Research ArticleClinical Studies
Open Access

Effect of Pembrolizumab on Lymph Node Dissection in Patients Who Experienced Bladder Cancer Recurrence Following Radical Cystectomy

YOSHIHIKO TASAKI, TAKASHI NAGAI, TAKU NAIKI, YUSUKE NODA, RYOSEI OKAWA, MISATO TOMITA, YOSUKE SUGIYAMA, YOSHIHISA MIMURA, KUNIHIRO ODAGIRI, NANAMI ITO, YUJI HOTTA, NOBUHIKO SHIMIZU, TOSHIKI ETANI, SHUZO HAMAMOTO, ATSUSHI OKADA, YOKO FURUKAWA-HIBI and TAKAHIRO YASUI
In Vivo July 2025, 39 (4) 2196-2208; DOI: https://doi.org/10.21873/invivo.14015

Abstract

Background/Aim: Pelvic lymph node dissection is recommended to improve the prognosis in patients with bladder cancer undergoing radical cystectomy. Although several studies have reported an association between lymph node dissection and the efficacy of immune checkpoint inhibitors, evidence specific to bladder cancer remains lacking. This study aimed to investigate the effect of pembrolizumab on lymph node dissection during radical cystectomy in patients with bladder cancer.

Patients and Methods: A total of 61 patients treated with pembrolizumab were divided into those who experienced recurrence after radical cystectomy with lymph node dissection (resection group, n=45) and those with unresectable advanced bladder cancer (unresectable group, n=16). The median overall survival (mOS) and progression-free survival (PFS) were analyzed in both groups. Additionally, the association of the characteristics and number of dissected lymph nodes with the efficacy of pembrolizumab was examined in the resection group.

Results: No significant differences were observed in mOS and mPFS between the resection group and the unresectable group (mOS, p=0.90; mPFS, p=0.11, respectively). In the resection group, the mOS and mPFS were not associated with lymph node positivity or negativity (mOS, p=0.52; mPFS, p=0.53, respectively). However, among patients in the resection group who had undergone neoadjuvant therapy, those with >14 resected lymph nodes exhibited significantly shorter mPFS compared with those with <14 resected lymph nodes (p=0.03).

Conclusion: Lymph node resection was not associated with prognosis and efficacy of pembrolizumab in patients with bladder cancer. However, as the resection of more than 14 lymph nodes was associated with a poorer prognosis and reduced efficacy of pembrolizumab, treatment strategies should be carefully tailored based on the extent of lymph node dissection and the administration of neoadjuvant therapy.

Keywords:

Introduction

Radical cystectomy is a key treatment for patients with muscle-invasive bladder cancer (1, 2). The National Comprehensive Cancer Network and Japanese Urological Association guidelines recommend bilateral pelvic lymph node dissection to reduce the risk of recurrence and improve the prognosis of patients with bladder cancer undergoing radical cystectomy. Furthermore, adjuvant therapies have been developed to further reduce the risk of recurrence (3). Despite these advancements, approximately 40% of patients experience recurrence within 1 year (3).

The 5-year survival rate of patients with advanced and metastatic bladder cancer is approximately 8%, making it one of the most aggressive human malignancies (4). Pembrolizumab has significantly transformed the treatment strategies and improved the prognosis of patients with advanced metastatic bladder cancer (5, 6). Large-scale clinical trials have demonstrated that patients who received pembrolizumab monotherapy or combined with enfortumab vedotin therapy have significantly longer overall survival (OS) compared with those who received chemotherapy (5, 6).

Pembrolizumab is an immune checkpoint inhibitor that targets anti-programmed death-1 and exerts antitumor effects by activating lymphocytes (7). Lymphocytes, produced and matured in the bone marrow and thymus, accumulate in the lymph nodes, where they play an important role in tumor surveillance. Therefore, lymph node dissection may negatively influence the efficacy of pembrolizumab in patients with advanced and metastatic bladder cancer who underwent radical cystectomy with bilateral pelvic lymph node dissection. However, evidence regarding the association between lymph node dissection and the efficacy of pembrolizumab in patients with advanced and metastatic bladder cancer remains limited.

This study aimed to examine the association between lymph node dissection and pembrolizumab efficacy in patients who developed bladder cancer recurrence following radical cystectomy.

Patients and Methods

Study design. This retrospective study included 105 patients diagnosed with urothelial carcinoma who received pembrolizumab (200 or 400 mg/body every 3 or 6 weeks) between January 2017 and April 2024 at Nagoya City University Hospital, Anjo Kosei Hospital, and Nagoya East Medical Center (Figure 1). Forty-four patients with primary tumors in the upper urinary tract and those lacking data on lymph node dissection status were excluded, leaving 61 patients for analysis. The patients were divided into those with metastasis and advanced bladder cancer deemed unsuitable for radical cystectomy with lymph node dissection (unresectable group; n=16) and those who experienced recurrence following radical cystectomy with lymph node dissection (resection group; n=45). Additionally, the number of dissected lymph nodes was classified into 5, 10, 14 nodes based on data from previous reports (8, 9) and analyzed. This study was approved by the Ethics Committee of Nagoya City University Hospital (approval number: 60-22-0076) and conducted in accordance with the tenets of the Declaration of Helsinki.

Figure 1.
Figure 1.

Schema of patient enrollment in the study.

Efficacy assessment. All patients were followed up until death or loss of contact. OS was defined as the period from the initiation of pembrolizumab therapy to death. Meanwhile, progression-free survival (PFS) was defined as the period from the initiation of pembrolizumab treatment until disease progression.

Safety assessment. Immune-related adverse events (irAEs) were defined as symptoms resulting from immune system activation and/or requiring immunosuppressive treatment. The severity of irAEs was graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Statistical analysis. Categorical variables are presented as count and percentage. Fisher’s exact test was used to compare the differences in patient characteristics. OS and PFS were calculated and compared using the Kaplan-Meier method and log-rank test, respectively. Univariate and multivariate Cox regression analyses were conducted to identify factors associated with OS or PFS. A p-value of <0.05 was considered statistically significant. Statistical analyses were performed using GraphPad Prism 9 software and EZR [Saitama Medical Center, Jichi Medical University, Saitama, Japan, (10)].

Results

Patient characteristics. The patients’ clinical characteristics are summarized in Table I. The median follow-up duration in this study was 4.6 months (range=0.2-69.7). Approximately 14.8% (n=9) of the patients were aged <65 years. The cohort consisted of 51 male (83.6%) and 10 female (16.4%). Of the total patients, 98.4% (n=60) were diagnosed with urothelial carcinoma, and 1.6% (n=1) with adenocarcinoma. Prior to the initiation of pembrolizumab treatment, 73.8% (n=45) and 9.8% (n=6) of the patients obtained performance status scores of <2 and ≥2, respectively. The incidence rate of any grade irAEs was 31.1% (n=19), whereas that of grade ≥3 irAEs was 8.2% (n=5). No significant differences were observed between the unresectable and resection groups in terms of age, sex, histological subtype, performance status, incidence of any grade and grade ≥3 irAEs.

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Table I.

Clinical features of 61 patients with bladder cancer.

Impact of lymph node dissection on the efficacy of pembrolizumab. No significant differences were observed in the median OS (mOS) and PFS (mPFS) between the unresectable and resection groups (mOS: 4.6 vs. 9.7 months, p=0.90; mPFS: 2.2 vs. 4.4 months, p=0.11; Figure 2A and B). In total patients, univariate and multivariate Cox regression analyses showed no significant associations of OS and PFS with lymph node dissection (Table II and Table III). This finding suggests that lymph node dissection does not affect the efficacy of pembrolizumab.

Figure 2.
Figure 2.

Overall and progression-free survival in patients who underwent radical cystectomy and those who did not. Kaplan-Meier survival curves for (A) overall survival and (B) progression-free survival (unresectable group, n=16; resection group, n=45). p-Values are from log-rank test. mOS, Median overall survival; mPFS, median progression-free survival.

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Table II.

Univariate and multivariate Cox regression analysis of risk factors for overall survival in 61 patients with bladder cancer.

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Table III.

Univariate and multivariate Cox regression analysis of risk factors for progression-free survival in 61 patients with bladder cancer.

Analysis of the association between lymph node characteristics and clinical outcomes. To further evaluate the impact of the dissected lymph node characteristics on clinical outcomes, patients in the resection group were categorized based on the lymph node positivity status. In the resection group, no significant differences were observed in the mOS and mPFS between the positive and negative groups (mOS, 8.4 vs. 17.6 months, p=0.52; mPFS, 3.1 vs. 4.3 months, p=0.53; Figure 3A and B). While, in patients with resection who received neoadjuvant therapy (n=26), mOS and mPFS did not significantly differ between patients with positive lymph nodes and those with negative lymph nodes (mOS, 8.4 vs. 20.4 months, p=0.97; mPFS, 2.3 vs. 4.7 months, p=0.95; Figure 3C and D).

Figure 3.
Figure 3.

Analysis of survival according to positive or negative lymph nodes. Kaplan-Meier survival curves for (A) overall survival and (B) progression-free survival (lymph node dissection: positive; n=19, and lymph node dissection: negative; n=25) in the resection group. Kaplan-Meier survival curves for (C) overall survival and (D) progression-free (lymph node dissection: positive; n=11, and lymph node dissection: negative; n=15) in patients with resection who had received neoadjuvant therapy. p-Values are from log-rank test. mOS, Median overall survival; mPFS, median progression-free survival.

Analysis of the association between the number of dissected lymph nodes and clinical outcomes. We further investigated the association between the number of dissected lymph nodes and clinical outcomes. No significant differences were observed in mOS and mPFS between patients who underwent dissection of ≥5 or ≥10 lymph nodes and those who underwent dissection of <5 or <10 lymph nodes (Figure 4A-D). However, patients who underwent dissection of ≥14 lymph nodes had shorter mOS and mPFS compared with those who underwent dissection of <14 lymph nodes; however, these associations were significant at a level of 10% (mOS: 5.2 vs. 9.7 months, p=0.08; mPFS: 3.3 vs. 4.3 months, p=0.07; Figure 5A and B). Univariate and multivariate Cox regression analyses indicated that patients who underwent dissection of ≥14 lymph nodes tended to have an increased risk of poor prognosis and disease progression (Table IV and Table V). Among patients who received neoadjuvant therapy, mOS did not differ between those with ≥14 dissected lymph nodes and those with <14 dissected lymph nodes (mOS: 14.8 vs. 9.7 months, p=0.35; Figure 5C). However, mPFS was significantly shorter in patients with ≥14 dissected lymph nodes compared with those with <14 dissected lymph nodes (mPFS: 2.2 vs. 5.6 months, p=0.03; Figure 5D). Patient characteristics did not differ between groups with ≥14 and <14 dissected lymph nodes (Table VI).

Figure 4.
Figure 4.

Analysis of survival according to the number of dissected lymph nodes. Kaplan-Meier survival curves for (A) overall survival and (B) progression-free survival (<5 lymph nodes dissected: n=10, and ≥5 lymph nodes dissected: n=35) in the resection group. Kaplan-Meier survival curves for (C) overall survival and (D) progression-free survival (<10 lymph nodes dissected: n=19, and ≥14 lymph nodes dissected: n=26) in patients with resection. p-Values are from log-rank test. mOS, Median overall survival; mPFS, median progression-free survival.

Figure 5.
Figure 5.

Association between the extent of lymph node dissection and clinical outcomes. Kaplan-Meier survival curves for (A) overall survival and (B) progression-free survival (<14 dissected lymph nodes, n=31; ≥14 dissected lymph nodes, n=14) in patients with resection. Kaplan-Meier survival curves for (C) overall survival and (D) progression-free survival (<14 dissected lymph nodes, n=16; ≥14 dissected lymph nodes, n=10) in patients with resection who received neoadjuvant therapy. p-Values are from log-rank test. mOS, Median overall survival; mPFS, median progression-free survival.

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Table IV.

Univariate and multivariate Cox regression analysis of risk factors for overall survival in resection group (n=45).

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Table V.

Univariate and multivariate Cox regression analysis of risk factors for progression-free survival in resection group (n=45).

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Table VI.

Clinical features of 45 patients who dissected lymph nodes.

Discussion

Immune checkpoint inhibitors have revolutionized cancer treatment, significantly improving the prognosis of patients with various malignancies, including bladder cancer (3, 5, 6, 11-17). To optimize their therapeutic potential, ongoing research is focused on identifying biomarkers that predict the efficacy of immune checkpoint inhibitor and patient prognosis, including genetic expressions/mutations, blood parameters, irAEs, and lymph node dissection (18-28). Given the pharmacological mechanisms of these treatments, understanding the impact of lymph node dissection on treatment efficacy remains essential. This association has been investigated in patients with non-small cell lung cancer (24). Kawaguchi et al. found no significant differences in OS and PFS between patients who underwent and those who did not undergo lymph node dissection. This finding indicates that lymph node dissection does not affect immune checkpoint inhibitor efficacy in this setting (24). Consistent with lung cancer, Kanno et al. reported that lymph node dissection did not affect immune checkpoint inhibitor efficacy in patients with metastatic urothelial carcinoma (29). However, there is a lack of evidence on the efficacy of pembrolizumab associated with lymph node dissection for bladder cancer. Moreover, no studies have examined the relationship between immune checkpoint inhibitors and the number of dissected lymph nodes in bladder cancer. To our knowledge, this study is the first to report an association between the number of lymph nodes dissected and immune checkpoint inhibitor efficacy in patients with bladder cancer.

Radical cystectomy with bilateral pelvic lymph node dissection provides local control by reducing recurrence risk and improving long-term survival in patients with muscle-invasive bladder cancer (2, 8, 30). Therefore, all patients eligible for surgery undergo lymph node dissection. By contrast, pembrolizumab plays a central role in managing postoperative recurrence in patients with bladder cancer (5, 6). Given the critical role of lymph nodes in tumor surveillance, their dissection may potentially diminish the efficacy of pembrolizumab. To improve the prognosis of patients with advanced and metastatic bladder cancer, treatment strategies should be based on a comprehensive understanding of the patient’s treatment history, including previous surgical interventions and neo- or adjuvant therapies, prior to pembrolizumab treatment. Preclinical studies have suggested that lymph node dissection may reduce the efficacy of immune checkpoint inhibitors and negatively affect OS in murine models of neck squamous cell carcinoma (31). In the current study, no significant differences were found in mOS and mPFS between the unresectable and resection groups. These discrepancies may stem from variations in patient characteristics, cancer types, and immune checkpoint inhibitors used. Although further large-scale studies are warranted, our results suggest that lymph node dissection during radical cystectomy does not affect the efficacy of pembrolizumab in bladder cancer.

Although the optimal number of lymph nodes that should be removed during radical cystectomy remains undefined, most studies suggest that a higher number of resected lymph nodes is associated with improved clinical outcomes (8, 9). For example, Lemiński et al. reported that dissecting 10 and 15 lymph nodes was associated with better survival in patients with bladder cancer (9). By contrast, the current study found that patients with ≥14 dissected lymph nodes had poorer clinical outcomes compared to those with <14 dissected lymph nodes. In patients who received neoadjuvant therap y – designed to downstage the disease (32, 33) – the therapeutic benefit diminished when ≥14 lymph nodes were removed (Figure 5D). Consistent with our findings, Kawaguchi et al. reported that extensive lymph node dissection may reduce the efficacy of immune checkpoint inhibitors (24). Our data does not suggest avoiding lymph node dissection or neoadjuvant therapy. We and previous studies highlight the need for a treatment approach that prioritizes long-term local control and survival (8,9). Considering that extensive lymph node dissection may negatively affect the efficacy of pembrolizumab, determining the optimal pembrolizumab treatment strategy and duration should involve a thorough evaluation of patient’s previous treatment history, including the extent of lymph node dissection and neoadjuvant therapy.

Study limitations. The small sample size may limit the generalizability of our findings, and the retrospective nature of the study introduces potential selection bias. Hence, a prospective interventional study is warranted to validate these findings.

Conclusion

Lymph node dissection does not adversely affect the efficacy of pembrolizumab but may have an adverse effect depending on the extent of lymph node dissection. Our findings highlight the need for consideration of the treatment history of each patient, including the extent of lymph node dissection and the administration of neoadjuvant therapy, before initiation of pembrolizumab treatment in patients who experienced recurrence following radical cystectomy with lymph node dissection.

Footnotes

  • Authors’ Contributions

    Y. T. and T. Nagai designed and supervised the study. Y. T. and T. Nagai analyzed the majority of data. Y. T., T. Nagai, T. Naiki, Y. N., R. O., M. T., K. O., Y. M., Y. S., N. I., Y. Hotta, N. S., T. E., S. H., Y. H., and T. Y. performed data acquisition. Y. S. conducted the statistical analyses. Y. T. and T. Nagai wrote the manuscript. All Authors contributed to the interpretation of results, provided critical feedback, and approved the final manuscript.

  • Conflicts of Interest

    The Authors declare that they have no conflicts of interest.

  • Artificial Intelligence (AI) Disclosure

    No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.

  • Received April 2, 2025.
  • Revision received April 28, 2025.
  • Accepted April 30, 2025.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Effect of Pembrolizumab on Lymph Node Dissection in Patients Who Experienced Bladder Cancer Recurrence Following Radical Cystectomy
YOSHIHIKO TASAKI, TAKASHI NAGAI, TAKU NAIKI, YUSUKE NODA, RYOSEI OKAWA, MISATO TOMITA, YOSUKE SUGIYAMA, YOSHIHISA MIMURA, KUNIHIRO ODAGIRI, NANAMI ITO, YUJI HOTTA, NOBUHIKO SHIMIZU, TOSHIKI ETANI, SHUZO HAMAMOTO, ATSUSHI OKADA, YOKO FURUKAWA-HIBI, TAKAHIRO YASUI
In Vivo Jul 2025, 39 (4) 2196-2208; DOI: 10.21873/invivo.14015
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