Published online Nov 24, 2024. doi: 10.5306/wjco.v15.i11.1394
Revised: May 29, 2024
Accepted: August 5, 2024
Published online: November 24, 2024
Processing time: 205 Days and 8.8 Hours
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death global
Core Tip: Hepatocellular carcinoma (HCC) arising on a background of non-alcoholic fatty liver disease (NAFLD) is not well understood but patients tend to have poorer prognosis vs those with other HCC aetiologies. Currently all HCC patients are treated the same regardless of aetiology, and understanding of best treatment options for the NAFLD-HCC population is an urgent clinical need. This narrative review discusses NAFLD-HCC screening, pathophysiology, systemic treatment, and offers suggestions for future directions in this therapy area.
- Citation: Rzeniewicz K, Sharma R. Systemic treatment of hepatocellular carcinoma secondary to non-alcoholic fatty liver disease. World J Clin Oncol 2024; 15(11): 1394-1403
- URL: https://www.wjgnet.com/2218-4333/full/v15/i11/1394.htm
- DOI: https://dx.doi.org/10.5306/wjco.v15.i11.1394
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer death globally, with both incidence and mortality on the rise[1-3]. In the United Kingdom alone, mortality rates are projected to increase 10% between 2023-2025 and 2038-2040[4]. HCC typically occurs on the background of liver cirrhosis with the main aetiologies being hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, alcoholic liver disease and non-alcoholic fatty liver disease (NAFLD)[5]. However, a recent meta-analysis found significantly higher proportion of NAFLD-related HCC arises in non-cirrhotic livers compared with other aetiologies[6].
NAFLD incidence is increasing at an alarming level, with over half of the global adult population predicted to have the condition by 2040[7]. NAFLD is a heterogenous disease comprising non-alcoholic steatosis (or fatty liver) and non-alcoholic steatohepatitis (NASH); the latter ranges in severity from fibrosis to cirrhosis[8-10]. NAFLD is associated with type 2 diabetes mellitus, insulin resistance, cardiovascular disease and obesity, and is considered a hepatic manifestation of the metabolic syndrome[8-10]. NAFLD-HCC is much less understood than HCC arising on the background of alcoholic liver disease or viral hepatitis, and the population affected appears different: Patients tend to be older, have additional co-morbidities, and are diagnosed at more advanced stage disease[6,11,12]. This often means patients are unsuitable for some of the treatments and have worse prognosis.
The systemic treatment landscape for advanced HCC has undergone a major change in the recent years. Initially, introduction of single agent tyrosine kinase inhibitor (TKI) sorafenib conferred significant survival benefit vs placebo, and more recently, the combination of immune checkpoint inhibitor (ICI) + anti-vascular endothelial growth factor (VEGF) bevacizumab showed further benefits vs sorafenib, and have become standard of care[13]. However, although data of systemic agents from trials are limited specifically for the NAFLD-HCC aetiology, some evidence suggest that immunotherapy[14] may be less effective in this population[15].
HCC in the setting of NAFLD is more likely to be diagnosed at later stages, given non-cirrhotic patients are not routinely screened[16,17]. Further, NAFLD-HCC patients are typically older, and have high prevalence of type 2 diabetes mellitus, obesity, and cardiovascular and cerebrovascular disease[6,11,12]. This raises a number of treatment considerations for this population. Firstly, co-morbidities, especially cardiovascular, may preclude surgery. Secondly, obesity may have a negative effect on angiogenesis-targeting drugs such as bevacizumab[18]. On the other hand, obesity appears to be associated with better progression free survival and overall survival (OS) with ICIs in solid tumours[19-21]. Of note, a retrospective study found comparable efficacy of ICI atezolizumab + anti-VEGF bevacizumab in overweight and non-overweight HCC patients, including those with NAFLD[22]. Finally, although older age alone is unlikely to affect systemic treatment outcomes in NAFLD-HCC[23-25], there is an association between age and frailty in both non-cirrhotic[26] and cirrhotic NAFLD[27], and thus older age may negatively influence treatment options in NAFLD-HCC. Further
Overall, NAFLD-HCC has worse prognosis vs other aetiologies and its treatment represents an urgent unmet clinical need. In addition, based on emerging data on pathogenesis as described below, there may be inherent differences in HCC biology in those patients vs those with other aetiologies. This narrative review briefly considers NAFLD-HCC patho
The underlying pathophysiology of NAFLD-HCC is not well understood, with substantial proportion of HCC developing on the background of fibrotic rather than cirrhotic changes, highlighting complexity of the process. Accumulation of free fatty acids and resulting hepatic lipotoxicity is an important process driving endoplasmic reticulum and oxidative stress, inflammation, local tissue damage and fibrosis, all of which work together to advance progression of NAFLD via mechanisms effecting multiple metabolic pathways, autophagy and the immune system[16,28]. Importantly, hepatic oxidative stress drives carcinogenesis via DNA damage[16], but has also been implicated in activation of the tumour promoting interleukin (IL)-6 and/or Janus-activated kinase-signal transducer and activator of transcription (STAT) pathways, offering potential explanation for the uncoupling of fibrosis and HCC in the setting of NAFLD. Namely, it was shown in murine models that the obesity-driven oxidative hepatic environment was associated with development of inflammation, NASH and fibrosis via STAT-1, and - independently of NASH - with HCC via STAT-3[29].
Immune system plays an important role in the pathogenesis, with initial local inflammation driven by Kupffer cells, followed by hepatocyte damage, influx of platelets, neutrophils, and inflammatory monocytes[30]. The immune milieu changes over time with arrival of dysfunctional CD8+programmed cell death protein 1 (PD-1)+ T cells, which further drives increased lipid accumulation, lipid toxicity, and fibrotic response[30,31]. In murine models, mice with NASH were shown to have increased hepatic presence of CD8+PD1+ T cells with features of exhaustion and effector functions[31]. This would appear a prerequisite for successful immunotherapy with anti-PD-1 agents, however, although anti-PD-1 treatment expanded activated CD8+PD1+ T cells within tumours of mice with NASH-HCC, this did not lead to tumour regression[31]. Further, CD8+ T cell depletion significantly decreased liver damage and the incidence of HCC in mice with NASH[31]. Of note, scRNA-seq analysis demonstrated a resident-like liver CD8+PD1+ T cell population in patients with NAFLD/NASH that shared gene expression patterns with the detrimental hepatic CD8+PD1+ T cells from NASH mice[31]. Overall, preclinical and clinical studies on adaptive immunity thus far illustrate CD8+ T cells promote HCC in NASH, likely via impaired tumour surveillance and enhanced T cell-mediated tissue damage[31], and CD4+ T-cells to be protective in this setting[32,33]. This is likely an important finding given that it was previously found that increased numbers of tumour infiltrating CD8+ T cells correlated with improved survival and disease progression in human HCC[34], but this was not examined based on aetiology. Further, a subset of activated CD8+ T-cells was identified in viral HCC that correlated with better patient survival[35].
Currently, there are no specific guidelines for NAFLD-HCC treatment - all HCC are managed the same, regardless of aetiology.
Treatment of HCC is guided by Barcelona Clinic Liver Cancer (BCLC) staging[36]. Broadly, BCLC stages 0-A are treated with curative intent with surgery, radiotherapy, ablation and liver transplantation. Transarterial chemoembolization (TACE) and radioembolization are limited to BCLC stage B disease and systemic therapy is used for BCLC stage C where the aim is palliation[37]. Data mainly from retrospective studies suggest similar outcomes with resection, liver trans
Systemic treatment in HCC is used in unresectable/advanced disease with preserved liver function (Child-Pugh A) and Eastern Cooperative Oncology Group Performance Status 0-2[37]. Approved options are either combination atezolizumab + bevacizumab or single-agent TKIs[37]. A number of clinical trials testing various combination regimens have been completed/are ongoing, with a recent meta-analysis of available results finding combinations of ICI + anti-VEGF and ICI + ICI achieving greatest OS benefit vs the TKI sorafenib[14]. Whilst combination immunotherapy improves clinical outcomes, evidence from initial studies suggests that underlying aetiology of liver disease determines clinical benefit, and that treatment allocation should be stratified accordingly. This concept stemmed from the initial IMbrave150 trial, which illustrated a significant survival benefit vs sorafenib, establishing combination immunotherapy as the first line for advanced HCC [OS hazard ratio (HR) vs sorafenib 0.58 (95% confidence interval: 0.42-0.79; P < 0.001)][40]. However, in a subgroup analysis, the non-viral population did not benefit from combination therapy[40] (Table 1).
Trial | Line | Treatment arm | HCC aetiology1 | N (%)2 | OS HR (95%CI) |
ICI monotherapy | |||||
Checkmate-459[52] | 1 | Nivolumab (vs sorafenib) | Non-viral | 168 (45) | 0.95 (0.74-1.22) |
NAFLD/NASH | N/A | ||||
HBV | 0.77 (0.56-1.05) | ||||
HCV | 0.71 (0.49-1.01) | ||||
Keynote 240[46] | 2 | Pembrolizumab (vs placebo) | Non-viral | 163 (59) | 0.88 (0.64-1.20) |
NAFLD/NASH | N/A | ||||
HBV | 0.57 (0.35-0.94) | ||||
HCV | 0.96 (0.48-1.92) | ||||
RATIONALE-301[51] | 1 | Tislelizumab (vs sorafenib) | Non-viral | 82 (24) | 0.78 (0.55-1.12) |
NAFLD/NASH | N/A | ||||
HBV | 0.91 (0.73-1.14) | ||||
HCV | 0.64 (0.38-1.08) | ||||
Combination ICI + anti-VEGF | |||||
IMbrave150[40,44] | 1 | Atezolizumab + bevacizumab | Non-viral | 100 (30) | 1.05 (0.68-1.63) |
NAFLD/NASH | N/A | ||||
HBV | 0.51 (0.32.081) | ||||
HCV | 0.43 (0.22-0.87) | ||||
Combination ICI + TKI | |||||
COSMIC-312[47] | 1 | Atezolizumab + cabozantinib (vs sorafinib) | Non-viral | 169 (39) | 1.18 (0.78-1.79)3 |
NAFLD/NASH | 38 (15) | Not reported | |||
HBV | 74 (30) | 0.53 (0.33-0.87)3 | |||
HCV | 34 (28) | 1.1 (0.72-1.68)3 | |||
CARES-310[50] | 1 | Camrelizumab + rivoceranib (vs sorafenib) P3, 1L | Non-viral | 42 (15) | 0.71 (0.37-1.36) |
NAFLD/NASH | N/A | ||||
HBV | 208 (76) | 0.66 (0.50-0.87) | |||
HCV | 22 (8) | 0.45 (0.18-1.16) | |||
LEAP-002[45] | 1 | Pembrolizumab + lenvatinib (vs lenvatinib) P3, 1L | Not reported | N/A | N/A |
Combination ICI + ICI | |||||
Himalaya[41] | 1 | Durvalumab + tremelimumab | Non-viral | 161 (41) | 0.74 (0.57-0.95) |
NAFLD/NASH | N/A | ||||
HBV | 122 (31) | 0.64 (0.48-0.86) | |||
HCV | 110 (28) | 1.06 (0.76-1.49) | |||
TKI monotherapy | |||||
SHARP[49] | 1 | Sorafenib (vs placebo) | Non-viral | 107 (35) | Not reported |
NAFLD/NASH | N/A | ||||
REFLECT[48] | 1 | Lenvantinib (vs sorafenib) | Non-viral | 74 (16) | Reported only for alcohol |
NAFLD/NASH | N/A | ||||
RESORCE[43] | 2 | Regorafenib (vs placebo) | Non-viral | 143 (38) | Reported only for alcohol |
NAFLD/NASH | N/A | Not reported | |||
CELESTIAL[42] | 2 | Cabozantinib (vs placebo) | Non-viral | 179 (38) | 0.72 (54-0.96) |
NAFLD/NASH | 43 (9) | Not reported | |||
HBV | 0.69 (0.51-0.94) | ||||
HCV | 1.11 (0.72-1.71) | ||||
Anti-VEGF monotherapy | |||||
REACH-2[53] | 2 | Ramucirumab (vs placebo) | Non-viral | 72 (37) | 0.63 (0.38-1.06) |
NAFLD/NASH | 19 (10) | Not reported | |||
HBV | 0.84 (0.52-1.35) | ||||
HCV | 0.76 (0.44-1.33) |
No prospective, randomised controlled studies evaluated the efficacy and safety of systemic treatment options in NAFLD-HCC specifically. Available data are mainly from subgroup analysis of pivotal studies, where aetiologies were grouped broadly into viral vs non-viral; completed Phase 3 studies are shown in Table 1. Patients with known non-viral aetiology comprised between 15% and 59% of the population across those studies, with NAFLD/NASH accounting for around one-fourth of this subgroup (when reported)[40-53] (Table 1). Below we present a review of current aetiology-based evidence for NAFLD/NASH-HCC treatment.
As mentioned above, the pivotal IMbrave150 study sparked concern as to benefit of ICI in patients with HCC of non-viral aetiology40 (Table 1). Looking at evidence for ICI monotherapy, Checkmate-459 (nivolumab)[52] and Keynote-240 (pembrolizumab)[46] were both negative studies with OS HR of 0.85 (95%CI: 0.72-1.02) and 0.781 (0.611-0.998), respectively. The non-viral subgroup had numerically worse survival outcome compared with HBV and HCV in Checkmate-459, and placed in-between HBV and HCV in Keynote-240[46,52] (Table 1). In the recently reported RATIONALE, tislelizumab was shown non-inferior to sorafenib with higher overall response rate and more durable responses [superiority was not met; OS HR of 0.85 (95%CI: 0.71-1.02)][51]. Here, too, the HR for OS for the non-viral subgroup placed between the two viral aetiologies[51] (Table 1), suggesting that aeitology did not determine outcome.
A meta-analysis of CheckMate-459, IMbrave150 and KEYNOTE-240 showed that although ICI improved survival in the overall population (HR = 0.77; 95%CI: 0.63-0.94), survival benefit was observed in patients with HBV-HCC (n = 574; P = 0.0008) and HCV-HCC (n = 345; P = 0.04), but not in patients with non-viral HCC (n = 737; P = 0.39)[31]. This was confirmed by another aetiology-based analysis of those three studies[54]. A number of trials studied combinations of ICI + TKI/ICI (Table 1). In COSMIC-312, the interim analysis of OS showed no clear benefit of atezolizumab + cabozantinib vs sorafenib for the non-viral population[47]. Of note, in this study, whilst there was OS benefit for the HBV-HCC group, no benefit was also observed for the HCV-HCC group[47]. Authors of another combination study, CARES-310, concluded that camrelizumab + rivoceranib vs sorafenib offered similar benefits in terms of progression-free survival (PFS) and OS in viral and non-viral populations[50], however, the vast majority of patients (76%) had HBV, and confidence intervals for OS crossed 1 for both HCV-HCC and non-viral HCC. Finally, in Himalaya, the survival benefit with durvalumab + tremelimumab vs sorafenib (overall population HR = 0.78, 95%CI: 0.65-0.93; P = 0.0035) was maintained in the non-viral and HBV subgroups, but not in the HCV subgroup[41].
The most recent aetiology-based meta-analysis of eight randomised trials of ICI-based systemic therapy found significant survival advantage across both non-viral and viral aetiologies (HR = 0.79, 95%CI: 0.72-0.86, P < 0.001), with the largest estimated benefit for those with HBV (HBV: HR = 0.70, P < 0.001; HCV: HR = 0.78, P = 0.04; non-viral: HR = 0.87, P = 0.02)[55]. Overall, the authors were of opinion that it is premature to conclude that patients with non-viral liver disease do not benefit from ICI-based therapy[55].
However, a recent retrospective, propensity score matched study of patients with non-viral advanced HCC who were treated with atezolizumab + bevacizumab, or lenvatinib, or sorafenib showed that treatment with lenvatinib is associated with a significant survival benefit vs atezolizumab + bevacizumab, in particular in patients with NAFLD/NASH-related HCC (OS HR = 0.46; 95%CI: 0.26-0.84; P = 0.0110; and PFS HR = 0.55; 95%CI: 0.38-0.82; P = 0.031); of note, no difference in OS and PFS was found in comparison of sorafenib vs atezolizumab + bevacizumab[56].
Thus, although the majority of the above studies report no survival benefit with ICI in the non-viral subgroups, this is certainly not uniform. The heterogeneity of study populations, lines of treatment, and the exploratory nature of subgroup analysis make data difficult to interpret. In addition, the control arm performed a lot better in some studies. Furthermore, mixed results among the two viral subgroups suggest that the issue of ICI efficacy is more complex and likely influenced by multiple factors related to the individual patient. Finally, the non-viral subgroup is itself a heterogeneous group, most often comprising alcoholic liver disease, NAFLD/NASH, and other aetiologies, and thus this population cannot be taken to simply represent those with NAFLD/NASH-HCC. Only COSMIC 312 reported data on 38 patients with NAFLD/NASH again illustrating the limitations of the published studies in drawing firm conclusions with regards to the efficacy of ICI in this patient group[47].
First line options in HCC are single-agent sorafenib or lenvatinib, with cabozantinib and regorafenib in second line[37]. No data on non-viral aetiology were reported in the registration trials of sorafenib (SHARP)[49], lenvatinib (REFLECT)[48], and regorafenib[43] (Table 1). In the phase 3 study of cabozantinib (CELESTIAL), the HR for OS in the non-viral group was 0.72 (95%CI: 0.54-0.96), which was similar to overall population (0.76, 95%CI: 0.63-0.92) and HBV, and numerically better than HCV[42] (Table 1). Further, in an international cohort study of 5201 HCC patients treated with sorafenib, those with NAFLD (n = 183) had the same OS vs those without (HR = 0.99, 95%CI: 0.84-1.18, P = 0.98), and safety profile was similar[57].
Single-agent ramucirumab is a standard of care option beyond first-line for those patients with an alpha-fetoprotein greater than 400 ng/mL[37]. In REACH-2 study, OS HR with this agent was 0.63 (95%CI: 0.38-1.06) in the non-viral population, which, again - although CIs were crossing 1 - was similar to the overall population [0.74 (95%CI: 0.56-0.99)], and numerically better than for HCV and HBV subgroups[53] (Table 1).
Finally, an aetiology based meta-analysis of five randomised controlled studies of systemic treatment with TKI/anti-VEGF (n = 2083) showed that OS benefit was unaffected by the underlying driver of HCC [HR for viral was 0.81 (95%CI: 0.71-0.92) and for non-viral was 0.82 (95%CI: 0.67-1.01); P = 0.8828][54]. Thus, based on the available data, it would appear outcomes with single-agent TKI and ramucirumab may be similar in the NAFLD and overall HCC population, however samples in individual studies are small and the same caveats regarding non-viral group composition apply as in the ICI studies.
NAFLD-HCC is a relatively uncharacterised yet growing clinical problem and there are several key questions future efforts should endeavour to answer. The current treatment gaps centre around pathophysiology of HCC in the setting of NAFLD and the clinical safety and efficacy of systemic treatments specifically in the NAFLD-HCC population. Further understanding of the pathophysiology is essential to develop treatment strategies. Emerging data are mainly preclinical and suggest HCC in NASH may be driven by impaired immunological surveillance and dysfunctional CD8+T-cells[31] as well as aberrant STAT-1 signalling, whilst in the absence of NASH, STAT-3 signalling has been suggested to promote NAFLD-HCC[29]. Delineating immunological milieu as well as contribution of any alterations to commonly implicated signalling pathways across natural progression from fatty liver to HCC, with or without fibrosis and cirrhosis, would likely offer some answers. This will likely involve preclinical studies involving mice studies, as well as translational studies with a bench-to-bedside approach and the use of multiomics.
Prospective clinical trials specifically of patients with NAFLD/NASH-HCC are urgently needed given paucity of evidence in this space. Currently available data seem to point towards similar efficacy with TKI/anti-VEGF and potentially poor efficacy with ICI, however, this is based on results for non-viral subgroups, where NAFLD/NASH was the aetiology in approximately 25% of patients only, a subgroup of a subgroup. In addition, those subgroups were not pre-planned and analyses were not powered. Thus, generalisation of non-viral subgroup to mean ICI does not offer benefit in NAFLD/NASH-HCC is not substantiated by robust evidence currently. Moving forward, how best to select patients for such trials is a pertinent question. Ideally, patients should include full spectrum of NAFLD, from simple fatty liver to cirrhosis, to allow assessment of any differences in treatment response and identify any relevant variables. However, this may prove difficult in practice given there are no widely-accepted uniform diagnostic criteria for NAFLD, whilst diagnosis of NASH requires liver biopsy. In addition, the term NAFLD is contended by some experts as potentially stigmatising and not sufficiently reflective of the metabolic component[58]. A recent multi-society Delphi consensus from the NAFLD Nomenclature Consensus Group suggested replacement of the term NAFLD with metabolic dysfunction-associated steatotic liver disease (MASLD), and use cryptogenic steatotic liver disease in those with no metabolic parameters and no known cause; in addition, a new category, outside pure MASLD, termed MetALD was proposed to describe those with MASLD who consume greater amounts of alcohol per week[58]. This underscores another difficulty in obtaining evidence for aetiology-based approach, namely co-existence of multiple aetiologies in one patient. In a recent comprehensive review on global epidemiology of cirrhosis, it has been highlighted that many of the included studies did not account for multiple aetiologies, and the authors speculated that more than one cause of cirrhosis is present in a substantial proportion of patients, especially considering the growing prevalence of obesity and increasing alcohol consumption[59]. By extension, the prevalence and composition of mixed aetiology as underlying cause of HCC is not known, neither is its significance for tumorigenesis and treatment response. Despite these issues, there is an increasing interest in the role of aetiology on treatment outcomes, and as our understanding improves it is likely that in the next 5 years we will see the introduction of management tailored according to disease aetiology.
Further, aside from one retrospective study of sorafenib that found similar safety profile in NAFLD- and non-NAFLD-HCC, no studies or analyses examined the nature, frequency or severity of adverse events according to HCC aetiology. For example, is hypertension with TKIs or bevacizumab more common/severe in those with metabolic syndrome, and if so if this is clinically relevant. Finally, ICI use in those with prior liver (or any solid organ) transplantation carries a risk of organ rejection, and so best possible evidence on the benefits of treatment with ICI is needed to guide informed decision making in such situations.
NAFLD-HCC is an increasing patient group that urgently requires attention both in terms of investigating pathophy
1. | Rumgay H, Arnold M, Ferlay J, Lesi O, Cabasag CJ, Vignat J, Laversanne M, McGlynn KA, Soerjomataram I. Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol. 2022;77:1598-1606. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 17] [Cited by in F6Publishing: 710] [Article Influence: 355.0] [Reference Citation Analysis (0)] |
2. | Samant H, Amiri HS, Zibari GB. Addressing the worldwide hepatocellular carcinoma: epidemiology, prevention and management. J Gastrointest Oncol. 2021;12:S361-S373. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 67] [Cited by in F6Publishing: 78] [Article Influence: 26.0] [Reference Citation Analysis (0)] |
3. | Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209-249. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 50630] [Cited by in F6Publishing: 55695] [Article Influence: 18565.0] [Reference Citation Analysis (157)] |
4. | Cancer Research UK. Liver cancer statistics. [cited 18 September 2023]. Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/liver-cancer#heading-One. [Cited in This Article: ] |
5. | Suresh D, Srinivas AN, Kumar DP. Etiology of Hepatocellular Carcinoma: Special Focus on Fatty Liver Disease. Front Oncol. 2020;10:601710. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 33] [Cited by in F6Publishing: 72] [Article Influence: 18.0] [Reference Citation Analysis (0)] |
6. | Tan DJH, Ng CH, Lin SY, Pan XH, Tay P, Lim WH, Teng M, Syn N, Lim G, Yong JN, Quek J, Xiao J, Dan YY, Siddiqui MS, Sanyal AJ, Muthiah MD, Loomba R, Huang DQ. Clinical characteristics, surveillance, treatment allocation, and outcomes of non-alcoholic fatty liver disease-related hepatocellular carcinoma: a systematic review and meta-analysis. Lancet Oncol. 2022;23:521-530. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 154] [Cited by in F6Publishing: 157] [Article Influence: 78.5] [Reference Citation Analysis (0)] |
7. | Le MH, Yeo YH, Zou B, Barnet S, Henry L, Cheung R, Nguyen MH. Forecasted 2040 global prevalence of nonalcoholic fatty liver disease using hierarchical bayesian approach. Clin Mol Hepatol. 2022;28:841-850. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 99] [Cited by in F6Publishing: 86] [Article Influence: 43.0] [Reference Citation Analysis (0)] |
8. | Lazarus JV, Mark HE, Anstee QM, Arab JP, Batterham RL, Castera L, Cortez-Pinto H, Crespo J, Cusi K, Dirac MA, Francque S, George J, Hagström H, Huang TT, Ismail MH, Kautz A, Sarin SK, Loomba R, Miller V, Newsome PN, Ninburg M, Ocama P, Ratziu V, Rinella M, Romero D, Romero-Gómez M, Schattenberg JM, Tsochatzis EA, Valenti L, Wong VW, Yilmaz Y, Younossi ZM, Zelber-Sagi S; NAFLD Consensus Consortium. Advancing the global public health agenda for NAFLD: a consensus statement. Nat Rev Gastroenterol Hepatol. 2022;19:60-78. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 99] [Cited by in F6Publishing: 368] [Article Influence: 184.0] [Reference Citation Analysis (0)] |
9. | Spiers J, Brindley JH, Li W, Alazawi W. What's new in non-alcoholic fatty liver disease? Frontline Gastroenterol. 2022;13:e102-e108. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 4] [Cited by in F6Publishing: 6] [Article Influence: 3.0] [Reference Citation Analysis (0)] |
10. | European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64:1388-1402. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 2290] [Cited by in F6Publishing: 2936] [Article Influence: 367.0] [Reference Citation Analysis (4)] |
11. | Geh D, Anstee QM, Reeves HL. NAFLD-Associated HCC: Progress and Opportunities. J Hepatocell Carcinoma. 2021;8:223-239. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 13] [Cited by in F6Publishing: 37] [Article Influence: 12.3] [Reference Citation Analysis (0)] |
12. | Younossi ZM, Otgonsuren M, Henry L, Venkatesan C, Mishra A, Erario M, Hunt S. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology. 2015;62:1723-1730. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 495] [Cited by in F6Publishing: 569] [Article Influence: 63.2] [Reference Citation Analysis (0)] |
13. | Ntellas P, Chau I. Updates on Systemic Therapy for Hepatocellular Carcinoma. Am Soc Clin Oncol Educ Book. 2024;44:e430028. [PubMed] [DOI] [Cited in This Article: ] [Reference Citation Analysis (0)] |
14. | Fulgenzi CAM, Scheiner B, Korolewicz J, Stikas CV, Gennari A, Vincenzi B, Openshaw MR, Silletta M, Pinter M, Cortellini A, Scotti L, D'Alessio A, Pinato DJ. Efficacy and safety of frontline systemic therapy for advanced HCC: A network meta-analysis of landmark phase III trials. JHEP Rep. 2023;5:100702. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 20] [Cited by in F6Publishing: 24] [Article Influence: 24.0] [Reference Citation Analysis (0)] |
15. | Haber PK, Puigvehí M, Castet F, Lourdusamy V, Montal R, Tabrizian P, Buckstein M, Kim E, Villanueva A, Schwartz M, Llovet JM. Evidence-Based Management of Hepatocellular Carcinoma: Systematic Review and Meta-analysis of Randomized Controlled Trials (2002-2020). Gastroenterology. 2021;161:879-898. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 54] [Cited by in F6Publishing: 134] [Article Influence: 44.7] [Reference Citation Analysis (0)] |
16. | Loomba R, Friedman SL, Shulman GI. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell. 2021;184:2537-2564. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1037] [Cited by in F6Publishing: 935] [Article Influence: 311.7] [Reference Citation Analysis (36)] |
17. | Nahon P, Allaire M, Nault JC, Paradis V. Characterizing the mechanism behind the progression of NAFLD to hepatocellular carcinoma. Hepat Oncol. 2020;7:HEP36. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 10] [Cited by in F6Publishing: 7] [Article Influence: 1.8] [Reference Citation Analysis (0)] |
18. | Incio J, Ligibel JA, McManus DT, Suboj P, Jung K, Kawaguchi K, Pinter M, Babykutty S, Chin SM, Vardam TD, Huang Y, Rahbari NN, Roberge S, Wang D, Gomes-Santos IL, Puchner SB, Schlett CL, Hoffmman U, Ancukiewicz M, Tolaney SM, Krop IE, Duda DG, Boucher Y, Fukumura D, Jain RK. Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2. Sci Transl Med. 2018;10. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 110] [Cited by in F6Publishing: 140] [Article Influence: 28.0] [Reference Citation Analysis (0)] |
19. | Cortellini A, Bersanelli M, Buti S, Cannita K, Santini D, Perrone F, Giusti R, Tiseo M, Michiara M, Di Marino P, Tinari N, De Tursi M, Zoratto F, Veltri E, Marconcini R, Malorgio F, Russano M, Anesi C, Zeppola T, Filetti M, Marchetti P, Botticelli A, Antonini Cappellini GC, De Galitiis F, Vitale MG, Rastelli F, Pergolesi F, Berardi R, Rinaldi S, Tudini M, Silva RR, Pireddu A, Atzori F, Chiari R, Ricciuti B, De Giglio A, Iacono D, Gelibter A, Occhipinti MA, Parisi A, Porzio G, Fargnoli MC, Ascierto PA, Ficorella C, Natoli C. A multicenter study of body mass index in cancer patients treated with anti-PD-1/PD-L1 immune checkpoint inhibitors: when overweight becomes favorable. J Immunother Cancer. 2019;7:57. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 176] [Cited by in F6Publishing: 266] [Article Influence: 53.2] [Reference Citation Analysis (0)] |
20. | McQuade JL, Daniel CR, Hess KR, Mak C, Wang DY, Rai RR, Park JJ, Haydu LE, Spencer C, Wongchenko M, Lane S, Lee DY, Kaper M, McKean M, Beckermann KE, Rubinstein SM, Rooney I, Musib L, Budha N, Hsu J, Nowicki TS, Avila A, Haas T, Puligandla M, Lee S, Fang S, Wargo JA, Gershenwald JE, Lee JE, Hwu P, Chapman PB, Sosman JA, Schadendorf D, Grob JJ, Flaherty KT, Walker D, Yan Y, McKenna E, Legos JJ, Carlino MS, Ribas A, Kirkwood JM, Long GV, Johnson DB, Menzies AM, Davies MA. Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis. Lancet Oncol. 2018;19:310-322. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 465] [Cited by in F6Publishing: 486] [Article Influence: 81.0] [Reference Citation Analysis (0)] |
21. | Indini A, Rijavec E, Ghidini M, Tomasello G, Cattaneo M, Barbin F, Bareggi C, Galassi B, Gambini D, Grossi F. Impact of BMI on Survival Outcomes of Immunotherapy in Solid Tumors: A Systematic Review. Int J Mol Sci. 2021;22. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 7] [Cited by in F6Publishing: 20] [Article Influence: 6.7] [Reference Citation Analysis (0)] |
22. | Vithayathil M, D'Alessio A, Fulgenzi CAM, Nishida N, Schönlein M, von Felden J, Schulze K, Wege H, Saeed A, Wietharn B, Hildebrand H, Wu L, Ang C, Marron TU, Weinmann A, Galle PR, Bettinger D, Bengsch B, Vogel A, Balcar L, Scheiner B, Lee PC, Huang YH, Amara S, Muzaffar M, Naqash AR, Cammarota A, Zanuso V, Pressiani T, Pinter M, Cortellini A, Kudo M, Rimassa L, Pinato DJ, Sharma R. Impact of body mass index in patients receiving atezolizumab plus bevacizumab for hepatocellular carcinoma. Hepatol Int. 2023;17:904-914. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 6] [Cited by in F6Publishing: 12] [Article Influence: 12.0] [Reference Citation Analysis (0)] |
23. | Hajiev S, Allara E, Motedayеn Aval L, Arizumi T, Bettinger D, Pirisi M, Rimassa L, Pressiani T, Personeni N, Giordano L, Kudo M, Thimme R, Park JW, Taddei TH, Kaplan DE, Ramaswami R, Pinato DJ, Sharma R. Impact of age on sorafenib outcomes in hepatocellular carcinoma: an international cohort study. Br J Cancer. 2021;124:407-413. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 14] [Cited by in F6Publishing: 16] [Article Influence: 5.3] [Reference Citation Analysis (0)] |
24. | Lyu N, Yi JZ, Zhao M. Immunotherapy in older patients with hepatocellular carcinoma. Eur J Cancer. 2022;162:76-98. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1] [Cited by in F6Publishing: 1] [Article Influence: 0.3] [Reference Citation Analysis (0)] |
25. | Vithayathil M, D'Alessio A, Fulgenzi CAM, Nishida N, Schönlein M, von Felden J, Schulze K, Wege H, Saeed A, Wietharn B, Hildebrand H, Wu L, Ang C, Marron TU, Weinmann A, Galle PR, Bettinger D, Bengsch B, Vogel A, Balcar L, Scheiner B, Lee PC, Huang YH, Amara S, Muzaffar M, Naqash AR, Cammarota A, Personeni N, Pressiani T, Pinter M, Cortellini A, Kudo M, Rimassa L, Pinato DJ, Sharma R. Impact of older age in patients receiving atezolizumab and bevacizumab for hepatocellular carcinoma. Liver Int. 2022;42:2538-2547. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 18] [Cited by in F6Publishing: 15] [Article Influence: 7.5] [Reference Citation Analysis (0)] |
26. | Naimimohasses S, O'Gorman P, McCormick E, Ferguson D, Monaghan A, McGrath M, Robinson MW, Gormley J, Norris S. Prevalence of frailty in patients with non-cirrhotic non-alcoholic fatty liver disease. BMJ Open Gastroenterol. 2022;9. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 2] [Cited by in F6Publishing: 6] [Article Influence: 3.0] [Reference Citation Analysis (0)] |
27. | Skladany L, Molcan P, Vnencakova J, Vrbova P, Kukla M, Laffers L, Koller T. Frailty in Nonalcoholic Fatty Liver Cirrhosis: A Comparison with Alcoholic Cirrhosis, Risk Patterns, and Impact on Prognosis. Can J Gastroenterol Hepatol. 2021;2021:5576531. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 3] [Cited by in F6Publishing: 13] [Article Influence: 4.3] [Reference Citation Analysis (0)] |
28. | Rada P, González-Rodríguez Á, García-Monzón C, Valverde ÁM. Understanding lipotoxicity in NAFLD pathogenesis: is CD36 a key driver? Cell Death Dis. 2020;11:802. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 93] [Cited by in F6Publishing: 251] [Article Influence: 62.8] [Reference Citation Analysis (0)] |
29. | Grohmann M, Wiede F, Dodd GT, Gurzov EN, Ooi GJ, Butt T, Rasmiena AA, Kaur S, Gulati T, Goh PK, Treloar AE, Archer S, Brown WA, Muller M, Watt MJ, Ohara O, McLean CA, Tiganis T. Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC. Cell. 2018;175:1289-1306.e20. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 151] [Cited by in F6Publishing: 264] [Article Influence: 44.0] [Reference Citation Analysis (0)] |
30. | Pinter M, Pinato DJ, Ramadori P, Heikenwalder M. NASH and Hepatocellular Carcinoma: Immunology and Immunotherapy. Clin Cancer Res. 2023;29:513-520. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 45] [Cited by in F6Publishing: 45] [Article Influence: 45.0] [Reference Citation Analysis (0)] |
31. | Pfister D, Núñez NG, Pinyol R, Govaere O, Pinter M, Szydlowska M, Gupta R, Qiu M, Deczkowska A, Weiner A, Müller F, Sinha A, Friebel E, Engleitner T, Lenggenhager D, Moncsek A, Heide D, Stirm K, Kosla J, Kotsiliti E, Leone V, Dudek M, Yousuf S, Inverso D, Singh I, Teijeiro A, Castet F, Montironi C, Haber PK, Tiniakos D, Bedossa P, Cockell S, Younes R, Vacca M, Marra F, Schattenberg JM, Allison M, Bugianesi E, Ratziu V, Pressiani T, D'Alessio A, Personeni N, Rimassa L, Daly AK, Scheiner B, Pomej K, Kirstein MM, Vogel A, Peck-Radosavljevic M, Hucke F, Finkelmeier F, Waidmann O, Trojan J, Schulze K, Wege H, Koch S, Weinmann A, Bueter M, Rössler F, Siebenhüner A, De Dosso S, Mallm JP, Umansky V, Jugold M, Luedde T, Schietinger A, Schirmacher P, Emu B, Augustin HG, Billeter A, Müller-Stich B, Kikuchi H, Duda DG, Kütting F, Waldschmidt DT, Ebert MP, Rahbari N, Mei HE, Schulz AR, Ringelhan M, Malek N, Spahn S, Bitzer M, Ruiz de Galarreta M, Lujambio A, Dufour JF, Marron TU, Kaseb A, Kudo M, Huang YH, Djouder N, Wolter K, Zender L, Marche PN, Decaens T, Pinato DJ, Rad R, Mertens JC, Weber A, Unger K, Meissner F, Roth S, Jilkova ZM, Claassen M, Anstee QM, Amit I, Knolle P, Becher B, Llovet JM, Heikenwalder M. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021;592:450-456. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 259] [Cited by in F6Publishing: 725] [Article Influence: 241.7] [Reference Citation Analysis (1)] |
32. | Heinrich B, Brown ZJ, Diggs LP, Vormehr M, Ma C, Subramanyam V, Rosato U, Ruf B, Walz JS, McVey JC, Wabitsch S, Fu Q, Yu SJ, Zhang Q, Lai CW, Sahin U, Greten TF. Steatohepatitis Impairs T-cell-Directed Immunotherapies Against Liver Tumors in Mice. Gastroenterology. 2021;160:331-345.e6. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 29] [Cited by in F6Publishing: 51] [Article Influence: 17.0] [Reference Citation Analysis (1)] |
33. | Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, Stroncek DF, Terabe M, Kapoor V, ElGindi M, Han M, Thornton AM, Zhang H, Egger M, Luo J, Felsher DW, McVicar DW, Weber A, Heikenwalder M, Greten TF. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature. 2016;531:253-257. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 377] [Cited by in F6Publishing: 535] [Article Influence: 66.9] [Reference Citation Analysis (0)] |
34. | Flecken T, Schmidt N, Hild S, Gostick E, Drognitz O, Zeiser R, Schemmer P, Bruns H, Eiermann T, Price DA, Blum HE, Neumann-Haefelin C, Thimme R. Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma. Hepatology. 2014;59:1415-1426. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 224] [Cited by in F6Publishing: 278] [Article Influence: 27.8] [Reference Citation Analysis (0)] |
35. | Song G, Shi Y, Zhang M, Goswami S, Afridi S, Meng L, Ma J, Chen Y, Lin Y, Zhang J, Liu Y, Jin Z, Yang S, Rao D, Zhang S, Ke A, Wang X, Cao Y, Zhou J, Fan J, Zhang X, Xi R, Gao Q. Global immune characterization of HBV/HCV-related hepatocellular carcinoma identifies macrophage and T-cell subsets associated with disease progression. Cell Discov. 2020;6:90. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 29] [Cited by in F6Publishing: 86] [Article Influence: 21.5] [Reference Citation Analysis (0)] |
36. | Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia-Criado Á, Kelley RK, Galle PR, Mazzaferro V, Salem R, Sangro B, Singal AG, Vogel A, Fuster J, Ayuso C, Bruix J. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol. 2022;76:681-693. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1904] [Cited by in F6Publishing: 1991] [Article Influence: 995.5] [Reference Citation Analysis (58)] |
37. | Vogel A, Martinelli E; ESMO Guidelines Committee. Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice Guidelines. Ann Oncol. 2021;32:801-805. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 86] [Cited by in F6Publishing: 239] [Article Influence: 79.7] [Reference Citation Analysis (0)] |
38. | Foerster F, Gairing SJ, Müller L, Galle PR. NAFLD-driven HCC: Safety and efficacy of current and emerging treatment options. J Hepatol. 2022;76:446-457. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 48] [Cited by in F6Publishing: 142] [Article Influence: 71.0] [Reference Citation Analysis (0)] |
39. | Llovet JM, Willoughby CE, Singal AG, Greten TF, Heikenwälder M, El-Serag HB, Finn RS, Friedman SL. Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment. Nat Rev Gastroenterol Hepatol. 2023;20:487-503. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 107] [Reference Citation Analysis (0)] |
40. | Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382:1894-1905. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 2542] [Cited by in F6Publishing: 4016] [Article Influence: 1004.0] [Reference Citation Analysis (2)] |
41. | Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, Sukeepaisarnjaroen W, Kang YK, Van Dao T, De Toni EN, Rimassa L, Breder V, Vasilyev A, Heurgué A, Tam VC, Mody K, Thungappa SC, Ostapenko Y, Yau T, Azevedo S, Varela M, Cheng AL, Qin S, Galle PR, Ali S, Marcovitz M, Makowsky M, He P, Kurland JF, Negro A, Sangro B. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evid. 2022;1:EVIDoa2100070. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 416] [Cited by in F6Publishing: 434] [Article Influence: 217.0] [Reference Citation Analysis (0)] |
42. | Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, Cicin I, Merle P, Chen Y, Park JW, Blanc JF, Bolondi L, Klümpen HJ, Chan SL, Zagonel V, Pressiani T, Ryu MH, Venook AP, Hessel C, Borgman-Hagey AE, Schwab G, Kelley RK. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med. 2018;379:54-63. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1630] [Cited by in F6Publishing: 1616] [Article Influence: 269.3] [Reference Citation Analysis (0)] |
43. | Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, Meinhardt G, Han G; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56-66. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 2160] [Cited by in F6Publishing: 2547] [Article Influence: 363.9] [Reference Citation Analysis (0)] |
44. | Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Lim HY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Ma N, Nicholas A, Wang Y, Li L, Zhu AX, Finn RS. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76:862-873. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 309] [Cited by in F6Publishing: 730] [Article Influence: 365.0] [Reference Citation Analysis (0)] |
45. | Finn RS, Kudo M, Merle P, Meyer T, Qin S, Ikeda M, Xu R, Edeline J, Ryoo BY, Ren Z, Cheng AL, Galle PR, Kaneko S, Kumada H, Wang A, Mody K, Dubrovsky L, Siegel AB, Llovet JM. LBA34 Primary results from the phase III LEAP-002 study: Lenvatinib plus pembrolizumab versus lenvatinib as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2022;33:S1401. [DOI] [Cited in This Article: ] [Cited by in Crossref: 2] [Cited by in F6Publishing: 2] [Article Influence: 1.0] [Reference Citation Analysis (0)] |
46. | Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY, Breder V, Edeline J, Chao Y, Ogasawara S, Yau T, Garrido M, Chan SL, Knox J, Daniele B, Ebbinghaus SW, Chen E, Siegel AB, Zhu AX, Cheng AL; KEYNOTE-240 investigators. Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2020;38:193-202. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 682] [Cited by in F6Publishing: 1200] [Article Influence: 240.0] [Reference Citation Analysis (0)] |
47. | Kelley RK, Rimassa L, Cheng AL, Kaseb A, Qin S, Zhu AX, Chan SL, Melkadze T, Sukeepaisarnjaroen W, Breder V, Verset G, Gane E, Borbath I, Rangel JDG, Ryoo BY, Makharadze T, Merle P, Benzaghou F, Banerjee K, Hazra S, Fawcett J, Yau T. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23:995-1008. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 276] [Cited by in F6Publishing: 282] [Article Influence: 141.0] [Reference Citation Analysis (1)] |
48. | Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163-1173. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 3128] [Cited by in F6Publishing: 3437] [Article Influence: 572.8] [Reference Citation Analysis (0)] |
49. | Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 9016] [Cited by in F6Publishing: 9892] [Article Influence: 618.3] [Reference Citation Analysis (2)] |
50. | Qin S, Chan SL, Gu S, Bai Y, Ren Z, Lin X, Chen Z, Jia W, Jin Y, Guo Y, Hu X, Meng Z, Liang J, Cheng Y, Xiong J, Ren H, Yang F, Li W, Chen Y, Zeng Y, Sultanbaev A, Pazgan-Simon M, Pisetska M, Melisi D, Ponomarenko D, Osypchuk Y, Sinielnikov I, Yang TS, Liang X, Chen C, Wang L, Cheng AL, Kaseb A, Vogel A; CARES-310 Study Group. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet. 2023;402:1133-1146. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 97] [Cited by in F6Publishing: 179] [Article Influence: 179.0] [Reference Citation Analysis (2)] |
51. | Qin S, Kudo M, Meyer T, Bai Y, Guo Y, Meng Z, Satoh T, Marino D, Assenat E, Li S, Chen Y, Boisserie F, Abdrashitov R, Finn RS, Vogel A, Zhu AX. Tislelizumab vs Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2023;9:1651-1659. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 46] [Cited by in F6Publishing: 35] [Article Influence: 35.0] [Reference Citation Analysis (1)] |
52. | Yau T, Park JW, Finn RS, Cheng AL, Mathurin P, Edeline J, Kudo M, Harding JJ, Merle P, Rosmorduc O, Wyrwicz L, Schott E, Choo SP, Kelley RK, Sieghart W, Assenat E, Zaucha R, Furuse J, Abou-Alfa GK, El-Khoueiry AB, Melero I, Begic D, Chen G, Neely J, Wisniewski T, Tschaika M, Sangro B. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022;23:77-90. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 104] [Cited by in F6Publishing: 595] [Article Influence: 198.3] [Reference Citation Analysis (0)] |
53. | Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, Assenat E, Brandi G, Pracht M, Lim HY, Rau KM, Motomura K, Ohno I, Merle P, Daniele B, Shin DB, Gerken G, Borg C, Hiriart JB, Okusaka T, Morimoto M, Hsu Y, Abada PB, Kudo M; REACH-2 study investigators. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20:282-296. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1027] [Cited by in F6Publishing: 1151] [Article Influence: 230.2] [Reference Citation Analysis (0)] |
54. | Meyer T, Galani S, Lopes A, Vogel A. Aetiology of liver disease and response to immune checkpoint inhibitors: An updated meta-analysis confirms benefit in those with non-viral liver disease. J Hepatol. 2023;79:e73-e76. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 28] [Reference Citation Analysis (0)] |
55. | Rimini M, Rimassa L, Ueshima K, Burgio V, Shigeo S, Tada T, Suda G, Yoo C, Cheon J, Pinato DJ, Lonardi S, Scartozzi M, Iavarone M, Di Costanzo GG, Marra F, Soldà C, Tamburini E, Piscaglia F, Masi G, Cabibbo G, Foschi FG, Silletta M, Pressiani T, Nishida N, Iwamoto H, Sakamoto N, Ryoo BY, Chon HJ, Claudia F, Niizeki T, Sho T, Kang B, D'Alessio A, Kumada T, Hiraoka A, Hirooka M, Kariyama K, Tani J, Atsukawa M, Takaguchi K, Itobayashi E, Fukunishi S, Tsuji K, Ishikawa T, Tajiri K, Ochi H, Yasuda S, Toyoda H, Ogawa C, Nishimur T, Hatanaka T, Kakizaki S, Shimada N, Kawata K, Tanaka T, Ohama H, Nouso K, Morishita A, Tsutsui A, Nagano T, Itokawa N, Okubo T, Arai T, Imai M, Naganuma A, Koizumi Y, Nakamura S, Joko K, Iijima H, Hiasa Y, Pedica F, De Cobelli F, Ratti F, Aldrighetti L, Kudo M, Cascinu S, Casadei-Gardini A. Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis. ESMO Open. 2022;7:100591. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 4] [Cited by in F6Publishing: 70] [Article Influence: 35.0] [Reference Citation Analysis (0)] |
56. | Howell J, Samani A, Mannan B, Hajiev S, Motedayen Aval L, Abdelmalak R, Tam VC, Bettinger D, Thimme R, Taddei TH, Kaplan DE, Seidensticker M, Sharma R. Impact of NAFLD on clinical outcomes in hepatocellular carcinoma treated with sorafenib: an international cohort study. Therap Adv Gastroenterol. 2022;15:17562848221100106. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1] [Cited by in F6Publishing: 6] [Article Influence: 3.0] [Reference Citation Analysis (0)] |
57. | Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, Romero D, Abdelmalek MF, Anstee QM, Arab JP, Arrese M, Bataller R, Beuers U, Boursier J, Bugianesi E, Byrne CD, Narro GEC, Chowdhury A, Cortez-Pinto H, Cryer DR, Cusi K, El-Kassas M, Klein S, Eskridge W, Fan J, Gawrieh S, Guy CD, Harrison SA, Kim SU, Koot BG, Korenjak M, Kowdley KV, Lacaille F, Loomba R, Mitchell-Thain R, Morgan TR, Powell EE, Roden M, Romero-Gómez M, Silva M, Singh SP, Sookoian SC, Spearman CW, Tiniakos D, Valenti L, Vos MB, Wong VW, Xanthakos S, Yilmaz Y, Younossi Z, Hobbs A, Villota-Rivas M, Newsome PN; NAFLD Nomenclature consensus group. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Ann Hepatol. 2024;29:101133. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 183] [Cited by in F6Publishing: 194] [Article Influence: 194.0] [Reference Citation Analysis (0)] |
58. | Huang DQ, Terrault NA, Tacke F, Gluud LL, Arrese M, Bugianesi E, Loomba R. Global epidemiology of cirrhosis - aetiology, trends and predictions. Nat Rev Gastroenterol Hepatol. 2023;20:388-398. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 194] [Cited by in F6Publishing: 206] [Article Influence: 206.0] [Reference Citation Analysis (0)] |
59. | Portuguese AJ, Tykodi SS, Blosser CD, Gooley TA, Thompson JA, Hall ET. Immune Checkpoint Inhibitor Use in Solid Organ Transplant Recipients: A Systematic Review. J Natl Compr Canc Netw. 2022;20:406-416.e11. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 6] [Cited by in F6Publishing: 36] [Article Influence: 18.0] [Reference Citation Analysis (0)] |