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Keywords:

  • radiofrequency ablation;
  • hepatocellular carcinoma;
  • transcatheter arterial chemoembolization;
  • combination therapy;
  • local tumor progression;
  • survival

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

BACKGROUND:

To improve the efficacy of radiofrequency ablation (RFA) for the treatment of intermediate-sized hepatocellular carcinomas (HCCs), the authors compared RFA combined with transcatheter arterial chemoembolization (TACE) to RFA alone.

METHODS:

The authors randomly assigned 37 patients with solitary HCCs (diameter, 3.1-5.0 cm in the greatest dimension) to 2 groups: the TACE-RFA group, in which the patients received TACE followed by RFA on the same day, and the RFA group, in which the patients received only RFA.

RESULTS:

Technical success was achieved after 1.4 ± 0.5 RFA sessions in the RFA group and after 1.1 ± 0.2 RFA sessions in the TACE-RFA group (P < .01). The mean diameters of the longer and shorter axes of the RFA-induced ablated areas were 50 ± 8.0 mm and 41 ± 7.1 mm, respectively, in the RFA group and 58 ± 13.2 mm and 50 ± 11.3 mm, respectively, in the TACE-RFA group; the mean diameters of the shorter axes were significantly different (P = .012). The rates of local tumor progression at the end of the third year in the RFA and TACE-RFA groups were 39% and 6%, respectively (P = .012). The 3-year survival rates of the patients in the RFA and TACE-RFA groups were 80% and 93%, respectively (P = .369).

CONCLUSIONS:

In patients with intermediate-sized HCCs, RFA combined with TACE is more effective than RFA alone for extending the ablated area in fewer treatment sessions and for decreasing the local tumor progression rate. Cancer 2010. © 2010 American Cancer Society.

Hepatocellular carcinoma (HCC), which is the sixth most common cancer worldwide with 626,000 new cases every year, is a major health problem.1 In recent years, screening programs for high-risk patients have gained popularity, and many patients have been diagnosed with small-sized HCCs (diameter, 3 cm or less),2 whereas some patients have been diagnosed with intermediate-sized (diameter, 3.1-5.0 cm) or large-sized (diameter, >5 cm) HCCs. In a nationwide survey in Japan, 22.1% of HCC patients had HCCs with a maximum diameter of 3.1 to 5.0 cm at the initial diagnosis.3 Hepatectomy is considered as the first-line treatment for intermediate- or large-sized HCCs. However, many patients have poor hepatic reserve owing to underlying chronic liver disease; therefore, only 5% to 40% of the patients with HCCs are candidates for hepatectomy.4

Various local ablation therapies such as percutaneous ethanol injection5, 6 or percutaneous radiofrequency ablation (RFA) have been proposed as nonsurgical treatment options for small-sized HCCs, and excellent survival rates have been reported with these treatments.7, 8 Complete necrosis was achieved in 76% to 100% of the treated small-sized HCCs.8, 9 However, because of the limited coagulative necrosis induced by RFA alone, in larger HCCs, the percentage of cases showing complete necrosis varied between 29% and 70%.10 To obtain a larger therapeutic region, RFA has been combined with adjuvant therapies such as percutaneous instillation of sodium chloride solution11 or ethanol,12 temporary occlusion of the tumor blood supply,13, 14 and/or transcatheter arterial chemoembolization (TACE)15-17; however, most of these studies were pilot or retrospective studies.

In this study, we performed a randomized controlled trial to evaluate the therapeutic efficacy of combining RFA with TACE for treating intermediate-sized HCCs. The primary endpoint was the outcome of a midterm assessment of local tumor progression, and the secondary endpoints were safety and overall survival.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Patients

Between August 1, 2005 and April 30, 2009, we screened 42 consecutive patients who were diagnosed with intermediate-sized HCCs at Yokohama City University Medical Center. HCC was diagnosed on the basis of positive results in serum alpha-fetoprotein determination (serum alpha-fetoprotein level >20 μg/L) along with positive imaging findings, or on the basis of at least 2 coincident imaging findings that indicated HCC in high-risk patients.4 A total of 37 patients who satisfied the following eligibility criteria were enrolled in this study: (1) Eastern Cooperative Oncology Group performance status score of 2 or less; (2) Child-Pugh liver function class A or B; (3) the presence of a solitary lesion; (4) maximum tumor diameter of 3.1 to 5.0 cm; (5) the lesion could be detected by using ultrasonography (US); (6) the divergence of the hepatic artery was suitable for TACE; (7) no evidence of portal and/or venous thrombosis, extrahepatic metastasis, or uncontrollable ascites; (8) adequate hematologic function (platelet count >50 × 109 cells/L, hemoglobin >8.0 g/dL, and prothrombin time <80%); (9) adequate hepatic function (albumin >2.5 g/dL, total bilirubin <3 mg/dL, and alanine aminotransferase and aspartate aminotransferase levels <5× the upper limit of the normal range); and (10) adequate renal function (serum creatinine concentration <1.5× the upper limit of the normal range). Patients were excluded if they had previously received any treatment for hepatocellular carcinoma. Patients were also excluded if they met the criteria for surgical resection; these criteria were based on their liver profile (Child-Pugh class A or B, normal bilirubin level, controllable or no ascites, and indocyanine green retention rate at 15 minutes value ≤14%).18

All the patients provided written informed consent before enrollment in the study. The study was approved by the institutional ethical committee of our institute and complied with the provisions of the Good Clinical Practice guidelines, the Declaration of Helsinki, and local laws.

Study Design

This randomized controlled trial was conducted at the Clinical Research Coordinating Center of our institute. Data collection and management were performed by an author (S.M.) from the same department. The sample size was calculated on the assumption that the 1-year local tumor progression rates were 25% and 5% for the RFA and TACE-RFA groups, respectively. After setting the accrual and follow-up intervals at 3 years, the number of patients to be accrued was set at 40 to attain the requisite 80% power to confirm the superiority of the TACE-RFA group, with a 2-sided 5.0% significance level test. All eligible patients were randomly assigned to the 2 groups in a 1:1 ratio: the RFA group, in which the patients received RFA alone, and the TACE-RFA group, in which the patients received TACE followed by RFA. The randomization was centralized, and the assignment to the study groups was performed by a computer to achieve balance between the 2 groups; before randomization, the data were stratified according to sex (men vs women) and age (>70 years old vs ≤70 years old).

Treatment Procedures

Transcatheter arterial chemoembolization

Two authors (M.M. and M.K., who had 12 and 10 years experience, respectively, in performing interventional radiology procedures at the beginning of the study period) performed TACE. TACE was performed by selectively introducing a microcatheter into the right or the left hepatic artery or a segmental branch of the hepatic artery and injecting a mixture of iodized oil (Lipiodol; Andre Guerbet, Aulnaysous-Bois, France) and epirubicin hydrochloride (30-50 mg per body surface) (Farmorubicin; Pharmacia and Upjohn, Tokyo, Japan) until the mixture entered the intrahepatic branch of the portal vein. This procedure was followed by the introduction of a gelatin sponge (1 mm × 1 mm × 1 mm) (Spongel; Astellas Pharmaceutical, Tokyo, Japan or Gelpart; Nihonkayaku, Tokyo, Japan).

Radiofrequency ablation

Two authors (K.N. and M.M., who had 5 years experience in performing percutaneous RFA at the beginning of the study period) performed RFA. RFA was performed with a multitined, 15-gauge, and 15-cm-long expandable electrode with maximum dimensions of 3.5 cm or 4.0 cm (LeVeen Needle Electrode; Boston Scientific, Natick, Mass) or a 17-gauge internally cooled electrode with a 3-cm-long exposed tip (Cool-tip RFA System; Valleylab, Boulder, Colo). In most of the cases, we used a multitined expandable electrode; however, if tumors were located near large vessels, the gall bladder, diaphragm, or colon, we used an internally cooled electrode to avoid the complications caused by expandable electrodes. A conscious-sedation technique, in which a combination of pentazocine (15 mg Pentazin; Sankyo Pharmaceuticals, Tokyo, Japan) and hydroxyzine chloride (25 mg Atarax-P; Pfizer Japan, Tokyo, Japan) was intramuscularly administered to the patient, was performed before the treatment. Local anesthesia was performed by injecting 1% lidocaine hydrochloride (Xylocaine; Astra Japan, Tokyo, Japan). By using ultrasound guidance (LOGIQ 7; GE Healthcare, Milwaukee, Wis), the electrode was inserted into the tumor, and the position of the needle was verified. Radiofrequency (RF) energy was applied using a monopolar RF generator (RF3000 Generator; Boston Scientific or Series CC-1; Valleylab). For the patients of the TACE-RFA group, RFA was performed just after TACE, that is, on the same day. HCC was treated using several insertion methods19 to obtain sufficient ablative margins.

Outcomes and Assessments

The technical success of RFA or TACE-RFA was evaluated using contrast-enhanced computed tomography (CT) and/or contrast-enhanced US within 3 days after RFA. If residual vascularities were observed within the treated area, additional RFA was performed. Contrast-enhanced US was performed by 2 authors (K.N. and M.M. with 18 years and 13 years of experience, respectively, in abdominal US). Contrast-enhanced US scanning was performed after intravenous bolus injection of the contrast medium Levovist (Schering, Berlin, Germany), which was used between 2005 and 2006, or Sonazoid (Daiichi Sankyo, Tokyo, Japan), which was used between 2007 and 2009. The LOGIQ 7 ultrasound imaging system and a convex 3.5 CS probe (GE Healthcare) with a frequency of 3.5 MHz were used. Five authors (M.M., K.N., M.K., A.N., and K.T.) performed follow-up procedures. Contrast-enhanced CT was performed before the procedures and every 3 months during the study period. CT was performed using a 16-channel multidetector scanner (Aquilion 16; Toshiba Medical, Tokyo, Japan) with the following parameters: tube voltage, 120 kV; tube current in the automatic-milliampere-exposure setting; reconstruction section and interval thickness, 5 mm; detector configuration, 16 mm × 1 mm; pitch, 15; and gantry speed, 0.5 s/rotation. A nonionic contrast agent (iopamidol, Iopamiron 300, or Iopamiron 370; Bayer Healthcare, Osaka, Japan) was injected. Patients weighing <70 kg received 300 mg/mL of iodine, whereas those weighing 70 kg or more received 370 mg/mL of iodine. After injecting 100 mL of iopamidol at a rate of 3 mL/s through a catheter placed in the antecubital vein, the scanning time in the arterial phase was determined using an automatic bolus-tracking program (RealPrep; Toshiba Medical). Portal venous phase scanning was performed 70 seconds after the contrast agent injection, and equilibrium-phase images were acquired 180 seconds after the injection. Local tumor progression was diagnosed if the arterial-phase CT images showed residual vascularities within the treated area. The overall recurrence rate was measured from the date of randomization until the date of detection of local tumor progression or new HCC foci in the liver in the arterial-phase CT images. When up to 3 recurrent tumors were detected on a follow-up CT, percutaneous local ablation therapy was performed; TACE was performed for patients who were ineligible for percutaneous ablation therapy because of the presence of multiple (>3) recurrent HCCs without vascular invasion or extrahepatic metastasis. These treatments for recurrent HCCs were repeated until the development of uncontrolled ascites or intravascular tumor thrombus or until the serum bilirubin level was 3 mg/dL or higher. The overall survival was measured from the date of randomization until the date of death from any cause.

At 1 month after the procedure, we evaluated the serum levels of alpha-fetoprotein and protein induced by vitamin K absence or antagonist II (PIVKA-II). We calculated the rate at which the levels of these tumor markers were reduced by using the following formulae: alpha-fetoprotein reduction rate = (pretreatment alpha-fetoprotein level − post-treatment alpha-fetoprotein level)/(pretreatment alpha-fetoprotein level) and PIVKA-II reduction rate = (pretreatment PIVKA-II level − post-treatment PIVKA-II level)/(pretreatment PIVKA-II level).

We assessed the safety of all the patients receiving RFA and TACE by using the unified standardized Society of Interventional Radiology grading system.20 The pain experienced during the procedures was evaluated by adopting the Common Toxicity Criteria of the National Cancer Institute for reporting pain (Cancer Therapy Evaluation Program: Common Toxicity Evaluation Manual, version 3.0, August 9, 2006, available at: ctep.cancer. gov/reporting/ctc.html).

Statistical Analysis

The baseline characteristics of the patients were expressed as the mean ± standard deviation values. The intergroup differences in proportion were analyzed using the chi-square test. The mean quantitative values were compared using Student t test. The Kaplan-Meier method was used to calculate the survival rate, and the log-rank test was used to analyze the differences.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Among the 42 patients who were screened, 37 satisfied the eligibility criteria and underwent randomization; 18 patients were assigned to the RFA group, and 19 patients were assigned to the TACE-RFA group. The 18 patients in the RFA group included 12 men and 6 women with ages ranging from 48 to 84 years (mean, 73 years), and the 19 patients in the TACE-RFA group included 15 men and 4 women with ages ranging from 57 to 78 years (mean, 70 years). The mean tumor diameters in the RFA group and the TACE-RFA group were 3.7 ± 0.6 cm and 3.6 ± 0.7 cm, respectively. In the RFA group, 16 patients belonged to Child-Pugh class A, and the other 2 belonged to Child-Pugh class B, and in the TACE-RFA group, 18 patients belonged to Child-Pugh class A and 1 patient belonged to Child-Pugh class B. The pretreatment serum alpha-fetoprotein levels in the RFA group and TACE-RFA group were 499 ± 1014 μg/L and 621 ± 2304 μg/L, respectively. The pretreatment serum levels of PIVKA-II were 1364 ± 3470 μg/L and 640 ± 1654 μg/L in the RFA group and the TACE-RFA group, respectively. The pretreatment serum total bilirubin levels in the RFA group and the TACE-RFA group were 0.9 ± 0.3 mg/dL and 0.8 ± 0.2 mg/dL, respectively. The pretreatment serum albumin levels in the RFA group and the TACE-RFA group were 3.9 ± 0.6 g/dL and 3.7 ± 0.5 g/dL, respectively. The pretreatment serum prothrombin times in the RFA group and the TACE-RFA group were 100 ± 12% and 100 ± 15%, respectively. The pretreatment serum alanine aminotransferase levels in the RFA group and the TACE-RFA group were 55 ± 37 IU and 77 ± 53 IU, respectively. The mean follow-up time after randomization was 32 months (range, 15-46 months) in the RFA group and 30 months (range, 12-46 months) in the TACE-RFA group. There were no statistically significant differences between the values for these variables in the RFA group and the TACE-RFA group (Table 1).

Table 1. Baseline Characteristics of the Patients in the 2 Groups
CharacteristicsRFA Group, n=18TACE-RFA Group, n=19P
  1. RFA indicates radiofrequency ablation; TACE, transcatheter arterial chemoembolization; NS, not significant; ECOG, Eastern Cooperative Oncology Group; PIVKA-II, protein-induced vitamin K absence or antagonist II.

  2. Data are presented as mean ± standard deviation. RFA group consists of patients in whom RFA without TACE was performed; TACE-RF group consists of patients in whom TACE was followed by RFA.

  3. aStudent t test for unpaired data.

Age, mean y (range)73 (48-84)70 (57-78)NS
Sex (no. %)  NS
 Men12 (67)15 (79) 
 Women6 (33)4 (21) 
Etiology, No. (%)  NS
 Hepatitis C16 (89)17 (89) 
 Hepatitis B00 
 Alcohol abuse02 (11) 
 Other2 (11)0 
ECOG performance status, No. (%)  NS
 012 (67)12 (63) 
 16 (33)7 (37) 
Child-Pugh class, No. (%)  NS
 A16 (89)18 (95) 
 B2 (11)1 (5) 
Tumor diameter, cm3.7 ± 0.63.6 ± 0.7NS
Biochemical analysis   
 Albumin, g/dL3.9 ± 0.63.7 ± 0.5NS
 Total bilirubin, mg/dL0.9 ± 0.30.8 ± 0.2NS
 Prothrombin activity, %100 ± 12100 ± 15NS
 Alanine aminotransferase, IU55 ± 3777 ± 53NS
 Alpha-fetoprotein, μg/L499 ± 1014621 ± 2304NS
 PIVKA-II, μg/L1364 ± 3470640 ± 1654NS
Follow-up, mean mo (range)32 (15-46)30 (12-46)NS

Technical Success of the Treatment

Technical success was achieved in all 37 patients. In the RFA group and the TACE-RFA group, technical success was achieved after 1.4 ± 0.5 and 1.1 ± 0.2 RFA sessions, respectively (P < .01). The number of needle insertions in the RFA group and TACE-RFA groups were 2.5 ± 1.3 and 1.6 ± 0.6, respectively (P < .01) (Table 2). On the CT images, the mean diameter of the long axis of the lesion induced by RFA was 50 ± 8.0 mm in the RFA group and 58 ± 13.2 mm in the TACE-RFA group (Table 2); there was no statistically significant difference between the values for the 2 groups (P = .058). The mean diameter of the short axis in the TACE-RFA group was significantly larger than that in the RFA group (50 ± 11.3 mm vs 41 ± 7.1 mm, P = .012).

Table 2. Number of Treatment Sessions, the RF-Induced Ablated Area, and the Post-Treatment Levels of Tumor Markers
 RFA Group, n=18TACE-RFA Group, n=19Pa
  • RF indicates radiofrequency; RFA, RF ablation; TACE, transcatheter arterial chemoembolization; PIVKA-II, protein-induced vitamin K absence or antagonist II.

  • Data are presented as mean ± standard deviation. RF group consists of patients in whom RF ablation without TACE was performed; TACE-RF group consists of patients in whom TACE was followed by RF ablation. Alpha-fetoprotein reduction rate = (pretreatment alpha-fetoprotein level − post-treatment alpha-fetoprotein level)/(pretreatment alpha-fetoprotein level). PIVKA-II reduction rate = (pretreatment PIVKA-II level − post-treatment PIVKA-II level)/(pretreatment PIVKA-II level).

  • a

    Student t test for unpaired data.

No. of treatment sessions1.4 ± 0.51.1 ± 0.2<.01
No. of needle insertions2.5 ± 1.31.6 ± 0.6<.01
RF-induced ablation area   
 Long axis, mm50 ± 8.058 ± 13.2.058
 Short axis, mm41 ± 7.150 ± 11.3.012
Alpha-fetoprotein   
 Post-treatment serum level, μg/L55 ± 10253 ± 153.963
 Reduction rate, %32 ± 5839 ± 59.703
PIVKA-II   
 Post-treatment serum level, μg/L23 ± 625 ± 19.585
 Reduction rate, %67 ± 3546 ± 34.069

Midterm Outcomes

Local tumor progression rates in the RFA group were 39% at the end of the first, second, and third years. The local tumor progression rate in the TACE-RFA group was 6% at the end of the first, second, and third years. Statistically significant differences were observed between the local tumor progression rates in the 2 groups (log-rank test, P = .012) (Fig. 1). The overall recurrence rates in the RFA group were 44%, 63%, and 72% at the end of the first, second, and third years, respectively. The overall recurrence rates in the TACE-RFA group were 33% and 91% at the end of the first and second years, respectively. There was no statistically significant difference between the overall recurrence rates in the 2 groups (log-rank test, P = .390) (Fig. 2). The 1-, 2-, and 3-year survival rates of the patients in the RFA group were 89%, 89%, and 80%, respectively. The 1-, 2-, and 3-year survival rates of the patients in the TACE-RFA group were 100%, 93%, and 93%, respectively. There was no statistically significant difference between the survival rates in the 2 groups (log-rank test, P = .369) (Fig. 3).

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Figure 1. Local tumor progression rates in the 2 groups are shown. The local tumor progression rate in the transcatheter arterial chemoembolization (TACE)-radiofrequency (RF) ablation group was significantly lower than that in the RF group (log-rank test, P = .012).

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thumbnail image

Figure 2. Overall recurrence rates in the 2 groups are shown. There was no difference between the overall recurrence rates in the 2 groups (log-rank test, P = .390). TACE indicates transcatheter arterial chemoembolization; RF, radiofrequency.

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thumbnail image

Figure 3. Overall survival rates in the 2 groups are shown. There was no significant difference between the overall survival rates in the 2 groups (log-rank test, P = .369). TACE indicates transcatheter arterial chemoembolization; RF, radiofrequency.

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The mean post-treatment serum levels of alpha-fetoprotein in the RFA group and the TACE-RFA group were 55 ± 102 μg/L and 53 ± 153 μg/L, respectively. The mean rates of reduction in the alpha-fetoprotein levels in the RFA group and the TACE-RFA group were 32 ± 58% and 39 ± 59%, respectively. The mean post-treatment serum levels of PIVKA-II were 23 ± 6 μg/L and 25 ± 19 μg/L in the RFA group and the TACE-RFA group, respectively, and the mean rates of reduction in these levels were 67 ± 35% and 46 ± 34%, respectively. No significant difference in the 2 parameters was observed between the RFA group and the TACE-RFA group (Table 2).

Safety (Complications)

There were no severe side effects during the procedures; however, 6 patients (5 patients of the RFA group and 1 patient of the TACE-RFA group) experienced grade 1 to 2 pain lasting several hours. Major complications (Society of Interventional Radiology classification, C to E)20 that required a higher level of care or resulted in substantially longer hospital stay (>48 hours) were not observed in the patients of the 2 groups. Minor complications, including asymptomatic right pleural effusion, were noted within 3 days of the procedures in 2 patients of the RFA group and 1 patient of the TACE-RFA group (RFA group vs TACE-RFA group, P = .515); however, none of these patients required interventional-drainage procedures. No patient deaths were reported within 30 days of the procedures. The laboratory data indicated that there were no cases of delayed complications, including symptomatic complications or liver-function complications, at 1 to 3 months after the procedures.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

We conducted a randomized controlled trial to evaluate the advantages of combining RFA with TACE for treating patients with intermediate-sized (3.1-5.0 cm) HCCs. Our results showed that the local tumor progression rate in the TACE-RFA group was lower than that in the RFA group; however, there was no statistical difference between the overall survival rates and safety in the 2 groups.

RF-induced thermal ablation has proven to be a safe and effective modality for the treatment of small hepatic tumors in patients who are considered to be unsuitable for surgical intervention.7, 21, 22 The treatment time is shorter than that with ethanol injection,8 and the thermal lesions are larger than those obtained with a microwave electrode.23 However, the limited volume of coagulative necrosis obtained with RF systems and the occasionally irregular burn shape caused by the heat-sink activity of the large vessels in the proximity of the ablated area, have prevented the widespread use of RFA for the treatment of intermediate- to large-sized hepatic tumors. The results of the present study provide evidence that the area of coagulative necrosis, which was determined on the basis of the lengths of the long and short axes of the ablated area, was greater in the TACE-RFA group than in the RFA group, although several insertion techniques19 were applied to obtain an adequately large ablated area. TACE primarily expanded the short axis of the ablated area and led to a more spherical ablated area. A spherical ablated area may be more effective than a nonspherical ablated area in ensuring local tumor control, because the spherical ablated area may possess a margin that completely surrounds the target tumor.

TACE before RFA is beneficial because it enables better ablation than that achieved with RFA alone and possibly facilitates the effective treatment of patients with larger HCCs.24 The blood supply to a classical HCC is primarily provided by the hepatic artery; therefore, the efficacy of RF-induced ablation can be enhanced by occlusion of the hepatic artery. Moreover, despite the fewer needle-insertion sessions in the TACE-RFA group, the larger coagulation area included regions of the surrounding nontumorous liver parenchyma. These results suggest that the dual embolization of the hepatic artery and the portal venules by intra-arterial injection of iodized oil followed by application of gelatin sponge increases the RF-induced thermal effects. Nakamura et al reported the presence of iodized oil in the portal vein after TACE with iodized oil, and the amount of iodized oil observed correlated with the amount that was injected.25 They postulated that the iodized oil entered the portal vein through arterioportal communication. The detailed mechanism of this phenomenon has not been clarified; nevertheless, in our study, iodized oil was injected under radioscopic guidance until it entered the intrahepatic branch of the portal vein.

Goldberg et al showed that a combination of RFA and direct intratumoral doxorubicin injection markedly increases the extent of induced coagulation in an animal model,26 and that intravenous administration of liposomal doxorubicin enhances the effectiveness of RFA in an animal model27 and in human hepatic tumors.28 In this study, we used epirubicin hydrochloride, which is a stereoisomer of doxorubicin hydrochloride,29 as an anticancer agent in TACE. Although we could not clarify whether epirubicin hydrochloride had the same effect as doxorubicin hydrochloride, we speculate that TACE performed using a mixture of iodized oil and epirubicin hydrochloride may be beneficial in increasing the coagulation effect induced by RFA in the patients of the TACE-RFA group.

In the previous reports on the therapeutic efficacy of the combination of TACE and RFA, RFA was performed several days after TACE.15, 30, 31 In contrast, in this study, we performed the combination therapy on the same day, and the resultant local tumor progression rates were significantly lower than those achieved with RFA monotherapy. Yu et al evaluated the biodistribution properties of the transarterial Lipiodol-based therapeutic regimens in HCC patients.32 They used radioactive iodine-131–labeled Lipiodol and showed that Lipiodol was detected in the peripheral blood or urine within the first week of injection. On the basis of these results, we speculate that RFA performed as soon as possible after TACE led to the strongest embolization effect, which may have contributed to the large therapeutic area.

The post-treatment serum levels of alpha-fetoprotein and PIVKA-II and the reduction rates of these levels did not correlate with the outcomes of the different treatment procedures, that is, with the rate of local tumor recurrence. The pretreatment levels of these markers are useful predictors of local tumor progression.33, 34 However, their post-treatment levels have been considered to have limited efficacy as predictors of local tumor recurrence after TACE35 and percutaneous ablation.36 Elevated serum levels of alpha-fetoprotein, which reflect not only tumor-cell proliferation but also active disease with continuous necrosis and regeneration, are associated with an elevated risk of developing HCC.37, 38 Although the development of HCC is often followed by a steady increase in the alpha-fetoprotein levels,37 the neoplastic changes are not necessarily associated with the elevated alpha-fetoprotein levels. In fact, many HCC lesions do not express alpha-fetoprotein even in the advanced stages.39 Conversely, the post-treatment serum levels of the lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (alpha-fetoprotein-L3)40 are reported to be a useful predictor of HCC recurrence after TACE41 and percutaneous ablation.36, 42 Unfortunately, we did not measure the alpha-fetoprotein-L3 levels in the current study; however, we plan to include such measurements in our future studies.

Complete response to initial treatment has been reported to contribute to the long-term survival in HCC patients who have undergone RFA therapy.43, 44 However, in the present study, although there was a significant difference between the local tumor progression rates of the initially treated lesions in the TACE-RFA group and the RFA group, there were no differences between the overall survival rates in the 2 treatment groups. The enrolled patients were randomly assigned to 2 groups, which contained patients at a similar risk of overall recurrence; however, the discrepancy might be attributed to the relatively small number of patients and the relatively short follow-up period in this randomized trial.

The percentages of minor complications, which were evaluated by the Society of Interventional Radiology classification system,20 were relatively small in both treatment groups. No permanent adverse sequelae or treatment-related deaths were observed in either treatment groups. The combination therapy of TACE followed by RFA was shown to be relatively safe.

In conclusion, our initial results have shown that the combination therapy of TACE followed by RFA was safe and effective for extending the ablated area, thereby contributing to restricting local tumor progression in patients with intermediate-sized HCCs. Long-term follow-up with a large number of patients may be needed to confirm the survival benefits of this technique.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

This work was supported in part by a research grant from Yokohama City University (to M.M.).

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES
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