Real-World Outcomes Driving the Needle toward Simplification of Nonmuscle Invasive Bladder Cancer Risk Stratification.

Abstract

You have accessJournal of UrologyEditorials1 Aug 2022Real-World Outcomes Driving the Needle toward Simplification of Nonmuscle Invasive Bladder Cancer Risk Stratification Heather L. Huelster, and Wade J. Sexton Heather L. HuelsterHeather L. Huelster H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida More articles by this author , and Wade J. SextonWade J. Sexton H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002731AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail A patient’s visit for a new diagnosis of nonmuscle invasive bladder cancer (NMIBC) represents the start of a lifelong, sometimes winding journey of bladder cancer surveillance, intravesical therapies and surgical interventions. Recent data have demonstrated that patients have limited understanding and varying perceptions of modifiable risk factors for recurrence and progression,1 cancer control2 and long-term quality of life effects from treatment.3 Combined with the urological community’s focus on improving cancer outcomes in NMIBC care, evolving complex pathways of management based on nuanced risk stratification systems can be challenging to navigate for both patients and providers. In this issue of The Journal, Bree et al (page 284) critically examine oncologic outcomes as they relate to current guidelines’ risk stratification schema using a large real-world cohort of NMIBC tumors gathered from their single-institutional experience from 2000–2018.4 Analysis of 251 bacillus Calmette-Guérin (BCG)-treated Ta tumors demonstrated that high-grade (HG) Ta tumors have no difference in rates of recurrence, BCG unresponsiveness, any stage progression and progression to muscle-invasive or metastatic disease regardless of intermediate vs high risk classification by European Association of Urology (EAU) criteria.5 Rates of tumor recurrence in HG Ta patients were similar to recurrence rates in low-grade (LG) Ta, though no patients with LG Ta developed stage progression or metastatic disease over a median followup of nearly 4 years. Thus, they argue that the real-world outcomes after treatment of HG Ta tumors do not support a model stratifying HG Ta in practice and that all HG Ta lesions should be considered high risk. The strength of these institutional data lies in the details, specifically with regard to reporting rates of repeat transurethral resection and perioperative intravesical chemotherapy utilization reflective of current practice patterns. Unfortunately, one lack of detail is the intent of BCG with no reported rate of maintenance BCG utilization in each group, as BCG administration is reported only as a cumulative number of doses, though all met criteria for adequate BCG therapy as defined according to the U.S. Food and Drug Administration.6 However, the cohort examined here is inherently different than that used to inform the updated EAU classification schema. Last year’s update to the EAU NMIBC guidelines focused on incorporating the World Health Organization (WHO) 2004/2016 and WHO 1973 grading systems using 30 years of individual patient data from 3,401 NMIBCs resulting in differentiation of intermediate and high risk categorization of HG Ta tumors by quantifying clinical risk factors including age >70 years, multiple papillary tumors and tumor diameter >3 cm.7 This was a landmark study describing risk factors for progression of NMIBC after transurethral resection in patients who were not treated with BCG. However, the focus of these data for constructing the EAU guidelines raises the question of whether risk classification should be based on natural history of the untreated disease or current standard-of-care treatment approaches in consensus guidelines. Current AUA (American Urological Association) risk stratification for NMIBC also includes small (≤3 cm), solitary HG Ta tumors in the intermediate risk category, acknowledging heterogeneity of the intermediate risk group with poorly defined risks of recurrence and progression in available literature.8 Different than the EAU’s approach, the AUA/SUO (Society of Urologic Oncology) risk stratification system incorporates prior BCG exposure in consideration of prognosis. However, risk stratification is based on expert consensus from a panel informed by published data and no specific level A evidence. Incorporating utilization of adjuvant BCG in NMIBC risk stratification reflects the prognosis of many patients who seek understanding of their risks of recurrence and progression while receiving intravesical therapy. However, the updated EAU NMIBC prognostic factor risk groups are more reflective of the natural history of resected NMIBC and may be valuable in counseling BCG-naïve patients as well as informing selection for future trials of non-BCG-based adjuvant therapies. They may be less appropriate for risk categorization in trials evaluating BCG-adjunctive therapeutics, such as emerging agents like interleukin 15 superagonist N-803 and oncolytic viruses, directed at improving BCG efficacy or managing BCG failures. Additionally, inclusion of tumors later found to be BCG unresponsive represents an important category of patients at risk for adverse outcomes and is paramount to meaningful improvement in NMIBC management. Regardless of the classification schema referenced, the intermediate risk group provides a catch-all category for NMIBC tumors not specifically designated as at high or low risk of recurrence and progression, creating practical challenges with regard to optimization of management by providers and in research. Landmark SWOG trials demonstrating the benefit of maintenance BCG predated intermediate risk categorization. Thus, treatment recommendations focused on utilization of maintenance BCG for 3 years in high-risk versus 1 year in intermediate-risk disease are largely extrapolated from indirect comparisons of varying BCG regimens with intravesical chemotherapy.9 In the current setting of BCG shortage, patients identified as intermediate risk may receive partial-dose or forgo maintenance BCG altogether. The specific effect of BCG on reducing recurrence and progression in currently classified intermediate-risk NMIBC remains poorly delineated and has been proposed to lack cost-effectiveness.10 In the words of Leonardo Da Vinci, sometimes “simplicity is the ultimate sophistication.” The practical challenges and lack of specificity of evidence driving management of intermediate-risk NMIBC may eventually support elimination of this categorization in real-world practice. If simplification of risk stratification schemes is supported by clinical data, it is only advantageous to facilitating patient comprehension of their disease and clarity of provider recommendations in the early stages of NMIBC management as well. The demonstrated lack of difference in meaningful oncologic outcomes between EAU intermediate-risk and high-risk HG Ta tumors by Bree et al represents a push for HG Ta tumors to move within the spectrum of NMIBC toward high risk and may warrant future consideration by guideline panelists. Ongoing work is needed to validate these results and better inform NMIBC risk stratification strategies in consensus group guidelines.