Chemoembolization is the technique of injecting chemotherapy medication into the feeding arteries of a tumor along with particles designed to slow or stop the further arterial supply of oxygen and nutrients to that tumor. It has been performed since the late 1970s., It is one of several techniques used with the goal of treating either primary liver cancer or cancer metastatic to the liver. The most common primary liver cancer is hepatocellular carcinoma (HCC). Common types of metastases to the liver include those from the colon, breast, carcinoid, soft tissue sarcomas, and melanoma. Arterial chemoembolization also can be termed transarterial chemoembolization (TACE).
The liver is divided into lobes and segments; there are several classification schemes for describing these segments, but the most widely used is the Couinaud classification. In this classification, the segments and lobes are defined in part by their third order (third branch) portal venous supply and in part, by their systemic venous drainage.
The arterial liver supply is variable. The most common configuration is that of a single proper hepatic artery derived from the common hepatic artery in turn derived from the celiac artery, with the proper hepatic artery dividing into right and left branches to feed the right and left lobes of the liver, respectively. However, this configuration is probably present in less than 50% of humans; various sources give various percentages. Authors disagree regarding the terminology of the artery that supplies segment 4, which is termed a middle hepatic artery by some and a segment four branch by others. The caudate lobe has particularly variable supply, often with multiple branches from both the right hepatic artery and the left hepatic artery.
The following are the 3 common potential accessory arterial supplies to liver tumors:
The following 4 arteries should be kept in mind as common avenues for inadvertent chemoembolization (i.e., embolizing non-target healthy tissues):
Perhaps the most widely used guidelines for management of cancer in the United States are those created by the National Comprehensive Network (NCCN). The NCCN is a non-profit organization composed of selected hospitals, mostly university hospitals, that choose member physicians from multiple specialties to sit on panels that make national guidelines for cancer treatment.
According to the NCCN, determining whether or not TACE is indicated involves a process of elimination. On the one hand, TACE is not as effective as surgery (either transplant or partial hepatic resection) for curing HCC or metastatic disease and is not in and of itself considered to be a curative treatment. On the other hand, TACE is a more effective treatment than others on the spectrum of treatments that may be considered to be purely palliative. In a minority of situations, TACE either can change a patient's status from "incurable" to "curable" (by downsizing one or more tumors to qualify the patient for surgery) or provide complete permanent tumor necrosis. Thus, on the one hand, a candidate for TACE is someone who has such advanced tumor status and/or overall poor health so as not to be able to withstand surgery or to gain a survival benefit from it as a first line option. This same person, on the other hand, must be healthy enough to withstand the potential side effects and toxicity of TACE and to have good enough odds of gaining at least several months of additional survival at a reasonable quality of life. This process of elimination for discerning which treatment is the best first-line treatment for an individual patient is variable and often subjective, but guidelines do exist to allow for some objectivity.
When considering treatment options for HCC and metastatic disease to the liver, the NCCN relies on several sets of criteria or "scores." These include scores, such as the Child-Pugh-Turcotte score, which is often referred to only as Child-Pugh score, and the United Network for Organ Sharing (UNOS) score, which is commonly referred to instead as the Model for End-stage Liver Disease (MELD) score. The Child-Pugh score is a measure of liver function that depends on a patient's levels of creatinine, INR, total bilirubin, encephalopathy, and ascites. The UNOS score is a measure of liver and renal function. It depends on the creatinine, INR, total bilirubin, sodium, and recent use of hemodialysis.
Additionally, the decision for or against transplant relies on tumor burden. The predominantly used set of criteria to define this are called the Milan criteria, which were established based on a study of 48 patients at the University of Milan.. These criteria state that a patient is a candidate for liver transplant as a preferred first-line treatment for HCC if the liver contains no more than one tumor up to 5 cm in maximum span, or if there are multiple tumors, then there are no more than3e tumors with each tumor measuring no more than 3 cm in maximum span. Although these are the criteria used by the NCCN, there are alternative tumor burden criteria available, such as from the University of California, San Francisco.
The NCCN usually relies on the American Joint Committee on Cancer staging system to create algorithms for the treatment of various cancers based on cancer staging. However, the AJCC staging system does not take into account liver function, which is a critical component in determining prognosis and potential survival benefit. Multiple other HCC staging systems based on patient cohorts with accumulated survival data have been proposed that estimate the survival of newly diagnosed patients with HCC based on the severity of their tumor burden, liver function, and/or other health factors. HCC has a variable, poorly understood natural history based on its underlying etiology, for example, secondary to hepatitis C versus hepatitis B versus alcohol-induced versus other, and based on its molecular markers. The tumor size and number affect prognosis but may not be as meaningful a predictor of prognosis as the previously mentioned factors. For example, persons in China are relatively more susceptible to developing HCC from hepatitis B, persons in Japan are relatively more susceptible to developing HCC from hepatitis C, and Caucasians are relatively more susceptible to developing HCC from alcohol-induced cirrhosis or steatohepatitis. Consistent with the previous statements, research studies of these different populations that have compared survival in patients with untreated HCC against survival in patients having undergone various treatments for HCC have found moderately different survival estimates. Thus, the prognosis for a person with HCC is best determined by using a study that has evaluated persons with the same set of circumstances. Since staging is designed to correlate with prognosis in order to help decide how aggressive to be with treatment recommendations for a given person, the tumor staging system that is used should ideally be based on patients who correspond most similarly to the patient at hand or at least most closely to the population at that particular hospital.
Available staging systems include but are not limited to the following:
A review of the differences, strengths, and weaknesses of these and other staging systems is provided by Kinoshita and in the 2018 NCCN guidelines. There is much overlap between these systems, and the NCCN does not favor the use of one over another. The Barcelona Clinic Liver Cancer staging system (BCLC) is endorsed by the American Association for the Study of Liver Disease and is likely the most widely used staging system in the United States. It is the focus here and will be discussed in detail. The BCLC itself is a conglomeration of other staging systems, including the Child-Pugh score and the Eastern Cooperative Oncology Group (ECOG) Performance Status (PS).
The Child-Pugh and PST scoring systems and the BCLC treatment algorithm are presented in the graphics below.
In the BCLC, patients are divided into stages 0, A, B, C, and D from least to most severe condition. BCLC stage-B patients are an extremely heterogeneous group, ranging from having four subcentimeter tumors to having one tumor over 5 cm to having a liver to replaced with a tumor.
The BCLC and NCCN recommend TACE as first-line treatment if:
The following is a breakdown of patient factors that determine how TACE may be used based on the NCCN guidelines. All patients who are candidates for TACE below are either not a candidate for (ECOG PS greater than 0) or choose against hepatectomy/transplant, or Child-Pugh class A or B.
Patient with HCC
TACE intends to keep the patient a candidate for transplant ("bridging" therapy).
TACE intends to downstage the tumor(s) so that the patient qualifies for a transplant.
The intent of TACE is to palliate.
Patient with Metastasis to the Liver
TACE intends to cure.
The intent of TACE is to downstage to enable resection.
The intent of TACE is to palliate.
Relative contraindications to TACE include but are not limited to the following:
In general, no more than 50% of liver volume should be chemo-embolized at a time. Therefore, if a patient has a tumor occupying more than 50% of the liver volume, then that patient is best treated with 2 TACE procedures.
Portal vein thrombosis is not a contraindication to palliative TACE if there is adequate collateral hepatopetal flow to supply the liver parenchyma to be embolized. However, in patients with portal vein thrombosis, it is wise to avoid embolizing normal liver parenchyma as much as possible.
Many physicians treat bile duct obstruction before offering TACE, which could exacerbate bile duct obstruction.
The NCCN does not include TACE in its treatment algorithm for primary cholangiocarcinoma.
TACE can be divided into 2 major categories of chemotherapy delivery:
Conventional TACE (cTACE) is a mixture of three agents: lipiodol contrast agent, a chemotherapy drug, and an embolization agent. TACE using drug-eluting beads (TACE-DEB or DEB-TACE) uses resin beads that slowly release chemotherapy. Currently, only two chemotherapy drugs are FDA-approved for use in this manner. Doxorubicin is used to treat hypervascular primary hepatic tumors and metastases. Irinotecan is used to treat metastases from colorectal cancer.
Cross-sectional imaging with contrast-enhanced CT or MRI should be done for diagnostic and treatment planning purposes. Such imaging can determine whether there is anatomy or pathology that may prevent TACE from being safe or effective, such as whether the main portal vein is thrombosed.
No biopsy is necessary if:
The NCCN suggests biopsy consideration before treatment in the following presentations:
Prevention of Nontarget Embolization
To avoid inadvertently performing non-target chemoembolization, radiologists often will use platinum coils to embolize arteries near the artery planned for delivering chemotherapy (as discussed in the anatomy section above). Although it is not mandatory, some radiologists have patients undergo a "planning" arteriogram before the arteriogram for delivery of chemotherapy, at which time such coils would be placed.
TACE typically is performed using conscious sedation. Determination of periprocedural anesthesia risk is site dependent. Many hospitals require physicians to assess the patient using the American Society of Anesthesiology (ASA) physical classification system and a Mallampati score. If the patient is ASA class 4 or higher and/or has any other anesthetic risk factors, such as a high-risk airway, then some institutions and authors recommend that the patient should undergo consultation with an anesthesiologist and/or medical specialist, such as a cardiologist, to address the pertinent risk factors.
Many radiologists administer normal intravenous saline intravenously for hydration.
Because chemoembolization creates a bed of necrotic tissue, and such tissue may form an abscess, nearly all radiologists prescribe prophylactic antibiotics at the time of the procedure. Regimens should cover gram-positive cocci, gram-negative rods, and in the case of patients without an intact sphincter of Oddi from previous surgery, sphincterotomy or biliary drainage, anaerobes. This is discussed in more detail by the Society of Interventional Radiology (SIR) guidelines with regard to incidences of abscess infection,, and suggested antibiotic regimens.,,. If a bilioenteric anastomosis or biliary stent is present, then some radiologists also prescribe a bowel cleansing preparation, such as oral neomycin-erythromycin.
Parameters for prevention of bleeding complications (lab tests and medication withdrawal) are specified by the Society of Interventional Radiology 2013 guidelines.
Other Symptom Control
In patients being treated for carcinoid tumors, pre-procedure or intra-procedure administration of octreotide may prevent or diminish the side effects of serotonin release ("carcinoid crisis").
Other pre-procedure medications may include antiemetics and steroids. However, some radiologists only administer this post-procedure as routine or on an as-needed basis.
Arterial catheter access is obtained, and arteriography is performed to document the arterial supply to the single or multiple tumors.
Major complications occur in approximately 5 to 10 out of 100 people who undergo TACE. The most common major complications are:
The number of persons that need to be treated in order to prevent 1 death over a given time period (such as 1 year) has not been published, since no studies have evaluated an absolute risk reduction for TACE, and the number may be very high.
The Society of Interventional Radiology defined technical success as expected catheter placement and administration of the selected particles and drug, which should occur at a rate of at least 98%.
Clinical success is defined as successful tumor necrosis resulting in either down-staging or lengthened survival. No national organization is known to have set a recommended threshold for this parameter. Survival rates significantly improve in patients just missing meeting criteria for surgery who have:
Down-staging by the “best minimally invasive method” (for example, RFA, TACE, PEI, or some combination) was successful in 21 of 30 patients that met the following criteria as reported by Yao:
In a study that included patients under 65 years old who had no contraindications for liver transplant other than not meeting the Milan criteria, 34 of 62 were down-staged.
However, a given patient's chance of success for downstaging may be much lower if the patient does not share similar baseline characteristics.
HCC Lengthened Survival
Three randomized trials,, have demonstrated improved patient survival after TACE versus no HCC treatment at all. In each study, however, selected patients underwent repeat TACE sessions, meaning that it could not be concluded that an indivual session of TACE improves survival.
Patients at an intermediate stage (BCLC stage-B) were found to have a median survival of about 16 months. With 1 or more TACE sessions in the setting of HCC, patient survival extended to a median of up to 19 to 20 months.
The expected survival benefit for patients with tumors metastatic to the liver is even more variable than it is for patients with HCC, and results generally are not as encouraging as for patients with HCC. TACE is typically used for palliation only following systemic chemotherapy.
Alternatives to TACE depend on the patient's liver tumor and overall functional status as mentioned above. Other than opting for no treatment, other potential mainstream therapies accepted by the NCCN depending on the patient include:
Hepatic chemoembolization is done by an interventional radiologist in consultation with an oncologist. These patients are often followed by the primary caregiver or oncology nurse because they are at high risk of developing post-procedure complications. No randomized controlled trial has found a survival benefit for TACE over bland embolization. One randomized controlled trial compared TACE to radioembolization for patients with HCC and found that patients in the Y90 radioembolization group experienced a significantly longer median time to local progression of tumor (greater than 26 months) than patients in the TACE group (6.8 months). Despite this, these Y90 patients did not end up having a greater chance of undergoing a liver transplant and were not shown to benefit by having an overall increased rate of survival. A significantly greater proportion of patients in the TACE group developed side effects from treatment of diarrhea or hypoalbuminemia.
|||The current status of angiography in the evaluation of cancer patients., Reuter SR,, Cancer, 1976 Jan [PubMed PMID: 942883]|
|||Therapy for hepatocellular cancer with intrahepatic arterial adriamycin and 5-fluorouracil combined with whole-liver irradiation: a Northern California Oncology Group Study., Friedman MA,Volberding PA,Cassidy MJ,Resser KJ,Wasserman TH,Phillips TL,, Cancer treatment reports, 1979 Nov-Dec [PubMed PMID: 230895]|
|||Characterization of the middle hepatic artery and its relevance to living donor liver transplantation., Wang S,He X,Li Z,Peng Z,Tam NL,Sun C,Hu A,Huang J,, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 2010 Jun [PubMed PMID: 20517907]|
|||Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis., Mazzaferro V,Regalia E,Doci R,Andreola S,Pulvirenti A,Bozzetti F,Montalto F,Ammatuna M,Morabito A,Gennari L,, The New England journal of medicine, 1996 Mar 14 [PubMed PMID: 8594428]|
|||Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients., Okuda K,Ohtsuki T,Obata H,Tomimatsu M,Okazaki N,Hasegawa H,Nakajima Y,Ohnishi K,, Cancer, 1985 Aug 15 [PubMed PMID: 2990661]|
|||A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators.,, Hepatology (Baltimore, Md.), 1998 Sep [PubMed PMID: 9731568]|
|||Prognosis of hepatocellular carcinoma: the BCLC staging classification., Llovet JM,Brú C,Bruix J,, Seminars in liver disease, 1999 [PubMed PMID: 10518312]|
|||Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system, and the Cancer of the Liver Italian Program staging system: a study based on 926 patients., Leung TW,Tang AM,Zee B,Lau WY,Lai PB,Leung KL,Lau JT,Yu SC,Johnson PJ,, Cancer, 2002 Mar 15 [PubMed PMID: 11920539]|
|||Kudo M,Chung H,Osaki Y, Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score). Journal of gastroenterology. 2003 [PubMed PMID: 12673442]|
|||Kee KM,Wang JH,Lin CY,Wang CC,Cheng YF,Lu SN, Validation of the 7th edition TNM staging system for hepatocellular carcinoma: an analysis of 8,828 patients in a single medical center. Digestive diseases and sciences. 2013 Sep [PubMed PMID: 23703450]|
|||Staging systems for hepatocellular carcinoma: Current status and future perspectives., Kinoshita A,Onoda H,Fushiya N,Koike K,Nishino H,Tajiri H,, World journal of hepatology, 2015 Mar 27 [PubMed PMID: 25848467]|
|||Practice guidelines for adult antibiotic prophylaxis during vascular and interventional radiology procedures. Written by the Standards of Practice Committee for the Society of Interventional Radiology and Endorsed by the Cardiovascular Interventional Radiological Society of Europe and Canadian Interventional Radiology Association [corrected]., Venkatesan AM,Kundu S,Sacks D,Wallace MJ,Wojak JC,Rose SC,Clark TW,d'Othee BJ,Itkin M,Jones RS,Miller DL,Owens CA,Rajan DK,Stokes LS,Swan TL,Towbin RB,Cardella JF,, Journal of vascular and interventional radiology : JVIR, 2010 Nov [PubMed PMID: 21029949]|
|||Risk factors for liver abscess formation after hepatic chemoembolization., Kim W,Clark TW,Baum RA,Soulen MC,, Journal of vascular and interventional radiology : JVIR, 2001 Aug [PubMed PMID: 11487677]|
|||Chemoembolization of hepatic neoplasms: safety, complications, and when to worry., Gates J,Hartnell GG,Stuart KE,Clouse ME,, Radiographics : a review publication of the Radiological Society of North America, Inc, 1999 Mar-Apr [PubMed PMID: 10194787]|
|||Particle embolization for hepatocellular carcinoma., Brown KT,Nevins AB,Getrajdman GI,Brody LA,Kurtz RC,Fong Y,Blumgart LH,, Journal of vascular and interventional radiology : JVIR, 1998 Sep-Oct [PubMed PMID: 9756073]|
|||Moxifloxacin prophylaxis for chemoembolization or embolization in patients with previous biliary interventions: a pilot study., Khan W,Sullivan KL,McCann JW,Gonsalves CF,Sato T,Eschelman DJ,Brown DB,, AJR. American journal of roentgenology, 2011 Aug [PubMed PMID: 21785063]|
|||Effectiveness of an aggressive antibiotic regimen for chemoembolization in patients with previous biliary intervention., Patel S,Tuite CM,Mondschein JI,Soulen MC,, Journal of vascular and interventional radiology : JVIR, 2006 Dec [PubMed PMID: 17185688]|
|||Influence of a new prophylactic antibiotic therapy on the incidence of liver abscesses after chemoembolization treatment of liver tumors., Geschwind JF,Kaushik S,Ramsey DE,Choti MA,Fishman EK,Kobeiter H,, Journal of vascular and interventional radiology : JVIR, 2002 Nov [PubMed PMID: 12427817]|
|||Addendum of newer anticoagulants to the SIR consensus guideline., Patel IJ,Davidson JC,Nikolic B,Salazar GM,Schwartzberg MS,Walker TG,Saad WE,, Journal of vascular and interventional radiology : JVIR, 2013 May [PubMed PMID: 23622037]|
|||Quality improvement guidelines for transhepatic arterial chemoembolization, embolization, and chemotherapeutic infusion for hepatic malignancy., Brown DB,Nikolic B,Covey AM,Nutting CW,Saad WE,Salem R,Sofocleous CT,Sze DY,, Journal of vascular and interventional radiology : JVIR, 2012 Mar [PubMed PMID: 22284821]|
|||Drug-eluting bead therapy in primary and metastatic disease of the liver., Carter S,Martin Ii RC,, HPB : the official journal of the International Hepato Pancreato Biliary Association, 2009 Nov [PubMed PMID: 20495705]|
|||Complications associated with transcatheter arterial embolization for hepatic tumors., Sakamoto I,Aso N,Nagaoki K,Matsuoka Y,Uetani M,Ashizawa K,Iwanaga S,Mori M,Morikawa M,Fukuda T,Hayashi K,Matsunaga N,, Radiographics : a review publication of the Radiological Society of North America, Inc, 1998 May-Jun [PubMed PMID: 9599386]|
|||Hepatic tumors: predisposing factors for complications of transcatheter oily chemoembolization., Chung JW,Park JH,Han JK,Choi BI,Han MC,Lee HS,Kim CY,, Radiology, 1996 Jan [PubMed PMID: 8539401]|
|||A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation., Yao FY,Hirose R,LaBerge JM,Davern TJ 3rd,Bass NM,Kerlan RK Jr,Merriman R,Feng S,Freise CE,Ascher NL,Roberts JP,, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 2005 Dec [PubMed PMID: 16315294]|
|||Response to transarterial chemoembolization as a biological selection criterion for liver transplantation in hepatocellular carcinoma., Otto G,Herber S,Heise M,Lohse AW,Mönch C,Bittinger F,Hoppe-Lotichius M,Schuchmann M,Victor A,Pitton M,, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 2006 Aug [PubMed PMID: 16826556]|
|||Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival., Llovet JM,Bruix J,, Hepatology (Baltimore, Md.), 2003 Feb [PubMed PMID: 12540794]|
|||Lo CM,Ngan H,Tso WK,Liu CL,Lam CM,Poon RT,Fan ST,Wong J, Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology (Baltimore, Md.). 2002 May [PubMed PMID: 11981766]|
|||Barone M,Ettorre GC,Ladisa R,Schiavariello M,Santoro C,Francioso G,Vinciguerra V,Francavilla A, Transcatheter arterial chemoembolization (TACE) in treatment of hepatocellular carcinoma. Hepato-gastroenterology. 2003 Jan-Feb [PubMed PMID: 12630019]|
|||Y90 Radioembolization Significantly Prolongs Time to Progression Compared With Chemoembolization in Patients With Hepatocellular Carcinoma., Salem R,Gordon AC,Mouli S,Hickey R,Kallini J,Gabr A,Mulcahy MF,Baker T,Abecassis M,Miller FH,Yaghmai V,Sato K,Desai K,Thornburg B,Benson AB,Rademaker A,Ganger D,Kulik L,Lewandowski RJ,, Gastroenterology, 2016 Dec [PubMed PMID: 27575820]|