Medical Policy

Policy Num:      08.001.010
Policy Name:    High-Dose Rate Temporary Prostate Brachytherapy
Policy ID:          [08.001.010]   [Ac / B / M+ / P+]   [8.01.33]

Last Review:       February 13, 2025
Next Review:       August 20, 2025
 

Related Policies:

07.001.012 - Whole Gland Cryoablation of Prostate Cancer
08.001.012 - Charged-Particle (Proton or Helium Ion) Radiotherapy for Neoplastic Conditions
06.001.016 - Brachytherapy for Clinically Localized Prostate Cancer Using Permanently Implanted Seeds
06.001.056 - Intensity-Modulated Radiotherapy of the Prostate

High-Dose Rate Temporary Prostate Brachytherapy

Summary

Description

High-dose rate (HDR) temporary prostate brachytherapy is a technique for delivering a high-intensity radiation source directly to the prostate gland to treat cancer. The radiation source is administered through hollow catheters or needles inserted precisely into several areas of the prostate gland using ultrasound guidance and treatment planning computed tomography or ultrasound images. Radiation is applied to target areas until the prescribed dose is reached and is then removed. The goal of treatment is to induce direct tumor necrosis and reduce toxicity and surrounding tissue damage.

Summary of Evidence

For individuals who have localized prostate cancer who receive HDR temporary brachytherapy plus external-beam radiotherapy (EBRT), the evidence includes randomized controlled trials (RCTs), observational studies, and a systematic review. Relevant outcomes are overall survival (OS), disease-specific survival, and treatment-related morbidity. One of the RCTs found no statistically significant differences in outcomes between patients treated with HDR brachytherapy plus EBRT and those receiving radical prostatectomy. The other RCT found significantly better biochemical recurrence-free survival, but not better OS, in patients treated with HDR brachytherapy plus EBRT compared with EBRT alone. Among several controlled observational studies with matched analyses, one has reported 5-year OS rates for HDR brachytherapy plus EBRT similar to those of one of the RCTs. In another study, 4 year biochemical recurrence-free survival was significantly higher after HDR brachytherapy plus EBRT than after EBRT alone. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have localized prostate cancer who receive HDR temporary brachytherapy as monotherapy, the evidence includes large observational studies and systematic reviews. Relevant outcomes are OS, disease-specific survival, and treatment-related morbidity. A number of observational studies, controlled and uncontrolled, have been published. Systematic reviews have found biochemical recurrence-free survival rates of 80% to 100%. Long-term survival data are available from case series; one found an 8-year survival rate of 95% and another found an actutimes 10-year survival rate of 77%. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have treatment-resistant or recurrent prostate cancer and no disseminated disease who receive HDR temporary brachytherapy as salvage treatment with or without EBRT, the evidence includes a systematic review and meta-analysis of mostly retrospective studies and case series. Relevant outcomes are OS, disease-specific survival, and treatment-related morbidity. No RCTs were identified on use of HDR temporary brachytherapy as salvage treatment. A systematic review and meta-analysis of 16 prospective and retrospective trials on HDR brachytherapy in patients with locally recurrent prostate cancer found 2-year and 5-year recurrence-free survival of 77% and 60%. The odds ratios for 2-year and 5-year recurrence-free survival for HDR brachytherapy compared to radical prostatectomy was 1.26 (95% confidence interval [CI], 0.77 to 2.09) and 1.25 (95% CI, 0.88 to 1.78), respectively. The pooled rates for the radical prostatectomy comparator groups were not reported. The rates of severe gastrointestinal and genitourinary toxicities were lower than rates with radical prostatectomy. However, the meta-analysis was primarily an indirect comparison involving mostly non-comparative, retrospective studies and OS was not reported. Only 3 cases series have reported OS outcomes. In these series, median 5-year OS rates after salvage HDR brachytherapy ranged from 83% to 95.5%. Rates of grade 3 or 4 toxicities were relatively low. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable

Objective

The objective of this evidence review is to determine whether temporary high-dose rate brachytherapy alone or in combination with external-beam radiotherapy improves the net health outcome in patients with localized, treatment-resistant, or recurrent prostate cancer.

Policy Statements

High-dose rate prostate brachytherapy may be considered medically necessary as monotherapy or in conjunction with external-beam radiotherapy in the treatment of localized prostate cancer.

High-dose rate prostate brachytherapy is considered investigational in the treatment of prostate cancer when used as salvage therapy.

Policy Guidelines

High-dose rate (HDR) brachytherapy as monotherapy is being used in low- and intermediate-risk patients with localized prostate cancer. HDR brachytherapy combined with external-beam radiotherapy (3-dimensional conformal radiotherapy [3D-CRT], intensity-modulated radiotherapy, or proton beam therapy) may be used for more advanced or aggressive prostate cancers. Adequate dose escalation should be achieved with combination HDR temporary brachytherapy and 3D-CRT. Intensity-modulated radiotherapy should be limited only to cases in which 3D-CRT planning is not able to meet dose-volume constraints for normal tissue tolerance. Permanent low-dose rate brachytherapy using only implanted seeds is generally used in patients whose prostate cancer is considered low risk. Active surveillance is generally recommended for very low risk prostate cancer. Permanent brachytherapy combined with external-beam radiotherapy is used (sometimes along with androgen deprivation therapy) to treat higher risk disease.

Prostate cancer risk is often defined using the following criteria:

• Low risk: prostate-specific antigen (PSA) level of 10 ng/mL or less, Gleason score of 6 or less, and clinical stage T1c (very low risk) or T1-T2a.

• Intermediate risk: PSA level greater than 10 but 20 ng/mL or less, or Gleason score of 7, or clinical stage T2b-T2c.

• High risk: PSA level greater than 20 ng/mL or Gleason score of 8 to 10, or clinical stage T3a for clinically localized disease and T3b-T4 for locally advanced disease.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

High-dose rate brachytherapy is not a widely disseminated procedure, and thus patients seeking this therapy may request access to an out-of-network facility.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Brachytherapy for prostate cancer can be delivered in a variety of ways. Perhaps the most common technique uses radioactive seeds permanently implanted into the prostate tissue. These seeds contain isotopes that slowly emit radiation of relatively low energy. In contrast, temporary prostate brachytherapy involves the use of higher energy radioisotopes such as iridium 192. The latter isotopes deliver radiation at higher dose rates than permanent seeds and may be more effective in destroying rapidly dividing cancer cells. For implantation, needle catheters are placed into the prostate gland using transrectal ultrasound guidance. Once placed, a dosimetric plan is developed, and the radioactive source is inserted into each needle using an after loading device. The radioactive source is left in the needle for a predetermined time, called the "dwell" time. The radiation usually is delivered once or twice daily over several days. The dwell time can be altered at various positions along the needle's length to control dose distribution to the target volume and critical surrounding structures (eg, rectum, urethra). This strategy contrasts with permanent seed implantation in which dosimetry is calculated before needle placement and which cannot be altered after seed implantation. Treatment typically consists of delivering a dose of 4000 to 5000 centigray with external-beam radiotherapy (EBRT) to the prostate and periprostatic tissues, while high-dose rate (HDR) brachytherapy is used as the method of dose escalation to the prostate gland. Total boost doses vary. Additionally, studies are also being conducted using HDR brachytherapy as the sole treatment modality (monotherapy) for prostate cancer.

It is accepted that increasing doses of radiotherapy are associated with improved biochemical control (ie, stable levels of prostate-specific antigen), and thus there has been an interest in exploring different techniques of dose escalation, simultaneously limiting both early and late toxicities in surrounding tissues. In patients with the locally advanced disease, it has been hypothesized that local failure might be related to large tumor volume and radioresistant cell clones, both of which might respond to higher radiation doses. HDR brachytherapy has been primarily investigated as an adjunct to EBRT for dose escalation. Other techniques for dose escalation include EBRT using intensity-modulated radiotherapy for treatment planning and delivery, proton beam therapy (which may also use intensity-modulated radiotherapy), or EBRT combined with brachytherapy using interstitial seeds.

Regulatory Status

A number of devices have been cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process to deliver HDR brachytherapy to the prostate. The Martinez Prostate Template Set and the Photon Technologies HDR Prostate Template and Accessories are examples of radiation application devices. These devices are intended as accessories to commercially available HDR remote afterloader systems for prostate brachytherapy. FDA product code: JAQ.

Rationale

This evidence review was created in April 2000 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through November 20, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, 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. RCTs 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.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1 

High-Dose Rate Brachytherapy Plus External-Beam Radiotherapy

Clinical Context and Therapy Purpose

The purpose of high-dose rate (HDR) temporary brachytherapy plus external-beam radiotherapy (EBRT) in patients who have localized prostate cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

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

Populations

The relevant population of interest is patients with localized prostate cancer.

Interventions

The therapy being considered is HDR temporary brachytherapy plus EBRT.

Comparators

The following therapies are currently being used to make decisions about localized prostate cancer: EBRT, surgery, and cryoablation.

Outcomes

The general outcomes of interest are a locoregional recurrence, overall survival (OS), and adverse events. Regular follow-up (every 6 to 12 months) are suggested for the first 5 years posttreatment.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials studies 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

Zaorsky et al (2014) reviewed 38 prospective and retrospective studies (N=8008 patients) reporting on HDR brachytherapy boost with EBRT for prostate cancer.^1, Five-year freedom from biochemical failure rates were 85% to 100% for low-risk, 80% to 98% for intermediate-risk, 59% to 96% for high-risk patients, and 34% to 85% for locally advanced patients. In all risk groups, 5-year rates of cancer-specific survival, OS, local recurrence, and distant metastases were 99% to 100%, 85% to 100%, 0% to 8%, and 2% to 12%, respectively. Late Radiation Therapy Oncology Group (RTOG) grade 3 or 4 genitourinary (GU) or gastrointestinal (GI) toxicities occurred in less than 6% of patients. Comparisons of HDR brachytherapy with other radiation techniques were inconclusive. Interpretation of the results of this systematic review was limited by the number of reports from single-institution studies, the lack of comparative studies, and insufficient reporting on toxicity and quality of life.

Randomized Controlled Trials

In a multicenter open-label RCT in Sweden, Lennernäs et al (2015) allocated patients with localized and locally advanced (T1b-T3a, N0, M0) prostate cancer to open radical prostatectomy (RP; n=45) or to combined EBRT (3-dimensional conformal radiotherapy, 25´2 Gray [Gy]) and HDR brachytherapy (2´10 Gy) between 1996 and 2001 (n=44).^2, All patients received total androgen blockade that comprised a combination of leuprorelin and flutamide for 6 months. Follow-up assessments included digital rectal examinations if serum prostate-specific antigen (PSA) levels exceeded 10 ng/mL. Quality of life changes were assessed using the European Organization of Research and Treatment of Cancer Quality of Life Questionnaire C33.^3, Patients completed the RTOG/European Organization of Research and Treatment of Cancer Toxicity Scale at 12, 24, and 60 months posttreatment. No statistically significant between-group differences were reported for any of the European Organization of Research and Treatment of Cancer Quality of Life Questionnaire C33 variables or treatment-associated toxicities. Sixty-eight (76%) patients were alive at 10-year follow-up; 8 patients (6 in the RP group, 2 in the 3-dimensional conformal radiotherapy group; 9% total) died of prostate cancer, 13 (n=6 in the RP group, n=7 in the 3-dimensional conformal radiotherapy group) died of other causes.

Hoskin et al (2007) reported on a European single-center randomized trial of 220 patients conducted between 1997 and 2005. It compared EBRT at 55 Gy with EBRT at 35.75 Gy plus HDR brachytherapy in patients with prostate cancer.^4, With a median follow-up of 30 months, an improvement was reported in actutimes biochemical recurrence-free survival (BRFS), as well as a lower incidence of acute rectal discharge. Hoskin et al (2012) later reported on the longer-term follow-up of 218 patients from this phase 3 trial.^5, Seventy-six percent of the patients also received androgen-deprivation therapy. BRFS was greater in the combination treatment group after 4 years (median time to relapse, 116 months) than in the EBRT-only treatment group (median time to relapse, 74 months). Estimates of BRFS rates for the combination group at 5, 7, and 10 years were 75%, 66%, and 46% compared with 61%, 48%, and 39% for the EBRT-only group, all respectively (p=.04). However, OS did not differ significantly between treatment arms. Estimates of OS rates for the combination group at 5, 7, and 10 years were 88%, 81%, and 67% compared with 89%, 88%, and 79% for the EBRT-only group, all respectively (p=.2). Severe urinary symptoms (26% to 31%) and bowel events (6% to 7%) did not differ significantly between groups at 5 years or 7 years. Erectile dysfunction rates were not reported. Hoskin et al (2021) reported similar results at 12 years, with a higher rate of relapse-free survival in the combination group compared to EBRT-alone, but no difference between groups in OS.^6,

Observational Studies

Boehm et al (2016) published a single-center retrospective analysis of 5619 patients with clinically localized prostate cancer who were treated between 1999 and 2009 with HDR brachytherapy plus EBRT (n=419) or RP (n=5200).^7, Eligibility criteria included stage cT1 or cT2 prostate cancer, a prostate volume of 60 mL or less, no neoadjuvant androgen suppression therapy, and no urinary retention symptoms. HDR brachytherapy treatment (18 Gy in 2 fractions) preceded EBRT (50.4 Gy, 1.8 Gy per fraction with 5 fractions per week). In an unmatched analysis of the overall cohort (N=5619), 5-year OS rates were 97.1% in the RP group and 92.4% in the HDR brachytherapy plus EBRT group (p<.01). An analysis was also conducted after matching the 2 groups on a number of variables including age, cardiovascular disease, diabetes, PSA level, Gleason score, clinical stage, and years of treatment. Five-year OS rates in the matched cohort (n=1257) did not differ significantly between groups. Rates were 95.7% after RP and 92.4% after HDR brachytherapy plus EBRT (p=.5).

Khor et al (2013) reported on a matched pair analysis that compared 344 patients who received EBRT (46 Gy in 23 fractions) plus HDR brachytherapy (19.5 Gy in 3 fractions) with 344 patients who received only EBRT (74 Gy in 37 fractions) for intermediate- or high-risk prostate cancer.^8, Median biochemical follow-up was 60.5 months. Freedom from biochemical failure at 5 years was 79.8% (95% confidence interval [CI], 74.3% to 85.0%) for the HDR brachytherapy plus EBRT group and 70.9% (95% CI, 65.4% to 76.0%) for the EBRT-only group. However, significantly more grade 3 urethral strictures occurred with HDR brachytherapy (11.8%) than with EBRT (0.3%; p<.001).

Long-term outcomes of treatment with HDR brachytherapy and EBRT were reported by Yaxley et al (2017).^9, The analysis included 507 patients with localized prostate cancer who were followed for at least 6 years; the median follow-up was 10.3 years. For 271 men with a minimum follow-up of 10 years, the actutimes 10-year OS rate was 85%, and the actual 10-year disease-specific survival rate was 90%. The overall urethral stricture rate was 28.9% (28.9% for men treated before 2005 vs 4.2% for men treated after 2005).

Section Summary: High-Dose Rate Brachytherapy Plus External-Beam Radiotherapy

Two RCTs comparing HDR brachytherapy plus EBRT with an alternative therapy were identified. One RCT found no statistically significant differences in outcomes between patients treated with HDR brachytherapy and EBRT and those given RP. Another RCT found significantly better BRFS, but not better OS, in patients treated with HDR brachytherapy plus EBRT compared with EBRT alone. Among several controlled observational studies with matched analyses, one reported 5 year OS rates for HDR brachytherapy plus EBRT similar to those of one of the RCTs. In another study, 4-year BPFS was significantly higher after HDR brachytherapy plus EBRT than after EBRT alone. Long-term (at least 10 years) outcomes after HDR brachytherapy and EBRT were reported in a case series: the actutimes 10-year OS rate was 85%, and the disease-specific survival rate was 90%.

For individuals who have localized prostate cancer who receive HDR temporary brachytherapy plus external-beam radiotherapy (EBRT), the evidence includes randomized controlled trials (RCTs), observational studies, and a systematic review. Relevant outcomes are overall survival (OS), disease-specific survival, and treatment-related morbidity. One of the RCTs found no statistically significant differences in outcomes between patients treated with HDR brachytherapy plus EBRT and those receiving radical prostatectomy. The other RCT found significantly better biochemical recurrence-free survival, but not better OS, in patients treated with HDR brachytherapy plus EBRT compared with EBRT alone. Among several controlled observational studies with matched analyses, one has reported 5-year OS rates for HDR brachytherapy plus EBRT similar to those of one of the RCTs. In another study, 4 year biochemical recurrence-free survival was significantly higher after HDR brachytherapy plus EBRT than after EBRT alone. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2 

High-Dose Rate Brachytherapy as Monotherapy

Clinical Context and Therapy Purpose

The purpose of HDR temporary brachytherapy as monotherapy in patients who have localized prostate cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

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

Populations

The relevant population of interest is patients with localized prostate cancer.

Interventions

The therapy being considered is HDR temporary brachytherapy as monotherapy.

Comparators

The following therapies are currently being used to make decisions about localized prostate cancer: EBRT, surgery, and cryoablation.

Outcomes

The general outcomes of interest are a locoregional recurrence, OS, and adverse events. Regular follow-up (every 6 to 12 months) are suggested for the first 5 years posttreatment.

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

Anderson et al (2021) published a systematic review analyzing the evidence on HDR brachytherapy as monotherapy for prostate cancer.^10, The review included 7 studies (N=2123); all studies had at least 5 years of follow-up, a minimum of 80 patients, and BRFS outcomes. The median follow-up was 74 months. The 5-year BRFS rate was 95% (95% CI, 93% to 96%). Grade 3 or 4 GU and GI toxicity rates were low (2% and 0.3%, respectively).

Zaorsky et al (2015), in a comparative effectiveness review, assessed the relative clinical effectiveness of HDR brachytherapy as monotherapy and robotic arm stereotactic body radiotherapy (SBRT).^11, This review was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses conventions. Studies selected enrolled 35 or more men with localized (T1 to T2, N0 to Nx, M0) and locally advanced (T3 to T4, N0 to Nx, M0) prostate cancer who underwent either therapy and were followed for 12 or more months. To be included, studies had to report disease-related outcomes such as BRFS, PSA kinetics, and late GU or GI tract toxicities. For SBRT, BRFS rates were generally 90% or greater at up to 5 years; for HDR brachytherapy as monotherapy, rates were generally 85% or greater at up to 5 years. Median follow-up was 2.9 years, and the longest reported actutimes outcomes were at 8 years. For SBRT, late GU RTOG grade 3 or 4 toxicity rates ranged from 0% to 12%; RTOG late grade 3 or 4 GI toxicity rates ranged from 0% to 5%; for HDR brachytherapy, these rates were 0% to 26% and 0% to 16%, respectively.

Demanes and Ghilezan (2014) published a systematic review analyzing evidence on HDR brachytherapy as monotherapy for prostate cancer.^12, Thirteen studies met selection criteria; they presented clinical outcomes and toxicity data with follow-up ranging from 1.5 to 8.0 years. All risk groups (low, intermediate, high) were represented in selected articles, and a variety of dose and fractionation schedules were reported. Information on study designs, study quality, and other study and patient characteristics were very limited in this review. BRFS rates reported among the studies ranged from 79% to 100%, and local control rates ranged from 97% to 100%. Grade 3 GU toxicity rates, mainly related to urinary urgency or frequency, ranged from 0% to 16%; grade 3 GI tract toxicity rates ranged from 0% to 2%. Erectile functional preservation rates ranged from 67% to 89%.

Observational Studies

Hegde et al (2018) reported on 437 patients with intermediate-risk prostate cancer who were treated with HDR brachytherapy (n=137) or SBRT (n=300).^13, After a median follow-up of 4 years, the BRFS rate was 98.5% in the HDR brachytherapy group and 95.3% in the SBRT group (p=.17). There were no statistically significant differences in subgroup analyses (eg, comparing patients with a PSA level <10 and ≥10 ng/mL or clinical stage T1 with T2). OS and disease-specific survival were not reported.

A study by Chiang and Liu (2016) reported on a nonrandomized comparison of outcomes after HDR brachytherapy (n=161), RP (n=97), cryoablation (n=114), or high-intensity focused ultrasound (HIFU; n=12).^14, The study included patients with clinically localized prostate cancer (stage T3a or lower). The mean follow-up was approximately 3 years. In an unadjusted analysis, the length of PSA BRFS differed significantly across the 4 groups (p<.001). The mean number of months of BRFS was 21.2 in the HDR group, 22.1 in the RP group, 26.4 in the cryotherapy group, and 27.7 in the HIFU group. There was a longer duration of BRFS in the HDR brachytherapy group than in the other 3 groups. Moreover, patients treated with HDR brachytherapy had a significantly lower metastasis-free rate (90.7%) than those who received other treatments (94.8% in the RP group, 99.1% in the cryotherapy group, 99.2% in the HIFU group; p<.001). OS and disease-specific survival were not reported. The study was not randomized, and baseline differences across groups might have affected outcomes. For example, patients differed at baseline in a number of characteristics, including age, preoperative prostate volume, and Gleason score. The authors did not report adjusted analyses.

Strom et al (2015) published a nonrandomized comparative study assessing 413 men who had low- or intermediate-risk prostate cancer.^15, Patients received HDR brachytherapy (n=85), low-dose rate brachytherapy (n=249), or intensity-modulated radiotherapy (n=79). The median follow-up was 32 months. Primary outcomes were patient-reported and validated health-related quality of life (HRQOL) measures obtained before treatment and at 1, 3, 5, 12, and 18 months posttreatment. Sixty-percent of patients completed pre-and posttreatment HRQOL questionnaires. HRQOL outcomes were mixed. At 1 and 3 months posttreatment, HDR brachytherapy patients reported significantly less deterioration in urinary HRQOL than low-dose rate brachytherapy patients (p=.005). However, HDR brachytherapy patients had significantly worse sexual HRQOL than low-dose rate brachytherapy at 1, 6, 9, and 18 months after irradiation (p=.02, p=.003, p=.006, p=.02, respectively). At 18 months, the intensity-modulated radiotherapy group had significantly worse bowel HRQOL scores than either brachytherapy group (p=.007 for both comparisons).

Long-term survival data have also been reported in uncontrolled series. For example, Demanes et al (2011) reported on 298 patients with previously untreated low- to intermediate-risk localized prostate cancer (median PSA, 6.0 ng/mL) treated with HDR brachytherapy as monotherapy between 1996 and 2005, using 2 treatment protocols.^16, Forty-two Gy units in 6, 7-Gy fractions were delivered using computed tomography for treatment planning in 1 protocol; the other treatment planning delivered 38 Gy units in 4, 9.5-Gy fractions using ultrasonography. At 8-year follow-up, outcomes included 99% local control, 97% biochemical control (using the Phoenix definition of PSA nadir plus 2 ng/mL), 99% distant metastasis-free survival, 99% cause-specific survival, and 95% OS rate. Grade 2 urinary frequency or urgency was transient in 10% of patients, whereas grade 3 urinary retention was experienced in 3% of patients. GI toxicity was reported in less than 1% of patients.

Hauswald et al (2016) reported on 448 previously untreated men with low- to intermediate-risk localized prostate cancer patients treated with HDR brachytherapy.^17, Median follow-up was 78 months (range, 3 to 216 months). The actutimes 10-year OS rate was 76.7% (95% CI, 69.9% to 82.2%) and the actutimes 10-year BRFS rate was 97.8% (95% CI, 95.5% to 98.9%) The incidence of grade 3 or 4 GU toxicity during follow-up was 4.9%. No grade 3 or 4 GI toxicity occurred.

Section Summary: High-Dose Rate Brachytherapy as Monotherapy

A number of observational studies, controlled and uncontrolled, have been published. Systematic reviews have reported BRFS rates of 80% to 100%. One nonrandomized comparative study found similar rates of BRFS in patients treated with HDR brachytherapy and SBRT. However, another comparative study found significantly shorter BRFS and a lower metastases-free rate in patients who were treated with HDR brachytherapy compared with those treated with RP, cryotherapy, or HIFU. As a nonrandomized study, patients differences in baseline characteristics might have affected outcomes. Long-term survival data are available from case series; one found an 8-year OS rate of 95% and another reported an actutimes 10-year survival rate of 77%.

For individuals who have localized prostate cancer who receive HDR temporary brachytherapy as monotherapy, the evidence includes large observational studies and systematic reviews. Relevant outcomes are OS, disease-specific survival, and treatment-related morbidity. A number of observational studies, controlled and uncontrolled, have been published. Systematic reviews have found biochemical recurrence-free survival rates of 80% to 100%. Long-term survival data are available from case series; one found an 8-year survival rate of 95% and another found an actutimes 10-year survival rate of 77%. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 3 

High-Dose Rate Brachytherapy as Salvage Treatment

Clinical Context and Therapy Purpose

The purpose of HDR temporary brachytherapy as salvage treatment with or without EBRT in patients who have treatment-resistant or recurrent prostate cancer and no disseminated disease is to provide a treatment option that is an alternative to or an improvement on existing therapies.

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

Populations

The relevant population of interest is patients with treatment-resistant or recurrent prostate cancer and no disseminated disease.

Interventions

The therapy being considered is HDR temporary brachytherapy as salvage treatment with or without EBRT.

Comparators

The following therapies are currently being used to make decisions about localized prostate cancer: active surveillance, surgery, and cryoablation.

Outcomes

The general outcomes of interest are a locoregional recurrence, OS, and adverse events. Regular follow-up (every 6 to 12 months) are suggested for the first 5 years posttreatment.

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 Review

Valle et al (2020) published a systematic review and meta-analysis on the use of local salvage therapies after radiotherapy for prostate cancer.^18, Radical prostatectomy was compared to HDR brachytherapy plus other therapies including HIFU, cryotherapy, SBRT, and low-dose-rate brachytherapy. Only the comparison of RP to HDR brachytherapy is included in this review. The meta-analysis reported 2-year and 5-year recurrence-free survival rates and incidences of severe GU and GI toxicity. Sixteen studies evaluated HDR brachytherapy, and 4 of these were prospective studies (Table 1). Characteristics of the meta-analysis are summarized in Table 2. The covariate-adjusted estimates of 2-year and 5-year recurrence-free survival with HDR brachytherapy were 77% (95% CI, 70% to 83%; 14 studies; n=456) and 60% (95% CI, 52% to 67%; 7 studies; n=350), respectively. Severe GU toxicity occurred in 8% of patients (95% CI, 5.1 to 11; 16 studies; n=586) and severe GI toxicity occurred in 0% of patients (95% CI, 0 to 0.2; 15 studies; n=571). The authors also conducted a meta-regression to compare HDR brachytherapy to RP (Table 3). There was no difference between HDR brachytherapy and RP in 2-year recurrence-free survival and 5-year recurrence-free survival. However, severe GU toxicity and severe GI toxicity were lower with HDR brachytherapy versus RP. The results of the meta-analysis were limited by including mostly non-comparative, retrospective studies. In addition, OS was not reported.

Zhong et al (2021) published a similar systematic review and meta-analysis on salvage reirradiation options for locally recurrent prostate cancer.^19, The review included outcomes for low-dose brachytherapy, HDR brachytherapy, and EBRT. Only the HDR brachytherapy information is included in this review. Details are described in Tables 1 to 3.

Table 1. Studies Included in Systematic Review

Table 2. Systematic Review Characteristics

  NR: not reported.

Table 3. Systematic Review Results

  CI: confidence interval; GI: gastrointestinal; GU: genitourinary; HDR: high-dose rate; NA: not applicable; NR: not reported; RP: radical prostatectomy. aAcute toxicity/late toxicity bLate toxicity cBiochemical recurrence-free survival dGrade ≥3 

Case Series

Data on HDR brachytherapy as salvage treatment after failed prior radiotherapy are limited; there are no RCTs or nonrandomized comparative studies. Several key retrospective case series that were included in the meta-analyses that also discuss OS are described next.

Wojcieszek et al (2016) reported retrospectively on 83 men with locally recurrent prostate cancer treated with salvage HDR brachytherapy (30 Gy in three 10-Gy fractions).^21, Median follow-up was 41 months. OS rates were 93% at 3 years and 86% at 5 years. Biochemical disease-free survival was 76% at 3 years and 67% at 5 years. The most common adverse event was GU toxicity. Acute grade 2 GU toxicity occurred in 29 (33%) men and acute grade 3 GU toxicity in 1 (1%) man. Comparable rates for late GU toxicity were 32 (39%) for grade 2 and 11 (13%) for grade 3. No grade 4 toxicities were reported.

Chen et al (2013) retrospectively analyzed 52 men with locally recurrent prostate cancer treated with salvage HDR brachytherapy (36 Gy in 6 fractions).^22, Median follow-up was 59.6 months. At reporting, median survival had not yet been reached, but the estimated 5-year OS rate was 92% (95% CI, 80% to 97%), and the 5-year biochemical control rate using the Phoenix definition was 51% (95% CI, 34% to 66%). Acute (grade ≥2) GI tract events were not reported. Late grade 2 GI events occurred in 4% of patients. Acute grade 3 GU toxicity occurred in 2%, and late grade 3 GU toxicity occurred in 2%.

Jiang et al (2017) published a retrospective series assessing 29 patients with local failure after EBRT who received HDR brachytherapy as salvage therapy.^23, The minimum length of follow-up was 60 months. The 5-year OS rate was 95.5%, and the 5-year biochemical control rate was 45%. There were no grade 3 or 4 late GI toxicities, but 2 patients experienced grade 2 late GI toxicity. Two patients also experienced urinary incontinence and another experienced urinary tract obstruction.

Mäkelä et al (2023) reported on a retrospective, single-site observational study of 100 patients with locally relapsed prostate cancer after prior radiotherapy who were treated with salvage HDR brachytherapy (total dose, 24 Gy).^24, Concomitant androgen deprivation therapy was used by 69 patients. Median follow-up was 28 months (range, 13 to 68 months). There was only outcome data available in 55/100 patients. The 3-year biochemical disease-free survival and OS were 74% (95% CI, 60% to 87%) and 93% (95% CI, 84% to 100%), respectively. Acute grade 1 and grade 2 GU toxicity was observed in 58 and 12 patients, respectively. Acute grade 1 GI toxicity was observed in 8 patients. These results are limited by missing data on almost half of original participants, and its retrospective nature.

Section Summary: High-Dose Rate Brachytherapy as Salvage Treatment

No RCTs are available on use of HDR brachytherapy as salvage treatment. A meta-analysis of 16 prospective and retrospective trials on HDR brachytherapy in patients with locally recurrent prostate cancer found 2-year and 5-year recurrence-free survival of 77% (95% CI, 70 to 83%) and 60% (95% CI, 52 to 67%). Rates of severe GI and GU toxicities were lower than rates with RP. However, the meta-analysis was primarily an indirect comparison involving mostly non-comparative, retrospective studies, and OS was not reported. In case series that evaluated OS, median 5-year OS rates after salvage HDR brachytherapy ranged from 83% to 95.5%. Rates of grade 3 or 4 toxicities were relatively low.

For individuals who have treatment-resistant or recurrent prostate cancer and no disseminated disease who receive HDR temporary brachytherapy as salvage treatment with or without EBRT, the evidence includes a systematic review and meta-analysis of mostly retrospective studies and case series. Relevant outcomes are OS, disease-specific survival, and treatment-related morbidity. No RCTs were identified on use of HDR temporary brachytherapy as salvage treatment. A systematic review and meta-analysis of 16 prospective and retrospective trials on HDR brachytherapy in patients with locally recurrent prostate cancer found 2-year and 5-year recurrence-free survival of 77% and 60%. The odds ratios for 2-year and 5-year recurrence-free survival for HDR brachytherapy compared to radical prostatectomy was 1.26 (95% confidence interval [CI], 0.77 to 2.09) and 1.25 (95% CI, 0.88 to 1.78), respectively. The pooled rates for the radical prostatectomy comparator groups were not reported. The rates of severe gastrointestinal and genitourinary toxicities were lower than rates with radical prostatectomy. However, the meta-analysis was primarily an indirect comparison involving mostly non-comparative, retrospective studies and OS was not reported. Only 3 cases series have reported OS outcomes. In these series, median 5-year OS rates after salvage HDR brachytherapy ranged from 83% to 95.5%. Rates of grade 3 or 4 toxicities were relatively low. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

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

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2009 Input

In response to requests, input was received from 2 physician specialty societies (4 reviews) and 2 academic medical centers while this policy was under review in 2009. There was generally strong support for the use of high-dose rate (HDR) temporary brachytherapy (as monotherapy and with external-beam radiotherapy) as a treatment option for prostate cancer.

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 US professional society, an international society with US 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.

American College of Radiology

American College of Radiology Appropriateness Criteria (2014) for the use of HDR brachytherapy to treat prostate cancer were issued.^24, The College indicated HDR monotherapy, HDR plus external-beam radiotherapy, and HDR as salvage treatment might be appropriate treatment options. A 2020 practice parameter by the American College of Radiology, the American Brachytherapy Society, and the American Society for Radiation Oncology on radionuclide-based HDR brachytherapy also recommended that HDR monotherapy, HDR plus external beam radiotherapy, and HDR as salvage treatment are appropriate options for specific patients.^25,

National Comprehensive Cancer Network

The National Comprehensive Cancer Network guidelines (v.1.2023) on the treatment of prostate cancer state that brachytherapy monotherapy is indicated for patients with "very low, low, or favorable intermediate-risk prostate cancer, depending on life expectancy.".^26, For unfavorable intermediate-, high- and very high-risk cancers, combination brachytherapy, including HDR brachytherapy, with external-beam radiotherapy is indicated. Permanent low-dose radiotherapy or temporary HDR is indicated for local recurrence following external-beam radiotherapy or primary brachytherapy.

National Institute for Health and Care Excellence

In 2006, NICE published guidance on HDR brachytherapy in combination with external-beam radiotherapy for localized prostate therapy.^27, The guidance is as follows:

"Current evidence on the safety and efficacy of high dose rate (HDR) brachytherapy in combination with external-beam radiotherapy for localised prostate cancer appears adequate to support the use of this procedure provided that the normal arrangements are in place for consent, audit and clinical governance."

NICE notes that a multidisciplinary team should be involved in the planning and use of this procedure.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 4.

Table 4. Summary of Key Trials

  NCT: national clinical trial.

References

1. Zaorsky NG, Doyle LA, Yamoah K, et al. High dose rate brachytherapy boost for prostate cancer: a systematic review. Cancer Treat Rev. Apr 2014; 40(3): 414-25. PMID 24231548
2. Lennernäs B, Majumder K, Damber JE, et al. Radical prostatectomy versus high-dose irradiation in localized/locally advanced prostate cancer: A Swedish multicenter randomized trial with patient-reported outcomes. Acta Oncol. Jun 2015; 54(6): 875-81. PMID 25362844
3. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. Mar 03 1993; 85(5): 365-76. PMID 8433390
4. Hoskin PJ, Motohashi K, Bownes P, et al. High dose rate brachytherapy in combination with external beam radiotherapy in the radical treatment of prostate cancer: initial results of a randomised phase three trial. Radiother Oncol. Aug 2007; 84(2): 114-20. PMID 17531335
5. Hoskin PJ, Rojas AM, Bownes PJ, et al. Randomised trial of external beam radiotherapy alone or combined with high-dose-rate brachytherapy boost for localised prostate cancer. Radiother Oncol. May 2012; 103(2): 217-22. PMID 22341794
6. Hoskin PJ, Rojas AM, Ostler PJ, et al. Randomised trial of external-beam radiotherapy alone or with high-dose-rate brachytherapy for prostate cancer: Mature 12-year results. Radiother Oncol. Jan 2021; 154: 214-219. PMID 33011207
7. Boehm K, Schiffmann J, Tian Z, et al. Five-year biochemical recurrence-free and overall survival following high-dose-rate brachytherapy with additional external beam or radical prostatectomy in patients with clinically localized prostate cancer. Urol Oncol. Mar 2016; 34(3): 119.e11-8. PMID 26602027
8. Khor R, Duchesne G, Tai KH, et al. Direct 2-arm comparison shows benefit of high-dose-rate brachytherapy boost vs external beam radiation therapy alone for prostate cancer. Int J Radiat Oncol Biol Phys. Mar 01 2013; 85(3): 679-85. PMID 22954770
9. Yaxley JW, Lah K, Yaxley JP, et al. Long-term outcomes of high-dose-rate brachytherapy for intermediate- and high-risk prostate cancer with a median follow-up of 10 years. BJU Int. Jul 2017; 120(1): 56-60. PMID 27628127
10. Anderson EM, Kim S, Sandler HM, et al. High-dose-rate fractionated brachytherapy monotherapy for localized prostate cancer: a systematic review and meta-analysis. J Contemp Brachytherapy. Aug 2021; 13(4): 365-372. PMID 34484350
11. Zaorsky NG, Hurwitz MD, Dicker AP, et al. Is robotic arm stereotactic body radiation therapy “virtual high dose ratebrachytherapy” for prostate cancer? An analysis of comparative effectiveness using published data [corrected]. Expert Rev Med Devices. May 2015; 12(3): 317-27. PMID 25540018
12. Demanes DJ, Ghilezan MI. High-dose-rate brachytherapy as monotherapy for prostate cancer. Brachytherapy. 2014; 13(6): 529-41. PMID 25085454
13. Hegde JV, Collins SP, Fuller DB, et al. A Pooled Analysis of Biochemical Failure in Intermediate-risk Prostate Cancer Following Definitive Stereotactic Body Radiotherapy (SBRT) or High-Dose-Rate Brachytherapy (HDR-B) Monotherapy. Am J Clin Oncol. May 2018; 41(5): 502-507. PMID 27322703
14. Chiang PH, Liu YY. Comparisons of oncological and functional outcomes among radical retropubic prostatectomy, high dose rate brachytherapy, cryoablation and high-intensity focused ultrasound for localized prostate cancer. Springerplus. 2016; 5(1): 1905. PMID 27867812
15. Strom TJ, Cruz AA, Figura NB, et al. Health-related quality-of-life changes due to high-dose-rate brachytherapy, low-dose-rate brachytherapy, or intensity-modulated radiation therapy for prostate cancer. Brachytherapy. 2015; 14(6): 818-25. PMID 26452602
16. Demanes DJ, Martinez AA, Ghilezan M, et al. High-dose-rate monotherapy: safe and effective brachytherapy for patients with localized prostate cancer. Int J Radiat Oncol Biol Phys. Dec 01 2011; 81(5): 1286-92. PMID 21310546
17. Hauswald H, Kamrava MR, Fallon JM, et al. High-Dose-Rate Monotherapy for Localized Prostate Cancer: 10-Year Results. Int J Radiat Oncol Biol Phys. Mar 15 2016; 94(4): 667-74. PMID 26443877
18. Valle LF, Lehrer EJ, Markovic D, et al. A Systematic Review and Meta-analysis of Local Salvage Therapies After Radiotherapy for Prostate Cancer (MASTER). Eur Urol. Sep 2021; 80(3): 280-292. PMID 33309278
19. Zhong J, Slevin F, Scarsbrook AF, et al. Salvage Reirradiation Options for Locally Recurrent Prostate Cancer: A Systematic Review. Front Oncol. 2021; 11: 681448. PMID 34568012
20. Yang J, Xiong X, Liao X, et al. Nonsurgical salvage options for locally recurrent prostate cancer after primary definitive radiotherapy: a systematic review and meta-analysis. Int J Surg. May 01 2024; 110(5): 3008-3020. PMID 38348896
21. Wojcieszek P, Szlag M, Głowacki G, et al. Salvage high-dose-rate brachytherapy for locally recurrent prostate cancer after primary radiotherapy failure. Radiother Oncol. Jun 2016; 119(3): 405-10. PMID 27165612
22. Chen CP, Weinberg V, Shinohara K, et al. Salvage HDR brachytherapy for recurrent prostate cancer after previous definitive radiation therapy: 5-year outcomes. Int J Radiat Oncol Biol Phys. Jun 01 2013; 86(2): 324-9. PMID 23474112
23. Jiang P, van der Horst C, Kimmig B, et al. Interstitial high-dose-rate brachytherapy as salvage treatment for locally recurrent prostate cancer after definitive radiation therapy: Toxicity and 5-year outcome. Brachytherapy. 2017; 16(1): 186-192. PMID 28341011
24. Mäkelä L, Bergroth R, Taipale L, et al. Salvage HDR brachytherapy for prostate cancer: a high-volume center experience on 100 consecutive patients. Scand J Urol. 2023; 57(1-6): 36-40. PMID 36724186
25. Hsu IC, Yamada Y, Assimos DG, et al. ACR Appropriateness Criteria high-dose-rate brachytherapy for prostate cancer. Brachytherapy. 2014; 13(1): 27-31. PMID 24368283
26. ACR-ABS-ASTRO Practice Parameter for the performance of radionuclide-based high-dose-rate brachytherapy. Revised 2020. https://www.acr.org/-/media/ACR/Files/Practice-Parameters/HDR-BrachyRO.pdf. Accessed December 2, 2024.
27. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Prostate cancer. Version 4.2024. Updated May 17, 2024. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed December 2, 2024.
28. National Institute for Health and Care Excellence (NICE). High dose rate brachytherapy in combination with external-beam radiotherapy for localised prostate cancer [IPG174]. 2006; https://www.nice.org.uk/guidance/ipg174. Accessed December 2, 2024.

Codes

Applicable Modifiers

N/A

Policy History