Description
Cryoablation, also known as cryotherapy or cryosurgery, of prostate cancer is a technique in which cryoprobes are inserted percutaneously into the prostate gland to rapidly freeze and thaw tissue causing necrosis. This review evaluates evidence on the use of total (whole gland, definitive therapy) cryoablation. Subtotal (focal) cryoablation and alternative procedures are considered in evidence review 80161.

For individuals who are considering initial treatment for localized prostate cancer who receive whole gland cryoablation, the evidence includes several systematic reviews, 2 randomized controlled trials and many comparative and noncomparative observational studies. Relevant outcomes are overall survival, disease-specific survival, symptoms, functional outcomes, quality of life and treatment-related morbidity. High-quality data comparing cryoablation to external-beam radiotherapy, radical prostatectomy or active surveillance are lacking, but available data suggest similar overall survival and disease-specific survival rates compared to radical prostatectomy and external-beam radiotherapy. The evidence is sufficient to conclude that cryoablation leads to improvement in net health outcome. 

For individuals who need salvage treatment for recurrence of localized prostate cancer following radiotherapy who receive whole gland cryoablation, the evidence includes primarily noncomparative case series and a few retrospective studies comparing salvage cryoablation to salvage prostatectomy. Relevant outcomes are overall survival, disease-specific survival, symptoms, functional outcomes, quality of life and treatment-related morbidity. High-quality data comparing cryoablation to prostatectomy is mixed and evidence comparing cryotherapy to brachytherapy is lacking. Men in this group have few other options and prostatectomy can be difficult in tissue that has been irradiated. The evidence is sufficient to conclude that cryoablation leads to improvement in net health outcome.

Background 
Prostate Cancer
Prostate cancer is the most commonly diagnosed cancer and the third leading cause of cancer deaths among men in the United States, with an estimated 161,360 new cases and 26,730 deaths in 2017.¹ The diagnosis and grading of prostate cancer are performed by taking a biopsy of the prostate gland.

Treatment
Whole gland (also known as total) cryoablation is one of several methods used to treat clinically localized prostate cancer and may be considered an alternative to radical prostatectomy or external-beam radiotherapy. Additionally, whole gland cryoablation may be used for salvage of nonmetastatic relapse following initial therapy for clinically localized disease. Using percutaneously inserted cryoprobes, the glandular tissue is rapidly frozen and thawed to cause tissue necrosis. Cryosurgical ablation is less invasive than radical prostatectomy and recovery time may be shorter. External-beam radiotherapy requires multiple treatments, whereas cryoablation usually requires a single treatment.

Regulatory Status
Cryoablation of prostate cancer is a surgical procedure that uses previously approved and available cryoablation systems. As a surgical procedure, cryoablation of the prostate is not subject to FDA approval.

Related Policies
60110 Stereotactic Radiosurgery and Stereotactic Body Radiation Therapy
80114 Brachytherapy for Clinically Localized Prostate Cancer Using Permanently Implanted Seeds
80133 High-Dose Rate Temporary Prostate Brachytherapy
80147 Intensity-Modulated Radiotherapy of the Prostate
80161 Focal Treatments for Prostate Cancer

Policy
Cryoablation of the prostate may be considered MEDICALLY NECESSARY as treatment of clinically localized (organ-confined) prostate cancer when performed:

• As initial treatment or
• As salvage treatment of disease that recurs following radiation therapy.

Policy Guidelines
Coding
Please see the Codes table for details.

Benefit Application
BlueCard/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all devices approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational and, thus, these devices may be assessed only on the basis of their medical necessity.

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Primary Prostate Cryoablation
Clinical Context and Therapy Purpose
The purpose of whole gland cryoablation in patients considered initial treatment for localized prostate cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of whole gland cryoablation as initial treatment improve the net health outcomes in patients with localized prostate cancer?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals considering initial treatment for localized prostate cancer.

Interventions
The intervention of interest is cryoablation of the whole prostate gland. Cryoablation uses freezing to destroy tumor cells in a relatively noninvasive procedure, which can be conducted under spinal anesthesia.

Comparators
The following therapies and practices are currently being used to make decisions about localized prostate cancer: radiotherapy, radical prostatectomy, and active surveillance.

Outcomes
The general outcomes of interest are overall survival (OS), disease-free survival, cancer recurrence, and treatment-related adverse events (eg, sexual dysfunction, incontinence). Follow-up for treatment-related morbidity is months post-procedure. The follow-up to monitor for recurrence is measured in years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Gao et al. (2016) reported the results of a systematic review and meta-analysis comparing cryoablation with radiotherapy and radical prostatectomy for the treatment of localized prostate cancer.² The search included articles published up to December 2015. Because the pooled estimates combined primary and salvage treatment, the individual studies are presented in the following sections in lieu of pooled data here. Six studies described primary treatment (including the 2 RCTs described below,^3,4,5 2 prospective observational,^6,7 and 2 retrospective^8,9). Cryotherapy had a similar OS and disease-specific survival rate as radiotherapy and radical prostatectomy in trials of primary treatment. There was significantly more sexual bother for cryoablation (compared with radiotherapy) at all times reported (p < .01).

A network meta-analysis by Xiong et al. (2014) evaluated the comparative efficacy and safety of radical prostatectomy for several regimens of external beam radiotherapy (EBRT), cryoablation, and observational management.¹⁰ Evidence from 2005 to 2012 was included. This analysis incorporated evidence from 21 RCTs (N = 7350 patients) that reported on OS and prostate cancer-specific survival rates at 5 years, and late gastrointestinal (GI) and late genitourinary toxicities at 3 years. Reviewers used Bayesian network analysis with informative prior distributions based on external evidence for heterogeneity variances to compute odds ratios with 95% confidence intervals (CIs) for all pairwise comparisons of interventions. The rank order of superiority of each intervention was compared with all the others using the surface under the cumulative ranking (SUCRA) curve statistic. The SUCRA curve is expressed as a percentage that ranges from 0% if an intervention is certainly the worst to 100% if an intervention is certainly the best. If all interventions are equal, all SUCRA curve values will approximate a percentage of 50%. Overall, the network analysis showed no evidence of the superiority of any treatment for OS (based on SUCRA curve values that ranged from 18% [observational management] to 69% [conformal low-dose EBRT]). Cryoablation had a SUCRA curve value of 50%, which yielded a ranking of the fourth-best treatment. However, the SUCRA curve values for late GI (99%) and genitourinary (77%) events with cryoablation rated this intervention in first place for those specific outcomes. These analyses are consistent with a positive balance of benefits and harms associated with total cryoablation compared with radical prostatectomy, EBRT, and observational management.

Randomized Controlled Trials
Chin et al. (2008, 2012) reported on a randomized trial comparing cryoablation with EBRT in patients who had clinical stage T2C-T3B prostate cancer.^3,4 These patients had node-negative disease and had received 6 months of hormonal therapy, starting 3 months before treatment. Only 64 of the planned 150 patients were accrued; entry was limited due to changes in practice and difficulty beginning cryoablation at 1 of the sites. Twenty-one (64%) of 33 in the cryoablation group and 14 (45%) of 31 in the EBRT-treated group were classified as treatment failures. The mean biochemical disease-free survival (bDFS) was 41 months for the EBRT group and 28 months for the cryoablation group. The 4-year bDFS rate for the EBRT and cryoablation groups were 47% and 13%, respectively.³ The 8-year bDFS rate for the EBRT and cryoablation groups were 59.1% and 17.4%, respectively. Disease-specific survival rates and OS rates were very similar and, at the 8 year follow-up, the rates still did not differ significantly.⁴ Serious complications were uncommon in both groups. EBRT patients exhibited adverse GI effects more frequently. The trialists concluded that taking into account the relative deficiency in numbers and the original trial design, this prospective randomized trial indicated that the results of cryoablation were less favorable than those of EBRT and that cryoablation was suboptimal primary therapy in locally advanced prostate cancer.

Donnelly et al. (2010) reported on a randomized trial of 244 patients with newly diagnosed localized prostate cancer, during the period from 1997 through 2003, to compare cryoablation with EBRT.⁵ All patients began neoadjuvant androgen-deprivation therapy before local treatment and continued for a period of 3 to 6 months. The median follow-up was 100 months. At 36 months, the biochemical failure rate (prostate-specific antigen [PSA] nadir + 2 ng/mL) was 17.1% in the cryoablation group and 13.2% in the radiotherapy group. The OS rate at 5 years was 89.7% in the cryoablation group, and 88.3% in the radiotherapy group (p = .78). At 36 months, radiotherapy patients had significantly more positive prostate biopsies (22/76 patients) than the cryoablation group (7/91 patients; p < .001). Observed failure rates at 60 months were similar in both groups but were less likely with cryoablation at 84 months. Using the National Cancer Institute of Canada Common Toxicity Criteria, 12 cryoablation patients experienced 13, grade 3 adverse events versus 16, grade 3 adverse events in 14 radiotherapy patients. Urinary retention was the most common grade 3 adverse event in both treatment arms. The trialists were unable to establish that cryoablation was noninferior to radiotherapy at 36 months due to the wide CI. The trialists also noted several issues that limited interpretation of trial results, including the use of uncommonly low radiation dosages (68 gray, 70 gray, 73.5 gray, respectively), and early trial closure due to lack of patient enrollment.

In a second article from the Donnelly et al. (2010) trial,⁵ Robinson et al. (2009) reported on QOL outcomes in the same 244 patients.¹¹ With few exceptions, study participants reported QOL at high levels in both the cryoablation and radiotherapy treatment arms. Acute urinary dysfunction, which eventually resolved, occurred more often with cryoablation, as measured using the University of California at Los Angeles Prostate Cancer Index (mean urinary function after cryoablation was 69.4 vs. 90.7 after EBRT; p < .001; higher scores indicate better function and less bother). The University of California at Los Angeles Prostate Cancer Index sexual function decreased in both arms at 3 months. However, reduced sexual function was reported more frequently in the cryoablation arm (mean cryoablation, 7.2 vs. mean EBRT, 32.9; p < .001). Decreased sexual function continued at the 3-year evaluation, with the mean score 15 points lower in the cryoablation group.

Nonrandomized Comparative Studies
Many nonrandomized studies have assessed cryoablation for localized prostate cancer.^6-9,12-21 A sample is discussed here.

Aus (2008) reported that cryoablation using third-generation equipment and that long-term follow-up from these newer devices, which emerged around 2000, would be needed.²² The newer devices use more ultra-thin probes and argon gas (as opposed to liquid nitrogen) and create smaller ice balls. Lian et al. (2011) reported on early results of cryoablation using third-generation technology as a primary treatment for 102 patients with localized prostate cancer during the period of 2006 through 2009.²³ Only a single patient developed biopsy-confirmed prostate cancer recurrence. The PSA levels were elevated in 7 patients; however, biopsies were negative. Mild incontinence, urethral sloughing, and erectile dysfunction occurred in 4%, 4.9%, and 64% of patients, respectively.

Ball et al. (2006) reported on QOL outcomes on a subset of 719 patients with localized prostate cancer treated with various techniques including cryosurgical ablation.⁶ The authors reported that, in an older population, the tissue destruction resulting from cryoablation appeared to relieve obstructive and irritative urinary symptoms but at the sacrifice of sexual function compared with palladium 103 brachytherapy.

Registry Studies
Williams et al. (2012) compared data from the U.S. Surveillance, Epidemiology, and End Results Medicare-linked data on 10,928 patients with localized prostate cancer treated with primary cryoablation or brachytherapy.²⁴ Urinary and erectile dysfunction occurred significantly more frequently after cryoablation (41.4% and 34.7%) than brachytherapy (22.2% and 21%), respectively. Androgen-deprivation therapy was also used significantly more often after cryoablation than after brachytherapy, suggesting a higher rate of recurrence after cryoablation (1.4 vs. 0.5 per 100 person-years). Bowel complications, however, occurred significantly more frequently with brachytherapy (19%) than cryoablation (12.1%).

The Cryo Online Data Registry is a database established and supported by a cryoablation manufacturer. The data are maintained independently. Physicians submit standardized forms to the database and participation is voluntary. The Registry contains case report forms of pretreatment and posttreatment information for patients undergoing whole gland or partial gland (focal) prostate cryoablation. Patients are stratified into low-, intermediate-, and high-risk groups. Jones et al. (2008) reported the initial outcome for 1198 men with primary whole gland prostate cryoablation.²⁵ Mean follow-up was 24.4 months; 136 men had 5-year data. The 5-year bDFS rate (Phoenix definition) for the entire population was 73%; rates by category were 91%, 79%, and 62%, for the low-, intermediate-, and high-risk groups, respectively. The rectal fistula rate was 0.4%. Incontinence was reported by 5% of men, with 3% of men using pads. Twenty-five percent of men reported having sexual intercourse but only 9% did so without pharmaceutical or device assistance. Outcomes for 300 men in the Cryo Online Data Registry who underwent primary whole gland cryotherapy for high-grade (Gleason score ≥ 8), localized prostate cancer were published by Tay et al. (2016).²⁶ Mean follow-up was 28.4 months. The estimated 2- and 5-year bDFS rates were 77% (95% CI , 71% to 88%) and 59% (95% CI , 50% to 67%), respectively. At 12-month follow-up, complete continence was reported by 91% of men and potency by 17% of men. The incidence of recto-urethral fistulae was 1.3%. Urinary retention requiring intervention beyond temporary catheterization was reported by 3% of men.

Section Summary: Primary Prostate Cryoablation
Evidence for the use of whole gland cryoablation to treat localized prostate cancer comes from systematic reviews, 2 RCTs, and many comparative and noncomparative observational studies. The most recent systematic reviews have reported similar OS and disease-specific survival rates for whole gland cryoablation compared with radical prostatectomy and EBRT.

Salvage Prostate Cryoablation
Clinical Context and Therapy Purpose
The purpose of whole gland cryoablation in patients who have recurrent localized prostate cancer following radiotherapy is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of whole gland cryoablation improve the net health outcomes in patients with recurrence of localized prostate cancer following radiotherapy?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals in need of salvage treatment for recurrent localized prostate cancer after radiotherapy.

Interventions
The intervention of interest is cryoablation of the whole prostate gland. Cryoablation uses freezing to destroy tumor cells in a relatively noninvasive procedure, which can be conducted under spinal anesthesia.

Comparators
The following therapies and practices are currently being used to make decisions about recurrent localized prostate cancer: radical prostatectomy and brachytherapy.

Outcomes
The general outcomes of interest are OS, disease-free survival, cancer recurrence, and treatment-related adverse events (e.g., sexual dysfunction, incontinence). Follow-up for treatment-related morbidity is months post-procedure. The follow-up to monitor for recurrence is measured in years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
A health technology assessment by Ramsay et al. (2015),²⁷ identified 2 single-arm studies (Chin et al. [2001]²⁸; Robinson et al. [2006]²⁹) assessing salvage whole gland cryoablation. One study reported 1- and 4-year bDFS rates of 71% and 54%, respectively. Both reported functional outcomes. With a median follow-up of 19 months, the incontinence rate was 20%, bladder neck stenosis rate was 25%, and the recto-urethral fistula rate was 3%. The sexual dysfunction rate was 69% at 1 year and 52% at 2 years.

Mouraviev et al. (2012) reviewed the literature published between 1991 and 2012 to compare salvage cryoablation for radio-recurrent prostate cancer with other salvage treatments.³⁰ Reviewers found comparisons difficult to make because no prospective, randomized studies were identified and PSA failure was defined variously. However, they noted that studies had reported salvage cryoablation outcomes as being comparable to those for salvage radical prostatectomy (for an intermediate-term). The following criteria were identified as favorable prognostic factors for defining patients for salvage cryoablation: a PSA level less than 10 ng/mL, a Gleason score 8 or less, and a clinical-stage T1c or T2 before salvage cryoablation therapy.

Nonrandomized Comparative Studies
Peters et al. (2013) reported on results of retrospective data from 129 men from 5 Dutch centers.³¹ Forty-four men underwent salvage prostatectomy, 54 underwent salvage cryoablation, and 31 underwent salvage brachytherapy. The mean follow-up for each procedure was 29 months, 22 months, and 14 months, respectively. Biochemical failure occurred in 25 (81%) men in the brachytherapy group, 29 (66%) men in the prostatectomy group, and 33 (61%) men in the cryoablation group. Severe genitourinary and GI toxicity (grade > 3) using the Common Toxicity Criteria for Adverse events (v.3.0), definition was observed in up to 30% of patients in all 3 groups. There were 12 (27%), 5 (9%), and 14 (45%) deaths in the prostatectomy, cryoablation, and brachytherapy groups, respectively.

Case Series
Numerous case series have reported on the effect of salvage cryoablation for locally recurrent prostate cancer.^32-36 As results from these studies are generally consistent, only the most recent and largest studies with the longest follow-up are described below.

Chin et al. (2021) reported on mortality and morbidity in 268 men from 2 centers who underwent salvage cryoablation for locally recurrent prostate cancer following radiotherapy between 1992 and 2004.³² Median duration of follow-up was 124 months (interquartile range, 63 to 167 months). Overall survival rates at 5, 10, and 15 years were 90%, 77%, and 54%, respectively. Corresponding disease-specific survival rates were 94%, 81% and 70%. Initiation of neoadjuvant androgen deprivation therapy (ADT) during follow-up was associated with significantly better OS (hazard ratio [HR] 0.22; 95% CI 0.10 to 0.46) and disease-specific survival (HR 0.41; 95% CI 0.20 to 0.85) relative to no ADT. Development of castration-resistant prostate cancer occurred in 14%, 24%, and 26% of men at 5-, 10-, and 15-year follow-up. Incontinence was the most commonly reported adverse event during follow-up, reported by 55% of men, including 38% who reported mild or moderate incontinence and 16% reporting severe incontinence.

Wenske et al. (2013) reported on salvage cryoablation in a series of 396 consecutively treated patients who had failed cryoablation or radiotherapy.³³ Data were analyzed from 328 patients, with a median follow-up of 47.8 months (range, 1.6 to 203.5 months). Fifty-five (16.7%) of these patients received subtotal (focal) salvage cryoablation. At the 5- and 10-year follow-ups, disease-free survival rates were 63% and 35%, disease-specific survival rates were 91% and 79%, and OS rates were 74% and 45%, respectively. After salvage cryoablation, the median PSA nadir was 0.2 ng/mL (range, 0.01 to 70.70 ng/mL) at a median follow-up of 2.6 months (range, 2.0 to 67.3 months). The PSA nadir was the only predictor of recurrence (p < .001) and disease-specific survival (p = .012) based on multivariate analyses. Complications occurred in 0.6% to 4.6% of patients.

Registry Studies

Friedlander et al. (2014) compared salvage cryoablation with salvage radical prostatectomy in 440 men retrospectively identified in the U.S. Surveillance, Epidemiology, and End Results database who were treated between 1992 and 2009.³⁷ The authors used propensity score analyses to compare overall and prostate cancer-specific mortality. Overall mortality was significantly higher (21.6 vs. 6.1 deaths/100 person-years, p < .001) for prostatectomy than for cryoablation. Prostate cancer-specific death rates were numerically higher for prostatectomy than for cryoablation (6.5 vs. 1.4 deaths/100 person-years, p = .061).

Section Summary: Salvage Prostate Cryoablation
The evidence for the use of salvage prostate cryoablation in men with localized, recurrent prostate cancer following radiotherapy primarily includes case series and registry studies. Limited evidence from a single retrospective cohort study and one registry study suggests that salvage cryotherapy may be associated with better survival outcomes than prostatectomy, although confirmatory evidence from well-designed, prospective studies is lacking.

Summary of Evidence
For individuals who are considering initial treatment for localized prostate cancer who receive whole gland cryoablation, the evidence includes systematic reviews, 2 randomized controlled trials, and many comparative and noncomparative observational studies. Relevant outcomes are OS, disease-specific survival, symptoms, functional outcomes, QOL, and treatment-related morbidity. High-quality data comparing cryoablation with EBRT, radical prostatectomy, or active surveillance are lacking, but available data have suggested similar OS and disease-specific survival rates compared with radical prostatectomy and EBRT. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have salvage treatment for a recurrence of localized prostate cancer following radiotherapy who receive whole gland cryoablation, the evidence primarily includes case series and a few retrospective studies comparing salvage cryoablation with salvage prostatectomy or brachytherapy. Relevant outcomes are OS, disease-specific survival, symptoms, functional outcomes, QOL, and treatment-related morbidity. High-quality data comparing salvage cryoablation with salvage prostatectomy or brachtherapy are lacking, though limited evidence suggests that salvage cryotherapy may be associated with better survival outcomes than prostatectomy. Men with recurrent localized prostate cancer have limited treatment options and prostatectomy can be difficult in tissue that has been irradiated. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
In response to requests, input was received from 1 physician specialty society and 4 academic medical centers while this policy was under review in 2009. There was strong agreement that cryoablation should be considered medically necessary as an option in the initial treatment of organ-confined prostate cancer, as well as for use as salvage therapy for disease recurrence after radiotherapy.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Comprehensive Cancer Network
The National Comprehensive Cancer Network (NCCN) guidelines ( v.4 2022) for prostate cancer indicate cryosurgery and high-intensity focused ultrasound are options for radiotherapy recurrence in patients who have no evidence of metastatic disease.³⁸ NCCN does not recommend cryotherapy as routine primary therapy for localized prostate cancer due to limited long-term data comparing cryotherapy with radiation or radical prostatectomy.

American Urological Association et al.
In 2022, the American Urological Association and the American Society for Radiology Oncology issued a joint, updated guideline on the treatment of clinical localized prostate cancer; the guideline was additionally endorsed by the Society of Urologic Oncology.³⁹ In the guideline, treatment recommendations are stratified according to risk group, and ablative techniques are discussed in general with no recommendations specific to whole-gland cryoablation (Table 1).

Table 1. Treatment Recommendations Related to Cryoablation by Prostate Cancer Risk Group

Severity/Risk Group	Risk Definition	Treatment Recommendation	LOE	GOE	Clinical Considerations
Low-risk disease	PSA < 10 ng/mL AND Grade Group 1 AND clinical stage T1-T2a	For patients with low-risk prostate cancer, clinicians should recommend active surveillance as the preferred management option.	Strong	A	The Panel believes that the benefits of aggressive treatment do not outweigh the risk of treatment-related harms for most patients with low-risk disease. The Panel acknowledges that select patients with low-risk disease may elect definitive local therapy after an informed discussion between clinician and patient.
Intermediate-risk disease	PSA 10 – < 20 ng/mL OR Grade Group 2-3 OR clinical stage T2b-c	Clinicians should inform patients with intermediate-risk prostate cancer considering whole gland or focal ablation that there are a lack of high-quality data comparing ablation outcomes to radiation therapy, surgery, and active surveillance.	Expert opinion	¯	The Panel believes that ablation may be considered in select, appropriately informed patients (with clinical trial enrollment prioritized). Patients considering ablation should be counseled regarding side effects and recurrence risk and should be followed post-ablation with PSA, DRE, MRI, and biopsy tailored to their specific health and cancer characteristics.
High-risk disease	PSA > 20 ng/mL OR Grade Group 4-5 OR clinical stage T3	Clinicians should not recommend whole gland or focal ablation for patients with high-risk prostate cancer outside of a clinical trial.	Expert opinion	¯	There is a lack of data supporting treatment of high-risk disease with ablation.

DRE: digital rectal exam; GOE: grade of evidence; HIFU: high-intensity focused ultrasound; LOE: level of evidence; MRI: magnetic resonance imaging; PSA: prostate-specific antigen.

U.S. Preventive Services Task Force Recommendations
A systematic review of localized prostate cancer treatments was prepared by Fenton et al. (2018) for the Agency for Healthcare Research and Quality, updating the 2002 U.S. Preventive Services Task Force recommendation.⁴⁰ Reviewers found no studies comparing cryoablation with watchful waiting and no randomized trials or cohort studies evaluating overall survival or prostate cancer-specific mortality outcomes. The available evidence was mostly from uncontrolled studies, found to be very limited, and not sufficiently reliable to estimate the benefits or harms of cryoablation.

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 3.

Table 3. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT01727284	Technical Success, Safety, and Short and Long-Term Efficacy for MR-Guided Cryoablation of Prostate Bed Recurrences	100	Dec 2023
Unpublished
NCT01398657	Cryotherapy With or Without Short-term Adjuvant Androgen-Deprivation Therapy for High-Risk Localized Prostate Cancer — Open-Label Randomized Clinical Study	182	Jun 2016 (Unknown; last updated Nov 2012)
NCT02615223	A Prospective Multi-Center Study to Compare the QOL and Efficacy of Endocrine Therapy with or without Cryoablation for Stage IV Prostate Cancer	120	Dec 2018 (Unknown; last updated Jun 2017)
NCT02605226	A Prospective Multi-Center Study to Compare the QOL and Efficacy of External Beam Radiation Therapy or Cryoablation Therapy for Stage III Prostate Cancer (CRYO-PCA-III)	240	Dec 2018 (Unknown; last updated Jun 2017)
NCT03348722	START (Active Surveillance or Radical Treatment for Newly Diagnosed Patients with a Localized, Low Risk, Prostate Cancer): an Epidemiological Study of the Oncology Network of Piemonte and Valle d'Asosta, Italy	3000	Nov 2019 (Unknown; last updated Nov 2017)

NCT: national clinical trial.

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13. Donnelly BJ, Saliken JC, Ernst DS, et al. Prospective trial of cryosurgical ablation of the prostate: five-year results. Urology. Oct 2002; 60(4): 645-9. PMID 12385926
14. Ellis DS. Cryosurgery as primary treatment for localized prostate cancer: a community hospital experience. Urology. Aug 2002; 60(2 Suppl 1): 34-9. PMID 12206846
15. Long JP, Bahn D, Lee F, et al. Five-year retrospective, multi-institutional pooled analysis of cancer-related outcomes after cryosurgical ablation of the prostate. Urology. Mar 2001; 57(3): 518-23. PMID 11248631
16. Onik G. Image-guided prostate cryosurgery: state of the art. Cancer Control. Nov-Dec 2001; 8(6): 522-31. PMID 11807422
17. Robinson JW, Donnelly BJ, Saliken JC, et al. Quality of life and sexuality of men with prostate cancer 3 years after cryosurgery. Urology. Aug 2002; 60(2 Suppl 1): 12-8. PMID 12206843
18. Aus G, Pileblad E, Hugosson J. Cryosurgical ablation of the prostate: 5-year follow-up of a prospective study. Eur Urol. Aug 2002; 42(2): 133-8. PMID 12160583
19. De La Taille A, Benson MC, Bagiella E, et al. Cryoablation for clinically localized prostate cancer using an argon-based system: complication rates and biochemical recurrence. BJU Int. Feb 2000; 85(3): 281-6. PMID 10671882
20. Han KR, Cohen JK, Miller RJ, et al. Treatment of organ confined prostate cancer with third generation cryosurgery: preliminary multicenter experience. J Urol. Oct 2003; 170(4 Pt 1): 1126-30. PMID 14501706
21. Prepelica KL, Okeke Z, Murphy A, et al. Cryosurgical ablation of the prostate: high risk patient outcomes. Cancer. Apr 15 2005; 103(8): 1625-30. PMID 15747374
22. Aus G. Cryosurgery for prostate cancer. J Urol. Nov 2008; 180(5): 1882-3. PMID 18801502
23. Lian H, Guo H, Gan W, et al. Cryosurgery as primary treatment for localized prostate cancer. Int Urol Nephrol. Dec 2011; 43(4): 1089-94. PMID 21475948
24. Williams SB, Lei Y, Nguyen PL, et al. Comparative effectiveness of cryotherapy vs brachytherapy for localised prostate cancer. BJU Int. Jul 2012; 110(2 Pt 2): E92-8. PMID 22192688
25. Jones JS, Rewcastle JC, Donnelly BJ, et al. Whole gland primary prostate cryoablation: initial results from the cryo on-line data registry. J Urol. Aug 2008; 180(2): 554-8. PMID 18550117
26. Tay KJ, Polascik TJ, Elshafei A, et al. Primary Cryotherapy for High-Grade Clinically Localized Prostate Cancer: Oncologic and Functional Outcomes from the COLD Registry. J Endourol. Jan 2016; 30(1): 43-8. PMID 26414656
27. Ramsay CR, Adewuyi TE, Gray J, et al. Ablative therapy for people with localised prostate cancer: a systematic review and economic evaluation. Health Technol Assess. Jul 2015; 19(49): 1-490. PMID 26140518
28. Chin JL, Pautler SE, Mouraviev V, et al. Results of salvage cryoablation of the prostate after radiation: identifying predictors of treatment failure and complications. J Urol. Jun 2001; 165(6 Pt 1): 1937-41; discussion 1941-2. PMID 11371885
29. Robinson JW, Donnelly BJ, Coupland K, et al. Quality of life 2 years after salvage cryosurgery for the treatment of local recurrence of prostate cancer after radiotherapy. Urol Oncol. Nov-Dec 2006; 24(6): 472-86. PMID 17138127
30. Mouraviev V, Spiess PE, Jones JS. Salvage cryoablation for locally recurrent prostate cancer following primary radiotherapy. Eur Urol. Jun 2012; 61(6): 1204-11. PMID 22421081
31. Peters M, Moman MR, van der Poel HG, et al. Patterns of outcome and toxicity after salvage prostatectomy, salvage cryosurgery and salvage brachytherapy for prostate cancer recurrences after radiation therapy: a multi-center experience and literature review. World J Urol. Apr 2013; 31(2): 403-9. PMID 22903773
32. Chin JL, Lavi A, Metcalfe MJ, et al. Long-Term Outcomes of Whole Gland Salvage Cryotherapy for Locally Recurrent Prostate Cancer following Radiation Therapy: A Combined Analysis of Two Centers. J Urol. Sep 2021; 206(3): 646-654. PMID 33908799
33. Wenske S, Quarrier S, Katz AE. Salvage cryosurgery of the prostate for failure after primary radiotherapy or cryosurgery: long-term clinical, functional, and oncologic outcomes in a large cohort at a tertiary referral centre. Eur Urol. Jul 2013; 64(1): 1-7. PMID 22840351
34. Williams AK, Martinez CH, Lu C, et al. Disease-free survival following salvage cryotherapy for biopsy-proven radio-recurrent prostate cancer. Eur Urol. Sep 2011; 60(3): 405-10. PMID 21185115
35. Ng CK, Moussa M, Downey DB, et al. Salvage cryoablation of the prostate: followup and analysis of predictive factors for outcome. J Urol. Oct 2007; 178(4 Pt 1): 1253-7; discussion 1257. PMID 17698104
36. Ismail M, Ahmed S, Kastner C, et al. Salvage cryotherapy for recurrent prostate cancer after radiation failure: a prospective case series of the first 100 patients. BJU Int. Oct 2007; 100(4): 760-4. PMID 17662081
37. Friedlander DF, Gu X, Prasad SM, et al. Population-based comparative effectiveness of salvage radical prostatectomy vs cryotherapy. Urology. Mar 2014; 83(3): 653-7. PMID 24581527
38. National Comprehensive Cancer Network. Prostate Cancer. Version 4.2022. https://www.nccn.org/store/login/login.aspx?ReturnURL = https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf Accessed June 15, 2022.
39. American Urological Association (AUA). Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline. 2022; https://www.auanet.org/documents/Guidelines/PDF/Localized%20Prostate%20Cancer%20Guideline%20050922.pdf Accessed June 15, 2022.
40. Fenton JJ, Weyrich, MS, Durbin S, et al. U.S. Preventive Services Task Force. Evidence Summary for Prostate Cancer Screening. https://www.uspreventiveservicestaskforce.org/uspstf/document/evidence-summary/prostate-cancer-screening. Accessed June 15, 2022.
41. Centers for Medicare & Medicaid Services. National Coverage Determination (NCD) for Cryosurgery of Prostate (230.9). 2001; https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId = 123&ncdver = 1&bc = AAAAQAAAAAAA&. Accessed June 15, 2022

Coding Section

Codes	Number	Description
CPT	55873	Cryosurgical ablation of the prostate (includes ultrasonic guidance for interstitial cryosurgical probe placement)
HCPCS
ICD-10-PCS	C61	Malignant neoplasm of prostate
	C79.82	Secondary malignant neoplasm of genital organs
	D07.5	Carcinoma in situ prostate
	Z85.46	Personal history malignant neoplasm of prostate
ICD-10-PCS		ICD-10-PCS codes are only used for inpatient services; there is no specific ICD-10-PCS code for this procedure
	0V500ZZ, 0V503ZZ,0V504ZZ	Surgical, destruction, prostate, code by approach (open, percutaneous, percutaneous endoscopic)
Type of service	Surgery
Place of service	Inpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2014 Forward     

05/03/2023	Annual review, no change to policy intent. Updating rationale and references.
05/12/2022	Annual review, no change to policy intent. Updating rationale and references.
05/07/2021	Annual review, no change to policy intent. Updating guidelines, coding, rationale and references.
05/01/2020	Annual review, updating rationale and references. No change to policy intent.
05/01/2019	Annual review, no change to policy intent. Updating background, rationale and references.
05/16/2018	Annual review, no change to policy intent. Adding guidelines, updating rationale and references.
05/17/2017	Annual review, no change to policy intent. Updating background, description, rationale and references.
05/11/2016	Annual review, no change to policy intent. Updating regulatory status and related policies.
06/15/2015	Interim review, will change review month to June. Removing the following verbiage "Subtotal prostate cryoablation is considered INVESTIGATIONAL in the treatment of prostate cancer." as a new CAM policy is being generated to address focal treatment of prostate cancer. Also updated title, background, description, rationale and references.
06/01/2015	Annual review, no change to policy intent. Updating background, description, rationale and references. Adding coding.
05/26/2014	Annual review. Added related policies. Updated rationale and references. No change to policy intent.