Induction of complete tumor necrosis may reduce intrahepatic metastasis and prolong survival in patients with hepatocellular carcinoma undergoing locoregional therapy: a prospective study

T.-I. Huo1,2,*, Y.-H. Huang1,2, J.-C. Wu1,2, P.-C. Lee1, F.-Y. Chang1,2 and S.-D. Lee1,2

1 Taipei Veterans General Hospital, Division of Gastroenterology, Department of Medicine, Taipei, Taiwan; 2 National Yang-Ming University School of Medicine, Faculty of Medicine, Taipei, Taiwan, Republic of China

Received 21 November 2003; revised 19 January 2004; accepted 21 January 2004


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background:

Transarterial chemoembolization (TACE) and percutaneous acetic acid injection (PAI) are effective locoregional therapies for hepatocellular carcinoma (HCC). This study aimed to investigate whether HCC patients who had initial complete response to these treatments had a subsequent lower risk of intrahepatic metastasis.

Patients and methods:

A total of 152 patients who underwent locoregional therapy (94 received PAI and 58 received both TACE and PAI) for HCC (tumor size ≤5 cm) were prospectively evaluated.

Results:

In all, 60 (39%) patients had a complete tumor necrosis after treatment. The cumulative incidence of the development of intrahepatic metastasis was lower for patients with complete remission (P = 0.005) and for patients with smaller (≤3 cm) tumor size (P = 0.083). Cox multivariate survival analysis showed that absence of complete remission [relative risk (RR) 2.7; 95% confidence interval (CI) 1.4–5.3; P = 0.003] was the only independent factor that predicted the occurrence of intrahepatic metastasis. Patients with complete remission had a significantly better long-term survival than those without (P = 0.002), and the occurrence of intrahepatic metastasis over time independently predicted a decreased survival (RR 3.2; 95% CI 2.0–6.1; P = 0.019).

Conclusions:

Induction of complete tumor necrosis in HCC patients undergoing locoregional therapy may decrease the risk of intrahepatic metastasis and improve survival.

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


    Introduction
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world, with an increasing global annual incidence [1, 2]. Surgical resection is generally considered the standard treatment modality to achieve a long-term survival [35]. However, resection is only possible in a small proportion of patients due to compromised hepatic reserve and multifocality of tumors at the time of diagnosis. Liver transplantation is another treatment option, especially for patients with decompensated cirrhosis [6], but potential recipients far outnumber donors. Alternative non-surgical methods including transarterial chemoembolization (TACE) [711], percutaneous ultrasound-guided injection therapy using ethanol [1218] or acetic acid [1922], and radiofrequency thermal ablation [23] are commonly employed for HCC. In some series, these locoregional treatment modalities have been reported to be as effective as surgical resection [10, 17, 24].

For patients with unresectable disease, the goal of palliative locoregional therapy is to control symptoms and prolong survival [7, 11, 25]. 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 [7, 11, 25, 26]. Alternatively, some reports have suggested that by using 15–50% acetic acid, percutaneous acetic acid injection (PAI) has stronger necrotizing power than that of pure ethanol [20, 21], and may be equally effective as, or even superior to, ethanol injection in treating small HCC [19, 22]. However, given the above available treatment options, the induction of complete tumor necrosis after initial treatment to enter into a tumor-free status may be difficult to achieve, especially for those with large HCCs. Persistently viable (not completely ablated) tumors can show progressive neoplastic changes and facilitate intrahepatic metastasis, which has been considered a poor prognostic factor and may further increase the difficulty of managing the cancer [8, 22]. To determine the therapeutic significance of complete treatment response after locoregional therapy in patients with unresectable disease, in this study we have prospectively investigated whether the induction of complete response in HCC patients undergoing PAI alone or in combination with TACE may decrease the risk of intrahepatic metastasis and its prognostic impact on the long-term survival.


    Patients and methods
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Enrollment criteria
During a 5-year period from July 1998 and June 2003, patients who were diagnosed as HCC and admitted to our institution were prospectively evaluated. The following criteria were used to enroll eligible patients: not indicated for resection; Child-Pugh class A or B; tumor nodule measured ≤5 cm in greatest dimension; the number of tumor nodules was three or less; ultrasound detection of the lesion to allow for percutaneous injection; high tumor vascularity as determined in dynamic computed tomography (CT) scan or CT scan under arterial portography; no portal vein invasion or thrombosis, or extrahepatic metastasis. The HCC nodule(s) was considered unresectable if there were multifocal lesions, which 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 histologically verified 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) level >400 ng/ml [27]. The severity of the underlying cirrhosis was classified according to the Child-Pugh system [28]. The staging of HCC was according to the Cancer of the Liver Italian Program (CLIP) classification system [29]. The underlying hepatitis was considered hepatitis B virus infection if patients were seropositive for hepatitis B surface antigen (RIA kit; Abbott Laboratories, North Chicago, IL, USA) on at least two occasions.

Treatment and follow-up
TACE was carried out according to Seldinger’s technique for arterial embolization [30, 31]. The equipment 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, 100–150 ml radiocontrast medium (Telebrix; Laboratoire Guerbet, Aulnay-Sous-Bois, France or Ultravist, Schering, Berlin, Germany) was injected using a power injector (CT9000 ADV; Liebel-Flarsheim, St Louis, MO, USA) to evaluate the vascularity of the tumor (‘tumor stain’). The arteries supplying the tumor were catheterized superselectively, followed by infusion of a mixture of 20–30 mg adriamycin (Carlo Erba, Milan, Italy) and 5–10 ml Lipiodol (Laboratoire Guerbet). 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.

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, Germany) was injected with a 22-gauge spinal needle [22, 31]. Treatment was administered twice a week in an in-patient setting. Typically, one or two injections at a dose of 2–4 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 min to prevent reflux of acetic acid into peritoneal cavity. Two to four sessions were given for the lesions <3 cm in size and four to five sessions were given for the lesions between 3 and 5 cm. For patients with multiple tumors, PAI was performed first on the main tumor (the one with the largest diameter), followed by treating the smaller ones until all tumors were successfully treated.

A total of 166 patients were prospectively enrolled; none of them had undergone specific anticancer treatment before enrollment. Sixty-three patients received combination therapy of TACE and PAI (TACE-PAI group) and 103 patients who were not indicated for, or did not receive, TACE were treated with PAI therapy alone (PAI group). A portion of the study patients belonged to a previous clinical trial comparing the efficacy of PAI versus TACE-PAI therapy [31]. 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) feint or no tumor stain on hepatic angiography; (ii) feeding artery not accessible by catheter; (iii) deterioration of liver function as reflected by increase >1 mg/dl in serum total bilirubin level and decrease >0.5 g/dl in serum albumin. PAI therapy was then administered to the remaining viable part of tumor nodule as reflected by dynamic CT scan showing contrast enhancement in the arterial phase.

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 after the completion of initial treatment cycle in both TACE-PAI and PAI groups. An additional treatment cycle was 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 response
Complete treatment response (no neoplastic disease), according to WHO criteria [32], was defined as absence of contrast-enhanced area in CT scan and no tumor staining in angiography of the treated tumor. Detection of local residual disease was defined as a recurrent tumor within or adjacent to the treated tumor, and the occurrence of intrahepatic metastasis was defined as new tumor recurrence elsewhere, separate from the treated tumor. Patients were considered to have complete response only when all treated tumors in the same subject showed complete necrosis by contrast-enhanced CT and hepatic angiography. Residual or new intrahepatic tumor recurrence was detected by the CT showing contrast enhancement during arterial phase or angiography showing tumor staining. The primary and secondary end points of this study were patient treatment response and the development of intrahepatic metastasis, respectively.

Statistical methods and risk factor analysis
All statistical analyses were carried out using SPSS for Windows, release 11.0.1. The {chi}2-test or Fisher’s exact test (two-tailed) was used for categorical data, and the Mann–Whitney ranked sum test was used for continuous data. The survival curve of the association of complete tumor necrosis after treatment and the development of intrahepatic metastasis was estimated by the Kaplan–Meier method, and compared by the log-rank test. The patient- and tumor-related variables including age, sex, underlying hepatitis, Child-Pugh class, number and size of tumors, CLIP score, serum levels of albumin, bilirubin and AFP, prothrombin time ratio, treatment modality, and treatment response were included for analysis. The occurrence of intrahepatic metastasis over time was treated as a time-dependent covariate, and its association with overall survival was examined using a Cox multivariate analysis. Factors that were significant or marginally significant (P <0.1) in the univariate survival analysis were entered into a Cox proportional hazard model to determine the adjusted risk ratios. For all tests, a P value <0.05 was considered statistically significant.


    Results
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Assessment of treatment
Fourteen patients (nine receiving PAI and five TACE-PAI therapy) were lost to follow-up during or after treatment. These patients were excluded from final analysis because the status of tumor response was unknown and follow-up data were not available. The remaining 152 patients (113 male; mean age 67 ± 10 years, range 24–84) formed the basis this study, and their survival data were censored at the time of the last visit. The baseline demographics of the study patients are listed in Table 1. The mean follow-up duration was 22 ± 10 months (range 5–48). In all, 60 patients (39%) had complete tumor necrosis after treatment, and 92 patients (61%) still had local residual viable tumors as demonstrated by contrast-enhanced dynamic CT and angiography. Comparison of the clinical characteristics between patients with and without complete tumor necrosis are shown in Table 2. Patients with complete remission more often had small-sized (≤3 cm) HCC (65% versus 45%; P = 0.020) and more often underwent TACE-PAI combination therapy (52% versus 29%; P = 0.007) than those without complete remission.


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Table 1. Baseline demographics of the study patients
 

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Table 2. Comparison of the characteristics between patients with and without CR after initial treatment
 
Incidence of intrahepatic metastasis and its association with treatment response and long-term survival
The overall 1-, 2- and 3-year rates of intrahepatic metastasis were 9, 36 and 68%, respectively. Thirteen patients (22%) in the complete remission group developed intrahepatic metastasis during the follow-up period, compared with 37 patients (40%) among those without complete remission; the 1-, 2-, and 3-year cumulative rates was 4, 27 and 35% in the former and 12, 43 and 87% in the latter group, respectively (P = 0.005) (Figure 1). In addition, patients who had tumor size >3 cm more often developed intrahepatic metastasis during follow-up than those with tumor size ≤3 cm (P = 0.083) (Figure 2). Patients who underwent combination TACE and PAI therapy had a marginal benefit against intrahepatic metastasis compared with PAI therapy alone (P = 0.010). Comparison among other clinico-pathological factors showed insignificant differences in terms of their association with intrahepatic metastasis. The adjusted Cox multivariate analysis showed that the absence of complete remission [relative risk (RR) 2.7; 95% confidence interval (CI) 1.4–5.3; P = 0.003] was the only independent factor that predicted the development of intrahepatic metastasis. Analysis of overall survival showed that patients with complete tumor necrosis had a significantly better long-term survival compared with those without complete tumor necrosis (P = 0.002) (Figure 3). Of the 50 patients who developed intrahepatic metastasis, 23 (46%) died, compared with 19 of 102 patients (19%) (P = 0.001) without intrahepatic metastasis. The occurrence of intrahepatic metastasis over time during the follow-up period was identified as an independent risk factor of decreased survival (RR 3.2; 95% CI 2.0–6.1; P = 0.019). Other factors that independently predicted a poor survival were Child-Pugh class B (RR 1.9; 95% CI 1.2–3.8; P = 0.036) and a CLIP score of ≥2 (RR 2.8; 95% CI 1.6–4.9; P = 0.008).



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Figure 1. Comparison of the incidence of intrahepatic metastasis between patients undergoing locoregional therapy with (open circles) and without (filled circles) initial complete tumor necrosis.

 


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Figure 2. Comparison of the incidence of intrahepatic metastasis according to tumor size in HCC patients undergoing locoregional therapy. Open circles, tumor size >3 cm; filled circles, tumor size ≤3 cm.

 


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Figure 3. Comparison of the long-term survival between HCC patients undergoing locoregional therapy with (open circles) and without (filled circles) initial complete tumor necrosis.

 

    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Among the available treatment options of percutaneous approach for HCC, percutaneous injection therapy using ethanol or acetic acid has been frequently used during the past decade [1222]. The major limitation for percutaneous injection therapy is that it is indicated only for small (<3 or 4 cm) HCC nodules. Combination therapy using TACE and percutaneous acetic acid injection, which takes the advantage of combining the effect of ischemic necrosis induced by arterial embolization and coagulation necrosis by the injected tumor-killing agent, has been recently been shown to be effective, especially for large HCCs [31]. There have been very few studies to date that had investigated the clinical significance and impact of induction of initial complete response on the natural course of HCC patients undergoing non-surgical treatment. In this study, we specifically evaluated the treatment response in HCC patients treated with PAI alone or in combination with TACE, and its association with intrahepatic metastasis during the follow-up period. Consistent with previous studies [33, 34], our results suggest that induction of complete tumor necrosis may significantly reduce the occurrence of intrahepatic metastasis and prolong survival in HCC patients undergoing locoregional therapy.

The overall cumulative rate of intrahepatic metastasis at 3 years was 68% in this series. Such a high rate of recurrence is not unusual, because of the multicentric nature of the disease. It is noteworthy that the development of intrahepatic metastases in a substantial proportion of patients may be attributed to the multiple metachronous or unnoticed synchronous tumors that could not be detected even by the highly sensitive contemporary radiological imaging modalities used [35, 36]. Nevertheless, a high tumor recurrence rate is not a specific drawback of percutaneous or transarterial approach, because it is also found in cirrhotic patients with HCC treated with curative surgical resection [35, 36]. An important finding in this study is that the difference in the cumulative incidence of intrahepatic metastasis between those with and without initial complete response was most striking after 2 years of treatment (Figure 1), suggesting that complete tumor eradication could effectively suppress new carcinogenesis foci.

Various forms of locoregional therapy have been widely performed in treating unresectable HCCs, but complete cure of HCC cannot be expected. In many occasions, a small portion within the tumor nodule may still remain viable after repeated treatment such as TACE or percutaneous injection therapy. For patients with HCC, histological studies of resected HCC specimens after TACE procedure showed that complete necrosis occurred in only 22–50% of HCC lesions [3740]. Similarly, for patients who underwent percutaneous injection therapy, the injected chemical might not be able to effectively destroy the intra-tumoral septum and penetrate the entire tumor nodule [16, 20, 21]. Therefore, the residual viable cancer cells may facilitate tumor progression and induce intrahepatic metastasis, as shown in a previous study which suggested that in most instances, intrahepatic recurrences are considered to arise from intrahepatic metastasis by means of venous dissemination or microsatellites [41].

In addition to initial treatment response, large tumor size (>3 cm) was also identified as a risk factor that may predispose to intrahepatic metastasis. This result is in agreement with previous findings in surgical and non-surgical series. Large-sized tumor nodules more often had concomitant minute cancerous lesions, and it has been shown that tumor recurrence was frequent in patients with large HCC even when the tumor has been removed by surgical resection or liver transplantation [36, 36]. Patients with large HCC undergoing TACE [79] or percutaneous ethanol injection therapy [1217] were also often associated with a relatively poor long-term outcome. However, the significance of tumor size was excluded in the adjusted Cox multivariate model, suggesting that treatment response was a stronger and prevailing factor influencing intrahepatic metastasis.

The occurrence of new tumor over time in the remnant liver may compromise further active treatment, partly because it has frequently been linked with concurrent liver decompensation at the time of diagnosis [42]. To determine the prognostic impact of intrahepatic metastasis, this factor was analyzed as a time-dependent covariate, and was consistently identified as an independent factor predicting a decreased survival, with an increased risk ratio of up to 3.2-fold.

In conclusion, our results indicate that successful induction of initial complete treatment response may have important therapeutic implications. It could both reduce the incidence of intrahepatic metastasis and prolong survival in HCC patients who undergo locoregional ablation therapy. Aggressive initial anticancer treatment directed at inducing effective locoregional control may be necessary to achieve a more favorable long-term outcome.


    Acknowledgements
 
This study was supported by a grant from Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China.


    FOOTNOTES
 
* Correspondence to: Dr T.-I. Huo, Division of Gastroenterology Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China. Tel: +886-2-2871-2121, ext. 3352; Fax: +886-2-2873-9318/2876 1641; E-mail: tihuo{at}vghtpe.gov.tw Back


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 Discussion
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