Abstract
Background: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is poor despite treatment with sorafenib or other anti-angiogenic targeted-therapies. Patients with advanced HCC with prolonged survival may exhibit unique clinical characteristics. Patients and Methods: We reviewed patients with Barcelona Clinic Liver Cancer stage C HCC, who were enrolled in six clinical trials for first-line anti-angiogenic targeted-therapy between May 2005 and December 2010 in a single Institute. Patients with prolonged survival were identified as those who exhibited overall survival (OS) of more than two years; their clinical variables were analyzed. Results: Of the 189 enrolled patients, 22 (11.6%) patients with prolonged survival were identified. Their median OS was 58.7 (range=24.6-88.4) months, compared to an OS of 7.1 months for the overall patient cohort. A multivariate analysis showed that the patients with prolonged survival were less likely to have chronic hepatitis B virus infection, α-fetoprotein level >400 ng/ml, and liver involvement than were the remaining patients. In addition, the patients with prolonged survival experienced significantly higher response rates (50.0%) and disease control rates (86.4%) to the first-line targeted-therapy, and received more additional therapies than did the other patients. Seven patients remained disease-free for a median of 27.0 (range, 4.5-64.6) months after receiving additional locoregional therapies. Conclusion: Patients with advanced HCC who experienced prolonged survival exhibited certain clinical features and strong treatment responses to first-line anti-angiogenic targeted-therapies. Additional locoregional therapies could contribute to the long-term disease-free status in selected patients.
- Clinical features
- hepatocellular carcinoma
- HCC
- prolonged survival
- long-term survivors
- prognosis
- anti-angiogenic targeted therapy
- sorafenib
Hepatocellular carcinoma (HCC) is one of the most common malignancies and leading causes of cancer-related death globally (1). In 2008, approximately 750,000 patients were diagnosed with HCC and more than 695,000 patients died from the disease. Although patients with early-stage HCC may potentially be cured by surgery, local ablation, or liver transplantation, many patients eventually develop or present with metastatic or locally advanced diseases that are not amenable to curative locoregional therapies. For decades, prognosis of such patients has been reported as being extremely poor, yielding a median survival time in the range of 4-7 months (2-4).
In 2007, two randomized phase III studies demonstrated that sorafenib enhances survival of patients with advanced HCC (3, 4). Sorafenib is a multi-kinase inhibitor that primarily targets vascular endothelial growth factor receptor 2 and RAF kinase (5). Since then, molecular-targeted agents, especially those with anti-angiogenic activity, have become the primary treatment for advanced HCC. However, the efficacy of sorafenib and other anti-angiogenic targeted-therapies is modest, yielding objective tumor response rates of 3%-5% and typically a brief time-to-tumor progression. The median overall survival (OS) times of patients with advanced HCC are still in the range of 6.5-10.7 months (3, 4, 6, 7).
Patients with prolonged survival after therapy for advanced HCC are relatively uncommon and a long-term disease-free status remains rare. Several case reports have indicated that effective systemic therapy using sorafenib or anti-angiogenic therapies combined with aggressive locoregional treatment may prolong survival in selected patients (8-10). However, the characteristics of patients with prolonged survival after therapy for advanced HCC have not been systematically evaluated. Thus, we conducted this study to explore the clinical features of these patients based on a large cohort of such patients who were treated with first-line anti-angiogenic targeted-therapy.
Patients and Methods
Study population and variables. Between May 2005 and December 2010, patients who were diagnosed with Barcelona Clinic Liver Cancer (BCLC) stage C HCC and were enrolled in six clinical trials of first-line anti-angiogenic targeted therapy at the National Taiwan University Hospital (NTUH) in Taipei, Taiwan were enrolled in the current study. The clinical trials investigated regimens that combined sorafenib and tegafur/uracil (11), bevacizumab and capecitabine (12), thalidomide and tegafur/uracil (13), and bevacizumab and erlotinib (14), or compared sorafenib versus sunitinib (7), and sorafenib versus brivanib (6).
Data regarding the patients and their clinical variables were retrieved from chart records. The OS was measured from the date of enrollment in the clinical trials to the date of death or the last follow-up day (December 31, 2012), and analyzed as censored if the patients remained alive. Patients with prolonged survival were defined as patients who attained an OS of more than two years. This study was approved by the Institute Research Ethical Committee of the NTUH (201210044RIB).
Statistical methods. The statistical analyses were performed using SAS statistical software (version 9.1.3; SAS Institute Inc., Cary, NC, USA) and a 2-sided p-value of 0.05 or less was considered statistically significant. To explore the associations between patients who exhibited distinct survival and clinical parameters, a Chi-square test (or Fisher's exact test if indicated) was used to assess the nominal variables. A multivariate analysis of the risk factors associated with survival was performed using a stepwise multiple logistic regression model. The Kaplan–Meier method was used to estimate survival, which was univariately compared between patients with prolonged survival and other patients by using a log-rank test.
Results
Patients' characteristics and prognostic factors. A total of 189 patients were enrolled, with a median age of 56.8 years. Table I lists the patient demographics. Out of these patients 139 (73.5%) had chronic hepatitis B virus (HBV) infection, and 32 (16.9%) had chronic hepatitis C virus (HCV) infection. A majority (85.7%) of patients presented with tumor involvement in the liver and all but two patients had either macroscopic vascular invasion or extra-hepatic metastasis. Approximately half the patients received regimens containing sorafenib as the first-line treatment (Table I). The OS of the overall cohort was 7.1 months (range, 0.5-88.4 months; 95% confidence interval=6.0-8.2 months).
We identified 22 patients with prolonged survival (11.6%), with a median age of 58.3 years. Compared to others, patients with prolonged survival were less likely to have α-fetoprotein (AFP) level >400 ng/ml (p<0.001), liver involvement (p=0.001), and macroscopic vascular invasion (p=0.015) and more likely to have lower Cancer of the Liver Italian Program (CLIP) scores (p<0.001) and Okuda stage I disease (p=0.003). Patients with prolonged survival tended to be female and exhibit a good performance status; however, the associations of these factors with prolonged survival did not reach statistical significance. Extra-hepatic metastasis and first-line treatment regimens demonstrated no significant associations with prolonged survival.
The adjusted variables in the multivariate analysis comprised of sex, age, performance status, hepatitis virus infection status, AFP level, prior locoregional treatment, liver involvement, macroscopic vascular invasion, extra-hepatic metastasis, and first-line treatment regimen. The multivariate analysis showed that patients who demonstrated no HBV infection (p=0.022), AFP level ≤400 ng/ml (p<0.001), and no liver involvement (p<0.001) were more likely to have prolonged survival (Table II).
Treatment outcome. Patients with prolonged survival attained significantly higher response rates and disease control rates (50.0% and 86.4%) following first-line targeted therapy than did others (4.2% and 56.3%) (Table III). The progression-free survival of patients with prolonged survival and the remaining patients who had OS of two years or less was 13.0 months and 2.8 months, respectively (Figure 1A). The median OS of patients with prolonged survival and the remaining patients was 58.7 months and 6.1 months, respectively (Figure 1B). After first-line treatment failure, 59.1% of patients with prolonged survival received salvage systemic therapy, and 68.2% underwent locoregional treatment such as surgery, radiofrequency ablation (RFA), transarterial chemoembolization (TACE), or radiotherapy (Table III). By contrast, only 37.7% and 24.5% of the remaining patients underwent salvage systemic therapy and additional locoregional treatments, respectively.
Patients with prolonged disease-free status. As of December 31, 2012 (the last follow-up day), seven patients remained disease-free. The median disease-free survival was 27.0 (range=4.5-64.6) months. Of these 7 patients, 3 exhibited liver involvement, none exhibited macroscopic vascular invasion, and all exhibited extra-hepatic metastasis at the time of the advanced HCC diagnosis. Five out of the 7 patients responded to the first-line targeted therapy. The median time-to-tumor progression following first-line therapy was 10.7 (range=4.7-22.7) months. All patients received subsequent locoregional treatments after first-line treatment failure, including metastasectomy (n=6), resection of hepatic tumors (n=1), RFA of liver tumors (n=2), radiotherapy (n=2), and TACE (n=1) (Table IV).
Baseline characteristics.
Discussion
We identified a group of patients with advanced HCC who survived more than two years in the era of anti-angiogenic targeted therapy. After characterizing their clinical features, we found that patients with prolonged survival were less likely to exhibit chronic HBV infection, high AFP levels, and liver involvement, and more likely to exhibit lower CLIP scores and Okuda stage I disease than were other patients. The responses to the first-line anti-angiogenic targeted-therapy were remarkable among patients with prolonged survival; the majority of them received additional locoregional therapy.
HCC is a complex disease caused by diverse etiologies, including chronic hepatitis virus infections, alcohol consumption, and environmental carcinogens. Patients with advanced HCC, even those who have been enrolled in clinical trials, can be heterogeneous regarding their clinical presentation and prognosis. Previous studies conducted before the targeted-therapy era suggested that HCV-related HCC yielded better prognoses than did HBV-related HCC (15, 16). Sub-group analyses of recent phase III randomized trials also indicated that sorafenib may provide more survival benefits among patients of HCV-related advanced HCC compared to patients of HBV-related advanced HCC (7, 17), although the mechanism remains unclear. These reports are consistent with the current finding, which suggested that patients with prolonged survival were less likely to have chronic HBV infection than were other patients.
Multivariate analysis of prognostic factorsa associated with prolonged survivalb in patients with advanced hepatocellular carcinoma.
Treatment outcome.
Seven patients with prolonged survival who remained disease-free.
The current study also showed that patients with prolonged survival had lower CLIP scores compared to other patients; this corroborates prior studies that suggested CLIP scores can differentiate the prognoses of patients with advanced HCC (18, 19). CLIP scores emphasize on the prognostic significance of AFP levels and the extent of disease in the liver. In the current study, the multivariate analysis also indicated that a low AFP level (≤400 ng/ml) and no liver involvement are two independent prognostic factors associated with prolonged survival in our cohort of patients with advanced HCC.
The current findings demonstrated that patients with advanced HCC who experienced prolonged survival attained extraordinarily strong treatment efficacy following first-line anti-angiogenic targeted therapy; their response rate to the first-line treatment was 50%, the disease control rate was 86%, and the progression-free survival was 13 months. The molecular basis underlying this positive response to anti-angiogenic targeted-therapy remains unknown. Prior studies have demonstrated that phosphorylated extracellular signal regulated kinase (p-ERK) expression in HCC tissues was associated with prolonged time-to-tumor progression in patients treated with sorafenib (20); in addition, high serum insulin-like growth factor 1 levels correlated with improved progression-free survival and OS in patients with advanced HCC who received anti-angiogenic therapy (21) and high serum c-KIT levels and low serum hepatocyte growth factor levels tended to have increased survival benefits from sorafenib in patients with advanced HCC (22). Unfortunately, none of these biomarkers have been validated by independent patient cohorts.
Kaplan-Meier curves of progression-free (A) and overall (B) survival (OS) of patients with prolonged survival (OS >2 years) and the remaining patients (OS ≤2 years).
Seven (3.7%) out of the 189 patients with advanced HCC in the current cohort attained a prolonged disease-free status for a median of 27 months (range=4.5-64.6 months) after receiving definitive locoregional therapies for residual lesions in the liver or other metastatic sites. Whether aggressive locoregional treatments can enhance survival requires further investigation. However, this study corroborates several case reports, which have suggested that in certain cases, strong response to systemic therapy followed by effective and definitive locoregional therapies can yield a prolonged disease-free status (8-10).
The present study has several limitations. Firstly, the definition of patients with prolonged survival (OS >2 years) in patients with advanced HCC is arbitrary. However, compared to the short median survival times of patients treated with sorafenib in the phase III randomized trials (3, 4, 6, 7), 2-year survival seems sufficiently long to distinguish patients with prolonged survival from other patients. Secondly, although all patients underwent first-line therapy with anti-angiogenic agents, the six clinical trials comprised distinct regimens. Therefore, the study cohort is heterogeneous regarding treatment factors. Nevertheless, patients with prolonged survival exhibited remarkable responses to various first-line targeted-therapy regimens, suggesting that treatment regimens may not be a key factor contributing to prolonged survival in this cohort of patients with advanced HCC.
In conclusion, we found that patients with advanced HCC with prolonged survival tended to exhibit no HBV infection, low AFP level, no liver involvement at-diagnosis, and strong treatment responses to first-line anti-angiogenic targeted therapy. Such patients may be able to receive additional locoregional therapies and attain a long-term disease-free status.
Acknowledgements
This study was supported by grants from National Taiwan University Hospital, Yun-Lin Branch, Yunlin, Taiwan (NTUHYLN102.N003), National Clinical Trials and Research Center, Taipei, Taiwan (DOH101-TD-B-111-001), and the National Science Council, Taiwan (100CAP1020-2, NSC98-3112-B-002-038 and NSC-101-2314-B-002-141).
Footnotes
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Conflicts of Interest
The Authors have no conflicts of interest to declare.
- Received December 11, 2013.
- Revision received January 3, 2014.
- Accepted January 7, 2014.
- Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
