Abstract
Lenvatinib has been approved as one of the first‐line treatments for advanced hepatocellular carcinoma (HCC) due to its high treatment efficacy being non‐inferior to sorafenib. Previous studies have shown well‐controlled viremia contributes to the prognosis of HCC patients receiving first‐line sorafenib; hence, we postulated this association might also exist in HCC patients with lenvatinib treatment. From April 2018 to December 2021, 201 unresectable HCC patients with first‐line lenvatinib treatment in our institute were assessed. High‐effect nucleoside analogues were administered for hepatitis B virus (HBV) control, while direct‐acting antivirals were used for hepatitis C virus (HCV) elimination. Based on our previous study, well‐controlled viremia was defined as patients who had undetectable viremia, or who had been receiving antivirals at least 6 months before lenvatinib. This study enrolled 129 patients, including 85 patients with HBV‐related HCC (HBV‐HCC) and 44 patients with HCV‐related HCC (HCV‐HCC), respectively. Progression‐free survival (PFS) and overall survival (OS) rates between the two groups were not different. Before administration of lenvatinib, 57.1% of the HBV‐HCC patients and 88.4% of the HCV‐HCC patients had well‐controlled viremia, and their PFS (8.8 vs. 3.1 months, p < 0.001) and OS (30.2 vs. 12.8 months, p = 0.041) were better than those who had uncontrolled viremia; moreover, well‐controlled viremia reduced tumor progression in multivariate analysis (Hazard ratio: 0.41, 95% confidence interval: 0.25–0.68, p = 0.001) after adjusting for albumin–bilirubin grade and concurrent treatment. HBV or HCV infection was not associated with tumor progression of HCC patients receiving lenvatinib, but viremia, controlled or not, was.
Keywords: hepatitis B virus, hepatitis C virus, hepatocellular carcinoma, lenvatinib, well‐controlled viremia
1. INTRODUCTION
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third leading cause of cancer‐related deaths worldwide. 1 A high number of HCC patients are diagnosed at an advanced stage with the presence of major portal vein thrombosis or extrahepatic spread, which is unsuitable for curative therapies that include hepatic resection, liver transplantation, or radiofrequency ablation (RFA), and then induces poorer prognosis. 2 For patients with unresectable advanced HCC, systemic therapies are the main recommended treatment option. 3 , 4 According to the solid findings of clinical trials, atezolizumab (an anti‐programmed death‐ligand 1 (PD‐L1) check‐point inhibitor) plus bevacizumab (a vascular endothelial growth factor [VEGF] monoclonal antibody) is currently the recommended first‐line systemic treatment, 5 while tyrosine kinase inhibitors (TKI) including sorafenib or lenvatinib are used as first‐line treatment options only in cases where atezolizumab plus bevacizumab is not feasible. 6 , 7 , 8 From an economic aspect, although treatment response of combined immunotherapy is more effective than TKI, the high cost of atezolizumab plus bevacizumab confines its clinical application, leaving sorafenib or lenvatinib as the most common treatment for advanced HCC in real‐life clinical settings.
Approximately 80% of HCC etiologies are associated with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections. 9 Previous studies have reported that patients with HCV‐related hepatocellular carcinoma (HCV‐HCC) derived more clinical benefits from sorafenib than HBV‐related HCC (HBV‐HCC) 10 , 11 ; however, these studies did not mention the controlled or non‐controlled status of viremia. Under the era of highly effective antiviral drugs including nucleoside analogues (NAs) for HBV suppression or direct antiviral agents (DAAs) for HCV elimination, concurrent treatment of the underlying viral hepatitis and liver tumor has been proven to be beneficial for patients with HBV‐HCC or HCV‐HCC 12 , 13 , 14 , 15 , 16 ; consequently, in exploring the real impact of virus etiologies on HCC treatment, the status of viremia control in real life needs to be further clarified.
Our previous study reported that well‐controlled viremia, defined as patients having undetectable viremia or having received antiviral therapies at least 6 months before treatment, contributed to better prognosis in HCC patients receiving sorafenib, 17 although this influence of virus etiology on lenvatinib remains undetermined. Accordingly, this study was conducted to assess the efficacy and safety of concurrent lenvatinib and anti‐viral treatment for unresectable HCC patients with HBV or HCV infection in real life.
2. PATIENTS AND METHODS
2.1. Patients
Two hundred and twenty‐four unresectable HCC patients with Barcelona clinical liver cancer (BCLC) Stage B or C received lenvatinib in our institute, Kaohsiung Chang Gung Memorial Hospital, from April 2018 to December 2021. The dosage of lenvatinib was modified based on the manufacturer's recommendations. The administer of lenvatinib monotherapy or lenvatinib combined with other treatment options was according to the decision of clinicians. After lenvatinib failure, those patients who kept good liver function had the opportunities for post‐lenvatinib treatment. HBV‐HCC or HCV‐HCC patients receiving first‐line lenvatinib and having Child–Pugh Class A liver function were included. These enrolled patients were followed up till the last date of visit, death, or the end of October 2022. The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Chang Gung Medical Foundation (IRB No. 202300311B0).
2.2. Treatment effect
According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), 18 we used radiologic assessment as liver computer tomography (CT) or magnetic resonance imaging (MRI) every 2 months during lenvatinib treatment to evaluate the efficacy of lenvatinib therapy. Overall survival (OS) was defined as the time from treatment beginning to mortality or the end of observation, with progression‐free survival (PFS) defined accordingly (as for OS). Other treatment outcomes included objective response rate (ORR) defined as patients achieving complete response (CR) or partial response (PR) as well as disease control rate (DCR), meaning patients had CR, PR, or stable disease (SD).
2.3. Application of antiviral treatment
The application of antiviral treatments was based on the Asian‐Pacific Association for the Study of the Liver clinical practice guidelines. 19 , 20 Antiviral medications with high effect nucleoside analogues (NAs), including tenofovir alafenamide, tenofovir disoproxil fumarate, and entecavir were prescribed for HBV control, while DAAs were used for HCV elimination. In this study, according to our previous study, 17 well‐controlled viremia was defined as patients having undetectable viremia or having received antiviral therapies at least 6 months before lenvatinib.
2.4. Statistical analysis
The statistical analyses were performed using SPSS 22 software (SPSS Inc., Chicago, IL, USA). Continuous variables were expressed with mean ± SD or median with a range and compared by Student's t‐test, while chi‐squared tests were used to analyze categorical variables in comparing values between the two groups. The survival rates, both OS and PFS, were analyzed using the Kaplan–Meier method and were compared by log‐rank test in survival curve analysis; univariate and multivariate analyses of survival factors were performed through Cox proportional hazards regression models; while statistical significance was reached when p‐values were <0.05 in the two‐tailed test.
3. RESULTS
3.1. Baseline characteristics of enrolled patients
The current study enrolled 129 patients for further analysis after excluding 44 patients who had non‐HBV, non‐HCV, 2 patients with both HBV and HCV infection, 23 patients receiving other systemic therapies before, 16 patients with insufficient data and 10 patients being Child–Pugh Class B or C (Figure 1). There were separately 85 (65.9%) HBV‐HCC patients and 44 (34.1%) HCV‐HCC patients, with baseline characteristics shown in Table 1. The mean follow‐up interval was 13 months with no statistically significant difference between the two groups. Patients in the HCV‐HCC group were older with a higher proportion of females compared to the HBV‐HCC group while most patients had Child–Pugh score of 5 (79.8%) and were in BCLC Stage C (80.6%), with 55.8% patients in albumin–bilirubin (ALBI) Grade 1 and 44.2% in ALBI Grade 2, respectively.
FIGURE 1.
Flow chart of the study population.
TABLE 1.
Baseline characteristics of enrolled patients by virus etiology and by virus control.
| Total (n = 129) | HBV (n = 85) | HCV (n = 44) | p‐value | WV (n = 86) | UV (n = 43) | p‐value | |
|---|---|---|---|---|---|---|---|
| Follow‐up interval, months | 13.0 ± 8.8 | 12.4 ± 8.3 | 14.2 ± 9.8 | 0.291 | 12.9 ± 7.5 | 9.2 ± 6.8 | 0.007 |
| Age (years) | 65.7 ± 11.5 | 62.4 ± 11.1 | 72.2 ± 9.2 | <0.001 | 68.3 ± 10.9 | 60.5 ± 10.7 | <0.001 |
| Male sex, n (%) | 97 (75.2) | 74 (87.1) | 23 (52.3) | <0.001 | 55 (64) | 42 (97.7) | <0.001 |
| Child–Pugh score 5, n (%) | 103 (79.8) | 67 (78.8) | 36 (81.8) | 0.688 | 69 (80.2) | 34 (79.1) | 0.877 |
| 6, n (%) | 26 (20.2) | 18 (21.2) | 8 (18.2) | 17 (19.8) | 9 (20.9) | ||
| ALBI Grade 1, n (%) | 72 (55.8) | 49 (57.6) | 23 (52.3) | 0.560 | 74 (86) | 41 (95.3 | 0.109 |
| 2, n (%) | 57 (44.2) | 36 (42.4) | 21 (47.7) | 12 (14) | 2 (4.7) | ||
| BCLC stage, B, n (%) | 25 (19.4) | 16 (18.8) | 9 (20.5) | 0.824 | 20 (23.3) | 5 (11.6) | 0.115 |
| C, n (%) | 104 (80.6) | 69 (81.2) | 35 (79.5) | 66 (76.7) | 38 (88.4) | ||
| EHM, n (%) | 55 (42.6) | 36 (42.4) | 19 (43.2) | 0.928 | 42 (48.8) | 13 (30.2) | 0.044 |
| MVI, n (%) | 61 (47.3) | 42 (49.4) | 19 (43.2) | 0.502 | 32 (37.2) | 29 (67.4) | 0.001 |
| Tumor size ≥6 cm, n (%) | 45 (36) | 32 (38.6) | 13 (31) | 0.403 | 20 (24.1) | 25 (59.5) | <0.001 |
| AST, IU/L | 61.4 ± 45.5 | 63.4 ± 41.9 | 57.3 ± 52.3 | 0.514 | 50.2 ± 28.9 | 83.8 ± 62 | 0.002 |
| ALT, IU/L | 48.7 ± 33.1 | 51.3 ± 32.4 | 43.5 ± 34.1 | 0.216 | 42.3 ± 29.4 | 61.7 ± 36.5 | 0.004 |
| Bilirubin | 1.0 ± 0.5 | 1.0 ± 0.5 | 1.0 ± 0.5 | 0.607 | 1.0 ± 0.5 | 1.0 ± 0.4 | 0.69 |
| Albumin | 4.1 ± 0.5 | 4.1 ± 0.4 | 4.0 ± 0.5 | 0.387 | 4.1 ± 0.5 | 4.0 ± 0.5 | 0.122 |
| AFP, ng/mL | 7147 ± 1853 | 7435 ± 2177 | 6590 ± 4753 | 0.796 | 4118 ± 1218 | 13,202 ± 2626 | 0.036 |
| AFP ≥200, n (%) | 49 (38) | 31 (36.5) | 18 (40.9) | 0622 | 30 (34.9) | 19 (44.2) | 0.305 |
| Concurrent treatment, n (%) | 54 (41.9) | 38 (44.7) | 16 (36.4) | 0.363 | 38 (44.2) | 16 (37.2) | 0.449 |
| Lenvatinib stop, n (%) | 113 (87.6) | 74 (87.1) | 39 (88.6) | 0.797 | 75 (87.2) | 38 (88.4) | 0.85 |
| Post‐treatment, n (%) | 58 (51.3) | 36 (48.6) | 21 (51.2) | 0.989 | 41 (54.7) | 15 (39.5) | 0.127 |
| Second‐line systemic treatment, n (%) | 43 (38.4) | 30 (41.1) | 13 (33.3) | 0.421 | 29 (36.5) | 14 (43.2) | 0.563 |
| Chemotherapy, n | 14 | 12 | 2 | 7 | 7 | ||
| Atezolizumab + bevacizumab, n | 11 | 9 | 2 | 6 | 4 | ||
| Nivolumab, n (%) | 5 | 2 | 3 | 4 | 2 | ||
| Well‐controlled viremia, n (%) | 86 (67.7) | 48 (57.1) | 38 (88.4) | <0.001 | — | — | — |
| Anti‐viral treatment, n (%) | 96 (75) | 66 (77.6) | 30 (69.8) | 0.331 | 68 (80) | 28 (65.1) | 0.066 |
Abbreviations: AFP, alpha‐fetoprotein; ALBI grade, albumin‐bilirubin grade; ALT, alanine aminotransferase; AST, aspartate transaminase; BCLC, Barcelona clinic liver cancer; EHM, extra‐hepatic metastasis; MVI, macro‐vascular invasion; UV, uncontrolled viremia; WV, well‐controlled viremia.
No statistically significant difference was found between HBV‐HCC and HCV‐HCC groups in the proportion of extrahepatic metastasis (EHM), macrovascular invasion (MVI), tumor size, liver function, and alpha‐fetoprotein (AFP) level. During lenvatinib treatment, 41.9% of patients had also received other treatments concurrently, such as transarterial chemoembolization, RFA, and so on. In the follow‐up duration, 87.6% patients ceased using lenvatinib. Approximately, 51.3% could receive further treatment after lenvatinib failure, and 38.4% received sequential systemic therapies, of which the most frequently used second‐line systemic treatment agent was chemotherapy followed by atezolizumab plus bevacizumab, and nivolumab.
At lenvatinib initiation, 86 patients (66.7%) had undetectable viremia or had already received antiviral therapies for more than 6 months, with a total of 57.1% patients in the HBV‐HCC group and 88.4% patients in the HCV‐HCC group exhibiting well‐controlled viremia at the commencement of lenvatinib. In contrast, 43 patients (33.3%) belonged to the uncontrolled viremia group, with these patients exhibiting significantly higher proportion of MVI occurrences and larger tumor sizes as well as demonstrating more severe liver inflammation status and elevated AFP levels compared to the well‐controlled viremia group. Patients with well‐controlled viremia seemed to have a higher likelihood of undergoing concurrent treatments or post‐lenvatinib sequential therapies compared to those without such controlled viremia; however, these comparisons did not achieve statistical significance.
3.2. Treatment response
Treatment response was assessed by the follow‐up images. One hundred and ten patients (85.2%) had dynamic follow‐up CT or MRI (Table 2), including 76 patients in the HBV‐ HCC group and 34 patients in the HCV‐ HCC group respectively. Among these, 5% of patients had CR, 17% reached PR, 53% kept SD, and 35% became PD. In the HBV‐HCC group, 3 (3.9%) patients obtained CR, 11 (14.5%) patients reached PR, 35 (46.1%) patients maintained SD, and 27 (35.5%) patients had PD. Regarding the HCV‐HCC group, CR, PR, SD, PD percentages were 5.9%, 17.6%, 52.9%, and 23.5%, respectively. Based on viral control, CR, PR, SD, PD percentages were 6.7%, 14.7%, 54.7%, and 24% in the well‐controlled viremia group as well as 0%, 17.1%, 34.3%, and 48.6% in the uncontrolled viremia group.
TABLE 2.
Treatment response of HCC patients with Lenvatinib by virus etiology and viral control.
| Variables | Total (n = 129) | HBV (n = 85) | HCV (n = 44) | WV (n = 86) | UV (n = 43) |
|---|---|---|---|---|---|
| Treatment response evaluation, n (%) | 110 (85.2) | 76 (89.4) | 34 (77.2) | 75 (87.2) | 35 (81.4) |
| Complete response, n (%) | 5 (4.5) | 3 (3.9) | 2 (5.9) | 5 (6.7) | 0 (0) |
| Partial response, n (%) | 17 (15.5) | 11 (14.5) | 6 (17.6) | 11 (14.7) | 6 (17.1) |
| Stable disease, n (%) | 53 (48.2) | 35 (46.1) | 18 (52.9) | 41 (54.7) | 12 (34.3) |
| Progression disease, n (%) | 35 (31.8) | 27 (35.5) | 8 (23.5) | 18 (24) | 17 (48.6) |
| Objective response rate, % | 20 | 18.4 | 23.5 | 21.4 | 17.1 |
| Disease control rate, % | 68.2 | 64.5 | 76.5 | 76 | 51.4 |
| Death, n (%) | 51 (39.5) | 33 (38.8) | 18 (40.9) | 30 (34.9) | 21 (48.8) |
| Lenvatinib‐use, months | 6.8 ± 6.0 | 6.6 ± 5.6 | 7.4 ± 6.7 | 7.6 ± 6.1 | 4.3 ± 2.7 |
Abbreviations: HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; n, number; UV, uncontrolled viremia; WV, well‐controlled viremia.
Of these 110 patients, ORR was 20% and the DCR was 68.2%, respectively. The ORR of the HBV‐HCC group was 18.4% compared to 23.5% of the HCV‐HCC group whereas the DCR of the HBV‐HCC group was 64.5% compared to 76.5% of the HCV‐HCC group. Patients in the well‐controlled viremia group exhibited a higher percentage of ORR (21.4% vs. 17.1%) and DCR (76% vs. 51.4%) than those in the uncontrolled group.
The median durations of lenvatinib durability were 6.6 months in the HBV group, 7.4 months in the HCV group, 7.6 months in the well‐controlled viremia group, and 4.3 months in the uncontrolled viremia group, respectively.
3.3. Treatment safety
The comparison of treatment‐related adverse events (TRAE) was based on those patients who had complete medical records. There were 87 patients (70.7%) with recorded TRAE during lenvatinib treatment, and the proportions of total TRAE in the HBV‐HCC group were 67.5% compared to 76.7% in the HCV‐HCC group (Table 3), although no statistically significant difference (p‐value = 0.283) was found in total TRAE rates between the two groups. The most four common TRAEs in this study were hand‐foot‐skin reactions (HFSR; 24.4%), diarrhea (15.4%), hypertension (14.6%), and fatigue (13.1%). Twelve patients had TRAEs severer than Grade 3, including six patients with HFSR, four with fatigue, one with hypertension, and one with hepatic encephalopathy. The overall rate of TRAEs in the well‐controlled viremia group mirrored that in the uncontrolled group (69% vs. 74.4%). Similarly, their rates of severe TRAEs were also comparable (9.5% vs. 10.3%). Patients in the uncontrolled group had a higher percentage of jaundice than patients in the well‐controlled group (7.7% vs. 2.4%), but the comparison did not reach the statistically significance.
TABLE 3.
Treatment‐related adverse events (TRAE) in patients by virus etiology and viral control
| Total (n = 123) a | HBV (n = 80) a | HCV (n = 43) a | WV (n = 84) a | UV (n = 39) a | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Variables | Any, n (%) | Grade ≥3, n (%) | Any, n (%) | Grade ≥3, n (%) | Any, n (%) | Grade ≥3, n (%) | Any, n (%) | Grade ≥3, n (%) | Any, n (%) | Grade ≥3, n (%) |
| Total patients with TRAE, n (%) | 87 (70.7) | 12 (9.8) | 54 (67.5) | 7 (8.8) | 33 (76.7) | 5 (11.5) | 58 (69) | 8 (9.5) | 29 (74.4) | 4 (10.3) |
| Hand foot skin reaction, n (%) | 30 (24.4) | 6 (4.9) | 20 (25) | 4 (5) | 10 (23) | 2 (4.6) | 23 (27.4) | 4 (4.8) | 7 (17.9) | 2 (5.1) |
| Diarrhea, n (%) | 19 (15.4) | 0 | 12 (15.4) | 0 | 7 (16.1) | 0 | 13 (15.5) | 0 | 6 (15.4) | 0 |
| Hypertension, n (%) | 18 (14.6) | 1 (0.8) | 9 (11.4) | 0 | 9 (21.7) | 1 (2.3) | 12 (14.3) | 1 (1.2) | 6 (15.4) | 0 |
| Fatigue, n (%) | 16 (13.1) | 4 (3.3) | 11 (13.8) | 3 (3.8) | 5 (11.5) | 1 (2.3) | 13 (15.5) | 2 (2.4) | 3 (7.7) | 2 (5.1) |
| Poor appetite, n (%) | 8 (6.6) | 0 | 3 (3.8) | 0 | 5 (11.5) | 0 | 6 (7.1) | 0 | 2 (5.1) | 0 |
| Elevated T‐bil, n (%) | 5 (4.2) | 0 | 4 (5) | 0 | 1 (2.3) | 0 | 2 (2.4) | 0 | 3 (7.7) | 0 |
| Proteinuria, n (%) | 4 (3.3) | 0 | 3 (3.8) | 0 | 1 (2.3) | 0 | 3 (3.6) | 0 | 1 (2.5) | 0 |
| Dermatitis, n (%) | 4 (3.3) | 0 | 4 (5) | 0 | 0 | 0 | 2 (2.4) | 0 | 2 (5.1) | 0 |
| Hypothyroidism, n (%) | 1 (0.8) | 0 | 1 (1.3) | 0 | 0 | 0 | 1 (1.2) | 0 | 0 | 0 |
| Hepatic encephalopathy, n (%) | 1 (0.8) | 1 (0.8) | 0 | 0 | 1 (2.3) | 1 (2.3) | 1 (1.2) | 1 (1.2) | 0 | 0 |
Abbreviations: HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; n, number; UV, uncontrolled viremia; WV, well‐controlled viremia.
Comparison of treatment‐related adverse events was based on those patients who had medical records. The comparison of any TRAE between two groups was 0.283.
3.4. PFS and OS of patients with lenvatinib by virus etiology
Under lenvatinib treatment, HCV‐HCC patients seemed to have better PFS and OS rate than HBV‐HCC patients, but the comparison between these two groups was not significant. The PFS measures in HBV‐HCC and HCV‐HCC groups were 5.2 and 9.8 months respectively (p = 0.084; Figure 2A), with OS being 20.7 months in the HBV‐HCC group and 30.2 months in the HCV‐HCC group (p = 0.847; Figure 2B).
FIGURE 2.
(A) Progression‐free survival (PFS) of patients with lenvatinib by virus etiology. (B) Overall survival (OS) of patients with Lenvatinib by virus etiology.
3.5. PFS and OS of patients with lenvatinib by virus control
Patients with well‐controlled viremia had better prognosis than those with uncontrolled viremia under lenvatinib treatment, with PFS being significantly longer in the well‐controlled viremia group compared to the uncontrolled viremia group (8.8 vs. 3.1 months, p < 0.001; Figure 3A), as was the OS (30.2 vs. 12.8 months, p = 0.041; Figure 3B).
FIGURE 3.
(A) Progression‐free survival (PFS) of patients with lenvatinib by virus suppression. (B) Overall survival (OS) of patients with Lenvatinib by virus suppression.
3.6. PFS and OS of HBV patients with lenvatinib by virus control
As well‐controlled viremia showed better survival rates, we posited whether the results were the same in different subgroups, divided by different virus etiology. In the HBV‐HCC group, well‐controlled HBV viremia had better PFS than those with uncontrolled HBV viremia (6.9 vs. 3.1 months, p < 0.001; Figure 4A). Likewise, well‐controlled HBV‐HCC patients also had better OS than uncontrolled HBV‐HCC patients (unreached vs. 12.1 months, p = 0.005; Figure 4B). In the HCV‐HCC group, due to the higher proportion of well‐controlled viremia (38 patients, 88.4%), the case number in the subgroup of uncontrolled HCV viremia was relatively small (six patients) for further analysis.
FIGURE 4.
(A) Progression‐free survival (PFS) of hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) patients with lenvatinib by virus suppression. (B) Overall survival (OS) of HBV‐related HCC patients with Lenvatinib by virus suppression.
3.7. Factors associated with PFS
By univariate analysis, sex, ALBI grade, and well‐controlled viremia were associated factors with PFS (Table 4). By multivariate analysis, well‐controlled viremia (hazard ratio [HR]: 0.41, 95% confidence interval [CI]: 0.25–0.68, p = 0.001) was still associated with PFS for patients receiving lenvatinib after adjusting for ALBI grade and concurrent treatment. Neither by univariate nor multivariate analysis did different virus etiologies (HBV or HCV) contribute to the PFS.
TABLE 4.
Factors associated with PFS.
| Univariate analysis | Multivariate analysis | ||||||
|---|---|---|---|---|---|---|---|
| Variable | Comparison | HR | 95% CI | p‐value | HR | 95% CI | p‐value |
| Age | Increase per year | 0.98 | 0.96–1.00 | 0.058 | |||
| Sex | Female versus male | 0.57 | 0.33–0.99 | 0.047 | |||
| ALBI grade | II versus I | 1.95 | 1.22–3.14 | 0.006 | 2.01 | 1.22–3.31 | 0.006 |
| BCLC stage | C versus B | 1.16 | 0.68–2.01 | 0.586 | |||
| Metastasis | Yes versus no | 0.79 | 0.50–1.24 | 0.308 | |||
| MVI | Yes versus no | 1.41 | 0.90–2.21 | 0.132 | |||
| AFP ≥200 ng/mL | Yes versus no | 1.42 | 0.89–2.27 | 0.142 | |||
| Concurrent treatment | Yes versus no | 0.72 | 0.46–1.12 | 0.146 | 0.62 | 0.39–0.99 | 0.044 |
| Etiology | HCV versus HBV | 0.45 | 0.39–1.07 | 0.087 | |||
| Well‐controlled viremia | Yes versus no | 0.39 | 0.24–0.65 | <0.001 | 0.41 | 0.25–0.68 | 0.001 |
Abbreviations: AFP, alpha‐fetoprotein; ALBI grade, albumin‐bilirubin grade; BCLC stage, Barcelona clinical liver cancer stage; CI, confidence interval; HBV, hepatitis B virus; HCV, hepatitis C virus; HR, hazard ratio; MVI, macrovascular invasion; PFS, progression‐free survival.
3.8. Factors associated with OS
Well‐controlled viremia, ALBI grade, serum AFP level, and whether receiving post‐Lenvatinib treatment were all associated with mortality for patients with lenvatinib treatment by univariate analysis (Table 5). By multivariate analysis, ALBI grade, serum AFP level, or whether receiving post‐lenvatinib treatment were still associated factors with OS.
TABLE 5.
Factors associated with OS.
| Univariate analysis | Multivariate analysis | ||||||
|---|---|---|---|---|---|---|---|
| Variable | Comparison | HR | 95% CI | p‐value | HR | 95% CI | p‐value |
| Age | Increase per year | 0.99 | 0.97–1.02 | 0.525 | |||
| Sex | Female versus male | 0.97 | 0.52–1.79 | 0.911 | |||
| ALBI grade | II versus I | 2.47 | 1.41–4.33 | 0.002 | 1.83 | 1.03–3.27 | 0.013 |
| BCLC stage | C versus B | 0.95 | 0.49–1.81 | 0.864 | |||
| Metastasis | Yes versus no | 1.09 | 0.63–1.90 | 0.756 | |||
| MVI | Yes versus no | 1.41 | 0.90–2.21 | 0.132 | |||
| AFP ≥200 ng/mL | Yes versus no | 2.50 | 1.44–4.35 | 0.001 | 2.04 | 1.16–3.59 | 0.013 |
| Concurrent treatment | Yes versus no | 0.58 | 0.32–1.04 | 0.069 | |||
| Post‐treatment | Yes versus no | 0.36 | 0.20–0.56 | 0.001 | 0.39 | 0.21–0.70 | 0.002 |
| Etiology | HCV versus HBV | 0.95 | 0.53–1.68 | 0.847 | |||
| Well‐controlled viremia | Yes versus no | 0.55 | 0.31–0.98 | 0.045 | |||
Abbreviations: AFP, alpha‐fetoprotein; ALBI grade, albumin‐bilirubin grade; BCLC stage, Barcelona clinical liver cancer stage; CI, confidence interval; HBV, hepatitis B virus; HCV, hepatitis C virus; HR, hazard ratio; MVI, macro‐vascular invasion; OS, overall survival.
4. DISCUSSION
The combination of atezolizumab plus bevacizumab has been currently recommended as first‐line treatment for advanced HCC due to more efficacious treatment response. 5 According to current HCC treatment guidelines, either sorafenib or lenvatinib is also recommended as first‐line treatment options if atezolizumab plus bevacizumab is not feasible, 8 but the high price of these combined immunotherapies limits their application in real life. In Taiwan, the National Health Insurance (NHI) scheme does not pay for immunotherapeutic medical expenses, although tyrosine kinase inhibitors including sorafenib or lenvatinib are reimbursed by the above program, so they are the most frequently used first‐line agents for patients with advanced HCC in Taiwan.
In the Phase III REFLECT trial, enrolled patients with unresectable HCC in BCLC Stage B or C and preserved liver function with Child–Pugh Class A, lenvatinib showed non‐inferior efficacy to sorafenib in overall survival. 7 A Korean study reported that lenvatinib treatment (vs. sorafenib; HR = 0.461, 95% CI 0.264–0.804; p = 0.006) independently predicted a higher probability of HCC progression for patients with unresectable HCC. 21 Our previous study also indicated that lenvatinib had better PFS (5.2 vs. 3.3 months, p = 0.019) but similar OR (13.3 vs. 11.8 months, p = 0.714) in advanced stage HCC patients compared to sorafenib by propensity score‐matching analysis. 22 Another study in Taiwan, which compared the use of lenvatinib and sorafenib in patients with advanced HCC, showed that ORR (36.4% vs. 11.4%, p = 0.023) and DCR (81.9% vs. 56.9%, p = 0.039) were both higher in the lenvatinib group compared with the sorafenib group. 23 Lenvatinib seems to reduce more risk of HCC progression compared to sorafenib in clinical practice.
Previous studies have discussed both virus etiology and suppression influence in patients with sorafenib treatment 16 , 17 ; however, studies of the virus influence in patients with lenvatinib treatment are less plentiful. In the patients treated with sorafenib, antiviral therapy use was one of the independent prognostic factors for overall survival of HBV‐HCC patients. 24 Lee et al. enrolled 559 patients with tyrosine kinase inhibitor (518 with sorafenib use and 41 with lenvatinib use) as first‐line treatment with results indicating that antiviral therapy might lead to better OS in patients with advanced HBV‐HCC. 24 Casadei Gardini et al. reported that there was better OS in HBV‐HCC patients with lenvatinib treatment than with sorafenib treatment (HR 0.82 95% CI: 0.60–1.15), but there was no difference between lenvatinib and sorafenib efficacy (HR 0.91 95% CI 0.41–2.01) in HCV‐HCC patients. 25
According to an analysis of two Phase III studies, HCV was predictive of a greater survival benefit with sorafenib. 10 , 11 To our knowledge, there is still a lack of studies discussing the efficacies of HBV or HCV viremia in patients using lenvatinib treatment. The current study is the first to evaluate HBV and HCV groups with lenvatinib treatment, where the HCV‐HCC group appeared to show better ORR and DCR (ORR: HCV vs. HBV = 23.5% vs. 18.4%, p = 0.72; DCR: HCV vs. HBV = 76.5% vs. 64.5%, p = 0.64) as well as longer PFS and OS than the HBV‐HCC group (PFS: HCV vs. HBV = 9.8 vs. 5.2 months, p = 0.084; OS: HCV vs. HBV = 30.2 vs. 20.7 months, p = 0.847), but the differences were not statistically significant. Tracing back to the characteristic of the patients, there was a higher rate of well‐controlled viremia in the HCV‐HCC group than in the HBV‐HCC group (88.4% vs. 57.1%). We speculated that the trend of better survival in the HCV‐HCC group could be related to the higher well‐controlled viremia rate in this group. Factors associated with survival were analyzed in both univariate and multivariate analysis in the study.
In terms of the influence of viremia control, patients within the uncontrolled viremia group presented with a notably higher frequency of MVI instances and larger tumor sizes compared to those within the well‐controlled viremia group. In addition, this uncontrolled viremia group displayed more pronounced liver inflammation status and elevated levels of AFP in contrast to the well‐controlled viremia group. Patients with well‐controlled viremia exhibited a higher percentage of concurrent treatment and post‐treatment compared to those with non‐controlled viremia; however, the difference between the two groups was not statistically significant (44.2% vs. 37.2%, p = 0.449 for concurrent treatment; 54.7% vs. 39.5%, p = 0.127 for post‐treatment). Conducting a larger sample‐sized study could lead to a more significant comparison of concurrent treatment and post‐treatment outcomes between patients with well‐controlled viremia and those without.
For neither PFS nor OS was the virus etiology accredited as a predictor. As for treatment safety, comparison of TRAE rates between HBV‐HCC and HCV‐HCC groups was also insignificant. In conclusion, the virus etiology did not contribute to significant impact on either prognosis or TRAE rates in HCC patients receiving lenvatinib.
As in our previous sorafenib study, 17 patients with well‐controlled viremia also had longer survival than the uncontrolled group in patients with lenvatinib treatment. These findings were significant in both PFS (well controlled vs. uncontrolled = 8.8 vs. 3.1 months, p < 0.001) and OS (well controlled vs. uncontrolled = 30.2 vs. 12.8 months, p = 0.041) analyses. Well‐controlled viremia might lead to a less compromised immune system. Chronic viral infections like HBV and HCV can suppress the immune response, creating an environment where cancer cells can thrive. 26 By controlling the viral load, the immune system might regain some of its effectiveness in recognizing and targeting cancer cells, thus slowing down tumor progression. In addition, lenvatinib is a targeted therapy that inhibits angiogenesis and tumor growth by targeting VEGF and FGF receptors. 7 Well‐controlled viremia might enhance the drug's effectiveness by providing a less conducive environment for tumor growth, allowing lenvatinib to exert its anti‐tumor effects more effectively.
In the multivariate analysis examining factors associated with PFS, well‐controlled viremia emerged as an independent predictor. However, when examining OS, the univariate analysis indicated a superior outcome for the well‐controlled viremia group, while the significance diminished in the multivariate analysis. Instead, factors such as ALBI grade, serum AFP level and whether patients had received post‐lenvatinib treatment all contributed to better OS; consequently, the effect of well‐controlled viremia might have been masked by the influence of these other factors during the multivariate analysis.
It is important to acknowledge the potential confounding effects of these additional variables when interpreting the results. The complexity of prognostic analyses necessitates careful consideration of multiple factors that could influence patient outcomes. Despite the diminished significance in the multivariate OS analysis, the initial findings of improved PFS and univariate OS analysis highlight the potential importance of well‐controlled viremia in patients receiving lenvatinib treatment for HCC. Further research with larger sample sizes and exploration of additional potential confounders could help validate and elucidate these observations.
The current study further focused on HBV‐HCC patients and indicated that well‐controlled HBV viremia in these patients also had significantly better PFS (6.9 vs. 3.1 months, p < 0.001) and OS (unreached vs 12.1 months, p = 0.005) than those with uncontrolled HBV viremia. Our finding was consistent with the results of previous studies, suggesting that concurrent anti‐HBV treatment with sorafenib in advanced HCC leads to a better outcome. 12 , 13 Likewise, well‐controlled HBV viremia by antiviral therapies could really ameliorate the prognosis for advanced HBV‐HCC patients receiving lenvatinib.
Regarding HCV‐HCC patients, due to excellent elimination rates of new generation DAAs, patients with uncontrolled viremia are becoming reduced in number compared with HCV‐cured patients. Especially, as the application of DAAs is also reimbursed by the NHI program in Taiwan, the real impact of viremia influence on HCV‐HCC patients is becoming more problematic for further analysis owing to imbalanced sample size between treated and untreated patients.
There are some limitations in the current study. First, this is a single center and retrospective study, so more validating cohorts are necessary to further confirm the findings of our study. Second, confounding bias might exist due to the incompatible baseline characteristics in different groups such as sex, age, and the proportions of well‐controlled viremia; furthermore, inconsistency caused by different pathogenetic and clinicopathological features of HBV and HCV infection might induce these varieties. Third, the case number of the current study is relatively small, so further large sample‐sized studies are required to eliminate possible select bias.
5. CONCLUSION
In real‐life practice, HBV or HCV infection was not associated with the progression of HCC patients receiving first‐line lenvatinib, but well‐controlled viremia could indeed reduce the risk of tumor progression. Accordingly, when clinicians attempt to administer lenvatinib in HBV‐HCC or HCV‐HCC patients, concurrent use of antivirals for viremia control is necessary for those patients with detectable viremia.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
ACKNOWLEDGMENTS
The authors thank Nien‐Tzu Hsu and the Biostatistics Center of Kaohsiung Chang Gung Memorial Hospital for assistance in statistical analysis.
Hsiao Y‐W, Sou F‐M, Wang J‐H, Chen Y‐H, Tsai M‐C, Hu T‐H, et al. Well‐controlled viremia reduces the progression of hepatocellular carcinoma in chronic viral hepatitis patients treated with lenvatinib. Kaohsiung J Med Sci. 2023;39(12):1233–1242. 10.1002/kjm2.12757
REFERENCES
- 1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. [DOI] [PubMed] [Google Scholar]
- 2. Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019;380(15):1450–1462. [DOI] [PubMed] [Google Scholar]
- 3. Kudo M, Kawamura Y, Hasegawa K, Tateishi R, Kariyama K, Shiina S, et al. Management of hepatocellular carcinoma in Japan: JSH consensus statements and recommendations 2021 update. Liver Cancer. 2021;10(3):181–223. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Shiina S, Gani RA, Yokosuka O, Maruyama H, Nagamatsu H, Payawal DA, et al. APASL practical recommendations for the management of hepatocellular carcinoma in the era of COVID‐19. Hepatol Int. 2020;14(6):920–929. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894–1905. [DOI] [PubMed] [Google Scholar]
- 6. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–390. [DOI] [PubMed] [Google Scholar]
- 7. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first‐line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non‐inferiority trial. Lancet. 2018;391(10126):1163–1173. [DOI] [PubMed] [Google Scholar]
- 8. Reig M, Forner A, Rimola J, Ferrer‐Fàbrega J, Burrel M, Garcia‐Criado Á, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol. 2022;76(3):681–693. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. McGlynn KA, Petrick JL, London WT. Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis. 2015;19(2):223–238. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Jackson R, Psarelli EE, Berhane S, Khan H, Johnson P. Impact of viral status on survival in patients receiving sorafenib for advanced hepatocellular cancer: a meta‐analysis of randomized phase III trials. J Clin Oncol. 2017;35(6):622–628. [DOI] [PubMed] [Google Scholar]
- 11. Bruix J, Cheng AL, Meinhardt G, Nakajima K, De Sanctis Y, Llovet J. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies. J Hepatol. 2017;67(5):999–1008. [DOI] [PubMed] [Google Scholar]
- 12. Lim S, Han J, Kim GM, Han KH, Choi HJ. Hepatitis B viral load predicts survival in hepatocellular carcinoma patients treated with sorafenib. J Gastroenterol Hepatol. 2015;30(6):1024–1031. [DOI] [PubMed] [Google Scholar]
- 13. Xu L, Gao H, Huang J, Wang H, Zhou Z, Zhang Y, et al. Antiviral therapy in the improvement of survival of patients with hepatitis B virus‐related hepatocellular carcinoma treated with sorafenib. J Gastroenterol Hepatol. 2015;30(6):1032–1039. [DOI] [PubMed] [Google Scholar]
- 14. Kuo YH, Wang JH, Chang KC, Hung CH, Lu SN, Hu TH, et al. The influence of direct‐acting antivirals in hepatitis C virus related hepatocellular carcinoma after curative treatment. Invest New Drugs. 2020;38(1):202–210. [DOI] [PubMed] [Google Scholar]
- 15. Seko Y, Moriguchi M, Takahashi A, Yamaguchi K, Umemura A, Okuda K, et al. Hepatitis C virus eradication prolongs overall survival in hepatocellular carcinoma patients receiving molecular‐targeted agents. J Gastroenterol. 2022;57(2):90–98. [DOI] [PubMed] [Google Scholar]
- 16. Kuwano A, Yada M, Nagasawa S, Tanaka K, Morita Y, Masumoto A, et al. Hepatitis C virus eradication ameliorates the prognosis of advanced hepatocellular carcinoma treated with sorafenib. J Viral Hepat. 2022;29(7):543–550. [DOI] [PubMed] [Google Scholar]
- 17. Kuo YH, Huang TH, Wang JH, Chen YY, Tsai MC, Chen YH, et al. Well‐controlled viremia predicts the outcome of hepatocellular carcinoma in chronic viral hepatitis patients treated with sorafenib. Cancers. 2022;14(16):3971. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–247. [DOI] [PubMed] [Google Scholar]
- 19. Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian‐Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016;10(1):1–98. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Omata M, Kanda T, Wei L, Yu ML, Chuang WL, Ibrahim A, et al. APASL consensus statements and recommendation on treatment of hepatitis C. Hepatol Int. 2016;10(5):702–726. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Kim S, Kim KH, Kim BK, Park JY, Ahn SH, Kim DY, et al. Lenvatinib is independently associated with the reduced risk of progressive disease when compared with sorafenib in patients with advanced hepatocellular carcinoma. J Gastroenterol Hepatol. 2021;36(5):1317–1325. [DOI] [PubMed] [Google Scholar]
- 22. Kuo YH, Lu SN, Chen YY, Kee WM, Yen YH, Hung CH, et al. Real‐world lenvatinib versus sorafenib in patients with advanced hepatocellular carcinoma: a propensity score matching analysis. Front Oncol. 2021;11:737767. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Lee SW, Yang SS, Lien HC, Peng YC, Ko CW, Lee TY. Efficacy of lenvatinib and sorafenib in the real‐world first‐line treatment of advanced‐stage hepatocellular carcinoma in a Taiwanese population. J Clin Med. 2022;11(5):1444. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Lee IC, Lee PC, Chao Y, Chi CT, Wu CJ, Hung YP, et al. Application and impact of antiviral therapy for patients with HBV‐related hepatocellular carcinoma receiving sorafenib and lenvatinib treatment. Viruses. 2022;14(11):2355. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Casadei Gardini A, Puzzoni M, Montagnani F, Marisi G, Tamburini E, Cucchetti A, et al. Profile of lenvatinib in the treatment of hepatocellular carcinoma: design, development, potential place in therapy and network meta‐analysis of hepatitis B and hepatitis C in all Phase III trials. Onco Targets Ther. 2019;12:2981–2988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Alqahtani SA, Colombo M. Treatment for viral hepatitis as secondary prevention for hepatocellular carcinoma. Cell. 2021;10(11):3091. [DOI] [PMC free article] [PubMed] [Google Scholar]