Prostate cancer is found mainly in older men.
Prostate cancer is often curable. About 90% of new cases of prostate cancer are caught early, and almost 100% of men with these early cancers survive 5 years or more after being diagnosed. 1 Treatment Overview
Different types of treatment are available for patients with prostate cancer.
Four types of standard treatment are as followings:

Watchful waiting This is closely monitoring a patient’s condition without giving any treatment until symptoms appear or change. This is usually used in older men with other medical problems and early-stage disease.

SurgeryPatients in good health who are younger than 70 years old are usually offered surgery as treatment for prostate cancer. The following types of surgery are used: pelvic lymphadenectomy,radical prostatectomy,retropubic prostatectomy,perineal prostatectomy and transurethral resection of the prostate (TURP).

Impotence and leakage of urine from the bladder or stool from the rectum may occur in men treated with surgery. In some cases, a technique known as nerve-sparing surgery can be used. This type of surgery may save the nerves that control erection. However, men with large tumors or tumors that are very close to the nerves may not be able to have this surgery.

Radiation therapyThere are two types of radiation therapy:external radiation and internal radiation.the later uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated. Impotence and urinary problems may occur in men treated with radiation therapy.Hormone therapy The therapy is aimed to remove hormones or blocks their action and stops cancer cells from growing, may include the following:

Luteinizing hormone-releasing hormone agonists can prevent the testicles from producing testosterone. Examples are leuprolide, goserelin, and buserelin.

• Antiandrogens can block the action of androgens such as flutamide and bicalutamide.
• Drugs that can prevent the adrenal glands from making androgens include ketoconazole and aminoglutethimide.
• Orchiectomy is to remove one or both testicles, to decrease hormone production.

Hot flashes, impaired sexual function, loss of desire for sex, and weakened bones may occur in men treated with hormone therapy.
Alternative therapies
Researchers are studying ways to kill cancer cells with heat. One treatment being studied is high-intensity focused ultrasound, or HIFU. The sound waves produced by HIFU are 10,000 times stronger than regular ultrasound. The sound waves are aimed at the prostate and its cancer, and the intense heat destroys the prostate. Other forms of heat treatment under study use electrodes, microwaves, and magnetic metal rods to heat and destroy the prostate.
Cryosurgery is a treatment that uses an instrument to freeze and destroy prostate cancer cells. This type of treatment is also called cryosurgery.During the past years,the therapy has been paid a great attention, become an important alternative modality for localized and recurrent prostate cancer.
History of the cryosurgery for prostate cancer
Cryosurgery,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. The 1966 advent of probes cooled by liquid nitrogen in closed circulation marks the beginning of modern cryosurgery. One of the first applications of this new technology was the transurethral cryoablation of benign prostatic hyperplastic tissue, followed shortly thereafter by the treatment of prostate cancer via an open perineal approach. The transperineal approach was introduced in 1974, initially using a single digitally guided cryoprobe repositioned as needed during the procedure.
Early series 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 lack of ability to accurately monitor cryoprobe placement and ice-ball formation.
The major advances in the past 15 years, which have reinvigorated investigation into the use of cryosurgery for prostate cancer, have included the use of real-time transrectal ultrasound (TRUS) monitoring of probe placement and freezing, the simultaneous use of multiple cryoprobes, and the standard use of urethral warming catheters.
A significant recent development is the introduction of cryosurgery probes based on 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. Moreover, argon-based probes have a much smaller diameter, thus permitting direct, sharp transperineal insertion, avoiding the need for tract dilation and facilitating more conformal cryosurgery by allowing placement of more probes.

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

Antineoplastic effects of cryosurgery
Cryosurgery exerts its antineoplastic effects via a number of proposed pathways, including direct cytolysis via extracellular and intracellular ice crystal formation, intracellular dehydration and pH changes, ischemic necrosis via vascular injury, cryoactivation of antitumor immune responses, and induction of apoptosis. Endothelial damage leads to platelet aggregation and microthrombosis.
Additional injury occurs during warming, with osmotic cellular swelling and vascular hyperpermeability. A number of factors affect the efficiency of tissue destruction, including the velocity of cooling, nadir temperature, the duration of freezing, the velocity of thawing, the number of freeze-thaw cycles, and the existence of large blood vessels, which act as heat sinks. In general, a minimum freezing temperature of -40°C (-40°F) for 3 minutes is thought to be necessary for efficient tumor eradication (Shinohara, 1996; Hoffmann, 2002; Han, 2004).
Indication of cryosurgery
The extent and pathologic character of the patient's disease are importance factors in choosing a proper therapy for prostate cancer. One of the great advantages of cryosurgery is the flexibility of the procedure to be tailored to treat both high-and low-risk patients as well as patients in whom failed radiation therapy has failed.
Primary treatment
As with any other treatment for prostate cancer, appropriate patient selection is critical and preprocedure tumor characteristics are strong indicators of outcome. 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) are expected to have the best outcomes. Patients with higher-grade, more-extensive, or more-advanced disease are at higher risk for local extension, metastatic spread, or both. In most series, cryosurgery is currently 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.
Cryoablation has also been used for local disease control in patients with known metastatic disease on systemic therapy who require palliative maneuvers for local symptoms.
Salvage treatment
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 and radical prostatectomy are options; however, most patients in this position receive 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 of disease, the treating physician must be reasonably confident that the failure of radiation is truly attributable to persistent or recurrent local disease and not to occult metastatic disease. To this end, inclusion criteria for reported series of salvage cryosurgery have generally included imaging tests (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%.
Some investigators have confirmed the presence of viable, treatable local disease via prostate biopsy. 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 may be considered, which can be performed via laparoscopy or minilaparotomy.
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.
Contraindications of cryosurgery
Relative contraindications include the following:

1. Prior transurethral resection of the prostate with a large tissue defect
2. Significant symptoms of urinary obstruction prior to treatment
3. Large prostate size: 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.
4. History of abdominoperineal resection for rectal cancer, rectal stenosis, or other major rectal pathology

Pre-procedures of cryosurgery
Lab Studies:

1. Prostate-specific antigen: A preprocedure PSA test is important for assessing risk and establishing a baseline from which the PSA level can be tracked after treatment.
2. Urine culture
3. CBC count (with platelet count)
4. Coagulation tests (ie, prothrombin time, activated partial thromboplastin time)

Imaging Studies:

1. Transrectal ultrasonography
1. Modern cryoablation is performed under TRUS guidance, and a preprocedure scan is required to (1) plan treatment, (2) assist in clinical staging by identifying any hypoechoic or hypervascular lesions (as well as extracapsular extension or seminal vesical involvement), (3) estimate the prostate volume, and (4) identify any large transurethral resection defect.
2. In most cases, TRUS will have already been performed to obtain the prostate biopsy specimen by which the disease was diagnosed.
2. Bone scintigraphy
1. Nuclear scintigraphy (bone scan) is the most sensitive and readily available test for detecting metastatic disease to the bones.
2. Scintigraphy is recommended as a staging test in patients who present with a PSA level of more than 10 ng/mL, a Gleason score of more than 7, or indications of bone pain.
3. Computed tomography of the abdomen and pelvis
1. The goal of cross-sectional imaging in the setting of prostate cancer is to detect local extension or metastases to the lymph nodes.
2. CT scans are recommended only for 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.
4. Magnetic resonance imaging of the abdomen and pelvis
1. The sensitivity of MRI for lymph node metastasis detection is not superior to that of CT scanning.
2. The use of endorectal coils and adjunctive magnetic resonance spectroscopy may improve the utility of this test for local staging in the future, but it is currently not recommended for routine clinical practice.

Histology study
TRUS-guided biopsy is the current criterion standard for diagnosis and grading of prostate cancer. The vast majority of prostate cancers are adenocarcinomas of the prostate, and these are graded based on the Gleason grading system, which assesses the pattern of glandular organization and differentiation (Gleason, 1974). Each tumor is assigned 2 numbers, 1 through 5, increasing with progressive dedifferentiation. The first number is the predominant pattern, and the second is the less-frequent pattern. The 2 numbers are added to produce a total Gleason score of 2-10.

Neoadjuvant androgen ablation
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). However, in a subset analysis of retrospective series, neoadjuvant androgen ablation it has not been shown to improve outcomes.
Surgical management
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 because the identification of lymph node metastases is a relative contraindication for aggressive local therapy for prostate cancer. Lymphadenectomy may be performed laparoscopically or via a minilaparotomy with low morbidity. 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, even if resected lymph nodes prove to be free of disease.
Procedure of cryosurgery
Cryosurgery may be performed with the patient under general or regional anesthesia. After anesthesia is induced, the patient is placed in a lithotomy position. A Councill-tip urethral catheter is placed, and the bladder is distended with saline to displace the peritoneal contents from the treatment area. A TRUS probe is inserted into the rectum, and the anatomic configuration of the prostate and tumor, if ultrasonically identifiable, is confirmed.

Until recently, cryosurgery technique used relatively large cannulae requiring prior tract dilation. Hollow, diamond-tipped, 18-gauge needles were placed into the prostate transperineally under TRUS guidance. Six needles were placed bilaterally in the anteromedial, posterolateral, and posteromedial regions. (All needles must be placed at least 8 mm from the urethra.) 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.

Figure 1. Diagram showing the transperineal approach of prostate cryosurgery. The cryoprobes are placed percutaneously through the perineum using transrectal ultrasound for guidance. The approach is identical in concept to brachytherapy of the prostate. Reproduced with permission from Endocare, Inc, Irvine, California.

Figure 2. Transrectal ultrasound showing the ice as it extends toward the rectum. The freezing front (FF) is exquisitely seen as a hyperechoic (white) line extending toward the rectum (R). The seminal vesicle (SV) and uro-genital diaphragm (UG) can be identified. The ability to visualize the freezing as it encompasses the prostate and approaches the rectum gives a "freezing radiation source" greater control than traditional brachytherapy.

Picture 1. Diagram illustrating dimensions of a typical ice ball as seen end-on (left) and from the side (right).

Picture 2. Transrectal ultrasound image of the prostate illustrating placement of the cryoprobes and urethral warming catheter.

Picture 3. Transrectal ultrasound imaging of prostate during cryoablation. The leading edge of the ice ball, growing posteriorly, is echodense and casts a dark acoustic shadow anteriorly.

Picture 4. Transrectal ultrasound imaging illustrating the ice ball now extending posteriorly to the muscularis propria of the rectum. All prostate tissue is now included within the margin of the ice ball.

Modern third-generation cryosurgery systems (eg, Galil [Galil Medical USA; Woburn, Mass], CRYOcare [Endocare; Irvine, Calif]) use smaller, needle-shaped probes, which can be placed percutaneously, directly into the prostate without dilation. Up to 30 such probes may be placed to achieve a more uniform freezing pattern, as is displayed in Image 2. A computer software systems currently under development will most likely facilitate both preoperative planning and real-time monitoring of progression of therapy.
Thermosensors are placed, either through additional 18-gauge needles or via direct puncture, to monitor the temperature at the apex, 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 cryosurgery 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 observed to ensure that the target tissue temperature is reduced uniformly to at least -40°C to ensure complete tissue necrosis. The rapidity of freezing increases cytotoxicity within the ice ball margin and reduces damage beyond it.
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. 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.

Postoperative management

After cryosurgery is performed, 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 cryosurgery 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.
Routinely evaluate the patient after cryosurgery 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.

Complications
Impotence

Cryosurgery impairs the penile arterial blood supply and damages the cavernosal nerves responsible for erectile function. This combined neurovascular insult results in impotence in 40%-100% of treated patients (Bahn, 2002), 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 cryosurgery than after surgery or radiation therapy; accordingly, some patients have reportedly recovered erectile function as many as 2 years after treatment. One report indicated that 95% of subjects who were potent before cryosurgery became impotent and that 5% regained their potency at a mean of 16 months (Bahn, 2002).
A pooled analysis of 975 patients treated at 5 institutions from 1993-1998 revealed an impotence rate of 93% (Long, 2001). However, a different 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 (Robinson, 2002).
Postprocedural potency is the quality-of-life domain for which cryosurgery remains clearly inferior relative 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 this treatment approach among patients for whom erectile function is important.

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% (Cohen, 1996) to 27% (Cox, 1995) for patients given cryosurgery as primary treatment. Among the largest single series of patients who underwent primary cryosurgery, 4.3% required at least 1 urinary pad per day, and 11.6% had lesser degrees of incontinence (Bahn, 2002); Long et al reported a 7.5% incontinence rate (Long, 2001). Among patients undergoing cryosurgery for salvage treatment after failure of radiation therapy, the prevalence of incontinence is higher, ranging from 7.9% (Ghafar, 2001) to 95.5% (Bales, 1995), with rates of 20% (Chin, 2001) to 73% (Pisters, 1997) in the largest series. In a recent review of complications of cryosurgery, the rates of incontinence using modern technique and equipment were estimated to be 5% for primarytherapy and 10% for salvage therapy (Ahmed, 2005).

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% (Wong, 1997). In another report, urethral warming reduced the rate of sloughing causing obstruction from 54% to 14% (Cespedes, 1997.)
Data from a pooled analysis likewise revealed obstruction requiring transurethral resection of the prostate in 10% of patients receiving urethral warming via an approved catheter versus 44% in other patients (Long, 2001). In contemporary series, the overall rate of sloughing has ranged from 3.8%-23% for patients receiving primary cryosurgery (Wieder, 1995; Shinohara, 1997; Han, 2003) and from 5%-44% for those undergoing salvage treatment (Pisters, 1997; De La Taille, Urology, 2000).
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.

Pelvic and rectal pain

One to 11% of patients receiving primary cryosurgery (Coogan, 1995; Cox, 1995; Han, 2003) and 21%-77% of those receiving salvage therapy for radiation failure (Bales, 1995; Pisters, 1997) have pelvic and/or rectal pain. 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 cryosurgery 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 (Shinohara, 1996).

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% (Long, 1998) to 3% (Cox, 1995) of primary cryosurgery patients. In a large, recent series of salvage cases, however, only 4 cases were reported among 118 patients (Chin, 2001).

This complication may occur as late as several months after treatment and typically presents with watery diarrhea or pneumaturia. Diagnosis is confirmed with a voiding cystourethrogram or CT scan. 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 (Ahmed, 2005).

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 cryosurgery for recurrence after radiotherapy (Bales, 1995; Pisters, 1997). This complication can usually be avoided by careful TRUS monitoring of the trigone and ureteral orifices during treatment.

Small bowel obstruction

In a recent series, only 1 of 176 subjects developed a bowel obstruction following cryosurgery. 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.

Clinical efficacy and outcome
Primary treatment
Local control

Among patients undergoing rebiopsy 3-24 months after treatment with a standard 5-probe cryosurgery system, 7.7%-25% (Bahn, 1995; Wake, 1996; Chin, 2003) have been found to have residual malignant glands, and 42%-71% (Bales, 1995; Shinohara, 1996; Chin, 2003) have been found to have focal areas of viable benign epithelium. A number of 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% for subjects with clinical stage T1 or T2 disease compared with 21% for those with T3 disease (Connolly, 1996). Persistent or recurrent cancer is more likely among tumors located in the prostatic apex or seminal vesicles compared with those located in the mid gland or base (Shinohara, 1997).
A 2001 pooled analysis stratified patients into the following risk groups: (1) low-risk patients had a PSA level less than or equal to 10 ng/mL, Gleason score less than or equal to 6, and clinical stage T1 or T2a disease; (2) intermediate-risk patients had a PSA level more than 10 ng/mL, Gleason score equal to or more than 7, or clinical stage T2b disease or higher; and (3) high-risk patients had 2 or 3 of these adverse risk factors (Long, 2001). 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 cryosurgery patients (Shinohara, 1996) and from 29% to 9% among a group treated with salvage cryosurgery for radiation failure (Pisters, 1997). 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 (Wong, 1997); another series reported a positive biopsy rate of only 2.5% by using 6-8 cryosurgery probes rather than the conventional 5 probes (Lee, 1999).

Biochemical failure

Initially, PSA levels following cryosurgery rise sharply and then fall, reaching a nadir within 3 months after treatment in most patients. Because this treatment modality does not ablate every gland in the prostate at the microscopic level, a persistently detectable PSA level following cryosurgery may not indicate persistent disease. The target nadir has not been established with as great a degree of certainty as that following surgery, but a clear correlation exists between the nadir achieved initially and the eventual disease progression. 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 (Shinohara, 1997). Similarly, positive biopsy rates were 1.5%, 10%, and 55% for 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 based on a PSA threshold of 0.5 ng/mL to define failure; rates were 76%, 71%, and 45% using a threshold of 1 ng/mL (Long, 2001). A report of cryosurgery 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 (Ellis, 2002). Prepelica et al recently reported a series of 65 men with high-risk prostate cancer, defined as PSA > 10 ng/mL and/or Gleason score > 8. They found an 83.3% bDFS rate based on the American Society for Therapeutic Radiology and Oncology (ASTRO) definition at median 35-month follow-up. Fifty percent of patients achieved a nadir PSA <4 ng/mL, and 35% achieved a nadir of <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 cryosurgery (Prepelica, 2005).
The largest 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 (2001) 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 (Bahn, 2002). 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 (Bahn, 2002).

Table 1 Outcomes of cryosurgery on prostate cancer

Salvage therapy
Patients who experience disease progression after radiation therapy have few options for potentially curative therapy. Cryosurgery 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. Recent 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 (Pisters, 1997), although these results came at the price of higher complication rates (Cespedes, 1997). 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 (Pisters, 1997).
A biochemical failure-free survival rate of 66% at 12 months was reported in a series of 43 salvage patients, with lower complication rates (De La Taille, Urology, 2000); additionally, a PSA nadir of more than 0.1 ng/mL following treatment predicted eventual recurrence (De La Taille, Urology, 2000). 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 (Ghafar, 2001).
In a large series, also using an argon-based system, 118 subjects with recurrent disease after radiation therapy underwent cryoablation, including 5 who had received permanent interstitial implants (Chin, 2001). Negative biopsy findings were reported in 94% of these patients; the 7 who had persistent disease received second ablation procedures. Ninety-seven percent had PSA nadirs less than 0.5 ng/mL; 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 (Chin, 2001). Preprocedure PSA levels of more than 10 ng/mL, Gleason scores of more than 8, and stage T3-T4 disease predicted biochemical failure.
Seven-year outcomes for 59 patients treated with cryosurgery for failure after radiation were recently reported (Bahn, 2003). 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 (Bahn, 2003).
Discussion
Standardization of cryosurgery
Developments in technology have rekindled interest in cryosurgery as a viable alternative to other, more standard local therapies. Outcomes have now been reported as late as 7 years following treatment and seem to compare favorably with contemporary series of patients with prostate cancer who receive radiation therapy, particularly with respect to late failure rates (Bahn, 2002) and among higher-risk patients (Long, 2001). Note, however, that even the largest cryosurgery 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 cryosurgery.
A number of improvements in technology and clinical algorithms may be expected to facilitate ongoing improvements in cryosurgery outcomes in terms of cancer control and quality of life.
Prostate parenchyma-sparing cryosurgery
It is suggested that prostate parenchyma-sparing cryosurgery may improve outcomes in terms of continence and potency. Despite the multifocal nature of prostate cancer, an analysis of 112 radical prostatectomy specimens 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 (Rukstalis, 2002). A similar approach in a small series of 9 patients treated with focal, unilateral nerve-sparing cryosurgery; 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 (Onik, 2002).

Unilateral cryosurgery
In a pilot program at the University of California at San Francisco, 8 patients with localized prostate cancer likewise have been treated with unilateral cryosurgery. 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.

Saline Injection Into Denonvilliers' Fascia
A major theoretical criticism of prostate cryosurgery involves the anatomy of the pelvis with the close proximity of the prostate capsule to the rectal mucosa. Inadequate space between the prostate and the rectum can result in freezing the rectal mucosa with resultant urethro-rectal fistula. Subsequently, fear of causing urethrorectal fistula may stop the freezing process prematurely (even if there is enough room for adequate freezing) and thus lead to a high incidence of tumor recurrence. Even for the experienced cryosurgeon, cryosurgery was at times a nerve-wracking balancing act between adequate treatment and rectal injury.

Probably the most important advance in the technique of prostate cryosurgery leading to the reproducibility of results involves the injection of saline into Denonvilliers' fascia at the time of freezing to temporarily increase the space between the rectum and prostate (Fig 3). This saline injection technique has used in more than 200 patients, demonstrating that this maneuver virtually eliminates the risk of rectal freezing and the complication of urethro-rectal fistula without increasing morbidity.It was demonstrated that in more than 25 patients that the procedure can be successfully applied in patients in whom radiation therapy has failed. [22]

Figure 3a-b. (A) This diagram shows a needle being placed into Denonvilliers' fascia at the time of cryosurgery. The rectum (R) is abutting the prostate capsule with Denonvilliers' fascia being a potential space. (B) Saline is injected into Denonvilliers' fascia and the space between the rectum and the prostate capsule has been artificially increased. This protects the rectum from freezing and allows adequate freezing beyond the prostate to encompass and cancer that has extended through the capsule.

The elimination of the fear of rectal freezing has several consequences that improve the effect results of cryosurgery. First, with the rectum protected, freezing can be sufficiently extended outside the prostate to bring the -35°C isotherm to the capsule of the prostate, thus ensuring adequate temperatures for cancer destruction everywhere within the prostate. The position of the -35°C temperature isotherm changes in relation to the freezing margin as the iceball grows, being closer to the freezing margin with smaller ice volumes. With more freezing room, cryoprobes can be placed farther into the peripheral zone of the gland, where 80% of cancers reside, making the destructive temperature zone easier to reach the capsule with less freezing volume. This also exposes these cancers to faster freezing rates and colder temperatures, both of which improve the cancer destruction. Second, freezing can be extended far enough outside the prostate to also include extracapsular extension of cancer, thereby improving the local control of cancer in high-risk patients. The arrangement of the cryoprobes can be placed into the posterior urethral region to encompass the confluence of the seminal vesicle, thus preventing recurrence in this region. Third, with this move of cryoprobes into the peripheral zone, the freezing of the periurethral tissue is adequate but less intense, which may decrease over time the rate of urethral sloughing.
Temperature Monitoring in Critical Areas and Improved Cryosurgical Protocols
For reliable destruction of cancer by freezing, temperatures must reach certain critical limits. At least two freeze-thaw cycles with temperatures reaching -35°C are needed to reliably destroy prostate cancer cells. [35] These parameters as well as the improvement that can occur in clinical results when temperature is monitored by thermocouples placed in critical areas in the prostate and two full freeze-thaw cycles are carried out. Wong et al [9] had 10 local failures in their first 12 cases with only ultrasound monitoring and six failures in the next 66 cases after thermocouple monitoring was carried out. They also demonstrated another major advantage of cryosurgery, ie, the ability to re-treat local failures. Using thermo-couple monitoring to re-treat their previous failures, a negative biopsy rate of 94% (72 of 77 patients) was achieved at 30 months.
Saliken et al [26] reported a similar experience involving 69 patients. Ten patients initially had positive biopsies, with the majority of them occurring early in their cryosurgical experience. Ultimately, after re-treatment, 68 (98%) of 69 patients had negative biopsies.
Argon-Based Cryosurgical Equipment
The original LN2-based freezing equipment has now been replaced by argon gas systems(Endocare,Joule-Thompson). These systems allow faster freezing rates, which improves the reliability of cancer destruction. The more precise control of the freezing process by gas systems also adds to the safety of the procedure by allowing the freezing process to be stopped in a more timely fashion.

Increasing the number of probes from 5 to 8 has allowed a more uniform freezing temperature to be achieved throughout the gland, which also improves results. Lee et al [36] showed an advantage to using 6-8 argon gas probes over 5 liquid nitrogen probes. Using re-treatment as an option, they achieved a negative biopsy rate of 96% (157 of 163 patients). Even with normal glands and residual PSA remaining after cryosurgery, this does not necessarily equate with treatment failure. Pisters et al [2] reported on 7 patients with locally advanced cancer who had cryosurgery followed by RP. In 4 patients who had no evidence of cancer in the gland, some normal glands were still identified.

Increasing the number of probes beyond 8 could have a potentially negative effect. A "cryoseed system" (Galil Medical Inc, Haifa, Israel) that utilizes 17-gauge needle probes to create a 1-cm diameter iceball was not able to totally ablate the prostate gland based on reported PSA results. [37] These poor results are probably the result of the short freezing length of these probes and the difficulty in accurately overlapping the freezing zones along the length of the gland. All of the data currently used to gain acceptance of cryosurgery was developed with cryosurgical probes that freeze the length of the gland in one freeze; departing from this concept jeopardizes much of what has been learned about how to obtain consistent results using cryosurgery.
Improvements of guiding techniques
Since the freezing capabilities of cryoprobes are predictable, planning software is already being developed to direct proper cryoprobe placement based on gland size and shape. Planning software will shortly be coupled to guidance software and hardware, which will simplify what now is a totally freehand approach to cryoprobe placement.
While ultrasound is inexpensive and readily available, it still is highly operator dependent and difficult to use by novices. Other cross-sectional imaging techniques such as magnetic resonance imaging (MRI) have the potential to simplify and standardize cryosurgical procedures. As opposed to ultrasound, where ice causes shadowing and shows only the leading edge of the iceball, both MRI and computed tomography (CT) show the full extent of the freezing (Fig 4). Using thermodynamic equations, these images can then be used to noninvasively calculate temperatures within the ice-ball (Fig 5) and automatically control the cryoprobes to create a specific freezing shape and profile (Fig 6).



Figure 4a-c. (A) Sagittal MRI of a dog prostate. The cryoprobe extends from the perineum of the dog into the anterior portion of the prostate. (B) Axial MRI of the dog prostate prior to freezing. The probe is seen as a dark circle in the anterior portion of the left side of the prostate. (C) Axial MRI of the dog during freezing. The freezing appears on the MRI as a dark signal void the freezing front (FF) extends into the prostate. Note that anterior margin of the freezing can also be seen and that the freezing is asymmetric with less freezing extending anteriorly due to the large amount of blood flow in the anterior venous complex. These details cannot be appreciated on ultrasound due to shadowing that occurs beyond the freezing front.

Figure 5. MRI of a jello phantom showing calculated temperatures within the iceball. The freezing has extended out from the probe with the edge of the freezing (FF) noted by the white line. The different shades of gray within the iceball represent the calculated temperatures within the iceball. The temperatures are calculated on a computer by knowing the position of the freezing front and cryoprobe from the MRI and the temperature of the cryoprobe tip. The temperatures can be represented on the image also as isothermal lines. Alternatively, a cursor can be placed before the freeze on a structure of interest, and the temperature at that point can be continuously displayed.

Figure 6. Computer control of freezing based on MRI imaging. In this diagram, freezing is followed in a jello phantom over time proceeding from image A through image I. The phantom is imaged as the white circle on the gray background. Three cryoprobes, the dark circles, have been placed within the phantom and are being imaged in cross-section in a triangular arrangement. The cryoprobes have been circled with an oddly shaped line, which represents the shape and extent of freezing that the computer will try to reproduce by turning the cryoprobes on and off appropriately. The computer modulates the ice shape based on feedback on the extent of freezing from the MRI image. As the iceball grows over time, the freezing from each probe eventually coalesces and reproduces as closely as possible the shape that was specified.
Combination therapy
Innovative combination therapy may also play a role in the future. Clarke et al recently reported in vitro data suggesting that the combination of 5-fluorouracil (5-FU) and cryosurgery 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-cryosurgery 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 (Clarke, 2001; Clarke, 2004). Other biological response modifiers, such as antifreeze proteins, may also improve the efficiency of the freezing process (Pham, 1999), as may improved imaging modalities.
Chao et al indicatd that the local use of TNF-alpha can dramatically increase the threshold temperature of cryo-destruction to human prostate cancer cells by more than 10 degrees C (p <0.01). It is known that vascular-mediated injury is responsible for defining the edge of the cryolesion in microvascular-perfused tissue, and therefore pre-induced inflammation can augment cryoinjury. The local use of TNF-alpha to pre-inflame prostate cancer promises to increase both the ability of freezing to destroy cancer as well as improve the ability of ultrasound or other iceball-monitoring techniques to predict the outcome of the treatment.

Chao BH, He X, Bischof JC.Pre-treatment inflammation induced by TNF-alpha augments cryosurgical injury on human prostate cancer. Cryobiology. 2004 Aug;49(1):10-27.

Conclusion
A major goal of prostate cancer research in general is the identification and development of pretreatment prognostic indicators based on biopsy tissue, serum, and/or urine, which can predict with better accuracy the likely natural history of a given patient's tumor. Patients with low risks of disease progression would be candidates for active surveillance alone, whereas those with more aggressive tumor characteristics could receive early, multimodal therapy. Given all the progress that has been made in the past decade, cryosurgery will likely play an increased role in the future management of prostate cancer.

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