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1
Department of Diagnostic Radiology, National Cancer Center Hospital, 5-1-1,
Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
2
Department of Internal Medicine, National Cancer Center Hospital, Tokyo
104-0045, Japan.
Received August 2, 2000;
accepted after revision September 6, 2000.
Address correspondence to K. Takayasu.
Abstract
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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MATERIALS AND METHODS. For 54 consecutive patients with 71 small
hepatocellular carcinomas (
5 cm) with no more than two associated lesions,
targeted oily chemoembolization was performed with an emulsion of doxorubicin
hydrochloride mixed with iodized oil or a suspension of zinostatin stimalamer
followed by gelatin sponge particles. When local recurrence or a new lesion
appeared, follow-up targeted oily chemoembolization was performed.
RESULTS. For 52 of 71 lesions, the catheterization to a subsegmental or more distal feeding artery could be performed. Local recurrence was recognized in 33.2% at 1 year and 37.8% at 2 and 3 years. The significant factors that affected local recurrence were tumor size (p = 0.005) and degree of deposition of iodized oil within the lesion (p = 0.049). The survival rates at 1, 2, and 3 years were 93.3%, 77.1%, and 77.1%, respectively. The significant factors affecting survival rate were tumor thrombus in large vessels (p = 0.0001), appearing after the first chemoembolization, and maximum tumor size (p = 0.022).
CONCLUSION. Single targeted transarterial oily chemoembolization with the unified helical CT and angiography system had a low local recurrence rate for small hepatocellular carcinoma, and follow-up embolization resulted in a good survival rate. Tumor size along with degree of intratumoral iodized oil deposition and tumor thrombus along with maximum tumor size were significant factors affecting local recurrence and survival rate, respectively.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-fetoprotein measurement
for high-risk patients who are positive for hepatitis B virus surface antigen
or antihepatitis C virus antibodies, or both, small hepatocellular carcinomas
less than 3 cm in diameter can be easily found and have recently been treated
by surgery or percutaneous ethanol injection in large numbers of patients. Although surgery and percutaneous ethanol injection have shown good survival rates, 5-year survival rates after surgery (n = 16,728) and after percutaneous ethanol injection (n = 2,081) were 48.2% and 40.8%, respectively [2]; the number of patients for whom both treatments is indicated is not as large because of advanced-stage hepatocellular carcinoma or associated liver dysfunction. According to the Japanese liver cancer study group [2], transarterial oily chemoembolization accounted for 48.4% of all treatments, followed by surgery for 28.6%, percutaneous ethanol injection for 24.2%, and radiofrequency for 3.1% (some patients underwent two or more treatments in the same day) in a total of 15,804 patients with hepatocellular carcinoma registered during the 2 years (1994-1995) of the study group [2]. Transarterial oily chemoembolization has been widely used [3,4,5,6,7,8,9,10] for inoperable hepatocellular carcinoma or postoperatively recurrent hepatocellular carcinoma [11], or both, because the treatment is minimally invasive and repeatable. However, the local control rate with transarterial oily chemoembolization was much lower than that of surgery and percutaneous ethanol injection. Viable cancer cells are frequently found within the septum or pseudocapsule and in the surrounding area as histologically confirmed in resected specimens after transarterial oily chemoembolization [12, 13].
For analysis of factors affecting the local control rate and survival, we
performed one-session transarterial oily chemoembolization for small
hepatocellular carcinoma ( 5 cm), using a thin catheter seeking the
smallest feeding artery and the unified system of helical CT and angiography,
both of which were arranged in a line to form a common couch in one suite
[14]. To our knowledge, ours
is the first study of a series of cases performed this way.
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5 cm) associated with no more
than two lesions (3 cm) and treatment with transarterial oily
chemoembolization with the unified helical CT and angiography system
[14]. The following 18
patients were excluded: 10 patients with solitary hepatocellular carcinoma
underwent surgery, six received percutaneous ethanol injection immediately
before transarterial oily chemoembolization, and two failed to have
superselective catheterization for targeted transarterial oily
chemoembolization. The remaining 54 patients were included in the study. The study population comprised 35 men and 19 women, with an average age of 65.5 years (age range, 44-82 years). Twenty-one patients (38.9%) had previously undergone surgery for hepatocellular carcinoma: wedge resections for one lesion in 11 patients and for more than two lesions in six, subsegmentectomy in two, and left lateral segmentectomy and right lobectomy in one each. The mean interval between surgery and transarterial oily chemoembolization was 1222 days (range, 218-3303 days).
Fifty-four patients had 71 lesions: 38 had one lesion, 15 had two, and one
had three. The mean size of the largest tumor was 2.1 cm (range, 0.5-5.0 cm).
TNM classification [15] was
stage I for 20 patients, stage II for 20, stage III for 3, and stage IV for
11. Abdominal and thoracic helical CT, sonography, or MR imaging confirmed the
absence of metastasis to lymph nodes (N0) and distant organs (M0). Liver
function according to the Child classification
[16] was grade A in 28
patients, grade B in 21, and grade C in five. Six patients had positive
findings for hepatitis B surface antigen; 48, for antihepatitis C virus
antibodies; four, for both: and four had negative findings for both. The
average level of -fetoprotein was 862 ng/mL (range, 4-13,509 ng/mL).
Nineteen patients showed -fetoprotein levels greater than 200
ng/mL.
The diagnosis of hepatocellular carcinoma was made clinically in these
patients with sonography, CT, MR imaging, hepatic angiography, combination of
CT and angiography, and with measurements of -fetoprotein. Unenhanced
tumor such as an early hepatocellular carcinoma or adenomatous hyperplasia was
excluded. The histopathology of noncancerous hepatic parenchyma in the
resected specimens was chronic hepatitis in six patients and cirrhosis in
15.
Method of Targeted Oily Chemoembolization with the Unified System of
Helical CT and Angiography
"Targeted transarterial oily chemoembolization" is defined as a
superselective catheterization in the subsegmental or more distal artery
followed by oily chemoembolization, in which the entire process is assisted
and the achievement is confirmed by findings of the unified helical CT and
angiography system.
The unified system of helical CT and angiography (Interventional-CT; Toshiba, Tokyo, Japan) [14] consists of helical CT (X-vision; Toshiba) and angiography units in which digital subtraction angiography equipment with a C-arm (Angiorex, CAS-8000V; Toshiba) is arranged in a linear configuration to form a common couch, facilitating quick transportation of the patient from one unit to the other for CT during arterial portography and CT arteriography without risking dislodgment of the catheter.
Before transarterial oily chemoembolization, the following baseline study was carried out in all patients with the unified CT and angiography system for precise information about the number and exact location of lesions in the entire liver: CT during arterial portography [17] (Fig. 1A) followed by the common or proper hepatic arteriography and CT arteriography [18] of the proper hepatic or the right or left hepatic artery when it derives independently. Hepatic arteriography in the right anterior oblique position was performed, if necessary. On the basis of the baseline study findings, the feeding artery was determined. Subsequently, a 2.7-French 100-cm-long microcatheter (Rapid transit TM; Cordis, Miami, FL) with a double angle—shaped 0.016-inch 150-cm-long guidewire covered by hydrophilic polymer (Radifocus; Terumo, Japan) was advanced through a 5-French catheter into the peripheral portion of the feeding artery as close to the lesion as possible (Fig. 1B), and follow-up CT arteriography was performed to confirm the possible feeding artery supplying the targeted lesion and the expected extent of embolization of the noncancerous portion (Fig. 1C). If the predicted noncancerous hepatic portion to be embolized was large enough to deteriorate hepatic functional reserve, the catheter tip was advanced in the more peripheral part of the feeding artery (Fig. 1D). Follow-up CT angiography was performed (Fig. 1E), followed by transarterial oily chemoembolization with an emulsion of 30 mg of doxorubicin hydrochloride (Adriamycin; Adria, Dublin, OH) dissolved in 3 mL of iopamidol (Iopamiron, 300mg I/mL; Schering, Tokyo) mixed with 5 mL of iodized oil (Lipiodol Ultra-Fluid; Guerbet, Paris, France), or followed by a suspension of 4 mg of zinostatin stimalamer (a lipophilic anticancer agent containing 4 mL of iodized oil) (Smancs; Yamanouchi, Tokyo, Japan) [19] and then by gelatin sponge particles (Gelfoam; Upjohn, Kalamazoo, MI). The end point of transarterial oily chemoembolization was cessation of arterial blood flow. If deposition of iodized oil in the lesion was inadequate, another feeding artery was sought (Fig. 1F), and CT arteriography was performed again to confirm the feeder supplying the lesion with an undeposited portion (Fig. 1G). Transarterial oily chemoembolization was carried out again. Finally, complete deposition of the iodized oil in the lesion was confirmed by unenhanced CT to complete treatment (Fig. 1H)
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For CT during arterial portography and CT arteriography, 370 mg I/mL of ioversol (Optiray; Yamanouchi) diluted to 92 mg I/mL by saline solution (1:3) was used. CT during arterial portography was performed with the catheter tip placed in the superior mesenteric artery, 90 mL of contrast medium was injected after administration of 10 µg of prostaglandin E1 at a rate of 3 mL/sec, and CT was begun 20 sec after the start of the injection. For CT arteriography in the hepatic arteries, the following adequate dose of contrast medium that never regurgitates was injected: 60 mL for CT arteriography through the proper or common hepatic artery at a speed of 2 mL/sec, 30 mL for the segmental artery at a speed of 1 mL/sec, and 6-10 mL for subsegmental or more peripheral arteries at a speed of 0.3-0.5 mL/sec. CT was started 8-10 sec later. The following parameters were used: slice thickness, 5-7 mm; pitch, 1:1.
On the second or third day after transarterial oily chemoembolization,
blood was collected for measuring albumin, total bilirubin, aspartate
aminotransferase, and alanine aminotransferase. Follow-up CT with measurement
of -fetoprotein was performed 1 month after transarterial oily
chemoembolization and every 3 months thereafter. If the enhanced area was
located within or abutting the embolized lesion, it was diagnosed as a local
recurrence; a lesion newly appearing at a different site from the initially
treated lesion was defined as a recurrence at a different site. For treating
recurrent foci at a local and different area, follow-up targeted transarterial
oily chemoembolization with the unified machine or percutaneous ethanol
injection was performed. Informed consent was obtained from all patients.
The follow-up period between transarterial oily chemoembolization and the outcome of the patient was 556 days on the average (range, 163-1280 days).
Analysis of Factors Affecting Local Recurrence and Survival After One
Session of Oily Chemoembolization
To analyze factors affecting local recurrence after one session of
transarterial oily chemoembolization for 71 hepatocellular carcinoma lesions,
the following factors were evaluated (Table
1): tumor diameter measured on CT, minimum distance between the
margin of tumor and the liver surface, grade of liver function according to
Child classification (A, B, C), degree of deposition of iodized oil in the
lesion classified by unenhanced CT performed immediately after transarterial
oily chemoembolization (excellent, 100% deposition of iodized oil in the
lesion; good, 51-99%; poor, 50%) and in the noncancerous hepatic portion
around the lesion (excellent, deposited completely around the lesion
[Fig. 1H]; good, deposition
between excellent and poor; poor, 50% deposition), location of lesion
(right, left, or caudate lobe), location of hepatic artery embolized (right
hepatic, right anterior, posterior or left hepatic artery versus more
peripheral artery), anticancer agent used (doxorubicin hydrochloride,
zinostatin stimalamer), and use of gelatin sponge particles.
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Statistical Analyses
All analyses were performed by SAS statistical software. Univariate
analyses such as survival and recurrence-free rates were estimated by the
Kaplan-Meier method [20] and
evaluated by the log-rank test. A landmark analysis
[21,
22] was used to evaluate
significant survival risk of events observed during a follow-up period, such
as local recurrence, recurrence at a different site, tumor thrombus in large
vessels, and temporal alteration of liver function based on Child
classification. A landmark of 12 months was determined on the basis of 90% and
70% of the patients eventually developing local recurrence and tumor thrombus,
respectively, 12 months after the first transarterial oily chemoembolization,
and of 70% of the patients living at that time. For multivariate analysis, Cox
proportional hazards model
[23] was used with PHREG
(Proportional Hazard REGression) procedure of SAS. The events observed during
the follow-up were included in the multivariate Cox regression model by
defining them as time-dependent covariates. Methods of stepwise selection and
best subset selection in the PHREG procedure were used to identify important
prognostic factors (p < 0.05 [two-tailed test] was statistically
significant).
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Twenty-three lesions (32.4%) in 20 patients (37.0%) showed local recurrence after the first transarterial oily chemoembolization. One-year, 2-year and 3-year local recurrence rates were 33.2%, 37.8%, and 37.8%, respectively (Fig. 2). The univariate analysis of factors showed only tumor size to be statistically significant. The multivariate analysis with the Cox proportional hazards model for affecting local recurrence showed tumor size and the degree of deposition of the iodized oil within the lesion (excellent versus good and poor) to be significant (Table 2). With respect to the relationship between the tumor size and the local recurrence rate, there was a statistically significant difference among three groups with different tumor sizes (Fig. 3). The larger the tumor size, the higher the local recurrence rate and the earlier the local recurrence appeared. Other factors such as grade of Child classification, degree of iodized oil deposition in the surrounding noncancerous portion, location of the lesion, site of the embolized hepatic artery, anticancer agent used, and gelatin sponge used were not statistically significant.
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The outcome of the 23 local recurrent foci was as follows: 15 lesions treated by repeated targeted transarterial oily chemoembolization and three lesions, by percutaneous ethanol injection; one lesion, associated with tumor thrombus in the portal vein and bone metastases, by systemic chemotherapy; and in four lesions, therapy not chosen until the end of the observation period.
Survival Rate for 54 Patients After Transarterial Oily
Chemoembolization
The 1-year, 2-year, and 3-year survival rates were 93.3%, 77.1%, and 77.1%,
respectively (Fig. 4). Eight
patients died of intra- and extra- hepatic extension of cancer, and one died
of hepatic failure after rupture of the esophageal varix. During the follow-up
period, recurrent metachronous foci in different sites of the liver were
recognized in 33 patients. The 1- and 2- year rates of recurrence at different
areas were 39.3% and 91.0%, respectively. In addition, the recurrence pattern
recognized on CT was a solitary lesion with an average diameter of 1.6 cm
(range, 0.5-6.0 cm) in 22 patients, multiple lesions developing in one lobe
and both hepatic lobes in five each, and tumor thrombus of the portal vein in
one. For treatment, follow-up targeted transarterial oily chemoembolization
was performed in 22 patients an average of 1.4 times (range, 1-4 times),
percutaneous ethanol injection was performed in two patients, and no therapy
was performed in nine patients. Five patients had tumor thrombus in a major
vein (four portal and one hepatic), and four did not undergo any therapy in
the observation period.
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The following four factors during the observation period after
transarterial oily chemoembolization were significant by the univariate
analysis: maximum tumor size, local recurrence, tumor thrombus, and
logarithmic value of -fetoprotein. The multivariate analysis showed
that the tumor thrombus in the portal or hepatic vein and the largest tumor
size were significant factors affecting the survival of the patient
(Table 2). No statistical
significance was recognized in other factors such as Child classification,
hepatitis B surface antigen, antihepatitis C virus, past history of
hepatectomy, alteration of Child classification between pre- and
posttransarterial oily chemoembolization, number of lesions, stage of
hepatocellular carcinoma, metachronous recurrence at a different site, the
site of embolized artery, and anticancer agent used.
Complications of Targeted Transarterial Oily Chemoembolization
All 54 patients were discharged with a mean hospital stay of 6.3 days
(range, 5-10 days). No patient died as a result of transarterial oily
chemoembolization. High temperature more than 38°C lasting less than 3
days after transarterial oily chemoembolization was observed in 39 patients
(72.2%); abdominal pain requiring a sedative and nausea or vomiting was
observed in nine patients (16.7%) each; and elevation of aspartate
aminotransferase or alanine aminotransferase more than 500 U/L was observed in
two patients (3.7%). These complications could be controlled by palliative
therapy.
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Conventional transarterial oily chemoembolization has been developed with the introduction of the unique carrier of anticancer agent, iodized oil, and a microcatheter that makes segmental [6] or subsegmental [8] transarterial oily chemoembolization possible. It is now widely performed as a palliative treatment for advanced hepatocellular carcinoma. However, without assistance of sectional imaging such as CT at transarterial oily chemoembolization, superselective catheterization into the real feeding artery to obtain complete necrosis of the hepatocellular carcinoma lesion was not always successful. Therefore, inadvertent misembolization occurred. The targeted lesion was not embolized, and instead, the noncancerous hepatic portion that should be preserved was misembolized resulting in severe hepatic damage (Fig. 5A,5B). This kind of misembolization was not found immediately after transarterial oily chemoembolization but usually 1 month later by follow-up CT.
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With the advent of the unified system for helical CT and angiography, the previously mentioned difficulty of the conventional transarterial oily chemoembolization has been overcome, and several advantages have been added. Using selective arteriography of the feeding artery followed by CT arteriography and repeating these studies after advancing the microcatheter to a more distal artery (Fig. 1A,1B,1C,1D,1E,1F,1G,1H), we found it possible to achieve targeted transarterial oily chemoembolization, strengthening the effect of chemoembolization on the targeted lesion and reducing the damage to the surrounding noncancerous portion. Because of this method, relatively larger amounts of anticancer agent and embolization material can be injected per tumor. The amount of anticancer agent and iodized oil used in the conventional transarterial oily chemoembolization was presumed to be reduced to two thirds. The amount of gelatin sponge has been drastically reduced. Much more iodized oil can be injected with nearly all tumor vessels embolized, and consequently, the caliber of vessels for gelatin sponge is rendered much smaller. As a result, the incidence of abdominal pain after chemoembolization has remarkably decreased, and some patients could be discharged without pain and fever 6 days after transarterial oily chemoembolization. Reported severe inadvertent complications such as hepatic biloma, abscess, septicemia, chemical cholangitis, gastrointestinal bleeding, and hepatic infarction [24] were not encountered.
Another merit of this unified machine is the capability of confirming on CT and at the completion of treatment whether the targeted lesion is completely treated by transarterial oily chemoembolization. By performing unenhanced CT immediately after transarterial oily chemoembolization, distinction can be made between primarily incomplete deposition of iodized oil and secondarily incomplete deposition as a result of washout of iodized oil from the initially completely deposited lesion. This distinction is important to verify the mechanism of local recurrence and to assess the characteristics of anticancer agents used for embolization therapy in the future, namely, whether it has an affinity for tumor vessels.
In our study, the local recurrence rate with single-session targeted
transarterial oily chemoembolization with the unified CT and angiography
system was 33.2%, 37.8%, and 37.8% at 1, 2, and 3 years, respectively
(Fig. 2). The results of one
session of subsegmental transarterial oily chemoembolization for small
hepatocellular carcinomas ( 4 cm) reported by Matsui et al.
[8] (18% at 1 year, 30% at 2
years, and 33% at 3 years) were superior to ours even though they did not use
this kind of unified system. The reason for the difference may be mainly the
size of tumor that we ( 5 cm) and they ( 4 cm) treated because the
larger the tumor size, the higher the local recurrence rate
(Fig. 3). In our study, all
local recurrences were recognized in 1.5 years after transarterial oily
chemoembolization (Fig. 2).
This recurrence rate suggests that follow-up is needed for at least 2
years.
Cox proportional hazards model suggests tumor size and the degree of deposition of iodized oil within the lesion as significant factors affecting the local recurrence. In relation to the tumor size, large hepatocellular carcinomas (2.5-5 cm) showed a higher local recurrence rate and earlier appearance than smaller ones (Fig. 3). The reason for higher local recurrence with a large lesion may be increased numbers of feeding arteries that result in inhomogeneous deposition of iodized oil and extension of cancer cells beyond the fibrous capsule and into the portal vein. The degree of deposition of iodized oil and tumor necrosis are well correlated [25, 26].
Iodized oil is also deposited in the noncancerous portion, and it is partially accounted for by retention of iodized oil in the portal vein, which receives flow from the hepatic artery via the peribiliary plexus [27]. This retention is perhaps related to reduction of the local recurrence. The marginal portion of the lesion receives both arterial and portal blood flows, and the portal blood flow increases reciprocally after ligation of the artery [28]. However, no statistical significance for the degree of deposition of iodized oil in the surrounding noncancerous parenchyma was recognized in our study. For conventional transarterial oily chemoembolization, gelatin sponge particles are thought to be indispensable for strengthening the anticancer effect as verified by pharmacokinetics [29] and histopathologic study [12]. In targeted transarterial oily chemoembolization, there was no statistically significant difference in recurrence rate between the groups with and without gelatin sponge. Gelatin sponge might not be as important as previously believed because superselectively injected iodized oil probably occupies almost the entire vascular bed in the lesion, producing a strong effect similar to stopping the blood flow with gelatin sponge.
In our study, the following survival rates were obtained with transarterial oily chemoembolization: 93.3% at 1 year and 77.1% at 2 and 3 years (Fig. 4). Comparing the 3-year survival rate with conventional transarterial chemoembolization [30] or transarterial oily chemoembolization [31], segmental transarterial oily chemoembolization [6], and subsegmental transarterial oily chemoembolization [8] (Table 3), we found that our results were comparable with those of Matsui et al. [8], even though transarterial oily chemoembolization with the unified CT and angiography system is theoretically superior to subsegmental transarterial oily chemoembolization alone. The significant factors affecting the survival were tumor thrombus in the portal vein and maximal tumor size. According to the Japanese liver cancer study group [32] that analyzed prognostic factors in 5800 patients who underwent resection for hepatocellular carcinoma, tumor size and portal involvement were found to be the significant prognostic factors.
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Recently, prospective and randomized trials of chemoembolization with [10] and without [33] iodized oil comparing it with supportive therapy were conducted outside Japan. Their results showed no significant difference in survival rate between the two groups and suggested no benefit of transarterial chemoembolization or transarterial oily chemoembolization for hepatocellular carcinoma. Their studies consisted of scheduled periodic embolization from the proper [33] or right or left hepatic artery [10] without evaluation of transarterial oily chemoembolization on CT; embolization of liver parenchyma certainly deteriorates the liver function with a shortening of survival time. Ernst et al. [34] reported that the group that received repeated transarterial chemoembolization based on the tumor response showed a significantly better survival rate than the group that received scheduled follow-up transarterial chemoembolization. We believe that the repeated transarterial oily chemoembolization should be performed when local recurrence or a new lesion or both are found on follow-up CT [35]. The targeted transarterial oily chemoembolization with combined CT-angiography system seems best for control of small lesions because it maximizes therapeutic effect for hepatocellular carcinoma and minimizes damage to the noncancerous hepatic portion.
Acknowledgments
We thank Kunio Okuda, Professor Emeritus of Internal Medicine, Chiba School
of Medicine, for his critical review.
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