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8.01.14 Section: Effective Date: Therapy Subsection: Therapy Subject: Original Policy Date: September 9, 2011 Brachytherapy for Clinically Localized Prostate Page: Cancer Using Permanently Implanted Seeds Last Review Status/Date: October 15, 2016 1 of 12 September 2016 Brachytherapy for Clinically Localized Prostate Cancer Using Permanently Implanted Seeds Description Brachytherapy is a procedure in which a radioactive source (eg, radioisotope "seeds") is permanently or temporarily implanted to treat localized prostate cancer. The radiation in brachytherapy penetrates only short distances and is intended to deliver tumoricidal radioactivity directly to the tumor to improve local control, while sparing surrounding normal tissue. Focal (subtotal) prostate brachytherapy is a form of organ-preserving therapy for small localized prostate cancers. This policy only reviews permanent low-dose rate brachytherapy in prostate cancer. Background Brachytherapy is a procedure in which a radioactive source (eg, radioisotope "seeds") is used to treat localized prostate cancer. 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. Local tumor control has been reported to be 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 those with low-risk disease; temporary (high-dose rate, HDR) brachytherapy is typically reserved for intermediate- or high-risk patients. This policy only reviews permanent LDR brachytherapy in prostate cancer. The proposed biologic advantages of brachytherapy compared to external beam radiation therapy (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 40-60 centrigray per hour (cGy/h), whereas conventional fractionated EBRT dose rates exceed 200 cGy/min. 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, LDRs cause ongoing tumor destruction in the setting of normal tissue repair. In addition, brachytherapy is performed as a single procedure in the outpatient setting, which may represent a patient preference issue compared to the multiple sessions required to deliver EBRT. The total doses of radiotherapy (RT) that can be delivered may also vary between EBRT and brachytherapy, especially with newer forms of EBRT such as 3D conformal radiation therapy and intensity-modulated radiation therapy (IMRT). 8.01.14 Section: Therapy Subsection: Therapy Subject: Effective Date: October 15, 2016 Original Policy Date: September 9, 2011 Brachytherapy for Clinically Localized Prostate Page: Cancer Using Permanently Implanted Seeds 2 of 12 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 RT, concerns exist with the long-term risk of treatmentrelated 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 either iodine-125 or palladium-103. Use of cesium-131 is also being studied. Use of iodine-125 requires more seeds, thus reducing dosimetric dependence on any single seed. Post-implant dosimetric assessment should be performed to ensure the quality of the implant and optimal source placement (ie, the targeted tumor areas receive the predetermined radiation dosages while nearby structures and tissues are preserved). Permanent brachytherapy may be used alone as monotherapy or may be combined with EBRT (together known as combined modality therapy [CMT]) as a way to boost the dose of RT delivered to the tumor; CMT 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. Focal or subtotal prostate brachytherapy is a form of more localized, organ-preserving therapy for small localized prostate cancers. With this approach, brachytherapy “seeds” are placed only in the areas where the tumor has been identified rather than throughout the whole prostate gland. This is done in an effort to reduce the occurrence of adverse events that may be associated with brachytherapy, including urinary, bowel, and sexual dysfunction. Regulatory Status A large number of permanently implanted seeds for brachytherapy of prostate cancer have become available since 1999. The U.S. Food and Drug Administration (FDA) has cleared these devices through its 510(k) process, including I-Seed® (Theragenics Corp.), Proxcelan™ Cs-131 (IsoRay Medical), and BrachySource® Brachytherapy Seed Implants (C.R. Bard). The FDA device classification is: “Source, Brachytherapy Radionuclide.” FDA product code: KXK. Related Policies 6.01.10 7.01.79 8.01.10 8.01.33 Stereotactic Radiosurgery and Stereotactic Body Radiation Therapy Cryoablation of Prostate Cancer Charged Particle (Proton or Helium Ion) Radiation Therapy High-Dose Rate Temporary Prostate Brachytherapy 8.01.14 Section: Therapy Subsection: Therapy Subject: Effective Date: October 15, 2016 Original Policy Date: September 9, 2011 Brachytherapy for Clinically Localized Prostate Page: Cancer Using Permanently Implanted Seeds 3 of 12 Policy *This policy statement applies to clinical review performed for pre-service (Prior Approval, Precertification, Advanced Benefit Determination, etc.) and/or post-service claims. Brachytherapy using permanent transperineal implantation of radioactive seeds may be considered medically necessary in the treatment of localized prostate cancer when used as monotherapy or in conjunction with external beam radiation therapy (EBRT) (see Policy Guidelines). Focal prostate brachytherapy is considered investigational in the treatment of prostate cancer. Policy Guidelines Permanent 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 EBRT (3-dimensional conformal, radiotherapy [3DCRT], intensity-modulated, or proton) is used, sometimes along with androgen deprivation to treat higher risk disease. Adequate dose escalation should be achieved with combination permanent brachytherapy and 3D-CRT. Intensity-modulated radiotherapy [IMRT] should be limited only to cases in which 3D-CRT planning is not able to meet dose volume constraints for normal tissue tolerance. Prostate cancer risk is often defined using the following criteria: Low risk: PSA [prostate-specific antigen] 10 ng/mL or less, Gleason score 6 or less, and clinical stage T1c (very low risk) or T1-T2a. Intermediate risk: PSA > 10 but 20 ng/mL or less, or Gleason score 7, or clinical stage T2b-T2c. High Risk: PSA >20 ng/mL or Gleason score 8–10, or clinical stage T3a for clinically localized disease and T3b-T4 for locally advanced disease. Permanent low-dose rate (LDR) brachytherapy, as monotherapy, in the treatment of localized prostate cancer may be best used in men older than 60 years with small volume cancer of low-risk disease (Gleason sum, <7; PSA score, <10 mg/mL; stage T1c). (1) Patients in their 50s or younger may not be considered ideal candidates for brachytherapy based on concerns regarding the durability of treatment and quality-of-life outcomes. However, favorable outcomes in men 60 years or younger treated with brachytherapy for localized prostate cancer have been reported. Ideally, the cancer should be within a prostate with a volume of less than 60 mL. Patients with locally advanced prostate cancer may be undertreated by permanent brachytherapy alone. The procedure is usually performed in two stages: a prostate volume study followed at a later date by the implant itself, which is performed in the operating room with the patient under general or epidural anesthesia. Iodine or palladium is the typical isotope used; and the selection of isotope is usually based on physician preference. A CT (computed tomography) scan is usually performed at some stage after the procedure to determine the quality of the seed placement. 8.01.14 Section: Therapy Subsection: Therapy Subject: Effective Date: October 15, 2016 Original Policy Date: September 9, 2011 Brachytherapy for Clinically Localized Prostate Page: Cancer Using Permanently Implanted Seeds 4 of 12 Rationale Evaluating treatment options for clinically localized prostate cancer is difficult because there is minimal evidence comparing various treatments, including active surveillance, in terms of improving clinically meaningful patient outcomes. Assuming that an intervention can improve outcomes, 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, eg, brachytherapy is associated with equivalent or superior long-term outcomes compared to alternative therapies including various types of RT. These data are not currently available. The lack of randomized controlled trial (RCT) makes it difficult to reach strict evidence based conclusions regarding the comparative efficacy of brachytherapy with other treatments for localized prostate cancer. The framework often used in analyzing treatments of localized prostate cancer, given the lack of comparative studies and lack of information regarding impact on survival, is to evaluate the effect of the treatment on surrogate endpoints (eg, biochemical free survival) and treatment-related complications. Brachytherapy has become widely accepted among physicians and its speed and convenience compared to EBRT 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. Permanent Low-Dose Rate Brachytherapy Alone or Combined With EBRT Systematic Reviews 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, because very few studies that compared results from treatment options were identified. (1) Additionally, variations in methods of evaluating outcomes and reporting results complicated the analysis. The PCRSG only included studies on EBRT that used a minimum 72 Gy conformal or intensity-modulated radiation therapy (IMRT). In low-risk and intermediate-risk prostate cancer, biochemical relapse-free survival (BRFS) was higher on average with brachytherapy over RP 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. A 2009 review was conducted on both brachytherapy (permanent) and proton beam therapy. (2) This report concluded that brachytherapy was at least comparable to IMRT for localized prostate cancer in terms of clinical effectiveness. This review also concluded that brachytherapy was a high-value technology compared with IMRT. Despite identifying 166 studies that met their review criteria for this report, only 1 study compared these treatments: a single-center evaluation of toxicity rates in 2 different case series of brachytherapy or IMRT. Nearly all other studies were relatively small single- 8.01.14 Section: Therapy Subsection: Therapy Subject: Effective Date: October 15, 2016 Original Policy Date: September 9, 2011 Brachytherapy for Clinically Localized Prostate Page: Cancer Using Permanently Implanted Seeds 5 of 12 center case series of a single modality with evidence further limited by variability in population demographics, disease risk status, and measures of treatment success and treatment-related complications. In this review, at 5 years after diagnosis, survival estimates ranged from 60% to 90% for active surveillance and 77% to 97% for brachytherapy. This review also estimated acute and late radiation toxicities based on studies identified. This analysis of toxicity was based on studies that used standardized scoring criteria and, in general, involved a level of severity of 2 or more. For acute gastrointestinal (GI) toxicity, the rate was estimated at 2% for brachytherapy and 18% for IMRT; and for chronic GI toxicity, these rates were 4% and 7%, respectively. For genitourinary (GU) toxicity, acute rates were about 30% for both therapies and about 15% for chronic toxicity. Erectile dysfunction was 32% in the brachytherapy studies. Seed migration is a unique risk with permanent brachytherapy. It occurs when 1 or more seeds dislodge and travel to nearby organs (eg, bladder, lung). Although seed migration has been reported in 6% to 55% of patients, reports of harm are limited to individual case studies. Permanent Low-Dose Rate Brachytherapy Alone Systematic ReviewsA 2011 Cochrane review by Peinemann et al evaluated literature on low-dose brachytherapy for prostate cancer. (3) The review focused on the only identified RCT, Giberti et al. (4) The Giberti trial compared brachytherapy with RP and was considered to have a high risk of bias. Peinemann et al also conducted a systematic review of brachytherapy in 2011.5 In this review, the Giberti RCT and 30 nonrandomized studies were included, all of which were found to also have a high risk of bias. Randomized Controlled Trials The 2009Giberti RCT reported results for 200 low-risk prostate cancer patients randomized to RP or brachytherapy. (4) Biochemical progression-free survival (BPFS) rates at 5 years were 90% for RP and 91.7% for brachytherapy. Both treatment groups experienced decreases in quality of life at 6 months and 1 year posttreatment, although brachytherapy patients reported more urinary disorders but better erectile function than the RP group. At 5-year follow-up, functional outcomes did not differ between arms. Crook et al also reported on quality-of-life outcomes at 5 years in 168 patients after RP or brachytherapy in the SPIRIT (Surgical Prostatectomy Versus Interstitial Radiation Intervention) Trial. (6) In this study, 34 patients were randomized, and another 134 patients were allowed to select a treatment group. SPIRIT was closed after 2 years due to poor patient accrual. At a median of 5.2-year follow-up, the brachytherapy patients scored better in patient satisfaction and urinary and sexual function than RP patients. Nonrandomized Studies In a 1:1 matched-pair design, Pickles et al prospectively followed 278 low- and intermediate-risk, localized prostate cancer patients treated with brachytherapy or conformal EBRT (139 patients in each group). (7) The biochemical control (nadir + 2) at 5 years was 95% in the brachytherapy group versus 85% in the EBRT group (p<0.001). This rate was unchanged at 7 years in the brachytherapy group but decreased to 75% in the EBRT group. Brachytherapy patients experienced more urinary complaints, whereas EBRT patients had more rectal and bowel issues. 8.01.14 Section: Therapy Subsection: Therapy Subject: Effective Date: October 15, 2016 Original Policy Date: September 9, 2011 Brachytherapy for Clinically Localized Prostate Page: Cancer Using Permanently Implanted Seeds 6 of 12 Coen et al compared high-dose EBRT (79.2-Gy equivalent) delivered using photons and protons with permanent LDR in a case-matched analysis of 282 patients (141 matches) with localized, low- and intermediate-risk prostate cancer. (8) Biochemical failure (nadir + 2) at 8 years was 7.7% in the highdose EBRT group and 16.1% in the brachytherapy group (p=0.42). However, because case-matching may not account for important patient selection differences, the groups may not be similar. Nepple et al analyzed data prospectively from 2 centers to compare prostate cancer treatment mortality outcomes in men without comorbidities. (9) The analysis included 4459 men treated with RP, 972 men treated with brachytherapy, and 1261 men treated with EBRT. After treatment, median follow-up was 7.2 years. Brachytherapy did not significantly increase prostate cancer mortality compared with RP 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 to 2.31) and EBRT (HR=1.71; 95% CI, 1.40 to 2.08) compared with RP. Williams et al compared data from the U.S. Surveillance, Epidemiology, and End Results (SEER) Medicare-linked data on 10,928 patients with localized prostate cancer treated with primary cryoablation or brachytherapy. (10) Urinary dysfunction occurred more frequently with cryoablation (41.4%) than with brachytherapy (22.2%), p<0.001. Erectile dysfunction was also more common after cryo9ablation34.7%) than brachytherapy (21.0%), p<0.001. In addition, use of androgen deprivation therapy occurred 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%). A 2016 analysis by Pham et al evaluated outcomes of permanent brachytherapy alone in men with large prostates (>60 mL). (11) The study included 2076 men with prostate cancer from a prospectively collected database who were treated with iodine-125 brachytherapy without androgen deprivation therapy. Two hundred sixty-nine (13%) of the 2076 patients had prostate volumes greater than 60 mL (median volume, 72.5 mL). Men with prostates volumes greater than 60 mL were significantly older than men with prostates volumes of 60 mL or less, and a significantly larger proportion had Gleason score of 6 and higher initial PSA levels. Median follow-up was 55 months. The 5-year biochemical relapse-free survival (BPFS), the primary efficacy outcome, was 96.7% (95% CI, 94.4% to 98.9%) in men with prostates volumes greater than 60 mL and 92.9% (95% CI, 91.4% to 94.3%) in men with prostates volumes of 60 mL or less (p=0.02). Men with prostate volumes greater than 60 mL had significantly higher rates of grade 3 and 4 GU and GI toxicity at 5 years (7.2%) than men with prostates volumes of 60 mL or less (3.2%; p<0.001). In multivariate analyses, a prostate volume greater than 60 mL was a statistically significant predictor for better BRFS and for higher rates of late grade 3 and 4 GU toxicity. Section Summary: Permanent Low-Dose Rate Brachytherapy Alone One RCT compared brachytherapy and RP and found similar 5-year BRFS rates, quality of life, and functional outcomes. A number of observational studies and systematic reviews of the published literature found similar or better biochemical control rates and similar adverse event rates with brachytherapy and other treatments (eg, RP, EBRT, cryotherapy). 8.01.14 Section: Therapy Subsection: Therapy Subject: Effective Date: October 15, 2016 Original Policy Date: September 9, 2011 Brachytherapy for Clinically Localized Prostate Page: Cancer Using Permanently Implanted Seeds 7 of 12 Permanent Low-Dose Rate Brachytherapy Combined With EBRT Randomized Controlled Trials Merrick et al randomized 247 intermediate- to high-risk prostate cancer patients to brachytherapy with 20-Gy or 44-Gy EBRT. (12) At a median follow-up of 9 years, no statistically significant differences were found in BPFS, cause-specific survival, and overall survival (OS) between the 2 groups of supplemental EBRT. At 8- and 10-year follow-ups 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. Nonrandomized Studies 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. (13) Late GU and/or 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 previously noted, these adverse effects rates with combined modality therapy (CMT) were higher than often reported for either brachytherapy or EBRT treatment alone. Estimates of biochemical failure were 18% using the Phoenix definition and 21% using the American Society for Radiation Oncology’s definition and were similar to either treatment alone. Long-term results are also available from large cohorts treated at single institutions. For example, Sylvester et al reported on results of treatment with 45 Gy of EBRT followed by permanent brachytherapy. In this series, androgen deprivation therapy was not used. (14) This report was based on a series of 223 consecutive patients treated between 1987 and 1993; patients had stage T1 to T3 disease. Permanent brachytherapy was performed with radioactive palladium or iodine 4 weeks after EBRT. Fifteen-year BPFS was 88% in the low-risk group, 80% in the intermediate-risk group, and 53% in the high-risk group. In addition, long-term outcomes were compared with those of 2 institutions that had results for RP. Results were similar across Gleason score categories (eg, the relapse-free survival was 25%-30% for those with a Gleason score 7 for the 3 series of patients but varied for other prognostic factors such as PSA level). In another single-center report, results were summarized for CMT using 3-dimensional conformal radiotherapy followed by permanent (palladium) brachytherapy. (15) This study involved 282 intermediate- and high-risk patients. Patients were treated from 1992 to 1996. Fourteen-year freedom from biochemical progression in the intermediate-risk group was 87% and 72% in the high-risk group. In a retrospective analysis by Koontz et al, 199 patients with low- to high-risk prostate cancer were treated with low-dose rate brachytherapy and 46-Gy EBRT from June 1997 through August 2007. (16) Overall BPFS and PSA control at 5 years were 87% and 92%, respectively. In the high-risk group (n=66), overall BPFS and PSA control at 5 years were 81% and 86%, respectively. Section Summary: Permanent Low-Dose Rate Brachytherapy Combined With EBRT One RCT and a number of observational studies have been published. A 2012 comparative effectiveness report found that brachytherapy plus EBRT produced similar or better outcomes than surgery or brachytherapy alone. The RCT evaluated brachytherapy with 1 of 2 doses of EBRT and found no significant between-group differences in progression or survival outcomes and high rates of disease-specific survival for the entire study population (eg, 98% at 8 years). 8.01.14 Section: Therapy Subsection: Therapy Subject: Effective Date: October 15, 2016 Original Policy Date: September 9, 2011 Brachytherapy for Clinically Localized Prostate Page: Cancer Using Permanently Implanted Seeds 8 of 12 Focal Prostate Brachytherapy Alone or Combined With EBRT Evidence in the published literature on focal prostate brachytherapy is limited. Reports have primarily focused on methods to delineate and evaluate tumor areas to identify appropriate candidates for focal prostate therapy and treatment-planning approaches. Original clinical reports on patient outcomes after focal brachytherapy are limited. In a 2014 systematic review, Valerio et al reviewed studies on focal prostate cancer therapies. (17) However, only 1 series by Nguyen et al18 was included in the systematic review reported on focal brachytherapy. In the Nguyen study, 318 men received brachytherapy only to the peripheral zone. In low-risk and intermediate-risk cases, freedom from PSA failure (nadir + 2) was 95.1% and 73% at 5 years and 80.4% and 66.4% at 8 years, respectively. Many questions remain including treatment effectiveness, patient selection criteria, and posttreatment monitoring approaches. Ongoing and Unpublished Clinical Trials Some currently unpublished trials that might influence this review are listed in Table 1. Table 1. Summary of Key Trials NCT No. Trial Name Ongoing NCT00063882 A Phase III Study Comparing Combined External Beam Radiation and Transperineal Interstitial Permanent Brachytherapy With Brachytherapy Alone for Selected Patients With Intermediate Risk Prostatic Carcinoma NCT00936390 A Phase III Prospective Randomized Trial of Dose-Escalated Radiotherapy With or Without Short-Term Androgen Deprivation Therapy for Patients With Intermediate-Risk Prostate Cancer NCT01368588 Androgen Deprivation Therapy and High Dose Radiotherapy With or Without Whole-Pelvic Radiotherapy in Unfavorable Intermediate or Favorable High Risk Prostate Cancer: A Phase III Randomized Trial NCT: national clinical trial. Planned Enrollment Completion Date 588 Jan 2017 1520 Dec 2020 2580 Jul 2027 Practice Guidelines and Position Statements National Comprehensive Cancer Network National Comprehensive Cancer Network guidelines for prostate cancer (v.3.2016) (19) note that LDR brachytherapy as monotherapy is indicated for patients with low-risk cancers and selected patients with low-volume immediate-risk cancers. Intermediate-risk cancers may be treated by combining LDR brachytherapy with EBRT (40-50 Gray [Gy]) and ±4 to 6 months of neoadjuvant/concomitant/adjuvant androgen deprivation therapy (ADT). Patients with high-risk cancers may be treated with a combination of EBRT (40-50 Gy) and LDR brachytherapy ±2 to 3 years of neoadjuvant/concomitant/adjuvant ADT. The guidelines further state that patients with very large or very small prostates (size cutoffs were not discussed), symptoms of bladder outlet obstruction, or previous transurethral resection of the prostate 8.01.14 Section: Therapy Subsection: Therapy Subject: Effective Date: October 15, 2016 Original Policy Date: September 9, 2011 Brachytherapy for Clinically Localized Prostate Page: Cancer Using Permanently Implanted Seeds 9 of 12 are more difficult to implant and may suffer increased risk of adverse effects. In cases of enlarged prostate, neoadjuvant ADT may be used to shrink the prostate. However, increased toxicity would be expected and prostate size may not decline. American Brachytherapy Society The American Brachytherapy Society (ABS) Prostate Low-Dose Rate Task Group provides the following patient selection criteria for monotherapy: clinical stage T1b or T2b and Gleason score of 6 or less, and PSA score of 10 or less ng/mL. (20) ABS guidelines also indicate monotherapy may be used in select higher risk patients and for salvage of select radiotherapy failures. For boost, patient selection criteria include: clinical stage T2c or greater and/or Gleason score 7 or more and/or PSA level greater than 10 ng/mL. These guidelines also note inadequate information exists to recommend supplemental EBRT based on perineural invasion, percent positive biopsies, and/or magnetic resonance imaging-detected extracapsular penetration. American College of Radiology and American Society for Radiation Oncology The American College of Radiology (ACR) and American Society for Radiation Oncology (ASTRO) guidelines on permanent brachytherapy indicate permanent LDR brachytherapy is appropriate in lowto intermediate-risk patients.(21-23) These guidelines also note EBRT may be added to permanent brachytherapy in high-risk protocols. ACR/ASTRO exclusion criteria for permanent brachytherapy include: life expectancy less than 5 years; unacceptable operative risk; poor anatomy that prevents a quality implant; positive lymph nodes by pathology; significant obstructive uropathy, and distant metastases. ACR and ASTRO also note intensity-modulated radiotherapy is a widely used treatment option for many indications including prostate tumors. ACR also developed appropriateness criteria for permanent brachytherapy. ACR found brachytherapy offers “favorable morbidity profiles and durable biochemical control rates for patients with low-, intermediate-, and high-risk features.” Favorable outcomes are noted as being dependent on having a quality implant. The role of EBRT in addition to permanent brachytherapy for higher risk patients is uncertain. U.S. Preventive Services Task Force Recommendations Not applicable Summary of Evidence The evidence for permanent LDR brachytherapy alone or in combination with external beam Radiotherapy (EBRT) in patients who have localized prostate cancer consists of 2 randomized controlled trials and nonrandomized comparative or observational studies. Clinical outcomes of importance are overall survival (OS) and treatment-related morbidity. High-quality studies that differentiate superiority of any type of radiation technique are not available. In general, however, the RCT results suggest LDR brachytherapy is at least similar to either surgery (radical prostatectomy [RP]) or EBRT in terms of biochemical recurrence-free survival and functional outcomes; indirect comparison of some observational studies suggests OS rates with LDR brachytherapy are similar to those achieved with alternatives including RP and EBRT. Limitations of the evidence include patient 8.01.14 Section: Therapy Subsection: Therapy Subject: Effective Date: October 15, 2016 Original Policy Date: September 9, 2011 Brachytherapy for Clinically Localized Prostate Page: Cancer Using Permanently Implanted Seeds 10 of 12 heterogeneity; variability in treatment protocols; short follow-up periods; inconsistency in reporting important health outcomes (eg, survival vs biochemical progression-free survival rates), and inconsistency in reporting or collecting outcomes. These limitations notwithstanding, the body of evidence on permanent LDR brachytherapy, used as monotherapy or in conjunction with EBRT to treat localized prostate cancer, is sufficient to demonstrate improvements in health outcomes. The evidence for permanent LDR brachytherapy alone or in combination with EBRT for focal treatment in patients who have localized prostate cancer consists of few observational studies. Clinical outcomes of importance are OS and treatment-related morbidity. The body of evidence on permanent LDR brachytherapy, used as focal monotherapy or in conjunction with EBRT to treat localized prostate cancer, is insufficient to demonstrate improvements in health outcomes. Medicare National Coverage Brachytherapy sources and services for administration and delivery of brachytherapy are covered by Medicare. References 1. Grimm P, Billiet I, Bostwick D, et al. Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group. BJU Int. Feb 2012;109 Suppl 1:22-29. PMID 22239226 2. Institute for Clinical and Economic Review (ICER). Brachytherapy/proton beam therapy for clinically localized, low-risk prostate cancer. http://www.icer-review.org/bt-pbt/. Accessed June 27, 2016. 3. Peinemann F, Grouven U, Hemkens LG, et al. Low-dose rate brachytherapy for men with localized prostate cancer. Cochrane Database Syst Rev. 2011(7):CD008871. PMID 21735436 4. Giberti C, Chiono L, Gallo F, et al. Radical retropubic prostatectomy versus brachytherapy for low-risk prostatic cancer: a prospective study. World J Urol. Oct 2009;27(5):607-612. PMID 19455340 5. Peinemann F, Grouven U, Bartel C, et al. Permanent interstitial low-dose-rate brachytherapy for patients with localised prostate cancer: a systematic review of randomised and nonrandomised controlled clinical trials. Eur Urol. Nov 2011;60(5):881-893. PMID 21763066 6. Crook JM, Gomez-Iturriaga A, Wallace K, et al. Comparison of health-related quality of life 5 years after SPIRIT: Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial. J Clin Oncol. Feb 1 2011;29(4):362-368. PMID 21149658 7. Pickles T, Keyes M, Morris WJ. Brachytherapy or conformal external radiotherapy for prostate cancer: a single-institution matched-pair analysis. Int J Radiat Oncol Biol Phys. Jan 1 2010;76(1):43-49. PMID 19570619 8. Coen JJ, Zietman AL, Rossi CJ, et al. Comparison of high-dose proton radiotherapy and brachytherapy in localized prostate cancer: a case-matched analysis. Int J Radiat Oncol Biol Phys. Jan 1 2012;82(1):e25-31. PMID 21470787 9. Nepple KG, Stephenson AJ, Kallogjeri D, et al. Mortality after prostate cancer treatment with radical prostatectomy, external-beam radiation therapy, or brachytherapy in men without comorbidity. Eur Urol. Sep 2013;64(3):372-378. PMID 23506834 10. Williams SB, Lei Y, Nguyen PL, et al. Comparative effectiveness of cryotherapy vs brachytherapy for localised prostate cancer. BJU Int. Jul 2012;110(2 Pt 2):E92-98. PMID 22192688 11. Pham YD, Kittel JA, Reddy CA, et al. Outcomes for prostate glands >60 cc treated with low-dose-rate brachytherapy. Brachytherapy. Mar-Apr 2016;15(2):163-168. PMID 26796717 8.01.14 Section: Therapy Subsection: Therapy Subject: Effective Date: October 15, 2016 Original Policy Date: September 9, 2011 Brachytherapy for Clinically Localized Prostate Page: Cancer Using Permanently Implanted Seeds 11 of 12 12. Merrick GS, Wallner KE, Butler WM, et al. 20 Gy versus 44 Gy of supplemental external beam radiotherapy with palladium-103 for patients with greater risk disease: results of a prospective randomized trial. Int J Radiat Oncol Biol Phys. Mar 1 2012;82(3):e449-455. PMID 22196131 13. Lawton CA, Yan Y, Lee WR, et al. Long-term results of an RTOG Phase II Trial (00-19) of external-beam radiation therapy combined with permanent source brachytherapy for intermediate-risk clinically localized adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys. Apr 1 2012;82(5):e795-801. PMID 22330999 14. Sylvester JE, Grimm PD, Blasko JC, et al. 15-Year biochemical relapse free survival in clinical Stage T1-T3 prostate cancer following combined external beam radiotherapy and brachytherapy; Seattle experience. Int J Radiat Oncol Biol Phys. Jan 1 2007;67(1):57-64. PMID 17084544 15. Dattoli M, Wallner K, True L, et al. Long-term outcomes after treatment with brachytherapy and supplemental conformal radiation for prostate cancer patients having intermediate and high-risk features. Cancer. Aug 1 2007;110(3):551-555. PMID 17577217 16. Koontz BF, Chino J, Lee WR, et al. Morbidity and prostate-specific antigen control of external beam radiation therapy plus low-dose-rate brachytherapy boost for low, intermediate, and high-risk prostate cancer. Brachytherapy. Apr-Jun 2009;8(2):191-196. PMID 19433320 17. Valerio M, Ahmed HU, Emberton M, et al. The role of focal therapy in the management of localised prostate cancer: a systematic review. Eur Urol. Oct 2014;66(4):732-751. PMID 23769825 18. Nguyen PL, Chen MH, Zhang Y, et al. Updated results of magnetic resonance imaging guided partial prostate brachytherapy for favorable risk prostate cancer: implications for focal therapy. J Urol. Oct 2012;188(4):11511156. PMID 22901567 19. National Comprehensive Cancer Network. Prostate cancer. Clinical Practice Guidelines in Oncology, v.3.2016. http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed June 27, 2016. 20. American Brachytherapy Society, Prostate Low-Dose Rate Task Group, Merrick GS, et al. Prostate Low-Dose Rate Task Group: Patient Selection Criteria for Monotherapy Clinical Stage T1b-T2b and Gleason Score of 6 or Less. n.d. https://www.americanbrachytherapy.org/guidelines/prostate_low-doseratetaskgroup.pdf. Accessed June 27, 2016. 21. Frank SJ, Arterbery VE, Hsu IC, et al. American College of Radiology Appropriateness Criteria permanent source brachytherapy for prostate cancer. Brachytherapy. Sep-Oct 2011, amended 2014;10(5):357-362. PMID 21497562 22. ACR-ASTRO. Practice Guideline for Intensity Modulated Radiation Therapy (IMRT). 2011, amended 2014; http://www.acr.org/~/media/ACR/Documents/PGTS/guidelines/IMRT.pdf. Accessed June 27, 2016. 23. Rosenthal SA, Bittner NH, Beyer DC, et al. American Society for Radiation Oncology (ASTRO) and American College of Radiology (ACR) practice guideline for the transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys. Feb 1 2011;79(2):335-341. PMID 21106306 8.01.14 Section: Therapy Subsection: Therapy Subject: Effective Date: October 15, 2016 Original Policy Date: September 9, 2011 Brachytherapy for Clinically Localized Prostate Page: Cancer Using Permanently Implanted Seeds 12 of 12 Policy History Date Action September 2011 New Policy Reason December 2012 Update Policy Policy updated with literature review; investigational policy statement added on focal or subtotal prostate brachytherapy. Information on use of IMRT added to Policy guidelines. References updated September 2013 Update Policy Policy updated with literature review; policy statements unchanged. References updated, 13, 15, 16 added. September 2014 Update Policy September 2015 Update Policy Policy updated with literature review, policy statements unchanged. References 1 and 25-26 added. Policy updated with literature review, reference added. Policy statements added. Policy statements unchanged. September 2016 Update Policy Policy updated with literature review through June 7, 2016; reference 11 added. Policy statements unchanged. Keywords Brachytherapy for Prostate Cancer Prostate Cancer, Brachytherapy Radioactive Seeds This policy was approved by the FEP® Pharmacy and Medical Policy Committee on September 16, 2016 and is effective October 15, 2016. Signature on file Deborah M. Smith, MD, MPH