hepatocellular carcinoma ( hcc ) is the third - leading cause of cancer mortality worldwide , with an increasing incidence in the west [ 13 ] . while liver transplantation offers the best hope of cure , it is constrained by the availability of donor organs worldwide . survival is limited however by , on average , a 60% long - term rate of intrahepatic recurrence . lipiodol is an ester of fatty acids derived from poppy seed oil that has been used to diagnose and treat hcc . this compound was initially used as a radiological contrast medium and was found to have higher uptake in hcc , relative to normal liver tissue . it contains an iodine moiety , which can be exchanged for iodine ( i ) , to create a compound that delivers targeted , internal , beta , and gamma radiation . early studies showed that injection of i lipiodol into the hepatic artery at angiography could induce tumor necrosis and significantly prolong survival in inoperable patients . the treatment has been used since the 1990s as palliation for hcc , as it is well - tolerated with few complications or side effects [ 8 , 9 ] . long - term data from 2 rcts have not provided evidence for the use of adjuvant i lipiodol after curative resection for hcc . a meta - analysis of all published studies was recently published by the authors of this paper . this suggested a significant survival benefit to adjuvant treatment with i lipiodol , 5 years after surgery . the current study was done to add to the database of patients , who have had this treatment . a retrospective study was undertaken of all patients undergoing a curative liver resection for hcc at royal prince alfred hospital in sydney . patients who received surgery and adjuvant i lipiodol were compared to those who had a resection only . the outcome factors were disease - free survival ( dfs ) and overall survival ( os ) . allocation to ablation , liver resection , or transplant was by milan criteria   in the years 19942003 and by university of california , san francisco criteria   from 2004 onwards . the standard preoperative workup included multiphase , computed tomography ( ct ) , or contrast - enhanced magnetic resonance imaging ( mri ) . major vascular invasion seen on imaging or at laparotomy was not a contraindication to resection . patients were excluded if there were positive microscopic margins and if they died within 30 days . where there was concern about liver function , angiography with hepatic venous pressure gradients ( hvpg ) was used . eligibility for a major liver resection was limited to disease confined to the liver , preserved liver function ( child - pugh grade a ) , and a hvpg less than 12  mmhg [ 14 , 15 ] . those with cirrhosis and poorer liver function were limited to a nonanatomical resection or nonoperative treatment if the former was not possible . , resection was deferred if there were unsuspected metastases or extensive disease in the presence of cirrhosis . allocation to treatment with adjuvant i lipiodol was by surgeon or oncologist preference in consultation with patients . an interventional radiologist gained access to the hepatic artery and the medication was administered by a nuclear medicine physician . a test dose of technetium macroaggregated albumin was given immediately prior to the treatment dose of lipiodol , to assess for arterial anomalies or pulmonary shunting . patients with significant flow to the lungs had their dose adjusted , to minimize the risk of radiation pneumonitis . patients were excluded , in whom there was a significant arterial anomaly predisposing to extrahepatic i deposition . other exclusion criteria were severe allergy to iodine , severe renal disease , pregnancy , and breastfeeding . treatment with the full dose was based on the remnant liver volume in early years and was changed to 2.0  gbq per patient after 2010 . patients spent 1 night in hospital and were discharged home for 6 days of isolation . a gamma camera image was taken prior to discharge to assess for abnormal deposition of i. lugol 's iodine was given 5 days prior to and 1 week following treatment , to protect the thyroid . screening for recurrence was done with ct at 6 months after surgery by the surgeon and then patients were either referred to the liver outpatient clinic or their general practitioner . biannual imaging with ct was standard follow - up . recurrence was defined as a hypervascular lesion on ct with early washout that was confirmed by a second imaging modality . if two imaging modalities were not available , a single study suggesting recurrence associated with a serum alpha - fetoprotein ( afp ) greater than 6.0  iu / ml was diagnostic . the date of recurrence was taken when any of the above criteria were first met . patients who died prior to imaging follow - up were censored at the time of surgery . retrospective data were collected for consecutive patients who had surgery between the years 1993 and 2011 . exclusion criteria were macroscopically positive margins ( n = 6 ) , microscopically positive margins ( n = 23 ) , missing data ( n = 17 ) , and death within 30 days of surgery ( n = 6 ) or if the initial liver resection was performed elsewhere ( n = 9 ) . in addition , four patients were excluded because of atypical pathology showing fibrolamellar hcc ( n = 1 ) , cholangio - hcc ( n = 2 ) , or hcc with a synchronous liver adenocarcinoma ( n = 1 ) . data were collected regarding patient age , sex , ethnicity , and the etiology of underlying chronic liver disease . the presence of major vascular invasion was noted on preoperative imaging or in the operative notes . significant pathological details included resection margin , focality , microvascular invasion , nodal status , grade , preoperative afp , and the presence and degree ( child - pugh class ) of cirrhosis . tumor size was taken as the maximum diameter of the largest tumor nodule , in the resected specimen . the ajcc 2010 stage   was calculated for each patient based on supplied pathological data . the date and variety of palliative treatments were recorded , as well as the calculated activity of i for each patient . statistics were carried out using spss version 23 ( ibm spss , new york , usa ) . those with p value less than or equal to 0.1 on univariate analysis were included in a multivariate analysis . there were 52 patients , who had a surgical resection only , and 58 patients had a resection and adjuvant , i lipiodol . the baseline demographics , tumor characteristics , and chronic liver disease status of these patients are shown in table 1 . the median activity of i lipiodol administered was 1.8  gbq ( range 0.93.6 ) and treatment was administered at a median of 86 days after surgery . age , sex ratio , tumor size , multifocality , microvascular invasion , differentiation , margin status , etiology , and stage of chronic liver disease were similar , in both groups . significantly more patients of asian ethnicity received adjuvant treatment with lipiodol ( 28 versus 40 , p = 0.046 ) . a second patient was observed to have asymptomatic uptake in the muscles of the lower limb . both patients were observed as inpatients , and the first was given oral proton pump inhibitors . the median follow - up period was 66 months ( 95% ci , 3696 months ) . during this time , there were 35 ( 67% ) recurrences in the surgery only group and 38 ( 66% ) recurrences in the adjuvant i lipiodol group ( hr 0.93 , 95% ci 0.591.5 , p = 0.75 ) . the number of intrahepatic recurrences was 29 ( 56% ) in the surgery only group and 33 ( 57% ) in the adjuvant group . the median dfs was 30 ( 95% ci , 2238 ) months in the surgery group and 25 ( 95% ci , 1436 ) months in the surgery and i lipiodol group ( p = 0.74 ) . the 1- , 3- , and 5-year dfs were 72% ( 95% ci , 6084% ) , 43% ( 95% ci , 2957% ) , and 26% ( 95% ci , 1240% ) in the surgery group and 70% ( 95% ci , 5882% ) , 39% ( 95% ci , 2553% ) , and 29% ( 95% ci , 1543% ) in the adjuvant lipiodol group ( figure 1 ) . twenty - five ( 48% ) patients died in the surgery only group and 20 ( 34% ) died in the adjuvant lipiodol group ( hr 0.66 , 95% ci , 0.371.2 , p = 0.16 , figure 2 ) . the median overall survival for the surgery only group was 63 ( 95% ci , 18107 ) months and median survival time was not reached in the adjuvant lipiodol group ( p = 0.16 ) . the 1- , 3- , and 5-year os were 83% ( 95% ci , 7393% ) , 64% ( 95% ci , 5078% ) , and 52% ( 95% ci , 3668% ) in the surgery group and 96% ( 95% ci , 92100% ) , 72% ( 95% ci , 6084% ) , and 61% ( 95% ci , 4775% ) in the adjuvant lipiodol group .   table 2 shows the treatments given on diagnosis of disease recurrence . patients in the treatment group had significantly more repeat liver resections ( 13 versus 4 ) , on diagnosis of intrahepatic recurrence ( p = 0.034 ) . conversely , patients in the control group were more likely to have medical treatments ( i.e. , either sorafenib , sandostatin , temozolomide , or thalidomide ) than the treatment group ( 9 versus 1 , p = 0.005 ) on diagnosis of recurrence . factors associated with survival included ajcc stage ( p = 0.001 ) , multifocality ( p = 0.001 ) , and microvascular invasion ( p = 0.001 , table 3 ) . multivariate analysis showed that there was no variable that was an independent predictor for poorer dfs associated with resection ( table 4 ) . univariate cox regression analysis of the same variables affecting os is shown in table 3 . factors associated with survival were ajcc stage ( p = 0.001 ) , differentiation ( p = 0.001 ) , multifocality ( p = 0.001 ) , and microvascular invasion ( p = 0.001 ) . these variables and multifocality ( hr 3.5 , 95% ci 1.67.6 ) , microvascular invasion ( hr 2.6 , 95% ci 1.24.4 ) , and differentiation ( hr 2.2 , 95% ci 1.33.7 ) were associated with poorer os ( table 4 ) . this study does not provide evidence that adjuvant i lipiodol alters dfs or os after resection of hcc . the cohort is the largest sample studied to date , and the median follow - up is just greater than 5 years . the findings suggest that the role of adjuvant treatment may not be as broad as initially suggested by the landmark hong kong trial ( hkt ) . the early results of the hkt provided strong evidence that patients given a single dose of adjuvant i lipiodol after resection had longer dfs and os compared to those who only had resection . with a median follow - up of 34 months at initial reporting , the hazard ratio ( hr ) for dfs was 2.7 ( 95% ci 1.07.1 ) and os 3.1 ( 1.09.9 ) . thus there was a significant survival benefit , although the wide confidence intervals suggested the strength of this effect was uncertain . a follow - up paper at 66 months showed this survival benefit disappeared at 8 years after randomization . there was evidence , however , that i lipiodol significantly delayed the onset of intrahepatic recurrence from 7 to 19 months . the hkt stopped accruing patients early due to the strong survival benefit seen on interim analysis . ultimately it was underpowered ; hence the failure to detect a long - term benefit may have been due to type 2 error . a recent , large , multicentre rct from singapore ( designated ahcc03 ) also found an insignificant benefit to survival , after a median follow - up of 80 months . although it remains the largest prospective study to date ( n = 103 ) , it too failed to accrue enough subjects and was powered at 50% . the authors concluded that treatment may prolong survival , but the trial itself could not demonstrate this . hence the data from rcts do not support a survival benefit with adjuvant i lipiodol . on the other hand , multiple retrospective studies of adjuvant lipiodol have demonstrated significantly improved dfs in patients treated with adjuvant i lipiodol [ 2 , 23 , 24 ] . the populations studied in these trials were different from the rcts in that more advanced tumours , higher grade cirrhosis , and macroscopically positive margins were included in the analyses . it is unclear why these populations , which objectively have a worse prognosis , have better dfs after treatment with i lipiodol . the results of the current paper are different from the previously published retrospective studies in that no significant benefit to survival was shown . the current study had patients with a relatively high rate of microvascular invasion ( 34% ) , similar to the ahcc03 trial ( 28% ) . this is significantly greater than the hkt ( 4.6% ) , and this may be the factor that renders adjuvant treatment with i lipiodol less effective . it is conceivable that a targeted , arterially delivered therapy may be less effective , if tumour cells have already spread into the bloodstream . significantly more patients in the treatment arm had repeat liver resections for intrahepatic recurrence . on the other hand , the study institution patients referred for adjuvant lipiodol treatment are often followed up by surgeons , while other patients are seen by oncologists . significantly more patients of asian ethnicity were referred for treatment with i lipiodol as well ; however ethnicity was not found to be a significant covariate on either univariate or multivariate regression . furthermore , the aetiology of chronic liver disease was similar in both groups , despite the racial difference . it is unclear why more asian patients would be referred for treatment with lipiodol and it may represent bias in referrer or patient preference . results from this study do not support the routine use of adjuvant , radiolabelled lipiodol following excision of hcc to prolong survival . a high rate of microvascular invasion may suggest that treatment with adjuvant lipiodol is less likely to be effective .
background . survival after liver resection for hcc is compromised by a high rate of intrahepatic recurrence . 
 adjuvant treatment with a single , postoperative dose of intra - arterial i131 lipiodol has shown promise , as a means of prolonging disease - free survival ( dfs ) . methodology . 
 dfs and overall survival ( os ) after a single dose of postoperative i131 lipiodol were compared to liver resection alone , for treatment of hepatocellular carcinoma ( hcc ) . 
 data were collected retrospectively for patients who had a curative resection for hcc between december 1993 and september 2011 . 
 seventy - two patients were given i131 lipiodol after surgery and 70 patients had surgery alone . 
 results . 
 the dfs at 1 , 3 , and 5 years was 72% , 43% , and 26% in the surgery group and 70% , 39% , and 29% in the adjuvant i131 lipiodol group ( p = 0.75 ) . 
 the 1- , 3- , and 5-year os was 83% , 64% , and 52% in the surgery group and 96% , 72% , and 61% in the adjuvant i131 lipiodol group ( p = 0.16 ) . 
 conclusion . 
 this retrospective study has found no significant benefit to survival , after adjuvant treatment with i131 lipiodol .