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Cell — Nature Reviews Genetics Issa J-P CpG island methylator phenotype in cancer. Nature Reviews Cancer Science Hepatology — Gastroenterology — :e Epigenetics — Aging Albany NY Oncotarget Nature Communications Genome Research — BMC Cancer Cancer Cell — Proceedings of the National Academy of Sciences — Clinical Cancer Research — Journal of Gastroenterology and Hepatology — Journal of Biological Chemistry — Clinics and Research in Hepatology and Gastroenterology — Nucleic Acids Research — Current Biology — Journal of Cellular Biochemistry — Journal of Hepatology — RNA Biology — European Journal of Gastroenterology and Hepatology — Cancer Research — Journal of Cancer.

Gastroenterology — Biochemistry — Journal of International Medical Research — Annals of Surgical Oncology — Oncology Letters — Genes — Cancer Discovery — Cancer Cell 32 — :e Current Biology R—R Nature Reviews Genetics — Sawan C, Herceg Z Histone modifications and cancer.


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Treating Hepatocellular Carcinoma: A Fight Against the Odds

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Correspondence to Edward Kai-Hua Chow. Reprints and Permissions. Search all SpringerOpen articles Search. Abstract In recent years, large scale genomics and genome-wide studies using comprehensive genomic tools have reshaped our understanding of cancer evolution and heterogeneity. Liver cancer—hepatocellular carcinoma HCC Liver cancer is the second most lethal cancer worldwide [ 1 ]. Schematic diagram displaying CpG annotations of genomic regions.

Full size image. Chromatin modifiers and HCC Chromatin modifiers or remodelers are an important class of proteins that take part in the regulation of accessibility to chromatin and positioning of nucleosome in the DNA [ 60 ]. Histone deacetylation and HCC Besides DNA methylation, ncRNAs and chromatin remodelers, histone modifications comprise another group of epigenetic mechanisms that play important roles in regulating gene expression and changes in chromatin structure. Conclusions The liver cancer epigenome is highly complex and is adapted to changing environmental and developmental cues.

However, there are several data regarding clinical outcomes in elderly patients with or without HCC who underwent LT [ 60 , 68 - 72 ]. Randell et al. They emphasized that although elderly patients should not be completely excluded as candidates for LT, careful consideration during the evaluation process is required. Zetterman et al. Previous studies regarding comparison of clinical outcomes in younger and elderly patients treated with surgical resection for hepatocellular carcinoma. Taner et al. They concluded that advanced age itself is not considered a contraindication for LT.

Overall, although LT for elderly patients is not always contraindicated, thoughtful consideration for LT and careful observation after LT are needed. Since its introduction in Japan in , RFA has rapidly gained popularity because of its excellent antitumor effect, safety and low invasiveness. More recently, several investigators have used RFA to treat selected patients with resectable HCC with favorable clinical outcomes, and RFA is gradually gaining popularity in the treatment of resectable HCC in many countries, in addition to Japan [ 78 ]. In general, elderly patients have a high incidence of comorbidity such as cardiovascular disease, diabetes mellitus and chronic renal disease, and are considered high-risk patients for SR [ 22 - 34 , 53 - 55 , 62 ].

Thus, radical SR of HCC may be less feasible in elderly patients than in younger patients in several aspects, and RFA therapy may be an acceptable alternative [ 74 - 80 ]. This suggested that increased age was closely associated with mortality in patients who underwent RFA for HCC, as well as in those who underwent surgery. Shiina et al. In their multivariate analysis, increasing age was significantly associated with OS [HR, 1. Takahashi et al. The major complication rates were 2. They concluded that RFA treatment might be safe and effective in elderly patients, as well as younger HCC patients [ 22 ].

The 1- and 3-year local tumor progression rates after RFA were We concluded that clinical outcomes in the elderly group were poorer than those in the younger group, although RFA in the elderly patients was a safe procedure. Overall, whether elderly patients with HCC treated with ablative therapies have comparable clinical outcomes as compared with younger patients remains controversial.

Previous reports with regard to comparison of survival of ablative therapies in elderly patients and younger patients are summarized in Table 2. TACE is a procedure whereby an embolizing agent after intra-arterial injection of an anticancer drug is injected into the hepatic artery to deprive the tumor of its major nutrient source via embolization of the nutrient artery, resulting in ischemic necrosis of the tumor [ 81 - 88 ]. However, a recent study demonstrated that the prognostic factors affecting the survival of HCC patients treated with TACE included: 1 tumor stage; 2 tumor markers; and 3 hepatic functional reserve [ 82 ].

Yau et al. Both the overall median survival Likewise, Cohen et al. Advanced age was not associated with the rate of adverse events. This suggested that radioembolization is well-tolerated and effective for elderly as well as younger patients. Reports of previous studies regarding of comparison of clinical outcomes in younger and elderly patients treated with locoregional therapies for hepatocelluar carcinoma.

There has long been a lack of concrete evidence to support systemic chemotherapy for unresectable advanced HCC [ 91 ]. According to the Japanese guidelines, sorafenib is recommended for unresectable, advanced, Child-Pugh class A HCC with vascular invasion or distant metastasis, as well as for patients intolerant to TACE or in whom the procedure of TACE is anatomically unsuitable [ 42 , 94 , 95 ]. Systemic chemotherapy for advanced cancer is often either modified or withheld for the management of elderly patients with advanced cancer for fear of potential toxicity [ 96 - 98 ].

Furthermore, several adverse events associated with sorafenib have been reported [ 92 - 95 , 99 - ]. Especially in elderly patients with advanced HCC who undergo sorafenib therapy, caution is needed for the expected SAEs, because they have higher comorbidity and poorer PS, and SAEs cause treatment discontinuation [ 96 - 98 ].

Wong et al.

Hepatocellular carcinoma

The median progression-free survival time was similar in the elderly and younger groups 2. Grade 3 or 4 SAEs were observed in They concluded that the survival benefits and overall treatment-related SAEs of sorafenib are comparable in elderly and younger patients with advanced HCC. Likewise, a study from Italy investigated the impact of age on the effects of sorafenib therapy in patients with HCC and LC [ 97 ]. Grade 3 and 4 SAEs were more frequent in the younger than the older group On the contrary, Morimoto et al.

There is one report about the usefulness of a reduced starting dose of sorafenib in elderly patients with advanced HCC [ 98 ].

Quality of life did not show any significant change during the study. The results emphasized the usefulness of reduced dose sorafenib in elderly patients with HCC. However, there is still a lack of sufficient evidence of clinical usefulness and safety of sorafenib therapy in elderly patients with advanced HCC.

Further cumulative clinical evidence is needed. We reviewed the clinical characteristics and outcomes of each therapy in elderly patients with HCC. Etiology of background liver disease, male to female ratio, degree of liver fibrosis, proportion of patients with comorbidity, and tumor characteristics differ considerably between elderly and younger patients with HCC.

However, further clinical evidence is needed to confirm these results. The authors have not received any financial support for this article and have no conflicts of interest to declare. Kudo M. Radiofrequency ablation for hepatocellular carcinoma: updated review in Treatment options in hepatocellular carcinoma today. Scand J Surg. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Management of HCC. J Hepatol.

Hepatocellular carcinoma. N Engl J Med. Changing trends in hepatitis C infection over the past 50 years in Japan. Partitioning linear trends in age-adjusted rates. Cancer Causes Control. Labour and Welfare. Abridged life tables for Japan Ministry of Health. Do young hepatocellular carcinoma patients with relatively good liver function have poorer outcomes than elderly patients? J Gastroenterol Hepatol.

Effect of aging on risk for hepatocellular carcinoma in chronic hepatitis C virus infection. Kiyosawa K, Tanaka E. Characteristics of hepatocellular carcinoma in Japan. Hepatol Res. The changing pattern of epidemiology in hepatocellular carcinoma.


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Dig Liver Dis. Trans-arterial chemo-embolization is safe and effective for very elderly patients with hepatocellular carcinoma. World J Gastroenterol. Hepatocellular carcinoma: current management and perspectives for the future. Ann Surg. Sex- and age-specific carriers of hepatitis B and C viruses in Japan estimated by the prevalence in the 3,, first-time blood donors during Wyles DL. Antiviral resistance and the future landscape of hepatitis C virus infection therapy. J Infect Dis. Am J Gastroenterol. Asselah T, Marcellin P. Interferon free therapy with direct acting antivirals for HCV.

Liver Int. Percutaneous radiofrequency ablation for hepatocellular carcinoma: clinical outcome and safety in elderly patients. J Gastrointestin Liver Dis. Efficacy and safety of radiofrequency ablation for elderly hepatocellular carcinoma patients. Younger hepatocellular carcinoma patients have better prognosis after percutaneous radiofrequency ablation therapy.

J Clin Gastroenterol. Hepatic resection is justified for elderly patients with hepatocellular carcinoma. World J Surg. Long-term outcomes and prognostic factors of elderly patients with hepatocellular carcinoma undergoing hepatectomy. J Gastrointest Surg. In general, many elderly patients are not receiving optimal therapy for malignancies, because it is often withheld because of perceived minimal survival advantage and the fear of potential toxicity [ 30 - 35 ]. The treatment of HCC has significantly improved in the past few decades.

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The optimal therapy should be selected for individual patients with HCC based on the assessment of performance status PS , tumor-related factors, liver-function-related factors and comorbidity [ 1 - 5 , 36 - 40 ]. However, current guidelines for the management of HCC do not satisfy strategies according to age [ 41 , 42 ]. As described earlier, the proportion of elderly patients with HCC and their average age is increasing in Japan [ 6 , 10 - 12 ]. These trends have led to a rising demand in our country for investigations related to clinical characteristics and outcomes of therapy in elderly patients with HCC.

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In this review, we mainly refer to current knowledge of clinical characteristics and outcome in elderly patients with HCC who underwent different treatment approaches i. The clinical course of liver diseases in elderly patients may differ in several aspects from that in younger patients, although there are no liver diseases specific to those of advanced age [ 43 ].

The process of liver carcinogenesis in elderly patients seems to be a distinctive factor. In previous studies, elderly patients with HCC were more likely to be women [ 14 , 21 - 34 , 44 ].

This may have been associated with a larger female elderly population because of their longer life expectancy. In other words, the proportion of women in the population is known to gradually increase with age [ 8 ]. The peak age of HCC occurrence in women is delayed by around 5 years as compared with that in men [ 45 ]. This finding may be explained by the fact that most HBV carriers acquire the virus via vertical transmission in the perinatal period, whereas most HCV carriers are infected at a later stage in life.

The peak age of HCC occurrence thus varies considerably worldwide because of the different distribution of etiological factors. Oishi et al. Factors other than hepatitis virus or alcohol, or genetic disturbance may be related to the development of HCC in some elderly patients [ 47 ].

The prevalence of a normal liver in elderly patients with HCC is reported to be higher than that in younger patients [ 24 - 33 , 43 ]. These observations suggest that aging itself is a risk factor linked to liver carcinogenesis. Aberrant DNA methylation, which is observed in the normal aging process, may also be associated with HCC development in elderly patients [ 52 ]. A recent report by Miki et al. Their results also indicate that aging itself is a risk factor for HCC development.

Several studies reported that the number of HCC nodules in elderly patients was smaller than that in younger patients [ 24 - 34 , 43 , 53 - 55 ]. Multicentric liver carcinogenesis is associated with the degree of background liver fibrosis [ 56 , 57 ]. Less advanced liver fibrosis in elderly patients may explain these observations. The degree of background liver fibrosis and tumor-related factors may differ considerably between the two groups. Aging is closely associated with liver carcinogenesis. Although there is no specific age limitation for surgery for HCC in Japan, elderly patients may have shorter long-term survival after surgery as compared with younger patients because of their expected life span [ 8 , 24 - 33 , 53 , 60 ].

SR for HCC in elderly patients thus deserves serious consideration. SR is considered the initial first-line treatment for resectable HCC because of its generally good outcome, and the lack brain-dead liver donors in Japan [ 12 ]. There have been several studies regarding the outcome and safety in elderly patients with HCC treated with SR [ 24 - 33 , 47 , 53 - 55 , 61 , 62 ]. Sato et al. This suggested that increased age was closely associated with mortality in patients who underwent surgery for HCC.

Kaibori et al. The overall survival OS rates at 3, 5 and 7 years were The corresponding 3-, 5- and 7-year disease-free survival DFS rates were The corresponding recurrence-free survival RFS rates were Thus, we concluded that SR appears to be a safe and feasible procedure for the treatment of HCC in elderly patients.

Portolani et al. They concluded that major resection in elderly patients with HCC must be reserved for selected cases, although they claimed that limited liver resection is a valid option for the treatment of HCC in elderly patients. Interestingly, there is one report from Japan regarding the outcome of repeat hepatectomy for recurrent HCC in elderly patients with HCC [ 34 ]. Repeat hepatectomy may be a safe procedure in some elderly patients with HCC.

Liver Cancer | MD Anderson Cancer Center

Previous studies regarding comparison of survival of SR in elderly patients and younger patients are summarized in Table 1. LT is considered as an important treatment option in western countries even in patients with decompensated cirrhosis of various causes [ 4 , 63 - 65 ]. Given the Milan criteria are satisfied, living-donor partial LT for the treatment of decompensated cirrhosis complicated with HCC has been covered by the national health insurance system in Japan since [ 66 ].

Living-donor LT is the major choice of treatment because of the shortage of brain-dead donors in Japan [ 4 , 63 - 67 ]. There is an arbitrary age limit for LT because of the increased comorbidity in elderly patients [ 68 ]. However, there are several data regarding clinical outcomes in elderly patients with or without HCC who underwent LT [ 60 , 68 - 72 ]. Randell et al. They emphasized that although elderly patients should not be completely excluded as candidates for LT, careful consideration during the evaluation process is required.

Zetterman et al. Previous studies regarding comparison of clinical outcomes in younger and elderly patients treated with surgical resection for hepatocellular carcinoma. Taner et al. They concluded that advanced age itself is not considered a contraindication for LT. Overall, although LT for elderly patients is not always contraindicated, thoughtful consideration for LT and careful observation after LT are needed. Since its introduction in Japan in , RFA has rapidly gained popularity because of its excellent antitumor effect, safety and low invasiveness.

More recently, several investigators have used RFA to treat selected patients with resectable HCC with favorable clinical outcomes, and RFA is gradually gaining popularity in the treatment of resectable HCC in many countries, in addition to Japan [ 78 ]. In general, elderly patients have a high incidence of comorbidity such as cardiovascular disease, diabetes mellitus and chronic renal disease, and are considered high-risk patients for SR [ 22 - 34 , 53 - 55 , 62 ]. Thus, radical SR of HCC may be less feasible in elderly patients than in younger patients in several aspects, and RFA therapy may be an acceptable alternative [ 74 - 80 ].

This suggested that increased age was closely associated with mortality in patients who underwent RFA for HCC, as well as in those who underwent surgery. Shiina et al. In their multivariate analysis, increasing age was significantly associated with OS [HR, 1. Takahashi et al. The major complication rates were 2.

They concluded that RFA treatment might be safe and effective in elderly patients, as well as younger HCC patients [ 22 ]. The 1- and 3-year local tumor progression rates after RFA were We concluded that clinical outcomes in the elderly group were poorer than those in the younger group, although RFA in the elderly patients was a safe procedure. Overall, whether elderly patients with HCC treated with ablative therapies have comparable clinical outcomes as compared with younger patients remains controversial.

Previous reports with regard to comparison of survival of ablative therapies in elderly patients and younger patients are summarized in Table 2. TACE is a procedure whereby an embolizing agent after intra-arterial injection of an anticancer drug is injected into the hepatic artery to deprive the tumor of its major nutrient source via embolization of the nutrient artery, resulting in ischemic necrosis of the tumor [ 81 - 88 ].

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However, a recent study demonstrated that the prognostic factors affecting the survival of HCC patients treated with TACE included: 1 tumor stage; 2 tumor markers; and 3 hepatic functional reserve [ 82 ]. Yau et al. Both the overall median survival Likewise, Cohen et al. Advanced age was not associated with the rate of adverse events. This suggested that radioembolization is well-tolerated and effective for elderly as well as younger patients. Reports of previous studies regarding of comparison of clinical outcomes in younger and elderly patients treated with locoregional therapies for hepatocelluar carcinoma.

There has long been a lack of concrete evidence to support systemic chemotherapy for unresectable advanced HCC [ 91 ]. According to the Japanese guidelines, sorafenib is recommended for unresectable, advanced, Child-Pugh class A HCC with vascular invasion or distant metastasis, as well as for patients intolerant to TACE or in whom the procedure of TACE is anatomically unsuitable [ 42 , 94 , 95 ]. Systemic chemotherapy for advanced cancer is often either modified or withheld for the management of elderly patients with advanced cancer for fear of potential toxicity [ 96 - 98 ].

Furthermore, several adverse events associated with sorafenib have been reported [ 92 - 95 , 99 - ]. Especially in elderly patients with advanced HCC who undergo sorafenib therapy, caution is needed for the expected SAEs, because they have higher comorbidity and poorer PS, and SAEs cause treatment discontinuation [ 96 - 98 ]. Wong et al. The median progression-free survival time was similar in the elderly and younger groups 2. Grade 3 or 4 SAEs were observed in They concluded that the survival benefits and overall treatment-related SAEs of sorafenib are comparable in elderly and younger patients with advanced HCC.

Likewise, a study from Italy investigated the impact of age on the effects of sorafenib therapy in patients with HCC and LC [ 97 ]. Grade 3 and 4 SAEs were more frequent in the younger than the older group On the contrary, Morimoto et al. There is one report about the usefulness of a reduced starting dose of sorafenib in elderly patients with advanced HCC [ 98 ]. Quality of life did not show any significant change during the study. The results emphasized the usefulness of reduced dose sorafenib in elderly patients with HCC.

However, there is still a lack of sufficient evidence of clinical usefulness and safety of sorafenib therapy in elderly patients with advanced HCC. Further cumulative clinical evidence is needed. We reviewed the clinical characteristics and outcomes of each therapy in elderly patients with HCC.