Effective for dates of service on or after May 1, 2015 refer to: Blue Cross and Blue Shield of Alabama Radiation Therapy Management RTM Policies

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1 Effective for dates of service on or after May 1, 2015 refer to: Blue Cross and Blue Shield of Alabama Radiation Therapy Management RTM Policies Name of Policy: Brachytherapy for Clinically Localized Prostate Cancer Using Permanently Implanted Seeds Policy #: 499 Latest Review Date: June 2014 Category: Therapy Policy Grade: C Background/Definitions: As a general rule, benefits are payable under Blue Cross and Blue Shield of Alabama health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage. The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage: 1. The technology must have final approval from the appropriate government regulatory bodies; 2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes; 3. The technology must improve the net health outcome; 4. The technology must be as beneficial as any established alternatives; 5. The improvement must be attainable outside the investigational setting. Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are: 1. In accordance with generally accepted standards of medical practice; and 2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient s illness, injury or disease; and 3. Not primarily for the convenience of the patient, physician or other health care provider; and 4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient s illness, injury or disease. Page 1 of 15

2 Description of Procedure or Service: 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. 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 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, 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 radiation therapy 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). 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 Page 2 of 15

3 therapy delivered to the tumor. Again, CMT can be performed with permanent or temporary brachytherapy; however, use with permanent brachytherapy is more common. The brachytherapy boost is typically done two to six weeks after completion of EBRT, although the sequence can vary. 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 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. Policy: Effective for dates of service on or after May 1, 2015 refer to Blue Cross and Blue Shield of Alabama Radiation Therapy Management RTM Policies Effective for dates of service prior to May 1, 2015: Brachytherapy using permanent transperineal implantation of radioactive seeds for the treatment of prostate cancer meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage when: used as monotherapy or in conjunction with external beam radiation therapy (EBRT). the tumor is localized the prostate cancer is considered low risk (See Key Points for prostrate cancer risk levels) Blue Cross and Blue Shield of Alabama does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. Blue Cross and Blue Shield of Alabama administers benefits based on the members' contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination. Key Points: This policy was originally created in 1997 and was updated regularly with searches of the MEDLINE database. The most recent literature review was performed for the period of April 2013 through May 26, 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 Page 3 of 15

4 outcomes compared with 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 end points (such as biochemical-free survival) and treatmentrelated complications. Brachytherapy has become widely accepted among physicians and its speed and convenience compared with external beam radiotherapy (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. Systematic Reviews Rodrigues et al in 2013, reported on a systematic review that analyzed 36 articles on brachytherapy for low- or intermediate-risk prostate cancer. No evidence was found indicating the efficacy of brachytherapy compared with EBRT or radical prostatectomy (RP). However, non-comparative studies were included in the analysis due to the lack of available randomized controlled trials (RCTs) thus limiting interpretation of the conclusions. 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. 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). The authors concluded, in low-risk and intermediate-risk prostate cancer, PSA progression-free survival 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. Peinemann et al reported on results from a Cochrane review of brachytherapy in The authors focused the review on the only identified RCT (Giberti et al) reported next. The Giberti study compared brachytherapy with RP and was considered to have a high risk of bias. Peinemann et al also reported on results from a systematic review of brachytherapy in 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. 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 et al analyzed 75 studies (10 RCTs, 65 nonrandomized comparative studies) on RT for clinically localized prostate cancer. RTs included brachytherapy, Page 4 of 15

5 high-dose rate (HDR) brachytherapy, and EBRT (conformal radiation, IMRT, 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 with 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 with EBRT delivered at lower dosages. A 2009 review was conducted on both brachytherapy (permanent) and proton beam therapy. 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. The review mentions that brachytherapy is a more established therapy than IMRT. Despite identifying 166 studies that met their review criteria for this report, only one study involved an internal comparison of these treatments: a single-center evaluation of toxicity rates in two 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 five 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 two 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 onef 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 Most of the data on brachytherapy consists of uncontrolled case series. 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, <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 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. Randomized, Controlled Trials In Giberti et al, 200 low-risk prostate cancer patients were randomized to either RP or brachytherapy for low-risk prostate cancer. Biochemical disease-free survival rates at five years were 90% for RP and 91.7% for brachytherapy. Both treatment groups experienced decreases in quality of life at six months and one-year posttreatment, although brachytherapy patients reported more urinary disorders but better erectile function than the RP group. At five-year Page 5 of 15

6 follow-up, functional outcomes did not differ in either arm of the study. Crook et al also reported on quality-of-life outcomes at five years in 168 patients after RP or brachytherapy in the SPIRIT: Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial. In this study, 34 patients were randomized, while the other 134 patients were allowed to select a treatment group. SPIRIT was closed after two 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 RP. Nonrandomized, Comparative Studies Ragde et al report on the 10-year follow-up of patients with prostate cancer treated with brachytherapy. 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 et al prospectively followed 278 low- and intermediaterisk, localized prostate cancer patients treated with either brachytherapy or conformal EBRT (139 patients in each group). The authors reported that biochemical control (nadir + 2) at five years was 95% in the brachytherapy group versus 85% in the EBRT group (p<0.001). This rate was unchanged at seven 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 et al compared 454 patients treated with either LDR brachytherapy (206 patients) or HDR brachytherapy (171 patients) at William Beaumont Hospital (WBH) during the period of 1993 through 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 seven, and clinical stage T1c-T2a disease. The HDR brachytherapy dosages were 9.5 Gy 4 at WBH and 7 Gy 6 at CET. Treatment outcomes at five 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 cause-specific survival rates at five 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 GU tract toxicities were seen in the LDR group. Potency was 30% in the LDR group and 20% in the HDR groups. Coen et al 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, lowand intermediate-risk prostate cancer. Biochemical failure (nadir + 2) at eight years was 7.7% in the high-dose EBRT group and 16.1% in the brachytherapy group (p=0.42). Further study is warranted; because case-matching may not account for important patient characteristics, the groups may not be similar. Page 6 of 15

7 Nepple et al analyzed data obtained prospectively from two centers to compare prostate cancer treatment mortality outcomes in men without comorbidities. The analysis included 4459 men treated with RP compared with 972 men treated with brachytherapy and 1261 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 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. 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%). Kollmeier et al reported on 236 men, age 60 or younger, treated with brachytherapy with or without EBRT. The prostate cancer-specific survival rate was 99% at a median follow-up of 83 months. GU toxicity at two or more was 14% and GI toxicity was 3%. Potency remained at last follow-up in 51% of the men who were potent before treatment. Buckstein et al also reported on 131 men, age 60 or younger, treated with brachytherapy with or without EBRT. Only one 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=0.008). Brachytherapy combined with 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 et al randomized 247 intermediate- to high-risk prostate cancer patients to receive brachytherapy with either 20 Gy or 44 Gy EBRT. At a median follow-up of nine years, no statistically significant differences were found in biochemical progression-free survival (BPFS), cause-specific survival, and overall survival (OS) between the two groups of supplemental EBRT. This suggests outcomes were influenced by quality brachytherapy implants rather than an increased radiation dosage of EBRT. At eight and ten 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. Nonrandomized, Comparative Studies In 2008, key studies were reviewed by Hurwitz. This summary included results of two Phase 2 cooperative group studies that were designed to assess toxicity, and participants were followed Page 7 of 15

8 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 intermediaterisk 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 (3D- CRT) followed by iodine-125 brachytherapy. These patients had stage T1-2b disease; if the Gleason score was less than seven, 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 fouryear 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. The 18-month estimate of late Grade 3 GU and GI toxicity was 3.3% (CI, 0.1% to 6.5%), and no late Grade 4 or 5 toxicity had been noted at the time of this earlier report. In the second Phase 2 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 adverse effects from the androgen deprivation were frequently noted. 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. 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 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. 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 four weeks after EBRT. In this series, the authors reported 15-year 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 with those of two institutions that had results for RP. Results were similar across Gleason score categories, e.g., the relapse-free survival was 25% to 30% for those with Gleason score of 7 for the three series of patients but 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 CMT in low-risk patients. In another report from one center, results were summarized for CMT using 3D-CRT followed by permanent (palladium) brachytherapy. This study involved 282 consecutive patients; 119 were intermediate risk and 124 were high risk. Page 8 of 15

9 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 et al, 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 Overall BRFS and PSA control at five years were 87% and 92%, respectively. In the high-risk group of 66 patients, overall BRFS and PSA control at five 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 are limited. In a 2013 systematic review, Valerio et al reviewed studies on focal prostate cancer therapies. However, only one series by Nguyen et al 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 (defined as nadir + 2) was 95.1% and 73% at five years and 80.4% and 66.4% at eight years, respectively. Many questions remain including treatment effectiveness, patient selection criteria, and posttreatment monitoring approaches. In 2012, Langley et al reported on a consensus meeting convened to address issues on focal LDR brachytherapy for prostate cancer including optimal patient selection, disease characterization and localization, treatment protocols and outcome measures. 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. Practice Guidelines and Position Statements National Comprehensive Cancer Network guidelines for prostate cancer (v ) note that the cancer-control rates for brachytherapy appear comparable with surgery for low-risk tumors with medium-term follow up. The guidelines also add that for intermediate- and high-risk cancer, brachytherapy may be combined with EBRT (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 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. 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 six, and prostate-specific antigen (PSA) equal to or <10 ng/ml. The 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 includes: clinical stage T2c Page 9 of 15

10 or greater and/or Gleason score seven or more and/or PSA 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. In an Institute for Clinical and Economic Review report, it is noted a criterion standard treatment approach for the management of low-risk prostate cancer is not available. This report found there are no randomized controlled trials comparing brachytherapy with other treatment approaches and limited high-quality data are available, making it difficult to compare the effectiveness of treatment options. The report concludes 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 radiotherapy (IMRT), 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 low-dose rate (LDR) brachytherapy is appropriate in low- to intermediate-risk patients. 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 five 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. 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 Key Words: Brachytherapy, external beam radiation therapy, EBRT, radioactive seeds, radioisotope seeds, transperineal implantation Approved by Governing Bodies: 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. 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 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. Page 10 of 15

11 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 six, and PSA equal to or less than 10 ng/ml. 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 seven and/or PSA greater than 10 ng/ml. These guidelines also note inadequate information exists to recommend supplemental XBRTbased on perineural invasion, percent positive biopsies, and/or MRI-detected extracapsular penetration. 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. 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. 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 five 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. The ACR also developed appropriateness criteria for permanent brachytherapy. 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. Benefit Application: Coverage is subject to member s specific benefits. Group specific policy will supersede this policy when applicable. ITS: Home Policy provisions apply. FEP: Special benefit consideration may apply. Refer to member s benefit plan. FEP does not consider investigational if FDA approved. Will be reviewed for medical necessity. Page 11 of 15

12 Current Coding: CPT Codes: Transperineal placement of needles or catheters into prostate for interstitial radioelement application, with or without cystoscopy Ultrasound, transrectal; prostate volume study for brachytherapy treatment planning Brachytherapy isodose plan; simple (calculation[s] made from 1 to 4 sources, or remote afterloading brachytherapy, 1 channel), includes basic dosimetry calculation(s) (Effective January 1, 2015) Brachytherapy isodose plan; intermediate (calculation[s] made from 5 to 10 sources, or remote afterloading brachytherapy, 2-12 channels), includes basic dosimetry calculation(s) (Effective January 1, 2015) Brachytherapy isodose plan; complex (calculation[s] made from over 10 sources, or remote afterloading brachytherapy, over 12 channels), includes basic dosimetry calculation(s) (Effective January 1, 2015) Radiation treatment delivery, >= 1 MeV; simple Interstitial radioelement application, simple, intermediate, or HCPCS codes: G0458 G6003 G6004 G6005 G6006 complex Low dose rate (ldr) prostate brachytherapy services, composite rate (Effective January 1, 2013) Radiation treatment delivery, single treatment area,single port or parallel opposed ports, simple blocks or no blocks: up to 5mev (Effective January 1, 2015) Radiation treatment delivery, single treatment area,single port or parallel opposed ports, simple blocks or no blocks: 6-10mev (Effective January 1, 2015) Radiation treatment delivery, single treatment area,single port or parallel opposed ports, simple blocks or no blocks: 11-19mev (Effective January 1, 2015) Radiation treatment delivery, single treatment area,single port or parallel opposed ports, simple blocks or no blocks: 20mev or greater (Effective January 1, 2015) Previous Coding: Brachytherapy isodose calculation; simple, intermediate, or complex (Deleted January 1, 2015) Radiation treatment delivery, single treatment area, code range (used for external beam radiation therapy) (Deleted January 1, 2015) Page 12 of 15

13 References: 1. ACR-ASTRO. Practice Guideline for Intensity Modulated Radiation Therapy (IMRT) Available online at: Last accessed May 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): Buckstein M, Carpenter TJ, Stone NN et al. Long-term outcomes and toxicity in patients treated with brachytherapy for prostate adenocarcinoma younger than 60 years of age at treatment with minimum 10 years of follow-up. Urology 2013; 81(2): 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 2011 Apr 4. [Epub ahead of print] 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): 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): Frank SJ, Arterbery VE, Hsu IC et al. American College of Radiology Appropriateness Criteria permanent source brachytherapy for prostate cancer. Brachytherapy 2011; 10(5): 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): 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): 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: Hurwitz MD. Technology Insight: Combined external-beam radiation therapy and brachytherapy in the management of prostate cancer. Nat Clin Pract Oncol 2008; 5(11): Institute for Clinical and Economic Review (ICER). Brachytherapy/proton beam therapy for clinically localized, low-risk prostate cancer. Available online at: Kollmeier MA, Fidaleo A, Pei X et al. Favourable long-term outcomes with brachytherapybased regimens in men </=60 years with clinically localized prostate cancer. BJU Int [Epub ahead of print] 14. 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 1:7-16. Page 13 of 15

14 16. 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 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): 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): 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 National Comprehensive Cancer Network. Prostate cancer. Clinical Practice Guidelines in Oncology, v Available online at: Last accessed May National Cooperative Cancer Network. Prostate cancer. Clinical Practice Guidelines in Oncology, v Available online at: Last accessed July 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 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 2012; 188(4): 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: 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): 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 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): 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): Rodrigues G, Yao X, Loblaw DA et al. Low-dose rate brachytherapy for patients with lowor intermediate-risk prostate cancer: A systematic review. Can Urol Assoc J 2013; 7(11-12): Page 14 of 15

15 30. 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): 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): The American Brachytherapy Society (ABS) Prostate Low-Dose Rate Task Group. Available online at: Last accessed July 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 Williams SB, Lei Y, Nguyen PL et al. Comparative effectiveness of cryotherapy vs brachytherapy for localized prostate cancer. BJU Int 2012; 110(2 Pt 2):E Zietman AL. Localized prostate cancer: brachytherapy. Curr Treat Options Oncol 2002; 3(5): Policy History: Medical Policy Group, July 2102 (4) Medical Policy Administration Committee, July 2012 Available for comment July 12 through August 27, 2012 Medical Policy Group, November 2012: 2013 Coding Update-added G0458-ldr prostate brachytherapy services Medical Policy Group, September 2013 (4): 2013 Updates to Key Points, Approved Governing Bodies, and References Medical Policy Panel, June 2014 Medical Policy Group, June 2014 (4): Updated Key Points and References. No changes to the policy section at this time. Medical Policy Group, November 2014: 2015 Annual Coding update. Added codes to current coding, revised current coding for code 77402, and added Previous coding section to include codes and HCPCS section added to include new codes G6003-G6006. Medical Policy Group, February 2015: Added Care Core Draft link Available for comment February 12 through April 30, 2015 Medical Policy Group, May 2015: Changed RTM link from Draft to Current, removed Draft from header. Medical Policy Group, October 2015: Added/removed evicore Draft link and comment period This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a caseby-case basis according to the terms of the member s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment. This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield s administration of plan contracts. Page 15 of 15