Liver-confined Hepatocellular Carcinoma Research Articles

Recent update of proton beam therapy for hepatocellular carcinoma: A systematic review and meta-analysis.

Although access to proton beam therapy (PBT) is limited worldwide, its use for the treatment of hepatocellular carcinoma (HCC) is gradually increasing with the expansion of new facilities. Therefore, we conducted a systematic review and meta-analysis to investigate the updated evidence of PBT for HCC. The MEDLINE, EMBASE, Cochrane Library, and Web of Science databases were systematically searched for studies that enrolled patients with liver-confined HCC that were treated with PBT for a cure up to February 2024. A total of 1858 HCC patients receiving PBT from 22 studies between 2004 and 2023 were selected for this meta-analysis. The median proportion of Child-Pugh class A was 86% (range: 41-100%), and the median tumor size was 3.6 cm (range: 1.2-9 cm). The median total dose ranged from 55 GyE to 76 GyE (median, 69 GyE). The pooled rates of 3- and 5-year local progression-free survival after PBT were 88% (95% confidence interval [CI], 85-91%) and 86% (95% CI, 82-90%), respectively. The pooled 3- and 5-year overall rates were 60% (95% CI, 54-66%) and 46% (95% CI, 38-54%), respectively. The pooled rates of grade 3 hepatic toxicity, classic radiation-induced liver disease (RILD), and non-classic RILD were 1%, 2%, and 1%, respectively. The current study supports PBT for HCC and demonstrates favorable long-term survival and low hepatic toxicities compared with other published studies on other radiotherapy modalities. However, further studies are needed to identify the subgroups that will benefit from PBT.

Safety and Preliminary Efficacy of Pembrolizumab Following Transarterial Chemoembolization for Hepatocellular Carcinoma: The PETAL Phase Ib Study.

Transarterial chemoembolization (TACE) may prime adaptive immunity and enhance immunotherapy efficacy. PETAL evaluated safety, preliminary activity of TACE plus pembrolizumab and explored mechanisms of efficacy. Patients with liver-confined hepatocellular carcinoma (HCC) were planned to receive up to two rounds of TACE followed by pembrolizumab 200 mg every 21 days commencing 30 days post-TACE until disease progression or unacceptable toxicity for up to 1 year. Primary endpoint was safety, with assessment window of 21 days from pembrolizumab initiation. Secondary endpoints included progression-free survival (PFS) and evaluation of tumor and host determinants of response. Fifteen patients were included in the safety and efficacy population: 73% had nonviral cirrhosis; median age was 72 years. Child-Pugh class was A in 14 patients. Median tumor size was 4 cm. Ten patients (67%) received pembrolizumab after one TACE; 5 patients after two (33%). Pembrolizumab yielded no synergistic toxicity nor dose-limiting toxicities post-TACE. Treatment-related adverse events occurred in 93% of patients, most commonly skin rash (40%), fatigue, and diarrhea (27%). After a median follow-up of 38.5 months, objective response rate 12 weeks post-TACE was 53%. PFS rate at 12 weeks was 93% and median PFS was 8.95 months [95% confidence interval (CI): 7.30-NE (not estimable)]. Median duration of response was 7.3 months (95% CI: 6.3-8.3). Median overall survival was 33.5 months (95% CI: 11.6-NE). Dynamic changes in peripheral T-cell subsets, circulating tumor DNA, serum metabolites, and in stool bacterial profiles highlight potential mechanisms of action of multimodal therapy. TACE plus pembrolizumab was tolerable with no evidence of synergistic toxicity, encouraging further clinical development of immunotherapy alongside TACE.

Predictive Value of Tumor Volume on Local Control in Hepatocellular Carcinoma Treated with Image Guided Hypofractionated Radiation Treatment

External beam radiation treatment (EBRT) is an important local treatment in liver-confined hepatocellular carcinoma (HCC) patients who are not candidates for curative therapy. EBRT dose, technique and prognostic factors are evolving. We hypothesized that tumor volume to liver volume ratio can be a predictor of local control (LC) in patients treated with hypo-fractionated radiation (HFRT) in HCC MATERIALS/METHODS: We retrospectively reviewed 50 patients of HCC treated with HFRT at our institution. HFRT schedule was chosen such that the radiation dose to the remaining liver and other organs at risk (OAR) met the standard dosimetric constraints. Image guided techniques were used for motion management, internal target volume (ITV) and planning target volume (PTV) delineation. Tumor to Liver Ratio (TLR) was defined as ratio of PTV volume to whole liver volume. TLR ≤ 0.3 was considered as low volume disease and TLR > 0.3 was considered as high-volume disease. The radiation dose ranged from 45 Gy to 67.5 Gy in 5 - 15 fractions. The biologically equivalent dose (BED) for tumor ranged from 58.5 Gy10 to 100 Gy10. Local control (LC) was evaluated by Kaplan-Meier analysis, with log-rank test for groups stratified as per TLR. Multivariate Cox regression analysis was performed to identify additional prognostic factors. The mean duration of follow-up was 24 months. The median age was 69 years (range 50 - 90) and 76% were males. 32 patients had CP-A class cirrhosis while 17 had CP-B and 1 had CP-C class. BCLC stage A, B, C and D was seen in 2, 14, 33 and 2 patients, respectively. Portal vein thrombosis was present in 9 patients and prior trans-arterial chemo embolization (TACE) was done in 23 patients. The median volume of PTV was 551 cc (range 52 - 1990 cc). The TLR ranged from 0.04 - 0.67 with a median of 0.29. The median BED radiation dose was 78.4 Gy10 (range - 58.5 Gy10 to 100 Gy10). Nine patients had local recurrence with overall LC rate of 82%. The LC was better in low volume tumors, with the TLR cut-off of 0.3 as a significant factor associated with LC (p = 0.007). The 1-year actuarial LC with TLR ≤ 0.3 was 88% as compared 61% in TLR of > 0.3 (p = 0.007). BED ≥60 Gy10 was associated with better 1 year LC as compared to BED < 60 Gy10 (89% vs 62%; p = 0.11). ALBI grade 1 was associated with better 1 year LC as compared to ALBI grade 2 (80% versus 75%; p = 0.40). On multivariate analysis, high volume disease and TLR >0.3 were significant prognostic factor for LC. HFRT has good 1-year local control of 82% in carefully selected unresectable HCC. Radiation with BED greater than 60 Gy10 and ALBI grade 1 showed a trend towards better LC. Smaller tumors had better LC with a PTV to liver ratio (TLR) of < 0.3. This information can help in identifying the poor responders, intensifying the radiation treatment and adding additional therapy to improve the oncological outcomes.

Therapeutic Outcome of Stereotactic Body Radiotherapy for Small Hepatocellular Carcinoma Lesions – A Systematic Review and Network Meta-analysis

Surgical resection, stereotactic body radiotherapy (SBRT) and radiofrequency ablation (RFA) have seldom been compared for small hepatocellular carcinoma (HCC). We explored the treatment outcomes of SBRT for small HCC by conducting a network meta-analysis (NMA). We compared the efficacy and safety of surgical resection, RFA and SBRT for liver-confined small HCC (three or fewer lesions with a diameter ≤5 cm). The study endpoint included the odds ratios of the 1-, 3- and 5-year progression/recurrence/disease-free survival (disease progression-free survival; DPFS) and overall survival rates, as well as severe complications. Forty-five studies included 21 468 patients. In the NMA with comparable data, SBRT had comparable 1-, 3- and 5-year DPFS but significantly worse pooled long-term overall survival (3- and 5-year overall survival) than surgical resection (odds ratio 1.39, 95% confidential interval 1.3–1.89; odds ratio 1.33, 95% confidence interval 1.06–1.69, respectively). SBRT was associated with significantly better pooled 1-year DPFS compared with RFA (odds ratio 0.39, 95% confidence interval 0.15–0.97), with the remaining outcomes being comparable. SBRT had significantly less incidence of severe complications compared with surgical resection (odds ratio 0.62, 95% confidence interval 0.42–0.88) and RFA (odds ratio 0.2, 95% confidence interval 0.03–0.94). In conclusion, for small HCCs (≤5 cm) with one to three nodules, SBRT may be favourable to reduce the risks of severe complications. In terms of DPFS, SBRT may be recommended as an alternative first-line therapy for RFA and surgical resection. The results regarding overall survival should be interpreted with caution, considering the potentially uneliminated bias. There is a clear need for well-designed randomised trials to conclusively identify real differences in efficacy between these treatments, especially SBRT and surgical resection.

Potential candidates for liver resection in liver-confined advanced HCC: a Chinese multicenter observational study.

Advanced hepatocellular carcinoma (HCC) is characterized as symptomatic tumors [performance status (PS) score of 1-2], vascular invasion and extrahepatic spread, but patients with PS1 alone may be eliminated from this stage. Although liver resection is used for liver-confined HCC, its role in patients with PS1 alone remains controversial. Therefore, we aimed to explore its application in such patients and identify potential candidates. Eligible liver-confined HCC patients undergoing liver resection were retrospectively screened in 15 Chinese tertiary hospitals, with limited tumor burden, liver function and PS scores. Cox-regression survival analysis was used to investigate the prognostic factors and develop a risk-scoring system, according to which patients were substratified using fitting curves and the predictive values of PS were explored in each stratification. From January 2010 to October 2021, 1535 consecutive patients were selected. In the whole cohort, PS, AFP, tumor size and albumin were correlated with survival (adjusted P<0.05), based on which risk scores of every patient were calculated and ranged from 0 to 18. Fitting curve analysis demonstrated that the prognostic abilities of PS varied with risk scores and that the patients should be divided into three risk stratifications. Importantly, in the low-risk stratification, PS lost its prognostic value, and patients with PS1 alone achieved a satisfactory 5-year survival rate of 78.0%, which was comparable with that PS0 patients (84.6%). Selected patients with PS1 alone and an ideal baseline condition may benefit from liver resection and may migrate forward to BCLC stage A.

Recurrence of Hepatocellular Carcinoma After Complete Radiologic Response to Trans-Arterial Embolization: A Retrospective Study on Patterns, Treatments, and Prognoses.

There is limited information about the long-term outcomes and patterns of progression in patients who have unresectable, liver-confined hepatocellular carcinoma (HCC) with complete response (CR) to transarterial embolization and do not undergo resection or transplantation (LT). A retrospective review analyzed participants in a randomized trial comparing hepatic artery embolization (HAE) and drug-eluting bead transarterial chemoembolization (DEB-TACE) with doxorubicin who had CR according to modified response evaluation criteria in solid tumors (mRECIST). The overall survival (OS), incidence and patterns of progression, and factors associated with progression were assessed. Of the 101 patients in the trial, 37 with CR were included in this study. This cohort had 17 patients treated with HAE (46 %), and 20 patients managed with DEB-TACE (54 %). The median age was 67 years (range, 42-82 years). Most of the cohort were male (86.5 %) and Caucasian (78 %). The median pre-treatment Model for End-Stage Liver Disease (MELD) score was 10, and 70 % of the cohort had Barcelona Clinic Liver Cancer (BCLC) stage B or C. The median follow-up period was 49 months (95 % confidence interval [CI], 9-108 months), and the median OS was 25 months (95 % CI, 18.9-30.9 months). The 3- and 5-year survival rates were respectively 31 % (95 % CI, 16.7-45.9 %) and 18 % (95 % CI, 6.8-32.1 %). The 1- and 2-year cumulative incidences of progression were respectively 76 % (95 % CI, 57.7-86.8 %) and 92 % (95 % CI, 74.5-97.6 %). The most common first site of progression was the previously treated hepatic site or local site (32 %, 12/37). The 3-year cumulative incidence of progression was 65 % (95 % CI, 46.4-78.4 %) for the local site. Patients with advanced-stage HCC and CR to embolization do not have durable responses and experience inevitable disease progression. Most patients with progression have liver-confined disease and should be evaluated for additional consolidative treatments.

Radiologic Response as a Prognostic Factor in Advanced Hepatocellular Carcinoma with Macroscopic Vascular Invasion after Transarterial Chemoembolization and Radiotherapy

Introduction: We evaluated the radiologic response rate of combined transarterial chemoembolization (TACE) plus radiotherapy (RT) in treatment-naïve patients with liver-confined hepatocellular carcinoma (HCC) with macroscopic vascular invasion (MVI) and analyzed its clinical importance in overall survival (OS) outcomes. Methods: Patients who were treated with TACE plus RT as a first-line treatment for HCC with MVI between January 2010 and December 2015 were retrospectively reviewed. Radiologic response was assessed according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) at 2 and 4 months after completion of RT. Landmark analysis at 2 and 4 months, and time-dependent Cox regression analysis using response as a time-dependent covariate were performed for univariable and multivariable analyses. Results: The 2-month landmark analysis included 427 patients, and the 4-month landmark analysis included 355 patients after excluding patients without imaging studies for response evaluation at 4 months. Radiologic responses were observed in 210 (49.2%) patients at 2 months and 181 (51.8%) patients at 4 months. In multivariable analyses, radiologic response was identified as an independent prognosticator for OS at 2 months (median OS: responders, 23.1 months vs. nonresponders, 8.0 months; hazard ratio [HR], 3.194; p < 0.001) and 4 months (median OS: responders, 26.5 months vs. nonresponders, 9.3 months; HR, 4.534; p < 0.001). Conclusion: Radiologic response assessed by mRECIST was a significant prognostic factor for OS in patients with advanced-stage HCC showing MVI treated with combined TACE plus RT.

Arterial chemoembolisation with cisplatin versus epirubicin for hepatocellular carcinoma (ACE 500 study): A multicentre, randomised controlled phase 2/3 trial

BackgroundTransarterial chemoembolisation (TACE) is a treatment option for hepatocellular carcinoma (HCC), but the optimum agent for TACE remains unclear. We compared the efficacy of TACE with cisplatin versus with epirubicin in patients with unresectable HCC. MethodsThis multicentre, randomised, phase 2/3 trial was performed at 21 hospitals in Japan. Patients with liver-confined HCC, performance status 0–2, and Child-Pugh class A/B were randomised to receive TACE with cisplatin or epirubicin. Patients were stratified in accordance with the institution, Child-Pugh class, tumour size, tumour thrombosis, α-fetoprotein and prior treatment. The primary end-point was overall survival in the intention-to-treat population. Tumour response was evaluated in accordance with the Response evaluation criteria in solid tumours criteria. FindingsBetween 2008 and 2012, 455 patients were randomly assigned to undergo TACE with cisplatin (n = 228) or epirubicin (n = 227). Eleven patients were ineligible, and 444 patients were included in the full analysis. Twelve patients not receiving TACE were excluded, and 432 patients were included in the safety analysis set. In phase 2, disease control rates in cisplatin (91·7%) and epirubicin (91·8%) groups exceeded the predefined threshold of 70%, and the study proceeded to phase 3. After a median follow-up of 32·7 months (IQR = 15·3–49·3), median overall survival periods were 2·93 years (95% CI 2·60–3·79) and 2·74 years (95%CI 2·26–3·21), respectively (hazard ratio 0·90 [95% CI 0·71–1·15], p = 0·22). Median times to treatment failure were 1·38 and 1·46 years (hazard ratio 1·09 [95% CI 0·88–1·35], p = 0·88), response rates were 65·3% and 60·6% (p = 0·31), and serious adverse event rates were 49·8% and 48·3% (p = 0·56), respectively. No treatment-related deaths occurred in either group. InterpretationIn our phase 2/3 randomised trial, cisplatin is not significantly superior to epirubicin in TACE for patients with HCC.

Therapeutic outcome and related predictors of stereotactic body radiotherapy for small liver-confined HCC: a systematic review and meta-analysis of observational studies

Background and purposeStereotactic body radiotherapy (SBRT) is a promising ablative modality for hepatocellular carcinoma (HCC) especially for those with small-sized or early-stage tumors. This study aimed to synthesize available data to evaluate efficacy and explore related predictors of SBRT for small liver-confined HCC (≤ 3 lesions with longest diameter ≤ 6 cm).Materials and methodsA systematic search were performed of the PubMed and Cochrane Library databases. Primary endpoints were overall survival (OS) and local control (LC) of small HCC treated with SBRT, meanwhile, to evaluate clinical parameters associated with treatment outcome by two methods including subgroup comparisons and pooled HR meta-analysis. The secondary endpoint was treatment toxicity.ResultsAfter a comprehensive database review, 14 observational studies with 1238 HCC patients received SBRT were included. Pooled 1-year and 3-year OS rates were 93.0% (95% confidence interval [CI] 88.0–96.0%) and 72.0% (95% CI 62.0–79.0%), respectively. Pooled 1-year and 3-year LC rates were 96.0% (95% CI 91.0–98.0%) and 91.0% (95% CI 85.0–95.0%), respectively. Subgroup comparisons regarding Child–Pugh class (stratified by CP-A percentage 100%, 75–100%, 50–75%) showed there were statistically significant differences for both 1-year and 3-year OS rate (p < 0.01), while that regarding number of lesions, pretreatment situation, age (median/mean age of 65), macrovascular invasion, tumor size, and radiation dose (median BED10 of 100 Gy), there were no differences. In subgroup comparisons for LC rate, it showed number of lesions (1 lesion vs. 2–3 lesions) was significantly associated with 1-year LC rate (p = 0.04), though not associated with 3-year LC rate (p = 0.72). In subgroup comparisons categorized by other factors including pretreatment situation, age, CP-A percentage, macrovascular invasion, tumor size, and radiation dose, there were no significant differences for 1- or 3-year LC rate. To further explore the association between CP class and OS, the second method was applied by combining HR and 95% CIs. Results indicated CP-A was predictive of better OS (p = 0.001) with pooled HR 0.31 (95% CIs 0.11–0.88), which was consistent with subgroup comparison results. Concerning adverse effect of SBRT, pooled rates of grade ≥ 3 hepatic complications and RILD were 4.0% (95% CI 2.0–8.0%) and 14.7% (95% CI 7.4–24.7%), respectively.ConclusionThe study showed that SBRT was a potent local treatment for small liver-confined HCC conferring excellent OS and LC persisting up to 3 years, even though parts of included patients were pretreated or with macrovascular invasion. CP-A class was a significant predictor of optimal OS, while number of lesions might affect short term tumor control (1-year LC). Tumor size and radiation dose were not vital factors impacting treatment outcome for such small-sized HCC patients. Because of the low quality of observational studies and heterogeneous groups of patients treated with SBRT, further clinical trials should be prospectively investigated in large sample sizes.

Efficacy and Toxicity of Stereotactic Body Radiotherapy for Early to Advanced Stage Hepatocellular Carcinoma – Initial Experience From an Australian Liver Cancer Service

AimsIntrahepatic progression remains the predominant mode of cancer-related death in hepatocellular carcinoma (HCC) underscoring the need for effective local therapies. We report our initial experience with liver stereotactic body radiotherapy (SBRT) in the management of early to advanced stage HCC at an Australian tertiary liver cancer service. Materials and methodsPatients with liver-confined HCC unsuitable for surgical resection or thermal ablation treated with SBRT between October 2013 and December 2018 were retrospectively evaluated. The primary end point was freedom from local progression. Secondary end points were progression-free survival, disease-specific survival, overall survival and toxicity. ResultsNinety-six patients were treated for 112 lesions (median size 3.8 cm, range 1.5–17 cm). The median follow-up was 13 months (range 3–65). Forty-six patients had received prior local therapies (median 1, range 1–5), 83 (86%) patients had cirrhosis with baseline Child–Pugh scores of A (88%) and B7–8 (12%). Fifty-nine (61%) patients had Barcelona Clinic Liver Cancer (BCLC) stage 0/A disease and 37 (39%) had stage B/C. Macrovascular invasion was present in 20 (21%). The median biologically effective dose (BED10) was 86 and 60 Gy for the BCLC 0/A and B/C cohorts, respectively. Freedom from local progression at 18 months was 94% for BCLC 0/A and 74% for BCLC B/C. Progression-free survival and overall survival at 12 months were 80 and 95% for BCLC 0/A and 40 and 71% for BCLC B/C, respectively. Five patients (7%) with cirrhosis and without disease progression had an increase in Child–Pugh score >1 within 3 months of SBRT, four of whom had intercurrent infections. Clinical toxicities grade ≥2 were reported in 20% of patients. ConclusionSBRT is an effective ablative modality for early stage HCC with low rates of significant toxicity. Lower dose SBRT can provide durable local control for advanced stage HCC. However, out-of-field relapse remains common, providing a rationale to investigate SBRT in combination with other therapies.

Validation of the six-and-twelve criteria among patients with hepatocellular carcinoma and performance score 1 receiving transarterial chemoembolization.

BACKGROUNDTransarterial chemoembolization (TACE) is recommended for patients with intermediate hepatocellular carcinoma (HCC) according to treatment guidelines. However, a large number of patients with advanced HCC also receive TACE in clinical practice, especially for those with liver-confined HCC and Eastern Cooperative Oncology Group score (ECOG) 1. In view of previous studies, such patients have different prognoses from advanced HCC patients with macrovascular invasion or extrahepatic spread; therefore, patients with ECOG 1 alone might be classified into the intermediate stage and benefit from TACE treatment, but a study particularly focusing on such patients and exploring the effectiveness of TACE therapy is lacking.AIMTo investigate treatment outcomes of TACE in HCC patients with ECOG 1 alone and propose a specific prognostic model.METHODSPatients from 24 Chinese tertiary hospitals were selected in this nationwide multicenter observational study from January 2010 to May 2016. Overall survival (OS) was estimated using Kaplan–Meier curves and compared by the log-rank test. Multivariate Cox regression was used to develop the potential prognostic models. The discriminatory ability of the models was compared and validated in various patient subgroups. The individual survival prediction for six-and-twelve (6&12) criteria, defined as the algebraic sum of tumor size (cm) and tumor number, was illustrated by contour plot of 3-year survival probability and nomogram.RESULTSA total of 792 eligible patients were included. During follow-up, median OS reached 18.9 mo [95% confidence interval (CI): 16.9-21.0]. Three independent multivariate analyses demonstrated that tumor size, tumor number, α-fetoprotein level, albumin–bilirubin grade and total bilirubin were prognostic factors of OS (P < 0.05). The previously proposed 6&12 criteria was comparable or even better than currently proposed with the highest predictive ability. In addition, the 6&12 criteria was correlated with OS in various subgroups of patients. The patients were stratified into three strata with score ≤ 6, > 6 but ≤ 12, and > 12 with different median OS of 39.8 mo (95%CI: 23.9-55.7), 21.1 mo (95%CI: 18.4-23.8) and 9.8 mo (95%CI: 8.3-11.3), respectively (P < 0.001).CONCLUSIONTACE is effective for advanced HCC patients with ECOG 1 alone, and the 6&12 criteria may help with clinical decision-making.

Exploratory Analysis to Identify Candidates Benefitting from Combination Therapy of Transarterial Chemoembolization and Sorafenib for First-Line Treatment of Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Observational Study

Introduction: The benefits of combining transarterial chemoembolization (TACE) and sorafenib (TACE-S) over TACE alone for treatment of unresectable hepatocellular carcinoma (HCC) remain controversial. Yet, such populations are heterogeneous in terms of baseline characteristics. Objective: To investigate the predictors of survival benefits from added sorafenib and identify the potential candidates for TACE-S. Methods: This multicenter observational study was conducted in 17 Chinese tertiary hospitals for patients with unresectable, liver-confined HCC. Eligible patients with performance status score of ≤1 and Child-Pugh score of ≤7 were treated with TACE or TACE-S. Interactions between treatment and baseline variables were evaluated to find indicators for survival benefits, based on which the patients were stratified. Multivariate models adjusted for baseline characteristics or propensity score were used to compare overall survival (OS) and time to tumor progression (TTP). Results: From January 2009 to December 2015, 1,719 consecutive patients received TACE (n = 1,406) or TACE-S (n = 313). Although TACE-S compared with TACE improved TTP (adjusted hazard ratio [HR] 0.75, p = 0.008), no difference in OS was observed (adjusted HR 0.87, p = 0.090). Nevertheless, the tumor burden (sum of maximum diameter of largest tumor [cm] and tumor number) and albumin-bilirubin (ALBI) score independently predicted the survival benefits from added sorafenib (interaction p< 0.001). For patients with either moderate tumor burden (7–13) or low ALBI score (no more than –2.8) defined as candidates, TACE-S prolonged OS (adjusted HR 0.73, p = 0.003) and TTP (adjusted HR 0.72, p = 0.014) compared to TACE alone, whereas its superiority disappeared in non-candidates. Conclusions: Not all unresectable HCC patients but those with moderate tumor burden or low ALBI score achieve survival benefits from TACE-S compared with TACE alone. Future randomized controlled trials focusing on the subset are warranted.

Combined radiotherapy and transarterial chemoembolization as a first-line treatment for hepatocellular carcinoma with macroscopic vascular invasion.

452 Background: To evaluate the long-term clinical outcome of respiratory-gatedconformal radiotherapy in combination withtransarterial chemoembolization (TACE)asafirst-line treatment foradvanced hepatocellular carcinoma (HCC) with macroscopic vascular invasion (MVI). Methods: This was a retrospective analysis of patientswho were diagnosed with HCC showing MVI who received TACE plus radiotherapy as their initial treatment between 2010 and 2015. Inclusion criteria were Child-Pugh A or B hepatic function and Eastern Cooperative Oncology Group performance score 0–2. None of the patients had a previous history of radiotherapy to the liver or extrahepatic metastasis. Results: A total of 467 patients were included in the study. Patients were between 34 and 87 years of age, and 89.3% were male. The median maximum tumor diameter was 9.8 cm and 297 patients (63.6%) had Child-Pugh A hepatic function. Two hundred and eighty (60%) patients had multiple tumors; 45% of tumors showed bilobar involvement. Unilateral portal vein invasion was observed in 206 (44.1%) patients and main/bilateral portal veinor multiple vascular invasion were observed in 261 (55.9%) patients. The median overall survival was 12.5 months, with one- and two-year survival rates of 52% and 28%, respectively. Larger tumor size, multiple tumors, infiltrative tumor type, Child-Pugh class B, and alpha-fetoprotein ≥ 200 ng/ml were independent predictors of overall survival. Grade ≥ 3 hepatic and gastrointestinal toxicities were observed in 3 (0.6%) and 5 (1.1%) patients, respectively. Conclusions: Radiotherapy combined with TACE as an initial treatment was a safe and effective modality for advanced HCC patients with MVIand could be considered as first-line therapy in patients with liver-confined HCC showing MVI.

Effect of transarterial chemoembolization plus external beam radiotherapy on survival of patients with hepatocellular carcinoma showing macroscopic vascular invasion compared with sorafenib: A randomized trial.

210 Background: Sorafenib is the sole treatment option for advanced stage hepatocellular carcinoma (HCC) with macroscopic vascular invasion (MVI) with unsatisfactory response rate and survival benefit. Combined transarterial chemoembolization (TACE) plus external beam radiotherapy (RT) has shown promising results in these patients by observational studies. Here, we report the efficacy and safety of TACE plus RT compared to sorafenib in patients with advanced HCC and MVI. Methods: This study was a randomized, open-label trial at an academic tertiary care center. Between 2013 and 2016, 90 treatment-naive patients with liver-confined HCC showing MVI were randomly assigned to receive sorafenib (400 mg twice-daily; n = 45; sorafenib group) or TACE (every 6 weeks) plus RT (within 3 weeks after the first TACE; n = 45; TACE+RT group). Primary endpoint was 12-week the progression-free survival (PFS) rate by intention-to-treat analysis. Radiologic response was assessed by independent review according to Response Evaluation Criteria in Solid Tumors (version 1.1). Crossover of treatment was permitted after confirming disease progression. Results: All patients had portal vein invasion of HCC and Child-Pugh class A liver function. The median maximal tumor diameter was 9.7 cm. At week 12, the PFS rate was significantly higher in the TACE+RT group than the sorafenib group (77.8% vs. 26.7%; P&lt; 0.001). The TACE+RT group showed significantly higher radiologic response rate (33.3% vs. 2.2% at 24 weeks; P&lt; 0.001), significantly longer median time to disease progression (30 weeks vs. 8 weeks; P&lt; 0.001), and significantly longer overall survival (55 weeks vs. 43 weeks; P= 0.04), compared with the sorafenib group. No patients in the TACE+RT group discontinued treatment due to hepatic decompensation. Conclusions: In patients with advanced HCC showing MVI, first-line treatment with TACE+RT was well-tolerated and provided improved progression-free survival, objective response rate, time to disease progression, and overall survival, compared with sorafenib treatment. Clinical trial information: NCT01901692.

Transarterial Chemoembolization with Small Drug-Eluting Beads in Patients with Hepatocellular Carcinoma: Experience from a Cohort of 421 Patients at an Italian Center

PurposeTo assess the safety, tolerability, and efficacy of small drug-eluting embolic (DEE) agents (70–150 μm) for chemoembolization of hepatocellular carcinoma (HCC). Materials and MethodsThis single-center, single-arm, retrospective study involved 421 patients (mean age, 66.1 y ± 9.8 [standard deviation]) with Barcelona Clinic Liver Cancer (BCLC) stage A (n = 88), B (n = 140), or C (n = 193) HCC and Child–Pugh class A (n = 233) or B (n = 188) cirrhosis. Patients had a mean of 7.2 lesions ± 4.8 (range, 1–21; mean diameter of target lesion, 21.4 cm ± 8.1; unilobar, n = 132; bilobar, n = 289; portal vein involvement, n = 193). One (n = 320) or 2 (n = 101) vials of small DEEs loaded with doxorubicin 50 mg per vial were delivered selectively (ie, segmentally) or superselectively (ie, directly into the tumor-feeding vessel) until complete delivery or stasis/near-stasis. Treatment was repeated in patients with partial response or stable disease at 1- or 3-month follow-up (mean, 2.0 cycles ± 0.9). Adverse events within 30 days of chemoembolization, response per modified Response Evaluation Criteria In Solid Tumors (mRECIST), and survival were assessed. ResultsWithin 30 days after treatment, no deaths or bleeding events occurred, but all patients had at least 1 episode of postembolization syndrome (pain, fever, and/or nausea/vomiting; 27.1% grade 3/4 per National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0) and increased bilirubin and liver aminotransferase levels (0.2% and 5.9% grade 3/4, respectively). Overall response rates were 94.5% at 3 months and 99.5% at 6 months. Median overall survival was 42.0 months (95% confidence interval, 38.0–43.0 mo). ConclusionsChemoembolization with small DEE agents is well tolerated and an effective treatment for a broad range of patients with liver-confined HCC.

Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial

Transarterial chemoembolisation (TACE) is the standard of care for patients with intermediate stage hepatocellular carcinoma, while the multikinase inhibitor sorafenib improves survival in patients with advanced disease. We aimed to determine whether TACE with sorafenib improves progression-free survival versus TACE with placebo. We did a multicentre, randomised, placebo-controlled, phase 3 trial (TACE 2) in 20 hospitals in the UK for patients with unresectable, liver-confined hepatocellular carcinoma. Patients were eligible if they were at least aged 18 years, had Eastern Cooperative Oncology Group performance status of 1 or less, and had Child-Pugh A liver disease. Patients were randomised 1:1 by computerised minimisation algorithm to continuous oral sorafenib (400 mg twice-daily) or matching placebo combined with TACE using drug-eluting beads (DEB-TACE), which was given via the hepatic artery 2-5 weeks after randomisation and according to radiological response and patient tolerance thereafter. Patients were stratified according to randomising centre and serum α-fetoprotein concentration (<400 ng/mL and ≥400 ng/mL). Only the trial coordinator was unmasked to treatment allocation before patient progression during the study. The primary endpoint was progression-free survival defined as the interval between randomisation and progression according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) or death due to any cause, and was analysed by intention-to-treat. Safety was analysed by intention-to-treat. The trial has been completed and the final results are reported. The trial is registered at EudraCT, number 2008-005073-36, and ISRCTN, number ISRCTN93375053. Between Nov 4, 2010, and Dec 7, 2015, the trial enrolled 399 patients and was terminated after a planned interim futility analysis. 86 patients failed screening and 313 remaining patients were randomly assigned: 157 to sorafenib and 156 to placebo. The median daily dose was 660 mg (IQR 389·2-800·0) sorafenib versus 800 mg (758·2-800·0) placebo, and median duration of therapy was 120·0 days (IQR 43·0-266·0) for sorafenib versus 162·0 days (70·0-323·5) for placebo. There was no evidence of difference in progression-free survival between the sorafenib group and the placebo group (hazard ratio [HR] 0·99 [95% CI 0·77-1·27], p=0·94); median progression-free survival was 238·0 days (95% CI 221·0-281·0) in the sorafenib group and 235·0 days (209·0-322·0) in the placebo group. The most common grade 3-4 adverse events were fatigue (29 [18%] of 157 patients in the sorafenib group vs 21 [13%] of 156 patients in the placebo group), abdominal pain (20 [13%] vs 12 [8%]), diarrhoea (16 [10%] vs four [3%]), gastrointestinal disorders (18 [11%] vs 12 [8%]), and hand-foot skin reaction (12 [8%] and none). At least one serious adverse event was reported in 65 (41%) of 157 patients in the sorafenib group and 50 (32%) of 156 in the placebo group, and 181 serious adverse events were reported in total, 95 (52%) in the sorafenib group and 86 (48%) in the placebo group. Three deaths occurred in each group that were attributed to DEB-TACE. Four deaths were attributed to study drug; three in the sorafenib group and one in the placebo group. The addition of sorafenib to DEB-TACE does not improve progression-free survival in European patients with hepatocellular carcinoma. Alternative systemic therapies need to be assessed in combination with TACE to improve patient outcomes. Bayer PLC and BTG PLC.

The role of radiofrequency ablation of hepatocellular carcinoma in cirrhosis: from guidelines to real practice - a literature review

The epidemiologic features of hepatocellular carcinoma (HCC) in cirrhosis have been changing over the last decades as documented in field cohorts where the prevalence of elderly patients with severe comorbidities is progressively increasing. This may account, at least in clinical practice, for changing of treatment modalities for liver-confined HCC and for the worldwide increased popularity of percutaneous ablation which is undoubtedly more easily applied to weak patients. Radiofrequency ablation (RFA) is the standard reference technique for percutaneous ablation and it is currently included among the curative therapies of early HCC in cirrhosis by international guidelines. In particular, for single HCC<2 cm, RFA should be the first choice therapy, being effective as surgery but less invasive and less expensive. For larger HCCs (not exceeding 4 cm), RFA competes with resection in terms of survival benefit even though the latter provides better local disease control and longer disease-free survival. For non-resectable HCC greater than 4 cm, a treatment combining RFA and transarterial chemoembolization (TACE) can be performed to expand the ablated area. However, this approach needs to be standardized. Microwave (MWA) is a new ablative procedure potentially able to overcome some technical limits of RFA. The effectiveness of MWA is still under investigation even though preliminary results are encouraging. Emerging data from clinical practice outline the increasing role of ablative procedures for treatment of HCC in cirrhosis in the near future.

Stereotactic body radiation therapy: A novel treatment modality for inoperable hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common malignancy in the world and the most common cause of cancer-related death. Surgical resection is the standard of care for solitary liver-confined HCC and provides the best long-term survival, however, most HCCs are diagnosed at an intermediate to advanced stage, and few meaningful therapeutic options are available at this point. Stereotactic body radiation therapy (SBRT) is a type of external beam radiation therapy (EBRT) that delivers radiotherapy (RT) accurately and precisely to the tumor, more so than conventionally fractionated RT. Several series report high rates of local control and low incidence of complications in SBRT for inoperable HCC. Herein, we discuss the emerging role of SBRT as well as current indications, implementation, efficacy and toxicities after SBRT. It was noted that SBRT was a safe and effective therapeutic option for HCC lesions unsuitable for standard locoregional therapies, with acceptable local control rates and low treatment-related toxicity. The significant correlation between local control (LC) and higher doses and between LC and overall survival (OS) supports the clinical value of SBRT in these patients.

サイバーナイフによる肝細胞癌局所治療の経験

We evaluated local control of hepatocellular carcinoma (HCC) treated with Cyberknife, stereotactic body radiation therapy (SBRT). CyberKnife, SBRT system with real-time tumor tracking has good efficacy and low toxicity.54 patients with 67 liver-confined HCC were treated with Cyberknife. Fiducials were implanted in the liver before treatment and were used as markers to track the lesion's movement. A total dose of 30 to 60 Gy in three fractions was prescribed to the 80%isodose line. Treatment response was evaluated by RECICL, CR: 82%, PR: 16%, PD: 2%. The local control rate was 92.3%at 1 year. Cyberknife was a safe, effective, noninvasive option for patients with HCC.

Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma: Prognostic Factors of Local Control, Overall Survival, and Toxicity

PurposeStereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) has been evaluated in several recent studies. The CyberKnife® is an SBRT system that allows for real-time tracking of the tumor. The purpose of this study was to evaluate the prognostic factors for local control and overall survival following this treatment.Patients and Methods75 patients with 96 liver-confined HCC were treated with SBRT at the Oscar Lambret Comprehensive Cancer Center. Fiducials were implanted in the liver before treatment and were used as markers to track the lesion’s movement. Treatment response was scored according to RECIST v1.1. Local control and overall survival were calculated using the Kaplan and Meier method. A stepwise multivariate analysis (Cox regression) of prognostic factors was performed for local control and overall survival.ResultsThere were 67 patients with Child-Turcotte-Pugh (CTP) Class A and eight patients with CTP Class B. Treatment was administered in three sessions. A total dose of 40–45 Gy to the 80% isodose line was delivered. The median follow-up was 10 months (range, 3–49 months). The local control rate was 89.8% at 1 and 2 years. Overall survival was 78.5% and 50.4% at 1 and 2 years, respectively. Toxicity mainly consisted of grade 1 and grade 2 events. Higher alpha-fetoprotein (aFP) levels were associated with less favorable local control (HR=1.001; 95% CI [1.000, 1.002]; p=0.0063). A higher dose was associated with better local control (HR=0.866; 95% CI [0.753, 0.996]; p=0.0441). A Child-Pugh score higher than 5 was associated with worse overall survival (HR= 3.413; 95% CI [1.235, 9.435]; p=0.018).ConclusionSBRT affords good local tumor control and higher overall survival rates than other historical controls (best supportive care or sorafenib). High aFP levels were associated with lesser local control, but a higher treatment dose improved local control.