Prevention of IVR: a need for investigation

Prevention of IVR: a need for investigation Abstract Intravesical recurrence (IVR) after RNU for UTUC is a frequent event, occurring in 20–50% of patients, mostly in the first postoperative year. Several retrospective studies have shown that predictors of IVR include clinical characteristics, surgical features and as well pathological characteristics (previous history of bladder cancer, pathological stage, lymph node involvement, cis, endoscopic distal ureter, etc.) management. Two prospective studies provide level I evidence for the safety and efficacy of intravesical single postoperative chemotherapy for patients treated with radical nephroureterectomy (RNU) for UTUC in order to prevent IVR. However, some questions remain unanswered. Yamashita et al. in the current issue of the journal have shown that early ureteral ligation during RNU decreases the risk of IVR in patients with pelvycalyceal upper tract urothelial carcinoma. This study despite its limitations represent a step towards improved outcomes for our patients with UTUC, the relatively low morbidity of the procedure added to the potential benefit associated with this early ligation make it an easy implementation in daily practice. upper tract urothelial carcinoma, early ligation, intravesical recurrence, prevention Intravesical recurrence (IVR) after RNU for UTUC is a frequent event, occurring in 20–50% of patients, mostly in the first postoperative year (1,2), thus requiring intense bladder surveillance (i.e. cytology and cystoscopy). However, the ideal surveillance regimen has yet to be defined. The vast majorities of IVR are non-muscle invasive and therefore seem to not impact the survival outcomes of these patients. The understanding of that phenomenon has yield to two hypotheses the so-called ‘tumor seeding’ as well as the ‘field change’. No prospective studies have been undertaken yet in order to determine the prognostic factors of IVR after RNU for UTUC. Several retrospective studies have shown that predictors of IVR include clinical characteristics, surgical features and as well pathological characteristics (previous history of bladder cancer, pathological stage, lymph node involvement, cis, endoscopic distal ureter, etc.) management (1,2). Moreover, an immediate postoperative intravesical instillation of chemotherapy has been proposed in order to reduce the risk of IVR after RNU. To date, three prospective randomized trials have investigated this topic. In 2001, Sakamoto et al. failed to demonstrate the efficacy of a combination of mitomycin C (MMC) and cytosine arabinoside in 27 patients treated with RNU for UTUC (3). Conversely, O’Brien et al. demonstrated that a single postoperative administration of intravesical MMC reduces the probability of IVR following RNU by 11% (absolute risk reduction). In other words, nine patients need to be treated to prevent one IVR (ODMIT-C trial) (4). More recently, Ito et al. confirmed these findings and showed, for the first time, that intravesical chemotherapy (THP) is associated with a lower IVR rate even after adjusting for the effects of standard clinicopathological features (2 years intravesical rates: 16.9% versus 42.2% in the control group, respectively; P = 0.025) (5). These later two studies provide level I evidence for the safety and efficacy of intravesical single postoperative chemotherapy for patients treated with RNU for UTUC. However, some questions remain unanswered. Yamashita et al. in the current issue of the journal have shown that early ureteral ligation during RNU decreases the risk of IVR in patients with pelvycalyceal upper tract urothelial carcinoma (6). In these patients, the 1- and 2-year IVR-free survival rates in the early ureteral ligation group were 89% and 86%, compared with 74% and 64% in the control group (P = 0.025). The authors have to be congratulated for conducting a Phase 2 surgical trial in this challenging field of upper tract urothelial carcinoma (6). However, some limitations of the study have to be underlined. First, the study despite being a prospective Phase 2 clinical trial was not designed as a Phase 3 randomized controlled study. Thus, the control arm was a retrospective historical control arm making these comparisons less robust despite propensity score matching. Second, only 22 patients (14.9%) received an immediate postoperative instillation of THP after the RNU. While these numbers were adjusted for in the control arm, the question of whether the benefit of early ligation could be balanced with the lack of immediate postoperative instillation is under debate. Third, due to the small sample size of the trial and to the exclusion of patients with a previous history of bladder cancer, subgroup analyses were not possible. The potential impact of well-established prognostic factors for IVR such as type of distal bladder cuff management (i.e. endoscopic, extravesical or transvesical) and history of previous bladder cancer remains unclear (2). Finally, this study represent a step towards improved outcomes for our patients with UTUC, the relatively low morbidity of the procedure added to the potential benefit associated with this early ligation make it an easy implementation in daily practice. Conflict of interest statement None declared. References 1 Novara G, De Marco V, Dalpiaz O, et al.  . Independent predictors of metachronous bladder transitional cell carcinoma (TCC) after nephroureterectomy for TCC of the upper urinary tract. BJU Int  2008; 101: 1368– 74. Google Scholar CrossRef Search ADS PubMed  2 Xylinas E, Rink M, Cha EK, et al.  . Impact of distal ureter management on oncologic outcomes following radical nephroureterectomy for upper tract urothelial carcinoma. Eur Urol  2014; 65: 210– 7. Google Scholar CrossRef Search ADS PubMed  3 Sakamoto N, Naito S, Kumazawa J, et al.  . Kyushu University Urological Oncology G: prophylactic intravesical instillation of mitomycin C and cytosine arabinoside for prevention of recurrent bladder tumors following surgery for upper urinary tract tumors: a prospective randomized study. Int J Urol  2001; 8: 212– 6. Google Scholar CrossRef Search ADS PubMed  4 O’Brien T, Ray E, Singh R, Coker B, Beard R. British Association of Urological Surgeons Section of O: prevention of bladder tumours after nephroureterectomy for primary upper urinary tract urothelial carcinoma: a prospective, multicentre, randomised clinical trial of a single postoperative intravesical dose of mitomycin C (the ODMIT-C Trial). Eur Urol  2011; 60: 703– 10. Google Scholar CrossRef Search ADS PubMed  5 Ito A, Shintaku I, Satoh M, et al.  . Prospective randomized phase II trial of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma: the THP Monotherapy Study Group Trial. J Clin Oncol  2013; 31: 1422– 7. Google Scholar CrossRef Search ADS PubMed  6 Yamashita S, Ito A, Mitsuzuka K, et al.  . Efficacy of early ureteral ligation on prevention of intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma: a prospective single-arm multicenter clinical trial. Jpn J Clin Oncol  2017; 47: 870– 5. Google Scholar CrossRef Search ADS PubMed  © The Author 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Japanese Journal of Clinical Oncology Oxford University Press

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Abstract

Abstract Intravesical recurrence (IVR) after RNU for UTUC is a frequent event, occurring in 20–50% of patients, mostly in the first postoperative year. Several retrospective studies have shown that predictors of IVR include clinical characteristics, surgical features and as well pathological characteristics (previous history of bladder cancer, pathological stage, lymph node involvement, cis, endoscopic distal ureter, etc.) management. Two prospective studies provide level I evidence for the safety and efficacy of intravesical single postoperative chemotherapy for patients treated with radical nephroureterectomy (RNU) for UTUC in order to prevent IVR. However, some questions remain unanswered. Yamashita et al. in the current issue of the journal have shown that early ureteral ligation during RNU decreases the risk of IVR in patients with pelvycalyceal upper tract urothelial carcinoma. This study despite its limitations represent a step towards improved outcomes for our patients with UTUC, the relatively low morbidity of the procedure added to the potential benefit associated with this early ligation make it an easy implementation in daily practice. upper tract urothelial carcinoma, early ligation, intravesical recurrence, prevention Intravesical recurrence (IVR) after RNU for UTUC is a frequent event, occurring in 20–50% of patients, mostly in the first postoperative year (1,2), thus requiring intense bladder surveillance (i.e. cytology and cystoscopy). However, the ideal surveillance regimen has yet to be defined. The vast majorities of IVR are non-muscle invasive and therefore seem to not impact the survival outcomes of these patients. The understanding of that phenomenon has yield to two hypotheses the so-called ‘tumor seeding’ as well as the ‘field change’. No prospective studies have been undertaken yet in order to determine the prognostic factors of IVR after RNU for UTUC. Several retrospective studies have shown that predictors of IVR include clinical characteristics, surgical features and as well pathological characteristics (previous history of bladder cancer, pathological stage, lymph node involvement, cis, endoscopic distal ureter, etc.) management (1,2). Moreover, an immediate postoperative intravesical instillation of chemotherapy has been proposed in order to reduce the risk of IVR after RNU. To date, three prospective randomized trials have investigated this topic. In 2001, Sakamoto et al. failed to demonstrate the efficacy of a combination of mitomycin C (MMC) and cytosine arabinoside in 27 patients treated with RNU for UTUC (3). Conversely, O’Brien et al. demonstrated that a single postoperative administration of intravesical MMC reduces the probability of IVR following RNU by 11% (absolute risk reduction). In other words, nine patients need to be treated to prevent one IVR (ODMIT-C trial) (4). More recently, Ito et al. confirmed these findings and showed, for the first time, that intravesical chemotherapy (THP) is associated with a lower IVR rate even after adjusting for the effects of standard clinicopathological features (2 years intravesical rates: 16.9% versus 42.2% in the control group, respectively; P = 0.025) (5). These later two studies provide level I evidence for the safety and efficacy of intravesical single postoperative chemotherapy for patients treated with RNU for UTUC. However, some questions remain unanswered. Yamashita et al. in the current issue of the journal have shown that early ureteral ligation during RNU decreases the risk of IVR in patients with pelvycalyceal upper tract urothelial carcinoma (6). In these patients, the 1- and 2-year IVR-free survival rates in the early ureteral ligation group were 89% and 86%, compared with 74% and 64% in the control group (P = 0.025). The authors have to be congratulated for conducting a Phase 2 surgical trial in this challenging field of upper tract urothelial carcinoma (6). However, some limitations of the study have to be underlined. First, the study despite being a prospective Phase 2 clinical trial was not designed as a Phase 3 randomized controlled study. Thus, the control arm was a retrospective historical control arm making these comparisons less robust despite propensity score matching. Second, only 22 patients (14.9%) received an immediate postoperative instillation of THP after the RNU. While these numbers were adjusted for in the control arm, the question of whether the benefit of early ligation could be balanced with the lack of immediate postoperative instillation is under debate. Third, due to the small sample size of the trial and to the exclusion of patients with a previous history of bladder cancer, subgroup analyses were not possible. The potential impact of well-established prognostic factors for IVR such as type of distal bladder cuff management (i.e. endoscopic, extravesical or transvesical) and history of previous bladder cancer remains unclear (2). Finally, this study represent a step towards improved outcomes for our patients with UTUC, the relatively low morbidity of the procedure added to the potential benefit associated with this early ligation make it an easy implementation in daily practice. Conflict of interest statement None declared. References 1 Novara G, De Marco V, Dalpiaz O, et al.  . Independent predictors of metachronous bladder transitional cell carcinoma (TCC) after nephroureterectomy for TCC of the upper urinary tract. BJU Int  2008; 101: 1368– 74. Google Scholar CrossRef Search ADS PubMed  2 Xylinas E, Rink M, Cha EK, et al.  . Impact of distal ureter management on oncologic outcomes following radical nephroureterectomy for upper tract urothelial carcinoma. Eur Urol  2014; 65: 210– 7. Google Scholar CrossRef Search ADS PubMed  3 Sakamoto N, Naito S, Kumazawa J, et al.  . Kyushu University Urological Oncology G: prophylactic intravesical instillation of mitomycin C and cytosine arabinoside for prevention of recurrent bladder tumors following surgery for upper urinary tract tumors: a prospective randomized study. Int J Urol  2001; 8: 212– 6. Google Scholar CrossRef Search ADS PubMed  4 O’Brien T, Ray E, Singh R, Coker B, Beard R. British Association of Urological Surgeons Section of O: prevention of bladder tumours after nephroureterectomy for primary upper urinary tract urothelial carcinoma: a prospective, multicentre, randomised clinical trial of a single postoperative intravesical dose of mitomycin C (the ODMIT-C Trial). Eur Urol  2011; 60: 703– 10. Google Scholar CrossRef Search ADS PubMed  5 Ito A, Shintaku I, Satoh M, et al.  . Prospective randomized phase II trial of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma: the THP Monotherapy Study Group Trial. J Clin Oncol  2013; 31: 1422– 7. Google Scholar CrossRef Search ADS PubMed  6 Yamashita S, Ito A, Mitsuzuka K, et al.  . Efficacy of early ureteral ligation on prevention of intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma: a prospective single-arm multicenter clinical trial. Jpn J Clin Oncol  2017; 47: 870– 5. Google Scholar CrossRef Search ADS PubMed  © The Author 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

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Japanese Journal of Clinical OncologyOxford University Press

Published: Mar 1, 2018

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