Transcatheter Arterial Chemoembolization of Liver Tumors: Effects of Embolization Protocol on Injectable Volume of Chemotherapy and Subsequent Arterial Patency

Geschwind, Jean François H.; Ramsey, Douglas E.; Cleffken, Berry; Wal, Bart C. H. van der; Kobeiter, Hicham; Juluru, Krishna; Hartnell, George G.; Choti, Michael A.

doi:10.1007/s00270-002-2524-6

Cited by 93 publications

(63 citation statements)

References 23 publications

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“…In most cases, the obstructed HA that supplies the HCC will resume its blood flow. This observation is supported by the fact that the arteriogram performed in the second or later embolization usually showed that the previously embolized HA was no longer occluded (25). Our results showed that a transient HAL, 40-50 min (the reported half-life of TPZ), is sufficient to induce TPZ to efficiently kill the tumor cells.…”

Section: Discussionsupporting

confidence: 73%

Hypoxia-activated cytotoxic agent tirapazamine enhances hepatic artery ligation-induced killing of liver tumor in HBx transgenic mice

Lin

Yeh

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Transarterial chemoembolization (TACE) is the main treatment for intermediate stage hepatocellular carcinoma (HCC) with Barcelona Clinic Liver Cancer classification because of its exclusive arterial blood supply. Although TACE achieves substantial necrosis of the tumor, complete tumor necrosis is uncommon, and the residual tumor generally rapidly recurs. We combined tirapazamine (TPZ), a hypoxia-activated cytotoxic agent, with hepatic artery ligation (HAL), which recapitulates transarterial embolization in mouse models, to enhance the efficacy of TACE. The effectiveness of this combination treatment was examined in HCC that spontaneously developed in hepatitis B virus X protein (HBx) transgenic mice. We proved that the tumor blood flow in this model was exclusively supplied by the hepatic artery, in contrast to conventional orthotopic HCC xenografts that receive both arterial and venous blood supplies. At levels below the threshold oxygen levels created by HAL, TPZ was activated and killed the hypoxic cells, but spared the normoxic cells. This combination treatment clearly limited the toxicity of TPZ to HCC, which caused the rapid and near-complete necrosis of HCC. In conclusion, the combination of TPZ and HAL showed a synergistic tumor killing activity that was specific for HCC in HBx transgenic mice. This preclinical study forms the basis for the ongoing clinical program for the TPZ-TACE regimen in HCC treatment.hypoxia | hepatocellular carcinoma | orthotopic | transarterial embolization H epatocellular carcinoma (HCC), the sixth most common solid malignancy, accounts for approximately three-quarters of a million deaths worldwide every year (1). Over the past two decades, the incidence of HCC has remained high in Asia and has steadily increased in the United States and Europe (1). Treatment for HCC largely depends on the stage of the disease. Diagnosis is usually delayed, as ∼30-40% of the patients are already in the intermediate stage at their initial visit, and transarterial chemoembolization (TACE) is the most commonly used treatment for these patients (2). However, TACE achieves only a 20-30% tumor remission rate, and recurrence is common, resulting in a 3-y survival rate of only ∼30% (3). This poor survival rate needs to be improved.The mechanism by which arterial embolization preferentially kills HCC but spares adjacent liver tissues arises from the unique dual blood supply to the liver. Normal liver receives 75% of its blood supply from the portal vein (PV) and the remaining 25% from the hepatic artery (HA) (4). In contrast, HCC almost exclusively receives its blood supply from the HA (5). Based on this unique pattern, embolization has been used to selectively block the arterial blood supply to HCC, causing transient but profound ischemia and depriving HCC cells from essential oxygen and nutrients, thus killing the tumors.However, because of the heterogeneity of the tumor vessels within HCC, the embolization of the tumor-feeding arteries usually results in different degrees of ischemia and hypoxia, rang...

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Section: Discussionsupporting

confidence: 73%

Hypoxia-activated cytotoxic agent tirapazamine enhances hepatic artery ligation-induced killing of liver tumor in HBx transgenic mice

Lin

Yeh

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…(31)(32)(33)(34)(35) Use of lipiodol TACE in the treatment of HCC is based on meta-analyses of RCTs comparing embolization or chemoembolization versus conservative management. (14,15) A recent Cochrane meta-analysis (36) whose methodology has been criticized by several experts (37,38) -questioned the evidence supporting the beneficial effect of TACE over no intervention on survival in patients with HCC.…”

Section: Discussionmentioning

confidence: 99%

Lipiodol transarterial chemoembolization for hepatocellular carcinoma: A systematic review of efficacy and safety data

et al. 2016

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Transarterial chemoembolization (TACE) using lipiodol-based regimens, including the administration of an anticancer-in-oil emulsion followed by embolic agents, is widely used in the treatment of hepatocellular carcinoma (HCC). This approach has been supported by meta-analyses of randomized, controlled trials (RCTs) performed more than a decade ago. We performed a systematic review to understand current efficacy and safety data of lipiodol TACE in treatment of HCC. A search of the literature published between January 1, 1980 and June 30, 2013 was performed using MEDLINE and EMBASE databases. All potentially relevant publications were reviewed and articles were selected based on predefined inclusion and exclusion criteria. Of a total of 1,564 articles reviewed, 101 articles, including a total of 10,108 patients treated with lipiodol TACE, were selected for the efficacy analysis. Objective response rate was 52.5% (95% confidence interval [CI]: 43.6-61.5). Overall survival (OS) was 70.3% at 1 year, 51.8% at 2 years, 40.4% at 3 years, and 32.4% at 5 years. Median OS was 19.4 months (95% CI: 16.2-22.6). A total of 217 articles presenting precise description on numbers of adverse events (AEs) were selected for the safety review: In these studies, a total of 21,461 AEs were reported in 15,351 patients. Liver enzyme abnormalities were the most commonly observed AE, followed by the symptoms associated with postembolization syndrome. Overall mortality rate was 0.6% and the most common cause of death was related to acute liver insufficiency. Conclusions: In a systematic literature review, survival figures of HCC patients undergoing lipiodol TACE appear to be in line with those reported in previous RCTs, and no new or unexpected safety concerns were identified. (HEPATOLOGY 2016;64:106-116) SEE EDITORIAL ON PAGE 23H epatocellular carcinoma (HCC) is the thirdleading cause of cancer-related death worldwide. (1) Unlike most solid cancers, future incidence and mortality rates for HCC were projected to largely increase in several regions around the world over the next several years, mostly as a result of the dissemination of hepatitis C virus infection. (2,3) Despite the widespread implementation of surveillance programs of at-risk populations, the majority of patients with HCC are diagnosed late, when curative treatments-including liver transplantation, hepatic resection, and image-guided ablation-cannot be applied. (4) Transarterial chemoembolization (TACE) is widely used in treatment of HCC patients unsuitable for radical therapies. The data collected in the Global Investigation of therapeutic DEcisions in hepatocellular

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“…Transarterial chemoembolization (TACE) is widely used to treat HCC patients who are not suitable candidates for curative treatments (2)(3)(4)(5). The most common embolic agent used in TACE is lipiodol, which can be mixed with surgical glues (cyanoacrylates) or with ethanol for interventional procedures.…”

Section: Resultsmentioning

confidence: 99%

Therapeutic effects of transarterial infusion of lipiodol and ethanol in various ratios in a rabbit VX2 tumor model

Gao

Qian²,

Chen³

et al. 2015

Diagn Interv Radiol

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Transcatheter Arterial Chemoembolization of Liver Tumors: Effects of Embolization Protocol on Injectable Volume of Chemotherapy and Subsequent Arterial Patency

Cited by 93 publications

References 23 publications

Hypoxia-activated cytotoxic agent tirapazamine enhances hepatic artery ligation-induced killing of liver tumor in HBx transgenic mice

Hypoxia-activated cytotoxic agent tirapazamine enhances hepatic artery ligation-induced killing of liver tumor in HBx transgenic mice

Lipiodol transarterial chemoembolization for hepatocellular carcinoma: A systematic review of efficacy and safety data

Therapeutic effects of transarterial infusion of lipiodol and ethanol in various ratios in a rabbit VX2 tumor model

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