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Therapeutic Efficacy of Transcatheter Arterial Chemoembolization as Compared With Hepatic Resection in Hepatocellular Carcinoma Patients With Compensated Liver Function in a Hepatitis B Virus–Endemic Area: A Prospective Cohort Study

From the Departments of Internal Medicine, Surgery, and Radiology, and Liver Research Institute, Seoul National University Hospital, and Department of Applied Statistics, Korea National Open University, Seoul, Korea.

Address reprint requests to Hyo-Suk Lee, MD, Department of Internal Medicine, Seoul National University Hospital, 28 Yungun-dong, Chongno-gu, Seoul 110-744, Korea; email: hsleemd{at}snu.ac.kr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Identifying a special subgroup of hepatocellular carcinoma (HCC) patients who may benefit from transcatheter arterial chemoembolization (TACE) when compared with the standard treatment of hepatic resection (HR) warrants research in Asian countries.

PATIENTS AND METHODS: From January 1993 to December 1994, 182 patients with operable HCC (Child-Pugh class A and International Union Against Cancer [UICC] stage T1-3N0M0) were enrolled. After initial TACE and lipiodol computed tomography, 91 received HR and 91, who refused the operation, received repeated sessions of TACE. After stratification according to the tumor stage (UICC and Cancer of the Liver Italian Program [CLIP]) and lipiodol retention pattern, the survival rates of the two treatment groups were compared. The median follow-up period was 83 months.

RESULTS: As of December 31, 2000, 48 patients who underwent HR and 68 patients who underwent TACE had died. In a subgroup analysis according to tumor stage, the HR group survival rate was significantly higher than the TACE group in both UICC T1-2N0M0 (P = .0058) and CLIP 0 (P = .0027) subgroups. However, there was no significant difference in either UICC T3N0M0 (P = .7512) or CLIP 1-2 (P = .5366) subgroups. Even in patients with UICC T1-2N0M0 HCC, when lipiodol was compactly retained, the survival rate of the HR group was comparable to that of the TACE group (P = .0596).

CONCLUSION: TACE proved to be as effective as HR in the subpopulations with UICC T3N0M0 or CLIP 1-2 HCC and adequate liver function, and even with UICC T1-2N0M0 HCC when lipiodol was compactly retained in the tumor. In such cases, the choice of treatment modality between TACE and HR may be left to the patient’s preference.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
HEPATOCELLULAR carcinoma (HCC) is one of the most common malignant tumors worldwide,¹ and the overall results of its treatment remains unsatisfactory.² In patients with advanced HCC at the initial diagnosis, transcatheter arterial chemoembolization (TACE) has been widely carried out and is currently the most common nonsurgical treatment for HCC in Asian countries.³ However, the therapeutic efficacy of TACE has not been confirmed by randomized, controlled trials in these areas. In fact, three prospective randomized studies performed recently in Western countries failed to provide any evidence of a survival benefit in patients treated with TACE when compared to untreated patients.^4-6 However, the therapeutic results from these Western studies cannot be extrapolated to Asian countries because there may be differences in the natural history and presentation of HCC between the two populations. These differences probably are the result of the variance in the causes of the underlying chronic liver disease.⁷ Furthermore, these differences may also result from a bias in Western studies, such as the selection of patients with an extremely poor prognosis and early mortality. Therefore, there is a need for an independent evaluation of the therapeutic efficacy of TACE among Asian patients with HCC who have a better natural prognosis.

From an oncology point of view, evaluating the therapeutic efficacy of TACE in terms of survival requires a comparison with an absence of treatment in a randomized controlled study. However, such an approach would raise critical ethical concerns, especially in Asian countries, because a number of patients would be left untreated.^3,8 Another suitable method could be a comparison with the standard treatment of hepatic resection (HR) in various patient subpopulations, especially patients who generally have a less advanced tumor stage and better liver function. However, such an approach would also raise a methodologic problem; namely, that randomization of the nonsurgical procedures of TACE and the surgical procedures of hepatic resection is not realistic because of different levels of invasiveness.⁹ HR is considered more invasive than TACE because the hospital death rate is higher and the duration of initial hospitalization and the cumulative duration of hospitalization between the first treatment and death are significantly longer in those that receive HR rather than TACE even in patients with an underlying Child-Pugh class A liver function.⁹ An alternative method adopted in this study was to enroll all patients with resectable HCC and Child-Pugh class A liver function in a single institute during the same period of time and to assign the treatment modality according to the patient’s own preference. This study aimed to compare prospectively the survival rates between HR and TACE patients, with the two treatment groups closely matched or stratified according to the prognostic variables, and to find the specific subgroup of HCC patients who may benefit from TACE.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Study Design and Patients
Between January 1993 and December 1994, a total of 828 new HCC patients, who were admitted to the liver unit of Seoul National University Hospital, were prospectively screened. Of these, 190 patients were considered operable (Child-Pugh class A and International Union Against Cancer [UICC] stage T1-3N0M0) and, as a result, were consecutively enrolled as candidates for this study.¹⁰ The diagnosis of HCC and underlying cirrhosis was confirmed as described previously.¹¹ The underlying hepatic function was assessed using the Child-Pugh classification.¹² The tumor extension was initially evaluated by spiral dynamic abdominal computed tomography (s-CT). Because the most important issue in staging HCC is to distinguish UICC T1-3 lesions from UICC T4 lesions, in order to identify HR candidates, the most sensitive imaging technique, namely, lipiodol computed tomography (L-CT),^13,14 was routinely performed about 1 to 2 weeks after the initial TACE treatment to detect both principal and satellite tumors¹⁵ and to assess the lipiodol deposition pattern within the tumors in all enrolled patients.¹⁶ Among 190 patients, the extent of HCC was not evaluated by L-CT in five patients because of the failure of hepatic angiography for technical reasons such as hepatic artery anomalies or a dissection. Eight of the remaining 185 patients, initially classified as UICC T1-3, were confirmed to have UICC T4 lesions because of the presence of satellite nodules in the opposite lobe and were excluded from the study. A total of 182 patients, consisting of the remaining 177 patients and the five patients who could not be evaluated by L-CT, were included in the present study and all gave informed consent for the procedures performed.

A database on all 182 patients was created and the various pretreatment variables at the initial TACE treatment including age, sex, serum alpha-fetoprotein (AFP) level, positivity of hepatitis B surface antigen and antibody to hepatitis C virus (anti-HCV), and Okuda¹⁷ and UICC T stage¹⁰ were recorded. The HCC stage was also analyzed retrospectively according to the Cancer of the Liver Italian Program (CLIP) scoring system, a new prognostic system, recently proposed by the CLIP group,¹⁸ and prospectively validated to predict the prognosis better than the Okuda and UICC staging systems.^19,20 The Child-Pugh class was not included as a pretreatment variable because all the patients enrolled were in class A. The results of the treatments, admissions, and deaths were recorded.

Treatment and Follow-Up
Of the 182 patients, 91, including the five who did not undergo hepatic angiography because of technical reasons, received HR (HR group), and 91, who preferred a less invasive treatment and therefore refused surgery, received repeated sessions of TACE (TACE group). TACE was performed with the infusion of iodized oil (lipiodol, Andre Guerbet, Aulnay-sous-Bois, France) and doxorubicin hydrochloride (Adriamycin, Kyowa Hakko Kogyo, Tokyo, Japan) emulsion through segmental or subsegmental hepatic arteries, especially for small solitary tumors whenever it was possible. When we failed to catheterize tumor feeders or a large tumor was supplied by multiple segmental hepatic arteries, TACE was performed through the right or left hepatic arteries. When an initial blockade of the hepatic artery was insufficient because of the large tumor size or arterioportal shunting, an embolization was performed with gelatin sponge particles (Gelfoam, Upjohn, Kalamazoo, MI) soaked in crystalline mitomycin (Mitomycin-10, Kyowa Hakko Kogyo) and a nonionic contrast medium (iopromide [Ultravist 370], Schering, Berlin, Germany) as previously described.²¹ In the HR group, minor resections less than a segmentectomy were performed in 49 patients, segmentectomies were performed in 25 patients, lobectomies were performed in 16 patients, and trisegmentectomy was performed in one patient. There were no perioperative mortality or life-threatening morbidity cases after HR. Some morbidities such as wound problems, prolonged ascites, pleural effusion, minor abdominal bleeding, biliary fistula, and abdominal abscess were noticed in the HR group but improved with conservative management. As a treatment variable after TACE or HR, the changes in the serum AFP level and the pattern of lipiodol uptake were evaluated. Lipiodol labeling was considered compact when the oily contrast medium was clearly visible and well dispersed throughout the tumor, and was considered noncompact in all other cases.¹⁶

In the subsequent follow-up of patients in both groups, the biochemical liver function tests and the AFP levels were repeated every 1 to 2 months. In AFP-secreting HCC, the recurrences were initially evaluated according to the changes in the AFP level compared with the baseline level. S-CT was performed when a recurrence was suspected because of an elevation in the once-decreased AFP levels and was also performed at least every 6 months, although the AFP levels remained decreased. In AFP-nonsecreting HCC, ultrasonography or s-CT was performed every 2 to 6 months where necessary. In both treatment groups, if new tumor nodules were evident on ultrasonography or on s-CT, and in the TACE group if the initial lesions appeared to revascularize because of washout of lipiodol, a subsequent TACE treatment was applied for these recurrent HCCs in both groups. The median number of TACE procedures including initial and subsequent sessions for the treatment of recurrent HCC was one (range, zero to 12) for the HR group and six (range, one to 18) for the TACE group.

Statistical Analysis
The main end point evaluated for both the HR group and the TACE group was the survival from the date of the initial TACE. Patients lost to follow-up were censored at the date of the last observation. The survival curves were estimated according to the Kaplan-Meier method and compared statistically by a log-rank test. To compare the survival rates of the two treatment groups, the patients were stratified according to the tumor stage (UICC T stage and CLIP score) and the pattern of lipiodol retention on L-CT. The survival rates of the two treatment groups were compared within each stratification. Comparisons were made using a Student’s t test for continuous variables and with either a ² test or Fisher’s exact test for the categorical variables. The SAS Version 6.12 (SAS Institute, Inc, Cary, NC) software package was used.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Baseline Characteristics
The two groups were well balanced statistically with respect to most of the baseline characteristics such as sex, serum AFP level, CLIP and Okuda stage, and pattern of lipiodol retention. However, the patients in the TACE group were significantly older (P = .0002) and exhibited more anti-HCV positivity (P = .027) than the HR group. More patients in the TACE group had UICC stage T3 lesions than those in the HR group (P = .003) (Table 1).

Among the 182 patients, the survival rate of the HR group was significantly higher than in the TACE group (P = .0038), the median survival times being 66 and 37 months, respectively (Fig 1). The survival rate of patients with compact lipiodol retention was significantly higher than those with noncompact retention (P = .0013), the median survival times being 51 and 30 months, respectively (Fig 2). In a comparison of the survival rates between the groups with the different UICC T stages, little difference in the survival rate between the UICC stage T1 and T2 group was found (P = .7166). However, the survival rate was significantly higher than the UICC T3 group (UICC T1 v T3, P = .1001; UICC T2 v T3, P = .0046). According to the CLIP score, there was little difference observed in the survival rates between the CLIP 1 and 2 groups (P = .4192). However, the survival rate of the CLIP 0 group was higher than that of the CLIP 1 or 2 groups (CLIP 0 v 1, P = .1024; CLIP 0 v 2, P = .0490).

View larger version (14K): [in this window] [in a new window]   Fig 1. Kaplan-Meier survival curves in the 182 patients with resectable hepatocellular carcinoma and Child-Pugh class A liver function according to the treatment modality.

View larger version (16K): [in this window] [in a new window]   Fig 2. Kaplan-Meier survival curves in patients with resectable hepatocellular carcinoma and Child-Pugh class A liver function according to the pattern of lipiodol uptake.

View larger version (27K): [in this window] [in a new window]   Fig 3. Kaplan-Meier survival curves according to the treatment modality in patients with UICC T1-2 (A) or T3 hepatocellular carcinoma (B), and in patients with CLIP score 0 (C) or 1-2 (D).

View larger version (14K): [in this window] [in a new window]   Fig 4. Kaplan-Meier survival curves according to the treatment modality in patients with compact lipiodol uptake pattern and UICC T1-2 hepatocellular carcinoma (A) or CLIP score 0 (B).

View larger version (14K): [in this window] [in a new window]   Fig 5. Kaplan-Meier survival curves according to the treatment modality in patients with UICC T1-2 hepatocellular carcinoma and compact lipiodol uptake pattern and serum AFP level below (A) or above (B) 400 ng/mL.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

The practical reasons that hamper the conduct of randomized controlled trials in this study include the different levels of invasiveness between surgery and TACE.⁹ Because of this impracticality, it was considered that the best obtainable evidence would be derived from cohort studies featuring patients consecutively enrolled and well matched to each other according to the prognostic factors. Furthermore, this was a single-institute study, and the TACE procedure and supportive care received by all patients were identical throughout the period of the study. There is no consensus on the standard method of TACE. Even the use of lipiodol is controversial. However, lipiodol has been reported to improve survival,^23,24 and the lipiodol uptake pattern serves as a reasonable prognostic index.^25,26 Therefore, lipiodol was used in TACE procedures in all patients. The beneficial effect of TACE and patient tolerance was assessed 4 weeks after the first course of TACE. Subsequent TACE sessions were approved only in the presence of a clear sign of recurrent intrahepatic disease.²⁷

The HR group, as a whole, demonstrated a survival rate superior to that of the TACE group (Fig 1), possibly because of the superiority of HR relative to TACE in tumor ablation, although HR is of course far more invasive.⁹ However, another more plausible explanation may lie in the imbalances in the baseline prognostic characteristics between the two groups, which may have favored the HR group (Table 1). As seen in Table 1, the two groups differed in age and viral etiology, and moreover in the UICC tumor stages. The elderly Koreans in this study generally preferred the less invasive TACE procedure. Therefore, the mean age of the TACE group was significantly higher than that of the HR group. Even in a hepatitis B virus (HBV)-endemic area such as Korea, the etiologic role of HCV outweighs that of HBV in the development of HCC in the elderly,^28,29 and HCV-associated HCC is more closely involved in multicentric carcinogenesis than is HBV-associated HCC.^30-32 Consequently, more HCV-associated advanced-stage HCC cases (UICC T3) were included in the TACE group. Among three variables imbalanced between the two groups, age and viral etiology are not usually considered to be significant prognostic factors in HCC because the previous studies did not show statistical differences in the survival rates between different viral etiology groups or between different age groups.^29,33 The data in this study were further analyzed according to the pretreatment variable of the tumor stage (UICC and CLIP) to identify the subgroups that benefited the most from TACE.

Various studies have suggested that small-encapsulated tumors with long-term lipiodol retention are more susceptible to extensive tumor necrosis after TACE.^34,35 Stefanini et al²⁶ reported that patients with a compact uptake of lipiodol in the tumor had a higher probability of survival than patients with a less compact uptake. The present study also demonstrated that all patients with compact lipiodol retention, regardless of the treatment modality, exhibited a significantly higher survival rate than those with a noncompact uptake (Fig 2). Therefore, the lipiodol uptake pattern after TACE can be considered to be a posttreatment prognostic marker.²⁵ In fact, among the patients with a compact lipiodol retention pattern in this study, no difference in the pattern of the serum AFP level changes after treatment was found between the HR and TACE groups, suggesting that compact lipiodol retention after TACE reflects effective tumor necrosis by TACE comparable to that by HR (Table 2). Therefore, in investigating the efficacy of TACE, this factor needs to be included as a prognostic variable.

Among the many prognostic factors, the tumor size, number of tumors, portal vein invasion, and liver function are key predictors of HCC prognosis.^36-38 All patients enrolled on this study had the same liver function as assessed by the Child-Pugh score. Therefore, the three other factors were the most important prognostic factors, having already been integrated into the UICC and CLIP staging systems. In addition to these three factors, the CLIP score also includes the serum AFP level (400 ng/mL). Once largely ignored, tumor-node-metastasis staging has recently been shown to be a good predictor of prognosis in HCC patients treated with HR,³⁷ although no significant difference between the UICC stage 1 and 2 HCC survival rates after HR was found.^37-39 In this study, a similar lack of a significant difference in survival rates after either HR or TACE was observed between the UICC T1 and 2 HCC groups. Therefore, the patients in each group were stratified into two groups of UICC T1-2 and 3. The survival rate of the TACE group was significantly lower in the UICC T1-2 and CLIP 0 but not in the UICC T3 and CLIP 1-2 (Fig 3), which also supports the observation that TACE is as effective as HR in more advanced HCC.¹⁷

In treating HCC, both HR and TACE have their own intrinsic drawbacks. The main drawback of tumor resection is subsequent hepatic decompensation and the high recurrence rate. Surgical resection should be proposed only in patients with an extremely well-preserved liver function because even in patients with Child-Pugh class A disease, as shown by Bruix et al,⁴⁰ more than 50% of those patients experienced hepatic decompensation after surgery, and this decompensation was associated with an impairment of their long-term survival. The recurrence rates may exceed 70% after 5 years^41,42 and the recurrence pattern is usually multifocal.⁴³ Therefore, it requires second-line therapy such as TACE, which is considered to be effective in terms of survival rate with respect to the treatment of intrahepatic recurrences of HCC after HR.⁴⁴ In comparison, obstruction of the hepatic artery by TACE may also deteriorate the patient’s liver function. However, this situation is transient and self-limited in patients with a compensated liver function.^45-47 In fact, all patients on this study recovered to their baseline status. In other words, the complete ablation of the original tumor achieved by HR might be counterbalanced by the deteriorated liver function, particularly in patients with advanced HCC. In comparison, TACE may have less of an effect on inhibiting tumor growth, but it is less associated with a worsening of liver function. This assumption is supported by (1) much less dramatic changes in the serum AFP level in the TACE group than in the HR group (Table 2) and (2) the consistent observation of a tendency toward a lower survival rate in the HR group than in the TACE group during the first year of follow-up (Figs 1 and 3). Therefore, the observed similarity in survival rates between the TACE and HR groups in the UICC T3 and CLIP 1-2 HCC stages may be because of the more substantial loss of hepatic function from HR than from TACE, despite the more complete tumor ablation in the HR group.

In this study, even in the relatively early tumor stages of UICC T1-2 where the HR group survival rate was significantly higher than the TACE group as a whole, the TACE group survival rate was not significantly different from that of the HR group when lipiodol retention was compact (Fig 4A). In contrast, this beneficial effect associated with compact lipiodol retention was not found in patients with CLIP 0 HCC, who featured a single HCC with a serum AFP level less than 400 ng/mL (Fig 4B). Among the UICC T1-2 HCC patients with a serum AFP level less than 400 ng/mL, the HR group displayed a significantly higher survival rate regardless of the pattern of lipiodol retention (Fig 5A). In contrast, there was no significant difference in survival rates between the HR and TACE group in the UICC T1-2 HCC patients with a serum AFP level greater than 400 ng/mL and compact lipiodol retention. This is because of the tendency in the HR group toward a lower survival among patients with a serum AFP level above 400 ng/mL, compared with those below, rather than any tendency toward a higher survival among the equivalent patients in the TACE group (Fig 5). A tendency toward a lower survival rate in the HR group with a serum AFP level above 400 ng/mL may be associated with early recurrence after HR.^48-50

The assessment of quality of life in addition to survival time in patients with cancer is being increasingly emphasized when evaluating the effects of cancer treatment.⁵¹ Unfortunately, the present study was not formally designed to assess quality of life; therefore, further study is needed to prospectively investigate differences in the quality of life achieved by TACE and HR, especially in subgroups that showed similar survival times, and which might be useful for discriminating between the efficacies of TACE and HR.

In summary, we identify a subset of patients that if well selected can benefit from TACE. HR results in a survival rate significantly higher than TACE in cases of UICC T1-2 HCC with noncompact lipiodol retention or with compact retention and a serum AFP level below 400 ng/mL, and accordingly in CLIP 0. In contrast, the survival rate of the TACE group was comparable to that of the HR group in cases of UICC T1-2 HCC with compact lipiodol retention and in UICC T3 and CLIP 1-2. Thus, in the latter tumor stages, the choice of treatment modality between TACE and HR may be left to the patient’s preference.

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Submitted February 4, 2002; accepted July 22, 2002.

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