Cancer Research and Treatment

Original Articles

Genitourinary cancer

Neoadjuvant Cisplatin-Based Chemotherapy Followed by Selective Bladder Preservation Chemoradiotherapy in Muscle-Invasive Urothelial Carcinoma of the Bladder: Post Hoc Analysis of Two Prospective Studies: Sung Wook Cho, Sung Hee Lim, Ghee Young Kwon, Chan Kyo Kim, Won Park, Hongryull Pyo, Jae Hoon Chung, Wan Song, Hyun Hwan Sung, Byong Chang Jeong, Se Hoon Park; Cancer Res Treat. 2024;56(3):893-897. Published online February 15, 2024; DOI: https://doi.org/10.4143/crt.2024.015

Purpose
Bladder preservation chemoradiotherapy (CRT) in patients with a clinical complete response (cCR) following cisplatin-based neoadjuvant chemotherapy (NAC) is a promising treatment strategy for muscle-invasive bladder urothelial carcinoma (MIBC). A combined analysis of raw data from two prospective phase II studies was performed to better evaluate the feasibility of selective bladder preservation CRT.
Materials and Methods
The analysis was based on primary efficacy data from two independent studies, including 76 MIBC patients receiving NAC followed by bladder preservation CRT. The efficacy data included metastasis-free survival (MFS) and disease-free survival (DFS). For the present analysis, starting point of survival was defined as the date of commencing CRT.
Results
Among 76 patients, 66 had a cCR following NAC. Sixty-four patients received gemcitabine and cisplatin (GC) combination chemotherapy in neoadjuvant setting, and 12 received nivolumab plus GC. Bladder preservation CRT following NAC was generally well-tolerated, with low urinary tract symptoms being the most common late complication. With a median follow-up of 64 months, recurrence was recorded in 43 patients (57%): intravesical only (n=20), metastatic only (n=16), and both (n=7). In 27 patients with intravesical recurrence, transurethral resection, and Bacillus Calmette-Guerin treatment was given to 17 patients. Salvage cystectomy was performed in 10 patients. Median DFS was 46.3 (95% confidence interval [CI], 25.1 to 67.5) months, and the median MFS was not reached. Neither DFS nor MFS appeared to be affected by any of the baseline characteristics. However, DFS was significantly longer in patients with a cCR than in those without (hazard ratio, 0.465; 95% CI, 0.222 to 0.976).
Conclusion
The strategy of NAC followed by selective bladder preservation CRT based on the cCR is feasible in the treatment of MIBC. A standardized definition of cCR is needed to better assess disease status post-NAC.

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News and prospects on radiotherapy for bladder cancer: Is trimodal therapy becoming the gold standard?
Olivier Riou, Christophe Hennequin, Jonathan Khalifa, Paul Sargos
Cancer/Radiothérapie.2024; 28(6-7): 623. CrossRef

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Single Early Intravesical Instillation of Epirubicin for Preventing Bladder Recurrence after Nephroureterectomy in Upper Urinary Tract Urothelial Carcinoma: Jong Hoon Lee, Chung Un Lee, Jae Hoon Chung, Wan Song, Minyong Kang, Hwang Gyun Jeon, Byong Chang Jeong, Seong Il Seo, Seong Soo Jeon, Hyun Hwan Sung; Cancer Res Treat. 2024;56(3):877-884. Published online January 17, 2024; DOI: https://doi.org/10.4143/crt.2023.1219

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Purpose
We aimed to assess the effectiveness of early single intravesical administration of epirubicin in preventing intravesical recurrence after radical nephroureterectomy for upper tract urothelial carcinoma.
Materials and Methods
Patients with upper tract urothelial carcinoma who underwent radical nephroureterectomy between November 2018 and May 2022 were retrospectively reviewed. Intravesical epirubicin was administered within 48 hours if no evidence of leakage was observed. Epirubicin (50 mg) in 50 mL normal saline solution was introduced into the bladder via a catheter and maintained for 60 minutes. The severity of adverse events was graded using the Clavien-Dindo classification. We compared intravesical recurrence rate between the two groups. Multivariate analyses were performed to identify the independent predictors of bladder recurrence following radical nephroureterectomy.
Results
Epirubicin (n=55) and control (n=116) groups were included in the analysis. No grade 1 or higher bladder symptoms have been reported. A statistically significant difference in the intravesical recurrence rate was observed between the two groups (11.8% at 1 year in the epirubicin group vs. 28.4% at 1 year in the control group; log-rank p=0.039). In multivariate analysis, epirubicin instillation (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.20 to 0.93; p=0.033) and adjuvant chemotherapy (HR, 0.29; 95% CI, 0.13 to 0.65; p=0.003) were independently predictive of a reduced incidence of bladder recurrence.
Conclusion
This retrospective review revealed that a single immediate intravesical instillation of epirubicin is safe and can reduce the incidence of intravesical recurrence after radical nephroureterectomy. However, further prospective trials are required to confirm these findings.

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The role of intravesical chemotherapy following nephroureterectomy in upper tract urothelial carcinoma: A systematic review and meta-analysis
Stefano Moretto, Andrea Piccolini, Andrea Gallioli, Roberto Contieri, Nicolomaria Buffi, Giovanni Lughezzani, Alberto Breda, Michael Baboudjian, Bas WG van Rhijn, Morgan Roupret, Alessandro Uleri, Benjamin Pradere
Urologic Oncology: Seminars and Original Investigations.2025; 43(3): 191.e1. CrossRef

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Adjuvant Chemotherapy for Upper Tract Urothelial Carcinoma: A Real-World, Retrospective Study: Junho Lee, Sung Hee Lim, Jae Hoon Chung, Wan Song, Hyun Hwan Sung, Byong Chang Jeong, Se Hoon Park; Cancer Res Treat. 2024;56(3):871-876. Published online January 16, 2024; DOI: https://doi.org/10.4143/crt.2023.1226

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Purpose
The aim of this retrospective study was to evaluate the efficacy of adjuvant cisplatin-based chemotherapy in patients with locally advanced upper tract urothelial carcinoma (UTUC), administered following radical nephroureterectomy.
Materials and Methods
Patients with UTUC, arising from renal pelvis or ureter, staged pT3/T4 or N+ were treated with adjuvant chemotherapy following surgery. The chemotherapy consisted of gemcitabine 1,000 mg/m² on days 1 and 8, cisplatin 70 mg/m² on day 1. Treatment was repeated every 3 weeks for up to 4 cycles. Endpoints included disease-free survival (DFS), metastasis-free survival (MFS), and safety.
Results
Among 89 eligible patients, 85 (95.5%) completed at least 3 cycles of adjuvant chemotherapy. Chemotherapy was well tolerated, the main toxicities being mild-to-moderate gastrointestinal toxic effects and pruritus. With a median follow-up of 37 months, median DFS was 30 months (95% confidence interval, 22 to 39), and the median MFS was not reached. The 3-year DFS and MFS were 44% and 56%, respectively. Multivariate analyses revealed that the main factor associated with DFS and MFS was the lymph node involvement, whereas age, T category, grade, or the primary site of UTUC were not significantly associated with DFS or MFS.
Conclusion
Adjuvant cisplatin-based chemotherapy after radical surgery of pT3/T4 or N+ UTUC was feasible and may demonstrate benefits in DFS and MFS. Whether novel agents added to the chemotherapy regimen, as a concurrent combination or maintenance, impacts on survival or reduces the development of metastases remains to be studied.

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Cisplatin/gemcitabine

Reactions Weekly.2024; 2027(1): 127. CrossRef

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Neoadjuvant Nivolumab Plus Gemcitabine/Cisplatin Chemotherapy in Muscle-Invasive Urothelial Carcinoma of the Bladder: Hongsik Kim, Byong Chang Jeong, Joohyun Hong, Ghee Young Kwon, Chan Kyo Kim, Won Park, Hongryull Pyo, Wan Song, Hyun Hwan Sung, Jung Yong Hong, Se Hoon Park; Cancer Res Treat. 2023;55(2):636-642. Published online October 6, 2022; DOI: https://doi.org/10.4143/crt.2022.343

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Purpose
The activity and safety of neoadjuvant nivolumab plus gemcitabine/cisplatin (N+GC) were tested in patients with muscle-invasive bladder urothelial carcinoma (MIBC).
Materials and Methods
In a prospective phase II trial, patients with cT2-T4a N0 MIBC who were eligible for cisplatin and medically appropriate to undergo radical cystectomy (RC) were enrolled. Treatment with nivolumab 3 mg/kg on days 1 and 15 plus GC (cisplatin 70 mg/m2 on day 1, and gemcitabine 1,000 mg/m2 on days 1, 8, and 15) was repeated every 28 days up to 3 or 4 cycles, depending on the surgery schedules. The primary endpoint was pathologic complete response (pCR, ypT0). Secondary endpoints included pathologic downstaging (≤ ypT1), disease-free survival (DFS), and safety.
Results
Between September 2019 and October 2020, 51 patients were enrolled. Neoadjuvant N+GC was well tolerated. Among 49 patients who completed neoadjuvant N+GC, clinical complete response (cCR) was achieved in 59% of intent-to-treat (ITT) population. RC was performed in 34 (69%) patients. pCR was achieved in 24% (12/49) of ITT population and 35% (12/34) of RC patients. Median DFS was not reached. Over a median follow-up of 24 months, 12 patients experienced disease recurrence and were treated with palliative therapy or surgery. Although 12 patients declined surgery and were treated with concurrent chemoradiotherapy, DFS was longer in patients with cCR after neoadjuvant therapy than those without. Preoperative programmed death-ligand 1 (PD-L1) did not correlate with pCR or pathologic downstaging rates.
Conclusion
Neoadjuvant N+GC was feasible and provided meaningful pathologic responses in patients with MIBC, regardless of baseline PD-L1 expression (ONO-4538-X41; CRIS.nih.go.kr, KCT0003804).

Citations

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Evaluating Neoadjuvant Immunochemotherapeutic Response for Bladder Carcinoma Using Amide Proton Transfer-Weighted MRI
Lingmin Kong, Bei Weng, Qian Cai, Ling Ma, Wenxin Cao, Yanling Chen, Long Qian, Yan Guo, Junxing Chen, Huanjun Wang
Academic Radiology.2025;[Epub] CrossRef
Current and Future Role of Circulating DNA in the Diagnosis and Management of Urothelial Carcinoma
Joaquim Bellmunt, Brian M. Russell, Bernadett Szabados, Begoña P. Valderrama, Rosa Nadal
American Society of Clinical Oncology Educational Book.2025;[Epub] CrossRef
Efficacy and safety of neoadjuvant PD-1 inhibitors or PD-L1 inhibitors for muscle invasive bladder cancer: a systematic review and meta-analysis
Shibo Huang, Yanping Huang, Chunyan Li, Yiwen Liang, Miaoyan Huang, Raoshan Luo, Weiming Liang
Frontiers in Immunology.2024;[Epub] CrossRef
What’s new about the tumor microenvironment of urothelial carcinoma?
João Queirós Coelho, Maria João Ramos, Ridhi Ranchor, Rita Pichel, Laura Guerra, Hugo Miranda, Joana Simões, Sérgio Xavier Azevedo, Joana Febra, António Araújo
Clinical and Translational Oncology.2024; 26(7): 1549. CrossRef
A bibliometric insight into neoadjuvant chemotherapy in bladder cancer: trends, collaborations, and future avenues
Yi Huang, Chengxiao Liao, Zefeng Shen, Yitong Zou, Weibin Xie, Qinghua Gan, Yuhui Yao, JunJiong Zheng, Jianqiu Kong
Frontiers in Immunology.2024;[Epub] CrossRef
Bladder-sparing treatment using tislelizumab combined with gemcitabine/cisplatin in selected patients with muscle-invasive bladder cancer: a real-world study
Cheng Luo, Shuhang Luo, Wumier Wusimanjiang, Zongren Wang, Ping Liu, Bin Wang, Dan Yuan, Hao Lin, Abai Xu, Nan Deng, Kaihui Wu, Xuejin Zhu, Peng Xu, Junxing Chen, Bin Huang
Clinical and Translational Oncology.2024; 26(7): 1759. CrossRef
Neoadjuvant Cisplatin-Based Chemotherapy Followed by Selective Bladder Preservation Chemoradiotherapy in Muscle-Invasive Urothelial Carcinoma of the Bladder: Post Hoc Analysis of Two Prospective Studies
Sung Wook Cho, Sung Hee Lim, Ghee Young Kwon, Chan Kyo Kim, Won Park, Hongryull Pyo, Jae Hoon Chung, Wan Song, Hyun Hwan Sung, Byong Chang Jeong, Se Hoon Park
Cancer Research and Treatment.2024; 56(3): 893. CrossRef
Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer
Thomas Powles, James W.F. Catto, Matthew D. Galsky, Hikmat Al-Ahmadie, Joshua J. Meeks, Hiroyuki Nishiyama, Toan Quang Vu, Lorenzo Antonuzzo, Pawel Wiechno, Vagif Atduev, Ariel G. Kann, Tae-Hwan Kim, Cristina Suárez, Chao-Hsiang Chang, Florian Roghmann, M
New England Journal of Medicine.2024; 391(19): 1773. CrossRef
Klassische Chemotherapie, Immuntherapie oder adjuvante Strahlentherapie – Wie können wir die onkologischen Ergebnisse der radikalen Zystektomie verbessern?
Pia Paffenholz, Stefanie Zschäbitz
Die Urologie.2024; 63(10): 994. CrossRef
Recent developments in perioperative combination therapy in muscle-invasive bladder cancer
Jan-Jaap J. Mellema, Bas W.G. van Rhijn, Michiel S. van der Heijden
Current Opinion in Urology.2023; 33(5): 404. CrossRef

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Genitourinary Cancer

Effects of Complete Bladder Cuff Removal on Oncological Outcomes Following Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: Hyunsoo Ryoo, Jungyu Kim, Taejin Kim, Minyong Kang, Hwang Gyun Jeon, Byong Chang Jeong, Seong Il Seo, Seong Soo Jeon, Hyun Moo Lee, Hyun Hwan Sung; Cancer Res Treat. 2021;53(3):795-802. Published online December 28, 2020; DOI: https://doi.org/10.4143/crt.2020.919

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Purpose
This study aimed to evaluate the effects of bladder cuff method on oncological outcomes in patients who underwent radical nephroureterectomy (RNU) for upper tract urothelial carcinoma.
Materials and Methods
The records of 1,095 patients treated with RNU performed at our hospital between 1994 and 2018 were retrospectively reviewed; 856 patients with no bladder tumor history were enrolled in the present study. The management of bladder cuff was divided into two categories: extravesical ligation (EL) or transvesical resection (TR). Survival was analyzed using the Kaplan-Meier method and Cox regression analyses were performed to determine which factors were associated with intravesical recurrence (IVR)–free survival (IVRFS), cancer-specific survival (CSS), and overall survival (OS).
Results
The mean patient age was 64.8 years and the median follow-up was 37.7 months. Among the 865 patients, 477 (55.7%) underwent the TR and 379 (44.3%) the EL. Significantly higher IVRFS (p=0.001) and OS (p=0.013) were observed in the TR group. In multivariable analysis, IVR, CSS, and OS were independently associated with the EL. Among 379 patients treated with the EL, eight underwent remnant ureterectomy. Based on radical cystectomy–free survival, significant difference was not observed between the two groups. However, significantly higher IVRFS was observed in the TR group when the tumor was located in the renal pelvis.
Conclusion
Intramural complete excision of the distal ureter during RNU should be the gold standard approach compared with EL for the management of distal ureter in terms of oncological outcomes.

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Single Early Intravesical Instillation of Epirubicin for Preventing Bladder Recurrence after Nephroureterectomy in Upper Urinary Tract Urothelial Carcinoma
Jong Hoon Lee, Chung Un Lee, Jae Hoon Chung, Wan Song, Minyong Kang, Hwang Gyun Jeon, Byong Chang Jeong, Seong Il Seo, Seong Soo Jeon, Hyun Hwan Sung
Cancer Research and Treatment.2024; 56(3): 877. CrossRef
Violation of onco-surgical principles is associated with survival outcomes in upper tract urothelial carcinomas after radical nephroureterectomy
Ioannis Patras, Johan Abrahamsson, Axel Gerdtsson, Martin Nyberg, Ymir Saemundsson, Elin Ståhl, Anne Sörenby, Åsa Warnolf, Johannes Bobjer, Fredrik Liedberg
Scandinavian Journal of Urology.2024; 59: 131. CrossRef
Differential effect of surgical technique on intravesical recurrence after radical nephroureterectomy in patients with upper tract urothelial cancer: a systematic review and Meta-analysis
Ichiro Tsuboi, Akihiro Matsukawa, Mehdi Kardoust Parizi, Jakob Klemm, Robert J Schulz, Anna Cadenar, Stefano Mancon, Sever Chiujdea, Tamás Fazekas, Marcin Miszczyk, Ekaterina Laukhtina, Tatsushi Kawada, Satoshi Katayama, Takehiro Iwata, Kensuke Bekku, Koi
World Journal of Urology.2024;[Epub] CrossRef
The impact of bladder cuff excision on outcomes after nephroureterectomy for upper tract urothelial carcinoma: An analysis of the ROBUUST 2.0 registry
Courtney Yong, James E. Slaven, Zhenjie Wu, Vitaly Margulis, Hooman Djaladat, Alessandro Antonelli, Giuseppe Simone, Raj Bhanvadia, Alireza Ghoreifi, Farshad Sheybaee Moghaddam, Francesco Ditonno, Gabriele Tuderti, Stephan Bronimann, Sohail Dhanji, Benjam
Urologic Oncology: Seminars and Original Investigations.2024; 42(11): 373.e1. CrossRef
A new nomogram for predicting extraurothelial recurrence in patients with upper urinary tract urothelial carcinoma following radical nephroureterectomy
Hao Wu, Dan Jia, Xianyu Dai, Hongliang Cao, Fulin Wang, Tong Yang, Lei Wang, Tao Xu, Baoshan Gao
Frontiers in Oncology.2024;[Epub] CrossRef
Perioperative and oncological outcomes of distal ureter management during nephroureterectomy for upper urinary tract urothelial carcinoma: a systematic review and meta-analysis
Andrea GALLIOLI, Michael BABOUDJIAN, Pietro DIANA, Marco MOSCHINI, Evanguelos XYLINAS, Francesco DEL GIUDICE, Ekaterina LAUKHTINA, Francesco SORIA, Andrea MARI, José D. SUBIELA, Mathieu ROUY, Angelo TERRITO, Giuseppe BASILE, Joan PALOU, Benjamin PRADERE,
Minerva Urology and Nephrology.2023;[Epub] CrossRef
Predicting and Decreasing Bladder Tumor Recurrence Following Nephroureterectomy
Hiroko Miyagi, Elizabeth A. Di Valerio, Padraic O’Malley, Wayne G. Brisbane, Li-Ming Su, Paul L. Crispen
Frontiers in Urology.2022;[Epub] CrossRef
Inadvertent radical nephrectomy leads to worse prognosis in renal pelvic urothelial carcinoma patients: A propensity score-matched study
Feixiang Wu, Pan Zhang, Lingxun Li, Shiqing Lin, Jianhong Liu, Yi Sun, Yuanlong Wang, Chengjun Luo, Yu Huang, Xiao Yan, Meng Zhang, Guixi Liu, Kun Li
Frontiers in Oncology.2022;[Epub] CrossRef

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Atezolizumab in Patients with Pretreated Urothelial Cancer: a Korean Single-Center, Retrospective Study: Joon Young Hur, Youjin Kim, Ghee-Young Kwon, Minyong Kang, Hyun Hwan Sung, Hwang Gyun Jeon, Byong Chang Jeong, Seong Il Seo, Seong Soo Jeon, Hyun Moo Lee, Su Jin Lee, Se Hoon Park; Cancer Res Treat. 2019;51(4):1269-1274. Published online January 9, 2019; DOI: https://doi.org/10.4143/crt.2018.604

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Purpose
Treatment targeting immune checkpoint with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors has demonstrated efficacy and tolerability in the treatment of metastatic urothelial carcinoma (mUC). We investigated the efficacy and safety of atezolizumab in mUC patients who failed platinum-based chemotherapy.
Materials and Methods
A retrospective study using the Samsung Medical Center cancer chemotherapy registry was performed on 50 consecutive patients with mUC treated with atezolizumab, regardless of their PD-L1(SP142) status, as salvage therapy after chemotherapy failure between May 2017 and June 2018. Endpoints included overall response rate (RR), progression-free survival (PFS), and safety.
Results
Among 50 patients, men constituted 76% and the median age was 68 years (range, 46 to 82 years). Twenty-three patients (46%) received atezolizumab as second-line therapy. PD-L1 (SP142) status IC0/1 and IC2/3 were found in 21 (42%) and 21 (42%) of patients, respectively; in eight patients (16%), PD-L1 (SP142) expression was not available. Atezolizumab was generally well tolerated, with pruritus and fatigue being the most commonly observed toxicities. As a result, partial response was noted in 20 patients (40%), with 12 (24%) stable diseases. RRwas higherin IC2/3 (62%) than in IC0/1 patients (24%, p=0.013). The median PFS was 7.4 months (95% confidence interval, 3.4 to 11.4 months). As expected, PFS also was significantly longer in IC2/3 patients than in IC0/1 (median, 12.7 vs. 2.1 months; p=0.005). PFS was not significantly influenced by age, sex, performance status, number of previous chemotherapy, site of metastases, or any of the baseline laboratory parameters.
Conclusion
In this retrospective study, atezolizumab demonstrated clinically efficacy and tolerability in unselected mUC patients who failed platinum-based chemotherapy.

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Real-world data of atezolizumab in patients with previously treated locally advanced or metastatic urothelial bladder cancer
Rocío Díaz Acedo, Mercedes Galvan Banqueri, Silvia Artacho Criado, Eva María Fernández Parra, Rocío Jiménez Galán, Ana Isabel Gago Sánchez, Juan Francisco Marín Pozo, María José Martínez Bautista
International Journal of Clinical Pharmacy.2024; 46(2): 382. CrossRef
Subsequent Systemic Therapy following Platinum and Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma
Joohyun Hong, Hyun Hwan Sung, Byong Chang Jeong, Se Hoon Park
Biomedicines.2022; 10(8): 2005. CrossRef
Systemic treatment for advanced urothelial cancer: an update on recent clinical trials and current treatment options
Inkeun Park, Jae Lyun Lee
The Korean Journal of Internal Medicine.2020; 35(4): 834. CrossRef

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