Cryotherapy in Prostate Cancer 

Introduction

Cryotherapy—the ablation of tissue by local induction of extremely cold temperatures—has its earliest antecedent in 19th-century London, where Arnott applied ice-salt mixtures to cancers of the breast and cervix.^[1] The 1966 advent of probes cooled by liquid nitrogen in closed circulation marks the beginning of modern cryotherapy.^[2]

One of the first applications of this new technology was the transurethral cryoablation of benign prostatic hyperplastic tissue,^[3] followed shortly thereafter by the treatment of prostate cancer via an open perineal approach.^[4] The transperineal approach was introduced in 1974, initially using a single digitally guided cryoprobe that was repositioned as needed during the procedure.^[5]

Early series of cryotherapy achieved effective tissue ablation, and complications were considered to be less severe than those of radical surgery at the time. The major impediment to early acceptance of the modality, however, was the inability to accurately monitor cryoprobe placement and ice-ball formation.

Major advances in the past 15 years, which have reinvigorated investigation into the use of cryotherapy for prostate cancer, have included the use of real-time transrectal ultrasonography (TRUS) monitoring of probe placement and freezing,^[6] the simultaneous use of multiple cryoprobes, and the standard use of urethral warming catheters.^[7]

A significant recent development was the introduction of cryotherapy probes that use argon gas rather than liquid nitrogen. Argon rapidly cools the probe tip to -187°C (-304.6°F) and can be rapidly exchanged with helium at 67°C (152.6°F) for an active thawing phase, producing a faster response to operator input and significantly speeding 2-cycle treatment.^[8]

Moreover, argon-based probes have a much smaller diameter. Thus, they permit direct, sharp transperineal insertion, avoiding the need for tract dilation and facilitating more conformal cryosurgery by allowing placement of more probes.^[9]

In recent years, cryotherapy has seldom been used in community urological practice despite the initiation of Medicare reimbursement for the procedure in 1999. According to American Urological Association (AUA) polls, the percentage of urologists performing cryosurgery from 1997-2001 remained constant at 2%, but the average annual number of procedures performed by each urologist increased from 4 to 24. In contrast, the percentage of urologists performing brachytherapy over the same period rose from 16% to 51%, with the annual number of procedures per urologist rising from 15 to 16.5.^[10]

However, ongoing technical advances and recently reported results from academic centers suggest that cryotherapy may be poised to capture an increased role as an alternative to other, more standard approaches to management of localized prostate cancer.

Outcomes have now been reported as late as 7 years following treatment and seem to compare favorably with contemporary series of patients who receive radiation therapy, particularly with respect to late failure rates^[11] and among higher-risk patients.^[12]

Note, however, that even the largest cryotherapy studies have been retrospective examinations of largely single-institution experiences. Moreover, they used disparate definitions of clinical risk, biochemical failure, continence, and potency. These definitions all need to be standardized for cryotherapy.

For fair comparisons to be made with other modalities, prospective studies, ideally randomized, must be conducted; such studies should use consistent definitions, even across treatment modalities, and must control for clinical risk parameters. Given the relative paucity of alternatives for patients who experience biochemical progression after radiotherapy, cryosurgery may also prove a good alternative for those whose tumors appear to remain localized despite progression.

Cryobiology

Cryotherapy exerts its antineoplastic effects via numerous proposed pathways. These include the following:

• Direct cytolysis via extracellular and intracellular ice crystal formation
• Intracellular dehydration and pH changes
• Ischemic necrosis via vascular injury
• Cryoactivation of antitumor immune responses
• Induction of apoptosis

Along with cold-induced damage, additional injury occurs during warming, with osmotic cellular swelling and vascular hyperpermeability.

Endothelial damage leads to platelet aggregation and microthrombosis. Histologic changes, including necrosis, hyalinization, and inflammation, can persist for at least a year following treatment, as can residual indolent cancer. Hyalinization may be more prominent in more effectively treated prostates (ie, those with no residual cancer).^[13]

Factors that affect the efficiency of tissue destruction include the following:

• Velocity of cooling
• Nadir temperature
• Duration of freezing
• Velocity of thawing
• Number of freeze-thaw cycles
• Proximity of large blood vessels, which act as heat sinks

In general, a minimum freezing temperature of -40°C (-40°F) for 3 minutes is believed to be necessary for efficient tumor eradication.^{[14, 15, 16]}

Indications

Cryotherapy can be used for primary treatment of prostate cancer and for salvage treatment of disease refractory to radiation therapy.

Primary Treatment

A 2008 research summary by the Agency for Healthcare Research and Quality (AHRQ) concluded that, because of the lack of relevant randomized controlled trials, whether cryotherapy is more or less effective than other therapies in the treatment of localized prostate cancer is unknown.^[17]

In 2008, the AUA published a Best Practice Statement on the use of cryosurgery for the treatment of localized prostate cancer.^[18] The statement concluded that level II-2/3 evidence exists to support offering cryotherapy to men with clinically organ-confined prostate cancer with a negative metastatic evaluation finding. In high-risk men, including those with clinical stage T3 disease, data are more sparse; multimodal therapy may be necessary.^[18]

As with any other treatment for prostate cancer, appropriate patient selection is critical, and preprocedure tumor characteristics are strong indicators of outcome. The best outcomes can be expected in patients with low-risk tumor features (ie, serum prostate-specific antigen [PSA] level ≤10 ng/mL, diagnostic biopsy Gleason score ≤6, clinical stage T1c or T2a).

Patients with higher-grade, more-extensive, or more-advanced disease are at higher risk for local extension, metastatic spread, or both. Cryoablation has, however, been used for local disease control in patients with known metastatic disease who are receiving systemic therapy but require palliative maneuvers for local symptoms.^[19]

Salvage treatment

The AUA Best Practice Statement concluded that level II-3 evidence supports the consideration of cryotherapy in men in whom radiation therapy has failed, particularly those with biopsy-proven local persistence or recurrence, clinically localized disease, and a PSA level of less than 10 ng/mL.^[18]

Few local treatment alternatives are available for patients who do not achieve a low PSA nadir or who experience a rising PSA level after radiotherapy. Additional brachytherapy^[20] and radical prostatectomy^[21] are options; however, most patients in this position undergo systemic androgen deprivation therapy, which may control the cancer for several years but does not offer the possibility of definitive cure.

Cryosurgery has recently been established as a viable alternative for patients in whom radiotherapy has failed. Tumor cells resistant to radiotherapy, androgen withdrawal, and chemotherapy may remain vulnerable to the physical trauma of freezing and thawing.

Candidates for such salvage treatment should be carefully selected. In particular, if the goal is cure, the treating physician must be reasonably confident that the failure of radiation is truly attributable to persistent or recurrent local disease rather than to occult metastatic disease.

To this end, inclusion criteria for reported series of salvage cryotherapy have generally included imaging tests (ie, nuclear scintigraphy and pelvic cross-sectional imaging [CT scanning or MRI]) to rule out metastases to the bones and pelvic lymph nodes, respectively. However, the sensitivity of these tests, particularly for lymph node involvement, is less than 50%,^[22] and the likelihood of positive test results despite a low PSA level is quite low.^[23]

Some investigators have confirmed the presence of viable, treatable local disease via prostate biopsy.^[24] In patients with high-risk features, such as a preradiation PSA level of more than 20 ng/mL, Gleason score of 8-10, or a rapidly rising PSA level after radiation, a pelvic lymphadenectomy, which can be performed via laparoscopy or minilaparotomy, may be considered.

Independent of prostate cancer, patients should have a life expectancy of at least several years, and they should understand the increased risks of adverse effects in the context of salvage therapy. Most reported procedures have been performed in patients whose conditions have proven refractory to external-beam radiotherapy, but success has also been reported in patients with disease refractory to brachytherapy.^[24]

Contraindications

Relative contraindications to cryotherapy include prior transurethral resection of the prostate (TURP) with a large tissue defect, as well as significant symptoms of urinary tract obstruction. A history of abdominoperineal resection for rectal cancer, rectal stenosis, or other major rectal pathology is a relative contraindication.

In most contemporary series, cryotherapy is associated with higher rates of impotence than other local treatment alternatives. Therefore, patients for whom preservation of erectile function is a high priority are probably less-than-ideal candidates.

Larger prostates can be problematic because of the difficulty in achieving a uniformly cold temperature throughout the gland. Even with multiple probes, complete ablation of glands larger than 50 cm³ is difficult, and multiple probe insertions and prolonged freezing times may be required. In these cases, the prostate may be cytoreduced with neoadjuvant hormonal ablation before cryoablation.^[14] )

Cryotherapy is not used to stage or treat pelvic lymph nodes, so patients at high risk of lymph node metastasis may not be ideal candidates for cryotherapy. The AUA Best Practice Statement suggests that such patients may warrant prior or concurrent lymph node dissection.^[18] These patients may also be more appropriately managed with a different primary treatment modality.

Bone Scintigraphy

Nuclear scintigraphy (bone scan) is the most sensitive and readily available test for detecting metastatic disease to the bones. Scintigraphy is recommended as a staging test in patients who present with a PSA level that exceeds 10 ng/mL, a Gleason score of more than 7, or indications of bone pain.

Other Imaging Studies

The goal of cross-sectional imaging in the setting of prostate cancer is to reveal local extension or metastases to the lymph nodes. Unfortunately, the sensitivity of available imaging modalities remains low.

CT scans reveal only 25-45% of lymph node metastases and 55-75% of cases of bulky local extension. CT scanning is therefore recommended only in patients at high risk of advanced disease (eg, those with a PSA level of more than 20 ng/mL, a Gleason score of 8-10, or clinical stage T3-T4 disease).^[25]

The sensitivity of MRI for lymph node metastasis detection is not superior to that of CT scanning.^[22] The use of endorectal coils and adjunctive magnetic resonance spectroscopy may eventually improve the utility of this test for local staging, but it is currently not recommended for routine clinical practice.

Reducing Prostate Size

A large prostate volume (>50 cm³) can lower the technical feasibility of complete cryoablation. For example, neoadjuvant androgen ablation with a 3-month depot injection of a luteinizing hormone–releasing hormone agonist usually reduces the prostate to 60-70% of its original size. Androgen ablation may also reduce the tumor burden in patients with stage T3 disease (ie, gross extracapsular extension or seminal vesicle involvement).

In the setting of interstitial radiotherapy (brachytherapy), neoadjuvant androgen ablation has indeed been shown to effectively reduce prostate size, although it does not affect oncologic outcomes but does diminish quality-of-life outcomes, particularly in terms of potency rates.^{[26, 27]}

Neoadjuvant androgen ablation has not been prospectively evaluated in the context of cryotherapy; however, in a subset analysis of retrospective series, it has not been shown to improve outcomes.^[28] Indeed, in one large analysis, subjects receiving neoadjuvant therapy had worse biochemical outcomes than those receiving cryotherapy alone, although those in the neoadjuvant group also had more aggressive tumor characteristics on average.^[12]

Regional Lymphadenectomy

Patients at high risk for lymph node metastasis who are contemplating cryosurgery but have negative findings on cross-sectional imaging studies may undergo regional lymphadenectomy to assess for metastasis. Lymphadenectomy may be performed laparoscopically or via a minilaparotomy with low morbidity.

Identification of lymph node metastases is a relative contraindication for aggressive local therapy for prostate cancer. Even if resected lymph nodes prove to be free of disease, significant risk factors for lymph node metastases, such as a PSA level of more than 20 ng/mL or a Gleason score of 8-10, predict failure after any local treatment.

Subtotal Prostate Cryotherapy

Interest is growing in focal therapy for prostate cancer, using targeted radiation or energy-based ablation techniques to treat a focus of cancer while sparing the rest of the prostate and surrounding structures. The goal is better quality-of-life preservation among men with low-risk, presumably localized tumors.

The primary difficulty is that prostate cancer is frequently multifocal and its distribution cannot be reliably identified by any currently available imaging modality. Furthermore, even extended-template biopsies may undersample the prostate, resulting in understaging, undergrading, and/or underappreciation of multifocality.

A few small series of focal, unilateral, or otherwise subtotal cryotherapy have been reported, but this approach should be considered experimental. The AUA Best Practice Statement concluded, based on level III evidence, that cases of subtotal prostate cryosurgery should be described and collected prospectively in a database and studied more rigorously before a treatment recommendation can be made.^[18]

Relevant Anatomy

The prostate gland rests in the pelvis on the urogenital diaphragm. It lies inferior to the bladder, anterior to the rectum (from which it is separated by Denonvilliers aponeurosis [fascia]), and posterior to the Retzius retropubic space. It is bounded bilaterally by the levator ani musculature. The prostate surrounds the prostatic urethra.

The prostate receives its blood supply from the inferior vesical and middle rectal branches of the internal iliac arteries and drains via the Santorini dorsal venous plexus. Innervation is via the pelvic plexus arising from the T10-T12 and S2-S4 nerve roots. The neurovascular bundles run inferolaterally to the prostate and are critical determinants of penile erectile function.

The prostate is divided into zones that describe the ductal drainage systems. The posterior peripheral zone accounts for 70% of the prostate volume and is the location of 60-70% of prostate cancers. The transition zone accounts for only 5% of normal prostate volume but is the site of all benign prostatic hyperplasia and is therefore frequently enlarged. From 10-20% of prostate cancers are located in the transition zone. The central zone accounts for 25% of prostate volume and is involved in 5-10% of prostate cancers.

Anesthesia

Cryosurgery may be performed with the patient under general or regional anesthesia.

Equipment

Modern third-generation cryotherapy systems (eg, Galil [Galil Medical USA; Woburn, Mass], CRYOcare [Endocare; Irvine, Calif]) use small, needle-shaped probes, which can be placed percutaneously, under transrectal ultrasonographic guidance, directly into the prostate. (See the image below.)

Until recently, cryotherapy technique used relatively large cannulae requiring prior tract dilation. Eighteen-gauge needles were placed into the prostate. Once all needles were positioned, each was passed with a 0.038 J-tip guidewire to the proximal extent of the prostatic capsule, after which the needle was removed. The tract was then dilated over the wire, a 12F cannula was placed, and the wire was removed.

In contrast, older systems used relatively large cannulae, which necessitated a more complex technique: 6 hollow, diamond-tipped, 18-gauge needles were placed transperineally under TRUS guidance in the anteromedial, posterolateral, and posteromedial regions of the prostate. A 0.038 J-tip guidewire was passed through each needle; the needle was removed, the tract was dilated over the wire, a 12F cannula was placed, and the wire was removed.

In the future, computer software systems currently under development will most likely facilitate both preoperative planning and real-time monitoring of progression of therapy.^[29]

Positioning

For cryosurgery, the patient is placed in a lithotomy position.

Laboratory Studies

A preprocedure prostate-specific antigen (PSA) test is important for assessing risk and establishing a baseline from which the PSA level can be tracked after treatment. Other preprocedure laboratory studies include the following:

• Urine culture
• Complete blood count (with platelet count)
• Coagulation tests (ie, prothrombin time, activated partial thromboplastin time)

Transrectal Ultrasonography

Cryoablation is performed under TRUS guidance. In addition, a TRUS scan is required before the cryoablation procedure, for the following reasons:

• To plan treatment
• To assist in clinical staging by identifying any hypoechoic or hypervascular lesions (as well as extracapsular extension or seminal vesical involvement)
• To estimate the prostate volume
• To identify any large transurethral resection defect

In most cases, TRUS has already been performed to obtain the prostate biopsy specimen by which the disease was diagnosed.

Bowel Preparation

Before cryotherapy is performed, patients undergo a light bowel preparation consisting of oral magnesium citrate on the day before treatment and an enema the morning before treatment.

A Councill-tip urethral catheter is placed, and the bladder is distended with saline to displace the peritoneal contents from the treatment area. A transrectal ultrasonography (TRUS) probe is inserted into the rectum, and the anatomic configuration of the prostate and tumor, if ultrasonically identifiable, is confirmed.

Using a cryotherapy system, probes are placed into the prostate transperineally under TRUS guidance (see the image below). Probes are placed bilaterally in the anteromedial, posterolateral, and posteromedial regions, to the proximal extent of the prostatic capsule. (All needles must be placed at least 8 mm from the urethra.) Up to 30 such probes may be placed to achieve a more uniform freezing pattern.^{[9, 16]}

Thermosensors are placed, as shown below, either via direct puncture (in third-generation systems) or through additional 18-gauge needles (in older systems), to monitor the temperature at the apex, at the external sphincter, along the Denonvilliers aponeurosis, and at the edge of the tumor. The Councill-tip urethral catheter is exchanged over a guidewire for a urethral warmer. Warm saline irrigation is started through the warmer

With modern cryotherapy systems, each cryoprobe may be fixed in place by freezing each to -10°C to create a small ice ball; this step may be omitted if a perineal template is used. Ice within the prostate casts a dense acoustic shadow, obscuring all anatomic detail anterior to the ice; therefore, the anterior probes must be activated first

The anterior ice balls are extended posteriorly and laterally, including a 2- to 4-mm margin into the lateral periprostatic tissues and beyond the apex. If tumor extracapsular extension is suspected, the ice is propagated further laterally on the involved side.

In addition to continuous TRUS monitoring, the thermosensors are monitored to ensure that the target tissue temperature is reduced uniformly to at least -40°C to ensure complete tissue necrosis. Recent in vitro data suggest that the rapidity of freezing increases cytotoxicity within the ice ball margin and reduces damage beyond it.^[30] (See the image below)

The anterior probes are then thawed with helium, and the posterior probes are activated. The posterior ice balls are extended into, but not beyond, the rectal muscularis propria.

If the apex is inadequately frozen, the probe may be withdrawn toward the apex and reactivated. If seminal vesicle involvement is considered likely, an additional probe may be placed into the seminal vesicle. Two freeze-thaw cycles are performed; 2-cycle therapy has been proven in vivo to result in more complete coagulative necrosis than a single cycle and achieves killing at a critical temperature of -41°C (-41.8°F) rather than the -62°C (-79.6°F) required for a single cycle.^[31]

After the second cycle, the cryoprobes and/or cannulae are removed, and, if large-bore cannulae were used, the perineal insertion sites are closed with 4-0 chromic suture. The urethral warmer remains in place until all thawing is complete; it is then exchanged for a Foley catheter, or a suprapubic tube is placed.

The following technical measures were explicitly recommended by the AUA Best Practice Statement panel:^[18]

• Use of rapid freezing for better tissue destruction
• Use of thermocouples for temperature monitoring
• Freezing to -40°C
• Use of passive (slow) thawing
• Use of a double freeze-thaw cycle

Cryotherapy is usually performed in an outpatient setting. A urethral catheter is left in place for 3 weeks following treatment to minimize the likelihood of tissue sloughing and urinary retention. Urinary retention after cryotherapy is quite common because of local urethral edema. Some investigators have reported leaving the urethral warming catheter in place for several hours after the procedure in an attempt to minimize injury to the urethra,^[8] but this maneuver has not been well studied.

Outcomes with Cryotherapy for Local Control

Among patients undergoing rebiopsy 3-24 months after treatment with a standard 5-probe cryotherapy system, 7.7-25% have been found to have residual malignancy of the glands,^{[32, 33, 34]} and 42-71% have been found to have focal areas of viable benign epithelium.^{[35, 36, 34]} Numerous disease- and treatment-related factors have been shown to predict rates of local control.

In one series, for example, the likelihood of positive biopsy findings was 9% in subjects with clinical stage T1 or T2 disease, compared with 21% in those with T3 disease.^[37] Persistent or recurrent cancer is more likely among tumors located in the prostatic apex or seminal vesicles than those located in the mid gland or base.^[35]

A 2001 pooled analysis stratified patients into the following risk groups^[12] :

• Low risk - PSA level of 10 ng/mL or less, Gleason score of 6 or less, and clinical stage T1 or T2a disease
• Intermediate risk - PSA level more than 10 ng/mL, Gleason score of 7 or more, or clinical stage T2b disease or higher
• High risk - Two or 3 of these adverse risk factors

The distribution of patients among the risk groups was 25%, 34%, and 41%, respectively. The positive biopsy rate in the series was 18% overall: 12% among low- and intermediate-risk patients and 24% among high-risk patients.

The use of 2 freeze-thaw cycles rather than 1 reduced the positive biopsy rate from 64% to 11% in a series of primary cryotherapy patients^[35] and from 29% to 9% among a group treated with salvage cryotherapy for radiation failure.^[19] Other technical advances have also produced improvements.

One series reported a reduction of the positive biopsy rate from 83% to 10% as a result of introducing the use of thermosensors during treatment^[38] . Another series reported a positive biopsy rate of only 2.5% with the use of 6-8 cryotherapy probes rather than the conventional 5 probes.^[39]

Biochemical failure (primary therapy)

Defining biochemical recurrence after local prostate cancer treatment is controversial; by one recent count, 152 different definitions were used in surgical and radiation studies published between 1991 and 2004—53 in prostatectomy series and 99 in radiation series.^[40] This variation in definition creates great difficulty in comparing outcomes across treatment modalities and is no less of a problem in the case of cryotherapy.

PSA thresholds of 0.4, 0.5, and 1 ng/mL have all been used, as have both the original American Society for Therapeutic Radiology and Oncology (ASTRO) definition of 3 consecutive rises after a nadir and the updated Phoenix definition of nadir plus 2 ng/mL.^[18] The ASTRO and Phoenix definitions tend to delay identification of treatment failure relative to threshold definitions, thereby artificially improving success rates in survival analyses.^{[41, 42]}

No specific definition was endorsed by the AUA Best Practice Statement.^[12] However, tissue response to cryotherapy should be more rapid than the response to radiation therapy, so a nadir should be reached more rapidly—within 3 months of treatment in most cases following a sharp posttreatment rise. Therefore, threshold definitions may be more appropriate than the ASTRO or Phoenix definitions.

Cryotherapy does not ablate every gland in the prostate at the microscopic level. Consequently, the target nadir has not been established with certainty, although the nadir achieved initially clearly correlates with the eventual disease progression. A report of cryotherapy experiences in a community setting indicated that 84% of the patients reached a PSA nadir of less than 0.4 ng/mL, although the follow-up period was quite short.^[43]

Biochemical failure, defined as a rise in PSA level of 0.2 ng/mL after a nadir of less than 0.5 ng/mL, was reported to be lowest in subjects whose PSA nadirs were less than 0.1 ng/mL.^[35] Similarly, positive biopsy rates were 1.5%, 10%, and 55% in subjects with nadir levels of less than 0.1, 0.1-0.5, and more than 0.5 ng/mL, respectively.

In a pooled analysis with a median follow-up of 24 months, actuarial 5-year biochemical disease-free survival (bDFS) rates were 60%, 45%, and 36% for low-, intermediate-, and high-risk patients, respectively, when failure was defined on the basis of a PSA threshold of 0.5 ng/mL. When a threshold of 1 ng/mL was used, bDFS rates were 76%, 71%, and 45%, respectively.^[12]

Prepelica et al reported a series of 65 men with high-risk prostate cancer, defined as a PSA level of 10 ng/mL or higher and/or a Gleason score of 8 or higher and found an 83.3% bDFS rate based on the ASTRO definition at median 35-month follow-up. Fifty percent of patients achieved a nadir PSA of less than 4 ng/mL, and 35% achieved a nadir of less than 1 ng/mL.

The morbidity rate in this study was low, with 2 patients reporting incontinence, 2 patients reporting rectal pain, and 2 patients reporting urinary retention. Of note, roughly two thirds of the patients in this cohort had received neoadjuvant hormonal therapy, the survival impact of which is still unclear in association with cryotherapy.^[44]

One of the larger series of patients to date, with the longest follow-up, included 590 subjects followed for a mean of 5.4 years. The reported 7-year bDFS rates were stratified by the same risk definitions used by Long et al^[12] but used several different definitions.

Using an absolute PSA threshold of 0.5 ng/mL to define failure (as in many surgical series), the bDFS rates were 61%, 68%, and 61% for low-, intermediate-, and high-risk subjects.^[11] Adapting the ASTRO definition of failure (ie, 3 successive rises in PSA level), the bDFS rates were 92%, 89%, and 89%.

Thirteen percent of subjects had positive biopsy findings; of these, 32 underwent repeat cryoablation, with 7-year bDFS rates comparable to those who had primary cryoablation only: 68% using the 0.5 ng/mL threshold and 91% using the ASTRO definition. Relatively few late failures occurred beyond 24-36 months.^[11]

Jones et al^[45] recently published the largest series of patients undergoing cryotherapy as primary treatment, all of whom were included in the industry-sponsored Cryo On-Line Data (COLD) registry. The series included 1198 men managed by 27 physicians. The median pretreatment PSA level was 6.8 ng/mL (mean, 9.6 ± 8.6 ng/mL), and various Gleason scores were represented (median, 7). Of note, 49.5% of these men received hormone therapy prior to cryoablation. The mean follow-up period was 24.4 ± 25.9 months.

Five-year actuarial biochemical recurrence-free survival rates were reported to be 77.1% ± 2.1% and 72.9% ± 2.1% using the ASTRO and Phoenix definitions, respectively. Risk-stratified outcomes are listed in the table below. One caveat is that this report somewhat misuses the Phoenix definition, which is intended to predict outcomes only at a point 2 years short of median follow-up; thus, to report 5-year outcomes, 7 years of follow-up should be available.^[46] Therefore, outcomes may be expected to worsen somewhat with further follow-up.

Table 1. Study Outcomes (Open Table in a new window)

Outcomes with Salvage Cryotherapy

Patients who experience disease progression after radiation therapy have few options for potentially curative therapy. Cryotherapy has been offered to such patients if they have no evidence of metastatic disease and their progression is thought to be restricted to persistent or recurrent local cancer.

Contemporary series have demonstrated promising results for this treatment approach. Using 2 freeze-thaw cycles, a negative biopsy rate of 93% and a biochemical failure-free survival rate of 66% was achieved in a series of 150 subjects,^[19] although these results came at the price of higher complication rates.^[54] Subjects with preoperative PSA levels of more than 10 ng/mL or biopsy Gleason scores of more than 8 were most likely to experience disease recurrence.^[19]

A biochemical failure-free survival rate of 66% at 12 months was reported in a series of 43 salvage patients, with lower complication rates^[55] ; additionally, a PSA nadir of more than 0.1 ng/mL following treatment predicted eventual recurrence.^[55] With the use of an argon-based cryosurgery system to treat 38 patients with biochemical recurrence after radiation, PSA nadirs less than 0.1 ng/mL were reported in 81.5% and bDFS rates of 86% and 74% were reported at 1- and 2-year follow-up, respectively.^[56]

In a large series that also used an argon-based system, 118 subjects with recurrent disease after radiation therapy underwent cryoablation, including 5 who had received permanent interstitial implants.^[24] Negative biopsy findings were reported in 94% of these patients; the 7 who had persistent disease underwent second ablation procedures.

PSA nadirs less than 0.5 ng/mL occurred in 97% of subjects; at a median of 18.6 months of follow-up, 34% remained below this level (68% had PSA levels < 4 ng/mL). Ten patients had developed metastatic disease.^[24] As in Pisters and colleagues' 1997 study,^[19] preprocedure PSA levels of more than 10 ng/mL, Gleason scores of more than 8, and stage T3-T4 disease predicted biochemical failure.

Pisters et al recently reported outcomes for salvage cryotherapy among 279 men from the COLD registry, the largest salvage series to date: These patients had significant recurrent/persistent disease, with a mean precryotherapy PSA level of 7.6 ± 8.2 ng/mL and a mean Gleason score of 7.5, and 51% of these patients received hormone therapy prior to cryotherapy, for a mean of 13 months.

After a follow-up duration of 21.6 ± 24.9 months, 17% of the patients had a PSA level of less than 0.2 ng/mL at 5 years of follow-up. The actuarial biochemical recurrence-free survival rate was 58.9% ± 5.7% and 54.5% ± 4.9% at 5 years using the ASTRO and Phoenix definitions, respectively.

Forty-six patients underwent biopsy after cryotherapy; results were positive in 32.6%.^[57] It should be noted that the follow-up in this study, as in the COLD registry study of primary therapy,^[45] was insufficient to properly report 5-year outcomes using these definitions.^[46]

Multiple prostate cancer studies over the past few years have generated increased awareness of the importance of PSA kinetics, which are assessed with measurements such as PSA velocity (PSAV) and PSA doubling time (PSADT) at various stages of prostate cancer management. To date, only one study has examined PSA kinetics in relation to cryotherapy.

Spiess et al analyzed 49 patients undergoing salvage cryotherapy for failure after radiation therapy for predictors of biochemical outcomes, and they found that both precryotherapy PSA levels of greater than 10 ng/mL and a PSADT of less than or equal to 16 months predicted biochemical recurrence after cryotherapy.^[58]

Of note, the median presalvage PSA level was 5.9 ng/mL, and 51% of the patients had a preradiation Gleason grade of 8 or greater.^[58] Studies of salvage radiotherapy following surgery have found consistently that PSA level at time of radiotherapy predicts outcome,^[59] as have studies of salvage prostatectomy following radiation therapy failure.^[60] Thus, earlier use of cryotherapy at lower postradiation PSA levels may improve outcomes, but this issue has not yet been studied in depth.

Longer-term salvage data are also becoming available. Bahn et al reported on 7-year outcomes for 59 patients treated with cryotherapy for failure after radiation. The bDFS rate was 59% using a PSA threshold of 0.5 ng/mL and 69% using a threshold of 1 ng/mL. Notably, no patient had local recurrence upon repeat biopsy; all failures were presumably due to distant progression.^[61]

Complications

Complications of cryotherapy include the following:

• Impotence
• Incontinence
• Tissue sloughing
• Pelvic and rectal pain
• Penile numbness
• Rectourethral fistula
• Urethral stricture
• Hydronephrosis
• Small-bowel obstruction

Impotence

Cryotherapy impairs the penile arterial blood supply^[62] and damages the cavernosal nerves responsible for erectile function.^[63] This combined neurovascular insult results in impotence in 40-100% of treated patients,^[11] depending on such factors as the use of multiple freeze-thaw cycles, the size of the ice ball generated, preoperative potency, the instruments used to assess potency, and the follow-up interval since treatment.

Greater nerve regeneration is possible after cryotherapy than after surgery or radiation therapy; accordingly, some patients have reportedly recovered erectile function up to 2 years after treatment. One report indicated that 95% of subjects who were potent before cryotherapy became impotent and that 5% regained their potency at a mean of 16 months.^[11]

A pooled analysis of 975 patients treated at 5 institutions from 1993-1998 revealed an impotence rate of 93%.^[12] However, another report indicated that, 3 years after cryoablation, 5 (13%) of 38 subjects had regained potency and 13 (34%) were potent with the help of erectile aids.^[64] In a large recent series, Jones et al noted that, of patients potent at the time of therapy (29.5% of the cohort), only 25% returned to intercourse posttreatment, and only 8.8% without the use of medications or other assistance.^[45]

Aggressive penile rehabilitation has a growing place in the management of erectile function after prostatectomy and may also have a role after cryotherapy. For example, Ellis et al reported that a penile rehabilitation program resulted in recovery of erectile function following cryotherapy in 41% of patients at 1 year and 51% at 4 years.^[43]

Nonetheless, postprocedural potency is the quality-of-life domain for which cryotherapy remains clearly inferior to other local treatment modalities for prostate cancer. Until the return-of-potency rate improves, the risk of impotence will likely continue to be an impediment to wider use of cryotherapy among patients in whom erectile function is important.

One group of investigators has studied a method of nerve-sparing cryotherapy in a canine model by using active helium-based warming of the neurovascular bundles during freezing of the prostate. Unfortunately, nerve preservation was not completely reproducible; moreover, the warming also resulted in incomplete ablation of prostatic tissue adjacent to the nerves.^[65]

Incontinence

As with impotence, reported rates of incontinence depend greatly on the definitions of continence and the methods of assessment. These rates vary from 4%^[50] to 27%^[66] in patients undergoing cryotherapy as primary treatment. Among the largest single series of patients who underwent primary cryotherapy, 4.3% required at least one urinary pad per day, and 11.6% had lesser degrees of incontinence^[11] ; Long et al reported a 7.5% incontinence rate.^[12]

Among patients undergoing cryotherapy for salvage treatment after failure of radiation therapy, the prevalence of incontinence is higher, ranging from 7.9%^[56] to 95.5%,^[36] with rates of 20%^[24] to 73%^[19] in the largest series. In the Chin et al study, one third of the patients reporting incontinence had near-total or total incontinence.^[24]

In a recent review of complications of cryotherapy, the rates of incontinence among patients treated with modern technique and equipment were estimated to be 5% for primary therapy and 10% for salvage therapy.^[67]

Tissue sloughing

Cryosurgery induces necrosis in the treated prostate tissue. If the urethra freezes during treatment, its mucosal barrier fails, thus exposing the necrotic prostate tissue to the urinary tract and a risk of infection. This tissue may then slough into the urethra (typically, 3-8 wk posttreatment), producing irritative and obstructive voiding symptoms, pyuria, and, possibly, urinary retention.

The use of urethral warming devices significantly reduces the risk of this complication. One series reported a reduction from 85% to 37%.^[38] In another report, urethral warming reduced the rate of sloughing causing obstruction from 54% to 14%.^[54] Data from a pooled analysis likewise revealed obstruction requiring transurethral resection of the prostate (TURP) in 10% of patients undergoing urethral warming via an approved catheter versus 44% in other patients.^[12]

In contemporary series, the overall rate of sloughing has ranged from 3.8-23% in patients receiving primary cryotherapy^{[49, 14, 52]} and from 5-44% in those undergoing salvage treatment.^{[19, 55]} In a recent large series of salvage cryotherapy, transurethral resection of sloughed tissue was necessary in 3.2% of patients.^[57]

Conservative treatment includes antibiotics and urinary drainage; continuous intermittent self-catheterization may help dislodge obstructing tissue. In some cases, transurethral removal or resection of necrotic tissue may be required. Nearly 50% of patients requiring transurethral resection after cryotherapy develop incontinence^[14] ; therefore, resection must be as limited as possible.

Pelvic and rectal pain

Pelvic and/or rectal pain is reported by 1-11% of patients receiving primary cryotherapy^{[66, 52, 48]} and 21-77% of those receiving salvage cryotherapy for radiation failure.^{[19, 36]} The etiology of this pain is unclear but may include rectal wall ischemia, freezing of the pelvic floor musculature and/or pubic bone, or extravasation of urine into the periprostatic tissues. Urinoma or abscess must be excluded in these patients. The pain is best managed with anti-inflammatory medications.

Penile numbness

In early studies, approximately 10% of patients treated with cryotherapy developed penile numbness attributable to injury to the dorsal nerve of the penis. This injury was attributed to cryotrauma to the pudendal nerve associated with excessive freezing of the anterior probes. This complication was usually temporary, resolving spontaneously in approximately 2-3 months.^[14]

Rectourethral fistula

Complete freezing of tissues posterior to the prostate, with urinary extravasation and possible subsequent infection, can lead to fistula formation, which is reported in 0%^{[49, 68]} to 3%^[66] of primary cryotherapy patients. In their series of 590 cases, Bahn et al reported only 2 cases of fistula formation^[11] ; Long et al, likewise, reported a 0.5% rate of fistula formation among 975 patients,^[12] and Jones et al reported a 0.4% rate among 1198 patients who underwent cryosurgery as primary therapy.^[45]

Rates may be higher among salvage patients—up to 11% in one report.^[12] In one large series of salvage cases, however, only 4 cases were reported among 118 patients^[24] ; among 279 salvage patients recently reported, the fistula rate was 1.2%.^[57]

Rectourethral fistula may not develop until several months after treatment. Patients typically present with watery diarrhea or pneumaturia. Diagnosis is confirmed with voiding cystourethrography or CT scanning.

Conservative treatment consists of Foley catheter drainage, possibly facilitated by fistula tract fulguration. Any formal fistula repair (eg, a repair involving a muscle transposition flap) should be delayed 4-6 months to allow the inflammatory process to subside and should involve a multidisciplinary approach that includes colorectal surgeons and urologists.^[67]

Urethral stricture

Urethral stricture results from extensive tissue sloughing, usually at the bladder neck. This is a rare complication when urethral warming is used and can usually be successfully managed with transurethral incision or balloon dilation.

Hydronephrosis

Hydronephrosis, attributed to cryoinjury of the ureteral orifice or distal ureter as a result of deep seminal vesical or bladder neck freezing, has been reported in 0-36% of subjects undergoing salvage cryotherapy for recurrence after radiotherapy.^{[19] [36]} This complication can usually be avoided by careful monitoring of the trigone and ureteral orifices during treatment with transrectal ultrasonography (TRUS).

Small-bowel obstruction

In one series, only 1 of 176 subjects developed a bowel obstruction following cryotherapy. This result was attributed to ice-ball extension into the peritoneal cul-de-sac. Such extension is usually preventable by identification of the cul-de-sac on TRUS images and by distention of the bladder before the procedure in order to displace the peritoneal contents.^[28]

Long-term Monitoring

Routinely evaluate the patient after cryotherapy to assess for the development of late complications and to assess for symptoms or signs of clinical recurrence. Monitor the PSA level at regular intervals.

Patient Education

For patient education information, see eMedicine's Prostate Health Center and Cancer and Tumors Center, as well as Prostate Cancer.

Future Directions

A number of improvements in technology and clinical algorithms may be expected to facilitate ongoing improvements in cryotherapy outcomes in terms of cancer control and quality of life. Varying the intensity and extent of cryoablation should allow patients and physicians to contemplate tradeoffs between quality of life and cancer control certainty.

Gould,^[51] for example, has described a technique of total cryosurgery, in which no urethral warming catheter is used and the urethra is intentionally ablated along with the entire prostate gland. He achieved PSA nadirs of less than 0.2 ng/mL at 6 months in 96% of his patients compared with 49% for standard cryotherapy and 73% for a contemporary series of patients who underwent radical perineal prostatectomy. This degree of biochemical control came at the cost of obstruction that required transurethral resection in most patients and significant incontinence in 18.5%.^[51]

A novel simulator system, which promises to facilitate training in cryosurgical techniques, has recently been introduced.^[69]

At the other frontier, Rukstalis et al have suggested that prostate parenchyma-sparing cryosurgery may improve outcomes in terms of continence and potency. Despite the multifocal nature of prostate cancer, in an analysis of 112 radical prostatectomy specimens, they found that assuming the largest tumor would be the one detected by biopsy, restricting treatment to 9 of 12 prostate zones, and thereby sparing the contralateral neurovascular bundle, could be accomplished with a 21% risk of significant (ie, >0.5 mL) residual disease.^[70]

Onik et al have tested a similar approach in a small series of 9 patients treated with focal, unilateral nerve-sparing cryotherapy; with a mean follow-up of 36 months, all had stable PSA levels, 6 patients had biopsy specimens with negative findings, and 7 of the 9 were potent.^[71]

In a pilot program at the University of California at San Francisco, 8 patients with localized prostate cancer likewise have been treated with unilateral cryotherapy. All are disease-free, either based on PSA criteria or based on negative biopsy results. No patient developed a urethral fistula or significant tissue sloughing. Significantly, although only 2 of the patients were potent before treatment, both reported no change in their erections after the limited cryosurgical treatment. Onik et al reported on a larger series (55 men) who underwent treatment only of the area of the prostate known to harbor cancer. With a mean of 3.6 years follow-up, 95% had stable PSA levels (ASTRO definition), and 86% of potent patients retained their erectile function.^[72] While such approaches should still be considered experimental, they hold significant promise as the indications and approaches to focal therapy continue to evolve.

Innovative combination therapy may also play a role in the future. Clarke et al have reported in vitro data suggesting that the combination of 5-fluorouracil (5-FU) and cryotherapy produces efficient prostate cancer cell death at temperatures as high as -15°C, via a mix of necrosis, Bax-mediated apoptosis, and freeze rupture.

In theory, this approach to chemo-cryotherapy could improve oncologic outcomes by achieving more uniform tumor death, while decreasing adverse effects by reducing the ice-ball size required to achieve a higher target temperature.^{[73, 74, 75]} Other biological response modifiers, such as antifreeze proteins, may also improve the efficiency of the freezing process,^[76] as may improved imaging modalities.