Management of Hepatocellular Carcinoma Associated with NAFLD: Comparison
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Please note this is a comparison between Version 2 by Wendy Huang and Version 1 by Alin Mihai Vasilescu.

Non-alcoholic fatty liver disease (NAFLD) has gained attention due to its increasing prevalence worldwide becoming a global epidemic. The increasing incidence of NAFLD and the concurrent increase in the number of hepatocellular carcinoma (HCC) cases at a global level is a matter of concern. HCC has several risk factors, of which NAFLD and its associated metabolic disturbances—type 2 diabetes mellitus, obesity, and dyslipidemia—are of great interest due to their accelerating rise in incidence worldwide. There is a high amount of data derived from basic and clinical studies that reveal the molecular pathways that drive NAFLD-associated HCC. Based on these findings, new prevention, surveillance, and treatment strategies are emerging. 

  • non-alcoholic fatty liver disease
  • hepatocellular carcinoma
  • management
  • hepatic resection
  • ablation
  • liver transplantation
  • transcatheter arterial chemoembolization (TACE)
  • systemic therapy

1. Introduction

Over the past few decades, liver cancer incidence and death have both been steadily increasing. With a total of 905,677 new cases reported in 2020, liver cancer constituted the sixth most prevalent cancer globally. Liver cancer still has a poor prognosis despite recent improvements. In terms of cancer-related deaths in 2020, liver cancer came in third with 830,180 fatalities [16][1]. HCC has several risk factors, of which NAFLD and its associated metabolic disturbances—type 2 diabetes mellitus, obesity, and dyslipidemia—are of great interest due to their accelerating rise in incidence worldwide [12][2].

The therapeutic management of HCC is complex and, according to the recommendations of current guidelines, it requires a multidisciplinary team consisting of hepatologists, oncologists, and surgeons specialized in liver surgery and transplantation, as well as radiologists. However, data from the literature show that only half of patients diagnosed with HCC are subsequently evaluated by a multidisciplinary team. Currently, the treatment recommendations for HCC are based on the BCLC classification and do not differ from one etiology to another, but do take into consideration the presence of liver cirrhosis and consequently liver function [41][3]. Placing patients in a specific therapeutic strategy depends on the BCLC classification, taking into account patient heterogeneity, patient wishes, ongoing clinical trials, and local limitations. There are scarce data regarding both treatment modalities and long-term survival in NAFLD-HCC, taking into consideration that these patients frequently have several comorbidities, such as type 2 diabetes mellitus, cardiovascular disease, and obesity. For instance, Wang et al. demonstrated that cirrhotic patients with type 2 diabetes and HCC have lower overall survival rates after curative hepatectomy compared to those without diabetes [47][4]. The authors concluded that diabetes may reduce the OS of HCC patients by exacerbating existing liver fibrosis, resulting in severe liver failure.

2. Hepatic Resection

In patients with HCC without liver cirrhosis and impaired liver function, hepatic resection represents the first option for treatment [30,31][5][6]. However, despite progress having been made in the last years in improving the survival rate in those with liver resection, the recurrence rate has not shown major changes. Research studies that assessed the overall survival (OS) and recurrence-free survival (RFS) in patients with NAFLD-associated HCC showed optimistic results (Table 1). It appears that OS at 5 years after liver resection for NAFLD-associated HCC ranges from 51.5% to 97%, whereas RFS at 5 years ranges from 36.3% to 66% [48,49,50,51,52,53,54][7][8][9][10][11][12][13]. However, there is an ongoing debate regarding the outcomes after resection in patients with NAFLD-associated HCC vs. other liver diseases. It appears that the presence of metabolic and cardiovascular comorbidities, which are often found in patients with NAFLD, has a negative impact on the OS after liver resection for HCC [55][14]. A meta-analysis that aimed to evaluate the outcome after hepatic resection for HCC in NAFLD vs. other liver diseases in approximately 7200 patients found a better RFS and OS in those with NAFLD [56][15]. Furthermore, a lower RFS was found in a study that compared NAFLD-associated HCC with HCV-related HCC (44.6% vs. 62.5%) [52][11]. Still, it is important to acknowledge that the high post-surgical mortality in patients with NAFLD is mainly due to the metabolic comorbidities, which should be carefully diagnosed and managed.
Table 1.
Overall survival (OS) and recurrence-free survival (RFS) in patients with NAFLD-associated HCC after liver resection.
Ref. Type of Study Patients (n) and Characteristics Overall Survival Rate * Recurrence-Free Survival **
Koh et al. [33][16] Retrospective N = 996 HCC patients, 844 with non-NAFLD HCC and 152 with NAFLD HCC 70.1% 45.4%
Reddy et al. [34][17] Retrospective N = 214 HCC patients, 52 with NASH and 162 with HCV or ALD 59% 48%
Liang et al. [35][18] Retrospective N = 177 HCC patients, 75 with NASH and 102 with alcoholic or viral hepatitis 87% 51%
. There are several studies regarding long-term outcomes after liver transplantation in NAFLD-associated HCC (Table 2). The OS and RFS rates range from 59% to 88% and 48% to 68%, respectively [49,60,61,62,63,64][8][27][28][29][30][31]. Although some studies reported similar outcomes after liver transplantation for HCC in NAFLD and other etiologies [49[8][32],65], there are some studies that raised concerns regarding worse OS in those with NAFLD. For instance, a comprehensive analysis from the European Transplant Registry, which included patients with liver transplantation for different etiologies, reported lower OS in NAFLD-HCC compared to alcoholic liver disease-related HCC [60][27]. On the other hand, the same authors found no difference in terms of OS rates at 10 years when compared to chronic HCV infection and cryptogenic cirrhosis (73%). In contrast with these results, an American study found no difference in OS rates after liver transplantation in NAFLD-associated HCC vs. alcoholic liver disease-associated HCC [49][8]. These differences could be attributed to different national listing and scoring systems. Overall, it seems that NAFLD has no significant impact on OS after liver transplantation for HCC compared to other causes of liver disease, but it needs to be taken into consideration due to the high complication rates after surgery due to metabolic syndrome-associated comorbidities.
Table 2.
Overall survival (OS) and recurrence-free survival (RFS) in patients with NAFLD-associated HCC after liver transplantation.
Ref. Type of Study Patients (n) and Characteristics Overall Survival Rate * Recurrence-Free Survival
Reddy et al. [34][17] Retrospective N = 214 HCC patients, 52 with

NASH and 162 patients with HCV or ALD		 59% 48% at 5 years
Haldar et al. [44][33] Retrospective N = 68,950 recipients, 1071 with NASH-HCC and 19,134 with HCC of other etiologies 68.6% n/a
Wong C.R. et al. [45][34] Retrospective N = 17,644 HCC patients, 406 patients with NAFLD, 1854 with HCV, 1342 with HBV, and 1024 with ALD 60% n/a
Vigano et al. [36][19]
Rajendran et al. [46][35Retrospective ]N = 192 HCC patients, 96 with NASH and 96 with HCV 65.6% 37%
Retrospective N = 20,672 HCC patients, 2071 with NASH HCC and 18,601 with HCC of other etiologies 76.3% n/a Billeter et al. [37][20] Retrospective N = 365 HCC patients, 62 with NASH and 303 with HCV 71.3% 36.3%
Sadler et al. Yang et al. [38][21] Retrospective N = 1483 HCC patients, 96 with NAFLD HCC and 1387 with HBV HCC 51.4% 38.8%
Wakai et al. [39][22] Retrospective N = 225 HCC patients, 17 with NAFLD HCC, 61 with HBV, and 147 with HCV 59% 66%
* Five-year overall survival rate. ** Five-year recurrence free survival.

3. Ablation

Radiofrequency ablation (RFA) is a non-surgical treatment method that is currently recommended in patients with stage 0 (tumors smaller than 2 cm) or A, according to the BCLC classification, with OS rates similar to resection [41][3]. Regarding NAFLD-associated HCC, a recent study that evaluated the OS rates in patients treated with RFA for HCC in NAFD and other liver diseases reported no significant differences [50][9]. However, data from another study show that the presence of type 2 diabetes impairs the outcome after RFS, though metformin therapy has a positive impact on OS [57][23]. Despite the good efficacy and safety of microwave ablation of HCC, there are no data regarding the outcome in patients with NAFLD.

4. Liver Transplantation

According to the European Liver Transplant Registry, the survival rate at 10 years after liver transplantation for HCC is 51%, irrespective of underlying etiology [58][24]. The current guidelines recommend liver transplantation as the first choice in patients with HCC who do not meet the eligibility criteria for liver resection but are within the Milan criteria [30,31,32][5][6][25]. However, since many believe that the Milan criteria are too strict, nowadays there are many centers that offer liver transplantation in patients with HCC outside the Milan experience, with good results [59][26]
[
47
]
[
4
] Retrospective N = 929 HCC patients, 60 with NASH and 869 with other etiologies 80% 68%
Malik et al. [48][7] Retrospective N = 17 NASH HCC patients 88% at 2.5 years n/a
* Five-year overall survival rate.
Considering that nowadays there are numerous centers that offer liver transplantation beyond the Milan criteria, patients with NAFLD and HCC have also benefited from the extended indications. Rajendran et al. evaluated the outcomes of liver transplantation in patients with NAFLD-related HCC and found that there were no survival differences in populations within or beyond the Milan criteria [62][29].

5. Neoadjuvant and Adjuvant Therapies

Currently, there is no recommendation for adjuvant and neoadjuvant therapies use in HCC management because of the low efficacy and poor safety profile of the agents studied until now. Although HCC has very high rates of recurrence after resection or ablation (up to 70% at 5 years after curative treatment), there has been no therapy able to modify the outcome in these patients. There are several ongoing phase III randomized controlled trials that are evaluating the efficacy of adjuvant therapies after curative treatment with nivolumab, pembrolizumab, atezolizumab + bevacizumab, and durvalumab [66][36].

6. Transcatheter Arterial Chemoembolization

In patients with unresectable HCC and preserved liver function with no evidence of vascular invasion or extrahepatic spread, categorized as BCLC class B, the first-line treatment is transcatheter arterial chemoembolization (TACE). The classic method for TACE, consisting of the administration of an anticancer-in-oil emulsion followed by embolic agents, has been replaced in the last few years with a more efficient alternative that offers the possibility of introducing an embolic drug-eluting bead (DEB) providing a better efficacy and safety profile [67][37]. Data from several studies that assessed the pharmacokinetic profile of DEBs loaded with doxorubicin reported excellent features with lower systemic drug exposure and significantly reduced liver toxicity compared with conventional TACE [68,69,70][38][39][40]. In NAFLD-associated HCC, data about TACE efficacy are still scarce, with few studies mentioning its feasibility [71,72][41][42]. In a recent study, Young et al. retrospectively compared the median OS in patients with HCC and NAFLD vs. other etiologies after TACE and found that there were no significant differences [73][43]. In contrast with these results, another study conducted by Wu et al., which included 57 patients with HCC of different etiologies who had performed 100 TACE procedures, reported a negative impact of obesity on post-therapy residual disease and the time-to-progression interval [74][44]. Consequently, the low scientific evidence for TACE in NAFLD-associated HCC does not currently sustain a clear recommendation for including this procedure in the treatment strategy.

7. Systemic Therapy

Data regarding systemic therapy in NAFLD-associated HCC are lacking and the indication of treatment is derived from HCC cases of other etiologies. The first agent for systemic therapy in HCC was sorafenib, which was introduced in 2007 based on the excellent results from the SHARP trial and has been used as a first-choice therapy for advanced-stage HCC (BCLC C) for over 10 years [74][44]. Data from the SHARP phase III trial showed that the efficacy of sorafenib varied depending on the etiology of HCC, being more effective in those with chronic HCV infection [75][45]. Interestingly, it has been recently demonstrated by a cohort study that included HCC patients with several etiologies of liver disease that the efficacy of sorafenib was similar in NAFLD patients when compared to other etiologies [76][46]. Recent advances in the field of immunotherapy for HCC have introduced new agents in the management of advanced-stage HCC, with promising results. The REFLECT trial demonstrated an improved OS of lenvatinib compared to sorafenib (13.6 vs. 12.3 months) [77][47]. Interestingly, lenvatinib showed an improvement of 1.5 months in terms of progression-free survival in patients with NAFLD-associated HCC compared to viral-related HCC [78][48]. Regorafenib has been recently recommended based on the improved survival rates in viral and non-viral HCC when compared to placebo (10.6 vs. 7.8 months), but due to the low incidence of NAFLD patients in the pivotal trial, there are no data regarding the efficacy of the drug in this cohort [79][49]. Similarly, the trials that evaluated cabozantinib and ramucirab, which, along with lenvatinib, are recommended as second-line choices when sorafenib fails, did not offer any data on their efficacy in NAFLD patients [80,81][50][51]. The cytotoxicity of these drugs is, however, a matter of concern nowadays. For instance, the side effects of antiangiogenic medications, such as sorafenib, may include hypertension, renal toxicity, arterial thromboembolism, bleeding, cardiotoxicity, thyroid dysfunction, hand–foot skin reaction, rash, pruritus, alopecia, potentially fatal hepatotoxicity, toxic/metabolic encephalopathy, and muscle wasting. On the other hand, despite having significantly higher transaminases than patients receiving immune checkpoint inhibitors for other conditions (such as lung cancer or melanoma), patients with HCC have not experienced early treatment termination or treatment-related mortality [82][52].

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