Coverage Policy Manual
Policy #: 2015016
Category: Radiology
Initiated: May 2015
Last Review: November 2018
  Focal Treatments for Prostate Cancer

Description:
Prostate cancer is the second most common cancer diagnosed among men in the United States. Given the frequent uncertainty in predicting behavior of individual localized prostate cancers, and the substantial adverse effects associated with whole-gland treatments, investigators have sought to minimize morbidity associated with radical treatment while reducing tumor burden to an extent that reduces the chances for rapid progression to incurability. This approach is termed “focal treatment”. Focal treatment seeks to ablate either an “index” lesion (defined as the largest cancerous lesion with the highest grade tumor thought to be the lesion that will drive the natural history of this typically multifocal disease), or, alternatively, to ablate additional non-index lesions or all other areas of known cancer. Several ablative methods which have been used to remove cancerous lesions in localized prostate cancer are addressed in this Policy.
 
Five ablative methods are considered in this Policy: focal laser ablation (FLA); high-intensity focused ultrasound (HIFU); cryoablation; radiofrequency thermal ablation (radiofrequency ablation, RFA); and, photodynamic therapy (PDT). All of these methods currently rely on ultrasound guidance to the tumor focus of interest.
 
No comparative evidence is available that assesses the use of the focal ablation techniques addressed in this Policy versus current standard treatment of prostate cancer, and therefore, no conclusions can be drawn between outcomes of focal therapies versus radical treatments versus active surveillance. In addition, no studies have been conducted that examine which, if any, of the focal techniques leads to better functional and oncologic outcomes. The body of evidence on the use of focal therapies for localized prostate cancer comprises case series or other observational studies; they are highly heterogeneous and inconsistently report clinical outcomes. Although high cancer-specific survival rates have been reported, the short follow-up periods and small sample sizes preclude conclusions on the effectiveness of any of these techniques. In addition, there is no standardization as to which and how many identified cancerous lesions should be treated. Although the adverse effect rates associated with focal therapies appear to be superior to those associated with radical treatments such as radical prostatectomy or external beam radiation therapy (EBRT), the evidence is limited in its reporting and scope. Therefore, the use of any focal therapy modality to treat patients with localized prostate cancer is considered investigational.
 
Regulatory Status
 
Focal Laser Ablation
The Visualase® Thermal Therapy System was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process. It is indicated for use to necrotize or coagulate soft tissue through interstitial irradiation or thermal therapy under magnetic resonance imaging (MRI) guidance in cardiothoracic surgery, dermatology, otolaryngology, gastroenterology, general surgery, gynecology, head and neck surgery, neurosurgery, plastic surgery, orthopedics, pulmonology, radiology and urology, for wavelengths 800 nm to 1064 nm. FDA product code: LLZ, GEX, FRN.
 
High-Intensity Focused US
On July 31, 2014, the FDA advisory panel voted not to recommend approval of the Ablatherm® Integrated Imaging High Intensity Focused Ultrasound.51 This device would be the first of its kind to be approved in the United States. It failed to obtain FDA marketing approval at this time because members of the Gastroenterology and Urology Panel of FDA’s Advisory Committee voiced a number of concerns about the lack of available data from the technology sponsor’s research results that were presented as part of FDA’s premarket approval (PMA) process.
 
Cryotherapy
Some of the cryotherapy devices that are cleared for marketing by FDA through the 510(k) process for cryoablation of the prostate are: Visual-ICE® (Galil Medical), Ice Rod CX, CryoCare® (Galil Medical), and IceSphere (Galil Medical). FDA product code: GEH.
 
Radiofrequency Ablation
Radiofrequency ablation devices have been cleared through the 510(k) process by FDA for the general use of soft tissue cutting and coagulation and ablation by thermal coagulation. Under this general indication, RFA may be used as a method to ablate tumors. FDA product code: GEI.
 
Photodynamic Therapy
FDA has granted approvals to several photosensitizing drugs and light applicators. Photofrin® (porfimer sodium) and psoralen are photosensitizers used in the treatment of cancer. FDA has cleared ultraviolet lamps through the 510(k) process. FDA product code: FTC.
 
Coding
There is no specific CPT code for these treatments. It is likely they are reported with CPT code 53899 unlisted procedure, urinary system or CPT code 55899 unlisted procedure, male genital system.
 
Cryosurgical Ablation of Prostate Cancer is addressed in a separate policy # 2003002.
  

Policy/
Coverage:
Focal Treatment for Prostate Cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria Focal Treatment for Prostate Cancer is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 

Rationale:
Localized Prostate Cancer and Current Management
Prostate cancer is the second most common cancer diagnosed among men in the United States. According to the National Cancer Institute (NCI), nearly 240,000 new cases are expected to be diagnosed in the United States in 2013 and are associated with around 30,000 deaths. Autopsy studies in the pre-PSA screening era have identified incidental cancerous foci in 30% of men 50 years of age, with incidence reaching 75% at age 80 years (Dall’Era, 2008). However, NCI Surveillance Epidemiology and End Results data show age-adjusted cancer-specific mortality rates for men with prostate cancer have declined from 40 per 100,000 in 1992 to 22 per 100,000 in 2010. This decline has been attributed to a combination of earlier detection via prostate specific antigen (PSA) screening and improved therapies.
 
Localized prostate cancers may appear very similar clinically at diagnosis (Bangma, 2007). However, they often exhibit diverse risk of progression that may not be captured by accepted clinical risk categories (eg, D’Amico criteria) or prognostic tools that are based on clinical findings, including PSA titers, Gleason grade, or tumor stage (Johansson, 2004; Ploussard, 2011; Harnden. 2008; Brimo, 2012; Eylert, 2012). In studies of conservative management, the risk of localized disease progression based on prostate cancer-specific survival rates at 10 years may range from 15% (Eastham, 2008; Bill-Axelson, 2005), to 20% (Thompson, 2013) to perhaps 27% at 20-year follow-up (Albertsen, 2005). Among elderly men (≥70 years) with this type of low-risk disease, comorbidities typically supervene as a cause of death; these men will die with prostate cancer present, rather than from the cancer. Other very similar-appearing low-risk tumors may progress unexpectedly rapidly, quickly disseminating and becoming incurable.
 
The divergent behavior of localized prostate cancers creates uncertainty whether or not to treat immediately (Borley, 2009; Freedland, 2011). A patient may choose definitive treatment upfront (Ip, 2011). Surgery (radical prostatectomy), or EBRT are most commonly used to treat patients with localized prostate cancer (Freedland, 2011; Thompson, 2007). Complications most commonly reported with radical prostatectomy or EBRT and with the greatest variability are incontinence (0%-73%) and other genitourinary toxicities (irritative and obstructive symptoms); hematuria (typically ≤5%); gastrointestinal and bowel toxicity, including nausea and loose stools (25%-50%); proctopathy, including rectal pain and bleeding (10%-39%); and erectile dysfunction, including impotence (50%-90%) (Thompson, 2007).
 
American Urological Association (AUA) guidelines suggest patients with low- and intermediate-risk disease have the option of entering a “active surveillance” protocol, that takes into account patient age, patient preferences, and health conditions related to urinary, sexual, and bowel function (Thompson, 2007). With this approach the patient will forgo immediate therapy, but continue regular monitoring until signs or symptoms of disease progression are evident, at which point curative treatment is instituted (Whitson, 2010; Albertsen, 2010).
 
Focal Treatment of Localized Prostate Cancer
Given the uncertainty in predicting behavior of individual localized prostate cancers, and the substantial adverse effects associated with definitive treatments in patients with such disease, investigators have sought a middle ground that seeks to minimize morbidity associated with radical treatment in those who may not actually require it while reducing tumor burden to an extent that reduces the chances for rapid progression to incurability. This approach is termed “focal treatment,” in that it seeks to remove - using any of several ablative methods described next in the Background of this Policy - cancerous lesions at high risk of progression, leaving behind uninvolved glandular parenchyma. The overall goal of focal treatment is to minimize the risk of early tumor progression and preserve erectile, urinary and rectal functions by reducing damage to the neurovascular bundles, external sphincter, bladder neck and rectum (Jacome-Pita, 2014; Nguyen, 2011; Lindner, 2011; Iberti, 2011; Lecornet, 2010). Although focal treatment is offered as an alternative middle approach to management of localized prostate cancer, several key issues must be considered in choosing it. These include patient selection, lesion selection, therapy monitoring, and the modality used to ablate lesions.
 
A proportion of men with localized prostate cancer have been reported to have, or develop, serious misgivings and psychosocial problems in accepting active surveillance, sometimes leading to inappropriately discontinuing it (Tay, 2015). Thus, appropriate patient selection is imperative for physicians who must decide whether to recommend active surveillance or focal treatment for individual patients who refuse radical therapy or for whom it is not recommended due to the adverse balance of certain harms with unclear long-term benefit (Passoni, 2014).
 
Proper lesion selection is a second key consideration in choosing to undertake focal treatment of localized prostate cancer. Although prostate cancer has always been regarded as a multifocal disease, clinical evidence shows that between 10% and 40% of men who undergo radical prostatectomy for presumed multifocal disease actually have a unilaterally confined discrete lesion which when removed would “cure” the patient (Scales, 2007; Mouraviev, 2007a; Mouravie, 2007b). This view presumably drove the use of region-targeted focal treatment variants, such as hemi-ablation of the half of the gland containing tumor, or subtotal prostate ablation via the “hockey stick” method (Muto, 2008). While these approaches could be curative, the more extensive the treatment, the more likely the functional adverse outcomes would approach those of radical treatments.
 
The concept that clinically indolent lesions usually comprise most of the tumor burden in a patient with organ-confined prostate cancer led to development of the lesion-targeted strategy, which is referred to as “focal therapy” in this Policy (Kasivisvanathan, 2013). This involves treating only the largest and highest grade tumor (referred to as the “index lesion”), which has been shown in pathologic studies to determine clinical progression of disease (Mouraviev, 2011; Mouraviev, 2009). This concept is supported by molecular genetics evidence that suggests a single index tumor focus is usually responsible for disease progression and metastasis (Liu, 2009; Guo, 2012). The index lesion approach leaves in place small foci less than 0.5 cm3 in volume, with Gleason score less than 7 that are considered unlikely to progress over a 10- to 20-year period (Ahmed, 2008; Stamey, 1993; Nelson, 2006). This also leaves available subsequent definitive therapies as needed should disease progress.
 
Identification of prostate cancer lesions - disease localization - particularly the index lesion, is critical to oncologic success of focal therapy. The ability to guide focal ablation energy to the tumor, and assess treatment effectiveness, are additionally important to treatment success. At present, no single modality meets the requirements for all three activities (Passoni. 2014; Kasivisvanathan, 2013). Systematic transrectal ultrasound (TRUS)‒guided biopsy alone has been investigated, but is considered insufficient for the purpose of patient selection and disease localization for focal therapy (van den, 2014; Mayes, 2011; Sinnott, 2012; Gallina, 2012; Briganti, 2012). A 5mm transperineal prostate mapping (TPM) biopsy using a brachytherapy template is the current recommended standard by the European Association of Urology in their 2012 guidelines (Heidenreich, 2015). TPM can provide 3-dimensional coordinates of cancerous lesions, and has about 87% to 95% accuracy rates in detecting and ruling out clinically significant cancer of all sizes (Crawford, 2013; Hu. 2012). However, TPM is resource intensive, requires general anesthesia, and has been associated with adverse events including urinary retention (6%), prostatitis (4%), and local events such as perineal hematoma, bruising or pain (5%) (Tisvian, 2013). The risks of complications of general anesthesia, and the cost of processing multiple biopsy specimens, have been considered to limit the practicality and widespread applicability of this approach (Tay, 2015).
 
Multi-parametric magnetic resonance imaging (mp-MRI), typically including T1, T2, diffusion-weighted imaging and dynamic contrast-enhanced imaging, has been recognized as a promising modality to risk-stratify prostate cancer and select patients and lesions for focal therapy (Tay, 2015; Kasivisvanathan, 2013; van den, 2014). Evidence is available to show mp-MRI can detect high grade, large prostate cancer foci with performance similar to TPM (Arumainayagam, 2013). In this cohort study, for the primary end point definition (lesion, ≥4 mm; and Gleason score, ≥3+4), with TPM as the reference standard, sensitivity, negative predictive value, and negative likelihood ratios with mp-MRI were 58% to 73%, 84% to 89%, and 0.3 to 0.5, respectively. Specificity, positive predictive value, and positive likelihood ratios were 71% to 84%, 49% to 63%, and 2.0 to 3.44, respectively. The negative predictive value of mp-MRI appears sufficient to rule out clinically significant prostate cancer and may have clinical use in this setting. However, although mp-MRI technology has capability to detect and risk-stratify prostate cancer, several issues constrain its widespread use for these purposes. Thus, it is still necessary to histologically confirm suspicious lesions using TPM; mp-MRI requires highly specialized MRI-compatible equipment; biopsy within the MRI scanner is challenging; and, interpretation of prostate MRI images requires experienced uro-radiologists (Dickinson, 2011).
 
Some controversy exists as to the proper end points for focal therapy of prostate cancer. The primary end point of focal ablation of clinically significant disease with negative biopsies evaluated at 12 months after treatment is generally agreed on according to a European consensus report (van den, 2014). The clinical validity of MRI to analyze the presence of residual or recurrent cancer compared with histologic findings is offered as a secondary end point. However, MRI findings alone are not considered sufficient in follow-up. Finally, although investigators indicate PSA levels should be monitored, they are not considered as valid end points because the utility of PSA kinetics in tissue preservation treatments has not been established (Ahmed, 2008).
 
Methods Used for Focal Treatment of Localized Prostate Cancer
Five ablative methods for which clinical evidence is available are considered in this Policy: FLA; HIFU; cryoablation; RFA; and PDT (Jacome-Pita, 2014; Nguyen, 2011; Iberti, 2011; Lecornet, 2010; Muto, 2008; Kasivisvanathan, 2013; Ahmed, 2008; van den, 2014; NICE, 2012a, NICE, 2012b). Each method requires placement of a needle probe within a tumor volume followed by delivery of some type of energy that causes destruction of the tissue in a controlled manner. All of these methods currently rely on ultrasound guidance to the tumor focus of interest.
 
Focal laser ablation refers to the destruction of tissue using a focused beam of electromagnetic radiation emitted from a laser. It is accomplished through transperineal or transrectal introduction of a laser fiber into the cancer focus, with emission of energy. Tissue is destroyed by FLA through thermal conversion of the focused electromagnetic energy into heat, causing coagulative necrosis. Other terms for FLA include photothermal therapy, laser interstitial therapy, and laser interstitial photocoagulation (Lee, 2014).
 
High-intensity focused ultrasound (US) works by focusing high-energy US waves on a single location, which increases the local tissue temperature to over 80°C. This causes a discrete locus of coagulative necrosis of approximately 3 x 3 x 10 mm. The surgeon uses a transrectal probe to plan, carry out, and monitor treatment in a real-time sequence to ablate the entire gland, or small discrete lesions.
 
Cryoablation induces cell death through direct cellular toxicity from disruption of the cell membrane caused by ice-ball crystals and vascular compromise from thrombosis and ischemia secondary to freezing below -30°C. It is performed by transperineal insertion under TRUS guidance of a varying number of cryoprobe needles into the tumor, using a TPM template.
 
 
Radiofrequency thermal ablation (RFA) uses energy produced by a 50-watt generator with a frequency of 460 kHz. The energy is transmitted to the tumor focus through 15 needle electrodes inserted transperineally under US guidance into the tissue. It produces an increase in tissue temperature causing coagulative necrosis.
 
PDT involves the use of an intravenous photosensitizing agent that distributes to prostate tissue, followed by delivery of light via transperineally inserted needles. The light induces a photochemical reaction that causes production of reactive oxygen species that are highly toxic and reactive with tissue causing functional and structural damage, hence cell death. A major concern with PDT is that real-time monitoring of tissue effects is not possible, and the variable optical properties of prostate tissue complicate assessment of necrosis and treatment progress.
 
Systematic Review
A recent, high-quality systematic review (SR) published by Valerio et al in 2014 compiles the bulk of evidence available in the literature on the technologies included in this Policy.52 This SR was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Liberati, 2009). Only studies that reported actual focal-therapy outcomes were included. Specific categories of data to be collected were prespecified. The electronic database searches for this SR included MEDLINE, EMBASE, Web of Science, and the Cochrane Review database. The search strategy was well-documented, dating from inception of each database through October 31, 2012. Study selection criteria were prespecified, with dual review and data extraction, and senior author arbitration as needed. The quality of included studies was assessed according to the Oxford Centre for Evidence-based Medicine level of evidence for therapy. This SR and its summarized statistics serve as the basis for this Policy. Because no evidence exists to directly compare focal treatments, individual studies are not reported in detail, nor are ablative methods discriminated.
 
A total of 25 series were included that evaluated focal therapy in the primary setting. The quality of evidence was low to medium, with no study yielding a level of evidence greater than 2b (individual cohort study). Twelve series used high-intensity focused ultrasound (HIFU) (N=226); 6 series (N=1400) used cryoablation (1 study included 1160 of the 1400); 3 used focal laser ablation (FLA) (N=16); 1 used radiofrequency ablation (RFA) (N=14); and 1 used photodynamic therapy (PDT) (N=6). In 2 series focal treatments were mixed or included brachytherapy.
 
Patients in 12 series included in this SR had disease defined as low risk (n=1109 [56%]), intermediate risk (n=704 [36%]), and high risk (n=164 [8%]); risk categories were not available in 13 series. Median age of patients in the studies ranged from 56 years to 73 years. The prostate specific antigen (PSA) level of patients ranged from 3.8 to 24 ng/mL. An individual Gleason score was available in 20 series, with 1503 men having Gleason score <6; 521 with Gleason score 7; and, 82 with Gleason score higher than 8. Median follow-up periods for the reported focal therapy series were 0 to 10.6 years. Disease was localized as follows: transrectal ultrasound (TRUS) biopsy in 2 series; TRUS biopsy with Doppler ultrasound (US) in 2 series; TRUS biopsy plus magnetic resonance imaging (MRI) in 6 series; TMB and multiparametric MRI (mp-MRI) in 4 series; preoperative assessment was not reported in 11 studies.
 
In all studies where such data were reported in the Valerio SR, all known areas of cancer were treated; in no study was it explicitly stated that the index lesion was ablated and that other lesions were left untreated. Biochemical control based on PSA levels was reported in 5 series using the RTOG-ASTRO Phoenix Consensus Conference criteria (Roach, 2006). Other definitions used to define biochemical control were ASTRO (5 series), Stuttgart (1 series) and Phoenix plus PSA velocity greater than 0.75 ng/mL annually (1 series). Biochemical control rates ranged from 86% at 8-year follow-up (n=318) to 60% at 5-year (n=56). Because the follow-up was too short, progression to metastatic disease was not reported in most of the studies in the Valerio review; in those where information was available, metastatic progression rates were very low (0%-0.3%). Although a cancer-specific survival rate of 100% was reported in all series, this must be considered in the context of the small numbers of patients in individual studies and the short follow-up (only 3 studies had follow-up >5 years).
 
Across all studies, the median length of hospital stay was 1 day; other perioperative outcomes were poorly reported. Across studies, the most frequent complications associated with treatment of prostate cancer-urinary retention, urinary stricture, and urinary tract infection-occurred in 0% to 17%, 0% to 5%, and 0% to 17%, respectively, of patients. Only 5 studies reported all 3 complications. Validated questionnaires were used in 9 series to report urinary functional outcomes; physician-reported rates were used in 5 studies. According to questionnaires, the pad-free continence rate varied between 95% and 100%, whereas the range of leak-free rates was 80% to 100%. Validated questionnaire data showed erectile functional rates in 54% to 100%, while physician-reported data showed erectile functional rates of 58% to 85%. Other adverse outcomes were poorly reported, particularly quality-of-life data, with only 3 studies reporting the latter.
 
The literature review prepared for this Policy extended beyond the ending date stated for the Valerio SR. This extended search did not identify additional articles that would affect the conclusions in the Policy.
 
 
Some currently unpublished trials that might influence this policy are listed below:
Ongoing
  • (NCT00877682) Regional Cryoablation for Localized Adenocarcinoma of the Prostate; planned enrollment 100; completion date April 2016.
  • (NCT02328807) Focal Prostate Radio-Frequency Ablation for the Treatment of Prostate Cancer; planned enrollment 30; completion date November 2016.
  • (NCT02303054) MRI-US Fusion Biopsy-Guided Focal Radio-Frequency Ablation of the Prostate in Men with Localized Prostate Cancer (FUSAblate Trial); planned enrollment 21; completion date September 2016.
  • (NCT02016040) Focal Therapy Using High Intensity Focused Ultrasound (Ablatherm®) for Localized Prostate Cancer; planned enrollment 25; completion date September 2016.
  • (NCT01310894) A European Randomized Phase 3 Study to Assess the Efficacy and Safety of TOOKAD ® Soluble for Localized Prostate Cancer Compared to Active Surveillance; planned enrollment 413; completion date September 2015.
 
No comparative evidence is available that assesses the use of the focal ablation techniques addressed in this Policy versus current standard treatment of prostate cancer, and therefore, no conclusions can be drawn between outcomes of focal therapies versus radical treatments versus active surveillance. In addition, no studies have been conducted that examine which, if any, of the focal techniques leads to better functional and oncologic outcomes. The body of evidence on the use of focal therapies for localized prostate cancer comprises case series or other observational studies; they are highly heterogeneous and inconsistently report clinical outcomes. Although high cancer-specific survival rates have been reported, the short follow-up periods and small sample sizes preclude conclusions on the effectiveness of any of these techniques. In addition, there is no standardization as to which and how many identified cancerous lesions should be treated. Although the adverse effect rates associated with focal therapies appear to be superior to those associated with radical treatments such as radical prostatectomy or external beam radiation therapy, the evidence is limited in its reporting and scope.
 
Practice Guidelines and Position Statements
 
National Comprehensive Cancer Network
The National Comprehensive Cancer Network guidelines for prostate Cancer (v1.2015) state that cryosurgery (cryotherapy or cryoablation) is an evolving minimally invasive therapy that achieves damage to tumor tissue through local freezing.
 
National Institute for Health and Care Excellence
The National Institute for Health and Care Excellence (NICE) issued guidance on the use cryoablation for localized prostate cancer in 2012 (NICE, 2012a). The conclusion was that current evidence on focal therapy using cryoablation for localized prostate cancer raises no major safety concerns. However, evidence on efficacy is limited in quantity and there is a concern that prostate cancer is commonly multifocal. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
 
NICE also issued guidance on the use of focal therapy using HIFU for localized prostate cancer in 2012 (NICE, 2012b).The conclusion was that current evidence on HIFU for localized prostate cancer raises no major safety concerns. However, evidence on efficacy is limited in quantity and there is a concern that prostate cancer is commonly multifocal. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
 
American Urological Association
The American Urological Association (AUA) issued guidelines on the management of clinically localized prostate cancer in 2007 which were reviewed and validity confirmed in 2011 (AUA, 2011).  AUA guidelines include the following recommendation regarding focal treatments: In addition to treatment modalities described and evaluated (eg, radical prostatectomy, external beam radiation, active surveillance) by the panel, a number of additional treatments, as well as combinations of treatments have been used for the management of clinically localized prostate cancer. These treatments include cryotherapy, HIFU, high-dose interstitial prostate brachytherapy, and combinations of treatments (eg, EBRT, interstitial prostate brachytherapy). The panel did not include other treatment options due to a combination of factors, including limited published experience and short-term follow up.
 
National Cancer Institute
The National Cancer Institute (NCI) updated their information on prostate cancer treatments in 2014 (NCI, 2014). NCI indicates cryotherapy and HIFU are new treatment options currently being studied in national trials. There is no recommendation for or against these treatments.
 
U.S. Preventive Services Task Force Recommendations
The U.S. Preventive Services Task Force published recommendations for prostate cancer screening. However, there are no recommendations for focal treatment of prostate cancer.
 
2016 Update
A literature search conducted through February 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Clinical Studies
A matched cohort study published in 2015 included 317 men who underwent focal cryoablation with 317 men who underwent whole-gland cryoablation (Mendez, 2015). Patients in the study were entered in the Cryo Online Data (COLD) registry between 2007 and 2013. The median age at the time of the procedure was 66±7 [SD] years, and median follow-up time was 58 months. All patients were preoperatively potent men who had low-risk disease according to the D'Amico risk criteria and were matched according to age at surgery. Outcomes included biochemical recurrence (BCR) free-survival, defined according to the American Society for Radiation Oncology (ASTRO) and Phoenix criteria and assessed by Kaplan-Meier curves. Only patients with prostate-specific antigen (PSA) nadir data were included in oncologic outcome analysis. Functional outcomes were assessed at 6, 12, and 24 months after the procedure for erectile function (defined as ability to have intercourse with or without erectile aids), urinary continence, urinary retention, and rates of fistula formation. After surgery, 30% (n=95) and 17% (n=55) of the men who underwent whole-gland cryoablation and focal cryoablation, respectively, underwent biopsy, with positive biopsy rates of 12% and 14%, respectively. BCR-free survival rates at 60 months according to the Phoenix definition were 80% and 71% in the whole-gland and focal therapy cohorts, respectively, with a hazard ratio of 0.827 (p > 0.1). According to the ASTRO definition, BCR-free survival was 82% and 73%, respectively (p > 0.1). Erectile function data at 24 months were available for 172 whole-gland and 160 focal therapy treated men. Recovery of erection function was achieved in 47% and 69% of patients in the whole-gland and focal therapy cohorts, respectively (p=0.001). Urinary function data at 24 months were available for 307 whole-gland and 313 focal therapy patients. Urinary continence rates were 99% and 100% for the whole-gland and focal therapy groups, respectively (p=0.02). Urinary retention at 6, 12, and 24 months was reported in 7%, 2%, and 0.6%, respectively, in the whole-gland treated patients versus 5%, 1%, and 0.9%, respectively, in the focal therapy cohort. One fistula was reported in each group.
 
Summary of Evidence
The evidence for focal ablation therapy in patients who have primary, localized prostate cancer includes 1 high-quality systematic review, 1 registry cohort study, and numerous observational studies. Relevant outcomes include overall survival (OS), disease-specific survival (DSS), symptoms, change in disease status, functional outcomes, quality of life, treatment-related mortality and treatment-related morbidity.
 
The evidence is highly heterogeneous and inconsistently reports clinical outcomes. No prospective, comparative evidence is available on the use of any focal ablation technique described in this evidence review versus current standard treatment of localized prostate cancer, including radical prostatectomy, external beam radiotherapy, or active surveillance. Methods have not been standardized to determine which and how many identified cancerous lesions should be treated for best outcomes. No evidence supports which, if any, of the focal techniques leads to better functional outcomes. Although high DSS rates have been reported, the short follow-up periods and small sample sizes preclude conclusions on the effect of any of these techniques on OS rates. The adverse effect rates associated with focal therapies appear to be superior to those associated with radical treatments such as radical prostatectomy or external beam radiotherapy, however, evidence is limited in its quality, reporting and scope.
 
Therefore, the evidence is insufficient to determine the effects of the technology on health outcomes.
 
2017 Update
A literature search conducted using the MEDLINE database through April 2017 did not reveal any new information that would prompt a change in the coverage statement. A summary of the key identified literature is summarized below.
 
Cryoablation
In 2016, Lian et al reported long-term results of a case series of 40 low- to intermediate-risk patients treated with primary focal cryoablation between 2006 and 2013 by a single urologist in China (Lian, 2016). Biochemical recurrence was defined using the Phoenix definition and treatment failure was defined as at least 1 positive biopsy or BCR. Mean follow-up was 63 months (range, 12-92 months). Two (5%) of 40 patients met the criteria for biochemical failure and 4 (10%) patients experienced treatment failure. Of the men who were potent before cryotherapy, 20 (77%) remained potent after treatment. Ninety-eight percent of the men were completely continent during follow-up.
 
Laser Ablation
Additional case series and nonrandomized studies have assessed of focal laser ablation (Lepor, 2015; Ward, 2012) since the Valerio review. Studies were small (range, 8-25 men), single arm, lacked long-term follow-up (range, 3-6 months) and did not report clinical outcomes (eg, progression-free survival, overall survival).
 
Photodynamic Therapy
Preliminary results from a trial of TOOKAD, a soluble vascular-targeted photodynamic therapy (VTP), were presented in 2016 at the 31st Annual European Association of Urology Congress but have not yet been published. A total of 413 men with low-risk prostate cancer were randomized and followed for 2 years (206 in VTP plus active surveillance; 207 in active surveillance without VTP) (Emberton, 2016). It was reported that 28% of the patients in the VTP group versus 58% of the control group experienced disease progression (hazard ratio, 0.34; 95% confidence interval, 0.24 to 0.46; p<0.001) and more patients in the VTP group (49%) versus surveillance group (14%) had negative biopsies at 2 years. These results cannot be reviewed in full until publication.
 
Additional nonrandomized studies have assessed of photodynamic therapy since the Valerio review. A prospective, multicenter phase 2/3 trial by Taneja et al treated 30 men using photodynamic therapy. Follow-up was limited to 6 months and trialists did not report important clinical outcomes (eg, progression-free survival, overall survival) (Taneja, 2016).
 
The National Comprehensive Cancer Network guidelines for prostate cancer (v.3.2016) state that cryosurgery (cryotherapy or cryoablation) is an “evolving minimally invasive therapy that damages tumor tissue through local freezing.” It further states that “other emerging therapies such as high intensity focused ultrasound (HIFU) and vascular-targeted photodynamic (VTP), also warrant further study” (NCCN, 2016).
 
In 2014, NICE issued guidance on diagnosis and management of prostate cancer. The recommendations stated that neither cryotherapy or HIFU should be offered to men with localized prostate cancer or locally advanced prostate cancer outside of controlled trials comparing their use with established interventions NICE, 2014.
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2018. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.  
 
 PRACTICE GUIDELINES AND POSITION STATEMENTS
American Urological Association et al
The American Urological Association, along with the American Society for Radiation Oncology and the Society for Urologic Oncology, updated their joint guidelines on the management of clinically localized prostate cancer in 2017 (Sanda, 2017). The guidelines included the following recommendation on focal treatments:
 
“Clinicians should inform low-risk prostate cancer patients who are considering focal therapy or high intensity focused ultrasound (HIFU) that these interventions are not standard care options because comparative outcome evidence is lacking. (Expert Opinion)”
 
“Clinicians should inform intermediate-risk prostate cancer patients who are considering focal therapy or HIFU that these interventions are not standard care options because comparative outcome evidence is lacking. (Expert Opinion)”
 
“Cryosurgery, focal therapy and HIFU treatments are not recommended for men with high-risk localized prostate cancer outside of a clinical trial. (Expert Opinion)”

CPT/HCPCS:
53899Unlisted procedure, urinary system
55899Unlisted procedure, male genital system
C9747Ablation of prostate, transrectal, high intensity focused ultrasound (hifu), including imaging guidance

References: National Institute for Health and Care Excellence (NICE).(2015) Prostate cancer: diagnosis and management (CG175). 2014; https://www.nice.org.uk/guidance/cg175/resources/prostate-cancer-diagnosis-and-management-35109753913285. Accessed August 8, 2016.

Ahmed HU, Emberton M.(2008) Active surveillance and radical therapy in prostate cancer: can focal therapy offer the middle way? World J Urol. Oct 2008;26(5):457-467. PMID 18704441

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