Abstract
Sorafenib is the recommended first‐line treatment option for patients with advanced hepatocellular carcinoma (HCC). Hepatitis C virus (HCV)‐related advanced HCC (HCV–HCC) seemed to have a better response than hepatitis B virus (HBV)‐related HCC (HBV–HCC) in sorafenib use, but it was undetermined. Hence, we aimed to investigate the effect of sorafenib between HBV–HCC and HCV–HCC patients in Taiwan. From August 2012 to December 2016, 575 consecutive advanced HCC patients received sorafenib under the reimbursement of Taiwan national health insurance in our hospital. Radiologic assessment was performed at a 2‐month interval. Those patients with tumor progression or liver function deterioration were disallowed for further sorafenib use. Patients with HBV or HCV infection were, retrospectively, enrolled and followed till December 2018. There were 277 (62.4%) HBV–HCC patients and 167 (37.6%) HCV–HCC patients. Before sorafenib, 192 (69.3%) HBV–HCC patients who had used nucleoside analogs (NAs) for HBV management, whereas only 5 (3%) HCV–HCC patients received interferon‐based antiviral therapy. Overall survival (OS) of HCV–HCC patients was significantly superior to HBV–HCC patients without NAs (8.8 months vs. 4.9 months, p = 0.006), but was noninferior to HBV–HCC patients with NAs (8.8 months vs. 10.7 months, p = 0.54). Using propensity score matching, progression‐free survival (2.0 months vs. 2.1 months, p = 0.374) and OS (10.5 months vs. 9.6 months, p = 0.746) between HBV–HCC and HCV–HCC groups were not different. Antiviral therapy might increase survival benefits of advanced HBV–HCC patients underwent sorafenib use, leading to a comparable OS to HCV–HCC patients in Taiwan.
Keywords: hepatitis B virus, hepatitis C virus, hepatocellular carcinoma, Sorafenib
1. INTRODUCTION
Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the fourth leading cause of cancer‐related death worldwide. 1 Because the symptoms of early HCC are often inconspicuous, most patients are diagnosed at an advanced stage with symptom presentation. These patients often lose critical timely intervention of curative therapies such as hepatic resection (HR), radiofrequency ablation (RFA), or liver transplantation, so systemic treatment of advanced HCC is a great concern. As is known, the SHARPE trial (in Europe and United States) and the Asia‐Pacific study (in Asia‐Pacific regions) demonstrated that sorafenib significantly improved survival benefit for patients with advanced HCC. 2 , 3 Hepatitis B virus (HBV) infection is the main etiology of HCC development worldwide, especially in Asia. 4 In Taiwan, the vaccination program against HBV infection was initiated in 1984 and has reduced the incidence of HCC in children and adolescent successfully 5 ; however, HCC is still the leading cause in cancer incidence and mortality in Taiwan, with more than 7000 individuals dying of HCC annually. 6 Besides HBV infection, hepatitis C virus (HCV) is also one of the major etiologic agents for HCC, 7 with a prevalence of infection at approximately 4.4%, accounting for more than 30% of HCC occurrences according to prior studies. 8 , 9 Although the development of new direct antiviral agents (DAAs) in recent years could achieve a higher sustained viral response rate over 97% for HCV eradication, 10 HCV‐related HCC (HCV–HCC) is still a concerning issue for clinical physicians, especially for advanced HCC. The subgroup analysis in the SHARP trial found that HCV–HCC patients treated with sorafenib had relatively superior median overall survival (OS) than HBV‐related HCC (HBV–HCC) patients (14 months vs. 9.7 months), 11 although it was not a head‐to‐head comparison. In fact, the outcome of advanced HCC patients under sorafenib treatment between these groups remains unclear; so the present study attempted to elucidate the efficacy of sorafenib treatment for advanced HCC patients with HBV or HCV infection.
2. PATIENTS AND METHODS
2.1. Patients
From August 2012 to December 2016, there were 575 consecutive advanced HCC patients who received sorafenib under reimbursement of the Taiwan National Health Insurance (NHI) scheme in our institute—Kaohsiung Chang Gung Memorial Hospital. The criteria for sorafenib reimbursement were Barcelona Clinic Liver Cancer (BCLC) stage C HCC with macrovascular invasion or with extrahepatic metastasis and Child–Pugh (CP) liver function class A. All patients received 400 mg of sorafenib twice daily, with the dosage modified on presentation of adverse effects (AE) according to the manufacturer's recommendations, while sorafenib monotherapy or combined therapy was administered depending on the decision of clinical physicians. After sorafenib termination, post‐sorafenib treatments were offered to those patients who still maintained good liver function reserve. Combined treatments including HR, hepatic RFA, transcatheter arterial chemical embolization (TACE) or radiotherapy, and post‐sorafenib treatments including palliative extrahepatic surgery, TACE, systemic chemotherapy, radiotherapy, hepatic arterial infusion chemotherapy, thalidomide, or clinical trial agents have been reported in our previous study. 12 Patients with HBV–HCC or HCV–HCC were recruited and followed till December 2018, with the demographics and clinical characteristics of recruited patients recorded and further analyzed. This current study was approved by the Institution Review Board of Kaohsiung Chang Gung Memorial Hospital.
2.2. Assessment of sorafenib response
The radiologic assessment by liver computed tomography (CT) or magnetic resonance imaging (MRI) was performed based on modified Response Evaluation Criteria in Solid Tumors every 2 months during sorafenib treatment. Treatment response was defined as complete response; partial response; progression disease (PD); and stable disease, while clinical tumor response was assessed by RECIST version 1.1 based on contrast‐enhanced abdominal CT or MRI. 13 If patients had tumor progression (TP) or liver function deterioration (LD) in CP Class B or C, continued reimbursement of sorafenib use was not allowed.
2.3. Management of antiviral therapy
Antiviral therapies with nucleoside analogs (NAs) for HBV included lamivudine, telbivudine, entecavir, or tenofovir disoproxil fumarate (TDF). All NAs use was recommended to the patients according to the Asian‐Pacific Association for the Study of the Liver (APASL) clinical practice guidelines of chronic hepatitis B. 14 For patients who had been receiving antiviral therapy with NAs before sorafenib, their NAs drug treatments continued. Regarding anti‐HCV therapy, a few patients received antiviral treatment with peg‐interferon plus ribavirin according to the APASL clinical practice guidelines of chronic hepatitis C. 15
2.4. Statistical analysis
The result of OS and progression‐free survival (PFS) was expressed as Kaplan–Meier method; continued variables were expressed with mean ± SD or median with a range, while propensity scoring was also used for control of selection bias and performed using binary logistic regression to generate a propensity score for each patient with HBV–HCC or HCV–HCC. The variables included in the propensity model were age, sex, cirrhosis status, CP score, liver function tests, APRI, FIB4, tumor pattern, combined treatment, and post‐sorafenib treatment. All P values of <0.05 by the two‐tailed test were considered significant. All statistical analysis was carried out using SPSS 20.
3. RESULTS
3.1. Clinical characteristics between HBV–HCC and HCV–HCC groups
Figure 1 shows the flowchart of patient enrollment among 575 advanced HCC patients under sorafenib treatment. After excluding patients with HBV plus HCV, non‐HBV, non‐HCV, or without etiology records, a total of 444 patients including 277 (62.4%) HBV–HCC and 167 (37.6%) HCV–HCC was enrolled. Table 1 shows clinical characteristics of all enrolled patients. HCV–HCC patients were older, and had more severe liver inflammation status compared with HBV–HCC patients. No matter whether patients were HBV or HCV, approximately 70% experienced dosage reduction due to the concern of AE under sorafenib treatment. The interval of sorafenib use was 4 months in both HBV and HCV groups, with the most common reason for termination being TP: 66.1% for the HBV group and 70% for the HCV group, respectively. PFS rates and OS rates between HBV and HCV groups were equal (PFS: 2.1 months vs. 2.1 months, p = 0.582; OS: 8.8 months vs. 8.8 months, p = 0.623) (Figure 2(A,B)). The differences of patients with combined treatment or with post‐sorafenib treatment were insignificant in both groups. A total of 37% HBV–HCC patients and 31.9% HCV–HCC patients received combined treatment with sorafenib, whereas 40% HBV–HCC patients and 42.5% HCV–HCC patients could maintain good liver function reserve and afford post‐sorafenib treatments after sorafenib termination. In general, OS of patients with combined treatment was superior to patients with sorafenib monotherapy (11.1 months vs. 7.5 months, p = 0.005). Furthermore, patients being able to afford post‐sorafenib treatment had longer survival after sorafenib termination than those who could not (15.8 months vs. 4.7 months, p < 0.001).
FIGURE 1.
Flowchart of all enrolled patients
TABLE 1.
Demographics and clinical characteristics of enrolled HBV–HCC patients and HCV–HCC patients
| HBV–HCC (N = 277) | HCV–HCC (N = 167) | p‐Value | |
|---|---|---|---|
| Follow‐up interval, mean ± SD, months | 11.9 ± 13.6 | 12.3 ± 14 | 0.629 |
| Sorafenib use interval, months | 6.7 ± 8.2 | 4.2 ± 5.4 | 0.06 |
| Male sex, n (%) | 240 (86.6) | 121 (72.5) | <0.001 |
| Age (years) | 58.7 ± 11.1 | 67.1 ± 8.8 | <0.001 |
| Cirrhosis, n (%) | 245 (88.4) | 157 (94) | 0.052 |
| Child–Pugh score 5, n (%) | 190 (69.3) | 110 (66.3) | 0.608 |
| Child–Pugh score 6, n (%) | 87 (30.7) | 56 (33.7) | |
| Tumor pattern, EHM, n (%) | 113 (40.8) | 54 (32.3) | 0.017 |
| MVI, n (%) | 98 (35.4) | 82 (49.1) | |
| Both, n (%) | 66 (23.8) | 31 (18.6) | |
| AFP ≥200 ng/ml, n (%) | 140 (51.7) | 91 (55.2) | 0.479 |
| AST, IU/L | 78.2 ± 79.5 | 93.7 ± 92.2 | 0.036 |
| ALT, IU/L | 56.8 ± 65.2 | 74.9 ± 65.2 | 0.009 |
| APRI | 1.51 ± 1.6 | 2.26 ± 2.2 | <0.001 |
| FIB4 | 5.1 ± 4.5 | 6.9 ± 4.7 | <0.001 |
| Tumor size, cm | 6.9 ± 5.2 | 5.2 ± 4 | <0.001 |
| Tumor size ≥10 cm, n (%) | 71 (28) | 25 (16.1) | 0.006 |
| Antiviral drug use, n (%) | 192 (69.3) | 5 (3) | <0.001 |
| Combined treatment, n (%) | 102 (37) | 53 (31.9) | 0.404 |
| Post‐sorafenib treatment, n (%) | 108 (40) | 71 (42.5) | 0.603 |
| Daily dose (mg) | 578 ± 198 | 558 ± 210 | 0.123 |
| Dose reduction, n (%) | 193 (69.7) | 124 (74.7) | 0.257 |
| Response (CR/PR/SD/PD) | 8/2/27/194 | 1/3/23/124 | 0.185 |
| Disease control rate, % | 16 | 20.9 | 0.55 |
| Withdraw reasons (TP/LD/AE/lost follow‐up) | 183/53/15/4 | 117/36/8/4 | 0.329 |
| Death, n (%) | 202 (73.2) | 117 (70.5) | 0.539 |
Abbreviations: AE, adverse effect; APRI, AST‐platelet ratio index; CR, complete response; EHM, extrahepatic metastasis; FIB‐4, fibrosis 4; LD, liver function deterioration; HBV–HCC, HBV‐related HCC; HCV–HCC, HCV‐related HCC; MVI, macrovascular invasion; N, number; PD, progression disease; PR, partial response; SD, stable disease; TP, tumor progression.
FIGURE 2.
(A) Progression‐free survival rates of hepatitis B virus (HBV)–hepatocellular carcinoma (HCC) patients and hepatitis C virus (HCV)–HCC patients. (B) Overall survival rates of HBV–HCC patients and HCV–HCC patients
3.2. Clinical characteristics between HBV–HCC and HCV–HCC groups after propensity score matching analysis
The propensity score matching model analysis showed that there were 109 matched patients in both HBV–HCC and HCV–HCC groups, and appeared well‐matched in confounding factors including age, sex, cirrhosis status, CP score, liver function tests, APRI, FIB4, tumor pattern, combined treatment, and post‐sorafenib treatment between the two groups (Table 2). However, PFS rates and OS rates did not show significant difference even after propensity score matching (PFS: 2 months in HBV group vs. 2.1 months in HCV group, p = 0.374; OS: 10.5 months in HBV group vs. 9.6 months in HCV group, p = 0.746) (Figure 3(A,B)).
TABLE 2.
Demographics and clinical characteristics of HBV–HCC patients and HCV–HCC patients after propensity score matching
| HBV–HCC (N = 109) | HCV–HCC (N = 109) | p‐Value | |
|---|---|---|---|
| Follow‐up interval, mean ± SD, months | 11.7 ± 13.6 | 12.9 ± 14 | 0.491 |
| Male sex, n (%) | 91 (83.5) | 89 (81.7) | 0.721 |
| Age (years) | 64.7 ± 8.5 | 64.9 ± 8.1 | 0.826 |
| Cirrhosis, n (%) | 99 (90.8) | 99 (90.8) | 1 |
| Child–Pugh score 5, n (%) | 77 (70.6) | 76 (69.7) | 0.568 |
| Child–Pugh score 6, n (%) | 32 (29.4) | 33 (30.3) | |
| Tumor pattern, EHM, n (%) | 44 (40.4) | 42 (38.5) | 0.851 |
| MVI, n (%) | 45 (41.3) | 49 (45) | |
| Both, n (%) | 20 (18.3) | 18 (16.5) | |
| AFP ≥200, n (%) | 55 (50.5) | 56 (51.4) | 0.892 |
| AST, IU/L | 77.9 ± 72.3 | 80.2 ± 50.4 | 0.781 |
| ALT, IU/L | 57.7 ± 57.5 | 66.8 ± 55.2 | 0.232 |
| APRI | 1.71 ± 1.7 | 1.89 ± 1.8 | 0.449 |
| FIB4 | 5.8 ± 4.3 | 6 ± 4.1 | 0.788 |
| Tumor size, cm | 6.4 ± 5.2 | 5 ± 4 | 0.07 |
| Tumor size ≥10 cm, n (%) | 21 (21.4) | 16 (16.2) | 0.344 |
| Combined treatment, n (%) | 39 (35.8) | 40 (36.7) | 0.888 |
| Post‐sorafenib treatment, n (%) | 54 (49.5) | 53 (48.6) | 0.892 |
| Daily dose (mg) | 578 ± 198 | 566 ± 210 | 0.684 |
| Dose reduction, n (%) | 80 (73.4) | 83 (76.1) | 0.64 |
| Response (CR/PR/SD/PD) | 1/0/13/95 | 1/0/17/91 | 0.734 |
| Disease control rate, % | 12.8 | 16.5 | 0.33 |
| Withdraw reasons (TP/LD/AE/lost follow‐up) | 93/7/4/1 | 85/18/3/1 | 0.256 |
| Death, n (%) | 82 (75.2) | 78 (72.2) | 0.615 |
Abbreviations: AE, adverse effect; APRI, AST‐platelet ratio index; CR, complete response; EHM, extrahepatic metastasis; FIB‐4, fibrosis 4; LD, liver function deterioration; HBV–HCC, HBV‐related HCC; HCV–HCC, HCV‐related HCC; MVI, macrovascular invasion; N, number; PD, progression disease; PR, partial response; SD, stable disease; TP, tumor progression.
FIGURE 3.
(A) Progression‐free survival rates of hepatitis B virus (HBV)–hepatocellular carcinoma (HCC) patients and hepatitis C virus (HCV)–HCC patients after propensity score matching. (B) Overall survival rates of HBV–HCC patients and HCV–HCC patients after propensity score matching
3.3. Impact of NAs on HBV–HCC
During sorafenib treatment, 192 (69.3%) HBV–HCC patients had used NAs for antiviral management, whereas 85 patients did not. HBV–HCC patients with antiviral therapy showed significantly better OS than those without (10.7 months vs. 4.9 months, p = 0.001) (Figure 4(A)). Regarding HCV–HCC patients, only 5 (3%) had used antiviral therapy with peg‐interferon plus ribavirin before sorafenib treatment; hence, the influence of antiviral therapy on HCV–HCC patients was unremarkable. OS rate of HCV–HCC patients was significantly superior to that of HBV–HCC patients without antiviral therapy (8.8 months vs. 4.9 months, p = 0.006), but was noninferior to HBV–HCC patients with antiviral therapy (8.8 months vs. 10.7 months, p = 0.54). Individual use of NAs was based on decisions of clinical physicians, including entecavir (n = 128), TDF (n = 35), telbivudine (n = 23), and lamivudine (n = 6) therapies. OS of each NA for HBV–HCC patients under sorafenib was 11 months for entecavir, 13.4 months for TDF, 8.1 months for telbivudine, and 10.1 months for lamivudine, respectively (Figure 4(B)). Although the OS of TDF was longer than entecavir, there was no significant difference (p = 0.665).
FIGURE 4.
(A) Overall survival rates among hepatitis B virus (HBV)–hepatocellular carcinoma (HCC) patients with antiviral treatment or without antiviral treatment and hepatitis C virus (HCV)–HCC patients. (B) Overall survival rates of HBV–HCC patients based on different nucleoside analogs
4. DISCUSSION
Despite the development of new tyrosine kinase inhibitors and immunotherapeutic agents for second‐line or third‐line treatments of advanced HCC in recent years, sorafenib remains the standard first‐line systemic therapy based on HCC treatment guidelines. 16 Since the success of sorafenib, all randomized clinical trials of new agents have needed to use sorafenib as the control arm in the first‐line setting; however, results from these clinical randomized trials as well as from postmarket surveys as a reflection of “real‐world” practice have not really exceeded the efficacy of sorafenib in the past decade. 17 In Taiwan, sorafenib has been reimbursed for advanced HCC patients under the NHI program since August 2012, but only those patients with HCC in BCLC stage C and CP class A could be reimbursed. Sorafenib would be terminated if radiologic TP or LD were found in the bimonthly reassessment, so the start and stop rules of sorafenib in our enrolled patients appear more consistent based on the strict reimbursed criteria, reducing the possible influence of selection bias. Although the survival benefit of sorafenib has been demonstrated, its median OS is still limited in clinical practice and is seldom longer than 1 year. The present study showed that the median OS of sorafenib use was approximately 8.8 months, which was superior to the 6.5 months of the Asian‐Pacific trial but comparable to other real‐world studies in Taiwan. 18 , 19 A recent large‐scaled analysis enrolling 9738 advanced HCC patients from the Taiwan national database indicated that patients who received locoregional therapy plus sorafenib had significantly better survival rates than those who underwent only sorafenib treatment. 20 The 1‐ and 3‐year OS rates were 46.22 and 12.24% in patients with additional locoregional therapy as well as 20.29 and 6.76% in patients treated with sorafenib only (p < 0.0001). It was also found that patients administered sorafenib combined with other locoregional therapies such as HR, RFA, TACE or RTO had better OS rates than those receiving sorafenib only (11.1 months vs. 7.5 months, p = 0.005). Comparing the era of the Asian‐Pacific trial, clinical physicians became more experienced in the management of sorafenib‐related AE and could earlier shift sorafenib to other sequential effective treatments, thereby probably prolonging survival after sorafenib termination.
The present study indicated that patients who still maintained good liver function reserve at the time of sorafenib cessation could have more opportunities to receive further treatments, possibly leading to better prognosis. Previous studies have reported that combining NAs with sorafenib use possessed survival benefits for HBV–HCC patients. 21 , 22 Antiviral therapy for the management of HBV infection could help reduce liver hepatic inflammation and preserve liver function during antitumor treatment. Actually, higher risk for reactivation is likely observed in patients who are not on antiviral therapy. Xu et al. indicated that patients treated with NAs had significantly improved OS compared with patients who received no NAs (16.47 months vs. 13.1 months, p = 0.03). 22 The current study also found HBV–HCC patients with antiviral therapy had longer OS than those without antiviral therapy (10.7 months vs. 4.9 months, p = 0.0001). Individual NAs use such as entecavir (n = 128), TDF (n = 35), telbivudine (n = 23), and lamivudine (n = 6) depends on the decision of the clinical physicians. The median OS rate of the two most‐used NAs, entecavir and TDF, was 11 and 13.4 months, respectively, although TDF seemed to have superior OS compared with entecavir, but there was no statistical significance.
The subgroup analysis of SHARP trial reported that HCV–HCC patients seemed to have longer OS than HBV–HCC patients under sorafenib treatment. 11 One small study found HBV–HCC had better OS under sorafenib treatment. 23 The recent exploratory pooled analysis of two Phase 3 studies indicated that the survival benefit of sorafenib might be greater in subjects with HCV infection 11 ; however, the present study found that there was no difference of sorafenib‐related survival benefit in HBV and HCV groups, with PFS rate being 2.1 months and OS rate being 8.8 months in both groups. Even when using the propensity score matching model to correct confounding factors, the matched PFS rate and OS rate still showed no significant difference between HBV and HCV groups. The explanation of this discrepancy between our study and the exploratory study is problematic, but in general, HBV–HCC patients tend to have larger‐sized tumors and are at more advanced stages, while HCV–HCC patients are usually related to worse liver function and less advanced tumors. 24
The reasons for the divergent responses by viral etiology remain unclear. Preclinical data demonstrated that sorafenib had the potential to inhibit viral replication of HCV, and thereby could suppress the inflammatory status linked to HCV–HCC 25 ; however, in our study, the OS between HBV–HCC and HCV–HCC was not different under sorafenib treatment and was approximately 8.8 months for each group. Unlike Western countries, HBV infection is more prevalent in Taiwan and antiviral therapy could be used under the reimbursement of our NHI scheme when patients met the criteria, so accordingly, over two‐thirds of HBV–HCC patients had been receiving antiviral therapy before sorafenib administration and continued their NAs under reimbursement of the Taiwan NHI with sorafenib use. In the era before effective DAAs, only a few HCV–HCC patients received antiviral therapy with peg‐IFN plus ribavirin before sorafenib, so the impact of antiviral therapy on HCV–HCC patients was not remarkable.
The present study indicated that HCV–HCC patients had superior OS to HBV–HCC patients without antiviral therapy (8.8 months vs. 4.9 months, p = 0.006), but was noninferior to HBV–HCC patients with antiviral therapy (8.8 months vs. 10.7 months, p = 0.54). The influence of antiviral therapy combination on HBV–HCC patients might partially explain why their median OS was improved and close to HCV–HCC patients undergoing sorafenib treatment.
The current study still has some limitations. First, before the era of DAAs, few HCV–HCC patients received antiviral therapy before sorafenib use, so the real influence of antiviral therapy on HCV–HCC patients with sorafenib could not be identified. Further studies enrolling more HCV–HCC patients after HCV eradication induced by DAA might help to elucidate this issue. Second, insufficient information concerning the HBV DNA level of each HBV–HCC patient at the time of sorafenib commencement could have affected the understanding of real liver inflammation status. Third, there was a difference of baseline characteristics between our HBV–HCC and HCV–HCC groups. Propensity score matching analysis was performed to control selection bias and confounding tumor factors; however, small sample size limited the evidence level of analysis.
5. CONCLUSION
In Taiwan, patients with advanced HCV–HCC had similar outcomes compared with HBV–HCC in sorafenib use. Antiviral therapies could help to improve the OS of HBV–HCC patients undergoing sorafenib treatment. Furthermore, HCV–HCC patients had median OS superior to HBV–HCC patients without antiviral therapy, but this was noninferior to those with antiviral therapy.
CONFLICT OF INTEREST
The authors declare no conflicts of interest.
ACKNOWLEDGMENTS
The authors thank Ms Nien‐Tzu Hsu and the biostatistics center of Kaohsiung Chang Gung Memorial Hospital for excellent statistics works.
Lee Y‐C, Wang J‐H, Chen C‐H, et al. Sorafenib use in hepatitis B virus‐ or hepatitis C virus‐related hepatocellular carcinoma: A propensity score matching study. Kaohsiung J Med Sci. 2021;37:894–902. 10.1002/kjm2.12413
Sheng‐Nan Lu and Yuan‐Hung Kuo contributed equally to this work.
Funding information Chang Gung Memorial Hospital, Grant/Award Number: CMRPG8F0443
Contributor Information
Sheng‐Nan Lu, Email: juten@ms17.hinet.net.
Yuan‐Hung Kuo, Email: 0104kuo@gmail.com.
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