Trends in the use and efficacy of adjuvant immunotherapy in muscle-invasive urothelial carcinoma
Shingo Hatakeyama
MD
1✉ Phone81-172-39-5091 Email
Naoki Fujita 1
Mizuki Kobayashi 2 Email
Shuya Kandori 3 Email Email
Daiki Ikarashi 4
Hiroki Fukuhara 5 Email
Takuma Sato 6 Email
Shingo Myoen 7 Email
Motohide Uemura 8 Email
Takamitsu Inoue 9 Email
Masaaki Oikawa 10
Yasuhiro Kaiho 10 Email Email
Jun Miyazaki 9 Email
Yoshiyuki Kojima 8 Email
Hisanobu Adachi 7 Email
Akihiro Ito 6 Email Email
Norihiko Tsuchiya 5 Email
Wataru Obara 4
Hiroyuki Nishiyama 3 Email
Tomonori Habuchi 2 Email
Chikara Ohyama 1 Email Email
1 Department of Urology Hirosaki University Graduate School of Medicine 5 Zaifu-chou 036-8562 Hirosaki Japan
2 Department of Urology Akita University Graduate School of Medicine Akita Japan
3 Department of Urology, Institute of Medicine University of Tsukuba Tsukuba Japan
4 Department of Urology Iwate Medical University Morioka Japan
5 Department of Urology Yamagata University Graduate School of Medicine Yamagata Japan
6 Department of Urology Tohoku University Graduate School of Medicine Sendai Japan
7 Department of Urology Miyagi Cancer Center Natori Japan
8 Division of Urology Fukushima Medical University Fukushima Japan
9 Department of Renal and Urological Surgery International University of Health and Welfare Narita Hospital Narita Japan
10 Division of Urology, Faculty of Medicine Tohoku Medical and Pharmaceutical University Sendai Japan
Shingo Hatakeyama1*, Naoki Fujita1, Mizuki Kobayashi2, Shuya Kandori3, Daiki Ikarashi4, Hiroki Fukuhara5, Takuma Sato6, Shingo Myoen7, Motohide Uemura8, Takamitsu Inoue9, Masaaki Oikawa10, Yasuhiro Kaiho10, Jun Miyazaki9, Yoshiyuki Kojima8, Hisanobu Adachi7, Akihiro Ito6, Norihiko Tsuchiya5, Wataru Obara4, Hiroyuki Nishiyama3, Tomonori Habuchi2, Chikara Ohyama1
1 Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
2 Department of Urology, Akita University Graduate School of Medicine, Akita, Japan
3 Department of Urology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan
4 Department of Urology, Iwate Medical University, Morioka, Japan
5 Department of Urology, Yamagata University Graduate School of Medicine, Yamagata, Japan
6 Department of Urology, Tohoku University Graduate School of Medicine, Sendai, Japan
7 Department of Urology, Miyagi Cancer Center, Natori, Japan
8 Division of Urology, Fukushima Medical University, Fukushima, Japan
9 Department of Renal and Urological Surgery, International University of Health and Welfare Narita Hospital, Narita, Japan
10 Division of Urology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
*Corresponding author: Shingo Hatakeyama, MD, Department of Urology, Hirosaki University Graduate School of Medicine, 5 Zaifu-chou, Hirosaki 036-8562, Japan; Tel: 81-172-39-5091; Fax: 81-172-39-5092; E-mail: shingoh@hirosaki-u.ac.jp, ORCID; https://orcid.org/0000-0002-0026-4079
Keywords:
adjuvant immunotherapy
cystectomy
nephroureterectomy
prognosis
urothelial carcinoma
Running head
Trend in use and efficacy of adjuvant immunotherapy
Word count: abstract: 238; text word count (including abstract): 1653
Shingo Hatakeyama; shingoh@hirosaki-u.ac.jp, Naoki Fujita; naonao707012@hirosaki-u.ac.jp, Mizuki Kobayashi; qqc83rkd@piano.ocn.ne.jp, Shuya Kandori; shuya79@md.tsukuba.ac.jp, Daiki Ikarashi; dikara@iwate-med.ac.jp, Hiroki Fukuhara; hiroki_fukuhara@yahoo.co.jp, Takuma Sato; takumasato@uro.med.tohoku.ac.jp, Shingo Myoen; shingomyoen3024@msn.com, Motohide Uemura; muemura@fmu.ac.jp, Takamitsu Inoue; takmitz@gmail.com, Masaaki Oikawa; ywpkx125@yahoo.co.jp, Yasuhiro Kaiho; kaiho@tohoku-mpu.ac.jp, Jun Miyazaki; jmiyazaki@iuhw.ac.jp, Yoshiyuki Kojima; ykojima@fmu.ac.jp, Hisanobu Adachi; nobu012@gmail.com, Akihiro Ito; itoaki@uro.med.tohoku.ac.jp, Norihiko Tsuchiya; norihiko.tsuchiya@gmail.com, Wataru Obara; watao@iwate-med.ac.jp, Hiroyuki Nishiyama; nishiuro@gmail.com, Tomonori Habuchi; thabuchi@gmail.com, Chikara Ohyama; coyama@hirosaki-u.ac.jp
Abstract
We investigated trends in the use of perioperative therapy and the efficacy of adjuvant immunotherapy on the prognosis of patients with muscle-invasive urothelial carcinoma (MIUC). The usage and trends in neoadjuvant and adjuvant therapy were determined, and the efficacy of adjuvant immunotherapy was assessed using propensity score-adjusted Cox multivariate analysis. We investigated 1383 patients with muscle-invasive bladder cancer and 1124 patients with upper tract urothelial carcinoma; 1095 (43.7%) patients received neoadjuvant therapy and 366 (14.6%) patients received adjuvant therapy. Adjuvant therapy usage rate increased from 30.3% before 2022 to 61% after 2022 in patients with pathological high-risk cancer (pT3-4, ypT2-4, or pN+). The adjuvant immunotherapy usage rate increased from 2.8% before 2022 to 67.5% after 2022. Sixty-three (18.9%) of the 334 patients with pathological high-risk cancer who were treated with adjuvant therapy were treated with adjuvant immunotherapy. The propensity score-adjusted Cox multivariate analysis showed that adjuvant immunotherapy significantly improved disease-free survival (Hazard ratios (HR) 0.23, P = 0.021) and overall survival (HR 0.15, P = 0.006) compared with conventional adjuvant chemotherapy. In conclusion, the introduction of adjuvant immunotherapy led to the increased use of adjuvant therapy and improved prognoses in patients with MIUC in real-world practice.
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Introduction
Muscle-invasive urothelial carcinoma (MIUC) is a lethal disease with a 5-year survival rate of 50%−60%, even in the absence of distant metastases 1–4. Neoadjuvant chemotherapy (NAC), radical cystectomy (RC) or nephroureterectomy (RNU), and extended pelvic lymph node dissection have not improved the prognosis of patients with MIUC 5–12. Although adjuvant chemotherapy may improve survival 13, toxic chemotherapy is not feasible in all patients due to advanced age, impaired renal function, and frailty. Disease-free survival (DFS) improved with adjuvant nivolumab in patients with high-risk MIUC in the CheckMate 274 trial 14.
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Nivolumab was approved in Japan on March 28, 2022, as an adjuvant immunotherapy for MIUC. The effects of nivolumab on overall survival (OS) have not been determined because more time is needed. Furthermore, a similar study (IMvigor 010 trial) evaluating the effects of adjuvant atezolizumab after radical surgery failed to show efficacy, leading to questions about the consistency of the results 15. Thus, the benefits of adjuvant immune checkpoint inhibitors (ICIs) in clinical practice are unclear 16, 17. We evaluated trends in the use of perioperative therapy and efficacy of adjuvant ICIs in patients with muscle-invasive bladder carcinoma (MIBC) and upper tract urothelial carcinoma (UTUC) in a real-world practice.
Results
Baseline characteristics
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The median patient age was 71.0 years. Table 1 shows the baseline characteristics of the patients, including 1383 patients with MIBC and 1124 patients with UTUC. The eGFR in patients with UTUC was significantly lower than the eGFR in patients with MIBC (P < 0.001). The NAC administration rate in patients with UTUC was 20.5%. Pathological high-risk disease occurred in 46.9% and 40.2% of patients with MIBC and UTUC, respectively (Table 1). Patient treatment journeys are shown in a Dendrogram (Fig. 1A) and a Sankey diagram (Fig. 1B). NAC was administered to 1095 (43.7%) patients and adjuvant therapy was administered to 366 (14.6%) patients. In the NAC and non-NAC groups, 12.1% and 16.5% of patients, respectively, received adjuvant therapy.
Table 1
Background of patients
 
MIBC
UTUC
Number of patients, n
1383
1124
Age, years (IQR)
70 (64, 75)
73 (65, 78)
Male, n
1073 (77.6%)
803 (71.4%)
ECOG PS > 1, n
35 (2.5%)
14 (1.2%)
eGFR, mL/min/1,73m2 (IQR)
64.3 (52.4, 77.0)
57.0 (45.7, 70,7)
cT > 2, n
605 (43.7%)
401 (35.7%)
cN+, n
183 (13.2%)
134 (11.9%)
Neoadjuvant chemotherapy, n
865 (62.5%)
230 (20.5%)
Cisplatin-based, n
528 (38.2%)
125 (11.1%)
Pathological high-risk (pT3-4, ypT2-4, or pN+), n
649 (46.9%)
452 (40.2%)
Variant histology, n
159 (11.5%)
68 (6.0%)
Adjuvant chemotherapy, n
186 (13.4%)
181 (16.1%)
Cisplatin-based, n
110 (8.0%)
99 (8.8%)
Adjuvant immunotherapy, n
44 (3.2%)
22 (2.0%)
Median follow up, months
42.3 (17.3, 96.7)
35.8 (15.5, 74.8)
Nonurothelial tumor recurrence, n
431 (31.2%)
253 (22.5%)
Deceased, n
604 (43.7%)
333 (29.6%)
Fig. 1
Treatment journeys of patients shown as a Dendrogram and Sankey diagram. (A) Display of the treatment journey using a dendrogram. (B) Display of the treatment journey using a Sankey diagram.
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Table 2
Background of patients with pathological high-risk (pT3-4, ypT2-4, or pN+).
 
No adjuvant
Adjuvant chemotherapy
Adjuvant ICIs
Number of patients, n
764
274
63
Age, years (IQR)
72 (66, 78)
69 (62, 75)
73 (67, 76)
Male, n
537 (70.3%)
206 (75.2%)
44 (69.8%)
ECOG PS > 1, n
29 (3.8%)
6 (2.2%)
0 (0%)
eGFR, mL/min/1,73m2 (IQR)
57.7 (44.9, 71.5)
58.8 (48.1, 73.5)
55.0 (38.8, 63.5)
UTUC, n
282 (36.9%)
148 (54.0%)
22 (34.9%)
Neoadjuvant chemotherapy, n
434 (17.5%)
36 (13.1%)
61 (96.8%)
pT > 2 or ypT > = 2, n
732 (95.8%)
262 (95.6%)
61 (96.8%)
pN+, n
179 (23.4%)
100 (36.5%)
20 (31.7%)
Variant histology, n
134 (17.5%)
36 (13.1%)
11 (17.5%)
Type of adjuvant immunotherapy
      
nivolumab, n
0 (0%)
0 (0%)
60 (0%)
Atezolizumab, n
0 (0%)
0 (0%)
3 (0%)
Median follow up, months
30.8 (11.4, 75.1)
34.3 (17.0, 71.5)
14.8 (8.1, 21.8)
Nonurothelial tumor recurrence, n
497 (65.1%)
174 (63.5%)
18 (28.6%)
Deceased, n
334 (43.7%)
110 (40.1%)
4 (6.35)
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Primary outcome: trends in the use of perioperative therapy
The use of neoadjuvant chemotherapy increased from 2005 to 2024, reaching 70.5% in 2024. The use of adjuvant therapy gradually decreased from 2005 to 2021 but increased after the approval of nivolumab in 2022 (Fig. 2A). However, the use of adjuvant therapy increased in patients with pathological high-risk disease (Fig. 2B). The adjuvant therapy usage rate was 30.3% before 2022 but increased 2-fold (61.0%) after 2022 (Fig. 2C). Of the adjuvant therapies, the use of chemotherapy gradually decreased, while the use of ICIs rapidly increased (Fig. 2D). The use of adjuvant ICIs was 67.5% after 2022 (Fig. 2E). After 2022, adjuvant chemotherapy was mainly administered in patients without NAC, and adjuvant ICIs were mainly used for patients with NAC (Fig. 2F). In patients with pathological high-risk UTUC, the use of ICIs in combination with NAC increased rapidly (Fig. 3A). The main regimen for adjuvant therapy changed from chemotherapy (23.0%) to ICIs (54.3%) after 2022 (Fig. 3B).
Fig. 2
Trends in perioperative therapy use. (A) Trends in the use of neoadjuvant and adjuvant therapies in all patients with MIBC or UTUC. (B) Trends in the use of adjuvant therapies in patients with pathological high-risk disease. (C) Comparison of adjuvant therapy use in patients with pathological high-risk disease before 2022 and after 2022. (D) Trends in the use of adjuvant therapies (chemotherapy or immunotherapy) in patients with pathological high-risk disease. (E) Comparison of the type of adjuvant therapy in patients with pathological high-risk disease before 2022 and after 2022. (F) Differences in the rate of NAC use between adjuvant chemotherapy and immunotherapy.
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Fig. 3
Trends in the use of perioperative therapy in UTUC. (A) Trends in the use of neoadjuvant and adjuvant therapies in patients with pathological high-risk UTUC. (B) Comparison of the type of adjuvant therapy in patients with pathological high-risk disease before 2020, 2020−2021, and after 2022.
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Secondary outcomes: effects of adjuvant immunotherapy on oncological outcomes
Of the 1101 patients with pathological high-risk disease, 766, 268, and 63 patients received no adjuvant therapy, adjuvant chemotherapy, and adjuvant ICIs, respectively. The unadjusted DFS and OS were not significantly different between the adjuvant chemotherapy and ICIs (Fig. 4A and 4B). However, IPTW-adjusted Cox regression analyses showed significant differences in DFS (P = 0.021) and OS (P = 0.006) between adjuvant chemotherapy and ICIs (Fig. 4C and 4D).
Fig. 4
The prognostic impact of adjuvant immunotherapy on prognosis. (A) Unadjusted disease-free survival in patients with pathological high-risk MIUC. (B) Unadjusted overall survival in patients with pathological high-risk MIUC. (C) Background-adjusted disease-free survival in patients with pathological high-risk MIUC. (D) Background-adjusted overall survival in patients with pathological high-risk MIUC.
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Discussion
Trends in perioperative treatment and the effects of adjuvant immunotherapy associated with the development of new treatment strategies in patients with MIUC were investigated. The CheckMate 274 and IMvigor 010 trials showed inconsistent results 15, 18, highlighting the fragility of evidence and the need to evaluate outcomes from clinical trial to practice. We confirmed the rapid increase in adjuvant ICI use and observed improved prognoses in patients with MIUC, despite the short observation period. The recent AMBASSADOR trial demonstrated the efficacy of adjuvant pembrolizumab in patients with high-risk MIUC 19. Thus, the efficacy of adjuvant ICIs was confirmed 20–22. However, outcome disparities between upper- and lower-tract diseases were reported (HR 1.27 vs. 0.66) 19. Further research is needed to determine if this disparity can be explained by the small number of UTUC cases 23 or whether other factors were involved.
Regarding the use of adjuvant ICIs in combination with NAC, our results showed that, in most cases, adjuvant ICIs were administered after NAC. This result is in line with the results of a sub-analysis of the CheckMate 274 trial showing that adjuvant nivolumab may be highly effective after NAC. Interestingly, the use of NAC plus adjuvant ICIs in UTUC is comparable to that in MIBC. Level 1 evidence supporting adjuvant chemotherapy was reported in the POUT study 24. Thus, the choice between adjuvant chemotherapy and ICIs for patients with high pathological risk is a dilemma in clinical practice. Of the 42 patients with pathological high-risk UTUC after 2022 in our study, 23 (54.8%) patients were treated with adjuvant chemotherapy but did not receive NAC, 1 patient (2.4%) received adjuvant ICIs without NAC, and 18 (42.9%) patients received adjuvant ICIs plus NAC. These findings indicate a tendency to choose adjuvant chemotherapy without NAC and adjuvant ICIs with NAC for patients with high pathological risk UTUC. Although the observation period was short, recent real-world data indicate that the beneficial effects of adjuvant nivolumab may be higher in patients treated with NAC compared with patients who were not treated with NAC 16. Further investigation is needed to determine whether this selection is beneficial.
Several limitations of this study should be acknowledged. First, due to the retrospective study design, we could not control for selection bias and other potential confounders. Second, the statistical analysis may be underpowered due to the small sample size and short observation period in patients treated with adjuvant ICIs. Third, this study included a single population and the results may not be generalizable. Despite these limitations, this is the first study to show the trends in adjuvant ICI use and the impact on prognoses in patients with MIUC. Further studies are required to determine the optimal strategies for selecting treatments for patients with MIUC.
In conclusion, the introduction of adjuvant immunotherapy led to increased adjuvant therapy use, which may have improved prognoses in patients with MIUC in real-world practice.
Patients and methods
Design and ethics statement
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We conducted this retrospective, multi-institutional study in accordance with the Declaration of Helsinki. The need for informed consent to participate was waived by an Institutional Review Board by the ethics committee of the Hirosaki University School of Medicine (approval no. 2023–063–1) and all participating hospitals. Written consent was not obtained from patients who decided not to participate (opt-out approach).
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This study was performed in accordance with appropriate guidelines and the experimental protocol that was approved by the ethics committee of the Hirosaki University School of Medicine (2023–063–1).
Patient selection, demographics, and surgical procedures
Between January 1994 and April 2024, 2521 patients with MIUC (MIBC and UTUC) but no distant metastases who received RC or RNU at 10 academic centers were enrolled in the study. After excluding 14 patients with insufficient clinical data, 1383 patients with MIBC and 1124 patients with UTUC were included in the study (Fig. 1A). The following variables were collected and analyzed: age, sex, Eastern Cooperative Oncology Group performance status (ECOG PS), estimated glomerular filtration rate (eGFR), clinical stage, pathological stage, the use of adjuvant therapy, the type of adjuvant therapy, the year of treatment, DFS, and OS. The tumor stage and grade were stratified based on the 8th edition of the TNM classification 25. Patients with MIBC underwent open or robotic RC, urinary diversion, and standard pelvic lymph node dissection. Patients with UTUC underwent open or laparoscopic RNU, including kidney and ureter removal, and ipsilateral bladder cuff. Regional lymph node dissection was performed at the discretion of the attending physician 26.
Neoadjuvant or adjuvant therapy
Neoadjuvant chemotherapy regimens were selected according to our guideline for cisplatin eligibility based on the Galsky criteria 27, 28. The marginal criteria included ECOG PS 1, eGFR 50–60 mL/min/1.73 m2, NYHA class II heart failure, and age > 80 years, and patients with two or more marginal factors were classified as cisplatin ineligible. Indications for NAC included MIBC ≥ T2, UTUC ≥ T2, or cN + disease. NAC cycles were repeated every 21 days for up to four cycles. Adjuvant chemotherapy or ICIs were indicated for patients with a high pathological risk, including pT3−4, ypT2−4, positive surgical margin, or pN+. Two or three cycles of adjuvant chemotherapy (either gemcitabine plus cisplatin, gemcitabine plus carboplatin, or methotrexate, vinblastine, doxorubicin, and cisplatin) were administered to eligible patients, if their postoperative status was suitable for toxic chemotherapy 2, 29.
Outcomes
Primary outcomes included trends and usage rates of NAC and adjuvant therapy. Treatments with NAC and adjuvant therapy were evaluated using Sankey diagrams. NAC and adjuvant therapy usage rates were assessed for different time periods. Secondary outcomes included the effects of adjuvant therapy on DFS and OS in patients with pathological high-risk (pT3−4, ypT2−4, or pN+) disease. DFS was defined as the time of primary treatment to nonurothelial tumor recurrence. Superficial urothelial recurrence was not included in DFS. OS was defined as the time from the primary treatment to any cause of death.
Statistical analyses
Statistical analyses were conducted using BellCurve for Excel 4.07 (Social Survey Research Information Co., Ltd., Tokyo, Japan), GraphPad Prism 7.00 (GraphPad Software, San Diego, CA, USA), and R: 4.0.2 (The R Foundation, Vienna, Austria). Groups were compared using the Mann–Whitney U and Fisher’s exact tests. Quantitative variables were expressed as medians with interquartile ranges. The OS rate was estimated using the log-rank test. The effects of adjuvant therapy on DFS and OS were evaluated with background-adjusted multivariable Cox regression analyses using the inverse probability treatment weighting (IPTW) method. Hazard ratios (HR) with 95% confidence intervals were calculated after controlling for potential confounders, including patient age, sex, ECOG PS, tumor type (UTUC), variant histology, NAC, pT stage, and type of adjuvant therapy.
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Acknowledgement
The authors would like to thank Soichiro Ogawa, Kazuyuki Numakura, Takahiro Yoneyama, Shintaro Narita, and Yuki Fujita for their invaluable help with data collection. The authors would also like to thank Enago (www.enago.jp) for the English language review.
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Funding:
This study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI grants 20K09517 (S.H.).
Disclosure of conflicts of interest: Shingo Hatakeyama received honoraria from Janssen Pharmaceutical K.K., Astellas Pharma Inc., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Bayer AG, Pfizer Inc., Bristol-Myers Squibb, Merck Biopharma Co., Ltd., Kaneka Corporation, and Nipro Corporation. Hiroyuki Nishiyama received honoraria from Astellas, BMS, Janssen, MSD, Ono, and Pfizer, and a grant from Chugai and Astellas. The other authors have no conflicts of interest to declare. Tomonori Habuchi received honoraria from Janssen Pharmaceutical K.K., Nippon Kayaku Co., LTD., Takeda Pharmaceutical Company Ltd., Astellas Pharma Inc., Daiichi Sankyo Company, Ltd., AstraZeneca K.K., Sanofi S.A., Novartis Pharmaceuticals and Bayer AG. Tomonori Habuchi also received research funding supports from Mochida Pharmaceutical Co., Novartis Pharmaceuticals Co, LTD., Pharmaceuticals Co, LTD. and Sysmex Co. Wataru Obara received honoraria from Astellas Pharma Inc., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb, Merck Biopharma Co., Ltd., Takeda Pharmaceutical Company Ltd., Merck Biopharma. Norihiko Tsuchiya received honoraria from Janssen Pharmaceutical K.K., Pfizer Inc., Takeda Pharmaceutical Co. Ltd., Astellas Pharma Inc., Ono Pharmaceuticals Co., Ltd., MSD K.K., Merk & Co., Inc. Other authors have no conflicts of interest to declare.
Data sharing and data accessibility: The data that support the findings of this study are available from the corresponding author upon reasonable request.
Consent to Participate: Written consent was not obtained in exchange for the public disclosure of study information (opt-out approach).
Consent for Publication: All authors approved for the publication.
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Author Contribution
Author contributions: conception and design; Shingo Hatakeyamaacquisition of data; Shingo Hatakeyama, Naoki Fujita, Mizuki Kobayashi, Shuya Kandori, Daiki Ikarashi, Hiroki Fukuhara, Takuma Sato, Shingo Myoen, Motohide Uemura, Takamitsu Inoue, Masaaki Oikawa, Yasuhiro Kaiho, Jun Miyazaki, Yoshiyuki Kojima, Hisanobu Adachi, Akihiro Ito, Norihiko Tsuchiya, Wataru Obara, Hiroyuki Nishiyama,analysis and interpretation of data; Shingo Hatakeyamadrafting of the manuscript; Shingo Hatakeyamacritical revision of the manuscript for important intellectual content; Shingo Hatakeyama, Naoki Fujita, Mizuki Kobayashi, Shuya Kandori, Daiki Ikarashi, Hiroki Fukuhara, Takuma Sato, Shingo Myoen, Motohide Uemura, Takamitsu Inoue, Masaaki Oikawa, Yasuhiro Kaiho, Jun Miyazaki, Yoshiyuki Kojima, Hisanobu Adachi, Akihiro Ito, Norihiko Tsuchiya, Wataru Obara, Hiroyuki Nishiyama, Tomonori Habuchi, Chikara Ohyamastatistical analysis; Shingo Hatakeyama obtaining funding; Shingo Hatakeyamaadministrative, technical, or material support; Tomonori Habuchisupervision; Chikara Ohyama
acquisition of data; Shingo Hatakeyama, Naoki Fujita, Mizuki Kobayashi, Shuya Kandori, Daiki Ikarashi, Hiroki Fukuhara, Takuma Sato, Shingo Myoen, Motohide Uemura, Takamitsu Inoue, Masaaki Oikawa, Yasuhiro Kaiho, Jun Miyazaki, Yoshiyuki Kojima, Hisanobu Adachi, Akihiro Ito, Norihiko Tsuchiya, Wataru Obara, Hiroyuki Nishiyama,
analysis and interpretation of data; Shingo Hatakeyama
drafting of the manuscript; Shingo Hatakeyama
critical revision of the manuscript for important intellectual content; Shingo Hatakeyama, Naoki Fujita, Mizuki Kobayashi, Shuya Kandori, Daiki Ikarashi, Hiroki Fukuhara, Takuma Sato, Shingo Myoen, Motohide Uemura, Takamitsu Inoue, Masaaki Oikawa, Yasuhiro Kaiho, Jun Miyazaki, Yoshiyuki Kojima, Hisanobu Adachi, Akihiro Ito, Norihiko Tsuchiya, Wataru Obara, Hiroyuki Nishiyama, Tomonori Habuchi, Chikara Ohyama
statistical analysis; Shingo Hatakeyama
obtaining funding; Shingo Hatakeyama
administrative, technical, or material support; Tomonori Habuchi
supervision; Chikara Ohyama
Declarations
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Competing Interests
Disclosure of conflicts of interest: Shingo Hatakeyama received honoraria from Janssen Pharmaceutical K.K., Astellas Pharma Inc., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Bayer AG, Pfizer Inc., Bristol-Myers Squibb, Merck Biopharma Co., Ltd., Kaneka Corporation, and Nipro Corporation. Hiroyuki Nishiyama received honoraria from Astellas, BMS, Janssen, MSD, Ono, and Pfizer, and a grant from Chugai and Astellas. The other authors have no conflicts of interest to declare. Tomonori Habuchi received honoraria from Janssen Pharmaceutical K.K., Nippon Kayaku Co., LTD., Takeda Pharmaceutical Company Ltd., Astellas Pharma Inc., Daiichi Sankyo Company, Ltd., AstraZeneca K.K., Sanofi S.A., Novartis Pharmaceuticals and Bayer AG. Tomonori Habuchi also received research funding supports from Mochida Pharmaceutical Co., Novartis Pharmaceuticals Co, LTD., Pharmaceuticals Co, LTD. and Sysmex Co. Wataru Obara received honoraria from Astellas Pharma Inc., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb, Merck Biopharma Co., Ltd., Takeda Pharmaceutical Company Ltd., Merck Biopharma. Norihiko Tsuchiya received honoraria from Janssen Pharmaceutical K.K., Pfizer Inc., Takeda Pharmaceutical Co. Ltd., Astellas Pharma Inc., Ono Pharmaceuticals Co., Ltd., MSD K.K., Merk & Co., Inc. Other authors have no conflicts of interest to declare.
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Data Availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Yes
Total words in MS: 3175
Total words in Title: 13
Total words in Abstract: 192
Total Keyword count: 5
Total Images in MS: 4
Total Tables in MS: 2
Total Reference count: 29