JU INSIGHT: All High-Grade Ta Tumors Should be Classified as High Risk: Bacillus Calmette-Guerin Response in High-Grade Ta Tumors

By: Kelly K. Bree, MD; Patrick J. Hensley, MD; Niyati Lobo, MD; Nathan A. Brooks, MD; Graciela M. Nogueras-Gonzalez; Charles C. Guo, MD; Neema Navai, MD; H. Barton Grossman, MD; Colin P. Dinney, MD; Ashish M. Kamat, MD | Posted on: 01 Aug 2022

Bree KK, Hensley PJ, Lobo N et al: All high-grade ta tumors should be classified as high risk: bacillus calmette-guérin response in high-grade ta tumors. J Urol 2022; 208: 284.

Study Need and Importance

Optimal management of patients with bladder cancer necessitates accurate risk stratification. Unfortunately, risk stratification paradigms vary amongst different nonmuscle-invasive bladder cancer guidelines. Currently, the American Urological Association/Society of Urologic Oncology guidelines recommend that small high-grade (HG) Ta tumors be considered intermediate-risk (IR) rather than high-risk (HR). Similarly, while previous iterations of the European Association of Urology (EAU) guidelines have included all HG tumors as HR, the 2021 guidelines provide new prognostic risk groups in which some HG Ta tumors are considered IR. The 2021 prognostic risk groups are based upon individual patient data from nonmuscle-invasive bladder cancer cases treated with or without intravesical chemotherapy, but not Bacillus Calmette-Guérin (BCG) immunotherapy. Thus, we sought to investigate the response to BCG in all Ta tumors and compared responses based upon EAU classification as IR or HR.

“Currently, the American Urological Association/Society of Urologic Oncology guidelines recommend that small high-grade (HG) Ta tumors be considered intermediate-risk (IR) rather than high-risk (HR).”

What We Found

When we studied patients who received adequate BCG (defined as at least 5 of 6 induction instillations plus at least 2 additional instillations, as a component of either maintenance or re-induction therapy) from 2000–2018 at our institution and stratified them based upon 2021 EAU prognostic risk groups, we found that 37 (16%) had IR low-grade (LG) Ta, 92 (40%) had IR HG Ta and 101 (44%) had HR HG Ta tumors. Oncologic behavior of IR HG Ta tumors was more in alignment with HR HG Ta tumors than IR LG Ta tumors regarding BCG unresponsiveness (HR HG Ta 13%, IR HG Ta 14%, IR LG Ta tumors 0.0%, p=0.003) and progression to muscle-invasive disease or metastasis (HR HG Ta 5.9%, IR HG Ta 6.5%, IR LG Ta 0.0%, p=0.3, see Table). Rates of recurrence, BCG unresponsiveness and progression were similar, irrespective of the number of EAU risk factors present (ie age >70 years, tumor size ≥ 3cm, multifocality).

Table. Response to BCG among Ta tumors stratified by EAU risk groups

Characteristic	IR LG Ta			IR HG Ta			HR HG Ta
Characteristic	N	%	95% CI	N	%	95% CI	N	%	95% CI	p-value
# of doses of BCG										0.7
N	37			92			101
Median	18 (13–27)			18 (12–24)			21 (13–24)
Recurrence	12	32	18,50	34	37	27,48	39	39	29,49	0.8
BCG Unresponsive	0	0		13	14	7.8,23	13	13	7.0,21	0.03
Progression on BCG (any stage)	0	0		12	13	6.9,22	13	13	7.0,21	0.04
Progression to MIBC or distant metastatic disease	0	0		6	6.5	2.4,14	6	5.9	2.2,12	0.3
Estimates were given as median (quartile 1, quartile 3) or frequency (percentage). p values were calculated using Kruskal-Wallis test for continuous and Fisher’s exact test for categorical variables.

Limitations

This study was a retrospective review from a single institution.

Interpretation for Patient Care

Among patients treated with adequate BCG, rates of BCG unresponsiveness and progression were similar in all patients with HG Ta tumors, irrespective of the number of EAU clinical risk factors, and were uniformly higher than IR LG Ta tumors. These data suggest that all HG Ta tumors are at risk for progression and should be treated as HR.