hepatocellular carcinoma ( hcc ) in adult men is the 5th most frequently diagnosed cancer worldwide , and is the 2nd leading cause of cancer - related death in the world . in adult women , it is the 7th most commonly diagnosed cancer and the 6th leading cause of cancer death . in the united states ( us ) , the annual incidence of hcc was at least 6 per 100,000 in 2010 . hcc is typically an aggressive tumor that arises in the setting of underlying chronic liver disease in most cases . although the preferred therapy is surgical resection , the majority of patients are not eligible because of tumor extent or underlying liver dysfunction . for patients who are not eligible for resection or liver transplantation , treatment options include percutaneous ethanol injection ( pei ) , radiofrequency ablation ( rfa ) , transarterial chemoembolization ( tace ) , transarterial radioembolization ( tare ) , radiotherapy ( rt ) , and doxorubicin . pei and rfa are considered curative treatments ( cts ) for early - stage hcc . the selection of treatment is determined by the severity of underlying liver disease , the size and distribution of the intrahepatic tumors , the vascular supply , and the patient 's overall performance status . in taiwan , hcc is still the 2nd leading cause of death from cancer . the etiology differs from those in the west , as in asia , it is more frequently related to hepatitis b virus ( hbv ) infection . since hbv infections are endemic in asia , more than 80% of cases are encountered in this region . a large proportion of the population is at risk of developing chronic liver disease and , therefore , hcc . in addition to surgery , therapeutic modalities such as pei and rfa are also potentially curative . it should be noted that the term  curative  in this sense is meant to imply  resulting in complete local control of the original lesion .  recently , 2 cochrane analyses concluded that there was insufficient evidence to determine whether segmental resection was more effective than rfa or pei because of the limited quality of the evidence . on the contrary , rt , chemotherapy , and liver tace should be considered  palliative ,  which implies that it statin use for preventing hcc risk was reported in hbv and hepatitis c virus ( hcv ) carriers . however , it is well - known for preventive use , not for treatment or an additive effect with other medical treatments . numerous previous epidemiologic studies showed the chemopreventive effects on the hcc risk , and some basic studies demonstrated the mechanism of the anticancer effect on hcc cells or animal models . but to the present , there are no clinical or epidemiologic data clarifying the effect of statins and cts such as surgery , rfa , or pei . if hcc patients receive cts ( rfa , pei , or surgery ) , statin use might still be a question . our study estimated the effect of statin use in hcc patients who received different cts and attempted to answer the aforementioned question . two cohorts from the taiwan national health insurance ( nhi ) database and cancer registry databases were combined for the analysis . hcc patients treated from january 1 , 2001 to december 31 , 2010 were included in the study . the follow - up duration was from the index day to december 31 , 2012 . research - oriented datasets were released through the collaboration center of health information application ( cchia ) that include all of the original claims data and registration files for beneficiaries enrolled under the cchia from the bureau of nhi in taiwan . more than 99% of the population of taiwan was covered in 2012 , and taiwan launched the cchia program in 1995 . therefore , the researchers have been allowed to trace all utilizations of medical services from cchia for all hcc patients in taiwan . our protocols were reviewed and approved by the institutional review board at taipei medical university ( tmu - jirb no . there is rich cancer information in the cancer registry database such as the clinical stage , treatment modalities , pathologic data , and death from specific diseases . all enrolled patients were confirmed by the nhi and cchia , and fresh hcc patients had no other cancers or distant metastases . the inclusion criteria were having hbv carrier - related or -unrelated hcc ( international classification of diseases [ icd ] , 9th revision , clinical modification codes [ icd-9 codes ] 070.2 , 070.3 , and v02.61 ) ( identified according to the icd-9 , clinical modification [ icd-9-cm ] codes 155.0 and 155.2 , and the icd for oncology , 3rd edition [ icd - o-3 ] codes c22.0 and c22.1 ) , being aged > 20 years , and having undergone surgical resection , rfa , or pei as a ct . all hbv subjects without a subsequent outpatient visit or emergency visit for a diagnosis of hbv within 12 months were excluded because they were considered not to have chronic hepatitis disease . the index day of hcc was the beginning date of the 1st treatment for hcc patients , such as surgical resection , rfa , pei , tace , rt , or chemotherapy . exclusion criteria were : diagnosed with cancer before hcc was confirmed , undergone tace , rt , or chemotherapy as palliative - intent treatment , a liver transplantation , one 's gender not known , distant metastasis , hcc has been diagnosed before hbv , statin use only before hcc was diagnosed , and younger than 20 years . the aim of our study was to evaluate the effects of statin use in hcc patients who received ct such as surgery , rfa , or pei . secondary endpoints were survival benefits if statins were used in surgical treatment or nonsurgical treatment . the defined daily dose recommended by the who is a unit for measuring a prescribed amount of a drug . it is the assumed average maintenance dose per day of a drug consumed for its main indication in adults . to examine the dose - effect relationship , we categorized statin into 4 groups in each cohort as our previous protocols . possible confounding factors of comorbidities included hbv ( icd-9 0702 and 0703 , and a - code v0261 ) , hcv ( icd-9 07041 , 07044 , 07051 , and 07054 , and a - code v0262 and 0707 ) , other viral hepatitis ( icd-9 , and a - code v0269 ) , alcohol - related disease ( icd-9 291 , 303 , 305 , 5710 , 5711 , 5712 , and 5713 , and a - code a213 , a215 , and a347 ) , acute coronary syndrome ( icd-9 410414 ) , cerebrovascular accident ( icd-9 430438 ) , chronic obstructive pulmonary disease ( copd ) ( icd-9 490496 ) , diabetes mellitus ( icd-9 250 , and a - code a181 ) , liver cirrhosis ( icd-9 571.2 , 571.5 , 571.6 , 572.2 , 572.3 , 572.4 , 572.8 , and 573.0 ) , liver failure ( icd-9 570 ) , renal failure ( icd-9 584586 ) , hypertension ( icd-9 401405 ) , hyperlipidemia ( icd-9 272.0272.2 ) , and peptic ulcers ( icd-9 531534 ) . comorbidities were included within 6 months before and after the index date of hcc , as the main diagnosis code for the 1st admission or more than 2 repeated main diagnosis codes in an outpatient department . the age , gender , american joint committee on cancer clinical cancer stage , comorbidity condition , metformin , aspirin , acetylcholinesterase ( ace ) inhibitors , and anti - hbv or anti - hcv drugs were also adjusted for or stratified in the analysis . the cumulative incidence function of death was estimated by the kaplan  meier method , and statin use and nonuse among ct modalities were compared by a log - rank test . the time dependent cox proportional hazard model was used to calculate hazard ratios ( hrs ) for death among hbv - related hcc patients with ct modalities with / without statin use . the hrs were adjusted for age , gender , baseline comorbidities , metformin , aspirin , ace inhibitors , anti - hbv or anti - hcv drugs , and clinical stage in the multivariate analysis . a stratified analysis was conducted to evaluate the effect of statin use between hbv- and non - hbv - related hcc patients of a similar age or clinical stage . 9.3 ( sas , cary , nc ) . a value of p  <  0.05 was considered the 2-tailed significance level in total , 18,892 hcc patients were included in the study , and the mean follow - up duration was 1.74 years . there were 708 patients in the group with ct and statin use , and 6438 patients in the group with ct without statin use ( table 1 ) . as to cts , 5372 subjects received surgical treatment , and 1774 received nonsurgical treatments . there were 226 patients in the group with palliative treatment and statin use , and 11,520 patients in the group with palliative treatment without statin use ( table 1 ) . in the statin use group , the mean age was higher than that in the nonstatin group , and the follow - up time was longer in the statin use group . aspirin and metformin were more frequently used in the statin use group . as to comorbidities , there were more - complicated comorbidities in the statin use group , such as liver cirrhosis , hypertension , diabetes , copd , acute coronary syndrome , and cerebral vascular disease . hcc deaths ( disease - specific survival ) in the nonstatin use group were significant higher than those in the statin use group . in a further analysis , we estimated the risks of hcc - specific deaths and all - cause deaths according to the statin status and hcc treatment stratified by the american joint committee on cancer stage ( table 2 ) . baseline characteristics of hcc patients who did not receive palliative treatment by statin status . risk of hcc deaths and all - cause deaths by the statin status and hcc treatment . as shown in table 2 , hcc patients who received treatment with statin use had a lower death rate per 1000 person - years in all stages compared to patients who received treatment without statin use . in order to understand the effect of statin use in hbv / non - hbv - related hcc patients with different treatments , hcc groups were separated into hbv - related hcc and hbv - unrelated hcc cases as shown in table 3 . our data demonstrated that after the time - dependent cox proportional hr was adjusted for age , stage , gender , nucleoside / nucleotide analogues , interferons , aspirin , metformin , cirrhosis , liver failure , hypertension , diabetes , copd , acute coronary syndrome , and cerebral vascular disease , surgery was significantly better in all - cause deaths in hbv - related hcc and hbv - unrelated hcc . the adjusted hrs ( ahrs ) of all - cause deaths increased in hcc patients who received rfa / pei compared to those who received surgery ( p  <  0.0001 and p  <  0.05 , with ahrs of 1.81 and 1.16 , respectively , for hbv or non - hbv hcc ) . figure 1  a shows kaplan  meier survival curves in different stages with surgical or nonsurgical ( rfa / pei ) cts . our data showed that surgery was significantly superior to nonsurgical treatments in the overall survival of hcc patients ( p  <  0.0001 , p  <  0.0001 , and p = 0.005 , respectively , for stages i  iii ) . in all stages , however , if hcc patients received nonsurgical cts with statins , the advantages of surgery disappeared . regardless of whether rfa / pei with statin was compared with surgery with / without statins , the all - cause death risk and hcc risk did not statistically significantly differ ( table 3 ) . 1  b still shows better overall survival with surgery and statin use compared to rfa / pei and statin use ( p = 0.0003 and p = 0.019 , respectively , for stages i and iii ) ; fig . 1 d demonstrates that overall survival was statistically equal if hcc patients received rfa / pei and statins compared to surgery alone without statins . risk of all - cause and disease - specific deaths of hcc patients by curative treatment and statin status ( time - dependent ) . ( b ) surgery  +  statins versus rfa / pei  +  statins . ( b ) surgery  +  statins versus rfa / pei  +  statins . ( b ) surgery  +  statins versus rfa / pei  +  statins . ( b ) surgery  +  statins versus rfa / pei  +  statins . pei = percutaneous ethanol injection , rfa = radiofrequency ablation . as to non - ct for hcc patients , statins may have an adjuvant effect in hcc patients even in those who received non - cts ( table 3 ) . the ahrs of all - cause deaths and hcc deaths were lower in hcc patients who received palliative treatment with statin use compared to those who received no treatment ( ahrs of 0.45 , 0.160 , 0.590 , and 0.70 , respectively , for stages i  iv ) . the cumulative incidence function of death was determined by the kaplan  meier method ( fig . 1  c ) , and statin use and nonuse among non - ct modalities were compared by a log - rank test . treatment options are divided into surgical therapies ( resection ) and nonsurgical therapies ( pei , rfa , tace , rt , and systemic therapy ) . pei and rfa are considered cts for hcc , whereas tace , rt , and systemic chemotherapy are standards of care for intermediate stages . the benefits of rfa relative to surgical resection for potentially resectable hcc were addressed in 3 randomized trials . a meta - analysis of all 3 trials done by weis et al concluded that there was moderate quality evidence from 2 trials with a low risk of bias that hepatic resection was significantly superior to rfa in terms of overall ( hr 0.56 , 95% confidence interval [ ci ] 0.400.78 ) and 2-year survival ( hr 0.38 , 95% ci 0.170.84 ) . however , when data from the 3rd trial were added , the difference became statistically nonsignificant ( for overall survival , hr 0.71 , 95% ci 0.441.15 ) . a later cochrane analysis concluded that there was insufficient evidence to determine whether segmental resection was more effective than pei because of the limited quality of the evidence . despite those inconclusive data , our outcomes demonstrated that surgery was preferable and were compatible with huang and chen studies , in that the ahrs of all - cause deaths increased in hcc patients who received rfa / pei compared to those who received surgery ( p  <  0.0001 and p  <  0.05 , with ahrs of 1.81 and 1.16 , respectively , for hbv or non - hbv hcc ) . figure 1  a shows that the kaplan  meier survival curve for each stage with surgery had a statistically longer survival time compared to no surgery ( rfa / pei ) . the protective effects of statins or metformin in a previous study of hcc were reported by chen et al . possible mechanisms for statin use decreasing the risk of cancer include : inhibition of the mevalonate pathway , enhancing tumor - specific apoptosis , inhibition of the proteasome pathway , and inhibition of hepatitis virus replication and cholesterol synthesis . our study demonstrated that statin use resulted in greater reductions in the all - cause death risk and hcc death risk in hbv - related hcc compared to hbv - unrelated hcc with non - cts . the ahrs of all - cause deaths and hcc deaths were lower in hcc patients who received palliative treatment with statin use compared to those who received no treatment ( ahrs of 0.45 , 0.160 , 0.590 , and 0.70 , respectively , for stages i  iv ) ( table 3 ) . our outcomes might echo previous studies which reported that statins can inhibit cholesterol synthesis and hepatitis virus replication , thus causing the risk of hcc recurrence to decrease and be transferred to survival benefits . in this study understanding the effects of additional statin use as adjuvant therapy for different therapies in hbv- or non - hbv - related hcc patients could be valuable . the other is whether the size and location of the tumor relative to the patient 's underlying liver function will permit resection without excess morbidity and mortality . among the reasons for a tumor being unresectable are the extent of intrahepatic disease , extrahepatic extension , an inadequate functional hepatic reserve , and involvement of the confluence of the portal or hepatic veins . rfa or pei has been used in patients who do not meet the resectability criteria for hcc and yet are candidates for a liver - directed procedure based on the presence of liver - only disease . unfortunately , the 3 major randomized controlled trials , a meta - analysis study , and our study all showed inferior outcomes with rfa or pei . finding a safe , statin use reduced the risk for hcc in hbv- or hcv - infected patients in a dose - dependent manner an shown by tsan et al studies . we estimated the outcomes of statins effects with surgical or nonsurgical cts in hcc patients . to our best knowledge , this is the 1st article to compare statins effects in surgical and nonsurgical cts in hcc patients . in table 3 , surgery was a superior therapy for hcc patients as it decreased the all - cause death risk over time as determined by the cox proportional hr adjusted for age , stage , gender , nucleoside / nucleotide analogues , interferons , aspirin , metformin , cirrhosis , liver failure , hypertension , diabetes , copd , acute coronary syndrome , and cerebral vascular disease . figure 1  a also shows a better overall survival curve with surgery in each stage and for nonstratified stages of hcc patients . after statin use with rfa / pei considered nonsurgical cts for hcc patients compared to surgery alone , no statistically significant findings were obvious ( table 3 ) . figure 1  d also shows no significant overall survival benefits in each stage of hcc patients with surgery alone or nonsurgical cts . this outcome implies that rfa / pei  +  statins might be an alternative choice for hcc patients who do not meet the criteria to receive surgery . statins herein improved the survival of hcc patients with rfa / pei and statin use . the outcomes seemed comparable to surgery alone . in our past study ( unpublished ) , palliative therapeutic methods combined with statin use resulted in a lowest risk of death . statins prolonged the survival of patients with advanced hcc who received palliative treatment , suggesting their value as an adjuvant treatment . a better time for palliative treatment with statin use is in early - stage hcc with the greatest reduction in deaths . for patients who can not tolerate palliative treatments , statin use only might be a possible mortality - reducing drug , especially in hbv - related early - stage hcc patients ( > 50% reduction in hcc deaths ) . analogously , in the current data , table 3 also shows that the ahrs of all - cause deaths and hcc deaths were lower in hcc patients who received palliative treatment with statin use compared to those who received no treatment ( ahrs of 0.45 , 0.160 , 0.590 , and 0.70 , respectively , for stages i  iv ) . the cumulative incidence function of death was determined by the kaplan  meier method ( fig . 1  c ) , and statin use and nonuse among non - ct modalities were compared by a log - rank test . only one - half of patients initially thought to be resectable and referred for surgery actually have resectable tumors . unfortunately , most rcts showed that rfa and pei had inferior results compared to surgery . in our study , the ahrs of all - cause deaths increased in hcc patients who received rfa / pei compared to those who received surgery ( p  <  0.0001 and p  <  0.05 , with ahrs of 1.81 and 1.16 , respectively , for hbv and non - hbv hcc ) . figure 1  a shows that surgery was significantly superior to nonsurgical treatments in the overall survival of hcc patients ( p  <  0.0001 , p  <  0.0001 , and p = 0.005 , respectively , for stages i  iii ) . in a nonstage - stratified analysis , however , if hcc patients received nonsurgical cts ( rfa or pei ) with statins , the advantages of surgery disappeared . there are few articles that discussed how to improve outcomes of nonsurgical , locoregional therapies for hcc patients . our results suggest that if a patient can not tolerate surgical resection , rfa or pei might be insufficient . the addition of statin use with rfa or pei could improve outcomes and increase the survival rate of hcc patients , for both hbv and non - hbv patients . limitations of this study are that the actual statin dose and duration were not measured , so the actual dose - response effect was unclear . different kinds of statins were not separated in the analysis , and the potential effects of specific statins are unknown . ultimately , it will take a large randomized trial with a suitable regimen in well - selected patients comparing standard approaches to obtain this important information . additionally , the diagnoses of hcc and all other comorbid conditions were completely dependent on icd codes . nonetheless , charts and interview patients have been randomly reviewed by the nhi bureau of taiwan and cchia to verify the accuracy of the diagnoses . subsequent heavy penalties for malpractice or discrepancies would be done when hospitals with outlier chargers or practice may undergo an audit . finally , there are no information on tobacco use , alcohol consumption , dietary habits , socioeconomic status , laboratory data , educational level , or the body - mass index in the databases , which may also be risk factors in the survival analysis . however , these limitations are unlikely to have compromised the results , given the magnitude and statistical significance of the observed effects in the current study . if hcc patients can not meet the surgical criteria , the addition of statin use with rfa or pei might improve their survival .