Abstract
Introduction:
We sought to determine if outcomes of Bacillus Calmette-Guerin (BCG) therapy in patients with non-muscle-invasive bladder cancer (NMIBC) vary by race.
Methods:
A retrospective chart review was conducted on 149 patients treated with BCG for intermediate- and high-risk NMIBC between 2001 and 2018, and who were followed up for cancer recurrence through March 2019.
The primary outcomes were disease-free survival (DFS), low-grade disease-free survival (LGDFS), high-grade disease-free survival (HGDFS), and progression-free survival (PFS) at five years. Kaplan-Meier survival curves stratified by race (African American vs non-African American) were analyzed for all the above outcomes and multivariate Cox regression analyses were also performed to compare recurrence differences by race, after adjusting for age, sex, initial stage and grade.
Results:
Of the 149 patients, 37.6% were Caucasian, 24.8% were African American, 26.8% were Hispanic, and 10.7% were of other/unknown race. Disease stage at initial presentation was 65.1% Ta, 34.9% T1, and 18.1% CIS. African American patients (N=37) did not have evidence for worse outcomes compared to non-African American patients when considering DFS (54.1% vs. 65.7%, p = 0.202), HGDFS (58.8% vs. 71.7%, p = 0.158), and PFS (83.8% vs. 92.6%, p = 0.117) at five years. Multivariate analysis did not reveal statistically significant racial differences in recurrence or progression.
Conclusions:
African Americans with NMIBC did not have worse disease recurrence and progression after receiving intravesical BCG treatment. Although there did appear to be a trend towards worse oncologic outcomes in African Americans, larger studies are needed to validate this finding.
Keywords: Mycobacterium bovis, Urinary Bladder Neoplasms, Disease-Free Survival, Progression-Free Survival, African Americans
Introduction
Intravesical Bacillus Calmette-Guerin (BCG) is the first-line treatment for intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC).1,2 The protective effect of this bladder-sparing therapy often requires maintenance, and side effects leading to decreased quality of life can be particularly difficult to tolerate.3 Even with adherence to BCG treatment schedules, disease recurrence and progression commonly occur.
Several large-scale studies have identified factors that affect the risk of disease recurrence and progression. Such factors include age, grade, stage, tumor number, tumor size, history of recurrence, and concomitant carcinoma in situ (CIS).2,4,5 Current NMIBC prediction models do not consider the effect of race on disease recurrence and progression. However, the aforementioned studies that have shaped clinical practice guidelines are comprised of patient cohorts that are majority Caucasian, with consistent underrepresentation of African American populations.2,4,5
Although data is lacking regarding oncologic outcomes for African Americans with NMIBC, African Americans with advanced bladder cancer have been shown to experience worse overall and disease-specific survival. 6,7 The leading theory for this disparity is that unequal access to healthcare results in African Americans receiving delayed diagnosis and inadequate treatment. 7,8 For example, African Americans are more likely to present with tumors featuring aggressive pathologic factors, such as high grade, advanced stage, and variant histology.3,9,10 A study of bladder cancer patients employed by the Department of Defense (DoD) found there were no significant racial differences in overall and recurrence-free survival, theorizing that since all the patients received high-quality healthcare through the DoD, racial disparities in survival might be reduced if healthcare is equally accessible.11 However, inadequate access to healthcare might not completely account for differences in bladder cancer survival, as a recent study found that bladder cancer-specific mortality at 20 years was persistently higher for African Americans after adjusting for income, treatment, and tumor characteristics.12
The effect of race on response to BCG for NMIBC remains unclear. Some studies report that race has no effect on BCG response, but the percentage of non-Caucasian participants is often small (<10% of participants).13 Our study is the first to evaluate NMIBC disease response to first induction course of BCG in a multiracial population.
Materials and Methods
In accordance with an Institutional Review Board-approved protocol, we performed a retrospective chart review of patients who received intravesical BCG at Montefiore Medical Center in the Bronx. We identified 163 patients who received BCG from billing codes for BCG administration; 14 patients were excluded from analysis because of unclear bladder cancer treatment history or absent follow-up after administration of induction BCG. A total of 149 patients were included in the analysis, with the start of the first induction course of BCG (administered at any institution) ranging from October 2001 to November 2018.
The starting date of the first induction course of BCG was set as the initial time point for survival analysis, with analysis of disease recurrence and progression carried out for five years after that starting date. If patients were not followed for the full five years after the start of induction BCG, patients were censored at the time of their last in-person medical follow-up documented in the chart or on their reported death date. The last date of follow-up of the cohort was in March 2019.
The primary outcomes were disease recurrence and progression at five years. Disease recurrence was further classified as low-grade (LG) and high-grade (HG) recurrence. Progression was defined as an increase in stage from CIS or Ta to T1 or greater, or an increase in low to high grade. CIS was considered to be HG disease. The presence of mixed LG and HG on pathology was analyzed as HG. A formal restaging transurethral resection (TUR) was defined as a repeat TUR within 90 days of the initial resection.
Race was categorized from self-reported data as Caucasian, African American, Hispanic, other, or unknown. Patients with unknown race were not included in the univariate analysis for race but were included in other subgroup analyses. Univariate analysis was performed with Kaplan-Meier survival curves constructed for disease-free survival (DFS), low-grade disease-free survival (LGDFS), high-grade disease-free survival (HGDFS), and progression-free survival (PFS) comparing African American patients with non-African American patients; the differences in survival were analyzed with the Log Rank test. Student’s t-test, one-way ANOVA, and Chi-square tests were used to compare demographic and clinical distributions for continuous normally-distributed variables (age) or categorical variables (race, sex) between patients grouped by outcome or by race. A p <0.05 was considered statistically significant (all tests were two-sided). Multivariate analysis was also used to examine associations of DFS, LGDFS, HGDFS and PFS with demographic and clinical outcomes in separate Cox regression models. Data analyses were performed using SPSS Version 25 and Stata Version 15.
Results
The racial distribution of patients was as follows: 37.6% Caucasian, 24.8% African American, 26.8% Hispanic, and 10.7% other (8.1% other, 2.7% unknown). Table 1 describes the demographic and clinical characteristics of the population, stratified by race. The mean ± SD follow-up time was 32.9 ± 19.7 months, and there was no difference in follow-up time between races. Overall there were no racial differences by demographic and lifestyle characteristics (age, sex, smoking status, body mass index (BMI)) or by clinical characteristics (initial grade/stage, restaging TUR, BCG course/response). The only exception was the presence of CIS, which was more prevalent in Caucasians (23.2%) and other (37.5%) vs. African Americans (10.8%) and Hispanics (10.0%) (p=0.043).
Table 1.
Background Demographic and Clinical Characteristics of the Study Population
| Overall | Caucasian | African American | Hispanic | Other | p | |
|---|---|---|---|---|---|---|
| No. Patients (%) | 149 | 56 (37.6) | 37 (24.8) | 40 (26.8) | 16 (10.7) | |
| Mean ± SD Age at Start of BCG | 68.1 ± 11.6 | 68.0 ± 12.8 | 68.9 ± 10.1 | 66.9 ± 12.2 | 69.9 ± 9.9 | 0.804 |
| Mean ± SD Time Followed (Months) | 32.9 ± 19.7 | 35.8 ± 18.9 | 32.2 ± 18.8 | 33.6 ± 21.2 | 22.1 ± 18.5 | 0.105 |
| No. Sex (%) | 0.632 | |||||
| Female | 37 (24.8) | 13 (23.2) | 12 (32.4) | 8 (20.0) | 4 (25.0) | |
| Male | 112 (75.2) | 43 (76.8) | 25 (67.6) | 32 (80.0) | 12 (75.0) | |
| No. BMI (%) | 0.211 | |||||
| Obese | 48 (32.3) | 16 (28.6) | 15 (40.5) | 14 (35.0) | 3 (18.8) | |
| Non-Obese | 82 (55.0) | 31 (55.4) | 19 (51.4) | 19 (47.5) | 13 (81.3) | |
| Unknown | 19 (12.8) | 9 (16.1) | 3 (8.1) | 7 (17.5) | 0 (0.0) | |
| No. Smoking Status (%) | 0.490 | |||||
| Current Smoker | 32 (21.5) | 12 (21.4) | 10 (27.0) | 8 (20.0) | 2 (12.5) | |
| Former Smoker | 71 (47.7) | 25 (44.6) | 14 (37.8) | 24 (60.0) | 8 (50.0) | |
| Never Smoker | 35 (23.5) | 13 (23.2) | 10 (27.0) | 6 (15.0) | 6 (37.5) | |
| Unknown | 11 (7.4) | 6 (10.7) | 3 (8.1) | 2 (5.0) | 0 (0.0) | |
| No. Initial Stage (%) | 0.615 | |||||
| Ta | 97 (65.1) | 40 (71.4) | 23 (62.2) | 25 (62.5) | 9 (56.3) | |
| T1 | 52 (34.9) | 16 (28.6) | 14 (37.8) | 15 (37.5) | 7 (43.8) | |
| No. CIS (%) | 27 (18.1) | 13 (23.2) | 4 (10.8) | 4 (10.0) | 6 (37.5) | 0.043 |
| No. Grade (%) | 0.772 | |||||
| Low | 18 (12.1) | 8 (14.3) | 5 (13.5) | 3 (7.5) | 2 (12.5) | |
| High | 131 (87.9) | 48 (85.7) | 32 (86.5) | 37 (92.5) | 14 (87.5) | |
| No. Restaging TUR (%) | 49 (32.9) | 13 (23.2) | 15 (40.5) | 15 (37.5) | 6 (37.5) | 0.273 |
| No. Salvage Therapy (%) | 27 (18.1) | 15 (26.8) | 6 (16.2) | 4 (10.0) | 2 (12.5) | 0.169 |
| No. BCG Responders (%) | 105 (70.5) | 40 (71.4) | 23 (62.2) | 29 (72.5) | 13 (81.3) | 0.527 |
| No. Course of Maintenance BCG (%) | 62 (41.6) | 23 (41.1) | 16 (43.2) | 16 (40.0) | 7 (43.8) | 0.989 |
| No. Second Course of Induction BCG (%) | 18 (12.1) | 9 (16.1) | 5 (13.5) | 3 (7.5) | 1 (6.3) | 0.529 |
Compliance with induction BCG course (receiving 5/6 doses within 8 weeks) was achieved in 90.0% of patients (88.9% of African Americans vs. 90.4% of non-African Americans, p = 0.797). Of the 122 patients with a documented surveillance cystoscopy following induction BCG, 83.6% had a cystoscopy within 4 months of the start of their induction BCG course (80.0% of African Americans vs. 85.1% of non-African Americans, p = 0.495). 35.6% of patients had at least 2 doses of maintenance BCG with sufficient details of the maintenance course documented for analysis. The average length of maintenance BCG course was 14.7 ± 3.9 days (13.4 ± 1.9 days for African Americans vs. 15.1 ± 4.3 days for non-African Americans, p = 0.131).
At five years, 57 patients (38.3%) had disease recurrence, 13 patients (8.7%) had LG disease recurrence, 44 patients (29.5%) had HG disease recurrence, and 14 patients (9.4%) had disease progression (Table 2). Recurrence and progression after BCG did not significantly differ across race, sex, BMI, smoking status, CIS, initial tumor stage, or restaging TUR. Initial tumor grade affected the type of recurrence: initial LG tumor was associated with greater LG recurrence, and initial HG tumor was associated with greater HG recurrence (p = 0.035).
Table 2.
Recurrence and Progression after Intravesical BCG; RC = Recurrence, LG RC = Low-Grade Recurrence, HG RC = High-Grade Recurrence
| No RC | All RC | p | LG RC | p | HG RC | p | No Progression | Progression | p | |
|---|---|---|---|---|---|---|---|---|---|---|
| No. Patients (%) | 92 (61.7) | 57 (38.3) | 13 (8.7) | 44 (29.5) | 135 (90.6) | 14 (9.4) | ||||
| Mean ± SD Age at Start of BCG | 67.9 ± 11.7 | 68.5 ± 11.7 | 0.761 | 70.5 ± 10.8 | 0.425 | 68.2 ± 12.1 | 0.894 | 68.0 ± 11.8 | 69.6 ± 10.0 | 0.626 |
| Mean ± SD Time Followed (Months) | 33.1 ± 20.3 | 32.5 ± 18.9 | 0.869 | 39.7 ± 17.2 | 0.122 | 30.4 ± 19.1 | 0.467 | 33.0 ± 20.1 | 31.7 ± 16.2 | 0.813 |
| No. Race (%) | 0.070 | 0.268 | 0.144 | 0.241 | ||||||
| African American | 20 (21.7) | 17 (29.8) | 3 (23.1) | 14 (31.8) | 31 (23.0) | 6 (42.9) | ||||
| Non-African American | 71 (77.2) | 37 (64.9) | 9 (69.2) | 28 (63.6) | 100 (74.1) | 8 (57.1) | ||||
| Unknown | 1 (1.1) | 3 (5.3) | 1 (7.7) | 2 (4.5) | 4 (3.0) | 0 (0.0) | ||||
| No. Sex (%) | 0.309 | 0.118 | 0.526 | 0.783 | ||||||
| Male | 72 (78.3) | 40 (70.2) | 8 (61.5) | 32 (72.7) | 102 (75.6) | 102 (75.6) | ||||
| Female | 20 (21.7) | 17 (29.8) | 5 (38.5) | 12 (27.3) | 33 (24.4) | 4 (28.6) | ||||
| No. BMI (%) | 0.072 | 0.225 | 0.093 | 0.100 | ||||||
| Obese | 27 (29.3) | 21 (36.8) | 7 (53.8) | 14 (31.8) | 44 (32.6) | 4 (28.6) | ||||
| Non-Obese | 50 (54.3) | 32 (56.1) | 5 (38.5) | 27 (61.4) | 72 (53.3) | 10 (71.4) | ||||
| Unknown | 15 (16.3) | 4 (7.0) | 1 (7.7) | 3 (6.8) | 19 (14.1) | 0 (0.0) | ||||
| No. Smoking Status (%) | 0.555 | 0.149 | 0.835 | 0.771 | ||||||
| Never Smoker | 22 (23.9) | 13 (22.8) | 3 (23.1) | 10 (22.7) | 31 (23.0) | 4 (28.6) | ||||
| Current Smoker | 17 (18.5) | 15 (26.3) | 5 (38.5) | 10 (22.7) | 30 (22.2) | 2 (14.3) | ||||
| Former Smoker | 47 (51.1) | 24 (42.1) | 5 (38.5) | 19 (43.2) | 65 (48.1) | 6 (42.9) | ||||
| Unknown | 6 (6.5) | 5 (8.8) | 0 (0.0) | 5 (11.4) | 9 (6.7) | 2 (14.3) | ||||
| No. Initial Stage (%) | 0.822 | 0.544 | 0.930 | 0.829 | ||||||
| Ta | 60 (65.2) | 37 (64.9) | 8 (61.5) | 29 (65.9) | 88 (65.2) | 9 (64.3) | ||||
| T1 | 32 (34.8) | 20 (35.1) | 5 (38.5) | 15 (34.1) | 47 (34.8) | 5 (35.7) | ||||
| No. CIS (%) | 16 (17.4) | 11 (19.3) | 0.921 | 0 (0.0) | 0.228 | 11 (25.0) | 0.520 | 23 (17.0) | 4 (28.6) | 0.337 |
| No. Initial Grade (%) | 0.580 | 0.047 | 0.133 | 0.814 | ||||||
| LG | 12 (13.0) | 6 (10.5) | 4 (30.8) | 2 (4.5) | 16 (11.9) | 2 (14.3) | ||||
| HG | 80 (87.0) | 51 (89.5) | 9 (69.2) | 42 (95.5) | 119 (88.1) | 12 (85.7) | ||||
| No. Restaging TUR (%) | 32 (34.8) | 17 (29.8) | 0.716 | 1 (7.7) | 0.045 | 16 (36.4) | 0.723 | 43 (31.9) | 6 (42.9) | 0.282 |
| No. Salvage Therapy (%) | 0 (0.0) | 27 (47.4) | 0.000 | 3 (23.1) | 0.000 | 24 (54.5) | 0.000 | 23 (17.0) | 4 (28.6) | 0.322 |
African American patients did not have worse survival compared to non-African American patients for DFS (54.1% vs. 65.7%, p = 0.202), HGDFS (58.8% vs. 71.7%, p = 0.158), and PFS (83.8% vs. 92.6%, p = 0.117) after five years of follow-up (Figure 1).
Figure 1.
Kaplan-Meier overall survival by race: (A) disease-free survival; (B) low-grade disease-free survival; (C) high-grade disease-free survival; (D) progression-free survival.
On multivariate analysis, the odds of high-grade recurrence was 1.61 (95% CI 0.83–3.08) and the odds of progression was 2.31 (95% CI 0.79–6.74) for African Americans in comparison to non-African Americans after adjusting for age, sex, initial stage and grade. Initial HG disease was inversely associated with LG recurrence (HR=0.19; 95% CI 0.05 – 0.76) in multivariate models.
Discussion
African Americans did not have worse DFS, LGDFS, HGDFS, or PFS than patients of other races at five years. Previous studies have attributed decreased survival in African Americans to presentation with more aggressive disease. For example, Prout et al. found that African Americans were more likely to be initially diagnosed with stage T1 or greater bladder cancer compared to Caucasians (OR 2.0; 95% CI 1.3–2.9).14 Our results do not reflect such a discrepancy in tumor characteristics at the time of diagnosis: 37.8% of African American patients presented with T1 disease (vs. 34.3% of non-African Americans, p = 0.694) and 86.5% of African American patients presented with HG disease (vs. 88.9% of non-African Americans, p = 0.695).
Initial presentation with CIS, an aggressive tumor type, was lower in African Americans (10.8%) and Hispanics (10.0%) than in Caucasians (23.2%) and other races (37.5%) (p = 0.043). Analysis was limited by the small number of cases of CIS (N=27), but there were no associations with CIS and recurrence or progression.
The leading explanation for racial differences in bladder cancer survival is that socioeconomic disparities cause unequal access to healthcare leading to worse survival. Our results do not show a racial disparity in survival for NMIBC because the study is limited to patients who are able to access healthcare readily enough to be diagnosed with bladder cancer at an early stage. This inherent aspect of the study design provides a crude way of controlling for large disparities in access to healthcare, in comparison to studies finding a racial difference in survival for bladder cancer of any stage.6,7 Also, our study did not show any difference in PFS, which could be partially explained by the likelihood that patients who are able to access the healthcare system early enough to be diagnosed with NMBIC as opposed to MIBC are also more likely to receive appropriate treatment that reduces their risk of disease progression. Indeed, our results indicate there was no difference in healthcare utilization between races, as marked by similar rates of timely surveillance cystoscopy (within 4 months of induction BCG) and compliance with induction BCG (5/6 doses within 8 weeks) and maintenance BCG (2/3 doses within 4 weeks).
Discovering the genetic components to BCG response is an area of active research that may give rise to explanations for racial differences in NMIBC survival besides differential access to healthcare. For example, polymorphisms in several immune response genes in a Portuguese population have been identified as potential biomarkers to predict response to BCG and consequently stratify patients according to risk of recurrence.15 Another study evaluating the innate immune response to strains of Mycobacterium tuberculosis found that macrophages from Filipino participants responded with less robust IL-1 and IL-6 production in comparison to macrophages from Chinese and Caucasian participants.16 Although these studies do not include African Americans, they raise the possibility that genetic differences in the innate immune system response could lead to differences in clinical response to BCG treatment.
There is a lack of studies evaluating racial differences in the efficacy of immunotherapy for cancer treatment,17 but there is some evidence that African American patients would be likely to have a more robust immune response following administration of BCG. For instance, African Americans have a higher rate of single nucleotide polymorphisms associated with a low level of IL-10 production and therefore greater immune activation in response to IFN-alpha therapy.18 However, there is also evidence that African Americans might have a less robust response to BCG, considering a study of immune cell proliferation after administration of the influenza vaccine that showed a weaker cell-mediated response mounted by African Americans in comparison to Caucasians and Hispanics.19
The recent shortage of BCG in 2019 has necessitated prioritizing the induction of BCG therapy in patients with high-risk NMIBC (HG, T1, or CIS), with some patients unable to receive full doses of BCG or receive maintenance therapy.20 Current scoring groups for the stratification of bladder cancer into low-, intermediate-, and high-risk groups do not take race into consideration,2 and there is a lack of evidence regarding the relative efficacy of BCG treatment for NMIBC across racial groups. Our study does not show a difference in BCG efficacy; however, if future studies demonstrate a worse response to BCG in one racial group, this may impact rationing strategies during periods of BCG shortages (i.e., prioritizing full doses of BCG and maintenance BCG with more frequent surveillance for a race with a less robust response to BCG).
Advantages of our study include a racially diverse population treated at a single institution, minimizing the potential effects of differential access to care. Detailed information on tumor pathology, recurrence, and treatment course was verified by direct chart review of each patient. The main limitations of this study are its small sample size and the retrospective nature of the study. Also, the racial composition of our patient population did not allow consideration of differences in BCG response in an Asian population.
Conclusions
Race does not appear to impact response to BCG, with African American patients experiencing similar rates of NMIBC recurrence and progression at five years. Although there is a trend towards worse oncologic outcomes in African Americans, larger prospective studies are needed to determine if there is a differential response to BCG.
Key of Definitions
- BCG
Bacillus Calmette-Guerin
- NMIBC
non-muscle-invasive bladder cancer
- DFS
disease-free survival
- LGDFS
low-grade disease-free survival
- HGDFS
high-grade disease-free survival
- PFS
progression-free survival
- CIS
carcinoma in situ
- LG
low-grade
- HG
high-grade
- TUR
transurethral resection
- SES
socioeconomic status
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