Photodynamic Diagnosis (PDD) in Flexible Cystoscopy
Photodynamic Diagnosis (PDD) in Flexible Cystoscopy
Photodynamic diagnostic (PDD) is a technique where a photodynamic drug is installed
 preoperatively in the bladder. Mucosa cells with a higher metabolism than normal urothelial
 cells, e.g. cancer cells, absorbs this drug which is utilized during cystoscopy where blue
 light is absorbed by the drug, making the surgeon able to distinguish tumor cells from normal
 cells and thus being able to identify flat lesions and small papillomas missed in white light
 cystoscopy.

 The use of PDD at this primary transurethral resection of bladder tumour (TURB) has been
 shown to be associated with a lower recurrence rate within the first year, probably mostly
 owing to a higher detection rate of small papillomas and dysplasia that therefore can be
 relevantly treated at an early stage.

 Despite the use of PDD at the primary TURB, a high number of patients experience an early
 recurrence and patients with carcinoma in situ (CIS) treated with bacillus Calmette-Guerin
 (BCG) may have recurrence of their CIS or recurrence of papillomas despite the peroperative
 use of PDD.

 Whereas the use of PDD is well established in the TURB setting, the use of PDD in the
 follow-up setting with flexible cystoscopy in the outpatient clinic is not investigated.
 Feasibility studies have been successful but the clinical relevance and benefits have not
 been investigated so far.

 Thesis The thesis of the study is that the use of PDD in the outpatient clinic in patients
 with a high recurrence risk undergoing follow-up flexible cystoscopy will result in diagnosis
 of papillomas earlier than by the use of conventional flexible cystoscopy in white light.
 Thus, a higher number of tumours can be treated in the outpatient setting without the need
 for procedures in general anesthesia. Furthermore, the number of follow-up cystoscopies can
 be reduced if PDD is used at the first cystoscopy following TURB.

 Aims To investigate whether the use of PDD when performing a flexible cystoscopy in the
 outpatient clinic can reduce the number of recurrences of large size papillomas that cannot
 be treated by simple fulguration without general anesthesia. Furthermore, to investigate
 whether the use of PDD in follow-up cystoscopy in patients with earlier complete response to
 BCG on CIS, can increase the detection rate of CIS recurrences.
Background Bladder cancer is a very heterogeneous disease ranging from minimal pathology in
 small non-invasive Ta-tumors of low malignancy (Papillary Urothelial Neoplasm of Low
 Malignant Potential or low grade Ta tumours) easily fulgurated upon cystoscopy to deeply
 invasive metastasizing disease with fatal course despite aggressive treatment. Moreover,
 urothelial pathology ranges from flat lesions not visible in regular white light to massive
 bulky tumors.

 In advanced tumor stages with deeply invasive T1-tumours or muscle invasive disease (T2) the
 highest risk is progression is tumour, nodes, metastases (TNM) stage and the largest
 challenge thus to prevent this with aggressive radical treatment. In the lowest tumor stages
 with non-invasive Ta-tumors and even superficially infiltrating non-muscle invasive tumors,
 the vast majority of patients do not progress regarding stage but more than half of the
 patients experience a recurrence of tumor at the same stage in the bladder. These recurrences
 are time consuming, expensive to treat because of the high number, and is affecting quality
 of life because they result in a need for frequent follow-up visits and recurrent procedures.
 Flat lesions recur frequently after intravesical treatment and is associated with a high risk
 of progression if left untreated.

 Recurrent tumors are mostly treated by a transurethral resection of the bladder (TURB) in
 general anesthesia. However, if recognized at a very early stage, these tumors can be safely
 fulgurated in the outpatient clinic. Moreover, the recognition of flat lesions or even
 carcinoma in situ (CIS) at an earlier stage is presumed to be associated with a lower risk of
 progression to more advanced tumor stages.

 Therefore, a reduction of the size and number of recurrences and early recognition of flat
 lesions is desired.

 Early recurrences within the first year following the primary TURB are thought to arise in
 small areas of flat dysplasia, CIS, or small sub-visible papillomas not recognized at the
 primary procedure.

 PDD is a technique where a photodynamic drug is installed preoperatively in the bladder.
 Mucosa cells with a higher metabolism than normal urothelial cells, e.g. cancer cells,
 absorbs this drug which is utilized during cystoscopy where blue light is absorbed by the
 drug, making the surgeon able to distinguish tumor cells from normal cells and thus being
 able to identify flat lesions and small papillomas missed in white light cystoscopy.

 The use of PDD at this primary TURB has been shown to be associated with a lower recurrence
 rate within the first year, probably mostly owing to a higher detection rate of small
 papillomas and dysplasia that therefore can be relevantly treated at an early stage.

 Despite the use of PDD at the primary TURB, a high number of patients experience an early
 recurrence and patients with carcinoma in situ (CIS) treated with bacillus Calmette-Guerin
 (BCG) may have recurrence of their CIS or recurrence of papillomas despite the peroperative
 use of PDD.

 Whereas the use of PDD is well established in the TURB setting, the use of PDD in the
 follow-up setting with flexible cystoscopy in the outpatient clinic is not investigated.
 Feasibility studies have been successful but the clinical relevance and benefits have not
 been investigated so far.

 Thesis The thesis of the study is that the use of PDD in the outpatient clinic in patients
 with a high recurrence risk undergoing follow-up flexible cystoscopy will result in diagnosis
 of papillomas earlier than by the use of conventional flexible cystoscopy in white light.
 Thus, a higher number of tumours can be treated in the outpatient setting without the need
 for procedures in general anesthesia. Furthermore, the number of follow-up cystoscopies can
 be reduced if PDD is used at the first cystoscopy following TURB.

 Aims To investigate whether the use of PDD when performing a flexible cystoscopy in the
 outpatient clinic can reduce the number of recurrences of large size papillomas that cannot
 be treated by simple fulguration without general anesthesia.

 Methods

 The study is designed as a prospective, randomized study with randomization between
 conventional white light flexible cystoscopy or PDD flexible cystoscopy. The study includes
 the following category of patients that have the highest risk of tumor recurrence:

 • All patients coming for first outpatient flexible cystoscopy 4 month after TURB without
 subsequent BCG instillations.

 Patients will be informed of the study before the visit and if patient accept is given,
 randomization will be made at the time of cystoscopy. Patients in the PDD-arm will receive
 the intravesical instillation of Hexvix 1 hour prior of cystoscopy. Cystoscopy will be made
 with the Storz flexible PDD-cystoscope.

 Patients will be handled and followed according to the national Danish bladder tumor
 guidelines. This includes follow-up cystoscopy 4 and 12 months following the primary TURB in
 patients with low grade Ta tumors and follow-up cystoscopy at four months interval the first
 2 years following diagnosis in patients with high grade tumors or CIS. If tumor recurrence is
 diagnosed, size of the largest tumor is estimated based on the intervals: less than 5 mm,
 5-10 mm, 11-20 mm, and more than 20 mm. All tumor recurrences and suspicious areas in the
 mucosa will be histologically verified either by resection or biopsy before fulguration.

 Follow-up cystoscopies in the outpatient clinic are performed in white light (WL) in both
 arms.

 Primary endpoint:

 • Tumor recurrence found in outpatient flexible cystoscopies following but not including the
 cystoscopy 4 months after TURB where intervention is made. Patients are dichotomized
 regarding recurrence as primary endpoint in "any recurrence at any cystoscopy" versus "no
 recurrences" at cystoscopy 8 or 12 months of the primary TURB.

 Secondary outcomes:

 -  Number of procedures in general anesthesia within 12 months of the TURB

 -  Tumor recurrence of more than 5 mm, 10 mm, and more than 20 mm within 12 months of the
 TURB

 -  Progression in stage within 12 months of the TURB

 -  Identification of flat lesions including CIS

 Statistics Power calculation is made as one-sided testing at a 5% significance level with
 risk of type I error (alpha) of 0.05 and risk of type II error (beta) of 0.20. Given a
 recurrence rate of 35% within the first 12 month and presuming 15% of all patients have
 recurrence found at the 4 months cystoscopy leaves at minimum 20% for detection at 8 and 12
 months cystoscopy. This recurrence rate s slightly underestimated because patients with
 recurrences after 4 months also have a high risk of recurrence at the following cystoscopies.
 Recurrence rate is estimated to be reduced by one third (absolute 7%) to 13 % at the 8 and 12
 months cystoscopy by the use of PDD at 4 months cystoscopy. Thus, a number of 696 patients is
 needed when using equal sized groups of 348 in each of the randomization arms.

 Ethics The study has been approved by the Regional Science Ethics Committee (Number
 1-10-72-76-15) and the Danish Data Protection Agency (Number 1-16-02-111-15). The study will
 be reported on clinicaltrials.gov before initiation. The study has been submitted for
 approval at the Danish Health And Medicines Authority. The local good clinical practice
 (GCP)-units will be allocated to the trial.

 Timeframe The study is planned to begin February 2016. Inclusion of patients all 696 patients
 is expected to be terminated within an 18 month period. Follow-up of the last patient
 included can be made 8 months following the inclusion giving an estimated time of study
 analysis in the end of 2018.

 Set-up The study will be performed as a single surgeon, multi center study. Thus, one surgeon
 will be performing all cystoscopies at all three locations. Moreover the nurses involved in
 handling the cystoscopes and patients at each of the three locations will be limited to two
 at each location. This is to ensure the quality of the study and especially to reduce the
 risk of unintentional damage to the equipment including the cystoscopes.

 The three study locations will be:

 -  The outpatient clinic in Herlev at Herlev Hospital

 -  The outpatient clinic in Holstebro at Hospital of West Denmark

 -  The outpatient clinic at Aarhus University Hospital Based on patient catchment area of
 the involved centers, it is expected to include 40% at Herlev Hospital (approximately
 280 patients), 35% at Aarhus University Hospital (approximately 245 patients), and 25%
 at Hospital of West Denmark (approximately 175 patients). These are expected numbers
 subject to changes and will depend on inclusion rates at the involved centers.

 Additional project regarding health economics, logistics and time used for flexible PDD Along
 with the major project, two additional projects will be performed. One is a research year
 student looking at health economics by using flexible PDD. In this, time spend for the
 additional examination and biopsy will be compared to the time saved in case of a reduced
 recurrence rate leading to fewer TURB's and cystoscopies. Moreover, the finances saved by
 reducing the number of TURB's and cystoscopies will be compared with the additional cost by
 using PDD. The other project is a nurse led study evaluating the feasibility and logistics by
 implementing flexible PDD in the outpatient clinic. These studies will be evaluating all
 three involved clinics to give a more valid insight than one-center studies.
Inclusion Criteria:

 -  All patients coming for first outpatient flexible cystoscopy 4 month after TURB
 without subsequent BCG instillations

 Exclusion Criteria:

 -  Muscle invasive bladder cancer (MIBC)

 -  BCG treatment within the last year