Trial Title:
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)
NCT ID:
NCT05962541
Condition:
Non-muscle-invasive Bladder Cancer
Non-Muscle Invasive Bladder Urothelial Carcinoma
High Risk Non-Muscle Invasive Bladder Urothelial Carcinoma
Conditions: Official terms:
Carcinoma
Urinary Bladder Neoplasms
Carcinoma, Transitional Cell
Non-Muscle Invasive Bladder Neoplasms
Study type:
Interventional
Study phase:
Phase 4
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
Italian, single-center, phase IV, open-label, randomized controlled trial, with patients
randomized in a 1:1 ratio to one of two arms
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
PDD-TURBT with hexaminolevulinate (Hexvix®)
Description:
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]).
Arm group label:
PPD-TURBT (no Re-TURBT)
Other name:
Hexvix®
Intervention type:
Device
Intervention name:
Power Led Saphira (TM)
Description:
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).
Arm group label:
PPD-TURBT (no Re-TURBT)
Summary:
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.
Detailed description:
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=284. Accounting for 15% withdrawal/loss
to follow up, n=327 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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. 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.
2. Patients with a TUR-confirmed diagnosis of NMIBC and candidate for second look and
resection (Re-TURBT) according to EAU Guidelines [6].
3. 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).
4. Patients who did or did not receive previous BCG immunotherapy (i.e., BCG naïve and
non-naïve patients).
5. Fit to undergo all procedures listed in protocol.
6. Able to provide written informed consent.
Exclusion Criteria:
1. Contraindication to TURBT and/or Re-TURBT.
2. Initial TURBT diagnosis of MIBC (i.e., T2) or locally advanced BCa (i.e., T3-T4).
3. Preoperative evidence of metastatic disease (i.e., cN1 - N3 and/or cM1).
4. Visual evidence of low-risk NMIBC (solitary tumor, < 1 cm) before initial TURBT.
5. Visual evidence of MIBC on preliminary cystoscopy (i.e., non-papillary or sessile
mass attached directly by its base without a stalk).
6. 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].
7. Concomitant Upper tract (kidney or ureteric) tumours on imaging.
8. Contraindication to adjuvant intravesical BCG immunotherapy.
9. Unfit to undergo any procedures listed in protocol.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
January 2025
Completion date:
February 2030
Lead sponsor:
Agency:
University of Roma La Sapienza
Agency class:
Other
Source:
University of Roma La Sapienza
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05962541
