Cryosurgery as primary treatment for localized prostate cancer

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1 Int Urol Nephrol (2011) 43: DOI /s UROLOGY ORIGINAL PAPER Cryosurgery as primary treatment for localized prostate cancer Huibo Lian Hongqian Guo Weidong Gan Xiaogong Li Xiang Yan Wei Wang Rong Yang Feng Qu Changwei Ji Received: 19 January 2011 / Accepted: 22 March 2011 / Published online: 8 April 2011 Ó Springer Science+Business Media, B.V Abstract Objective To present the early results of the use of third-generation cryotherapy as primary treatment for localized prostate cancer in China. Patients and methods From January 2006 to December 2009, 102 patients underwent primary cryosurgery for clinically localized prostate cancer. All patients underwent a dual freeze thaw cycle using third-generation cryotechnology with ultrathin 17-gauge cryoneedles. Results The prostate-specific antigen (PSA) level for all patients at the last follow-up visit was less than 0.5 ng/ml in 94 patients (92.2%) and 0.5 ng/ml or more in 8 (7.8%). One patient (1.0%) had recurrent prostate cancer confirmed by prostate biopsy and was treated with salvage cryotherapy. Seven other patients (6.9%) had an elevated PSA level after cryotherapy despite negative posttreatment biopsies and a metastatic evaluation. Of 102 patients, 1 patient was incontinent preoperatively. Of the remaining 101 patients, 4 patients (4.0%) developed mild incontinence requiring 1 to 2 pads per day. Urethral sloughing occurred in 5 of the 102 patients (4.9%) H. Lian H. Guo (&) W. Gan X. Li X. Yan W. Wang R. Yang F. Qu C. Ji Department of Urology, Affiliated Drum Tower Hospital, Medical College of Nanjing University, Zhong-Shan Road No. 321, Nanjing, Jiangsu, China dr.ghq@163.com and in 1 of these patients (1.0%) required transurethral resection of sloughing. The rates of erectile dysfunction were 64.1%. No urethral strictures, rectourethral fistulas, urinary retention, or chronic pelvic pain was reported. The median inpatient stay after cryoablation was 3.2 days. Conclusion Early results suggest that cryotherapy offers a safe and effective alternative for the primary treatment of localized prostate cancer. Additional studies with longer follow-up are necessary to determine the sustained efficacy of this procedure. Keywords Prostate cancer Treatment Cryotherapy Cryoablation Introduction With the increase in the aging population and improved diagnosis, the annual incidence of prostate cancer (PCa) has increased steadily over the last few decades. More than seventy percent of these cancers will be discovered while they are still localized [1]. The protracted natural history of clinically localized PCa has confounded the development of a national consensus regarding the optimal treatment for this disease. This conundrum is further complicated by stage migration and lead time bias, both associated with prostate-specific antigen (PSA)-based early detection strategies and the resultant increase in the detection of small volume clinically localized cancers [2].

2 1090 Int Urol Nephrol (2011) 43: Prostate cryotherapy is a minimally invasive surgery capable of using controlled freeze and thaw cycles to destroy the disease and was recognized by the American Urological Association (AUA) as a therapeutic option for localized PCa in Because cryotherapy is relatively new, there are no published long-term data on the efficacy of cryosurgery on metastasis-free, prostate cancer-specific, or overall survival as there are with other more established forms of therapy. However, cryosurgery continues to gain acceptance as an appropriate treatment option for localized PCa with some compelling advantages over the conventional standard treatment options. The decision by our practice to investigate the role of cryoablation as a primary treatment for localized PCa was influenced by the emergence of third-generation cryotherapy, acceptable 7-year results examining biochemical disease-free survival [3], and several potential advantages, including its outpatient, minimally invasive nature, reasonable hospital cost, relatively expedient postoperative recovery, and preservation of health-related quality of life [1]. We present the first 102 consecutive patients to be treated at our center. Data were collected retrospectively for all patients. We believe these are the first published results of a large series of third-generation cryosurgery for localized PCa in China. Patients and methods From January 2006 to December 2009, 102 patients underwent targeted cryoablation of the prostate. All patients were diagnosed with clinically localized PCa (T1c * T2c) by ultrasound-guided transperineal prostatic biopsy, PSA level, Gleason score and examinations of computed tomography (CT) or magnetic resonance imaging (MRI), and whole-body bone scanning. Patient demographics are summarized in Table 1. The reason for large number of impotent patients preoperatively is that some potent patients refused cryotherapy when they were counseled that erectile dysfunction (ED) occurs more frequently after cryotherapy than other local treatments. All cryoablation procedures were performed using the Cryo-Hit System (Galil Medical Ltd, Israel) by a single urologist. All patients were placed in a modified lithotomy position after induction with general anesthesia. After introducing a guidewire Table 1 Patient demographics and tumor characteristics Parameter Value Age (year) Median 69 Range Pre-treatment PSA (ng/ml) Median 10.8 Range Clinical T stage T1c 49 T2a 35 T2b 13 T2c 5 Biopsy Gleason score TRUS volume (ml) Median 32 Range Pre-existing incontinence 1 Pre-existing ED 63 PSA prostate-specific antigen TRUS transrectal ultrasound ED erectile dysfunction along the urethra, a urethral-warming catheter was placed with warm fluid circulating through it at a temperature of 40 C (Fig. 1), and the scrotum was elevated off the perineum. The template was placed in stepper, approximate to perineum, and the grid was overlaid on ultrasound screen. The template and Fig. 1 Photograph showing urethral-warming catheter

3 Int Urol Nephrol (2011) 43: ultrasound grid were verified alignment with first needle. All needles were tested before insertion (Fig. 2). Under transrectal ultrasound (TRUS) guidance, 1.47-mm 17G IceSeed cryoneedles were placed into the prostate by way of the perineum using a brachytherapy grid (Fig. 2). Two single-point temperature-monitoring probes were placed at Denonvilliers fascia and the urinary sphincter, respectively. The number of cryoneedles varied with prostate size. Cryoneedles were placed 5 mm from the prostate capsule and 1 cm apart. Particular care was taken not to place cryoneedles too close to the posterior prostate capsule, the closest relationship with the rectal wall. Freezing with argon gas to\- 40 C was initiated and monitored using the temperature-monitoring probes, and TRUS guidance, which revealed an acoustic shadow as the ice-ball formed (Fig. 3). The urinary sphincter was maintained at temperatures greater than 0 C, and freezing was stopped when the iceball reached the anterior rectal wall and the posterior prostatic capsule was at least 20 C. After maintaining -40 C or the lowest temperature below -25 C for 10 min, a passive thaw was initiated until the temperature reached a plateau. At this point, active thawing with helium was started. Two cycles of rapid freeze thaw was carried out, ensuring the temperature in the prostate and just outside it was below a therapeutic value of -40 C. At the end of the procedure, the needles and probes were removed and pressure applied to the perineal area for 10 min to reduce bruising. The urethral-warming catheter was Fig. 3 Ultrasonogram of longitudinal and transverse image of the ice-ball at the end of the freeze-cycle exchanged for an 18F Foley catheter 30 min after completion of the procedure. The patients were followed up with physical examination and PSA measurement every 3 months, and with radiologic imaging (MRI, or CT) when clinically indicated. PSA failure was defined as a PSA level of 0.5 ng/ml or greater after cryosurgery [4 8]. Prostate biopsies were performed routinely 6 after treatment and/or on suspicious PSA findings. Impotence was assessed by using the International Index of Erectile Function-5 (IIEF-5), and incontinence was assessed by using the International Consultation Committee on Incontinence Questionnaire Short Form (ICI-Q-SF). Results Fig. 2 Photograph showing the intraoperative set-up with the template and cryoneedles used Prostate cryoablation was well tolerated by the patients with minimal requirements for pain medication and without the need for blood transfusions, and no postoperative deaths occurred. The mean length of stay in the hospital for the patients after cryoablation was 3.2 day (median 3, range 1 5). The median follow-up was 30 months (range 9 56). Of 102 patients, 1 patient was incontinent preoperatively. Of the remaining 101 patients, 4 patients (4.0%) developed mild incontinence requiring 1 2 pads per day. As a rule, we left the Foley catheter in place for 1 week after cryoablation until a spontaneous voiding pattern was restored. No patients experienced urinary retention. Urethral sloughing occurred in 5 of

4 1092 Int Urol Nephrol (2011) 43: the 102 patients (4.9%). Transurethral resection of sloughing was required in 1 of these patients (1.0%) and was performed 1.5 months after the procedure, while catheter drainage was required in the other patients nonoperatively. Thirty-nine of the 102 patients were potent preoperatively. ED developed in 25 of 39 patients (64.1%), and 14 patients (35.9%) remained potent after the procedure. Universal and often transient impotence immediately after the procedure was expected because of the damage that occurs to the neurovascular bundles [9]. No urethral strictures, rectourethral fistulas, or chronic pelvic pain was reported. The biochemical outcomes were as follows. There was an initial reduction in PSA level for all patients at 3 months after treatment. Of the 102 patients, 94 (92.2%) had a PSA level of less than 0.5 ng/ml and 8 (7.8%) had a PSA level of 0.5 ng/ml or more. 1 patient (1.0%) with a posttreatment-elevated PSA level had recurrent PCa by a positive prostate biopsy at 33 months of follow-up. The recurrent disease was at the right prostatic apex (Gleason score 3? 3 = 6). Otherwise, the laboratory and imaging data did not show any evidence of disseminated disease. The patient elected a repeat cryoprocedure was asymptomatic and clinically without a detectable PSA level at the last follow-up visit. In seven other patients with an elevated PSA level after cryotherapy, the prostate and seminal vesicle biopsies were negative and a thorough metastatic laboratory and imaging evaluation did not disclose recurrent disease. The overall survival rate was 100%. Discussion This is the first published series reporting results of third-generation cryotherapy as primary treatment for localized PCa in China. The data show the early outcomes and complication rates for patients treated for primary disease and show that there was an initial reduction in PSA level for all patients at 3 months after treatment and a PSA nadir of \0.5 ng/ml in 92.2%. The procedures were well tolerated. No rectourethral fistula and urinary retention after catheter removal occurred, and there was only a 4.0% occurrence of mild incontinence. Several investigators have compared their results with those in the published reports for radical prostatectomy and radiotherapy (including brachytherapy) and have consistently concluded that cryoablation appears to be at least equivalent in terms of efficacy [3 5, 10, 11]. The results of this study, although with a shorter follow-up, have also substantiated this claim, because the outcomes are comparable with those of other reports of cryoablation efficacy. As with other therapies for PCa, posttreatment PSA-level measurements are an integral part of follow-up. However, there is no established uncontroversial definition of successful outcome for cryoablation or for any other treatment of localized prostate cancer. This dilemma of defining biochemical failure makes comparisons of the various treatments problematic especially when comparing total removal of the prostate to therapies that leave the prostate in situ. Because the urethra is preserved during cryosurgical ablation, there is always the potential that PSA-producing tissue will be preserved. For these reasons, a totally undetectable PSA level will not usually be attainable in the long term. Akdas et al. [12] have shown that a PSA level of 0.4 ng/ml is not unexpected when 1 g of prostatic tissue has been preserved in men free of PCa. Thus, a PSA level of 0.5 ng/ml, which is just on the threshold of PSA detection, may be appropriate for radical surgery but is reasonable for cryoablation. In this study, we have used a PSA level of 0.5 ng/ml or more to suggest biochemical failure. All 8 patients who had a postoperative PSA level of 0.5 ng/ml or more underwent a thorough investigation, including multicore prostate and seminal vesicle biopsies and a metastatic imaging evaluation (bone scan, abdominal/pelvic MRI or CT). Ultimately, these data might reflect our insufficient knowledge of PCa tumor biology, with a lack of valid prognosticators that can distinguish between effective PCa treatment and possible relapse in the postoperative period. Certainly, more data from experimental and clinical trials are needed to shed more light on the pathophysiology and clinical outcome of frozen cancer and glandular prostatic tissue in the postoperative period and its implication for PSA behavior [8]. In many of the earlier published series describing the use of cryosurgery to treat PCa, follow-up biopsy was a part of the treatment protocol. The use of multiple biopsy results after cryoablation provides an accurate appraisal of local control of cancer, which is

5 Int Urol Nephrol (2011) 43: the goal of cryoablation therapy. Biopsies were generally performed 6 12 months after treatment or for cause, such as rising PSA levels. The reported incidence of negative biopsy after one or more treatments is high, ranging from 87 to 98% [3, 4, 13]. We biopsied all participants 6 months after treatment, and the incidence of negative biopsy is 100%. 8 patients (7.8%) had a PSA level of 0.5 ng/ml or more and were offered a prostate and seminal vesicle biopsie, but only one patient (1.0%) had recurrent PCa by a positive prostate biopsy. There are several reasons why PSA readings may be elevated despite multiple negative biopsy results, including (1) preservation of residual normal glandular tissue, (2) incomplete ablation of cancer, (3) distant metastasis, or (4) a combination of these [3]. Mouraviev and Polascik [14] recently summarized in tabular form the more common complications associated with primary cryosurgery of the prostate. It is thought that the high morbidity presented in earlier series could be attributed to the use of liquid nitrogen-based systems, older ultrasound techniques, and banning of the urethral warmer by the United States (US) Food and Drug Administration (FDA). The introduction of third-generation cryotechnology and recent modifications in the technique of prostate cryoablation have enabled cryosurgeons to treat these tumors safely and with significantly decreased complications [14 18]. Our data have also confirmed a minimal rate of side effects. 4 patients (4.0%) reported mild incontinence requiring 1 2 pads per day after therapy, compared to the published rate of 4.4% [3]. The currently reported incidence of urethral sloughing in patients undergoing cryosurgery with the use of a urethralwarming catheter ranges from 0 to 15% [18 20], and urethral sloughing occurred in 5 of the 102 patients (4.9%) in the present series. No patients developed fistulae in the present series, consistent with the risk of \1% reported in a recent study [10]. The most common complication was ED. The incidence of ED reported in the literature ranges from 49% to 94% at one year [3 5, 21]. This complication occurs more frequently after cryotherapy than other local treatments, e.g., nerve-sparing radical prostatectomy. For this reason, cryosurgery is generally considered suitable as a treatment option in men who are not concerned with erectile function, and previously potent patients should be counseled accordingly. In conclusion, the present preliminary results suggest that cryotherapy offers a safe and effective alternative for the primary treatment of localized PCa. The short-term oncologic efficacy using this system appears favorable, and the side-effect profile is low, especially compared with older-generation cryotherapy system [22]. 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