from year. Low Intermediate High the beginning of the study to the end 60% Total Gland ( Fig. 1 ). Focal cryoablation represented 2.1% SubTotal Gland 50% 600 (1/47) of all cryotherapy procedures within 567 40% 537 500 the COLD Registry in 1999. By 2007, the rate 475 458 30% had risen to 38.2% (293/768) and continued 400 Percent to increase, despite an observed decrease in 353 20% 300 293 whole-gland treatments during the ﬁ nal 2 249 263 10% 200 203 168 years of the study period. An analysis of the 160 0%

Number of procedures 100 1999 2000 2001 2002 2003 2004 2005 2006 2007 variations in patients within each risk group 69 99 46 43 Year during this period found that the proportion 0 1212 of patients within each risk group had not 1999 2000 2001 2002 2003 2004 2005 2006 2007 changed ( Fig. 2 ), despite the increased use Year of focal cryoablation. In other words, a trend shown in Fig. 3 . No signiﬁ cant difference in towards using focal cryoablation only in cryoablation cohort ’ s ability to achieve biochemical recurrence was observed patients with the lowest risk disease was biochemical recurrence-free survival was between whole-gland- and focal not observed. The majority of patients compared with that of the whole-gland cryoablation-treated patients for each risk treated with cryoablation had a low- or cryoablation cohort in the same time period, category. intermediate-risk disease proﬁ le. the results were similar (75.5% biochemical recurrence-free survival at 2 years after Prostate biopsy was performed after The biochemical recurrence-free rate after whole-gland cryoablation). Biochemical treatment because of increased post- focal cryoablation was 75.7%, 2 years after recurrence-free survival by risk group after treatment serum PSA level in 14.1% of the treatment ( Table 2 ). When the focal both whole-gland and focal cryoablation is study cohort ( Table 3 ). Surprisingly, the

FIG. 3. Time to Failure * (ASTRO) for Full Gland/Focal Gland by Risk The morbidity of primary focal cryoablation, Biochemical recurrence-free 100 whole-gland cryoablation and salvage survival (ASTRO) after focal cryoablation during this study period is and whole-gland prostate 75 presented in Table 4 . Rectourethral ﬁ stula cryoablation stratiﬁ ed by risk was extremely rare and had occurred in only group. 1/1160 patients in the focal cryoablation 50 cohort compared with 0.4% of patients in the whole-gland cohort. For the focal and Percent Survived Percent 25 whole-gland cohorts, complete urinary continence after cryoablation was very high 0 (98.4% and 96.9%, respectively). Temporary 0612 18 24 30 36 42 48 54 60 Time in Months urinary retention after cryoablation was a Full Gland - Low Risk Full Gland - Intermediate Risk Full Gland - High Risk rare event that had occurred in 1.1% of the Focal Gland - Low Risk Focal Gland - Intermediate Risk Focal Gland - High Risk focal and 1.6% of the whole-gland Note: Percent Surviving is calculated from Kaplan-Meier product limit estimates. Deaths are censored at the last recorded visit. cryoablation cohort. Patients who had ‡ Time to failure is defined as: 3 rises in PSA (≥ 6 months after surgery). Failure occurs midpoint between NADIR and the first rise reported the ability to have sexual intercourse before focal cryoablation were Time in months: 0 6 12 18 24 30 36 Number left (Whole gland) more likely to have maintained this ability low risk 593 442 350 273 230 230 230 intermediate risk 1097 817 632 483 405 303 303 after treatment (58.1%) than patients in the high risk 760 554 420 320 255 255 255 whole-gland cohort (32.3%). Number left (Organ Preserving) low risk 338 234 166 111 92 92 92 intermediate risk 264 188 121 80 52 52 52 high risk 67 43 28 28 28 28 28 DISCUSSION

There was a > 1000 fold increase in the use of focal cryoablation during the study TABLE 2 Biochemical recurrence-free survival after focal cryoablation compared with matched period, despite the paucity of literature on patients undergoing whole-gland cryoablation during the same time period its oncological effi cacy or associated morbidity. The present study, which presents Biochemical recurrence-free survival prospectively maintained patients treated Organ preservation prostate Whole-gland prostate with the intent to preserve a portion of the Time from cryosurgery cryoablation, % cryoablation, % prostate from cryoablation, is the largest 6 months 84.2 83.3 report with the longest follow-up currently 12 months 80.7 78.7 available. A selection criterion for choosing 24 months 75.7 75.5 between organ-sparing cryotherapy and 36 months 75.7 75.1 other options is not available in the registry. Nevertheless, in the present review we found that focal cryoablation offered men selected for this treatment an oncological TABLE 3 Comparison of biopsy results after focal cryoablation and whole-gland cryoablation effi cacy similar to whole-gland cryotherapy over the same time period, with improved Focal cryoablation, Whole-gland urinary continence, preservation of erectile n = 1160 cryoablation, n = 4099 function and decreased urinary retention. No. patients who underwent a biopsy 163 (14.1) 841 (20.6) Rectourethral fi stula was extremely rare, after prostate cryoablation (%) with only one case reported. Positive biopsy of those who underwent 43 (26.3) 125 (14.9) biopsy (%) We now have a basis upon which we can Positive biopsy of entire cohort, % 3.7 3.0 move this treatment approach forward to better examine patient selection, treatment templates, effi cacy and perioperative morbidity in a larger prospective and biopsy rate in the focal cryoablation cohort patients ] vs 3% [ 125/4099 patients ] ; cooperative fashion. was lower than that in the whole-gland chi-squared test, P = 0.26), but with the low cryoablation cohort (14.0% [ 163/1160 number of patients undergoing biopsy in The movement towards a preservation patients ] vs 20.6% [ 841/4099 patients ] ; each group, these fi ndings are of limited approach to a cancerous organ is a familiar chi-squared test, P < 0.001). The overall value. The median (mean) Gleason score of one in oncology. At one time, if cancer was positive biopsy rate for the focal the identifi ed cancer in the 43 patients with found in any solid organ, the entire organ cryoablation cohort was the same as that in a positive post-focal cryoablation biopsy was removed. Efforts for the past 20 years the whole-gland cohort (3.7%, [ 3/1160 was 6 (6.12). have been focused on more sensitive and

specifi c means of identifying even a small TABLE 4 Comparison of treatment-associated morbidity at 12 months focus of PCa within the gland, which was then enough to justify radical therapy using Morbidity by procedure type surgery or radiation in most practices. ( number of patients in whom suffi cient pre- and post-procedure However, the concept of empiric radical information was available for analysis ) No. of patients (%) therapy has failed the test of time for most Urinary Incontinence solid cancers, and organ preservation has Focal (507) 8 (1.6) become the standard management for Whole-gland (2099) 65 (3.1) breast, renal, lung and colon cancers [ 5,6 ] . Salvage (299) 33 (12.3) New-onset erectile dysfunction In urology, this same concept has led to Focal (291) 122 (41.9) widespread use of organ-sparing techniques Whole-gland (639) 432 (67.6) for kidney and non-muscle-invasive bladder Salvage (60) 36 (60.0) cancer. For bladder cancer, a ‘ fi eld change ’ Rectourethral fi stula phenomenon has tempered the use of focal Focal (1160) 1 (0.1) cryoablation in patients with high grade Whole-gland (4099) 18 (0.4) cancer and has mandated the development Salvage (594) 9 (1.5) of adjunctive intravesical therapies. However, Urinary retention (> 30 days) it must be recognized that the majority of PCa is not considered to be as lethal as high Focal (518) 6 (1.2) grade bladder cancer, so the fear of Whole-gland (2177) 34 (1.6) incurability should logically be less stifl ing Salvage (282) 12 (4.3) to the creative advance of treatments that preserve organ function.

In 1990, most urologists believed that men where active surveillance criteria have been reports, the short-term benefi ts of active diagnosed with PCa had clinically signifi cant retrospectively applied to patients who surveillance may not outweigh the disease that required radical therapy. With chose radical prostatectomy at diagnosis, a long-term consequences for a substantial the introduction of serum PSA testing and substantial proportion of men who might number of patients and, although the widespread PCa screening, the promise of have been considered potential active authors strongly advocate its use, active altering the dismal prognosis of this disease surveillance candidates have had aggressive surveillance remains an exceedingly and offering a cure, with earlier diagnosis at tumour features [ 11 – 13 ] . Most notably, these uncommon option for patients with a lower stage, has been more frequent. Thus, studies consistently report that more than small-volume PCa in the USA. the face of this disease has changed. Since 50% of cancers in these patients are 1997, there has been a 100% increase in upgraded to Gleason grade 7 or higher Limiting cancer treatment to just the incidence of PCa from 90 000 to 180 000 tumours. Thus, there is concern that malignancy and immediate surrounding cases per year, during which time the treatment delays caused by active tissue within the preserved primary organ is number of men with metastases at surveillance may be associated with an a transition that is familiar to patients and presentation declined 30% from 35 000 to impaired chance of curability [ 13,14 ] . This physicians; however, the prostate is not 29 000 cases per year [ 7,8 ] ; however, concern is further compounded by the lack anatomically amenable to partial extirpation comparatively younger men with apparently of reliable triggers for intervention including of the peripheral zone. With the advent of early-stage, low grade, small-volume disease PSA kinetics [ 15,16 ] . directly applied, precisely controlled ablative accounted for the majority of the overall technology (cryoablation, high-intensity increase in incidence. Reports from a prospective active focused ultrasound, photodynamic therapy surveillance study in Toronto, Canada, and laser-induced interstitial therapy), the Although the prognosis for PCa is now very showed that 26% (117/450) of patients who concept of organ-sparing therapy went from different from what it was 20 years ago, the had been treated initially with active improbable to plausible, and the explosion aggressiveness of our treatment has not surveillance and who subsequently had of its use in this dataset shows its appeal to changed commensurately; when treatment undergone defi nitive therapy (surgery or the urology community. is deemed necessary or desired, physicians radiation) experienced a 50% rate of continue to depend on radical therapies for biochemical recurrence during a median Cryoablation became the de facto energy all men. Recently, both medical professionals follow-up period of 6.8 years; this rate is source of choice in the USA because it was and the lay population have expressed substantially higher than that predicted the only technology approved both by the concern about over-treating PCa, and the using preoperative nomograms and the Food and Drug Administration for the assumption that immediate radical highest risk inclusion criteria that still destruction of soft tissue and by Medicare treatment is needed has been challenged defi ned eligibility for that trial [ 17 – 19 ] . for the treatment of PCa. Cryotherapy also [ 9,10 ] .. However, the active monitoring and Conversion to radical therapy during active has the advantage of having a long history delayed intervention approach is not surveillance has been reported for 14 – 39% of effective tumour treatment in different without concerns; consistently, in studies of patients with PCa [ 20 – 23 ] . Given these parts of the body, including treatment of the

entire prostate gland. The rocky early start outcomes of biochemical recurrence and Registry data show not only that focal that prostate cryoablation experienced has biopsy-proven recurrence are similar to cryoablation is used widely in the urological been mitigated largely by major technical disease-specifi c outcomes for men treated community but also that it provides advances in the procedure, such as with whole-gland cryoablation. For focal promising short-term outcomes for well improved urethral warmer design and cryoablation to be implemented successfully, selected patients with PCa. Morbidity was third-generation technologies based on the it must not only deliver effective cancer low, although > 40% of patients experienced Joule – Thompson effect, and cryoablation control but must also deliver improved impotence, and 26% of patients that has been shown to be effective and safe urinary continence and sexual function. underwent biopsy for rising PSA levels when used to treat the entire prostate gland These data show minimal impact on urinary after therapy had persistent cancer. We [ 24,25 ] . function, but also show clearly that emphasize that additional study is needed to maintenance of sexual function is certainly determine the proper indications and The concept of managing PCa as chronic not assured after focal cryoablation. techniques for using focal cryoablation to disease, using targeted destruction of Additional study is needed on the treat PCa as well as the expected outcomes identifi able disease, and possibly using differences between treatment templates of such treatment; to this end, the data in chemopreventive agents to inhibit the and ablative energies to determine optimum the COLD Registry offer the largest and formation of new carcinomas, is being protocols for PCa treatment. most substantial collection of information accepted increasingly in preference to the on the use of focal cryotherapy for PCa alternative treatment options for patients The present study is also limited by the use treatment. with newly diagnosed PCa, who prefer some of the ASTRO defi nition of biochemical treatment to no treatment or to radical recurrence; a defi nition developed for treatment. patients treated primarily with radical ACKNOWLEDGEMENTS radiation therapy. Although this defi nition The biology of index lesion targeting was not developed for patients treated by The authors wish to acknowledge Kristi M. becomes central to the concept of other methods, it has been widely applied Speights, Associate Scientifi c Editor, M.D. successful focal therapy [ 26 ] . The outside of the radiation-treated patient with Anderson Cancer Center for her outstanding multifocality of PCa may not affect its PCa. We would, however, expect the kinetics editorial contributions. clinical course, as > 80% of secondary of serum PSA after focal therapy using any satellite lesions are low grade and < 0.5 cm3 ablative energy to be different from those The M.D. Anderson Cancer Center is (the threshold believed by numerous observed after radical therapy, thus the use supported by a Core grant (CA16672). The authorities to be associated with clinical of serum PSA as a surrogate marker for COLD Registry is supported by an disease progression). The presence and cancer treatment after focal cryoablation unrestricted educational grant from volume of these secondary cancer foci have remains unknown. Healthtronics, Austin, TX, USA. been found to be unrelated to biochemical recurrence after radical prostatectomy, Another limitation is the dependence on although it should be acknowledged that participants in the COLD Registry to provide CONFLICT OF INTEREST these low-risk areas are removed if surgery appropriate treatment and outcome details, is performed, so their ultimate risk is not a problem common to multi-site treatment John F. Ward received an unrestricted established [ 27,28 ] . registries. The duration of follow-up is not Research Grant from Healthtronics. J. long enough to determine whether the Stephen Jones is a Speaker for Healthtronics. In the present paper, we do not suggest that natural course of the disease was altered focal therapy has a proven role in the care through targeted cryoablation, but the of patients with PCa, but it must be present study does provide a study cohort REFERENCES conceded that the data that support any large enough to evaluate short-term treatment option, including active oncological effi cacy, which serves to 1 Hall GS , Kramer CE , Epstein JI . surveillance, are inadequate. The data encourage continued exploration of this Evaluation of radical prostatectomy presented in the present paper represent the potentially paradigm-shifting therapy. specimens. A comparative analysis of largest single series to date to report on Finally, the fi nancial sponsorship of the sampling methods . Am J Surg Pathol cancer-specifi c and quality-of-life outcomes COLD Registry must be considered, as should 1992 ; 16 : 315 – 24 for patients treated with cryoablation with the measures taken to mitigate its effects 2 Andreoiu M , Cheng L . Multifocal the intent to provide organ preservation. on any analyses using this data. prostate cancer: biologic, prognostic, and therapeutic implications . Hum A major limitation of these data is the lack In conclusion, organ-sparing therapy has Pathol 2 0 1 0 ; 41 : 781 – 93 of defi ned criteria for treating the patient slowly become the standard therapy for 3 D ’Amico AV , Moul J , Carroll PR , Sun L , with focal cryoablation and not having most solid tumours, but its role in treating Lubeck D , Chen MH . Cancer-specifi c specifi ed ablative templates. Despite this PCa has been limited by high rates of mortality after surgery or radiation for limitation, the data suggest urologists are multifocality and anatomical challenges. We patients with clinically localized prostate prudently selecting most patients for focal are not insinuating that focal cryoablation is cancer managed during the prostate- cryoablation and individualizing the proven to play a role in the successful specifi c antigen era . J Clin Oncol 2003 ; treatment to the patient; the cancer-specifi c treatment of PCa, however, the COLD 21 : 2163 – 72

4 Consensus statement: guidelines for misclassifi cation vary according to 22 Krakowsky Y , Loblaw A , Klotz L . PSA following radiation therapy. biopsy criteria? J Urol 2 0 1 0 ; 183 : Prostate cancer death of men treated American Society for Therapeutic 539 – 44 with initial active surveillance: clinical Radiology and Oncology Consensus 14 van den Bergh RC , Steyerberg EW , and biochemical characteristics . J Urol Panel . Int J Radiat Oncol Biol Phys 1997 ; Khatami A et al . Is delayed radical 2 0 1 0 ; 184 : 131 – 5 37 : 1035 – 41 prostatectomy in men with low-risk 23 Khatami A , Aus G , Damber JE , Lilja H , 5 Brkovic D , Riedasch G , Staehler G . screen-detected prostate cancer Lodding P , Hugosson J . PSA doubling [ Status of organ preserving surgery in associated with a higher risk of time predicts the outcome after active renal cell carcinoma ] . Urologe A 1997 ; unfavorable outcomes? Cancer 2 0 1 0 ; surveillance in screening-detected 36 : 103 – 8 116 : 1281 – 90 prostate cancer: results from the 6 Macmillan RD , Purushotham AD , 15 Ross AE , Loeb S , Landis P et al . European randomized study of George WD . Local recurrence after Prostate-specifi c antigen kinetics during screening for prostate cancer, Sweden breast-conserving surgery for breast follow-up are an unreliable trigger for section . Int J Cancer 2007 ; 120 : 170 – cancer . Br J Surg 1996 ; 83 : 149 – 55 intervention in a prostate cancer 4 7 Jemal A , Siegel R , Xu J , Ward E . surveillance program . J Clin Oncol 2 0 1 0 ; 24 Jones JS , Rewcastle JC , Donnelly BJ , Cancer statistics, 2010 . CA Cancer J Clin 28 : 2 8 1 0 – 6 Lugnani FM , Pisters LL , Katz AE . 2 0 1 0 ; 60 : 277 – 300 16 Whitson JM , Carroll PR . Active Whole Gland Primary Prostate 8 Cooperberg MR , Broering JM , Kantoff surveillance for early-stage prostate Cryoablation: initial results from the PW , Carroll PR . Contemporary trends in cancer: defi ning the triggers for Cryo On-Line Data Registry . J Urol 2008 ; low risk prostate cancer: risk assessment intervention . J Clin Oncol 2 0 1 0 ; 28 : 180 : 554 – 8 and treatment . J Urol 2007 ; 178 : S14 – 9 2807 – 9 25 Donnelly BJ , Saliken JC , Brasher PM 9 Klotz L . Active surveillance versus 17 Klotz L , Zhang L , Lam A , Nam R , et al . A randomized trial of external radical treatment for favorable-risk Mamedov A , Loblaw A . Clinical results beam radiotherapy versus cryoablation localized prostate cancer . Curr Treat of long-term follow-up of a large, active in patients with localized prostate Options Oncol 2006 ; 7 : 355 – 62 surveillance cohort with localized cancer . Cancer 2 0 1 0 ; 116 : 323 – 30 10 Stattin P , Holmberg E , Bratt O , prostate cancer . J Clin Oncol 2 0 1 0 ; 28 : 26 Ahmed HU . The index lesion and the Adolfsson J , Johansson JE , Hugosson 126 – 31 origin of prostate cancer. N Engl J Med J . Surveillance and deferred treatment 18 Stephenson AJ , Scardino PT , Eastham 2009 ; 361 : 1704 – 6 for localized prostate cancer. Population JA et al . Preoperative nomogram 27 Nelson BA , Shappell SB , Chang SS based study in the National Prostate predicting the 10-year probability of et al . Tumour volume is an independent Cancer Register of Sweden . J Urol 2008 ; prostate cancer recurrence after radical predictor of prostate-specifi c antigen 180 : 2423 – 9 ; discussion 2429 – 30 prostatectomy . J Natl Cancer Inst 2006 ; recurrence in patients undergoing 11 Thaxton CS , Loeb S , Roehl KA , Kan D , 98 : 715 – 7 radical prostatectomy for clinically Catalona WJ . Treatment outcomes of 19 Kattan MW , Zelefsky MJ , Kupelian PA , localized prostate cancer . BJU Int 2006 ; radical prostatectomy in potential Scardino PT , Fuks Z , Leibel SA . 97 : 1169 – 72 candidates for 3 published active Pretreatment nomogram for predicting 28 Villers A , McNeal JE , Freiha FS , surveillance protocols . Urology 2 0 1 0 ; 75 : the outcome of three-dimensional Stamey TA . Multiple cancers in the 414 – 8 conformal radiotherapy in prostate prostate. Morphologic features of 12 Smaldone MC , Cowan JE , Carroll PR , cancer . J Clin Oncol 2000 ; 18 : 3352 – 9 clinically recognized versus incidental Davies BJ . Eligibility for active 20 Hardie C , Parker C , Norman A et al . tumors . Cancer 1992 ; 70 : 2313 – 8 surveillance and pathological outcomes Early outcomes of active surveillance for for men undergoing radical localized prostate cancer . BJU Int 2005 ; Correspondence: John F. Ward, Department prostatectomy in a large, community 95 : 956 – 60 of Urology, University of Texas, M. D. based cohort . J Urol 2 0 1 0 ; 183 : 138 – 43 21 van den Bergh RC , Vasarainen H , van Anderson Cancer Center, PO Box 301439, 13 Ploussard G , Salomon L , Xylinas E der Poel HG et al . Short-term outcomes Houston, TX 77230-1439, USA. et al . Pathological fi ndings and prostate of the prospective multicentre ‘ Prostate e-mail: [email protected] specifi c antigen outcomes after radical Cancer Research International: Active prostatectomy in men eligible for active Surveillance ’ study . BJU Int 2 0 1 0 ; 105 : Abbreviations : PCa , prostate cancer ; surveillance – does the risk of 956 – 62 IRB , Institutional Review Board.