Accepted Article
Hepatitis B viral load predicts survival in HCC patients treated with Sorafenib1
Seungtaek Lim1, Jungwoo Han2, Gun Min Kim3, Kwang-Hyub Han4,5, Hye Jin Choi3,5
Department of Internal Medicine, Konyang University Hospital, Daejon1 Department of Pediatric Hemato-Oncology, Yonsei Cancer Center, Yonsei University Health System2 Division of Medical Oncology3, Division of Gastroenterology4, Department of Internal Medicine, Severance Hospital Liver Cancer Special Clinic5, Yonsei University College of Medicine, Seoul
Corresponding author: Hyejin Choi MD Division of Medical Oncology, Department of Internal Medicine Yonsei University College of Medicine 50 Yonsei-ro, Seodaemun-gu Seoul 120-752(Korea)
Tel.: 82-2-2228-8135, Fax: 82-2-393-3652, E-mail: [email protected]
Running Title: HBV viral load and sorafenib treatment
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/jgh.12898
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Word Count: 212 words (abstract), 2585 words (main text) Abstract
Background and aim: Sorafenib is now considered as a standard treatment for advanced hepatocellular carcinoma (HCC). We evaluated the effect of hepatitis B virus (HBV) DNA titers on prognosis in HCC patients treated with sorafenib.
Methods: From 2008 to 2012, 78 HBV-related HCC patients who received sorafenib treatment at Severance Hospital were included in our analysis. The effect of pretreatment HBV DNA levels on clinical outcomes for use in predicting prognosis
after treatment with sorafenib was examined by univariate and multivariate analysis.
Results: Median overall survival and median progression free survival were 5.2 months (95% confidence interval [CI]: 4.0-6.4) and 3.5 months (95% CI: 2.3–4.7), respectively.
Multivariate analysis revealed high levels of HBV DNA (>2,000 IU/mL) to be an independent risk factor for worse overall survival (P=0.005; hazard ratio [HR], 2.85) and disease progression among patients who did not receive concomitant prophylactic antiviral therapy during sorafenib treatment (P=0.008; HR, 87.4). Moreover, viral reactivation occurred more frequently in patients who did not receive concomitant prophylactic antiviral therapy than in those who did (4/38 vs. 0/40; P=0.025).
Conclusions: Higher HBV DNA levels prior to sorafenib treatment were associated
with poorer prognosis and increased viral reactivation thereafter. These results suggest the potential usefulness of prophylactic antiviral therapy when treating HBV-related HCC patients with sorafenib.
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Key words: Hepatocellular carcinoma, Sorafenib, Viral load
Introduction
Hepatocellular carcinoma ranks among the fifth most common malignancies
worldwide1, accounting for an estimated 650,000 deaths per year2,3. While only 10-20% of patients are candidates for curative surgery, unresectable tumors in the remaining 80% are indicated for systemic therapy. However, until recently, systemic therapies have not shown a survival gain over the best supportive care 4. Sorafenib is a multiple tyrosine kinase inhibitor that targets vascular endothelial
growth factor receptors-2 and -3, platelet-derived growth factor receptor β, c-KIT, FLT-3, and RET5-7. Previously, in two large, randomized, phase III studies, treatment with sorafenib prolonged survival in patients with advanced hepatocellular carcinoma8, 9. As well, in exploratory subgroup analyses of data from the SHARP trial, the efficacy of sorafenib in comparison to a placebo were consistently observed in patients with advanced HCC, irrespective of disease etiology, baseline tumor burden, performance status, tumor stage, and prior therapy10. Hepatitis B virus (HBV) is associated with 70% of all HCC cases world-wide11.
Previous studies demonstrated that baseline HBV DNA levels could predict overall survival in HCC patients undergoing systemic chemotherapy12 and transarterial
chemoembolization (TACE)13. However, to date, researchers have yet to clarify the prognostic value of pretreatment HBV DNA levels on disease progression and survival prior to initiating treatment with sorafenib in HCC patients. Therefore, we attempted to delineate the effect of initial serum HBV DNA levels on clinical outcomes, including
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overall survival and progression of HCC, for predicting prognosis after treatment with
sorafenib.
Patients and methods
Patients
In this retrospective study, a total of 286 patients were identified who were
diagnosed with HBV-related HCC and received sorafenib between January 1, 2005 and
December 31, 2012 at Yonsei University College of Medicine in Seoul, S. Korea. To minimize selection bias arising from the retrospective nature of this study, we predetermined inclusion and exclusion criteria before chart review and tried to adhere to it. Diagnosis of HCC should be made by histological diagnosis or by clinical diagnosis using the guidelines set by the Korean Liver Cancer Study group (in patients with a history of chronic hepatitis B or C and/or liver cirrhosis; typical appearance of HCC, either by two dynamic imaging examinations or by one dynamic technique combined with elevated serum a-fetoprotein [AFP] ≥ 200ng/mL)14. To avoid confounding factors, we included only antiviral naïve patients, defined as patients who had never been treated
with antiviral therapy or had received treatment for less than 4 weeks. We also excluded from our analysis patients who had previously received systemic chemotherapy prior to treatment with sorafenib, who had no data on HBV-DNA levels, and who had no evaluable lesion at the time they started sorafenib. Patients who underwent other anticancer treatments, such as radiation therapy, TACE, or chemotherapy (intra-arterial or intravenous), concomitantly with sorafenib treatment were also excluded. Meanwhile,
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localized therapy prior to sorafenib treatment, such as radiofrequency ablation, radiation
therapy with or without concurrent intra-arterial chemotherapy, TACE, or TACI, was permitted. After reviewing all the medical records of 286 patients consecutively, a total of 78 patients who satisfied all of the inclusion criteria were included in our analysis. This study was approved by the Institutional Review Board of Severance
Hospital and was conducted in accordance with the Helsinki Declaration of 1975.
Prognostic Clinical Variables
The following variables were included as potential prognostic covariates: age;
sex; Eastern Co-Operative Group (ECOG) performance score; Child Pugh Classification; prothrombin time; HBV DNA level; serum levels of total bilirubin, albumin, alanine transaminase (ALT), creatinine, alpha-fetoprotein (AFP), and hemoglobin; presence of ascites; tumor volume (≥ 50%); vascular involvement; bilobular involvement; tumor nodule number (≥3); greatest tumor dimension (≥5cm); and modified UICC stage15. Serum levels of HBV DNA were measured by quantitative PCR assay (Cobas AmpliPrep/Cobas TaqMan HBV Test; Roche Molecular Systems
Inc., Branchburg, New Jersey; detection limit, 20 IU/ml)16.
Definition of Viral Status
Patients with pretreatment HBV DNA levels higher than 2,000 IU/mL before
sorafenib administration were considered to have a high viral load. After sorafenib treatment, patients with HBV levels two-fold or higher than their baseline levels were
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considered as exhibiting increased serum HBV DNA activity. Hepatitis exacerbation was defined as a two-fold or greater increase in ALT or AST from baseline level, along with increased serum HBV DNA activity.
Radiological assessment of treatment responses
Treatment responses were assessed by CT scans or MRI imaging at intervals of
2 months. Radiologic responses were evaluated using the response evaluation criteria in solid tumors (RECIST)17.
Statistical analysis
Survival time was measured from the date when the first dose of sorafenib was
administered to the date of death or last contact using the Kaplan-Meier method. Survival curves were compared by log-rank test according to HBV titers along with baseline clinical variables which were identified in previous clinical studies. Using the
variables shown to be significantly associated with clinical outcomes in univariate analysis, a Cox proportional hazard model was constructed to perform multivariate analysis. SPSS software, version 18.0 (SPSS, Chicago, Ill) was used to conduct the statistical analyses. All P-values less than 0.05 were considered as statistically
significant.
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Patient characteristics
A total of 78 patients were included in this study. Diagnosis of HCC in 47
patients was confirmed by pathologic results, whereas 31 patients were diagnosed based on clinical criteria14. Patient characteristics are summarized in Table 1. The median age of the patients was 56.5 years (range, 36-82); 62 were male (79.5%). Ninety percent of the patients had an Eastern Co-Operative Group (ECOG) performance score of 0 or 1. Thirty-six (46.2%) patients exhibited vascular invasion. Most patients had extensive tumor involvement (93.6% were UICC stage IVA or IVB). Evidence of cirrhosis was found in 49 (62.8 %) patients, 59% of whom were classified as Child-Pugh grade A or B. The virologic statuses of all patients were as follows: 72 (92.3%) patients were
HBs antigen positive and 18 (25.4%) patients were HBe antigen positive. Forty patients (51.3%) had HBV DNA levels higher than 2,000 IU/mL, while the remaining 38 (48.7%) had HBV DNA levels lower than 2,000 IU/mL. The associations between HBV DNA levels and clinical variables are shown in Table 2. Notably, higher HBV DNA levels were correlated with advanced Child Pugh Score, larger tumor size, bilobular involvement, multinodularity, and vascular invasion. None of the 78 patients had received antiviral therapy prior to undergoing
sorafenib treatment. Since there has been no guideline about concomitant antiviral prophylaxis in the patients treated with sorafenib, the decision is generally up to physician’s choice. Among whole patients, 46 patients were started on prophylactic
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antiviral treatment concomitantly with sorafenib, and they are in a higher proportion of higher pretreatment HBV DNA (>2,000 IU/mL) (76.1% vs. 15.6%, P2,000 IU/mL) as an independent risk factor of worse overall survival as well as high levels of AFP (defined as >400ng/ml), advanced Child-Pugh score, greater tumor
volume, and vascular invasion (Fig. 2, Table 3). When we stratified patients according to concomitant administration of antiviral therapy, pretreatment DNA levels remained an independent prognostic factor for survival in both the antiviral therapy group and the no antiviral therapy group (data not shown).
Disease progression
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The median progression free survival (PFS) was 3.5 months (95% CI, 2.35-
4.65) (Fig 1B). As for survival, univariate and multivariate analyses were also performed to investigate the effect of virologic and clinical variables on disease progression (Table 4). Univariate analysis revealed higher HBV DNA levels, as well as high AFP level, worse Child Pugh grade, larger tumor size (≥5cm), larger tumor volume (≥50%), presence of vascular invasion, bilobular involvement, multinodularity (≥3), and
worse ECOG performance status, to be significant prognostic factors for disease
progression. However, in multivariate analysis, only high AFP level and Child-Pugh score remained significant. When we performed univariate and multivariate analysis of patients who did
not receive concomitant antiviral therapy along with sorafenib, high pretreatment HBV DNA levels were shown to be an independent prognostic factor for disease progression (Table 5), (Fig 3A). In contrast, among patients who did receive concomitant
prophylactic antiviral therapy, only AFP level was shown to be an independent prognostic factor for disease progression; in this patient population, pretreatment HBV DNA levels were not associated with disease progression in either univariate or multivariate analysis (Fig 3B).
Pretreatment HBV DNA levels and hepatitis exacerbation during sorafenib treatment
In total, 4 patients among the entire study population experienced viral
reactivation while receiving sorafenib treatment. Patients who were administered concomitant prophylactic antiviral therapy experienced significantly less viral
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reactivation than those who did not (0 in 40 vs. 4 in 38; P=0.025 by Fisher’s exact test). Two of these four patients experienced hepatitis exacerbation.
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Discussion
The association between HBV and HCC is well known, as HBV has been
shown to influence HCC development18. HCC risk has been shown to increase in proportion to HBV DNA levels19, and antiviral treatments with nucleoside analogues, such as lamivudine and entecavir reduced the incidence of HCC development20-22 and
the risk of recurrence after curative resection of early HCC in HBV patients23-28. Previous studies showed that higher pretreatment HBV DNA level12,13 was also
correlated with worse survival outcomes in patients with advanced HCC treated with systemic chemotherapy12 or TACE13. Meanwhile, the effects of pretreatment HBV DNA levels on clinical outcomes in patients treated with sorafenib have not been determined. Therefore, in this study, we set out to evaluate the effect of pretreatment HBV DNA levels on disease progression and overall survival in HCC patients treated with sorafenib, and found that higher pretreatment HBV DNA levels (>2,000 IU/mL) predicted worse overall survival therein. Pretreatment HBV DNA level was also associated with disease progression. Interestingly, the association was found only in patients who did not receive antiviral prophylaxis. In patients receiving antiviral prophylaxis, there was no difference in PFS according to HBV DNA level. This finding is hypothesis-generating; antiviral treatment might have overcome the worse prognosis associated with higher viral load. A number of studies have attempted to identify prognostic factors for sorafenib
treatment in HCC patients. Kim et al. demonstrated that Child Pugh Score, AFP, vascular invasion, and extrahepatic spread were independent prognostic factors for overall survival29. In another study30, serum AFP, CLIP score, intrahepatic tumor
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morphology, and portal vein invasion were significant prognostic factors. Consistent with these results, we also identified higher AFP, advanced Child Pugh grade, larger
tumor involvement, and vascular invasion as significant prognostic factors, in addition to higher viral load. Of note, higher viral load remained an independent prognostic
factor even after adjustment for these parameters. Although the underlying mechanism for the adverse effects of higher viral load
on the prognosis of HCC patients is not clear, several explanations have been proposed: First, the integration of HBV DNA into cellular genes is essential for cell signaling, proliferation, and viability, and induces overexpression of these genes, which may
confer a selective growth advantage to liver cells31. Additionally, production of HBV X protein can act as a transactivator on various cellular genes to modulate apoptosis, cell proliferation, and responses to DNA damage31. Second, compared to other etiologies,
HBV-related HCC exhibits a distinct pattern of genetic mutations, with greater chromosome instability and a higher prevalence of loss of heterozygosity, which consequently result in tumor aggressiveness32 Third, frequent expression of variant estrogen receptors in HBV-related HCC has been shown to account for a rapid tumor growth33,34. Finally, the upregulation of adhesion molecules on the cells lining the sinusoids caused by viral replication could enhance tumor development and spread35. Another important question that has yet to be sufficiently addressed is whether
sorafenib influences the replication status of HBV. Previously, an increase in serum HBV DNA level was reported in 20% to 50% of hepatitis B carriers undergoing cytotoxic chemotherapy36,37 or treatment with immune-modulatory agents, such as rituximab and infliximab. Additionally, Sezgin et al. previously described a renal cell carcinoma patient who experienced hepatitis B flare during treatment with everolimus38.
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Thus, after other studies demonstrated that prophylactic antiviral therapy reduces the frequency of HBV reactivations39-42, current treatment guidelines have recommended HBV carriers scheduled for cancer chemotherapy to undergo prophylactic antiviral therapy, regardless of their serum HBV DNA levels14,43. Nevertheless, data on associations between sorafenib and HBV reactivation are limited. In one retrospective
study, which investigated sorafenib monotherapy in an HBV endemic area, viral reactivation was not observed30. In contrast, we observed significantly less viral reactivation in patients who received concomitant antiviral prophylaxis than in patients who did not. Although this result suggests the possible influence of sorafenib on B-viral reactivation, as well as a potential role for prophylactic antiviral therapy, the small number of included patients and the retrospective nature of this study prohibit us from making more definite conclusions. Taken together, nonetheless, the effect of sorafenib
on HBV reactivation and the efficacy of prophylactic antiviral therapy in patients treated with sorafenib should be evaluated in future studies. We defined >2,000 IU/mL as a cutoff value. The risk of progressive liver
disease is reported to increase at the threshold of 10,000 copies/ml (approximately >2000 IU/mL)19 and several guidelines44,45 are using this value as a cut-off to start
antiviral treatment in patients with HBe negative B-viral patients. In addition, same value was used in previous article by Yu et al which demonstrated the association between viral load and HCC prognosis13. Hence, we presumed it as a clinically relevant cut off value for higher viral load. This study has several limitations. First, this study was conducted in a single
center with a small number of patients. Thus, one should be cautious in generalizing the results of this study to an entire population. Second, because this study was performed
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retrospectively based on chart review, there may be significant selection bias although we adhered to inclusion and exclusion criteria set by before medical chart reviewing to minimize this fault. In addition, patients with higher viral load were associated with advanced Child Pugh Score, larger tumor size, bilobular involvement, multinodularity, and vascular invasion, which are inherent adverse prognostic factors. Although higher
viral load remained an independent prognostic factor after adjustment of these factors, the results should be interpreted with caution. Third, even though treatment was administered largely based on guidelines set by the Korean Liver Cancer Study Group, there were some differences in treatment protocols and follow up strategies, such as interval at which follow-up CT was performed. Fourth, while we used RECIST criteria to evaluate treatment responses, individual responses were evaluated by the patients’ primary physicians and were not confirmed by an independent reviewer. Nevertheless, this is the first study to report on the effect of serum HBV DNA levels on clinical outcomes in HCC patients treated with sorafenib. In conclusion, we demonstrated that high HBV DNA levels prior to treatment
with sorafenib adversely affect disease progression and overall survival. Furthermore, our study results showed that viral reactivation and hepatitis exacerbation can occur during sorafenib treatment and might be prevented by concomitant antiviral therapy. Future studies are warranted to test the usefulness of concomitant prophylactic antiviral therapy during treatment of HCC patients with sorafenib to improve prognoses and to prevent viral reactivation.
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Acknowledgements The authors would like to thank Anthony Thomas Milliken (Editing Synthase, Seoul, Korea) for his help with the editing of this manuscript.
Conflicts of interest: The authors declare no commercial associations that might represent a conflict of interest in relation to this manuscript.
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Accepted Article Tables
Table 1. Baseline characteristics of the patients (N=78) Characteristic
Age
Median
56.5 (36-82)
Number of male patients
62 (79.5)
HBs antigen-positivity
72 (92.3)
HBV DNA level > 2,000 IU/mL
40 (51.3)
HBe antigen-positivity
18 (25.4)*
ECOG performance status
0
22 (28.2)
1
48 (61.5)
2
8 (10.3)
Median baseline laboratory results
Total bilirubin (mg/dL)
0.9 (0.4-3.2)
Albumin (g/dL)
3.4 (2.0-4.7)
Prothrombin time (sec)
12.4 (10.3-26.1)
ALT (IU/L)
33.5 (1-736)
Creatinine (mg/dL)
0.8 (0.4-11.2)
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Hemoglobin (g/dL)
Alpha-fetoprotein (ng/mL)
12.6 (8.4-18.0)
648 (1.18-120,000)
Child Pugh grade
No cirrhosis
29 (37.2)
A
30 (38.5)
B
16 (20.5)
C
3 (3.8)
Tumor volume ≥ 50%
55 (70.5)
Bilobular involvement
34 (43.6)
Nodules ≥ 3
45 (57.7)
Greatest dimension ≥ 5.0cm
55 (70.5)
Vascular invasion
36 (46.2)
UICC tumor-node-metastasis stage
III
5 (6.4)
IVA
18 (23.1)
IVB
55 (70.5)
Abbreviation: ECOG, Eastern Cooperative Oncology Group; ALT, alanine aminotransferase
* HBe antigen was examined in only 72 patients.
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Table 2. Comparison of clinical variables according to HBV DNA level HBV DNA P ≥ 2,000 IU/mL (n=40)
< 2,000 IU/mL (n=38)
AFP ≥400ng/mL
27 (67.5%)
13 (34.2%)
0.116
ECOG PS 2
7 (17.5%)
1 (2.6%)
0.057
Child Pugh grade B or C
15 (37.5%)
4 (10.5%)
0.008
Tumor involvement ≥ 50%
17 (42.5%)
12 (31.6%)
0.318
Maximum size ≥ 5cm
35 (87.5%)
20 (52.6%)
0.001
26 (65%)
8 (21.1%)
Hepatitis B viral load predicts survival in HCC patients treated with Sorafenib1
Seungtaek Lim1, Jungwoo Han2, Gun Min Kim3, Kwang-Hyub Han4,5, Hye Jin Choi3,5
Department of Internal Medicine, Konyang University Hospital, Daejon1 Department of Pediatric Hemato-Oncology, Yonsei Cancer Center, Yonsei University Health System2 Division of Medical Oncology3, Division of Gastroenterology4, Department of Internal Medicine, Severance Hospital Liver Cancer Special Clinic5, Yonsei University College of Medicine, Seoul
Corresponding author: Hyejin Choi MD Division of Medical Oncology, Department of Internal Medicine Yonsei University College of Medicine 50 Yonsei-ro, Seodaemun-gu Seoul 120-752(Korea)
Tel.: 82-2-2228-8135, Fax: 82-2-393-3652, E-mail: [email protected]
Running Title: HBV viral load and sorafenib treatment
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/jgh.12898
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Word Count: 212 words (abstract), 2585 words (main text) Abstract
Background and aim: Sorafenib is now considered as a standard treatment for advanced hepatocellular carcinoma (HCC). We evaluated the effect of hepatitis B virus (HBV) DNA titers on prognosis in HCC patients treated with sorafenib.
Methods: From 2008 to 2012, 78 HBV-related HCC patients who received sorafenib treatment at Severance Hospital were included in our analysis. The effect of pretreatment HBV DNA levels on clinical outcomes for use in predicting prognosis
after treatment with sorafenib was examined by univariate and multivariate analysis.
Results: Median overall survival and median progression free survival were 5.2 months (95% confidence interval [CI]: 4.0-6.4) and 3.5 months (95% CI: 2.3–4.7), respectively.
Multivariate analysis revealed high levels of HBV DNA (>2,000 IU/mL) to be an independent risk factor for worse overall survival (P=0.005; hazard ratio [HR], 2.85) and disease progression among patients who did not receive concomitant prophylactic antiviral therapy during sorafenib treatment (P=0.008; HR, 87.4). Moreover, viral reactivation occurred more frequently in patients who did not receive concomitant prophylactic antiviral therapy than in those who did (4/38 vs. 0/40; P=0.025).
Conclusions: Higher HBV DNA levels prior to sorafenib treatment were associated
with poorer prognosis and increased viral reactivation thereafter. These results suggest the potential usefulness of prophylactic antiviral therapy when treating HBV-related HCC patients with sorafenib.
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Key words: Hepatocellular carcinoma, Sorafenib, Viral load
Introduction
Hepatocellular carcinoma ranks among the fifth most common malignancies
worldwide1, accounting for an estimated 650,000 deaths per year2,3. While only 10-20% of patients are candidates for curative surgery, unresectable tumors in the remaining 80% are indicated for systemic therapy. However, until recently, systemic therapies have not shown a survival gain over the best supportive care 4. Sorafenib is a multiple tyrosine kinase inhibitor that targets vascular endothelial
growth factor receptors-2 and -3, platelet-derived growth factor receptor β, c-KIT, FLT-3, and RET5-7. Previously, in two large, randomized, phase III studies, treatment with sorafenib prolonged survival in patients with advanced hepatocellular carcinoma8, 9. As well, in exploratory subgroup analyses of data from the SHARP trial, the efficacy of sorafenib in comparison to a placebo were consistently observed in patients with advanced HCC, irrespective of disease etiology, baseline tumor burden, performance status, tumor stage, and prior therapy10. Hepatitis B virus (HBV) is associated with 70% of all HCC cases world-wide11.
Previous studies demonstrated that baseline HBV DNA levels could predict overall survival in HCC patients undergoing systemic chemotherapy12 and transarterial
chemoembolization (TACE)13. However, to date, researchers have yet to clarify the prognostic value of pretreatment HBV DNA levels on disease progression and survival prior to initiating treatment with sorafenib in HCC patients. Therefore, we attempted to delineate the effect of initial serum HBV DNA levels on clinical outcomes, including
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overall survival and progression of HCC, for predicting prognosis after treatment with
sorafenib.
Patients and methods
Patients
In this retrospective study, a total of 286 patients were identified who were
diagnosed with HBV-related HCC and received sorafenib between January 1, 2005 and
December 31, 2012 at Yonsei University College of Medicine in Seoul, S. Korea. To minimize selection bias arising from the retrospective nature of this study, we predetermined inclusion and exclusion criteria before chart review and tried to adhere to it. Diagnosis of HCC should be made by histological diagnosis or by clinical diagnosis using the guidelines set by the Korean Liver Cancer Study group (in patients with a history of chronic hepatitis B or C and/or liver cirrhosis; typical appearance of HCC, either by two dynamic imaging examinations or by one dynamic technique combined with elevated serum a-fetoprotein [AFP] ≥ 200ng/mL)14. To avoid confounding factors, we included only antiviral naïve patients, defined as patients who had never been treated
with antiviral therapy or had received treatment for less than 4 weeks. We also excluded from our analysis patients who had previously received systemic chemotherapy prior to treatment with sorafenib, who had no data on HBV-DNA levels, and who had no evaluable lesion at the time they started sorafenib. Patients who underwent other anticancer treatments, such as radiation therapy, TACE, or chemotherapy (intra-arterial or intravenous), concomitantly with sorafenib treatment were also excluded. Meanwhile,
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localized therapy prior to sorafenib treatment, such as radiofrequency ablation, radiation
therapy with or without concurrent intra-arterial chemotherapy, TACE, or TACI, was permitted. After reviewing all the medical records of 286 patients consecutively, a total of 78 patients who satisfied all of the inclusion criteria were included in our analysis. This study was approved by the Institutional Review Board of Severance
Hospital and was conducted in accordance with the Helsinki Declaration of 1975.
Prognostic Clinical Variables
The following variables were included as potential prognostic covariates: age;
sex; Eastern Co-Operative Group (ECOG) performance score; Child Pugh Classification; prothrombin time; HBV DNA level; serum levels of total bilirubin, albumin, alanine transaminase (ALT), creatinine, alpha-fetoprotein (AFP), and hemoglobin; presence of ascites; tumor volume (≥ 50%); vascular involvement; bilobular involvement; tumor nodule number (≥3); greatest tumor dimension (≥5cm); and modified UICC stage15. Serum levels of HBV DNA were measured by quantitative PCR assay (Cobas AmpliPrep/Cobas TaqMan HBV Test; Roche Molecular Systems
Inc., Branchburg, New Jersey; detection limit, 20 IU/ml)16.
Definition of Viral Status
Patients with pretreatment HBV DNA levels higher than 2,000 IU/mL before
sorafenib administration were considered to have a high viral load. After sorafenib treatment, patients with HBV levels two-fold or higher than their baseline levels were
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considered as exhibiting increased serum HBV DNA activity. Hepatitis exacerbation was defined as a two-fold or greater increase in ALT or AST from baseline level, along with increased serum HBV DNA activity.
Radiological assessment of treatment responses
Treatment responses were assessed by CT scans or MRI imaging at intervals of
2 months. Radiologic responses were evaluated using the response evaluation criteria in solid tumors (RECIST)17.
Statistical analysis
Survival time was measured from the date when the first dose of sorafenib was
administered to the date of death or last contact using the Kaplan-Meier method. Survival curves were compared by log-rank test according to HBV titers along with baseline clinical variables which were identified in previous clinical studies. Using the
variables shown to be significantly associated with clinical outcomes in univariate analysis, a Cox proportional hazard model was constructed to perform multivariate analysis. SPSS software, version 18.0 (SPSS, Chicago, Ill) was used to conduct the statistical analyses. All P-values less than 0.05 were considered as statistically
significant.
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Patient characteristics
A total of 78 patients were included in this study. Diagnosis of HCC in 47
patients was confirmed by pathologic results, whereas 31 patients were diagnosed based on clinical criteria14. Patient characteristics are summarized in Table 1. The median age of the patients was 56.5 years (range, 36-82); 62 were male (79.5%). Ninety percent of the patients had an Eastern Co-Operative Group (ECOG) performance score of 0 or 1. Thirty-six (46.2%) patients exhibited vascular invasion. Most patients had extensive tumor involvement (93.6% were UICC stage IVA or IVB). Evidence of cirrhosis was found in 49 (62.8 %) patients, 59% of whom were classified as Child-Pugh grade A or B. The virologic statuses of all patients were as follows: 72 (92.3%) patients were
HBs antigen positive and 18 (25.4%) patients were HBe antigen positive. Forty patients (51.3%) had HBV DNA levels higher than 2,000 IU/mL, while the remaining 38 (48.7%) had HBV DNA levels lower than 2,000 IU/mL. The associations between HBV DNA levels and clinical variables are shown in Table 2. Notably, higher HBV DNA levels were correlated with advanced Child Pugh Score, larger tumor size, bilobular involvement, multinodularity, and vascular invasion. None of the 78 patients had received antiviral therapy prior to undergoing
sorafenib treatment. Since there has been no guideline about concomitant antiviral prophylaxis in the patients treated with sorafenib, the decision is generally up to physician’s choice. Among whole patients, 46 patients were started on prophylactic
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antiviral treatment concomitantly with sorafenib, and they are in a higher proportion of higher pretreatment HBV DNA (>2,000 IU/mL) (76.1% vs. 15.6%, P2,000 IU/mL) as an independent risk factor of worse overall survival as well as high levels of AFP (defined as >400ng/ml), advanced Child-Pugh score, greater tumor
volume, and vascular invasion (Fig. 2, Table 3). When we stratified patients according to concomitant administration of antiviral therapy, pretreatment DNA levels remained an independent prognostic factor for survival in both the antiviral therapy group and the no antiviral therapy group (data not shown).
Disease progression
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The median progression free survival (PFS) was 3.5 months (95% CI, 2.35-
4.65) (Fig 1B). As for survival, univariate and multivariate analyses were also performed to investigate the effect of virologic and clinical variables on disease progression (Table 4). Univariate analysis revealed higher HBV DNA levels, as well as high AFP level, worse Child Pugh grade, larger tumor size (≥5cm), larger tumor volume (≥50%), presence of vascular invasion, bilobular involvement, multinodularity (≥3), and
worse ECOG performance status, to be significant prognostic factors for disease
progression. However, in multivariate analysis, only high AFP level and Child-Pugh score remained significant. When we performed univariate and multivariate analysis of patients who did
not receive concomitant antiviral therapy along with sorafenib, high pretreatment HBV DNA levels were shown to be an independent prognostic factor for disease progression (Table 5), (Fig 3A). In contrast, among patients who did receive concomitant
prophylactic antiviral therapy, only AFP level was shown to be an independent prognostic factor for disease progression; in this patient population, pretreatment HBV DNA levels were not associated with disease progression in either univariate or multivariate analysis (Fig 3B).
Pretreatment HBV DNA levels and hepatitis exacerbation during sorafenib treatment
In total, 4 patients among the entire study population experienced viral
reactivation while receiving sorafenib treatment. Patients who were administered concomitant prophylactic antiviral therapy experienced significantly less viral
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reactivation than those who did not (0 in 40 vs. 4 in 38; P=0.025 by Fisher’s exact test). Two of these four patients experienced hepatitis exacerbation.
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Discussion
The association between HBV and HCC is well known, as HBV has been
shown to influence HCC development18. HCC risk has been shown to increase in proportion to HBV DNA levels19, and antiviral treatments with nucleoside analogues, such as lamivudine and entecavir reduced the incidence of HCC development20-22 and
the risk of recurrence after curative resection of early HCC in HBV patients23-28. Previous studies showed that higher pretreatment HBV DNA level12,13 was also
correlated with worse survival outcomes in patients with advanced HCC treated with systemic chemotherapy12 or TACE13. Meanwhile, the effects of pretreatment HBV DNA levels on clinical outcomes in patients treated with sorafenib have not been determined. Therefore, in this study, we set out to evaluate the effect of pretreatment HBV DNA levels on disease progression and overall survival in HCC patients treated with sorafenib, and found that higher pretreatment HBV DNA levels (>2,000 IU/mL) predicted worse overall survival therein. Pretreatment HBV DNA level was also associated with disease progression. Interestingly, the association was found only in patients who did not receive antiviral prophylaxis. In patients receiving antiviral prophylaxis, there was no difference in PFS according to HBV DNA level. This finding is hypothesis-generating; antiviral treatment might have overcome the worse prognosis associated with higher viral load. A number of studies have attempted to identify prognostic factors for sorafenib
treatment in HCC patients. Kim et al. demonstrated that Child Pugh Score, AFP, vascular invasion, and extrahepatic spread were independent prognostic factors for overall survival29. In another study30, serum AFP, CLIP score, intrahepatic tumor
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morphology, and portal vein invasion were significant prognostic factors. Consistent with these results, we also identified higher AFP, advanced Child Pugh grade, larger
tumor involvement, and vascular invasion as significant prognostic factors, in addition to higher viral load. Of note, higher viral load remained an independent prognostic
factor even after adjustment for these parameters. Although the underlying mechanism for the adverse effects of higher viral load
on the prognosis of HCC patients is not clear, several explanations have been proposed: First, the integration of HBV DNA into cellular genes is essential for cell signaling, proliferation, and viability, and induces overexpression of these genes, which may
confer a selective growth advantage to liver cells31. Additionally, production of HBV X protein can act as a transactivator on various cellular genes to modulate apoptosis, cell proliferation, and responses to DNA damage31. Second, compared to other etiologies,
HBV-related HCC exhibits a distinct pattern of genetic mutations, with greater chromosome instability and a higher prevalence of loss of heterozygosity, which consequently result in tumor aggressiveness32 Third, frequent expression of variant estrogen receptors in HBV-related HCC has been shown to account for a rapid tumor growth33,34. Finally, the upregulation of adhesion molecules on the cells lining the sinusoids caused by viral replication could enhance tumor development and spread35. Another important question that has yet to be sufficiently addressed is whether
sorafenib influences the replication status of HBV. Previously, an increase in serum HBV DNA level was reported in 20% to 50% of hepatitis B carriers undergoing cytotoxic chemotherapy36,37 or treatment with immune-modulatory agents, such as rituximab and infliximab. Additionally, Sezgin et al. previously described a renal cell carcinoma patient who experienced hepatitis B flare during treatment with everolimus38.
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Thus, after other studies demonstrated that prophylactic antiviral therapy reduces the frequency of HBV reactivations39-42, current treatment guidelines have recommended HBV carriers scheduled for cancer chemotherapy to undergo prophylactic antiviral therapy, regardless of their serum HBV DNA levels14,43. Nevertheless, data on associations between sorafenib and HBV reactivation are limited. In one retrospective
study, which investigated sorafenib monotherapy in an HBV endemic area, viral reactivation was not observed30. In contrast, we observed significantly less viral reactivation in patients who received concomitant antiviral prophylaxis than in patients who did not. Although this result suggests the possible influence of sorafenib on B-viral reactivation, as well as a potential role for prophylactic antiviral therapy, the small number of included patients and the retrospective nature of this study prohibit us from making more definite conclusions. Taken together, nonetheless, the effect of sorafenib
on HBV reactivation and the efficacy of prophylactic antiviral therapy in patients treated with sorafenib should be evaluated in future studies. We defined >2,000 IU/mL as a cutoff value. The risk of progressive liver
disease is reported to increase at the threshold of 10,000 copies/ml (approximately >2000 IU/mL)19 and several guidelines44,45 are using this value as a cut-off to start
antiviral treatment in patients with HBe negative B-viral patients. In addition, same value was used in previous article by Yu et al which demonstrated the association between viral load and HCC prognosis13. Hence, we presumed it as a clinically relevant cut off value for higher viral load. This study has several limitations. First, this study was conducted in a single
center with a small number of patients. Thus, one should be cautious in generalizing the results of this study to an entire population. Second, because this study was performed
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retrospectively based on chart review, there may be significant selection bias although we adhered to inclusion and exclusion criteria set by before medical chart reviewing to minimize this fault. In addition, patients with higher viral load were associated with advanced Child Pugh Score, larger tumor size, bilobular involvement, multinodularity, and vascular invasion, which are inherent adverse prognostic factors. Although higher
viral load remained an independent prognostic factor after adjustment of these factors, the results should be interpreted with caution. Third, even though treatment was administered largely based on guidelines set by the Korean Liver Cancer Study Group, there were some differences in treatment protocols and follow up strategies, such as interval at which follow-up CT was performed. Fourth, while we used RECIST criteria to evaluate treatment responses, individual responses were evaluated by the patients’ primary physicians and were not confirmed by an independent reviewer. Nevertheless, this is the first study to report on the effect of serum HBV DNA levels on clinical outcomes in HCC patients treated with sorafenib. In conclusion, we demonstrated that high HBV DNA levels prior to treatment
with sorafenib adversely affect disease progression and overall survival. Furthermore, our study results showed that viral reactivation and hepatitis exacerbation can occur during sorafenib treatment and might be prevented by concomitant antiviral therapy. Future studies are warranted to test the usefulness of concomitant prophylactic antiviral therapy during treatment of HCC patients with sorafenib to improve prognoses and to prevent viral reactivation.
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Acknowledgements The authors would like to thank Anthony Thomas Milliken (Editing Synthase, Seoul, Korea) for his help with the editing of this manuscript.
Conflicts of interest: The authors declare no commercial associations that might represent a conflict of interest in relation to this manuscript.
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Accepted Article Tables
Table 1. Baseline characteristics of the patients (N=78) Characteristic
Age
Median
56.5 (36-82)
Number of male patients
62 (79.5)
HBs antigen-positivity
72 (92.3)
HBV DNA level > 2,000 IU/mL
40 (51.3)
HBe antigen-positivity
18 (25.4)*
ECOG performance status
0
22 (28.2)
1
48 (61.5)
2
8 (10.3)
Median baseline laboratory results
Total bilirubin (mg/dL)
0.9 (0.4-3.2)
Albumin (g/dL)
3.4 (2.0-4.7)
Prothrombin time (sec)
12.4 (10.3-26.1)
ALT (IU/L)
33.5 (1-736)
Creatinine (mg/dL)
0.8 (0.4-11.2)
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Hemoglobin (g/dL)
Alpha-fetoprotein (ng/mL)
12.6 (8.4-18.0)
648 (1.18-120,000)
Child Pugh grade
No cirrhosis
29 (37.2)
A
30 (38.5)
B
16 (20.5)
C
3 (3.8)
Tumor volume ≥ 50%
55 (70.5)
Bilobular involvement
34 (43.6)
Nodules ≥ 3
45 (57.7)
Greatest dimension ≥ 5.0cm
55 (70.5)
Vascular invasion
36 (46.2)
UICC tumor-node-metastasis stage
III
5 (6.4)
IVA
18 (23.1)
IVB
55 (70.5)
Abbreviation: ECOG, Eastern Cooperative Oncology Group; ALT, alanine aminotransferase
* HBe antigen was examined in only 72 patients.
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Table 2. Comparison of clinical variables according to HBV DNA level HBV DNA P ≥ 2,000 IU/mL (n=40)
< 2,000 IU/mL (n=38)
AFP ≥400ng/mL
27 (67.5%)
13 (34.2%)
0.116
ECOG PS 2
7 (17.5%)
1 (2.6%)
0.057
Child Pugh grade B or C
15 (37.5%)
4 (10.5%)
0.008
Tumor involvement ≥ 50%
17 (42.5%)
12 (31.6%)
0.318
Maximum size ≥ 5cm
35 (87.5%)
20 (52.6%)
0.001
26 (65%)
8 (21.1%)
