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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 33  |  Issue : 2  |  Page : 86-92

The comparison of efficacy between the connaught and tice strains of bacillus calmette-guérin in patients with non-muscle-invasive bladder cancer in Taiwan


1 Department of Urology, National Taiwan University Hospital; Department of Urology, Cardinal Tien Hospital, Taipei, Taiwan
2 Department of Urology, Cardinal Tien Hospital; Department of Life Science, College of Science, National Taiwan Normal University, Taipei, Taiwan
3 Department of Urology, National Taiwan University Hospital, Taipei, Taiwan

Date of Submission23-Sep-2021
Date of Decision06-Nov-2021
Date of Acceptance26-Nov-2021
Date of Web Publication29-Mar-2022

Correspondence Address:
Chung-Hsin Chen
Department of Urology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/UROS.UROS_141_21

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  Abstract 


Purpose: The purpose of the study is to compare the efficacy of Bacillus Calmette-Guérin (BCG) strains, Connaught (ImmuCyst®), and TICE (OncoTICE®) in patients with nonmuscle invasive bladder cancer (nMIBC). Materials and Methods: Patients with nMIBC who underwent transurethral resection between March 1997 and December 2017 were enrolled. TICE was used due to the Connaught strain shortage since 2012; hence, direct comparison of the two strains could not be performed. An intravesical instillation (IVI) regimen of mitomycin-C, doxorubicin, and cisplatin (MDP) was used as the reference for comparison. The MDP group was separated into two cohorts (MDP-1 and MDP-2) that matched the same time period of Connaught and TICE treatment. Patients who did not complete the IVI course before disease recurrence or progression or were not followed up for at least 24 months were excluded. Results: A total of 730 patients were included in the analysis. There were 67 (9.2%), 38 (5.2%), and 625 (85.6%) patients who received the Connaught, TICE, and MDP treatment, respectively. During a median follow-up duration of 59 months, the recurrence rates of the Connaught, MDP-1, TICE, and MDP-2 groups were 10.5%, 22.8%, 28.9%, and 23.0%, respectively. Both BCG groups had higher tumor grades and more instances of carcinoma in situ than their corresponding MDP cohorts. The Connaught and TICE strains had similar effects in preventing tumor recurrence (Connaught vs. MDP, P = 0.876; TICE vs. MDP, P = 0.556). In the multivariable Cox proportional hazard model that included all patients, the Connaught and TICE groups had a similar risk (hazard ratio = 0.784 and 0.850) of recurrence compared to the MDP protocol. Although progression events were more frequently noticed in the Connaught group, the small number of events limited the analysis. Conclusion: The BCG strains, Connaught and TICE, had similar efficacy in reducing bladder tumor recurrence in nMIBC patients. Both strains resulted in similar bladder recurrence-free survival rates to chemotherapeutic agents.

Keywords: Bacillus Calmette-Guérin, bladder tumor, chemotherapy, progression, recurrence, transurethral resection


How to cite this article:
Kuo CC, Chiang BJ, Yu JY, Hsieh YT, Chen CH, Pu YS. The comparison of efficacy between the connaught and tice strains of bacillus calmette-guérin in patients with non-muscle-invasive bladder cancer in Taiwan. Urol Sci 2022;33:86-92

How to cite this URL:
Kuo CC, Chiang BJ, Yu JY, Hsieh YT, Chen CH, Pu YS. The comparison of efficacy between the connaught and tice strains of bacillus calmette-guérin in patients with non-muscle-invasive bladder cancer in Taiwan. Urol Sci [serial online] 2022 [cited 2022 Jun 29];33:86-92. Available from: https://www.e-urol-sci.com/text.asp?2022/33/2/86/341252




  Introduction Top


Cancer of the urinary bladder is the fourth most common malignancy in men and the eighth leading cause of cancer-related death in men in the United States.[1] Among all patients with bladder cancer, 70%–80% initially present with superficial disease (stage Ta-T1 or carcinoma in situ [CIS]), also known as nonmuscle-invasive bladder cancer (nMIBC). The standard treatment for nMIBC is transurethral resection (TUR) of all visible tumors.[2] However, the tumor recurrence rate in patients with nMIBC within 5 years after TUR is 50%–70%.

Considerable efforts have been made to reduce the risk of recurrence and progression of nMIBC with the use of intravesical instillation (IVI).[3] The most commonly used agents are bacillus Calmette-Guérin (BCG), mitomycin-C, and gemcitabine.[2] Although several reports have demonstrated no difference in recurrence rates between patients receiving BCG and those receiving mitomycin-C, a meta-analysis showed that the tumor recurrence rate was significantly lower in high-risk nMIBC patients treated with BCG.[4] In addition, IVI with a maintenance protocol significantly reduced tumor recurrence compared with patients not receiving maintenance.[2],[5]

There are several BCG strains used in clinical practice for treating nMIBC. The two most common are ImmuCyst® (Sanofi Pasteur, France) from the Connaught strain and OncoTICE® (Merck, USA) from the TICE strain. The shortage of ImmuCyst® since 2012 has resulted in physicians using other BCG strains. However, few studies have compared the efficacy and adverse events among BCG strains in the Asian population. In this study, we compared ImmuCyst® and OncoTICE® in Taiwanese patients with nMIBC by an indirect matching-cohort method.


  Materials and Methods Top


Patient population

Between March 1997 and December 2017, 1530 patients with newly diagnosed nMIBC at our institution were enrolled. Patients with recurrent nMIBC (n = 175) or nonurothelial carcinoma (n = 23) were excluded. All patients underwent complete TUR of primary bladder tumors, followed by the predetermined protocol, which was designed based on the BCG maintenance protocol[5],[6] and included cystoscopic surveillance and IVI. Patients who did not receive IVI or did not finish predetermined protocol were excluded (n = 300). Among patients without subsequent recurrences, those who were not followed up for at least 24 months were excluded from the analysis (n = 232). Patients with previous or synchronous upper urinary tract urothelial carcinoma were treated with nephroureterectomy and bladder cuff resection. Patients who underwent IVI with agents other than ImmuCyst®, OncoTICE®, and our chemotherapeutic protocol of mitomycin-C, doxorubicin, and cisplatin (MDP)[6] were also excluded (n = 70). The MDP protocol involved weekly instillation with mitomycin-C, doxorubicin, and cisplatin; the details have been previously reported.[6] The final number of eligible patients was 730 [Figure 1]. This study involved no more than minimal risk to the subjects, and the waiver of informed consent was approved by the NTUH Institutional Review Board (201305059RINC) on June 7, 2013, and was renewed annually.
Figure 1: Study flowchart

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Intravesical instillation regimens and surveillance protocol

Three regimens (ImmuCyst®, OncoTICE®, and MDP) for IVI were included and compared. The shortage of ImmuCyst® at our institution since December 2012 prompted us to shift to OncoTICE®. Hence, there was no overlap in the time of administration of ImmuCyst® and OncoTICE® at our institution. To compare the efficacy of the three regimens, we further separated the patients who received the MDP protocol into two cohorts (MDP-1 and MDP-2) with the same time period as ImmuCyst® and OncoTICE®, respectively. Therefore, cohort 1 included the patients with either ImmuCyst® or MDP-1 and cohort 2 contained the patients with either OncoTICE® or MDP-2.

The BCG protocol included one dose of 30 mg of mitomycin-C (Kyowa Hakko Kogyo Co., Tokyo, Japan) administered within 24 h after TUR to minimize intraoperative tumor seeding,[7] followed by 6 weekly instillations of BCG (81 mg/vial for ImmuCyst® or 12.5 mg/vial for OncoTICE®) after gross hematuria was resolved. The MDP protocol involves weekly sequential instillations of mitomycin-C, doxorubicin, and cisplatin. This protocol included two cycles of MDP administered in the first 6 weeks, with the first dose of mitomycin-C administered within 24 h after TUR, followed by a maintenance schedule that was similar to the BCG maintenance protocol reported by Lamm et al.[5] Three weekly instillations were given after each negative cystoscopic result after TUR at 3, 6, 12, 18, 24, 30, and 36 months [Figure 2]. Two additional cystoscopies without IVI were performed at 48 and 60 months after TUR.
Figure 2: The dosing schedule of intravesical instillation regimens of Bacillus Calmette-Guérin and MDP

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Collection of clinicopathologic data

Potential risk factors for bladder recurrence and progression were retrieved from medical records, including age at diagnosis, tumor stage and grade, tumor multiplicity, presence of carcinoma in situ (CIS), previous or synchronous upper urinary tract urothelial carcinoma, adjuvant regimens of IVI, and chronic kidney disease or end-stage renal disease (ESRD). Tumor grading was classified according to the World Health Organization/International Society of Urological Pathology 1998 system.[8] Tumor staging was performed using the 1997 American Joint Committee on Cancer-Union for International Cancer Control system.[9]

Definition of recurrence and progression

Bladder recurrence was defined as histologically proven recurrent bladder urothelial carcinoma that was diagnosed more than 8 weeks after TUR. Recurrence within 8 weeks after TUR was considered a result of incomplete resection of the primary bladder tumor and was excluded from the analysis. The rationale for such exclusion was that residual tumors were observed in 34%–52% of cases in second or restaging TURs that were performed 2–8 weeks after the initial TUR.[10],[11] In addition, induction instillation therapies took 6 weeks to complete. Progression was defined as recurrent cancer invading the muscle layer or newly developed distant metastases. The duration of recurrence-free survival (RFS) and progression-free survival (PFS) was calculated from the date of the initial TUR to recurrence or progression, respectively.

Statistical methods

All statistical analyses were performed with the IBM SPSS Statistics 25. Contingency tables were constructed with data compared by the Chi-square test. The Kaplan–Meier method and the log-rank test were used to calculate and compare the survival curves. The Cox proportional hazard model was used to identify independent factors that affected recurrence and progression. All statistical tests were two-sided, with P < 0.05 indicating statistical significance.


  Results Top


Patient demographics

A total of 730 patients were finally included in the analysis, with a median age of 66.2 years (range: 29–97 years) and a median follow-up duration of 59 months (range: 24–123 months) [Table 1]. Among them, 67 and 38 patients received IVI of ImmuCyst® and OncoTICE®, respectively. The MDP-1 and MDP-2 groups, which received IVI for the same length of time as the ImmuCyst® and OncoTICE® groups, contained 334 and 291 patients, respectively. Separate comparison analyses were performed between the ImmuCyst® and MDP-1 groups and the OncoTICE® and MDP-2 groups. There were no differences in sex ratio, age, tumor multiplicity, presence of ESRD, and previous or synchronous upper urinary tract urothelial carcinoma between the BCG and MDP groups in both time-matched cohorts. The OncoTICE® group had more clinical T1 tumors (55.3%) than the MDP-2 group (33.0%, P = 0.011). Both BCG groups had significantly more high-grade tumors than the corresponding MDP cohorts (ImmuCyst®, 70.1%; MDP-1, 53.6%; P = 0.015; OncoTICE®, 100%; MDP-2, 61.2%; P < 0.001). CIS lesions were more frequently identified in the BCG groups than in the corresponding MDP groups (ImmuCyst®, 13.4%; MDP-1, 2.7%; P = 0.001; OncoTICE®, 92.1%; MDP-2, 18.6%; P < 0.001).
Table 1: Demographics of patients receiving different regimens of intravesical therapy

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Bladder tumor recurrence

During a median follow-up period of 59 months (range: 24–123 months), the tumor recurrence rates in the ImmuCyst®, MDP-1, OncoTICE®, and MDP-2 groups were 10.5%, 22.8%, 28.9%, and 23.0%, respectively [Table 2]. The 5-year RFS rates were 79.0%, 75.3%, 71.4%, and 75.2% for the four groups, respectively. No significant differences in RFS rate were observed between the ImmuCyst® and MDP-1 groups (log-rank test: P = 0.479) or the OncoTICE® and MDP-2 groups (log-rank test: P = 0.366) [Figure 3]a.
Table 2: Recurrence and progression outcomes for patients receiving different regimens of intravesical therapy

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Figure 3: (a) The bladder recurrence-free survival and (b) The progression-free survival among the patients having different regimens of intravesical instillation

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Multivariable analysis of bladder tumor recurrence [Table 3] in the combination of cohort-1 and cohort-2 revealed that male patients (hazard ratio [HR]: 1.397, P = 0.059) and tumor multiplicity (HR: 1.422, P = 0.023) significantly elevated the risk of bladder tumor recurrence. There was no difference in tumor recurrence between the MDP-1 and MDP-2 cohorts. Moreover, IVI with either ImmuCyst® or OncoTICE® did not significantly reduce tumor recurrence compared with IVI with the MDP protocol. No obvious difference in recurrence was identified between the ImmuCyst® and the OncoTICE® groups.
Table 3: Univariate and multivariate analysis of risk factors for recurrence

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Tumor progression

A total of 8, 3, 0, and 5 patients experienced tumor progression in the ImmuCyst®, MDP-1, OncoTICE®, and MDP-2 groups during the follow-up period, respectively. PFS was significantly lower in the ImmuCyst® group than in the MDP-1 group (log-rank test, P < 0.001), but no significant difference was noted between the OncoTICE® and MDP-1 groups (log-rank test, P = 0.551) [Figure 3]b. The small number of cases with progression in each group made it unfeasible to conduct an extensive multivariable analysis of tumor progression.


  Discussion Top


Our study found no significant differences between Taiwanese nMIBC patients treated by IVI with either BCG strain of Connaught or TICE in the rate of bladder tumor recurrence. In addition, we noted a slightly lower rate of bladder tumor recurrence in the BCG group than in the chemotherapy group. This finding is compatible with that seen in previous studies in which the maintenance BCG protocol benefited nMIBC patients.[2],[5] Witjes et al. reported that the TICE strain had similar efficacy to the Connaught strain in reducing bladder tumor recurrence when the maintenance protocol was used.[12] All our patients who received IVI with BCG underwent the maintenance protocol. The outcomes of treatment with the Connaught and TICE strains were similar. Witjes et al. also noted that the Connaught strain was more effective than the TICE strain in reducing the rate of bladder tumor recurrence in patients without maintenance therapy.[12] However, our cohort excluded patients without a maintenance protocol; therefore, further analysis could not be performed.

Previous studies have shown that no specific BCG strain has significantly superior efficacy compared with any other strain.[13],[14],[15] However, a significantly higher rate of progression was observed in our patients who were given the Connaught strain than in patients in the corresponding MDP group. This difference might be related to selection bias. Physicians at the time of diagnosis of cohort 1 tended to prescribe the Connaught BCG strain for patients with higher-grade tumors. This was because our MDP protocol was not yet established at that time, and its efficacy was not well known during the early 2000s. With the establishment of the efficacy of the MDP protocol in 2012,[6] we were comfortable administering either BCG or MDP for all nMIBC patients. However, there was persistence of a selection bias after 2012. Patients with CIS were more likely to be administered BCG than chemotherapeutic agents. In the comparison of demographics in cohort 2, CIS was more prominent in the TICE group (86%) than in the MDP group (20.6%). However, the progression rates of the patients in the TICE and MDP groups were similar. Because of the minimal progression rates in cohort 2, the results were inconclusive; further studies with a large sample size should be conducted.

In contrast, some prospective randomized trials showed that the Connaught strain had better efficacy in reducing the rate of bladder tumor recurrence than the TICE strain.[16],[17] Birkhaeuser et al. found that the Connaught strain significantly improved the 5-year RFS rate (75%) compared with the TICE strain (46%).[16] Rentsch et al. also found a higher 5-year RFS rate with the Connaught strain (74%) than with the TICE strain (48%).[17] These results were different from those of our study, possibly due to differences in study design (prospective vs. retrospective), race (western vs. Asian), or conduct of the maintenance protocol.

CIS is an important prognostic factor for patients with bladder cancer, reflecting the high possibility of tumor recurrence or progression.[18] Our cohort also revealed its predictive value in the univariable analysis (HR: 1.399). After adjustment in the multivariable model, the significance of predicting tumor recurrence was lost. A possible reason for this is the strong interaction between the use of the TICE strain and the existence of CIS in cohort 2. In other words, the TICE strain improved the outcomes of patients with CIS.

Upper urinary tract urothelial carcinoma is a rare disease worldwide,[19] but it is common in Taiwan.[20] About 30% of patients with upper urinary tract urothelial carcinoma experience bladder tumor recurrence after radical nephroureterectomy.[21] Therefore, a strong association between upper urinary tract urothelial carcinoma and bladder cancer is well known. In addition, bladder cancer patients with a history of upper urinary tract urothelial carcinoma in our cohort tended to have higher rates of cancer recurrence than those without such history. The possible mechanisms for this phenomenon might include the different carcinogens, persistent exposure to carcinogens, compliance with IVI with either BCG or chemotherapeutic agents, and other comorbidities of patients with and without a history of upper urinary tract urothelial carcinoma.

Our study had several limitations. First, this retrospective study was designed to have selection bias. To compensate for the bias related to the time of IVI use, we performed the analysis in two time-associated cohorts. After confirmation of similar demographics and outcomes of MDP groups between cohorts, we enrolled all patients in the final model for bladder tumor recurrence. Second, the absence of an overlapping period for the use of the Connaught and TICE strains made direct comparison between them impossible. Therefore, we considered the continuously used protocol, MDP, as a reference for comparison. Third, the shortage of the Connaught strain resulted in extensive patient selection bias. To mitigate this limitation, we used a multivariable model that included as many clinical factors as possible.


  Conclusion Top


The BCG strains Connaught and TICE had similar efficacy in reducing bladder tumor recurrence in nMIBC patients. Both strains provided similar bladder tumor RFS rates compared with chemotherapeutic agents. The progression outcome was not well explored in this study because of the small numbers of progression events.

Acknowledgment

We thank all the collaborators who participated in the collection of data of patients with nonmuscle invasive bladder cancer. Thank you for providing our patient list and helping us solve some problems that were encountered in data collection.

Financial support and sponsorship

Nil.

Conflicts of interest

Dr. Chung-Hsin Chen, Prof. Yeong-Shiau Pu, are editorial board members at Urological Science, had no roles in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.



 
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