© 2004 Foundation for Promotion of Cancer Research
Extrahepatic Spread from Hepatocellular Carcinoma: Who are Candidates for Aggressive Anti-cancer Treatment?
1 Division of Hepatobiliary and Pancreatic Medical Oncology and 2 Division of Upper Abdominal Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
For reprints and all correspondence: Hiroshi Ishii, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. E-mail: hirishii{at}east.ncc.go.jp
Received August 4, 2004; accepted September 23, 2004
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Abstract |
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 TOP Abstract INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: There is no standard treatment for patients with extrahepatic spread from hepatocellular carcinoma. The aim of this retrospective study was to identify candidates for aggressive intervention or new drug trial among such patients.
Methods: Retrospective exploration was performed to extract a patient cohort step by step using univariate and multivariate analyses.
Results: There were 201 subjects from the past 12 years. The 1-, 3- and 5-year survival rates were 31.0, 9.2 and 4.5%, respectively. The upper limit of the 95% confidence interval of median survival time did not reach 3 months in patients with a performance status of 2 or worse, or with Child–Pugh grades B or C. After excluding those, univariate and multivariate analyses were performed in the remaining 124 subjects. Three independent prognostic factors—brain metastasis, number of metastatic tumors and primary tumor status—were identified. The final cohort was set at 121 after excluding three with brain metastasis. Among these 121, there were 11 with a solitary metastatic tumor and T1/2 primary tumor. In this subgroup, 10 underwent complete removal of the metastatic tumor, and the median survival time exceeded 5 years.
Conclusion: Candidates for anti-cancer treatment should meet the following requirements: a performance status of 0 or 1, a Child–Pugh grade A and no brain metastasis. Among these, challenging locoregional intervention was acceptable only for patients with solitary metastatic tumor and T1/2 primary tumor.
Key Words: liver neoplasm • metastasis • prognosis • surgery • ablation
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INTRODUCTION |
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According to the TNM staging system, the presence of extrahepatic spread (EHS) from hepatocellular carcinoma (HCC) is categorized as advanced cancer. The American Joint Committee on Cancer defines regional lymph node and distant metastasis as stages IIIC and IV, respectively (1). The Liver Cancer Study Group of Japan criteria classify nodal or distant metastasis into stage IVB (2). These staging systems are based on EHS corresponding to systemic disease derived from advanced intrahepatic tumor (3).
Based on the principles of clinical oncology, locoregional therapy is not indicated for patients with systemic disease in general. Because there is no highly effective systemic chemotherapy for HCC (4), the Barcelona Clinic Liver Cancer group suggested that the clinical trial of a new drug is the only treatment option for HCC patients with EHS (5). The role of local therapy for EHS from HCC is uncertain.
In recent years, there have been a few reports of metastases from T1 primary HCC (6,7). Yamamoto et al. (8) reported that EHS without intrahepatic recurrence occurred in 5% after hepatectomy. This population, i.e. patients having T0–1 with N1 or M1, may not be small and will become gradually larger with the development of definitive local therapies such as hepatectomy and percutaneous needle ablation (8–12). As for T0–1 HCC patients, there have been several reports of successful surgery for EHS from HCC (12–17). These reports generally conclude that an aggressive surgical approach to EHS from HCC might offer the best chance for long-term survival in selected patients.
In order to select the proper patients for aggressive locoregional intervention or a new agent trial, prognostic analysis is important. However, there have been few studies regarding the long-term survival of HCC patients with EHS (18). Accordingly, we reviewed our 12-year experience and analyzed it to identify candidates for anti-cancer treatment. The goal of the current study was to propose a treatment strategy for EHS from HCC based on survival aspects.
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SUBJECTS AND METHODS |
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PATIENTS
Since the day our hospital opened, in July 1992, we have recorded all patients admitted to our division. This database has been renewed generally three times a week at our morning conference. We obtained a list of HCC patients with EHS from the database, and surveyed all case records in the list. We collected each patient's baseline data at the time of EHS and their treatment histories. These included age, gender, performance status according to the Eastern Cooperative Oncology Group criteria (19), hepatitis B surface antigen, hepatitis C antibody, alcohol intake, Child–Pugh grade (20), prior treatment, serum level of
-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II), extra- and intrahepatic tumor status, treatment after EHS and cause of death. Intrahepatic tumor status was evaluated by dynamic computed tomography (CT) in all cases. As for cause of death, we defined death as being from a hepatic cause when patients had obvious jaundice, encephalopathy and/or symptomatic ascites 2 weeks before death. Cancer death due to other than a hepatic cause, perhaps due to EHS, was regarded as being from a non-hepatic cause.
ANALYSIS AND STATISTICS
The aim of the current study was to identify cohorts of HCC patients with EHS suitable for future clinical trials or practical local treatments. For this purpose, we performed exploratory analysis, and selected a patient cohort step by step if necessary.
We divided the patients into two or more appropriate subgroups according to their backgrounds, and evaluated the survival rates in each subgroup. Continuous variables were grouped by a convenient value near the median value (age and PIVKA-II) or potential prognostic value (AFP). Survival curves were calculated by the Kaplan–Meier method (21). An overall survival was measured from the first day of (anti- cancer or palliative) treatment for EHS to the day of death from any causes or the last day of follow-up.
Differences in survival were evaluated by log-rank tests. The Cox proportional hazards model (22) was used to determine the most significant variables related to survival. Forward and backward stepwise regression procedures based on the partial likelihood ratio were used to determine which factors were the major independent predictors of survival. The variables entered into the Cox regression included those found to be associated with survival based on the log-rank tests.
All analyses were performed using the statistical software SPSS 11.0 J for Windows. Statistical significance was defined as a two-sided P-value of 
0.05.
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RESULTS |
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Between July 1992 and March 2004, 201 HCC patients with EHS had been admitted to our division consecutively. Of the 201, 69 had EHS at the first presentation, and 132 had EHS as a recurrence after prior treatments. Of the 132, 61 had received hepatectomy, 32 percutaneous needle ablation, 36 transcatheter arterial chemoembolization, and three external beam radiotherapy, as the first treatment for primary HCC. The median duration between the first prior treatment and EHS was 23.2 months [95% confidence interval (CI) 19.3–27.2].
At the time of EHS, the median serum total bilirubin and albumin levels were 1.0 mg/dl (range 0.4–10.3) and 3.3 g/dl (range 1.7–4.7), respectively. In calculating the Child–Pugh score, one patient could not be assessed because his laboratory data were lost. The median serum AFP and PIVKA-II levels were 236.5 ng/ml (range 1.7–368 000) and 72 mAU/ml (range <0.004–418 000), respectively. AFP and PIVKA-II were not examined in three and 28 patients, respectively, at the time of EHS. Ascites was seen in 49 patients. The intrahepatic tumor status and sites of metastasis are shown in Table 1. Of the 59 patients with vascular invasion, 44 showed portal vein invasion, 10 hepatic vein invasion and five both portal and hepatic vein invasion. Diagnosis of HCC was confirmed histologically in five patients by autopsy, 85 by surgical resection and 56 by needle biopsy. In the remaining 55, HCC was diagnosed by typical dynamic CT findings.
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The first additional treatment after EHS was palliative care in 58 and systemic chemotherapy in 14. The remaining 129 received various local treatments for intra- and/or extrahepatic tumor(s) (Table 2). Other than a systemic chemotherapy trial, local treatments were chosen practically by consideration of potential benefit.
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Of the 201, 176 (88%) died, 15 were still alive and 10 were lost to follow-up at the time of analysis (March 1, 2004). Of the 176, 38 died in other hospitals. The cause of death was evaluated in the remaining 138 (69%) who died in our hospital. Of the 138, 136 (99%) were cancer-related deaths, one was treatment-related death and one was apoplectic death without brain metastasis. Of the 136, 110 (81%) died of a hepatic cause, and 26 died of a non-hepatic cause (respiratory insufficiency due to lung metastasis, 10; cachectic death without obvious hepatic failure, 14; and cerebral hemorrhage due to brain metastasis, two).
The overall survival curve is shown in Figure 1. Median survival time was 4.6 months (95% CI 3.0–6.1). The 1-, 3- and 5-year survival rates were 31.0, 9.2 and 4.5%, respectively. The relationship between background factors and survival times is shown in Table 1. The 95% CI upper limit of median survival time did not reach 3 months in 77 patients with a performance status of 2, or the Child–Pugh grade B or C. At the next step, we excluded the 77, because they had an extremely poor prognosis and should have received the best supportive care. Accordingly, the remaining 124 were subjects for further analysis.
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The univariate analysis of the 124 is shown in Table 3. Subgroups for the analysis were chosen in consideration of the preliminary results shown in Table 1. As to size of the primary tumor, a categorized criterion of 2 cm was a better prognostic indicator than that of 5 cm or 50% of the liver (Table 1). Accordingly, primary tumor status was graded by the Liver Cancer Study Group of Japan criteria (2), i.e. T1 fulfilled the three factors of solitary, <2 cm and no vascular invasion; T2 fulfilled two of the three factors; T3 fulfilled one factor; and T4 fulfilled none of the three factors. Performance status, hepatitis B surface antigen, AFP, T category of the primary tumor, brain metastasis, number of metastatic tumors and organs, and local treatment for metastatic tumor were associated with survival by log-rank tests (Table 3). Among them, brain metastasis, number of metastatic tumors and T category of the primary tumor were identified as independent prognostic factors by Cox regression. The same factors were identified with forward and backward analysis. Table 4 shows the relative risk of each factor calculated by forward analysis.
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At the final step, we excluded the three patients with brain metastasis, because they were not suitable for a new agent trial or challenging local therapy. In the remaining 121, we grouped the T categories into T1/2 and T3/4, because the relative risk of T2 was not significantly unfavorable compared with that of T1 (Table 4). Finally, we divided the cohort into four subgroups: group A, solitary metastatic tumor and T1/2; group B, solitary metastatic tumor and T3/4; group C, multiple metastatic tumors and T1/2; and group D, multiple metastatic tumors and T3/4. Figure 2 and Table 5 show the overall survival curves, causes of death and local therapies for metastatic or primary tumor(s) according to the four subgroups. In group A, 10 of the 11 patients underwent removal of metastatic tumor, and the median survival time exceeded 5 years.
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DISCUSSION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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EHS is generally derived from advanced primary HCC, and has a poor prognosis. The survival times of metastatic HCC patients after systemic chemotherapy have been reported to be 4.6–7.2 months median, and 10–20% at 1 year (4,15). However, a recent report from the Liver Cancer Study Group of Japan showed that the 1-, 3- and 5-year survival rates of N1 or M1 patients were 55.7, 26.5 and 15.5%, respectively, after hepatectomy (23). On the other hand, several authors reported long-term survivors after aggressive surgery for EHS from HCC (12–17). These results suggested the potential benefit of locoregional treatment for intra- and/or extrahepatic tumor in HCC patients with EHS. In order to extract the benefit, patient selection is essential. The current study was conducted to identify suitable candidates for aggressive anti-cancer treatments.
In the first step, we excluded the cohort with absolutely poor prognosis, i.e. patients with poor performance status or poor hepatic reserve. Next, we examined the prognostic factors in the remaining cohort. Among various metastatic sites, brain metastasis was identified to be an independent prognostic factor. We excluded patients with brain metastasis, because they were not appropriate for investigational treatment. Finally, we divided the remaining patients into four subgroups (groups A–D) based on the identified prognostic factors.
In group A, 10 of the 11 patients received surgery for EHS. Table 5 suggests that some patients escaped death from EHS and consequently might survive longer. So, we supposed group A could be regarded as good candidates for aggressive intervention; however, this fraction was only 5% of all patients with EHS.
Groups B and C showed almost the same prognosis. One- or two-thirds of the patients in these two groups received various local therapies; however, their survival benefit was marginal. Multivariate analysis did not demonstrate an impact on favorable survival by the local therapies for EHS or primary tumor. The lack of impact of local therapies for primary tumor disappointed us, because the fact that 81% of the patients died of a hepatic cause before metastatic death suggested the potential benefit of those therapies. As to new agent trials, however, this population was suitable for an evaluation of toxicity and efficacy, because one-half of the patients survived for 1 year.
Group D showed a relatively poor prognosis with a median survival time of <6 months. In this group, a challenging locoregional approach should be avoided, and careful patient enrollment is necessary for a new agent trial.
There were some limitations in the current study, which were inevitable in such a retrospective analysis. First, a full metastatic work-up was not performed in all patients. Chest CT and bone scintigraphy were examined if EHS was suspected by chest X-ray and the patient complained of pain, respectively. Accordingly, we might have missed subclinical metastasis, whereas Si et al. (24) reported that the prevalence of EHS was 42% in HCC patients receiving a full metastatic work-up. Secondly, the strategy and indication for treatments after EHS were not identical. Locoregional treatments had been performed based on potential benefits in our past experiences; however, a prospective study is necessary to prove the real benefit for patients in groups A to C.
In summary, among HCC patients with EHS, those with poor performance status, poor hepatic reserve or brain metastasis should receive supportive care. The candidates for anti-cancer treatment were the remaining patients. Among them, challenging locoregional intervention was acceptable only for patients with solitary metastatic tumor and T1/2 primary tumor. Good candidates for a clinical trial of a new agent or aggressive local therapy were patients with solitary metastatic tumor or T1/2 primary tumor. The frequency of these was 5 and 27%, respectively, of all of the HCC patients with EHS in the current study.
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References |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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