https://doi.org/10.4081/aiua.2025.14264
Prognostic value of combined tumor regression grade and TNM stage in muscle-invasive bladder cancer treated with neoadjuvant chemotherapy and radical cystectomy
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Published: 30 September 2025
Introduction: Tumor regression grade (TRG) is a recognized prognostic marker in several solid tumors treated with neoadjuvant therapy, but its clinical relevance in muscle-invasive bladder cancer (MIBC) remains under investigation. This study aimed to evaluate the prognostic value of TRG and its integration with pathological TNM staging in patients with MIBC treated with neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC).
Materials and methods: We conducted a retrospective analysis of 51 patients with MIBC who received platinum-based NAC followed by RC and lymphadenectomy between 2013 and 2024. TRG was assessed according to the Fleischmann classification and combined with ypTNM stage to categorize patients as complete, partial or non-responders. Overall survival (OS) and disease-free survival (DFS) were estimated using Kaplan–Meier analysis, and independent prognostic factors were identified through Cox regression models.
Results: Complete response (ypT≤1, ypN0, TRG1) was observed in 43.1% of patients. Median OS was 19 months, with 3- and 5-year OS rates of 28.6% and 14.3%, respectively. Complete responders demonstrated significantly improved OS and DFS (p<0.001). On multivariable analysis, absence of nodal involvement (p=0.047) and complete response (p=0.012) were independently associated with better OS. Negative surgical margins showed a trend toward improved survival (p=0.064).
Conclusions: TRG is a reproducible and clinically meaningful histopathologic scoring system that enhances prognostic stratification when combined with pathological TNM staging. Its integration into routine post-NAC assessment may improve postoperative decision-making and help identify patients who could benefit from tailored surveillance or adjuvant strategies.
Downloads
1. Stein J, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. Clin Oncol. 2001;19:666-675. DOI: https://doi.org/10.1200/JCO.2001.19.3.666
2. Grossman H, Natale R, Tangen C, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003; 349:859-66. DOI: https://doi.org/10.1056/NEJMoa022148
3. Collaboration. ABCM. Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet. 2003; 361:1927-1934. DOI: https://doi.org/10.1016/S0140-6736(03)13580-5
4. Van Der Heijden A, Bruins H, Carrion A, et al. European Association of Urology guidelines on muscle-invasive and metastatic bladder cancer. Eur Assoc Urol. 2025; 87:582-600. DOI: https://doi.org/10.1016/j.eururo.2025.02.019
5. Motterle G, Andrews JR, Morlacco A, Karnes RJ. Predicting response to neoadjuvant chemotherapy in bladder cancer. Eur Urol Focus. 2020; 6:642-649. DOI: https://doi.org/10.1016/j.euf.2019.10.016
6. Yuh B, Ruel N, Wilson T, et al. Pooled analysis of clinical outcomes with neoadjuvant cisplatin and gemcitabine chemotherapy for muscle invasive bladder cancer. J Urol. 2013; 189:1682-1686. DOI: https://doi.org/10.1016/j.juro.2012.10.120
7. Rosenblatt R, Sherif A, Rintala E, et al. Pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer. Eur Urol. 2012; 61:1229-1238. DOI: https://doi.org/10.1016/j.eururo.2011.12.010
8. Hinsenveld FJ, Noordman BJ, Boormans JL, et al. Prediction of pathological response following neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer: the PRE-PREVENCYS trial. BMC Cancer. 2021; 21:1-11. DOI: https://doi.org/10.1186/s12885-021-08840-2
9. Morgan M, Koorey D, Painter D, et al. Histological tumour response to pre-operative combined modality therapy in locally advanced rectal cancer. Color Dis. 2002; 4:177-183. DOI: https://doi.org/10.1046/j.1463-1318.2002.00330.x
10. Becker K, Langer R, Reim D, et al. Significance of histopathological tumor regression after neoadjuvant chemotherapy in gastric adenocarcinomas: A summary of 480 cases. Ann Surg. 2011; 253:934-939. DOI: https://doi.org/10.1097/SLA.0b013e318216f449
11. Fareed K, Ilyas M, Kaye P, et al. Tumour regression grade (TRG) analyses in patients with resectable gastro-oesophageal adenocarcinomas treated with platinum-based neoadjuvant chemotherapy. Histopathology. 2009; 55:399-406. DOI: https://doi.org/10.1111/j.1365-2559.2009.03404.x
12. Fleischmann A, Thalmann GN, Perren A, Seiler R. Tumor regression grade of urothelial bladder cancer after neoadjuvant chemotherapy. A novel and successful strategy to predict survival. Am J Surg Pathol. 2014; 38:325-332. DOI: https://doi.org/10.1097/PAS.0000000000000142
13. Voskuilen CS, Oo HZ, Genitsch V, et al. Multicenter validation of histopathologic tumor regression grade after neoadjuvant chemotherapy in muscle-invasive bladder carcinoma. Am J Surg Pathol. 2019; 43:1600-1610. DOI: https://doi.org/10.1097/PAS.0000000000001371
14. Gronostaj K, Czech AK, Fronczek J, et al. The prognostic value of tumor regression grades combined with TNM classification in patients with muscle-invasive bladder cancer who underwent neoadjuvant chemotherapy followed by radical cystectomy. Clin Genitourin Cancer. 2019; 17:e1203-e1211. DOI: https://doi.org/10.1016/j.clgc.2019.09.003
15. Seiler R, Oo HZ, Todenhöfer T, et al. Tumor regression grading after neoadjuvant chemotherapy in bladder cancer: Validation in an independent cohort. Eur Urol Suppl. 2017; 16:e685. DOI: https://doi.org/10.1016/S1569-9056(17)30454-2
16. Nakagawa T. Lymph node dissection for bladder cancer: Current standards and the latest evidence. Int J Urol. 2021; 28:7-15. DOI: https://doi.org/10.1111/iju.14398
17. Amin MB, Greene FL, Edge SB, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. 2017; 67:93-99. DOI: https://doi.org/10.3322/caac.21388
18. Zargar H, Espiritu PN, Fairey AS, et al. Multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol. 2015; 67:241-249. DOI: https://doi.org/10.1016/j.eururo.2014.09.007
19. Veskimäe E, Espinos EL, Bruins HM, et al. What is the prognostic and clinical importance of urothelial and nonurothelial histological variants of bladder cancer in predicting oncological outcomes in patients with muscle-invasive and metastatic bladder cancer? A European Association of Urology muscle invasive and metastatic bladder cancer guidelines panel systematic review. Eur Urol Oncol. 2019; 2:625-642. DOI: https://doi.org/10.1016/j.euo.2019.09.003
20. Mamede I, Silva C, Alves AC, et al. Adjuvant immunotherapy in high-risk muscle-invasive urothelial cancer: an updated meta-analysis of randomized controlled trials. Clin Genitourin Cancer 2025; 23:102288. DOI: https://doi.org/10.1016/j.clgc.2024.102288
21. Crupi E, de Padua TC, Marandino L, et al. Circulating tumor DNA as a predictive and prognostic biomarker in the perioperative treatment of muscle-invasive bladder cancer: a systematic review. Eur Urol Oncol. 2024; 7:44-52. DOI: https://doi.org/10.1016/j.euo.2023.05.012
How to Cite
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.