Hepatic arterial infusion chemotherapy with anti-angiogenesis agents and immune checkpoint inhibitors for unresectable hepatocellular carcinoma and meta-analysis

BACKGROUND Hepatic arterial infusion chemotherapy(HAIC)has been proven to be an ideal choice for treating unresectable hepatocellular carcinoma(uHCC).HAIC-based treatment showed great potential for treating uHCC.However,large-scale studies on HAIC-based treatments and meta-analyses of first-line treatments for uHCC are lacking.AIM To investigate better first-line treatment options for uHCC and to assess the safety and efficacy of HAIC combined with angiogenesis inhibitors,programmed cell death of protein 1(PD-1)and its ligand(PD-L1)blockers(triple therapy)under real-world conditions.METHODS Several electronic databases were searched to identify eligible randomized controlled trials for this meta-analysis.Study-level pooled analyses of hazard ratios(HRs)and odds ratios(ORs)were performed.This was a retrospective single-center study involving 442 patients with uHCC who received triple therapy or angiogenesis inhibitors plus PD-1/PD-L1 blockades(AIPB)at Sun Yat-sen University Cancer Center from January 2018 to April 2023.Propensity score matching(PSM)was performed to balance the bias between the groups.The Kaplan-Meier method and cox regression were used to analyse the survival data,and the log-rank test was used to compare the suvival time between the groups.RESULTS A total of 13 randomized controlled trials were included.HAIC alone and in combination with sorafenib were found to be effective treatments(P values for ORs:HAIC,0.95;for HRs:HAIC+sorafenib,0.04).After PSM,176 HCC patients were included in the analysis.The triple therapy group(n=88)had a longer median overall survival than the AIPB group(n=88)(31.6 months vs 14.6 months,P<0.001)and a greater incidence of adverse events(94.3%vs 75.4%,P<0.001).CONCLUSION This meta-analysis suggests that HAIC-based treatments are likely to be the best choice for uHCC.Our findings confirm that triple therapy is more effective for uHCC patients than AIPB.

Predicting the prognosis of hepatic arterial infusion chemotherapy in hepatocellular carcinoma

Hepatic artery infusion chemotherapy(HAIC)has good clinical efficacy in the treatment of advanced hepatocellular carcinoma(HCC);however,its efficacy varies.This review summarized the ability of various markers to predict the efficacy of HAIC and provided a reference for clinical applications.As of October 25,2023,51 articles have been retrieved based on keyword predictions and HAIC.Sixteen eligible articles were selected for inclusion in this study.Comprehensive literature analysis found that methods used to predict the efficacy of HAIC include serological testing,gene testing,and imaging testing.The above indicators and their combined forms showed excellent predictive effects in retrospective studies.This review summarized the strategies currently used to predict the efficacy of HAIC in middle and advanced HCC,analyzed each marker's ability to predict HAIC efficacy,and provided a reference for the clinical application of the prediction system.

Efficacy of hepatic arterial infusion chemotherapy and its combination strategies for advanced hepatocellular carcinoma:A network meta-analysis

BACKGROUND With the rapid progress of systematic therapy for hepatocellular carcinoma(HCC),therapeutic strategies combining hepatic arterial infusion chemotherapy(HAIC)with systematic therapy arised increasing concentrations.However,there have been no systematic review comparing HAIC and its combination strategies in the first-line treatment for advanced HCC.AIM To investigate the efficacy and safety of HAIC and its combination therapies for advanced HCC.METHODS A network meta-analysis was performed by including 9 randomized controlled trails and 35 cohort studies to carry out our study.The outcomes of interest comprised overall survival(OS),progression-free survival(PFS),tumor response and adverse events.Hazard ratios(HR)and odds ratios(OR)with a 95% confidence interval(CI)were calculated and agents were ranked based on their ranking probability.RESULTS HAIC outperformed Sorafenib(HR=0.55,95%CI:0.42-0.72;HR=0.51,95%CI:0.33-0.78;OR=2.86,95%CI:1.37-5.98;OR=5.45,95%CI:3.57-8.30;OR=7.15,95%CI:4.06-12.58;OR=2.89,95%CI:1.99-4.19;OR=0.48,95%CI:0.25-0.92,respectively)and transarterial chemoembolization(TACE)(HR=0.50,95%CI:0.33-0.75;HR=0.62,95%CI:0.39-0.98;OR=3.08,95%CI:1.36-6.98;OR=2.07,95%CI:1.54-2.80;OR=3.16,95%CI:1.71-5.85;OR=2.67,95%CI:1.59-4.50;OR=0.16,95%CI:0.05-0.54,respectively)in terms of efficacy and safety.HAIC+lenvatinib+ablation,HAIC+ablation,HAIC+anti-programmed cell death 1(PD-1),and HAIC+radiotherapy had the higher likelihood of providing better OS and PFS outcomes compared to HAIC alone.HAIC+TACE+S-1,HAIC+lenvatinib,HAIC+PD-1,HAIC+TACE,and HAIC+sorafenib had the higher likelihood of providing better partial response and objective response rate outcomes compared to HAIC.HAIC+PD-1,HAIC+TACE+S-1 and HAIC+TACE had the higher likelihood of providing better complete response and disease control rate outcomes compared to HAIC alone.CONCLUSION HAIC proved more effective and safer than sorafenib and TACE.Furthermore,combined with other interventions,HAIC showed improved efficacy over HAIC monotherapy according to the treatment ranking analysis.

Current research status of transarterial therapies for hepatocellular carcinoma

With continuous advancements in interventional radiology,considerable progress has been made in transarterial therapies for hepatocellular carcinoma(HCC)in recent years,and an increasing number of research papers on transarterial therapies for HCC have been published.In this editorial,we comment on the article by Ma et al published in the recent issue of the World Journal of Gastrointestinal Oncology:“Efficacy and predictive factors of transarterial chemoembolization combined with lenvatinib plus programmed cell death protein-1 inhibition for unresectable HCC”.We focus specifically on the current research status and future directions of transarterial therapies.In the future,more studies are needed to determine the optimal transarterial local treatment for HCC.With the emergence of checkpoint immunotherapy modalities,it is expected that the results of trials of transarterial local therapy combined with systemic therapy will bring new hope to HCC patients.

Successful Treatment of Intra-Arterial Peplomycin Infusion for Recurrent Oral Florid Papillomatosis

A 56-year-old woman had noticed the erosion of oral mucosa and tongue 8 years ago. The mucosal lesions had been initially diagnosed as oral lichen planus and resistant to various treatments with prednisolone, etretinate and mizoribine and so on. One year ago, rapidly growing verrucous lesion occurred on her upper lip. Although we administered intralesional radiation therapy, the tumor recurred and new whitish lesions on the buccal mucosa and hard palate occurred 9 months after treatment. We confirmed an anatomical blood supply to the tumors by a fluorescent real-time imaging system and subsequently administered the intra-arterial infusion of peplomycin through retrograde catheters from bilateral superficial temporal arteries under the final diagnosis as oral florid papillomatosis (OFP). The tumors were dramatically shrunk and did not recur 16 months after treatment. OFP is known as clinically multiple whitish and verrucous lesions over the oral cavity and lip and a subtype of SCC with high differentiation. We suppose that an intra-arterial infusion therapy of peplomycin should be considered as the curative treatment for OFP.

Hepatic artery infusion chemotherapy using mFOLFOX versus transarterial chemoembolization for massive unresectable hepatocellular carcinoma:a prospective non.randomized study

Background: Transarterial chemoembolization(TACE) is recommended as the standard care for unresectable hepatocellular carcinoma(HCC) at Barcelona Clinic Liver Cancer(BCLC) stage A-B. However, the efficacy of TACE on large(> 10 cm) stage A-B HCC is far from satisfactory, and it is proposed that hepatic artery infusion chemotherapy(HAIC)might be a better first-line treatment of this disease. Hence, we compared the safety and efficacy of HAIC with the modified FOLFOX(mFOLFOX) regimen and those ofTACE in patients with massive unresectable HCC.Methods: A prospective, non-randomized, phase II study was conducted on patients with massive unresectable HCC. The protocol involved HAIC with the mFOLFOX regimen(oxaliplatin, 85 mg/m^2 intra-arterial infusion; leucovorin,400 mg/m^2 intra-arterial infusion; and fluorouracil, 400 mg/m2 bolus infusion and 2400 mg/m^2 continuous infusion)every 3 weeks and TACE with 50 mg of epirubicin, 50 mg of lobaplatin, 6 mg of mitomycin, and lipiodol and polyvinyl alcohol particles. The tumor responses, time-to-progression(TTP), and safety were assessed.Results: A total of 79 patients were recruited for this study: 38 in the HAIC group and 41 in the TACE group. The HAIC group exhibited higher partial response and disease control rates than did the TACE group(52.6% vs. 9.8%, P < 0.001;83.8% vs. 52.5%, P = 0.004). The median TTPs for the HAIC and TACE groups were 5.87 and 3.6 months(hazard radio[HR] = 2.35,95% confidence interval [CI] = 1.16-4.76, P = 0.015). More patients in the HAIC group than in the TACE group underwent resection(10 vs. 3,P = 0.033). The proportions of grade 3-4 adverse events(AE) and serious adverse events(SAE) were lower in the HAIC group than in the TACE group(grade 3-4 AEs: 13 vs. 27, P = 0.007;SAEs: 6 vs. 15,p = 0.044). More patients in the TACE group than in the HAIC group had the study treatment terminated early due to intolerable treatment-related adverse events or the withdrawal of consent(10 vs. 2,P = 0.026).Conclusions: HAIC with mFOLFOX yielded significantly better treatment responses and less serious toxicity than did TACE. HAIC might represent a feasible and promising first-line treatment for patients with massive unresectable HCC.

Chemoembolization alone vs combined chemoembolization and hepatic arterial infusion chemotherapy in inoperable hepatocellular carcinoma patients

AIM: To compare the efficacy and safety of chemoem-bolization alone or chemoembolization combined with hepatic arterial infusion chemotherapy(HAIC),including oxaliplatin(OXA),5-fluorouracil(5-FU) and folinic acid(CF),in inoperable hepatocellular carcinoma(HCC) without distant metastasis. METHODS: Eighty-four inoperable HCC patients were enrolled. Thirty-ninepatient sunderwent chemoembolization alone,and the other 45 patients underwent chemoembolization + HAIC(OXA/5-FU/CF) treatment non-randomly. The progression free survival(PFS),objective response rate(ORR),disease control rate(DCR) and adverse reactions were compared between the two groups.RESULTS: A significant difference in the ORR was observed between the chemoembolization alone and chemoembolization + HAIC groups. There was no statistically significant difference in DCR between the two groups. The median PFS(m PFS) showed a significant difference between the two groups. For patients with BCLC stage A/B disease,with or without vessel invasion,the chemoembolization + HAIC group showed better m PFS when compared to chemoembolization alone,but no significant difference was found in patients with BCLC stage C disease. The parameter of pain(grade Ⅲ-Ⅳ) in the chemoembolization + HAIC group was increased statistically. CONCLUSION: Chemoembolization combined with HAIC with OXA/5-FU/CF may be safe and more effective than chemoembolization alone for inoperable HCC patients without distant metastasis.

Continuous regional arterial infusion for the treatment of severe acute pancreatitis: a meta-analysis

BACKGROUND： Continuous regional arterial infusion（CRAI） is a drug delivery system, which dramatically increases the drug concentration in the pancreas. Previous clinical and basic studies have demonstrated the possible therapeutic efficacy of CRAI for severe acute pancreatitis（SAP）. This meta-analysis of all published randomized controlled trials（RCTs） was conducted to assess the efficacy and safety of CRAI for the treatment of SAP. DATA SOURCES： Up to August 10, 2014, RCTs comparing CRAI with intravenous infusion for SAP in PubM ed, Embase, EBSCO, MEDLINE, Science Citation Index Expanded, Cochrane Library, China Academic Journals Full-Text Database, Chinese Biomedical Literature Database, and Chinese Scientific Journals Database were selected by two independent reviewers. The relative risk（RR） and their 95% confidence intervals（CI） for duration of elevated serum amylase and urine amylase, duration of abdominal pain, infection rate, incidence of complication, overall mortality, curative rate, hospital stay and details of subgroup analysis were extracted. Meta-analyses were made using the software Review Manager（RevM an version 5.10）.RESULTS： Six RCTs with 390 patients meeting the inclusion criteria were included in the final analysis. Compared with intravenous infusion route, CRAI significantly shortened the duration of elevated urine amylase（MD=-2.40, 95% CI=-3.20,-1.60; P〈0.00001） and the duration of abdominal pain（MD=-1.46, 95% CI=-1.94,-0.98; P〈0.00001）, decreased the incidence of complication（RR=0.35, 95% CI=0.15, 0.81; P=0.01） and overall mortality（RR=0.25, 95% CI=0.08, 0.78;P=0.02）, shortened the duration of hospital stay（MD=-10.36, 95% CI=-17.05,-3.68; P=0.002）, and increased the curative rate（RR=1.66, 95% CI=1.13, 2.46; P=0.01）. No mortality and catheter-related infections due to CRAI administration was reported in these studies. Subgroup analysis showed that the combination of drug administration via CRAI did not significantly improve the outcomes.CONCLUSION： CRAI is effective for the treatment of SAP, and the combination of drug administration via CRAI did not have a significant effect on the improvement of the outcomes.

Treatment strategies for advanced hepatocellular carcinoma:Sorafenib vs hepatic arterial infusion chemotherapy

Sorafenib is used worldwide as a first-line standardsystemic agent for advanced hepatocellular carcinoma(HCC) on the basis of the results of two large-scale Phase Ⅲ trials. Conversely,hepatic arterial infusion chemotherapy(HAIC) is one of the most recommended treatments in Japan. Although there have been no randomized controlled trials comparing sorafenib with HAIC,several retrospective analyses have shown no significant differences in survival between the two therapies. Outcomes are favorable for HCC patients exhibiting macroscopic vascular invasion when treated with HAIC rather than sorafenib,whereas in HCC patients exhibiting extrahepatic spread or resistance to transcatheter arterial chemoembolization,good outcomes are achieved by treatment with sorafenib rather than HAIC. Additionally,sorafenib is generally used to treat patients with Child-Pugh A,while HAIC is indicated for those with either Child-Pugh A or B. Based on these findings,we reviewed treatment strategies for advanced HCC. We propose that sorafenib might be used as a first-line treatment for advanced HCC patients without macroscopic vascular invasion or Child-Pugh A,while HAIC is recommended for those with macroscopic vascular invasion or Child-Pugh A or B. Additional research is required to determine the best second-line treatment for HAIC non-responders with Child-Pugh B through future clinical trials.

Prognostic factors for transarterial chemoembolization combined with sustained oxaliplatin-based hepatic arterial infusion chemotherapy of colorectal cancer liver metastasis

Objective： To investigate the prognostic factors in chemorefractory colorectal cancer liver metastasis（CRCLM）patients treated by transarterial chemoembolization（TACE） and sustained hepatic arterial infusion chemotherapy（HAIC）.Methods： Between 2006 and 2015, 162 patients who underwent 763 TACE and HAIC in total were enrolled in this retrospective study, including 110 males and 52 females, with a median age of 60（range, 26–83） years.Prognostic factors were assessed with Log-rank test, Cox univariate and multivariate analyses.Results： The median survival time（MST） and median progression-free survival（PFS） of the 162 patients from first TACE/HAIC were 15.6 months and 5.5 months respectively. Normal serum carbohydrate antigen 19-9（CA19-9, 〈37 U/m L）（P〈0.001） and carbohydrate antigen 72-4（CA72-4, 〈6.7 U/m L）（P=0.026）, combination with other local treatment（liver radiotherapy or liver radiofrequency ablation）（P=0.034） and response to TACE/HAIC（P〈0.001） were significant factors related to survival after TACE/HAIC in univariate analysis. A multivariate analysis revealed that normal serum CA19-9（P〈0.001）, response to TACE/HAIC（P〈0.001） and combination with other local treatment（P=0.001） were independent factors among them.Conclusions： Our findings indicate that serum CA19-9 〈37 U/m L and response to TACE/HAIC are significant prognostic indicators for this combined treatment, and treated with other local treatment could reach a considerable survival benefit for CRCLM. This could be useful for making decisions regarding the treatment of CRCLM.

Hepatic arterial infusion chemotherapy in hepatocellular carcinoma with portal vein tumor thrombosis

AIM: To evaluate the prognostic factors and efficacy of hepatic arterial infusion chemotherapy in hepatocellular carcinoma with portal vein tumor thrombosis. METHODS: Fifty hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) were treated using hepatic arterial infusion chemotherapy (HAIC) via a subcutaneously implanted port. The epirubicin-cisplatin-5-fluorouracil (ECF) chemotherapeutic regimen consisted of 35 mg/m 2 epirubicin on day 1, 60 mg/m 2 cisplatin for 2 h on day 2, and 500 mg/m 2 5-fluorouracil for 5 h on days 1-3. The treatments were repeated every 3 or 4 wk. RESULTS: Three (6%) of the 50 patients achieved a complete response (CR), 13 (26%) showed partial responses (PR), and 22 (44%) had stable disease (SD).The median survival and time to progression were 7 and 2 mo, respectively. After 2 cycles of HAIC, CR was achieved in 1 patient (2%), PR in 10 patients (20%) and SD in 26 patients (52%). Significant pre-treatment prognostic factors were a tumor volume of < 400 cm 3 (P = 0.01) and normal levels of protein induced by vitamin K absence or antagonist (PIVKA)-Ⅱ (P = 0.022). After 2 cycles of treatment, disease control (CR + PR + SD) (P = 0.001), PVTT response (P = 0.003) and α-fetoprotein reduction of over 50% (P = 0.02) were independent factors for survival. Objective response (CR + PR), disease control, PVTT response, and combination therapy during the HAIC were also significant prognostic factors. Adverse events were tolerable and successfully managed. CONCLUSION: HAIC may be an effective treatment modality for advanced HCC with PVTT in patients with tumors < 400 cm 3 and good prognostic factors.

Continuous regional arterial infusion therapy with gabexate mesilate for severe acute pancreatitis

AIM： To evaluate the efficacy of continuous regional arterial infusion therapy （CRAI） with gabexate mesilate and antibiotics for severe acute pancreatitis （SAP）. METHODS： We conducted a prospective study on patients who developed SAP with or without CRAI. Out of 18 patients fulfilled clinical diagnostic criteria for SAP in Japan, 9 patients underwent CRAI, while 9 patients underwent conventional systemic protease inhibitor and antibiotics therapy （non-CRAI）. CRAI was initiated within 72 h of the onset of pancreatitis. Gabexate mesilate （2400 mg/d） was continuously administered for 3 to 5 d. The clinical outcome including serum inflammation-related parameters were examined. RESULTS- The duration of abdominal pain in the CRAI group was 1.9 =1：0.26 d, whereas that in the non-CRAI group was 4.3 ±0.50. The duration of SIRS in the CRAI group was 2.2 ± 0.22 d, whereas that in the non- CRAI group was 3.2 ± 0.28. Abdominal pain and SIRS disappeared significantly in a short period of time after the initiation of CRAI using gabexate mesilate. The average length of hospitalization significantly differed between the CRAI and non-CRAI groups, 53.3 ± 7.9 d and 87.4± 13.9 d, respectively. During the first two weeks, levels of serum CRP and the IL6/IL10 ratio in the CRAI group tended to have a rapid decrease compared to those in the non-CRAI group. CONCLUSION： The present results suggest that CRAI using gabexate mesilate was effective against SAP.

Transarterial embolization and low-dose continuous hepatic arterial infusion chemotherapy with oxaliplatin and raltitrexed for hepatocellular carcinoma with major portal vein tumor thrombus

AIM To determine the efficacy and safety of transarterial embolization and low-dose continuous hepatic arterial infusion chemotherapy with oxaliplatin and raltitrexed in hepatocellular carcinoma(HCC) with major portal vein tumor thrombus(MPVTT).METHODS eighty-six patients with MPVTT accepted routine embolization. The catheter was kept in the hepatic artery and oxaliplatin(50 mg in 250 m L of glucose) was infused by pump for 4 h,followed by raltitrexed(2 mg in 100 m L of 0.9% saline) infusion by pump for the next 1 h. The efficacy and safety were evaluated afterthe transarterial chemoembolization(TACe).RESULTS Full or partial embolization was achieved in 86 cases,where all the cases received low dose continuous hepatic arterial infusion chemotherapy. Complete responses(CRs),partial responses(PRs),stable disease(SD),and disease progression(PD) for intrahepatic disease were observed in 0,45,20,and 21 patients,respectively. The 1-,2-and 3-year overall survival rates of the 86 patients were 40.7%,22.1%,and 8.1% respectively,and the median survival time was 8.7 mo. Complication was limited. CONCLUSION TACE with low dose continuous hepatic arterial infusion of oxaliplatin and raltitrexed could be an option in MPVTT patient; it was shown to be effective in patients with advanced HCC with MPVTT with less toxicity.

Sorafenib combined with embolization plus hepatic arterial infusion chemotherapy for inoperable hepatocellular carcinoma

BACKGROUND There is little evidence of combining sorafenib with hepatic arterial infusion chemotherapy(HAIC)after transarterial chemoembolization(TACE)for intermediate and advanced hepatocellular carcinoma(HCC).It is important to identify that patients with intermediate and advanced HCC are most likely to benefit from this combination therapy.AIM To investigate the safety and clinical outcomes of sorafenib combined with HAIC with folinic acid,5-fluorouracil(5-FU),and oxaliplatin(FOLFOX)after TACE for intermediate and advanced HCC.METHODS This prospective phase II study enrolled patients with intermediate and advanced HCC who underwent treatment with sorafenib combined with TACEHAIC.All patients initially received the standard 400 mg dose of sorafenib twice daily before TACE-HAIC.Participants at our institute with intermediate and advanced HCC underwent routine TACE.Then,the catheter used for embolization was kept in place in the hepatic artery,and oxaliplatin was intraarterially administered for 6 h,followed by 5-FU for 18 h,and folinic acid was intravenously administered for 2 h.The primary endpoints were safety,as evaluated by the Common Terminology and Criteria for Adverse Events version 4.0,and 12-mo progression-free survival(PFS),as analyzed by the Kaplan-Meier method.As secondary endpoints,the objective response rate(ORR)was evaluated by the modified Response Evaluation Criteria for Solid Tumors,and survival time[overall survival(OS)]was analyzed by the Kaplan-Meier method.RESULTS Sixty-six participants at our institute with intermediate and advanced HCC were enrolled in this prospective study(mean age,53.3±11.7 years).Approximately 56.1%of participants had Barcelona Clinic Liver Cancer(BCLC)stage C disease,and 43.9%had BCLC stage B disease.The ORR was 42.4%.The disease control rate was 87.9%.The grade 3-4 toxicities consisted of thrombocytopenia(4.5%),neutropenia(3.0%),and elevated aspartate aminotransferase(12.2%).Hand-foot skin reaction was also observed(40.9%).The median PFS was 13.1 mo(13.5 mo in the BCLC stage B participants and 9.4 mo in the BCLC stage C participants).The 6-mo,12-mo,and 24-mo PFS rates were 75.0%,54.7%,and 30.0%,respectively.The median OS was 21.8 mo.CONCLUSION Sorafenib combined with HAIC(FOLFOX)after TACE may be a feasible treatment choice for intermediate and advanced HCC because this treatment met the prespecified endpoint of a 6-mo PFS rate exceeding 50%and had good patient tolerance.Prospective randomized controlled trials are needed to confirm the effect of this combination therapy.

Safety and efficacy of hepatic arterial infusion chemotherapy with raltitrexed and oxaliplatin post-transarterial chemoembolization for unresectable hepatocellular carcinoma

Objective:To investigate the safety,efficacy,and prognostic factors of hepatic arterial infusion chemotherapy(HAIC)with raltitrexed and oxaliplatin post-transarterial chemoembolization(TACE)for unresectable hepatocellular carcinoma(uHCC).Methods:Thirty-seven patients with uHCC who received HAIC with raltitrexed and oxaliplatin post-TACE between June 2014 and December 2016 at our hospital were recruited.The primary endpoint was overall survival(OS),and secondary endpoint was progression-free survival(PFS).The overall response rate(ORR)was evaluated using the modified Response Evaluation Criteria in Solid Tumors.Toxicity was assessed according to the Common Terminology Criteria for Adverse Events(v4.0).The OS and prognostic factors were analyzed using the Kaplan-Meier method,log-rank test,and Cox regression models.Results:Three(8.1%)patients achieved complete response,17(46.0%)patients achieved partial response,and the ORR was54.0%.The median OS and median PFS were 19.0 months and 12.0 months,respectively.The common toxicities included grade 3-4 increased aspartate aminotransferase levels(8/37,21.6%),grade 1-2 hyperbilirubinemia(75.7%,28/37),nonspecific abdominal pain and fever,and grade 2-3 thrombocytopenia(18.9%,7/37);no patients developed grade 3-4 neutropenia.Univariate analysis showed that the tumor diameter(≤50 mm,p=0.028),Barcelona Clinic Liver Cancer(BCLC)stage(p=0.012),hepatitis B virus DNA level(p=0.033),and derived neutrophil-to-lymphocyte ratio(dNLR;derived neutrophils/leukocytes minus neutrophils)(p=0.003)were predictive factors for prognosis.Multivariate analysis showed that patients with BCLC stage B disease(p=0.029)and dNLR<2 before therapy(p=0.004)had better prognosis.Conclusions:HAIC with raltitrexed and oxaliplatin post-TACE is a safe and efficacious therapy for patients with uHCC;in particular,those with BCLC stage B and dNLR<2 have better prognosis.

Effect of double platinum agents, combination of miriplatintransarterial oily chemoembolization and cisplatinhepatic arterial infusion chemotherapy, in patients with hepatocellular carcinoma: Report of two cases

Hepatocellular carcinoma(HCC) is one of the most common cancers and the third highest cause of cancerassociated mortality worldwide. The treatment of HCC is complicated by its variable biological behavior and the frequent coexistence of chronic liver disease, particularly cirrhosis. To date, multiple treatment modalities have been developed according to the stage of the tumor and the hepatic functional reserve, including transarterial treatments such as transarterial chemoembolization, transarterial oily chemoembolization(TOCE), and hepatic arterial infusion chemotherapy(HAIC). We conducted a phase I and II study of the combination therapy with double platinum agents, miriplatin and cisplatin, and confirmed its safety and efficacy. Here, we describe two cases of unresectable HCC who were successfully treated by miriplatin-TOCE/cisplatin-HAIC combination therapy, resulting in complete responses with no significant adverse events. This report will provide that the combination therapy can be the therapeutic option for HCC patients in the advanced stage.

A successful treatment by hepatic arterial infusion therapy for advanced,unresectable biliary tract cancer

Biliary tract cancers(BTC)are relatively rare tumors, and the prognosis is extremely poor.There has been no standard chemotherapy for advanced BTC.However, recently,gemcitabine(GEM)have been used against BTC as the most active agent,and promising response rates and overall survival times with tolerable drug toxicities have been observed.In this article,two cases of advanced intrahepatic cholangiocarcinoma and unresectable metastatic gallbladder(GB)cancer are reported.They were treated with hepatic arterial infusion(HAI)chemotherapy using a combination of GEM and cisplatin,along with the systemic administration of GEM.As a consequence,multiple liver tumors,the GB cancer and metastatic lymph nodes regressed without severe drug toxicities,and favorable results(the overall survival times were 16 and 14 mo, respectively)were achieved.In conclusion,HAI therapy using GEM combined with cisplatin may be a useful and well-tolerated option for advanced BTC,especially in cases where multiple liver metastases are detected.

Is hepatic arterial infusion chemotherapy effective treatment for advanced hepatocellular carcinoma resistant to transarterial chemoembolization?

AIM:To evaluate the effectiveness of hepatic arterial infusion chemotherapy(HAIC) for advanced hepatocellular carcinoma(HCC) resistant to transarterial chemoembolization(TACE).METHODS:This study was conducted on 42 patients who received HAIC for advanced HCC between 2001and 2010 at our hospital.5-fluorouracil(5-FU) was administered continuously for 24 h from day 1 to day 5 every 2-4 wk via an injection reservoir.Intra-arterial cisplatin or subcutaneous interferon was administered in combination with the 5-FU.The patients enrolled in this retrospective study were divided into two groups according to whether or not they fulfilled the criteria for resistance to TACE proposed by the Japan Society of Hepatology in 2010(written in Japanese);one group of patients who did not fulfill the criteria for TACE resistance(group A,n = 23),and another group who fulfilled the criteria for TACE resistance(group B,n = 19).We compared the outcomes in terms of the response and survival rates between the two groups.RESULTS:Both the response rate and tumor suppression rate following HAIC were significantly superior in group A than in group B(response rate:48% vs 16%,P = 0.028,tumor suppression rate:87% vs 53%,P = 0.014).Furthermore,both the progression-free survival rate and survival time were significantly superior in group A than in group B(3-,6-,12-,and 24-mo = 83%,70%,29% and 20% vs 63%,42%,16% and 0%,respectively,P = 0.040,and 9.8 mo vs 6.2 mo,P = 0.040).A multivariate analysis(Cox proportional hazards regression model) showed that resistance to TACE was an independent predictor of poor survival(P = 0.007).CONCLUSION:HAIC administrating 5-FU was not effective against advanced HCC resistant to TACE.Other tools for treatment,i.e.,molecular-targeting agents may be considered for these cases.

Relationship between therapeutic efficacy of arterial infusion chemotherapy and expression of P-glycoprotein and p53 protein in advanced hepatocellular carcinoma

AIM： To investigate the relationship between the chemotherapeutic drug efficacy and the expression of P-glycoprotein （PGP） and p53 protein in advanced hepatocellular carcinoma （HCC）. METHODS： The study was conducted on 41 patients with advanced HCC who were treated by repeated arterial infusion chemotherapy. Biopsy specimens from the tumor were collected before the start of treatment in all the patients, and the specimens were stored frozen until immunohistochemical staining, which was performed after the start of treatment, to detect PGP and p53 protein expressions. Twenty of the fortyone patients were treated with an anthracycline drug （epirubicin hydrochloride; anthracycline group）, and the remaining 21 were treated with a non-anthracycline drug （mitoxantrone hydrochloride in 11 patients and carboplatin in 10 patients; non-anthracycline group）. The relationship between the chemotherapeutic efficacy and the results of immunostaining were compared between the two groups. RESULTS： Before the start of the treatment, PGPpositive rate was 90.2% （strongly-positive, 36.6%） and p53 protein-positive rate was 34.1% （strongly-positive, 19.5%）. In the anthracycline group, the response rate was 40.0%. The number of patients showing poor response to the treatment was significantly larger in the patients with strongly positive PGP expression （P= 0.005）, and their prognoses were poor （P= 0.001）. in the nonanthracycline group, the response rate was 42.9%,and there was no significant relationship between the chemotherapeutic drug efficacy and the PGP or p53 protein expression. When only the data from the 11 patients treated with anthraquinone drug, mitoxantrone, were analyzed, however, the number of patients who showed poor response to treatment was significantly higher among the p53-positive patients （P= 0.012）, irrespective of the survival outcome. CONCLUSION： The chemotherapeutic efficacy with an anthracycline drug for advanced HCC can be predicted by immunohistochemical analysis of PGP expression. Similarly, immunostaining to evaluate p53 protein may be useful to predict the response in patients treated with an anthraquinone drug.

Sorafenib plus hepatic arterial infusion chemotherapy with oxaliplatin versus sorafenib alone for advanced hepatocellular carcinoma

Objective:To compare the efficacy of sorafenib plus hepatic arterial infusion chemotherapy(HAIC)with oxaliplatin to that of sorafenib alone in patients with advanced hepatocellular carcinoma(HCC).Methods:This was a retrospective,single-center trial.Between April 3,2017 and July 2,2018,104 patients with Child-Pugh A and advanced HCC received either 400 mg of sorafenib orally twice daily plus HAIC with oxaliplatin(oxaliplatin 85 mg/m^2,every 3 weeks via repetitive catheterization)(n=46,soraOXA group)or 400 mg of only sorafenib orally twice daily(n=58,sorafenib group).Overall survival,progression-free survival,objective response rate,and treatment-related adverse events were compared.Results:The median overall survival was 9.37 months(95%CI,7.05-11.68)in the soraOXA group versus 4.8 months(95%CI,2.98-6.62)in the sorafenib group(HR 0.46[95%CI,0.29-0.72];P<0.001).The soraOXA group also showed a higher objective response rate(16[34.8%]vs 1[1.7%];P<0.001)and a longer progressionfree survival rate(5.5 months[95%CI,2.32-8.68]vs 2.4 months[95%CI,1.65-3.15],HR 0.54[95%CI,0.36-0.81],P=0.003)than the sorafenib group.There was no significant difference in the overall incidence of any grade adverse events,grade 3/4 adverse events,serious adverse events,or incidence of treatment termination due to adverse events between the two groups.Conclusion:Compared with sorafenib alone,sorafenib plus HAIC with oxaliplatin showed favorable treatment outcomes in patients with advanced HCC.The merits of this approach need to be established with a prospective trial.