Comparative Effectiveness of Intravesical BCG-Tice and BCG-Moreau in Patients With Non–muscle-invasive Bladder Cancer

Journal Pre-proof Comparative effectiveness of intravesical BCG-Tice and BCG-Moreau in patients with non-muscle invasive bladder cancer David D’Andrea, Francesco Soria, Mohammad Abufaraj, Mario Pones, Paolo Gontero, André T. Machado, Ricardo Waksman, Dmitry V. Enikeev, Petr V. Glybochko, Sanarelly Pires Adonias, William Carlos Nahas, Shahrokh F. Shariat SF, Daher C. Chade PII:

S1558-7673(19)30325-8

DOI:

https://doi.org/10.1016/j.clgc.2019.10.021

Reference:

CLGC 1383

To appear in:

Clinical Genitourinary Cancer

Received Date: 25 August 2019 Revised Date:

23 October 2019

Accepted Date: 28 October 2019

Please cite this article as: D’Andrea D, Soria F, Abufaraj M, Pones M, Gontero P, Machado AT, Waksman R, Enikeev DV, Glybochko PV, Adonias SP, Nahas WC, Shariat SF SF, Chade DC, Comparative effectiveness of intravesical BCG-Tice and BCG-Moreau in patients with nonmuscle invasive bladder cancer, Clinical Genitourinary Cancer (2019), doi: https://doi.org/10.1016/ j.clgc.2019.10.021. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.

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Comparative effectiveness of intravesical BCG-Tice and BCG-

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Moreau in patients with non-muscle invasive bladder cancer

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David D’Andrea1, Francesco Soria1,2, Mohammad Abufaraj1,3, Mario Pones1, Paolo Gontero2,

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André T. Machado4, Ricardo Waksman4, Dmitry V. Enikeev5, Petr V. Glybochko5, Sanarelly

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Pires Adonias4, William Carlos Nahas4, Shahrokh F. Shariat SF1,5,6,7, Daher C. Chade4

6 7 8 9 10 11 12 13 14 15

1 Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria 2 Division of Urology, Department of Surgical Sciences, AOU Città della Salute e della Scienza di Torino, Molinette Hospital, Turin, Italy 3 Division of Urology, Department of Special Surgery, Jordan University Hospital, The 2 University of Jordan, Amman, Jordan 4 Department of Urology, University of São Paulo Medical School and Institute of Cancer, São Paulo, Brazil 5 Institute for urology and reproductive health, Sechenov University, Moscow, Russia 6 Department of Urology, Weill Cornell Medical College, New York, NY 7 Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX

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Corresponding author Shahrokh F. Shariat

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Departmet of Urology

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Medical University of Vienna

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Währinger Gürtel 18-20

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1090 Vienna, Austria

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[email protected]

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+43 1 40400 26150

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Keywords: non-muscle invasive bladder cancer; BCG; strain; recurrence; progression

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ABSTRACT

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OBJECTIVE To compare the efficacy two bacillus Calmette Guérin (BCG) strains, BCG-Tice vs

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BCG-Moreau, in the treatment of non-muscle invasive bladder cancer (NMIBC).

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MATERIALS AND METHODS We retrospective reviewed clinical data from patients treated

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with BCG for NMIBC at three academic centers. Inverse probability of treatment weighting

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(IPW)–adjusted Kaplan-Meier curves and Cox proportional hazards regression analyses were

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used to compare recurrence-free (RFS) and progression-free survival (PFS) of patients in the

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two treatment groups. In addition, we performed exploratory analyses of treatment effect

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according to the receipt of adequate BCG treatment, high-risk disease, age, gender, smoking

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status, pathological stage and pathological grade

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RESULTS A total of 321 (48.6 %) patients were treated with BCG-Tice and 339 (51,4 %) with

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BCG-Moreau. IPW-adjusted Cox proportional hazard regression analysis did not show a

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difference in RFS (HR 0.88; 95%CI 0.56-1.38; p = 0.58) or PFS (HR 0.55; 95%CI 0.25-1.21, p =

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0.14) between BCG-Tice and BCG-Moreau. On subgroups analyses, we could not identify an

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association of BCG strains with outcomes.

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CONCLUSIONS There was no difference in RFS and PFS between BCG-Tice and BCG-Moreau

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strains in the adjuvant treatment of NMIBC. However, we confirmed the importance of

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maintenance therapy for achieving a sustainable response in patients with intermediate and

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high-risk NMIBC.

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INTRODUCTION

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Intravesical immunotherapy with bacillus Calmette-Guérin (BCG) is the most effective

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adjuvant therapy for intermediate and high-risk non-muscle-invasive bladder cancer

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(NMIBC) 1-4.

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There are, however, several different subtypes available. Despite originating all from

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subcultures of the same Mycobacterium, passaging and subculturing through different

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distributors over the last decades may have, selected mycobacteria with differential

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biological activity profiles, virulences and reactogenicities 5-8.

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However, due to heterogeneity of retrospective series9, lack of power and failure to

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administer maintenance cycles in prospective trials 10-12, there is a lack of robust evidence

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regarding superiority of a strain over the other. Therefore, current guidelines do not make

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any recommendation regarding the use of a specific strain 3,13,14. Identification of a more

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efficient strain and assessing its optimal administration schedule may improve oncological

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outcomes in NMIBC, specifically because of the worldwide shortage in BCG availability 8.

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In this study, we performed a head-to-head comparison of BCG-Tice versus BCG-Moreau in

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the adjuvant intravesical therapy of NMIBC. In pre-planned analyses, we performed

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inversed probability weighting (IPW) to maximally adjust for the differences in populations

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and we performed sub analyses in patients treated with adequate BCG 15 as well as high-risk

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NMIBC according to the EAU guidelines 3.

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MATERIALS AND METHODS

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Patients population

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Following institutional review board approval, we retrospective reviewed clinical data

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identifying 660 patients treated with BCG for NMIBC at three academic centers. Patients

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with a history of upper tract urothelial cancer were not included. All patients had NMIBC.

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Transurethral resection and instillation therapy

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All patients underwent TURB for bladder cancer. Enhanced imaging modalities (i.e.

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photodynamic diagnosis or narrow-band imaging) where used based on institutional

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availability and physician discretion. A second look resection was performed 2-6 weeks after

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initial treatment based on pathologic and intraoperative findings in accordance with the

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guidelines at the time 3. Concomitant upper urinary tract urothelial carcinoma was excluded

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using in all patients.

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BCG therapy consisted of a six weekly intravesical instillations delivered within 6 weeks of

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the last TURB. The duration of maintenance therapy was based on guidelines at that time

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and institutional standards. Adequate BCG treatment was defined as at least one of the

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following:

83 84 85 86

1. At least five of six doses of an initial induction course plus at least two of three doses of maintenance therapy 2. At least five of six doses of an initial induction course plus at least two of six doses of a second induction course 15

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At the university of University of São Paulo all patients were treated with BCG-Moreau,

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while at the University of Vienna and Turin all patients were treated with BCG-Tice.

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Pathologic evaluation

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All surgical specimens were processed according to standard pathologic procedures and

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staged based on the TNM classification. Tumor grade was assigned according to the 2004

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World Health Organization system.

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Follow-up

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Due to the retrospective nature of the study, there was no standardized follow-up. Patient

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received clinical and radiological follow-up based on guidelines at that time and physician

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discretion. Generally, patient underwent physical examination, cytology and cystoscopy

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after the first induction cycle. In case of suspected recurrence, patients underwent re-

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biopsy. If urinary cytology was positive but cystoscopy was unremarkable, bladder and

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prostatic urethra biopsies in addition to upper urinary tract workup were performed.

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Disease recurrence was defined as high-grade tumor relapse in the bladder. Progression was

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defined as tumor relapse at stage T2 or higher in the bladder. Cause of death was attributed

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through chart or death records reviews 16. Tumor recurrence in the upper urinary tract was

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not considered as tumor recurrence but rather as a second primary tumor.

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Statistical analysis

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Statistical analyses were performed in different steps. First, we performed multiple

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imputation by using chained equations to handle missing data that were assumed to be

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missing at random. Fifteen imputed data sets were generated using predictive mean

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matching for numeric variables, logistic regression for binary variables and bayesian

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polytomous regression for factor variables. Second, we used IPW to reduce the bias of

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unweighted estimators and adjust for covariates imbalance between treatment groups.

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Specifically, propensity scores obtained from a logistic regression model that predicted

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receipt of BCG-Moreau or BCG-Tice were used. Post-weighting balance in covariates was

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evaluated by using standardized mean differences. In addition, kernel density plots were

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used to compare pre- and post-IPW adjustment propensity score distributions in the

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treatment groups. Third, we compared recurrence-free survival (RFS) and progression-free

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survival (PFS) between treatment groups using IPW-adjusted Kaplan-Meier curves. Fourth,

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we used IPW-adjusted Cox proportional hazard to calculate the IPW-adjusted hazard ratio

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(HR) and 95% confidence interval (CI) of BCG-Moreau versus BCG-Tice. Finally, we

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performed exploratory analyses to determine the IPW-adjusted HR of BCG-Moreau vs BCG-

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Tice according to the receipt of adequate BCG treatment 15, high-risk disease 3, age, gender,

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smoking status, pathological stage and pathological grade. Statistical significance was

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considered at p < 0.05. All tests were two-sided. Statistical analyses were performed using R

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(R project, Vienna, Austria).

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RESULTS

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A total of 321 (48.6 %) patients were treated with the Tice strain and 339 (51,4 %) were

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treated with the Moreau strain. Within a median follow-up of 41 months (IQR 24 -60), a

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total of 177 (36.6%) patients had a high-grade recurrence; 92 (28.7%) of the patients treated

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with the BCG-Tice strain and 85 (25.1%) of those treated with the BCG-Moreau strain. Unweighted and Weighted Baseline Patient Characteristics

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Unweighted and weighted clinicopathologic features of the patients, stratified by BCG

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strain, are shown in Table 1. Standardized differences of unweighted comparisons showed

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that both treatment groups differed significantly with respect to tumor characteristics of

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interest.

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After IPW adjustment, all relevant standardized differences were less than 10%, which

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indicated that pathologic tumor features before treatment with BCG were subsequently

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comparable (supplementary figure s1). Propensity score distribution between treatment

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groups achieved adequate balance after IPW adjustment (supplementary figure s2). Strain comparison

139 140

IPW-adjusted Cox proportional hazard regression analysis did not show a difference in RFS

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(HR 0.88; 95%CI 0.56-1.38; p = 0.58) or PFS (HR 0.55; 95%CI 0.25-1.21, p = 0.14) between

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BCG-Tice and BCG-Moreau. Figure 1 shows the IPW-adjusted survival curves for RFS and

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PFS.

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A total of 357 (59,5%) patients received adequate BCG treatment. On exploratory analyses,

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we investigated the effect of BCG strains in patients adequately treated with BCG and found

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no association with RFS (HR 1.97, 95%CI 0.85 – 4.58, p = 0.12) or PFS (HR 0.48, 95%CI 0.12 –

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1.84, p = 0.28). Moreover, also in patients who were not adequately treated with BCG, the

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strain used was not associated with RFS (HR 0.87, 95%CI 0.53-1.43, p = 0.59) or PFS (HR

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0.68, 95%CI 0.29-1.55, p = 0.36) (Figure 2). However, the use maintenance cycles was

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significantly associated with RFS (HR 0.32, 95%CI 0.21 – 0.49, p < 0.01) and PFS (HR 0.28,

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95%CI 0.12 – 0.66, p <0.01).

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We investigated the effect of BCG strains in patients with high-risk bladder cancer and

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found no association with in RFS (HR 1.79, 95%CI 0.82 – 3.89, p = 0.14) or PFS (HR 0.52,

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95%CI 0.14 – 1.88), p = 0.32) (supplementary figure s3). The number of events in the

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intermediate risk was too low (28 recurrences and 9 progressions) to perform a clinically

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significant analysis.

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Finally, we investigate the differential effect of the strains in subpopulations of patients

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according to age, gender, smoking status, pathological stage and pathological grade. The

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IPW-adjusted HRs are shown in Figure 3.

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DISCUSSION

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There is a lack of robust evidence showing difference in efficacy between various BCG

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strains

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oncologic outcomes in patients with NMIBC using IPW-adjusted analyses and found no

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association with RFS or PFS. To our knowledge, our study is the first head-to-head

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comparison between these two strains.

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These findings are in accordance with previous reports and metanalyses of randomized

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trials comparing other strains. A Swiss randomized trial comparing BCG-Connaught with

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BCG-Tice found a significantly longer 5-yr RFS for patients treated with BCG-Connaught (p =

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0.01). To explain this difference, the authors investigated the immune cell stimulation in a

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mice model and found that BCG-Connaught induced a greater overall immune-cell

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recruitment to the bladder compared with BCG-Tice (p < 0.05) 11. Despite these findings, the

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clinical applicability of this trial is limited by the lack of maintenance administration and

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because recurrence was defined as “a return of tumor of any stage and grade confirmed by

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TURBT and histologic or cytologic assessment”. Indeed, urine cytology can be highly variable

175

18

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Several other randomized trials comparing different available strains have been performed

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10,12,19-21

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be considered that these trials suffered from a lack of statistical power and/or the use of

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induction therapy only. Moreover, none of these studies included modern visualization

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technologies such as photodynamic diagnosis 22.

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Despite the retrospective nature of our study, we expand upon these trials as we evaluated

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and compared the efficacy of BCG-Moreau and BCG-Tice in a significant number of patients

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treated with maintenance cycles.

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As reported by the SWOG 8507 and the EORTC-GU 30962 trials, the administration of at

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least one year of maintenance with a 3-week schedule is necessary to achieve adequate

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oncologic disease control

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category “BCG-unresponsive disease” after adequate treatment, defined as high-grade

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recurrence after induction plus at least one maintenance course of BCG, was defined

9,17

. To fill this gap, we investigated the effect of BCG-Tice and BCG-Moreau on

.

. However, no one could demonstrate superiority of a strain over the other. It must

23,24

. In a recent consensus statement, the importance of the

15

.

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While an analysis according to this definition could be interestingly, it is not a validated end

190

point.

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We investigated the efficacy of the strains in patients who received adequate BCG

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treatments and found no association of the strains with RFS or PFS (both p > 0.1). However,

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we noticed a trend in RFS in favor of BCG-Moreau (HR 1.97 for BCG-Tice) if adequate BCG

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treatment was administered. If patients were non treated adequately, BCG-Moreau patients

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were more likely to experience disease recurrence (HR 0.87 for BCG-Tice). An explanation

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for this observation could be that patients treated with BCG-Moreau received more

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maintenance cycles compared to BCG-Tice patients. This would suggest that the optimal

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efficacy of each strain may be dependent on different maintenance protocols. Indeed, a

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similar observation was made in a retrospective series of more than 2,000 patients

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comparing the effect of BCG-Tice with that of BCG-Connaught 9. Authors found that patients

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treated with BCG-Connaught had a significantly longer RFS compared to those treated with

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BCG-TICE if only induction was administered (HR 1.48, p < 0.001). However, when

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maintenance was given, BCG-Tice was more effective than BCG-Connaught for the time to

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first recurrence (HR 0.66, p = 0.019). Moreover, no difference between strains efficacy could

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be observed in PFS (HR 1.08, p = 0.55).

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Despite all its strengths, our study is not devoid of limitations which are mainly inherent to

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its retrospective design. First and foremost, it has to be considered that patients treated

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with BCG-Moreau were significantly longer on maintenance therapy compared to those

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treated with BCG-Tice. As we learned from other trials, maintenance is of paramount

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importance to obtain a sustainable response. Second, there was a significant difference in

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pathological stage between groups. Indeed, patients in the BCG-Tice group had significantly

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more pT1 tumors compared to those in the BCG-Moreau cohort. Despite adjusting for the

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effect of these confounders in multivariable models, prospective trials, with clearly defined

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treatment response, are required to confirm or reject our findings. Finally, in the age of

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molecular medicine, we did not control for important pathologic and molecular features

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that could help assess the biological and clinical potential of NMIBC 25-28.

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CONCLUSIONS

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Our retrospective analysis did not show any difference in RFS and PFS between BCG-Tice

219

and BCG-Moreau strains. However, we confirmed the importance of maintenance cycles for

220

achieving a sustainable response in patients with intermediate and high-risk NMIBC.

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Prospective designed trials are required to confirm these findings in light of the BCG-

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shortage.

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Ethical statement

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Disclosure of potential conflicts of interest: nothing to disclose

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Research involving human participants and/or animals. Informed consent: retrospective

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analysis, no informed consent needed

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Authors’ Contribution statement

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Protocol/project development: Shahrokh F. Shariat, Daher C. Chade, David D'Andrea

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Data collection or management: David D’Andrea, Francesco Soria, Paolo Gontero, Mario

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Pones, André T. Machado, Ricardo Waksman, Sanarelly Pires Adonias, William Carlos Nahas

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Data analysis: David D’Andrea

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Manuscript writing/editing: David D’Andrea, Mohammad Abufaraj, Francesco Soria, Paolo

234

Gontero, Dmitry V. Enikeev, Petr V. Glybochko, Daher C. Chade, Shahrokh F. Shariat

235

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Table 1 Baseline characteristics of 660 patients treated with adjuvant intravesical BCG-Tice or BCG-Moreau for non-muscle invasive bladder cancer in unweighted and weighted study population Unweighted Weighted Strain Moreau Tice SMD Moreau Tice SMD n 339 321 339.67 321.00 Age, median (IQR) 63 (56 – 72) 69 (62 – 76) 0.462 68 (59 – 78) 69 (62 – 76) 0.083 Male gender, n (%) 245 (72.3) 288 (89.7) 0.456 247.1 (72.8) 288.0 (89.7) 0.445 Exposure to chemical compounds, n (%) 68 (20.1) 65 (20.2) 0.005 71.3 (21.0) 65.0 (20.2) 0.018 Smoking status, n (%) 0.194 0.306 Never smoker 77 (22.7) 61 (19.0) 88.3 (26.0) 61.0 (19.0) Former smoker 166 (49.0) 188 (58.6) 147.6 (43.5) 188.0 (58.6) Current smoker 96 (28.3) 72 (22.4) 103.7 (30.5) 72.0 (22.4) Recurrent NMIBC, n (%) 106 (31.3) 69 (21.5) 0.223 110.5 (32.5) 69.0 (21.5) 0.250 Pathological T stage, n (%) 0.610 0.084 Ta 176 (51.9) 76 (23.7) 80.1 (23.6) 76.0 (23.7) Tis 5 (1.5) 10 (3.1) 6.2 (1.8) 10.0 (3.1) T1 158 (46.6) 235 (73.2) 253.4 (74.6) 235.0 (73.2) High Grade (WHO 2004), n (%) 236 (69.6) 275 (85.7) 0.393 289.3 (85.2) 275.0 (85.7) 0.014 Number of tumors, median (IQR) 1 (1 – 3) 1 (1 – 2) 0.378 1 (1 – 2) 1 (1 – 2) 0.016 Tumor size (cm), median (IQR) 3 (1.50 – 4) 2 (1 – 3) 0.469 2 (1.29 – 3) 2 (1 – 3) <0.001 Concomitant CIS, n (%) 16 (4.7) 72 (22.4) 0.535 95.8 (28.2) 72.0 (22.4) 0.133 Detrusor muscle in specimen, n (%) 256 (75.5) 196 (61.1) 0.314 257.2 (75.7) 196.0 (61.1) 0.319 Number of induction BCG instillations, median (IQR) 8 (8 – 8) 6 (6 – 6) 1.399 8 (6 – 8) 6 (6 – 6) 1.076 Receipt of maintenance BCG istillations, n (%) 237 (69.9) 126 (39.3) 0.647 112.1 (33.0) 126.0 (39.3) 0.130 Number of maintenance BCG instillations, median (IQR) 6 (0 – 12) 0 (0 – 3) 0.658 0 (0 – 6) 0 (0 – 3) 0.022 IQR = interquartile range; CIS = carcinoma in situ; NMIBC = non-muscle invasive bladder cancer; BCG = Bacillus Calmette-Guérin; SMD = standardized mean difference 333 334

335 336 337

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Figure 1. Inverse probability weighted Kaplan-Maier analysis for recurrence-free (A) and progression-free (B) survival in patients treated with intravesical Bacillus Calmette-Guérin (BCG) for non-muscle invasive bladder cancer, stratified by BCG strain

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Figure 2. Inverse probability weighted Kaplan-Maier analysis for recurrence-free and progression-free survival in patients adequately treated with Bacillus Calmette-Guérin (BCG) (A and B) and in patients who did not receive adequate BCG treatment (C and D) for nonmuscle invasive bladder cancer, stratified by BCG strain.

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Figure 3. Forrest plot depicting inverse probability weight–adjusted hazard ratios of BCGTice versus BCG-Moreau in patients with non-muscle invasive bladder cancer according to age, gender, smoking status, pathologic stage and pathological grade.

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Supplementary figure s1. Covariates balance before adjustment and after inverse probability weighting in patients treated with adjuvant intravesical BCG-Moreau or BCG-Tice for non-muscle invasive bladder cancer.

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Supplementary figure s2. Kernel density plots showing the distribution of propensity scores in patients treated with adjuvant intravesical BCG-Moreau or BCG-Tice for non-muscle invasive bladder cancer before adjustment (dotted line) and after inverse probability weighting (solid line).

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Supplementary figure s3 Inverse probability weighted Kaplan-Maier analysis for recurrencefree (A) and progression-free (B) survival in patients with high-risk non-muscle invasive bladder cancer treated with intravesical Bacillus Calmette-Guérin (BCG), stratified by BCG strain

Micro abstract

We compared the oncologic outcomes of patients treated with BCG-Tice vs BCG- Moreau for non-muscle-invasive bladder cancer using inverse-probability survival analyses and found no significant difference in recurrence (RFS) and progression-free survival (PFS) between strains. However, the use maintenance cycles was significantly associated with improved RFS and PFS. Prospective designed trials are required to confirm these findings in light of the BCG-shortage.

Clinical practice points 1. Current body of evidence does not support the superiority of a BCG strain over the other 2. We compared the oncologic outcomes of patients treated with BCG-Tice vs BCGMoreau for non-muscle-invasive bladder cancer 3. Multivariable IPW-adjusted Cox proportional hazard regression analysis did not show a significant difference in RFS or PFS 4. The use maintenance cycles was significantly associated with RFS and PFS 5. Prospective designed trials are required to confirm these findings in light of the BCGshortage