Abstract
Objectives
To evaluate the impact of personalized dwell‐time (DT) reductions on symptom prevalence and systemic toxicities in patients undergoing Bacillus Calmette–Guérin (BCG) instillation for non‐muscle invasive bladder cancer (NMIBC).
Methods
Within a multinational randomized controlled trial (North‐REG Dwell Time Study [NCT04701151]), 225 patients provided daily electronic patient‐reported outcomes data during BCG induction and maintenance cycles. Participants were randomized 1:1, stratified by clinical site, sex, and concomitant carcinoma in situ, to either a standard care arm (control) or an intervention arm. Toxicity was analysed using a ‘worst‐day’ principle to capture peak symptom burden. All patients initially received a standard 120‐min DT. In the intervention group, algorithm‐guided DT reductions (to 60 or 30 min) were triggered by real‐time symptom severity, whereas the control group maintained a 120‐min DT.
Results
At baseline, 69% vs. 71% (control vs. intervention) of participants reported pre‐existing symptoms, primarily lower urinary tract symptoms such as pollakiuria and urgency. During induction, the intervention group experienced significantly lower rates of urgency at week 3 (34% vs. 47%, P = 0.04) and week 6 (32% vs. 49%, P = 0.01). Significant reductions were also observed during maintenance at week 9 for systemic symptoms (30% vs. 61%, P < 0.001) and fatigue (22% vs. 47%, P = 0.001). Total adherence to the 15‐instillation protocol was 38% in the intervention group and 40% in the control group.
Conclusion
Daily electronic patient‐reported outcomes monitoring revealed that patients with NMIBC have a high baseline symptom burden prior to BCG therapy. Symptom‐guided DT reductions may reduce local urgency and systemic toxicity and improve treatment tolerability. However, treatment completion does not seem to be affected.
Keywords: non‐muscle‐invasive bladder cancer, BCG, patient reported outcome measures, drug‐related toxicity, randomized controlled trial
Abbreviations
- BCG
Bacillus Calmette‐Guérin
- CIS
carcinoma in situ
- DT
dwell time
- ePROM
electronic patient‐reported outcome measure
- GAG
glycosaminoglycan
- LUTS
lower urinary tract symptoms
- NMIBC
non‐muscle‐invasive bladder cancer
- SE
side effect
- TURBT
transurethral resection of bladder tumour
- UTI
urinary tract infection
Introduction
Non‐muscle‐invasive bladder cancer (NMIBC) represents a substantial global health burden because of high recurrence rates, intensive surveillance regimens, and repeated intravesical treatments [1]. Bacillus Calmette–Guérin (BCG) remains the most effective adjuvant therapy for intermediate‐ and high‐risk disease, significantly reducing both recurrence and progression [2]. To optimize oncological outcomes, guidelines recommend induction therapy followed by maintenance treatment for up to 3 years [3]. However, adherence to guidelines remains a major clinical challenge. Side effects occur in up to 70% of patients and are the primary cause of treatment discontinuation [4]; in a large multinational study, only 16% of patients completed the full 3‐year maintenance schedule [5].
Monitoring of BCG‐related toxicity in routine practice typically occurs during weekly outpatient visits, during which clinicians rely on patients’ retrospective recollection of symptoms. This approach introduces recall bias and may lead to underreporting [6]. Furthermore, symptoms arising between visits are rarely documented in a systematic manner [7, 8]. As a result, important aspects of symptom burden during treatment may remain unrecognized [9].
Another underexplored aspect of BCG tolerability is the burden of lower urinary tract symptoms (LUTS) present before initiation of therapy. Transurethral resection of the bladder tumour (TURBT) is known to cause irritative urinary symptoms that can persist for weeks and may overlap with early BCG‐related toxicity [10, 11]. Without structured baseline assessment, distinguishing treatment‐induced symptoms from pre‐existing or surgery‐related complaints may be challenging. A Scandinavian cohort has shown that LUTS are frequently already present before the first BCG instillation [12]. Furthermore, large‐scale epidemiological studies suggest that more than 60% of the general aging population is affected by LUTS, establishing a high symptomatic ‘floor’ even before cancer treatment starts [13, 14, 15].
Several strategies have been explored to improve BCG tolerability, including dose reduction, fewer instillations, and shortened dwell‐time (DT). Reducing the number of instillations has been shown to compromise oncological outcome, most notably in the NIMBUS trial [16]. In contrast, shorter DT may improve tolerability without apparent loss of efficacy in selected patients [12, 17].
Few structured tools are available for capturing real‐time patient‐reported side effects during BCG therapy, and, to our knowledge, no dedicated BCG‐specific patient‐reported outcomes measure (PROM) has been widely adopted in clinical practice.
The aim of this observational study was to characterize side effects associated with BCG instillations and distinguish them from pre‐existing morbidity using electronic PROMs (ePROMs) collected as part of the North‐REG Dwell Time Study.
Methods
Study Design and Setting
This study represents an observational analysis within the North‐REG Dwell Time Study (NCT04701151), a multinational, randomized controlled trial conducted across 10 clinical sites in Denmark, Sweden, and Iceland (See Data S1 for protocol). The study employed an open‐label design to compare a standard intravesical DT as control group, with a symptom‐guided, reduced DT approach as intervention group. The study adhered to the principles of the Declaration of Helsinki [18].
Participants and Randomization
Eligible participants were adults scheduled for intravesical BCG due to intermediate‐ or high‐risk NMIBC (Ta high grade [HG], T1 HG/low grade [LG], with or without carcinoma in situ [CIS]). A key criterion was access to a smartphone to facilitate daily ePROM participation. Participants were randomized 1:1 to an intervention or a control group, stratified by clinical site, sex, and the presence of concomitant CIS.
Daily ePROM Monitoring and Symptom Assessment
Toxicity was captured in real time using a customized ePROM system delivered through daily SMS‐based links. Each link contained a questionnaire that was returned directly into the study database once completed. To our knowledge, no validated BCG‐specific PROM suitable for integration with the planned real‐time toxicity algorithm was available. Therefore, a customized questionnaire was developed (Data S2: B) covering 11 symptom domains and corresponding sub‐questions, including:
Local Symptoms: Urgency, pollakiuria, dysuria, haematuria, incontinence, and suspected urinary tract infection.
Systemic Symptoms: Fever, chills, muscle/joint pain, dizziness, nausea, and fatigue.
Concomitant supportive pharmacological treatments (e.g., paracetamol, nonsteroidal anti‐inflammatory drugs, anticholinergics, or beta‐3 agonists) were permitted and utilized in both the intervention and the control groups to palliate local symptoms according to standard clinical practice.
As previously published, the questionnaire underwent a face‐validity assessment by 10 patients in the outpatient clinic. Patients currently undergoing BCG treatment reviewed the questionnaire items for clarity and comprehension. Based on patient feedback, minor wording adjustments were made to ensure the terminology was intuitive and easily understood by the elderly population [19].
A baseline questionnaire captured symptoms following TURBT before treatment initiation. During the 6‐week induction treatment and subsequent maintenance cycles at 3, 6, and 12 months, questionnaires were sent the day after each instillation and for the 5 consecutive days. The initial SMS was sent at 8.00 PM, followed by two reminders if the questionnaire had not been completed within 2 and 4 h. To ensure data integrity, participants were contacted by telephone the following day if they had not responded.
The ‘Worst‐Day’ Data Aggregation Principle
To ensure a comprehensible presentation of the longitudinal data, we applied a ‘worst‐day’ principle for all statistical analyses. Although the real‐time clinical algorithm utilized data from all 5 days (e.g., evaluating average voiding frequency across the week, as detailed in Data S2: B), the analytical data presented in this manuscript reduces each instillation week to a single data point representing the highest reported severity grade for each symptom.
The Treatment Protocol and Dwell‐Time Interventions
All participants received intravesical therapy with a standard dose of BCG (strain RIVM, medac).
Control Group
Patients randomized to the control group received a fixed 120‐min DT for all instillations. Although they completed the same daily ePROM monitoring, their reported symptoms did not result in any alterations to their scheduled DT. If the participant experienced a grade 3 side effect (SE), permanent treatment cessation was enforced (See Data S2: C).
Intervention Group
In the intervention group, DT reductions were triggered directly by the daily ePROM output. A database‐integrated decision‐support algorithm evaluated the severity of the SE to determine the DT for the upcoming instillation:
Grade 0 SE (none/mild): 120‐min DT.
Grade 1 SE (moderate): reduction to 60‐min DT.
Grade 2 SE (moderate/severe): reduction to 30‐min DT.
Grade 3 SE (severe): permanent treatment cessation.
Adequate BCG was defined as at least five of six instillations in the introduction cycle and two of three instillations in the first maintenance cycle [2].
Statistical Analysis
Symptom transitions from baseline were visualized using Sankey diagrams to illustrate how pre‐existing LUTS influenced the subsequent toxicity. Statistical significance was defined as P < 0.05, and all analyses were performed using R version 4.4.2 [20]. Although the collection of daily ePROM data was a predefined endpoint in the original study protocol, the specific analytical strategy applied in this manuscript—specifically the ‘worst‐day’ data aggregation used to present longitudinal symptom trends—was developed post hoc.
Results
Participants and Recruitment
From February 2021 to August 2024, a total of 242 participants were randomized. Enrolment was terminated before the target of 314 participants had been reached because of slow recruitment. In total, 17 patients were excluded: 14 withdrew consent, one required clean intermittent catheterization, one developed a new primary malignancy, and one was excluded for other clinical reasons. The final population included 225 patients (113 control; 112 intervention) who received at least one instillation (Table 1).
Table 1.
Characteristics of 225 patients included in the North‐REG dwell‐time study.
| Patient characteristic | Control, N = 113 | Intervention, N = 112 | Overall, N = 225 |
|---|---|---|---|
| Sex | |||
| Female | 20 (18) | 22 (20) | 42 (19) |
| Male | 93 (82) | 90 (80) | 183 (81) |
| Age | 70 (65–77) | 70 (64–77) | 70 (65–77) |
| Country | |||
| Denmark | 82 (71) | 75 (67) | 157 (69) |
| Iceland | 3 (2.6) | 5 (4.4) | 8 (3) |
| Sweden | 29 (26) | 32 (28) | 61 (28) |
| Median complete BCG instillations per patient | 11 (6–15) | 12 (6–15) | 11 (6–15) |
| Tumour classification | |||
| CIS only | 16 (14) | 10 (9.0) | 26 (12) |
| T1 | 59 (52) | 66 (59) | 125 (56) |
| Ta HG | 38 (33) | 35 (32) | 73 (32) |
| Concomitant CIS | 22 (19) | 28 (25) | 50 (22) |
| n (%) |
Data are presented as n (%) or median (interquartile range) unless otherwise indicated. BCG, Bacillus Calmette–Guérin; CIS, carcinoma in situ; HG, high‐grade.
The completion rate for the full 15‐instillation protocol was 38% (42/112) in the intervention group and 40% (46/113) in the control group, showing no statistically significant difference (P = 0.8). Premature treatment cessation occurred in 61% (138/225) of the entire cohort, with grade 3 SEs being the primary objective driver, accounting for 43% (59/138) of all discontinuations (Data S2: D). Within the intervention group, the symptom‐guided algorithm led to a final DT distribution where 33% (14/42) completed treatment on a 1‐h schedule and 45% (19/42) on a 30‐min schedule, leaving 21% (9/42) on the standard 2‐h DT.
A granular, week‐by‐week tracking of patient retention, the timing of dropouts across induction and maintenance cycles, and the exact distribution of DT reductions is provided in Data S2: E.
The ePROM response rate was 95% in both groups.
Baseline Symptom Prevalence
At baseline, before the first BCG instillation, the symptom prevalence was high, with local and/or systemic symptoms reported by 71% (80/112) of patients in the intervention group and 69% (78/113) in the control group (P = 0.7) (Table 2). This baseline burden was predominantly characterized by LUTS. Specifically, pollakiuria was reported by 62% (69/112) in the intervention group versus 59% (67/113) in the control group (P = 0.7), whereas urinary urgency affected 35% (39/112) and 32% (36/113) of patients, respectively (P = 0.6).
Table 2.
Reported electronic patient‐reported outcome measures (ePROMs) of participants by treatment group at baseline, during induction treatment (week 3 and 6) and maintenance (week 9, 12 and 15).
| ePROM | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Characteristic | Baseline | Week 3 | Week 6 | Week 9 | Week 12 | Week 15 | ||||||||||||
| Control N = 113 | Intervention N = 112 | P‐value† | Control N = 108 | Intervention N = 104 | P‐value† | Control N = 102 | Intervention N = 98 | P‐value† | Control N = 72 | Intervention N = 73 | P‐value† | Control N = 56 | Intervention N = 60 | P‐value‡ | Control N = 46 | Intervention N = 42 | P‐value‡ | |
| Local symptoms | 76 (67) | 79 (71) | 0.6 | 98 (91) | 95 (91) | 0.9 | 95 (93) | 89 (91) | 0.5 | 67 (93) | 65 (89) | 0.4 | 53 (95) | 56 (93) | >0.9 | 44 (96) | 40 (95) | >0.9 |
| Urgency | 36 (32) | 39 (35) | 0.6 | 51 (47) | 35 (34) | 0.044 | 50 (49) | 31 (32) | 0.012 | 44 (61) | 34 (47) | 0.079 | 29 (52) | 27 (45) | 0.5 | 25 (54) | 22 (52) | 0.9 |
| Pollakiuria | 67 (59) | 69 (62) | 0.7 | 91 (84) | 86 (83) | 0.8 | 90 (88) | 82 (85) | 0.4 | 65 (90) | 63 (86) | 0.5 | 52 (95) | 55 (92) | 0.7 | 44 (96) | 39 (93) | 0.7 |
| Dysuria | 9 (8.0) | 6 (5.4) | 0.4 | 25 (23) | 13 (13) | 0.043 | 20 (20) | 11 (11) | 0.10 | 32 (44) | 23 (32) | 0.11 | 20 (36) | 21 (35) | >0.9 | 14 (30) | 14 (33) | 0.8 |
| Haematuria | 4 (3.6) | 4 (3.7) | >0.9 | 39 (36) | 34 (33) | 0.6 | 41 (41) | 29 (30) | 0.10 | 38 (53) | 28 (38) | 0.081 | 25 (45) | 19 (32) | 0.2 | 19 (41) | 13 (31) | 0.3 |
| UTI | 3 (2.7) | 3 (2.7) | >0.9 | 5 (4.6) | 3 (2.9) | 0.7 | 2 (2.0) | 4 (4.1) | 0.4 | 0 (0) | 0 (0) | 3 (5.4) | 4 (6.7) | >0.9 | 4 (8.7) | 4 (9.5) | >0.9 | |
| Incontinence | 8 (7.1) | 6 (5.4) | 0.6 | 25 (23) | 23 (22) | 0.9 | 28 (27) | 19 (19) | 0.2 | 14 (19) | 19 (26) | 0.3 | 11 (20) | 12 (20) | >0.9 | 7 (15) | 8 (19) | 0.6 |
| Systemic symptoms | 10 (8.8) | 16 (14) | 0.2 | 54 (50) | 41 (39) | 0.12 | 49 (49) | 35 (36) | 0.068 | 44 (61) | 22 (30) | <0.001 | 28 (51) | 22 (37) | 0.12 | 23 (50) | 21 (50) | >0.9 |
| Dizziness | 3 (2.7) | 3 (2.7) | >0.9 | 9 (8.3) | 8 (7.7) | 0.9 | 8 (7.9) | 7 (7.1) | 0.8 | 2 (2.8) | 5 (6.8) | 0.4 | 2 (3.6) | 3 (5.0) | >0.9 | 4 (8.7) | 3 (7.1) | >0.9 |
| Nausea | 0 (0) | 2 (1.8) | 0.2 | 8 (7.4) | 10 (9.6) | 0.6 | 10 (9.9) | 6 (6.1) | 0.3 | 6 (8.3) | 6 (8.2) | >0.9 | 7 (13) | 5 (8.3) | 0.4 | 4 (8.7) | 2 (4.8) | 0.7 |
| Chills | 0 (0) | 1 (0.9) | 0.5 | 14 (13) | 7 (6.7) | 0.13 | 11 (11) | 9 (9.2) | 0.7 | 13 (18) | 6 (8.2) | 0.079 | 7 (13) | 4 (6.7) | 0.3 | 8 (17) | 4 (9.5) | 0.3 |
| Muscle and joint pain | 2 (1.8) | 5 (4.5) | 0.3 | 16 (15) | 11 (11) | 0.4 | 13 (13) | 11 (11) | 0.7 | 12 (17) | 10 (14) | 0.6 | 5 (9.1) | 8 (13) | 0.5 | 9 (20) | 6 (14) | 0.5 |
| Fever | 0 (0) | 0 (0) | 4 (3.7) | 4 (3.8) | >0.9 | 6 (5.9) | 0 (0) | 0.029 | 3 (4.2) | 1 (1.4) | 0.4 | 1 (1.8) | 2 (3.3) | >0.9 | 1 (2.2) | 0 (0) | >0.9 | |
| Fatigue | 7 (6.2) | 8 (7.1) | 0.8 | 40 (37) | 27 (26) | 0.083 | 36 (36) | 25 (26) | 0.12 | 34 (47) | 16 (22) | 0.001 | 19 (35) | 17 (28) | 0.5 | 15 (33) | 14 (33) | >0.9 |
| Local and/or systemic symptoms | 78 (69) | 80 (71) | 0.7 | 101 (94) | 99 (95) | 0.6 | 96 (94) | 90 (92) | 0.5 | 69 (96) | 66 (90) | 0.3 | 54 (96) | 56 (93) | 0.7 | 44 (96) | 41 (98) | >0.9 |
Data are presented as n (%) unless otherwise indicated. UTI, urinary tract infection. Bold values indicate statistical significance (P < 0.05). †Pearson's chi‐squared test. ‡Fisher's exact test.
Induction and Maintenance ePROM
During the induction phase (weeks 1–6), the prevalence of urinary urgency was significantly lower in the intervention group than in the control group at week 3 (34% vs. 47%, P = 0.04) and at week 6 (32% vs. 49%, P = 0.01). Additionally, dysuria was significantly less frequent in the intervention group at week 3 (13% vs. 23%, P = 0.04).
During the maintenance phase (weeks 7–15), the intervention group had a significantly lower rate of overall systemic symptoms at week 9 (30% vs. 61%, P < 0.001) and a lower prevalence of fatigue (22% vs. 47%, P = 0.001). At week 15, there were no significant differences in local or systemic symptom rates between the two groups.
The prevalence of pollakiuria did not differ significantly between the groups throughout the study period (Table 2).
Treatment Compliance and Delays
There were no significant differences between the control and intervention groups regarding treatment completion or instillation delays. The rate of adequate BCG exposure was similar between the control (73%) and intervention (70%) groups (P = 0.5), as was the proportion of patients initiating maintenance therapy (77% vs. 72%, P = 0.4) (see Table 3). Overall, any dose delay occurred in 55% of control patients and 50% of intervention patients (P = 0.5). Furthermore, the specific number of delayed doses (0, 1, or ≥2 delays) did not differ significantly between the cohorts (P = 0.7).
Table 3.
Instillation data from all participants.
| Instillation data | Overall N = 225 | Control N = 113 | Intervention N = 112 | P‐value† |
|---|---|---|---|---|
| Days from TURBT to first BCG | 39 (32; 46) | 40 (33; 47) | 37 (31; 44) | 0.3 |
| Total instillations (n) | 12 (6; 15) | 12 (7; 15) | 12 (6; 15) | 0.8 |
| Adequate BCG received | 161 (72) | 83 (73) | 78 (70) | 0.5 |
| Initiated maintenance | 168 (75) | 87 (77) | 81 (72) | 0.4 |
| Any instillation delayed | 118 (52) | 62 (55) | 56 (50) | 0.5 |
| Number of delayed instillations | ||||
| 0 | 107 (48) | 51 (45) | 56 (50) | 0.7 |
| 1 | 50 (22) | 27 (24) | 23 (21) | |
| ≥2 | 68 (30) | 35 (31) | 33 (29) |
Data are presented as n (%) or median (Q1; Q3) unless otherwise indicated. BCG, Bacillus Calmette–Guérin; TURBT, transurethral resection of the bladder tumour. †Wilcoxon rank sum test; Pearson's Chi‐squared test.
Oncological Outcomes
Regarding oncological outcomes, reducing the DT did not negatively impact efficacy. Recurrence within 1 year was observed in 24 patients (21%) in the control group and 22 patients (20%) in the intervention group (P = 0.8). Similarly, progression occurred in six patients (5.3%) in the control arm and five (4.5%) in the intervention arm (P = 0.8).
Sankey Diagrams – Urgency during Induction and Maintenance Treatment
Sankey diagrams were created to visualize the development of SEs by the categorization in grade: none (green), mild (yellow), and severe (red).
Longitudinal tracking via Sankey diagrams showed that the proportion of patients in the control group reporting severe urgency was 32% (36/113) at baseline and 49% (50/102) at week 6, whereas the prevalence in the intervention group was 35% (39/112) at baseline and 32% (31/98) at week 6 (Fig. 1).
Fig. 1.
Sankey diagram depicting urgency from baseline, and week 1 through 6 for the (A) intervention group, where dwell‐time could be 120, 60, or 30 min depending on the severity of side effects, and (B) control group, where dwell‐time was fixed for 120 min.
Across both study arms, an increase in urgency rates was recorded at weeks 7, 10, and 12, coinciding with the initiation of new maintenance cycles, after which the distribution of urgency severity remained stable through the subsequent monitoring weeks within each respective cycle (Fig. 2).
Fig. 2.
Sankey diagram depicting urgency at week 7 through 15 for the (A) intervention group, where dwell‐time could be 120, 60, or 30 min depending on the severity of side effects, and (B) control group, where dwell‐time was fixed for 120 min. Main., maintenance.
Discussion
This multicentre study characterized the symptom burden in patients undergoing BCG treatment using daily ePROM monitoring and a ‘worst‐day’ analysis principle. The findings suggest that baseline LUTS contribute substantially to the symptom profile observed during BCG therapy and support the potential value of personalized, symptom‐guided treatment.
The Symptomatic Floor: Pre‐Existing LUTS
The primary finding of this study is the high prevalence of local symptoms present before the initiation of BCG therapy, establishing a substantial ‘symptomatic floor’. Nearly 70% of patients reported pre‐existing symptoms at baseline, heavily dominated by pollakiuria (60–61%) and urinary urgency (32–35%). This clinical pattern likely reflects surgical sequelae from the recent TURBT, which is known to cause irritative LUTS that persist for several weeks after the procedure [9, 10]. These findings furthermore align with those from other epidemiological studies showing that a significant proportion of the aging population experiences LUTS independent of cancer treatment [13, 14, 15]. Documenting this baseline burden is clinically important, as pre‐existing surgical symptoms or age‐related complaints may otherwise be misinterpreted as early BCG‐induced toxicity. Without adjusting for post‐TURBT symptoms, clinicians risk over‐reporting adverse events, potentially leading to unnecessary treatment alterations or premature discontinuation [8]. In addition, improved recognition of baseline symptoms may facilitate more informed shared decision‐making.
Impact of Dwell‐Time Reduction on Toxicity and Adherence
The data suggest that, although pollakiuria was nearly universal during BCG treatment, urgency trajectories appear to be associated with the duration of intravesical exposure. The significantly lower prevalence of urgency in the intervention group at week 3 (34% vs. 47%, P = 0.04) and week 6 (32% vs. 49%, P = 0.01) indicates that symptom‐guided reduction of DT effectively mitigates one of the most bothersome local toxicities. These findings are consistent with previous observations suggesting that shortened DT may improve tolerability without clearly compromising oncological efficacy in selected patients [12, 17].
Unfortunately, the reduction in peak symptom burden did not result in a higher completion rate. The completion rate for the full 15‐instillation protocol remained virtually identical between the study arms: 38% in the intervention group and 40% in the control group (P = 0.8). It is crucial to distinguish statistical significance from clinically meaningful benefit in this context. Although DT reduction achieved statistically significant improvements in selected symptoms, the lack of increased treatment completion renders the overall clinical effect of these findings uncertain regarding adherence. Because grade 3 SEs remained the primary driver for permanent cessation across both groups, accounting for 43% of all discontinuations, the data indicate that, although shortening DT to 60 or 30 min improves the tolerability of moderate toxicities, it does not prevent the severe, protocol‐mandated toxicities that dictate permanent treatment discontinuation. This lack of adherence benefit contrasts with strategies focused on reducing the number of instillations, which can improve compliance but has been shown to compromise oncological outcomes, most notably in the NIMBUS trial [16]. At week 9, during the maintenance phase, a significant reduction in systemic symptoms (30% vs. 61%, P < 0.001) and fatigue (22% vs. 47%, P = 0.001) was also observed in the intervention group, suggesting that cumulative toxicity may potentially be reduced through early DT adjustment.
Importantly, although this trial was primarily designed to evaluate tolerability and patient‐reported symptoms, oncological data demonstrated no significant differences in recurrence or progression rates at 1 year. A dedicated analysis with extended follow‐up is currently under way to comprehensively evaluate the long‐term oncological safety and efficacy of a reduced BCG DT.
Strengths and Limitations
A major methodological strength of this study was the deployment of a customized daily ePROM system, which achieved an exceptionally high 95% response rate in both treatment arms. Traditional clinical monitoring typically relies on retrospective patient recollection during weekly clinic visits, a method prone to recall bias that frequently leads to the systematic underreporting of transient symptoms. Utilizing a daily tracking system combined with a ‘worst‐day’ data aggregation principle allowed this study to accurately capture daily symptom transitions and peak toxicity trajectories immediately following each instillation.
Several limitations must be considered when interpreting these results. First, enrolment was terminated prematurely at 242 patients instead of the targeted 314 because of slow recruitment. Therefore, the study is underpowered, preventing any definitive oncological conclusions regarding secondary endpoints. Second, the customized ePROM questionnaire utilized for real‐time tracking has not undergone formal psychometric validation. This lack of testing for reproducibility and measurement bias is a notable limitation. Although established, validated quality‐of‐life tools for NMIBC exist, such as the European Organisation for Research and Treatment of Cancer (EORTC) QLQ‐NMIBC24, these are designed for comprehensive, periodic evaluation. Utilizing a 24‐item questionnaire for daily tracking of acute, transient symptoms would likely have induced substantial questionnaire fatigue, severely compromising our high response rate. Third, our statistical approach evaluated numerous symptoms across multiple time points. Consequently, we must acknowledge the risk of type I errors, and it is possible that some statistically significant findings occurred by chance because of the multiple testing.
Furthermore, the external validity and real‐world feasibility of this intervention must be addressed. The study relied on automated daily SMS reminders and continuous database integration – infrastructure that is currently unavailable in most urological centres worldwide, limiting the immediate real‐world applicability of daily ePROM tracking.
Finally, the study protocol did not include a renewed baseline assessment immediately before entering the maintenance phase. Consequently, we cannot definitively determine whether the symptom spikes observed at the start of maintenance reflect cumulative BCG toxicity or newly developed, unrelated LUTS.
Perspectives
Our finding that 70% of patients experience significant LUTS before BCG initiation highlights that the bladder is already highly vulnerable before treatment begins. Administering bolus instillations into an already irritated bladder likely exacerbates this burden. Consequently, there is a critical need for alternative approaches. Emerging continuous, slow‐release delivery systems, such as TAR‐200, may be particularly advantageous for this demographic, as they spread the pharmacological burden over time and avoid acute mucosal toxicity [21]. Alternatively, incorporating supportive therapies aimed at restoring the glycosaminoglycan layer, such as intravesical hyaluronic acid, could proactively mitigate pre‐existing LUTS and improve overall BCG tolerability [22]. Furthermore, novel agents have reduced instillation frequencies (nadofaragene) [23]. Future studies should evaluate these agents and supportive strategies using real‐time symptom tracking.
Conclusion
Daily ePROM monitoring reveals that patients with NMIBC have a high baseline symptom burden before BCG therapy. Symptom‐guided DT reduction significantly reduced local urgency and systemic toxicity, thereby improving treatment tolerability. However, this personalized approach did not improve treatment completion or overall adherence to the recommended BCG regimen in this study.
Disclosure of Interests
Lene Munk has received research funding from Medac and lecture honoraria from Institut Biochimique SA. Charlotte Graugaard‐Jensen has received institutional support, grants, and travel support from Medac. Juan Luis Vásquez has received consulting fees from Photocure and lecture fees from Olympus and Medac; has a planned, issued, or pending patent (An Electrode Assembly for Improved Electric Field Distribution); and has participation on advisory boards for Johnson & Johnson, Medac, and MSD. Tomas Thiel has received lecture honoraria from Boston Scientific; travel support from Storz Medical; and institutional payment for advisory board participation from Medac. Jørgen Bjerggaard Jensen has received research grants from Medac; grants or contracts from the Danish Cancer Society, Medac, Photocure ASA, Roche, Ferring, Olympus, Intuitive Surgery, Astellas, Cepheid, Nucleix, Urotech, Pfizer, AstraZeneca, MeqNordic, Laborie, OneMed, AMBU, and Cystotech; consulting fees from Cystotech; lecture fees from Medac, Olympus, Photocure ASA, Conmed, and Urotech; and travel support from Medac and J&J and has participated in advisory boards for Ferring, Genentech, Roche, Cepheid, Urotech, Olympus, AMBU, Johnson & Johnson, and Cystotech. Vanaja Kumarasegaram has received lecture honoraria from Olympus. Maria Skydt Lindgren has received lecture honoraria from Medac. Rikke Vilsbøll Milling, Josephine Maria Hyldgaard, Peter Blak Hjort, Gitte Wrist Lam, Knud Fabrin, Simone Buchardt Brandt, Lasse Bro, Viveka Ströck, and Sigurður Guðjónsson have no conflicts of interest.
Funding
This study received funding from Medac.
Supporting information
Data S1 Dwell time Protocol.
Data S2 Supplementary material.
Acknowledgements
The authors express their sincere gratitude to the patients who participated in this study and diligently completed the ePROM questionnaires. We also highly appreciate the dedication and support of the clinical and nursing staff at the participating urological departments for their invaluable assistance with patient recruitment and study coordination.
Contributor Information
Lene Munk, Email: lenemunk@clin.au.dk.
Charlotte Graugaard‐Jensen, Email: graugaard@clin.au.dk.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1 Dwell time Protocol.
Data S2 Supplementary material.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.