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1 Department of Medicine, Saga Social Insurance Hospital, 3-8-1, Hyogo-minami,
Saga-shi, Saga-ken 849-8522, Japan.
2 Second Department of Medicine, Kurume University School of Medicine, 67
Asahi-Machi, Kurume-shi, Fukuoka-ken 830-0011, Japan.
Received March 31, 2003;
accepted after revision May 27, 2003.
Address correspondence to S. Sumie
(syuuji{at}mx21.tiki.ne.jp).
Abstract
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SUBJECTS AND METHODS. Thirty-seven patients with hepatocellular carcinoma and unresectable tumors were enrolled. In the hepatic artery infusion chemotherapy group (n = 16), cisplatin (10 mg/person, on days 1–5) and subsequent 5-fluorouracil (250 mg/person, on days 1–5) were administered for four serial courses. In the transcatheter arterial Lipiodol chemoembolization group (n = 21), an emulsion of Epirubicin (20–30 mg/person) and Lipiodol was administered every 3–4 weeks.
RESULTS. The tumor response rates (complete response plus partial response for all cases) of the hepatic artery infusion chemotherapy and transcatheter arterial Lipiodol chemoembolization groups were 56.3% and 23.8%, respectively, showing the significantly higher rate in the former than in the latter group. The cumulative survival rates between the two groups were not significantly different; whereas in those patients whose tumors were classified as TNM stage IV or as having the maximal tumor size of greater than 5 cm, patients tended to have higher survival rates in the hepatic artery infusion chemotherapy group than in the transcatheter arterial Lipiodol chemoembolization group. Univariate analysis identified the serum aspartate aminotransferase value as solely significant. Patients' adverse reactions were successfully managed by treatment of symptoms. Adverse events, such as obstructions of the catheter or hepatic artery or infection around the catheter, rarely occurred.
CONCLUSION. Hepatic artery infusion chemotherapy had a better antitumor effect than transcatheter arterial Lipiodol chemoembolization and may be a useful therapeutic option for more advanced hepatocellular carcinoma.
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We have previously reported the usefulness of repeated hepatic artery infusion chemotherapy using low-dose cisplatin and 5-fluorouracil for advanced hepatocellular carcinoma, particularly for those patients with portal vein tumor thrombosis of the main trunk [12]. Other investigators have also described a relatively favorable prognosis in patients with advanced hepatocellular carcinoma treated with hepatic artery infusion chemotherapy using low-dose cisplatin and 5-fluorouracil [13, 14].
Transcatheter arterial iodized oil (Lipiodol, Guerbet, Aulnay-sous-Bois, France) chemoembolization has become one of the conventional and effective treatments for patients with unresectable hepatocellular carcinoma [15–17]. Anticancer agents that have been used in transcatheter arterial Lipiodol chemoembolization include Epirubicin (Farumorubicin; Kyowa Hakko Kogyo, Tokyo, Japan) [18–20], carboplatin [15], cisplatin [21, 22], doxorubicin [16, 17, 23], and mitomycin-C [20]. The aim of the study was to compare the effects of the two therapies in patients with advanced hepatocellular carcinoma.
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-fetoprotein, lens clinaris agglutinin reactive -fetoprotein,
and des-gamma carboxy prothrombin
[11]. Tumor biopsy was
performed in cases in which imaging findings were not consistent with features
characteristic of hepatocellular carcinoma or when levels of tumor markers
were not elevated. Because of the advanced stage of the disease, as assessed
by large size, multiplicity, or vascular involvement, all 37 patients were
considered unsuitable for surgical resection or nonsurgical regional tumor
ablations, such as percutaneous ethanol injection, microwave coagulation
therapy, and radiofrequency tumor ablation. Recent reports have shown that the
tumor features of the relatively early stage of hepatocellular carcinoma were
as follows: a nodule 5 cm or less in diameter in single hepatocellular
carcinoma and no more than three tumor nodules, each 3 cm or less in diameter,
in patients with multiple tumors
[4,
24]. The enrolled patients had
a single nodule of greater than 5 cm or had more than three nodules. After being presented with the clinical results of previous studies of hepatic artery infusion chemotherapy and transcatheter arterial Lipiodol chemoembolization for patients with advanced hepatocellular carcinomas [12, 14–16, 18, 19], patients themselves selected the therapeutic option of either hepatic artery infusion chemotherapy or transcatheter arterial Lipiodol chemoembolization, on the basis of informed consent. Sixteen and 21 patients were treated by hepatic artery infusion chemotherapy and transcatheter arterial Lipiodol chemoembolization, respectively.
Table 1 shows the patients' profiles. Hepatic reserve was evaluated using the Child-Pugh classification [25]. Tumor stage was determined by the TNM classification according to the International Union Against Cancer [26]. Maximal tumor diameter was stratified as follows: less than or equal to 5 cm and greater than 5 cm. The study protocol was approved by the institutional ethics review committees and a signed consent form was obtained from each subject.
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Hepatic Artery Infusion Chemotherapy
Celiac angiography was performed by the Seldinger method, using the
transfemoral arterial approach. Arteriography of the celiac trunk and superior
mesenteric artery was performed to visualize the arterial vascularization of
the liver and to evaluate portal vein patency, respectively. After detection
of the tumor and its supplying artery, a 4- or 5-French heparin-coated
catheter was placed in the proper or common hepatic artery. The gastroduodenal
artery and the right gastric artery were occluded with steel coils as
indicated to prevent gastroduodenal injury from the anticancer agents.
Patients received repeated arterial infusion of chemotherapeutic agents via an
injection port implanted in a subcutaneous pocket in the right lower quadrant.
The injection port was implanted for all patients. One course of chemotherapy
consisted of daily administration of cisplatin (Randa, Nippon Kayaku, Tokyo,
Japan) (10 mg/person, on days 1–5) followed by 5-fluorouracil (5-FU,
Kyowa Hakko Kogyo, Tokyo, Japan) (250 mg/person, on days 1–5). Both
cisplatin and 5-fluorouracil were administered by a mechanical portable
infusion pump, set for 1 hr and 5 hr, respectively. The dosage of cisplatin
and 5-fluorouracil was determined according to previous studies
[12,
13]. In principle, patients
were to receive consecutively four serial courses of chemotherapy, and such
patients were considered to have a completed hepatic artery infusion
chemotherapy.
Transcatheter Arterial Lipiodol Chemoembolization
Angiography was performed by the Seldinger method similar to hepatic artery
infusion chemotherapy. After the detection of tumor vessels and their
supplying artery, an emulsion of Epirubicin (20–30 mg/person) and
Lipiodol (2–4 mL) was administered every 3–4 weeks into the
feeding artery under fluoroscopic guidance. The dosage of Lipiodol was
determined according to the location of the tumor, tumor size, number of
tumors, and functional hepatic reserve. We did not use occlusion agents
(gelatin sponge) after infusion of the drug to avoid reported complications
such as hepatic artery occlusion or stenosis and development of arterial
collaterals including periportal collaterals and right inferior phrenic artery
[20,
23]. The catheter was
introduced as peripherally as possible using a microcatheter to avoid
deterioration of liver function associated with therapy. The total dose of
Epirubicin was set at 200 mg.
Evaluation of Therapeutic Response
All patients always underwent sonography every 2–3 months, and CT was
always performed every 6 months. Every patient periodically underwent
sonography and CT with the previously cited intervals. The product of the
largest perpendicular diameters of the tumor was calculated, and the rate of
tumor reduction was calculated from the following equation:
 |
The maximal reduction rate 3–6 months later associated with each therapy was used in the evaluation of efficacy. Response to therapy was categorized into one of four categories using the following criteria: complete response, complete disappearance of the tumor and no evidence of new lesions for 4 weeks; partial response, reduction of tumor size exceeding 50% of all the measurable lesions and no evidence of new lesions for 4 weeks; no change, a reduction of less than 50% of all the measurable lesions and no evidence of new lesions for 4 weeks; progressive disease, an increase in tumor size or appearance of a new lesion. Either a complete response or a partial response was considered effective.
Statistical Analysis
Data were reported as the median (range). Patients' profiles were compared
using the Mann-Whitney U test, chi-square test, and Fisher's exact
probability test. The cumulative survival rate was calculated using the
Kaplan-Meier analysis [27],
The survival rates were compared by the log-rank test. Survival was confirmed
until December 31, 2000. Differences were considered statistically significant
when the p value was less than 0.05.
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-fetoprotein levels, plasma des-gamma carboxy prothrombin levels, serum
aspartate aminotransferase levels, tumor size, or tumor stage.
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Table 3 shows the
relationship among the size of tumor, treatment used, and tumor response. In
the total number of patients, the tumor response was significantly higher in
the hepatic artery infusion chemotherapy group than in the transcatheter
arterial Lipiodol chemoembolization group (p = 0.043). When the
patients were stratified by the tumor size (5 cm), the tumor responses were
comparable between the groups (maximal tumor size 
5 cm, p =
0.115; maximal tumor > 5 cm, p = 0.558).
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Figure 1 shows a comparison of the cumulative survival rates between the two groups. In the hepatic artery infusion chemotherapy group, the 1-, 2-, and 3-year cumulative survival rates of the 16 patients were 81.2%, 56.2%, and 37.4%, respectively. In the transcatheter arterial Lipiodol chemoembolization group, the 1-, 2-, and 3-year cumulative survival rates of the 21 patients were 76.2%, 33.3%, and 28.6%, respectively. The median survival periods of the hepatic artery infusion chemotherapy group and the transcatheter arterial Lipiodol chemoembolization group were 2.7 years (range, 0.58–5.0 years) and 1.7 years (range, 0.48-4.1 years), respectively. No significant difference was observed in relation to the cumulative survival rates between the two groups (p = 0.228).
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Comparisons of the cumulative survival rates among those patients who were stratified according to the tumor stage of the TNM classification are shown in Figures 2 and 3. The cumulative survival rates were not significantly different between patients with hepatocellular carcinoma classified as tumor stage II or III (p = 0.837) (Fig. 2); whereas in patients with tumors classified as tumor stage IV, the cumulative survival rates tended to be higher in the hepatic artery infusion chemotherapy group compared with the transcatheter arterial Lipiodol chemoembolization group (p = 0.131) (Fig. 3).
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Figure 4 shows a comparison of the cumulative survival rates between the two groups in those patients whose maximal tumor size was less than or equal to 5 cm. The survival rates were comparable between the two groups (p = 0.566).
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Figure 5 shows a comparison of the cumulative survival rates between the two groups in those patients whose maximal tumor was greater than 5 cm. The difference did not reach the significant level (p = 0.271), although the hepatic artery infusion chemotherapy group had higher survival rates than the transcatheter arterial Lipiodol chemoembolization group.
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Table 4 shows the results of univariate analysis of potential prognostic factors. The serum aspartate aminotransferase value (p = 0.017) was found to be a significant prognostic factor. The hepatic reserve stratified by Child-Pugh stage (p = 0.097) also tended to be significant.
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Table 5 shows complications that occurred in this study. Patients' gastrointestinal adverse reactions and fever were successfully managed by medical treatment of symptoms. Deteriorations in the laboratory data were transient and mild, and they returned to normal ranges within a few weeks. An obstruction of the hepatic artery rarely occurred during these transcatheter therapies. Infection or obstruction of the catheter was also a rare event. No patients developed evidence of liver failure such as hepatic encephalopathy or overt jaundice during the studies.
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Figure 6A, 6B, 6C, 6D shows a representative patient with hepatocellular carcinoma who was treated by hepatic artery infusion chemotherapy. This patient had a main tumor of 43 x 37 mm in segment II of the liver accompanied by multiple nodules in both lobes of the liver, suggesting intrahepatic metastasis of hepatocellular carcinoma. After therapy, the main tumor was markedly reduced in size, and most of the other intrahepatic nodules had disappeared. Consequently, a single residual nodule in segment VII of the liver was shown. This patient was classified as having a partial response; however, complete response was achieved after the adjuvant percutaneous ethanol injection therapy for this residual tumor. This patient was doing well at the end of the observation, with a survival period of 48.9 months.
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We have previously reported the usefulness of hepatic artery infusion chemotherapy with cisplatin and 5-fluorouracil for advanced hepatocellular carcinoma with portal vein tumor thrombosis [12], and other investigators have also reported the usefulness of this treatment [13, 14]. Thus, in the present study, we assessed the efficacy of hepatic artery infusion chemotherapy using low-dose cisplatin and 5-fluorouracil for advanced hepatocellular carcinoma without portal vein tumor thrombosis by comparing treatment results with those patients with advanced hepatocellular carcinoma who were treated by transcatheter arterial Lipiodol chemoembolization using Epirubicin.
Patients' adverse reactions that occurred in this study were mild and tolerable. An obstruction of the hepatic artery rarely occurred, and adverse events associated with the catheter were also uncommon. Thus, transcatheter arterial Lipiodol chemoembolization and hepatic artery infusion chemotherapy in this study were thought to be acceptable procedures to treat advanced hepatocellular carcinoma.
The therapeutic response to hepatic artery infusion chemotherapy was significantly better than that to transcatheter arterial Lipiodol chemoembolization, whereas the cumulative survival rates were not different between the two treatment groups. In those patients with hepatocellular carcinoma classified as tumor stage IV, cumulative survival rates tended to be higher in those who were treated by hepatic artery infusion chemotherapy than in those who were treated by transcatheter arterial Lipiodol chemoembolization (Fig. 3). In those patients with hepatocellular carcinoma who had the maximal tumor diameter of greater than 5 cm, cumulative survival rates tended to be higher in those who were treated by hepatic artery infusion chemotherapy than in those who were treated by transcatheter arterial Lipiodol chemoembolization (Fig. 5). We therefore suggest that hepatic artery infusion chemotherapy may be preferable to transcatheter arterial Lipiodol chemoembolization as a therapeutic option for hepatocellular carcinoma patients with more advanced-stage disease.
Transcatheter arterial Lipiodol chemoembolization for hepatocellular carcinoma using an emulsion of anticancer agents and iodized oil has usually been followed by the injection of gelatin sponge particles. In our study, we did not use occlusion agents such as gelatin sponge in order to avoid the following adverse effects: hepatic artery occlusion or stenosis or the development of arterial collaterals such as periportal collateral and right inferior phrenic artery [20, 23]. Repeated hepatic artery chemotherapy could be precluded by these events. Furthermore, damage to the noncancerous portion of the liver due to embolization using gelatin sponge has also been reported [21]. Although a recent randomized controlled study showed the usefulness of chemoembolization using gelatin sponge [17], the survival advantage was found in the relatively early stage of hepatocellular carcinoma. On the other hand, a randomized controlled trial did not find a statistical survival advantage of chemoembolization using embolic materials in patients with hepatocellular carcinoma [21]. Thus, the survival benefit of transarterial chemoembolization using or not using occlusion agents might be a debatable issue. We did not use occlusion agents because of these controversies and our concern for safety during the procedures; nevertheless, the effect of adding the gelatin sponge could be evaluated by further studies.
Univariate analysis showed that only the serum aspartate aminotransferase level influenced the prognosis, although the Child-Pugh stage also tended to be significant. The protocol of the present two interventional chemotherapies was not found to be the prognostic indicator. Several investigators have also shown that aspartate aminotransferase level [29] and Child-Pugh stage [30] were independent predictive factors for survival. We presume that patients with preserved hepatic reserve or lower serum aspartate aminotransferase levels are more tolerant of adverse reactions induced by anticancer agents or arterial embolization, thus allowing continuation of this interventional chemotherapy.
Liver transplantation has been widely accepted as a useful therapy for advanced hepatocellular carcinoma. Liver transplantation offers the advantages of removal of the entire liver, thereby eliminating the problem of multiplicity, vascular involvement, and replacement with a functional liver, allowing patients with advanced cirrhosis to be treated. Long-term results, however, are disappointing at present because of the high recurrence rate [7]. In an attempt to reduce the recurrence rate in patients undergoing liver transplantation for advanced hepatocellular carcinoma, a multimodal neoadjuvant protocol was designed and reported to be useful [4–6, 8]. Spreafico et al. [5] and Cherqui et al. [6] reported the efficacy of transcatheter arterial Lipiodol chemoembolization for hepatocellular carcinoma in patients who were waiting for liver transplantation. Stone et al. [8] reported the efficacy of neoadjuvant chemotherapy with doxorubicin. The present hepatic artery infusion chemotherapy may therefore be regarded as having such a neoadjuvant effect in liver transplantation for advanced hepatocellular carcinoma.
Although a controlled randomization is considered to be the optimal method for identifying the best therapeutic option, the final selection of the procedure was based on the informed consent in this study. The patients themselves decided on the treatment with hepatic artery infusion chemotherapy or transcatheter arterial Lipiodol chemoembolization. Patients' characteristics between the two procedures were found to be comparable (Table 2). Thus, the results of this study were not thought to be influenced by a selection bias of the present therapeutic choice.
Bland embolization (Lipiodol without chemotherapy) may be regarded as another of the useful therapeutic methods to treat advanced hepatocellular carcinomas as in this study. Nagasue et al. [31] reported that an arterial Lipiodol injection as a preoperative therapy was effective in patients with resectable hepatocellular carcinomas, and Chang et al. [22] reported that an addition of cisplatin (50 mg) did not enhance the therapeutic effect of transcatheter arterial embolization for treatment of hepatocellular carcinoma. Although using the anticancer agents may have adversely affected the quality of life in patients with advanced hepatocellular carcinoma, we have carefully observed and treated these patients and found that the side effects associated with the administration of Epirubicin were successfully managed in this study.
In conclusion, hepatic artery infusion chemotherapy using low-dose cisplatin and 5-fluorouracil was found to have a better antitumor effect than that of transcatheter arterial Lipiodol chemoembolization with Epirubicin, whereas the cumulative survival rates were comparable between the two treatment groups. We suggest that the present hepatic artery infusion chemotherapy may potentially be a first-line chemotherapeutic regimen for far advanced hepatocellular carcinoma.
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