Abstract
Background
Cabozantinib was found to be effective as a second- or third-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) in the phase 3 CELESTIAL trial. So far, as immunotherapy has substituted molecular target agents as the primary systemic therapy for advanced HCC, cabozantinib is extensively used in the latest real-world clinical practice in a greatly different position than that shown by the CELESTIAL trial. In the current analysis, we examined the safety and effectiveness of cabozantinib administration in real-life settings for patients with advanced HCC.
Methods
We retrospectively obtained data from patients with advanced HCC who received cabozantinib in three institutions in Japan between 14 September 2018 and 30 November 2021.
Results
During the study period, 23 patients with advanced HCC received cabozantinib. Our cohort included 21.7% of patients with Child–Pugh class B, and 52.2% of patients in fourth line or later. The median progression-free survival of patients given cabozantinib was 3.7 months. Regarding patients with Child–Pugh class B or administration in fourth line or later, the discontinuation rate due to adverse events in patients who initialized at 40 or 20 mg was lower than those who initialized at 60 mg (42.9% versus 75.0%). Patients who were able to continue treatment with cabozantinib for more than 3 months were more likely to undergo dose reduction than those who did not (85.7% versus 25.0%).
Conclusions
Cabozantinib has recently been administered to a diverse range of patients, including those who were not enrolled in the CELESTIAL trial. Deliberate dose reduction could potentially offer clinical benefits to patients with impaired liver function. Furthermore, managing adverse events by reducing the dose could play a crucial role in extending the duration of treatment with cabozantinib.
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In the latest real-world clinical practice, Cabozantinib is often administered for advanced hepatocellular carcinoma patients, encompassing various patient populations, in contrast to the findings from the CELESTIAL trial. The use of cabozantinib may provide clinical benefits to patients with advanced hepatocellular carcinoma and compromised liver function by intentionally reducing the dose. Managing adverse events by reducing the dose of cabozantinib may play a critical role in extending the duration of treatment. |
1 Introduction
Primary liver cancer is the sixth most prevalently diagnosed cancer and the fourth highest cause of cancer deaths globally, and hepatocellular carcinoma (HCC) is the most prevalent malignant primary liver cancer [1]. Monitoring high-risk populations, such as patients with chronic hepatitis and cirrhosis due to hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol consumption, and metabolic syndrome, has increased the early diagnosis of patients with HCC [2,3,4]. However, numerous HCC patients are diagnosed at heightened stages and their long-term survival remains poor, with a 5 year survival rate of less than 20% [5, 6].
1.1 Current Role of Cabozantinib in Advanced Hepatocellular Carcinoma
The landscape of systemic therapy options for advanced HCC has been fast growing and changing rapidly for over a decade. While sorafenib was the only optional systemic therapy for advanced HCC for several years after its implementation in 2007 [7, 8], several agents became available in the late 2010s after exhibiting efficacy in randomized clinical trials in both first- and second-line patients with advanced HCC. Lenvatinib was noninferior to sorafenib in the first-line setting, and regorafenib, cabozantinib, and ramucirumab indicated significantly enhanced survival than placebo as a second-line setting [9,10,11,12]. As the first combination immunotherapy in advanced HCC, atezolizumab plus bevacizumab indicated superiority to sorafenib in both overall survival (OS) and progression-free survival (PFS) [13]. Furthermore, durvalumab plus tremelimumab showed considerably prolonged OS than sorafenib treatment in patients with advanced HCC [14]. Nowadays, two combination immunotherapy regimens and five molecular target agents (MTAs) were found to be effective against advanced HCC in global phase 3 randomized control trials and an extensive variety of sequential treatments are being created for clinical practice [7,8,9,10,11,12,13,14].
Cabozantinib is a multikinase inhibitor to control many biological processes such as cellular proliferation, differentiation, and angiogenesis, including MET, VEGFR-2, and AXL [15]. The phase 3 CELESTIAL trial, which was implemented at the time when sorafenib was the only standard front-line agent and before immunotherapy was developed, indicated that cabozantinib was superior to placebo with both OS and PFS in advanced HCC patients who failed one or more systemic chemotherapy regimens, including sorafenib [11]. Based on the CELESTIAL trial, cabozantinib was authorized for second-line systemic therapy for advanced HCC.
However, as stated above, immunotherapy has substituted MTAs as the primary systemic therapy for advanced HCC. Furthermore, several MTAs and one anti-VEGF-R2 antibody could be the treatment option for the second line or later. In other words, cabozantinib is often applied in the latest real-world clinical practice in a significantly different position than that demonstrated by the CELESTIAL trial. With the repositioning of existing agents due to the rapid growth of systemic therapy for advanced HCC, there is still no data on the current safety and efficacy of cabozantinib under the latest real-world clinical practice. The present study sought to assess the safety and efficacy of cabozantinib administration in a real-life setting for patients with advanced HCC.
2 Methods
2.1 Study Design and Selection of Patients
We retrospectively obtained data from patients with advanced HCC who received cabozantinib in three institutions in Japan between 14 September 2018 and 30 November 2021. Data were locked on 28 February 2022. The present study was authorized by the Research Ethics Committee of the Graduate School of Medicine, Chiba University (no. 3091). We had access to information that could recognize individual patients during or after data collection. Patient data were anonymized and deidentified before analysis.
2.2 Treatment with Cabozantinib
The proposed starting dose for cabozantinib in HCC is 60 mg orally once per day. However, patients were allowed to use the initializing dose of 40 or 20 mg orally once per day to maintain performance status, adequate bone marrow, and both liver and renal functioning by the decision of HCC treatment specialists. Dose reductions or interruptions were made based on toxicity and were recommended as 40 or 20 mg, as given in the summary of product characteristics. We applied dynamic contrast-enhanced computed tomography or magnetic resonance imaging at baseline and every 1–2 months after initializing treatment for the assessment of tumor response. Cabozantinib was administered until the physician ascertained a clear progression of disease on radiological imaging or until the incidence of adverse events (AEs) inhibited the continuation of treatment.
2.3 Clinical Parameters
Clinical parameters acquired for this analysis were as follows: baseline demographic data (e.g., sex, age, etc.), etiology, Child–Pugh class, alpha-fetoprotein, radiological assessment, Eastern Cooperative Oncology Group performance status, and Barcelona Clinic liver cancer stage. Radiological assessments were examined according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [19]. Separately, the Common Terminology Criteria for Adverse Events version 5.0 established by the National Cancer Institute was employed to assess AEs.
2.4 Statistical Analysis
Kaplan–Meier plots of medians with 95% confidence intervals (CIs) were used for calculating OS. The censoring date was described as the date of the previous follow-up. PFS after cabozantinib was determined using Kaplan–Meier plots of medians with 95% CIs, with the date of progression described as the date of the last radiological assessment without progression. Time-to-treatment-failure (TTF) after cabozantinib was determined using Kaplan–Meier plots, which displayed medians with 95% CIs. The date of treatment failure was considered as the date when the treatment was discontinued for any reason, such as disease progression, discontinuation due to AEs, or death. We used the log-rank test to assess the statistical significance of the differences in OS, PFS, and TTF.
The level of significance was set as p < 0.05. All statistical analyses were performed using the Statistical Package for the Social Sciences version 25 statistical software (SPSS, IBM, Armonk, NY, USA).
3 Results
3.1 Baseline Characteristics of the Study Population
During the study period, 23 patients with advanced HCC collected cabozantinib at three Japanese institutions. The baseline characteristics of 23 patients are outlined in Table 1. The median age was 73 years (range, 52–84 years). Most of the etiology was HCV (n = 7, 30.4%), followed by HBV (n = 6, 26.0%) and alcohol abuse (n = 5, 21.7%). At the time of cabozantinib administration, most of the patients were Child–Pugh class A (n = 18, 78.3%), whereas five (21.7%) were Child–Pugh class B. At the baseline radiological assessments, 5 patients (21.7%) and 15 patients (65.2%) of patients were observed to have macrovascular invasion and extrahepatic metastasis, respectively. Five patients (21.7%) had received sorafenib (n = 2, 8.7%) or lenvatinib (n = 3, 13.0%) before cabozantinib treatment. Six patients (26.0%) had acquired 2 systemic therapy lines before initiation of cabozantinib and 12 (52.2%) patients had at least 3 prior therapy lines, respectively. Thirteen patients (56.5%) had been treated with atezolizumab plus bevacizumab prior to receiving cabozantinib.
3.2 Efficacy of the Whole Population of the Present Study
At the cutoff date, the median observation period was 3.5 months (95% CI 2.0–6.2 months) and 22 patients (95.6%) had quit cabozantinib. Discontinued rates due to disease progression and AE were 47.8% (11 patients) and 47.8% (11 patients), respectively. The median duration of treatment with cabozantinib was 1.8 months (95% CI 1.0–3.3 months). Overall, 18 patients (78.2%) had at least one follow-up imaging and these patients could be evaluated for tumor response. According to RECIST 1.1, none of the assessed patients indicated a complete response, 1 patient (4.4%) had a partial response, 12 patients (52.2%) indicated stable disease, and 5 patients (21.7%) had progressive disease, respectively. Taken together, we detected an overall response rate (ORR) of 4.4% and a disease control rate (DCR) of 56.6%. The median PFS and OS were 3.7 months (95% CI 1.5–8.9 months) and 4.3 months (95% CI 2.1–8.8 months), respectively (Table 2). When comparing the outcomes based on liver function, patients initiated in Child–Pugh class A had a median PFS of 9.2 months (95% CI 0–20.5 months), whereas those in Child–Pugh class B had a PFS of 0.5 months (95% CI not applicable) (p = 0.001). Similarly, the median OS for patients in Child–Pugh class A was 6.9 months (95% CI 3.3–10.5 months), while for those in Child–Pugh class B, it was 2.1 months (95% CI 0–5.6 months) (p < 0.001). Furthermore, the median TTF for patients in Child–Pugh class A was 2.1 months (95% CI 1.9–2.2 months), and for those in Child–Pugh class B, it was 0.5 months (95% CI 0.2–0.7 months) (p < 0.001). When comparing based on the treatment lines of cabozantinib, patients administered in the third line or earlier had a median PFS of 9.2 months (95% CI 2.6–15.9 months), whereas those administered in the fourth line or later had a median PFS of 3.7 months (95% CI not applicable) (p = 0.148). Similarly, the median OS for patients administered in the third line or earlier was 3.2 months (95% CI 0–19.3 months), while for those administered in the fourth line or later, it was 4.3 months (95% CI 1.2–7.3 months) (p = 0.708). Furthermore, the median TTF for patients administered in the third line or earlier was 2.1 months (95% CI 1.5–2.6 months), and for those administered in the fourth line or later, it was 1.1 months (95% CI 0–2.9 months) (p = 0.144).
3.3 Safety of the Whole Population of the Present Study
The occurrence of cabozantinib-related AEs is presented in Table 3. AEs of any grade and grade 3 or higher notwithstanding causality were observed in 100% and 56.5% of the patients in our cohort, respectively. The most frequently occurring AEs were aspartate aminotransferase increased (17 patients, 73.9%), increased alanine aminotransferase (15 patients, 65.2%), hypoalbuminemia (12 patients, 52.2%), thrombocytopenia (11 patients, 47.8%), and fatigue (11 patients, 47.8%). The most prevalent grade 3 or higher AEs were palmar-plantar erythrodysesthesia (3 patients, 13.1%), thrombocytopenia (2 patients, 8.7%), hypertension (2 patients, 8.7%), proteinuria (2 patients, 8.7%), and anemia (2 patients, 8.7%).
Table 4 highlights drug dosing intensity and modification in our study population. The prescribed starting dose of cabozantinib in patients with HCC is 60 mg. In our cohort, 15 patients (65.2%) received 60 mg of cabozantinib, whereas 1 patient (4.4%) started with 40 mg and 7 patients (30.4%) had 20 mg as an initial dose. Ten patients (43.5%) had dose reductions, 13 patients (56.5%) had drug interruption, and 11 patients (47.8%) had discontinuation due to AEs. The most prevalent facilitators of dose reduction and drug interruption were proteinuria (n = 4, 17.4%) and diarrhea (n = 4, 17.4%). The most prevalent cause of discontinuation due to AEs was proteinuria (n = 4, 17.4%). The median duration of drug exposure with cabozantinib was 1.4 months (95% CI 0.8–2.5 months) and the median average daily dose was 22.9 mg (95% CI 12.8–40.8 mg).
We divided the study population into two groups: patients with Child–Pugh class A and second- or third-line treatment with cabozantinib who met the inclusion criteria for the CELESTIAL trial (group A, n = 8) and patients who did not meet the inclusion criteria for the CELESTIAL trial (group B; patients who received cabozantinib for Child–Pugh class B or after fourth-line treatment, n = 15). Figure 1 depicts the clinical course of cabozantinib in the two groups. In group A, 12.5% of patients began at 40 or 20 mg as the initial dose, and 46.6% of patients were in group B. The discontinuation rate due to AEs was 25.0% in group A and 60.0% in group B. Focusing on the starting dose in group B, 75.0% of patients who began at 60 mg experienced discontinuation due to AEs, and 42.9% of patients who initialized at 40 or 20 mg experienced discontinuation due to AEs. The median average daily doses were 22.8 mg for group A and 22.9 mg for group B. We also analyzed the patients according to the albumin bilirubin (ALBI) grade [20], but no additional insights were obtained compared with those stratified according to the Child–Pugh class (data not shown).
Finally, we investigated the factors that allowed for long-term treatment with cabozantinib while minimizing treatment discontinuation due to AEs. Initially, the patients in our study were categorized into two groups based on their ability to sustain cabozantinib treatment for a minimum of 3 months. Out of the seven (30.4%) patients who were able to continue cabozantinib for at least 3 months, none belonged to Child–Pugh class B at the beginning of the treatment, and 57.1% had initiated cabozantinib as a second- or third-line therapy. Although all of these patients started cabozantinib at a dose of 60 mg, 85.7% required a dose reduction. However, 28.6% of patients discontinued the treatment due to AEs.
4 Discussion
We assessed the safety and effectiveness of cabozantinib administration for patients with advanced HCC in real-life settings using a retrospective cohort. Cabozantinib was authorized as second-line therapy based on the CELESTIAL trial [11], which recruited only patients with Child–Pugh class A and mainly patients in second-line treatment before the approval of immunotherapy. However, in clinical practice, cabozantinib has been administered to several patients with advanced HCC. The outcomes of the current study indicate cabozantinib has real-life potential in the treatment of advanced HCC, where immunotherapy is the major treatment.
In the era of immunotherapy, cabozantinib might be prevalently administered to patients with poor liver function or at a late line. In our cohort, 21.7% of patients were treated in Child–Pugh class B, and 52.2% of patients were treated in the fourth line or later. Initiation in patients with poor liver function and late-line initiation were more common, but the ORR was 4.4%, DCR was 56.6%, and the median PFS was 3.7 months, similar to the findings of the CELESTIAL trial [11]. These findings were also comparable to those of a recent multicenter retrospective study (ORR, 3.6–6.8%; DCR, 38.6–66.3%; median PFS, 3.2–5.1 months) [16,17,18].
Although cabozantinib might be clinically beneficial in difficult-to-treat patient populations, another very critical point is to administer it while avoiding discontinuation due to AEs. Despite the inclusion of patients with poor liver function or at the late line, 56.5% of AEs of grade 3 or higher were detected, irrespective of causality, and these outcomes were similar to those of the CELESTIAL trial [11]. In our cohort, 15 patients (65.2%) received 60 mg of cabozantinib, whereas 1 patient (4.4%) started with 40 mg and 7 patients (30.4%) had 20 mg as the initial dose, and we presume that this change in starting dose was a key reason for its application while avoiding discontinuations due to AEs. Indeed, we segmented our cohort into two groups: patients with Child–Pugh class A and who received second- or third-line treatment with cabozantinib and met the inclusion criteria for the CELESTIAL study (group A) and patients who did not meet the inclusion criteria for the CELESTIAL study (group B). Then, we evaluated comprehensively the course of oral administration in each group. Focusing on the starting dose in group B, there were fewer discontinuations due to AEs in patients who initialized at 40 or 20 mg, unlike those who started at 60 mg (42.9% versus 75.0%). The analysis according to ALBI grade showed similar findings. A recent study by Tomonari T et al. suggested that considering a reduced dose of cabozantinib based on the patients’ condition should be part of clinical practice [21].
Furthermore, our results indicate that the clinical benefit can be improved by flexibly modifying the dose of cabozantinib, both before and during treatment. Patients who were able to continue treatment with cabozantinib for more than 3 months were more likely to have their cabozantinib dose reduced compared with those who did not (85.7% versus 25.0%). Managing AEs through dose modification of cabozantinib could be the key to extending the duration of treatment.
The clinical course of systemic therapy in patients with advanced HCC primarily starts with combined immunotherapy, followed by sequencing of MTAs [22]. Many MTAs, when utilized in late-line settings, have been found to have reduced therapeutic efficacy and a high AE discontinuation rate [23, 24]. Cabozantinib could be a promising choice, as it has demonstrated sufficient effectiveness in enhancing the chances of long-term treatment through careful initiation of dose reduction and subsequent dose adjustments during treatment.
This study had several limitations that require attention. Firstly, the clinical data in this study were collected retrospectively. Secondly, the sample size in this study was inadequate for conducting accurate analyses, especially in subgroup comparisons. It is important to note that the data were obtained from Japan, a region with a substantial elderly population and a distinct medical insurance system compared with other countries. To elucidate the role of cabozantinib in an era where combined immunotherapy is the primary approach for HCC treatment, a global prospective study should be designed to validate the safety and efficacy of cabozantinib.
5 Conclusions
The latest real-world clinical practice has shown that cabozantinib is commonly prescribed to patients with advanced HCC across various patient populations, unlike the findings from the CELESTIAL trial. In patients with impaired liver function, initiating dose reduction could potentially offer clinical advantages. Effectively managing AE through dose reduction may also play a critical role in extending the duration of treatment with cabozantinib.
References
Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019;380:1450–62.
Kokudo N, Hasegawa K, Akahane M, et al. Evidence-based clinical practice guidelines for hepatocellular carcinoma: the Japan Society of Hepatology 2013 update (3rd JSH-HCC guidelines). Hepatol Res. 2015;45.
Kudo M, Matsui O, Izumi N, et al. JSH consensus-based clinical practice guidelines for the management of hepatocellular carcinoma: 2014 update by Liver Cancer Study Group of Japan. Liver Cancer. 2014;3:458–68.
Kudo M. Japan’s successful model of nationwide hepatocellular carcinoma surveillance highlighting the urgent need for global surveillance. Liver Cancer. 2012;1:141–3.
Kawano Y, Sasaki A, Kai S, et al. Short- and long-term outcomes after hepatic resection for hepatocellular carcinoma with concomitant esophageal varices in patients with cirrhosis. Ann Surg Oncol. 2008;15:1670–6.
Stefaniuk P, Cianciara J, Wiercinska-Drapalo A. Present and future possibilities for early diagnosis of hepatocellular carcinoma. World J Gastroenterol. 2010;16:418–24.
Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.
Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia–Pacific region with advanced hepatocellular carcinoma: a phase III randomized, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25–34.
Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163–73.
Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56–66.
Rimassa L, Cicin I, Blanc JF, et al. Outcomes based on age in the phase 3 Celestial trial of cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2018;36:4090.
Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20:282–96.
Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–905.
Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1:EVIDoa2100070.
Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tu- mor growth. Mol Cancer Ther. 2011;10:2298–308.
Finkelmeier F, Scheiner B, Leyh C, et al. Cabozantinib in advanced hepatocellular carcinoma: efficacy and safety data from an international multicenter real-life cohort. Liver Cancer. 2021;10:360–9.
Tovoli F, Dadduzio V, De Lorenzo SD, et al. Real-life clinical data of cabozantinib for unresectable hepatocellular carcinoma. Liver Cancer. 2021;10:370–9.
Bang YH, Lee CK, Yoo C, et al. Real-world efficacy and safety of cabozantinib in Korean patients with advanced hepatocellular carcinoma: a multicenter retrospective analysis. Ther Adv Med Oncol. 2022;14:17588359221097934.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.
Johnson PJ, Berhane S, Kagebayashi C, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J Clin Oncol. 2015;33:550–8.
Tomonari T, Joji T, Ogawa C, et al. Effect of renal and hepatic impairment on the pharmacokinetics of cabozantinib multicenter retrospective study of initial treatment outcome and feasibility of initiating dose reduction of cabozantinib in unresectable hepatocellular carcinoma. Hepatol Res. 2022;hepr.13845 (Online ahead of print).
Ogasawara S, Koroki K, Kanzaki H, et al. Changes in therapeutic options for hepatocellular carcinoma in Asia. Liver Int. 2022;42:2055–66.
Tomonari T, Sato Y, Tanaka H, et al. Potential use of lenvatinib for patients with unresectable hepatocellular carcinoma including after treatment with sorafenib: real-world evidence and in vitro assessment via protein phosphorylation array. Oncotarget. 2020;11:2531–42.
Nakagawa M, Inoue M, Ogasawara S, et al. Clinical effects and emerging issues of atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma from Japanese real-world practice. Cancer. 2023;129:590–9 (Online ahead of print).
Acknowledgements
The authors are grateful to the following people for their contributions to data management: Satomi Nakamura, Ryoko Arai, and Yuka Iwase. The authors would like to thank Enago (http://www.enago.jp) for the English language review.
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Sadahisa Ogasawara received honoraria from Bayer, Leverkusen, Germany; Eisai, Tokyo, Japan; Eli Lilly, Indianapolis, IN, USA; Chugai Pharma, Tokyo, Japan; AstraZeneca, Cambridge, UK; and Merck & Co., Inc., Kenilworth, NJ, USA, consulting or advisory fees from Bayer, Eisai, Merck & Co., Inc., Chugai Pharma, Eli Lilly, and AstraZeneca, and research grants from Bayer, AstraZeneca, and Eisai. Naoya Kato received honoraria from Bayer, Eisai, Sumitomo Dainippon Pharma, Tokyo, Japan, and Merck & Co., Inc.; consulting or advisory fees from Bayer and Eisai; and research grants from Bayer and Eisai. The other authors have no conflicts of interest to declare.
Author Contributions
Hiroaki Kanzaki, Sadahisa Ogasawara, Tomomi Okubo, Norio Itokawa, Ryohei Yoshino, Kentaro Fujimoto, Tadayoshi Kogure, Sae Yumita, Takamasa Ishino, Keita Ogawa, Terunao Iwanaga, Miyuki Nakagawa, Kisako Fujiwara, Ryuta Kojima, Keisuke Koroki, Masanori Inoue, Kazufumi Kobayashi, Naoya Kanogawa, Soichiro Kiyono, Masato Nakamura, Takayuki Kondo, Ryo Nakagawa, Shingo Nakamoto, Ryosuke Muroyama, Ei Itobayashi, and Masanori Atsukawa made a substantial contribution to the conception and design, acquisition of data, analysis, and interpretation of data. Hiroaki Kanzaki, Sadahisa Ogasawara, Jun Kato, and Naoya Kato drafted the article or revised it critically for important intellectual content. All authors approved the final version of the manuscript to be published.
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All procedures performed in this study involving human participants were conducted following the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Formal consent by written signature was not required for this type of study based on Japanese regulations. The Chiba University Research Ethics Committee also approved this point. The Chiba University Research Ethics Committee approved this study (No. 3091).
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Kanzaki, H., Ogasawara, S., Okubo, T. et al. Cabozantinib for Advanced Hepatocellular Carcinoma in the Latest Real-World Practice: A Multicenter Retrospective Analysis. Drugs - Real World Outcomes 10, 513–520 (2023). https://doi.org/10.1007/s40801-023-00379-x
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DOI: https://doi.org/10.1007/s40801-023-00379-x