Sequential transarterial chemoembolization and percutaneous acetic acid injection therapy versus repeated percutaneous acetic acid injection for unresectable hepatocellular carcinoma: a prospective study

T.-I. Huo1,+, Y.-H. Huang1, J.-C. Wu1, J.-H. Chiang2, P.-C. Lee1, F.-Y. Chang1 and S.-D. Lee1

1 Department of Medicine, 2 Department of Radiology, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan, Republic of China

Received 14 May 2003; revised 11 June 2003; accepted 11 August 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

Transarterial chemoembolization (TACE) and percutaneous acetic acid injection (PAI) are effective treatments for hepatocellular carcinoma (HCC). We have conducted a prospective study to compare the efficacy of sequential TACE and PAI (TACE-PAI) versus repeated PAI therapy for HCC.

Patients and methods:

A total of 108 HCC patients with tumor size <=5 cm were enrolled. Fifty-three patients were treated with TACE–PAI and 55 patients were treated with PAI alone.

Results:

Objective responses were achieved in 72 of 80 nodules (90%) in the TACE–PAI group compared with 51 of 62 nodules (82%) in the PAI group (P = 0.217) during 24 ± 10 months of follow-up. Patients in the TACE–PAI group had a significantly lower cumulative tumor recurrence rate from the treated nodule (P = 0.004) or newly developed tumor elsewhere in liver (P = 0.010). Complete tumor necrosis in large (3–5 cm) HCCs was more frequently encountered in the TACE–PAI group (64% versus 37%; P = 0.034). There was no significant survival difference between the two groups with small (<=3 cm) HCC (P = 0.569), whereas PAI therapy was an independent poor prognostic predictor [relative risk 3.0 (95% confidence interval 1.2–7.6); P = 0.017] in the large HCC group.

Conclusions:

Sequential therapy with TACE and PAI is superior to repeated PAI alone for patients with large HCC.

Key words: arterial embolization, hepatocellular carcinoma, liver cirrhosis, percutaneous acetic acid injection


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor worldwide, and as recently reported [1, 2] has an annual incidence that is increasing globally. Surgical resection is the standard treatment modality to achieve long-term survival [35]. However, resection is possible in only a small proportion of patients due to compromised hepatic reserve and multifocality of tumors. Liver transplantation is another treatment option, especially for those patients with decompensated cirrhosis [6], but potential recipients far outnumber donors. Alternative non-surgical methods include transarterial chemoembolization (TACE) [711], and percutaneous ultrasound-guided ablation therapy including injection of ethanol [1218] or acetic acid [1922] and radio-frequency thermal ablation [23].

For patients with unresectable disease, the goal of palliative treatment is to control symptoms and prolong survival [24]. TACE using iodized oil and chemotherapeutic agents combines the effect of targeted chemotherapy with that of ischemic necrosis induced by arterial embolization. It can be administered repeatedly and can prolong survival in patients with unresectable hypervascular HCC [11, 25, 26]. Several studies have reported that a combination of TACE and ultrasound-guided percutaneous ethanol injection was more effective and yielded a better survival rate compared with TACE alone [2729]. On the other hand, some reports suggest that by using 15–50% acetic acid, percutaneous acetic acid injection (PAI) has stronger necrotizing power compared with that of pure ethanol [20, 21], and may be equally effective or even superior to ethanol injection in treating small HCC [19, 22]. However, the efficacy and survival benefit of sequential therapy using TACE and PAI have not been specifically assessed. To determine whether sequential therapy can achieve a better treatment response and prolong long-term survival, we have prospectively evaluated the therapeutic efficacy of sequential TACE and PAI compared with that of PAI alone in treating patients with unresectable HCC.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Enrollment criteria
During a 4-year period from July 1998 to June 2002, patients diagnosed with HCC and admitted to our institution were prospectively evaluated. The following criteria were used to enroll eligible patients: (i) not indicated for resection; (ii) Child–Pugh class A or B; (iii) tumor nodule measuring <=5 cm in its greatest dimension; (iv) number of tumor nodules three or less; (v) ultrasound detection of the lesion to allow for percutaneous injection; (vi) high tumor vascularity as determined in dynamic computed tomography (CT) scan or CT scan under arterial portography; (vii) no main portal vein involvement or extrahepatic metastasis. The HCC nodule(s) was considered unresectable if there were multifocal lesions that made extended resection necessary to eradicate all tumors, or the hepatic reserve was insufficient with an indocyanine green 15-min retention rate >30%. The diagnosis of HCC was verified histologically by needle biopsy, or based on the findings of typical radiological features in at least two image examinations including ultrasound, contrast-enhanced dynamic CT, magnetic resonance imaging (MRI) and hepatic angiography, or by a single positive imaging technique associated with serum {alpha}-fetoprotein (AFP) levels >400 ng/ml [30]. The severity of the underlying cirrhosis was classified according to the Child–Pugh system. The underlying hepatitis was considered hepatitis B virus infection if patients were seropositive (RIA kit, Abbott Laboratories, North Chicago, IL, USA) for hepatitis B surface antigen (HBsAg) on at least two occasions.

Treatment and follow-up
TACE was carried out according to Seldinger’s technique of arterial embolization [31]. The equipment used for selective common or proper hepatic artery angiography was LCN (GE Medical Systems, Waukesha, WI, USA) or Diagnost 3 (Philips, Amsterdam, The Netherlands). Hepatic arteriography and superior mesenteric arterial portovenography were performed to define the size and location of tumor nodules. During the sequential scanning of the liver, radiocontrast medium (Telebrix, Guerbet, Paris, France or Ultravist, Schering, Berlin, Germany) 100–150 ml was injected using a power injector (CT9000 ADV; Liebel-Flarsheim, St Louis, MI, USA) to evaluate the vascularity of the tumor (‘tumor stain’). The arteries supplying the tumor were catheterized superselectively followed by an infusion of a mixture of doxorubicin 20–30 mg (Carlo Erba, Milan, Italy) and lipiodol 5–10 ml (Laboratoire Guerbet, Aulnay-Sous-Bois, France). The aim was to deliver a sufficient amount of emulsion to the tumoral areas without retrograde flow. Under fluoroscopic control, the feeding arteries were subsequently embolized with 2–3 mm strips of Gelfoam (Upjohn, Kalamazoo, MI, USA) until complete flow stagnation was achieved.

In the TACE–PAI group, TACE was performed up to a maximum of three courses or discontinued when any of the following conditions developed: (i) faint or no tumor stain on hepatic angiography; (ii) feeding artery not accessible by catheter; and (iii) deterioration of liver function as reflected by an increase of >1 mg/dl in serum total bilirubin level and a decrease of >0.5 g/dl in serum albumin. A dynamic CT scan was performed 1 month after the completion of TACE, and PAI was then administered to the remaining viable part of the tumor nodule as reflected by a CT scan showing contrast enhancement in the arterial phase.

The equipment used for PAI was a commercially available ultrasound scanner with a puncture probe with guide device (Aloka, Tokyo, Japan). Sterile 50% acetic acid (Merck, Darmstadt, Gemany) was injected with a 22-gauge spinal needle [22]. Treatment was administered twice a week in an inpatient setting. Typically, one or two injections at a dose of 2–5 ml acetic acid were given during each treatment session. Acetic acid was slowly injected until the echogenic area appearing immediately after injection covered the entire tumor. After the injection was complete, the needle was left in place for 1–2 min to prevent reflux of acetic acid into the peritoneal cavity. Three to four sessions were given for lesions <=3 cm and four to six sessions were given for lesions >3 and <=5 cm. For patients with multiple tumors, PAI was performed first on the main tumor (one with the largest diameter), followed by treating the smaller ones until all tumors were successfully treated.

Post-treatment follow-up included ultrasound scan and measurement of serum AFP levels every 2 months and contrast-enhanced dynamic CT every 3–4 months. MRI and/or hepatic angiography were carried out as supplemental examinations. Treatment response was evaluated 1 month after the second treatment cycle of PAI in both the TACE–PAI and PAI groups. Additional treatment cycles were administered once tumor recurrence or viable tumor was found. When patients developed a diffuse, infiltrative HCC, they were considered non-responsive and not treated.

Assessment of treatment
Objective responses accounted for complete (no neoplastic disease) and partial responses (reduction of total tumor load >50%) as defined by World Health Organization (WHO) criteria [32]. Complete tumor necrosis was defined as absence of a contrast-enhanced area on the CT scan and no tumor staining following angiography of the treated tumor. Detection of local residual disease was defined as a recurrent tumor within or adjacent to the treated tumor, and new nodular recurrence was defined as a recurrence elsewhere separate from the treated tumor. Residual or new tumors were detected by dynamic CT showing contrast enhancement during the arterial phase or hepatic angiography showing tumor staining. Primary and secondary end points for this study were patient survival and tumor recurrence, respectively.

Statistical methods and risk factor analysis
Assumptions were a 3-year survival of 40% in the PAI group and 70% in the TACE–PAI group based on our and others’ previous series [1922]. Fifty patients were needed in each group to detect an increase in survival, with a two-sided type I error of 5% and a power of 80% (SPSS SamplePower 2.0).

All statistical analyses were carried out using SPSS for Windows, release 11.0.1 (SPSS, Chicago, IL, USA). Chi-square or Fisher’s exact tests (two-tailed) were used for categorical data, and Mann–Whitney ranked sum test was used for continuous data. The overall survival and cancer-free survival were estimated by the Kaplan–Meier method and compared with the log-rank test. Patient- and tumor-related variables including age, sex, underlying hepatitis, Child–Pugh class, number and size of tumor, ascites, serum levels of albumin, bilirubin and AFP, prothrombin time ratio, history of esophageal varices bleeding or hepatic encephalopathy and treatment modality were included for analysis. Factors that were significant or marginally significant (P <0.1) in univariate survival analysis were entered into a Cox proportional hazard model to determine the risk ratios. For all tests, a value of P <0.05 was considered statistically significant.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
According to the entry criteria, a total of 108 patients were enrolled and allocated to either treatment on a case-controlled basis. The nature of this trial and the potential treatment-related complications were explained fully to the patients according to the standards of the Declaration of Helsinki and informed consent was obtained from all patients. Fifty-three patients received sequential TACE and PAI (TACE–PAI group) and the remaining 55 patients, who did not receive TACE therapy, were treated with PAI alone. There were nine patients (five in the TACE–PAI group and four in the PAI group) who did not complete the treatment, or for whom the follow-up period was <6 months. They were included in the intention-to-treat analysis and their survival data were censored at the time of the last visit. The comparisons of the baseline demographics between the two groups of patients are given in Table 1. No significant differences were noted between the two groups of patients, except that serum albumin in the TACE–PAI group was higher than that in the PAI group (3.7 ± 0.5 versus 3.4 ± 0.5 g/dl; P = 0.003).


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Table 1. Baseline demographics of the study patients
 
Treatment response
The application of TACE was given for 1.9 ± 0.4 (range 1–3) courses in the TACE–PAI group, and PAI was given for 3.1 ± 0.4 (range 2–5) and 3.7 ± 0.5 (range 2–6) sessions in each treatment cycle for the TACE–PAI and PAI groups, respectively. Assessment of treatment response was possible in the 142 tumor nodules among 99 patients who had been followed-up for at least 6 months. Objective response was achieved in 72 of 80 nodules (90%) in the TACE–PAI group, compared with 51 of 62 nodules (82%) in the PAI group (P = 0.217). For 3–5 cm-sized tumor nodules, 30 of 47 nodules (64%) in TACE–PAI group had a complete response compared with 11 of 30 nodules (37%; P = 0.034) in the PAI group. No significant difference in the complete response rate was noted between the two groups of patients with small (<=3 cm) HCCs (83% in TACE–PAI group versus 84% in PAI group; P = 1.0).

Survival analysis
The average follow-up period was 24 ± 10 months. The overall 1- and 3-year survival rates were 100% and 69% for the TACE–PAI group and 96% and 32% for the PAI group, respectively (P = 0.008; Figure 1A). The independent prognostic factors predicting a poor survival were the presence of ascites {relative risk (RR) 6.3 [95% confidence interval (CI) 2.0–19.7]; P = 0.002} and a history of encephalopathy [RR 4.1 (95% CI 1.5–11.3); P = 0.007] in the Cox multivariate analysis; PAI treatment was associated with a poor survival at a marginal significance (P = 0.103).



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Figure 1. Comparison of (A) overall survival and (B) cancer-free survival between hepatocellular carcinoma patients treated with transarterial chemoembolization–percutaneous acetic acid injection (TACE–PAI) and PAI.

 
Tumor recurrence and cancer-free survival
Thirty (63%) patients of the TACE–PAI group had a tumor recurrence after 22 ± 8 months (range 7–35) of treatment, whereas tumor recurrence developed in 33 (63%) of the PAI group after 17 ± 6 months (range 6–28 months) of treatment. The cancer-free survival was significantly better in the TACE–PAI group (P = 0.003; Figure 1B). Multivariate analysis showed that tumor size >3 cm [RR 3.3 (95% CI 1.7–6.9); P = 0.005] and PAI treatment [RR 2.1 (95% CI 1.3–5.5); P = 0.024] were independent risk factors for a shorter cancer-free survival among all patients. Of the TACE–PAI group, 28 (58%) patients had viable part of the treated lesions, whereas 17 (35%) had newly developed lesions elsewhere in the liver. Of the PAI group, 31 (60%) patients had viable tumors, whereas 19 (36%) had new lesions elsewhere in the liver. The difference in the pattern of tumor recurrence was not significantly different between the two groups. However, patients in the TACE–PAI group had a significantly lower cumulative recurrence rate either from the treated nodule (P = 0.004) or newly developed tumors elsewhere in the liver (P = 0.010).

Overall survival and cancer-free survival stratified by tumor size
For patients with small (<=3 cm) HCCs, there was no significant overall survival difference between the TACE–PAI and PAI groups. The 1- and 3-year survival rates were 100% and 73% for the TACE–PAI group and 100% and 49% for the PAI group, respectively (P = 0.569; Figure 2A). However, for patients with large (>3 cm) HCCs, the survival was significantly better in the TACE–PAI group. The 1- and 3-year survival rates were 100% and 64% for the TACE–PAI group and 90% and 22% for the PAI group, respectively (P = 0.003; Figure 2B). Multivariate survival analysis in this group indicated that a history of encephalopathy [RR 9.4 (95% CI 1.6–54.1); P = 0.012] and PAI treatment [RR 3.0 (95% CI 1.2–7.6); P = 0.017) were independent prognostic factors predicting a poor survival.



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Figure 2. Comparison of overall survival between patients treated with transarterial chemoembolization–percutaneous acetic acid injection (TACE–PAI) and PAI according to tumor size. Patients with tumor size (A) <=3 cm and (B) >3 cm between two treatment groups.

 
The cancer-free survival was compared between the two groups stratified by tumor size. There were no significant differences in cancer-free survival between the two groups of patients with tumor sizes <=3 cm (P = 0.217). However, for patients with a tumor size >3 cm, cancer-free survival was significantly better in the TACE–PAI group compared with that of the PAI group (P = 0.001).

Side-effects
Transient fever, abdominal pain and elevation of liver enzymes were present in the majority of patients after TACE. Side-effects of PAI treatment were relatively mild. Most patients experienced transient mild to moderate local pain during or after acetic acid injection, which could be controlled with additional analgesics. No serious complications that necessitated intensive care were encountered with either therapy.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Percutaneous injection therapy using pure ethanol or acetic acid has been widely used to treat HCC [1222], especially in some instances when resection or TACE was not indicated [18]. The major drawback of percutaneous injection therapy is that it is only indicated for small (<3 cm) HCC nodules. Combination therapy using TACE and percutaneous ethanol injection—which takes advantage of the combined effect of ischemic necrosis induced by arterial embolization and coagulation necrosis induced by the injected tumor-killing agent—has been proposed for treating large HCCs [28, 29]. In this study, we have specifically compared the treatment effect, tumor recurrence and long-term survival between patients treated with TACE–PAI and PAI alone. Our results suggest that combination therapy may be a better treatment option in a subset of HCC patients.

It was reported that acetic acid has a strong ability to penetrate cells and can dissolve lipids and extract collagen from intra-tumoral septa and capsule that frequently contain viable cancer cells [20, 21]. Therefore, acetic acid is theoretically superior to ethanol in treating patients with HCC, since the texture of the tumor and its resistance to perfusion with ethanol may make percutaneous ethanol injection less effective [19]. In addition, PAI has the advantage of a reduced number of treatment sessions, as well as a smaller injected volume in each treatment course compared with that of percutaneous ethanol injection [22]. There has been only one study to date that has assessed the effect of PAI with or without previous TACE for large (>3 cm) HCC [21]. However, the case number in that report was too small to draw any firm conclusions. Our study included a larger patient population, which may allow for a comparison between the two groups of patients. We found that sequential TACE–PAI was a safe procedure and may be considered as a treatment alternative for patients with 3–5 cm sized HCC.

Although both TACE–PAI and PAI therapy may achieve a similar degree of objective response after treatment, large-sized tumor nodules showed complete necrosis more often in the TACE–PAI group and thus this group had a lower recurrence rate. In this study, about two-thirds of patients eventually developed a tumor recurrence. Such a high rate of recurrence is not unusual and is possibly related to the multiple metachronous or unnoticed synchronous tumors that could not even be detected by highly sensitive imaging modalities [33]. Nevertheless, a high tumor recurrence rate is not a specific drawback of PAI or TACE, because it is also found in cirrhotic patients with HCC treated with any other modality, including surgical resection [3, 4]. Our results showed that sequential TACE–PAI therapy could effectively delay the time interval to recurrence, especially in patients with large HCC. Another interesting finding of this study was that there was no significant difference in cancer-free survival between the two groups of patients with small (<=3 cm) HCC. In fact, a high rate of complete tumor necrosis has been achieved in both groups (83% versus 84% in the TACE–PAI and PAI groups, respectively), indicating that PAI therapy alone may have similar therapeutic efficacy compared with that of combination therapy.

Tumor size has been shown to be an important prognostic predictor in HCC patients undergoing surgical resection [35], liver transplantation [6], TACE [7, 9] and percutaneous ethanol injection [1417]. When survival was stratified by tumor size, we found that treatment modality was not a prognostic predictor in the small (<=3 cm) HCC group, whereas PAI therapy was a significant risk factor independently predicting a poor survival among the patients with large HCC. These findings were consistent with the result that patients with large HCC receiving sequential TACE–PAI therapy less frequently developed a tumor recurrence.

In conclusion, sequential therapy using TACE and PAI may achieve a lower tumor recurrence rate and could prolong survival in patients with large HCC. For patients with small HCC, PAI alone is sufficient and there is no additional benefit of combination therapy with TACE. Careful pre-treatment patient evaluation and selection may provide a better clinical outcome.


    Acknowledgements
 
We thank Professor Yue-Cune Chang (Department of Mathematics, Tamkang University, Taiwan) for his help with the statistical analysis. This study was supported by a grant from Taipei Veterans General Hospital, Taipei, Taiwan.


    Footnotes
 
+ Correspondence to: Dr T.-I. Huo, Division of Gastroenterology Department of Medicine Taipei Veterans General Hospital, Taipei, Taiwan. Tel: +886-2-2871-2121; Fax: +886-2-2873-9318; E-mail: tihuo{at}vghtpe.gov.tw Back


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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