Abstract
Background/Aim: Thymic carcinoma is a rare cancer with poor prognosis in unresectable cases. Treatment efficacy of carboplatin+paclitaxel (CP), lenvatinib, S-1, and sunitinib remains uncertain, with some patients experiencing increased post-treatment liver metastasis. Patients and Methods: We performed a retrospective analysis of patients with metastatic thymic carcinoma who received chemotherapy between 2006 and 2023 at the National Cancer Center Hospital. We evaluated the clinical outcomes [progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), liver metastasis response rate (LMRR), and liver metastasis control rate (LMCR)] of CP, lenvatinib, S-1, and sunitinib. Results: A total of 178 patients were evaluated, with 78.1% having stage IV disease. Most patients had squamous cell carcinoma (85.4%), and 39 patients had liver metastases (21.9%). The most frequently administered treatments as 1st-, 2nd-, and 3rd- line were CP (85.5%), S-1 (58.3%), and sunitinib (28.4%). The median PFS was 6.8, 9.4, 4.5, and 3.4 months in CP, lenvatinib, S-1, and sunitinib. CP showed an ORR of 41.6% and LMRR of 40.9%. The reverse response, in which only liver metastasis increased despite shrinkage of other lesions, was observed in lenvatinib (20%), S-1 (3.4%), and sunitinib (8.3%). Conclusion: CP and lenvatinib provided effective outcomes in metastatic thymic carcinoma, aligning with previous findings. S-1 and sunitinib also show clinical activity but with variable responses in liver metastases. These results highlight the importance of tailored treatment strategies, particularly for patients with liver involvement.
Thymic carcinoma is a rare cancer and often results in poor prognosis in unresectable cases (1). Cytotoxic chemotherapy plays a crucial role in achieving prolonged disease control for patients who have advanced thymic carcinoma (2). A multitude of retrospective studies and phase II trials have been conducted to investigate the efficacy of cytotoxic chemotherapy, and use of immune checkpoint inhibitors and molecular-targeted agents (3-5). Based on these studies, platinum-based chemotherapy has been recommended as the first-line treatment in several practice guidelines (6, 7).
Nevertheless, there is a paucity of data regarding the second or subsequent chemotherapy regimens because the evidence is largely derived from single-arm trials with small patient populations. The National Comprehensive Cancer Network (NCCN) guidelines list lenvatinib, sunitinib, pemetrexed, everolimus, paclitaxel, gemcitabine, 5-fluorouracil, etoposide, ifosfamide, and pembrolizumab as potential 2nd- or later-line systemic therapeutic alternatives for thymic carcinoma (6). Notably, in 2021, lenvatinib was approved in Japan for unresectable thymic carcinoma treatment based on the results of the REMORA trial and was considered eligible for reimbursement (4). In clinical practice settings in Japan, carboplatin + paclitaxel (CP), lenvatinib, S-1 (oral fluorouracil), and sunitinib have also been used. However, the clinical impact of these regimens remains unclear.
Liver metastasis has been identified as a poor prognostic factor for metastatic thymic carcinoma (8). It has been reported that the type of tumor histology can influence the locations of metastases (9). Intriguingly, some patients undergoing chemotherapy may experience enlargement only at the liver metastasis site with no notable changes at other metastatic sites.
Given the limited available literature, we conducted this retrospective study to determine the overall outcome of each therapeutic alternative in clinical practice and the treatment outcomes for liver metastases and other lesion cites.
Patients and Methods
Study design and patients. We retrospectively reviewed medical records of patients with metastatic or recurrent thymic carcinoma who underwent chemotherapy between January 2006 and March 2023 at the National Cancer Center Hospital (Tokyo, Japan). Baseline characteristics of each patient included sex, age, histological type, clinical staging, Eastern Cooperative Oncology Group performance status (ECOG PS), presence of liver metastases, history of radiation therapy, and whole-body computed tomography (CT) findings. We also checked for the presence of liver metastasis before the start of each treatment and conducted a liver-specific evaluation in patients who were assessable according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
Pathological diagnosis of thymic carcinoma was based on the 2015 World Health Organization (WHO) classification system. Clinical staging was performed using the Masaoka-Koga staging system in combination with the 8th edition of the Tumor, Node, Metastasis (TNM) Classification of thymic epithelial tumors (10).
This study was approved by the National Cancer Center Institutional Review Board Ethics Committee (no. 2015-355) and conducted in accordance with the Declaration of Helsinki and its subsequent amendments.
Treatment and dosing. We evaluated the clinical outcomes of four treatments: CP, lenvatinib, S-1, and sunitinib. The dosage for the four regimens was as follows: CP involved administering carboplatin [area under the curve (AUC) 6, day 1] and paclitaxel (200 mg/m2, day 1) every three weeks for up to six cycles. Lenvatinib (24 mg) was orally administered once daily. The initial dose of S-1 was determined based on the body surface area (BSA): 80 mg daily for four weeks-on and two weeks-off based on BSA <1.25 m2, 100 mg daily for 1.25 m2 < BSA <1.5 m2, and 120 mg daily for BSA >1.5 m2. Sunitinib (37.5 mg) was orally administered once daily.
Outcome definitions. Patients typically underwent CT assessments every 3-6 months. Patient response to treatment was evaluated according to RECIST version 1.1 (11). Progression-free survival (PFS) was calculated from the date of first administration to progressive disease (PD) or death from any cause, whichever occurred first. Overall survival (OS) was measured from the date of the initiation of chemotherapy to death from any cause, or censored at the date of data cutoff (June 20, 2023).
In addition, objective response rate (ORR), disease control rate (DCR), liver metastasis response rate (LMRR), and liver metastasis control rate (LMCR) were analyzed. The response rate was calculated only for those patients who underwent CT evaluation and RECIST estimation. Similarly, LMRR was limited to those patients who underwent CT evaluation and liver lesion size measurement.
Statistical analysis. Descriptive statistical analyses were performed for categorical and continuous variables. The association between liver metastasis and PFS or OS was analyzed using Cox proportional hazards regression models and reported as hazard ratio (HR) and 95% confidence interval (CI). All statistical analyses were performed using the STATA ver. 15.0 (Stata, College Station, TX, USA). Survival curves were estimated using the Kaplan–Meier method, and a two-sided significance level was defined as p<0.05.
Results
Patient characteristics and treatment modalities. Our analysis included 200 patients with thymic carcinoma treated at the National Cancer Center Hospital between January 2006 and March 2023. We excluded 17 patients who were treated for lung cancer or neuroendocrine carcinoma and five who were treated with radical chemoradiotherapy. Finally, a total of 178 patients were included in this study. Out of 178 patients, 152 were treated at our hospital from the first-line therapy, and 26 patients received treatment at our hospital from the second or later-line therapy. The CONSORT diagram for this study is shown in Figure 1.
CONSORT diagram. The CONSORT diagram shows the patient selection process used in the study.
Patient characteristics are presented in Table I. The median age was 59 years (range=19-84 years). Most patients were men (133/178, 63.5%) and had an ECOG PS score of 0 or 1 (172/178, 96.6%). Different disease stages at diagnosis were as follows: recurrence in 34 (19.1%), Masaoka-Koga stage III in five (2.8%), and stage IV in 139 (78.1%) patients. The primary histological subtype was squamous cell carcinoma (152/178, 85.4%), whereas the remaining patients had adenocarcinoma (n=5, 2.8%), basaloid carcinoma (n=2, 1.1%), poorly differentiated adenocarcinoma (n=11, 6.2%), and not specified (n=7, 4.5%). At diagnosis, 39 patients (21.9%) had liver metastasis. Fifty-nine (33.2%) of the individuals underwent radiation therapy before treatment or between treatments. Radiation therapy and each chemotherapy were conducted independently. Different treatment regimens for each line are presented in Table II. The most frequent regimens in each line of treatment were as follows: CP (130/152, 85.5%) for the 1st line, S-1 (74/127, 58.3%) for the 2nd line, and sunitinib (25/88, 28.4%) for the 3rd line therapy. The lines for each treatment are presented in Table III. The most frequent lines of treatment for different regimens were as follows: 1st line (130/143, 90.9%) for CP, 2nd line (29/68, 42.7%) for lenvatinib, 2nd line (74/103, 71.9%) for S-1, and 3rd line (25/39, 64.1%) for sunitinib. The flow of the treatment sequence can be found in the Sankey diagram of Figure 2. The initial lenvatinib dose was 24 mg in 43/68 (63.2%), 20 mg in 19/68 (28.0%), and 18 mg or less in 6/68 (8.8%) patients. Among the 70 patients who received lenvatinib, 58 (85.3%) required dose reduction due to adverse events, and the frequency of dose reduction was as follows: once for 19 (27.9%) patients, twice for 19 (27.1%) patients, and three or more times for 20 (29.5%) patients. Details of dose reductions due to adverse events are shown in Table IV.
Patient characteristics.
Chemotherapy of each treatment line.
Treatment line of each regimen.
Sankey diagram. The flow of each treatment sequence.
Dose details of lenvatinib.
Treatment efficacy. The median PFS (mPFS) of the first line therapy and median OS (mOS) were 6.9 months [95% confidence interval (CI)=6.2-7.8] and 42.9 (95%CI=32.6-58.9) months, respectively, as shown in Figure 3A and B. The mPFS for each line of treatment was as follows: 1st line, 6.9 months (95%CI=6.2-7.8); 2nd line, 6.2 months (95%CI=4.4-8.3); 3rd line, 4.6 months (95%CI=2.9-6.9) (Supplementary Figure 1). As for the comparison between patients with and without liver metastasis, mPFS was significantly shorter in patients with liver metastasis 6.1 months (95%CI=4.6-7.4) vs. 7.1 months (95%CI=6.3-9.6) (HR=1.72, p=0.01, 95%CI=1.12-2.62), and mOS was 27.6 months [95%CI=16.4-not reached (NR)] vs. 49.0 months (95%CI=38.2-58.9) (HR=1.51, 95%CI=0.83-2.74, p=0.18) (Figure 3C and D). The mPFS and mOS for each treatment regimen are described in Figure 4. mPFS and mOS were as follows: CP, 6.8 months (95%CI=6.2-7.6) and 42.7 months (95%CI=32.0-50.8) (Figure 4A); lenvatinib, 8.6 months (95%CI=6.7-12.7) and 30.3 months (95%CI=20.8-60.6) (Figure 4B); S-1, 4.5 months (95%CI=2.9-6.6) and 26.9 months (95%CI=16.9-31.7) (Figure 4C); sunitinib, 3.4 months (95%CI=2.2-10.0) and 17.3 months (95%CI=7.7-26.6) (Figure 4D). The mPFS of the 1st line and 2nd- or later-line with lenvatinib was 10.5 months (95%CI=4.6-NR) and 8.5 months (95%CI=6.2-13.1), (HR=0.76 [0.32-1.80], p=0.53) (Supplementary Figure 2).
Progression-free survival (PFS) and overall survival (OS) of all patients. A, B) PFS and OS of all patients. C, D) PFS and OS by the presence or absence of liver metastases.
Progression-free survival (PFS) and overall survival (OS) for each treatment regimen: A) Carboplatin + paclitaxel. B) Lenvatinib. C) S-1. D) Sunitinib.
Comparison of tumor response according to RECIST and liver metastasis for all treatment regimens. Tumor response was assessed in 137 of 143 patients treated with CP, 64 of 68 patients treated with lenvatinib, 97 of 103 patients treated with S-1, and 37 of 39 patients treated with sunitinib. Responses to different treatment regimens evaluated using RECIST are shown in Table V. Changes in tumor size from baseline for those patients who underwent RECIST estimation are illustrated in Figure 5-1. The ORR and DCR, respectively, for each treatment were as follows: for CP, 41.6% (57/137) and 90.5% (124/137) (Table V, Figure 5-1A); for lenvatinib, 34.4% (22/64) and 87.5% (56/64) (Table V, Figure 5-1B); for S-1, 27.8% (27/97) and 63.9% (62/97) (Table V, Figure 5-1C); for Sunitinib, 21.6% (8/37) and 59.4% (22/37) (Table V, Figure 5-1D).
Waterfall response plot. 1: Waterfall response plot for all treatment regimens: A) carboplatin+paclitaxel. B) Lenvatinib. C) S-1. D) Sunitinib. Changes in tumor size from baseline for those patients who underwent RECIST evaluation. 2: Comparison of tumor response by RECIST and liver metastasis for all treatment regimens: A) carboplatin+paclitaxel. B) lenvatinib. C) S-1. D) sunitinib. Liver metastasis and overall RECIST tumor size changes in patients who underwent RECIST estimation. PR: Partial response; SD: stable disease; PD: progressive disease; RECIST: Response Evaluation Criteria in Solid Tumors; LMPR: liver metastases partial response; LMSD: liver metastases stable disease; LMPD: liver metastases progressive disease.
Comparison of tumor response rate by RECIST and liver metastasis for all treatment regimens.
The LMRR was assessed in 22 patients treated with CP, 20 patients treated with lenvatinib, 29 patients treated with S-1, and 12 patients treated with sunitinib. The LMRR for each treatment regimen are presented in Table V. Comparisons of changes in tumor size from baseline evaluated using RECIST and liver metastasis for all treatment regimens are shown in Figure 5-2. The LMRR and LMCR, respectively, for each treatment regimen were as follows: for CP, 40.9% (9/22) and 90.9% (20/22) (Table V, Figure 5-2A); for Lenvatinib, 15.0% (3/20) and 55.0% (11/20) (Table V, Figure 5-2B); for S-1, 37.9% (11/29) and 55.2% (16/29) (Table V, Figure 5-2C); for Sunitinib, 16.7% (2/12) and 41.7% (5/12) (Table V, Figure 5-2D). The reverse response, in which only liver metastasis increased despite the shrinkage of other lesions, was observed in 20% (4/20) patients treated with lenvatinib, 3.4% (1/29) treated with S-1, and 8.3% (1/12) treated with sunitinib. Liver metastasis increased by more than two times that of other lesions in 25% (5/20) of patients treated with lenvatinib, 10.3% (3/29) treated with S-1, and 8.3% (1/12) treated with sunitinib (Figure 5-2B, C, D).
Discussion
We investigated the clinical outcomes of four treatment options for thymic carcinoma based on the estimation of the PFS and OS by treatment line and treatment regimen, as well as ORR and DCR. In addition, we evaluated the treatment outcome of liver metastases.
CP combination therapy has been reported to have a relatively favorable ORR of 22-36% in multiple phase II trials and is generally considered as the 1st line chemotherapy (12, 13). This study showed that the CP regimen was most frequently used as 1st line chemotherapy, with a favorable ORR of 41.6% and a DCR of 90.5%. Development of targeted therapy for the treatment, such as multikinase inhibitors, have shown a response in patients with thymic carcinoma. Lenvatinib is a multikinase inhibitors targeting on vascular endothelial growth factor receptor (VEGFR) 1-3, RET, KIT, platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR) 1-4 and unique from sunitinib in terms of inhibiting FGFR. The REMORA trial involving 42 patients treated with lenvatinib reported an ORR of 38% and an mPFS of 9.3 months (4). In our study, the most frequent use of lenvatinib was as 2nd- or later-line therapy, with an ORR of 34.4%, DCR of 87.5%, and mPFS of 8.6 months despite frequent dose reduction. The first-line lenvatinib is included in this series and is plausible in terms of efficacy. Maintaining a relative dose through adequate treatment strategies is required to achieve maximum treatment efficacy. Moreover, we provided detailed data on lenvatinib dose reduction. Unlike other regimens, lenvatinib required dose reduction in a significant number of patients owing to its adverse events. However, considering that 85.3% of patients required dose reduction and 57.4% underwent two or more dose reductions while achieving therapeutic effectiveness and continuing treatment, it is possible to continue treatment with a multi-stage dose reduction strategy. In terms of toxicity control, a so-called weekend off schedule for lenvatinib is an option, applying 24 mg dosing quaque die (QD) from Monday to Friday, and off on Saturday and on Sunday, still maintaining AUC at 75%, compared to a decreased AUC to 45% with a dose reduction to 8 mg daily. This strategy for hepatic cell carcinoma can most likely be applied to thymic carcinomas (14).
S-1 therapy as a 2nd- or later-line therapy for thymic carcinoma has been reported in a few phase II studies, with an ORR of 25-30.8%, DCR of 75-80.8%, mPFS of 4.3-5.4 months, and mOS of 22.7-27.4% (15, 16). Our study also demonstrated similar results with an ORR of 27.8%, DCR of 63.9%, mPFS of 4.5 months, and mOS of 26.9 months, indicating similar therapeutic effectiveness of S-1 in clinical setting as that in phase II trials. This fluoropyrimidine agent will replace capecitabine, as S-1 is commonly used as a local drug in East Asia.
A phase II study of sunitinib for chemotherapy-refractory thymic carcinoma and thymoma was reported in 2015, with the following findings: ORR, 26%; DCR, 91%; mPFS, 7.2 months; and OS, not reached (5). In our study, the values of ORR, DCR, mPFS, and mOS were 21.6%, 59.4%, 3.4 months, and 17.3 months, respectively. The reason for worse treatment outcomes compared with the previous report might be that the patients received sunitinib as the 3rd- or later-line of treatment. In addition, after approval of lenvatinib in 2021, sunitinib has not been recommended for use as per the Japanese guidelines. Therefore, lenvatinib has mainly been used as the 2nd- or later-line therapy since 2021 in Japan.
Several reports have described liver metastasis from thymic carcinoma (8, 9). Khandelwal et al. reported ten thymic carcinoma cases; although the number of cases was limited, liver metastases were observed in half of the cases (5/10) (9). Okuma et al. reported 286 patients with thymic carcinoma and observed liver metastasis in 15.7% of patients (8). They also revealed that liver metastases were associated with poor prognosis. In our study, 21.9% (39/178) of patients had liver metastases before treatment initiation. We also demonstrated worse outcomes of patients with liver metastasis (mPFS: 6.1 months, mOS: 27.6 months) compared with patients without liver metastasis (mPFS: 7.1 months, mOS: 49.0 months). Therefore, response of liver metastasis to treatment is important for controlling disease progression. However, previous trials of treatments, such as CP, lenvatinib, S-1, and sunitinib have not documented the details of response of liver metastasis to treatment (4, 5, 12, 13, 15). This study is the first to focus on the responses of both the entire lesion and liver metastasis to treatment. Liver metastases and other lesions showed parallel responses to CP. However, 20% of patients treated with lenvatinib, 3.4% with S-1, and 8.3% with sunitinib exhibited responses that reversed those of other lesions. In addition, in 25% of patients treated with lenvatinib, 10.3% with S-1, and 8.3% with sunitinib, liver metastases increased by more than two times compared to other lesions. Therefore, when treating patients with lenvatinib, S-1, or sunitinib, it is important to consider the gap in treatment response between liver metastases and primary tumor site.
Study limitations. First, it is a retrospective study conducted at a single institution. Second, imaging studies were performed as part of standard clinical care without a predefined interval. Although the PECATI study (17) indicates that lenvatinib combined with pembrolizumab may also have the potential to become a treatment option, reports on thymic carcinoma treatment data for a large number of patients at a single institution are scarce and valuable.
Conclusion
This retrospective analysis represents one of the largest single-institute evaluations of metastatic or recurrent thymic carcinoma. Our findings affirm that CP and lenvatinib yield therapeutic outcomes consistent with prior studies, supporting their roles as first- and second-line therapies, respectively. S-1 and sunitinib exhibited moderate effectiveness and warrant further comparative studies, potentially in phase III trials, to better define their roles in treatment sequencing. Additionally, the varied response of liver metastases, especially in patients receiving lenvatinib, S-1, or sunitinib, highlights the complexity of treating thymic carcinoma with multi-site involvement. This study underscores the importance of monitoring differential treatment responses in liver metastases and supports the need for tailored therapeutic strategies to optimize outcomes for this challenging malignancy.
Acknowledgements
The Authors would like to thank Editage (https://www.editage.jp) for English language editing. This study was awarded the Best Poster in ESMO 2022.
Footnotes
Authors’ Contributions
ATT, YO, and YG designed the study. ATT and MA collected the clinical data. ATT performed statistical data analyses, interpreted the results, and wrote the manuscript. ATT and YO drafted the manuscript. MT advised on the visualization. All Authors reviewed and approved the final version of the manuscript.
Supplementary Material
Available using DOI: https://doi.org/10.6084/m9.figshare.27610773.v1
Conflicts of Interest
YO reports receiving personal fees from AstraZeneca.K.K during the conduction of the study; grants from AbbVie K.K. and Roche; and personal fees from Nippon Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharma Co. Ltd., Ely Lilly K.K., Ono Pharma Co. Ltd., Pfizer Taiho Pharma Co. Ltd., and Taiho Pharma Co. Ltd. outside of the submitted work. YG reports receiving personal fees from AstraZeneca.K.K during the conduction of the study; grants from AbbVie, AZK, Kyorin, and Preferred Network; grants and personal fees from Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Novartis, Ono, and Pfizer; and personal fees from Boehringer Ingelheim, Chugai, Guardant Health Inc., Illumina, Merck Sharp & Dohme, Taiho, and Thermo Fisher outside of the submitted work. Dr. Yamamoto reports receiving personal fees from AstraZeneca.K.K during the conduction of the study; grants from Astellas, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Carna Biosciences, Chugai, Chiome Bioscience Inc., Daiichi Sankyo, Eisai, Eli Lilly, Genmab, GlaxoSmithKline, Janssen Pharma, Kyowa-Hakko Kirin, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical Co., Ltd., Otsuka, Pfizer, Quintiles, Shionogi, Sumitomo Dainippon, Takeda, and Taiho; and personal fees from Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Cimic, Eisai, Lilly, Ono Pharmaceutical Co., Ltd., Otsuka, Pfizer, Sysmex, and Takeda, outside of the submitted work. ATT, MA, YI, and MT have nothing to disclose. YS reports receiving personal fees from AstraZeneca.K.K during the conduction of the study; personal fees from Bristol-Myers Squibb, Chugai, and Eli Lilly; grants and personal fees from Ono; and grants from Janssen and Japan Clinical Research Operations K.K. outside of the submitted work. TY reports receiving personal fees from AstraZeneca.K.K during the conduction of the study; grants and personal fees from Amgen, Bristol-Myers Squibb, Chugai, Merck Sharp & Dohme, Novartis, and Ono; grants from AbbVie, Daiichi Sankyo, and Takeda; and personal fees from ArcherDX, Eli Lilly, Roche, and Taiho outside of the submitted work. HH reports receiving personal fees from AstraZeneca.K.K during the conduction of the study; grants and personal fees from Chugai, Merck Sharp & Dohme, Novartis, Ono, and Roche; grants from AbbVie, Bristol-Myers Squibb, Daiichi Sankyo, Genomic Health, Janssen, Merck Biopharma; and personal fees from Eli Lilly and Kyowa-Kirin, outside of the submitted work. NY reports receiving personal fees from AstraZeneca.K.K during the conduction of the study; grants from Astellas, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Carna Biosciences, Chugai, Chiome Bioscience Inc., Daiichi Sankyo, Eisai, Eli Lilly, Genmab, GlaxoSmithKline, Janssen Pharma, Kyowa-Hakko Kirin, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical Co., Ltd., Otsuka, Pfizer, Quintiles, Shionogi, Sumitomo Dainippon, Takeda, and Taiho; and personal fees from Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Cimic, Eisai, Lilly, Ono Pharmaceutical Co., Ltd., Otsuka, Pfizer, Sysmex, and Takeda, outside of the submitted work. YuO reports receiving grants, personal fees, and nonfinancial support from AstraZeneca.K.K during the conduction of the study; personal fees from Amgen, AnHeeart Therapeutics Inc., Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Chugai, Kyowa-Hakko Kirin, Merck Sharp & Dohme, Nippon Kayaku, Ono Pharmaceutical Co., Ltd., Pfizer, and Taiho; grants and personal fees from Eli Lilly; grants and nonfinancial support from Kyorin; grants from Daiichi Sankyo, Dainippon-Sumitomo, Janssen, Kissei, LOXO, Novartis, Takeda, and Taiho, outside of the submitted work.
- Received October 27, 2024.
- Revision received November 5, 2024.
- Accepted November 7, 2024.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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