Abstract
Background: The efficacy of molecular-targeted agents (MTAs) has been demonstrated in recent years. However, the results of multidisciplinary treatment including hepatic resection are still unclear. The present study evaluated the outcomes of MTA treatment for advanced, unresectable hepatocellular carcinoma (HCC), with the goal of achieving liver resection, in our department. Patients and Methods: Nine patients in whom Lenvatinib had been administered to achieve conversion surgery for unresectable HCC were included in this study. The patient characteristics were as following: median tumor size of 10 cm, vascular invasion in 5 cases, multiple tumors in 2 cases, median treatment duration of 8 weeks, dose reduction due to side effects in 4 patients, and discontinuation of treatment in 1 patient due to tumor growth. Results: The efficacy by modified Response Evaluation Criteria in Solid Tumors (mRECIST) was partial response in 3, sustained disease in 5 and progressive disease in 1, while the liver resection rate was 88%. Four patients (50%) had recurrence after resection, and the median recurrence-free survival was 12.7 months; however, treatment for recurrence was successful and all patients are alive. Conclusion: Lenvatinib may improve the prognosis of HCC with vascular invasion and multiple lesions by achieving radical resection at the appropriate time for patients with tumor shrinkage.
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a leading cause of death even after curative treatment. In the advanced stage of HCC with macrovascular invasion, such as to the portal vein, hepatic vein, and inferior vena cava (IVC), there are quite a few treatments available (1, 2). However, the Barcelona Clinic Liver Cancer (BCLC) recommends that systemic treatment, such as with a molecular-targeted agent (MTA), be considered as the first choice for such cases (3). Sorafenib has been the first choice of the treatment for advanced, unresectable HCC after SHARP trial from 2008 (4). The phase III clinical trial of Lenvatinib for advanced HCC showed (REFLECT trial) showed that Lenvatinib was not inferior to sorafenib with respect to overall survival (OS) (13.6 vs. 12.3 months, HR=0.92, 95%CI=0.79-1.06) (5).
However, a strategy that combines surgery with Lenvatinib for advanced HCC has not yet been established. Clinical reports on liver resection for advanced HCC after MTA are limited. The influence of liver function by MTA and the effectiveness is still unclear. The aim of this study was to clarify the influence of preoperative chemotherapy with Lenvatinib for advanced HCC relative to liver function, recurrence, and prognosis.
Patients and Methods
A total of nine patients scheduled for conversion surgery from 2019 to 2020 at Nagasaki University Hospital were enrolled in this study. These patients were not indicated for liver resection (LR) initially because their HCC was classified as BLCL-B or BLCL-C on imaging. Hepatic resection was performed based on the preoperative tumor progression and liver function test findings, as previously described (6). Imaging of the tumor to determine its resectability included radiographic assessments via ultrasonography (US), multidetector computed tomography (MDCT), and magnetic resonance imaging (MRI) preoperatively in all patients. The preoperative liver function status was determined based on the liver function test, indocyanine green retention test for 15 min (ICG-R15), liver scintigraphy [represented by the liver-to-liver-plus-heart ratio at 15 minutes after 99mTc Galactosyl serum albumin (GSA) loading (LHL15)], the Child-Pugh classification, and the albumin-bilirubin index (ALBI). The following data were collected before chemotherapy and surgery for each patient: age, sex, virus status, Child-Pugh classification ICG R15 and LHL15. The effectiveness in each patient was evaluated by the Response Evaluation Criteria In Solid Tumors (RECIST) system and the modified RECIST system.
Ethical standards. This case series was approved by the clinical ethical committee (number: 19102143) at Nagasaki university hospital and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Statistical analysis. Recurrence-free survival rates were assessed with the Kaplan-Meier method and compared using the log-rank test. Comparison of liver function test and tumor marker was assessed with paired t-test. Statistical analyses were performed using the SPSS Version 24.0 software package (Tokyo, Japan).
Follow-up. After surgery, patients were followed for their serum alpha-fetoprotein (AFP) level and serum protein induced by vitamin K absence II (PIVKA-II) level, as well as US, CT, or MRI findings every two to three months; if indicated, chest CT or bone scintigraphy was performed to detect concurrent extrahepatic recurrence. If tumor recurrence was found, we selected the best treatment: chemotherapy or trans-arterial chemoembolization for intrahepatic multiple recurrence, radiofrequency ablation for single, small recurrence with liver dysfunction, or repeat hepatectomy for single intrahepatic recurrence for patients with a preserved liver function.
Results
Patient characteristics. The clinical background data of the included patients are shown in Table I. The median age was 60 (58-83) years old. The median tumor size was 10.0 (215.3) cm. BCLC-B was noted in two patients and BCLC-C in seven patients due to portal of venous tumor thrombus on imaging, which contained two extrahepatic metastases in the lung. Only one patient received preoperative trans-arterial chemoembolization (TACE) to avoid spontaneous rupture in the previous hospital. The liver function in all patients was stable (Child-Pugh Grade A). The median period of Lenvatinib treatment was 8 (4-50) weeks.
Eight patients had a sustained disease (SD), and one had a progressive disease (PD) according to the RECIST system. Two patients had a partial response (PR), six had SD, and one had PD according to the modified RECIST system. Of the nine patients, eight received liver resection and lung resection after Lenvatinib treatment. The rate of conversion surgery was 88% (8/9). The median follow-up period was 23.2 (7-28) months. The rate of recurrence was 62.5% (5/8), and the recurrence site was the liver in 3, lymph node in 1, peritoneum in 1, and left adrenal grand in 1 patient (with duplicates). The treatment for recurrence is shown in Table I; it included transaterial chemoembolization (TACE) in one, Lenvatinib in two, Atezorizumab with Bevacizumab in one, and best supportive care in one patient. The median recurrence-free survival was 12.7 months (Figure 1). All patients survived follow-up because of successful treatment for recurrence.
Summary of patients who received Lenvatinib treatment to achieve conversion surgery.
Recurrence-free survival rate (a) and overall survival rate (b) for advanced hepatocellular carcinoma (HCC) with Lenvatinib treatment after liver resection.Treatment by LEN for conversion surgery and recurrence-free survival.
Trends in the liver function and tumor markers after Lenvatinib treatment for conversion surgery. The ALBI after Lenvatinib treatment was worse than before treatment in one case, however, there was no significant difference of ALBI between pre- and post-Lenvatinib treatment. The ICGR15 and liver scintigram also did not significantly affect the liver function after Lenvatinib treatment. Tumor marker levels (AFP, PIVKAII) were also not significantly changed even after Lenvatinib treatment (Table II).
Liver function test findings and tumor marker levels in eight cases that achieved conversion surgery during perioperative Lenvatinib treatment.
Discussion
In the 2000s, sorafenib, a multi-kinase inhibitor, demonstrated efficacy for unresectable HCC in the sorafenib hepatocellular carcinoma (HCC) assessment randomized protocol (SHARP) (4) and Asia-Pacific trial (7), becoming the first choice of treatment for patients with unresectable HCC. Although sorafenib has been used for advanced HCC, preoperative therapy by sorafenib has been reported in case reports and small-sized case series. REFLECT trials reported that Lenvatinib gained a higher overall response rate than sorafenib (19% vs. 7% according to RECIST 1.1 and 41% vs. 12% according to mRECIST criteria) (5). Lenvatinib reportedly showed a better response and greater tolerability in cases of advanced HCC than sorafenib, suggesting that Lenvatinib might be beneficial for conversion surgery (5).
Arita et al. reviewed cases of conversion surgery for advanced HCC (8). They summarized eight case reports (9-16) and two cohort studies (17, 18). In most of the case reports, one or two patients received conversion surgery after showing a good response to Lenvatinib treatment; however, the conversion rate among similar patients in each institute was not shown. Yamamura et al. reviewed conversion surgery for advanced HCC following TMA and immune check point inhibitors. It may be difficult to produce solid evidence for conversion surgery. To conduct a randomized control trial, patients should be assigned to either conversion surgery or continuous molecular therapy when determined to be resectable (19).
Zhu et al. reported successful conversion surgery in patients receiving combination therapy of MTA (Lenvatinib/Apatinib) and any anti-PD-1 antibody drug. Ten patients achieved conversion surgery with R0 resection out of 63 treated with combination therapy for initially unresectable HCC (17). Shindo et al. reported conversion surgery after Lenvatinib treatment in 16 out of 107 patients treated by Lenvatinib for unresectable HCC. Of those 16 patients, 9 achieved R0 resection after 3.5 months of Lenvatinib treatment. The median overall survival time in those 9 patients was 11.0 months (18). In the present case series, we achieved a high rate of conversion surgery in patients with advanced HCC (BCLC grade B and C). Initially technically resectable cases might have been included in this series, especially concerning vascular invasion; however, we defined oncologically unresectable cases as those showing macrovasuclar invasion, such as BCLC grade C.
Regarding the effectiveness of Lenvatinib treatment for advanced HCC, the present study showed that eight patients had SD and one had PD according to the RECIST system, while two patients had PR, six had SD, and one had PD according to the modified RECIST system. The arterial vascularity of HCC was dramatically reduced in the first four weeks after Lenvatinib treatment, even though the tumor size did not change. The tumor marker levels were not significantly changed by Lenvatinib treatment in this series. The ALBI in one patient in our series was worse after treatment than before, but our coauthor Sasaki reported that an older age (≥72 years old) was associated with a deterioration in the liver function within 8 weeks, the ALBI score was significantly higher in the older group at 4 and 8 weeks after Lenvatinib administration (20). In addition, we evaluated specific liver function findings, such as the ICGR15 and liver scintigram, during Lenvatinib treatment. Lenvatinib did not affect the specific liver function, and even though one patient had a worse ICGR test result after Lenvatinib treatment than before, they had a good clinical course after liver resection by a laparoscopic approach.
Several limitations associated with the present study need to be mentioned. First, this study was a small retrospective investigation at a single center. Second, Lenvatinib did not suppress the recurrence rate, which was relatively high in this study. Treatment for recurrence had a good response in this case series. A larger number of cases with Lenvatinib treatment for advanced HCC is needed to determine whether perioperative Lenvatinib treatment improves the recurrence rate after liver surgery.
In conclusion, Lenvatinib may improve the prognosis of HCC with vascular invasion and multiple lesions by facilitating radical resection at the appropriate time for advanced HCC patients.
Acknowledgements
The Authors wish to thank our colleagues in the Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, for their kind cooperation and support. Some cases were registered in the Japanese registry of clinical trial (jRCTs) No. 031190057 and obtained from an Investigator Initiated Study sponsored by Eisai.
Footnotes
Authors’ Contributions
MH, TH and SE designed and drafted the manuscript. AS, RS, TT, TH, HM, TA, KK, HM and SO collected data and assisted in preparing the manuscript. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors who have taken part in this study declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
- Received April 13, 2022.
- Revision received May 14, 2022.
- Accepted May 17, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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