Brachytherapy for Clinically Localized Prostate Cancer Using Permanently Implanted Seeds. Original Policy Date

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1 MP Brachytherapy for Clinically Localized Prostate Cancer Using Permanently Implanted Seeds Medical Policy Section Therapy Issue 12/2013 Original Policy Date 12/2013 Last Review Status/Date Revised with literature search/12/20136:2012 Return to Medical Policy Index Disclaimer Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. Description Brachytherapy is a procedure in which a radioactive source (e.g., 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. Brachytherapy is a procedure in which a radioactive source (e.g., 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 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, 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

2 represent a patient preference issue compared to the multiple sessions required to deliver EBRT. The total doses of radiation therapy that can be delivered may also vary between EBRT and brachytherapy, especially with newer forms of EBRT such as 3-dimensional conformal radiation therapy (3D CRT) and intensity-modulated radiation therapy (IMRT). Brachytherapy, generally, is not indicated for patients with a large prostate or those with a urethral stricture, as the procedure results in short-term swelling of the prostate, which can lead to urinary obstruction. As with all forms of radiation therapy, there are concerns regarding the long-term risk of treatment-related secondary malignancies. There also are reports that suggest that the clinician s level of experience with brachytherapy is correlated 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, i.e., the targeted tumor areas receive the predetermined radiation dosages while nearby structures and tissue 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 radiation therapy delivered to the tumor. Again, 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. Policy Brachytherapy using permanent transperineal implantation of radioactive seeds may be consideredmedically 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 or subtotal 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 (3D-conformal,

3 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. 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 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. The procedure is usually performed in two stages: a prostate volume study (CPT code 76873) 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 are the typical isotopes 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. Rationale This policy was originally created in 1997 and was updated regularly with searches of the MEDLINE database. The most recent literature search was performed through March The following is a summary of the key literature to date. Evaluating treatment options for clinically localized prostate cancer is difficult because there is minimal evidence comparing various treatments, including active surveillance ( watchful waiting ), in terms of improving clinically meaningful patient outcomes. Even 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, for example, brachytherapy is associated with equivalent or superior long-term outcomes compared to alternative therapies including various types of radiation therapy. These data are not currently available. The lack of these trials makes it difficult to reach strict scientific 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 (such as biochemical-free survival) and treatment-related complications. Brachytherapy has become widely accepted among physicians and its speed and convenience compared to external-beam radiation 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

4 frequently reframed as an issue of patient preference, even while acknowledging that the decision must be made based on incomplete data. 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, since 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 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 (2) The authors focused the review on the only identified randomized controlled trial (RCT), Giberti et al., (3) reported below. 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 (4) In this review, the Giberti RCT (3) 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. (5) 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. A 2009 review was conducted on both brachytherapy (permanent) and proton-beam therapy. (6) This report concluded that brachytherapy was at least comparable to intensity-modulated radiation therapy (IMRT) for localized prostate cancer in terms of clinical effectiveness. This review also concluded that brachytherapy was a high-value technology compared to IMRT. The review also mentions that brachytherapy is a more established therapy than IMRT. Despite identifying 166 studies that met their review criteria for this report, only 1 study involved an internal comparison of these treatments: a single-center evaluation of toxicity rates in 2 different case series of brachytherapy or IMRT. Nearly all of the other studies were relatively small single-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

5 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 one or more seeds become dislodged and travel to nearby organs such as the bladder or lung. While this has been reported in 6% to 55% of patients, reports of harm are limited to individual case studies. Brachytherapy used as monotherapy The vast majority of the data on brachytherapy consists of uncontrolled case series, which typically report results in terms of prostate-specific antigen (PSA) outcomes, as opposed to final health outcomes. 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 lowrisk disease (Gleason sum <7, PSA <10 mg/ml, and stage T1c). (7) 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 with a volume of less than 60 ml. Patients with locally advanced prostate cancer may be undertreated by permanent brachytherapy alone. Randomized, controlled trials In Giberti et al., 200 low-risk prostate cancer patients were randomized to either radical retropubic prostatectomy or brachytherapy for low-risk prostate cancer. (3) Biochemical disease-free survival rates at 5 years were 90% for prostatectomy 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 prostatectomy group. At 5-year follow-up, functional outcomes did not differ in either arm of the study. Crook and colleagues also reported on quality-of-life outcomes at 5 years in 168 patients after radical prostatectomy or brachytherapy in the SPIRIT: Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial. (8) In this study, 34 patients were randomized, while the other 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 years follow-up, the brachytherapy patients scored better in patient satisfaction and urinary and sexual function than prostatectomy. Non-randomized, comparative studies Ragde and colleagues report 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. (9) Among low-risk patients, the freedom from increasing PSA levels was approximately 80%. However, without a comparison group, it is difficult to reach conclusions regarding the relative efficacy of various treatment options. In a 1:1 matched-pair design, Pickles and colleagues prospectively followed 278 low- and intermediate-risk, localized prostate cancer patients treated with either brachytherapy or conformal EBRT (139 patients in each group). (10) The authors reported that biochemical

6 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 while EBRT patients had more rectal and bowel issues. The authors concluded brachytherapy is favored over EBRT in these populations of patients. In a nonrandomized study, Martinez and colleagues compared 454 patients treated with either LDR brachytherapy (206 patients) or highdose rate (HDR) brachytherapy (171 patients) at William Beaumont Hospital (WBH) during the period of 1993 through (11) The patients at WBH selected which treatment option they would receive. Also included in the study analysis were 77 patients who received HDR brachytherapy at California Endocurietherapy (CET) during the period of 1996 through All of the patients selected for this study were low to intermediate risk and had PSA levels equal to or less than 12 ng/ml, Gleason scores of equal to or less than 7, and clinical stage T1c-T2a disease. The HDR brachytherapy dosages were 9.5 Gy x 4 at WBH and 7 Gy x 6 at CET. Treatment outcomes at 5 years included biochemical control rates of 89% in the LDR group at WBH, 91% in the HDR group at WBH, and 88% in the HDR group at CET. Overall and causespecific survival rates at 5 years were not statistically different between groups. The HDR groups experienced statistically significant lower rates of dysuria, urinary frequency/urgency, and acute rectal pain. Rates of diarrhea, rectal bleeding, and acute urinary incontinence and retention were similar. Most toxicities were grade 1 in both groups, but more grade 3 acute genitourinary toxicities were seen in the LDR group. Potency was 30% in the LDR group and 20% in the HDR groups. Coen and colleagues compared high-dose EBRT (79.2 Gy equivalent) delivered using photons and protons to permanent LDR in a case-matched analysis of 282 patients (141 matches) with localized, low- and intermediate-risk prostate cancer. (12) Biochemical failure (nadir + 2) at 8 years was 7.7% in the high-dose EBRT group and 16.1% in the brachytherapy group (p=0.42). Further study is warranted; since case-matching may not account for important patient characteristics, the groups may not be similar. 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. (13) 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 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%). Brachytherapy combined with external-beam radiation therapy (EBRT) Permanent brachytherapy has also been combined with EBRT as a way to boost the total amount of radiation delivered to the prostate cancer; thus increasing the likelihood of increased patient survival. Randomized, controlled trials Merrick and colleagues randomized 247 intermediate- to high-risk prostate cancer patients to receive brachytherapy with either 20 Gy or 44 Gy EBRT. (14) 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

7 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. Non-randomized, comparative studies In 2008, key studies were reviewed by Hurwitz. (15) This summary included results of 2 Phase II cooperative group studies that were designed to assess toxicity, and participants were followed up to provide an assessment of treatment efficacy. This subsequent follow-up was to compare results to prior reports from single-institution studies. Patients in these studies had intermediate-risk disease and were treated by EBRT followed by permanent brachytherapy. In the first study (RTOG 0019), 138 patients were treated with 45 Gy of 3D-conformal radiation therapy followed by iodine-125 brachytherapy. These patients had stage T1-2b disease; if the Gleason score was less than 7, PSA was between 10 and 20, but if the Gleason score was 7, then PSA had to be 20 or less. Thus, these patients are in the intermediate-risk group. The 4- year rate of biochemical recurrence in this intermediate group was 19% using American Society for Radiation Oncology (ASTRO) criteria. Grades 3 and 4 late GU toxicity was 13%, and for late GI toxicity, the rate was 3%. Comments were made that these rates were higher than are often reported for either treatment alone. However, the total radiation dose was also higher. In this study, use of androgen deprivation was at the discretion of the treating practitioner. Lee et al. reported on complication rates in this study at an earlier time. (16) The 18-month estimate of late grade 3 GU and GI toxicity was 3.3% (confidence interval [CI]: %), and no late grade 4 or 5 toxicity had been noted at the time of this earlier report. In the second Phase II study (CALBG 99809), 68 patients had 45 Gy of EBRT followed by permanent brachytherapy (radioactive iodine or palladium). All patients in this series received androgen deprivation, and side effects from the androgen deprivation were noted frequently. At a median follow-up of 38 months, no treatment failures (biochemical failures) were noted. Long-term grades 2 and 3 toxicities were noted in 16% of the patients. 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. (17) 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. 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, no androgen deprivation therapy was used. (18) This report was based on a series of 223 consecutive patients treated between 1987 and 1993 at the Seattle Prostate Institute; patients had stage T1 T3 disease. Permanent brachytherapy was performed with radioactive palladium or iodine 4 weeks after EBRT. In this series, the authors reported 15-year biochemical relapse-free survival (BRFS) in the low-risk group of 88%, 80% in the intermediate-risk group, and 53% in the high-risk group. In addition, while this was a case series, long-term outcomes were compared to those of two institutions that had results for radical prostatectomy. Results were similar across Gleason score categories, e.g., the relapsefree survival was 25% to 30% for those with Gleason score 7 for the 3 series of patients but

8 were variable for other prognostic factors such as PSA. The authors noted that when they initiated their study, they included low-risk patients but that they now would not use combined modality therapy (CMT) in low-risk patients. In another report from one center, results were summarized for CMT using 3D-conformal radiation therapy followed by permanent (palladium) brachytherapy. (19) This study involved 282 consecutive patients; 119 were intermediate risk and 124 were high risk. Patients were treated from 1992 to In this series, 14-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 and colleagues, 199 patients with low- to high-risk prostate cancer were treated with LDR brachytherapy and 46 Gy EBRT during the period of June 1997 through August (20) Overall BRFS and PSA control at 5 years were 87% and 92%, respectively. In the high-risk group of 66 patients, overall BRFS and PSA control at 5 years were 81% and 86%, respectively. The authors concluded EBRT plus LDR brachytherapy provides excellent results even in high-risk cancer patients with acceptable morbidity. Focal (subtotal) prostate brachytherapy 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 have not been published. Many questions remain including treatment effectiveness, patient selection criteria, and post-treatment monitoring approaches. In 2012, Langley and colleagues reported on a consensus meeting convened to address issues on focal low-dose rate (LDR) brachytherapy for prostate cancer including optimal patient selection, disease characterization and localization, treatment protocols and outcome measures. (21) The consensus criteria developed for patient selection included life expectancy greater than 10 years, PSA 15 ng/ml or less, unilateral disease 0.5 ml or less, Gleason score 6-7, and tumor stage T2b or less. Ongoing Trials An April 2012 search of online site ClinicalTrials.gov identified several active studies on brachytherapy for prostate cancer treatment. In a randomized Phase III trial, the effectiveness of brachytherapy with or without EBRT will be evaluated in intermediate-risk prostate cancer patients (NCT ). Brachytherapy used alone in the treatment of intermediate-risk prostate cancer patients is being studied in NCT In a Phase II, prospective trial, brachytherapy will be evaluated for patients with locally recurrent prostate cancer after EBRT (NCT ). A randomized Phase III 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 (NCT ). In a randomized controlled trial, radical prostatectomy will be compared to brachytherapy in patients with low-risk prostate cancer (NCT ). A prospective, randomized, multicenter, Phase III trial to compare radical prostatectomy and radiotherapy (EBRT, HDR, and LDR brachytherapy) to active surveillance in the Study of Active Surveillance Therapy Against Radical Treatment in Patients Diagnosed With Favorable Risk Prostate Cancer [START] trial (NCT ) was

9 terminated. The study was unable to meet its target for patient accrual. Finally, in a Phase II study, focal prostate brachytherapy will be studied in patients with early stage, low-volume prostate cancer (NCT ). Summary Brachytherapy is a procedure in which a radioactive source (e.g., 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. Permanent brachytherapy provides freedom from biochemical recurrence at acceptable risk and, based on many case series and single-institution studies with long-term follow-up, may be considered as an option in the treatment of localized prostate cancer; while brachytherapy combined with EBRT is considered an option in patients with intermediate- and high-risk prostate cancer. This treatment approach provides radiation dose to the prostate and extraprostatic coverage as well. While quality studies differentiating superiority of any type of radiation technique are not available, the available evidence for permanent brachytherapy in the treatment of localized prostate cancer when used as monotherapy or in conjunction with EBRT is sufficient to demonstrate improvements in net health outcomes and may be considered medically necessary. There are limited data in published literature on focal brachytherapy. Available reports have focused on methods for delineating and evaluating tumor areas to identify appropriate candidates for focal prostate therapy. Reports on patient outcomes after focal brachytherapy have not been published. Given the lack of available studies and evidence, focal or subtotal prostate brachytherapy is considered investigational. Practice Guidelines and Position Statements The National Comprehensive Cancer Network (NCCN) guidelines for prostate cancer (v ) note that the cancer-control rates for brachytherapy appear comparable to surgery for low-risk tumors with medium-term follow up. (22) The guidelines also add that for intermediate-risk cancer, brachytherapy may be combined with external-beam radiation therapy (40 50 Gy) with or without androgen deprivation, but the complication rate increases. 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. The American Brachytherapy Society (ABS) Prostate Low-Dose Rate Task Group provides the following patient selection criteria for monotherapy: clinical stage T1b-T2b and Gleason score equal to or less than 6, and PSA equal to or less than 10 ng/ml. (23) The ABS guidelines also indicate monotherapy may be used in select higher risk patients and for salvage of select radiation therapy failures. For boost, patient selection criteria includes: clinical stage T2c or greater and/or Gleason score equal to or greater than 7 and/or PSA greater than 10 ng/ml. These guidelines also note inadequate information exists to recommend supplemental EBRTbased on perineural invasion, percent positive biopsies, and/or magnetic resonance imaging [MRI]-detected extracapsular penetration.

10 In an Institute for Clinical and Economic Review (ICER) report, it is noted a gold standard treatment approach for the management of low-risk prostate cancer is not available. (24) This report found there are no randomized controlled trials comparing brachytherapy to other treatment approaches and limited high-quality data available, making it difficult to compare the effectiveness of treatment options. The report concluded rates of survival and tumor recurrence are similar in each of the following treatment options for low-risk prostate cancer: active surveillance, brachytherapy, intensity-modulated radiation therapy, robot-assisted laparoscopic prostatectomy, and proton beam therapy. The American College of Radiology (ACR) and American Society for Therapeutic Radiation Oncology (ASTRO) guidelines on permanent brachytherapy indicate permanent LDR brachytherapy is appropriate in low- to intermediate-risk patients. (25) 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-ASTRO also notes IMRT is a widely used treatment option for many indications including prostate tumors. (26) The ACR also developed appropriateness criteria for permanent brachytherapy. (27) The 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 upon having a quality implant. The role of EBRT in addition to permanent brachytherapy for higher risk patients is uncertain. 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 2012; 109 Suppl 1: Peinemann F, Grouven U, Hemkens LG et al. Low-dose rate brachytherapy for men with localized prostate cancer. Cochrane Database Syst Rev 2011; (7):CD Giberti C, Chiono L, Gallo F et al. Radical retropubic prostatectomy versus brachytherapy for low-risk prostatic cancer: a prospective study. World J Urol 2009; 27(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 2011; 60(5): Bannuru RR, Dvorak T, Obadan N et al. Comparative evaluation of radiation treatments for clinically localized prostate cancer: an updated systematic review. Ann Intern Med 2011; 155(3):171-8.

11 6. Institute for Clinical and Economic Review (ICER). Brachytherapy/proton beam therapy for clinically localized, low-risk prostate cancer. Available online at: Last accessed April Zietman AL. Localized prostate cancer: brachytherapy. Curr Treat Options Oncol 2002; 3(5): 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 2011; 29(4): Ragde H, Elgamal AA, Snow PB et al. Ten-year disease free survival after transperineal sonography-guided iodine-125 brachytherapy with or without 45-gray external beam irradiation in the treatment of patients with clinically localized, low to high Gleason grade prostate carcinoma. Cancer 1998; 83(5): 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 2010; 76(1): Martinez AA, Demanes J, Vargas C et al. High-dose-rate prostate brachytherapy: an excellent accelerated-hypofractionated treatment for favorable prostate cancer. Am J Clin Oncol 2010; 33(5): 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 2012; 82(1):e Williams SB, Lei Y, Nguyen PL et al. Comparative effectiveness of cryotherapy vs brachytherapy for localised prostate cancer. BJU Int 2011 [Epub ahead of print]. 14. 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 2012; 82(3):e Hurwitz MD. Technology Insight: Combined external-beam radiation therapy and brachytherapy in the management of prostate cancer. Nat Clin Pract Oncol 2008; 5(11): Lee WR, DeSilvio M, Lawton C et al. A phase II study of external beam radiotherapy combined with permanent source brachytherapy for intermediate-risk, clinically localized adenocarcinoma of the prostate: preliminary results of RTOG P Int J Radiat Oncol Biol Phys 2006; 64(3): 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 2012; 82(5):e 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 2007; 67(1):57-64.

12 19. 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 2007; 110(3): 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 2009; 8(2): Langley S, Ahmed HU, Al-Qaisieh B et al. Report of a consensus meeting on focal low dose rate brachytherapy for prostate cancer. BJU Int 2012; 109 Suppl 1: National Comprehensive Cancer Network. Prostate cancer. Clinical Practice Guidelines in Oncology, v Available online at: Last accessed April Grills IS, Martinez AA, Hollander M et al. High dose rate brachytherapy as prostate cancer monotherapy reduces toxicity compared to low dose rate palladium seeds. J Urol 2004; 171(3): Ollendorf DA, Hayes J, McMahon P et al. Management options for low-risk prostate cancer: a report on comparative effectiveness and value. Boston, MA: Institute for Clinical and Economic Review, December Available online at: Last accessed April 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 2011; 79(2): ACR-ASTRO Practice Guideline for Intensity Modulated Radiation Therapy (IMRT) Available online at: x. Last accessed May Frank SJ, Arterbery VE, Hsu IC et al. American College of Radiology Appropriateness Criteria permanent source brachytherapy for prostate cancer. Brachytherapy 2011; 10(5): Codes Number Description CPT Transperineal placement of needles or catheters into prostate for interstitial radioelement application, with or without cystoscopy Ultrasound, prostate volume study for brachytherapy treatment planning (separate procedure) Brachytherapy isodose calculation, code range Radiation treatment delivery, single treatment

13 area, code range (used for EBRT) Interstitial radioelement application, code range ICD-9 Procedure Implantation/insertion of radioactive elements ICD-9 Diagnosis 185 Malignant neoplasm of the prostate HCPCS C1715 Brachytherapy needle C1728 Catheter, brachytherapy seed administration C2634 Brachytherapy source, nonstranded, high activity, iodine-125, greater than 1.01 mci (NIST), per source C2635 Brachytherapy source, nonstranded, high activity, palladium-103, greater than 2.2. mci (NIST), per source C2636 Brachytherapy linear source, nonstranded, palladium-103, per 1 mm C2637 Brachytherapy source, nonstranded, ytterbium- 169 C2638 Brachytherapy source, stranded, iodine-125, per source C2639 Brachytherapy source, non-stranded, iodine- 125, per source C2640 Brachytherapy source, stranded, palladium- 103, per source C2641 Brachytherapy source, non-stranded, palladium-103, per source C2642 Brachytherapy source, stranded, cesium-131, per source C2643 Brachytherapy source, nonstanded, cesium- 131, per source C2698 Brachytherapy source, stranded, not otherwise specified, per source C2699 Brachytherapy source, nonstranded, not otherwise specified, per source Q3001 Radioelements for brachytherapy, any type, each ICD-10-CM (effective 10/1/13) C61 Malignant neoplasm of prostate ICD-10 PCS (effective 10/1/13) DV1097Z, DV1098Z, DV1099Z, DV109BZ, DV109CZ, DV109YZ DV10B7Z, DV10B8Z, ICD-10-PCS codes are only used for inpatient services. Radiation oncology, male reproductive system, brachytherapy, prostate, high dose rate, code by isotope (cesium 137, iridium 192, iodine 125, palladium 103, californium 252, other isotope) Radiation oncology, male reproductive system,

14 Type of Service Place of Service DV10B9Z, DV10BBZ, DV10BCZ, DV10BYZ 0VH001Z, 0VH031Z, 0VH041Z, 0VH071Z, 0VH081Z Oncology Outpatient brachytherapy, prostate, low dose rate, code by isotope (cesium 137, iridium 192, iodine 125, palladium 103, californium 252, other isotope) Surgical, male reproductive system, insertion, prostate, radioactive element, code by approach Index Brachytherapy for Prostate Cancer Prostate Cancer, Brachytherapy Radioactive Seeds