Editorial by Richard J. Sylvester on pp. 266–268 of this issue
Long-term Efficacy of Maintenance Bacillus Calmette-Guérin versus Maintenance Mitomycin C Instillation Therapy in Frequently Recurrent TaT1 Tumours without Carcinoma In Situ: A Subgroup Analysis of the Prospective, Randomised FinnBladder I Study with a 20-Year Follow-up
The long-term prospective data on bacillus Calmette-Guérin (BCG) and mitomycin C (MMC) instillation therapy are limited.
Objective
To compare the long-term benefit of BCG and MMC maintenance therapy in patients with recurrent bladder carcinoma.
Design, setting, and participants
Eighty-nine patients with frequently recurrent TaT1 disease without carcinoma in situ (CIS) were eligible. Originally, the patients were enrolled in the prospective FinnBladder I study between 1984 and 1987 and randomised to receive BCG or MMC. Both regimens involved five weekly instillations, followed by monthly instillations for 2 yr. Because of alkalinising the urine and adjusting the dose to bladder capacity, the average concentration of MMC was low: 30–40 mg in 150–200 ml of phosphate buffer. Overall median follow-up time was 8.5 yr, whereas the median follow-up time of the patients who were still alive was 19.4 yr.
Measurements
Primary end points were time to first recurrence and overall mortality. Secondary end points were progression and disease-specific mortality.
Results and limitations
Thirty-six of 45 patients (80.0%) in the MMC group experienced recurrence in contrast to 26 of 44 patients (59.1%) in the BCG group. This finding was reflected in significantly lower cumulative incidence estimates in the BCG group (p = 0.005). There was a weak trend for fewer progressions (p = 0.1) and cancer-specific deaths (p = 0.2) in the cumulative incidence analysis, as 4 patients versus 10 patients progressed and 4 patients versus 9 patients died from the disease in the BCG group versus the MMC group, respectively. No difference existed in the overall mortality. The study population, however, was too small for conclusive evidence about progression or survival.
Conclusions
An intensive intravesical BCG immunotherapy results in a sustained and significant long-term reduction in recurrence in frequently recurrent bladder carcinoma. The relatively low progression rate during the long follow-up suggests that it may be difficult to show significant differences in overall mortality with a substantially larger but otherwise similar study population.
Trial registration
Registration was not considered to be necessary at this stage of the follow-up because the study was initiated as early as 1984 and the last randomisation took place in July 1987, that is, long before the current requirements concerning study registrations were implemented.
Introduction
Up to 80% of urinary bladder cancer patients present with non–muscle-invasive disease, which may be treated by transurethral resection (TUR) with curative intent. The natural course of low- and intermediate-risk superficial bladder tumours is relative benign, with the risk of progression at only 0.8–6% in 5 yr [1]; however, as many as 31–62% of superficial tumours will recur after primary treatment [1]. Although the risk for progression is relatively low, even in frequently recurring tumours, every recurrence increases patient inconvenience and the costs of the health care system.
The choice between chemotherapy and immunotherapy largely depends on the main concern: recurrence or progression. According to the 2008 European Association of Urology guidelines, adjuvant chemotherapy or bacillus Calmette-Guérin (BCG) instillations are effective in preventing recurrence [2]. The efficacy of mitomycin C (MMC) instillation therapy varies significantly among the largest studies [3], [4], [5]. It seems that BCG maintenance therapy, rather than chemotherapy, reduces or at least delays progression [6], [7], [8].
Only a few studies [8], [9], [10] exist with a sufficient follow-up time to determine the long-term benefit of intravesical chemotherapy or immunotherapy instillations. In the present study, with an overall follow-up of approximately 20 yr, our principal focus was on the durability of response to instillation therapy as well as on the possible impact of instillation therapy on overall mortality.
Section snippets
Materials and methods
The study was approved by the ethical committee by the Helsinki University Hospital Department of Surgery. An oral informed consent was obtained from the patients before randomisation. The first peer-reviewed analysis of this multicentre study was published in 1991 [11]. Briefly, the material consisted of 109 eligible patients with frequently recurrent TaT1 tumours and/or carcinoma in situ (CIS) who were randomised in 1984–1987 to receive either MMC or BCG. The method of randomisation was based
Results
Table 1 provides the distribution of patient characteristics by treatment group. Of the 89 eligible patients randomised in 1984–1987, 44 belonged to the BCG group and 45 belonged to the MMC group. The overall median follow-up time based on survival data was 8.5 yr (range: 1.0–22.3), whereas the median follow-up time of the 17 patients who were still alive was 19.4 yr (range: 13.0–22.3).
Discussion
Our finding of the superiority of BCG over MMC in time to recurrence is consistent with the results of two large meta-analyses with a considerably shorter median follow-up time [3], [4]. In a meta-analysis of 2749 patients with intermediate- to high-risk tumours, Böhle et al [3] found a significant superiority of BCG over MMC, with 61% of the patients in the BCG group and 53% in the MMC group being recurrence free after a median follow-up time of 29 mo. In contrast, Shelley et al [4] found no
Conclusions
An intensive intravesical BCG immunotherapy results in a sustained and significant long-term reduction in recurrence in frequently recurrent bladder carcinoma. The small overall number of patients allows no definitive conclusions to be drawn from the present study about progression and cancer-specific or overall mortality. The relatively low percentage of patients with progression observed during the long follow-up justifies the conclusion that even with a substantially larger but otherwise
Bacillus Calmette-Guérin (BCG) therapy using the Southwest Oncology Group (SWOG) maintenance protocol is the standard in non–muscle-invasive bladder cancer (NMIBC). Maintenance with monthly instillations is also widely used, but evidence comparing the two maintenance protocols is scarce.
To compare monthly and SWOG instillation schedules in maintenance BCG therapy.
We retrospectively identified patients with NMIBC treated with maintenance BCG according to either the monthly or the SWOG instillation regimen in two tertiary care centers in Finland between 2009 and 2019.
We compared discontinuation rates of the monthly and SWOG maintenance protocols due to toxicity, and recurrence and progression rates by protocols. Baseline characteristics were compared with the Wilcoxon rank sum test, chi-square test, and Fisher’s exact test. The Kaplan-Meier method and Cox proportional hazards model were used to evaluate the discontinuation of BCG due to toxicity and oncological efficacy.
We identified 723 patients, of whom 545 (75%) and 178 (25%) received maintenance according to the monthly and SWOG protocols, respectively. The median follow-up time was 66 (interquartile range: 45–99) mo. In the monthly and SWOG groups, 131 (24%) and 50 (28%) patients, respectively, discontinued BCG due to toxicity, with no difference in a univariate or multivariate analysis (hazard ratio 1.01, 95% confidence interval [CI]: 0.73–1.40, p = 0.940). The 5-yr recurrence-free survival rates in the monthly and SWOG groups were 65% (95% CI: 61–69%) and 71% (95% CI: 64–79%, p = 0.370), respectively. The 5-yr progression-free survival rates were 89% (95% CI: 86–92%) and 91% (95% CI: 86–96%, p = 0.240), respectively.
Monthly maintenance is a comparable alternative to the SWOG protocol.
In this study, we compared two schedules of intravesical bacillus Calmette-Guérin (BCG) treatment used in the treatment of non–muscle-invasive bladder cancer. We found that there were no significant differences between the two instillation schedules in terms of tolerability or efficacy.
Delay in treatment is a prognostic factor in muscle-invasive bladder cancer.
To evaluate clinical outcomes associated with delays in diagnosis and treatment for patients with non–muscle invasive bladder cancer (NMIBC).
In this retrospective study we analyzed data for patients treated at our center between November 2008 and December 2016 for intermediate risk (IR) or high risk (HR) NMIBC with an additional intravesical treatment.
Time delays from diagnosis to first transurethral resection (TT-TUR), from resection to restaging resection (TT-reTUR), and from the last resection to first instillation (TT-INST) of bacillus Calmette-Guérin (BCG) or mitomycin C (MMC) were documented. To identify the interval of time from which recurrence rates significantly increased, we used nonparametric series regression. Recurrence-free survival (RFS) and progression-free survival for patients in each time delay category were compared using the Kaplan-Meier method. Factors associated with tumor recurrence were analyzed in a multivariable model.
A total of 434 patients were included, of whom 168 (38.7%) had IR and 266 (61.3%) had HR NMIBC. Among the patients, 34.6% had reTUR, 63.6% received BCG, and 36.4% received MMC. The median TT-TUR, TT-reTUR, and TT-INST was 4.0 wk, 6.5 wk, and 7.0 wk, respectively. At 40 mo the rate of recurrence was 28.4% and the rate of progression was 7.3%. Nonparametric analysis revealed that each week in delay increased the risk of recurrence, starting from week 6 for TT-TUR for IR and HR cases, and starting from week 7 for TT-INST for IR cases. RFS was significantly lower with TT-TUR > 6 wk among patients in the IR (p < 0.001) and HR (p = 0.04) groups, and with TT-INST >7 wk for patients in the IR group (p = 0.001). TT-reTUR >7 wk had a significant negative impact on progression (p < 0.017). Multivariable analysis revealed that for IR and HR cases, multifocality (p = 0.02 and p = 0.007) and TT-TUR >6 wk (p = 0.001 and p = 0.03) were independent predictors of recurrence, while TT-INST >7 wk predicted recurrence (p = 0.04) for IR NMIBC.
Our results suggest that delays of >6 wk to first TUR in IR and HR NMIBC, and >7 wk to first instillation in IR cases are associated with increases in the risk of recurrence. TT-reTUR of >7 wk is also associated with higher risk of progression.
We evaluated the impact of treatment delays on outcomes for patients with intermediate- and high-risk bladder cancer not invading the bladder wall muscle. We found that delays from diagnosis to first bladder resection, from first resection to repeat resection, and from last resection to bladder instillation treatment increase the rates of cancer recurrence and progression. The medical team should avoid delays in treatment, even for low-grade bladder cancer.
Three RCTs of intermediate- and high-risk tumours compared BCG with epirubicin and interferon (IFN) [110], epirubicin alone [111], or MMC [112] and confirmed the superiority of BCG for prevention of tumour recurrence (LE: 1a). The effect is long-lasting [111,112] and was also observed in a separate analysis of patients with intermediate-risk tumours [111]. An IPD meta-analysis demonstrated a 32% reduction in the risk of recurrence for BCG compared to MMC in trials with BCG maintenance, but a 28% increase for patients treated without BCG maintenance (LE: 1a) [105].
The European Association of Urology (EAU) has released an updated version of the guidelines on non–muscle-invasive bladder cancer (NMIBC).
To present the 2021 EAU guidelines on NMIBC.
A broad and comprehensive scoping exercise covering all areas of the NMIBC guidelines since the 2020 version was performed. Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries. Previous guidelines were updated, and the level of evidence and grade of recommendation were assigned.
Tumours staged as Ta, T1 and carcinoma in situ (CIS) are grouped under the heading of NMIBC. Diagnosis depends on cystoscopy and histological evaluation of tissue obtained via transurethral resection of the bladder (TURB) for papillary tumours or via multiple bladder biopsies for CIS. For papillary lesions, a complete TURB is essential for the patient’s prognosis and correct diagnosis. In cases for which the initial resection is incomplete, there is no muscle in the specimen, or a T1 tumour is detected, a second TURB should be performed within 2–6 wk. The risk of progression may be estimated for individual patients using the 2021 EAU scoring model. On the basis of their individual risk of progression, patients are stratified as having low, intermediate, high, or very high risk, which is pivotal to recommending adjuvant treatment. For patients with tumours presumed to be at low risk and for small papillary recurrences detected more than 1 yr after a previous TURB, one immediate chemotherapy instillation is recommended. Patients with an intermediate-risk tumour should receive 1 yr of full-dose intravesical bacillus Calmette-Guérin (BCG) immunotherapy or instillations of chemotherapy for a maximum of 1 yr. For patients with high-risk tumours, full-dose intravesical BCG for 1–3 yr is indicated. For patients at very high risk of tumour progression, immediate radical cystectomy should be considered. Cystectomy is also recommended for BCG-unresponsive tumours. The extended version of the guidelines is available on the EAU website at https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/.
These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice.
The European Association of Urology has released updated guidelines on the classification, risk factors, diagnosis, prognostic factors, and treatment of non–muscle-invasive bladder cancer. The recommendations are based on the literature up to 2020, with emphasis on the highest level of evidence. Classification of patients as having low, intermediate, or and high risk is essential in deciding on suitable treatment. Surgical removal of the bladder should be considered for tumours that do not respond to bacillus Calmette-Guérin (BCG) treatment and tumours with the highest risk of progression.
To examine recent treatment trends for non-muscle-invasive bladder cancer (NMIBC), and specifically, to assess whether there was a change in use radical cystectomy (RC) between 2008 and 2015 using data from the Surveillance, Epidemiology, and End Results database.
We identified patients presenting with high-grade T1 (T1HG) NMIBC at diagnosis during the study period. Treatment was dichotomized into “RC” and “local treatment” (which included transurethral resection and intravesical therapies). We then employed multivariable logistic regression models to assess the odds of undergoing RC across the study period. Additionally we examined the rates of RC for T1HG NMIBC during the period of BCG-shortage, defined as 2012-2015.
We identified 21,817 individuals diagnosed with T1HG bladder cancer during the study period. The majority of patients underwent local treatment (94.5%). During the shortage period, the rate of RC for T1HG NMIBC was significantly lower compared to the preshortage era (5.1% vs 5.9%, P = .007). Across the study period, the utilization of RC for T1HG NMIBC decreased significantly (odds ratio 0.99 per quarter, 95% confidence interval 0.98-0.99, P = .017).
In our cohort of patients diagnosed with T1HG bladder cancer, we found a significant decrease in the use of radical cystectomy across the study period. Contrary to the hypothesis of increasing rates of RC in the face of BCG shortage, the rate of RC was significantly higher in the pre-shortage era. Further examination of NMIBC treatment patterns will be necessary to assess the impact of BCG availability on therapeutic pathways and oncologic outcomes in patients with high-grade NMIBC.
However, for high- and low-grade recurrent or multifocal tumors, complete resection of the tumor should be associated with adjuvant therapy, such as nonspecific immunotherapy, bacillus Calmette-Guérin (BCG), or intravesical chemotherapy, to reduce the risk of recurrence and progression [2]. BCG bladder instillation with at least 1 yr of maintenance therapy is the most effective option and the only adjuvant treatment to reduce the progression rate [3–5]. Meta-analyses have estimated that BCG bladder instillation with maintenance, as compared with intravesical chemotherapy, reduces the risk of recurrence by 31–61% [6–8].
Between 2013 and 2016, global production of bacillus Calmette-Guérin (BCG) was dramatically reduced due to the collapse of the factory producing BCG Connaught.
To evaluate the clinical and economic impact of BCG shortage on a cohort of non–muscle-invasive bladder cancer (NMIBC) patients treated during the period of restricted supply.
This retrospective, before and after, cost-consequence study included patients with intermediate- and high-risk NMIBC. Those resected between November 2011 and September 2013 (control group) were compared with those resected between October 2013 and December 2016 (study group).
The primary endpoint was the rate of tumor recurrence from 30 d after transurethral resection to the end of follow-up at 24 mo; the secondary endpoints included the average cost of primary treatment, average cost of treatment of recurrence, and excess cost due to BCG shortage per patient.
A total of 402 patients were included: 191 in the control group and 211 in the study group. The rate of recurrence at 24 mo was significantly higher in the study group than in the control group (46.9% vs 16.2%; relative risk: 0.7, 95% confidence interval [0.60; 0.82]; p < 0.001). The increased cost due to the decrease in BCG production was estimated to be €783 per patient with a new diagnosis of NMIBC during the period of restricted supply. This is a retrospective analysis at the level of our unit. A more precise evaluation would require a study of a larger cohort of patients.
The shortage of BCG between October 2013 and December 2016 had a significant medical and economic impact; there was an increased rate of bladder cancer recurrence, and the total cost of care for intermediate- and high-risk NMIBC was higher.
In this report, we analyzed the medical and economic impact of bacillus Calmette-Guérin (BCG) shortage that occurred between 2013 and 2016. We found a significant increase of bladder cancer recurrence and progression, and an increase in the number of patients who had to be treated by cystectomy. BCG shortage also had a significant impact on the total cost. Since there are no alternatives to BCG for high-risk non–muscle-invasive bladder cancer patients, BCG production has to be maintained by any means.
In addition to the direct antitumor effect, antitumor immunotherapeutic effects of Mycobacterium species have also been suggested [7]. Notably, Mycobacterium bovis Bacillus Calmette-Guérin (BCG) therapy for non-muscle invasive bladder cancer (NMIBC) is one of the few examples of successful immunotherapy in clinical use [8]. The cell wall skeleton of BCG (BCG-CWS) has also been used as an effective adjuvant for immunotherapy in patients for postoperative treatment of cancer [9].
A therapeutic strategy capable of skewing toward a Th1-type immune response is crucial for cancer treatment. Recently, we reported Mycobacterium paragordonae (Mpg) as a potential live vaccine for mycobacterium infections. In this study, we explored the immunotherapeutic potential of heat-killed Mpg (HK-Mpg) in a mouse tumor xenograft model and elucidated its underlying antitumor mechanisms. MC38 cells derived from murine colon adenocarcinoma were implanted by subcutaneously injecting mice. The anticancer effects of HK-Mpg therapy were compared with HK-M. bovis BCG, an effective adjuvant for cancer immunotherapy. HK-Mpg treatment enhanced tumor reduction and mouse survival. Furthermore, HK-Mpg treatment synergistically enhanced the anticancer therapeutic effect of cisplatin. In addition, HK-Mpg enhanced inflammatory cytokine production and recruitment of immune cell into tumor-infiltrating sites and splenocytes in vaccinated mice. Our mechanistic study demonstrates that HK-Mpg therapy elicits a strong antitumor immune response in mice, mainly through natural killer cell-mediated oncolytic activity via the activation of dendritic cells (DCs) and by enhancing inflammatory cytokines production such as IL-12 from DC. Hence, HK-Mpg can be a potential immunotherapy adjuvant, enhancing the effect of cancer chemotherapy.
