Abstract
Background/Aim: Lenvatinib is a tyrosine kinase inhibitor (TKI) more effective against hepatocellular carcinoma (HCC) than sorafenib, making lenvatinib a first-line treatment option for patients with unresectable HCC. In patients treated with sorafenib, post-progression survival (PPS) rather than progression-free survival (PFS) is essential for overall survival (OS). However, the importance of PPS for OS in patients treated with lenvatinib is uncertain, and optimal treatment after lenvatinib failure has not yet been established. Patients and Methods: The present study investigated the correlations of PFS and PPS with OS in studies of HCC patients treated with lenvatinib by weighted linear regression analysis. Furthermore, the contribution of treatment regimens after lenvatinib failure to OS were evaluated in daily clinical practice. Results: An analysis of 20 studies with 4,054 patients found that PPS had a stronger correlation with OS (r=0.869, p<0.001) than did PFS (r=0.505, p=0.007). Analysis of 79 patients with unresectable HCC treated with first-line lenvatinib showed that subsequent treatment was the most significant contributor to OS. Second-line sorafenib was administered to 25 patients, with late transition to third-line treatment being highest among patients who received second-line treatment. Conclusion: PPS contributes significantly to OS in HCC treatment with TKIs, with multi-sequential treatment being a key determinant of longer OS.
- Hepatocellular carcinoma
- tyrosine kinase inhibitor
- lenvatinib
- sorafenib
- post-progression survival
- sequential therapy
Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third most frequent cause of cancer-related deaths worldwide (1). HCC is frequently diagnosed at an advanced stage of disease, most patients are ineligible for curative therapies, such as surgical resection (1). Systemic chemotherapies with combined immunotherapy or tyrosine kinase inhibitors (TKIs) are recommended for patients with unresectable HCC (2-4). Among them, combined immunotherapy has become a standard treatment for advanced HCC, with an apparent survival benefit compared with sorafenib, the first TKI approved for unresectable HCC (5). However, immunotherapy has shown reduced anti-tumor effects in patients with non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH)-associated HCC (6), which is regarded as the most frequent etiology of HCC (7). Furthermore immune-related adverse events, usually unexpected and sometimes fatal, are found during treatment with combined immunotherapies (8). Recently, systemic chemotherapies have been considered for patients with early stage disease (2, 9). Duration of treatment is expected to be longer, and therefore the significance of TKIs might be increasing. Among TKIs showing survival benefits, sorafenib and lenvatinib are recommended as first-line treatment for patients with unresectable HCC (10, 11). However, these TKIs, especially sorafenib, do not have strong direct anti-tumor effects per se, with studies showing that longer post-progression survival (PPS) can significantly prolong overall survival (OS) (12).
Lenvatinib is a TKI that has been approved for the treatment of patients with unresectable HCC. Lenvatinib has shown better anti-tumor effects and longer progression-free survival (PFS), while having non-inferior survival benefits, compared with sorafenib (11). The superior anti-tumor effect of lenvatinib has been reported to be comparable to that of initial transcatheter arterial chemo-embolization (TACE) (9). Furthermore, recent real-world data showed that lenvatinib might have superior survival benefits especially for advanced HCC with major portal vein invasion than sorafenib (13, 14). However, second-line treatments after lenvatinib include sorafenib (15, 16), regorafenib (16), ramucirumab (17-19), atezolizumab plus bevacizumab (Atez+Bev) (20), and continued lenvatinib (21), but post progression treatment regimens after lenvatinib failure have not yet been established. In addition, the significance of PPS during lenvatinib treatment remains unclear.
The present study evaluated the significance of PPS in lenvatinib treatment by investigating the correlations of PFS and PPS with OS. In addition, to validate post progression treatment after lenvatinib, treatment outcomes and post progression therapies were retrospectively analyzed in patients who received first-line lenvatinib.
Patients and Methods
Selection of studies assessing the effects of lenvatinib on survival in patients with HCC. The MEDLINE database was searched for PubMed citations up to May 2022 that included the keywords “hepatocellular carcinoma” and “lenvatinib”. Studies providing clinical data on patients with unresectable HCC who received first-line lenvatinib, which reported OS, PFS or time to progression (TTP), were also selected. Duplicate studies and studies reporting treatment in an adjuvant or neo-adjuvant setting were excluded. In present study, combination therapies with lenvatinib and other treatment, such as immunotherapy and locoregional therapy were also excluded to precisely evaluate the value of PPS in lenvatinib itself. This systematic review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines and checklist for the reporting of systematic reviews (22). Median PPS in each cohort was determined by subtracting median PFS/TTP from median OS, as described (12). The weighted linear regressions of PFS/TTP and PPS with OS were subsequently evaluated.
Patients. Data from patients with unresectable HCC who received first-line lenvatinib (Lenvima®; Eisai Co. Ltd. Tokyo, Japan) at Toyama University Hospital or its related facilities (Toyama Red-Cross Hospital, Nanto Municipal Hospital, Saiseikai Toyama Hospital, Shinseikai Toyama Hospital) from June 2018 to December 2021 were evaluated. HCC was diagnosed based on typical histological, pathological, and radiological findings and/or increased expression of tumor markers. Macrovascular invasion (MVI) and extrahepatic metastasis (EHM) were evaluated in all patients by computed tomography (CT) and/or magnetic resonance imaging (MRI) before lenvatinib treatment. The presence of both anti-hepatitis C virus (HCV) antibody and HCV-RNA was defined as positive for HCV infection, and the presence of hepatitis B surface antigen was defined as positive for hepatitis B virus (HBV) infection. Patients without HCV or HBV, including those with alcoholic and nonalcoholic fatty liver diseases and autoimmune liver diseases were defined as having ‘non-viral’ HCC. Liver cirrhosis was diagnosed by hepatologists with over 20 years of experience, based on imaging modalities, such as ultrasound, CT and/or elastography, and the titers of fibrosis markers, such as platelet counts, Fib-4 index, and other fibrosis markers. The study was conducted in accordance with the Declaration of Helsinki, the protocol of this multi-center study was approved by the institutional ethics committee of Toyama University Hospital (R2019131), and all participants provided written informed consent.
Staging and treatment of HCC. HCCs were staged according to the Barcelona Clinic Liver Cancer (BCLC) staging system (23). Hepatic reserve function was evaluated by Child-Pugh classification (24) and modified albumin-bilirubin (mALBI) score, which was shown to be a more accurate indicator of hepatic reserve function and have a better predictive value than Child-Pugh score (25). HCC treatment was determined by discussions among hepatologists, surgeons, and radiologists at each institution according to Japanese practice guidelines for HCC (26). Systemic lenvatinib was considered for patients with unresectable HCC and sufficient hepatic reserve function. In patients with BCLC-B or A considered as unresectable HCC, treatment with transcatheter arterial chemoembolization (TACE) was firstly considered. However, patients with TACE-refractory (27) or TACE-unsuitable (28) were considered for lenvatinib administration.
Lenvatinib treatment. Patients weighing <60 kg were administered 8 mg/day lenvatinib, and patients weighing ≥60 kg were administered 12 mg/day lenvatinib before going to sleep. Anti-tumor response was evaluated by CT or MRI using modified RECIST (mRECIST) criteria every 8 or 12 weeks during lenvatinib treatment (29). A complete response (CR) was defined as the disappearance of any arterial enhancement in the target tumor, a partial response (PR) was defined as a >30% reduction in the sum of the diameters of viable lesions, progressive disease (PD) was defined as a >20% increase in the sum of these diameters, and stable disease (SD) was defined as non-PR and non-PD. The objective response rate (ORR) was calculated as the percentage of patients achieving either CR or PR, and the disease control rate (DCR) was calculated as the percentage of patients achieving CR, PR, and SD. The best tumor response at each examination was documented. Adverse events (AEs) during treatment were evaluated based on the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0. If a patient experienced a CTCAE grade ≥3 treatment-related adverse event, the lenvatinib dosage was reduced or interrupted until the AE improved to grade 1 or 2, with dose reductions determined according to the weekends-off method (i.e., 12 mg/day to 8 mg/day or 8 mg/day to 4 mg/day, −1Lv; 12 mg/day to 8 mg/day or 8 mg/day to 4 mg/day with weekends off method, - 2Lv; or 12 mg/day to 4 mg/day weekends off method or 8 mg/day to 4 mg every two days, −3Lv) (30). Treatment was discontinued when any unacceptable serious AEs or clinically significant tumor progression occurred.
Treatment after lenvatinib failure. Before October 2020, sorafenib was considered second-line treatment after lenvatinib failure; after approval of Atez+Bev in Japan in October 2020, sorafenib continued to be considered as second-line treatment for patients with decreased liver function or general conditions who were deemed unsuitable for Atez+Bev treatment. The initial dose of sorafenib was based on the final dose of lenvatinib. Patients who received final doses of −1Lv, −2Lv and −3Lv lenvatinib were started on sorafenib doses of 400 mg/day, 400 mg every 2 days, and 200 mg every 2 days, respectively. If patients experienced AEs related to sorafenib, the dose of sorafenib was reduced until the AEs improved. Sorafenib was continued until disease progression or intolerant AEs. Third-line treatment after cessation of sorafenib was considered in patients who could tolerate these agents.
Statistical analyses. Categorical variables were compared using the chi-square test or Fisher’s exact test, as appropriate. Continuous variables were analyzed using the Mann-Whitney U-test. Correlations between two variables were evaluated using weighted linear regression analysis. Survival outcomes were analyzed using the Kaplan-Meier method and compared by log-rank tests. Univariate and multivariate analysis of factors associated with survival outcomes were evaluated using the Cox proportional hazards model. Statistical analyses were performed using SPSS version 19.0 (IBM, Armonk, NY, USA), with p-values <0.05 considered statistically significant.
Results
Association between overall survival and post-progression survival in patients treated with lenvatinib. A first search of the PubMed database identified 629 studies. After screening of these studies, 24 cohorts in 21 studies that included 4,200 patients were identified (Figure 1). A phase II trial and a randomized phase III trial were included (11, 31). Ten reports were retrospective studies that included Japanese patients with unresectable HCC (16, 32-40). In addition, four retrospective studies from China (41-44) and three from Korea (45-47) were included, as were a prospective study from Japan (48) and a retrospective multinational study (49) (Table I). In patients treated with lenvatinib, PFS/TTP was moderately correlated with OS (r=0.514, p=0.007, Figure 2A), whereas PPS showed a stronger correlation with OS (r=0.877, p<0.001, Figure 2B), indicating that PPS is strongly associated with OS in patients with unresectable HCC being treated with lenvatinib.
PRISMA flow diagram. OS: Overall survival; PFS: progression-free survival.
Published studies of lenvatinib as first-line treatment for hepatocellular carcinoma (HCC) and reporting progression-free survival/time to progression (PFS/TTP) and overall survival (OS).
Findings of weighted linear regression analyses from published studies of patients treated with lenvatinib. The size of the circle represents the number of patients included in the study. r: Correlation index; p: p-value. (A) Relationship between median progression-free survival and overall survival. (B) Relationship between median post-progression survival and overall survival.
Characteristics of patients treated with lenvatinib. The primary patient cohort included in this study consisted of 79 patients, including 63 (79.7%) men and 16 (20.3%) women, of a median age of 75 years (Table II). HCV had been eradicated before lenvatinib treatment in 17 patients (17/19, 89.5%), and HBV-DNA was suppressed within normal limit by nucleos(t)ide analogues in 7 patients (7/7, 100%). In the present cohort, no patient with co-infection of HBV and HCV was found. Of these patients, 49 (62.0%) had cirrhosis, and 53 (68.8%) had HCCs of non-viral etiology, 30 (38.0%) had BCLC-C tumors, 25 (31.6%) were positive for MVI, and 14 (17.7%) were positive for EHM. This study included 49 (62.0%) with BCLC-B, and 28 (57.1%) of these 49 patients had been treated with TACE (median 2 sessions; range=1-9 sessions) before lenvatinib administration and were considered refractory to TACE. Of the 49 BCLC-B patients, 13 (26.5%) were within up-to 7 criteria, and 36 (73.5%) were not. Most patients (75, 94.9%) were Child-Pugh grade A, but 25 (31.6%) and one (1.3%) were mALBI 2b and 3, respectively (Table II).
Characteristics of patients with hepatocellular carcinoma treated with first-line lenvatinib.
Results of lenvatinib treatment. The median lenvatinib treatment period was 3.3 months (range=0.1-11.8 months), and the median observation period after lenvatinib administration was 9.6 months (range=1.0-39.7 months). During the observation period, 58 (73.4%) patients discontinued lenvatinib treatment, with the most frequent cause being PD in 47 (59.5%) patients. The best ORR according to mRECIST was 40.5% and the best DCR was 79.7%. Median PFS was 7.2 months (95%CI=6.6-8.3 months), and median OS was 13.4 months (95%CI=9.2-17.6 months) (Figure 3A and B). The most frequent CTCAE grade ≥2 AEs during lenvatinib treatment were hypertension (41/79, 51.9%), proteinuria (21/79, 26.6%) and fatigue (18/79, 22.8%). Other AEs observed in 10% of patients included anorexia (12/79, 15.2%), diarrhea (9/79, 11.4%), and liver dysfunction (8/79, 10.1%). AEs requiring treatment cessation included fatigue with anorexia (4/79, 5.1%), proteinuria (3/79, 3.8%), perforation of the gastro-intestinal tract (2/79, 2.5%), and hepatic encephalopathy (2/79, 2.5%).
Survival after lenvatinib treatment. (A) Progression-free survival (PFS) after lenvatinib administration. Median PFS [95% confidence interval (CI)] is shown at the right upper column. (B) Overall survival (OS) after lenvatinib administration.
Treatment after lenvatinib cessation. Multivariate analysis that included variables selected by univariate analyses showed that mALBI (grade 1 or 2a; HR=2.381, p=0.006) and treatment after lenvatinib cessation (HR=5.848, p<0.001) were significantly predictive of overall survival (Table III). Kaplan–Meier analyses showed that median OS was significantly longer in patients who did than did not receive post-lenvatinib treatment [23.3 months (95%CI=17.7-28.9 months) versus 8.5 months (95%CI=3.2-13.9 months)] (Figure 4).
Multivariate analysis of factors predictive of overall survival in hepatocellular patients treated with lenvatinib.
Overall survival (OS) with and without post treatment (Tx) after lenvatinib administration.
Sorafenib as second-line treatment after lenvatinib. After lenvatinib discontinuation, 39 patients received further treatment. Of the other 40 patients who received no further treatment, 21 had decreased liver function, 12 had decreased general conditions, five continued on lenvatinib treatment, and three were lost to follow-up. Of the 39 patients who received additional treatment, 25 received sorafenib; eight received loco-regional therapies, including five who received TACE, two who received ablation therapy and one who underwent hepatic resection; and six received Atez+Bev (Table IV). More patients with BCLC-C did than did not receive sorafenib as second-line treatment. Hepatic function in patients who received second-line sorafenib was relatively well-preserved at 1-month after sorafenib administration. ORR and DCR in the 25 patients who received second-line sorafenib were 12% (3/25) and 52% (13/25), respectively. PFS from sorafenib administration was 5.7 months (95%CI=0.8-10.6 months). Patients who failed second-line sorafenib were more likely to receive further treatment than those who were not treated with sorafenib. Third-line treatments after sorafenib failure included regorafenib in nine patients, Atez+Bev in six patients, and ramucirumab, hepatic resection, and TACE in three patients each.
Characteristics of patients who received second-line treatment after lenvatinib.
Discussion
In the present study, PPS showed a higher correlation with OS than did PFS during lenvatinib treatment. Although lenvatinib had a stronger anti-tumor effect and better PFS than sorafenib, the significance of PPS during lenvatinib treatment was similar to that of sorafenib. Also, in daily clinical practice, treatment after lenvatinib resulted in longer survival, with sorafenib after lenvatinib failure showing clinical benefits in patients with advanced HCC.
The correlation between PPS and OS differs among various types of cancer. In patients receiving chemotherapy, PFS shows a moderate correlation with OS in breast cancer (50), but a strong correlation in pancreatic cancer (51). Thus, both initial treatment and sequential therapies are strongly predictive of OS in breast cancer patients, whereas first-line agents with a strong anti-tumor effect are required for OS in pancreatic cancer patients. These differences are likely regulated by the malignant potential of the cancer itself and by the anti-tumor effect of chemotherapy. The correlation between PFS and OS in HCC takes a middle position between breast and pancreatic cancers (52, 53). Combined immunotherapy, such as Atez+Bev has shown distinct anti-tumor effects and superior PFS in patients with advanced HCC (5). PPS showed a greater correlation with OS also in patients treated with Atez+Bev than PFS (unpublished data). These findings suggest the need to consider PPS and its management in the pharmaceutical treatment of patients with unresectable HCC.
The significance of post-progression treatment after TKIs including lenvatinib has been confirmed by other studies (54, 55). Agents used to treat patients after lenvatinib failure have included sorafenib (15, 16), regorafenib (16), ramucirumab (17-19), Atez+Bev (20), and continued lenvatinib (21). ORRs and DCRs have been reported to be 1.8-15.3% and 20.8-69.2%, respectively, in patients treated with second-line sorafenib (15, 16); 13.6% and 36.3%, respectively, in patients treated with second-line regorafenib (16); 0-3.8% and 28.6-80%, respectively, in patients treated with second-line ramucirumab (17-19); and 7.7% and 79.5%, respectively, in patients treated with second-line Atez+Bev (20). Transition to third-line treatment was highest in patients treated with second-line sorafenib (71-80%) than in patients treated with second-line regorafenib (44%), although third-line treatment rates were not reported in patients who received second-line ramucirumab and Atez+Bev. Second-line treatment with cabozantinib was reported to be more effective than with sorafenib, with survival benefits, after lenvatinib failure in thyroid cancer patients (56). In the present study, the effectiveness of cabozantinib as second-line treatment after lenvatinib could not be evaluated due to the lack of related studies. Although there may have been some bias due to the observation period, sorafenib could be a treatment after lenvatinib failure.
Lenvatinib resistance has been associated with enhanced activation of epidermal growth factor receptor (EGFR) (57, 58). Although sorafenib is a multikinase inhibitor that mainly blocks platelet-derived growth factor receptor and vascular endothelial growth factor receptor signaling (59), it has also been shown to inhibit EGFR signaling by blocking ERK5 phosphorylation (60). Although the precise mechanism underlying the effectiveness of sorafenib in lenvatinib-resistant HCC remains unclear, sorafenib might be a therapeutic option for lenvatinib-resistant HCC.
The usefulness of sequential therapies with TKIs was confirmed by sequential treatment with sorafenib and regorafenib (61). Maintenance of hepatic reserve function during lenvatinib treatment is essential for eligibility for treatment after lenvatinib failure and for attaining PPS (62). In the present study, mALBI grade was maintained in patients who received second-line sorafenib, allowing more patients to transit to third-line treatment. The sorafenib dose modification schedule described in the present study was found to be effective in the management of AEs without reducing anti-tumor effects (63, 64). In addition, anti-tumor responses with sorafenib after lenvatinib were relatively better in the present study as compared with previous ones. Some factors, not only hepatic reserve function but also the timing of lenvatinib cessation, might have contributed to it. Further studies are required for this to be clarified. On the other hand, in the present study, about half of patients with first-line lenvatinib treatment could not receive the second-line treatment, and the main reason was decreased liver function. A recent study showed that elderly patients tend to decrease liver function after lenvatinib treatment (65). Additional studies are needed to determine methods that maintain hepatic reserve function during treatment with TKIs.
The present study had several limitations, including its retrospective design and relatively limited number of patients in latter cohort study. Furthermore, all treatment decisions were made by individual physicians under the Japanese social health-care insurance system. Atez+Bev was found to have greater anti-tumor effects than sorafenib without impairing hepatic reserve function (5) suggesting the need for further investigations of Atez+Bev in the treatment of HCC. In clinical settings, Atez+Bev is a standard treatment for HCC classified as BCLC-C. Patients with BCLC-C and some with BCLC-B who are refractory or intolerant to Atez+Bev may benefit from subsequent treatment with lenvatinib. Furthermore, recent real-world studies suggested that the anti-tumor effects of lenvatinib are superior in HCC with NAFLD/NASH as compared with not only those of sorafenib but also Atez+Bev (66, 67). HCC patients with NAFLD/NASH might be candidates of the first-line lenvatinib treatment. Further prospective studies are desired for such patients. On the other hand, a recent study showed that anti-tumor responses to second-line treatment with TKIs, such as lenvatinib or sorafenib after Atez+Bev were similar to responses to first-line treatment (68). Lenvatinib showed significantly longer PFS than sorafenib, although OS was similar between these TKIs as shown in the phase III trial (68), suggesting that second-line lenvatinib after first-line Atez+Bev may benefit these patients. Post-progression treatment after second-line lenvatinib should be investigated in future. In the present systematic review about PPS in lenvatinib, most studies were retrospective and Japanese-oriented. Further prospective studies including non-Japanese patients are desired to confirm the significance of PPS and post-progression treatment in lenvatinib treatment.
In conclusion, PPS is significantly associated with OS in HCC treatment with lenvatinib. Sorafenib following lenvatinib failure shows a modest anti-tumor effect, with good tolerability and manageable toxicities, making it suitable for sequential TKI therapy.
Acknowledgements
The Authors thank English Service for Scientists for English language editing.
Footnotes
Authors’ Contributions
KT conceptualized the study. KT, YT, YM, ES, YK, NM, AM, YH, MM, TT, and YS contributed to patients’ treatment and data collection. KT performed statistical analyses and wrote the first draft of the manuscript. YS and IY supervised the study. All Authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
The Authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Received October 16, 2022.
- Revision received October 25, 2022.
- Accepted October 27, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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