Stesura Seveso Archivio Italiano di Urologia e Andrologia 2022; 94, 4424 ORIGINAL PAPER No conflict of interest declared. INTRODUCTION Bladder cancer (BC) represents the seventh most diag- nosed cancer in men worldwide, and the tenth one con- sidering both genders. Moreover, Europe is considered one of the countries with the highest incidence with an age-standardized rate of 20 per 100,000 person/years for men (compared to 9.5 worldwide) and 4.6 for women (compared to 2.4 worldwide) (1). Furthermore, it is one of the malignancies with a high economic burden due to its treatments and follow-up (2). Hence, a correct diagnosis and staging are of utmost importance for correct treatment. Transurethral resection of the bladder (TURB) is considered the gold standard to ascertain BC diagnosis, and plan further treatments and can be a curative procedure for early-stage disease (pTa/T1 tumours) (3-5). Nonetheless, guidelines also rec- ommend performing a second TURB in specific clinical scenarios, mainly: after an incomplete first TURB, when there are doubts about the completeness of the first resec- tion, in case of the absence of detrusor muscle in the specimen (except for Ta LG/G1 tumours and primary CIS) and when there is the presence of T1 tumours (6, 7). Second TURB (reTURB) has the intent to eradicate all the tumour burden since there is a consistent risk of leaving residual tumours and consequently of recurrence (1, 8, 9). To improve the correct tumour identification and improve staging and treatment, Hexaminolevulinate Photodynamic Diagnostics (PDD)-guided TURB has been proposed and demonstrated to be more sensitive than conventional procedures (10-13). For these reasons, European guidelines propose to use methods to improve tumor visualization including PDD (1). The aim of our study was to evaluate the advantage of using PDD at first TURB on the rate of residual and evaluate if using this technology, we could safely omit a reTURB, without com- promising oncological outcomes. Objective: Bladder cancer (BC) is considered one of the malignancies with moderate-high incidence, high rate of recurrence and costly management. Diagnosis and staging are thus important for therapeutic purpos- es. Considering the risk of residual tumour and understaging, in specific cases, international guidelines recommend performing a second transurethral resection of the bladder (reTURB). Our study aimed to evaluate the impact of hexaminolevulinate Photodynamic Diagnostics (PDD) at first TURB on the rate of residual tumour. Materials and Methods: We retrospectively analysed patients undergoing TURB in our centre between 2012 and 2020. Eighty- two patients had a re-TURB after a first complete TURB with a delay < 3 months. Patients who had an incomplete first resection were excluded. We compared patients who underwent standard white light cystoscopy/TURB and then hexaminolevulinate PDD- guided reTURB (group A, n = 49) and patients with PDD-cys- toscopy/TURB at the first procedure then white light cystoscopy/reTURB (group B, n = 33). The residual tumour rate at reTURB as well as median recurrence-free survival (RFS) were compared between the two groups. Results: Residual tumour at reTURB was detected in 48.8% of cases in our cohort, with a significant difference between the two groups (71.4% in group A versus 12.5% in group B, p < 0.001). After a median follow-up of 22 months, the median RFS was 15 months in Group A and 32 months in Group B, but this differ- ence was not significant (p = 0.7). Conclusions: Using PDD at the time of the initial TURB had a statistically significant impact on the rate of residual tumour at the reTURB. Nevertheless, the percentage of residual tumour even with the use of PDD does not allow for safely omitting sec- ond resection. Performing a reTURB with PDD for patients who did not have it initially, provides the same benefit in terms of recurrence-free survival. KEY WORDS: Bladder cancer; Hexvix; TURB; Second resection; Residual tumor. Submitted 9 October 2022; Accepted 19 November 2022 Could we safely omit a Repeat Transurethral Resection of the Bladder (re-TURB) after Hexaminolevulinate Photodynamic Diagnostics (PDD)-TURB? Vito Lorusso 1, 2, 3, Laure Doisy 1, Antonio Maria Granata 2, Andrea Gregori 2, Celeste Manfredi 4, Lorenzo Spirito 4, Carmine Sciorio 5, Luca Giuseppe Maria Ciancimino 5, Samuele Molteni 5, Michele Morelli 6, Luigi Cirillo 7, Luigi Napolitano 7, Jochen Walz 1, Geraldine Pignot 1 1 Department of Urology, Institut Paoli-Calmettes Cancer Center, Marseille, France; 2 Department of Urology, ASST Fatebenefratelli-Sacco Hospital, Milan, Italy; 3 University of Milan, Milan, Italy; 4 Urology Unit, Department of Woman, Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy; 5 Department of Urology, ASST Lecco, Ospedale Alessandro Manzoni, Lecco, Italy; 6 Department of Urology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; 7 Department of Neurosciences, Science of Reproduction and Odontostomatology, University of Naples Federico II, Naples, Italy. DOI: 10.4081/aiua.2022.4.424 Summary 425Archivio Italiano di Urologia e Andrologia 2022; 94, 4 Re-TURB after PDD-TURB MATERIALS AND METHODS We retrospectively analysed patients undergoing TURB in our centre between 2012 and 2020. Eighty-two patients had a reTURB after a first complete TURB with a delay < 3 months. Patients who had an incomplete first resection were excluded. We compared patients who underwent standard white light cystoscopy/TURB and then hexam- inolĂ©vulinate PDD-guided reTURB (Group A, n = 49) and patients with PDD-cystoscopy/TURB at the first proce- dure then white light cystoscopy/reTURB (Group B, n = 33). The residual tumour rate at reTURB as well as medi- an recurrence-free survival were compared. Comparisons of the proportions were done by the 𝛘ÂČ test. Kaplan-Meier curves were used to analyze time to recurrence and to compare the two groups. The statistical analysis was done with SPSS version 25 (SPSS Inc., Chicago, IL, USA). RESULTS No statistically significant differences were observed between the two groups in terms of age, sex, history of bladder cancer, stage, grade, presence of CIS, presence of muscle and multifocality (Table 1). Residual tumour at reTURB was detected in 48.8% of cases in our cohort, with a significant difference between the two groups (71.4% in group A versus 12.5% in group B, p < 0.001). After a median follow-up of 22 months, the median recur- rence-free survival (RFS) was 15 months in group A and 32 months in group B (Figure 1), but this difference was not significant (p = 0.7). DISCUSSION In this retrospective study, we compared patients who underwent standard white light cystoscopy/TURB then PDD-guided reTURB and patients with PDD-cys- toscopy/TURB at the first procedure then white light cys- toscopy/reTURB. After the first resection, there was a risk of disease recurrence due to a regrowth of undetected lesions. We found that PDD cystoscopy at the time of the initial TURB had a statistically significant impact on the rate of residual tumor at the reTURB. In fact, we found that residual tumor rates at reTURB were 71.4% and 12.5% in Group A and B respectively. Our result corrob- orated data from previously published studies. Since its first use in 1994, the benefits of fluorescent light cys- toscopy with hexaminolevulinate (HAL) in non-muscle- invasive bladder cancer (NMIBC) have been reported in many trials. Nowadays PDD is widely used for the diag- nosis and treatment of superficial bladder cancer. In NMIBC the possible benefits of using PDD- guided TURB were higher detection rates, a high- er rate of complete resection, and fewer residual tumors (14). Several studies reported an increased tumor detection rate by HAL-PDD with a most pronounced benefit for CIS lesions (15). Riedel et al. found lower residual tumor rates for Ta and T1 tumors using PDD, while Filbeck et al. found a statistically significant reduction of residual tumors only in Ta tumors (16, 17). Albarghouth et al. showed that the use of PDD significantly reduces the risk of residual tumors compared with conventional TURB. In the same study, they have also shown that PDD can significantly improve 3 and 12-month recurrence-free sur- vival especially in low and interme- diate-risk tumors, and 1-year pro- gression-free survival in high-risk tumors (18). Burger et al. conduct- Table 1. Baseline characteristic and postoperative variable statistics of patient (n = 82). Blue Light Cystoscopy at First TURB P value No-Group A (n = 49) Yes-Group B (n = 33) N % N % Age (years), median (SD) 69 (9) - 71 (9) - 0.7 a Sex F 8 47 9 52 0.23 b M 41 63 24 36 Stage Ta 11 73 4 26 0.23 b T1 38 56 29 43 Presence of CIS Yes 32 64 18 36 0.32 b No 17 53 15 46 Presence of muscle Yes 9 69 4 30 0.44 b No 40 58 29 42 Multifocality Yes 29 60 19 39 0.8 b No 20 58 14 41 R+ Yes 14 33 28 66.7 < 0.001 b No 35 87 5 12.5 Recidive Yes 36 61 23 39 0.7 b No 13 56 10 43 RFS 15 32 0.7 c F: Female; M: Male; CIS: Carcinoma in situ; R+: Residual tumor; RFS: Recurrence free survival; a Student t Test; b Chi Test; c Log-rank Test. Figure 1. Kaplan-Meier curves for recurrence-free survival time. Archivio Italiano di Urologia e Andrologia 2022; 94, 4 V. Lorusso, L. Doisy, A.M. Granata, et al. 426 ed a meta-analysis confirming that HAL-PDD cystoscopy significantly improves the detection of bladder tumours leading to a reduction of recurrence at 9-12 month (19). Mariappan et al. found that HAL-PDD-assisted TURB was associated with a significantly lower risk of early recur- rence compared to white light TURB. Moreover, recur- rence rate at the first follow-up cystoscopy in the study cohort was 13.6% and 30.9% in the two settings respec- tively (20). Gakis et al. systematically reviewed literature reporting a significantly lower rate of progression in patients treated with PDD compared to white light TURB (21). In a recent meta-analysis Sun et al. reported that cys- toscopy with aminolevulinic acid (ALA) or HAL was asso- ciated to a reduced residual tumor rate compared with standard cystoscopy in NMIBC and RFS was higher in the first case at the 12- to 24-month follow-up (22). Even if we confirmed that the use of PDD allows reduc- ing residual tumour rate, we did not find a statistically significant difference in terms of RFS. This can be explained by the design of our study which establishes the use of PDD in both groups but at different times. Probably the difference in terms of RFS favouring the group who perform PDD initially, which is also marked at the beginning of follow-up, tends to be mitigated later by the delayed use of PDD in the other group as shown by the Kaplan-Meier curves. We also conceived this study to question if the use of PDD at the initial TURB would allow for the omission of a re- resection that, meaning a second surgical procedure, can have an impact not only for the patient (psychological, surgical or medical-related complications) but also for the healthcare systems in terms of costs. However, despite the advantages of the PDD technique, considering the biolog- ical characteristic of bladder cancer and the percentage of the residual tumour even after PDD cystoscopy we do not consider it safe to spare a second resection. Our study is not devoid of limitations: mainly its retro- spective nature and the small sample size. Concluding, reTURB even with the aid of PDD technolo- gy seems to be necessary. Even if all studies showed a reduced risk of residual tumour, none of them suggested to avoid a reTURB. CONCLUSIONS The quality of the initial TURB, when performed by using PDD, had a statistically significant impact on the rate of residual tumour at the reTURB. Nevertheless, the per- centage of residual tumour even after PDD cystoscopy is not negligible and cannot allow to safely avoid a second resection. Performing a reTURB with PDD for patients who did not have it initially, provides the same benefit in terms of recurrence free survival. REFERENCES 1. Babjuk M, Burger M, Capoun O, et al. European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (Ta, T1, and Carcinoma in Situ). Eur Urol. 2022; 81:75-94. 2. Sievert KD, Amend B, Nagele U, et al. 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Correspondence Vito Lorusso, MD vito.lorusso@unimi.it Laure Doisy, MD doisyl@ipc.unicancer.fr Antonio Maria Granata, MD antonio.granata@asst-fbf-sacco.it Andrea Gregori, MD andrea.gregori@asst-fbf-sacco.it Celeste Manfredi, MD manfredi.celeste@gmail.com Lorenzo Spirito, MD lorenzo.spirito@unicampania.it Carmine Sciorio, MD carminesciorio@gmail.com Samuele Molteni, MD sa.molteni@asst-lecco.it Luca Giuseppe Maria Ciancimino, MD lucaciancimino91@gmail.com Michele Morelli, MD michelemorelli4@gmail.com Luigi Cirillo, MD cirilloluigi22@gmail.com Luigi Napolitano, MD (Corresponding Author) luiginap89@gmail.com Department of Neurosciences, Reproductive Sciences and Odontostomatology, Urology Unit, University of Naples "Federico II", Naples, Italy Via Sergio Pansini n 5, Naples (NA), Campania (Italy) Jochen Walz, MD walzj@ipc.unicancer.fr Geraldine Pignot, MD pignotg@ipc.unicancer.fr