Lenvatinib combined with sintilimab plus transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma

BACKGROUND Recently,combination therapy has shown a better trend towards improved tumour response and survival outcomes than monotherapy in patients with hepatocellular carcinoma(HCC).However,research on triple therapy[lenvatinib+sintilimab+transarterial chemoembolization(TACE)]as a first-line treatment for advanced HCC is limited.AIM To evaluate the safety and efficacy of triple therapy as a first-line treatment for advanced HCC.METHODS HCC patients with Barcelona Clinic Liver Cancer stage C treated with triple therapy were enrolled.All patients were treated with lenvatinib every day and sintilimab once every 3 wk.Moreover,TACE was performed every 4-6 wk if necessary.The primary outcome of the study was overall survival(OS).The secondary outcomes were the objective response rate(ORR),disease control rate(DCR),and incidence of adverse events.RESULTS Forty HCC patients who underwent triple therapy were retrospectively analysed from January 2019 to January 2022.With a median follow-up of 8.5 months,the 3-,6-,and 12-mo OS rates were 100%,88.5%,and 22.5%,respectively.The ORR and DCR were 45%and 90%,respectively.The median progressive free survival and median OS were not reached.Common complications were observed in 76%of the patients(grade 3,15%;grade 4,2.5%).CONCLUSION Combination therapy comprising lenvatinib,sintilimab and TACE achieved promising outcomes in advanced HCC patients and had manageable effects.

Nanomedicine-boosting icaritin-based immunotherapy of advanced hepatocellular carcinoma

Traditional treatments for advanced hepatocellular carcinoma(HCC),such as surgical resection,transplantation,radiofrequency ablation,and chemotherapy are unsatisfactory,and therefore the exploration of powerful therapeutic strategies is urgently needed.Immunotherapy has emerged as a promising strategy for advanced HCC treatment due to its minimal side effects and long-lasting therapeutic memory effects.Recent studies have demonstrated that icaritin could serve as an immunomodulator for effective immunotherapy of advanced HCC.Encouragingly,in 2022,icaritin soft capsules were approved by the National Medical Products Administration(NMPA)of China for the immunotherapy of advanced HCC.However,the therapeutic efficacy of icaritin in clinical practice is impaired by its poor bioavailability and unfavorable in vivo delivery efficiency.Recently,functionalized drug delivery systems including stimuli-responsive nanocarriers,cell membrane-coated nanocarriers,and living cell-nanocarrier systems have been designed to overcome the shortcomings of drugs,including the low bioavailability and limited delivery efficiency as well as side effects.Taken together,the development of icaritin-based nanomedicines is expected to further improve the immunotherapy of advanced HCC.Herein,we compared the different preparation methods for icaritin,interpreted the HCC immune microenvironment and the mechanisms underlying icaritin for treatment of advanced HCC,and discussed both the design of icaritin-based nanomedicines with high icaritin loading and the latest progress in icaritinbased nanomedicines for advanced HCC immunotherapy.Finally,the prospects to promote further clinical translation of icaritin-based nanomedicines for the immunotherapy of advanced HCC were proposed.

Evolution of systemic therapy of advanced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) commonly occurs in hepatitis B endemic areas, especially in Asian countries. HCC is highly refractory to cytotoxic chemotherapy. This resistance is partly related to its tumor biology, pharmacokinetic properties, and both intrinsic and acquired drug resistance. There is no convincing evidence thus far that systemic chemotherapy improves overall survival in advanced HCC patients. Other systemic approaches, such as hormonal therapy and immunotherapy, have also disappointing results. Recently, encouraging results have been shown in using sorafenib in the treatment of advanced HCC patients. In this review, we concisely summarize the evolution of developments in the systemic therapy of advanced HCC.

Sorafenib in treatment of patients with advanced hepatocellular carcinoma:a systematic review

BACKGROUND: Sorafenib has become the standard first-line treatment for patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the efficacy and safety of sorafenib in advanced HCC patients and explore its true value for specific subgroups. DATA SOURCES: A computer-based systematic search from January 2005 to June 2011 with 'sorafenib' and 'advanced hepatocellular carcinoma' as search terms was performed for possible clinical trials. Hazard ratios (HR) and their 95% confidence intervals (CI) for overall survival (OS) and time to progression (TTP), rates of partial response (PR), rates of toxicity effects, and details of subgroup analysis were extracted. Meta-analyses were done using the software Review Manager (version 5.0). RESULTS: Six trials with 1164 patients were included. Based on three randomized controlled trials, the pooled HR (sorafenib/ placebo) was 0.66 for OS (95% CI: 0.56-0.78; P<0.00001) and 0.57 for TTP (95% CI: 0.47-0.68; P<0.00001). The pooled odds ratio (OR) for PR was 2.96 (95% CI: 0.96-9.15; P=0.06). For three single-arm trials, the pooled HR was 0.69 for OS (95% CI: 0.56-0.84; P=0.0002) and 0.64 for TTP (95% CI: 0.52-0.78; P<0.00001). The pooled OR for PR in three single-arm trials was 3.56 (95% CI: 1.22-10.39; P=0.02). Subgroup analysis indicated that sorafenib was less effective in patients with extrahepatic spread (with: P=0.13 vs without: P<0.0001), with normal alpha-fetoprotein level (AFP) (P=0.15 vs elevated: P=0.0006), and with elevated level of serum bilirubin (P=0.06 vs normal: P=0.0009). Sorafenib-based therapy significantly increased the risk of grade 3/4 hand-foot skin reaction, diarrhea, fatigue, and rash/desquamation.CONCLUSIONS: Sorafenib-based therapy benefits advanced HCC patients. Meanwhile, sorafenib is less effective for patients with extrahepatic spread, with normal AFP level and with elevated level of bilirubin.

Twenty-four hour intra-arterial infusion of 5-fluorouracil,cisplatin,and leucovorin is more effective than 6-hour infusion for advanced hepatocellular carcinoma

AIM. To evaluate the time dependence of intra-arterial 5-fluorouracil （5-FU） therapy for advanced hepatocellular carcinoma （aHCC）. METHODS： Thirty-seven adult Japanese patients who had aHCC and liver cirrhosis were treated with combined intra-arterial 5-FU, cisplatin （CDDP）, and leucovorin （LV）. The Japan Integrated Staging score （JIS score） of each patient was 3 or more. The patients were divided into two groups, alter which the 15 patients in group S were treated with 6-h infusion chemotherapy （LV at 12 mg/h, CDDP at 10 mg/h, and 5-FU at 250 mg/m^2 per 4 h） and the 22 patients in group L were treated with 24-h infusion chemotherapy （LV at 12 mg/h, CDDP at 10 mg/h, and 5-FU at 250 mg/m^2 per 22 h）. Continuous infusion chemotherapy was performed v/a the proper hepatic artery every 5 d for 4 wk using an implanted drug reservoir. RESULTS： The percentages of patients with a partial response after 4 wk of chemotherapy were 6.7% in group S and 31.8% in group L. The survival of group L was significantly better than that of group S, with the median survival time being 496 d in group L and 226 d in group S （P 〈 0.05）. CONCLUSION： Continuous 24-h intra-arterial infusion is more effective for aHCC and can markedly prolong survival time as compared to 6-h infusion.

Efficacy of hepatic arterial infusion chemotherapy in advanced hepatocellular carcinoma

AIM:To investigate the efficacy of hepatic arterial infusion chemotherapy(HAIC) using floxuridine(FUDR) in patients with advanced hepatocellular carcinoma(HCC) confined to the liver.METHODS:Thirty-four patients who had advanced HCC with unresectability or unsuccessful previous therapy in the absence of extrahepatic metastasis were treated with intra-arterial FUDR chemotherapy at ourhospital between March 2005 and May 2008.Among the 34 patients,9 patients were classified as Child class C,and 18 patients had portal vein tumor thrombus(PVTT).One course of chemotherapy consisted of continuous infusion of FUDR(0.3 mg/kg during day 1-14) and dexamethasone(10 mg on day 1,4,7 and 11),and this treatment was repeated every 28 d.RESULTS:Two patients(5.9%) displayed a complete response,and 12 patients(35.3%) had a partial response.The tumor control rate was 61.8%.The median overall survival times were 15.3 mo,12.4 mo and 4.3 mo for the patients who were classified as Child class A,Child class B and Child class C,respectively(P = 0.0392).The progression-free survival was 12.9 mo,7.7 mo and 2.6 mo for the patients who were classified as Child class A,Child class B and Child class C,respectively(P = 0.0443).The cumulative survival differed significantly according to the Child-Pugh classification and the presence of PVTT.In addition to hepatic reserve capacity and PVTT,the extent of HCC was an independent factor in determining a poor prognosis.The most common adverse reactions to HAIC were mucositis,diarrhea and peptic ulcer disease,but most of these complications were improved by medical treatment and/or a delay of HAIC.CONCLUSION:The present study demonstrates that intra-arterial FUDR chemotherapy is a safe and effective treatment for advanced HCC that is recalcitrant to other therapeutic modalities,even in patients with advanced cirrhosis.

Chemotherapy with enteric-coated tegafur/uracil for advanced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, including Japan. Although the development of imaging modalities has made the early diagnosis of HCC possible, surgically resectable cases are relatively uncommon because of hepatic function reserve and/or an advanced stage at presentation. Several modalities, such as transcatheter arterial chemoembolization, percutaneous ethanol injection, microwave coagulation therapy and radiofrequency ablation are reportedly useful in treating patients with non-resectable disease. However, unfortunately, many HCC patients have tumor recurrence. The overall prognosis of patients with HCC is very poor, and treatment of the advanced form is still problematic. In this article, we review the clinical efficacy and toxicity of enteric-coated tegafur/uracil in the treatment of patients with advanced non-resectable HCC.

Clinical study of FOLFOX4 regimen for patients of advanced hepatocellular carcinoma

Objective:The aim of our study was to observe the efficiency and toxicity of oxaliplatin (L-OHP) combined with CF/5-FU in patients with advanced primary hepatocellular carcinoma.Methods:Twenty patients with advanced primary hepatocellular carcinoma had recurrence/metastasis after multiple courses of TACE (cisplatin and epirubicin,etc.).All patients were treated with FOLFOX4 regimen of the combination of oxaliplatin and leucovorin and 5-fluorouracil.Treatment was repeated every 2 weeks until disease progression or unacceptable adverse effects occurred.The efficiency was evaluated according to RECIST criteria,and toxicities according to American National Cancer Institute Common Toxicity Criteria (NCI CTC),respectively.Results:Twenty patients were assessable for the objective efficiency and for toxicity.No patient achieved complete response (CR),4 patients were partial response (PR),8 patients were stable disease (SD),8 patients were disease progression (PD);Time to tumor progression (TTP) of the patients ranged from 1.5 to 4.8 months,median TTP was 2.2 months;Overall survival (OS) of the patients ranged from 3 to 10.2 months,median OS was 5 months.The 2 patients' serum AFP level decreasing.Sixteen patients relieved the symptoms obviously,stabilized or raised up Karnofsky Score.The toxicities were mainly grade I-II arrest of bone marrow (50%),mild neurotoxicity (30%) and mild reaction of gastrointestinal tract (40%).Conclusion:FOLFOX4 regimen is effective and safe for patients with advanced primary hepatocellular carcinoma.It can be worthy of further clinical investigation.

Combination of TACE and FOLFOX4 in the treatment of unresectable advanced hepatocellular carcinoma:a prospective cohort study

Objective The aim of the study was to assess the effectiveness and safety of a combined therapy with transcatheter arterial chemoembolization(TACE)and FOLFOX4,in patients with unresectable advanced hepatocellular carcinoma(HCC).Methods In this study,patients with advanced HCC,that received treatment between November 2015 and October 2017,were recruited.Among these,30 patients were treated with TACE only(TACE group);whereas 33 patients were treated with a combination of FOLFOX4 chemotherapy and TACE(combination group).Survival analyses,including overall survival(OS)and progression free survival(PFS)analysis,were performed for both groups.Following this,the responses of patients to treatment were evaluated every 3 months,and the toxic and adverse events were observed.Results The median follow-up time was 9.2 months(3-36 months).In the combination group,at 3 months,a disease control rate(DCR)of 60.6%,and a median OS of 9.1 months was obtained[95%confidence interval(CI)6.5-11.7].In the TACE group,the DCR and OS were 33.3%and 5.5 months(95%CI 4.3-6.7),respectively.On the other hand,the PFS in the combination and TACE groups were observed as 5.6 months(95%CI 3.6-7.6)and 2.6 months(95%CI 2.0-3.2),respectively.Both these findings indicate a statistically significant difference(P=0.01)between both the groups.Similar TACE associated adverse events were observed in both groups.In the combination group,frequently observed FOLFOX4 related adverse effects included nausea(90.9%),leukopenia(75.8%),thrombocytopenia(69.7%),and vomiting(69.7%).Most adverse reactions were between grades I-III and were alleviated after symptomatic treatments.Conclusion The combination of TACE with FOLFOX4 therapy has better effectivity and safety than TACE alone.

Real-life multi-center retrospective analysis on nivolumab in difficult-to-treat patients with advanced hepatocellular carcinoma

BACKGROUND Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related death worldwide.The landscape of the systemic treatment for advanced HCC is changing quickly,and recently,the standard of care became either atezolizumab plus bevacizumab or tremelimumab plus durvalumab in the single tremelimumab regular interval durvalumab regimen.Nivolumab monotherapy has proven to be effective sometimes for advanced HCC and could be a valuable treatment option for patients outside current treatment indications and reimbursement criteria for the standard of care.This is a particular population of interest.AIM To evaluate the real-world effectiveness of nivolumab monotherapy in patients with advanced HCC who are not eligible for other treatment.METHODS We conducted a retrospective,multicentric study including 29 patients with advanced HCC from 3 Belgian tertiary hospitals.All patients had had prior chemotherapy or were intolerant or ineligible for treatments.All study subjects received nivolumab 3 mg/kg in monotherapy,administered once every two weeks intravenously.Treatment continued until disease progression,severe adverse events or death.Data were retrieved from patients'medical records.The outcome parameters such as radiological response according to response evaluation criteria in solid tumors(RECIST)criteria,the biological response through the evolution of the alpha-fetoprotein(AFP)level,and clinical response considering both the Child–Pugh(CP)score and the World Health Organization(WHO)performance status(PS)were reported.A safety profile was also reported.Statistical analysis was performed using the SPSS Statistics 27 statistical software package.RESULTS The radiological overall response rate(defined as complete or partial response according to the immune RECIST and modified RECIST criteria)to nivolumab monotherapy was 24.1%.The biological overall response rate(defined as a decrease of≥25%in AFP blood level)was 20.7%.Radiological and biological responses were significantly associated both with each other(P<0.001)and with overall survival(P<0.005 for radiological response and P<0.001 for biological response).Overall survival was 14.5 mo(+/-2.1),and progression-free survival was 10.9 mo(+/-2.3).After 4 mo of treatment,78.3%of patients remained clinically stable or even showed improvement in WHO PS.Grade 3 adverse events occurred in 17.2%of patients,none had grade 4 adverse events,and no patients ceased nivolumab due to adverse events.CONCLUSION Nivolumab monotherapy is a good treatment choice in frail patients with HCC who are ineligible for the standard of care or other validated systemic treatments.

Conversion therapy for unresectable hepatocellular carcinoma:Advances and challenges

Recently,the World Journal of Gastrointestinal Oncology published an article entitled“Pathologically successful conversion hepatectomy for advanced giant hepatocellular carcinoma after multidisciplinary therapy:A case report and review of the literature”,in which the authors shared their successful experience with complete surgical resection after multidisciplinary conversion therapy.The study by Chu et al demonstrates the great challenges that the advanced hepatocellular carcinoma(HCC)poses to surgical oncology,reveals the complexity of conversion therapy for unresectable HCC,emphasizes the important role of a multidisciplinary management model in conversion therapy,and enriches our understanding of the dynamics of personalized treatment for different patients.At present,conversion therapy is a hot research topic in the treatment of unresectable HCC,which has brought new hope to many patients with moderately advanced HCC.However,there are still many urgent problems to be solved in conversion therapy.Here,we would like to further discuss the advances and challenges of conversion therapy for unresectable HCC with the authors and the general readers.

Multikinase inhibitor-based immunotherapy doublet for advanced hepatocellular carcinoma:its efficacy still needs to be determined

The current landscape for advanced hepatocellular carcinoma(HCC)has evolved drastically in recent years,with the ever-increasing development of novel standard first-line therapeutic strategies(e.g.,the combination of atezolizumab and bevacizumab)and the approval of several new agents for second line strategies,such as regorafenib and cabozantinib(1,2).Although a large number of treatment options are available for advanced HCC patients,multikinase inhibitor(MKI)-based immunotherapy doublet has become notably complex,especially after the publication of the COSMIC-312 trial(3).This study evaluated the efficacy and safety of cabozantinib combined with atezolizumab versus sorafenib as the first-line treatment of patients with advanced HCC.Although the primary endpoint of progression-free survival(PFS)was significantly improved with treatment using cabozantinib combined with atezolizumab compared with sorafenib in the COSMIC-312 trial,the overall survival(OS)did not improve,and the response rate was lower than expected(3).Nevertheless,this was a crucial randomized controlled trial(RCT)evaluating the efficacy of MKI-based immunotherapy doublet as the first-line systemic therapy for advanced HCC,paving the way for future investigations to determine the underlying mechanism of these connections.We have several concerns with the interpretation of this study.

Oncolytic virus-based hepatocellular carcinoma treatment:Current status,intravenous delivery strategies,and emerging combination therapeutic solutions

Current treatments for advanced hepatocellular carcinoma(HCC)have limited success in improving patients’quality of life and prolonging life expectancy.The clinical need for more efficient and safe therapies has contributed to the exploration of emerging strategies.Recently,there has been increased interest in oncolytic viruses(OVs)as a therapeutic modality for HCC.OVs undergo selective replication in cancerous tissues and kill tumor cells.Strikingly,pexastimogene devacirepvec(Pexa-Vec)was granted an orphan drug status in HCC by the U.S.Food and Drug Administration(FDA)in 2013.Meanwhile,dozens of OVs are being tested in HCC-directed clinical and preclinical trials.In this review,the pathogenesis and current therapies of HCC are outlined.Next,we summarize multiple OVs as single therapeutic agents for the treatment of HCC,which have demonstrated certain efficacy and lowtoxicity.Emerging carrier cell-,bioengineered cell mimetic-or nonbiological vehicle-mediated OV intravenous delivery systems in HCC therapy are described.In addition,we highlight the combination treatments between oncolytic virotherapy and other modalities.Finally,the clinical challenges and prospects of OV-based biotherapy are discussed,with the aim of continuing to develop a fascinating approach in HCC patients.

Relationship between outcomes and relative dose intensity of lenvatinib treatment in patients with advanced hepatocellular carcinoma

Background and aims:Lenvatinib(LEN)is a newly developed tyrosine kinase inhibitor,and is approved as a first-line treatment for advanced hepatocellular carcinoma(HCC)in Japan.This retrospective multi-center study investigated the effect of the relative dose intensity(RDI)of LEN on response rate,progression-free survival(PFS),and overall survival(OS).Methods:This retrospective study enrolled 123 patients with advanced HCC who were treated with LEN at six hospitals in Japan between March 2018 and December 2019.These patients were divided into two groups:RDI≥70%(RDI 70 group,N=70)or RDI<70%(control group,N=53)in the first 30 days.The following data were compared between groups:patient backgrounds,adverse events,treatment out-comes,PFS,and OS.PFS and OS were analyzed using the Kaplan-Meier method,followed by the log-rank test.To identify significant factors that contributed to response,PFS,and OS,multivariate analysis was performed using factors for which P-values were<0.10 in univariate analysis.Results:The proportion of patients with Child-Pugh class 5A was significantly greater in the RDI 70 group than that in the control group(64.3%vs.28.3%,P<0.01).Dose interruption due to adverse events was significantly more common in the control group.The response rate was significantly higher in the RDI 70 group than that in the control group(35.7%vs.11.3%,P<0.01).Median PFS was significantly longer in the RDI 70 group(9.4 vs.4.7 months,P<0.01).Multivariate analysis showed that RDI≥70%(hazard ratio(HR)=0.55,P=0.025),hypertension grade≥2(HR=0.47,P=0.019),and response(HR=0.52,P=0.033)were independently associated with improved PFS.Median OS was also significantly longer in the RDI 70 group(20.0 vs.13.3 months,P=0.045).Multivariate analysis showed that female sex(HR=0.33,P=0.034)and disease control(HR=0.31,P<0.01)were independently associated with improved OS.RDI≥70%was not statistically significant in multivariate analysis.Conclusions:Our study revealed the importance of achieving RDI≥70%in the first 30 days of treatment to maximize the effects of LEN。

Transarterial chemoembolization combined with radiofrequency ablation in the treatment of large hepatocellular carcinoma with stage C

BACKGROUND The combination therapy of transarterial chemoembolization and radiofrequency ablation(TACE-RFA)shows promising efficacy in large hepatocellular carcinoma(HCC).Data on the clinical efficacy and safety of TACE-RFA for large HCC with barcelona clinic liver cancer(BCLC)stage C are lacking in China.AIM To determine the safety and efficacy of TACE-RFA for large,advanced HCC.METHODS Patients of HCC with BCLC stage C who were treated with TACE-RFA or TACE alone at our institute from August 2008 to January 2017 were retrospectively reviewed.The complications were observed.The associations between overall survival(OS)and treatment method were analysed.RESULTS Data were collected from 102 HCC patients.Among them,64 underwent TACERFA and 38 underwent TACE.The combination of TACE and RFA was safe.All complications were controllable.The median OS in the TACE-RFA group was significantly longer than that in the TACE group(8.0 mo vs 4.0 mo,P=0.000).The 6-,12-and 24-mo survival rates of the combination group were 68.8%,34.4%,and 10.9%,respectively,while those of the TACE group were 36.8%,7.9%,and 0%(P<0.05).CONCLUSION TACE-RFA has an advantage over TACE alone in improving OS in large HCC patients with BCLC stage C.

RECENT ADVANCES IN CLINICAL RESEARCH OF HEPATOCELLULAR CARCINOMA IN CHINA

Hepatocellular carcinoma (HCC), the second cancer killer in rural areas and the third cancer killer in cities, has resulted in 110000 annual deaths in China, which amounts to 40% of liver cancer deaths in the world.