Clinical Policy Title: Enhanced cystoscopy for bladder cancer

Clinical Policy Title: Enhanced cystoscopy for bladder cancer Clinical Policy Number: 13.01.04 Effective Date: April 1 2017 Initial Review Date: February 15 2017 Most Recent Review Date: March 6, 2018 Next Review Date: March 2019 Policy contains: Non-muscle invasive bladder cancer. Blue light or fluorescent cystoscopy. Photodynamic diagnosis. Hexaminolevulinate. Related policies: None. ABOUT THIS POLICY: Select Health of South Carolina has developed clinical policies to assist with making coverage determinations. Select Health of South Carolina 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 peerreviewed 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 Select Health of South Carolina 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. Select Health of South Carolina 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. Select Health of South Carolina s clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, Select Health of South Carolina will update its clinical policies as necessary. Select Health of South Carolina s clinical policies are not guarantees of payment. Coverage policy Select Health of South Carolina consider the use of photodynamic diagnosis to be clinically proven and, therefore, medically necessary for the cystoscopic detection of non-muscle invasive bladder cancer when the following criteria are met (National Comprehensive Cancer Network [NCCN], 2018; Chang, 2016; National Institute for Health and Clinical Excellence [NICE], 2015; European Association of Urology [EAU], 2017; U.S. Food and Drug Administration [FDA], 2010b): Performed after or concurrent with white light cystoscopy. Photodynamic diagnosis uses the fluorescence agent hexaminolevulinate, marketed in the United States as Cysview (Cato Research Ltd., Durham, North Carolina) in combination with the Karl Storz D-Light C Photodynamic Diagnostic system (Karl Storz Endoscopy-America Inc., El Segundo, California). For the following clinical indications: At the time of the first three-month cystoscopy in all patients with a history of intermediate- to high-risk non-muscle invasive bladder cancer. 1

Exception: patients with low-risk single small non-recurrent low-grade papillary cancers (stage ta), as the expected three-month recurrence rate is less than 15 percent. To guide transurethral resection. Limitations: Contraindications to hexaminolevulinate include porphyria, gross hematuria, intravesical immunotherapy, or chemotherapy within 90 days, or known hypersensitivity to hexaminolevulinate or aminolevulinate derivatives (FDA, 2010b). Repetitive administrations of hexaminolevulinate are not medically necessary (FDA, 2010b). Photodynamic diagnosis using 5-aminolevulinic acid is considered an off-label use and not medically necessary. Alternative covered services: Cytology with urinalysis. White light cystoscopy. Upper urinary tract imaging. Random bladder biopsies. Background Bladder cancer accounts for approximately 5 percent of all new cancers in the United States. It is the fourth most common cancer in men, but it is less common in women (American Cancer Society, 2017). The natural history of bladder cancer ranges from a low-grade variant to high-grade disease (Zlatev, 2015). About half of all bladder cancers are found while the cancer is non-invasive or in situ and still confined to the inner layer of the urothelium. About one in three bladder cancers have invaded into deeper layers but are still only in the bladder. High recurrence rates are associated with bladder cancer, often requiring repeat treatment and lifelong surveillance (Zlatev, 2015). The American Joint Committee on Cancer Tumor, Node, Metastasis (TNM) staging system is used to classify the location and extent of bladder cancer (2017; Table 1): Table 1. TNM staging system for bladder cancer TX: Main tumor cannot be assessed due to lack of information. T0: No evidence of a primary tumor. Ta: Non-invasive papillary carcinoma. Tis: Non-invasive flat carcinoma (flat carcinoma in situ, or carcinoma in situ). 2

T1: The tumor has grown from the layer of cells lining the bladder into the connective tissue below. It has not grown into the muscle layer of the bladder. T2: The tumor has grown into the muscle layer: T2a: The tumor has grown only into the inner half of the muscle layer. T2b: The tumor has grown into the outer half of the muscle layer. T3: The tumor has grown through the muscle layer of the bladder and into the fatty tissue layer that surrounds it. T3a: The spread to fatty tissue can only be seen by using a microscope. T3b: The spread to fatty tissue is large enough to be seen on imaging tests or to be seen or felt by the surgeon. T4: The tumor has spread beyond the fatty tissue and into nearby organs or structures. It may be growing into any of the following: the stroma (main tissue) of the prostate, the seminal vesicles, uterus, vagina, pelvic wall, or abdominal wall. T4a: The tumor has spread to the stroma of the prostate (in men), or to the uterus and/or vagina (in women). T4b: The tumor has spread to the pelvic wall or the abdominal wall. For therapeutic purposes, tumors confined to the mucosa and can be treated by transurethral resection and/or intravesical instillations are often referred to as non-muscle invasive bladder cancer. These include papillary tumors confined to the mucosa and invading the lamina propria (stage Ta and T1, respectively) and flat, high-grade tumors that are confined to the mucosa (Tis). However, Tis and T1 lesions can demonstrate a high malignant potential (EAU, 2015, updated 2017). The most common tests used to detect bladder cancer are cytology with urinalysis and transurethral intravesical illumination using white light cystoscopy with biopsy. Cytology detects morphological changes in intact, exfoliated cells. It can identify high-risk disease reliably but tends to miss low-grade or early-stage tumors. White light cystoscopy is unreliable for determining low- and high-grade cancer, assessing level of invasion, differentiating non-papillary and flat malignant lesions (e.g., carcinoma in situ) from inflammation, detecting smaller or satellite tumors, and visualizing submucosal tumor margins during transurethral resection. These limitations can lead to incomplete tumor resection and under-staging, which can increase the risk of cancer persistence, recurrence, and progression (of highgrade cancer) to more lethal disease (Zlatev, 2015; Lopez, 2014). Photodynamic diagnosis in urology: Photodynamic diagnosis in urology (also called blue light cystoscopy or fluorescent cystoscopy) applies the principle of fluorescence under ultraviolet light to distinguish suspicious lesions from non-cancerous mucosa. Innovations in transurethral intravesical illumination using fluorescent markers, which show selective absorption by malignant cells, provide additional contrast enhancement. The goal of these modifications is to improve optical diagnosis beyond standard white light cystoscopy, resulting in more effective use of both bladder sparing management for low-grade cancer and more aggressive treatment for high-grade cancer (Zlatev, 2015; Lopez, 2014). 3

Clinical application of photodynamic diagnosis in bladder cancer involves two agents: the heme precursor 5-aminolevulinic acid and its derivative hexaminolevulinate. The U.S. Food and Drug Administration (FDA) has approved 5-aminolevulinic acid for topical use in dermatology; intravesical evaluation of the bladder is an off-label use (FDA, 1999). Hexaminolevulinate is available in the United States as Cysview performed in combination with the Karl Storz D-Light C Photodynamic Diagnostic system for the cystoscopic detection of non-muscle invasive bladder cancer in patients suspected or known to have lesion(s) on the basis of a prior white light cystoscopy (FDA, 2010a and b). Cysview/blue light cystoscopy may be used during an endoscopic examination of the bladder and during resection of bladder cancer. FDA approval highlights the importance of performing a thorough white light examination first, as some lesions may be missed with Cysview/blue light. Cysview is available for single use as a kit with 100-mg hexaminolevulinate powder and a 50-mL solvent, which is instilled in the bladder; the safety of repetitive Cysview administrations has not been assessed. Currently, hexaminolevulinate is not approved for patients who received intravesical immunotherapy or chemotherapy within 90 days, as false-positive results may occur from inflammatory lesions, previous biopsy sites, or in patients previously treated with bacillus Calmette-Guérin (FDA, 2010b). Searches Select Health of South Carolina searched PubMed and the databases of: UK National Health Services Centre for Reviews and Dissemination. Agency for Healthcare Research and Quality s National Guideline Clearinghouse and other evidence-based practice centers. The Centers for Medicare & Medicaid Services (CMS). We conducted searches on January 15, 2018. Search terms were: Urologic Diseases (MeSH), Urologic Neoplasms (MeSH), Urinary Tract Infections (MeSH), Urinary Tract (MeSH), and Cystoscopy (MeSH). 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 4

We found five systematic reviews/meta-analyses, three evidence-based guidelines, and no costeffectiveness analyses for this policy. Moderate quality evidence from randomized controlled trials (RCTs), nonrandomized controlled trials, and cross-sectional studies comprised the majority of the evidence in the secondary analyses (Gakis, 2016; Chou, 2015; Di Stasi, 2015; Lee, 2015; Burger, 2013). Studies enrolled persons with known or suspected bladder cancer. They compared photodynamic diagnosis using hexaminolevulinate and, to a lesser extent, 5-aminolevulinic acid as an adjunct to white light cystoscopy during initial diagnosis and transurethral resection. The role of photodynamic diagnosis as a replacement for white light cystoscopy has not been evaluated. Most studies reported data by lesion, which may hyperinflate estimates of diagnostic accuracy, as opposed to analysis by patient (i.e., intention-to-treat analyses) that is generally more relevant to assess clinical effectiveness. Cystoscopies were performed in a hospital inpatient setting. Since applying photodynamic diagnosis with 5-aminolevulinic acid during cystoscopy is considered an off label use, this policy will restrict discussion to photodynamic diagnosis using hexaminolevulinate. Photodynamic diagnosis is a reasonably safe procedure, as no serious side effects were noted. The harms associated with any cystoscopy procedure are discomfort, subsequent dysuria and bleeding, and the possibility of urinary tract infection or acute retention. Hexaminolevulinate is contraindicated in patients with porphyria, gross hematuria, intravesical immunotherapy or chemotherapy within 90 days, or known hypersensitivity to hexaminolevulinate or aminolevulinate derivatives. Although repetitive use of hexaminolevulinate has not been evaluated in prospective clinical trials, there are reports that some clinicians may begin repetitive, off-label use of hexaminolevulinate at 6- or 12- month intervals after initial detection of bladder cancer due to fear of missing recurrences that are difficult or impossible to detect with white light cystoscopy (Hayes, 2016 ). One retrospective study with 180 patients and another study that summarized data from six controlled trials (4,324 total patients) and a European registry found no statistically significant differences in the frequency or grade of adverse events between single- and repeat-use of blue light cystoscopy with hexaminolevulinate (Lane, 2017; Witjes, 2014). A registry study that will address the safety and efficacy of repetitive use of hexaminolevulinate in urologists' practices in the United States is underway (ClinicalTrials.gov identifier: NCT02660645). There is consistent evidence that a single application of photodynamic diagnosis added to white light cystoscopy improves the detection and resection of non-muscle invasive bladder cancer. Photodynamic diagnosis detects significantly more Ta, T1, and carcinoma in situ tumors than white light cystoscopy alone. This benefit extends to most subgroups, including more aggressive, higher risk primary and recurrent bladder cancer. However, the benefits must be weighed against the higher false positive rate (corresponding to lower specificity) of photodynamic diagnosis plus white light cystoscopy, which may result in an increase in unnecessary biopsies. 5

The added value of enhanced detection with respect to the risk of recurrence, recurrence-free survival, mortality, progression to muscle-invasive bladder cancer, or cost-effectiveness has not been established. Limited evidence with a high potential for bias suggests photodynamic diagnosis with white light cystoscopy may reduce recurrence rates up to one year, and possibly longer, but the findings were conflicting across studies. Photodynamic diagnosis can miss some high grade lesions found on white light cystoscopy. Use of single-dose adjuvant chemotherapy following transurethral resection of bladder tumor, which alone can reduce recurrence rates, was inconsistently reported or accounted for across studies. Most studies reported a relatively short follow-up period (up to 12 months), which is insufficient to detect changes to invasive cancer, and used various definitions for disease progression. More comparative prospective studies are needed to define the optimum use of photodynamic diagnosis relative to white light cystoscopy. Evidence-based guidelines by the American Urological Association/ Society of Urologic Oncology (AUA/SUO), NICE, and the EAU recommend photodynamic diagnosis-guided transurethral resection for persons with suspected bladder cancer, when available, based on the ability of photodynamic diagnosis to enhance detection and lower recurrence (Chang, 2016; NICE, 2015; EAU, 2015, updated 2017). There is general agreement, based on expert opinion, that photodynamic diagnosis is one of several diagnostic options for patients with a history of non-muscle invasive bladder cancer with normal white light cystoscopy and positive cytology. Other options include prostatic urethral biopsies, upper tract imaging, ureteroscopy, and random bladder biopsies. The EAU further recommends photodynamic diagnosisguided biopsy instead of random biopsies when carcinoma in situ or high-grade tumor is suspected (e.g., positive cytology or recurrent tumor with previous history of a high-grade lesion) based on moderate quality evidence, and either random biopsies or photodynamic diagnosis-guided biopsies after intravesical treatment (at three or six months) in patients with carcinoma in situ based on expert opinion. Policy updates: In 2018, we added two guideline updates on management of bladder cancer: one by the National Comprehensive Cancer Network (2018) and the other by the EAU (2017). Their recommendations for blue light cystoscopy are consistent with the previous findings, and no policy changes are warranted. Summary of clinical evidence: Citation NCCN (2018) Bladder Cancer Guideline EAU (2015, updated 2017) Content, Methods, Recommendations Blue light cystoscopy may be considered in conjunction with white light cystoscopy and clinical expertise to improve staging accuracy. Data are still limited, and white light cystoscopy remains the mainstay of bladder cancer imaging. 6

Citation Current guideline: non-muscle invasive bladder cancer Chang (2016) for the AUA/SUO Guideline: diagnosis and treatment of non-muscle invasive bladder cancer Gakis (2016) Impact of white light cystoscopy + hexaminolevulinate vs. white light cystoscopy-guided transurethral resection of bladder tumor in non-muscle invasive bladder cancer on rate of progression Chou (2015) for AHRQ Content, Methods, Recommendations Fluorescence-guided biopsy and resection are more sensitive than conventional procedures for detecting malignant tumors, particularly carcinoma in situ, but less specific. Hexaminolevulinate fluorescence cystoscopy has a beneficial effect on recurrence rate in patients with transurethral resection, but its effect on progression rate, survival, and clinical management is unclear. Use photodynamic diagnosis biopsy instead of random biopsies when bladder carcinoma in situ or high-grade tumor is suspected (e.g., positive cytology, recurrent tumor with previous history of a high-grade lesion). (B: moderate certainty that there are moderate benefits that outweigh the risks/burdens). Use random biopsies or photodynamic diagnosis-guided biopsies after intravesical treatment (at three or six months) in patients with carcinoma in situ. (C) Use random biopsies or photodynamic diagnosis-guided biopsies during follow-up in patients with positive cytology and no visible tumor in the bladder (B). Recommendations based on AHRQ systematic review (Chou, 2015) and expert opinion. Recommend offering blue light cystoscopy at the time of transurethral resection, if available, to increase detection and decrease recurrence (Moderate recommendation; Evidence Strength: Grade B [i.e., moderate certainty that there are moderate benefits that outweigh the risks/burdens]). In a patient with a history of non-muscle invasive bladder cancer with normal cystoscopy and positive cytology, consider prostatic urethral biopsies, upper tract imaging, enhanced cystoscopic techniques (blue light cystoscopy, when available), ureteroscopy, or random bladder biopsies. (Expert Opinion in the absence of evidence). Systematic review and meta-analysis of four RCTs and one retrospective study (1,301 total patients; 644 underwent hexaminolevulinate- and 657 white light-based transurethral resection). Overall quality: moderate with low-to-moderate risk of bias for most randomized studies and low risk of bias for the retrospective study. Limited by variation in definitions of disease progression and length of follow up. Median follow-up (months): white light cystoscopy + hexaminolevulinate 27.6 (range 1 to 55.1) vs. white light cystoscopy alone 28.9 (range 1 to 53). Limited evidence suggests the detection and resection of non-muscle invasive bladder cancer with white light cystoscopy +hexaminolevulinateguided transurethral resection reduces the risk of progression more than white light cystoscopy alone. Emerging approaches to diagnosis and Systematic review and meta-analysis of 13 studies (photodynamic 7

Citation treatment of non-muscle invasive bladder cancer: photodynamic diagnosis or narrow band imaging vs. white light cystoscopy Di Stasi (2015) Hexaminolevulinate in the detection of non-muscle invasive bladder cancer Lee (2015) Content, Methods, Recommendations diagnosis only). Overall quality: low-to-moderate with moderate-to-high risk of publication bias and performance bias related to knowledge of the type of initial cystoscopy performed. Photodynamic diagnosis cystoscopy with 5-aminolevulinic acid or hexaminolevulinate vs. white light cystoscopy: No difference in risk of mortality or progression to muscle-invasive bladder cancer. Only one trial was designed to minimize performance bias by blinding the cystoscopist to instillation of the photosensitizer and found no effect. Lower risk of recurrence with photodynamic diagnosis at short-, moderate, and long-term follow up, but findings were inconsistent and susceptible to bias. No clear difference in risk of false positives or renal or genitourinary events (two trials). More research is needed to clarify advantages of photodynamic diagnosis over white light cystoscopy alone. Systematic review of eight prospective RCTs, seven prospective withinpatient comparisons, and one observational comparative controlled trial (3,895 total patients with 2,313 total lesions). Studies were limited by lack of standard data collection methods. White light cystoscopy + hexaminolevulinate photodynamic diagnosis increased overall tumor detection rate vs. white light cystoscopy alone: Detection by lesion Proportion difference type (95% confidence interval [CI]) Ta, T1 and Tis 19% (0.152 to 0.236) Carcinoma in situ 15.7% (0.069 to 0.245) Ta 5.9% (0.014 to 0.103) T1 1.2%, (0.033 to 0.057) Fifteen percent of patients (95% CI 0.098 to 0.211) had at least one additional tumor seen with photodynamic diagnosis. Insufficient data to assess recurrence rates, but trends favor of hexaminolevulinate-photodynamic diagnosis at three, six and 12 months. Statistically significant difference in the pooled percentage of false positives: White light cystoscopy 15.65 (SD = 7.06) vs. blue light cystoscopy 22.35 (SD = 9.24) (p < 0.05). Technology-assisted transurethral resection for non-muscle invasive bladder cancer: 5-aminolevulinic acid fluorescence vs. hexaminolevulinate fluorescence vs. narrow band imaging Network meta-analysis of 15 RCTs comparing outcomes of resected nonmuscle invasive bladder cancer using photodynamic diagnosis with 5- aminolevulinic acid, hexaminolevulinate, or narrow band imaging. Overall quality: low with moderate to high risk of bias. Recurrence rates (odds ratio [OR], 95% CI): 5-aminolevulinic acid vs. hexaminolevulinate: (0.48, 0.26 to 0.95). 8

Citation NICE (2015) Guidance for bladder cancer diagnosis and management Burger (2013) Content, Methods, Recommendations 5-aminolevulinic acid vs. narrow band imaging (0.53, 0.26 to 1.09). Hexaminolevulinate vs. narrow band imaging (1.11, 0.55 to 2.1). Lower recurrence rates for all photodynamic diagnosis-and NBI-guided resected cancers vs. white light cystoscopy alone. No difference in progression rates for cancers resected by all methods. Recommend offering white-light-guided transurethral resection with one of the following: photodynamic diagnosis, narrow band imaging, cytology, or a urinary biomarker test (such as UroVysion using fluorescence in-situ hybridization, ImmunoCyt or a nuclear matrix protein 22 test) to people with suspected bladder cancer. This should be carried out or supervised by an urologist experienced in transurethral resection. White light cystoscopy vs. white light cystoscopy + hexaminolevulinate-blue light cystoscopy for detection and recurrence of non-muscle invasive bladder tumor Meta-analysis of raw data from nine studies with 1,345 patients with known or suspected non-muscle invasive bladder tumor. Overall quality: moderate to high with low risk of bias. Limited by variable data collection and short follow up of up to 12 months, which is insufficient to detect changes to invasive cancer. Data analysis was by patient (intention-to-treat) and by lesion. Hexaminolevulinate blue light cystoscopy significantly improves the detection of bladder tumors leading to a reduction of recurrence at 9 to 12 mo. The benefit is independent of the level of risk and is evident in patients with Ta, T1, carcinoma in situ, primary, and recurrent cancer. Previous intravesical therapy had no effect on tumor detection, but poorly documented. References Professional society guidelines/other: AJCC Cancer Staging System. American Joint Committee on Cancer website. https://cancerstaging.org/references-tools/pages/what-is-cancer-staging.aspx. Accessed January 15, 2018. Bladder cancer. American Cancer Society website. https://www.cancer.org/cancer/bladder-cancer.html. Accessed January 15, 2018. Bladder cancer: diagnosis and management. NICE Guideline 2. February 2015. National Institute for Health and Clinical Excellence website. https://www.nice.org.uk/guidance/ng2/evidence/full-guideline- 3744112. Accessed January 15, 2018. 9

Chang SS, Boorjian SA, Chou R, et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. J Urol. 2016; 196(4): 1021 1029. DOI: 10.1016/j.juro.2016.06.049. Guidelines on Non-muscle-invasive Bladder Cancer. 2017. European Association of Urology website. https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/. Accessed January 15, 2018. NCCN Guidelines Bladder Cancer. Version 1.2018. National Comprehensive Cancer Network website. www.nccn.org. Accessed January 15, 2018. Peer-reviewed references: Burger M, Grossman HB, Droller M, et al. Photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data. Eur Urol. 2013; 64(5): 846 854. DOI: 10.1016/j.eururo.2013.03.059. Chou R, Buckley D, Fu R, et al. Emerging Approaches to Diagnosis and Treatment of Non Muscle- Invasive Bladder Cancer. Comparative Effectiveness Review No. 153. (Prepared by the Pacific Northwest Evidence-based Practice Center under Contract No. 290-2012-00014-I.) AHRQ Publication No. 15(16)- EHC017-EF. Rockville, MD: Agency for Healthcare Research and Quality. October 2015. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Accessed January 15, 2018. Di Stasi SM, De Carlo F, Pagliarulo V, et al. Hexaminolevulinate hydrochloride in the detection of nonmuscle invasive cancer of the bladder. Ther Adv Urol. 2015; 7(6): 339 350. DOI: 10.1177/1756287215603274. FDA Approval Letter for NDA 20-965. 1999. Center for Drug Evaluation and Research. FDA website. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/1999/20965ltr.pdf. Accessed January 15, 2018. FDA. Karl Storz Endoskope. Photodynamic Diagnostic D-Light C System. Instruction Manual. 2010. FDA website. http://www.accessdata.fda.gov/cdrh_docs/pdf5/p050027c.pdf. Accessed January 15, 2018.(a) FDA. Summary Review for Regulatory Action. 022555Orig1s000. Cysview Hexaminolevulinate Hydrochloride for Intravesical Solution. 2010 FDA website. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022555orig1s000sumr.pdf. Accessed January 15, 2018.(b) Gakis G, Fahmy O. Systematic Review and Meta-Analysis on the Impact of Hexaminolevulinate- Versus White-Light Guided Transurethral Bladder Tumor Resection on Progression in Non-Muscle Invasive Bladder Cancer. Bladder Cancer. 2016; 2(3): 293 300. DOI: 10.3233/blc-160060. 10

Hayes Inc., Hayes Medical Technology Report. Hexaminolevulinate (Cysview, Hexvix ) for Bladder Cancer Detection. Lansdale, Pa. Hayes Inc.; 2012. Updated 2016. Lane GI, Downs TM, Soubra A, et al. Tolerability of Repeat Use of Blue Light Cystoscopy with Hexaminolevulinate for Patients with Urothelial Cell Carcinoma. J Urol. 2017; 197(3 Pt 1): 596 601. DOI: 10.1016/j.juro.2016.09.076. Lee JY, Cho KS, Kang DH, et al. A network meta-analysis of therapeutic outcomes after new image technology-assisted transurethral resection for non-muscle invasive bladder cancer: 5-aminolaevulinic acid fluorescence vs hexylaminolevulinate fluorescence vs narrow band imaging. BMC Cancer. 2015; 15: 566. DOI: 10.1186/s12885-015-1571-8. Lopez A, Liao JC. Emerging endoscopic imaging technologies for bladder cancer detection. Curr Urol Rep. 2014; 15(5): 406. DOI: 10.1007/s11934-014-0406-5. Witjes JA, Gomella LG, Stenzl A, et al. Safety of hexaminolevulinate for blue light cystoscopy in bladder cancer. A combined analysis of the trials used for registration and postmarketing data. Urology. 2014; 84(1): 122 126. DOI: 10.1016/j.urology.2014.03.006. Zlatev DV, Altobelli E, Liao JC. Advances in imaging technologies in the evaluation of high-grade bladder cancer. Urol Clin North Am. 2015; 42(2): 147 157, vii. DOI: 10.1016/j.ucl.2015.01.001. 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 Comments 52000 Cystourethroscopy (separate procedure) 52204 Cystourethroscopy, with biopsy(s) 52214 Cystourethroscopy, with fulguration (including cryosurgery or laser surgery) of trigone, bladder neck, prostatic fossa, urethra, or periurethral glands 11

CPT Code Description Comments 52224 52234 52235 52240 Cystourethroscopy, with fulguration (including cryosurgery or laser surgery) or treatment of MINOR (less than 0.5 cm) lesion(s) with or without biopsy Cystourethroscopy, with fulguration (including cryosurgery or laser surgery) and/or resection of SMALL bladder tumor(s) (0.5 to 2.0 cm) Cystourethroscopy, with fulguration (including cryosurgery or laser surgery) and/or resection of MEDUIUM bladder tumor(s) (2.0 to 5.0 cm) Cystourethroscopy, with fulguration (including cryosurgery or laser surgery) and/or resection of LARGE bladder tumor(s) ICD-10 Code Description Comments C67.0-C67.9 Neoplasm of bladder HCPCS Level II Code C9275 Description Injection, hexaminolevulinate hydrochloride, 100 mg, per study Comments 12