Abstract
Background/Aim: The efficacy and safety of bevacizumab for ovarian cancer have been reported in randomized phase III clinical trials. It is important to gather experience and data in a real-world setting. The objective of the present study was to evaluate the efficacy and safety of bevacizumab for patients with ovarian cancer in a real-world setting. Patients and Methods: For front-line settings, patients with FIGO stage III-IV ovarian cancer treated using bevacizumab and chemotherapy after debulking surgery (Chemo + Bev group, n=79), in addition to those treated with only chemotherapy after debulking surgery (Chemo group; n=66), at our institute were reviewed retrospectively. For recurrent settings, patients with recurrent ovarian cancers treated with bevacizumab and any chemotherapy were reviewed retrospectively (n=65). Results: In the front-line setting, the disease-free survival was significantly longer in the Chemo + Bev group compared with that in the Chemo group (p=0.021). Hypertension and proteinuria were found to be statistically more frequent in the Chemo + Bev group compared with that in the Chemo group (p=0.002 and p=0.004). In the recurrent setting, in platinum-sensitive patients, the response rate (RR) and the disease control ratio (DCR) were 78.4 and 94.1%, respectively. In platinum-resistant patients, the RR and the DCR were 28.6 and 57.1% respectively. The median progression-free survival was 18.3 and 7.1 months for platinum-sensitive recurrence and platinum-resistant recurrence, respectively. The major ≥ grade 3 adverse event was neutropenia. Conclusion: The present study provided encouraging real-world evidence of the efficacy and safety of bevacizumab for ovarian cancer in real-world.
Epithelial ovarian cancer is one of the most common gynecological malignancies and a common cause of death from cancer in women worldwide, accounting for >150,000 deaths each year (1-3). Epithelial ovarian and tubal cancer, and primary peritoneal cancer are all classed as Müllerian cancers (4), as these malignancies have similar characteristics and are therefore treated with similar therapeutic strategies (4). However, the majority of Müllerian cancer cases are diagnosed in the first instance at an advanced stage due to its insidious onset and progression and the lack of effective screening methods (1). The typical therapeutic strategy for advanced Müllerian cancers consists of maximal debulking surgery followed by platinum-based chemotherapy with maintenance therapy using some molecular-targeting agent such as bevacizumab, Olaparib, and/or niraparib (1). Although the initial response to first-line therapy is generally favorable, the majority of patients will relapse and develop resistance to platinum-based chemotherapy after prolonged treatment with chemotherapy (1).
Angiogenesis serves a key role in solid-tumor progression and metastasis (5). In epithelial ovarian cancer, vascular endothelial growth factor (VEGF) is frequently found to be abundantly expressed, the suppression of which has been found to improve survival in vivo (5). This is due to reduced tumor vascularization and angiogenesis (6). As a result, bevacizumab, which is a recombinant humanized monoclonal antibody targeting VEGF, has been developed (7).
There have been five representative randomized phase III clinical trials that reported the efficacy and safety of combination therapy using chemotherapy and bevacizumab for ovarian cancer under various clinical settings. ICON7 (8) and GOG0218 (9) demonstrated the efficacy and safety of bevacizumab with paclitaxel and carboplatin followed by bevacizumab maintenance as a front-line therapy. In addition, OCEANS (10) and GOG0213 (11) demonstrated the efficacy and safety of combination therapy consisting of chemotherapy and bevacizumab for platinum-sensitive recurrent ovarian cancer. AURELIA (12) also demonstrated the efficacy and safety of chemotherapy combined with bevacizumab for platinum-resistant recurrent ovarian cancer. These previous trials clearly demonstrate the evidence of efficacy and safety following bevacizumab treatment. However, patients who are eligible for clinical trials are not fully representative of the population in clinical routine practice, as clinical trials are more likely to contain patients with more favorable disease characteristics including good performance status, fewer underlying conditions, and with good organ functions compared with those from ‘real-world’ settings, due to their strict eligibility criteria. Therefore, it is of utmost importance to gather experience and obtain data from routine clinical practice to confirm this potential efficacy and safety in a real-world setting.
The purpose of the present study was to evaluate the efficacy and safety of adding bevacizumab to a chemotherapeutic regimen as a front-line therapy for patients with ovarian cancer and for recurrent patients in a real-world setting.
Patients and Methods
Ethics. The present study was performed in compliance with the Declaration of Helsinki (13). The Review Board of Osaka Metropolitan University Hospital approved the present study (approval no. 2023-001). Written informed consent was provided by all patients prior to treatment with bevacizumab at Osaka City University Hospital (Osaka, Japan).
Front-line setting.
Patients and treatments. Medical records of consecutive patients with advanced Müllerian cancers, diagnosed histologically, including those with Federation of Gynecology and Obstetrics (FIGO) (14) stages III-IV, were reviewed retrospectively. Patients were either treated with bevacizumab and chemotherapy for ≥1 cycle after primary debulking surgery between June 1st, 2014, and December 31st, 2020 (assigned to the Chemo + Bev group) or treated with only chemotherapy after primary debulking surgery at Osaka City University Hospital between January 1st, 2008 and April 30th, 2013 (assigned to the Chemo group). The treatment strategies were standard clinical treatment at each period. Primary debulking surgery referred to the surgery that patients underwent without any neoadjuvant chemotherapy. Patients from two different periods were chosen as bevacizumab was approved by the pharmaceuticals and medical devices agency in Japan for treating advanced Müllerian cancers in November 2013 (15). Therefore, no patients with advanced Müllerian cancers were treated with bevacizumab between January 2008 and April 2013. In the Chemo + Bev group treated between June 2014 and December 2020, patients with advanced Müllerian cancers were treated with bevacizumab unless there were contraindications for bevacizumab administration, such as active thromboembolism or tumor infiltration into gastrointestinal tracts. If the patient’s medical record was found to be incomplete, then they were excluded from the present study. In the Chemo + Bev group, after maximal debulking surgery, patients were treated with standard front-line paclitaxel-carboplatin (TC) chemotherapy [175 mg/m2 paclitaxel + carboplatin (area under the curve (AUC)=6 mg/ml/min)] or docetaxel-carboplatin [DC; docetaxel (70 mg/m2) + carboplatin (AUC=5 mg/ml/min)] every 3 weeks or equivalent combined with 15 mg/kg bevacizumab every 3 weeks or equivalent for cycles 1-6. Treatment response was then assessed by radiological assessments using computed tomography (CT) or magnetic resonance imaging (MRI) and measuring cancer antigen-125 (CA125) levels, which is measured as a clinical routine practice. If no disease progression was observed, bevacizumab alone as maintenance therapy was continued every 3 weeks or equivalent for cycles 7-22. Bevacizumab application was skipped at cycle 1 due to the risk of delayed wound healing if cycle 1 was initiated within 4 weeks of debulking surgery.
Baseline patients’ characteristics. Baseline patient characteristics, such as age, FIGO stage, histological type, primary site, and size of post-operative residual tumor were compared between the Chemo + Bev and the Chemo group to assess whether there were significant differences that could bias the results of the present study. The median age was 63 (range=41-81 years) and 61 (range=37-84 years) in the Chemo + Bev and the Chemo group, respectively.
Efficacy. To evaluate the efficacy of adding bevacizumab to the standard chemotherapeutic regimen for advanced Müllerian cancers, disease-free survival (DFS), overall survival (OS), response rate, and rate of platinum-resistant recurrence between the two groups were compared. DFS was defined as the duration between the date of primary debulking surgery and the date when disease recurrence was detected or mortality of any cause. OS was defined as the duration between the date of primary debulking surgery and the date the patient succumbed to the disease. The data were censored at the date of the last available assessment if the patients were lost to follow-up. Radiological assessments using CT or MRI were performed after cycles 3 and 6, whilst physical examination and CA125 evaluation were conducted after every cycle. After the initiation of bevacizumab maintenance, physical examination and CA125 evaluation were conducted every 3 months, and radiological assessments were conducted every year from the initiation of the first treatment or when CA125 levels were increased or when physical examination or ultrasound sonography detected any abnormal findings between the first treatment and disease progression. CA125 elevation alone was not considered recurrence when determining DFS. The response rate was evaluated among the patients with measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (16). Regarding the comparison of platinum-resistant recurrence, whether it was platinum-resistant recurrence or platinum-sensitive recurrence was defined depending on the platinum-free interval (PFI). If PFI was <6 months, that was defined as platinum resistant. By contrast, if PFI was ≥6 months, then it was defined as platinum sensitive. Platinum-resistant recurrence has limited treatment options compared to platinum-sensitive recurrence, leading to a poorer prognosis.
Safety. To evaluate the safety of adding bevacizumab to standard chemotherapeutic regimens for advanced Müllerian cancers, the incidence of ≥ grade 3 adverse events between the two groups was compared. Adverse events were assessed during each cycle using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (17).
Recurrent settings.
Patients and treatments. The medical records of consecutive patients with recurrent Müllerian cancers who were treated with bevacizumab and any chemotherapy at Osaka City University Hospital between April 1st, 2016, and December 31st, 2020 were reviewed retrospectively. If the medical record was incomplete, then it was excluded from the present study. The chemotherapy regimen was chosen depending on whether it was platinum-sensitive recurrence or platinum-resistant recurrence. Either TC or DC treatment every 3 weeks or equivalent was chosen for platinum-sensitive patients. Irinotecan (60 mg/m2 irinotecan on days 1, 8, and 15; every 4 weeks or equivalent)-cisplatin (60 mg/m2 cisplatin on only day 1), gemcitabine (GEM; 1,000 mg/m2 on days 1, 8, and 15) or pegylated liposomal doxorubicin (PLD; 50 mg/m2 on day 1 every 4 weeks or equivalent) was chosen for platinum-resistant patients. Platinum rechallenge was permitted if patient performance status and renal function remained sufficient on physical examination and based on a blood test, based on previous reports on the efficacy and safety of platinum-rechallenge for certain platinum-resistant patients that reported high response and disease control rates with platinum rechallenge (18, 19). Chemotherapy and bevacizumab were administered for cycles 6-10 unless the disease progressed, patients exhibited unacceptable toxicity such as persistent grade 3 proteinuria, uncontrollable hypertension, gastrointestinal perforation, and thromboembolic events, or at the request of the patient. Bevacizumab maintenance was then initiated every 3 weeks or equivalent until disease progression.
Baseline patient characteristics. Baseline patient characteristics, including age, FIGO stage, histology type, primary site, and experience of first-line bevacizumab administration, were obtained using medical records.
Efficacy. To evaluate the efficacy of the addition of bevacizumab to the chemotherapy regimen, PFS and response rate were analyzed. PFS was defined as the duration between the date of treatment initiation for recurrence and the date when disease progression was detected or mortality of any cause. Radiological assessments using CT or MRI were conducted after cycles 3, 6, and 10, whereas physical examination, and CA125 evaluation were conducted at every cycle. After the initiation of bevacizumab maintenance, physical examination, and CA125 evaluation were conducted every 3 months, and radiological assessments were conducted when CA125 levels were increased, or physical examination or ultrasound sonography detected any abnormal findings. The response rate was evaluated according to the RECIST guidelines (16).
Safety. To evaluate the safety of the addition of bevacizumab to the chemotherapeutic regimen for recurrent Müllerian cancers, ≥ Grade 3 adverse events were investigated. Adverse events were assessed during each cycle using CTCAE version 5.0 (17).
Statistical analysis. Data are presented using descriptive statistics in the form of frequency [N, (%)] for categorical data or median (range) for quantitative data. Differences among the groups were examined using a χ2 test or Fisher’s exact test for categorical data and a Mann–Whitney U-test for quantitative data. Survival was examined using the Kaplan–Meier method and log-rank tests. p<0.05 was considered to indicate a statistically significant difference. OS, DFS, and PFS were followed-up for 3 years. Statistical analysis was performed using the EZR version 1.3 software (Saitama Medical Center, Jichi Medical University, Saitama, Japan) (20).
Results
Front-line setting. Patients and treatments. A total of 79 patients in the Chemo + Bev group and a total of 66 patients in the Chemo group were included in the present study. The median number of cycles of chemotherapy was 6 (range=1-10) and 6 (range=1-12) in the Chemo+ Bev group and the Chemo group, respectively. In the Chemo + Bev group, the median number of bevacizumab administration cycles was 18 (range=1-21), and the completion rate of all 21 cycles of bevacizumab administration was 49.4% (39/79 cases). In total, 43.0% cases (34/79 cases) discontinued bevacizumab due to the progression of the primary disease, 5.1% cases (4/79 cases) discontinued bevacizumab due to proteinuria, and 2.5% cases (2/79 cases) discontinued bevacizumab due to voluntary refusal by the patient.
Baseline patient characteristics. Table I shows the patient characteristics of the two treatment groups. There was no significant difference in age, the primary site of malignancy, FIGO stage, histology type, the size of postoperative residual disease, chemo regimen between the two groups, and the number of cycles of chemotherapy.
Patient characteristics.
Efficacy. Table II shows the overall response rates of the two treatment groups, which were analyzed in the patients with measurable lesions. In total, the combined complete response (CR) + partial response (PR) rates were 85.4 and 69.1% in the Chemo + Bev and Chemo groups, respectively. The response rate in the Chemo + Bev group was significantly higher compared with that in the Chemo group (p=0.045). The disease control ratio, which is the sum of the incidence of CR, PR, and stable disease (SD), was found to be 93.5 and 78.2% in the Chemo + Bev and Chemo groups, respectively. The disease control rate in the Chemo + Bev group was significantly higher compared with that in the Chemo group (p=0.029).
Comparison of response rates between the two treatment groups.
Figure 1 shows the DFS for up to 3 years after the initiation of treatment in the two groups. The median DFS was 25.5 and 13.5 months in the Chemo + Bev and Chemo groups, respectively. The DFS was significantly longer in the Chemo + Bev group compared with that in the Chemo group (p=0.021).
Kaplan–Meier curves for the disease-free survival (DFS) in the chemotherapy (Chemo) + Bevacizumab (Bev) group and the Chemo group. The median DFS was 25.5 months (95%CI=20.5-29.8) and 13.5 months (95%CI=11.1-20.9) in the Chemo + Bev group and Chemo group, respectively. DFS of the Chemo + Bev group was significantly longer compared with that in the Chemo group (p=0.021).
Figure 2 shows the OS for up to 3 years after the initiation of the treatment in the two groups. The median OS of the two groups has not been reached. There was no significant difference in OS between the two groups. However, there was a tendency for the Chemo + Bev group towards a longer OS compared with that in the Chemo group (p=0.059).
Kaplan–Meier curves for overall survival (OS) in the chemotherapy (Chemo) + Bevacizumab (Bev) group and Chemo group. There was no significant difference in OS) between the two groups (p=0.0593).
Table III shows the rate of total recurrence, platinum-resistant recurrence, and platinum-sensitive recurrence. The total recurrent rate did not differ between the two groups (p=0.303); however, the rate of platinum-resistant recurrence was significantly lower in the Chemo + Bev group than that in the Chemo group (p<0.01). This showed that the addition of bevacizumab reduced the rate of platinum-resistant recurrence, resulting in a better prognosis.
Comparison of rate of total recurrence, platinum-resistant recurrence and platinum-sensitive recurrence between the two treatment groups.
Safety. Table IV shows the incidence of ≥ grade 3 adverse events in the two treatment groups. Specifically, among the ≥ grade 3 adverse events noted were neutropenia, febrile neutropenia, thrombocytopenia, anemia, stomatitis, hypertension, proteinuria, and gastrointestinal perforation. Regarding hypertension and proteinuria, which are considered to be common adverse effects following bevacizumab application (9, 10), they were significantly more frequent in the Chemo + Bev group compared with those in the Chemo group (p=0.002 and p=0.004 respectively). Apart from these two events, there was no significant difference in the incidence of the other ≥ grade 3 adverse events between the two treatment groups.
Comparison of adverse event incidence between the two treatment groups.
Recurrent settings.
Patients’ characteristics and treatments. A total of 65 patients were included in the present study. Table V shows the patients’ characteristics and the treatments they received. The median age of the patients was 62 (range=37-83 years). There were 61 patients (93.9%) with ovarian cancer, 1 (1.5%) with fallopian tube cancer, and 3 (4.6%) with primary peritoneal cancer. Regarding the FIGO stage, there were 10 patients (15.4%) with stage I, 6 patients (9.2%) with stage II, 36 patients (55.4%) with stage III, and 13 patients (20.0%) with stage IV cancer. The majority of histological types were high-grade serous carcinoma (63.1%), followed by clear cell carcinoma (16.9%), endometrioid carcinoma (7.7%), mucinous carcinoma (4.6%), and other cancers (7.7%). In total, 78.5% of the patients were platinum-sensitive, whereas 21.5% were platinum-resistant. 70.9% of the patients were administered TC, 10.7% were administered DC, 10.7% were administered irinotecan-cisplatin, 4.6% were administered PLD, and 3.1% were administered GEM. A total of 47.7% of the patients received first-line bevacizumab administration treatment whereas 52.3% had not received first-line bevacizumab administration or administration of any other molecular-targeting agents.
Characteristics of patients with recurrent disease.
Efficacy. Table VI shows the overall response rates of patients in the recurrent settings. For platinum-sensitive patients, the response rate and disease control ratio were 78.4 and 94.1%, respectively. For platinum-resistant patients, the response rate (CR + PR) and disease control ratio (CR + PR + SD) were 28.6 and 57.1%, respectively. In the total recurrent population, the response rate and disease control ratio were 67.7 and 86.2%, respectively.
Comparison of response rates between the two platinum status groups.
Figure 3 shows the PFS until 3 years from the initiation of treatment using bevacizumab for platinum-sensitive recurrence (Figure 3A) and platinum-resistant recurrence (Figure 3B). The median PFS was 18.3 and 7.1 months for platinum-sensitive recurrence and platinum-resistant recurrence, respectively.
Kaplan–Meier curves for the progression-free survival (PFS) of patients with recurrent disease. (A) Kaplan–Meier curves for the PFS of platinum-sensitive patients with recurrent disease. The median overall survival (OS) was 18.3 months (95%CI=15.0-23.7). (B) Kaplan–Meier curves for the PFS of platinum-resistant patients with recurrent disease. The median OS was 7.1 months (95%CI=2.2-18.1).
Safety. Table VII shows the incidence of ≥ grade 3 adverse events in the two groups. Among the ≥ grade 3 adverse events noted were neutropenia, febrile neutropenia, thrombocytopenia, anemia, hypertension, proteinuria, and gastrointestinal perforation. The most frequent ≥ grade 3 adverse event was neutropenia, which was observed in 78.5% of the patients, two of whom developed grade 3 febrile neutropenia.
Adverse event incidence in the recurrence group.
Discussion
In the present study, the efficacy and safety of adding bevacizumab to the standard chemotherapeutic regimen for treating patients with newly diagnosed advanced Müllerian cancer and first-recurrent Müllerian cancer in real-world settings were assessed. The efficacy and safety of bevacizumab have been previously demonstrated in large phase III trials [ICON7 (8), GIG0218 (9), OCEANS (10), and AURELIA (12)] and there are also some review articles about the efficacy and safety of bevacizumab available (21). However, patients who are eligible for clinical trials are not fully representative of patients in routine clinical practice. Therefore, it is worth evaluating the data from routine clinical practice to confirm the efficacy and safety in a real-world setting. For this reason, real-world studies are becoming increasingly important as a source of evidence for treatment efficacy and safety in clinical practice (22, 23).
In the present study, for front-line bevacizumab treatment settings, the median DFS was 25.5 months, which is longer compared with that reported in GOG0218 (14.1 months) (9) and comparable to that in the ROSiA study (25.5 months) (24), and the BOOST study (24.2 months) (25). In addition, the DFS in the Chemo + Bev group was significantly longer compared with that in the Chemo group. The reason for longer DFS in the present study compared with that in GOG0218 may be that the present study included patients without residual tumors after debulking surgery, which are considered to be at a lower risk of relapse (26). By contrast, such patients were excluded from GOG0218. Another reason could be the less frequent examination of recurrence in the current study using imaging modalities, such as CT or MRI, due to routine clinical practice, which is not as strict regarding the frequency of examination. There was no significant difference in the OS between the present study and that from the other previous phase III trials. However, there was a tendency towards a longer OS in the Chemo + Bev group in this study despite of the relatively small number of participants. This may be caused by the fact that there were no patients who were treated with any molecular-targeting agents after cancer relapse in the Chemo group. During the period in which patients in the Chemo group were included in the present study, there were no available molecular-targeting agents for ovarian cancer in Japan. In all previous phase III trials, such as ICON7 and GOG0218, there were crossovers with bevacizumab administration after cancer relapse (9, 10). Regarding response rates, the response rate in the Chemo + Bev group was significantly higher compared with that in the Chemo group, suggesting that the addition of bevacizumab to the standard chemotherapeutic procedure may improve the response rate to advanced Müllerian cancers. This improvement in the response rate to bevacizumab combined with standard chemotherapy had already been reported in ICON7 (8). Regarding platinum-resistant recurrence, which has limited treatment options and thus a worse prognosis; a previous study reported that the rate of platinum-resistant recurrence in patients treated with Bev was 18.4% compared to 38.6% in patients treated with chemotherapy only (27). The results of this study (the rate of platinum-resistant recurrence in patients treated with Bev was 15.2% compared to 44.3% in patients treated with chemotherapy only) are comparable to those of the previous study. Therefore, in ovarian cancer treatment, reducing the rate of platinum recurrence is essential even though the total recurrence rate is almost the same. The most common ≥ Grade 3 adverse events noted were neutropenia (82.3%), febrile neutropenia (3.8%), thrombocytopenia (19.0%), anemia (16.4%), stomatitis (1.3%), hypertension (12.7%), proteinuria (11.4%), and gastrointestinal perforation (2.5%), which are equivalent to the results reported by GOG0218 (9), except for proteinuria. The incidence of proteinuria was higher in the present study compared with that in GOG0218 (11.4 vs. 1.6%). A prospective observational study of safety and efficacy in Japanese patients (JGOG3022) reported an incidence of 12.6% for grade 3 proteinuria (15), which is consistent with the present study. However, for JGOG3022, differences in ethnicity may have contributed to the differences in the profiles and incidence rates of adverse events. In the comparison of adverse events between the Chemo + Bev group and the Chemo group, hypertension, and proteinuria were more frequently observed in the Chemo + Bev group compared with those in the Chemo group. However, there were no significant differences in the incidence of other adverse events. This suggests that when bevacizumab is administered alongside standard chemotherapy, close monitoring of blood pressure and proteinuria should be mandatory.
For recurrent settings, 78.5% of patients were platinum-sensitive and 21.5% were platinum-resistant. In addition, 47.7% of patients had a history of first-line bevacizumab maintenance. In platinum-resistant settings, the response rate was 78.4% and the median PFS was 18.3 months, which are equivalent to, or superior, compared with those reported in OCEANS (78.5% and 12.4 months, respectively) (10). The longer PFS was likely due to the less frequent examination of recurrence due to routine clinical practice being less strict regarding the frequency of examination compared with clinical trials. For platinum-resistant settings, the response rate was 28.6%, whereas the median PFS was 7.1 months, which were equivalent to those reported in AURELIA (27.3% and 6.7 months, respectively) (12). Regarding ≥ grade 3 adverse events for all recurrent settings, the profile and incidence rate did not appear to exhibit the large differences reported in OCEANS and AURELIA, as far as the available data in those trials were concerned. Also, previous real-world data studies on Japanese patients showed comparable data on adverse events (28, 29). There were no severe adverse events that directly led to mortality in the present study.
The limitations of the present study are the retrospective nature and that it is based on data from a single institute, where the total number of participants was relatively small compared with those in previous large phase III trials. In addition, there was no control group in which patients received standard chemotherapy alone in the recurrent settings. Although there was no control group in the recurrent settings, comparing the data to those reported in representative large phase III trials, the present study verified the efficacy and safety in a real-world setting. The upsides of this study were that the surgical procedure, which greatly contributes to a patient’s prognosis (26), is more likely to be homogeneous in a single-institutional study, and the treatment after recurrence, which often differs between institutes, was the same, leading to less bias induced by variations in surgical techniques and second-line treatments after recurrence. Furthermore, to the best of our knowledge, the present study included the largest number of patients in a single-institutional cohort for assessing the efficacy and safety of combination therapy using chemotherapy and bevacizumab for ovarian cancer in real-world settings, which contributes to the novelty of this study.
Conclusion
In conclusion, the present study provided encouraging evidence for the efficacy and safety of the addition of bevacizumab to standard chemotherapeutic regimens for the first-line treatment of advanced and/or recurrent Müllerian carcinomas in a real-world setting.
Footnotes
Authors’ Contributions
TF and TS designed the present study. TF, TN, EU, YA, RT, KI, MY, TI, and TY collected and analyzed the data. TF and TS confirm the authenticity of all the raw data. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors declare that they have no competing interests in relation to this study.
Funding
The present study was funded by The Osaka Medical Research Foundation for Intractable Diseases, Osaka, Japan (grant no. 27-2-4).
- Received April 29, 2023.
- Revision received May 17, 2023.
- Accepted May 18, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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).
