Effect and Safety of Prophylactic Parecoxib for Pain Control of Transarterial Chemoembolization in Liver Cancer: A Single-Center, Parallel-Group, Randomized Trial.

OBJECTIVE: Pain is one of the most common side effects of transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma. The goal of this study is to compare the analgesic effect among celecoxib, parecoxib, and oxycodone in patients undergoing TACE. METHODS: This prospective study was a randomized, paralleled trial in which 213 patients were enrolled. Patients were assigned at the ratio of 1:1:1 to receive celecoxib, parecoxib, or controlled-release oxycodone 1 hour before TACE (T0) and once every 12 hours for 2 days after TACE. Pain scores, pain intensity, and adverse events in each time interval were evaluated and compared among the 3 groups. RESULTS: The mean pain score 12 hours after T0 in the parecoxib group (2.8) was lower than that in the celecoxib (4.4; P = .001) and oxycodone groups (4.2; P = .005). The number of patients suffering severe pain was 10 (14.7%) in the parecoxib, 25 (36.8%) in the celecoxib, and 23 (32.9%) in the oxycodone groups (P = .009). Twelve hours after T0, the incidence of grade 3 vomiting in the parecoxib group (2.9%) was significantly lower than that in the oxycodone group (17.1%; P = .006). In the multivariate analysis, nonparecoxib prophylactic analgesia (odds ratio [OR], 4.620; 95% confidence interval [CI], 1.877-11.370; P = .001) as well as embolization of the gallbladder (OR, 8.666; 95% CI, 2.402-31.262; P = .001) and normal liver parenchyma (OR, 3.278; 95% CI, 1.409-7.627; P = .006) were the independent factors of severe pain intensity 12 hours after T0. CONCLUSION: Parecoxib is superior to oxycodone and celecoxib for pain control with fewer adverse events. Therefore, we recommend parecoxib as a priority strategy for TACE-related pain control.

Arterial Chemotherapy of Oxaliplatin Plus Fluorouracil Versus Sorafenib in Advanced Hepatocellular Carcinoma: A Biomolecular Exploratory, Randomized, Phase III Trial (FOHAIC-1).

PURPOSE: Interventional hepatic arterial infusion chemotherapy of infusional fluorouracil, leucovorin, and oxaliplatin (HAIC-FO) displayed an encouraging safety profile and antitumor activity in a previous phase II trial and a propensity-score-matching study involving patients with locally advanced hepatocellular carcinoma (HCC). METHODS: In this open-label, phase III trial, patients with advanced HCC, previously untreated with systemic therapy, were randomly assigned in a 1:1 ratio to receive HAIC-FO or sorafenib. The primary end point was overall survival (OS) in the intention-to-treat population. An exploratory model for predicting the efficacy of HAIC-FO on the basis of genomic sequencing was developed. RESULTS: Between May 2017 and May 2020, 262 patients were randomly assigned. The median tumor size was 11.2 cm (interquartile range, 8.5-13.7 cm). Macrovascular invasion was present in 65.6%, and the percentage of patients with > 50% tumor volume involvement of the liver and/or Vp-4 portal vein tumor thrombosis was 49.2%. At data cutoff (October 31, 2020), median OS was 13.9 months for HAIC-FO and 8.2 for sorafenib (hazard ratio [HR] 0.408; 95% CI, 0.301 to 0.552; P < .001). Tumor downstaging occurred in 16 (12.3% of 130) patients receiving HAIC-FO, including 15 receiving curative surgery or ablation, and finally achieving a median OS of 20.8 months, with a 1-year OS rate of 93.8%. In high-risk subpopulations, OS was significantly longer with HAIC-FO than with sorafenib (10.8 months v 5.7 months; HR 0.343; 95% CI, 0.219 to 0.538; P < .001). A newly developed 15-mutant-gene prediction model identified 83% of patients with response to HAIC-FO. HAIC-FO responders had longer OS than HAIC-FO nonresponders (19.3 months v 10.6 months; HR 0.323; 95% CI, 0.186 to 0.560; P = .002). CONCLUSION: HAIC-FO achieved better survival outcomes than sorafenib in advanced HCC, even in association with a high intrahepatic disease burden.

Tumor-derived lactate inhibit the efficacy of lenvatinib through regulating PD-L1 expression on neutrophil in hepatocellular carcinoma.

BACKGROUND: Neutrophils play a controversial role in tumor development. The function of programmed cell death-1 ligand (PD-L1+) neutrophils, however, may inhibit the cytotoxicity of anti-tumor immunity. In this study, we elucidate the stimulators of PD-L1+ neutrophils in tumor microenvironment (TME) and explore the optimal combination to enhance the effect of lenvatinib by inhibiting PD-L1+ neutrophils in hepatocellular carcinoma. METHODS: Neutrophil infiltration after lenvatinib treatment was examined with RNA sequencing and multicolor flow cytometry analysis in patient samples, subcutaneous and orthotopic mouse models. Neutrophils and T cells were isolated from peripheral blood and tumor tissues and purified with magnetic beads for cytotoxicity assay. Metabolites and cytokines were detected by a biochemical analyzer manufactured by Yellow Springs Instrument (YSI) and proteome profiler cytokines array. In vitro screening of pathway inhibitors was used to identify possible candidates that could reduce PD-L1+ neutrophil infiltration. Further in vivo assays were used for verification. RESULTS: Lenvatinib increased neutrophil recruitment by inducing CXCL2 and CXCL5 secretion in TME. After entering TME, neutrophils polarized toward N2 phenotype. PD-L1 expression was simultaneously upregulated. Thus, lenvatinib efficacy on tumor cells hindered. The increasing PD-L1+ neutrophils positively corelated with a suppressive T cell phenotype. Further investigation indicated that JAK/STAT1 pathway activated by immune-cell-derived interferon γ and MCT1/NF-kB/COX-2 pathway activated by high concentrations of tumor-derived lactate could induce PD-L1+ neutrophils. The latter could be significantly inhibited by COX-2 inhibitor celecoxib. Further in vivo assays verified that Celecoxib decreased the survival of lactate-stimulated PD-L1+ neutrophil and promoted the antitumor effect of lenvatinib. CONCLUSIONS: PD-L1+ neutrophils decrease T cell cytotoxicity. Tumor-derived lactate induces PD-L1 expression on neutrophils via MCT1/NF-κB/COX-2 pathway. Thus, COX-2 inhibitor could reduce PD-L1+ neutrophil and restore T cell cytotoxicity. This may provide a potent addition to lenvatinib.

Hepatic Artery Infusion Chemotherapy Using Fluorouracil, Leucovorin, and Oxaliplatin versus Transarterial Chemoembolization as Initial Treatment for Locally Advanced Hepatocellular Carcinoma: A Propensity Score-Matching Analysis.

PURPOSE: To compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with a modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) regimen with that of transarterial chemoembolization as a locoregional treatment for patients with locally advanced hepatocellular carcinoma (HCC). METHODS: This retrospective study included adult patients with locally advanced HCC who received first-line treatment with either HAIC-mFOLFOX or conventional transarterial chemoembolization monotherapy from January 2015 to December 2016. The outcomes, including tumor response rates, evaluated via imaging assessment using the modified response evaluation criteria in solid tumors; overall survival; progression-free survival; and safety, were compared. The propensity score-matching methodology was used to reduce the influence of confounding factors on the outcomes. RESULTS: The study included 131 patients with locally advanced HCC who underwent transarterial chemoembolization and 101 who received HAIC-mFOLFOX as initial treatment. After propensity score matching (n = 67 in each group), patients who received HAIC-mFOLFOX had a higher objective response rate (43.3% vs 13.4%, P = .001), longer median overall survival (13.9 vs 6.0 months, P < .001), and longer median progression-free survival (6.4 vs 2.8 months, P = .001) than those who underwent transarterial chemoembolization. The survival benefit with HAIC-mFOLFOX was strengthened in patients with HCC with vascular invasion (hazard ratio: 0.379; 95% confidence interval: 0.237-0.607). HAIC-mFOLFOX was associated with lower incidences of severe adverse events (8.9% vs 22.9%) and liver toxicity than transarterial chemoembolization. CONCLUSIONS: Compared with transarterial chemoembolization, HAIC-mFOLFOX is a potentially safer and more effective locoregional therapy for patients with locally advanced HCC.

The guiding value of microvascular invasion for treating early recurrent small hepatocellular carcinoma.

INTRODUCTION: Hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI) have worse survival. Whether the presence of MVI indicates the necessity of more aggressive locoregional treatments for recurrences remains to be elucidated. METHODS: We reviewed patients who underwent curative hepatectomy for primary HCC in our institution, and 379 patients with recurrent HCC up to three nodules smaller than 3 cm were enrolled. The Kaplan-Meier method was adopted to compare the secondary recurrence-free survival (sRFS) and post-recurrence survival (PRS) among patients undergoing hepatectomy, RFA and transarterial chemoembolization plus RFA (TACE-RFA). Cox regression analyses were performed to identify independent prognostic factors. RESULTS: Both the sRFS and PRS of the MVI (-) group were significantly longer than those of the MVI (+) group (p = 0.001 and 0.011). For patients with MVI (-), no significant difference was found in sRFS or PRS among recurrent HCC patients receiving hepatectomy, RFA or TACE-RFA (p = 0.149 and 0.821). A similar trend was found in patients with MVI (+) (p = 0.851 and 0.960). Further analysis found that TACE-RFA provided better sRFS than hepatectomy or RFA alone in patients with MVI (+) and early recurrence within two years (p = 0.036 and 0.044). CONCLUSION: For HCC patients with MVI (+) and early small recurrence, TACE-RFA could achieve better prognosis than hepatectomy or RFA alone, while RFA alone provided comparable survival benefits compared with hepatectomy or TACE-RFA in other HCC patients with small recurrence.

Can Immediately Treating Subcentimeter Hepatocellular Carcinoma Improve the Survival of Patients?

BACKGROUND: With the development of imaging technology, an increasing number of subcentimeter hepatocellular carcinoma (HCC) has been detected. How to manage these lesions remains controversial and lacks evidence. We aimed to explore whether timely treating subcentimeter HCC is necessary considering the risks of false-positives and treatment failure. METHODS: In this retrospective study, we reviewed HCC patients treated with hepatectomy or ablation in our institution. Then, we enrolled 439 HCC patients with solitary lesion measuring up to 2 cm from November 1, 2009 to June 30, 2019. The baseline and clinical characteristics of these patients were collected. The patients were classified into primary and recurrent groups. The Kaplan-Meier method with Log-rank test was performed to compare the overall survival (OS) and recurrence-free survival (RFS) between patients with subcentimeter HCC and those with HCC measuring 1-2 cm. Univariate and multivariate analyses were adopted to identify prognostic factors for survival. RESULTS: The OS and RFS did not differ significantly between patients with subcentimeter HCC and those with HCC measuring 1-2 cm in the primary group (p = 0.12 and 0.75). Similar results were found in the recurrent group. In multivariate analysis, the albumin-bilirubin (ALBI) grade and serum alpha fetoprotein (AFP) level were significantly associated with OS and RFS in the primary group. The serum AFP level was the only factor that correlated with OS and RFS in the recurrent group. CONCLUSION: Routine screening for subcentimeter HCC is feasible. Considering uncertain diagnosis and treatment difficulties, it is more considerable to follow patients until lesions are larger than 1 cm and then provide curative treatments.

Ablation Reboots the Response in Advanced Hepatocellular Carcinoma With Stable or Atypical Response During PD-1 Therapy: A Proof-of-Concept Study.

Background: The anti-programmed cell death protein-1 (PD-1) inhibitor is one of the second-line therapies for advanced hepatocellular carcinoma (HCC) after sorafenib failure. The goal of this study is to evaluate the feasibility and safety of ablation on the tumor in patients with advanced HCC who had stable disease or atypical response during single anti-PD-1 therapy after sorafenib failure. Atypical response defined as mixed responses in different lesions of the same individual (e.g., active or stable lesions mixed with progressive lesions). Patients and Methods: This proof-of-concept clinical trial enrolled 50 patients treated with an anti-PD-1 inhibitor of nivolumab or pembrolizumab monotherapy between July 2015 and Nov 2017. Thirty-three cases with stable disease or atypical response to anti-PD-1 inhibitor received subtotal thermal ablation. The safety and the response of ablation during anti-PD-1 therapy were evaluated. The survival was estimated by the Kaplan-Meier curve. Results: Of all 50 patients treated with anti-PD-1 therapy, the rate of response, stable disease, atypical and typical progression were 10% (n = 5), 42% (n = 21) 32% (n = 16), and 12% (n = 6), respectively. Additional ablation improved efficacy with tolerable toxicity, and the response rate was increased from 10 to 24% (12/50). The median time to progression, progression-free survival, and overall survival was 6.1 months (95%CI, 2.6-11.2), 5 months (95%CI, 2.9-7.1), and 16.9 months (95%CI, 7.7-26.1), respectively. Conclusions: This proof-of-concept trial suggested that additional ablation may increase the objective response rate with tolerated toxicity and achieved a relatively better median survival, in advanced HCC patients who had stable or atypical progressive diseases during anti-PD-1 therapy, which may provide a potentially promising strategy to treat advanced HCC. Trial registration number: ClinicalTrials.gov identifier: NCT03939975.

Follow-up schedule for initial recurrent hepatocellular carcinoma after ablation based on risk classification.

BACKGROUND: To date, no standard follow-up guidelines exist regarding patients receiving ablation for initial recurrent hepatocellular carcinoma (HCC). We aimed to explore whether intensive follow-up could benefit these patients. METHODS: We reviewed the clinical data of patients who received complete ablation for initial HCC recurrence after curative treatments in our institution from January 2005 to June 2017. Risk factors for second recurrence of HCC were identified by univariate and multivariate analyses. Patients were classified into low- and high-risk groups according to the outcome of the classification and regression model. The patients were further categorized into short- (< 3 months) and long-interval (3-6 months) follow-up subgroups based on their surveillance in the first 2 years after complete ablation for initial recurrence. The Kaplan-Meier method with log-rank test was performed to compare the overall survival (OS) based on follow-up intervals in each risk group. We also validated our results by stratifying patients into subgroups with different numbers of risk factors and comparing the OS between patients with different follow-up intervals. RESULTS: A total of 361 patients were enrolled. The risk factors for secondary recurrence included the Barcelona Clinic Liver Cancer (BCLC) stage at initial recurrence and first recurrence-free survival after curative treatments for primary HCC (p < 0.001 and p = 0.002). Two risk groups (low and high) were identified. In both the low- and high-risk groups, the OS of patients was not associated with intervals of follow-up (p = 0.29 and 0.49). No significant difference was found in the rates of BCLC 0/A stage, tumor location or curative treatments for the second recurrence by different follow-up intervals in each risk group (p = 0.34 and 0.87; p = 0.69 and 0.97). The same tendency was found in subgroups with 0/1/2 risk factors for secondary recurrence during validation. CONCLUSION: The long-interval follow-up did not compromise the survival of patients with complete ablation for initial recurrent HCC.

Effects of Antiviral Therapy on HBV Reactivation and Survival in Hepatocellular Carcinoma Patients Undergoing Hepatic Artery Infusion Chemotherapy.

BACKGROUND: This study aimed to investigate the influence of hepatic artery infusion chemotherapy (HAIC) on hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg) positive patients with primary hepatocellular carcinoma (HCC) as well as evaluate the role of antiviral prophylaxis in these patients. METHODS: We enrolled 170 HBsAg-positive advanced HCC patients receiving HAIC using mFOLFOX regimen, of which 137 patients received antiviral prophylaxis. Risk factors for HBV reactivation were analyzed. The overall survival (OS) from the first application of HAIC were compared between antiviral and non-antiviral groups. RESULTS: A total of 25 patients (14.7%) developed HBV reactivation after HAIC, of which 16 patients received antiviral treatment and nine patients did not. The incidence of HBV reactivation was 11.7% (16/137) in antiviral group and 27.3% (9/33) in non-antiviral group respectively. No antiviral prophylactic was the only significant risk factor for HBV reactivation (OR=12.35, 95% confidence interval (CI) 4.35-33.33, p<0.001). Patients in antiviral group received more cycles of HAIC compared with non-antiviral group (3.11 ± 1.69 vs 1.75 ± 1.18, p<0.05) at the time of HBV reactivated. Seven of the 25 HBV reactivation patients developed hepatitis. OS in antiviral group was significantly longer than that of non-antiviral group (median 16.46 vs 10.68 months; HR=0.57; 95% CI, 0.36-0.91; p<0.05). CONCLUSIONS: HBV reactivation is more prone to occur in the HBsAg-positive HCC patients undergoing HAIC without antiviral prophylaxis. Regular monitoring of HBV DNA and antiviral prophylaxis are suggested to prevent HBV reactivation as well as prolong the OS of these patients. NAME OF THE TRIAL REGISTER: HAIC Using Oxaliplatin Plus Fluorouracil/Leucovorin for Patients with Locally Advanced HCC. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov/, identifier NCT02436044.

Survival benefits of computed tomography-guided thermal ablation for adrenal metastases from hepatocellular carcinoma.

Purpose: To evaluate the safety, efficacy, and survival outcomes of computed tomography (CT)-guided thermal ablation for adrenal metastases from hepatocellular carcinoma (HCC). Methods: This long-term retrospective study included 27 male patients (median age, 50 years; range, 34-77 years) with 29 adrenal metastatic tumors associated with HCC who underwent ablation between January 2004 and December 2015. The technical success rate, effectiveness rate, complications, and survival were recorded. Complications were assessed according to the Common Terminology Criteria for Adverse Events. Survival curves were estimated using the Kaplan-Meier method. A Cox regression model was used for the evaluation of factors predicting survival. Results: A total of 33 ablation sessions were performed for the 29 tumors. No ablation-related death was observed, and the incidence of complications was 87.9%. Grade 1-2 complications occurred in 23 of the 33 sessions (69.7%), and grade 3 hypertension was the only major complication, occurring in eight sessions (24.2%). The technical success and effectiveness rates were 93.1% (27 of 29 tumors) and 92.6% (25 of 27 patients), respectively. The median progression-free survival and overall survival (OS) durations for the 27 patients were 6.9 months and 16.8 months, respectively. The median OS duration was longer for patients with adrenal oligometastases (21.8 months) than for those with (12.8 months) multiple metastases (p = .037). Adrenal oligometastases were the only significant predictor of OS (p = .043). Conclusions: CT-guided ablation is a feasible and safe procedure for adrenal metastases from HCC, and it may be more beneficial for patients with adrenal oligometastases.