Transcatheter arterial chemo-lipiodol infusion for unresectable hepatocellular carcinoma in 96 high-risk patients

Materials and methods From January 2005 to April 2009, 96 patients underwent TACL. All patients had diffuse, infiltrative or multifocal tumours. Twenty-nine (30%) patients had an increased serum bilirubin level (≥2 mg/dl), and 75 patients (78%) had a low serum albumin level (<3.5 mg/dl). The Child–Pugh (CP) score was 9 or more in 13 (14%) patients. Sixty-five patients (68%) had major portal vein occlusion. Sixteen patients (17%) had biliary dilatation. Results TACL was technically successful in all patients. After TACL, 18 (19%) of the 96 patients showed tumour response using computed tomography (CT) criteria. The 30 day mortality and morbidity rates were 1 and 2%, respectively. The median survival period was 8.6 months, and the overall 6 month, 1, 2, and 3 year survival rates were 59, 44, 26, and 15%, respectively. Portal vein occlusion ( p < 0.001) was the only significant risk factor associated with the length of the survival period after TACL, whereas the CP score ( p = 0.498), serum bilirubin level ( p = 0.153), serum albumin level ( p = 0.399), and biliary obstruction ( p = 0.636) had no significant effect. Conclusions TACL can be performed safely in high risk HCC patients resulting in a median survival rate of 8.6 months in the present series. Introduction Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and is responsible for 500,000 deaths annually. 1 In addition, HCC is the fourth most common cause of cancer-related death because of its very poor prognosis. 2 Surgical treatments, including hepatic resection and liver transplantation, are considered the only curative treatments for HCC; however, only 30% of patients are able to benefit from this because of their advanced cancer stage at the time of diagnosis or the likely insufficient functioning of the remaining liver. 3,4 For palliative purposes, transcatheter arterial chemoembolization (TACE) is indicated for patients with unresectable HCC. As TACE increases the survival rates in patients with unresectable HCC, it is currently considered the primary therapy. 5–7 However, this treatment is not indicated for those with poor hepatic reserve, advanced tumour stage with major portal vein (PV) invasion or thrombosis, and/or biliary obstruction, as these factors have been associated with a poor prognosis and increased complications following TACE. 8–11 Transcatheter arterial chemo-infusion (TACI) is considered to be an option for these patients given its possible lower toxicity to the surrounding liver tissue with infusion alone. 4,5 Nevertheless, several studies have demonstrated that TACI has resulted in poor survival and tumour response rate when patients had such risk factors in the advanced cancer stage. 12–14 Yoshikawa et al. 15 indicated that transcatheter arterial chemo-lipiodol infusion (TACL) was more effective in tumour response and survival than TACI alone for the treatment of patients with unresectable HCC, which were in high-risk or non-high-risk groups. As by infusion of a lipiodol emulsion mixed with an anticancer drug via the hepatic artery, micro-embolization of tumour vessels and slow release of the anticancer drug from the lipiodol were both achieved. 15 Therefore, it was hypothesized that TACL may be a successful alternative for the palliative treatment of high-risk HCC patients. The purpose of the present study was to evaluate the clinical effectiveness of TACL in 96 high-risk patients with unresectable HCC. Materials and methods Patient population The study protocol was approved by our institutional review board, and informed consent was obtained for TACL. A retrospective review of the electronic medical database from January 2005 to April 2009, revealed that a total of 3349 patients with HCC underwent hepatic intra-arterial chemotherapy with or without embolization. Among these patients, a total of 96 high-risk patients underwent TACL. These patients included 79 men and 17 women ranging in age from 35–78 years (mean, 56.8 ± 9.66 years). Before the procedure, contrast-enhanced computed tomography (CT) with or without magnetic resonance imaging (MRI) was performed on all patients to evaluate the characteristics of the tumour. The patient and tumour characteristics identified in the present study are summarized in Table 1 . Patients were considered to be at high risk if they had one or more of the following risk factors: increased serum bilirubin level (≥2 mg/dl); low serum albumin level (<3.5 mg/dl); a Child–Pugh (CP) score of at least 9; multifocal and diffuse infiltrative disease; major PV thrombosis; and/or occlusion or biliary obstruction. 11 The distribution of the risk factors in the high-risk patient group was as follows ( Table 2 ), all patients had diffuse, infiltrative or multifocal tumours, thus indicating that the entire study group had at least one high-risk factor. Twenty-nine (30%) patients had an increased serum bilirubin level (≥2 mg/dl), the mean bilirubin level was 1.8 mg/dl (range 0.6–6.9 mg/dl). Of the 96 patients, 75 (78%) had a low serum albumin level at the time of their first TACL procedure. Seventy-four patients (77%) had liver cirrhosis. Forty-eight (50%) patients were CP class A, 43 (45%) patients were CP class B, and five (5%) were CP class C. The CP score was <9 in 83 (86%) patients and ≥9 in 13 (14%) patients. A total of 65 patients (68%) had compromised hepatopetal flow caused by the major portal vein (right, left, or main) occlusion/thrombosis. Sixteen patients (17%) had intrahepatic or extrahepatic biliary dilation. Six patients had only one risk factor, 25 patients had two risk factors, 36 patients had three risk factors, 17 patients had four risk factors, nine patients had five risk factors, and three patients had six risk factors. Transcatheter arterial chemo-lipiodol infusion Superior mesenteric and common hepatic arteriographies were initially performed to assess the anatomy, tumour burden, and portal vein patency. Cisplatin was then infused into the hepatic artery for 15 min. The infused dose of cisplatin was 2 mg/kg of each patient's weight. After catheterization of the feeding artery, an emulsion of iodized oil (lipiodol, Laboratoire Guerbet, Cedex, France) and cisplatin with a 1:1 ratio, was infused into the feeding arteries. In patients with extensive tumour, the emulsion was administered at the level of the right or left lobar hepatic artery. Follow-up and study endpoint Follow-up physical examination and laboratory tests, i.e., blood count and liver function tests, were performed at 1 month intervals. Tumour response was evaluated based on CT examinations obtained 1–3 months (mean 1.1 ± 0.37 months) after TACL. Using electronic callipers, measurement of tumour size was performed based on the consensus of two radiologists (H.J.Y., J.H.K) as the maximum diameter of the largest targeted index lesions, as proposed by the Response Evaluation Criteria in Solid Tumours. 16,17 In addition, necrosis (recognized by confluent lipiodol distribution or absence of enhancement) of the tumour was evaluated by two radiologists (J.H.K., H.K.Y) based on CT examinations after TACE because Response Evaluation Criteria in Solid Tumours alone do not reflect changes in tumour viability that may be associated with tumour response ( Table 3 ). 19 Repeated treatment was indicated when new or residual tumour was detected. Treatment was terminated if a patient could not tolerate the procedure because of a decline in their clinical status. The primary endpoint was survival. The secondary endpoint was the occurrence of mortality or morbidity after treatment. Definition and data analysis Technical success was defined as successful catheter placement and administration of selected agents. Tumour response was defined as tumour reduction in the maximal diameter by ≥30%, or significant (>50%) tumour necrosis despite no significant tumour size decrease. 18,19 The morbidity and mortality rates were evaluated after TACL. Morbidity was defined as clinical signs of subacute liver failure, i.e., encephalopathy or new/worsening of ascites, formation of a liver abscess or bilioma, acute renal failure, and/or hepatic infarction within 6 weeks after TACL. 11 Mortality was defined as death within 30 days of TACL. Post-embolization syndrome, including transient fever, nausea, vomiting, or abdominal pain, was not regarded as morbidity. The overall patient survival period was measured in months from the time of the initial TACL procedure. The following risk factors for the patient survival period after TACL were evaluated: serum bilirubin level; serum albumin level; CP score; major PV thrombosis; and/or occlusion or biliary obstruction. The cumulative survival curves were created according to the Kaplan–Meier method and were compared with the results of the log-rank test. Statistical analysis was conducted using SPSS software (version 14.0; SPSS, Chicago, IL, USA), and a two-sided p- value of less than 0.05 was considered to indicate statistical significance. Results Tumour response TACL was successful in all patients (100% technical success rate). There was a median of two sessions per patient (range 1–16 sessions). After the procedure, seven (7%) patients showed partial radiographic response, i.e., tumour reduction in maximal diameter by ≥30%, ( Fig. 1 ) and 11 (12%) patients showed significant tumour necrosis despite no significant decrease of tumour size. Fifty-eight (60%) patients showed no radiographic response to the procedure, and 20 (21%) patients showed progression of the tumour despite the therapy. Therefore, tumour response was achieved in 19% of the patients (18 of 96) in the present study. Mortality and morbidity Overall, 16 (17%) patients experienced nausea, vomiting, abdominal pain, or fever after the procedure; these symptoms resolved within 3 days. One patient died within 30 days after the procedure; this patient died of variceal bleeding unrelated to TACL. This patient had five risk factors at the time of his first TACL procedure. He had multifocal tumours, an increased serum bilirubin, and low serum albumin level (4.6 and 2.9 mg/dl, respectively), high CP score (10), and PV occlusion. Therefore, the 30 day mortality rate was 1%. Two patients (2%) experienced procedure-related morbidity. One patient had acute renal failure but recovered with medical treatment. After the acute renal failure had subsided, subacute hepatic failure, as demonstrated by ascites, occurred and as the patient's condition continued to worsen, supportive care was required. However, the patient died 2 months after undergoing the first TACL procedure. This patient had also five risk factors when he underwent TACL. The patient had infiltrative tumours, an increased serum bilirubin and low serum albumin level (2.6 and 2.7 mg/dl, respectively), high CP score (9), and PV occlusion. In the other patient, the serum bilirubin level increased to 8.7 mg/dl after TACL. His initial bilirubin level was 3.7 mg/dl. Physicians decided to observe this patient and to check the serum bilirubin level on a daily basis as part of medical treatment during hospitalization. However, after being hospitalized for 14 days, the patient's serum bilirubin level did not improve and was 8.5 mg/dl before he was released from the hospital. The patient died 41 days after TACL. He had four risk factors at the time of his first TACL procedure. He had infiltrative tumours, an increased serum bilirubin and low serum albumin level (3.7 and 2.4 mg/dl, respectively), and high CP score (10). Neither hepatic necrosis nor abscess occurred in any patient. Survival and factors associated with the patient survival period During the median follow-up period of 7.6 months (range 30 days to 46 months) after TACL, 77 patients died and 19 remained alive. The median survival period was 8.6 months [95% confidence interval (Cl), 4.9–12.2]. The overall 6-month, 1, 2, and 3-year survival rates were 59, 44, 26, and 15%, respectively ( Fig. 2 ). The Kaplan–Meier curve for the survival period after TACL according to the risk factors, is shown in Fig. 3 . Portal vein invasion ( p < 0.001) was the only significant risk factor associated with the length of the survival period after TACL for high-risk HCC patients, although the Child–Pugh score ( p = 0.498), serum bilirubin level ( p = 0.153), serum albumin level ( p = 0.399), and biliary obstruction ( p = 0.636) had no significant effect. Discussion The prognosis is very poor for high-risk patients with untreated HCC, with an overall median survival rate of 1–3.5 months. 20,21 TACE has been shown to prolong the survival period, although this benefit is not uniformly seen in all patients. Most previous analyses have indicated that advanced disease results in major PV invasion or thrombosis, poor hepatic reserve with increased serum bilirubin levels, and the presence of significant intrahepatic biliary dilation, all of which are considered as risk factors for adverse outcomes and/or poor survival after TACE. 1,6–11 TACL is a variation of TACE that also delivers high concentrations of chemotherapeutic agents to tumour tissue, but differs in that embolization using solid particles is not performed. In TACL, the chemotherapeutic solutions are emulsified in lipiodol, which serves to concentrate its uptake in the treated tumours. Lipiodol accumulates in tumours and is then retained for a long period of time. 22,23 By infusing a lipiodol emulsion mixed with an anticancer drug via the hepatic artery, micro-embolization of tumour vessels and slow release of the anticancer drug are expected. This method is the alternative modality used in many Asian countries, but to date only a few studies have examined the clinical outcome of this technique. 12–15 Moreover, to the authors' knowledge, there have only been a few studies that have used TACL for unresectable HCC, especially in high-risk patients. The present study examines the tumour response rates, procedure-related complication rates, and survival rates in a large number of high-risk patients with unresectable HCC who were treated with TACL. The present study found that TACL is a safe treatment option for unresectable HCC patients with risk factors. The procedure-related mortality was 1% (one of 96 patients) following TACL. The morbidity rate was 2% (two of 96 patients), and complications were adequately managed by medical treatment. No patient experienced hepatic infarction or abscess. TACE may produce more effective tumour necrosis than TACL; however, TACE can add to the rate of adverse events by damaging the non-tumour portion of the liver due to its intense embolization. 24 In the present study, 50% of the participating patients were CP class B or C and 68% had main PV obstruction; however, serious complications following TACL occurred in only two of the patients (2%) in the present study, which represents far lower rates than those reported following TACE in high-risk patients. 10,11 The 30 day mortality rate reported by Kiely et al. 10 was 11% (four of 36 patients), and the morbidity rate was 8% (three of 36 patients). The other study investigating the use of TACE for HCC in high-risk patients was by Kothary et al. and reported major adverse events, such as hepatic failure (including encephalopathy and/or ascites) in seven (13%) of 52 patients and a 30 day mortality rate of 8% (four of 52 patients). 11 The possible explanation for the low morbidity and mortality rates after TACL is that TACE most likely inflicts greater ischaemic damage than TACL because more aggressive embolization techniques and materials are used. In the present study, the median patient survival rate after TACL was 8.6 months. The overall 6-month, 1, 2, and 3-year survival rates were 59, 44, 26, and 15%, respectively. The survival rates of the present study were compared with those after TACE in high-risk patients with HCC, as reported by Kiely et al. and Kothary et al. whose median survival rates were 12.2 and 8.6 months, respectively. Overall 1 and 3 year survival rates of 47 and 20% in the study of Kiely et al. and 6 month, 1 and 2 year survival rates of 66.4, 43.1, and 20.5% in the study of Kothary et al. were reported. 10,11 The median survival rate in the present study is comparable with the survival rates in both of these previous studies reporting the clinical results of TACE for high-risk patients with HCC. 10,11 An increased bilirubin (≥2 mg/dl) level, low serum albumin (<3.5 mg/dl) level, high CP score (≥9), major PV obstruction, and biliary obstruction have all been regarded as poor prognostic factors related to the survival period after TACE for patients with HCC. 8,25–28 These risk factors were evaluated in order to determine the patient survival period after TACL, and PV occlusion ( p < 0.001) was found to be the only significant risk factor associated with the length of the survival period after TACL for high-risk patients with HCC. However, the CP score ( p = 0.498), serum bilirubin level ( p = 0.153), serum albumin level ( p = 0.399), and biliary obstruction ( p = 0.636) were not significantly associated with the length of the survival period after TACL in the present study. The results of the present study indicate that the degree of increased bilirubin or low albumin level, the CP score, or the presence of biliary obstruction does not influence the outcome for patients undergoing TACL. Therefore, TACL can be considered as an alternative treatment option for HCC patients with the aforementioned risk factors; however, PV occlusion significantly reduces the potential survival benefit. The presence of tumour thrombi in the portal vein indicates high potential risk for extensive tumour spread throughout the liver. 29 Furthermore, HCC with portal vein invasion is frequently associated with significant arterioportal shunts which interfere with TACL as anticancer drugs, either alone or mixed with iodized oil, pass easily through the shunts. 30 The principal limitations of this study are its non-randomized and retrospective study design, both of which have some inherent flaws. A prospective and randomized control trial will be required to enable definite conclusions to be drawn regarding the clinical efficacy of TACL for high-risk patients with HCC. In conclusion, TACL can be performed safely and may be effective in prolonging the survival of high-risk patients with HCC when considering comparison to historically reported survival. References 1 K. Takayasu S. Arii I. Ikai Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510 patients Gastroenterology 131 2006 461 469 2 F.X. Bosch J. Ribes M. Díaz Primary liver cancer: worldwide incidence and trends Gastroenterology 127 2004 S5 16 3 H. Shen D. Agarwal R. Qi Predictors of outcome in patients with unresectable hepatocellular carcinoma receiving transcatheter arterial chemoembolization Aliment Pharmacol Ther 26 2007 393 400 4 Y.H. Chung I.H. Song B.C. Song Combined therapy consisting of intraarterial cisplatin infusion and systemic interferon-alpha for hepatocellular carcinoma patients with major portal vein thrombosis or distant metastasis Cancer 88 2000 1986 1991 5 D.B. Brown J.F. Cardella D. Sacks Quality improvement guidelines for transhepatic arterial chemoembolization, embolization, and chemotherapeutic infusion for hepatic malignancy J Vasc Interv Radiol 17 2006 225 232 6 J.M. Llovet M.I. Real X. Montaña Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial Lancet 359 2002 1734 1739 7 C.M. Lo H. Ngan W.K. Tso Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma Hepatology 35 2002 1164 1171 8 J.W. Chung J.H. Park J.K. Han Hepatic tumours: predisposing factors for complications of transcatheter oily chemoembolization Radiology 198 1996 33 40 9 S. Savastano D. Miotto G. Casarrubea Transcatheter arterial chemoembolization for hepatocellular carcinoma in patients with Child's grade A or B cirrhosis: a multivariate analysis of prognostic factors J Clin Gastroenterol 28 1999 334 340 10 J.M. Kiely W.S. Rilling J.G. Touzios Chemoembolization in patients at high risk: results and complications J Vasc Interv Radiol 17 2006 47 53 11 N. Kothary J.L. Weintraub J. Susman Transarterial chemoembolization for primary hepatocellular carcinoma in patients at high risk J Vasc Interv Radiol 18 2007 1517 1527 12 S. Maeda S. Fujiyama M. Tanaka Survival and local recurrence rates of hepatocellular carcinoma patients treated by transarterial chemolipiodolization with and without embolization Hepatol Res. 23 2002 202 210 13 S.H. Ahn K.H. Han J.Y. Park Treatment outcome of transcatheter arterial chemoinfusion according to anticancer agents and prognostic factors in patients with advanced hepatocellular carcinoma (TNM stage IVa) Yonsei Med J 45 2004 847 858 14 K. Nouso Y. Ito K. Kuwaki Prognostic factors and treatment effects for hepatocellular carcinoma in Child C cirrhosis Br J Cancer 98 2008 1161 1165 15 M. Yoshikawa H. Saisho M. Ebara A randomized trial of intrahepatic arterial infusion of 4′-epidoxorubicin with Lipiodol versus 4′-epidoxorubicin alone in the treatment of hepatocellular carcinoma Cancer Chemother Pharmacol 33 Suppl. 1994 S149 S152 16 J.O. Park S.I. Lee S.Y. Song Measuring response in solid tumours: comparison of RECIST and WHO response criteria Jpn J Clin Oncol 33 2003 533 537 17 C.S. Georgiades K. Hong M. D'Angelo Safety and efficacy of transarterial chemoembolization in patients with unresectable hepatocellular carcinoma and portal vein thrombosis J Vasc Interv Radiol 16 2005 1653 1659 18 A.M. Covey M.A. Maluccio J. Schubert Particle embolization of recurrent hepatocellular carcinoma after hepatectomy Cancer 106 2006 2181 2189 19 J.H. Kim H.K. Yoon K.B. Sung Transcatheter arterial chemoembolization or chemoinfusion for unresectable intrahepatic cholangiocarcinoma: clinical efficacy and factors influencing outcomes Cancer 113 2008 1614 1622 20 B. Cady Natural history of primary and secondary tumours of the liver Semin Oncol 10 1983 127 134 21 L. Lladó J. Virgili J. Figueras A prognostic index of the survival of patients with unresectable hepatocellular carcinoma after transcatheter arterial chemoembolization Cancer 88 2000 50 57 22 T. Konno Targeting chemotherapy for hepatoma: arterial administration of anticancer drugs dissolved in Lipiodol Eur J Cancer 28 1992 403 409 23 Y. Yumoto K. Jinno K. Tokuyama Hepatocellular carcinoma detected by iodized oil Radiology 154 1985 19 24 24 A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma. Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire N Engl J Med 332 1995 1256 1261 25 J.W. Chung J.H. Park J.K. Han Hepatocellular carcinoma and portal vein invasion: results of treatment with transcatheter oily chemoembolization AJR Am J Roentgenol 165 1995 315 321 26 A.O. Chan M.F. Yuen C.K. Hui A prospective study regarding the complications of transcatheter intraarterial lipiodol chemoembolization in patients with hepatocellular carcinoma Cancer 94 2002 1747 1752 27 H. Shijo M. Okazaki H. Higashihara Hepatocellular carcinoma: a multivariate analysis of prognostic features in patients treated with hepatic arterial embolization Am J Gastroenterol 87 1992 1154 1159 28 P.G. Tarazov V.N. Polysalov K.V. Prozorovskij Ischemic complications of transcatheter arterial chemoembolization in liver malignancies Acta Radiol 41 2000 156 160 29 J.H. Kim H.K. Yoon S.Y. Kim Transcatheter arterial chemoembolization vs. chemoinfusion for unresectable hepatocellular carcinoma in patients with major portal vein thrombosis Aliment Pharmacol Ther 29 2009 1291 1298 30 S. Murata H. Tajima K. Nakazawa Initial experience of transcatheter arterial chemoembolization during portal vein occlusion for unresectable hepatocellular carcinoma with marked arterioportal shunts Eur Radiol 19 2009 2016 2023