Coverage Policy Manual
Policy #: 1998001
Category: Radiology
Initiated: February 1998
Last Review: August 2022
  Brachytherapy, Prostate, Low-dose Rate

Description:
In 2022, it has been estimated that 14% of all new cancer diagnoses will involve the prostate. In addition, as of 2019, estimates have suggested that over 3.2 million men in the U.S. are living with prostate cancer (NCI, 2022). There are also racial and ethnic disparities in prostate cancer, as shown by epidemiologic studies; in the U.S., Black men have a 1.5 times greater chance of developing prostate cancer than White men and are 2.2 times more likely to die due to prostate cancer (Borno, 2019).
 
Brachytherapy is a procedure in which a radioactive source (e.g., radioisotope "seeds") is used to provide extremely localized radiation doses. With brachytherapy, the radiation penetrates only short distances; this procedure is intended to deliver tumoricidal radioactivity directly to the tumor and improve local control while sparing surrounding normal tissue. Brachytherapy has been used for localized prostate cancer to provide local tumor control, which has been associated with lower distant metastasis rates and improved patient survival. Seeds can be permanently or temporarily implanted. Permanent (low-dose rate [LDR]) brachytherapy is generally used for low-risk disease; temporary (high-dose rate) brachytherapy is typically reserved for intermediate- or high-risk disease. This evidence review only assesses permanent LDR brachytherapy in prostate cancer.
 
The proposed biologic advantages of brachytherapy compared with external-beam radiotherapy (EBRT) are related to the dose delivered to the target and the dose delivery rate. The dose rate of brachytherapy sources is generally in the range of 40 to 60 centigray per hour, whereas conventional fractionated EBRT dose rates exceed 200 centigray per minute. Enhanced normal tissue repair occurs at the LDRs. Repair of tumor cells does not occur as quickly, and these cells continue to die during continued exposure. Thus, from a radiobiologic perspective, LDR radiation causes ongoing tumor destruction in the setting of normal tissue repair. Additionally, brachytherapy is performed as a single procedure in the outpatient setting, which many patients may find preferable to the multiple EBRT sessions. The total doses of radiotherapy that can be delivered may also vary between EBRT and brachytherapy, especially with newer forms of EBRT such as 3-dimensional conformal radiotherapy and intensity-modulated radiotherapy.
 
Brachytherapy has not been considered appropriate for patients with a large prostate or those with a urethral stricture because the procedure results in short-term swelling of the prostate, which can lead to urinary obstruction. As with all forms of radiotherapy, concerns exist with the long-term risk of treatment-related secondary malignancies. Reports have also suggested that the clinician's level of experience with brachytherapy correlates with disease recurrence rates.
 
Studies of permanent brachytherapy have generally used iodine 125 or palladium 103. Use of cesium 131 is also being studied. Iodine 125 requires more seeds, thus reducing dosimetric dependence on any single seed. Postimplant dosimetric assessment should be performed to ensure the quality of the implant and optimal source placement (i.e., targeted tumor areas receive the predetermined radiation dosages while nearby structures and tissues are preserved).
 
Permanent brachytherapy may be used as monotherapy or as combination therapy with EBRT as a way to boost the dose of radiotherapy delivered to the tumor; this combined modality therapy can be performed with permanent or temporary brachytherapy. The brachytherapy boost is typically done 2 to 6 weeks after completion of EBRT, although the sequence can vary. In some cases, patients also receive androgen deprivation therapy.
 
Focal or subtotal prostate brachytherapy is a form of more localized, organ-preserving therapy for small, localized prostate cancers. Brachytherapy seeds are placed only in the areas where the tumor has been identified rather than throughout the whole prostate gland. The aim of focal therapy is to reduce the occurrence of adverse events associated with brachytherapy, including urinary, bowel, and sexual dysfunction.
 
Regulatory Status
A large number of permanently implanted seeds for brachytherapy of prostate cancer are available. They have been cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process, including I-Seed® (Theragenics), Proxcelan™ Cs-131 (IsoRay Medical), and BrachySource® Brachytherapy Seed Implants (C.R. Bard). FDA product code: KXK.
 
See policy #2006019 for services relating to high-dose-rate brachytherapy (HDR-BT) for treatment of prostate cancer.

Policy/
Coverage:
Effective August 1, 2021, for members of plans that utilize a radiation oncology benefits management program, Prior Approval is required for this service and is managed through the radiation oncology benefits management program.
 
Effective April 01, 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Low risk of recurrence
Permanent low dose rate (LDR) brachytherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness and is covered for low risk* prostate cancer when the following condition is met:
      • Used as monotherapy.  
 
Intermediate risk of recurrence
Permanent low dose rate (LDR) brachytherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness and is covered for intermediate risk* prostate cancer when EITHER of the following conditions is met:
      • Used as monotherapy; or
      • Used in combination with external beam radiotherapy (EBRT)
 
High risk of recurrence
Permanent low dose rate (LDR) brachytherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness and is covered for high risk* prostate cancer when the following condition is met:
      • Used in combination with external beam radiotherapy (EBRT)
 
Local recurrence after radiotherapy
Permanent low dose rate (LDR) brachytherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness and is covered to treat recurrent localized disease* with no evidence of distant metastasis
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Low dose rate (LDR) brachytherapy is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of prostate cancer for any other indication not specifically listed as covered above.
 
For contracts without primary coverage criteria, Low dose rate (LDR) brachytherapy policy is considered investigational for the treatment of prostate cancer for any other indication not specifically listed as covered above. Investigational services are an exclusion in the member certificate of coverage.
 
 
 
NOTES:
 
Disease Definitions
 
Low-risk of recurrence (ALL must be present to qualify as low risk)
    • Stage T1-T2a
    • Gleason score of 6
    • Prostate-specific antigen (PSA) below 10 ng/Ml
 
Intermediate-risk of recurrence (ANY one characteristic)
    • Stage T2b to T2c
    • Gleason score of 7
    • PSA 10-20 ng/mL
 
High-risk of recurrence (ANY one characteristic)
    • Stage T3a
    • Gleason score 8-10
    • PSA greater than 20 ng/mL
 
Localized disease (BOTH must apply)
    • T stage of T1-3a (tumor has spread through the capsule on one or both sides but has not invaded the seminal vesicles or other structures)
    • N0 (no lymph node involvement)
 
Locally advanced disease (EITHER must apply)
    • Any T status with N1 disease (either no spread to lymph nodes or there has been spread to the regional lymph nodes)
    • T3b and above, no distant metastatic disease beyond local lymph nodes
 
Distant metastatic disease
    • Beyond the local lymph nodes
 
Effective Prior to April 01, 2021
The following services for the treatment of prostate cancer meet primary coverage criteria for effectiveness and are covered:
    • Radical prostatectomy for any stage of prostate cancer;
    • External beam radiotherapy;
    • Permanent seed brachytherapy alone;
    • Permanent seed brachytherapy and post-implant three-dimensional conformal radiotherapy (3DCRT).
 
Policy number 2006019, Brachytherapy, Prostate, High-Dose Rate Temporary, addresses the use of temporary high-dose rate brachytherapy for the treatment of prostate cancer.

Rationale:
The evaluation of treatment options for clinically localized prostate cancer is problematic because there is not yet convincing evidence that any treatment is more effective than watchful waiting in improving clinically meaningful patient outcomes. Even assuming that an intervention can improve outcomes compared to watchful waiting, the variable and often indolent natural history of clinically localized prostate cancer would require randomized trials with follow-up of 10 to 15 years to determine if brachytherapy is associated with equivalent or superior long-term outcomes compared to external bean radiation therapy (EBRT). These data are not currently available, and will not be available from direct comparable studies in the foreseeable future. The lack of these trials prohibits strict scientific conclusions regarding the comparative efficacy of brachytherapy and EBRT.  A search of the literature from 1997 to 2002 did not identify any studies that would alter these conclusions, and therefore the policy statement concludes that brachytherapy remains investigational and/or does not meet Primary Coverage Criteria.
 
The data on brachytherapy consists of uncontrolled case series, which typically report results in terms of PSA (prostate specific antigen) levels, as opposed to final health outcomes.
 
However, one study stands out.  Ragde and colleagues on the 10-year follow-up of patients with prostate cancer treated with brachytherapy, a duration of follow-up rate that is unusual for any treatment of prostate cancer. Among low-risk patients, the freedom from increasing PSA levels was approximately 80%. However, without a controlled trial, no scientific conclusions can be made regarding the relative efficacy of watchful waiting (particularly relevant in a low-risk population), external beam radiotherapy, prostate brachytherapy, or combined external beam and brachytherapy.
 
Nevertheless, brachytherapy has become widely accepted among physicians and its speed and convenience compared to external beam irradiation are appealing to patients. Therefore, given the baseline uncertainty regarding long-term outcomes associated with any or no treatment of clinically localized prostate cancer, decisions regarding any treatment option for prostate cancer are frequently reframed as an issue of patient preference, even while acknowledging that the decision must be made based on incomplete data. In general, many physicians consider prostate brachytherapy alone as a treatment option for men aged greater than 60 with small volume cancer of low or intermediate risk (Gleason sum <7, PSA < 10 mg/mL, stage T1c).  Patients in their 50s or younger may not be considered ideal candidates for brachytherapy based on concerns regarding the durability of treatment. Ideally, the cancer should be within a prostate of less than 60 mL volume. Patients with locally advanced prostate cancer may be under treated by brachytherapy alone, and therefore, these patients are commonly treated with external beam radiation therapy in conjunction with brachytherapy.
 
Other Information
Brachytherapy can be given either alone or in combination with EBRT. According to guidelines issued by the American Brachytherapy Society (ABS), brachytherapy alone may be recommended for patients with low-risk disease, while either brachytherapy or EBRT may be recommended for patients with intermediate disease and combined therapy with brachytherapy and EBRT may be recommended for those with high-risk disease.
 
2008 Update
The benefit of combining external beam radiation therapy with brachytherapy is being studied in a phase III trial “Interstitial Brachytherapy With or Without External Beam Radiation Therapy in Treating Patients With Prostate Cancer” (NCT00063882).
 
RATIONALE: Radiation therapy uses high-energy x-rays and other sources to damage tumor cells. Interstitial brachytherapy uses radioactive material placed directly into or near a tumor to kill tumor cells. Combining interstitial brachytherapy with external-beam radiation therapy may kill more tumor cells. It is not yet known whether interstitial brachytherapy is more effective with or without external-beam radiation therapy in treating prostate cancer.
 
PURPOSE: Randomized phase III trial to compare the effectiveness of interstitial brachytherapy with or without external-beam radiation therapy in treating patients who have prostate cancer.
 
2012 Update
A literature search was conducted using the MEDLINE database through June 2012. There was no new information identified that would prompt a change in the coverage statement. The following is a summary of the relevant identified publications.
 
In a 2012 comparative effectiveness report from the international Prostate Cancer Results Study Group (PCRSG), prostate-specific antigen (PSA)-free survival following various prostate cancer treatments, including brachytherapy, was noted to be difficult to evaluate, since very few studies that compared results from treatment options were identified (Grimm, 2012). Additionally, variations in methods of evaluating outcomes and reporting results complicated the analysis. The PCRSG only included studies on external-beam radiation therapy (EBRT) that used a minimum 72 Gy conformal or intensity-modulated radiation therapy (IMRT). The authors concluded, in low-risk and intermediate-risk prostate cancer, PSA progression-free survival was higher on average with brachytherapy over radical prostatectomy or EBRT. In intermediate-risk patients, outcomes were similar with brachytherapy with or without EBRT. With high-risk patients, combined brachytherapy with EBRT with or without androgen deprivation produced better outcomes than brachytherapy, surgery, or EBRT alone.
 
Peinemann and colleagues reported on results from a Cochrane review of brachytherapy in 2011 (Peinemann, 2011). The authors focused the review on the only identified randomized controlled trial (RCT), Giberti et al., reported below (Giberti, 2009). The Giberti study compared brachytherapy to radical prostatectomy and was considered to have a high risk of bias. Peinemann and colleagues also reported on results from a systematic review of brachytherapy in 2011 (Peinemann, 2011). In this review, the Giberti RCT (Giberti, 2009) and 30 nonrandomized studies were included; all of which were found to also have a high risk of bias. Heterogeneity and the poor quality of available studies limited the interpretation of findings. In both of these reviews, the authors concluded that RCTs are needed to determine the role of brachytherapy for localized prostate cancer. Similarly, in another 2011 systematic review, Bannuru and colleagues analyzed 75 studies (10 RCTs and 65 nonrandomized comparative studies) on radiation therapy for clinically localized prostate cancer (Bannuru, 2011). Radiation therapies included brachytherapy, high-dose rate (HDR) brachytherapy, and EBRT (conformal radiation, intensity-modulated radiotherapy, or proton therapy). The authors found the evidence was insufficient to compare the effectiveness of different forms of radiation treatments. Additionally, the effects of radiation treatments on patient survival were unclear compared to no treatment or no initial treatment. However, evidence considered to be of moderate strength showed higher EBRT dosages were consistently associated with increased long-term biochemical control rates compared to EBRT delivered at lower dosages.
 
Williams et al. compared data from the United States Surveillance, Epidemiology, and End Results (SEER) Medicare-linked data on 10,928 patients with localized prostate cancer treated with primary cryoablation or brachytherapy (Williams, 2011). Urinary and erectile dysfunction occurred significantly more frequently with cryoablation than brachytherapy (41.4% and 34.7% vs. 22.2% and 21%, respectively). The use of androgen deprivation therapy also occured significantly more often after cryoablation than brachytherapy, suggesting a higher rate of prostate cancer 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%).
 
Merrick and colleagues randomized 247 intermediate- to high-risk prostate cancer patients to receive brachytherapy with either 20 Gy or 44 Gy EBRT (Merrick, 2012). At a median follow-up of 9 years, no statistically significant differences were found in biochemical progression-free survival (BPFS), cause-specific survival, and overall survival (OS) between the 2 groups of supplemental EBRT. This suggests outcomes were influenced by quality brachytherapy implants rather than an increased radiation dosage of EBRT. At 8 and 10 years’ follow-up for the entire study population, BPFS was 93.2%, the cause-specific survival was 97.7%, and 96.9%, and OS was 80.8% and 75.4%, respectively.
 
Long-term results from the RTOG 0019 study were published in 2012, with data from 131 patients followed for a median of 8.3 years (Lawton, 2012). Late genitourinary (GU) and/or gastrointestinal (GI) tract toxicity greater than grade 3 was estimated to be 15% and most commonly included urinary frequency, dysuria, and proctitis. Grade 3 impotence was reported in 42% of patients. As noted above, these adverse effects rates with combined modality therapy (CMT) were higher than are often reported for either brachytherapy or EBRT treatment alone. Estimates of biochemical failure were 18% by the Phoenix definition and 21% by ASTRO’s definition and were similar to either treatment alone.
 
2013 Update
A literature search using the MEDLINE database was conducted through June 2013. There was no new information identified that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
 
Nepple et al. analyzed data obtained prospectively from 2 centers to compare prostate cancer treatment mortality outcomes in men without comorbidities (Nepple, 2013). The analysis included 4,459 men treated with radical prostatectomy compared to 972 men treated with brachytherapy and 1,261 men treated with EBRT. After treatment, there was a median follow-up of 7.2 years. Brachytherapy did not significantly increase prostate cancer mortality when compared to radical prostatectomy using Cox analysis or competing risk analysis; however, EBRT did increase prostate cancer mortality under Cox analysis. Overall mortality increased with both brachytherapy (hazard ratio [HR]: 1.78; 95% confidence interval [CI]: 1.37-2.31) and EBRT (HR: 1.71; 95% CI: 1.40-2.08) compared to radical prostatectomy.
 
Kollmeier et al. reported on 236 men, age 60 or younger, treated with brachytherapy with or without EBRT (Kollmeier, 2013). The prostate cancer-specific survival rate was 99% at a median follow-up of 83 months. Genitourinary toxicity >2 was 14% and gastrointestinal toxicity was 3%. Potency remained at last follow-up in 51% of the men who were potent before treatment. Buckstein and colleagues also reported on 131 men, age 60 or younger, treated with brachytherapy with or without EBRT (Buckstein, 2013).  Only 1 prostate cancer-related death occurred during median follow-up of 11.5 years. Potency remained at last follow-up in 69% of the men who were potent before treatment, However, the mean Sexual Health Inventory for Men score decreased significantly from 19.5 to 15.3 (p=.008).
 
Ongoing Trials
A search of online site ClinicalTrials.gov identified several active studies on brachytherapy for prostate cancer treatment. In a randomized Phase 3 trial, the effectiveness of brachytherapy with or without EBRT will be evaluated in intermediate-risk prostate cancer patients (NCT00063882). A randomized Phase 3 study of patients with intermediate- and high-risk localized prostate cancer will compare androgen suppression and elective pelvic nodal irradiation followed by high-dose 3-D conformal boost versus androgen suppression and elective pelvic nodal irradiation followed by Iodine-125 brachytherapy implant boost (NCT00175396). In another randomized Phase 3 trial, androgen-deprivation therapy and various approaches to radiation therapy including brachytherapy will be studied in 2,580 patients. (NCT01368588).
 
Practice Guidelines
The National Comprehensive Cancer Network (NCCN) guidelines for prostate cancer (v.2.2013) note that the cancer-control rates for brachytherapy appear comparable to surgery for low-risk tumors with medium-term follow up (NCCN, 2013). The guidelines also add that for intermediate- and high-risk cancer, brachytherapy may be combined with external-beam radiation therapy (40–50 Gy) with or without androgen deprivation, but the complication rates increase.
 
The guidelines state that patients with very large or very small prostates, symptoms of bladder outlet obstruction, or previous transurethral resection of the prostate (TURP) are more difficult to implant and may suffer increased risk of side effects. In cases of enlarged prostate, neoadjuvant androgen deprivation therapy may be used to shrink the prostate.
  
2014 Update
A literature search conducted through June 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Rodrigues et al, in 2013, reported on a systematic review that analyzed 36 articles on brachytherapy for low- or intermediate-risk prostate cancer (Rodrigues, 2013). No evidence was found indicating the efficacy of brachytherapy differed from external-beam radiation therapy (EBRT), or radical prostatectomy (RP). However, non-comparative studies were included in the analysis due to the lack of available RCTs thus limiting interpretation of the conclusions.
 
There is limited data in the published literature on focal prostate brachytherapy. Available reports have focused on methods for delineating and evaluating tumor areas to identify appropriate candidates for focal prostate therapy and treatment-planning approaches. Reports on patient outcomes after focal brachytherapy are limited.  In a 2013 systematic review, Valerio et al. reviewed studies on focal prostate cancer therapies (Valerio, 2013).  However, only 1 series by Nguyen et al. included in the systematic review, reported on focal brachytherapy (Nguyen, 2012). In the Nguyen study, 318 men received brachytherapy only to the peripheral zone. In low-risk and intermediate-risk cases, freedom from PSA failure (defined as nadir +2) was 95.1% and 73% at 5 years and 80.4% and 66.4% at 8 years, respectively.
 
Ongoing Trials
In a Phase 3, prospective, multi-center, randomized trial, 1,520 patients with intermediate-risk prostate cancer will be studied to compare dose-escalated radiotherapy (EBRT or EBRT with HDR or LDR brachytherapy) with or without short-term androgen deprivation therapy (NCT00936390).
 
2015 Update
A literature search conducted through May 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Brachytherapy Used as Monotherapy
Most of the evidence on brachytherapy used as monotherapy comprises uncontrolled case series. One large retrospective case series by Martinez and colleagues describes long-term outcomes (median followup 63 months, range 6-164 months) with LDR brachytherapy in 700 men treated between January 2000 and July 2012 At 5- and 10-years follow-up, overall survival was 94% (95% CI, 92, 96) and 84% (95% CI, 78, 90), respectively, while BRFS rates were 95% (95% CI, 93, 97) and 85% (95% CI, 79, 91). Other larger series show similar rates of BRFS, as summarized within the Martinez article (Martinez, 2015).
 
National Comprehensive Cancer Network
National Comprehensive Cancer Network guidelines for prostate cancer (v.1.2015) note that low-dose rate (LDR) brachytherapy as monotherapy is indicated for patients with low-risk cancers and selected patients with low-volume immediate-risk cancers (NCCN, 2015). Intermediate-risk cancers may be treated by combining LDR brachytherapy with EBRT (40-50Gy) and ±4 to 6 mo. neoadjuvant/concomitant/adjuvant ADT. Patients with high-risk cancers may be treated with a combination of EBRT (40-50Gy) and LDR brachytherapy ± 2 to 3 y neoadjuvant/concomitant/adjuvant ADT. The guidelines further state that patients with very large or very small prostates, symptoms of bladder outlet obstruction, or previous transurethral resection of the prostate are more difficult to implant and may suffer increased risk of adverse effects. In cases of enlarged prostate, neoadjuvant androgen deprivation therapy may be used to shrink the prostate. However, increased toxicity would be expected and prostate size may not decline.
 
2017 Update
A literature search conducted through June 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Randomized Controlled Trials
No randomized controlled trials (RCTs) were identified that compared low-dose rate (LDR) brachytherapy combined with external-beam radiotherapy (EBRT) to LDR brachytherapy or to EBRT alone in patients with clinically localized prostate cancer. One RCT, by Morris and colleagues addressed a related topic (Morris, 2017). Known as the ASCENDE-RT trial, all patients had androgen deprivation therapy (ADT) and EBRT and the investigators compared EBRT boost to a LDR brachytherapy boost. The primary outcome, biochemical progression-free survival (BPFS) at a median follow-up of 6.5 years, significantly favored the LDR brachytherapy group (p=0.004). In a subgroup analysis limited to patients with intermediate-risk prostate cancer ie clinically localized disease, BPFS was significantly higher in the brachytherapy boost group (p=0.003). Overall survival (OS) and disease-specific survival did not differ significantly in the LDR brachytherapy boost and EBRT boost groups.
 
Observational Studies
In 2017, Abugharib and colleagues reported on 579 patients with localized prostate cancer who were treated with LDR brachytherapy combined with EBRT (n=191) or EBRT alone (n=388) (Abugharib, 2017).  Patients were not randomized to treatment group, and ADT was given at the physician’s discretion to patients in both groups. After a median follow-up of 7.5 years, 13 (7%) patients in the combined treatment group and 77 (20%) patients in the EBRT alone group had biochemical recurrence. Actuarial BPFS up to 10 years was significantly higher in the combined treatment than in the EBRT-only group (p=0.014). In addition, local progression-free survival significantly favored the combined treatment group (p=0.042), but distant metastasis-free survival did not differ significantly between groups (p=0.21). There was no significant difference between groups in the rate of gastrointestinal (GI) toxicity (grade 2), but the combined treatment group had a significantly higher incidence of grade 3 genitourinary (GU) toxicity than the EBRT-only group.
 
Long-term rectal toxicity results were published by Serrano and colleagues from a study evaluating LDR on brachytherapy patients with prostate cancer (stage T1c-T2b) (Serrano, 2016).  A total of 245 patients were followed for at least 5 years (median follow-up, 7.5 years). Eighty-five (33.5%) patients received EBRT in addition to LDR brachytherapy. Sixteen (6.5%) patients developed rectal toxicity (grade 2) and 7 (2.9%) developed rectal toxicity (grade 3). Six of the 7 patients who developed rectal toxicity at grade 3 or higher had received combined treatment. The authors did not report the number of patients with rectal toxicity at grade 2 or higher who had EBRT only versus LDR brachytherapy plus EBRT. Moreover, survival outcomes were not reported.
 
Several observational studies have used matching to control for potential confounding due to lack of randomization. In 2017, Loblaw and colleagues evaluated data on men with clinically localized prostate cancer from the Genitourinary Radiation Oncologists of Canada (GUROC) prostate cancer database (Loblaw, 2017). They identified 458 treated with LDR brachytherapy, 64 treated with EBRT, and 90 treated with stereotactic ablative body radiotherapy (SABR), a high-precision EBRT technique. The investigators created 2 sets of matched cohorts to control for confounding factors: SABR versus LDR brachytherapy and SABR versus EBRT. Cohorts were matched on age, baseline PSA, T stage, and number of positive cores. The SABR versus LDR cohorts included 284 patients, 71 of whom received SABR and 213 of whom received LDR brachytherapy. Analysis of SABR versus LDR brachytherapy outcomes found no significant differences between groups in BPFS or OS either before matching (p=0.52 and p=0.71, respectively) or after matching (p=0.33 and 0.56, respectively).
 
Several large uncontrolled observational studies have also been published. A large multicenter study from
Italy, published in 2016 by Fellin and colleagues included with 2237 patients with clinically localized prostate cancer who were treated with LDR brachytherapy as monotherapy and followed for at least 2 years (Fellin, 2016). Median follow-up was 65 months. Three-, 5-, and 7-year OS rates were 96.7%, 94.0%, and 89.2%, respectively. Three-, 5-, and 7-year disease-specific survival rates were 99.7%, 99.5%, and 98.4%, respectively. A total of 207 patients experienced biochemical failure after a median of 42 months. The 3-, 5-, and 7-year BPFS rates were 95.7%, 91.9%, and 88.5%, respectively.
 
A 2016 systematic review by Baydoun and colleagues on focal therapy for prostate cancer identified the Nguyen et al series, described above and 1 other relevant series (Baydoun, 2017). That study, by Cosset and colleagues, included 21 patients who underwent permanent iodine seed implants for low-risk prostate cancer (Cosset, 2013). The study reported on toxicity but not on biochemical control or survival outcomes. One patient experienced mild rectal toxicity at 2 months and no rectal toxicity was reported at 6 or 12 months. The mean score on the International Index of Erectile Function 5 scale was 20.1 at baseline and 19.8 at 12 months. (This scale ranges from 0 to 25, with a higher score indicating better function.)
 
ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed below:
 
Ongoing:
(NCT02895854) LDR Brachytherapy Versus SBRT for Low and Intermediate Risk Prostate Cancer Patients (BRAVEROBO); planned enrollment 44; projected completion date December 2019.
 
(NCT02692105) Comparison of HDR vs. LDR Brachytherapy as Monotherapy for Intermediate Risk Prostate Cancer; planned enrollment 60; projected completion date April 2026.
 
2018 Update
A literature search was conducted through June 2018.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
PERMANENT LOW-DOSE RATE BRACHYTHERAPY PLUS EXTERNAL-BEAM RADIOTHERAPY
 
Randomized Controlled Trials
No randomized controlled trials (RCTs) were identified that compared low-dose rate (LDR) brachytherapy combined with external-beam radiotherapy (EBRT) with LDR brachytherapy or with EBRT alone in patients with clinically localized prostate cancer. One RCT, by Morris et al, addressed a related topic (Morris, 2017). Known as the ASCENDE-RT trial, all patients received androgen deprivation therapy (ADT) and EBRT, and the investigators compared EBRT boost with an LDR brachytherapy boost. The primary outcome (biochemical progression-free survival [BPFS]) at a median follow-up of 6.5 years significantly favored the LDR brachytherapy group (p=0.004). In a subgroup analysis limited to patients with intermediate-risk prostate cancer (ie, clinically localized disease), BPFS was significantly higher in the brachytherapy boost group (p=0.003). Overall survival (OS) and disease-specific survival did not differ significantly between the LDR brachytherapy boost and the EBRT boost groups.
 
Observational Studies
Abugharib et al reported on 579 patients with localized prostate cancer who were treated with
LDR brachytherapy plus EBRT or with EBRT alone (Abugharib, 2017). Patients were not randomized to a treatment group, and ADT was given at the physician’s discretion to patients in both groups. After a median follow-up of 7.5 years, 13 (7%) patients in the combined treatment group and 77 (20%) patients in the EBRT-alone group had a biochemical recurrence. Actuarial BPFS up to 10 years was significantly higher in the combined treatment than in the EBRT-only group (p=0.014). Additionally, local progression free survival significantly favored the combined treatment group (p=0.042), but distant metastasis-free survival did not differ significantly between groups (p=0.21). There was no significant difference between groups in the rate of gastrointestinal (GI) toxicity (grade 2), but the combined treatment group had a significantly higher incidence of grade 3 genitourinary (GU) toxicity than the EBRT-only group.
 
Serrano et al published long-term rectal toxicity results from a study evaluating LDR brachytherapy patients with prostate cancer (Serrano, 2016). A total of 245 patients were followed for at least 5 years (median follow-up, 7.5 years). Eighty-five (33.5%) patients received EBRT in addition to LDR brachytherapy. Sixteen (6.5%) patients developed rectal toxicity (grade 2) and 7 (2.9%) developed rectal toxicity (grade 3). Six of the 7 patients who developed grade 3 or 4 rectal toxicity had received combined treatment. The authors did not report the number of patients with grade 2, 3, or 4 rectal toxicity
who in either group. Moreover, survival outcomes were not reported.
 
PERMANENT LDR BRACHYTHERAPY AS MONOTHERAPY
 
Observational Studies
Several observational studies have used matching to control for potential confounding due to lack of randomization. Loblaw et al evaluated data on men with clinically localized prostate cancer from the Genitourinary Radiation Oncologists of Canada prostate cancer database (Loblaw, 2017). They identified 458 treated with LDR brachytherapy, 64 treated with EBRT, and 90 treated with stereotactic ablative body radiotherapy (SABR), a high-precision EBRT technique. The investigators created 2 sets of matched cohorts to control for confounding factors: SABR vs LDR brachytherapy and SABR vs EBRT. Cohorts were matched on age, baseline PSA level, T stage, and number of positive cores. The SABR vs LDR cohorts included 284 patients, 71 of whom received SABR and 213 of whom received LDR brachytherapy. Analysis of SABR vs LDR brachytherapy outcomes found no significant differences between groups in BPFS or OS either before matching (p=0.52 and p=0.71, respectively) or after matching (p=0.33 and 0.56, respectively).
 
Several large uncontrolled observational studies have also been published. A large multicenter study from
Italy, published by Fellin et al, included 2237 patients with clinically localized prostate cancer who were treated with LDR brachytherapy as monotherapy and followed for at least 2 years (Fellin, 2016). Median follow up was 65 months. Three-, 5-, and 7-year OS rates were 96.7%, 94.0%, and 89.2%, respectively. Three-, 5-, and 7-year disease-specific survival rates were 99.7%, 99.5%, and 98.4%, respectively. A total of 207 patients experienced biochemical failure after a median of 42 months. The 3-, 5-, and 7-year BPFS rates were 95.7%, 91.9%, and 88.5%, respectively.
 
FOCAL PROSTATE BRACHYTHERAPY ALONE OR COMBINED WITH EBRT
 
A 2017 systematic review by Baydoun et al assessing focal therapy for prostate cancer identified the
Nguyen series and another relevant series (Baydoun, 2017). That study, by Cosset et al, included 21 patients who underwent permanent iodine seed implants for low-risk prostate cancer (Cosset, 2013). The series reported on toxicity but not on biochemical control or survival outcomes. One patient experienced mild rectal toxicity at 2 months, and no rectal toxicity was reported at 6 or 12 months. The mean score on the International Index of Erectile Function 5 scale was 20.1 at baseline and 19.8 at 12 months. (This scale ranges from 0 to 25, with a higher score indicating better function.)
 
American College of Radiology
In 2017, the American College of Radiology published appropriateness criteria for permanent
brachytherapy for prostate cancer (ACR, 2017). Relevant recommendations are:
 
      • “PPB [permanent prostate brachytherapy] monotherapy remains an appropriate and effective curative treatment for low-risk prostate cancer patients.”
      • “PPB monotherapy can be considered for select intermediate-risk patients. Multiparametric MRI
[magnetic resonance imaging] may be useful in selecting such patients.”
      • “High-risk localized prostate cancer treated with PPB should be managed in conjunction with EBRT and ADT.”
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Delouya et al published a retrospective, single-center cohort study analyzing patients with D’Amico intermediate-risk prostate cancer treated with brachytherapy or EBRT (Delouya, 2017). Of the 475 patients identified, 222 were treated with brachytherapy and 253 with EBRT. Median follow-up for patients without biochemical failure was 56 months, and median time to biochemical failure was 44.5 months. The brachytherapy group had a significantly less biochemical failure than EBRT (5.4% vs 14.2%, respectively; p=0.036), and the 7-year biochemical recurrence-free survival rates were 91% and 83%, respectively. In multivariate analysis, only Cancer of the Prostate Risk Assessment (CAPRA) score was a significant predictor of biochemical failure. Of patients with CAPRA scores of 0, 1, or 2, a better outcome was observed in those treated with brachytherapy (p=0.042), but there was no difference in patients with CAPRA scores of 3, 4, or 5 (p=0.5). The study was limited by its retrospective design and did not report toxicity data.
 
2020 Update
A literature search was conducted through June 2020.  There was no new information identified that would prompt a change in the coverage statement.  
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Matsuoka et al reported on outcomes of focal LDR brachytherapy in 51 patients with low- to intermediate-risk prostate cancer. Propensity scoring was used to select an additional 51 pair-matched patients who received RP (Matsuoka, 2022). Patients were followed for a median of 5.7 years, and biochemical failure, additional treatment, and systemic salvage therapy in the focal LDR brachytherapy patients occurred in 24%, 20%, and 8% of patients, respectively. In the RP cohort, 6% of patients underwent systemic salvage therapy. Five-year OS in the focal LDR brachytherapy and RP cohorts were 98% and 100%, respectively (p=.947). Focal LDR brachytherapy patients also achieved greater GU function compared to the RP cohort.
 
In 2022, the ACR, American Brachytherapy Society (ABS), and the American Society for Radiation Oncology (ASTRO) jointly released a practice parameter for transperineal permanent brachytherapy of prostate cancer (Bittner, 2022). The practice parameter provides a framework for the appropriate use of low-dose rate (LDR) brachytherapy either as monotherapy or as a combination treatment with EBRT.
 
The American Brachytherapy Society convened a task force to provide evidence-based consensus recommendations for LDR brachytherapy for the primary treatment of prostate cancer (King, 2021). Relevant recommendations are:
 
"Brachytherapy monotherapy could be considered for patients with low-risk disease who decline active surveillance and favorable intermediate risk disease."
 
"Patients with unfavorable intermediate risk or high-risk disease could be considered for brachytherapy boost in combination with EBRT."

CPT/HCPCS:
55875Transperineal placement of needles or catheters into prostate for interstitial radioelement application, with or without cystoscopy
76965Ultrasonic guidance for interstitial radioelement application
77778Interstitial radiation source application, complex, includes supervision, handling, loading of radiation source, when performed
G0458Low dose rate (ldr) prostate brachytherapy services, composite rate

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