Abstract
Background/Aim: The purpose of this study was to ascertain a novel prognostic index via recursive partitioning analysis (RPA) in hepatocellular carcinoma (HCC) patients being treated with the combination of atezolizumab plus bevacizumab (ABE) in first-line setting. Patients and Methods: A total of 784 patients with HCC were included in the analysis. Results: RPA identified three groups of patients: high-risk [Child-Pugh B (CP-B) patients; CP-A and Albumin-Bilirubin (ALBI)-2 patients; CP-A and ALBI-1 patients with macrovascular invasion (MVI), and alpha-fetoprotein (α-FP) ≥400 ng/ml]; intermediate-risk [CP-A and ALBI-1 patients with aspartate aminotransferase (AST) normal value (NV), and αFP ≥400 ng/ml, but without MVI; CP-A and ALBI-1 patients with AST increased value (IV), and neutrophil-lymphocyte ratio (NLR) ≥3, but without MVI]; low-risk (CP-A and ALBI-1 patients with AST NV, and αFP <400 ng/ml, but without MVI; CP-A and ALBI-1 patients with AST IV, and NLR <3, but without MVI; CP-A and ALBI-1 patients with MVI, and αFP <400 ng/ml). Overall survival was 7.0 months in high-risk patients (20.8%), 14.2 months in intermediate-risk patients (19.1%), and 22.5 months in low-risk patients (60.1%). Conclusion: The ABE index allows for easy stratification of HCC patients treated with the combination of ABE in first-line setting.
- ABE index
- advanced hepatocellular carcinoma
- atezolizumab plus bevacizumab
- recursive partitioning analysis
Hepatocellular carcinoma (HCC) is the most common form of liver cancer and accounts for ~90% of cases (1). In recent years, the therapeutic armamentarium available for these patients has expanded. Sorafenib was approved in 2007 thanks to the results of two phase-III trials, SHARP and Asia Pacific (2, 3). Lenvatinib became available in 2017 due to the results of the REFLECT trial (4). The combination of the monoclonal antibody bevacizumab inhibiting the vascular-endothelial growth factor (VEGF) with atezolizumab, another monoclonal antibody inhibiting the programmed cell death ligand-1 (PD-L1), represents the first therapeutic doublet approved for HCC treatment. Indeed, the IMbrave150 trial demonstrated that this combination could obtain a median overall survival (OS) of 19.2 months and progression-free survival (PFS) of 6.9 months (5). Recently, an immunotherapeutic combination was approved by Food and Drug Administration based on the final data from the HIMALAYA trial. This combination comprises a single dose of tremelimumab (anti-cytotoxic T-lymphocyte antigen 4) with durvalumab obtaining a median OS of 16.4 months (6). Currently, atezolizumab plus bevacizumab (ABE) and lenvatinib are the two treatments most often chosen in the first-line setting. It has become crucial for clinicians to have prognostic tools available to correctly frame patients and be able to offer them the best treatment.
Literature data highlighted some prognostic factors for HCC patients being treated with ABE or lenvatinib, such as Child-Pugh (CP) score, albumin-bilirubin (ALBI) grade, and neutrophil-lymphocyte ratio (NLR) (7-19). As regards lenvatinib, relative dose intensity, prognostic nutritional index, body mass index, geriatric nutritional risk index, and muscle mass have also proved to be important prognostic factors (20-25). Recently, a complex prognostic index derived from a recursive partitioning analysis (RPA), the lenvatinib prognostic (LEP) index, has been validated (26, 27). Regarding ABE, few real-world studies have evaluated the potential prognostic factors in patients treated with this therapeutic combination. The purpose of this study was to ascertain a novel prognostic index via RPA in HCC patients being treated with the combination of ABE in first-line setting.
Patients and Methods
The study’s population consisted of 784 HCC patients from five countries (Italy, Germany, Portugal, Japan, and the Republic of Korea) being treated with ABE between October 2018 and April 2022. Patients were treated with ABE in first-line setting for intermediate [Barcelona Clinic Liver Cancer (BCLC)-B] or advanced (BCLC-C) HCC, judged ineligible for loco-regional procedures. Patients were included in the study if they had HCC histological or clinical diagnosis in accordance with recent international guidelines and if they had not received other prior systemic treatments for this neoplasm. All patients were treated with 15 mg/kg of body weight of bevacizumab and 1,200 mg of atezolizumab administered intravenously every 3 weeks as determined by the IMbrave150 trial (5). Treatment interruptions and/or dose reductions were allowed to manage adverse events (AEs). AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 (28).
The ethics committee of each involved center approved this trial (clinical trial number: 113/INT/2021), in agreement with the provisions of the Good Clinical Practice guidelines, the Declaration of Helsinki, the local laws, and the Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 regarding the protection of natural persons and the processing of personal data.
Statistical analysis. Results of the hematologic blood tests and clinical parameters were collected before starting treatment with ABE.
We applied survival tree regression to identify risk groups in the overall cohort after dichotomizing each variable. Beginning by the whole population, we conducted univariate Cox proportional hazards regression for each predictor variable. The criteria to identify groups at each level comprised the variable with the highest HR. We later dichotomized the whole population using the selected predictor variable and replicated the univariate Cox models among each group. We recursively replayed this process among each novel group till no variable met the criteria for selection. After establishing primary groups or “nodes”, HRs for each node were calculated relative to the lowest risk node. Kaplan–Meier methods were applied to evaluate survival for each node, and an overall log-rank test was calculated for the model. MedCalc package (MedCalc® version 16.8.4, Ostend, Belgium) was employed for statistical analysis.
Results
The clinical and laboratory characteristics of the overall cohort are shown in Table I.
Baseline characteristics of study population.
The first node split by the CP class states that the survival difference of CP-A versus CP-B patients is higher than the difference between any other patients’ subgroup. The same method has been recursively implemented to the arising subgroups, giving origin to the partitioning tree represented in Figure 1. Between the 725 CP-A patients, the most meaningful split was by ALBI grade, among ALBI-1 patients (n=692) and ALBI-2 patients (n=33). Between the 692 CP-A and ALBI-1 patients, the most considerable split was among patients with macrovascular invasion (MVI) (n=153) and patients without MVI (n=539). Between the 153 CP-A and ALBI-1 patients with MVI, the final split was among patients with alpha-fetoprotein (αFP) <400 ng/ml (n=82) and patients with αFP ≥400 ng/ml (n=71). Between the 539 CP-A and ALBI-1 patients without MVI, the most meaningful split was among patients with aspartate aminotransferase (AST) normal value (NV) (n=223) and patients with AST increased value (IV) (n=316). Within the latter patients’ subset, the final split was among patients with NLR <3 (n=199) and patients with NLR ≥3 (n=117). Between the 223 CP-A and ALBI-1 patients with AST NV and without MVI, the final split was among patients with αFP <400 ng/ml (n=190) and patients with αFP ≥400 ng/ml (n=33).
Groups of risk in accordance to RPA. Three risk groups were identified: high-risk (CP-B pt, CP-A and ALBI-2 pt, CP-A and ALBI-1 pt with MVI and αFP ≥400 ng/mL; in black), intermediate-risk (CP-A and ALBI-1 pt with AST NV and αFP ≥400 ng/mL without MVI, and CP-A and ALBI-1 with AST IV and NLR ≥3 and without MVI; in dark gray) and low-risk (CP-A and ALBI-1 pt with AST NV and αFP <400 ng/mL and without MVI, CP-A and ALBI-1 pt with AST IV and NLR <3 and without MVI, and CP-A and ALBI-1 pt with MVI and AFP <400 ng/mL; in light gray). αFP: alpha-fetoprotein; ALBI: Albumin-Bilirubin; AST: aspartate aminotransferase; CP: Child-Pugh; IV: increased value; mo: months; MVI: macrovascular invasion; NLR: neutrophil-lymphocyte ratio; NR: not reached; NV: normal value; OS: overall survival; pt: patients; RPA: recursive partitioning analysis.
In accordance with the RPA tree, we have found three groups of patients achieving different outcomes with regard to OS. The first group, named “high-risk”, comprises: CP-B patients, CP-A and ALBI-2 patients, and CP-A and ALBI-1 patients with MVI and αFP ≥400 ng/ml. The second group, named “intermediate-risk”, comprises: CP-A and ALBI-1 patients with AST NV and αFP ≥400 ng/ml and without MVI, and CP-A and ALBI-1 patients with AST IV and NLR ≥3 and without MVI. Finally, the third group, named “low-risk”, comprises: CP-A and ALBI-1 patients with AST NV and αFP <400 ng/ml and without MVI, CP-A and ALBI-1 patients with AST IV and NLR <3 and without MVI, and CP-A and ALBI-1 patients with MVI and αFP <400 ng/ml. We have denominated this score the Atezolizumab Bevacizumab prognostic index “ABE index”.
OS was 7.0 months (95%CI=6.0, 8.7 months) in high-risk patients (n=163, 20.8%), 14.2 months (95%CI=12.4, 15.7 months) in intermediate-risk patients (n=150, 19.1%), and 22.5 months (95% CI=17.0, 22.5 months) in low-risk patients (n=471, 60.1%) [high-risk HR=3.99 (95%CI=2.76, 5.77), intermediate-risk HR=1.76 (95%CI=1.26, 2.46), low-risk HR=1 (reference group), p<0.01] (Figure 2A). Receiver operating characteristic curve analysis displayed an area under the curve of 0.72 (95%CI=0.68, 0.76; p<0.01).
Median overall survival (OS) (A) and progression-free survival (PFS) (B) of risk groups in accordance with recursive partitioning analysis (RPA).
PFS was 5.3 months (95%CI=3.7, 5.8 months) in high-risk patients, 6.1 months (95%CI=5.5, 8.1 months) in intermediate-risk patients, and 9.4 months (95%CI=8.4, 10.8 months) in low-risk patients [high-risk HR=1.79 (95%CI=1.37, 2.35), intermediate-risk HR=1.47 (95%CI=1.14, 1.89), low-risk HR=1 (reference group); p<0.01] (Figure 2B).
The three groups had a dissimilar rate of progressive disease (PD) at the primary computed tomography (CT) response evaluation (high-risk: 29.4%, intermediate-risk: 24.0%, low-risk: 16.1%; p<0.01) and of patients who received a second line therapy (high-risk: 31.9%, intermediate-risk: 52.7%, low-risk: 54.7%; p<0.01) (Figure 3A). Median OS for subsequent anticancer treatments was 3.1 months (95%CI=2.4, 3.7 months) in high-risk patients, 7.9 months (95%CI=4.6, 9.4 months) in intermediate-risk patients, and 10.5 months (95%CI=8.6, 15.4 months) in low-risk patients [high-risk HR=3.36 (95%CI=2.17, 5.19), intermediate-risk HR=1.57 (95%CI=1.07, 2.31), low-risk HR=1.00 (reference group); p<0.01] (Figure 3B).
Disease control rate (DCR) and median overall survival (OS) for subsequent anticancer treatments of risk groups in accordance with recursive partitioning analysis (RPA). PD: Progressive disease.
Different safety profiles were reported by the three groups, in particular with regard to hypothyroidism (high-risk: 1.8%, intermediate-risk: 2.7%, low-risk: 6.1%; p=0.03), hypertension (high-risk: 17.2%, intermediate-risk: 22.7%, low-risk: 27.4%; p=0.03), and proteinuria (high-risk: 22.7%, intermediate-risk: 35.3%, low-risk: 28.7%; p<0.05) (Table II).
Safety profiles of the three risk groups identified by recursive partitioning analysis.
Discussion
By applying RPA to a real-world population of HCC patients treated in first-line setting with ABE, we have created an easy-to-use prognostic index, the ABE index. In our analysis, low-risk patients achieved better survival outcomes than the phase III IMbrave150 trial in terms of both OS (22.5 vs. 19.2 months) and PFS (9.4 vs. 6.9 months) (5). The low-risk group, therefore, allows us to identify patients who could potentially benefit most from this therapeutic combination even in terms of low percentages of PD at the first reevaluation. This is also in line with literature data suggesting that HCC patients benefit most from systemic treatments if they are administered in the early stages of the disease when liver function is still well preserved (29-33). This benefit also translates into median OS in subsequent anticancer treatments, which in our data was 10.5 months in low-risk patients and 3.1 months in high-risk patients. Patients who had better outcomes from first-line therapy with ABE maintained this greater benefit also in subsequent lines, most likely because they are those who, thanks to disease control, also maintained good liver function that allowed them to access the benefits of the following therapies. Low-risk patients are also those who have received the therapeutic combination for longer, resulting in greater exposure to the mechanisms determining the AEs’ onset. Indeed, our data show that hypertension (typically caused by bevacizumab), as well as hypothyroidism (typically associated with immunotherapy), were more frequent in low-risk patients than in the other groups. This phenomenon was also reported in a Japanese real-world study in which CP-A patients treated with ABE reported a higher percentage of proteinuria than CP-B patients, most likely because the latter have received the therapy for a shorter time (34).
Of particular importance for clinical practice are the prognostic factors characterizing the high-risk group because they allow the identification of patients who derive limited benefits from therapy with ABE (OS 7.0 months and PFS 5.3 months). These factors are represented by CP-B, ALBI-2, and αFP ≥400 ng/ml in patients with MVI.
There is numerous evidence that the most important prognostic factors in HCC patients are those representatives of liver function (35-39). In our analysis, the CP score was the first split node that allowed us to stratify two populations. This is in line with literature data on this particular subset of patients treated with ABE. In particular, a real-world study by D’Alessio and colleagues on 216 patients reported significant differences between patients with CP-A and patients with CP-B both in terms of OS (A 16.8 vs. B 6.7 months, p=0.0003) and in terms of PFS (A 7.6 vs. B 3.4 months, p=0.03) (40). It is worth noting that this study showed no differences in toxicity (AEs of any grade A 48% vs. B 46%) and PD rates (A 26% vs. B 32%) between the CP classes. Our results instead demonstrated higher PD rates at the first CT assessment and lower rates of AEs correlated with shorter duration of treatment in high-risk group, including CP-B patients. Probably, the results of D’Alessio et al. were influenced by the lower sample size compared to that of our study. Another real-world study conducted on 457 Japanese patients confirmed statistically significant differences in survival outcomes [OS: A not reached (NR) vs. B 6.4 months, p<0.001; PFS: A 7.5 vs. B 6.0 months, p=0.011]. Tanaka et al. also analyzed the differences between the individual scores constituting the CP classes, highlighting progressively worse OS and PFS as the score increased (34). This type of correlation was also found in patients receiving the other currently available first-line therapies, sorafenib and lenvatinib (7, 11, 35-37, 39). The second split node within RPA was the ALBI grade. Patients with CP-A but ALBI-2 composed the high-risk group, having achieved an OS of 8.0 months. A post hoc analysis on the possible impact of ALBI on the results of the phase III IMbrave150 trial also found that ALBI-2 patients had lower survival outcomes in terms of both OS (11.7 months) and PFS (5.6 months) compared to ALBI-1 patients (OS: NR; PFS: 8.8 months) (41). In a real-world setting, Tanaka and colleagues found that in CP-A patients, OS and PFS worsen significantly from ALBI-1 to ALBI-2b (34). Our work confirms that even in patients treated with ABE, as with other available first-line therapies, CP class and ALBI grade represent the most important prognostic factors capable of identifying patients who are likely to have a limited benefit from first-line therapy and for which it is necessary to carefully evaluate the relationship between possible benefits and risks associated with the treatment to be offered. Furthermore, the ABE index, being consistent with the literature data in real-world settings, is a reliable index to be used in clinical practice, even if further analyses on external cohorts of patients treated with ABE are desirable for its validation.
Very interesting data are represented by the subsequent split node, which helps to identify high-risk group. This is composed of CP-A and ALBI-1 patients with MVI. MVI is also among the factors that identify high-risk patients in the post hoc analyses of the phase III IMbrave150 trial (42, 43). In particular, Breder et al. demonstrated that patients with main trunk and/or contralateral portal vein invasion (Vp4) presented OS equal to 5.5 months and PFS equal to 2.8 months (43). In our analysis, in these patients, the factor that caused the greatest difference in OS was the baseline αFP levels. Patients with αFP ≥400 ng/ml composed the high-risk group and achieved an OS of 7.6 months. In contrast, patients with low baseline αFP levels were classified as low-risk having achieved an OS of 22.5 months. αFP is a well-known prognostic factor for HCC patients in both localized and advanced disease settings (7, 39, 44-47) and is part of another prognostic score, the CRAFITY score (48). This score was obtained from the univariate and multivariate analyses performed on 190 HCC patients treated with immunotherapy. In multivariate analysis, MVI was not a factor influencing the prognosis of these patients, while αFP ≥100 ng/ml and C-reactive protein ≥1 mg/dl were independent prognostic factors for OS also in multivariate analysis and constituted, in fact, the CRAFITY score. Patients who had neither of these two elevated values had OS of 27.6 months, while for patients with at least one of these criteria, OS was 11.3 and 6.4 months, respectively. In contrast to our study, the population included in these analyses was highly heterogeneous because it included patients treated with immunotherapy in different lines and with different drugs. Furthermore, the cut-off used for αFP was not the one that has mostly been identified in the literature as a discriminant of the prognosis in patients with HCC (39).
A separate discussion deserves NLR. It represents the split node able to discriminate between CP-A patients without MVI and with ALBI-1 and increased AST values, those who are part of intermediate-risk group (NLR ≥3: OS 13.9 months) from those who are part of low-risk group (NLR <3: OS NR). NLR is a particularly interesting prognostic factor for patients being treated with immunotherapy because it is representative of the state of activation of the immune system (48-53). Elevated NLR values can be determined by lymphopenia or neutrophilia. Lymphopenia can determine the ineffectiveness of the immune system’s response to tumor cells (54). Neutrophilia is associated with a high release of cytokines by macrophages recruited in the tumor microenvironment, which contribute to the creation of a chronic inflammatory state, in which the perpetually active immune system undergoes functional exhaustion (55). Regarding specifically HCC patients treated with ABE, NLR was found to be an independent prognostic factor also in two Japanese real-world studies (18, 19).
This study has some limitations, the most important being its retrospective design, thus there are some gaps in the data collected. This limit is partly offset by the large sample size, the fact that the population is homogeneous from a therapeutic point of view, and that it is made up of both Western and Eastern patients. Another limitation is represented by the fact that it is needed to further validate this index in an external cohort of patients, and above all to investigate its predictive role, applying it to patients treated with other available first-line therapies, such as lenvatinib and sorafenib.
In conclusion, the “ABE index” is a useful device because it is made up of factors widely used in clinical practice in HCC patients. It is also a useful tool because it can stratify HCC patients who are candidates for ABE from a prognostic point of view, identifying in an early manner those patients who could potentially benefit less from this therapeutic option.
Acknowledgements
HCC COLLABORATIVE GROUP: Naoya Sakamoto, Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan; Hideki Iwamoto, Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Tomoko Aoki, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan; Hong Jae Chon, Department of Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea; Vera Himmelsbach, Department of Internal Medicine 1, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany; Margarida Montes, Liver Unit-CHTMAD Vila Real, Portugal; Caterina Vivaldi, Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy; Caterina Soldà, Oncology Unit 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy; Atsushi Hiraoka, Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan; Takuya Sho, Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan; Takashi Niizeki, Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Naoshi Nishida, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan; Christoph Daniel Steup, Department of Internal Medicine 1, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany; Masashi Hirooka, Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan; Kazuya Kariyama, Department of Gastroenterology, Okayama City Hospital, Okayama, Japan; Joji Tani, Department of Gastroenterology and Hepatology, Kagawa University, Kagawa, Japan; Masanori Atsukawa, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan; Koichi Takaguchi, Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan; Ei Itobayashi, Department of Gastroenterology, Asahi General Hospital, Asahi, Japan; Shinya Fukunishi, Department of Gastroenterology, Osaka Medical and Pharmaceutical University, Osaka, Japan; Kunihiko Tsuji, Center of Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan; Toru Ishikawa, Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan; Kazuto Tajiri, Department of Gastroenterology, Toyama University Hospital, Toyama, Japan; Hironori Ochi, Hepato-biliary Center, Japanese Red Cross Matsuyama Hospital, Matsuyama, Japan; Satoshi Yasuda, Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan; Hidenori Toyoda, Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan; Chikara Ogawa, Department of Gastroenterology, Japanese Red Cross Takamatsu Hospital, Takamatsu, Japan; Takashi Nishimura, Department of Internal medicine, Division of Gastroenterology and Hepatology, Hyogo Medical University, Nishinomiya, Japan; Takeshi Hatanaka, Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Maebashi, Japan; Satoru Kakizaki, Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan; Noritomo Shimada, Division of Gastroenterology and Hepatology, Otakanomori Hospital, Kashiwa, Japan; Kazuhito Kawata, Department of Hepatology, Hamamatsu University School of Medicine, Hamamatsu, Japan; Fujimasa Tada, Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan; Hideko Ohama, Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan; Kazuhiro Nouso, Department of Gastroenterology, Okayama City Hospital, Okayama, Japan; Asahiro Morishita, Department of Gastroenterology and Hepatology, Kagawa University, Kagawa, Japan; Akemi Tsutsui, Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan; Takuya Nagano, Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan; Norio Itokawa, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan; Tomomi Okubo, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan; Taeang Arai, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan; Michitaka Imai, Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan; Hisashi Kosaka, Department of Surgery, Kansai Medical University, Osaka, Japan; Atsushi Naganuma, Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan; Yohei Koizumi, Department of Gastroenterology, Okayama City Hospital, Okayama, Japan; Shinichiro Nakamura, Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan; Masaki Kaibori, Department of Surgery, Kansai Medical University, Osaka, Japan; Hiroko Iijima, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Hyogo Medical University, Nishinomiya, Japan; Yoichi Hiasa, Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan; Valentina Burgio, Department of Medical Oncology, IRCCS San Raffaele Hospital, Milan, Italy; Angelo Della Corte, School of Medicine, Vita-Salute San Raffaele University, Milan, Italy; Francesca Ratti, Hepatobiliary Surgery Division, Liver Center, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy; Francesco De Cobelli, School of Medicine, Vita-Salute San Raffaele University, Milan, Italy; Luca Aldrighetti, Hepatobiliary Surgery Division, Liver Center, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Footnotes
Authors’ Contributions
Conception and design: All Authors. Acquisition of data (acquired and managed patients): All Authors. Analysis and interpretation of data: A. Casadei-Gardini, M. Persano, M. Rimini. Writing, review, and/or revision of the manuscript: A. Casadei-Gardini, M. Persano, M. Rimini. Final approval of manuscript: All Authors.
Conflicts of Interest
A.C.G. is an advisor for AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, GSK, and MSD; received grants and personal fees from Bayer, Eisai, and MSD. M.S. is an advisor for AMGEN, Eisai, MERCK, MSD, and SERVIER. M.K. received research grant from AbbVie, Astellas Pharma, Bayer, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Medico’s Hirata, MSD, Otsuka, Sumitomo Dainippon, Takeda, and Taiho; received advisory consulting fee from BMS, Chugai, Eisai, MSD, Ono pharmaceutical, and Taiho; received lecture fee from Bayer, Chugai, EA Pharma, Eisai, and MSD. L.R. received institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, and Zymeworks; lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi, and Servier; travel expenses from AstraZeneca; consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Servier, Taiho Oncology, and Zymeworks. F.P. has received consulting and lecture fees in the last two years from: Astrazeneca, Bayer, Bracco, EISAI, ESAOTE, Exact Sciences, IPSEN, MSD, Roche, Samsung, and Tiziana Life Sciences. The other Authors declare no conflicts of interest in relation to this study.
- Received December 31, 2022.
- Revision received January 21, 2023.
- Accepted February 16, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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