SALVAGE CRYOTHERAPY USING AN ARGON BASED SYSTEM FOR LOCALLY RECURRENT PROSTATE CANCER AFTER RADIATION THERAPY: THE COLUMBIA EXPERIENCE

0022-5347/01/1664-1333/0 THE JOURNAL OF UROLOGY Vol. 166, 1333 1338, October 2001 Copyright 2001 by AMERICAN UROLOGICAL ASSOCIATION, INC. Printed in U.S.A. SALVAGE CRYOTHERAPY USING AN ARGON BASED SYSTEM FOR LOCALLY RECURRENT PROSTATE CANCER AFTER RADIATION THERAPY: THE COLUMBIA EXPERIENCE MOHAMED A. GHAFAR, CHRISTOPHER W. JOHNSON, ALEXANDER DE LA TAILLE, MITCHELL C. BENSON, EMILIA BAGIELLA, MARIE FATAL, CARL A. OLSSON AND AARON E. KATZ* From the Department of Urology, College of Physicians and Surgeons of Columbia University, New York, New York ABSTRACT Purpose: Cryosurgical ablation of the prostate has been reported as potential treatment for radioresistant clinically localized prostate cancer. We report our experience with the safety and efficacy of salvage cryosurgery using the argon based CRYOCare system (Endocare, Inc, Irvine, California). Materials and Methods: Between October 1997 and September 2000, 38 men with a mean age of 71.9 years underwent salvage cryosurgery for recurrent prostate cancer after radiation therapy failed. All patients had biochemical disease recurrence, defined as an increase in prostate specific antigen (PSA) of greater than 0.3 ng./ml. above the post-radiation PSA nadir. Subsequently prostate biopsy was positive for cancer. Pre-cryosurgery bone scan demonstrated no evidence of metastatic disease. In addition, these patients received 3 months of neoadjuvant androgen deprivation therapy before cryotherapy. Results: The PSA nadir was 0.1 or less, 1 or less and greater than 1 ng./ml. in 31 (81.5%), 5 (13.2%) and 2 (5.3%) patients, respectively. Biochemical recurrence-free survival calculated from Kaplan-Meier curves was 86% at 1 year and 74% at 2 years. Reported complications included rectal pain in 39.5% of cases, urinary tract infection in 2.6%, incontinence in 7.9%, hematuria in 7.9% and scrotal edema in 10.5%. The rate of rectourethral fistula, urethral sloughing and urinary retention was 0%. Conclusions: Our study supports cryosurgery of the prostate as safe and effective treatment in patients in whom radiation therapy fails. Using the CRYOCare machine resulted in a marked decrease in complications. KEY WORDS: prostate, prostatic neoplasms, cryosurgery, recurrence, radiation Prostate cancer is the most common cancer in American men. 1 It is estimated that there may be 180,400 new cases this year and 31,400 deaths are expected. Recent studies have shown that a significant number of newly diagnosed patients undergo some type of radiation to the prostate gland via external beam, seed implantation or the 2 techniques combined. 2 In the past patients with radiation recurrent disease had a limited number of therapeutic options. 3 Currently otherwise healthy men may be considered candidates for salvage radical prostatectomy. This surgical procedure is associated with significant morbidity 1 and most urologists have considered other palliative therapy, such as hormone deprivation or watchful waiting. 4, 5 Recently salvage cryosurgical ablation of the prostate with ultrasound guidance has earned renewed interest among urologist. 5 The goal of cryosurgery is ablation of the whole prostate gland, rendering the patient free of disease. The procedure is percutaneous and less invasive than salvage open surgery. The latest techniques of cryosurgery allow urologists to monitor the formation of the ice ball in visual and thermal fashion with ultrasound and temperature sensors. These devices enhance the accuracy of tissue freezing. They also help to decrease the morbidity of the procedure by sparing the surrounding structures, including the bladder, rectum and Accepted for publication April 4, 2001. Supported by the Irwin White Fellowship for Prostate Cancer Research. * Financial interest and/or other relationship with Endocare, Inc. 1333 external urinary sphincter. We report the experience at our institution using an argon based cryosurgical system in patients with radiation refractory, localized prostate cancer. MATERIALS AND METHODS Patient eligibility. Between October 1997 and September 2000, 38 men with a mean age of 71.9 years underwent cryoablation of the prostate for clinically localized, stages T1-T3, radioresistant, recurrent prostate cancer. All patients had been treated with external beam radiation at least 18 months before this evaluation. Patients were considered candidates for cryosurgery when they had biochemically and biopsy proved disease recurrence and negative bone scan. Biochemical recurrence was defined as an increase in prostate specific antigen (PSA) of greater than 0.3 ng./ml. above the PSA nadir. The PSA nadir was defined as the lowest serum PSA measured during post-cryosurgery followup. PSA 0.1 ng./ml.. or less was considered undetectable. Biopsy of the prostate and seminal vesicles was performed under transrectal ultrasound guidance. A study exclusion criterion was recurrent prostate cancer invading the seminal vesicles. After this point in screening patients eligible for study participation underwent further staging with open or laparoscopic pelvic lymph node dissection. Those with disease in the lymph nodes were excluded from study. Patients then received androgen ablation therapy for 3 months before cryosurgery. Cryosurgical ablation. All cryosurgery was performed by 1

1334 SALVAGE CRYOTHERAPY FOR RECURRENT PROSTATE CANCER AFTER RADIATION surgeon (A. E. K.) using the technique of Onik 6 and Pisters 7 et al and the CRYOCare system, which applies argon and helium gases to freeze and thaw tissue, respectively. Cryosurgery was done with the patients under spinal anesthesia. Patients received a Fleets enema on the morning of the procedure and 500 mg. Flagyl (Abbott Laboratories, North Chicago, Illinois) intravenously at the start of the procedure. Under flexible cystoscopic guidance a 10Fr suprapubic catheter was placed and the bladder remained distended. A urethral warming catheter was inserted before freezing the tissue (CMSI, Baltimore, Maryland). The catheter was warmed to 38 C and remained in place for 2 hours after the completion of the procedure. In addition, before the start of the freezing cycle 6 cryoprobes were placed into the prostate under transrectal ultrasound guidance, including 2 anterior, 2 posteromedial and 2 posterolateral probes (fig. 1). Simultaneously thermocouple devices or temperature monitor probes were placed adjacent to each of the 2 neurovascular bundles, the apex, Denonvilliers space and in the external sphincter. Freezing was initiated by activating the 2 anterior probes, which was followed by starting the 2 posterior probes. A double freeze-thaw technique was applied in all cases. The outer edge of the ice ball had a hyperechoic appearance and was readily visualized on transrectal ultrasound. Freezing was completed when certain criteria was met, that is temperature was less than 40C at each neurovascular bundle, apical temperature was less than 10C and all prostatic tissue appeared to have frozen, as visualized on ultrasound Patients were discharged home the following morning. They received oral antibiotics (500 mg. ciprofloxacin twice daily) for 5 days. The suprapubic tube remained open and patients were instructed to clamp the tube on postoperative day 4. One week after cryosurgery patients presented to the office for suprapubic tube removal The external genitalia and perineum were examined to determine the extent of swelling, obstruction, urethral sloughing, urinary infection, rectal fistula, edema and ecchymosis. Serum PSA was measured and digital rectal examination was done 6 weeks after cryosurgery and every 3 months thereafter. At each followup visit patients were asked whether they had incontinence, defined as patient report of a lack of urinary control requiring more than 1 pad daily. They were also questioned during the examination about other potential complications, such as rectal pain. TABLE 1. Patient characteristics No. pts. 38 Mean age (range) 71.9 (54.5 81.7) Mean mos. followup (range) 20.7 (3 37) Mean ng./ml. preop. serum PSA (range): 7.5 (0.4 28) No. less than 4 (%) 12 (31.6) No. 4 10 (%) 19 (50) No. greater than 10 (%) 7 (18.4) Mean preop. Gleason score (range) 7.0 (6 10) No. ng./ml. PSA nadir (%): Less than 0.1 31 (81.5) 0.1 1 5 (13.2) Greater than 1 2 (5.3) No. co-morbidity (%): Hypertension 14 (36.8) Coronary artery disease 6 (15.8) Diabetes 8 (21) Mean yrs. from radiation therapy to cryosurgery (range) 6.1 (2 11) Data analysis. Commercial software was used for data analysis. Data were summarized as the mean and range for continuous variables and in frequency tables for categorical variables. Univariate analysis was performed using the chisquare test and survival was projected using Kaplan-Meier survival curves. Multivariate analysis was done using the Cox proportional hazard regression model. RESULTS Subjects and complications. Mean followup was 20.7 months (range 3 to 37). Mean patient age was 71.9 years (range 54 to 81.7). Mean serum PSA before hormonal therapy was 7.5 ng./ml. Table 1 lists patient characteristics and table 2 lists complications during followup. In 2 of the 3 patients (7.9%) in whom post-cryosurgery incontinence required 1 or 2 pads daily an artificial urinary sphincter was placed postoperatively. The incidence of urethrorectal fistula, bladder outlet obstruction and urethral sloughing was 0%. The most common complication was transient rectal pain 1 to 2 weeks in duration in 15 men (39.6%). Scrotal swelling in 4 cases (10.5%) was attributable to serosanguineous drainage around the prostate that usually resolved within 2 weeks. No patients died and in only 1 distant disease developed in the penis. Multivariate analysis was performed to evaluate independently factors that may predispose patients to postcryosurgery biochemical recurrence (table 3). Included in this analysis were certain risk factors, including post-cryosurgery PSA nadir, and pre-cryosurgery Gleason score and PSA (fig. 2). Biochemical recurrence-free survival calculated from Kaplan-Meier curves was 86% at 12 months and 74% at 24 (fig. 3). DISCUSSION After radiation therapy serum PSA usually starts to decrease within a few months and histological tumor clearance progresses for 12 to 18 months. 8 However, in a significant number of patients there is local recurrence. 9, 10 After recurrence is suspected on digital rectal examination or due to increasing serum PSA tissue is needed for confirmation. The FIG. 1. Position of 6 probes in prostate. RNVB, right neurovascular bundle. DENON, Denonvilliers space. LNVB, left neurovascular bundle. TABLE 2. Complications after cryosurgery Complication No. (%) Incontinence 3 (7.9) Urinary tract infection 1 (2.6) Hematuria 3 (7.9) Obstruction 0 Perineal, rectal pain 15 (39.5) Urethral sloughing 0 Rectal fistula 0 Lower urinary tract symptoms 6 (15.8) Swelling 4 (10.5)

SALVAGE CRYOTHERAPY FOR RECURRENT PROSTATE CANCER AFTER RADIATION 1335 TABLE 3. Multivariate analysis to define the independent predictors of PSA recurrence after cryosurgery No. Pts. Risk Ratio (95% CI) p Value PSA 10 or less vs. greater 31 Vs. 7 0.77 (0.07 8.5) 0.80 than 10 ng./ml. Gleason sum 7 or less vs. 21 Vs. 0.40 (0.08 2.1) 0.30 greater than 7 PSA nadir 0.1 or less vs. greater than 0.1 ng./ml. 17 31 Vs. 7 3.90 (0.8 19.7) 0.07 case requires repeat staging with transrectal ultrasound guided biopsy and bone scan to rule out distant metastasis. Currently patients with clinically localized, radioresistant disease have limited treatment options. Additional radiation therapy is not acceptable because these tumors are clearly radioresistant and re-treatment them places patients at higher risk for radiation induced complications. 11 Cytotoxic chemotherapy is not curative and should be administered only as palliation at late stages of disease. 12 Salvage radical prostatectomy is a technically challenging procedure that has been associated with high co-morbidity and prolonged hospitalization. 13 15 Treatment strategies for radioresistant localized prostate cancer focus on the 2 objectives of local tumor control and increased patient survival 16 For salvage cryosurgery to become a reasonable therapeutic option acceptable complication and disease-free survival rates are necessary that match or surpass existing treatment options. Radiation therapy causes periurethral fibrosis and functional impairment, such that the effect of further local radiation therapy results in a high rate of complications. In our series urinary incontinence was present in only 7.9% of cases. This dramatic decrease in the incontinence rate over that in previously published reports was likely due to surgeon ability to monitor the temperature within the external FIG. 2. Biochemical recurrence-free survival stratified by serum PSA. A, nadir after cryosurgery. B, before cryosurgery

1336 SALVAGE CRYOTHERAPY FOR RECURRENT PROSTATE CANCER AFTER RADIATION FIG. 3. Biochemical recurrence was defined as PSA increase 0.3 ng./ml. or more above PSA nadir sphincter. Using this technique temperature monitor probes are placed percutaneously through the perineum. With the aid of a flexible cystoscope a thermocouple device may be accurately placed within the sphincter. When the temperature readings within the sphincter reach values less than 0C, the ice ball may be thawed, preventing damage to the area and enabling the patient to remain continent. In our series we did not observe any rectal fistulas, which may have been attributable to improved ultrasound technology and placement of a temperature monitor probe in Denonvilliers space. Thermocouples are not without problems since they read the temperature at the tip of the probe. Therefore, any movement of the devices from the original positions may provide the surgeon a false reading. The position of the devices must be confirmed and reassessed before and after each freeze-thaw cycle. In addition to thermocouples, we believe that continuous warming of the urethra has helped to decrease the morbidity of this procedure in the modern era of cryosurgery. The urethral warming system applied was approved by the Food and Drug Administration to maintain the integrity of the urethral mucosa and, thus, prevent urethral sloughing during the freezing cycle. In our study the warmer remained in the urethra during freezing and for an additional 2 hours postoperatively. This innovation affected major improvement in the incidence of urethral sloughing and obstruction. None of our patients had these complications. This degree of success has not been reported in any 17, 18 other series. The potential liability of a urethral warming system is that periurethral cancer may be left behind. Although it is theoretically possible, we believe that the benefits of a warming system outweigh the risks, especially in patients who have received irradiation. The major concern is that previous radiation impedes the normal degradation of necrotic tissue in the prostatic urethra, which would contribute to bladder outlet obstruction after cryosurgery. 19 Compared to previously published studies of various treatment modalities for recurrent prostate cancer after radiation therapy we noted a favorable complication rate (table 4). 20 25 Bonney et al reported equal survival of patients undergoing cryosurgery compared to radical prostatectomy for all stages of disease. 26 They observed that biochemical recurrence-free survival calculated from Kaplan-Meier curves was 86% at 12 months and 74% at 24. In our study a PSA nadir greater than 0.1 ng./ml. was not an independent predictor of biochemical recurrence after cryotherapy, most probably due to the small number of patients. Nadir PSA in our study may have been an artifact as a result of 3 months of previous neoadjuvant hormonal therapy in addition to cryosurgery. We have routinely administered hormones before cryosurgery for a number of reasons. Androgen deprivation leads to prostate gland downsizing, which increases the efficacy of cryosurgery. Large prostate volume may prevent adequate freezing of the whole prostate gland, leading to inadequate cell kill. 27 In addition, despite a negative metastatic evaluation on bone scan and lymph node biopsy a significant number of these patients may have microscopic disease beyond the prostate gland and into the peripheral circulation. Hormonal therapy has additional advantage of clearing these hematogenous micrometastasis in recurrent radioresistant prostate cancer, although up to 40% of patients with distant metastasis do not respond to hormonal therapy. 28 TABLE 4. Comparison of complications of various treatment options for radioresistant prostate cancer References Treatment No. Pts. % Incontinence % Obstruction % Rectal Injury % Urethral Sloughing Pontes et al 20 Radical prostatectomy 43 30 2.3 9 Not available Ahlering et al 21 Radical prostatectomy 11 64 Not available Not available Not available Rogers et al 22 Radical prostatectomy 40 58 Not available 15 2.5 Lee et al 23 Cryosurgery 46 9 Not available 8.7 Not available Amling et al 24 Radical prostatectomy 108 23 Not available 6 Not available Miller et al 25 Cryosurgery 33 9 4 0 5.1 Present series Cryosurgery 38 7.9 0 0 0

SALVAGE CRYOTHERAPY FOR RECURRENT PROSTATE CANCER AFTER RADIATION 1337 CONCLUSIONS Cryosurgery guided by ultrasound monitoring is effective clinical therapy for recurrent localized radioresistant prostate cancer. It is less invasive and causes less trauma and fewer side effects than salvage radical prostatectomy. Refinement in the cryosurgical technique and use of the argon based system with thermocoupling devices may result in less morbidity than previously reported. REFERENCES 1. Parker, S. L., Tong, T., Bolden, S. et al: Cancer statistics, 1997. CA Cancer J Clin, 47: 5, 1997 2. Mettlin, C. J. and Murphy, G.: The National Cancer Data Base report on prostate cancer. Cancer, 74: 1640, 1994 3. Katz, A.: Cryosurgery in the radiation failure patient. Proceedings of the World Congress of Cryosurgery, Orlando, Florida, October 30, 1998 4. Drachenberg, D. E.: Treatment of prostate cancer: watchful waiting, radical prostatectomy, and cryoablation. Semin Surg Oncol, 18: 37, 2000 5. Corral, D. A., Pisters, L. L. and von Eschenbach, A. C.: Treatment options for localized recurrence of prostate cancer following radiation therapy. Urol Clin North Am, 23: 677, 1996 6. Onik, G. M., Cohen, J. K., Reyes, G. D. et al: Transrectal ultrasound-guided percutaneous radical cryosurgical ablation of the prostate. Cancer, 72: 1291, 1993 7. Pisters, L. L., von Eschenbach, A. C., Scott, S. M. et al: The efficacy and complications of salvage cryotherapy of the prostate. J Urol, 157: 921,1997 8. Goad, J. R., Chang, S. J., Ohori, M. et al: PSA after definitive radiotherapy for clinically localized prostate cancer. Urol Clin North Am, 20: 727, 1993 9. Kabalin, J. N., Hodge, K. K., McNeal, J. E. et al: Identification of residual cancer in the prostate following radiation therapy: role of transrectal ultrasound guided biopsy and prostate specific antigen. J Urol, 142: 326, 1989 10. Crook, J., Robertson, S. and Esche, B.: Proliferative cell nuclear antigen in postradiotherapy prostate biopsies. Int J Radiat Oncol Biol Phys, 30: 303, 1994 11. Cumes, D. M., Goffinet, D. R., Martinez, A. et al: Complication of 125 iodine implantation and pelvic lymphadenectomy for prostatic cancer with special reference to patients who had failed external beam therapy as their initial mode of therapy. J Urol, 126: 620, 1981 12. Chatelain, C.: Adjuvant cytotoxic chemotherapy in association with radical surgery or radical radiation treatment in presumably localized prostatic cancer. Acta Oncol, 30: 259, 1991 13. Shrader-Bogen, C. L., Kjellberg, J. L., McPherson, C. P. et al: Quality of life and treatment outcomes: prostate carcinoma patients perspectives after prostatectomy or radiation therapy. Cancer, 79: 1977, 1997 14. Pisters, L. L. and Wajsman, Z.: Salvage surgery following full dose radiation therapy for prostate cancer. In: Atlas of Surgical Oncology. Edited by K. I. Bland, C. P. Karakousis and E. M. Copeland, III. Philadelphia: W. B. Saunders, p. 605, 1995 15. Litwin, M. S., Hays, R. D., Fink, A. et al: Quality-of-life outcomes in men treated for localized prostate cancer. JAMA, 273: 129, 1995 16. Mobley, W. C., Loening, S. A., Narayana, A. S.: Combination perineal cryosurgery and external radiation therapy for adenocarcinoma of prostate. Urology, 24: 11, 1984 17. Cox, R. L. and Crawford, E. D.: Complications of cryosurgical ablation of the prostate to treat localized adenocarcinoma of the prostate. Urology, 45: 932, 1995 18. Wieder, J., Schmidt, J. D., Casola, G. et al: Transrectal ultrasound-guided transperineal cryoablation in the treatment of prostate carcinoma: preliminary results. J Urol, 154: 435, 1995 19. Bales, G. T., Williams, M. J., Sinner, M.: Short-term outcomes after cryosurgical ablation of the prostate in men with recurrent prostate carcinoma following radiation therapy. Urology, 46: 676, 1995 20. Pontes, J. E., Montie, J., Klein, E. et al: Salvage surgery for radiation failure in prostate cancer. Cancer, suppl., 71: 976, 1993 21. Ahlering, T. E., Lieskovsky, G. and Skinner, D. G.: Salvage surgery plus androgen deprivation for radioresistant prostatic adenocarcinoma. J Urol, part 2, 147: 900, 1992 22. Rogers, E., Ohori, M., Kassabian, V. S. et al: Salvage radical prostatectomy: outcome measured by serum prostate specific antigen levels. J Urol, 153: 104, 1995 23. Lee, F., Bahn, D. K., McHugh, T. A. et al: Cryosurgery of prostate cancer. Use of adjuvant hormonal therapy and temperature monitoring: a one year follow-up. Anticancer Res, 17: 1511, 1997 24. Amling, C. L., Lerner, S. E., Martin, S. K. et al: Deoxyribonucleic acid ploidy and serum prostate specific antigen predict outcome following salvage prostatectomy for radiation refractory prostate cancer. J Urol, 161: 857, 1999 25. Miller, R. J., Jr., Cohen, J. K., Shuman, B. et al: Percutaneous, transperineal cryosurgery of the prostate as salvage therapy for post radiation recurrence of adenocarcinoma. Cancer, 77: 1510, 1996 26. Bonney, W. W., Fallon, B., Gerber, W. L. et al: Cryosurgery in prostatic cancer: survival Urology, 19: 37, 1982 27. Derakhshani, P., Neubauer, S., Braun, M. et al: Cryoablation of localized prostate cancer. Experience in 48 cases, PSA and biopsy results. Eur Urol, 34: 181, 1998 28. Kozlowski, J. M. and Grayhack, J. T.: Carcinoma of the prostate. In: Adult and Pediatric Urology, 2nd ed. Edited by J. Y. Gillenwater, J. T. Grayhack, S. S. Howards et al. St. Louis: Mosby-Year Book, vol. 2, p. 1277, 1991 EDITORIAL COMMENTS There are 2 recent reports documenting salvage cryoablation of the prostate after previous radiation therapy. The first report by Chin et al presented results on 118 patients, 1 and the present series by Ghafar et al describes 38 patients. Both studies used the CRYOcare system, and it is noteworthy that the frequency and severity of complications in both series were less than those noted in earlier publications. Conspicuous by its absence from table 4 in the present article is the M.D. Anderson data on 150 patients published in 1997, which revealed a considerably higher complication rate, including incontinence in 73% of patients, obstructive symptoms in 67% and severe perineal pain in 8%. 2 It appears that improvements in techniques as described by Ghafar et al have led to decreased morbidity and an incontinence rate of only 7.9%. It is noteworthy, however, that these data were compiled from physician records, and not from a validated patient questionnaire now recognized as the optimal method to assess morbidity. 3 In the series of Chin et al, severe incontinence was noted in 6.7% of patients and an additional 3.3% had a rectalurethral fistula, while there were no such fistulas in the present report. The diminished posttreatment complication rate appears to be related to improved urethral warming, better spacing of the cryoprobes and improved monitoring of the freezing with the thermocouples. Despite fewer severe complications, it is still difficult to engender a great deal of enthusiasm for post-radiation therapy cryoablation for several reasons. First, the number of patients with persistent or recurrent carcinoma of the prostate after radiation therapy who are appropriate for additional local therapy is relatively small. In retrospective reviews of any post radiation therapy salvage therapy the denominator of patients originally treated is never known. Presumably, the criteria for salvage cryoablation surgery are the same as those for salvage prostatectomy, which are an apparent locally confined, biopsy proved recurrence in a relatively young, healthy patient whose disease would have been suitable for definitive surgery at initial presentation. Many patients in whom radiation therapy fails now do not meet these criteria because they had a more advanced lesion at initial diagnosis and, thus, distant disease is highly likely or they are now considerably older and another aggressive local therapy may not be necessary. Thus, one should be cautious; just because a patient has an increasing PSA and documented local recurrence, does not mean that he is an appropriate candidate for another aggressive local therapy with attendant morbidity. The most distressing situation is a severe and often difficult to fix complication in someone in whom treatment was ill advised. The observation that a biopsy after cryoablation is frequently negative is really not convincing about the efficacy of the treatment. It is not surprising if there is a modest volume of cancer after radiation therapy and 90% of the cancer has been eliminated with cryoablation that a biopsy will be negative for a time until the lesion re-grows larger. While a positive biopsy is certainly meaningful, a

1338 SALVAGE CRYOTHERAPY FOR RECURRENT PROSTATE CANCER AFTER RADIATION negative biopsy does not preclude the presence of 1 or several foci of remaining cancer in the prostate. PSA data are more valuable but frequently confounded by neoadjuvant or adjuvant androgen deprivation. Another disconcerting aspect of cryoablation is the entire concept of preservation of the urethra and directly adjacent tissue. Donnelly et al examined a whole-mount reconstruction of the prostate in 2 patients dying of a nonprostate cancer who had undergone apparently successful cryoablation based on an undetectable PSA and negative biopsies. 4 In 1 patient there was viable tissue only around the urethra but in the other patient there was an appreciable margin of prostatic glands surrounding the urethra for several mm. In 350 whole-mount radical prostatectomy specimens Leibovich et al found that the nearest focus of cancer was within 5 mm. of the urethra in 84% of cases and cancer touched the urethra in 17% of cases. 5 There is certainly no noninvasive method to identify such proximity of cancer to the urethra. The failure of cryoablation to destroy the tissue immediately around the urethra may well be associated with recurrences as additional followup is available. Noteworthy also in the series of Chin et al is that in 50% of patients post-cryoablation biopsies demonstrated residual, viable prostate glands. 1 It appears that the complication rate from salvage cryoablation after radiation therapy may be diminishing through better urethral warming, better spacing of the cryoprobes and improved monitoring of the freezing with the thermocouples. Whether the complications from cryoablation will be less or more than those obtained with salvage surgery will never be subjected to a randomized clinical trial but some information might be available from a comparison now under way at the Mayo Clinic and M.D. Anderson. 6 Skepticism should still be maintained about the appropriateness of postradiation therapy salvage treatment in many patients who have locally recurrent prostate cancer but who are also at a high risk for systemic disease, as any further local treatment that has morbidity may be ill advised. In addition, there is still uncertainty regarding the ability of cryoablation to destroy all epithelium in the prostate and, thus, all cancer and at the same time avoid serious complications. James E. Montie Department of Urology The University of Michigan Medical Center Ann Arbor, Michigan 1. Chin, J. L., Pautler, S. E., Mouraviev, V. et al: Results of salvage cryoablation of the prostate after radiation: identifying predictors of treatment failure and complications. J Urol, 165: 1937, 2001 2. Cespedes, R. D., Pisters, L. L., von Eschenbach, A. C. et al: Long-term followup of incontinence and obstruction after salvage cryosurgical ablation of the prostate: results in 143 patients. J Urol, 157: 237, 1997 3. Wei, J. T., Dunn, R. L., Marcovich, R. et al: Prospective assessment of patient reported urinary continence after radical prostatectomy. Urology, 164: 744, 2000 4. Donnelly, B. J., Saliken, J. C., Ali-Ridha, N. et al: Histological findings in the prostate two years following cryosurgical ablation. Can J Urol, 8: 1237, 2001 5. Leibovich, B. C., Blute, M. L., Bostwick, D. G. et al: Proximity of prostate cancer to the urethra: implications for minimally invasive ablative therapies. Urology, 56: 726, 2000 6. Pisters, L.: Editorial comment. J Urol, 165: 141, 2001 Ghafar et al report experience with salvage cryotherapy in 38 patients using the argon based system. All patients received 3 months of hormonal therapy before salvage cryotherapy. The main message of this study is that when the argon based system is used with careful thermocouple monitoring, salvage cryotherapy can be performed with a relatively much lower rate of complications than in earlier series (references 7 and 19 in article). In particular, the authors should be congratulated on the low incidence of incontinence (8%) in their series, which is much lower than the 60% to 95% rate reported in the aforementioned series. Although the morbidity is lower in this series, the overall effectiveness of salvage cryotherapy deserves close scrutiny. In particular, is salvage cryotherapy really as effective as salvage radical prostatectomy? The available evidence would suggest that it is difficult to ablate or eliminate completely all prostatic epithelium with cryotherapy. In a small study of neoadjuvant cryotherapy before radical prostatectomy 4 of 7 patients had pt0 disease with no residual tumor in the radical prostatectomy specimen, suggesting that cryotherapy may cure some patients. 1 However, all patients had residual viable benign glands, emphasizing how difficult it is to destroy all prostatic epithelium. 1 Unfortunately, Ghafar et al did not include routine post-cryotherapy biopsies as part of followup of their patients. Of 110 patients who underwent prostate biopsies 6 months after salvage cryotherapy at our institution 23% had positive biopsies for cancer 1 and 28% had biopsies showing viable benign glands (reference 7 in article). At 2-year followup 74% of the patients in the present series were biochemically free of disease. Mean followup in this series is relatively short (20.7 months), and I anticipate that with longer followup more patients will have disease recurrence. Our long-term results showed that only 40% of patients undergoing salvage cryotherapy were disease-free at 5 years. 2 These long-term results are disappointing and do not appear as good as the long-term results of salvage radical prostatectomy (reference 24 in article). We recently compared biochemical outcome following salvage cryotherapy at M. D. Anderson to salvage radical prostatectomy at the Mayo Clinic. 3 Patients with pre-salvage treatment PSA greater than 10 ng./ml. or recurrence Gleason score greater than 8 were excluded from study to minimize bias. None of the patients received androgen deprivation until post-salvage biochemical failure. A uniform definition of biochemical failure (2 increases above nadir) was applied to both groups. Biochemical progression occurred in 40 of 60 (67%) patients treated with cryotherapy and 16 of 56 (29%) treated with radical prostatectomy (p 0.0002). 3 I believe that salvage prostatectomy and salvage cryotherapy are appropriate for different patient groups. In particular, younger healthy patients should consider salvage prostatectomy for cure. Older patients and those with co-morbid conditions may wish to consider salvage cryotherapy. Although many patients undergoing salvage cryotherapy are not cured, it may improve local control and delay the initiation of long-term hormonal therapy with all of its side effects. Ghafar et al convincingly demonstrate that by using the argon based system and extensive thermocouple monitoring, salvage cryotherapy can be safely performed. Louis Pisters Department of Urology University of Texas M. D. Anderson Cancer Center Houston, Texas 1. Pisters, L. L., Dinney, C. P. N., Pettaway, C. A. et al: A feasibility study of cryotherapy followed by radical prostatectomy for locally advanced prostate cancer. J Urol, 161: 509, 1999 2. Izawa, J. I., Madsen, L. M., Scott, S. et al: Long term follow-up of salvage cryotherapy for locally recurrent prostate cancer following radiation therapy. J Urol, 165: 331, abstract 1359, 2001 3. Leibovich, B. C., Zincke, H., Blute, M. L. et al: Recurrent prostate cancer after radiation therapy: salvage prostatectomy versus salvage cryosurgery. J Urol, 165: 389, abstract 1595, 2001