Comparison of spinal versus general anaesthesia in high-risk non-muscle invasive bladder cancer: study protocol for a randomised controlled trial

Abstract

Introduction

The impact of anaesthesia modality on oncological outcomes in patients with high-risk non-muscle invasive bladder cancer (NMIBC) remains uncertain. Emerging evidence suggests that anaesthetic agents and techniques may influence tumour biology and recurrence through immunomodulatory and neuroendocrine pathways. However, prospective randomised trials comparing spinal and general anaesthesia in this population are lacking.

Methods and analysis

This single-centre, prospective, parallel-arm randomised controlled trial will enrol 370 patients with clinically suspected high-risk NMIBC undergoing transurethral resection of bladder tumour. Participants will be randomised 1:1 to receive either spinal or general anaesthesia. The primary endpoint is time to recurrence over a 104-week follow-up period. Secondary endpoints include time to progression, Bacillus Calmette–Guérin (BCG) unresponsiveness and a composite oncological event. Additional secondary outcomes include postoperative opioid consumption (morphine equivalents), obturator jerk occurrence, acute urinary retention and tolerance to immediate intravesical chemotherapy. Safety outcomes will include treatment-emergent adverse events, Clavien-Dindo graded surgical complications, haemorrhagic events and anaesthesia-related risks. Exploratory endpoints involve perioperative biomarker analyses. Data will be analysed on an intention-to-treat basis.

Ethics and dissemination

Recruitment has not yet started. It is expected to begin in December 2025 and to be completed by June 2029. The planned follow-up period for each participant is 104 weeks. This manuscript is based on protocol V.1.0, dated March 2025. Results will be disseminated through peer-reviewed journals and conference presentations

Trial registration number

NCT06982690.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• Prospective, randomised controlled design comparing spinal and general anaesthesia in high-risk non-muscle invasive bladder cancer (NMIBC).

• Incorporation of mechanistic biomarker analyses to investigate perioperative immunomodulatory and neuroendocrine effects.

• Use of a homogeneous high-risk NMIBC population enhances internal validity but may limit applicability to lower-risk disease.

• Blinding of anaesthesia modality is not feasible, potentially introducing performance bias despite standardised perioperative protocols.

• Single-centre setting improves procedural consistency but may reduce generalisability.

Introduction

Bladder cancer is the 10th most commonly diagnosed malignancy worldwide, with urothelial carcinoma accounting for over 95% of cases.¹ Clinically, bladder cancer exhibits substantial heterogeneity in biological behaviour and prognosis, ranging from indolent lesions suitable for surveillance to aggressive tumours requiring radical intervention. Non-muscle invasive bladder cancer (NMIBC)—comprising Ta, T1 and carcinoma in situ (CIS) lesions—represents 75–85% of newly diagnosed cases.^{2 3} Despite initial treatment with transurethral resection of bladder tumour (TURBT), NMIBC is associated with high recurrence rates (60–80%) and a progression risk of 10–30%, particularly among high-risk patients.^{4 5} Once progression to muscle-invasive bladder cancer (MIBC) occurs, outcomes worsen considerably, with 50–70% developing metastases and a 5-year survival rate below 10% in metastatic settings.^{6 7}

Current NMIBC management emphasises risk-adapted intravesical therapy (eg, Bacillus Calmette–Guérin (BCG) or chemotherapy), lifelong cystoscopic surveillance and early radical cystectomy for selected high-risk cases.^{8 9} However, limitations such as BCG shortages, treatment-related toxicities and surgical ineligibility in elderly or comorbid patients underscore the need to identify modifiable perioperative factors that may influence oncological outcomes.

Anaesthetic technique as a modifiable risk factor

Anaesthetic technique during TURBT is one such factor. Both general anaesthesia (GA) and spinal anaesthesia (SA) are widely used, yet they differ significantly in their effects on neuroendocrine stress response, opioid exposure and immune modulation—mechanisms increasingly implicated in cancer recurrence and metastasis.¹⁰,¹³ If anaesthetic technique affects recurrence risk, it could represent an immediately actionable and cost-effective intervention to improve outcomes in NMIBC, particularly in high-risk subgroups.

Scientific rationale

Surgical stress and anaesthesia can alter perioperative immune dynamics, potentially facilitating tumour progression and recurrence.¹⁴,¹⁷ GA commonly involves volatile anaesthetics (eg, sevoflurane) and systemic opioids (eg, fentanyl), both associated with immunosuppression, enhanced angiogenesis and increased tumour cell viability. Sevoflurane has been shown to activate hypoxia-inducible factors (HIF-1α, HIF-2α), vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP), thereby promoting tumour growth and neovascularisation.¹⁸,²⁰ Furthermore, it impairs immune surveillance by reducing natural killer cell activity and shifting cytokine balance from T helper cell 1 (Th1) to T helper cell 2 (Th2).^{21 22}

Opioids, particularly μ-opioid receptor agonists, may further suppress antitumour immunity. Fentanyl has been implicated in promoting epithelial–mesenchymal transition and stemness in several cancer models.²³,²⁶ Additionally, both volatile agents and opioids may exacerbate systemic inflammation and stress-induced tumour cell dissemination.^{11 27 28}

In contrast, SA—typically with intrathecal bupivacaine—attenuates perioperative stress responses, preserves immune function and reduces proinflammatory cytokine release.²⁹,³¹ Preclinical evidence suggests bupivacaine may exert direct antitumour effects, including apoptosis induction and inhibition of cancer cell proliferation and migration.^{32 33} SA also reduces opioid requirements and neuroinflammation, further supporting its immunoprotective profile.³⁴

Moreover, SA provides superior pelvic muscle relaxation and facilitates obturator nerve block, minimising obturator reflex-induced bladder wall injury—a known risk factor for recurrence.³⁵,³⁸ It has also been associated with fewer postoperative complications, including lower risks of delirium and cardiopulmonary events, making it especially advantageous in elderly patients.^{39 40}

Study justification and knowledge gap

While retrospective studies in colorectal and gynaecologic oncology suggest regional anaesthesia may reduce recurrence and improve survival, limited data exist for bladder cancer.^{41 42} In NMIBC, where recurrence is common and surveillance is resource-intensive, any safe intervention that may reduce recurrence risk warrants rigorous evaluation.

Our recent meta-analysis⁴³ involving 2913 patients with NMIBC undergoing TURBT revealed that SA was associated with significantly lower recurrence rates compared with GA (risk ratio (RR) 0.811, 95% CI 0.724 to 0.909; p<0.001). The protective effect was particularly evident in high-risk subgroups (RR 0.700, 95% CI 0.545 to 0.896; p=0.005), along with prolonged time to recurrence (hazard ratio (HR) 0.546, 95% CI 0.384 to 0.776; p=0.001). These findings suggest a potential role for SA in improving oncological outcomes among patients with aggressive NMIBC phenotypes.

However, existing studies³⁵,^{3744 45} are limited by design heterogeneity, potential selection bias and incomplete characterisation of patient and tumour profiles. Moreover, mechanistic data are lacking. Biomarker-based studies evaluating immune and neuroendocrine modulation in this context are needed.

We hypothesise that SA, compared with GA, is associated with reduced tumour recurrence following TURBT in NMIBC, particularly among high-risk patients. We propose a prospective clinical trial incorporating serial biomarker assessment—including VEGF, interleukin 6 (IL-6), interleukin 10 (IL-10), transforming growth factor beta (TGF-β) and cortisol—to evaluate immunological and stress-related mechanisms underlying this effect.

This study may yield mechanistic insights and generate clinically actionable evidence supporting SA as a recurrence-modifying strategy in NMIBC.

Methods

Study design

This is a prospective, randomised, controlled, single-centre, parallel-group trial comparing SA versus GA in patients undergoing TURBT for high-risk NMIBC. Patients will be enrolled and randomised prior to TURBT and followed for 104 weeks. Recruitment is expected to begin in December 2025 and be completed by June 2029. The study is registered with NCT06982690 and has received ethics approval from the institutional review board of National Taiwan University Hospital (IRB number 202411115RINE). Written informed consent will be obtained from all participants, with the consent form provided in online supplemental supplement 1. The overall study design is illustrated in figure 1.⁴⁶ The schedule of protocol-specified study visits is outlined in figure 2, and detailed assessments are summarised in online supplemental table 1; Week -4 to Week 8 and online supplemental table 2; Week 12 to Week 104.⁴⁶

Figure 1. Diagrammatic representation of the study protocol.⁴⁶ ALT, alanine aminotransferase; AST, aspartate aminotransferase; BCG, Bacillus Calmette–Guérin. Cre, creatinine; CTU, computed tomography urography; GA, general anaesthesia; MIBC, muscle-invasive bladder cancer; mITT, modified Intention-to-Treat; MRU, magnetic resonance urography; NMIBC, non-muscle invasive bladder cancer; SA, spinal anaesthesia; UC, urothelial carcinoma.

Figure 2. Timeline of protocol-specified study visits.⁴⁶.

Study objectives

The study aims to investigate the effect of SA versus GA on clinical outcomes, complications and biomarker changes to identify the most effective anaesthetic approach and improve treatment outcomes in patients with high-risk NMIBC.

Efficacy objective

Primary efficacy objective

To evaluate whether SA is superior to GA in prolonging time to recurrence in patients with high-risk NMIBC within 104 weeks following TURBT.

Secondary efficacy objectives

To compare the effects of SA versus GA on:

• Time to event (any recurrence, progression or death) in patients with high-risk NMIBC up to Week 104.

• Time to BCG unresponsiveness up to Week 104.

• Time to progression up to Week 104.

• Time to BCG intolerance up to Week 104

• Incidence of recurrence up to Week 104.

Additional secondary objectives

To assess the following perioperative outcomes and safety-related indicators:

• Changes from baseline in safety-related parameters, including vital signs and body temperature (BT).

• Tolerance of immediate post-TURBT intravesical mitomycin C chemotherapy.

• Frequency of obturator reflex during TURBT.

• Incidence of acute urinary retention (AUR) after Foley catheter removal.

• Postoperative analgesic consumption, measured as total morphine equivalent dose (MED) administered within the first 48 hours following surgery.

Safety objectives

To evaluate and compare the overall safety of SA versus GA during and after TURBT. Safety assessments will include:

• Frequency and severity of treatment-emergent adverse events (AEs).

• Surgical complications graded by the Clavien-Dindo classification.

• Organ injury, including bladder perforation, vascular or bowel injury.

• Haemorrhagic complications.

• Malignant hyperthermia or anaesthesia-related allergic reactions (especially related to sevoflurane).

• Conversion of TURBT to laparoscopic or open surgery.

• Conversion from SA to GA due to anxiety or surgical complications.

• Requirement for perioperative blood transfusions.

• Delay of immediate postoperative mitomycin C instillation or initiation of BCG therapy.

• Occurrence of cerebrospinal fluid leakage or postdural puncture headache.

• Discontinuation or intolerance of BCG instillation due to toxicity or severe infection.

• Discontinuation of anaesthesia due to drug-related AEs.

Exploratory objectives

To explore the effects of anaesthesia modality (SA vs GA) on perioperative inflammatory and neuroendocrine responses in patients with NMIBC:

• Inflammatory biomarkers: VEGF, HIF, TGF-β1, IL-6, IL-10 and neutrophil-to-lymphocyte ratio (NLR).

• Neuroendocrine biomarkers: plasma norepinephrine, epinephrine and cortisol levels.

Participants

Inclusion criteria

Participants must meet all of the following criteria to be eligible for the study:

• Age ≥40 years for male subjects, or postmenopausal status for female subjects.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0–2.

• Histologically confirmed or clinically suspected diagnosis of urothelial carcinoma of the bladder.

• American Society of Anesthesiologists (ASA) physical status classification of I or II.

• History of any other adequately treated Stage I or II malignancy (excluding urothelial carcinoma), with no evidence of disease recurrence for at least 5 years.

• Adequate renal function, defined as serum creatinine within institutional upper limit of normal (ULN).

• Adequate hepatic function, defined as total bilirubin ≤ULN and alanine aminotransferase and aspartate aminotransferase ≤ULN.

• Ability to comprehend the study requirements and provide written informed consent.

Exclusion criteria

Participants will be excluded if they meet any of the following conditions:

• MIBC (≥cT2), concurrent upper tract urothelial carcinoma (UTUC) or other active malignancies.

• History of, or concurrent urothelial carcinoma involving the upper urinary tract (renal pelvis, ureter) or urethra.

• Clinical or radiographic evidence suggestive of MIBC or metastatic urothelial carcinoma.

• Known immunodeficiency or current use of immunosuppressive therapy.

• Chronic use of anti-inflammatory medications (eg, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids) or beta-adrenergic blockers.

• Presence of a difficult airway or significant cardiopulmonary comorbidities (eg, severe aortic stenosis, decompensated congestive heart failure or advanced pulmonary disease) precluding safe administration of GA.

• Elevated intracranial pressure secondary to intracranial neoplasm, recent trauma or central nervous system infection; or local infection at the site of proposed SA.

• Serious, uncontrolled medical conditions (eg, recent major trauma, orthopaedic fracture) or active systemic infection that may interfere with the safe administration of either anaesthesia modality.

• Known hypersensitivity or contraindication to any of the anaesthetic agents used in the study, including propofol, fentanyl, sevoflurane or bupivacaine.

• Personal or familial history of malignant hyperthermia.

• Documented bleeding diathesis or coagulation disorder.

• Pregnancy or lactation at the time of enrolment.

• Any physical, psychological or logistical condition that, in the judgement of the investigator, may impair the subject’s ability to comply with the protocol or complete scheduled follow-up assessments.

Recruitment: Patients will be recruited from outpatient clinics and urology wards prior to TURBT. Eligible patients will be approached, and those who consent will be randomised.

Randomisation and blinding

Eligible patients will be randomised in a 1:1 ratio to SA or GA using a computer-generated sequence. Allocation will be concealed using sealed opaque envelopes. Investigators and participants cannot be blinded due to the nature of anaesthesia; however, endpoint assessors and statisticians will remain blinded.

Interventions

Patients will be randomised 1:1 to receive either SA or GA during TURBT.

Dosage and administration in the spinal anaesthesia arm

A total of 10–12 mg of 0.5% bupivacaine will be administered into the cerebrospinal fluid of the subarachnoid space using a 25-gauge Quincke spinal needle via an 18-gauge introducer (adjusted by body height). Midazolam (2–5 mg) may be used to decrease anxiety, alleviate discomfort, improve haemodynamic stability and induce a feeling of calmness during SA.

Dosage and administration in the general anaesthesia arm

Induction will be performed with propofol (0.5–1.5 mg/kg) and fentanyl (1–2 µg/kg), and anaesthesia will be maintained with sevoflurane (1–3 vol %) via a laryngeal mask or endotracheal intubation. Rocuronium (0.5–0.6 mg/kg) will be used for induction, maintenance and occurrence of obturator jerk.

All patients will undergo standard TURBT with postoperative intravesical mitomycin C therapy as clinically indicated.

Study procedures

This prospective randomised controlled trial is designed to evaluate the effects of SA versus GA on recurrence rates and immunological responses in patients with high-risk NMIBC undergoing TURBT. The study timeline spans 104 weeks and is structured as follows:

Screening phase (Week -4 to Day -1)

• Patients will undergo eligibility assessments within 4 weeks prior to surgery (W-4 to D-1), including:

  • Medical history and physical examination.

  • Performance status assessment (ECOG).

  • Laboratory tests (complete blood count, renal and liver function).

  • Cystoscopy, imaging (CT urography (CTU) or MRI) and urine cytology to confirm high-risk NMIBC.

  • Informed consent acquisition.

Intervention phase (Day 0 to Day 7)

• Day 0: Randomisation and TURBT under either SA or GA.

  • Blood samples will be collected at 08:00 preoperatively for baseline inflammatory and neuroendocrine biomarkers.

  • The type of anaesthesia administered (SA vs GA) will follow institutional protocols with standardised agents.

  • All participants will undergo bipolar TURBT using saline irrigation and bipolar cutting loops. Postresection, a three-way urethral catheter will be inserted.

  • Postoperative management

    • SA Group: Subjects will remain in a supine position and abstain from oral intake for 6 hours postoperatively.

    • GA Group: Oral hydration will be withheld for approximately 6 hours postoperatively to mitigate the risk of nausea and vomiting.

  • Intravesical chemotherapy: Within 6 hours post-TURBT, a single instillation of mitomycin C (40 mg in 40 mL sterile water) will be administered intravesically and retained for 1–2 hours, unless contraindicated due to bladder perforation or mitomycin C allergy.

• Day 1 (D1)

  • Postoperative blood samples will be drawn at 08:00 to evaluate changes in inflammatory and neuroendocrine markers.

  • Postoperative recovery, pain assessment and AEs monitoring.

• Day 3–7 (D3–D7)

  • Short-term clinical recovery assessments.

  • Catheter removal and discharge planning.

BCG induction phase (Week 1 to Week 6)

• Starting within 1–2 weeks post-TURBT:

  • All patients will receive six weekly instillations of BCG as per guidelines.

  • Weekly visits (W1–W6) for BCG administration, AE monitoring and urinary symptom assessment.

Re-TURBT (Week 7 to Week 8)

• A second-look resection will be performed between Week 7 and Week 8 to assess for residual tumour, in line with European Association of Urology guidelines for high-risk NMIBC.

• Anaesthesia administration: Participants will receive the same anaesthesia modality as assigned during the initial TURBT to maintain consistency:

• Participants will undergo a pathological evaluation during the outpatient department visit following re-TURBT. Subjects will be excluded from the study if the pathological report meets either of the following criteria:

  • The tumour is definitively classified as low-risk NMIBC, characterised by low-grade Ta lesions without additional high-risk features.

  • The resected specimen lacks identifiable muscularis propria (detrusor muscle), rendering accurate staging and risk stratification infeasible.

BCG maintenance phase (Week 12 to Week 104)

Patients will undergo BCG maintenance therapy starting at Week 12 and continuing through Week 104, consisting of:

• Intravesical BCG administration: Three weekly instillations every 12 weeks (ie, at Weeks 12, 24, 36, 48, 60, 72, 84 and 96). Each instillation will use one-third of the BCG vial dose.

• Tumour surveillance

  • Cystoscopy and urine cytology at Weeks 12, 24 and every 12 weeks thereafter.

  • Upper urinary tract and abdominal/pelvic imaging at baseline, Week 52 and Week 104 using CTU, magnetic resonance urography (MRU) or retrograde ureteropyelography with CT or ultrasonography, as clinically indicated.

Sample size calculation

A recent randomised controlled trial from Korea reported a larger difference (HR ≈ 0.54).⁴⁷ These findings, together with results from our meta-analysis,⁴³ support the plausibility of the assumed effect size.

An expected first-year recurrence rate of 50% for patients with high-risk NMIBC receiving GA was derived from pooled data of 2596 patients across seven European Organisation for Research and Treatment of Cancer trials.⁴ Based on these parameters, a minimum of 88 patients per group would provide 80% power to detect the specified difference at a two-sided alpha level of 0.05.

To accommodate an estimated 20% attrition rate and considering that approximately 60% of patients with NMIBC are classified as high-risk at diagnosis, the total sample size was inflated to 370 participants (185 per arm). This cohort will undergo TURBT under the assigned anaesthetic modality prior to definitive pathological risk stratification.

Data collection and management

All study data will be collected using a standardised electronic case report form (CRF) integrated into a Good Clinical Practice (GCP)-compliant electronic data capture system. Baseline data include demographics, tumour characteristics, comorbidities and anaesthesia records. Follow-up assessments will occur at Weeks 6, 12 and every 12 weeks thereafter through Week 104.

Clinical evaluations include cystoscopy, urine cytology and radiographic imaging (eg, CTU or ultrasound), performed according to institutional standard-of-care. Events will be adjudicated by a blinded independent endpoint committee. All AEs and protocol deviations will be documented and monitored by the Data and Safety Monitoring Board.

Data accuracy and completeness will be ensured by double data entry and regular audits. All data will be anonymised and stored in secure, access-controlled databases. Data management procedures and statistical programming will follow the International Council for Harmonisation E6(R2) GCP guidelines and comply with institutional and regulatory requirements.

Routine follow-up assessments every 12 weeks (Weeks 12 to Week 104) include

• Urine analysis.

• Urine culture.

• Urine cytology.

• Cystoscopy.

• Recording of previous and concomitant medications.

Imaging protocol

• Baseline, Week 52 and Week 104 upper urinary tract evaluations will use CTU, MRU or retrograde ureteropyelography with CT or ultrasonography, depending on patient-specific considerations:

  • MRU may be preferred in patients with renal insufficiency (glomerular filtration rate >30 mL/min) or contrast allergy and may be performed without gadolinium contrast using T2 and diffusion-weighted sequences.

  • Non-contrast CT combined with retrograde ureteropyelography may be used when both iodinated and gadolinium-based contrast agents are contraindicated.

AE monitoring

• Any AE potentially related to intravesical BCG will be recorded and followed up through relevant imaging and clinical assessments of the upper tract and abdominal/pelvic organs.

Abnormal findings management

• If both cystoscopy and urine cytology are negative, BCG maintenance continues.

• If either test is abnormal:

  • Renal echography will be performed.

    • If negative: proceed to mapping biopsy or TURBT.

    • If hydronephrosis is noted: advanced imaging (CTU, MRU or retrograde ureteropyelography with CT or ultrasonography) is warranted prior to mapping biopsy and diagnostic ureteroscopy.

Urgent evaluation trigger

• If gross haematuria occurs between scheduled follow-ups, immediate evaluations including urine cytology, cystoscopy and upper tract imaging (CTU, MRU or retrograde ureteropyelography with CT) will be conducted.

Statistical methods

This study aims to compare the efficacy and safety of SA versus GA in patients with high-risk NMIBC undergoing TURBT.

Statistical analyses will be performed using SAS V.9.4 (SAS Institute, Cary, North Carolina, USA) or an equivalent software package.

Study populations

1. Intent-to-Treat (ITT) Population The ITT population will include all randomised participants, regardless of whether they received the allocated anaesthetic technique or completed follow-up. This set preserves the benefits of randomisation and provides a conservative estimate of treatment effect

2. Modified Intent-to-Treat (mITT) Population Because the scientific objective of this trial is to evaluate recurrence outcomes specifically in high-risk NMIBC, the mITT population will exclude participants whose final pathological diagnosis is not high risk (e.g., low-risk, intermediate-risk NMIBC, or benign pathology). Participants with low- or intermediate-risk findings will continue regular clinical follow-up per protocol but will not be included in mITT efficacy analyses. The mITT population will serve as the primary analysis set for efficacy outcomes.

3. Per-Protocol (PP) Population The PP population will consist of participants who received the assigned anaesthetic intervention and completed follow-up without major protocol deviations that may affect assessment of the primary endpoint.The PP population will be used for supportive evaluations of treatment effect under protocol-adherent conditions.

4. Modified Per-Protocol (mPP) Population Similar to the mITT definition, the mPP population will additionally exclude participants whose final pathology does not confirm high-risk NMIBC. Only participants with high-risk pathology and full protocol adherence will be included. This population will be used for sensitivity analyses to assess the robustness of the primary findings.

5. Safety population: The safety population will include all participants who received at least one dose of the assigned intervention. AEs will be analysed in this group.

Supportive analyses will be conducted in the ITT population, and sensitivity analyses will be performed in the modified per-protocol (mPP) population.

Statistical analysis

Baseline characteristics will be summarised using descriptive statistics. Continuous variables will be presented as means and SD or medians and IQRs, depending on the data distribution. Categorical variables will be expressed as counts and percentages.

Primary efficacy analysis set: The primary efficacy analysis of the primary endpoint (time to first recurrence) will be conducted in the modified intention-to-treat (mITT) population. Supportive analyses will be performed in the ITT population. A single prespecified sensitivity analysis will be performed in the modified per-protocol (mPP) population to evaluate robustness to protocol adherence.

Safety analysis set: All safety analyses will be conducted in the safety population, defined as all participants who receive at least one dose of the assigned anaesthetic intervention, regardless of protocol adherence or final pathological diagnosis.

.

Efficacy endpoints

Primary efficacy endpoints

The primary efficacy endpoint is time to recurrence, defined as the number of days from TURBT to the earliest occurrence of any of the following events: gross haematuria, positive urine cytology, relapse of any-grade bladder tumour, newly diagnosed UTUC with pathological confirmation, radiographically detected tumour metastasis or cancer-specific death beyond 90 days from initial diagnosis. Subjects without recurrence events will be censored at their last follow-up. Recurrence will be assessed up to Week 104.

Time to recurrence will be analysed using the Kaplan-Meier method. Group comparisons between SA and GA will be conducted using a two-sided log-rank test stratified by sex. The HR and 95% CI will be estimated via a stratified Cox proportional hazards model.

Sensitivity analyses for the cumulative 104-week recurrence rates will include both conservative and optimistic imputation scenarios for missing data to assess the robustness of the intervention effect.

Secondary efficacy endpoints

Secondary endpoints include:

• Time to composite oncological event, defined as recurrence of high-grade tumour, T1 disease, tumour >3 cm, multifocality, variant histology, lymphovascular invasion, CIS, disease progression or cancer-specific death.

• Time to BCG unresponsiveness, defined according to standard guidelines as recurrence after adequate BCG therapy or progression within 6 months.

• Time to progression, including pathological progression (Ta/CIS to T1 or higher), radiological metastasis (cN+ or M+) or cancer-specific death.

• Time to BCG intolerance, including predefined criteria such as severe cystitis or inability to tolerate intravesical therapy.

• Incidence of recurrence, defined as the proportion of participants with any documented recurrence.

All time-to-event endpoints will be analysed in the same manner as the primary endpoint, whereas incidence of recurrence will be analysed as a dichotomous secondary endpoint using Fisher’s exact test.

Additional secondary efficacy analysis

The additional secondary analysis will be conducted using the efficacy analysis set.

In addition to time-to-event endpoints, we will evaluate:

• Change from baseline in physiological parameters including BT, respiratory rate and pulse rate measured pre-TURBT and post-TURBT, and immediately before leaving the operating room.

• Tolerance of immediate post-TURBT intravesical chemotherapy, assessed by completion rate and early termination due to discomfort or adverse reactions.

• Incidence of obturator jerk during TURBT.

• Incidence of AUR after Foley catheter removal.

• Postoperative anaesthesia-related drug consumption, expressed as MED in milligrams. MED will be calculated to quantify the cumulative dose of analgesics used in the postanaesthesia recovery period and within 24 hours post-TURBT.

Categorical variables (eg, obturator jerk, AUR) will be analysed using Fisher’s exact test. Continuous variables (eg, physiological parameters, MED) will be analysed using mean per cent change from baseline with 95% CIs and compared between SA and GA groups.

Postoperative MED will be analysed as a continuous variable. Between-group differences will be evaluated using Student’s t-test or Mann-Whitney U test, depending on normality.

If appropriate, multivariable linear regression will be used to adjust for potential confounders such as age, sex, ASA physical status, tumour characteristics and postoperative MED.

Safety endpoints

Safety analyses will be performed on PP populations. All subjects undergoing randomisation and receiving TURBT will be included in the safety set.

Safety endpoints include:

• Frequency, severity (Common Terminology Criteria for Adverse Events (CTCAE)) and classification (Clavien-Dindo) of AEs.

• Specific events of interest:

  • Drug-related toxicity or allergy.

  • Anaesthetic complications, including conversion from SA to GA.

  • Postoperative hydronephrosis requiring nephrostomy or ureteral stenting.

  • BCG instillation discontinuation or intolerance.

  • Bladder perforation.

  • Conversion to open surgery due to intraoperative injuries.

AEs will be monitored continuously and assessed up to Week 104.

Exploratory biomarker analysis

To explore the effects of anaesthesia modality (SA vs GA) on perioperative inflammatory and neuroendocrine responses in patients with NMIBC:

• Inflammatory biomarkers: VEGF, HIF, TGF-β1, IL-6, IL-10 and NLR.

• Neuroendocrine biomarkers: plasma norepinephrine, epinephrine and cortisol levels.

All biomarkers will be measured at 08:00 on Study Day 0 (preoperative) and Day 1 (postoperative).

Changes from baseline in inflammatory and neuroendocrine biomarkers will be analysed in each treatment group.

Within-group comparison: paired t-tests or Wilcoxon signed-rank tests will be used to compare baseline and post-treatment biomarker levels within each treatment group.

Between group comparison: differences between the SA and GA groups in biomarker changes will be analysed using an independent two-sample t-test or Mann-Whitney U test for normally and non-normally distributed data, respectively.

Handling of missing data

Missing data for time-to-event outcomes will be censored at the last known follow-up date. For secondary and continuous endpoints, missing values will be imputed using multiple imputation under the assumption that data are missing at random. Sensitivity analyses will be performed to evaluate the robustness of the results under alternative assumptions.

Specifically, two complementary scenarios will be explored:

• Optimistic scenario: Participants with missing recurrence data will be assumed to remain event-free throughout follow-up.

• Conservative scenario: Missing data will be imputed as recurrence (event occurred) or as the worst possible outcome, depending on the endpoint.

The consistency of treatment effects across these imputation models will be examined to ensure the validity and robustness of the trial conclusions.

Subgroup analyses

Subgroup analyses will examine treatment effects based on the following factors:

• Age (<65 vs ≥65 years).

• Gender (male vs female).

• Tumour stage (high-risk vs. intermediate-risk vs. low-risk NMIBC).

• Comorbidities (eg, diabetes, hypertension).

Subgroup analyses will examine treatment effects according to age (<65 vs ≥65 years), gender, tumour stage and comorbidities (eg, diabetes, hypertension). The credibility of any observed subgroup effects will be appraised using the ICEMAN instrument.

Statistical significance

All statistical tests will be two-sided, and a p value of <0.05 will be considered statistically significant. For primary and secondary outcomes, 95% CIs will be reported.

Concomitant medications and prohibited/restricted treatments

All concomitant medications administered from 4 weeks prior to the date of informed consent through Week 104 will be documented in the CRF. This includes any medication, therapy or intervention that may influence study outcomes or interact with anaesthetic agents used during the perioperative period.

Prohibited and restricted treatments (Week 4 to Week 9)

To minimise confounding effects on biomarker profiles and immunomodulatory outcomes, the following medications are prohibited from 4 weeks prior to surgery (Week 4) through Week 9:

• Anti-inflammatory agents: including NSAIDs and COX-2 inhibitors.⁴⁸

• Opioid analgesics: including codeine and tramadol.⁴⁹

• Systemic corticosteroids: such as cortisol, prednisone and dexamethasone.⁵⁰

• Beta-blockers: due to potential interference with immune and stress-related biomarkers.⁵¹

Fentanyl and bupivacaine, both used in anaesthesia regimens, are CYP3A4 substrates, while propofol may inhibit CYP3A4.⁵² Concomitant administration of strong or moderate CYP3A4 inhibitors (eg, ketoconazole, erythromycin, indinavir, nefazodone, nelfinavir) may elevate fentanyl and bupivacaine levels and should be used with caution. CYP3A4 inducers (eg, rifampicin) may lower the effectiveness of these agents and are prohibited during this period.⁵³

Permitted pain management options include acetaminophen, antidepressants, therapeutic massage, acupuncture, transcutaneous electrical nerve stimulation, infrared radiation and low-intensity extracorporeal shock wave therapy.⁵⁴

Additionally, elective surgery unrelated to bladder cancer is prohibited from Week 4 to Week 9 to avoid perioperative physiological stress that may confound study outcomes.⁵⁵

Precautions during extended follow-up (Week 9 to Week 104)

From Week 9 to Week 104, the use of the following medications is permitted under specific precautions:

• NSAIDs, COX-2 inhibitors, opioid analgesics (codeine, tramadol), antiepileptic drugs (carbamazepine, diazepam, clonazepam) and beta-blockers are allowed only for short-term use (≤2 weeks, no more than three times annually) and at standard therapeutic dosages. The duration, frequency and dosage of use will be recorded in the CRF.

Discussion

This randomised controlled trial is designed to provide high-quality evidence on whether anaesthesia modality—spinal versus general—affects oncological outcomes in patients with high-risk NMIBC. Existing retrospective and observational studies have suggested potential associations between regional anaesthesia and improved recurrence outcomes, but prospective randomised data remain scarce.⁴⁷

The methodological strengths of this trial include a rigorous randomised design, standardised perioperative management protocols and the inclusion of mechanistic biomarker analyses to explore immunomodulatory and neuroendocrine pathways.^{12 15} The homogeneous high-risk NMIBC population improves internal validity and enhances the ability to detect clinically relevant differences between groups. Additionally, evaluating perioperative outcomes such as postoperative opioid consumption, obturator jerk occurrence and tolerance to immediate intravesical chemotherapy ensures that findings will be relevant to routine clinical practice.

Several limitations should be acknowledged. Due to the nature of anaesthesia techniques, blinding is not feasible, which may introduce performance bias despite standardised care protocols. The single-centre design, while ensuring procedural consistency, may limit generalisability to other healthcare settings. Recruitment and retention of elderly patients with comorbidities may pose logistical challenges, particularly for long-term follow-up. Finally, while the primary follow-up period of 104 weeks was chosen for feasibility and endpoint maturity, an observational extension up to 5 years is planned, leveraging routine clinical surveillance to capture long-term recurrence and progression data.

In summary, this study is expected to generate robust evidence regarding the influence of anaesthesia modality on oncological and perioperative outcomes in high-risk NMIBC. Its methodological design will address existing gaps in the literature and may lay the foundation for future research exploring anaesthesia as a modifiable factor in cancer care.

Trial status

Recruitment has not yet started. It is expected to begin in December 2025 and to be completed by June 2029. The planned follow-up period for each participant is 104 weeks. This manuscript is based on protocol V.1.0, dated March 2025.

Ethics and dissemination

The study is prospectively registered on ClinicalTrials.gov (Identifier: NCT06982690), and ethical approval has been granted by the National Taiwan University Hospital Institutional Review Board (IRB No. 202411115RINE). Participant recruitment had not started. Any protocol amendments will be submitted to the IRB for approval before implementation. The findings of this trial will be disseminated through peer-reviewed journal publication and academic conferences. Participant confidentiality will be strictly maintained in all forms of data dissemination.