HCC is a common malignant tumor which ranks 2nd among all cancer diseases that cause death. China has a significant number of cases of hepatitis, as well as cases of liver cancer, accounting for more than half of new liver cancer cases worldwide each year. In a newly published survey on the prevalence of malignant tumors in China, the annual incidence of liver cancer in the country ranks 4th among all cancer types, and the death toll ranks 2nd .[1] Although the physical examination mechanisms are constantly improving, there remains a large number of patients with liver cancer in the advanced stages when they are discovered.[2] At the same time, the prognosis of patients with liver cancer is poor because liver cancer is prone to intrahepatic dissemination and has the characteristics of intrahepatic polycentric carcinogenesis. Despite its limited efficacy, sorafenib has long been recommended as the preferred treatment for patients with advanced HCC.[3]
In 2017, a new multi-targeted drug named lenvatinib appeared in the treatment of advanced liver cancer. This drug can combine with vascular endothelial growth factor receptors (VEGFR) 1–3, fibroblast growth factor receptors (FGFR) 1–4 and platelet-derived growth factor (PDGF)-α to block tumor angiogenesis. At the same time, it can also inhibit other angiogenic tyrosine kinases activity involved in tumor proliferation, thus playing an anti-tumor role. According to the results of a Phase 3 multi-center randomized control clinical study (REFLECT) of advanced HCC using sorafenib, lenvatinib was non-inferior to sorafenib in terms of OS rate in the treatment of advanced HCC.[4] According to the results of this clinical study, several guidelines for the treatment of liver cancer, including that issued by CSCO, recommend lenvatinib as a first-line therapy for advanced HCC.
At present, real world data which meets the inclusion conditions of the REFLECT study has been reported.[5] It is believed that lenvatinib’s toxicity is acceptable in a real-world setting for patients with advanced liver cancer that meet the REFLECT study criteria, and the tumor has a good response rate (ORR of 40%). However, in clinical practice, the liver tumor volume of some HCC patients exceeds 50% of total liver volume, or the main portal vein tumor thrombus has already formed. These patients were excluded from the REFLECT study. For this group of patients, the safety and efficacy of the use of lenvatinib have not been reported. This study observed the use of lenvatinib on such patients in a real-world setting.
With the release of the results of the REFLECT study, the recommendations for the treatment of advanced HCC in the international guidelines for the treatment of liver cancer have been updated to include lenvatinib as a first-line treatment for advanced liver cancer. However, advanced liver cancer covers a wide range of patients, including those with tumors that exceed 50% of liver volume and those with main portal vein tumor thrombus. These patients were excluded from the REFLECT study due to their worse prognosis. Whether this population can tolerate lenvatinib treatment and what level of efficacy it has were unknown. For this reason, we specifically selected these two types of HCC patients as subjects. Radiotherapy is an important treatment method for patients with main portal vein tumor thrombus,[6] and the study results of the Ib phase of lenvatinib in combination with PD-1 inhibitors have been reported.[7] Therefore, in our study, some patients were treated systematically with radiotherapy or PD-1 inhibitors. At the same time, as it was conducted in a real-world setting, this study included patients who had previously been treated with targeted drugs or other topical treatment.
During the 12-week follow-up observation period, we observed that all patients showed AEs to different degrees, and the types of AEs were consistent with previous literature reports.[5, 8 & 9] In this study, however, the incidence of AEs was higher than previously reported. Among the numerous AEs in this study, fatigue, leukopenia and hoarseness occurred in the top three, with 90.5%, 76.2% and 71.4% respectively. In addition to the above three AEs, more than 50% of AEs included decreased appetite, proteinuria, hand-foot skin reaction, dysgeusia, nosebleed, pruritus, rash and constipation. However, among the patients observed in this study, the incidence of serious AEs was not high, and no AEs of Grade 4 were observed in any patient. Among the 21 observed cases, six (all treated with combination radiotherapy) developed Grade 3 leukopenia; three developed Grade 3 hand-foot skin reaction; two developed Grade 3 decreased appetite, rash and diarrhea; and one developed Grade 3 fatigue, hoarseness, nosebleed, thrombocytopenia and hypertension respectively. Since the Phase 1 study of lenvatinib in the treatment of liver cancer focused on its effect on liver function,[10] we also paid particular attention to this and examined the liver function and coagulation function of all patients every two weeks. Among all the patients, the liver function of three patients elevated from Child-Pugh A to B, which resulted in the reduction of lenvatinib, accounting for 18.8%. The Child-Pugh score elevated in seven patients, accounting for 33.3%, but none had Child-Pugh C liver function. The reasons for the high incidence of AEs were as follows: first, all the patients observed in this study were those who exceeded the inclusion criteria of the REFLECT study, so their disease development was more severe than that of the REFLECT study group, with worse tolerance. Second, some patients were more likely to have AEs after receiving radiotherapy or combination therapy such as PD-1 inhibitors. For patients with large liver tumors (accounting for more than 50% of liver volume) or portal vein tumor thrombus, their liver function reserve capacity was weaker due to the reduced number of normal liver cells and liver blood supply, and their liver function score was more likely to elevate under anti-tumor treatment.
Because the current follow-up time for this group of patients is short, it is impossible to accurately evaluate the efficacy of lenvatinib. Even so, we can still initially evaluate the efficacy of lenvatinib in patients with advanced liver cancer beyond REFLECT study indications. In this study, seven, seven and seven patients achieved PR, SD and PD respectively. The ORR was 33.3%, slightly lower than 40.6% in the REFLECT study[4] and 40.0%[5] in a Japanese study with a real-world setting. In addition, we closely monitored changes in tumor markers in this group of patients and found that at one month after administration, the tumor marker index of all patients decreased, with 70% of patients seeing a decrease of more than 50%. Nonetheless, we also found that the decline in tumor markers was not consistently maintained in all patients, as tumor marker levels elevated again in 40% of patients in the 12th week. This also indicates that some patients are likely to be resistant for three months’ administration of lenvatinib.
Among the patients observed in this group, the median PFS and OS were 5.3 months and 11.2 months,respectively; lower than the data in the Reflect study, which was considered to be related to the lateness of patients enrolled. The Reflect study included patients with stage B and some stage C patients, and excluded those with oversized tumors and portal tumor thrombus. The staging of the patients observed in our group was significantly later than in the Reflect study population. In addition to oral lenvatinib, some patients in this group also received local radiotherapy and PD-1 inhibitor therapy. After lenvatinib progressed, other targeted drugs were subsequently replaced, so they still obtained a relatively long Survival.
For patients with advanced HCC whose liver tumor volume is greater than or equal to 50% of liver volume or with main portal vein tumor thrombus, the current clinical treatment options are limited. Therefore, by observing the safety and efficacy of lenvatinib in these patients in a real-world setting, we can accumulate more experience for clinical practice. However, due to the limited participants in this study and the application of other treatments to some patients in combination with lenvatinib, the results of this study can only be used as a reference for the accumulation of clinical experience and further relevant clinical trials, and the longer-term clinical follow-up data and results are particularly important.