Hepatocellular carcinoma (HCC) ranks among the most common malignancies worldwide, and the prognosis for patients with HCC is typically poor. Chemoembolization has become the mainstay of treatment for patients with unresectable HCC. The authors review the use of transcatheter arterial chemoembolization as a therapy for these patients.
is a fourth-year Medical Student and
is an Associate Professor of Radiology, Surgery, and
Oncology, and the Director of Interventional Radiology in The
Russell H. Morgan Department of Radiology, The Johns Hopkins
University School of Medicine, Baltimore, MD.
Hepatocellular carcinoma (HCC) ranks among the most common
malignancies worldwide, and the prognosis for patients with HCC is
typically poor. The incidence of HCC has risen dramatically in the
United States in recent years, with a concomitant rise in the
incidence of hepatitis C.
There were an estimated 20,000 patients with HCC in the United
States in 2000, and the prevalence of HCC is expected to rise
dramatically in the next decade.
When untreated, HCC is uniformly fatal. Surgical resection provides
HCC patients with the only hope of complete remission; however, few
patients (15%) are candidates for surgery, and tumor recurrence
after partial hepatectomy is notoriously high (70%). The mean
survival for patients with unresectable HCC ranges from 3 to 6
months, so any techniques that prolong survival or improve quality
of life are beneficial. Typically, HCC is unaffected by systemic
chemotherapy (15% response rate), and it is associated with
considerable side effects. Consequently, several nonsurgical
techniques have been developed by interventional radiologists to
treat hepatic malignancies.
TACE and TAE
Transcatheter arterial chemoembolization (TACE) has become the
mainstay of treatment for unresectable HCC. Chemo-embolization
involves a localized intra-arterial infusion of chemotherapy, emul-
sified in oil, combined with some type of embolic material.
Transcatheter arterial chemoembolization is intended to deliver a
highly concentrated dose of chemotherapy to tumor cells, prolong
the contact time between the chemotherapeutic agents and the cancer
cells, and minimize systemic toxicity. Ideally, achieving these
goals will result in a tumor shrinkage, symptomatic relief,
improved quality of life, and increased patient survival.
Transcatheter arterial embolization without chemotherapy (TAE or
bland embolization) has often been mistakenly categorized as a form
of chemoembolization. Transcatheter arterial embolization simply
consists of embolizing the artery feeding a tumor, resulting in
subsequent ischemia and tumor necrosis. However, recent data
suggests that hypoxia without cytotoxicity (ie, TAE) is a potent
stimulator of angiogenesis, mutagenesis, and glucose consumption by
Hence, TAE may, in fact, be detrimental to cancer patients, since
this type of hypoxic stress triggers angiogenesis, thereby
promoting malignancy. A recent randomized trial has demonstrated
that chemoembolization is, in fact, more effective than TAE for
TACE: Theory and technique
The key to chemoembolization is the blood supply to liver tumors
from branches of the hepatic artery. While normal liver parenchyma
derives >75% of its blood supply from the portal vein,
hepatocellular tumors derive their blood supply nearly exclusively
from the hepatic artery.
Based on this anatomy, an arterial approach to anti-tumor therapy
is designed to spare the surrounding hepatic parenchyma, inducing
selective tumor necrosis. Since the precise mechanism for achieving
tumor response is not understood, and since the success of TACE
might be assessed in multiple ways, several variations of TACE
protocols have been used to combat HCC. No consensus exists as to
what constitutes the most effective TACE technique.
implies delivery of chemotherapeutic agents. Achieving high,
localized concentrations of chemotherapeutic agents within a tumor
is a main goal of TACE. The combination of highly concentrated
chemo-therapy and some degree of ischemia within a tumor is likely
to be synergistic in achieving a tumor response. The strategic
advantage of embolization over systemic chemotherapy is the greater
concentrations of anti-tumor agents within the tumor. It has been
reported that the concentration of chemotherapy within tumor tissue
can be up to 100 times higher following chemoembolization than
following systemic chemotherapy.
Because arterial embolization reduces inflow to tumors,
chemotherapeutic agents remain in contact with tumor cells for
prolonged periods of time. Not only does reduced blood flow prevent
washout of chemo-therapeutic agents, but tumor ischemia has been
shown to cause failure of transmembrane pumps in tumor cells,
resulting in an even greater retention of chemo- therapeutic
Several types of chemotherapy have been used for TACE, and
controversy persists regarding which drugs are most useful. The
most common single chemo-therapeutic agent is doxorubicin. However,
a recent study has suggested that cisplatin is more effective than
doxo-rubicin as a single agent against HCC.
Many interventional radiologists choose to use a combination of
chemotherapeutic agents in the belief that there is synergy between
the different agents. The combination of cisplatin, doxorubicin,
and mitomycin C is the most common combination drug regimen. In
1987, researchers found that poppyseed oil accumulates
preferentially in HCC.
Since then, poppyseed oil (Ethiodol, Savage Laboratories, Melville,
NY) has been the most widely used suspension medium for
chemotherapeutic agents. Oil is a key ingredient to the
chemoembolization procedure-it serves three purposes: it is drug
carrying and tumor seeking, and it is an embolic agent (occluding
vessels in the 30-mm range).
Several types of particulate embolic agents have been used in
conjunction with the ethiodal for chemoembolization, including
Gelfoam powder and pledgets (Upjohn, Kalamazoo, MI) and polyvinyl
alcohol (PVA; Cook Inc., Bloomington, IN). Gelfoam causes a
temporary vascular occlusion, with recanalization occurring in
approximately 2 weeks. Polyvinyl alcohol particles cause a
semipermanent arterial occlusion. When and how these embolic agents
should be delivered remains controversial. Some experts favor
mixing the embolic particles in a slurry with the chemotherapeutic
drugs and oil, whereas others prefer to infuse embolic particles
only after the chemotherapy-oil mixture has been injected. Recent
data suggest that the latter method allows increased volumes of
chemotherapy to be injected, and that delayed embolization improves
long-term arterial patency.
Maintenance of long-term arterial patency is important, since
permanent vascular occlusion prevents subsequent TACE procedures.
Chemoembolization provides better tumor response when repeated
multiple times, so long-term arterial patency may be critical to
the success of TACE.
Another objective of TACE is to selectively target tumor cells
while sparing as much functional liver tissue as possible. The
issue of how selectively the catheter should be placed (lobar or
segmental) during chemoembolization remains somewhat controversial,
and a variety of techniques have been used to target tumors. In the
case of multiple tumors in a single lobe, a less selective approach
is preferred (Figure 1), whereas a single lesion may allow
super-selective positioning of the catheter (Figure 2).
Impacts of chemoembolization
Assessing the efficacy of TACE is difficult, as evidenced by the
multiple factors that have been cited by different authors as
measures of success. These factors include patient survival,
imaging response (size reduction, fraction of tumor necrosis,
lipiodol retention rate), quality of life, and symptomatic
improvement. Given the short life expectancy of patients with HCC,
the most relevant of these measures of success is patient survival.
However, patient survival is also the most controversial of these
Numerous studies have shown that chemoembolization causes
substantial tumor necrosis (60% to 100%), especially when
intra-arterial chemotherapy is followed by particle embolization.
However, accurate prediction of the degree and consistency of
necrosis achieved after chemoembolization has proven difficult.
Since many tumors may be targeted selectively, tumor necrosis does
not appear to harm functional liver tissue, as demonstrated by a
recent study that found no worsening of liver function following
TACE in patients with Child's class A or B liver disease.
Although hepatic resection has been associated with an
improvement in patient quality of life,
few studies have examined the impact of TACE on quality of life.
Given the palliative nature of TACE, quality of life is a critical
measure of a successful outcome that has been overlooked.
Preliminary data suggest that TACE maintains baseline quality of
life throughout the course of treatment, and it reduces overall
Survival of TACE patients
Early on, several well-designed case-control and retrospective
studies demonstrated a benefit of TACE on patient survival when
comparing treated patients with untreated or historical controls.
Patients with small tumors have reported survival rates as high as
100% at 1 year and 53% at 5 years.
Patients with large tumors (>50% of the liver) have also shown
benefit from TACE. One case-control trial reported 59% survival at
1 year among patients treated with TACE compared with 0% in
The best nonrandomized trial of TACE studied 254 patients who were
stratified by Child-Pugh and Okuda staging.
In this trial, patients treated with TACE survived significantly
longer than did untreated controls. Survival rates in treated
patients were 64%, 38%, 27%, and 27% at 1, 2, 3, and 4 years,
respectively, as compared with 18%, 6%, and 5% at 1, 2, and 3
years, respectively, among patients treated with the best
supportive care possible.
Despite the promising findings reported by these nonrandomized
trials, most randomized controlled trials (RCTs) have failed to
confirm increased survival with TACE. However, nearly all the RCTs
fail to compare TACE patients with untreated controls. Instead, the
published RCTs have typically compared TACE with control groups
treated with hormonotherapy, radiotherapy, or systemic
chemotherapy. In addition, nearly all review articles and
meta-analyses that examine these RCTs fail to exclude the trials in
which control groups were treated.
To date, 6 RCTs have compared some form of TACE with supportive
The most publicized RCT of TACE was published in
The New England Journal of Medicine
This study was conducted by a consortium of French researchers who
enrolled 96 patients at 24 medical centers. The large number of
centers led to inconsistency in technique. Patients in the control
group had an unusually high survival rate (43% at 1 year), which
might be explained by the high proportion of patients with
alco-hol-induced cirrhosis (73%). Furthermore, a high rate of liver
failure was observed in the treatment group, which might be
partially explained by the mandatory 4 cycles of chemoembolization,
regardless of clinical symptomatology and tumor response.
A recent meta-analysis has demonstrated that 4 of the 6 RCTs
comparing TACE with untreated controls failed to show any impact of
TACE on patient survival.
Yet, each of these 4 RCTs was plagued by procedural variability and
serious flaws in trial design, which severely discredit the results
of these trials.
More recently, two well-designed randomized trials have shown a
positive impact of chemoembolization on survival. An RCT by Lo et
randomized patients to either chemoembolization (lipiodol,
cisplatin, and gelfoam) or supportive care. Patient survival was
found to be 57%, 31%, and 26% in the chemoembolization group,
versus 32%, 11%, and 3% at 1, 2, and 3 years, respectively, in the
supportive care group. A second RCT by Llovet et al
randomized 112 patients in Spain to TAE, TACE, or supportive care.
This trial was stopped early, since TACE and TAE demonstrated a
clear survival benefit, yielding 1- and 2-year survival rates of
82% and 63% for TACE, versus 63% and 27% for controls.
There is remarkable consistency in the results of these two trials
despite differences in their patient populations (Asian patients
with hepatitis B versus European patients with hepatitis C,
Despite a series of randomized trials that have not shown
increased survival, recent RCTs convincingly demonstrate that
chemoembolization improves patient survival. Chemoembolization has
become the mainstay of treatment for patients with unresectable
HCC. While TACE is not a cure for HCC, it is an effective therapy
that merits further study.