Salvage Cryosurgery of the Prostate After Radiation Failure

CRYOSURGERY AND BRACHYTHERAPY Salvage Cryosurgery of the Prostate After Radiation Failure John S. Lam, MD, Arie S. Belldegrun, MD Department of Urology, The David Geffen School of Medicine at UCLA, Los Angeles, CA Radiation therapy is one option for patients with localized prostate cancer. Despite advances in delivering radiation to the prostate gland with therapies such as brachytherapy and/or external beam radiation therapy, urologists will be faced with managing patients with rising prostate-specific antigen values and with positive biopsy results secondary to radiation-recurrent prostate cancer. If the cancer is detected early, salvage therapy can be initiated. Since salvage prostatectomy is associated with significant morbidity, patients are often left with the option of either watchful waiting or temporary palliation with hormone deprivation therapy, with its attendant toxicity. The introduction of third-generation cryotechnology using 17-gauge CryoNeedlesTM (Oncura, Inc., Plymouth Meeting, PA) and the recent modifications in the technique of salvage cryosurgery have enabled cryosurgeons to eradicate these tumors safely and with significantly decreased morbidity. Selection and management of patients, as well as the contemporary results of salvage cryosurgery, are discussed in this article. [Rev Urol. 2004;6(suppl 4):S27–S36] © 2004 MedReviews, LLC Key words: Cryosurgery • Radiorecurrent prostate cancer • Salvage therapy • Toxicity n estimated 230,110 men in the United States will receive a diagnosis of prostate cancer and approximately 29,900 deaths will result from this disease in 2004, making it the most commonly diagnosed cancer and the second leading cause of cancer death among American men.1 Treatment options for clinically localized prostate cancer include radical prostatectomy, radiation therapy (external beam radiation therapy [EBRT] and/or brachytherapy), or A VOL. 6 SUPPL. 4 2004 REVIEWS IN UROLOGY S27 Salvage Cryosurgery continued watchful waiting.2 Recent technological advances have increased the attractiveness of both EBRT and brachytherapy as primary therapies for localized prostate cancer to such an extent that nearly one third of newly diagnosed patients with prostate cancer are treated with these modalities each year.3,4 As more patients select minimally invasive treatment options such as EBRT and/or brachytherapy in the hopes of avoiding the morbidity associated with radical prostatectomy, urologists will see more failures from such therapies, despite modifications in radiation delivery methods to the gland, such as intensitymodulated radiation therapy (IMRT), 3-dimensional conformal radiation therapy (3DCRT), and computer-guided seed implantation. Radioresistant or recurrent prostate cancer is an aggressive form of localized prostate cancer that represents a serious health risk for patients treated with primary radiation therapy for clinically localized prostate cancer. According to the recent literature, the rate of biochemical failures has ranged from 20% to 66%.5,6 The majority of patients exhibit large volume and poorly differentiated disease at the time of diagnosis, which limits the ability of salvage therapy to eradicate the cancer. Early detection with serum prostate-specific antigen (PSA) monitoring and prostate needle biopsy following primary radiation therapy may identify residual adenocarcinoma at an earlier stage and increase the likelihood of successful salvage therapy. The goal of salvage therapy is to improve local control and possibly influence long-term survival. Radical prostatectomy, prostate cryosurgery, brachytherapy, and radiotherapy comprise the options for salvage treatment available for radiorecurrent prostate cancer. Salvage prostatectomy is associated with significant morbidity, and S28 VOL. 6 SUPPL. 4 2004 salvage brachytherapy or radiotherapy in the setting of a previously irradiated prostate is potentially associated with increased rectal and urinary toxicity. As a result, patients are often left with the option of either watchful waiting or temporary palliation with hormone deprivation therapy—and its attendant toxicity. Recent modifications in the technique of salvage cryosurgery have led to the ability to eradicate radiorecurrent prostate cancer safely and with decreased morbidity. Detection of Radiorecurrent Prostate Cancer Persistent prostate cancer following radiation therapy represents an aggressive disease state that results in cancer-related death in at least 27% of patients within 5 years of exhibiting a rising PSA level.7 Furthermore, recurrent neoplasms demonstrate a 24% increase in Gleason score 8-10 cancers and a 31% increase in aneuploid tumors when compared with pretreatment characteristics.8 In addition, these cancers are often large in volume and are associated with extracapsular extension and positive margins in 40% to 60% and lymph node metastases in 14% to 34% of cases.9 Clearly, recurrent prostate cancer following radiation therapy poses a serious health risk to men. Assessment of success following treatment of prostate cancer is based on biochemical or PSA control (biochemical no evidence of disease [bNED]) as well as clinical control. Radiation therapy injures both benign and malignant prostatic glandular epithelia, which ultimately results in clearance of damaged cells through apoptosis. This process may take many months following the completion of therapy, and diagnostic tests, including serum PSA measurement and prostate needle biopsy, must be interpreted with caution. Serum PSA levels decline slowly over 6 to 18 months after radi- REVIEWS IN UROLOGY ation, with a nadir value often reached as late as 33 months.10 In addition, PSA levels can rise following brachytherapy (“PSA bounce”) and may fluctuate during surveillance because of benign prostatic disease.11,12 The American Society for Therapeutic Radiology and Oncology (ASTRO) consensus panel attempted to deal with these confounding findings by defining biochemical failure after radiation therapy as three successive increases in PSA level separated by 3- to 4-month intervals after reaching a PSA nadir.13 This definition defines the point of biochemical failure as the time midway between the posttreatment PSA nadir and the first of the three consecutive rises in PSA level. Although this definition is now the standard in the radiation therapy literature, it may underestimate the ultimate biochemical failure rates and delay the diagnosis of a persistent cancer.14,15 A potentially more clinically useful parameter would be a PSA nadir below 0.5 ng/mL. Approximately 90% of patients who achieve this PSA nadir within 2 years remain free of recurrent disease.16 Additionally, any rise in PSA levels following the nadir is associated with a high risk of recurrent disease. The Mayo Clinic reported that patients with a preoperative PSA level of less than 10 ng/mL had better progression-free survival than those with higher levels (P = .05) following salvage prostatectomy for radiation-refractory prostate cancer.17 In addition, DNA ploidy was the strongest predictor of cancer-specific (P = .002) and progression-free (P = .002) survival.17 Once a meaningful elevation in the serum PSA level has been identified, transrectal ultrasonography (TRUS) and prostate needle biopsy are warranted. Biopsy findings must be interpreted with an understanding of the histologic effects of radiation on Salvage Cryosurgery prostate tissue. Severe radiation effects with both nuclear and cytoplasmic alterations are seen in many prostatic biopsies and may confound the diagnosis of residual cancer.18 It is possible that this explains the finding that 67% of patients with cancer on biopsy at 12 months following radiation will have a conversion to negative histologic results by 16 to 29 months.19 Given the delayed clearance of neoplastic cells after a course of EBRT or brachytherapy, one should perform any initial prostate biopsy at 12 to 18 months posttreatment. This could be coincident with a tic disease may obviate the patient being exposed to unnecessary local therapies. In this setting, pathologic confirmation of locally recurrent disease via prostate biopsy is warranted before consideration of invasive salvage therapies. The PSA doubling time following EBRT also appears to aid in predicting time to prostate cancer–specific death. D’Amico and coworkers23 reported that, in 381 patients who underwent EBRT for clinically localized prostate cancer, a short PSA doubling time (12 months or less) and delayed use of hormonal therapy Biopsy findings must be interpreted with an understanding of the histologic effects of radiation on prostate tissue. PSA nadir above 0.5 ng/mL or any rise in the serum PSA level. The incidence of positive biopsy results after primary radiation therapy varies widely in the literature but appears to be higher for EBRT than for brachytherapy.20 After it is determined that primary therapy has failed in a patient, local recurrences must be distinguished from systemic recurrences. Local failure has been defined as histologically proven active adenocarcinoma on repeated prostate biopsy in the absence of radiographic evidence of disease. Unfortunately, multiple studies have demonstrated the relative lack of sensitivity and specificity of most radiographic tests, including computed tomography (CT), magnetic resonance imaging, bone scanning, and more recently, monoclonal antibody–labeled nuclear scans (ProstaScint, Cytogen Corp, Princeton, NJ) for the diagnosis of systemic disease in biochemically recurrent prostate cancer.21,22 Despite these shortcomings, these modalities should be applied if recurrence is suspected, because the presence of overt metasta- were predictors of prostate cancer– specific death. These data suggest that a short posttreatment PSA doubling time may serve as a possible surrogate marker for risk of prostate cancer–specific death. Although similar analyses have not been performed for patients treated with brachytherapy, it is reasonable to expect that similar guidelines also may apply in this setting, because the treatment modality in both cases is radiation. Salvage Therapies for Locally Recurrent Disease Once radiorecurrent prostate cancer is confirmed in a patient with a low risk of systemic disease (ie, low-risk tumor features prebrachytherapy,24 negative restaging imaging, and greater than 12 months’ PSA doubling time) and a life expectancy of greater than 10 years, a number of potentially curative therapeutic options can be considered, including salvage prostatectomy, re-irradiation, and salvage cryosurgery. Hormonal deprivation and observation can be reserved for patients with a less than 10-year life expectancy or those who desire less invasive management options. Salvage radical prostatectomy has been the most commonly performed curative treatment for clinically localized prostate cancer after radiation therapy. This procedure is capable of eradicating the local lesion and providing long-term disease-specific survival. Despite the potential for successful extirpation of the cancer, the surgical procedure is complicated by the tissue effects of radiation and is associated with significant side effects. Radiation results in vascular occlusion with resulting tissue hypoxia, while alterations in basement membrane proteins lead to increased fibrosis. Therefore, anatomic planes between pelvic organs are often obliterated, with a poorly vascularized bladder and urethra available for surgical reconstruction. There is a high likelihood of postprostatectomy incontinence and impotence, as well as the possibility of rectal injury, which may necessitate fecal diversion (colostomy). Several clinical series have reported actuarial cancer-specific survival rates of 64% to 88% at 5 years with a PSA progression–free survival rate of 83%.9,17,25-27 However, the rate of pathologically organ-confined disease in most series is low, ranging from 5% to 36%, whereas the risks of rectal injuries (15%), bladder neck contractures, and urethral strictures (7%-28%) and severe urinary incontinence (23%64%) are relatively high.26 Salvage radiation or re-irradiation is a relatively new concept in clinical radiation oncology. Before the advent of effective means to accurately target the prostate, the dose of radiation was limited by the adverse effects on adjacent normal tissues. Following the development of more sophisticated targeting techniques such as 3DCRT and, more recently, IMRT, with the VOL. 6 SUPPL. 4 2004 REVIEWS IN UROLOGY S29 Salvage Cryosurgery continued ability to develop inverse treatment plans, investigators have successfully escalated the planned treatment dose and demonstrated an important relationship between dose and biochemical response in prostate cancer.28,29 This subsequently has allowed clinicians to dose-escalate to a maximum effective target dose above 80 Gy. Re-irradiation may be administered in combination with radiosensitizing agents such as chemotherapy to decrease the delivered dose, although such approaches currently are experimental. One of the largest series to examine the role of re-irradiation evaluated 49 men with a median pretreatment PSA level of 5.6 ng/mL (range, 1.579.1 ng/mL) who failed prior radiotherapy and subsequently went on to salvage brachytherapy.30,31 Among these men, 46 (94%) had undergone prior EBRT with a median primary treatment dose of 66.2 Gy (range, 20-70.2 Gy) and three men had received iodine-125 (I-125) radioactive seed implants as primary therapy. Thirty-seven patients (76%) received palladium-103 (Pd-103) implants, whereas 12 patients (24%) received I-125 implants. Although a minority of patients received additional thera- Figure 1. Gas-driven 17-gauge CryoNeedleTM (Oncura, Inc., Plymouth Meeting, PA). These gas-driven probes allow for a decrease in the diameter of the needle to 17-gauge (1.47 mm). History of Cryosurgery Cryosurgery—the ablation of tissue by local induction of extremely cold temperatures—has recently reemerged as a therapeutic modality that is a minimally invasive treatment option. Cryosurgical technology has been applied in the past to a wide variety of neoplasms, including brain, cervix, skin, renal, prostate, and liver.32-34 Firstgeneration cryosurgery for the prostate was used in the 1960s and 1970s with no TRUS guidance or urethral warming.35 Complications were common and often significant, including incontinence, urethral sloughing, and rectourethral fistula formation. The Salvage radiation or re-irradiation is a relatively new concept in clinical radiation oncology. pies before (11 [22%] received an orchiectomy or antiandrogens) or after reimplantation (4 received adjuvant radiotherapy, 8 received adjuvant hormones), salvage brachytherapy was associated with a 34% actuarial rate of biochemical disease–free survival at 5 years. Complications included rectal ulcers or bleeding requiring colostomy in 6%, significant dysuria in 6%, and the need for a channel transurethral resection of the prostate (TURP) in 14%. S30 VOL. 6 SUPPL. 4 2004 inability to precisely place cryoprobes or monitor the extent of freezing resulted in the abandonment of the technology until the late 1980s. The development and implementation of TRUS guidance36 and urethral warming37,38 significantly reduced the number of complications with secondgeneration cryosurgery. TRUS guidance allowed for accurate placement of probes, real-time monitoring, and control of freezing; in addition, visualization of the rectum protected it REVIEWS IN UROLOGY from injury. Urethral warmers significantly reduced the risk of urethral sloughing. The development of thirdgeneration cryosurgery included gas-driven 17-gauge CryoNeedlesTM (Oncura, Inc., Plymouth Meeting, PA) (Figure 1), which signaled the transition from liquid nitrogen–based to gas-driven systems. With these newer systems pressurized gas could be used to freeze (argon gas) and actively thaw (helium gas) the organ, using the Joule-Thomson effect, in which different gases undergo unique temperature changes when depressurized, according to unique gas coefficients.39,40 This transition from liquid to gas also permitted the use of smaller diameter probes, 17-gauge (1.47 mm) CryoNeedles that allow for direct transperineal needle placement through a template, without making incisions or using tract dilatation and insertion kits. Cryobiology The principles of cryosurgery, including mechanisms of cell injury and cell death, have been well studied.35,41 The three key factors involved in freezing injury are direct mechanical shock, osmotic shock, and cellular hypoxia. Mechanisms of action of cryosurgery include protein denaturation via dehydration, transfer of water from intracellular to extracellu- Salvage Cryosurgery lar space, rupture of cell membranes from ice crystal expansion, toxic concentration of cellular constituents, thermal shock from rapid supercooling, slow thawing, vascular stasis, and increased apoptosis.42 Freezing begins in the intracellular and extracellular compartments and in the microvascular network. At a temperature of 15ºC (5ºF), most of the extracellular environment is frozen, causing trapping of tissue and production of shearing forces that disrupt cellular structure. This process is known as mechanical shock. The delayed or indirect destructive effects of cryosurgery continue mostly because of disruption of vasculature resulting in tissue hypoxia and vascular thrombosis. Zacarian and associates43 found that at temperatures below 20ºC (4ºF), venules were more susceptible to injury than were arterioles. Freezing promotes stasis of blood, leading to thrombosis and subsequent coagulative necrosis of tissue. This process includes local edema with activation of the inflammatory cascade. Larson and colleagues44 studied the histologic impact of freezing and found that uniform coagulative necrosis of human prostatic tissue in vivo can be accomplished throughout a significantly larger zone with a double freeze rather than with a single freeze. A double freeze at temperatures below approximately 40ºC (40ºF) results in necrosis. These findings provide a basis for more optimal use of temperature monitoring during cryosurgery, which is essential to ensure effective treatment of the entire prostate gland with minimum risk of damage to adjacent tissues such as the rectum and external sphincter. Patient Selection and Evaluation When PSA levels rise in the patient who has undergone radiotherapy, the optimal time for intervention is unclear. Most radiation oncologists feel that PSA levels can fluctuate within the first 18 months. Currently, there is no consensus among urologists or radiation oncologists about when to intervene. At UCLA, the practice has been to wait at least 18 months following radiation. When considering salvage therapy, the clinician needs to take into account other variables, such as preexisting medical conditions, age of the patient, and patient preference. It has been the practice at UCLA to perform a biopsy of the prostate if the PSA rises above the nadir level and there are three consecutive rises. In addition, a history, physical examination, urinalysis, and urine culture should be performed before the biopsy to evaluate the possibility of prostatitis or a lower urinary tract infection. If a biopsy is undertaken, multiple cores should be obtained and the pathologist must be informed that the patient has had previous radiation. Performing a prostate biopsy in a radiated patient should be approached in the same manner as for a nonradiated patient, and no additional complications in performing biopsies in radiated patients have been encountered. Currently, there are no defined guidelines for urologists to follow that would enable them to properly select patients for salvage cryosurgery. The optimal candidates for salvage cryosurgery would be those patients who have a locally recurrent cancer without clinical evidence of metastatic deposits. If the PSA level is greater than 5 ng/mL and a prostate biopsy reveals recurrent disease, we would obtain a CT scan of the abdomen and pelvis, as well as a bone scan. There may be a role for performing an open or laparoscopic biopsy of the pelvic lymph nodes. Salvage radical prostatectomy series report that between 20% and 40% of patients will have prostate cancer metastases to the lymph nodes.25 Caution is advised for novice laparoscopic surgeons since the dissection of these nodes can be technically challenging because of potential adherence to the pelvic side wall and external iliac vessels. Pisters and associates45 identified clinical pretreatment factors associated with early treatment failure after salvage cryosurgery. From an analysis of 145 salvage cryosurgery patients, those with failure of initial radiation therapy with a PSA level of more than 10 ng/mL and Gleason score of the recurrent cancer of 9 or more were unlikely to have successful salvage. Izawa and colleagues46 analyzed 131 patients who had received definitive EBRT and had undergone salvage cryosurgery for locally recurrent prostate cancer and reported that androgen-independent local recurrences, Gleason score, and preradiation clinical stage were important factors that had an impact on disease-specific survival and diseasefree survival. Izawa and associates47 also reported that patients with initial clinical stage T1-2N0M0 disease and PSA levels no greater than 10 ng/mL have a higher rate of negative biopsy results after salvage cryosurgery. Androgen deprivation has been described in the literature as a way to decrease the prostate size in order to facilitate the cryosurgery32,48-53: the freeze will be faster, less gas will be required, and the risk of freezing the bladder and sphincter will be lower. At UCLA, androgen deprivation is used if the prostate volume is greater than 50 cm3. Others have reported that the use of androgen deprivation 3 months before the procedure increases the distance between the base of the prostate and the anterior rectal wall.54 On TRUS, there appears to be a thickening of the Denonvilliers’ fascia, which increases the safety zone. The iceball can therefore be allowed to VOL. 6 SUPPL. 4 2004 REVIEWS IN UROLOGY S31 Salvage Cryosurgery continued extend beyond the posterior aspect of the prostate with greater confidence. Relative contraindications to cryosurgery are similar to those in brachytherapy and include previous TURP with a large tissue defect, significant symptoms of urinary obstruction before treatment, large prostate size, and a history of abdominoperineal resection for rectal cancer, rectal stenosis, or other major rectal pathology. Prior TURP, especially if a large TURP defect is present, is sagittal view to assist in placing the needles. In this view, the length of the cryoneedles can easily be followed. The gland may be adherent to the anterior rectal wall as a result of the previous radiation, diminishing the thickness of the Denonvilliers’ fascia. This needs to be assessed by TRUS before freezing, so the surgeon can determine how to place the posterior cryoneedles and the Denonvilliers’ temperature probe appropriately. If the space between the anterior rectal sphincter be maintained above 15ºC (59ºF). Some investigators have advocated placing a suprapubic catheter during cryosurgery and leaving the urethral warming catheter in place for 2 hours following cryosurgery; however, we have found this to be unnecessary. At UCLA, patients are discharged home with a Foley catheter to be removed in 2 to 3 days. In addition, patients have been given -blocker therapy that is maintained for at least a month. Primary Cryosurgery: Results Relative contraindications to cryosurgery are similar to those in brachytherapy. associated with an increased risk of sloughing and urinary retention. Significant preoperative obstructive symptoms increase the likelihood of postoperative urinary retention. Large prostate size may result in pubic arch interference, which may preclude adequate placement of cryoneedles. Complete ablation of glands larger than 50 cm3 is difficult even with multiple cryoneedles, and multiple needle insertions and prolonged freezing times may be required. In these cases, the prostate may be cytoreduced with neoadjuvant hormonal ablation before cryosurgery. wall and posterior prostatic capsule is less than 5 mm, it may not be possible to drive the temperature down to 40ºC safely, and freezing should be terminated when the leading edge of the iceball has extended just beyond the capsule, even if the target temperature of 40ºC is not reached. When counseling patients about any salvage procedure, the risks of urinary incontinence need to be addressed. We routinely place a temperature probe by the external sphincter; this can be performed with the aid of a flexible cystoscope. The temperature probe is introduced through Data have been accumulated on 175 patients treated at several institutions in the United States using third-generation cryoneedles. At 12-month follow-up, 80 (73%) of 110 patients remained with a PSA level of ≤ 0.4 ng/mL, while 42 (76%) of 55 low-risk patients (Gleason score ≤ 6, PSA level ≤ 10 ng/mL, stage T2 or less) remained free from biochemical progression at 1 year..55,56 In general, results of recent series report biochemical disease–free rates of 60% to 90% at 5-year follow-up, depending on the PSA nadir used.54,55,57-62 Some series used PSA values of < 0.1 ng/mL, while others used the ASTRO criteria of three consecutive PSA rises. The rate of urethral sloughing in our study cohort of 175 patients was Salvage Cryosurgery: Technique There are some additional technical issues that need to be addressed in relation to the salvage cryosurgical patient. Salvage cryosurgery can be performed in the patient with recurrent disease following EBRT as well as brachytherapy. The previously placed radioactive seeds can be visualized quite well under TRUS and may cause some confusion, because their appearance sonographically is similar to the tip of the cryoneedles, especially in the transverse view. This can be overcome by utilizing the S32 VOL. 6 SUPPL. 4 2004 When counseling patients about any salvage procedure, the risks of urinary incontinence need to be addressed. the perineal skin and advanced until the impression of the tip of the probe can be seen in the sphincter. The placement can be documented by cystoscopy as well as by TRUS. The use of the external sphincter temperature probe has led to a dramatic reduction in urinary incontinence after salvage cryosurgery. We recommend that the temperature in the REVIEWS IN UROLOGY 6% (10 patients); five patients also required the use of pads for incontinence, but there were no reports of urinary-rectal fistulas. Other complications included penile tingling/ numbness (3%), pelvic pain (4%), and scrotal swelling (2%), which are comparable to other series. The impotence rate of 84% in the current series is comparable with that previ- Salvage Cryosurgery Table 1 PSA Follow-up and Complications of Recent Salvage Cryosurgical Series Year Han et al56 2004 Ghafer et al54 2001 Chin et al63 2001 Pisters et al52 1997 No. of patients 29 38 118 150 Technique Argon Argon Argon Nitrogen PSA nadir used (ng/mL) 0.4 0.3 0.5 < 0.2 Recurrence-free rate (%) 72 74 34 31 Mean follow-up (mo) 12 20 18 17 Fistula 0 0 3.3 1 Incontinence 9 7.9 6.7 73 Sloughing 0 0 5 - Retention/LUTS 3 4 8.5 67 Impotence - - - 72 Complications (%): PSA, prostate-specific antigen; LUTS, lower urinary tract symptoms. ously reported by others.58,59 Donnelly and colleagues60 reported that 47% of their patients had return of function at the 3-year follow-up. They hypothesized that since the nerves are not cut during cryosurgery, the potential to recover their function is maintained. Despite this report, we do not routinely use cryosurgery in patients who are interested in maintaining their potency. We feel that complete ablation of the neurovascular bundle is necessary to ensure complete eradication of tissue at the periphery of the prostate gland. Salvage Cryosurgery: Results Over the past decade, several institutions have published their salvage cryosurgery results. Many of the published series from the early 1990s had a significant number of complications.49-53 Bales and colleagues49 reported an early experience in 23 patients treated with cryosurgery that demonstrated an 86% negative biopsy result rate at 3 months fol- lowing the procedure but a 100% rate of adverse events. Despite the inability to adequately control and target ice formation, the introduction of lethal ice could eradicate radiorecurrent, locally aggressive cancer. The high morbidity presented in these early reports could be attributable to a number of factors. One factor was that temperature probes were not yet available at the time of these reports. In addition, there was a period when the urethral warming device was banned by the US Food and Drug Administration. Without proper warming of the urethra, urethral sloughing was prevalent, and pain, urinary retention, and incontinence resulted. Furthermore, several of these studies were performed using liquid nitrogen–based systems. Although the delivery of extremely cold temperatures into the prostate was rapid, the ability to control the growth of the iceball was limited, and improper placement of cryoprobes led to the development of rectal fistulas. The use of argon gas-based systems has led to the generation of recent publications on salvage cryosurgery (Table 1). In the UCLA experience, 29 patients have undergone salvage cryosurgery using the SeedNet™ system (Oncura, Inc., Plymouth Meeting, PA); the complication rates in these patients were either comparable to or less than those previously reported by other investigators.56 All the patients had biopsy-proven recurrence without metastatic spread. At 12-month follow-up, 13 of 18 patients who had salvage cryosurgery in our series remain with a PSA of ≤ 0.4 ng/mL. Similarly, Ghafar et al54 reported on the Columbia experience of 38 men who underwent salvage cryosurgery in which multiple temperature probes were used and all patients received 3 months of hormone deprivation. At a mean follow-up of 20 months, 74% of patients had a PSA of ≤ 0.1 ng/mL. Based on a PSA cutoff value of greater than 0.3 ng/mL above the PSA nadir, 65% of the patients remained free of biochemical recurrence at 3 years. Chin and colleagues63 recently reported their results of salvage cryosurgery using an argon-based system in 118 patients with biopsy-proven local recurrence following radiation therapy. Nearly all patients underwent posttreatment prostate biopsy, which identified persistent disease in only 3.1%. The posttreatment PSA nadir reached less than 0.5 ng/mL in 114 patients (96.6%), with 34% bNED at a mean follow-up of 18 months. It remains to be seen whether a long-term follow-up of these patients will lead to the development of salvage cryosurgery as a definitive option after radiation failure. Chin and associates64 also reported on the serial biopsy results in 106 patients who underwent salvage cryosurgery. Of 818 biopsy cores, a total of 23 (2.8%) VOL. 6 SUPPL. 4 2004 REVIEWS IN UROLOGY S33 Salvage Cryosurgery continued from 15 patients (14.2%) were positive. Salvage cryosurgical ablation of the prostate offers lower morbidity than salvage radical prostatectomy. Major complications such as rectourethral fistula, hydronephrosis, or renal failure, which were reported in the first prostate cryosurgery studies, disappeared with the technical evolution of the cryoprobes and greater surgeon experience. The major risk remains incontinence, but this risk is significantly lower than with salvage radical prostatectomy. The reported post-salvage cryosurgery urinary incontinence rates range from 0% to 83%.50-55,63 Long and associates65 reported a higher incontinence rate for patients who had radiation therapy (83%) versus patients who did not receive radiation (2%). Similarly, perineal pain (37% vs 2.3%) and urinary tract infection (39% vs 2.3%) were less frequent for patients who did not receive radiation. Derakhshani and coworkers66 reported an incontinence rate significantly higher in patients after salvage cryosurgery compared with patients who had primary cryosurgery (69% vs 1%). Lee and colleagues67 found that prior radiation therapy increased the risk of rectourethral fistula (8.7% vs 0.3%). However, the use of the external sphincter temperature probe has decreased urinary incontinence rates to less than 5% in the most recently reported salvage cryosurgery series. In a similar fashion, the complication of rectalurethral fistula is near 0% due to the high accuracy of the modern day TRUS combined with temperature monitoring at the anterior rectal wall. Sloughing of necrotic urethral tissue with secondary urinary obstruction has also been reduced in incidence from 10% to 15% to as low as 0% with alterations in technique and application of a urethral warming catheter. Urethral stricture rates have also been reduced with the use of S34 VOL. 6 SUPPL. 4 2004 a urethral warming catheter. Urinary frequency and urgency are common in the first few weeks after salvage cryosurgery and can be managed with anticholinergics. Perineal and rectal pain has been reported.54 This pain is self-limiting and others have managed it with warm baths and anti-inflammatory agents and if the pain persisted for more than a few weeks, nitroglycerin suppositories were found to be helpful. In addition, penile and scrotal edema can occur in 15% to patient quality of life (QoL) after salvage cryosurgery using a modified UCLA Prostate Cancer Index that measured health-related QoL. Surveys were sent to 150 patients treated at the MD Anderson Cancer Center, Houston, TX, and of 150 surveys, 112 (75%) were returned. Treatment without an effective urethral warming catheter was significantly associated with urinary incontinence (P < .003), perineal pain (P < .001), tissue sloughing (P < .003), and American Salvage cryosurgical ablation of the prostate offers lower morbidity than salvage radical prostatectomy. 20% of patients, which usually resolves in a week. Impotence rates in the literature range from 34% to 100% following cryosurgery.54-63 In the UCLA experience, only four patients (9%) reported the use of pads following salvage cryosurgical ablation of the prostate and no rectourethral fistulas developed.62 Similarly, Ghafer and coworkers54 reported a urinary incontinence rate of 7.9% and no cases of rectourethral fistula development among 38 patients. Chin and associates63 reported a urinary incontinence rate of 6.7% and rectourethral fistula rate of 3.3% in 118 patients as a result of salvage cryosurgery. The most common complication was perineal pain (including rectal pain and pain of the penis) in 26% of the cases. Edema of the scrotum and of the perineal area was the second most common complication, seen in 12% of our patients. Major complications such as incontinence, bladder obstruction, rectourethral fistula, and urethral stricture were not frequent; incontinence was a major problem for only 11% of our patients. None of the patients experienced urethral sloughing. Perrotte and colleagues68 evaluated REVIEWS IN UROLOGY Urological Association Symptom Score greater than 20 (P < .004). Impotence was higher in the double freeze-thaw cycle group (P < .05). However, this study was performed in patients who had undergone cryosurgery with older generation technology. Anastasiadis and colleagues69 compared QoL between 81 patients who underwent primary or salvage cryosurgery. Primary cryosurgery patients fared significantly better regarding physical (P = .005) and social (P = .024) functioning compared with salvage cryosurgery patients. The most prominent prostate-related symptom in both patient groups was sexual dysfunction, followed by urinary symptoms, which were significantly more severe in the salvage group (P = .001). Incontinence rates were 5.9% and 10% in the primary and the salvage groups, respectively. Severe erectile dysfunction was reported in 86% and 90% of the primary and the salvage groups, respectively. Conclusions Cryosurgery of the prostate appears to have a low morbidity and is effective in eradicating radiorecurrent tumors. With the development of Salvage Cryosurgery TRUS guidance, urethral warmers, and smaller needles, the morbidity associated with this treatment alternative has become comparable with that of other available treatment options. The use of 17-gauge cryoneedles in third-generation salvage cryosurgery for radiorecurrent prostate cancer may offer more precise prostate iceball formation and offer the flexibility to place more cryoneedles where necessary. Long-term follow-up of PSA outcome and survival are still needed. At present, third-generation cryosurgery should be considered in older or high-risk medical patients who would not otherwise be considered for radical prostatectomy and as salvage therapy in patients in whom EBRT or brachytherapy has failed. 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