Abstract
Background/Aim: We aimed to compare the outcomes between sorafenib and lenvatinib as first-line therapy for advanced hepatocellular carcinoma (HCC) with major portal vein tumor thrombosis (Vp3/4). Patients and Methods: This retrospective study enrolled 41 HCC patients with Vp3/4 and Child-Pugh A. Results: The outcomes in the lenvatinib group (n=13) were significantly better than those in the sorafenib group (n=28) [best objective response rate according to the modified Response Evaluation Criteria in Solid Tumors: 53.8% vs. 14.3%; p=0.0193, best disease control rate: 92.3% vs. 35.7%; p=0.0008, median overall survival (OS): not reached vs. 187 days; p=0.0040, respectively]. Lenvatinib treatment was the only significant predictor of better OS and time to tumor progression. No patient needed to discontinue lenvatinib treatment due to drug-related adverse events. Conclusion: Compared with sorafenib, lenvatinib treatment for advanced HCC with Vp3/4 may lead to more favorable outcomes.
Major portal vein tumor thrombosis (PVTT) is a well-known strong poor prognostic factor in patients with hepatocellular carcinoma (HCC) (1, 2). For patients with major PVTT, such as Vp3 (i.e., thrombosis in the first-order branches) and Vp4 (i.e., thrombosis in the main trunk of the portal vein and/or a portal vein branch contralateral to the primarily involved lobe), no established effective treatment options have been established (1, 3-5). Based on the Sorafenib HCC Assessment Randomized Protocol (SHARP) (6), sorafenib has been widely used as the only available first-line standard systemic therapy for advanced unresectable HCC [Barcelona Clinic Liver Cancer (BCLC) stage C] since 2007. In the SHARP study, the subgroup analyses showed a survival benefit for sorafenib, compared with placebo, for macroscopic vascular invasions (7). However, in the clinical setting, some investigators have reported that the efficacy of sorafenib for patients with PVTT was insufficient (8-13).
Based on the REFLECT trial (14), lenvatinib, along with sorafenib, has been clinically available since 2018 as an effective first-line therapy for advanced unresectable HCC. In the REFLECT trial, the objective response rate (ORR) of lenvatinib, according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST), was significantly higher than that of sorafenib. However, patients with Vp4 were excluded in the REFLECT trial. To the best of our knowledge, there have been no reports on the outcomes of lenvatinib in patients with Vp3/4. Accordingly, we aimed to investigate the clinical efficacy and safety of lenvatinib as first-line therapy for patients with advanced HCC and major PVTT (Vp3/4), in comparison with those of sorafenib.
Patients and Methods
Patients. At our hospital, 258 consecutive patients were initiated on sorafenib between June 2011 and March 2018 (n=206) or lenvatinib between April 2018 and September 2019 (n=52) as first-line treatment for advanced unresectable HCC; of these, 54 patients had major PVTT (Vp3/4). We excluded patients who had Child-Pugh B (n=13). The remaining patients with Vp3/4 and Child-Pugh A (n=41) were enrolled in this study and their outcomes underwent retrospective evaluation. There were 28 patients who were initiated on sorafenib treatment (sorafenib group) and 13 patients who were initiated on lenvatinib treatment (lenvatinib group). In addition, because the baseline alpha-fetoprotein (AFP) levels differed significantly between the 2 groups, propensity score matching was also performed to adjust for potential bias. Twenty-six propensity-matched patients (13 in the sorafenib group and 13 in the lenvatinib group) were chosen and their outcomes underwent retrospective evaluation. This study was approved by the ethics committee of Nagoya University Graduate School of Medicine (No. 2019-0031) and was performed in compliance with the 1975 Declaration of Helsinki. Informed consent was obtained in the form of an opt-out on the website.
Sorafenib and lenvatinib treatment. The starting dose of sorafenib (Nexavar, Bayer Yakuhin, Ltd., Osaka, Japan) was 800 mg/day administered orally. However, considering the possibility of having to discontinue sorafenib at an early stage because of adverse events (AEs), the initial dose was set at 400 mg/day for patients who were ≥80 years, those who had a body weight of ≤50 kg, those with poor renal function, and those who had a history of treatment for varices or ascites (15). Lenvatinib (Lenvima; Eisai Co., Ltd., Tokyo, Japan) was administered orally at a starting dose of 12 mg/day for patients with ≥60 kg body weight or 8 mg/day for patients with <60 kg body weight (14, 16). In cases that developed drug-related AEs, the dose was reduced, or the drug was temporarily interrupted until the symptoms resolved to grade 1 or 2, according to the guidelines provided by the manufacturer. Sorafenib or lenvatinib was continued until the occurrence of potentially fatal AEs or until clinical tumor progression.
Baseline characteristics of the patients with HCC.
Evaluation of antitumor responses. Antitumor response was evaluated according to the mRECIST. Four-phase (i.e., unenhanced, late arterial, portal venous, and equilibrium) contrast-enhanced computed tomography was performed at baseline and 6 weeks later, with a predetermined schedule, and every 4 to 10 weeks thereafter (15, 16). Sorafenib or lenvatinib monotherapy was evaluated based on the best antitumor response.
Best antitumor response according to the mRECIST.
Assessment of adverse events and changes in liver function. AEs were assessed according to the Common Terminology Criteria for Adverse Events version 4.0. Hand-foot skin reaction, rashes, fever, appetite loss, hypertension, diarrhea, and hepatic coma were routinely assessed, but proteinuria and hypothyroidism were assessed only in the lenvatinib group, because in the sorafenib group were not regularly examined. As a measure of changes in liver function, albumin-bilirubin (ALBI) score (17) was calculated at baseline and at 1, 2, 4, and 6 weeks.
Statistical analysis. Statistical analyses were performed using Easy R version 1.29 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) (18). Continuous variables were analyzed using the Mann–Whitney U-test, and categorical variables were analyzed using the Fisher's exact probability test. Overall survival (OS) was measured from the treatment initiation date until the date of death or last visit. Time to tumor progression (TTP) after treatment was measured from the treatment initiation date until the date of confirmation of the first radiologic progressive disease (PD). Treatment duration was measured from the treatment initiation date until the date of discontinuation of the drug. TTP, OS, and treatment duration were calculated using the Kaplan–Meier method, and differences in survival were evaluated by the log-rank test. The Cox proportional hazard model was used to identify the prognostic factors. Only factors with p<0.05 in the univariate analysis were subsequently assessed in the multivariate analysis. A p-value of <0.05 was considered statistically significant.
Results
Baseline patient characteristics. Table I shows the baseline characteristics of all 41 patients and those in the sorafenib (n=28) and lenvatinib (n=13) groups. There were 30 patients with Vp3 and 11 patients with Vp4. In this study, the starting dose of sorafenib was 800 mg/day in 21 patients; in 7 patients, the starting dose was 400 mg/day because of age ≥80 years (n=1), body weight of ≤50 kg (n=2), and history of treatment for varices or ascites (n=4). The starting dose of lenvatinib was 12 mg/day in 8 patients and 8 mg/day in 5 patients. There was a statistically significant difference in AFP levels between the two groups (AFP level <400/≥400 ng/ml, 6/22 in the sorafenib group vs. 10/3 in the lenvatinib group; p=0.0014). After propensity score matching, there were no significant differences among the baseline characteristics of the patients in the two groups.
Comparison of the cumulative OS and TTP between the sorafenib and lenvatinib groups. Cumulative OS (A) and TTP (B) in the sorafenib and lenvatinib groups before matching (n=41). Cumulative OS (C) and TTP (D) in the sorafenib and lenvatinib groups after matching (n=26). OS: Overall survival; TTP: time to tumor progression; MST: median survival time.
Antitumor responses. In all 41 patients, the best antitumor responses were partial response (PR) in 4, stable disease (SD) in 6, and PD in 18 in the sorafenib group and PR in 7, SD in 5, and PD in 1 in the lenvatinib group (Table II). Compared with the sorafenib group, the lenvatinib group had significantly higher best ORR (53.8% vs. 14.3%, p=0.0193) and best disease control rate (DCR) (92.3% vs. 35.7%, p=0.0008). After propensity score matching (n=26), the best antitumor responses were PR in 1, SD in 3, and PD in 9 in the sorafenib group and PR in 7, SD in 5, and PD in 1 in the lenvatinib group. Compared with the sorafenib group, the lenvatinib group had significantly higher best ORR (53.8% vs. 7.7%, p=0.0302) and best DCR (92.3% vs. 30.8%, p=0.0036).
OS and TTP. In all 41 patients, the median OS was significantly longer for the lenvatinib group than for the sorafenib group (not reached vs. 187 days, p=0.0040) (Figure 1A), and the median TTP was significantly longer for the lenvatinib group than for the sorafenib group (269 days vs. 53 days, p<0.0001) (Figure 1B). In 26 patients, after propensity score matching, the same trends for lenvatinib and sorafenib were seen with regard to median OS (not reached vs. 226 days, p=0.0050) (Figure 1C) and median TTP (269 days vs. 48 days, p=0.0001) (Figure 1D).
OS stratified by the best antitumor responses based on the mRECIST. Cumulative OS in the PR, SD, and PD group (A). Cumulative OS in the PR+SD and PD group (B). OS: Overall survival; mRECIST: modified Response Evaluation Criteria in Solid Tumors; PR: partial response; SD: stable disease; PD: progressive disease.
OS stratified by best antitumor responses. Overall, the cumulative OS stratified by best antitumor responses showed median OS of 511 days in the PR group (n=11), 226 days in the SD group (n=11), and 135 days in the PD group (n=19) (p=0.0001) (Figure 2A). The median OS was significantly longer in the PR group than in the SD+PD group (511 days vs. 151 days, p=0.0023) and was significantly longer in the PR+SD group than in the PD group (384 days vs. 135 days, p<0.0001) (Figure 2B).
Prognostic factors associated with good OS and good TTP. In the univariate analysis of all 41 patients, the baseline prognostic factors that were significantly associated with good OS were Eastern Cooperative Oncology Group performance status (ECOG-PS) score of 0, Child-Pugh score of 5, modified ALBI (mALBI) grade 1 or 2a, and lenvatinib treatment (Table III). On multivariate analysis, lenvatinib treatment remained as the significant independent predictor of good OS (HR=0.193; 95%CI=0.055-0.682; p=0.0106). Univariate analysis of the baseline prognostic factors associated with good TTP in all 41 patients showed age ≥68 years, ECOG-PS score of 0, mALBI grade 1 or 2a, and lenvatinib treatment as the significant variables (Table IV). On multivariate analysis, lenvatinib treatment remained as the significant independent predictor of good TTP (HR=0.162; 95%CI=0.047-0.563; p=0.0042).
Safety and treatment duration. Table V shows the frequency of AEs within 6 weeks after the initiation of treatment in all 41 patients. The most common AEs in the sorafenib group were hand-foot skin reaction (n=16), rashes (n=14), fever (n=14), appetite loss (n=11), and hypertension (n=8). The most common AEs in the lenvatinib group were appetite loss (n=9), hypertension (n=9), hand-foot skin reaction (n=5), and proteinuria (n=4). For AEs of any grade, rashes were more frequent in the sorafenib group than in the lenvatinib group. On the other hand, hypertension was more frequent in the lenvatinib group than in the sorafenib group. Overall, AEs of grade 3 or more had similar frequencies in both groups. However, two patients needed to discontinue sorafenib treatment due to severe AEs (a case of grade 3 rash and a case of grade 3 diarrhea). However, no patient needed to discontinue lenvatinib treatment due to drug-related AEs. The median treatment duration was significantly longer for the lenvatinib group than for the sorafenib group (359 days vs. 75 days, p=0.0031).
Changes in liver function. The changes in ALBI score within 6 weeks in all 41 patients are shown in Figure 3. In the sorafenib group, the ALBI scores [median±standard error (SE)] at baseline and at 1, 2, 4, and 6 weeks were −2.285±0.073, −1.995±0.074, −1.855±0.086, −1.870±0.121, and −1.930±0.111, respectively; compared with the ALBI scores at baseline, those at 1, 2, 4, and 6 weeks were significantly worsened. In the lenvatinib group, the ALBI scores (median±SE) at baseline and at 1, 2, 4, and 6 weeks were −2.340±0.114, −2.190±0.102, −1.850±0.118, −2.180±0.095, and −2.160±0.110, respectively; compared with the ALBI scores at baseline, those at 2 weeks were significantly worsened. The ALBI scores at 4 weeks were significantly worse in the sorafenib group than in the lenvatinib group (p=0.0443).
Univariate and multivariate analyses of the prognostic factors for good OS (n=41).
Univariate and multivariate analyses of the prognostic factors for good TTP (n=41).
Discussion
In the present study, we compared the outcomes between sorafenib and lenvatinib as first-line therapy for patients with advanced HCC and major PVTT (Vp3/4) in the clinical setting. We found that both best ORR and DCR according to the mRECIST were significantly higher in the lenvatinib group than in the sorafenib group. Moreover, both median OS and TTP were significantly longer for the lenvatinib group than for the sorafenib group, and lenvatinib treatment was the only significant and independent predictor of better OS and TTP. To our best knowledge, this was the first study that compared the outcomes of sorafenib and lenvatinib in advanced HCC with Vp3/4 in clinical practice.
Changes in the ALBI scores within 6 weeks in the sorafenib and lenvatinib groups. In the sorafenib group, the ALBI scores (median±SE) at baseline and at 1, 2, 4, and 6 weeks are −2.285±0.073, −1.995±0.074, −1.855±0.086, −1.870±0.121, and −1.930±0.111, respectively. In the lenvatinib group, the ALBI scores (median ± SE) at baseline and at 1, 2, 4, and 6 weeks are −2.340±0.114, −2.190±0.102, −1.850±0.118, −2.180±0.095, −2.160±0.110, respectively. ALBI: Albumin–bilirubin; SE: standard error.
There have been several reports on the antitumor response to sorafenib in patients with Vp3/4 in clinical practice (8-13). These reports showed ORRs of 1.8% to 10.0% and DCRs of 13.3% to 40.0% according to mRECIST. Similarly, our study showed that the best ORR and DCR were 14.3% and 35.7%, respectively. As for the prognosis, these reports showed median OS of 3.1 to 7.2 months and TTP of 2.0 to 2.7 months. Similarly, our study showed that the median OS and TTP were 187 days and 53 days, respectively. These results suggested that the efficacy of sorafenib for patients with Vp3/4 was modest and unsatisfactory.
However, there have been no reports on the outcomes of lenvatinib for patients with Vp3/4. In the present study, lenvatinib had best ORR and DCR of 53.8% and 92.3%, respectively and median OS and TTP of not reached and 269 days, respectively. Notably, the best ORR, best DCR, OS, and TTP were significantly better in the lenvatinib group than in the sorafenib group. Though there was a statistically significant difference in baseline AFP levels between the 2 groups, AFP level was not a significant factor associated with both OS and TTP. Additionally, we performed propensity-matched analysis to remove the possible biases between the 2 groups and found that the best ORR, best DCR, TTP, and OS remained to be significantly better in the lenvatinib group than in the sorafenib group. Therefore, lenvatinib, compared with sorafenib, may lead to favorable outcomes for patients with Vp3/4.
According to the clinical practice guidelines on the management of HCC (19, 20), only systemic therapy was recommended as the first-line option in patients with PVTT. However, alternative therapeutic approaches, such as hepatic arterial infusion chemotherapy (HAIC), have been performed for patients with PVTT in the clinical setting (3-5). There have been several reports that compared the outcomes between sorafenib and alternative therapeutic approaches, and most of these studies have reported better outcomes with the latter (9-12). Choi et al have compared the outcomes of sorafenib and HAIC prospectively and reported that compared with the sorafenib group (n=29), the HAIC group (n=29) had significantly better ORR (27.6% vs. 3.4%), DCR (79.3% vs. 27.6%), OS (14.9 months vs. 7.2 months), and TTP (4.4 months vs. 2.7 months) (12). They have also reported that the treatment option of HAIC was a significant prognostic factor for better outcomes. In the present study, the outcomes of lenvatinib were favorable in patients with Vp3/4, and lenvatinib treatment was a significant and independent factor for better OS and TTP. In the future, it would be necessary to compare the outcomes of lenvatinib and HAIC.
AEs within 6 weeks (n=41).
In the present study, AEs, except for those generally well known, did not occur in the sorafenib and lenvatinib groups (6, 14, 21). No patient other than two cases in the sorafenib group needed to discontinue sorafenib or lenvatinib treatment due to drug-related AEs. There have been a few reports on the changes in liver function during sorafenib or lenvatinib treatment (22, 23). Hiraoka et al. have reported that decline in hepatic function was common in the early stage (≤4 weeks, especially within 2 weeks) after introducing lenvatinib (23). Similarly, we found that the ALBI scores were the worst at 2 weeks in the sorafenib and lenvatinib groups. After 2 weeks, the ALBI scores in the lenvatinib group improved, compared with those in the sorafenib group. One of the reasons for the better recovery of liver function with lenvatinib than with sorafenib may be the stronger antitumor response, including PVTT regression, with the former. In the present study, the median treatment duration was significantly longer for the lenvatinib group than for the sorafenib group (359 days vs. 75 days, p=0.0031). One of the reasons for the longer treatment duration with lenvatinib than with sorafenib may be the stronger antitumor response and the higher safety.
There were several limitations in the present study. First, this was a retrospective and nonrandomized study. Second, the study was carried out at a single institution, and had a small sample size. Therefore, confirmation of our findings would require additional studies on a larger number of patients in an independent cohort.
In conclusion, for advanced HCC patients with Vp3/4, lenvatinib treatment may lead to more favorable outcomes, compared with those of sorafenib. Our results can help physicians decide the treatment of patients with major PVTT.
Acknowledgements
There was no grant or other financial support for this study.
Footnotes
Authors' Contributions
Conceptualization: Teiji Kuzuya; Methodology: Teiji Kuzuya; Formal analysis and investigation: Teiji Kuzuya and Masatoshi Ishigami; Data curation, Teiji Kuzuya, Masatoshi Ishigami, Takanori Ito, Yoji Ishizu, Takashi Honda and Tetsuya Ishikawa; Writing - original draft preparation: Teiji Kuzuya; Writing - review and Editing: Masatoshi Ishigami; Supervision: Mitsuhiro Fujishiro. All Authors approved the final draft of the manuscript.
Conflicts of Interest
Teiji Kuzuya received lecture fees from Eisai and Bayer. All other Authors declare no competing interests.
- Received February 22, 2020.
- Revision received March 1, 2020.
- Accepted March 4, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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