Cryotherapy in Prostate Cancer Technique

Updated: Jul 24, 2020
  • Author: Matthew R Cooperberg, MD, MPH; Chief Editor: Edward David Kim, MD, FACS  more...
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Technique

Approach Considerations

The use of a cryotherapy system involves placement of cryoprobes under ultrasonographic guidance bilaterally in the anteromedial, posterolateral, and posteromedial regions of the gland, to the proximal extent of the prostatic capsule.

Cryotherapy exerts its antineoplastic effects via numerous proposed pathways, including 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 after treatment, as can residual indolent cancer. Hyalinization may be more prominent in more effectively treated prostates (ie, those with no residual cancer). [70]

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) maintained for 3 minutes is believed to be necessary for efficient tumor eradication. [24, 71, 72]

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Cryotherapy for Prostate Cancer

Cryotherapy may be performed with the patient in a lithotomy position and under general or regional anesthesia. Before the procedure, the patient undergoes 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.

With the use of a cryotherapy system, probes are placed into the prostate transperineally under TRUS guidance (see the image below). The 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.) As many as 30 such probes may be placed to achieve a more uniform freezing pattern. [10, 72]

Example of third-generation prostate cryotherapy s Example of third-generation prostate cryotherapy setup, illustrating urethral warming catheter, 2 percutaneous temperature probes, and 3 cryotherapy probes. (This case was a salvage case of focal treatment for an ultrasonographically visible lesion, so only 3 cryoprobes were required.)

Thermosensors are placed 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 guide wire for a urethral warmer (see the image below). Warm saline irrigation is started through the warmer.

Transrectal sonogram of the prostate illustrating Transrectal sonogram of the prostate illustrating placement of the cryoprobes and urethral-warming catheter.

With modern cryotherapy systems, the cryoprobes may be fixed in place by freezing each probe 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 (see the image below); therefore, the anterior probes must be activated first.

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

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 (see the image below). If tumor extracapsular extension is suspected, the ice is propagated further laterally on the involved side.

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

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. In vitro data suggest that the rapidity of freezing increases cytotoxicity within the ice ball margin and reduces damage beyond it. [73]

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 (see the image below).

Transrectal sonogram illustrating the ice ball now Transrectal sonogram 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.

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. [74]

After the second cycle, the cryoprobes or cannulas are removed. If large-bore cannulas 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.

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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 [75] and damages the cavernosal nerves responsible for erectile function. [76] This combined neurovascular insult results in impotence in 40-100% of treated patients, [12] 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. [12]

A pooled analysis of 975 patients treated at 5 institutions from 1993-1998 revealed an impotence rate of 93%. [13] 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. [77] In a large series, Jones et al noted that of patients who were potent at the time of therapy (29.5% of the cohort), only 25% returned to intercourse after treatment, and only 8.8% did without the use of medications or other assistance. [43]  A meta-analysis that included 12 studies showed that the pooled incidence rate of impotence in patients after cryotherapy was 27%; a subgroup analysis revealed that the incidence was higher in patients who received cryotherapy after failed primary radiotherapy (61%). [78]

Aggressive penile rehabilitation has a growing place in the management of erectile function after prostatectomy and may also have a role after cryotherapy. [79] For example, Ellis et al reported that a penile rehabilitation program resulted in recovery of erectile function after cryotherapy in 41% of patients at 1 year and 51% at 4 years. [41]

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 for whom erectile function is important.

One group of investigators 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. [80]

Incontinence

With incontinence, as with impotence, reported rates depend greatly on the definitions used and the assessment methods employed. Incontinence rates range from 4% [48] to 27% [81] in patients undergoing cryotherapy as primary treatment. Among the largest single series of patients who underwent primary cryotherapy, 4.3% required at least 1 urinary pad per day, and 11.6% had lesser degrees of incontinence. [12] Long et al reported a 7.5% incontinence rate. [13]

Among patients undergoing cryotherapy for salvage treatment after failure of radiation therapy, the prevalence of incontinence is higher, ranging from 7.9% [54] to 95.5%, [34] with rates of 20% [23] to 73% [16] in the largest series. Chin et al found that one third of the patients reporting incontinence had near-total or total incontinence. [23]

In a 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. [82]

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 weeks after treatment), 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%. [36] In another report, urethral warming reduced the rate of sloughing causing obstruction from 54% to 14%. [52] Data from a pooled analysis likewise revealed obstruction necessitating transurethral resection of the prostate (TURP) in 10% of patients undergoing urethral warming via an approved catheter versus 44% in other patients. [13]

In contemporary series, the overall rate of sloughing has ranged from 3.8% to 23% in patients receiving primary cryotherapy [47, 24, 50] and from 5% to 44% in those undergoing salvage treatment. [16, 53] In a large series of salvage cryotherapy, transurethral resection of sloughed tissue was necessary in 3.2% of patients. [55]

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 [24] ; therefore, resection must be as limited as possible.

Pelvic and rectal pain

Pelvic or rectal pain is reported by 1-11% of patients receiving primary cryotherapy [81, 50, 46] and 21-77% of those receiving salvage cryotherapy for radiation failure. [16, 34] The etiology of this pain is unclear but may include rectal wall ischemia, freezing of the pelvic floor musculature 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. [24]

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% [47, 83] to 3% [81] of primary cryotherapy patients. In their series of 590 cases, Bahn et al reported only 2 cases of fistula formation. [12] Long et al, likewise, reported a 0.5% rate of fistula formation among 975 patients, [13] and Jones et al reported a 0.4% rate among 1198 patients who underwent cryosurgery as primary therapy. [43]

Rates may be higher among salvage patients—up to 11% in one report. [13] In one large series of salvage cases, however, only 4 cases were reported among 118 patients. [23] In a subsequent series involving 279 salvage patients, the fistula rate was 1.2%. [55]

Rectourethral fistula may not develop until several months after treatment. Patients typically present with watery diarrhea or pneumaturia. The diagnosis is confirmed by means of voiding cystourethrography or computed tomography (CT).

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. [82]

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. [16, 34] This complication can usually be prevented by careful monitoring of the trigone and ureteral orifices during treatment with TRUS.

Small-bowel obstruction

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

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