Neoadjuvant chemotherapy for muscle-invasive bladder cancer with variant histology and/or divergent differentiation

Radical cystectomy (RC) is the standard of care for muscle-invasive bladder cancer (MIBC), but RC alone only has a 5-year survival rate of about 50% (1). Therefore, neoadjuvant chemotherapy (NAC) is recommended to prevent potential metastases of cN0M0 MIBC, leading to a better patient prognosis. The National Comprehensive Cancer Network (NCCN) and European Association of Urology (EAU) guidelines indicate performing cisplatin-based NAC for MIBC if cisplatin is compatible with the patient (2,3). In the GETUG-AFU VESPER phase 3 clinical trial, provided unique, high-quality data comparing two regimens commonly used in clinical practice. In the result, NAC arm of dose dense-methotrexate, vinblastine sulfate, doxorubicin hydrochloride (adriamycin), and cisplatin (dd-MVAC) showed an improvement in organ-confined rate and 3-year progression-free survival (PFS) (4). A meta-analysis showed a significant survival benefit in favor of NAC (5). The recent meta-analysis reported that cisplatin-based NAC improves overall survival (OS) (8% at 5-year) (6). On the other hand, the clinical benefit of NAC to variant histology or divergent differentiation (VH/DD) was inconsistent (7). The guidelines do not clearly indicate the therapeutic efficacy of NAC for VH/DD except for small cell variant (2,3). Concurrent chemoradiotherapy or NAC followed by local treatment (RC or radiation therapy) is recommended for any patient with small cell component histology with localized disease, regardless of stage (including non-muscle invasive disease) (2,8). Herein, the post-hoc analysis of the VESPER trial was provided to investigate the clinical implications of NAC for VH/DD (9). Of the 437 patients who underwent NAC, 278 patients with VH/DD were studied. A VH/DD of more than 10% was used as the cutoff. The results showed that the presence of VH/DD was not associated with the inferior pathological response and PFS. However, PFS was shortened in the patients with ≥50% squamous differentiation and ≥50% micropapillary compared with pure urothelial carcinoma (UC). In one retrospective analysis, tumors with micropapillary differentiation, sarcomatoid differentiation, and adenocarcinoma had lower rates of nonorgan-confined disease but no statistically significant impact on OS. Also, squamous differentiation patients did not benefit from NAC (10). A US National Cancer Database study reported that NAC was associated with pathological downstaging for all MIBC histological subtypes, with improved OS for patients with UC, sarcomatoid variant UC, and neuroendocrine carcinoma (11). The difference from the results of these studies may lie in the rigorous pathological evaluation in the present study. Recently, the NIAGARA trial, NAC, and the use of durvalumab before and after RC showed that event-free survival and OS in the VH/DD group had lower hazard ratios with the use of durvalumab (12). However, the effect of neoadjuvant therapy is unknown because the pathological complete response (pCR) rate in VH/DD is not described.

This study included a central pathological review of 278 specimens obtained at transurethral resection of bladder tumor before NAC. The central pathology review in this study reported that 59% of the specimens had VH/DD. This number appears high compared to previous reports. The fact that the VH/DD rate was 25% before the central review suggests that non-expert pathologists in the genitourinary field tend to underestimate VH/DD and that more than half of VH/DD is missed in general pathological diagnoses. The authors described it as a limitation due to the difficulty of generalizing the results, but it also proves the high quality of this study.

The present results indicate that the clinical benefit of NAC for VH/DD is unclear. Based on these results, we would like to discuss the following two limitations and their backgrounds. First, the limitation of the current molecular and morphological pathology diagnosis. More detailed molecular diagnostic studies, genomic subtypes, immunophenotyping, and somatic mutations are expected to be applied to clinical practice (13). For instance, immunophenotypes are classified into three categories according to the distribution of lymphocytes in or around the cancer cell nest: desert, excluded, and inflamed. This immunophenotyping has been increasingly shown to be useful in predicting the response to immune checkpoint inhibition (ICI) (14). Second, the limitation of therapeutic efficacy of the conventional cisplatin-based NAC for VH/DD. Efforts are underway to improve the effectiveness of the NAC in MIBC. Neoadjuvant pembrolizumab monotherapy against MIBC, including 18 % of VH/DD, demonstrated pCR of 31% (15). In the LCCC1520 study, using gemcitabine and cisplatin plus pembrolizumab (NAC-ICI) for MIBC, including 28% of VH/DD, showed of 36% patients experiencing pCR (16). These studies evaluated the effects of neoadjuvant treatment in both pure UC and VH/DD patients, and the effect of treatment on VH/DD alone is unknown. In this study, there was no difference in the therapeutic effect for VH/DD overall, but differences were observed when focusing on specific VH/DD conditions. We hope that the diagnosis and evaluation of VH/DD will be performed from a molecular perspective, and as research into neoadjuvant treatment regimens progresses, leading to a clearer treatment strategy for VH/DD in the future.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-13/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-13/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Stein JP, Skinner DG. Radical cystectomy for invasive bladder cancer: long-term results of a standard procedure. World J Urol 2006;24:296-304. [Crossref] [PubMed]
2. Flaig TW, Spiess PE, Abern M, et al. NCCN guidelines Bladder Cancer, Version 5. 2024.
3. Witjes J A, Bruins H M, Cathomas R, et al. EAU guidelines on muscle-invasive and metastatic bladder cancer 2024. European Association of Urology 2024.
4. Pfister C, Gravis G, Flechon A, et al. Perioperative dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin in muscle-invasive bladder cancer (VESPER): survival endpoints at 5 years in an open-label, randomised, phase 3 study. Lancet Oncol 2024;25:255-64. [Crossref] [PubMed]
5. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol 2005;48:202-5; discussion 205-6. [Crossref] [PubMed]
6. Yin M, Joshi M, Meijer RP, et al. Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer: A Systematic Review and Two-Step Meta-Analysis. Oncologist 2016;21:708-15. [Crossref] [PubMed]
7. Witjes JA, Babjuk M, Bellmunt J, et al. EAU-ESMO Consensus Statements on the Management of Advanced and Variant Bladder Cancer-An International Collaborative Multistakeholder Effort†: Under the Auspices of the EAU-ESMO Guidelines Committees. Eur Urol 2020;77:223-50. [Crossref] [PubMed]
8. Myers AA, Fang AM, Moussa MJ, et al. Impact of systemic therapy on clinical T1 small-cell neuroendocrine carcinoma of the bladder. ESMO Open 2024;9:103964. [Crossref] [PubMed]
9. Allory Y, Culine S, Krucker C, et al. Impact of Divergent Differentiation and/or Histological Subtype of Urothelial Carcinoma on Patient Outcomes in the GETUG-AFU V05 VESPER Trial. J Urol 2024;211:564-74. [Crossref] [PubMed]
10. Vetterlein MW, Wankowicz SAM, Seisen T, et al. Neoadjuvant chemotherapy prior to radical cystectomy for muscle-invasive bladder cancer with variant histology. Cancer 2017;123:4346-55. [Crossref] [PubMed]
11. Chakiryan NH, Jiang DD, Gillis KA, et al. Pathological Downstaging and Survival Outcomes Associated with Neoadjuvant Chemotherapy for Variant Histology Muscle Invasive Bladder Cancer. J Urol 2021;206:924-32. [Crossref] [PubMed]
12. Powles T, Catto JWF, Galsky MD, et al. Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer. N Engl J Med 2024;391:1773-86. [Crossref] [PubMed]
13. Beckabir W, Zhou M, Lee JS, et al. Immune features are associated with response to neoadjuvant chemo-immunotherapy for muscle-invasive bladder cancer. Nat Commun 2024;15:4448. [Crossref] [PubMed]
14. Takahara T, Murase Y, Tsuzuki T. Urothelial carcinoma: variant histology, molecular subtyping, and immunophenotyping significant for treatment outcomes. Pathology 2021;53:56-66. [Crossref] [PubMed]
15. Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol 2018;36:3353-60. [Crossref] [PubMed]
16. Rose TL, Harrison MR, Deal AM, et al. Phase II Study of Gemcitabine and Split-Dose Cisplatin Plus Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer. J Clin Oncol 2021;39:3140-8. [Crossref] [PubMed]