Arterial chemotherapy for hepatocellular carcinoma in China: consensus recommendations.

Hepatocellular carcinoma (HCC) is one of the most common malignancies and the third leading cause of cancer-related deaths globally. Hepatic arterial infusion chemotherapy (HAIC) treatment is widely accepted as one of the alternative therapeutic modalities for HCC owing to its local control effect and low systemic toxicity. Nevertheless, although accumulating high-quality evidence has displayed the superior survival advantages of HAIC of oxaliplatin, fluorouracil, and leucovorin (HAIC-FOLFOX) compared with standard first-line treatment in different scenarios, the lack of standardization for HAIC procedure and remained controversy limited the proper and safe performance of HAIC treatment in HCC. Therefore, an expert consensus conference was held on March 2023 in Guangzhou, China to review current practices regarding HAIC treatment in patients with HCC and develop widely accepted statements and recommendations. In this article, the latest evidence of HAIC was systematically summarized and the final 22 expert recommendations were proposed, which incorporate the assessment of candidates for HAIC treatment, procedural technique details, therapeutic outcomes, the HAIC-related complications and corresponding treatments, and therapeutic scheme management.

A randomized phase II trial of hepatic arterial infusion of oxaliplatin plus raltitrexed versus oxaliplatin plus 5-fluorouracil for unresectable colorectal cancer liver metastases.

Background: The purpose was to compare the efficacy and safety of hepatic arterial infusion (HAI) of oxaliplatin plus raltitrexed (TOMOX) to those of oxaliplatin plus 5-fluorouracil (FOLFOX) for unresectable colorectal cancer liver metastases (CRCLM). Methods: Patients with unresectable CRCLM were randomly assigned to receive HAI of TOMOX or FOLFOX. The primary end points were progression-free survival (PFS) measured from the date of randomisation until the date of disease progression and objective response rate (ORR). The secondary end points were overall survival (OS) measured from the date of randomisation until the date of death from any cause, disease control rate (DCR), and adverse events. Results: 113 patients were randomly assigned. With a median follow-up of 39.5 months, the PFS was 5.8 months [95% CI, 4.838-6.762]) and 4.6 months [95% CI, 3.419-5.781; P = 0.840], and the median OS was 17.6 months [95% CI, 13.828-21.372] and 13.1 months [95% CI, 11.215-14.985; P = 0.178] for the FOLFOX and TOMOX arm, respectively. The ORR were 26.1% vs 22.4% and DCR were 80.4% vs 71.4% in the FOLFOX and TOMOX arms. The most common severe adverse event was elevation of liver enzymes and pain, which did not differ in the two arms. Conclusion: HAI chemotherapy was effective for unresectable CRCLM. HAI of FOLFOX has similar efficacy to TOMOX, and HAI of TOMOX had shorter arterial infusion time. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT02557490.

Hepatic Artery Injection of 131I-Metuximab Combined with Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma: A Prospective Nonrandomized, Multicenter Clinical Trial.

This prospective nonrandomized, multicenter clinical trial was performed to investigate the efficacy and safety of 131I-labeled metuximab in adjuvant treatment of unresectable hepatocellular carcinoma. Methods: Patients were assigned to treatment with transcatheter arterial chemoembolization (TACE) combined with 131I-metuximab or TACE alone. The primary outcome was overall tumor recurrence. The secondary outcomes were safety and overall survival. Results: The median time to tumor recurrence was 6 mo in the TACE + 131I-metuximab group (n = 160) and 3 mo in the TACE group (n = 160) (hazard ratio, 0.55; 95% CI, 0.43-0.70; P < 0.001). The median overall survival was 28 mo in the TACE + 131I-metuximab group and 19 mo in the TACE group (hazard ratio, 0.62; 95% CI, 0.47-0.82; P = 0.001). Conclusion: TACE + 131I-metuximab showed a greater antirecurrence benefit, significantly improved the 5-y survival of patients with advanced hepatocellular carcinoma, and was well tolerated by patients.

Real-world study of hepatic artery infusion chemotherapy combined with anti-PD-1 immunotherapy and tyrosine kinase inhibitors for advanced hepatocellular carcinoma.

Aim: We investigated the efficacy and safety of hepatic artery infusion chemotherapy (HAIC) combined with anti-PD-1 immunotherapy and tyrosine kinase inhibitors (TKIs) for advanced hepatocellular carcinoma (HCC). Method: This retrospective study included HCC patients treated with HAIC, TKIs and anti-PD-1 antibodies between May 2019 and November 2020 in our hospital. Primary end points were progression-free survival and safety. Results: Twenty-seven advanced HCC patients were analyzed. The median follow-up was 12.9 months (range: 4.0-24.0 months) and the median progression-free survival was 10.6 months. The objective response rate and disease control rate were 63.0 and 92.6%, respectively. No treatment-related deaths occurred. Conclusion: In patients with advanced HCC, treatment with HAIC, anti-PD-1 antibodies and oral TKIs was effective and safe.

Lay abstract Some tyrosine kinase inhibitors (TKIs) that inhibit tumor vessel growth, such as sorafenib and lenvatinib, have been recommended as first-line treatment for advanced hepatocellular carcinoma (HCC). In hepatic artery infusion chemotherapy, chemotherapeutic drugs can be delivered via a microcatheter to the tumor-supplying artery to increase the local drug concentration, leading to higher local disease control rates and less toxicity than systemic chemotherapy. The combination of anti-PD-1 immunotherapy plus TKIs was shown in a previous study to be a safe and effective treatment for advanced HCC. This study explored the safety and effectiveness of hepatic artery infusion chemotherapy, TKIs and an anti-PD-1 antibody for the treatment of advanced HCC and found that combination therapy is effective, with good tolerability.

Combination Therapy of Chemoembolization and Hepatic Arterial Infusion Chemotherapy in Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis Compared with Chemoembolization Alone: A Propensity Score-Matched Analysis.

BACKGROUND: Survival of patients with portal vein tumor thrombosis (PVTT) is extremely poor; transarterial chemoembolization (TACE) is a treatment for patients with HCC and PVTT. Some studies showed that hepatic arterial infusion chemotherapy (HAIC) might improve the survival of HCC with PVTT. There were few researches of combining TACE with HAIC for patients with HCC and PVTT. AIM: This study was aimed at comparing overall survival (OS) and progression-free survival (PFS) following treatment with conventional transarterial chemoembolization plus hepatic arterial infusion chemotherapy (cTACE-HAIC) or conventional transarterial chemoembolization (cTACE) alone in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT). METHODS: From January 2011 to December 2016, 155 patients with HCC and PVTT who received cTACE-HAIC (cTACE-HAIC group) (n = 86) or cTACE alone (cTACE group) (n = 69) were retrospectively evaluated. Propensity score matching (PSM) reduced the confounding bias and yielded 60 matched patient pairs. The tumors' responses were evaluated using the modified response evaluation criteria in solid tumors (mRECIST). OS and PFS of groups were compared using the Kaplan-Meier method, log-rank test, and Cox proportional hazard regression models. RESULTS: The median follow-up duration was 93 months (range: 1-93 months). The cTACE-HAIC group's OS (9.0 months) and PFS (6.0 months) were significantly longer than the cTACE group's OS (5.0 months) and PFS (2.0 months) (p = 0.018 and p = 0.045, respectively) in the matched cohort. Multivariate analyses showed that cTACE-HAIC was independently associated with OS (hazard ratio (HR) 0.602, p = 0.010) and PFS (HR 0.66, p = 0.038). The matched groups did not differ regarding grade 3 or 4 adverse events. CONCLUSION: cTACE-HAIC was superior to cTACE alone regarding OS and PFS in patients with HCC and PVTT. Treatment-associated toxicities were generally well tolerated.

Transarterial chemoembolization with hepatic arterial infusion chemotherapy plus S-1 for hepatocellular carcinoma.

BACKGROUND: Transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) have shown promising local benefits for advanced hepatocellular carcinoma (HCC). S-1, a composite preparation of a 5-fluorouracil prodrug, has proven to be a convenient oral chemotherapeutic agent with definite efficacy against advanced HCC. AIM: To evaluate the efficacy and safety of TACE followed by HAIC with or without oral S-1 for treating advanced HCC. METHODS: In this single-center, open-label, prospective, randomized controlled trial, 117 participants with advanced HCC were randomized to receive TACE followed by oxaliplatin-based HAIC either with (TACE/HAIC + S-1, n = 56) or without (TACE/HAIC, n = 61) oral S-1 between December 2013 and September 2017. Two participants were excluded from final analysis for withdrawing consent. The primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS), objective response rate, disease control rate and safety. RESULTS: In total, 115 participants (100 males and 15 females; mean age, 57.7 years ± 11.9) were analyzed. The median PFS and OS were 5.0 mo (0.4-58.6 mo) (95% confidence interval (CI): 3.82 to 6.18) vs 4.4 mo (1.1-54.4 mo) (95%CI: 2.54 to 6.26; P = 0.585) and 8.4 mo (0.4-58.6 mo) (95%CI: 6.88 to 9.92) vs 8.3 mo (1.4-54.4 m) (95%CI: 5.71 to 10.96; P = 0.985) in the TACE/HAIC + S-1 and TACE/HAIC groups, respectively. The objective response rate and disease control rate were 30.9% vs 18.4% and 72.7% vs 56.7% in the TACE/HAIC + S-1 and TACE/HAIC groups, respectively. Grade 3/4 adverse events had a similar frequency in both treatment groups. CONCLUSION: No improvements in tumor response rates, PFS or OS were observed with the addition of S-1 to TACE/HAIC in advanced HCC. Both treatment regimens had a similar safety profile.

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 TACE-HAIC. 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 intra-arterially 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.

Effect of primary tumor side on survival outcomes in metastatic colorectal cancer patients after hepatic arterial infusion chemotherapy.

AIM: To analyze the survival data between patients diagnosed with right-sided primary (RSP) tumors and patients diagnosed with left-sided primary (LSP) tumors after hepatic arterial infusion chemotherapy (HAIC) at our center. METHODS: A retrospective analysis of pretreated metastatic colorectal cancer patients who received HAIC from May 2006 to August 2015 was conducted. A Cox proportional hazard regression analysis was used to assess the long-term survival outcomes. The mean and median age of patients was 61 years (range 27-85 years). There were 115 males and 53 females in our study. RESULTS: One hundred sixty-eight patients were enrolled in this study. The overall response rate was 28.9% in LSP patients and 27.3% in RSP patients. The disease control rate was 76.3% in LSP patients and 69.7% in RSP patients. The median overall survival in response to HAIC was 16.3 mo in the LSP arm and 9.3 mo in the RSP arm (P = 0.164). The median progression-free survival was 5.7 mo in the LSP arm and 4.2 mo in the RSP arm (P = 0.851). CONCLUSION: There was no significant difference in survival between LSP patients and RSP patients after HAIC. Further prospective studies are needed to confirm these findings.

Diagnostic value evaluation of trefoil factors family 3 for the early detection of colorectal cancer.

AIM: The purpose of this study was to evaluate the diagnostic value of trefoil factor family 3 (TFF3) for the early detection of colorectal cancer (CC). METHODS: Serum TFF3 and carcino-embryonic antigen (CEA) were detected in 527 individuals, including 115 healthy control (HC), 198 colorectal adenoma (CA), and 214 CC individuals in the training group. RESULTS: Serum TFF3 showed no significant correlation with age, gender, or tumor location but showed significant correlation with the tumor stage. Serum TFF3 in the CC group was significantly higher than in the HC or CA group. The AUC values of TFF3 for discriminating between HC and CC and between CA and CC were 0.930 (0.903, 0.958) and 0.834 (0.796, 0.873). A multivariate model combining TFF3 and CEA was built. Compared to TFF3 or CEA alone, the multivariate model showed significant improvement (P < 0.001). For discriminating between HC and CC, HC and early stage CC, HC and advanced stage CC, CA and CC, CA and early stage CC, and CA and advanced stage CC in the training group, the sensitivities were 92.99%, 91.46%, 93.18%, 73.83%, 76.83%, and 81.82%, and the specificities were 91.30%, 91.30%, 93.91%, 88.38%, 77.27%, and 88.38%, respectively. After validation, the sensitivities were 89.39%, 85.71%, 90.79%, 72.73%, 71.43%, and 78.95%, and the specificities were 87.85%, 87.85%, 2.52%, 87.85%, 80.77%, and 87.50%, respectively. CONCLUSION: The multivariate diagnostic model that included TFF3 and CEA showed significant improvement over the conventional biomarker CEA and might provide a potential method for the early detection of CC.

Hepatic artery infusion with raltitrexed or 5-fluorouracil for colorectal cancer liver metastasis.

AIM: To evaluate the efficiency and safety of hepatic artery infusion chemotherapy (HAIC) using raltitrexed or 5-fluorouracil for colorectal cancer (CRC) liver metastasis (CRCLM). METHODS: A retrospective analysis of patients with unresectable CRCLM who failed systemic chemotherapy and were subsequently treated with HAIC at our institute from May 2013 to April 2015 was performed. A total of 24 patients were treated with 5-fluorouracil, and 18 patients were treated with raltitrexed. RESULTS: The median survival time (MST) from diagnosis of CRC was 40.8 mo in the oxaliplatin plus raltitrexed (TOMOX) arm and 33.5 mo in the oxaliplatin plus 5-fluorouracil (FOLFOX) arm (P = 0.802). MST from first HAIC was 20.6 mo in the TOMOX arm and 15.4 mo in the FOLFOX arm (P = 0.734). Median progression-free survival (PFS) from first HAIC was 4.9 mo and 6.6 mo, respectively, in the TOMOX arm and FOLFOX arm (P = 0.215). Leukopenia (P = 0.026) was more common in the FOLFOX arm, and hepatic disorder (P = 0.039) was more common in the TOMOX arm. There were no treatment-related deaths in the TOMOX arm and one treatment-related death in the FOLFOX arm. Analysis of prognostic factors indicated that response to HAIC was a significant factor related to survival. CONCLUSION: No significant difference in survival was observed between the TOMOX and FOLFOX arms. HAIC treatment with either TOMOX or FOLFOX was demonstrated as an efficient and safe alternative choice.

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

AIM: To compare the efficacy and safety of chemoembolization 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-nine patients underwent 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 (mPFS) 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 mPFS 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.

Low-dose, short-interval target vessel regional chemotherapy through the hepatic artery combined with transarterial embolization in gastric cancer patients with liver metastases after failure of first-line or second-line chemotherapy: a preliminary analysis.

The objective of this study is to evaluate the efficacy and safety of combining low-dose, short-interval target vessel regional chemotherapy delivered through the hepatic artery (TVRC) with transarterial embolization (TAE) in advanced gastric cancer (AGC) patients with liver metastases after failure of first-line or second-line chemotherapy. All AGC patients with hepatic metastases had an indwelling arterial catheter placed in the hepatic artery and hepatic metastases were embolized with ultrafluid lipiodol, followed by two to three TVRC treatments in one cycle. After 3 weeks, the efficacy of TVRC treatment was evaluated using computed tomography (CT) or MRI scans before starting the next cycle. Follow-up assessments were performed every 2 months. The patients received a median of 7 (2-33) TVRC treatments together with TAE. All 22 AGC patients received a total of 191 TVRC treatments, which included 80.1% FOLFOX, 11.0% FOLFIRI, and 8.9% DC treatments. The median time-to-progression was 5.97 months; the median survival time was 11.6 months; and the 1-year and 2-year survival rates were 45.5 and 9.1%, respectively. The median overall survival from the diagnosis of liver metastasis (mOS) was 19.3 months. The most common side effects were grade I-II of abdominal pain, nausea, and vomiting. Combining TAE and TVRC administration through the hepatic artery for AGC patients with liver metastases resulted in decreased overall dose of chemotherapy, alleviation of side effects, and increased QOL of patient. This approach can be used as salvage therapy for AGC patients with predominant liver metastases after failure of intravenous chemotherapy.

[Angiographic findings and interventional therapy for post-pancreaticoduodenectomy hemorrhage].

OBJECTIVE: To discuss the angiographic findings and the safety and efficacy of interventional therapy for post-pancreaticoduodenectomy hemorrhage. METHODS: The clinical data, features of angiography, interventional treatment technology and prognosis of 29 patients underwent post-pancreaticoduodenectomy bleeding between August 2009 and June 2012 were retrospectively analyzed in our hospital. RESULTS: In all 29 patients, 6 cases underwent gastrointestinal bleeding, 21 cases of abdominal bleeding, 2 cases had abdominal cavity and gastrointestinal bleeding, hemorrhage occurred 8 h - 72 d after surgery. Angiographic findings including: extravasation of contrast media, and pseudo aneurysm formation, local arterial intima not smooth, stenosis, distal artery branch expansion. The success rate of interventional techniques was 93.94%, hemostatic rate was 90%. 3 cases died. CONCLUSION: The embolization therapy is a safe and effective technique, should be as the first-line diagnostic and treatment choice for patients with post-pancreaticoduodenectomy bleeding.

Impact of serum vascular endothelial growth factor on prognosis in patients with unresectable hepatocellular carcinoma after transarterial chemoembolization.

OBJECTIVE: To investigate the expression level of serum vascular endothelial growth factor (VEGF) in patients with unresectable hepatocellular carcinoma (HCC) and its relationship with the clinicopathological characteristics, and to assess the impact of serum VEGF as a predictive factor for HCC prognosis during transarterial chemoembolization (TACE) treatments. METHODS: Serum VEGF levels were measured using enzyme-linked immunosorbent assay (ELISA) in 60 random patients who underwent TACE or transarterial infusion (TAI) for unresectable HCC between May and September 2008 and 12 healthy volunteers were also involved in this study to serve as control. All patients' clinicopathological features were retrospectively analyzed. Serum VEGF levels were correlated with clinicopathological features of the HCC patients. The patients' survival rates were analyzed with Kaplan-Meier survival curves and compared by the log-rank test. The prognostic significance of serum VEGF levels and factors related to survival rate were evaluated by univariate and multivariate analysis. RESULTS: The median serum VEGF level in the HCC patients was 285 pg/ml (range 14-1,207 pg/ml), significantly higher than that of healthy controls (P=0.021). The serum VEGF levels were significantly correlated with platelet counts (r=0.396, P=0.002) but not other clinicopathological features. Patients with serum VEGF level >285 pg/ml had worse overall survival compared with those with serum VEGF level <285 pg/ml (P=0.002). By multivariate analysis, the serum VEGF level was a significant prognostic factor. CONCLUSION: High serum VEGF levels may predict poor prognosis of HCC after TACE. This study highlights the importance of tumor biomarker as a prognostic predictor in TACE therapy for HCC, which has an intrinsic problem of unavailability of histopathological prognostic features.