Vesical Imaging-Reporting and Data System (VI-RADS) Followed by Photodynamic Trans-urethral Resection of Bladder Tumours (PDD-TURBT) to Avoid Secondary Resections (Re-TURBT) in Non-Muscle Invasive Bladder Cancers (NMIBCs) (CUT-less)

Vesical Imaging-Reporting and Data System (VI-RADS) Followed by Photodynamic Trans-urethral Resection of Bladder Tumours (PDD-TURBT) to Avoid Secondary Resections (Re-TURBT) in Non-Muscle Invasive Bladder Cancers (NMIBCs)

Non-inferiority, Phase IV, Open-label, Randomized Controlled Trial of Vesical Imaging- Reporting and Data System (VI-RADS) Followed by Primary Photodynamic Trans-urethral Resection of Bladder Tumours (PDD-TURBT) Versus Conventional White-light TURBT Plus Repeated-TURBT (Re-TURBT) in Non-Muscle Invasive Bladder Cancers (NMIBCs) Candidate for Second Look and Resection

Background: In European Association of Urology (EAU) Guidelines, the vast majority of non-muscle-invasive bladder cancers (NMIBCs) undergo a primary transurethral resection of the bladder tumor (TURBT) followed by a repeat TURBT (Re-TURBT). The Re-TURBT is recommended due to the possibility of residual bladder cancer but is unnecessary in many cases by constituting overtreatment. Currently, no diagnostic strategy or predictive tools have been implemented to further stratify who does or does not benefit from Re-TURBT. Recently, an MRI-based Vesical Imaging Reporting and Data System (VI-RADS) score has been developed to stage as to the preoperative probability of muscle invasion, which could potentially exclude those who do not require a Re-TURBT when a primary high-quality resection is delivered. As such, performing TURBT with standard white light (WL) cystoscopy is known to miss many bladder tumours, which may be poorly visible, and a technique known as with photodynamic diagnosis (PDD) results in lower residual tumor and lower early intravesical recurrence rates. PDD is performed using violet light to improve the detection of these lesions not easily visible with WL cystoscopy. Methods/Aims: The investigators propose an Italian, single-center, phase IV, open-label, non-inferiority, randomized controlled trial, in which participants (n=112) who had already received a mpMRI/VI-RADS score, are randomized to receive PDD-TURBT, no Re-TURBT versus standard of care represented by conventional WL-TURBT followed by WL-Re-TURBT. The primary outcome is proportions of early recurrence in the urinary bladder. Secondary outcomes will include proportions of late BCa recurrence, late disease-free interval, time to progression to MIBC, patient's quality of life assessment, and cost-analysis. Perspective: The CUT-less trial aims to respond to this unmet need through a non-inferiority randomized clinical study potentially shaping the perspective for a paradigm shift towards a more personalized, socially, and economically sustainable updated NMIBC therapeutic pathway. Implications: The current clinical trial proposal is aiming to achieve a paradigm shift in the oncological and socio-economical management of urothelial malignancies of the urinary bladder. Our first concern is indeed to guarantee a safe and ground-breaking strategy to manage the pathway of such patients in order to guarantee the non-inferior oncologic safety (and possibly superiority) when compared to the current standard of care. Additionally, if our hypotheses are confirmed, the investigators will be able to significantly relieve these patients from the oncologic burden of an already invasive and arduous bladder cancer care path. Finally, safely avoiding an unnecessary, expensive surgical procedure will bring significant social and economic benefits to the EU healthcare system and possibly worldwide.

BACKGROUND, STATE OF THE ART and RATIONALE FOR THE INTERVENTIONS The vast majority (75-80%) of bladder cancers (BCa) patients present with disease confined either to the mucosa (stage Ta, carcinoma in situ [CIS]) or the submucosa (stage T1) according to the tumor, node, and metastasis (TNM) classification system. These tumours that do not invade the detrusor muscle of the urinary bladder are defined as superficial, non-invasive, or non-muscle invasive bladder cancers (NMIBC) to differentiate them from the less common, but significantly more deadly muscle invasive bladder cancers (MIBC; stage T2 - T4). Although the initial procedure for surgical management of both NMIBC and MIBC tumours is a trans-urethral resection of bladder tumor (TURBT), it serves different purposes for NMIBC when compared with MIBC. For NMIBC, TURBT acts as both a diagnostic and a therapeutic procedure, but for MIBC patients, TURBT is only a diagnostic procedure, as additional radical intervention, such as radical cystectomy (RC), are usually required. However, there are many potential issues that can affect TURBT performance, including a high degree of operator dependence for optimal outcomes. Along these lines, one particular issue is that many of the so-called early BCa recurrences are actually incomplete resections during initial TURBT. Incomplete resections can lead also to understaging (i.e., inaccurate discrimination between NMIBC and MIBC), which can adversely affect the survival of the patient. Incomplete tumor resection and residual tumor rates vary between 33% and 76% for all cases, with rates of 27-72% and 33-78% for Ta and T1 tumours, respectively. Also, underestimation of tumor depth invasion at first TURBT has been demonstrated in up to 7-30% of cases, increasing up to 45-51% in those with T1 tumours where no detrusor muscle was sampled in the specimen after initial TURBT. Based on these above issues, European Association of Urology (EAU) Guidelines recommend a second look and resection (i.e., re-do TURBT [Re-TURBT]) 2 to 6 weeks following the primary TURBT in cases of (I) incomplete initial TURBT or doubt about completeness of a TURBT, (II) if there is no detrusor muscle in the specimen after initial TURBT, and (III) in all T1 tumours. As such, if Re-TURBT is to be considered an "emergency rescue" performed because of the suboptimal quality of the initial TURBT, this can result in significant detriments to the patient's quality of life (QoL) (e.g., second hospitalization, second anesthesia, potential risk for complications, delay in definitive treatment etc.). These can result in additional negative social implications (e.g., productivity loss, indirect costs etc.) and health-care-related costs (e.g., surgical procedure costs, in-hospital recovery costs, postoperative care etc.). The CUT-less study aims to address these major oncological, economic, and social unmet needs related to the current EAU BCa algorithm throughout a phase IV, open-label, non-inferiority randomized controlled trial. In particular, one of our aims is trying to avoid unnecessary Re-TURBT by utilizing intraoperative visually enhanced photodynamic assisted TURBT (PDD-TURBT) among those who had already been evaluated by multiparametric magnetic resonance (mpMR) image-based staging before the initial TURBT as a combined novel strategy. In doing so, the investigators hope to select for those in whom a Re-TURBT would normally be recommended, unnecessarily. The investigators will compare this cohort to one that follows the current standard of care algorithm, (i.e., conventional white light [WL] initial TURBT followed by WL-Re-TURBT). The investigators will examine the relative proportions of early BCa recurrence within the first 4.5 months after randomization. This would be the time between randomization, surgical TURBTs (i.e., 1.5 months) and first follow-up cystoscopy which is set at 3 months according to the International NMIBC Clinical trial Guidelines. The primary objectives of the CUT-less trial are indeed to provide the highest level of evidence demonstrating non-inferiority between of this novel multidisciplinary and translational approach integrating functional MRI and intraoperative visually assisted enhanced trans-urethral surgery and the current EAU BCa pathway. This will potentially lead to the redefinition of the criteria for Re-TURBT selection and will avoid unnecessary surgical procedures in up to half of diagnosed NMIBCs. The impact of such paradigm shift will transform the patient's perspective in their own BCa care and will limit the social and economic burden of BCa management across the EU and hopefully worldwide. STUDY AIMS, DESIGN and METHODOLOGICAL FRAMEWORK Overall aim To utilize our expertise in mpMRI of the bladder diagnostics for pre-TURBT staging purposes, intraoperative TURBT optical imaging enhancement by PDD-guided primary resection in order to potentially shift clinical practice. In doing so, the investigators seek to improve the therapeutic algorithm and personalization for NMIBC treatment by not performing those Re-TURBT procedures which could be safely omitted. Sample Size Calculation The cohort of interest will be represented by intermediate/high-risk NMIBCs who are currently those eligible for Re-TURBT according to EUA Guidelines. For the primary outcome of the proportion of early BCa recurrence (i.e., within 4.5 months follow-up) between the two arms, the investigators acknowledge that rates of early BCa recurrence detection among NMIBCs undergoing TURBT along with adjuvant intravesical BCG immunotherapy in a population, with equally distributed literature-defined risk factors for BCa recurrences, have been shown to be 10% according to available literature. For the non-inferiority hypothesis, using 80% power and a 5% one sided-alpha, using an estimate for detection rate of early BCa recurrence among intermediate/high-risk NMIBCs of 7.5% and using a margin of clinical unimportance of 10%, n=112 patients per arm will be required. The choice of 10% as the margin of non-inferiority represents a difference that would be considered clinically unimportant in the detection rate for the event of early BCa recurrence in a population already screened by mpMRI and VI-RADS score determination for the risk of disease understaging. To achieve this, prior to randomization, the investigators will screen potential eligible participants by VI-RADS score determination and will exclude patients suspected for MIBC (15-20%) and, from the remaining NMIBCs, exclude low risk disease (25-30%). Furthermore, the investigators predict 35-40% of these patients will be recruited based on willingness to participate or missed opportunities for recruitment. Thus, total subjects required in study would be n=224. Accounting for 15% withdrawal/loss to follow up, n=258 men will need to be recruited. GROUND-BREAKING AMBITION OF THE PROPOSAL AND ADVANCEMENT OF KNOWLEDGE OVER THE STATE OF THE ART BCa is a high priority area for research into both clinical and cost-effective management and the findings from the CUT-less trial will be relevant and important to patient needs over the next years across the EU and worldwide. TURBT is the standard of care both to diagnose and treat the vast majority of NMIBCs. Nonetheless, to overcome the intrinsic limitations of TURBT, to achieve the desired complete resection, and to correct potential staging errors, a second endoscopic procedure (i.e., Re-TURBT) is recommended by EUA Guidelines for most intermediate and high-risk NMIBCs categories. However, there is still no currently available strategy to select the ideal candidate for this. Notably, from a patient perspective, there are often considerable anxieties about transurethral resection procedures, risk of recurrences, and progression requiring additional therapies with potential mortality and long-term morbidity. TURBTs in general, are associated with possible significant postoperative and long-term complications and morbidity ranging from 5.1% to 43.3% according to the different series. Specifically, the potential for complications during Re-TURBT is not trivial and hemorrhage, the need for blood transfusion, or bladder perforation can negatively impact patient care and lead to delays in treatment, ultimately influencing survival outcomes. Any TUR itself is therefore associated with reduced QoL, including in both mental and physical health domains. Substantial reductions in health related QoL are most likely to come from repeated hospitalizations, surgical complications, invasive adjuvant intravesical treatments, and radical or palliative treatments for progression. As consequence, a secondary resection performed 2 to 6 weeks from the primary resection represents an additional burden in an already arduous BCa pathway. To our knowledge this surgical scenario has never been scrutinized in the framework of a RCT despite the lack of evidence to uniformly support Re-TURBT in every case. Moreover, both European and American series had reported that performing Re-TURBT did not impact long-term progression-free survival and that the tumor status at repeat TUR had only a marginal role in influencing long-term cancer-specific survival. Additionally, NMIBC is one of the most expensive cancers to manage on a per patient basis because of its high prevalence, high recurrence rate, need for adjuvant treatments, and the requirement for long-term surveillance protocols. Because of the protracted clinical course of early-stage disease, its prevalence relative to MIBC, and its procedure-oriented surveillance, the associated cumulative medical payments are generally more substantial than those for advanced disease. The average per capita spending for NMIBC is increasing in the last two decades, from €7000 to €9000. These increasing costs are mainly attributable to the more frequent use of endoscopy (e.g., cystoscopy, TURBT, Re-TURBT) and the adjuvant intravesical therapies. TURBT accounts for a substantial portion of total bladder treatment costs ranging from €3000 to €6000 depending on whether patients are discharged following the procedure or admitted for inpatient care. Given these urgent needs for optimizing the NMIBC algorithm, the CUT-less trial will explore a novel multidisciplinary approach for minimizing the burden of surgical exposure to patients and for resizing the costs to the EU health care systems by redefining the selection criteria for NMIBC candidates for Re-TURBT procedures. In conclusion, the currently available EAU Guidelines rely on conflicting and out of date evidence which do not offer a contemporary viewpoint as to the role of Re-TURBT. Our updated protocol which utilizes both mpMRI diagnostic imaging and PDD guided resections will be closely examined in the CUT-less trial, with goal of more personalized, both socially and economically sustainable updated NMIBC therapeutic pathways for use in the EU.

Non-muscle-invasive Bladder Cancer, Non-Muscle Invasive Bladder Urothelial Carcinoma, High Risk Non-Muscle Invasive Bladder Urothelial Carcinoma

Italian, single-center, phase IV, open-label, randomized controlled trial, with patients randomized in a 1:1 ratio to one of two arms

Standard of care consisting in primary WL TURBT followed by WL Re-TURBT within 2 - 6 weeks from initial WL TURBT

In order to undergo PDD-TURBT, all eligible patients in the experimental arm will be administered the photosensitizer hexaminolevulinate (85 mg in 50 ml of phosphate buffered saline, Hexvix®) on an inpatient setting through a urethral catheterization of the participant's bladder. During the PDD-TURBT surgery, the bladder will be illuminated with blue light (wavelength 380-450 nm). The operating rooms of the participant institutions will therefore need to have the specialized equipment consisting in the blue-light source (POWER LED SAPHIRA [TM]).

This is a light source based on LED technology. It can be used for both White Light (WL) and fluorescence applications in blue light (i.e., Photodynamic diagnosis PDD) for visualizing tumor lesions during trans-urethral resection of bladder tumors (PPD- TURBT).

The proportion of early BCa recurrences (i.e., within 4.5 months follow-up) in those non-muscle invasive bladder cancer (NMIBC) treated by standard of care (i.e., TURBT followed by Re-TURBT) compared to our novel algorithm proposal (i.e., primary PDD-TURBT followed by no Re-TURBT).

To determine the proportion of BCa late recurrences (i.e., after 4.5 months follow-up) in patients with NMIBC treated by standard of care compared to our novel algorithm proposal

To determine the proportion of progression from NMIBC to MIBC in patients with NMIBC treated by standard of care compared to our novel algorithm proposal.

To determine changes in health-related quality of life (HRQoL) resulting from the physical and psychological benefit together with any harms associated with each strategy and with subsequent additional interventions. We will use generic QoL for cost-effectiveness analysis (i.e., EuroQoL Group [EQ]-5D-3L).

To determine changes in health-related quality of life (HRQoL) resulting from the physical and psychological benefit together with any harms associated with each strategy and with subsequent additional interventions. We will use and specific validated questionnaires to assess the outcomes of interest in the NMIBC population (i.e., European Organisation for Research and Treatment of Cancer [EORTC]-QLQ-C30).

To determine changes in health-related quality of life (HRQoL) resulting from the physical and psychological benefit together with any harms associated with each strategy and with subsequent additional interventions. We will use and specific validated questionnaires to assess the outcomes of interest in the NMIBC population (i.e., European Organisation for Research and Treatment of Cancer [EORTC] QLQ-NMIBC24).

To perform a within-trial cost-effectiveness analysis to calculate incremental cost per Re-TURBT avoided and the cost-utility of the experimental approach as measured by the incremental cost per quality-adjusted life year (QALY) gained at 2 years and over patients' lifetime.

Inclusion Criteria: Female and Male patients at least 18 years old referred for clinical suspicion of primary or recurrent BCa who have been advised to undergo TURBT. Patients with a TUR-confirmed diagnosis of NMIBC and candidate for second look and resection (Re-TURBT) according to EAU Guidelines [6]. No imaging evidence (i.e., mpMRI/VI-RADS score 1 or 2) of muscle-invasive, locally advanced, or metastatic BCa (i.e., only confirmed CIS, Ta, T1, N0, M0 will be considered eligible). Patients who never received adjuvant Bacillus of Calmette-Guérin (BCG) immunotherapy (i.e., BCG naïve patients) for previous BCa history. Fit to undergo all procedures listed in protocol. Able to provide written informed consent. Exclusion Criteria: Contraindication to TURBT and/or Re-TURBT. Initial TURBT diagnosis of MIBC (i.e., T2) or locally advanced BCa (i.e., T3-T4). Preoperative evidence of metastatic disease (i.e., cN1 - N3 and/or cM1). Visual evidence of low-risk NMIBC (solitary tumor, < 1 cm) before initial TURBT. Visual evidence of MIBC on preliminary cystoscopy (i.e., non-papillary or sessile mass attached directly by its base without a stalk). TURBT diagnosis of NMIBCs not eligible for Re-TURBT according to EAU Guidelines (i.e., Ta-LG; Ta-HG with detrusor muscle in the specimen; primary CIS) [6]. Concomitant Upper tract (kidney or ureteric) tumours on imaging. Contraindication to adjuvant intravesical BCG immunotherapy. Unfit to undergo any procedures listed in protocol.

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