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Randomized Controlled Trial of Transarterial Lipiodol

Chemoembolization for Unresectable

Hepatocellular Carcinoma

Chung-Mau Lo, Henry Ngan, Wai-Kuen Tso, Chi-Leung Liu, Chi-Ming Lam, Ronnie Tung-Ping Poon,

Sheung-Tat Fan, and John Wong

This randomized, controlled trial assessed the efficacy of transarterial Lipiodol (LipiodolUltrafluide, Laboratoire Guerbet, Aulnay-Sous-Bois, France) chemoembolization in pa-tients with unresectable hepatocellular carcinoma. From March 1996 to October 1997, 80out of 279 Asian patients with newly diagnosed unresectable hepatocellular carcinomafulfilled the entry criteria and randomly were assigned to treatment with chemoembolizationusing a variable dose of an emulsion of cisplatin in Lipiodol and gelatin-sponge particles

injected through the hepatic artery (chemoembolization group, 40 patients) or symptomatictreatment (control group, 40 patients). One patient assigned to the control group second-arily was excluded because of unrecognized systemic metastasis. Chemoembolization wasrepeated every 2 to 3 months unless there was evidence of contraindications or progressivedisease. Survival was the main end point. The chemoembolization group received a total of192 courses of chemoembolization with a median of 4.5 (range, 1-15) courses per patient.Chemoembolization resulted in a marked tumor response, and the actuarial survival wassignificantly better in the chemoembolization group (1 year, 57%; 2 years, 31%; 3 years,26%) than in the control group (1 year, 32%; 2 years, 11%; 3 years, 3%; P .002). Whenadjustments for baseline variables that were prognostic on univariate analysis were made

with a multivariate Cox model, the survival benefit of chemoembolization remained signif-icant (relative risk of death, 0.49; 95% CI, 0.29-0.81; P .006). Although death from liver

failure was more frequent in patients who received chemoembolization, the liver functions ofthe survivors were not significantly different. In conclusion, in Asian patients with unresect-able hepatocellular carcinoma, transarterial Lipiodol chemoembolization significantly im-proves survival and is an effective form of treatment. (HEPATOLOGY 2002;35:1164-1171.)

Hepatocellular carcinoma is one of the most com-mon cancers worldwide, and the largest concen-tration of cases is in Asia.1 The prognosis is poor

because curative resection with partial hepatectomy orliver transplantation is applicable to only a small propor-tion of patients.2,3 For patients with unresectable disease,

the goal of palliative treatment is to prolong survival andto control symptoms. Transarterial Lipiodol (iodizedoil) (Lipiodol Ultrafluide, Laboratoire Guerbet, Aulnay-

Sous-Bois, France) chemoembolization4 combines the ef-fect of targeted chemotherapy5,6 with that of ischemicnecrosis induced by arterial embolization.7-9 Its efficacy inreducing tumor growth and in prolonging survival hasbeen suggested in nonrandomized studies.10-16 However,3 randomized, controlled trials17-19 from Europe and Af-

rica using different regimens of antitumor agents havefailed to show any significant benefit in survival whencomparing patients treated with chemoembolization tountreated controls. These studies included non-Asian pa-tients, and in the 2 trials from France, 3 quarters of thepatients had alcoholic liver disease. There are ethnic dif-ferences in the behavior of hepatocellular carcinoma,20

and the validity of the results of these trials may not beapplicable to Asian patients whose liver disease most com-monly is related to chronic hepatitis B virus infection.1,21

In addition, the efficacy and adverse effects of the treat-ment may be related to the regimen and technique of

From theCenterfor theStudyof Liver Disease, Universityof Hong Kong MedicalCenter, Queen Mary Hospital, Hong Kong, China.

Received July 31, 2001; accepted February 21, 2002.Address reprint requests to: Chung-Mau Lo, M.S., Department of Surgery, Uni-

versity of Hong Kong Medical Center, Queen Mary Hospital, Hong Kong, China.E-mail: chungmlo@hkucc.hku.hk; fax: (852) 28175475.

Copyright 2002 by the American Association for the Study of Liver Diseases.0270-9139/02/3505-0019$35.00/0doi:10.1053/jhep.2002.33156

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chemoembolization. Hence, we conducted a randomizedcontrolled trial to evaluate the regimen of transarterialLipiodol chemoembolization in patients with unresect-able hepatocellular carcinoma at our center.

Patients and Methods

Selection of Patients. Consecutive new patients withdiagnoses of unresectable hepatocellular carcinoma that

were based on histology, cytology, or persistently elevatedserum -fetoprotein levels ( 400 ng/mL) with typicalimaging findings were considered for entry into this sin-gle-center, open-label, randomized trial. Patients werenot included if they refused to participate or had 1 ormore of the following criteria: poor hepatic function(presence of hepatic encephalopathy, ascites not con-trolled by diuretics, history of variceal bleeding within last

three months, a serum total bilirubin level over 50mol/L, a serum albumin level below 28 g/L, or a pro-thrombin time of more than 4 seconds over the control);serum creatinine level of over 180 mol/L; history ofprevious treatment for the tumor or acute tumor rupture;presence of extrahepatic metastasis or vascular contrain-dications to chemoembolization (hepatic artery throm-bosis, main portal vein thrombosis or arteriovenousshunting); or poor performance status (Eastern Coop-erative Oncology Group performance status rating22

grade 4).Randomization. Randomization to either treatment

with chemoembolization (chemoembolization group) orsymptomatic treatment (control group) was performed

without stratification by drawing consecutively num-bered sealed envelopes. The protocol was approved by theethics committee of the Faculty of Medicine of the Uni-versity of Hong Kong, and informed consent was ob-tained from each patient.

Treatment Procedure. The control group receivedonly treatment for symptoms and complications. Patientsin the chemoembolization group underwent transarterialLipiodol chemoembolization after a standard protocol.

They were fasted overnight with intravenous fluid infu-sion for hydration. Intravenous amoxicillin-clavulanicacid (1.2 g), mannitol (20 g), and tropisetron (5 mg) weregiven before the procedure. The femoral artery was cath-eterized under local anaesthesia. Hepatic arteriographyand superior mesenteric arterial portovenography wereperformed to define the size and locations of tumor nod-ules and to exclude occlusion of the main portal vein. Theright or left hepatic artery feeding the tumor was super-selectively catheterized. Using the pumping method,4 anemulsion was prepared by mixing cisplatin (1 mg/mL)

with Lipiodol in a volume ratio of 1 to 1. Various

amounts of the emulsion, up to a maximum of 60 mL(containing 30 mg of cisplatin) were injected slowly un-der fluoroscopic monitoring according to the size of thetumor and the arterial blood flow. The aim was to delivera sufficient amount of the emulsion to the tumorous areas

without retrograde flow. If the tumor involved both lobesof the liver or if superselective catheterization was notpossible, the emulsion was injected into the proper he-patic artery distal to the origin of the gastroduodenal ar-tery. This was followed by embolization with smallgelatin-sponge (Spongostan; Ferrosan, Johnson & John-son Medical Ltd., Skipton, England) pellets of 1 mmdiameter mixed with 40 mg of gentamicin. After the pro-cedure, oral amoxicillin-clavulanic acid (375 mg 3 timesper day) and sucralfate (500 mg 4 times per day) wereadministered for 3 days. Discharge from the hospital wasdecided according to the clinical state. Chemoemboliza-

tion was repeated every 2 to 3 months and would be withheld or discontinued whenever vascular contraindi-cations, poor hepatic function (defined in section on se-lection of patients), severe adverse effects, or progressivedisease developed.

Assessment of Outcome. The primary outcome mea-sure was survival calculated from the date of randomiza-tion. Secondary outcome measures included the tumorresponse, patient tolerance, and liver function. The pa-tients were followed up monthly at the outpatient clinic.

Adverse effects that developed within 2 weeks after eachsession of chemoembolization were recorded. Follow-upassessments, including serum biochemistry, serum -fe-toprotein level, indocyanine green retention test,23 andcomputed tomography scan were repeated every 3months. Tumor response was assessed on the basis ofcomputed tomographic measurement of tumor size (de-termined as the product of the 2 largest diameters) andserum -fetoprotein. Complete response was defined ascomplete disappearance of tumor on imaging or normal-ization of serum -fetoprotein. Response was consideredtobemajoriftumorsizeorserum-fetoprotein decreasedby more than 50% of the baseline measurement and mi-

nor if the reduction was 50% or less but more than 25%.Stabilization corresponded to variations25% of the ini-tial value and progression to an increase of more than25%. Objective response was defined as the sum of com-plete and major responses. Follow-up was continuedthrough October 30, 2000.

Statistical Analysis. The 2-year survival rate of thecontrol group was estimated at 10% according to thepublished data on the natural course of Asian patients

with untreated Okuda stage I and II hepatocellular carci-noma.24 Based on our previous case series,13 reporting a38% 2-year survival in patients treated with the present

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regimen of chemoembolization, 40 patients were neededin each group to have a level of statistical significance of5% and a power of 80%.

Comparison between groups was made on an inten-tion-to-treat basis. Continuous variables were expressed

as median (interquartile range) and compared using theMann-Whitney U test. Categorical variables were com-pared with the 2 test or Fishers exact test. Spearmanscorrelation coefficient and linear regression were used toexpress the relationship between the dosage of cisplatin-Lipiodol emulsion and tumor size. Univariate analysis for13 baseline variables to identify predictors of survival wasperformed by estimating survival rate according to theKaplan-Meier method25 and comparing with the use ofthe log-rank test. For continuous variables, the cutoff wasset at the median value. In addition, a univariate Coxproportional hazards model was fit individually for each

continuous variable. The survival curves of the treatmentand control groups were then compared with stratifica-tion according to each statistically significant prognosticfactor. Finally, all the significant prognostic factors iden-tified from univariate analysis were put into a Coxproportional hazards model26 for multivariate analysis.Statistical analysis was performed with the SPSS (SPSSInc., Chicago, IL) computer software program.

Results

From March 1996 to October 1997, we evaluated 387Asian patients with newly diagnosed hepatocellular carci-noma. A total of 108 patients underwent surgery (partialhepatectomy, 104; cryotherapy, 4) and 199 of 279 pa-tients (71.3%) with disease not amenable to surgery werenot included in the study because of vascular contraindic-tions (53 patients), extrahepatic metastasis (26 patients),poor hepatic function (39 patients), refusal by patients(32 patients), previous treatment for the tumor (24 pa-tients) or acute tumor rupture (8 patients), poor perfor-mance status (11 patients), indication for percutaneousintralesional ethanol injection (2 patients), and others (4patients). The remaining 80 patients were allocated ran-

domly to the chemoembolization group (40 patients) orthe control group (40 patients). One patient assigned tothe control group was excluded secondarily because ofunrecognized pulmonary and bone metastases on com-puted tomography scan taken before randomization. Hereceived conservative treatment and survived for 3months. Thus, the data consisted of observations in 79patients. Sixty-three patients (80%) had positive serologytest results for hepatitis B surface antigen. Thirty-sevenpatients (47%) had Okuda stage I disease, and 42 (53%)had stage II disease. The 2 groups were well balanced inregard to the baseline characteristics (Table 1).

Chemoembolization Treatment. Forty patients as-signed to the chemoembolization group received a totalof 192 courses of chemoembolization, with each patientreceiving a median of 4.5 courses (range, 1-15). Twopatients were scheduled for continuation of chemoem-bolization as of the date of the latest follow-up. Theremaining 38 patients had treatment stopped because ofprogressive disease (12 patients), death (7 patients), poorliver function (6 patients), adverse effects (6 patients),patient refusal (3 patients), arteriovenous shunting (2 pa-tients), and hepatic artery thrombosis (2 patients).

Ninety-four courses (49%) of the chemoembolizationwere performed by selective injection into the right or lefthepatic artery. The median volume of cisplatin-Lipiodolemulsion injected in 1 course was 20 mL (range, 2-60),and the dosage was significantly related to the tumor size(r 0.70; P .001) (Fig. 1). The most common clinicaladverse effect was a self-limiting syndrome consisting offever, abdominal pain, and vomiting (Table 2). The me-dian hospital stay for each course of treatment was 2 days(range, 1-21).

Overall Survival. Two patients, 1 in each group,were lost and could not be contacted after a follow-up of

Table 1. Baseline Characteristics of the Study Patients

According to the Treatment Group

Chemoembolization

(N 40)

Control

(N 39)

Age (yr)* 62 (53-69) 63 (53-70)

Sex (men/women) 36/4 34/5

Serum hepatitis B surface antigen

(positive/negative) 34/6 29/10

Serum creatinine (mol/L)* 92 (82-102) 87 (78-98)

Serum total bilirubin (mol/L)* 14 (10-21) 13 (11-23)

Serum albumin (g/L)* 38 (32-42) 37 (33-40)

Serum alanine aminotransferase

(1 /L)* 51 (38-83) 53 (35-88)

Prothrombin t im e (s)* 11.5 (10 .9-12.4) 11.5 (10.8-12.5)

Serum -fetoprotein (ng/mL)* 505 (55-5,874) 500 (58-24,458)

Serum -fetoprotein (ng/mL; 20/

20-500/500) 6/14/20 8/12/19

Indocyanine green retention at 15

minutes (%)* 24 (6-33) 18 (6-38)

ECOG performance status rating

(0/1/2/3) 20/16/3/1 14/19/4/2

Presenting symptom (asymptomatic/symptomatic) 12/28 10/29

Diameter of largest tumor mass

(cm)* 7 (4-14) 7 (5-11)

Number of tumors

(solitary/multinodular) 17/23 15/24

Portal vein obstruction (right/left/

main) 6/3/0 7/5/0

Okuda stage (I/II) 19/21 18/21

NOTE. P .05 for all variables when the 2 groups are compared.

*Values are medians, with interquartile ranges shown in parentheses.

Assessed by computed tomography.

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4 months and 9 months. These were treated as censored

observations. At the time of the final analysis, 31 patientsof the chemoembolization group and 37 patients of thecontrol group had died. The causes of death were tumorprogression (20 in chemoembolization group and 34 incontrol group); hepatic failure (5 in chemoembolizationgroup and 1 in control group); gastrointestinal bleeding(4 in chemoembolization group); sepsis (2 in controlgroup); and rupture of tumor (2 in chemoembolizationgroup). The actuarial survival was significantly better inthe chemoembolization group than in the control group(Fig. 2). The estimated 1-year, 2-year, and 3-year survivalrates were 57%, 31%, and 26% for the chemoemboliza-

tion group and 32%, 11%, and 3% for the control group(relative risk of death in the chemoembolization group

was 0.50; 95% CI, 0.31-0.81; P .005). Univariate anal-ysis with log-rank test identified 5 significant prognosticfactors: study treatment, presenting symptom, unilobarportal vein obstruction, tumor size, and Okuda stage (Ta-ble 3). Tumor size also was a significant prognostic factor

when each continuous variable was put individually into aunivariate Cox model (P .03). Comparison of survivalbetween the chemoembolization and control groups strat-ified according to each of the other 4 prognostic factorsrevealed that the survival benefit of chemoembolization

was significant in each subgroup except for those withtumors larger than 5 cm in diameter or unilobar portalvein obstruction (Table 4). With multivariate analysis, 2of the 5 variables in the final Cox model were statisticallysignificant: treatment with chemoembolization and uni-lobar portal vein obstruction. Patients who received che-moembolization had a relative risk of death of 0.49 (95%CI, 0.29-0.81; P .006) as compared with those of thecontrol group, thus confirming the independent survivalbenefit of treatment with chemoembolization. The rela-tive risk of death for patients with unilobar portal veinobstruction was 2.71 (95% CI, 1.38-5.32; P .004).

Secondary End Points. Tumor response on com-puted tomography could be determined in 46 patients(28 in the chemoembolization group and 18 in the con-trol group) who survived more than 3 months and had ameasurable tumor on computed tomographic scan. In thechemoembolization group, there was no complete re-sponse, 11 major responses, 6 minor responses, 7 stabili-zations, and 4 progressions. In the control group, there

was no complete response, 1 major response, 2 minorresponses, 6 stabilizations, and 9 progressions. The rate ofobjective tumor response in measurable patients was sig-nificantly higher in the chemoembolization group than in

the control group (39% vs. 6 %; P .014).-Fetoprotein response could be assessed in 50 pa-

tients (29 in the chemoembolization group and 21 in thecontrol group) who had a baseline serum -fetoproteinlevel 20 ng/mL and survived more than 3 months. Inthe chemoembolization group, there were 9 complete re-sponses, 12 major responses, no minor response, 1 stabi-lization and 7 progressions. In the control group, there

was no complete response, 2 major responses, no minor

Fig. 1. Correlation between volume of cisplatin-Lipiodol emulsion

injected during the first course of treatment and the tumor size (linear

regression and Spearman correlation coefficient).

Fig. 2. Probability of survival in patients treated with chemoemboli-

zation and in patients of the control group (log-rank test, P .002).

Table 2. Complications of 192 Courses of

Chemoembolization in 40 Patients Assigned

to Receive Treatment

Complication No. of Complications (%)

Fever38C 63 (32.8)

Abdominal pain 50 (26.0)

Vomiting 32 (16.7)

Ascites 10 (5.2)

Gastrointestinal bleeding 8 (4.2)

Bleeding from femoral puncture site 3 (1.6)

Encephalopathy 3 (1.6)

Ruptured tumor 2 (1.0)

Pleural effusion 2 (1.0)

Liver abscess 1 (0.5)

Hematuria 1 (0.5)

Hypotension 1 (0.5)

Bradycardia 1 (0.5)

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response, 1 stabilization and 18 progressions. The rate ofobjective response was significantly higher in the chemo-embolization group than in the control group (72% vs.10%; P .001). Extrahepatic metastasis was found in 11patients in the chemoembolization group and 5 patientsin the control group (P .105).

Apart from a lower serum bilirubin level in the chemo-embolization group at 3 months (P .038), there was nosignificant difference in the liver function of the survivorsof the 2 groups, as assessed by serum bilirubin level, serumalbumin level, and indocyanine green retention rate (Ta-ble 5). Excluding the scheduled hospital admissions for

chemoembolization, the median number of admissionsfor adverse events was 1 (range, 0-8) in both the chemo-embolization group and the control group for a cumula-tive median of 13 days (range, 0-215) and 13 days (range,0-96), respectively (P .31).

Discussion

Hepatocellular carcinoma is a common form of malig-nancy in Asia. In some Western countries, a high inci-dence rate frequently is seen among Asian immigrants as

well.1 The causal factors in Asian patients are distinctlydifferent from those in western patients, and chronic hep-atitis B infection is the most common etiology. The treat-ment for hepatocellular carcinoma remains difficultbecause of the advanced tumor stage at diagnosis and theassociated cirrhosis. No single available therapy is appli-cable to all patients and the treatment should be cateredaccording to the clinical state of the individual patient.Hepatic resection offers a chance of cure for a minor pro-portion of patients with early tumor and preserved liverfunctions. Because of the shortage of organ donors, therole of liver transplantation remains limited. The majorityof the patients with unresectable hepatocellular carci-noma are treated by various palliative therapies. In con-sidering treatment for these patients with variable tumorstages and liver reserve, it is important to select those whomay potentially benefit from the procedure. In the presentstudy, advanced tumor with extrahepatic metastases or

portal vein thrombosis (the most common vascular con-traindication) and poor hepatic function were the 2 mainreasons for exclusion because these patients would defi-nitely not benefit from the study treatment. Hence, lessthan 30% of the patients with disease not amenable tosurgery could be included, and our results showed that

Table 3. Univariate Analysis of Prognostic Variables

for Survival

Characteristics

No. of

Patients

Probability of Survival (%)

P

12

Months

24

Months

36

Months

Study treatmentChemoembolization 40 57 31 26 .002

Control 39 32 11 3

Sex

Men 70 44 20 15 NS (.720)

Women 9 56 33 11

Age (yr)

60 34 35 15 12 NS (.274)

60 45 52 26 17

ECOG performance status

rating

0 34 43 18 9 NS (.384)

1-3 45 46 23 19

Presenting symptom

Asymptomatic 22 77 43 29 .004

Symptomatic 57 33 13 9

Tumor size (cm)

5 26 65 39 27 .019

5 50 37 13 9

Tumor number

Single 32 55 29 16 NS (.225)

Multiple 47 39 16 14

Unilobar portal vein

obstruction

Negative 58 60 27 18 .001

Positive 21 5 5 5

Okuda stage

I 37 61 35 23 .003

II 42 31 10 7

Serum albumin (g/L)

37 40 44 16 10 NS (.341)

37 39 46 27 19

Serum bilirubin (mol/L)

14 41 41 23 18 NS (.967)

14 38 49 19 11

Indocyanine green retention

at 15 minutes (%)

20 38 39 20 17 NS (.635)

20 41 50 23 13

-Fetoprotein (ng/mL)

500 40 54 32 19 NS (.059)

500 39 36 10 10 Table 4. Comparison of Survival Between the

Chemoembolization and Control Groups Stratified

by Baseline Prognostic Variables

Chemoembolization Control P

Presenting symptom

Asymptomatic 25.4 (17.5) 16.6 (2.5) .039

Symptomatic 11.2 (2.6) 5.2 (1.4) .019

Unilobar portal vein obstruction

Negative 18.0 (3.5) 9.2 (5.6) .008

Positive 5.1 (2.2) 2.6 (2.3) NS (.406)

Tumor size (cm)

5 29.8 (12.2) 11.5 (3.0) .003

5 11.2 (1.8) 5.3 (1.4) NS (.115)

Okuda stage

I 25.4 (9.1) 11.5 (5.8) .016

II 9.2 (4.1) 5.2 (1.5) .040

NOTE. Values are median survival times in months with standard errors in

parentheses.

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transarterial Lipiodol chemoembolization with the presentregimen induced a marked tumor response and signifi-cantly prolonged the survival of this selected group of

Asian patients with unresectable hepatocellular carci-noma and preserved liver functions. By adjusting for base-line prognostic factors in a Cox model, treatment withchemoembolization remained a significant independentfactor that reduced the hazard of death by half.

The differences in patient population and methodol-

ogy account for the differences between the positive resultof our trial as compared with the absence of survival bene-fit reported in previous randomized controlled trials.17-19

One trial from South Africa18 mostly included black ormixed-race patients with advanced tumors, and the con-clusion would not be valid for other patients. The other 2randomized trials from France17,19 included European pa-tients, mainly with alcohol-induced liver disease. Despiteobvious evidence of tumor response in both trials, thesurvival benefit might have been offset by the adverseeffects of chemoembolization because of the poor toler-ance of patients with alcoholic cirrhosis to this form oftreatment.19 In addition, there are ethnic differences inthe behavior of hepatocellular carcinoma20 and the natu-ral history of untreated disease in European patients27,28 ismuch better than that of Asians.24 It has been shown thatuntreated patients who had positive results for hepatitis Bsurface antigen had a worse prognosis.28 Our study in-cluded Asian patients with mostly hepatitis Brelatedhepatocellular carcinoma of Okuda stage I or II. The2-year survival rate of 11% in our control group was com-parable with our estimation based on the published datain Asian patients24 and was lower than the 26% 2-year

survival rate of untreated patients as reported in theFrench multicenter trial.19

The technique and regimen of chemoembolizationalso affect the outcome of treatment. In our study, weused cisplatin-Lipiodol emulsion and gelatin sponge par-ticles. This is the most generally accepted method forchemoembolization. However, our technique and regi-men differed from those of the previous trials in several

ways. First, to maximize the efficacy and to minimize

toxicity, chemoembolization was given by selective injec-tion into the feeding artery in nearly half of our cases.Second, we used a lower dosage of cisplatin in our trial(median of 10 mg) compared with that of the Frenchmulticenter trial19 (fixed dosage of 70 mg), and this mayaccount for the patients better tolerance of treatment.Third, in contrast to the fixed dosage of antitumor agentthat was used in the other studies,17-19we used a variabledosage of cisplatin-Lipiodol emulsion that was based onthe tumor size.11,13,14As chemoembolization is a form oftargeted therapy, the amount of drug required should betailored according to the size of the target to minimize theadverse effects caused by the excessive amount of drugdelivered to the normal liver tissue. Finally, we did not setany limit to the number of treatment courses in our trial.Provided the patient tolerated the procedure and the tu-mor continued to respond, chemoembolization was re-peated at regular intervals to continue the suppression oftumor growth. Half of the patients received more than 4courses of treatment and as many as 15 courses were givento 1 patient.

Using such a regimen, objective response rate in serum-fetoprotein level was 72% and in tumor size 39%. The

Table 5. Comparison of Liver Function as Assessed by the Serum Bilirubin Level, Serum Albumin Level, and Indocyanine

Green Retention Rate at 15 Minutes

Chemoembolization Group Control Group

P

No. of

Patients

Median

(Interquartile Range)

No. of

Patients

Median

(Interquartile Range)

Bilirubin (mol/L)3 Months 34 15 (10-31) 24 21 (14-42) .038

6 Months 24 14 (11-24) 13 17 (10-28) .987

9 Months 19 16 (10-20) 7 18 (12-32) .385

12 Months 17 13 (9-23) 9 15 (11-30) .517

Albumin (g/L)

3 Months 34 36 (31-40) 24 32 (26-37) .073

6 Months 24 35 (31-39) 13 35 (28-38) .425

9 Months 19 35 (31-37) 7 33 (28-36) .223

12 Months 17 33 (31-39) 9 34 (27-39) .499

Indocyanine green retention at 15 minutes (%)

3 Months 32 25 (14-43) 25 36 (20-52) .169

6 Months 25 25 (18-38) 13 26 (17-51) .433

9 Months 22 25 (20-34) 10 28 (15-48) .405

12 Months 17 26 (13-34) 9 32 (22-47) .146

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lower response rate in tumor size may be attributed to thepersistent Lipiodol staining in areas of the tumor thatmight not contain viable cancer cells. This benefit of tu-mor suppression was not offset by the adverseeffect on thefunction of the normal liver. Although there were more

deaths attributed to liver failure in patients who receivedchemoembolization, this might reflect partly the naturalcourse of the underlying liver disease when death causedby tumor progression has been effectively delayed withchemoembolization. On the other hand, for untreatedpatients with advanced tumor, tumor progression wasrecognized as the cause of death even though features ofliver failure were usually present. In any case, the adverseeffect on liver function was not observed in the survivors.

With a significantly longer survival in patients who re-ceived chemoembolization, the liver function of survivors

was at least no worse than that of the control group. In

addition, there was no significant increase in the need forhospital admission for adverse events. The 2-year survivalrate was increased to 31% and this was consistent with ourprevious experience.13

The prognosis of hepatocellular carcinoma is corre-lated with factors related to the extent of tumor and he-patic function.24,29-31 In our study, all the prognosticfactorsfor survival were related to tumor growth and none

was related to liver function, because patients with de-compensated cirrhosis were excluded. To further improvethe results of Lipiodol chemoembolization, we stratifiedthe patients according to the baseline prognostic vari-ables. The survival benefit of treatment was maintained inall the subgroups except those with large tumors or uni-lobal portal vein obstruction. However, it is important tonote that the comparison of survival between the treat-ment and control group after stratification may result in aloss of statistical power. Chemoembolization improvedthe median survival of patients with tumors larger than 5cm from 5.3 months to 11.2 months, although the differ-ence was not statistically significant (P .115). There

were only 21 patients with unilobar portal vein obstruc-tion, and it would be difficult to show a significant

survival benefit with chemoembolization in this subgroupof patients. Nevertheless, the presence of unilobar portalvein obstruction has remained with chemoembolizationtreatment as the 2 independent prognostic factors in themultivariate Cox model. The presence of unilobar portalvein obstruction increased the risk of death by almost 3times and the median survival with and without chemo-embolization was only 5.1 months and 2.6 months, re-spectively. Because the dismal prognosis is notsignificantly improved by chemoembolization, it may notbe appropriate to recommend this form of treatment forthis subgroup of patients.

In conclusion, transarterial Lipiodol chemoemboliza-tion using the present regimen prolongs the survival of aselected group of Asian patients with unresectable hepa-tocellular carcinoma and is an effective palliative treat-ment option. Whether non-Asian patients with this

disease condition will benefit from a similar regimen orother regimens of chemoembolization remains to be de-termined by further randomized controlled trials.

Acknowledgment: The authors thank Dr. To-WaiLeung of the Department of Clinical Oncology, TuenMun Hospital, for his constructive comments for themanuscript.

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