Postoperative Adjuvant Hepatic Arterial Infusion Chemotherapy With FOLFOX in Hepatocellular Carcinoma With Microvascular Invasion: A Multicenter, Phase III, Randomized Study.

PURPOSE: To report the efficacy and safety of postoperative adjuvant hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and oxaliplatin (FOLFOX) in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI). PATIENTS AND METHODS: In this randomized, open-label, multicenter trial, histologically confirmed HCC patients with MVI were randomly assigned (1:1) to receive adjuvant FOLFOX-HAIC (treatment group) or routine follow-up (control group). The primary end point was disease-free survival (DFS) by intention-to-treat (ITT) analysis while secondary end points were overall survival, recurrence rate, and safety. RESULTS: Between June 2016 and August 2021, a total of 315 patients (ITT population) at five centers were randomly assigned to the treatment group (n = 157) or the control group (n = 158). In the ITT population, the median DFS was 20.3 months (95% CI, 10.4 to 30.3) in the treatment group versus 10.0 months (95% CI, 6.8 to 13.2) in the control group (hazard ratio, 0.59; 95% CI, 0.43 to 0.81; P = .001). The overall survival rates at 1 year, 2 years, and 3 years were 93.8% (95% CI, 89.8 to 98.1), 86.4% (95% CI, 80.0 to 93.2), and 80.4% (95% CI, 71.9 to 89.9) for the treatment group and 92.0% (95% CI, 87.6 to 96.7), 86.0% (95% CI, 79.9 to 92.6), and 74.9% (95% CI, 65.5 to 85.7) for the control group (hazard ratio, 0.64; 95% CI, 0.36 to 1.14; P = .130), respectively. The recurrence rates were 40.1% (63/157) in the treatment group and 55.7% (88/158) in the control group. Majority of the adverse events were grade 0-1 (83.8%), with no treatment-related death in both groups. CONCLUSION: Postoperative adjuvant HAIC with FOLFOX significantly improved the DFS benefits with acceptable toxicities in HCC patients with MVI.

A novel treatment strategy using indocyanine green for transarterial chemoembolization in BCLC stage C hepatocellular carcinoma.

PURPOSE: The aim of our study was to propose a strategy based on indocyanine green (ICG) (SBI) to provide better clinical guidelines for transarterial chemoembolization (TACE) treatments for Barcelona clinic liver cancer (BCLC) stage C hepatocellular carcinoma (HCC) patients. MATERIALS AND METHODS: From October 2005 to December 2012, 112 BCLC stage C HCC patients initially treated with TACE were investigated, randomly divided into a training cohort (n = 79) and validation cohort (n = 33). In training group, the patients were grouped based on their 15 minutes ICG retention rate (ICG R15), different chemo drugs and dose of lipidol in TACE. Overall survival (OS) and progression-free survival (PFS) were analyzed in subgroups. Strategy based on ICG was built and verified in validation group. RESULTS: For those patients with ICG R15 values >10%, the lipiodol ≤10 mL group showed better survival than the lipiodol >10 mL group. For those patients with ICG R15 values ≤10%, the group that received triple-drug chemotherapy treatments with lipiodol diameter ratio values between 1 and 3 showed better survival than the other group. Patients who conformed with the SBI had better survival times than those who did not conform with the SBI, in both the training cohort (median OS 10.3 vs 5.1 months; P < .001; median PFS, 3.3 vs 2.1 months; P = .006) and the validation cohort (median OS 8.9 vs 7.1 months; P = .087; median PFS, 6.6 vs 2.3 months; P < .001). CONCLUSIONS: The SBI is suitable and may provide survival benefits for TACE treatments in BCLC stage C HCC patients.

Comparison of Stable and Unstable Ethiodized Oil Emulsions for Transarterial Chemoembolization of Hepatocellular Carcinoma: Results of a Single-Center Double-Blind Prospective Randomized Controlled Trial.

PURPOSE: To compare the stability of stable and unstable water-in-oil emulsions and the efficacy and safety of these emulsions in a single-center, prospective double-blind trial of transarterial chemoembolization for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: A total of 812 patients with inoperable HCC were randomized (stable emulsion, n = 402; unstable emulsion, n = 410). The 2 emulsions were prepared by using the same protocol except that different solvents were used for chemotherapy agents, including epirubicin, lobaplatin, and mitomycin C. The solvent in the stable emulsion arm was contrast medium and distilled water, and the solvent in the unstable emulsion arm was distilled water. The primary endpoint was overall survival (OS), and secondary endpoints were time to progression (TTP), tumor response, adverse events (AEs), and plasma epirubicin concentrations. RESULTS: In vitro, stable emulsions did not occur until 1 day, and unstable emulsions, with a lower peak plasma concentration (P = .001) in vivo, exhibited rapid separation of the oil and aqueous phases after 10 minutes. Median OS times in the stable and unstable emulsion arms were 17.7 and 19.2 months, respectively (P = .81). No differences were found in TTP, tumor response, and AEs except for myelosuppression (anemia, 3.5% vs 7.6%; thrombocytopenia, 11.5% vs 17.7%), which was significantly more severe and frequent in the unstable emulsion arm (P = .013). CONCLUSIONS: Chemoembolization is equally effective with the use of stable and unstable emulsions, but the use of a stable emulsion has the advantage of less myelosuppression and a favorable pharmacokinetic profile.

The Chinese medicine, Jianpi Huayu Decoction, inhibits the epithelial mesenchymal transition via the regulation of the Smad3/Smad7 cascade.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignant tumors in the world. In China, traditional medicine is commonly used in the treatment of cancer. Among these medicines, Jianpi Huayu Decoction (JHD) is a typical clinical prescription against multiple tumors. However, the exact function and targets of JHD are currently unknown. The aim of this study is to assess the efficacy of JHD against HCC. METHODS AND RESULTS: Hepatic carcinoma SMMC7221 cells were treated with JHD drug-serum in a dose- and time-dependent manner. Real-time PCR (RT-PCR), western-blot (WB), and immunofluorescence microscopy revealed that JHD increased both the mRNA and protein levels of Smad7 and decreased the protein level of p-Smad3. It subsequently increased the E-cadherin expression level and decreased those of N-cadherin and Vimentin. Metastasis and invasion were eventually inhibited, as determined by the wound healing and transwell invasion assays. Treatment of Tanshinone IIA (Tan IIA) showed similar results as JHD, indicating that it is most likely the main functional drug monomer of JHD. The in vivo assay in nude mice also revealed the efficacy of JHD to inhibit epithelial mesenchymal transition (EMT). CONCLUSION: JHD was shown to be an effective therapeutic strategy against HCC.

Clinical study of hepatectomy combined with Jianpi Huayu Therapy for hepatocellular carcinoma.

BACKGROUND: Traditional Chinese Medicine (TCM) possesses several advantages for treating patients with hepatocellular carcinoma (HCC). The theory of 'Jianpi Huayu Therapy' rooted from 'Jin Kui Yao Lue' is one of the most important therapies in this respect. This study was conducted to investigate the clinical effect and safety of hepatectomy combining with 'Jianpi Huayu Therapy' in the treatment of HCC. MATERIALS AND METHODS: One hundred and twenty patients with HCC were randomized allocated into hepatectomy combined with 'Jianpi Huayu Therapy' group (treatment group, n=60) and hepatectomy alone group (control group, n=60). Disease-free survival (DFS) and overall survival (OS) were the primary end-points. Liver function at the end of one week after surgery, complications, average days of hospitalization as well as performance status (PS) at the end of one month post operation were also compared. RESULTS: No significant differences existed between two groups on baseline analysis (p>0.05). No treatment related mortality occurred in either group. Post-operative complications were detected among 14 patients (23.3%) in the treatment group, and 12 (20.0%) in the control group (p=0.658). Alanine aminotransferase (ALT) at the end of one week after operation was lower in the treatment than control groups (p=0.042). No significant differences in other indexes of liver function were discovered between two groups. Average days of hospitalization reduced by 0.9 day in treatment group than in control (p=0.034). During follow-up, 104 patients (86.6%) developed recurrence. The rates of 1-, 3-, and 5-year DFS and median DFS for all patients were 77.4%, 26.3%, 9.0% and 25.6 months (range, 6.0~68.0), respectively (78.2%, 29.2%, 14.3% and 28.7 months for the 48 patients in the treatment group and 75.0%, 23.3%, 6.4%, and 22.6 months for the 56 patients in the control group (p=0.045)). 101 patients had died at the time of censor, with 1-, 3-, and 5-year overall survival rates and median survival for all patients of 97.5%, 76.4%, 40.5% and 51.2 months (range, 10.0~72.0), respectively (98.3%, 78.0%, 43.6% and 52.6 months, for treatment and 96.7%, 74.7%, 37.4%, and 49.8 months, for controls, respectively (p=0.048)). CONCLUSIONS: Hepatectomy combined with 'Jianpi Huayu therapy' was effective in the treatment of HCC, and reduced post-operative recurrence and metastasis and improved DFS and OS of HCC patients.

Roles played by chemolipiodolization and embolization in chemoembolization for hepatocellular carcinoma: single-blind, randomized trial.

BACKGROUND: The aim of our study was to compare the efficacy and safety of: 1) transarterial chemolipiodolization with gelatin sponge embolization vs chemolipiodolization without embolization, and 2) chemolipiodolization with triple chemotherapeutic agents vs epirubicin alone. METHODS: A single-blind, three parallel arm, randomized trial was conducted at three clinical centers with patients with biopsy-confirmed unresectable hepatocellular carcinoma. Arm 1 received triple-drug chemolipiodolization and sponge embolization, whereas Arm 2 received triple-drug chemolipiodolization only. Patients in arm 3 were treated with single-drug chemolipiodolization and sponge embolization. We compared overall survival and time to progression. Event-time distributions were estimated by the Kaplan-Meier method. All statistical tests were two-sided. RESULTS: From July 2007 to November 2009, 365 patients (Arm 1: n = 122; Arm 2: n = 121; Arm 3: n = 122) were recruited. The median tumor size was 10.9cm (range = 7-22cm), and 34.5% had macrovascular invasion. The median survivals and time to progression in Arm 1, Arm 2, and Arm 3 were 10.5 and 3.6 months, 10.1 and 3.1 months, and 5.9 and 3.1 months, respectively. Survival was statistically significantly better in Arm 1 than in Arm 3 (P < .001), whereas there was no statistically significant difference between Arm 1 and Arm 2 (P = .20). Objective response rates were 45.9%, 29.7%, and 18.9% for Arm 1, Arm 2, and Arm 3, respectively. CONCLUSIONS: Chemolipiodolization played an important role in transarterial chemoembolization, and the choice of chemotherapy regimen may largely affect survival outcomes. However, the removal of embolization from chemoembolization might not statistically significantly decrease survival.

[Chromaticity and optical spectrum colorimetry of the tongue color in different syndromes of primary hepatic carcinoma].

OBJECTIVE: In this study, the optical data of tongue color of different syndromes in primary hepatic carcinoma (PHC) were detected by optical spectrum colorimetry, and the chromaticity of tongue color was compared and analyzed. The tongue color characteristics of different syndromes in PHC and the relationship between different syndromes and tongue color were also investigated. METHODS: Tongue color data from 133 eligible PHC patients were collected by optical spectrum colorimetry and the patients were divided into 4 syndrome groups according to their clinical features. The syndrome groups were liver depression and spleen deficiency (LDSD), accumulation of damp-heat (ADH), deficiency of liver and kidney yin (DLKY), and qi stagnation and blood stasis (QSBS). The variation characteristics of chromaticity coordinates, dominant wavelength, excitation purity and the distribution in the International Commission on Illumination (CIE) LAB uniform color space were measured. At the same time, the differences of overall chromatism, clarity, chroma, saturation and hue were also calculated and analyzed. RESULTS: PHC patients in different syndrome groups exhibited differences in chromaticity coordinates. The dominant wavelength of QSBS was distinctly different from that of the other 3 syndromes. Excitation purity in the syndromes of LDSD, ADH and DLKY showed gradual increases (P<0.01). Different syndromes in the CIE LAB color three-dimensional space showed differences in tongue color distribution areas. The CIE hue-angle value of QSBS was negative, and different from that of the other 3 syndromes (P<0.01). CIE chroma in the syndromes of LDSD, ADH and DLKY showed gradual increases (P<0.01), the same as excitation purity. In the comparison of chromatism, tongue color variations in different syndromes were quantified by human observation. CONCLUSION: This study shows that tongue color diagnosis according to the syndrome classifications of traditional Chinese medicine can be quantified with optical spectrum colorimetry technology. Different syndromes in PHC exhibit distinct chromatisms of tongue color through the calculation and analysis of chromaticity parameters of CIE, combined with colorimetric system and CIE LAB color space, and these are consistent with the characteristics of clinical tongue color. Applying optical spectrum colorimetry technology to tongue color differentiation has the potential to serve as a reference point in standardizing traditional Chinese medicine syndrome classification in PHC.

Hepatic resection versus transarterial lipiodol chemoembolization as the initial treatment for large, multiple, and resectable hepatocellular carcinomas: a prospective nonrandomized analysis.

PURPOSE: To compare the survival outcomes between hepatic resection and transarterial lipiodol chemoembolization (TACE) used as the initial treatment in patients with large (≥5 cm), multiple, and resectable hepatocellular carcinomas. MATERIALS AND METHODS: This study had local ethical committee approval; all patients gave written informed consent. Between January 2004 and December 2006, 168 consecutive patients were prospectively studied. As an initial treatment, 85 patients underwent hepatic resection and 83 underwent TACE. Of the 29 of 83 patients in whom there was a good response to TACE, 13 underwent subsequent hepatic resection. The remaining 16 patients, who refused hepatic resection, underwent TACE and local ablation. Repeated TACE was performed in patients with stable disease or progressive disease after initial TACE. The differences in survival between groups and subgroups were calculated with the Kaplan-Meier method. Univariate and multivariate analyses were performed to clarify the prognostic factors for survival. RESULTS: The 1-, 3-, and 5-year overall survival rates for the initial hepatic resection group and the initial TACE group were 70.6%, 35.3%, 23.9% and 67.2%, 26.0%, 18.9%, respectively (P = .26). Complication rates were significantly higher in the initial hepatic resection group than in the initial TACE group (P < .01). The 1-, 3-, and 5-year overall survival rates in patients who underwent initial TACE and subsequent hepatic resection were 92.3%, 67.3%, and 50.5%, respectively, which were significantly higher than rates in patients treated with initial hepatic resection (P = .04) but were not significantly higher than in patients who responded well to TACE but refused hepatic resection (P = .07). Tumor size was the independent risk factor for survival. CONCLUSION: TACE might be a better initial treatment in patients with large, multiple, and resectable hepatocellular carcinomas; hepatic resection should be recommended to patients who respond well to TACE.

[Treatment of hepatic functional reserve injury after TACE in hepatocellular carcinoma with Chinese herbal medicines].

BACKGROUND & OBJECTIVE: Transcatheter arterial chemoembolization (TACE) has been proved to injure hepatic functional reserve. The current study was designed to evaluate the effect of Chinese herbal medicines in treatment of hepatic functional reserve injury after TACE. METHODS: Sixty-one advanced hepatocellular carcinoma patients were divided into two groups: groups A (Western medicine combined with Chinese herbal medicine group, n = 30) and group B (Western medicine group, n = 31). Western medicines were used to protect hepatic function and alleviate TACE syndrome in both group A and group B. Invigorating the spleen and activating blood circulation Chinese herbal medicines were added only in group A before and after TACE. Retention rate of Indocyanine green at 15 minutes (ICGR15) was measured in both group A and group B before 1st, 2nd TACE and one month after 2nd TACE respectively. RESULTS: Hepatic functional reserve before 1st TACE was 11.18% +/- 7.30% in group A and 11.83 +/- 7.18% in group B, (P > 0.05). Hepatic functional reserve before 2nd TACE was 11.69% +/- 5.13% in group A and 16.64 +/- 10.15% in group B, (P < 0.05). Hepatic functional reserve one month after 2nd TACE was 11.53% +/- 5.30% in group A and 19.80 +/- 11.26% in group B, (P < 0.05). CONCLUSIONS: Invigorating the spleen and activating blood circulation Chinese herbal medicine can prevent hepatic functional reserve injury after TACE.