Therapy For Early-stage Hepatocellular Carcinoma Research Articles

Preoperative prediction of microvascular invasion: new insights into personalized therapy for early-stage hepatocellular carcinoma.

Owing to advances in diagnosis and treatment methods over past decades, a growing number of early-stage hepatocellular carcinoma (HCC) diagnoses has enabled a greater of proportion of patients to receive curative treatment. However, a high risk of early recurrence and poor prognosis remain major challenges in HCC therapy. Microvascular invasion (MVI) has been demonstrated to be an essential independent predictor of early recurrence after curative therapy. Currently, biopsy is not generally recommended before treatment to evaluate MVI in HCC according clinical guidelines due to sampling error and the high risk of tumor cell seeding following biopsy. Therefore, the postoperative histopathological examination is recognized as the gold standard of MVI diagnosis, but this lagging indicator greatly impedes clinicians in selecting the optimal effective treatment for prognosis. As imaging can now noninvasively and completely assess the whole tumor and host situation, it is playing an increasingly important role in the preoperative assessment of MVI. Therefore, imaging criteria for MVI diagnosis would be highly desirable for optimizing individualized therapeutic decision-making and achieving a better prognosis. In this review, we summarize the emerging image characteristics of different imaging modalities for predicting MVI. We also discuss whether advances in imaging technique have generated evidence that could be practice-changing and whether advanced imaging techniques will revolutionize therapeutic decision-making of early-stage HCC.

Single-arm prospective study comparing ablation zone volume between time zero and 24h after microwave ablation of liver tumors.

Percutaneous thermal ablation is an effective treatment for primary and metastatic liver tumors and is a recommended local therapy for early-stage hepatocellular carcinoma (HCC). Reported evidence shows an increase in the ablation zone volume over the first 24-h post-liver ablation. This report compares ablation zone volumes immediately at the completion (T = 0) of 26 microwave ablations of liver tumors to 24-h post-procedure (T = 24) volumes. 20 patients, 13 (65%) males, underwent a total of 26 hepatic microwave ablations (MWA) under ultrasound guidance. Contrast-enhanced CT (CECT) or MRI was performed immediately and another CECT 24h post operatively. Evaluation of the ablation zone and comparison of the two post-operative scans were done using BioTrace software. The expansion of ablation zones on post-op CECTs was matched point by point per direction. The distance between each 2 points was measured and grouped by distance. The incidence of each specific distance was then converted into a percentage, first for each case separately, then for all cases altogether. Data were tested by a matched paired one-sided t test. The median lesion diameter was 1.5cm (range 0.5-3.3) with 16 (62%) HCC cases and 9 hepatic metastases (4 neuroendocrine carcinoma, 4 colorectal carcinomas, 1 breast carcinoma, 1 pancreatic cancer). The data show a consistent volume expansion greater than 30% (p = 7.7e-5) 24-h post-ablation, where the median expansion is 57%. Distances between T = 0 and T = 24 equal to 3-7mm occur in over 35% of the cases. The ablation zone expansion at 24-h post-op was not uniform. The final ablation zone is difficult to predict at the time of the procedure. The awareness of the ablation zone expansion is important when treating near-critical structures, managing the heat sink effect, and preserving liver parenchyma.

Radiation Segmentectomy for the Treatment of Hepatocellular Carcinoma: A Practical Review of Evidence

Radiation segmentectomy is a versatile, safe, and effective ablative therapy for early-stage hepatocellular carcinoma. Advances in radiation segmentectomy patient selection, procedural technique, and dosimetry have positioned this modality as a curative-intent and guideline-supported treatment for patients with solitary HCC. This review describes key radiation segmentectomy concepts and summarizes the existing literary knowledgebase.

Effect of Incomplete Cryoablation and Matrix Metalloproteinase Inhibition on Intratumoral CD8+ T-Cell Infiltration in Murine Hepatocellular Carcinoma.

Background Image-guided tumor ablation is the first-line therapy for early-stage hepatocellular carcinoma (HCC), with ongoing investigations into its combination with immunotherapies. Matrix metalloproteinase (MMP) inhibition demonstrates immunomodulatory potential and reduces HCC tumor growth when combined with ablative treatment. Purpose To evaluate the effect of incomplete cryoablation with or without MMP inhibition on the local immune response in residual tumors in a murine HCC model. Materials and Methods Sixty 8- to 10-week-old female BALB/c mice underwent HCC induction with use of orthotopic implantation of syngeneic Tib-75 cells. After 7 days, mice with a single lesion were randomized into treatment groups: (a) no treatment, (b) MMP inhibitor, (c) incomplete cryoablation, and (d) incomplete cryoablation and MMP inhibitor. Macrophage and T-cell subsets were assessed in tissue samples with use of immunohistochemistry and immunofluorescence (cell averages calculated using five 1-μm2 fields of view [FOVs]). C-X-C motif chemokine receptor type 3 (CXCR3)- and interferon γ (IFNγ)-positive T cells were assessed using flow cytometry. Groups were compared using unpaired Student t tests, one-way analysis of variance with Tukey correction, and the Kruskal-Wallis test with Dunn correction. Results Mice treated with incomplete cryoablation (n = 6) showed greater infiltration of CD206+ tumor-associated macrophages (mean, 1.52 cells per FOV vs 0.64 cells per FOV; P = .03) and MMP9-expressing cells (mean, 0.89 cells per FOV vs 0.11 cells per FOV; P = .03) compared with untreated controls (n = 6). Incomplete cryoablation with MMP inhibition (n = 6) versus without (n = 6) led to greater CD8+ T-cell (mean, 15.8% vs 8.29%; P = .04), CXCR3+CD8+ T-cell (mean, 11.64% vs 8.47%; P = .004), and IFNγ+CD8+ T-cell infiltration (mean, 11.58% vs 5.18%; P = .02). Conclusion In a mouse model of HCC, incomplete cryoablation and systemic MMP inhibition showed increased cytotoxic CD8+ T-cell infiltration into the residual tumor compared with either treatment alone. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Gemmete in this issue.

The long and winding road: Adjuvant therapy for early-stage hepatocellular carcinoma

Despite being the first positive phase 3 trial in the adjuvant setting for early-stage hepatocellular carcinoma, the IMbrave050 study raises a number of questions regarding patient selection, endpoint robustness, and the balance between efficacy and acceptable toxicity.1.

Pre-operative gamma-glutamyl transferase levels predict outcomes in hepatitis B-related hepatocellular carcinoma after curative resection

Surgical resection is a curative therapy for early-stage hepatocellular carcinoma (HCC); however, HCC recurrence is not uncommon. Identifying outcome predictors helps to manage the disease. Gamma-glutamyl transferase (GGT) may predict the development of HCC, but its role to predict the outcomes after surgical resection of HCC was unclear. This study aimed to investigate pre-operative GGT levels for outcome prediction in patients with hepatitis B virus (HBV)-related HCC. We conducted a retrospective cohort study to include patients with HBV-related HCC receiving surgical resection. Clinical information, HCC characteristics and usage of antiviral therapy were collected. A time-dependent Cox proportional hazard regression analysis were used to predict HCC recurrence and survival. A total of 699 consecutive patients with HBV-related HCC who received surgical resection with curative intent between 2004 and 2013 were included. After a median of 4.4 years, 266 (38%) patients had HCC recurrence. Pre-operative GGT positively correlated with cirrhosis, tumor burden and significantly increased in patients to develop HCC recurrence. Multivariable analysis demonstrated that pre-operative GGT ≥38 U/L increased 57% risk (hazard ratio [HR]: 1.57, 95% confidence interval [CI]: 1.20-2.06) of recurrent HCC after adjustment for confounding factors. Specifically, pre-operative GGT ≥38 U/L predicted early (<2 years) HCC recurrence (HR: 1.94, 95% CI: 1.30-2.89). Moreover, pre-operative GGT ≥38 U/L predicted all-cause mortality (HR: 1.73, 95% CI: 1.06-2.84) after surgery. Pre-operative GGT levels ≥38 U/L independently predict high risks of HCC recurrence and all-cause mortality in HBV-related HCC patients receiving surgical resection.

Insufficient ablation induces E3-ligase Nedd4 to promote hepatocellular carcinoma progression by tuning TGF-β signaling.

Thermal ablation is a main curative therapy for early-stage hepatocellular carcinoma (HCC). However, insufficient ablation has been shown to promote HCC progression. E3 ligases have been approved to play important roles in malignant tumors. Whether E3 ligases are involved in HCC progression caused by insufficient ablation remains unclear. Herein, using RNA-sequencing coupled with an in vitro loss-of-function screen, we found that the E3 ligase Neuronal Precursor cell-expressed Developmentally Downregulated 4 (Nedd4) was upregulated in HCC insufficient ablation tissues and promoted HCC cells migration. The upregulation of Nedd4 was induced by METTL14-mediated N6-methyladenosine modification after sublethal heat treatment. Knockdown of Nedd4 inhibited HCC metastasis and growth in vitro and in vivo. Mechanistically, Nedd4 enhanced TGF-β signal transduction mediated tumor progression by directly binding to TGF-β type I receptor (TGFBR1) and forming K27-linked ubiquitin at Lysine 391. Additionally, the adverse effect on HCC of sublethal heat treatment was mediated by Nedd4. Clinically, high Nedd4 expression was positively correlated with aggressive tumor phenotypes and poor prognosis in HCC patients. Patient-derived xenograft (PDX) model confirmed this conclusion. Collectively, this study demonstrated that Nedd4 induced by insufficient ablation plays a crucial role in promoting HCC progression and provides a novel therapeutic target for HCC.

Biochemical Safety of Ablative Yttrium-90 Radioembolization for Hepatocellular Carcinoma as a Function of Percent Liver Treated.

PurposeTransarterial radioembolization can serve as an ablative therapy for early-stage hepatocellular carcinoma (HCC). Given the volumetric variability of liver segments, this study aimed to characterize the safety of ablative radioembolization by determining percent liver treated (%LT) thresholds associated with biochemical toxicity.Patients and MethodsPatients with HCC receiving a single ablative radioembolization treatment using glass microspheres from 2017 through 2020 were reviewed. %LT was calculated as treatment angiosome volume divided by whole liver volume. Biochemical toxicities were defined as increases in Albumin-Bilirubin (ALBI) grade or Child-Pugh (CP) class compared to baseline and albumin or bilirubin adverse events (AEs) per the Common Terminology Criteria for Adverse Events. Receiver operating characteristic curves and multivariate logistic regression analyses were performed to assess the impact of %LT on toxicities.ResultsOf 141 patients analyzed, 53% (n=75) were ALBI 1, 45% (n=64) ALBI 2, 79% (n=111) CP-A, and 21% (n=30) CP-B. A %LT ≥14.5% was associated with grade/class increases in ALBI 2 (p≤0.01) and CP-B patients (p=0.026). In multivariate analysis, a %LT ≥14.5% was an independent predictor of increases in the ALBI 2 and CP-B groups (p<0.01). No significant %LT threshold was found for ALBI 1 and CP-A patients. No grade 3/4 albumin or bilirubin AEs were reported, while grade 2 AEs were related to an initial whole liver volume <1.3 L (p≤0.01).ConclusionPatients with ALBI 2 and CP-B liver function are less likely to have an increase in their respective grade/class when treating <14.5% of the liver using glass microspheres. ALBI 1 and CP-A patients showed no definitive %LT threshold for biochemical toxicity within the range of this study.

Differences in Survival Between First-Line Radiofrequency Ablation versus Surgery for Early-Stage Hepatocellular Carcinoma: A Population Study Using the Surveillance, Epidemiology, and End Results Database.

BackgroundThe first-line therapy for early-stage hepatocellular carcinoma (HCC) is unclear. This study was conducted to assess and compare survival after surgery vs. after radiofrequency ablation (RFA) for early-stage HCC.Material/MethodsData from HCC patients with a single tumor measuring 31–50 mm were extracted from the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2015. Overall survival (OS) and cancer-specific survival (CSS) were assessed and compared between surgery and RFA treatment. Propensity score matching was performed. Multiple imputations were used to create 5 sets of complete data. Fine and Gray competing risk multivariate regression models were used to control biases.ResultsThis study included 839 patients: 339 (40.41%) received RFA and 500 (59.59%) underwent surgery. Surgery improved the 5-year OS (63.95% vs. 37.13%, p<0.01) and CSS (64.01% vs. 38.29%, p<0.01) compared with RFA after propensity score matching. The competing risk regression models revealed that, compared with RFA, surgery resulted in better survival in the unmatched cohort with an adjusted sub-distribution hazard ratio of 0.689 (95% confident interval [CI], 0.562–0.868; p=0.001) and in the propensity-matched cohort with an adjusted sub-distribution hazard ratio of 0.642 (95% CI, 0.514–0.801; p<0.001).ConclusionsSurgery appears to be a better therapy choice than RFA for patients with early-stage HCC with a single tumor measuring 31–50 mm.

Ablation plus Transarterial Embolic Therapy for Hepatocellular Carcinoma Larger than 3 cm: Science, Evidence, and Future Directions.

Thermal ablation is widely regarded as definitive therapy for early-stage hepatocellular carcinoma, but its efficacy decreases in tumors greater than 3 cm. Extensive clinical studies have supported improved outcomes provided through combining transarterial embolic therapy with ablation in the treatment of larger tumors. This article will provide a survey of the science and data for combination therapy in both thermal and nonthermal ablation modalities, as well as describe emerging applications.

Health-Related Quality of Life Comparisons After Radical Therapy for Early-Stage Hepatocellular Carcinoma

BackgroundFor cancer patients, health-related quality of life (HRQoL) is as important as other key outcomes, such as overall survival and tumor-free survival. Liver transplantation (LT), resection, and radiofrequency ablation (RFA) are 3 radical therapies for hepatocellular carcinoma (HCC) that result in similar survival. The main objective of this study was to assess and compare long-term HRQoL scores for patients with early-stage (tumor diameter ≤3 cm) HCC after LT, resection, or RFA. MethodsA total of 128 HCC patients with a single tumor ≤3 cm and who agreed to undergo LT, resection, or RFA were included in the present analysis. Postoperative HRQoL was evaluated by using the Medical Outcomes Study 36-Item Short Form Health Survey questionnaire. The 3 groups were compared at the 6-month and 3-year time points. ResultsThe 3 groups showed comparable 3-year HCC recurrence rates (P > .05). Compared with the LT and resection groups, the RFA group had significantly higher scores for bodily pain, general health, and vitality 6 months after surgery (all P values < .05). Moreover, at 3 years after surgery, the RFA group had higher scores for bodily pain and vitality than the other 2 groups (P < .05) and a higher general health score than the resection group. Other aspects of HRQoL were comparable among the 3 groups at both time points. ConclusionsDue to its comparable HCC recurrence rate and superior long-term HRQoL scores relative to other radical therapies, RFA may be the first-choice treatment for solitary early-stage HCC.

The optimal threshold for α-fetoprotein and vitamin K absence or antagonist-II is still an open issue

Liver transplantation is an important therapy for early-stage hepatocellular carcinoma (HCC). Although patients within the Milan criteria that refer to tumor size ≤5 cm, tumor number ≤3 and no macrovascular invasion has excellent survival outcome, tumor recurrence is a major limitation of long-term survival in liver transplant patients (1,2). Currently, many centers have performed liver transplantation extended criteria beyond the Milan criteria (3).

Radiofrequency Ablation of Hepatocellular Carcinoma as First-Line Treatment: Long-term Results and Prognostic Factors in 162 Patients with Cirrhosis

To evaluate the long-term outcomes of radiofrequency ablation (RFA) as a first-line therapy for early-stage hepatocellular carcinoma (HCC) and determine the prognostic factors for survival. The institutional review board approved this retrospective study. From January 2006 to December 2007, 162 consecutive patients with cirrhosis (Child-Pugh class A and B, 137 and 25 patients, respectively) who underwent RFA as a first-line treatment for up to three HCCs with a maximum diameter of 5 cm (182 HCCs; mean diameter ± standard deviation, 2.59 cm ± 0.79; 17 multinodular forms) were included. After a mean follow-up of 50.3 months ± 19.9, results were analyzed for tumor recurrence, as well as overall and recurrence-free survival time. The Kaplan-Meier method and Cox proportional hazards regression model were used to evaluate the prognostic factors. The cumulative incidence of local tumor progression (LTP) was 14.5% at 5 years, with tumor size as the only significant predictive factor (relative risk = 2.13, P = .007). Overall 5-year survival and recurrence-free survival rates were 67.9% and 25.9%, respectively. Significant predictive factors for poor overall survival were Child-Pugh class B (relative risk = 2.43, P = .011), serum α-fetoprotein level (relative risk per 100 units = 1.01; P < .001), and presence of portosystemic collaterals (relative risk = 2.15, P = .025). The development of LTP significantly shortened median recurrence-free survival (28.0 months without LTP vs 12.0 months with LTP) and necessitated a higher number of interventional procedures (2.2 sessions without LTP vs 5.1 sessions with LTP). RFA is a safe and effective first-line treatment for early-stage HCC, with a 5-year survival rate of 67.9%. High serum α-fetoprotein level, advanced Child-Pugh class, and presence of portosystemic collateral vessels had a significant negative effect on overall survival.

Needle electrode position assessed using three-dimensional ultrasonography and outcome of radiofrequency ablation in hepatocellular carcinoma.

Radiofrequency ablation (RFA) is an established curative therapy for early-stage hepatocellular carcinoma (HCC). We assessed the positions of inserted needle electrodes using three-dimensional ultrasonography (3D-US) and examined the association between the electrode position and outcomes of RFA. Forty-seven patients with 49 HCC nodules treated with a cooled-tip RFA system were enrolled. Immediately after the first insertion of electrodes, 3D volume data were acquired. After RFA completion, the electrode position was assessed using the data. There were 18 central and 31 marginal pattern nodules. The total number of electrode insertions was significantly greater for the marginal nodules than for the central nodules (p=0.032). In the first session of RFA, 36 HCC nodules (central, n=14; marginal, n=22) were treated with single insertion of electrodes. The ratio of incompletely ablated nodules after the first session was greater for the marginal nodules than for the central nodules (p=0.025). Our study demonstrated that inserted electrode positions assessed using 3D-US are closely associated with outcomes of RFA and the number of electrode insertions.

Minshan Chen: combination of TACE and RFA can improve the treatment of HCC.

Transcatheter arterial chemoembolization (TACE) is the most widely used therapy for mid-stage hepatocellular carcinoma (HCC), while radiofrequency ablation (RFA) is commonly used as a therapy for early-stage HCC. This study combines RFA with TACE for the treatment of HCC. So where did this idea come from? Is there any plan for a follow-up research?

Emerging Therapeutic Approaches to Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most common solid malignancies worldwide, and its incidence is dramatically increasing in the United States. Unlike many other malignancies, treatment of HCC often involves management of two disease processes: liver cancer and cirrhosis. In addition to tumor-specific factors such as tumor size, number, and location, the surgeon also has to consider liver specific factors such as degree of fibrosis/ cirrhosis, extent of portal hypertension, and the size of the future liver remnant. As such, therapy for HCC is complex and can involve resection, transplantation, interventional radiology-based liver-directed therapies, and emerging systemic chemotherapeutic and targeted agents. To successfully treat this group of patients, surgical oncologists should be aware of the many and varied approaches to treating patients with HCC. Specifically, surgical oncologists need to know not only how to select patients and perform hepatic resection in appropriate patients with HCC, but also be familiar with the controversy surrounding management of early HCC and identify those factors that may make one therapeutic modality preferable compared with others. In addition, surgical oncologists need to be familiar with the role of intra-arterial regional therapy as ‘‘destination’’ therapy for unresectable HCC, as well as bridge therapy before transplantation/resection. Finally, surgical oncologists need to be aware of the emerging role of systemic chemotherapy for stage IV HCC, as well as its potential future role as adjuvant therapy. In this issue of Annals of Surgical Oncology, a series of review articles have been solicited to provide evidence-based data to equip the practicing surgical oncologist with the knowledge to understand these complex treatment issues. In the first article, surgical resection of HCC is addressed with a particular focus on patient selection, preoperative considerations, and perioperative management of patients. The selection of HCC patients for surgical resection continues to evolve and expand with advances in technology and improved perioperative care of the patient with cirrhosis. Specifically, preoperative portal vein embolization has made resection possible for a subset of patients who otherwise might not have been considered surgical candidates as a result of an anticipated small liver remnant. However, resection of large or multifocal HCC, as well as resection in those patients with portal hypertension, remains controversial. In the second article, another controversy in the management of HCC is addressed: therapy for early-stage HCC in patients with well-compensated cirrhosis. Among patients with a solitary tumor B5 cm in size or three or fewer tumors each B3 cm in size and no evidence of gross vascular invasion, the role of resection versus transplantation versus ablation is examined. Although the ideal treatment strategy for this subset of patients remains controversial, data on the relative indications and merits of each therapeutic approach are presented. In the third article, issues related to intra-arterial therapies for inoperable HCC are discussed. Unfortunately, many patients with HCC will present with advanced disease and will not be candidates for either surgical resection Acknowledgment: This educational review series, ‘‘Emerging Therapeutic Approaches to Hepatocellular Carcinoma,’’ has been supported by an educational grant from Onyx Pharmaceuticals/Bayer Healthcare Pharmaceuticals.

Initial Treatment Response Is Essential to Improve Survival in Patients with Hepatocellular Carcinoma Who Underwent Curative Radiofrequency Ablation Therapy

Objective: This study was undertaken to assess the outcome of potentially curative radiofrequency ablation (RFA) therapy for early-stage hepatocellular carcinoma (HCC) in patients with Child-Pugh stage A cirrhosis. Methods: This study retrospectively evaluated clinical outcomes in a cohort of 171 Child-Pugh stage A cirrhotic patients who received RFA for naïve HCC within the Milan criteria. The median follow-up period was 36.7 months. Results: Cumulative survival rates estimated by the Kaplan-Meier method for all patients were 98.8, 91.1 and 76.8% at 1, 3 and 5 years, respectively. Cumulative probabilities of local tumor recurrence at 1, 2 and 3 years were 9.0, 14.1 and 17.7%, respectively. Cumulative survival rates in patients without local tumor recurrence were 96.6, 94.6 and 84.4% at 1, 3 and 5 years, respectively, compared with patients with local tumor recurrence (96.6, 74.8 and 42.1% at 1, 3 and 5 years, respectively; p = 0.0002). Cox regression analysis showed that low serum albumin (p = 0.009, RR 3.04, CI 1.32–6.98), high range of PIVKA-II (prothrombin induced by vitamin K absence or agonist II) (p = 0.025, RR 2.57, CI 1.13–5.89), with multiple (less than 3) nodules (p = 0.021, RR 2.61, CI 1.15–5.91), and with local tumor recurrence (p = 0.004, RR 3.62, CI 1.51–8.69) were significant risk factors for death. Conclusion: Initial complete response of curative RFA therapy in patients with Child-Pugh stage A cirrhosis and early-stage HCC is associated with improved survival. Therefore, clinicians should aim to achieve complete ablation of all detectable HCC nodules with adequate safety margins.

Outcomes of Nontransplant Potentially Curative Therapy for Early-Stage Hepatocellular Carcinoma in Child-Pugh Stage A Cirrhosis Is Comparable with Liver Transplantation

Background: This study was undertaken to assess the outcome of potentially curative therapy for early-stage hepatocellular carcinoma (HCC) in patients with Child-Pugh stage A cirrhosis as well as to investigate the impact of low-dose interferon (IFN) therapy after curative therapy on survival. Methods: This study retrospectively evaluated clinical outcomes in a cohort of 224 Child-Pugh stage A cirrhotic patients who received either resection (53 cases) or radiofrequency ablation (RFA: 171 cases) for HCC within Milan criteria. Thirty patients were treated with low-dose maintenance IFN therapy after initial curative therapy. The median follow-up period was 36.7 months. Results: The 5-year survival rate of all patients was 74.9%, with similar rates for the resection and RFA groups (70.4 vs. 76.8%; p = 0.561). The 5-year HCC recurrence rate was higher in the RFA group than the resection group (85.3 vs. 73.2%; p = 0.012). The maintenance IFN-treated group maintained their liver function within Child-Pugh stage A for a significantly longer time (median time 36.9 vs. 32.2 months; p = 0.0025). Conclusion: The 5-year outcomes of resection and RFA in patients with Child-Pugh stage A cirrhosis and early stage HCC were comparable with liver transplantation. Low-dose, long-term maintenance IFN therapy after curative therapy was significantly beneficial on survival.