A randomised phase II/III trial of 3-weekly cisplatin-based sequential transarterial chemoembolisation vs embolisation alone for hepatocellular carcinoma.
ABSTRACT: Transarterial chemoembolisation (TACE) has not been shown to be superior to bland embolisation (TAE) for treatment of hepatocellular carcinoma (HCC).We conducted a randomised phase II/III trial in patients with untreated HCC. Patients were randomised to TAE with polyvinyl alcohol (PVA) particles alone or sequential TACE (sTACE) in which cisplatin 50?mg was administered intrarterially 4-6?h before PVA embolisation. Treatment was repeated 3-weekly for up to three treatments. The primary endpoint was overall survival and secondary endpoints were progression-free survival, toxicity and response. Target sample sizes for phase II and III were 80 and 322.The trial was terminated at phase II after 86 patients had been randomised. Patients were well matched for prognostic criteria. All three planned treatments were given to 57.1% (TAE) and 56.8% (TACE) patients. Grade 3/4 toxicity occurred in 63.5% and 83.7%, respectively (P=0.019). End-of-treatment RECIST response (CR+PR) was 13.2 and 32.6% (P=0.04) (mRECIST 47.3% and 67.4) and median overall survival and progression-free survival was 17.3 vs 16.3 (P=0.74) months and 7.2 vs 7.5 (P=0.59), respectively.Transarterial chemoembolisation according this novel schedule is feasible and associated with a higher response rate than TAE alone. The survival benefit of TACE over TAE remains unproven.
Project description:Recurrence of hepatocellular carcinoma (HCC) after transarterial chemoembolisation (TACE) is common due to neoangiogenesis. Cyclooxygenase-2 inhibitors and somatostatin analogues were reported to inhibit tumour angiogenesis. The pilot randomized controlled trial was aimed to prospectively evaluate the protocol of TACE combined with celecoxib and lanreotide (TACE+C+L) in patients with unresectable and advanced HCC. A total of 71 patients with HCC were enrolled and randomly assigned to either TACE (n=35) or TACE+C+L (n=36) group. Overall survival, disease control rate (DCR), and adverse events were assessed during a 3-year follow-up period. The median overall survival of the TACE+C+L group (15.0 months) was doubled compared to that of TACE group (7.5 months), p = 0.012. DCR of the TACE+C+L group was significantly higher than that of the TACE group either at 6 months (72.2% vs 42.9%, p = 0.012) or at 12 months (61.1% vs 28.6%, p = 0.006). The median overall survivals (13 months vs 4.5 months, p = 0.013) and DCR at 12 months (50% vs 13.6%, p = 0.008) of patients with advanced HCC in TACE+C+L groups were significantly higher than those in TACE group. No significant difference of adverse events was observed between the two groups. The occurrence of post-embolisation syndrome in TACE+C+L group was significantly lower than that in TACE group (16.7% vs 60.0%, p = 0.001). In conclusion, the regimen of TACE+C+L prolonged overall survival, enhanced tumour response, reduced post-embolisation syndrome and was well-tolerable in the patients with unresectable HCC. It may be more beneficial for advanced HCC.
Project description:Transcatheter arterial chemoembolisation (TACE) is the treatment of choice for intermediate stage hepatocellular carcinoma (HCC). Doxorubicin-loaded drug-eluting beads (DEB)-TACE is expected to improve the performance of conventional TACE (cTACE). The aim of this study was to compare DEB-TACE with cTACE in terms of time-to-tumour progression (TTP), adverse events (AEs), and 2-year survival.Patients were randomised one-to-one to undergo cTACE or DEB-TACE and followed-up for at least 2 years or until death. Transcatheter arterial chemoembolisation was repeated 'on-demand'.We enrolled 177 patients: 89 underwent DEB-TACE and 88 cTACE. The median number of procedures was 2 in each arm, and the in-hospital stay was 3 and 4 days, respectively (P=0.323). No differences were found in local and overall tumour response. The median TTP was 9 months in both arms. The AE incidence and severity did not differ between the arms, except for post-procedural pain, more frequent and severe after cTACE (P<0.001). The 1- and 2-year survival rates were 86.2% and 56.8% after DEB-TACE and 83.5% and 55.4% after cTACE (P=0.949). Eastern Cooperative Oncology Group (ECOG), serum albumin, and tumour number independently predicted survival (P<0.05).The DEB-TACE and the cTACE are equally effective and safe, with the only advantage of DEB-TACE being less post-procedural abdominal pain.
Project description:Objective:This study aimed at assessing the effects of transcatheter arterial chemoembolisation (TACE) and antiviral therapy on improving the prognosis of patients with hepatocellular carcinoma (HCC) after radical hepatectomy. Methods:This study reviewed the data of 120 patients with HCC who received either radical hepatectomy alone (control group), radical hepatectomy with postoperative TACE (TACE group) or radical hepatectomy with combined postoperative TACE, and antiviral therapy (combined group) from January 2000 to May 2015. To reduce the impact of the possible biases on the conclusion of this study to the minimum, the cases with similar demographic and clinicopathological characteristics were collected and 40 cases were assigned into each group. Recurrence, disease-free survival (DFS), and overall survival (OS) rates were compared. Results:Median follow-up period was 54.26?±?22.65 months with a range of 17-110 months. Recurrence after radical surgery was observed for 39 (97.5%) patients in the TACE group, 32 (80%) in the combined group, and 40 (100%) in the control group with median recurrence duration of 33, 43, and 16.5 months, respectively. Postoperative TACE with or without antiviral therapy significantly prolonged the DFS rate compared with radical hepatectomy alone (P = 0.000). TACE combined with antiviral therapy significantly extended the DFS rate compared with TACE alone (P = 0.008). Postoperative TACE with or without antiviral therapy also significantly prolonged the OS rate compared with radical hepatectomy alone (P = 0.000). In addition, antiviral therapy combined with TACE significantly extended the 5-year OS rate of patients compared with individual TACE and radical hepatectomy (67.5% versus 55% and 2.5%; P = 0.032). Conclusion:TACE is an appropriate therapy for HCC patients after radical hepatectomy. When combined with antiviral therapy, this treatment may further prolong the recurrence time and thus lead to high DFS and OS rates.
Project description:OBJECTIVES:To evaluate the predictive performance of the modified hepatoma arterial embolisation prognostic II (mHAP-II) score in a real-life western hepatocellular carcinoma (HCC) cohort treated with drug-eluting bead-TACE and compare the mHAP-II with other scores in this cohort. METHODS:One hundred seventy-nine HCC patients (mean age 77 (±?9) years, 87% male) with one or more drug-eluting bead (DEB)-TACE sessions using 100-300 ?m microspheres were retrospectively analysed. Performance analysis of the mHAP-II score was based on Mann-Whitney U tests, the Kaplan-Meier method, log-rank tests, receiver operating characteristics, Akaike's information criterion and Cox regression models. RESULTS:In this population, HCC risk factors were mainly alcohol abuse (31%) and hepatitis C (28%). The median survival of the entire cohort was 29.4 months. mHAP-II classification of the cohort was mHAP-II B (30%), C (41%) and D (23%) respectively. Survival of all subgroups differed significantly from each other (each p?<?0.05). Area under the curve for receiver operating characteristic was 0.60 and Akaike's information criterion was 21.8 (p?= 0.03), indicating a superior performance of mHAP-II score compared with HAP score and BCLC. Tumour number ??two (HR 1.54), alpha-fetoprotein >?400 ?g/l (HR 1.14), serum albumin <?3.6 g/dl (HR 1.63) and total bilirubin >?0.9 mg/dl (HR 1.58) contributed significantly in Cox proportional hazards regression (each p?<?0.05). CONCLUSION:The mHAP-II score can predict survival outcomes of western HCC patients undergoing DEB-TACE and further subdivide this heterogeneous group; however, certain limitations concerning the predictive power of mHAP-II score must be taken into account. KEY POINTS:• This retrospective study evaluated the predictive performance of the modified hepatoma arterial embolisation prognostic II (mHAP-II) score in a real-life western HCC cohort treated with drug-eluting bead-TACE. • Survival of all mHAP-II subgroups differed significantly, area under the curve for mHAP-II was 0.60 and Akaike's information criterion was 21.8. • The mHAP-II score can predict survival outcomes of western HCC patients undergoing DEB-TACE and further subdivide this heterogeneous group. However, because the study is underpowered, true survival prediction may be more difficult to infer.
Project description:<h4>Background</h4>The prognosis for patients with hepatocellular cancer (HCC) undergoing transarterial therapy (TACE/TAE) is variable.<h4>Methods</h4>We carried out Cox regression analysis of prognostic factors using a training dataset of 114 patients treated with TACE/TAE. A simple prognostic score (PS) was developed, validated using an independent dataset of 167 patients and compared with Child-Pugh, CLIP, Okuda, Barcelona Clinic Liver Cancer (BCLC) and MELD.<h4>Results</h4>Low albumin, high bilirubin or ?-fetoprotein (AFP) and large tumour size were associated with a two- to threefold increase in the risk of death. Patients were assigned one point if albumin <36 g/dl, bilirubin >17 ?mol/l, AFP >400 ng/ml or size of dominant tumour >7 cm. The Hepatoma arterial-embolisation prognostic (HAP) score was calculated by summing these points. Patients were divided into four risk groups based on their HAP scores; HAP A, B, C and D (scores 0, 1, 2 and >2, respectively). The median survival for the groups A, B, C and D was 27.6, 18.5, 9.0 and 3.6 months, respectively. The HAP score validated well with the independent dataset and performed better than other scoring systems in differentiating high- and low-risk groups.<h4>Conclusions</h4>The HAP score predicts outcomes in patients with HCC undergoing TACE/TAE and may help guide treatment selection, allow stratification in clinical trials and facilitate meaningful comparisons across reported series.
Project description:We extend an agent-based multiscale model of vascular tumour growth and angiogenesis to describe transarterial chemoembolisation (TACE) therapies. The model accounts for tumour and normal cells that are both nested in a vascular system that changes its structure according to tumour-related growth factors. Oxygen promotes nutrients to the tissue and determines cell proliferation or death rates. Within the extended model TACE is included as a two-step process: First, the purely mechanical influence of the embolisation therapy is modelled by a local occlusion of the tumour vasculature. There we distinguish between partial and complete responders, where parts of the vascular system are occluded for the first and the whole tumour vasculature is destroyed for the latter. In the second part of the model, drug eluding beads (DEBs) carrying the chemotherapeutic drug doxorubicin are located at destroyed vascular locations, releasing the drug over a certain time-window. Simulation results are parameterised to qualitatively reproduce clinical observations. Patients that undergo a TACE-treatment are categorised in partial and complete responders one day after the treatment. Another 90 days later reoccurance or complete response are detected by volume perfusion computer tomography (VPCT). Our simulations reveal that directly after a TACE- treatment an unstable tumour state can be observed, where regrowth and total tumour death have the same likeliness. It is argued that this short time-window is favorable for another therapeutical intervention with a less radical therapy. This procedure can shift the outcome to more effectiveness. Simulation results with an oxygen therapy within the unstable time-window demonstrate a potentially positive manipulated outcome. Finally, we conclude that our TACE model can motivate new therapeutical strategies and help clinicians analyse the intertwined relations and cross-links in tumours.
Project description:BACKGROUND:To compare the efficacy of three types of palliative therapy for advanced hepatocellular carcinoma (HCC), including transarterial chemoembolisation (TACE) monotherapy, sorafenib alone and their combination. METHODS:The databases of PubMed, Embase and Cochrane Library were retrieved. The odds ratio (OR) with its 95% confidence interval (CI) was used to investigate the binary variables, and the standardised mean difference (SMD) with its 95% CI was employed to evaluate the continuous variables. All statistical tests were performed by using Stata/SE, version 12.0. RESULTS:Thirty-one clinical studies, containing 5125 unique cases of patients with advanced HCC, were included. There were significant improvements in overall survival (OS) (pooled SMD = 2.54; 95% CI 1.74-3.34) and time to progression (TTP) (pooled SMD = 2.49; 95% CI 0.87-4.12) of the patients after receiving the combination therapy of TACE and sorafenib, compared to TACE monotherapy, and the OS in the combined treatment cohort was also longer than that in the sorafenib-alone cohort (pooled SMD = 2.92; 95% CI 1.72-4.13). The combination therapy group in comparison to the TACE group benefited a significantly increased overall response rate (ORR) (pooled OR = 2.61; 95% CI 1.43-4.77), 1-year (pooled OR = 2.96; 95% CI 1.71-5.14) and 2-year (pooled OR = 1.64; 95% CI 1.18-2.28) survival rates and reduced disease progression rate (DPR) (pooled OR = 0.47; 95% CI 0.33-0.68); in parallel, the ORR in the group was also significantly higher than that in the sorafenib-alone group (pooled OR = 3.62; 95% CI 1.28-10.22), although without a difference in the DPR (pooled OR = 0.28; 95% CI 0.05-1.48). In addition, we discovered that the 1-year (pooled OR = 1.39; 95% CI 0.84-2.29) and 2-year (pooled OR = 1.70; 95% CI 0.69-4.18) survival rates in the TACE monotherapy cohort were not significantly different to those in the sorafenib-alone cohort. CONCLUSION:The combination therapy is more effective than monotherapy in improving the prognostic outcomes of patients with advanced HCC. Therefore, we recommend it as the preferred treatment intervention for those patients.
Project description:Locoregional therapies for hepatocellular carcinoma (HCC) include endovascular treatments such as chemoembolization (TACE) and bland embolization (TAE). TACE is the most adopted technique, despite a lack of definitive evidence of superiority over TAE, which is less costly and better tolerated due to the absence of chemotherapy. However, few studies have reported data on TAE monotherapy for unresectable HCC. We report our results in a cohort of 230 patients with unresectable HCC treated with TAE (TAE with 40-100micron microparticles, TAE with microparticles plus n-butyl-2-cyanoacrylate, TAE with Lipiodol) over the course of seven years. Thirty-seven patients (14%) were down-staged during observation and also received a percutaneous ablation. We observed 1-, 2-, 3-, 4- and 5-year rates of 84,8%, 58,7%, 38,3%, 28,3%, and 18,7%. Patients who also received percutaneous treatment performed best. Our results broaden the body of evidence for the use of TAE in advanced HCC.
Project description:The optimal transcatheter embolization strategy for patients with unresectable hepatocellular carcinoma (HCC) remains elusive. We conducted a systematic review and network meta-analysis (NMA) of different embolization options for unresectable HCC.Medical databases were searched for randomized controlled trials evaluating bland transarterial embolization (TAE), conventional TACE, drug-eluting bead chemoembolization (DEB-TACE), or transarterial radioembolization (TARE), either alone or combined with adjuvant chemotherapy, or local liver ablation, or external radiotherapy for unresectable HCC up to June 2017. Random effects Bayesian models with a binomial and normal likelihood were fitted (WinBUGS). Primary endpoint was patient survival expressed as hazard ratios (HR) and 95% credible intervals. An exponential model was used to fit patient survival curves. Safety and objective response were calculated as odds ratios (OR) and accompanying 95% credible intervals. Competing treatments were ranked with the SUCRA statistic. Heterogeneity-adjusted effective sample sizes were calculated to evaluate information size for each comparison. Quality of evidence (QoE) was assessed with the GRADE system adapted for NMA reports. All analyses complied with the ISPOR-AMCP-NCP Task Force Report for good practice in NMA.The network of evidence included 55 RCTs (12 direct comparisons) with 5,763 patients with preserved liver function and unresectable HCC (intermediate to advanced stage). All embolization strategies achieved a significant survival gain over control treatment (HR range, 0.42-0.76; very low-to-moderate QoE). However, TACE, DEB-TACE, TARE and adjuvant systemic agents did not confer any survival benefit over bland TAE alone (moderate QoE, except low in case of TARE). There was moderate QoE that TACE combined with external radiation or liver ablation achieved the best patient survival (SUCRA 86% and 96%, respectively). Estimated median survival was 13.9 months in control, 18.1 months in TACE, 20.6 months with DEB-TACE, 20.8 months with bland TAE, 30.1 months in TACE plus external radiotherapy, and 33.3 months in TACE plus liver ablation. TARE was the safest treatment (SUCRA 77%), however, all examined therapies were associated with a significantly higher risk of toxicity over control (OR range, 6.35 to 68.5). TACE, DEB-TACE, TARE and adjuvant systemic agents did not improve objective response over bland embolization alone (OR range, 0.85 to 1.65). There was clinical diversity among included randomized controlled trials, but statistical heterogeneity was low.Chemo- and radio-embolization for unresectable hepatocellular carcinoma may improve tumour objective response and patient survival, but are not more effective than bland particle embolization. Chemoembolization combined with external radiotherapy or local liver ablation may significantly improve tumour response and patient survival rates over embolization monotherapies. Quality of evidence remains mostly low to moderate because of clinical diversity.CRD42016035796 (http://www.crd.york.ac.uk/PROSPERO).
Project description:Standard of practice involves using transarterial therapy for multifocal hepatocellular carcinoma (HCC) alone and sorafenib only for more advanced HCC, but the sorafenib and transarterial therapy combination may provide greater efficacy.To evaluate the safety and efficacy of concurrent sorafenib and transarterial therapy in HCC.Consecutive cases of HCC were treated with sorafenib and transarterial therapy, receiving sorafenib 2 to 4weeks before transarterial therapy. Baseline clinical parameters, adverse events (AEs) and survival were collected.A total of 47 patients received sorafenib and transarterial therapy. The majority of the patients were male (70%) with HCV (60%), median age of 60years, good performance status (0-1), stable cirrhosis (Child: A 72%; B 28%), unresectable tumour (stage: B 81%; C 19%) and median AFP of 24ng/mL. Median follow-up was 12months and median time on sorafenib was 6months. LC Bead TACE was used with a median frequency of 3. The majority of the patients (89%) experienced AEs. The most common AEs were fatigue (51%), hand-foot skin reaction (51%) and diarrhoea (43%). Grade 3 and 4 AEs included fatigue (13%) and hand-foot skin reaction (26%). Most patients required a dose reduction (66%). The main AE related to transarterial therapy was post-TACE syndrome (23%). The disease control rate was 68% at 6months. Overall median survival rate was 18.5months (95% CI 16.1-20.9months).Concurrent sorafenib and transarterial therapy is overall safe with no unexpected side effects and encouraging efficacy that warrants further study.