Abstract
Background/Aim: Surgical resection remains the mainstay of treatment for hepatocellular carcinoma (HCC). However, reducing the risk of postoperative recurrence is urgently needed. We planned a prospective observational study to investigate the efficacy and safety of adding sorafenib in a maintenance setting after surgery in HCC patients with high risk of recurrence. Patients and Methods: Patients with HCC (invasion of the hepatic vein or inferior vena cava or tumor size >7 cm or tumor to nontumor standardized uptake value ratio >2 by fluorodeoxyglucose positron emission tomography) who underwent macroscopically curative resection were eligible. Dose and schedule of sorafenib were set at 800 mg/day for six months after hepatic resection. The primary endpoint was progression-free survival, and the secondary endpoints were overall survival and safety. This study was registered with the UMIN Clinical Trials Registry (UMIN000013089). Results: Ten patients were evaluated. Six patients completed the pre-planned treatment. Three patients discontinued treatment because of disease progression (lung metastasis in two patients and liver metastasis in one), and one patient discontinued because of pneumonia. The most common drug-related adverse event was increased γ-glutamyl transpeptidase (γGTP). None of the patients suffered grade 4 adverse events. The median progression-free survival was 380 (range=38-1,555) days. The median overall survival was 1000 (range=850-1,705) days. Four patients survived without disease progression for more than 800 days. Conclusion: Although the sample size was limited, this is the first study to demonstrate the safety and efficacy of sorafenib in a maintenance setting after surgery for HCC patients with high risk of recurrence.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death globally (1-2). Surgical resection remains the mainstay of treatment for HCC, according to global guidelines and consensus (3-4). The Barcelona clinic liver cancer criteria restrict resection to patients with early stages of HCC (5). In contrast, many Asian treatment guidelines recommend liver resection for higher burden HCC, including cases with large or multifocal HCC, vascular invasion, or less than optimal synthetic liver function (6). Because some patients suffer from early postoperative recurrence, maintenance chemotherapy is recognized as important for improving the prognosis after curative resection in high-risk patients with HCC.
Previous studies identified high-risk patients with HCC who were more likely to develop early postoperative recurrence. Inferior vena cava tumor thrombus (IVCTT) is a manifestation of advanced hepatic vein invasion with a reported frequency of 1.4% (7). IVCTT is frequently associated with synchronous and metachronous extrahepatic metastasis, including metastases to the lung (8-13), related to direct cancer cell dissemination into the systemic circulation, and the overall survival (OS) rates at 1, 3, and 5 years were 38%, 20% and 13%, respectively (median: 9 months) (14). In our previous retrospective study, patients with a maximum tumor diameter of 7 cm or greater had a poor prognosis related to a high rate of lung metastasis (15). Furthermore, we reported that the tumor to nontumor standardized uptake value (SUV) ratio (TNR) by preoperative fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) was an independent prognostic factor for early recurrence (16, 17). Taken together, HCC with hepatic vein invasion, giant tumor (>7 cm), and high TNR (>2) by FDG-PET were defined as HCC with very high risk of recurrence. For these patients, hepatic resection is not sufficient, and initiating chemotherapy immediately after surgery may improve their prognosis. However, the safety and efficacy of this treatment strategy remains to be tested in a clinical trial.
Sorafenib is approved for use in patients with unresectable HCC based on two phase III randomized trials (18, 19). The phase III placebo-controlled STORM trial, which included 1602 patients from 28 countries with early-stage HCC following surgical resection or local ablation, found that adjuvant sorafenib did not significantly improve recurrence-free survival, time to recurrence, or overall survival. The authors concluded that no evidence of clinical benefit existed for adjuvant sorafenib therapy in such patients (20). However, this large study did not include patients with a very high risk of recurrence. Therefore, we examined the efficacy and safety of sorafenib after hepatic resection (in this trial, we named the treatment as maintenance therapy) for HCC patients with very high risk of recurrence.
Patients and Methods
Study design. We designed this multicenter, prospective study to explore the efficacy and feasibility of maintenance therapy with sorafenib. In the present study, we evaluated patients with very high risk of recurrence who had hepatic vein invasion [Vv2-3, a classification of Vv according to the Liver Cancer Study Group of Japan (21) or maximum tumor diameter >7 cm, or TNR> 2 by FDG-PET]. This study (KHBO1303) was registered with UMIN Clinical Trials Registry, number UMIN000013089 and initiated by the Kansai Hepato-Biliary Oncology Group (KHBO, Osaka, Japan). The protocol was approved by Kyoto University Graduate School and Faculty of Medicine, Ethics Committee (approval no. C0718), and written informed consent was obtained from each patient. Patient registration and data management were conducted at an independent data center - the Osaka International Cancer Institute. The Independent Data and Safety Monitoring Committee (IDSMC) independently reviewed the interim analysis and monitored protocol compliance, safety, and on-schedule study progress. The IDSMC considered stopping the trial from clinical and statistical points of view.
Preoperative assessments. Computed tomography (CT) and magnetic resonance imaging (MRI) performed before curative resection, were used for patient staging. All FDG-PET imaging procedures were performed as previously described (16). For the quantitative analysis of FDG uptake, regions of interest were manually defined on transaxial tomograms. The maximum SUV was calculated for the quantitative analysis of tumor FDG uptake as follows: SUV=C (kBq/ml)/ID (kBq)/body weight (kg), where C represents the tissue activity concentration measured by PET and ID represents the injected dose (16). Liver function was assessed by the Child-Pugh grading system (A or B) and indocyanine green (ICG 0.5 mg/kg; Daiichi Sankyo Company) clearance test at 15 min (ICGR15; less than 10%). Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, and levels of total bilirubin (T-Bil), alkaline phosphatase (ALP), creatinine (Cre), γGTP, hemoglobin (Hb), albumin (Alb), and platelet (Plt) counts were measured. The Eastern Cooperative Oncology Group performance status was 0 or 1 in this study.
Primary and secondary measures. The primary measure was progression-free survival (PFS), and the secondary measures were OS and safety. Treatment-related toxicity was assessed according to CTCAE version 4.0. Each visit included a physical examination, complete blood count and blood chemistry. Abdominal CT, chest CT and tumor markers were performed and analyzed every two months (±28 days). Intrahepatic recurrence was defined as the appearance of one or more intrahepatic lesions with a typical vascular pattern of HCC on dynamic imaging. Extrahepatic recurrence was defined with reference to the Response Evaluation Criteria in Solid Tumors version 1.1.
Treatment protocol. Patients started treatment within 2 to 8 weeks after curative resection and received 400 mg of oral sorafenib twice daily for 6 months. Sorafenib was given continuously unless intolerable toxicities and/or tumor progression occurred. Treatment interruptions and up to two levels of dose reductions (first to 400 mg once a day and then to 400 mg every other day) were allowed if drug-related adverse events were recorded.
Eligibility criteria. Eligible patients were men and women between the ages of 20 and 85 years with a confirmed diagnosis of HCC with vascular invasion (Vv2-3), tumor diameter >7 cm, or TNR >2 by FDG-PET after macroscopically curative resection for HCC. Other eligibility criteria included a Child-Pugh score of 5-7 and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were also required to have adequate bone marrow, liver, and renal function as assessed by laboratory tests, including Hb, T-Bil, Plt count, neutrophil count, AST, ALT, and serum Cre.
Key exclusion criteria. Exclusion criteria included previous history of sorafenib within 3 months before surgery, allergy with sorafenib, age within the childbearing range for women, severe complications, other active malignancies, severe renal disorders, severe bronchial asthma, severe heart disease, uncontrollable ascites, history of liver transplantation, uncontrollable esophageal varix, history of hepatic encephalopathy, receiving medical therapy affecting sorafenib, receiving herbal medicine, HIV-related disease, or patient inappropriate for study.
Statistical analysis. The preplanned sample size of 35 patients was calculated based on feasibility without statistical considerations. Efficacy endpoints were analyzed in the intention-to-treat population. Continuous variables are expressed as median values and range. PFS was calculated as the period from the date of baseline imaging to the first observation of disease progression or to death from any cause. OS was calculated from the date of baseline imaging to the date of death or the end of follow-up. We created a Swimmer’s Plot to depict individual disease timelines.
Results
Patient characteristics. From September 2015 to January 2018, ten HCC patients were recruited and received maintenance sorafenib for high-risk of tumor recurrence after curative resection (Vv2-: 3 cases, maximum tumor diameter >7 cm: 7 cases, TNR>2 by FDG-PET: 6 cases; note that some patients were included in more than one of these groups). The preplanned sample size was 35 patients; however, this study was terminated early due to slow accrual and ten patients were evaluated. All patients were evaluated for toxicity and efficacy. Table I shows the baseline characteristics of the patients. The median age was 69.5 years, and most patients were male. Predominant etiologies were HBV (50%) and Nonviral (50%). All patients had preserved liver function with Child Pugh status A. The median tumor size was 10 (4.0-16.3) cm. Five patients (50%) had portal vein tumor thrombus (PVTT) and three patients (30%, invasion of the main hepatic vein: 1 case, invasion with IVC: 2 cases) had hepatic vein tumor thrombus at hepatectomy. The median TNR was 2.45 (1.9-4.5). The median follow-up time was 1,017.5 days.
Patient characteristics.
Safety. All ten patients who received the maintenance therapy of sorafenib after hepatic resection were assessable for the safety analysis. Six patients completed the pre-planned treatment. Three patients discontinued treatment because of disease progression, and one patient because of pneumonia. Three patients needed dose reduction. Non-hematological adverse events (AEs) were mainly grade 1 or 2 in severity. Grade 3 AEs included hand-foot skin reaction, hypertension, and increased γGTP (Table II). Hematological AEs were mainly grade 1 or 2 in severity. Grade 3 AEs included neutropenia and anemia (Table III). The most commonly reported drug-related AE was increased γGTP. No deterioration in liver function or PS was observed at the end of treatment. None of the patients in the present study suffered grade 4 AEs.
Non-hematological adverse events.
Hematological adverse events.
Clinical efficacy. The median PFS was 380 (range=38-1,555) days. The median OS was 1,000 (range=850-1,705) days. During the treatment with sorafenib, two patients developed lung metastasis and one patient developed liver metastasis. After maintenance sorafenib therapy, no disease progression was observed in four patients (40%, Figure 1). Two cases of lung metastasis and one case of liver metastasis were observed (Table IV). Individual disease courses are shown in a Swimmer’s Plot (Figure 2).
Cases with no disease progression. (A) Case 3: FDG-PET shows intense uptake of FDG in the tumor [tumor to nontumor standardized uptake value ratio (TNR)=2.61]. (B) Case 4: CT scan shows a large hepatic mass in the right liver (tumor diameter=16.3 cm) with a tumor thrombus in the inferior vena cava through the right hepatic vein (arrow). (C) Case 8: CT scan shows a large hepatic mass in the right liver (tumor diameter=7.5 cm). (D) Case 10: FDG-PET shows intense uptake of FDG in the tumor (TNR=3.5).
Clinical courses of patients.
Swimmer Plot depicting the time course from the date of baseline imaging to death or date of last follow-up. Times in between blue lines represent progression free intervals.
Discussion
Early recurrence is common after liver resection for HCC with macrovascular invasion, multinodular or large HCC, and recurrence is still the main cause of death for these patients (13, 14). A phase III study (STORM trial) testing the efficacy of sorafenib in patients with early-stage HCC failed to demonstrate its efficacy (20). On the other hand, Li et al. and Wang et al. have reported on the efficacy of sorafenib in preventing hepatocellular carcinoma recurrence after resection (22, 23). Kelly et al. suggested that the lack of established predictive biomarkers for sorafenib responses made it difficult to define the indication for sorafenib in an adjuvant setting (24). However, Kawamura et al. reported that FDG uptake in unresectable HCC is a useful predictor of an extremely rapid response to lenvatinib (25). In a preclinical study using an orthotopic xenograft model of HCC, Feng et al. reported that sorafenib suppressed the development of postsurgical intrahepatic recurrence and abdominal metastasis, which consequently led to prolonged postoperative survival (26). In line with this preclinical data, Xia et al. demonstrated the safety and potential benefit of sorafenib related to a decrease in the incidence of HCC recurrence and extension of disease-free survival and OS rates for patients with locally advanced HCC after curative resection (27). Therefore, we tested the safety and efficacy of sorafenib for patients with very high risk of recurrence who had hepatic vein invasion (Vv2-3), maximum tumor diameter >7 cm, or TNR >2 by FDG-PET. In these patients, the risk of distant metastases, such as lung metastases, as well as intrahepatic recurrence, is very high; therefore, we considered initiating systemic chemotherapy using sorafenib after liver resection was appropriate and tested this in a prospective observational study.
The STORM trial reported that 50% of patients discontinued sorafenib at 1 year because of adverse events or consent withdrawal, which might be partly attributable to the negative results of this trial. These findings may also indicate that physicians and patients accepted the termination of adjuvant treatment related to adverse events because of the perception that the disease could be cured by surgery alone. In our study, three out of four patients discontinued the protocol treatment because of early recurrence. Therefore, only one patient discontinued treatment because of an adverse event of pneumonia, and three patients continued maintenance treatment after a dose reduction. We think that the high adherence to maintenance treatment was related to targeting patients with very high risk of recurrence. In addition, we considered that if the planned treatment was performed with careful management, it would contribute to higher adherence. No decline in liver function or PS was observed at the end of the treatment. Regarding efficacy, four out of ten patients had no recurrence despite advanced HCC. Recently, the importance of maintenance therapy has been recognized, and we think that our results support the idea of applying maintenance therapy after hepatic resection for HCC patients with very high risk of recurrence. Yamamoto et al. are paying attention to the relationship between adverse events and microbiomes, which is expected to contribute to the improvement of adherence to maintenance treatment (28).
After the introduction of sorafenib, many other promising drugs, including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors, have been developed, making significant advances in systemic therapy for HCC. However, a single agent yields limited clinical results. The overall response rate (ORR) was only 3.3% after sorafenib monotherapy (18), 4.0% for cabozantinib (29), and 6.5% for regorafenib (30). Lenvatinib was reported to have an ORR of approximately 18.8%, which is much higher than that of sorafenib (31). Atezolizumab is an antibody that targets programmed death ligand 1 (PD-L1), and bevacizumab is an antibody that targets vascular endothelial growth factor A (VEGF-A). The Phase III IMbrave150 trial showed that atezolizumab plus bevacizumab combination therapy had an improved survival benefit over sorafenib (32). The IMbrave150 study included high-risk HCC patients, defined as those with major PVTT, tumors occupying more than 50% of the liver, and bile-duct invasion. However, the prognostic effect of atezolizumab plus bevacizumab treatment on very high risk patients is still unsatisfactory. In this immunotherapy era, post-operative immunotherapy may also improve recurrence-free and OS (33-35).
The present study had some limitations. First, the relatively small size of the examined cohort limits the strength of the presented results. Second, there was no patient with HCC caused by HCV. The etiology might affect the efficacy of sorafenib in patients, especially in view of the results of the exploratory subgroup analyses of the SHARP trial, showing better outcomes in patients with HCC caused by HCV versus HBV (19). However, in the BIOSTORM study, the etiology (HCV or others) did not predict sorafenib benefit (36). Therefore, the impact of etiology is considered limited in this study. We think that maintenance therapy after curative resection might be a promising treatment option for HCC patients with high risk of recurrence. Therefore, randomized trials enrolling a larger cohort are needed to establish this strategy as a standard treatment.
Conclusion
Maintenance treatment remains a highly unmet need in HCC management, and further research of this strategy to prevent HCC recurrence is warranted. This is the first study to demonstrate the safety and efficacy of maintenance treatment with sorafenib in HCC patients with very high risk of recurrence after hepatic resection. These patients may benefit from maintenance therapy.
Acknowledgements
We thank J. Ludovic Croxford, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
Footnotes
Authors’ Contributions
SS, MK and EH contributed to the study conception and design. Data collection was performed by all authors. Analyses were performed by SS, MK and EH. The first draft of the manuscript was written by SS and MK. All the Authors commented on it and approved the final manuscript.
Conflicts of Interest
The Authors have no conflicts of interest to declare.
- Received September 28, 2022.
- Revision received October 22, 2022.
- Accepted October 25, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
