Patient-Reported Outcome Instruments in Non-Muscle-Invasive Bladder Cancer (NMIBC): A Systematic Review

Abstract

Introduction

Non-muscle-invasive bladder cancer (NMIBC) is a chronic and recurrent condition requiring repeated intravesical treatments and lifelong surveillance, imposing a substantial burden on patients. Patient-reported outcomes (PROs) are increasingly required by regulatory bodies and HTA bodies to capture treatment impact from the patient perspective, yet no consensus on the optimal PRO instruments for use in NMIBC trials exists. This systematic review evaluated PRO instruments used in NMIBC and appraised their psychometric evidence using a structured evidence-maturity framework informed by the consensus-based standards for the selection of health measurement instruments (COSMIN) methodology.

Methods

Six electronic databases (MEDLINE, CENTRAL, Embase, Scopus, Web of Science, and APA PsycINFO) were searched from January 2000 to 31 December 2024. Studies reporting the development, validation, or application of PRO instruments in adult NMIBC populations were eligible. Eligible instruments were required to be multi-item measures with psychometric validation, evidence of interpretability, or documented use in clinical trials. No language restrictions were applied. Conference abstracts and grey literature without peer-reviewed full texts were excluded. Data were extracted using Covidence, synthesized by instrument, and mapped against an NMIBC conceptual model. Evidence maturity was classified as tier 1 (well-established evidence base), tier 2 (moderate evidence base or context-specific validation), or tier 3 (preliminary evidence or under active development), on the basis of prespecified criteria. The COSMIN risk of bias checklist was used to appraise the methodological quality of included measurement property studies. Single-item measures were excluded from the main synthesis but are discussed in the context of future use.

Results

A total of 39 studies covering eight PRO instruments met the inclusion criteria. The European organization for research and treatment of cancer quality of life questionnaire—non-muscle-invasive bladder cancer 24-item module (EORTC QLQ-NMIBC24) and bladder cancer index (BCI) demonstrated strong validity, reliability, and responsiveness in NMIBC, covering urinary, sexual, and recurrence-related domains, and were classified as tier 1 (well-established evidence base). The European organisation for the research and treatment of cancer quality of life questionnaire core 30 (EORTC QLQ-C30), functional assessment of cancer therapy—general (FACT-G), and FACT-Bladder were classified as tier 2, having been validated across broader cancer populations but with limited NMIBC-specific evidence. The NMIBC-symptom index (SI), PRO-common terminology criteria for adverse events (CTCAE), and M.D. Anderson symptom inventory (MDASI) were classified as tier 3, as conceptually relevant instruments with promising early validation but insufficient NMIBC-specific psychometric evidence for regulatory-grade use. A new structured psychometric comparison facilitates direct cross-instrument comparison of internal consistency, test–retest reliability, construct validity, responsiveness, and minimally important difference estimates. Conceptual mapping revealed persistent gaps in the coverage of recurrence anxiety, cumulative treatment burden, and long-term survivorship domains. Single-item burden measures (FACT-GP5 and EORTC item library Q168) may serve as pragmatic complements to multi-item instruments in regulatory submissions.

Conclusion

On the basis of the available evidence, the EORTC QLQ-NMIBC24 and BCI currently provide the strongest psychometric foundation for use as primary PRO instruments in NMIBC clinical trials, though this recommendation should be interpreted in light of the methodological limitations noted above. Core measures (QLQ-C30 and FACT-G) remain valuable when used in combination with disease-specific modules. Persistent gaps in the measurement of recurrence anxiety and treatment burden highlight the need for complementary instruments and targeted single items to achieve fully regulatory-aligned PRO assessment in future NMIBC trials.

Trial Registration

This systematic review was registered in International Prospective Register of Systematic Reviews (PROSPERO) [CRD420251076486].

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s40487-026-00463-6.

Key Summary Points

Non-muscle-invasive bladder cancer requires lifelong surveillance and repeated intravesical treatments, placing a significant burden on patients that standard clinical end points often fail to capture, making patient-reported outcomes (PROs) increasingly important for regulatory approval, health technology assessment (HTA), and clinical trial design. Despite growing regulatory requirements from regulatory bodies (US Food and Drug Administration (FDA), European Medicines Agency (EMA)) and HTA agencies for robust PRO evidence in oncology, no consensus existed on which PRO instruments are most appropriate for NMIBC. This systematic review aims to contribute to addressing this evidence gap through a structured synthesis and appraisal of available instruments. Across 39 studies and eight PRO instruments, the EORTC QLQ-NMIBC24 and bladder cancer index emerged as the strongest, most validated tools for NMIBC trials (tier 1), offering comprehensive coverage of urinary, sexual, and recurrence-related domains with robust psychometric evidence. Widely used cancer measures, including the EORTC QLQ-C30, FACT-G, and FACT-Bladder, remain valuable as core instruments when used in combination with disease-specific modules, though their sensitivity to NMIBC-specific concerns is more limited (tier 2). Important gaps persist in the measurement of recurrence anxiety, fatigue, and cumulative treatment burden, indicating a need for complementary instruments and targeted single-item measures to achieve fully regulatory- and HTA-aligned PRO measurement in future NMIBC trials.

Introduction

Bladder cancer is the tenth most frequently diagnosed cancer worldwide and ranks as the 13th leading cause of cancer-related deaths, with over 570,000 new cases and approximately 210,000 deaths reported each year [1, 2]. Around 75% of patients with newly identified bladder tumors are initially diagnosed with non-muscle-invasive bladder cancer (NMIBC) [3, 4]. NMIBC encompasses tumors confined to the bladder mucosa (stage Ta, carcinoma in situ) or the lamina propria (stage T1). Although its prognosis is more favorable than muscle-invasive bladder cancer, NMIBC is characterized by high recurrence rates (50–70%) and a substantial risk of progression. Consequently, patients require intensive management, including repeated cystoscopic surveillance, adjuvant intravesical therapy, and long-term follow-up [3, 4]. This chronic disease trajectory imposes substantial burdens on patients, including urinary symptoms, treatment-related adverse effects, sexual dysfunction, anxiety associated with recurrence, and an overall cumulative burden of ongoing medical care [5].

Patient-reported outcomes (PROs) are critical for directly capturing patients’ experiences, offering valuable insights into these burdens. Regulatory bodies such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) increasingly mandate robust PRO data, such as quality of life (QOL) assessments, to support labeling claims and establish trial end points [6, 7]. In the European Union, health technology assessment agencies are also playing an increasingly important role in establishing robust standards for PRO evidence under the joint clinical assessment framework [8]. Most recently, the FDA has issued specific guidance on core PROs recommended for use in cancer clinical trials [9], further underscoring the need for validated, fit-for-purpose instruments. However, despite the importance of QOL in NMIBC, no consensus exists regarding the optimal PRO instruments for clinical trials, nor is there clear evidence on how existing tools meet regulatory expectations.

Several NMIBC-specific PRO instruments have been developed, including the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Non-Muscle-Invasive Bladder Cancer 24-Item Module (EORTC QLQ-NMIBC24) [10], the bladder cancer index (BCI) [11], and the Functional Assessment of Cancer Therapy-Bladder (FACT-Bl) [12]. These instruments target domains relevant to NMIBC and are generally used in conjunction with broader cancer-specific tools such as the EORTC QLQ-C30 [13] and FACT-G [14], which cover general cancer-related QOL concerns, but may overlook NMIBC-specific issues. Additional instruments, including the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) [15] and M.D. Anderson symptom inventory (MDASI) [16] are increasingly recognized as standard tools for assessing symptomatic toxicity and treatment burden in oncology. Although not initially developed for NMIBC, they may complement disease-specific instruments in trials of this population. Recent research has underscored the need to address domains such as recurrence anxiety and treatment burden more precisely [17, 18].

Moreover, simpler single-item measures, such as the Functional Assessment of Cancer Therapy – General Population item GP5 [FACT-GP5] (“I am bothered by side effects of treatment”) [19, 20] and the EORTC burden item Q168 [21], have gained regulatory interest as adjunctive tools for contextualizing PRO-CTCAE findings. Although these items are explicitly noted as examples in the FDA’s “Core PROs in Cancer Clinical Trials” guidance, and some recent trials show psychometric support for GP5 [9, 22]. There is as yet little published validation of GP5 or Q168 specifically in NMIBC-specific populations.

Previous work by Rutherford et al. (2017) proposed a conceptual model of the patient with NIMBC’s experience, identifying key domains such as urinary symptoms, treatment burden, emotional distress, and recurrence anxiety. This model clarified important areas to measure; however, it did not evaluate which instruments best capture these domains, nor their psychometric properties or regulatory readiness. This present systematic review aims to contribute to addressing this evidence gap by synthesizing evidence from published studies and mapping instruments against both conceptual and regulatory frameworks, offering practical guidance for regulators, trialists, and clinicians. Specifically, the review aims to: (1) identify PRO instruments employed in NMIBC trials and studies; (2) evaluate their psychometric properties, interpretability, and alignment with regulatory criteria; (3) map domain coverage against a conceptual model of NMIBC-related health concerns [18]; and (4) offer practical recommendations for selecting PRO tools tailored for regulatory driven NMIBC clinical trial design.

Protocol and Registration

This systematic review was conducted in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines [23]. The protocol was prospectively registered in PROSPERO (registration number: CRD420251076486). To appraise the methodological quality of included studies reporting on measurement properties, we applied the consensus-based standards for the selection of health measurement instruments (COSMIN) risk of bias checklist for systematic reviews of patient-reported outcome measures [24, 25]. This checklist was used to evaluate the quality of evidence for reliability, validity, responsiveness, and interpretability for each included instrument. It should be noted, however, that the evidence base for several instruments was limited, precluding a comprehensive COSMIN rating across all measurement property domains; findings should therefore be interpreted accordingly.

Eligibility Criteria

We included peer-reviewed studies published from 2000 onward that reported on the development, validation, or application of PRO instruments in adult patients (> 18 years) with NMIBC. Eligible instruments were required to be named, multi-item measures (bladder cancer–specific or generic) with evidence of psychometric validation, interpretability, or application in NMIBC clinical trials or observational studies.

We excluded single-item measures, ad hoc checklists, instruments applied only in muscle-invasive bladder cancer or radical cystectomy populations without NMIBC subgroup data, studies with fewer than ten patients, and conference abstracts or grey literature without peer-reviewed full texts. Additionally, instruments developed primarily for health utility assessment (e.g., quality-adjusted life years or cost-effectiveness analyses) were excluded.

Search Strategy and Selection Process

Six electronic searches were conducted in MEDLINE, CENTRAL, Embase, Scopus, Web of Science, and APA PsycINFO from January 2000 to December 2024. The search strategy combined controlled vocabulary and free-text terms for NMIBC, bladder cancer, quality of life, patient-reported outcomes, and named instruments (e.g., “EORTC QLQ-NMIBC24,” “bladder cancer index,” “FACT-Bladder,” “PRO-CTCAE”). The full Boolean search strings for all databases are provided in Supplementary File 1. Two reviewers (S.S., A.B.) independently screened titles and abstracts in Covidence, followed by full-text assessment against eligibility criteria. Discrepancies were resolved through discussion. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. Formal ethical approval was, therefore, not required.

Data Extraction and Synthesis

For each included study, we extracted: study design, patient population, instrument(s) used, purpose (development, validation, trial application), psychometric findings (reliability, validity, responsiveness), interpretability (e.g., meaningful change thresholds), and regulatory citations (e.g., FDA/EMA use). Extraction was managed in Covidence and cross-checked by both reviewers.

Instruments were then synthesized by tool rather than individual study, collapsing 39 included studies into grouped evidence summaries for each PRO measure. For each instrument, we summarized the number of studies, psychometric evidence, domain coverage, and regulatory readiness.

Conceptual Mapping

To assess coverage of NMIBC-relevant patient experience, instruments were mapped against the conceptual framework described by Rutherford et al. [18], which identifies key domains including urinary symptoms, treatment burden, sexual function, recurrence anxiety, fatigue, and emotional distress.

Evidence Maturity Framework

To facilitate synthesis, we developed a three-tier evidence maturity framework to classify each instrument by the extent of its validation in NMIBC populations and its potential suitability for regulatory use in FDA and EMA submissions. Instruments were classified on the basis of three dimensions: the degree of NMIBC-specific psychometric validation, the overall strength of the measurement property evidence, and documented application NMIBC in clinical trials (Table 1).

Table 1.

Evidence maturity framework for PRO instruments in NMIBC

Tier	Definition	Classification criteria
Tier 1 (well-established evidence base)	Validated in NMIBC with strong psychometric evidence and applied in clinical trials	At least two NMIBC-specific validation studies; demonstrated content validity, reliability (Cronbach’s α > 0.70), responsiveness, and interpretability; international use in NMIBC trials
Tier 2 (moderate evidence base/context-specific validation)	Validated in broader cancer populations with partial NMIBC evidence	Established psychometric validity in cancer populations; some NMIBC application; insufficient specific NMIBC-specific data to meet tier 1 criteria
Tier 3 (preliminary evidence/under active development)	Conceptually relevant but with limited NMIBC-specific validation	Early-stage development or feasibility studies only; limited psychometric data in NMBIC; not widely used in NMIBC trials
Single-item measures (regulatory relevance)	Not eligible for main tier synthesis; noted in discussion Not eligible for main tier synthesis; noted in discussion	Useful as complementary or anchor endpoints; growing endorsement from FDA and EMA

This framework is intended to reflect the current state of the evidence for each instrument and should not be interpreted as implying the superiority of one instrument family over another. Classifications are not fixed and may evolve as further validation studies are published or as regulatory guidance is updated.

Tier assignment followed prespecified criteria. Tier 1 (well-established evidence base) required at least two published NMIBC-specific validation studies demonstrating acceptable internal consistency (Cronbach’s α > 0.70), construct validity, and responsiveness to change, alongside documented use in NMIBC clinical trials. Tier 2 (moderate evidence base/context-specific validation) was assigned to instruments with established psychometric validity in broader cancer populations and at least partial application in NMIBC, but with insufficient NMIBC-specific validation data to meet tier 1 criteria. Tier 3 (preliminary evidence/under active development) was assigned to instruments with only early-stage or feasibility-level evidence in NMIBC, regardless of their validation status in other oncology settings. Single-item measures were not eligible for tier classification under the main synthesis but are discussed separately given their growing interest from regulatory agencies.

This framework has not been independently validated or externally benchmarked. The criteria and resulting classifications should; therefore; be interpreted as structured expert synthesis rather than definitive or prescriptive ratings, and we invite scrutiny and refinement from the wider PRO research community.

Ethical Approval

This systematic review was conducted and reported in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The review protocol was prospectively registered in the international prospective register of systematic reviews (PROSPERO; registration number CRD420251076486) prior to data extraction. As this study involved synthesizing previously published data and did not include primary data collection from human participants, formal ethical approval was not required. All included studies were peer-reviewed publications, and no individual patient data was accessed or analyzed. Data extraction and quality assessment were conducted independently by multiple reviewers to minimize bias and ensure methodological transparency. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Results

Identification and Selection of Studies

The PRISMA flow diagram of the literature search results is shown in Fig. 1. Our search yielded 1055 articles after removing duplicates. A manual search of relevant review articles and reference lists identified an additional 37 articles. The remaining articles were screened on the basis of titles and abstracts, and 456 were removed for irrelevance to our objectives. This resulted in 211 full-text articles reviewed for eligibility. Of those, 172 articles were excluded for the reasons stated in Fig. 1. Finally, a total of 39 studies were included in this systematic review for qualitative synthesis.

Fig. 1.

PRISMA flow diagram of study selection. NMIBC non-muscle invasive bladder cancer

Study Characteristics

Evidence was organized by instrument rather than by study, yielding eight major instruments for review: the European organization for research and treatment of cancer quality of life questionnaire–non-muscle invasive bladder cancer 24-item instrument (EORTC QLQ-NMIBC24), the bladder cancer index (BCI), the functional assessment of cancer therapy–bladder cancer (FACT-Bl), the functional assessment of cancer therapy–general (FACT-G), the European organization for research and treatment of cancer quality of life questionnaire–core 30 (EORTC QLQ-C30), the non-muscle invasive bladder cancer symptom index (NMIBC-SI), the patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE), and the M.D. Anderson symptom inventory (MDASI). Single-item measures with regulatory relevance were also noted, including the EORTC item library item 168 (IL168) and the FACT-General item GP5, which were considered separately in “Future Directions.” Table 2 summarizes the evidence base, domain coverage, psychometric performance, and regulatory readiness tier for each instrument. To facilitate direct cross-instrument comparison of key measurement properties, Table 3 presents a structured summary of internal consistency, test–retest reliability, construct validity, responsiveness, and minimally important difference (MID) or interpretability thresholds for each instrument, where data were available.

Table 2.

Evidence summary of PRO instruments used in NMIBC trials (organized by instrument)

Instrument	Number of supporting studiesa	Populations	Psychometric properties	NMIBC-relevant domain coverage	Regulatory readiness tier	Key references
EORTC QLQ-NMIBC24 (24 items; bladder cancer-specific module to be used with QLQ-C30)	Approximately 12 (development, validation, cross-cultural adaptations, and applications in NMIBC trials)	NMIBC only	Phase IV international validation across European and non-European cohorts (n approximately 1100); acceptable internal consistency (Cronbach’s α > 0.70 for urinary symptoms, future worries, sexual function, and sexual problems in men scales; α 0.57–0.65 for malaise and 0.49–0.62 for bloating/flatulence scales, both falling below the 0.70 threshold); strong construct validity against clinical variables and QLQ-C30; responsive to change during Bacillus Calmette–Guérin (BCG) and intravesical chemotherapy; cross-cultural translations available; MID not yet established	Urinary symptoms (frequency, urgency, hematuria, nocturia), intravesical treatment burden, sexual function, future-health worry and recurrence concerns (limited fear of recurrence (FoR) coverage); fatigue and global functioning captured via QLQ-C30	Tier 1 (well-established evidence base): disease-specific, validated in NMIBC, psychometrically robust, aligned with FDA, EMA, and HTA requirements when used with QLQ-C30 [7, 9]	[10, 13, 26, 27, 40–47]
Bladder cancer index (BCI) (36 items; urinary, bowel, and sexual domains with function and bother subscales)	Approximately 8 (validation and application in NMIBC and MIBC cohorts)	NMIBC and MIBC	Good reliability (Cronbach’s α 0.77–0.94 across domains and subdomains; test–retest correlations 0.73–0.95); confirmed construct validity discriminating by treatment group and disease stage; responsiveness not formally demonstrated in original validation study (cross-sectional design); MID established: 6–9 points (urinary domain), 5–8 points (bowel domain), 7–11 points (sexual domain)	Urinary, bowel, and sexual domains; limited coverage of treatment burden; no items addressing recurrence anxiety or future-health worry (FoR coverage: none)	Tier 1 (well-established evidence base): broad validation across bladder cancer populations, psychometrically robust, suitable for regulatory and HTA submissions when used alongside a cancer core questionnaire [7, 9]	[11, 29–34, 48]
FACT-Bladder (FACT-Bl) (39 items; extends FACT-G with 13-item bladder cancer subscale)	Approximately 5 (validation and application in bladder cancer cohorts)	Bladder cancer (primarily cystectomy and MIBC cohorts; limited NMIBC-specific use)	Acceptable reliability (Cronbach’s α 0.63–0.93 across subscales; ICC 0.58–0.80); construct validity confirmed against tumor burden and QLQ-C30 global health status; responsiveness demonstrated over 12 weeks in a urothelial cancer clinical trial; clinically meaningful thresholds estimated (FACT-Bl total 6–12 points; TOI 5–9 points); approximately one-third of bladder subscale items are cystectomy or stoma-specific, limiting precision in NMIBC populations	Urinary and sexual domains (more cystectomy-focused); limited coverage of treatment burden and recurrence anxiety; FoR coverage limited to general health worry items (GE3, GE5, GE6 from FACT-G)	Tier 2 (moderate evidence base/context-specific validation): validated in bladder cancer but with limited NMIBC-specific evidence; constrained regulatory and HTA fit when used in isolation	[12, 30, 49–51]
EORTC QLQ-C30 (30 items; generic cancer core questionnaire)	Approximately 13 (validation, application, and updated content validity)	Generic cancer (with NMIBC subgroups)	Extensively established reliability and validity across cancer types; content validity confirmed in 113 patients across Europe and the USA, with the 13 most frequently reported cancer-related concepts already covered by the QLQ-C30 conceptual framework[28] MID not reported in included NMIBC studies	Fatigue, pain, nausea, insomnia, emotional, social, cognitive, role, and physical functioning; global health status; not NMIBC-specific	Tier 2 (moderate evidence base/context-specific validation): required core instrument when using QLQ-NMIBC24; essential for regulatory and HTA submissions but not sufficient as a standalone NMIBC measure	[10, 13, 26, 28, 40, 41, 45, 46, 52–56]
FACT-G (28 items; generic oncology core questionnaire)	Approximately 3 (validation and applications in bladder cancer including NMIBC subsets)	Generic cancer (including bladder cancer)	Reliable (Cronbach’s α 0.65–0.89 across subscales; total score α 0.89) and valid; test–retest correlations 0.82–0.92; sensitivity to change demonstrated; GP5 single item has regulatory and HTA endorsement for treatment burden assessment	Global domains (physical, functional, social, and emotional well-being); treatment burden via GP5 only; FoR coverage limited to general health worry items (GE3, GE5, GE6) rather than recurrence-specific concerns	Tier 2 (moderate evidence base/context-specific validation): bladder-specific module required for comprehensive NMIBC assessment in regulatory and HTA contexts	[14, 57, 58]
NMIBC symptom index (NMIBC-SI) (23-item core index; optional 6-item cystoscopy index and 10-item intravesical index)	Approximately 1 (early development and validation)	NMIBC	Clinimetric rather than psychometric approach used; Cronbach’s α not applicable; strong test–retest reliability (ICC 0.89–0.91 across indexes); construct validity confirmed via confirmatory composite analysis and known-groups validity (treatment versus no-treatment groups, p = 0.004); responsiveness, interpretability thresholds, and longitudinal performance in diverse settings remain to be established	Urinary symptoms, treatment burden, recurrence anxiety; FoR, explicit recurrence-related	Tier 3 (preliminary evidence/under active development): strong conceptual foundation and promising early validation; further published evidence required before regulatory or HTA-grade use can be recommended	Early development reports [36]
PRO-CTCAE (selected items) (item library of 124 items representing 78 symptomatic adverse events)	Approximately 2 (validation in oncology trials; application in bladder cancer)	General oncology populations (not NMIBC-specific)	Valid and reliable for adverse event capture across cancer types (119 of 124 items meeting at least one validity criterion; ICC 0.53–0.96 across 49 prespecified items, median ICC 0.76); not validated specifically in NMIBC	Symptomatic toxicities including urinary frequency, fatigue, and pain; FoR coverage: none	Tier 3 (preliminary evidence/under active development): useful for toxicity capture and endorsed by FDA and National Cancer Institute (NCI); complementary to disease-specific instruments but not sufficient as a standalone NMIBC measure for regulatory or HTA purposes	[39, 59]
MDASI (13 symptom severity items and 6 interference items) [16]	Approximately 3 (application in cancer, including disease- and treatment-specific modules such as the MDASI-PeriOp-BLC)	Generic cancer core, with disease- and treatment-specific modules (e.g., bladder cancer perioperative version)	Reliable and valid in cancer populations; Cronbach’s α 0.82–0.94 across symptom and interference scales; widely translated; NMIBC-specific application very limited	Fatigue, pain, distress, and symptom interference with daily activities; NMIBC-specific domains (urinary symptoms, recurrence anxiety, treatment burden) not directly captured; FoR coverage: none	Tier 3 (preliminary evidence/under active development); valuable for generic symptom burden assessment but not sufficient as a standalone NMIBC measure for regulatory or HTA purposes	[60–62]

^aNumber of studies based on the 39 NMIBC articles included in Covidence and supplementary validation literatureBCI bladder cancer index, FACT-Bl functional assessment of cancer therapy-bladder, FACT-G Functional assessment of cancer therapy-general, ICC intraclass correlation coefficient, NMIBC non-muscle-invasive bladder cancer, PRO-CTCAE patient-reported outcomes version of the common terminology criteria for adverse events, QLQ-C30 quality of life questionnaire core 30, QLQ-NMIBC24 quality of life questionnaire non-muscle-invasive bladder cancer 24-item module, TOI trial outcome index

Table 3.

Summary of psychometric properties of PRO instruments included in the review

Instrument	Internal consistency (Cronbach’s α)	Test–retest reliability	Construct validity	Responsiveness	MID/Interpretability
EORTC QLQ-NMIBC24 [10]	α > 0.70 for urinary symptoms (α 0.85–0.89 across time points), future worries (α 0.88–0.91), sexual function, and sexual problems in men; α 0.57–0.65 for malaise and bloating/flatulence scales, which fell below the 0.70 threshold [10]	Not reported in Blazeby et al. 2014; the authors noted that international and test–retest data were still required at time of publication [10]	Confirmed: scales discriminated between patients with high and low QLQ-C30 physical function scores; men reported significantly better sexual function than women (p < 0.001) [10]	Demonstrated: malaise, future worries, bloating and flatulence, and urinary symptoms all changed significantly during intravesical treatment courses in high-risk patients [10]	Not yet established; MID data remain limited [28]
Bladder cancer index (BCI) [11, 48]	α 0.77–0.94 across urinary, bowel, and sexual domains and subdomains (urinary function 0.85, urinary bother 0.83, bowel function 0.77, bowel bother 0.77, sexual function 0.94, sexual bother 0.81) [10]	Test–retest correlations 0.73–0.95 across all domains and subdomains (urinary function 0.90, urinary bother 0.92, bowel function 0.82, bowel bother 0.87, sexual function 0.95, sexual bother 0.73) based on assessments 2–4 weeks apart [11]	Confirmed: BCI scores discriminated between clinically distinct treatment groups and by disease stage; moderate correlation with FACT-G and FACT-Bl supported criterion validity [11]	Not formally demonstrated in Gilbert et al. 2010, which was cross-sectional in design; responsiveness is referenced in the Discussion but not tested [11]	Aggregated MIDs using distribution- and anchor-based methods: 6–9 points for the urinary domain, 5–8 points for the bowel domain, and 7–11 points for the sexual domain [48]
FACT-Bladder (FACT-Bl) [12]	α 0.63–0.93 across subscales: PWB 0.82 (acceptable), FWB acceptable, EWB acceptable, SWB acceptable; bladder cancer subscale (BlCS) α 0.63, falling below the 0.70 threshold owing to high inter-item variability across symptom items [12]	ICC range 0.58–0.80 across subscales and summary scores; mean ICC 0.72; EWB (ICC 0.58) and SWB (ICC 0.66) fell below the 0.70 acceptability threshold; FACT-Bl total score ICC 0.80 [12]	Confirmed: known-group validity demonstrated against baseline tumor burden (difference in FACT-Bl total 11.72 points between low and high burden groups, p = 0.001) and QLQ-C30 global health status/QOL (difference 30.51 points, p < 0.0001) [12]	Demonstrated: FACT-Bl subscale and total scores were responsive to changes in urothelial cancer symptom severity over a 12-week period, with improvement in responders and deterioration in nonresponders [12]	Clinically meaningful thresholds estimated using anchor- and distribution-based methods: FACT-Bl total score 6–12 points; FACT-Bl trial outcome index 5–9 points; individual fatigue and pain items approximately 1–2 points [12]
EORTC QLQ-C30 [13, 28]	Extensively established across cancer types and populations; specific subscale α-values not reported in the included studies contributing to this review [13]	Not formally reported in the included NMIBC or bladder cancer studies contributing to this review	Confirmed: the 13 most frequently reported cancer-related concepts elicited from 113 patients across Europe and the USA were already covered by the QLQ-C30 conceptual framework, supporting updated content validity [28]	Well established across cancer types and treatment settings [13]	Not reported in included studies; scale-specific thresholds vary by population and domain [13]
FACT-G [14]	Subscale α range 0.65–0.89 (physical well-being 0.82, functional well-being 0.80, social well-being 0.69, emotional well-being 0.74, relationship with doctor 0.65); total score α = 0.89 [14]	Test–retest correlations at 3–7 days: physical well-being 0.88, functional well-being 0.84, social well-being 0.82, emotional well-being 0.82, relationship with doctor 0.83, total score 0.92 [14]	Confirmed: FACT-G total score discriminated by stage of illness (p < 0.01), ECOG performance status (p < 0.0001), and patient location; convergent validity supported by high correlation with FLIC (r = 0.79) [14]	Sensitivity to change demonstrated: FACT-G distinguished between patients with declining, stable, or improving performance status over 2 months (overall multivariate F p = 0.002) [14]	Not established for NMIBC
NMIBC-SI [36]	Not applicable: the NMIBC-SI uses a clinimetric rather than psychometric approach (composite/formative indicators), for which Cronbach’s α is explicitly inappropriate; no α values were calculated or reported [36]	ICC range 0.89–0.91 across the three indexes (core: ICC 0.89, 95% confidence interval (CI) 0.84–0.92; cystoscopy: ICC 0.89, 95% CI 0.87–0.91; intravesical: ICC 0.91, 95% CI 0.89–0.93) [36]	Confirmed via confirmatory composite analysis (CCA): all three composite models tested exhibited good fit; known-groups validity demonstrated by significant discrimination between no-treatment and any-treatment groups for the NMIBC-Core index (p = 0.004) [36]	Preliminary evidence: the instrument discriminated between no-treatment and chemo/BCG treatment groups, and between BCG and chemotherapy groups, providing evidence of clinical sensitivity [36]	Not yet established; further validation in patients with greater symptom burden is warranted [36]
PRO-CTCAE (selected items) [39]	Not applicable: PRO-CTCAE is an item library of 124 individually validated items representing 78 symptomatic adverse events; it is not a fixed scale and α is not applicable at item level [39]	ICC range 0.53–0.96 across 49 prespecified items assessed in a general oncology population (median ICC 0.76); 36 of 49 items achieved ICC greater than or equal to 0.70; not assessed specifically in NMIBC populations [58]	119 of 124 items met at least one construct validity criterion; all 124 items were associated in the expected direction with at least one QLQ-C30 functioning or global scale [39]	Demonstrated: statistically significant correlations between PRO-CTCAE item changes and corresponding QLQ-C30 scale changes for all 27 prespecified items (median r = 0.43, range 0.10–0.56) [39]	Not established for NMIBC
MDASI [16]	Cronbach’s α 0.82–0.94 across symptom and interference scales [16]	Not reported in the included studies contributing to this review	Confirmed across multiple cancer types and treatment settings [16]	Demonstrated in cancer treatment trials [16]	Not established for NMIBC

All reported values reflect data available in the 39 included studies and in the cited supplementary validation literature. Where data were not available in included studies, this is stated explicitly

BCI bladder cancer index, EWB emotional well-being, FACT-Bl functional assessment of cancer therapy-bladder, FACT-G Functional assessment of cancer therapy-general, FWB functional well-being, ICC intraclass correlation coefficient, MID minimally important difference, NMIBC non-muscle-invasive bladder cancer, NMIBC-SI non-muscle-invasive bladder cancer symptom index, PRO-CTCAE patient-reported outcomes version of the common terminology criteria for adverse events, PWB physical well-being, QLQ-C30 quality of life questionnaire core 30, QLQ-NMIBC24 quality of life questionnaire non-muscle-invasive bladder cancer 24-item module, SWB social and family well-being, TOI trial outcome index

EORTC QLQ-NMIBC24

The EORTC QLQ-NMIBC24 is the only bladder cancer-specific QOL module developed specifically for NMIBC, to date. It is designed to be administered alongside the EORTC QLQ-C30, providing disease-specific coverage that complements the core cancer questionnaire. The instrument captures urinary symptoms (frequency, urgency, hematuria), intravesical treatment burden, sexual function, and body image. Items 41–44 focus on future health, test results, and treatment concerns; although relevant, these reflect general future-health worry rather than recurrence-specific anxiety, so coverage of fear of recurrence (FoR) is rated as limited. The phase IV international validation study by Blazeby et al., 2014, confirmed good psychometric performance across diverse European and non-European cohorts, with acceptable internal consistency reliability (Cronbach’s α > 0·70 for most multi-item scales, noting that the malaise and bloating/flatulence scales fell below this threshold), strong construct validity against clinical variables, and responsiveness to change during intravesical treatment courses [10]. Subsequent work has mapped the instrument against conceptual models of the patient with NIMBC’s experience, affirming content coverage of the most salient domains [18]. Cultural and linguistic adaptations have been performed across multiple regions [26, 27], supporting its applicability in international trials. However, data on interpretability, including minimally important differences (MIDs) and responder thresholds, remain limited [28]. Because the QLQ-NMIBC24 was designed to be administered with the QLQ-C30, the core instrument intentionally captures domains such as fatigue, global well-being, and emotional functioning, rather than duplicating them in the module. This is consistent with EORTC’s modular development policy.

The QLQ-NMIBC24 is classified as a tier 1 (well-established evidence base) instrument, generally meeting FDA and EMA expectations for disease-specific PRO assessment when used in combination with the QLQ-C30.

Bladder Cancer Index (BCI)

The bladder cancer index is a bladder cancer-specific multidimensional measure that assesses urinary, bowel, and sexual domains, each with both function and bother subscales. Although originally developed and validated in populations that included patients with muscle-invasive bladder cancer undergoing radical cystectomy, the BCI has been applied in NMIBC cohorts and demonstrates robust psychometric performance, with evidence for reliability, construct validity, and responsiveness across bladder cancer treatment settings [11].

It provides comprehensive coverage of urinary, bowel, and sexual domains but does not include items addressing recurrence anxiety or future health worry; therefore, coverage of FoR is rated as none. Coverage of intravesical treatment burden is also limited. Linguistic validations and cross-cultural adaptations of the BCI are available in French [29], Hungarian [30], Japanese [31], Urdu [32], Spanish [33], and Arabic [34], supporting its applicability in international multi-site trials. Given its broad validation base and demonstrated application in NMIBC, the BCI is classified as a tier 1 (well-established evidence base) instrument.

Functional Assessment of Cancer Therapy–Bladder (FACT-Bl)

The FACT-Bl extends the FACT-G by adding a 13-item bladder cancer subscale (BlCS). This subscale includes urinary symptom items (e.g., frequency, pain/burning, hematuria, leakage) and sexual function items (e.g., sexual activity, interest, satisfaction), both of which are relevant to NMIBC populations. These domains demonstrate acceptable internal consistency (Cronbach’s α 0.63–0.93 across subscales) and construct validity in published bladder cancer cohorts, including some that include patients with NMIBC [12]. However, approximately one-third of the subscale items are specific to radical cystectomy or urostomy stoma (e.g., embarrassment with a urostomy bag, stoma care, body image following surgery). These items reduce precision for patients with NMIBC managed with bladder-sparing approaches (e.g., transurethral resection of bladder tumor (TURBT) and intravesical therapy) because they are not applicable in this setting. Furthermore, the instrument provides no explicit coverage of FoR anxiety and only limited indirect assessment of future-health worry through the FACT-G emotional well-being items. Only three emotional well-being items (GE3, GE5, GE6, inherited from FACT-G) assess general worry about health decline or dying, and they do not explicitly address FoR. Similarly, treatment burden associated with repeated intravesical therapy and surveillance is not assessed.

Psychometric evidence for NMIBC is specifically limited. Although FACT-Bl demonstrates overall reliability (ICC 0.58–0.80) and validity in bladder cancer cohorts, and responsiveness to changes in urothelial cancer symptom severity has been demonstrated over a 12-week period in a clinical trial setting [12], longitudinal data in NMIBC-only populations remain, with only small observational studies reporting changes over time.

The FACT-Bl provides robust coverage of urinary function and some aspects of sexual function but offers limited coverage of treatment burden and recurrence anxiety, and reduced specificity owing to radical cystectomy-related items. It is therefore classified as tier 2 (moderate evidence base/context-specific validation) for NMIBC, best used alongside a core instrument (FACT-G) and/or NMIBC-specific measures.

European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (EORTC QLQ-C30) (Core)

The QLQ-C30 is EORTC’s cancer core questionnaire, widely validated across cancer types. It covers global health, physical, emotional, cognitive, and social functioning, as well as symptom scales for fatigue, pain, nausea and vomiting, and insomnia, among others. Recent content validity updates work [28] confirmed that the 13 most frequently reported cancer-related concepts elicited from patients across Europe and the USA were already covered by the QLQ-C30 conceptual framework, supporting its continued relevance in contemporary oncology populations. Although not NMIBC-specific, it is required when using the EORTC QLQ-NMIBC24.The QLQ-C30 provides essential coverage of fatigue, functional limitations, and emotional well-being, complementing bladder-specific modules. It is classified as tier 2, reflecting its role as a required core instrument rather than an NMIBC-specific measure.

Functional Assessment of Cancer Therapy–General (FACT-G) (Core)

The FACT-G is a generic oncology core measure assessing physical, social, emotional, and functional well-being. It is reliable (subscale Cronbach’s α 0.65–0.89; total score α 0.89), valid, and widely used across cancer populations [14]. In NMIBC, it has been administered primarily in combination with FACT-Bl. Although it captures global QOL domains, FACT-Bl is required obtain a robust assessment of QOL in this population as it includes bladder-specific issues. FoR coverage is limited; items GE3, GE5, and GE6 reflect general health worries, rather than recurrence anxiety. The single-item GP5 (“I am bothered by side effects of treatment”) has attracted regulatory attention and is recommended by the FDA for use in clinical trials [9, 20, 22, 35]. As a core instrument, FACT-G is classified as tier 2, with the caution that a bladder-specific module is required for comprehensive QOL assessment. GP5 is discussed further under “Future Directions.”

Non-Muscle-Invasive Bladder Cancer Symptom Index (NMIBC-SI)

The NMIBC-SI is a recently developed, symptom-focused measure specifically designed for NMIBC. It assesses urinary symptoms, treatment burden, and aspects of recurrence anxiety across three indexes: a 23-item core symptom index (NMIBC-Core), a 6-item cystoscopy index (NMIBC-Cyst), and a 10-item intravesical therapy index (NMIBC-Intra) [36] assesses urinary symptoms, treatment burden, and aspects of recurrence anxiety. Development followed a rigorous, regulatory-aligned methodology grounded in qualitative patient and clinician interviews and a clinicometric rather than psychometric approach to item selection. Test–retest reliability is strong (ICC 0.89–0.91 across indexes), and known-groups validity has been demonstrated, with the instrument discriminating between patients receiving no treatment and those receiving any treatment, and between BCG and chemotherapy groups [36]. However, as a newly published tool, psychometric evidence on responsiveness in formal trial settings, interpretability thresholds, and longitudinal performance in diverse NMIBC populations remains limited. Accordingly, it is classified as tier 3 (preliminary evidence/under active development), reflecting strong conceptual relevance and promising early validation but the need for further evidence before regulatory-grade use.

Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) (Selected Items)

PRO-CTCAE is an item library developed by the US National Cancer Institute to capture symptomatic adverse events in clinical trials [15]. Selected PRO-CTCAE items, including those assessing urinary frequency, fatigue, and pain, have been evaluated among bladder cancer patient groups [37, 38], though not yet validated specifically in NMIBC-only cohorts. The library has demonstrated good construct validity (119 of 124 items meeting at least one validity criterion) and acceptable test–retest reliability (ICC 0.53–0.96 across prespecified items) in a large general oncology population [39]. Its strength lies in providing patient-centered reporting of symptomatic toxicities. However, PRO-CTCAE is not a fixed instrument and has not undergone NMIBC-specific validation. It does not capture recurrence-related concerns; FoR coverage is, therefor,e rated as none. Given these limitations, PRO-CTCAE is classified as tier 3, useful for toxicity capture but not sufficient as a standalone NMIBC QOL instrument.

M.D. Anderson Symptom Inventory (MDASI)

The M.D. Anderson Symptom Inventory (MDASI) is a multi-symptom PRO measure designed to capture both the severity of common cancer-related symptoms (13 core symptom items, including pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, cognitive complaints) and the degree to which these symptoms interfere with daily life (6 interference items: activity, work, walking, relations, mood, enjoyment of life) [16]. The instrument has demonstrated high internal consistency (Cronbach’s α 0.82–0.94) and broad applicability across cancer types and treatments, with multiple disease- and treatment-specific modules available.

The MDASI’s strengths include brief administration time (under 5 min), high patient acceptability, availability in multiple administration formats (paper, electronic, interactive voice response), and successful cross-cultural translations, making it feasible for international trials. It is widely recognized as a robust measure of general symptom burden and functional interference in oncology.

However, application in NMIBC has been very limited, and the instrument does not include urinary symptoms, FoR, or intravesical treatment burden, which are domains central to the patient with NIMBC’s experience. Although it may complement NMIBC-specific instruments by providing a broad assessment of symptom severity and interference, its lack of bladder-specific content constrains its regulatory fit in this context. Accordingly, the MDASI is classified as tier 3 (preliminary evidence/under active development), an instrument valuable for capturing generic symptom burden but not sufficient as a standalone measure in NMIBC trials.

Future Directions: Single-Item Burden Measures

Although excluded from the main synthesis under the review protocol criteria, two single-item measures warrant mention given their growing regulatory interest: EORTC item library 168 (“I am bothered by the burden of treatment”) and FACT-GP5 (“I am bothered by side effects of treatment”) are of growing regulatory interest [9]. Both the FDA and EMA have endorsed their inclusion in trial protocols as global tolerability anchors, complementing multi-item PRO instruments. Evidence for their use in NMIBC is currently limited and largely unpublished for Q168 or indirect for GP5; however, these items merit consideration in instrument selection in discussion and future recommendations.

Domain Coverage of PRO Instruments Mapped to the NMIBC Conceptual Model

Table 4 presents the mapping of each instrument against the NMIBC conceptual model from Rutherford et al. [18]. The QLQ-NMIBC24 and bladder cancer index provide the broadest coverage of NMIBC-relevant domains, including urinary symptoms, treatment burden, sexual function, and recurrence-related concerns.

Table 4.

Domain coverage of PRO instruments mapped to the NMIBC conceptual model

Instrument	Urinary symptoms	Sexual function	Treatment burden	Recurrence anxiety/future worries	Fatigue/sleep	Emotional distress	Social functioning
EORTC QLQ-NMIBC24	Yes	Yes	Yes	Yes	No (via QLQ-C30)	Partial	Partial
Bladder cancer index (BCI)	Yes	Yes	Limited	No	No	Limited	No
FACT-Bladder (FACT-Bl)	Yes	Yes	Limited	No	No	Limited	No
EORTC QLQ-C30 (core)	No	No	No	No	Yes	Yes	Yes
FACT-G (core)	No	No	Limited (GP5 only)	No	Yes	Yes	Yes
NMIBC symptom index (NMIBC-SI)	Yes	No	Yes	Yes	No	Limited	No
PRO-CTCAE (selected items)	Yes (selected items)	No	Yes (toxicity items)	No	Yes	Partial	No
MDASI	No	No	No	No	Yes	Yes	Yes

Domain coverage depends on item selection; the table reflects the most commonly used and available items in bladder cancer trials. Yes indicates comprehensive coverage; partial indicates some relevant items but incomplete domain coverage; limited indicates one or two items only, or indirect coverage; no indicates the domain is not assessed

The NMIBC-SI, developed by Rutherford and colleagues in line with FDA guidance, also provides detailed coverage of urinary symptoms, treatment burden, procedure- and treatment-specific experiences (e.g., cystoscopy, intravesical treatment), fatigue, and disrupted sleep. However, while the NMIBC-SI includes some items on future health worry (e.g., concern about sexual contamination during treatment), it does not yet include a multi-item scale that explicitly captures FoR as a distinct construct, as Rutherford et al. acknowledged in their original validation work. This explains why additional measures are recommended when QOL domains such as FoR or broader emotional distress are trial priorities.

Generic core cancer questionnaires (QLQ-C30, FACT-G) and FACT-Bladder provide coverage of broader aspects of QOL but are less tailored to NMIBC-specific experiences as expected. Symptom-focused tools such as PRO-CTCAE and MDASI capture treatment side effects and fatigue, and interference with functioning, but omit bladder-specific and recurrence-related concerns.

The mapping highlights that while multiple instruments provide strong coverage in certain domains (e.g., urinary symptoms, treatment side effects), persistent gaps remain in recurrence anxiety and emotional distress, indicating that combined use of disease-specific and core instruments, supplemented by dedicated single items, may be required to achieve a regulatory-ready measurement strategy.

Discussion

This systematic review demonstrates the regulatory relevance of several PRO instruments in NMIBC. From 39 eligible studies, we identified eight instruments with varying levels of evidence for validity, reliability, and interpretability in NMIBC populations. Among disease-focused measures, the EORTC QLQ-NMIBC24 [10] and the bladder cancer index (BCI) [11], emerged as the most extensively validated and well-developed instruments for NMIBC contexts. The QLQ-NMIBC24 was developed specifically within NMIBC populations and has demonstrated strong reliability, responsiveness, and conceptual coverage of urinary, sexual, and recurrence-related concerns, with limited assessment of recurrence anxiety [10]. The BCI, though initially designed for mixed populations of patients with bladder cancer, has also demonstrated good psychometric properties, including construct validity and test–retest reliability [11]. However, it contains no items addressing recurrence or future health worries. Both instruments have been applied in multiple NMIBC studies, positioning them as tier 1 (well established evidence-base) tools when used alongside a cancer core questionnaire. Generic core questionnaires, including the EORTC QLQ-C30 and FACT-G, and the bladder-specific FACT-Bladder, were classified as tier 2 instruments. The EORTC QLQ-C30 is one of the most widely validated oncology PRO measures [13], with updated evidence supporting its contemporary content validity [28]. The FACT-G provides a reliable assessment of general domains, including physical, functional, social, and emotional well-being [14], while the FACT-Bl extends this framework to bladder-specific concerns [12]. However, these instruments provide only a partial assessment of NMIBC-specific issues such as treatment burden and recurrence-related worry, which constrains their regulatory fit when used in isolation. The limitations of frequently used instruments merit explicit acknowledgment. Ceiling and floor effects have been observed in low-symptom NMIBC populations, where patients with minimal disease burden cluster at the upper end of functioning scales, reducing sensitivity to change. In addition, none of the tier 2 instruments adequately captures NMIBC-specific symptom domains, particularly recurrence anxiety and the cumulative burden of repeated surveillance procedures. Furthermore, their sensitivity to clinically meaningful change following intravesical treatment has not been consistently demonstrated in NMIBC populations, which limits their utility as primary end points in regulatory submissions. FoR coverage in these instruments is limited to general health worry items (e.g., FACT-G items GE3, GE5, GE6), rather than recurrence-specific concerns.

The NMIBC symptom index (NMIBC-SI), PRO-CTCAE, and MDASI were grouped as tier 3 (preliminary evidence/under active development). The NMIBC-SI, developed by in accordance with FDA guidance and directly addresses urinary and treatment-related symptoms, including procedure-specific and intravesical therapy modules. It uses a clinimetric rather than psychometric approach to item selection, and initial validation has demonstrated strong test–retest reliability (ICC 0.89–0.91) and known-groups validity across treatment groups [36]. Although it has conceptual strengths and high face validity, evidence on responsiveness in formal trial settings, interpretability thresholds, and longitudinal performance in diverse NMIBC populations remains limited, and further published validation is required before regulatory-grade use can be recommended [36]. The PRO-CTCAE, also developed under FDA/National Institutes of Health (NIH) leadership, is now recognized as the standard for capturing symptomatic adverse events in cancer trials [15]. Although not NMIBC-specific, it provides a flexible item library that can complement disease-specific tools by contextualizing treatment toxicity. The MDASI, in turn, offers reliable multidimensional coverage of general symptoms and interference [16] but lacks bladder-specific domains, and does not capture recurrence-related concerns. Therefore, these tools hold regulatory relevance but are best considered complementary to NMIBC-specific instruments rather than standalone solutions.

Mapping instruments to the Rutherford et al. conceptual model of patient with NIMBC’s experience [18] confirmed that most domains are covered across existing tools. The QLQ-NMIBC24 and BCI provided the broadest coverage of urinary and sexual function, as well as some treatment burden domains. The NMIBC-SI added strength in procedure- and treatment-specific experiences, and the QLQ-C30 and FACT-G were essential for capturing fatigue, global well-being, and broader emotional and social functioning. Nonetheless, recurrence anxiety and cumulative treatment burden remain insufficiently captured across all instruments, with existing measures relying mostly on single items or indirect proxies. A further limitation of the current evidence base is its predominant focus on patients receiving induction intravesical treatment and short-term post-treatment follow-up. PRO data from maintenance therapy phases and long-term survivorship cohorts are substantially underrepresented in the literature, which limits the applicability of current instrument recommendations to these clinically-important settings. Future research should specifically target PRO assessment during maintenance intravesical therapy and extended surveillance programs, where the cumulative burden of repeated procedures and persistent recurrence anxiety may be especially pronounced and where the choice of instrument may need to differ from that used during induction. Addressing these gaps is critical to fully aligning PRO measurement with both patient priorities and regulatory expectations. Single-item burden measures, such as the FACT-GP5 (“I am bothered by side effects of treatment”) [20] and the EORTC burden item Q168 [21] offer promising options. Both are increasingly cited in regulatory submissions, with the FDA explicitly encouraging their use to contextualize PRO-CTCAE data. Although neither has been validated in NMIBC, their conceptual relevance suggests they could help address important gaps in assessing treatment burden measurement when used alongside multi-item instruments.

On the basis of the available evidence, the QLQ-NMIBC24 and BCI currently represent the most extensively validated and NMIBC-relevant PRO instruments and should be prioritized for use in trials, though this recommendation should be interpreted in light of the methodological limitations noted above. The QLQ-C30 and FACT-G remain indispensable for capturing general cancer-related domains, while the FACT-Bl can provide additional bladder-specific insights. The NMIBC-SI and PRO-CTCAE represent important, regulatorily aligned developments that may complement existing measures as more validation evidence emerges. Persistent gaps in recurrence anxiety and treatment burden point to the need for targeted integration of single-item measures and continued refinement of NMIBC-specific tools. It should be noted that several validated FoR questionnaires are available, although we are not aware that any have been used in NMIBC studies. The full scales, subscales, or individual items could be considered for future research [63–65]. These findings provide a pragmatic framework to guide NMIBC trialists, clinicians, and regulators toward a fit-for-purpose, regulatory-aligned measurement strategy.

Strengths and Limitations

This systematic review has several strengths. First, it provides a comprehensive synthesis of PRO instruments in the NMIBC space, drawing on 39 peer-reviewed studies over the last 2 decades. By organizing evidence at the instrument level rather than at the individual article level, we provide a pragmatic framework for clinicians, trialists, and regulators. Second, instruments were systematically mapped against a published conceptual model of patient with NIMBC’s experience [18], ensuring that coverage was evaluated against domains relevant to patients, including urinary symptoms, future-health worry, recurrence anxiety, treatment burden, and fatigue. Third, the review applied an evidence maturity framework perspective to help align the findings with the practical considerations relevant for FDA and EMA submissions [6, 7]. Finally, the review adhered to PRISMA standards [23]. It was prospectively registered in PROSPERO and applied a COSMIN-informed appraisal of measurement properties to each included instrument.

This review also has limitations. Although the COSMIN methodology informed our appraisal approach, a formal study-level COSMIN risk of bias assessment was not applied to all included studies, and the evidence base for several instruments was too limited to permit comprehensive ratings across all measurement property domains. Evidence was limited to the English-language, peer-reviewed publications; therefore, relevant validation work reported in other languages, or in unpublished industry data or conference abstracts, may have been missed. The number of NMIBC-specific validation studies was small for several instruments, especially emerging tools such as the NMIBC- SI and PRO-CTCAE, an important factor that thereby limits the strength of conclusions about their psychometric robustness. Specifically, the NMIBC-SI is new, being published this year, and over time, we expect significantly more evidence to emerge to demonstrate its robust development and psychometric performance across future populations, studies, and other settings. Single-item measures of treatment burden (e.g., FACT-GP5, EORTC burden item Q168) were excluded from the main synthesis in line with protocol, although we acknowledge their growing regulatory relevance.

Furthermore, some included studies were small, cross-sectional, or conducted in mixed populations of patients with bladder cancer, which may limit generalizability. A further limitation concerns construct precision: some instruments included items on general future health worry rather than recurrence-specific concerns, which we classified as “limited” FoR coverage. This nuance should be considered when interpreting domain-level conclusions. Finally, although we aimed to assess regulatory readiness, this judgement inevitably involves an element of subjective interpretation, and classifications may evolve as agencies update guidance or additional validation studies become available.

Conclusions

This systematic review identified and appraised PRO instruments for NMIBC research through a regulatory lens, highlighting both strengths of the current evidence base and the areas requiring further development. On the basis of the available evidence, the EORTC QLQ-NMIBC24 and the BCI currently have the most extensive NMIBC-specific validation and appear best positioned for use as primary PRO instruments in NMIBC clinical trials, though the strength of this recommendation should be interpreted in light of the methodological limitations noted above.

The EORTC QLQ-C30 and FACT-G remain essential core instruments within their respective measurement systems. Both are designed to be administered alongside disease-specific modules, namely the QLQ-NMIBC24 or FACT-Bladder, respectively, to provide comprehensive coverage of health-related QOL. The FACT-Bladder extends this coverage to bladder-specific concerns but includes a number of items developed primarily for cystectomy populations, which limits its precision and specificity when applied to patients managed with bladder-sparing approaches such as transurethral resection and intravesical therapy.

Emerging instruments, including the NMIBC-SI, PRO-CTCAE, and MDASI are conceptually well-grounded and aligned with regulatory expectations; however, further validation in NMIBC-specific populations is required before they can be considered fully trial-ready. Across all instruments reviewed, persistent gaps remain in the measurement of recurrence anxiety and cumulative treatment burden. Most existing measures capture only general future-health worry rather than recurrence-specific concerns, and few address the burden of repeated intravesical procedures and long-term surveillance. Single-item measures such as the FACT-GP5 and EORTC item library Q168 offer a pragmatic and regulatorily endorsed complement to multi-item instruments and may help address these gaps in the interim. Taken together, these findings provide practical, evidence-informed guidance for selecting PRO instruments in NMIBC trials. They support a measurement strategy that combines validated disease-specific instruments with established core measures, supplemented where necessary by targeted single items to address priority gaps in domain coverage. This integrated approach offers a clear pathway toward more comprehensive, fit-for-purpose, regulatory-aligned PRO measurement in future NMIBC research.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contribution

Conception and design: Andrew Bottomley, Sunil Shrestha, Ingolf Griebsch, John Gore. Data acquisition: Sunil Shrestha, Andrew Bottomley. Data analysis and interpretation: Andrew Bottomley, Sunil Shrestha. Drafting the manuscript: Sunil Shrestha, Andrew Bottomley, Carolyn Gotay. Critical revision of the manuscript for scientific and factual content: Andrew Bottomley, Ingolf Griebsch, John Gore, Fran Curtis, Carolyn Gotay. Supervision: Andrew Bottomley, Ingolf Griebsch. All authors reviewed and approved the final version of the manuscript.

Funding

This review was funded by a grant from Ferring Pharmaceuticals. I.G. was an employee of Ferring Pharmaceuticals at the time of study, but he is now an employee of Genesis Research Group. Ferring Pharmaceuticals had no role in the design of the systematic review, the search strategy, study selection, data extraction, or interpretation of findings. The decision to submit the manuscript for publication was made independently by the authors. All other authors declare no competing interests related to this funding. Ferring Pharmaceuticals is also funding the Rapid Service Fee for this article.

Data Availability

All data generated or analyzed during this study are included in this published article/as supplementary information files. Primary data from individual studies can be requested from the original authors.

Declarations

Conflict of Interest

Ingolf Griebsch is an employee of Ferring Pharmaceuticals, which funded this work; however, Ferring Pharmaceuticals had no role in the design, execution, analysis, or reporting of this systematic review. A.B. owns Bottomley Consulting Group and has undertaken projects funded by pharmaceutical companies; Ferring Pharmaceuticals provided funding to Bottomley Consulting Group for this work. Andrew Bottomley was previously an employee of EORTC and was involved in the development of several EORTC quality of life measures, which are among the instruments evaluated in this review. Sunil Shrestha is an active member of the EORTC quality of life group and is involved in developing several EORTC quality of life measures. Carolyn C. Gotay, John Gore and Fran Curtis have no conflicts of interest to declare. To minimize the risk of bias arising from conflicts of interest, study selection, data extraction, and instrument classification were conducted independently by two reviewers (S.S., A.B.) using prespecified eligibility and tier classification criteria agreed upon prior to data extraction. Authors with declared interests in specific instruments abstained from tier classification decisions regarding those instruments.

Ethical Approval

This systematic review was conducted and reported in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The review protocol was prospectively registered in the international prospective register of systematic reviews (PROSPERO; registration number CRD420251076486) prior to data extraction. As this study involved synthesizing previously published data and did not include primary data collection from human participants, formal ethical approval was not required. All included studies were peer-reviewed publications, and no individual patient data was accessed or analyzed. Data extraction and quality assessment were conducted independently by multiple reviewers to minimize bias and ensure methodological transparency. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.