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Bacillus Calmette-Guérin (BCG) is currently the most clinically effective intravesical treatment for non–muscle-invasive bladder cancer (NMIBC), particularly for patients with high-risk NMIBC such as those with carcinoma in situ. BCG treatments could be optimized to improve patient safety and conserve supply by predicting BCG efficacy based on tumor characteristics or clinicopathological criteria.
The aim of this study is to assess the ability of specific clinicopathological criteria to predict tumor recurrence in patients with NMIBC who received BCG therapy along various treatment timelines.
A total of 1331 patients (stage Ta, T1, or carcinoma in situ) who underwent transurethral resection of a bladder tumor between 2006 and 2017 were included. Univariate analysis, including laboratory tests (eg, complete blood panels, creatinine levels, and hemoglobin A1c levels) within 180 days of BCG therapy initiation, medications, and clinical and demographic variables to assess their ability to predict NMIBC recurrence, was completed. This was followed by multivariate regression that included the elements of the Club Urológico Español de Tratamiento Oncológico (CUETO) scoring model and variables that were significant predictors of recurrence in univariate analysis.
BCG was administered to 183 patients classified as intermediate or high risk, and 76 (41.5%) experienced disease recurrence. An abnormal neutrophil-to-lymphocyte ratio measured within 180 days of induction BCG therapy was a significant predictor (
An abnormal neutrophil-to-lymphocyte ratio within 180 days of BCG therapy initiation is predictive of recurrence and could be suggestive of additional or alternative interventions.
Bacillus Calmette-Guérin (BCG) is currently the most clinically effective intravesical treatment for non–muscle-invasive bladder cancer (NMIBC), particularly for patients with high-risk NMIBC such as those with carcinoma in situ (CIS). Unfortunately, recent manufacturing insufficiencies have resulted in a worldwide, health-threatening BCG shortage [
The heterogeneous risk of cancer recurrence and progression in patients with NMIBC has led to the investigation of a wide range of methods and factors for predicting a patient’s prognosis, including the Club Urológico Español de Tratamiento Oncológico (CUETO) scoring model, which was designed for patients treated with BCG, and European Organization for Research and Treatment of Cancer nomograms [
Debate and uncertainty persist regarding the potential of various clinical risk factors. The overarching goal of this study is to identify and validate easily employable risk factors that predict BCG failure. Although immunological or cytokine-based markers, protein-based biomarkers, and gene-based biomarkers show potential, they require extra expenditure and testing because they are not collected in the normal course of clinical care. In contrast, clinicopathological criteria are often captured as part of the clinical workflow and are thus actionable at the time that treatment decisions are being made. The aim of this study, therefore, is to assess the ability of commonly used clinicopathological criteria or medications to predict recurrence in patients with NMIBC who were treated with intravesical BCG.
We conducted a retrospective cohort analysis following institutional review board (IRB) approval. From 2006 to 2017, a total of 1331 patients underwent transurethral resection (TUR) of a bladder tumor that was clinically staged as non–muscle invasive. Patients received care within a community health care system in the Midwest that includes 17 different hospitals dispersed across a wide geographic area that spans rural, suburban, and urban locations. Data captured during the normal course of clinical care were extracted and collated retrospectively from the cancer registry (ie, patient demographics, cancer diagnosis, recurrence, and treatment) and electronic health records (EHRs; ie, surgery and pathology reports, medication orders, laboratory tests, procedure codes, and billing diagnoses). We used a hybrid data extraction and preparation pipeline incorporating automated, semiautomated, and manual techniques. A detailed description of the pipeline can be found in our previous study [
We included patients with NMIBC and a primary or recurrent diagnosis of Ta or T1 urothelial carcinoma or CIS per the American Joint Committee on Cancer tumor size, node involvement, and metastasis system [
Recurrence following the index TUR was the primary outcome of interest in this study. Recurrence was defined as cancer returning more than 6 weeks after the index TUR. In contrast, a TUR occurring 2-6 weeks after the index TUR was defined as a Re-TUR (ie, a second-look TUR) instead of a recurrence. Progression, in this study, was defined as cancer upstaging to ≥stage T2 or patients requiring cystectomy. Bladder cancer recurrence and progression were identified using pathology reports and the dates of the events listed in the cancer registry. The date of decease was also captured in the cancer registry. The BCG instillation date was extracted from (1) procedure billing data, (2) medication administration records, (3) medication order records (ie, prescription), or (4) extracted from a free-text chemotherapy field in the cancer registry data.
Pathology reports were reviewed to determine tumor stage, size, quantity, and grade for each TUR. The tumor stage recorded was the highest stage confirmed by the pathologist. Tumor grade was captured in, or converted to, the 2004 World Health Organization grading system. Tumor size was stratified into small (≤3 cm) or large (>3 cm). CIS and lymphovascular invasion were extracted from the cancer registry. The study cohort is exclusively composed of patients with a primary cancer diagnosis; therefore, all patients with a prior incidence of NMIBC were excluded. Variant histology was extracted from the pathology reports, although all patients with variant histology in the data were staged T2 or higher in their index TUR and, thus, were excluded from the study. High-grade prostatic urethral involvement occurs when the cancer preferentially invades the prostatic urethra before the bladder muscle and was extracted from the pathology reports. Age was calculated based on the difference between the date of the index TUR and date of birth and was extracted from the cancer registry (along with sex).
Several clinical characteristics associated with the efficacy of BCG treatment were extracted from the EHR, including white blood cell, lymphocyte, neutrophil, monocyte, and platelet counts and levels of creatinine and hemoglobin A1c (
Clinicopathological criteria or medication definitions.
Type and clinicopathological criterion or medication | Description | |
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BCGa instillation | First instillation of BCG documented 0-90 days after TURb |
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Epirubicin | Epirubicin use documented 0-90 days after TUR |
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Tuberculostatic agents | Use of isoniazid isonicotinylhydrazide, rifampicin, rifambutin, fluoroquinolones (ofloxacin, ciprofloxacin, levofloxacin, and moxifloxacin), ethambutol, clarithromycin, aminoglycosides (gentamicin, amikacin, tobramycin, kanamycin, and neomycin), or doxycycline documented –30 to 90 days of induction BCG (index to median day of BCG administration if no BCG) |
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Spasmolytics or anticholinergics | Use of spasmolytics: oxybutynin documented –30 to 90 days of induction BCG (index to median day of BCG administration if no BCG) |
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Antiphlogistics | Use of antiphlogistics: fluticasone documented –30 to 90 days of induction BCG (index to median day of BCG administration if no BCG) |
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Topical steroids | Use of local topical steroids: betamethasone, clobetasol, diflorasone, fluocinoide, halobetasol, amcinonide, desoximetasone, propionate, triamcinolone, fluocinolone, hydrocortisone, desonide, alclometasone, and mometasone documented –30 to 90 days of induction BCG (index to median day of BCG administration if no BCG) |
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Nonsteroidal anti-inflammatory drugs | Use of nonsteroidal anti-inflammatory drugs: aspirin, ibuprofen, naproxen, nabumetone, celecoxib, diclofenac, etodolac, indomethacin, ketoprofen, ketorolac, and piroxicam documented –30 to 90 days of induction BCG (index to median day of BCG administration if no BCG) |
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General description |
Most recent (laboratory test) occurring 1-180 days after induction BCG computed 14 days before the next event (ie, TUR but not Re-TURc, recurrence, progression, or death) Difference between the most recent (laboratory test) occurring 1-180 days after induction BCG computed 14 days before next event and the most recent (laboratory test) occurring 90-0 days before induction BCG (index to median day of BCG administration if no BCG) |
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Lymphocyte count (normal: 20%-40% differential) | N/Ad |
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Neutrophil count (normal: 55%-70% differential) | N/A |
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Monocyte count (normal: 2%-8% differential) | N/A |
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Platelet count (K/μL) | N/A |
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White blood cell count (K/μL) | N/A |
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Creatinine level (mg/dL) | N/A |
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Hemoglobin A1c (mmol/mol) | N/A |
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General description |
Most recent (laboratory test) occurring 1-180 days after induction BCG computed 14 days before the next event (ie, TUR but not Re-TUR, recurrence, progression, or death) Difference between the most recent (laboratory test) occurring 1-180 days after induction BCG computed 14 days before next event and the most recent (laboratory test) occurring 90-0 days before induction BCG (index to median day of BCG administration if no BCG) |
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Derived neutrophil-to-lymphocyte ratio | N/A |
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Platelet-to-lymphocyte ratio | N/A |
aBCG: bacillus Calmette-Guérin.
bTUR: transurethral resection of a bladder tumor.
cRe-TUR: second-look transurethral resection of a bladder tumor.
dN/A: not applicable.
We additionally extracted medication information from the EHR for drugs that potentially interact with BCG, such as epirubicin (
The 2016 American Urological Association (AUA) risk guidelines for recurrence were used to stratify each index TUR as low, medium, or high risk [
We used the Mann-Whitney U test—using the Wilcox test function in the stats package (version 1.8.12) in R—to compare patients who received BCG and were designated as intermediate to high risk for recurrence and BCG failure. Variables with a Mann-Whitney U value of <0.1 were considered candidates for multivariate logistic regression. Various combinations of multivariate logistic regression were tested using the generalized linear model function in the stats package in R, and the one with the highest area under the receiver operating characteristic curve was selected.
Of the 1331 patients, 855 (64.24%) were intermediate to high risk according to the 2016 AUA guidelines, among whom 183 (21.4%) received an induction course of BCG (
Patient flowchart. AUA: American Urological Association; BCG: bacillus Calmette-Guérin; TUR: transurethral resection of a bladder tumor.
Next event and cohort characteristics at the initial transurethral resection of the bladder tumor by bacillus Calmette-Guérin status.
Characteristic | Received BCGa (n=183), n (%) | No BCG (n=672), n (%) | |
Sex (male) | 143 (78.1) | 507 (75.5) | .45 |
White | 175 (95.6) | 652 (97) | .35 |
African American | 6 (3.3) | 14 (2.1) | .34 |
Hispanic ethnicity | 3 (1.6) | 9 (1.3) | .73 |
Other ethnicity | 2 (1.1) | 6 (0.9) | .68 |
Stage Ta | 81 (44.3) | 433 (64.4) | <.001 |
Stage T1 | 104 (56.8) | 241 (35.7) | <.001 |
Low grade | 34 (18.6) | 320 (47.6) | <.001 |
High grade | 149 (81.4) | 354 (52.7) | <.001 |
Carcinoma in situ | 99 (54.1) | 99 (14.7) | <.001 |
Re-TURb | 32 (17.5) | 63 (9.4) | .002 |
Mitomycinc | 33 (18) | 44 (6.5) | <.001 |
Cisplatinc | 1 (0.5) | 2 (0.3) | .51 |
Gemcitabinec | 0 (0) | 2 (0.3) | .99 |
Recurrence | 76 (41.5) | 309 (45.9) | .28 |
Progression | 1 (0.5) | 4 (0.6) | .99 |
Death | 21 (11.5) | 158 (23.5) | <.001 |
aBCG: bacillus Calmette-Guérin.
bRe-TUR: second-look transurethral resection of a bladder tumor.
cChemotherapy agent used –30 to 90 days of initial index transurethral resection of the bladder tumor. There were no records of the use of lenalidomide, thiotepa, valrubicin, atezolizumab, and pembrolizumab.
Club Urológico Español de Tratamiento Oncológico scoring model or statistically significant clinicopathological criteria in univariate analysis among patients with intermediate- or high-risk non–muscle-invasive bladder cancer who received bacillus Calmette-Guérin (N=183) +1 to 180 days after induction.
Clinicopathological criterion | Missinga, n (%) | Recurrence (Mann-Whitney U test) |
Neutrophil count | 73 (60.1) | 0.009 |
Derived neutrophil-to-lymphocyte ratio | 73 (60.1) | 0.03 |
CUETOb, continuous | 182 (99.5) | 0.10 |
CUETO, categoricalc | 182 (99.5) | 0.07 |
CUETO, gender | 182 (99.5) | 0.61 |
CUETO, number of tumors | 182 (99.5) | 0.05 |
CUETO, CISd | 182 (99.5) | 0.33 |
CUETO, high-grade tumor | 182 (99.5) | 0.34 |
CUETO, age | 183 (0) | 0.75 |
aWe have complete data for CUETO and age (N=183), and 0% of the data are missing. For other CUETO, we have data for 182 patients, and the data are 99.5% complete. We have 60.1% of data (from 73 patients) for neutrophil count within that time span, with 39.9% not having a recorded lab test for this in the timespan.
bCUETO: Club Urológico Español de Tratamiento Oncológico.
cCUETO, categorical: ≤4, 0 points; 5 or 6, 1 point; 7-9, 2 points; and ≥10, 3 points.
dCIS: carcinoma in situ.
A univariate model with only a neutrophil-to-lymphocyte ratio of +1 to 180 days after BCG induction had an area under the receiver operating characteristic curve of 64.55% (
Area under the receiver operating characteristic curve for recurrence prediction. Time span: 1-180 days after bacillus Calmette-Guérin induction. CUETO: Club Urológico Español de Tratamiento Oncológico; Neutrophil: neutrophil count (differential); Lymphocyte: lymphocyte count (differential); Neutrophil Lymphocyte: derived neutrophil-to-lymphocyte ratio.
Coefficients from multivariate regression with Club Urológico Español de Tratamiento Oncológico scoring model elements.
Coefficients | Estimate | SE | ||
(Intercept) | 0.64586 | 0.18476 | 3.496 (66) | <.001 |
Gender | 0.02581 | 0.04944 | 0.522 (175) | .60 |
Number of tumors | 0.0927 | 0.08056 | 1.151 (175) | .25 |
Carcinoma in situ | –0.02382 | 0.07126 | –0.334 (175) | .74 |
High-grade tumor | –0.07384 | 0.05686 | –1.299 (175) | .20 |
Age | –0.12589 | 0.07109 | –1.771 (175) | .08 |
Neutrophil-to-lymphocyte ratio | 0.03017 | 0.01492 | 2.022 (66) | .047 |
Our main finding was that in patients with intermediate- or high-risk NMIBC who received BCG, the neutrophil-to-lymphocyte ratio measured between +1 and 180 days after BCG instillation was predictive of subsequent BCG failure. Early detection of BCG failure could prevent metastatic NMIBC progression by intervening earlier in tumor development. In addition, in the era of BCG shortages around the country, if patients elect to switch to BCG-salvage regimes, early detection of BCG failure would also preserve BCG supply for the patients who truly need it. In this study, we evaluated whether common clinicopathological variables might be predictive of BCG failure in patients with elevated risk. BCG failure is broadly categorized as refractory, relapsing (ie, recurrence), unresponsive, and intolerant cases [
For patients who undergo BCG therapy, the CUETO risk model was designed to predict the probability of cancer recurrence and progression. However, in this cohort, the CUETO score was not a statistically significant differentiator for predicting recurrence after patients classified as low risk (AUA risk guidelines) were excluded from the cohort. This could be due to the poor generalizability of the CUETO scoring model. When external data were previously applied to these scores, the CUETO scoring model overestimated disease recurrence and demonstrated a poor ability to predict recurrence [
The clinicopathological criteria—neutrophils and lymphocytes—are consistent with those in the study by Vartolomei et al [
A second course of BCG induction may be reasonable for refractory or relapsing cases because approximately 25%-50% of these patients will respond to this subsequent induction [
Our data sets only contain data for patients before the halt in the production of the Connaught BCG strain by Sanofi Pasteur, thus precluding any impact analysis, although we expect that these effects are likely more recent than the 2017 stoppage, and we are unaware of the date corresponding to when stockpiles of that strain became unavailable [
Continuous monitoring of a patient’s clinicopathological criteria for the duration of NMIBC treatment to predict future recurrence events is a unique aspect of this study. Another unique aspect was to account for differences in markers of net functional immunity (eg, neutrophil count and lymphocyte count) over time, effectively evaluating whether the changes are predictive. Although the changes in neutrophil count were significant in univariate analysis (
Prior research by Tazeh et al [
In patients with intermediate- or high-risk NMIBC who received BCG, the neutrophil-to-lymphocyte ratio measured between +1 and 180 days after BCG instillation was predictive of subsequent BCG failure. In conjunction with existing risk stratification scores such as the CUETO score, the neutrophil-to-lymphocyte ratio could be used to predict BCG failure. Patients at increased risk for BCG failure could undergo additional surveillance, receiving maintenance intravesical chemotherapy instead of BCG, thereby preserving limited BCG supplies, or be considered for timely cystectomy. Additional retrospective and prospective studies are needed to validate these findings.
Additional statistical analysis at different time points.
American Urological Association
bacillus Calmette-Guérin
carcinoma in situ
Club Urológico Español de Tratamiento Oncológico
electronic health record
institutional review board
non–muscle-invasive bladder cancer
transurethral resection of a bladder tumor
This research was supported by the Advocate Aurora Oncology award. Mary Kissinger and Lisa Robinson, Advocate Aurora Health Care Cancer Registry, and Advocate Aurora Research Institute Research Analytics assisted with data extraction. Glenn Allen reviewed the data. The authors acknowledge the significant efforts of Lorene Schweig for copyediting and manuscript formatting.
All authors provided substantial contributions to the conception and design of this work, its data analysis and interpretation, and helped draft and revise the manuscript. All authors are accountable for the integrity of this study. JP, JW, and K Ravvaz had access to all of the data. TD and K Richards did not have access to the data.
None declared.