Ignite Creation Date:
2024-05-06 @ 7:18 PM
Last Modification Date:
2024-10-26 @ 3:04 PM
Study NCT ID:
NCT05962541
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-03-22
First Post:
2023-07-13
Brief 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
Sponsor:
University of Roma La Sapienza
Organization:
University of Roma La Sapienza
Study Overview
Official Title:
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
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
CUT-less
Brief 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
MethodsAims The investigators propose an Italian single-center phase IV open-label non-inferiority randomized controlled trial in which participants n112 who had already received a mpMRIVI-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 patients 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
MethodsAims The investigators propose an Italian single-center phase IV open-label non-inferiority randomized controlled trial in which participants n112 who had already received a mpMRIVI-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 patients 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 ie 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 ie 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 patients quality of life QoL eg second hospitalization second anesthesia potential risk for complications delay in definitive treatment etc These can result in additional negative social implications eg productivity loss indirect costs etc and health-care-related costs eg 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 ie 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 45 months after randomization This would be the time between randomization surgical TURBTs ie 15 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 patients 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 intermediatehigh-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 ie within 45 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 intermediatehigh-risk NMIBCs of 75 and using a margin of clinical unimportance of 10 n112 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 n284 Accounting for 15 withdrawalloss to follow up n327 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 ie 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 51 to 433 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 eg 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
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 ie 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 ie 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 patients quality of life QoL eg second hospitalization second anesthesia potential risk for complications delay in definitive treatment etc These can result in additional negative social implications eg productivity loss indirect costs etc and health-care-related costs eg 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 ie 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 45 months after randomization This would be the time between randomization surgical TURBTs ie 15 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 patients 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 intermediatehigh-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 ie within 45 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 intermediatehigh-risk NMIBCs of 75 and using a margin of clinical unimportance of 10 n112 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 n284 Accounting for 15 withdrawalloss to follow up n327 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 ie 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 51 to 433 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 eg 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None