Clinical Policy Title: Brachytherapy for localized prostate cancer

Clinical Policy Title: Brachytherapy for localized prostate cancer Clinical Policy Number: 05.02.02 Effective Date: October 1, 2014 Initial Review Date: June 18, 2014 Most Recent Review Date: July 19, 2017 Next Review Date: July 2018 Related policies: Policy contains: Localized prostate cancer. Brachytherapy (BT) External beam radiation therapy (EBRT) Radical prostatectomy (RP) None. ABOUT THIS POLICY: Keystone First has developed clinical policies to assist with making coverage determinations. Keystone First s clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by Keystone First when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. Keystone First s clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. Keystone First s clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, Keystone First will update its clinical policies as necessary. Keystone First s clinical policies are not guarantees of payment. Coverage policy Keystone First considers the use of low-dose brachytherapy (BT) to be clinically proven and, therefore, medically necessary when all of the following criteria are met: Men with prostate cancer whose tumor is confined to the prostate gland. Prostate Specific Antigen (PSA) score is <10 ng/ml and the Gleason score is <6 Patient is assigned Stage T1 ort2, using the American Joint Committee on Cancer staging system. Stage T1 is defined as clinically not apparent/neither palpable nor visible, or incidental finding on tissues during Transurethral Resection of the Prostate. T2 is defined as confined within the prostate, one or both sides. In addition, high-dose BT is considered medically necessary when used as monotherapy or with external beam radiation therapy (EBRT) for prostate cancer patients with Stages T3 and T4. Limitations: 1

Temporary brachytherapy for prostate cancer is not clinically proven, and therefore is considered investigational/experimental. Alternative covered services: Watchful waiting, radical prostatectomy or external beam radiation. Background Brachytherapy (BT, or interstitial radiation) is a form of radiation therapy in which encapsulated sources of radiation ( seeds ), typically radioactive iodine-125 or palladium-103 are implanted directly into or adjacent to tumor tissues, such as prostate cancer. BT is based on the principle that radiation doses decrease as a function of the squared distance from the source, thus delivering intensive exposure to cancerous tissue while minimizing exposure and adverse effects to surrounding healthy tissue. Current standard prostate BT technique achieves a homogeneous dose distribution according to a customized template based on CT and ultrasound assessment of the tumor and computer-optimized dosimetry (ACS, 2017). Prostate cancer is the most common non-cutaneous malignancy in men, with 161,360 cases expected to be diagnosed in 2017 (Howlader, 2017). Ninety percent of men with prostate cancer are over age 60 and have disease believed to be localized to the prostate gland (clinically localized). Common treatments for clinically localized prostate cancer include watchful waiting, surgery to remove the prostate gland (radical prostatectomy, or RP), external beam radiation therapy (EBRT) and interstitial radiation therapy (BT). Prostate cancer is a clinically heterogeneous disease. A substantial proportion of prostate cancer cases detected with current screening methods will never cause symptoms during the patients lifetimes. Five-year PSA relapse-free survival with current brachytherapy techniques according to pre-treatment PSA levels are as follows (Fisher, 2012): Risk level Low 96.1 Intermediate 90.6 5-year actuarial survival (%) The Gleason score is a system of grading prostate cancer based on its microscopic appearance. It indicates the sum of predominant histological pattern (graded 1 to 5) and the next most common pattern. Gleason scores range from two to 10, indicating likelihood a tumor will spread. The higher the score is, the higher the likelihood of spread. Needle biopsy specimens (versus those from radical prostatectomy) provide insufficient tissue for complete Gleason scoring and cannot be scored lower than 6 (3 + 3). 2

Gleason, PSA levels and tumor staging together comprise risk stratification for prostate cancer referenced in the reviews tabulated under Summary of clinical evidence: Risk PSA (ng/ml) Gleason Tumor stage Low < 10 < 6 T1 T 2 Intermediate 10 20 7 T2 High > 20 8 10 T3 T4 Searches Keystone First searched PubMed and the databases of: UK National Health Services Centre for Reviews and Dissemination. Agency for Healthcare Research and Quality Guideline Clearinghouse and evidence-based practice centers. The Centers for Medicare & Medicaid Services (CMS). We conducted searches on May 15, 2017. Search terms were: brachytherapy prostate cancer. We included: Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. Guidelines based on systematic reviews. Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. Findings The American Society for Radiation Oncology (ASTRO) and American College of Radiology (ACR) guideline indicates transperineal permanent BT is appropriate for low- and intermediate-risk prostate cancer. Low-risk is defined as clinical stage T1b T2b, Gleason score equal to or less than 6, and prostate-specific antigen equal to or less than 10 ng/ml. Intermediate-risk is defined as clinical stage T2b T2c, Gleason score of 7, and PSA between 10 and 20. Exclusions include life expectancy under 5 years, unacceptable operative risk, poor anatomy preventing a quality implant, positive lymph nodes from pathology, significant obstructive uropathy, and distant metastases (Rosenthal, 2011). The ASTRO/ACR guidelines were corroborated by a 2017 guideline by the American Society of Clinical Oncology/Cancer Care Ontario Joint Guideline update (Chin, 2017). In general, survival rates for men with prostate cancer are high. A recent review of 14 studies of prostate cancer found that progression-free survival varied by study, among low-risk (85 to 100 percent) 3

and high-risk (79 to 92 percent) patients at 5 years (Sanchez-Gomez, 2017). Similar rates for low-, intermediate-, or high-risk prostate cancer were reported as 85 to 100, 80 to 98, and 59 to 96 percent, along with 34 to 85 percent for locally advanced patients (Zaorsky, 2014), figures that were maintained in a later article by the same research team (Zaorsky, 2016). A 2016 review of 6 studies (n= 34,338 males with metastatic prostate cancer) documented that survival for local treatment, radiotherapy, surgery, or BT was greater than those receiving no treatment at 3 years (64.2 vs. 44.5 percent) and 5 years (51.9 vs. 23.6 percent) (Carneiro, 2016). Another review of 6 studies of 3011 prostate cancer patients undergoing BT and followed 4 to 6 years found that 27.4 to 50.0 percent had a prostate-specific antigen bounce, defined as an increase of at least 0.2 ng/ml from the nadir (Bernstein, 2013). Some studies compare outcomes for various types of treatment for prostate cancer. The first of these compared BT with radical prostatectomy, but could identify only one randomized controlled trial, thus limiting any conclusions (Peinemann, 2011). Since this review, other articles have compared BT with other treatments: - A review of 36 randomized controlled trials showed brachytherapy had similar efficacy as radical prostatectomy in terms of quality of life and progression-free survival, and BT had better outcomes for patient satisfaction and sexual function (Wolff, 2015). - A review of 18 studies (n=6986) found overall survival and progression free survival in highrisk prostate cancer was lower for BT compared to radical prostatectomy, but cancerspecific mortality was equal; compared to radiation therapy, brachytherapy had a nonsignificantly higher 5-year progression free survival (Lei, 2015). - A comparison of low-dose rate BT and external beam radiation therapy for patients with low- or intermediate-risk prostate cancer patients found brachytherapy had fewer 2 nd primary cancers, lower rates of impotence, but higher rates of genitourinary and gastrointestinal toxicity (Rodrigues, 2013). - In a study of 3 systematic reviews and 4 prospective studies, comparing robotic prostatectomy for localized prostate cancer with BT, the latter group had more improved questionnaire scores for urinary and sexual domains 3 years after treatment, along with a lower incontinence rate (Martin-Lopez, 2015). Efficacy of combined BT and EBRT therapy for high-risk prostate cancer was established through several studies. Fifteen-year risk-free survival on 223 patients was 74 percent (Sylvester, 2007). The corresponding figure for a 14-year study of 282 patients was 81 percent (Dattoli, 2007). Five-year PSA control for 199 patients was 86 percent for high-risk patients, with Grade 3 morbidity at 3 percent (Koontz, 2009). One study reported on trends in BT use for intermediate- and high-risk prostate cancer. Using the U.S. National Cancer Database, researchers from Boston s Dana-Farber Cancer Institute at Brigham and Women s Hospital found that between 2004 and 2012, the percent of men with intermediate- and highrisk prostate cancer treated with BT plus EBRT fell from 19 to 11 in nonacademic centers, and from 15 to 8 percent in academic centers, prompting the authors to speculate that it is unclear whether academic 4

centers are prepared to train the next generation of residents in this critical modality (Orio, 2016). A summary of cost-effectiveness studies of prostate cancer treatment found BT, along with stereotactic body radiation therapy, to be more cost effective than intensity-modulated radiation therapy for low risk cases, and one study found brachytherapy to be more cost-effective than surgery; overall, watchful waiting was the most cost-effective approach to prostate cancer (Muralidhar, 2017). Policy updates: A total of 7 guidelines/other and 7 peer-reviewed references were added to this policy; 22 peerreviewed references were removed. Summary of clinical evidence: Citation Zaorsky (2016) Review of outcomes and toxicity of prostate cancer therapy Lei (2015) Content, Methods, Recommendations 26 trials (16 EBRT, 10 BT), studies of > 70 patients 5 year survival of BT patients are high (>85% low-risk, 69-97% intermediate, 63-80% hig No differences between BT and other therapies in overall survival, cancer-specific mortality, rate of distant metastases Survival outcomes of different treatments in highrisk prostate cancer Systematic review of 18 studies (n=6986) of treatment for high-risk prostate cancer Comparison of radical prostatectomy (RP), radiation therapy (RT), brachytherapy (BT), androgen-deprivation therapy (ADT), and watchful waiting (WW) RP had significantly better overall survival than RT or BT RP had similar cancer-specific mortality as did RT and BT BT had an insignificantly higher 5-year progression free survival as did RT Wolff (2015) Comparing effectiveness of various local prostate cancer therapies Demanes (2014) Evaluation of high-dose brachytherapy as monotherapy for prostate cancer 34 trials, survival based outcomes All major therapies found effective (EBRT, RP, BT) No strong evidence to support one therapy over another 13 studies, followed 1.5 to 8.0 years after treatment Progression-free survival for PSA was 79 to 100% Genitourinary and gastrointestinal toxicity were 0-16% and 0-2% 5

Rodrigues (2013) Evaluation of side effects from low dose BT, compared with EBRT and RP Flynn (2009) Localized prostate cancer survival by type of treatment Graham (2009) Research recommendations Wilt (2008) 36 studies, patients followed 6 months to 3 years post-treatment BT had less urinary incontinence and sexual impotency than EBRT BT had more urinary irritation and rectal morbidity than RP BT has equal efficacy to EBRT and RP 19 reviews, treatment options equivalent in terms of survival Key issue - early identification of men whose tumors will impact survival or quality of life More research is required into the identification of prognostic indicators to differentiate between men who may die with prostate cancer and those who might die from prostate cancer Greatest uncertainties are around the identification of which cancers are of clinical significance and over the choice of radical treatment, and in which settings they are appropriate. Research should include a rigorous examination of procedures, such as brachytherapy (localized disease only), cryotherapy and high-intensity focused ultrasound, as well as combinations. The endpoints should include survival, local recurrence, toxicity, and quality of life. Outcomes by type of treatment 18 trials, one pooled analysis of three trials, 14,595 patients Erectile dysfunction occurred frequently after all treatments (RP 58%; RT 43%; androgen deprivation 86%). A higher risk score incorporating histologic grade, PSA level and tumor stage was associated with increased risk for disease progression or recurrence regardless of treatment. References Professional society guidelines/other: American Cancer Society (ACS). Radiation Therapy for Prostate Cancer. Atlanta GA: ACS, 2017. https://www.cancer.org/cancer/prostate-cancer/treating/radiation-therapy.html. Accessed May 16, 2017. Chin J, Rumble RB, Kollmeier M, et al. Brachytherapy for patients with prostate cancer: American Society of Clinical Oncology/Cancer Care Ontario Joint Guideline update. J Clin Oncol. March 27, 2017:JCO2016720466. Ferrer M, Rueda JR, Latorre K, Gutierrez I. Catalan Agency for Health Technology Assessment and Research. Long term effectiveness of radical prostatectomy, brachytherapy and external 3D conformational radiotherapy in organ-confined prostate cancer. York UK: University of York Centre for Reviews and Dissemination, 2008. http://www.crd.york.ac.uk/crdweb/showrecord.asp?id=32008100273. Accessed May 15, 2017. 6

Flynn K, Adams E, Alligood E, Lawrence V. Systematic reviews for localized prostate cancer. Veterans Health Administration. Boston, MA: Office of Patient Care Services Technology Assessment Program; 2009. Graham J, Baker M, Macbeth F, Titshall V. Diagnosis and treatment of prostate cancer: summary of NICE guidance. Brit Med J. 2008;336(7644): 610 12. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2014. Bethesda MD: National Cancer Institute, April 2017. https://seer.cancer.gov/csr/1975_2014. Hsu IC, Yamada Y, Merrick G, et al. ACR Appropriateness Care: high-dose-rate brachytherapy for prostate cancer. Reston VA: American College of Radiology: 2013, 6 pp. http://www.guideline.gov/content.aspx?id=47697&search=brachytherapy+prostate+cancer. Accessed May 15, 2017. Merrick GS, Zelefsky MJ, Sylvester J, Nag S, Bice W. American Brachytherapy Society (ABS) Prostate Low- Dose Rate Task Group. https://www.americanbrachytherapy.org/guidelines/prostate_lowdoseratetaskgroup.pdf. Accessed May 15, 2017. National Comprehensive Cancer Network (NCCN). Prostate cancer. Clinical Practice Guidelines in Oncology. V.2.2014. http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed May 15, 2017. Podder TK, Beaulieu L, Baldwell B, et al. AAPM and GEC-ESTRO guidelines for image-guided robotic brachytherapy: report of Task Group 192. Med Phys. 2014;41(10):101501. Rodrigues G, Yao X, Loblaw A, runage M, Cin J, Genitourinary Cancer Disease Site Group. Low-dose rate brachytherapy for patients with low- or intermediate-risk prostate cancer. Toronto, Ontario: Cancer Care Ontario, October 31, 2012. https://www.guideline.gov/summaries/summary/47791/lowdose-ratebrachytherapy-for-patients-with-low-or-intermediaterisk-prostatecancer?q=prostate+cancer+brachytherapy. Accessed May 15, 2017. Rosenthal SA, Tittner 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):335 41. Wilt TJ, Shamliyan T, Taylor B, et al. Comparative effectiveness of therapies for clinically localized prostate cancer. Rockville, MD: Agency for Healthcare Research and Quality, 2008, 155 pages. https://innovations.ahrq.gov/qualitytools/comparative-effectiveness-therapies-clinically-localizedprostate-cancer-weighing. Accessed May 15, 2017. Peer-reviewed references: 7

Bernstein M, Ohri N, Hodge JW, et al. Prostate-specific antigen bounce predicts for a favorable prognosis following brachytherapy: a meta-analysis. J Contemp Brachytherapy. 2013;5(4):210 14. Carneiro A, Baccaglini W, Glina FP, et al. Impact of local treatment on overall survival of patients with metastatic prostate cancer: systematic review and meta-analysis. Int Braz J Urol. 2016. Doi: 10.1590/S1677-5538.IBJU.2016.0483. 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):551 55. Demanes DJ, Ghilezan M. High-dose-rate brachytherapy as monotherapy for prostate cancer. Brachytherapy. 2014;13(6):529 41. Fang FM, Wang YM, Wang CJ, Huang HY, Chiang PH. Comparison of the outcome and morbidity for localized or locally advanced prostate cancer treated by high-dose-rate brachytherapy plus external beam radiotherapy (EBRT) versus EBRT alone. Jpn J Clin Oncol. 2008;38(7):474 79. Fisher CM, Troncoso P, Swanson DA, et al. Knife or needles? A cohort analysis of outcomes after radical prostatectomy or brachytherapy for men with low- or intermediate-risk adenocarcinoma of the prostate. Brachytherapy. 2012;11:429 34. Kittel JA, Reddy CA, Smith KL, et al. Long-term efficacy and toxicity of low-dose-rate (125)I prostate brachytherapy as monotherapy in low-intermediate-, and high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2015;92(4):884 92. 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):191 96. Lei JH, Liu LR, Wei Q, et al. Systematic review and meta-analysis of the survival outcomes of first-line treatment options in high-risk prostate cancer. Sci Rep. 2015;5:7713. Martin-Lopez JE, Rodriguez-Lopez R, Romero-Tabares A, et al. Quality of life after brachytherapy for localized prostate cancer. Arch Esp Urol. 2015;68(2):142 51. Muralidhar V, Nguyen PL. Maximizing resources in the local treatment of prostate cancer: a summary of cost-effectiveness studies. Urol Oncol. 2017;35(2):76 85. 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. 8

Rodrigues G, Yao X, Loblaw DA, Brundage M, Chin JL. Low-dose rate brachytherapy for patients with low- or intermediate-risk prostate cancer : a systematic review. Can Urol Assoc J. 2013;7(11-12):463 70. Sanchez-Gomez LM, Polo-deSantos M, Rodriguez-Melcon JI, Angulo JC, Luengo-Matos S. High-dose rate brachytherapy as monotherapy in prostate cancer: a systematic review of its safety and efficacy. Actas Urol Esp. 2017;41(2):71 81. 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. Whiting PF, Moore TH, Jameson CM, et al. Symptomatic and quality of life outcomes following treatment for clinically localized prostate cancer: a systematic review. BJU Int. 2016;118(2):193 204. Wolff RF, Ryder S, Bossi A, et al. A systematic review of randomized controlled trials of radiotherapy for localized prostate cancer. Eur J Cancer. 2015;51(16):2345 67. Zaorsky NG, Doyle LA, Yamoah K, et al. High dose rate brachytherapy boost for prostate cancer: a systematic review. Cancer Treat Rev. 2014;40(3):414 25. Zaorsky NG, Shaikh T, Murphy CT, et al. Comparison of outcomes and toxicities among radiation therapy treatment options for prostate cancer. Cancer Treat Rev. 2016;48:50 60. CMS National Coverage Determinations (NCDs): No NCDs identified as of the writing of this policy. Local Coverage Determinations (LCDs): No LCDs identified as of the writing of this policy. Commonly submitted codes Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill accordingly. CPT Code Description Comment 77778 Interstitial radiation source application; complex 9

77799 Unlisted procedure, clinical brachytherapy ICD-10 Code Description Comment C61 Malignant neoplasm of the prostate HCPCS Level II Code Description Comment 10