Radioembolization is different from the TACE. Currently, the most popular radioembolization technique uses microspheres coated with Y 90 b-emitting isotope TheraSphere and SIR Sphere.
A few observational studies and retrospective analyses have reported the efficacy of radioembolization in the treatment of HCC[ 68 , 69 ]. Median survivals for intermediate stage HCC, however, vary widely between 7 and 27 mo between phase II studies, depending on the PS, extent of the disease and the degree of hepatic functional reserve. Salem et al[ 70 ] reported a large prospective study in patients treated with glass-based Y 90 microspheres TheraSphere showing that liver function and portal vein thrombosis were main predictors of survival.
Recently, a comparative analysis of radioembolization or TACE reported fewer side effects, better response rate and longer time to progression In another similar study by European Network on radioembolization with Y 90 resin microspheres. Sangro et al[ 69 ] reported similar safety profile and response rates.
Results of RCTs would provide the highest level of evidence, but based on these studies, it has been estimated that more than patients would be required to confirm the statistical equivalence or superiority of one treatment over other. Moreover, the relevant cost associated with radioembolization may limit a wide use of this technique. At present radioembolization appears to be safer in more advanced stage HCC including portal vein thrombosis and large tumor burden[ 69 , 71 , 72 ].
In recent years, waiting time for LT has progressively increased and despite priority for HCC within the Milan criteria, a significant rate of dropout from the waiting list occurs due to tumor progression.
Hence treatment of HCC in patients awaiting LT has become routine, primarily in an effort to prevent tumor progression, reduce dropout rate and to decrease the post-transplant HCC recurrence.
The risk of dropout for HCC within the Milan criteria correlates with the length of waiting time and initial tumor characteristics. Hence most transplant centers observe rather than treat these lesions until they grow to 2 cm. These patients are often considered for treatment while awaiting LT. Chemoembolization, radiofrequency ablation and ethanol injection all are effective in controlling tumor growth; however, there is no high level evidence that these modalities are effective in stopping tumor progression in patients on the waiting list, reducing dropout rate or decreasing post-transplant recurrence.
TACE has been widely used, as a bridge to transplant but there is no evidence-based data to support this practice. TACE has not been shown to decrease the dropout rates on waiting list[ 14 , 73 ], but most of the studies addressing this issue were heterogeneous in patient selection, TACE-related protocols and had variable waiting time on LT list.
It is unlikely that well-designed RCTs will address this issue in the future. Nevertheless, particularly in the United States, where continued waiting list priority depends on maintaining HCC within Milan criteria, use of nonsurgical HCC treatment will likely continue in an effort to prevent tumor progression and waiting list dropout.
TACE alone or combination with other treatments is recommended to bridge patients to transplant specifically when the waiting list time is more than six mo. Hepatocarcinogenesis is the result of genetic alterations affecting multiple signaling cascades resulting in uncontrolled growth of the hepatocytes. Systemic targeted therapies focus on the critical steps of the carcinogenic pathways, limiting widespread systemic toxicity. No single dominant or pathognomic pathway exists in the hepatocarcinogenesis.
Targeted molecular agents may block one or more steps in a targeted pathway or potentially more than one pathway to provide suitable results. Currently, sorafenib is approved for the treatment of HCC and represents a paradigm shift in the systemic treatment of HCC, and many new molecular therapies are under investigation. Multiple cellular kinases are involved in the development and progression of the HCC by promoting angiogenesis, cellular differentiation, proliferation and survival.
Sorafenib is an oral bi-aryl urea, which inhibits multiple cell surface and downstream kinases involved in tumor progression. Overexpression of these kinases is important in HCC proliferation and angiogenesis[ 80 , 81 ]. Two phase III randomized placebo-controlled trials, the SHARP trial conducted mainly in America and Europe[ 82 ] and a similar trial conducted in Asia[ 83 ] reported improved overall survival with sorafenib.
In the Asian study, the median overall survival was 6. Sorafenib was generally well tolerated; toxicities were mild to moderate in severity, predominantly including diarrhea, fatigue, and hand-foot skin reaction.
These two, phase III trials have established sorafenib as the preferred systemic therapy for advanced HCC although the role of sorafenib in intermediate HCC is less clear. Moreover, only small numbers of patients with Child-Pugh B have been included in clinical trials, so it is not possible to assess efficacy and safety of sorafenib in this group of patients. Sorafenib has also been used in combination with other systemic chemotherapeutic agents with a goal to improve efficacy.
All of these studies report some survival advantage over sorafenib alone. But most of the studies looking at the combination of sorafenib with other systemic therapies have small sample size.
Large randomized double-blind studies are needed to establish the role and toxicity profile of these combination regimens. A total of patients were randomized to receive either sorafenib or sunitinib This trial was terminated early due to increased side effects and futility concerns.
It was found to be effective in the treatment of the HCC with an acceptable safety profile in a single arm phase II clinical trial[ 91 ]. It showed somewhat promising results in the phase II trials as first line median overall survival: 10 mo and second line median overall survival: 9. The median length of overall survival was 9.
Median survival was 9. Tivantinib: Tivantinib is an oral MET receptor tyrosine kinase inhibitor. In a randomized, placebo-controlled, double-blind, phase II trial, tivantinib was used as a second line agent for the treatment of HCC in previously unresectable HCC who progressed or could not tolerate the first line systemic therapy[ 97 ]. Time to progression of HCC was longer in tivantinib group 1. A randomized, double-blinded, controlled phase III study METIV-HCC trial is currently underway to determine the efficacy and safety of tivantinib plus sorafenib vs sorafenib alone in the patients with previously unresectable cancer as a first line treatment agent.
Everolimus: Everolimus is an inhibitor of mTOR. As previously discussed, TACE works by blocking the hyper-vascular arterial blood supply of the tumor with the help of an embolic agent and injecting the chemotherapeutic drug.
As a result of TACE, a hypoxic environment is created around the surviving tumor cells. Hypoxia stimulates the expression of VEGF and hence the neovascularization of the surviving cells. Sorafenib appears to be a good choice to block the neovascularization at that stage. A phase III trial comparing linifanib to sorafenib as a first line targeted agent has recently been reported[ ]. Various studies have looked at the combination of TACE with sorafenib, where sorafenib was introduced few days to weeks after the first TACE sequential introduction or it was started prior to the planned TACE and only interrupted for few days around the procedure interrupted scheduling.
There has been reluctance to use combination of TACE and sorafenib due to fear of increased toxicity. The authors reported safety of concurrent sorafenib and transarterial therapy but without clear benefit of survival. The efficacy of combination treatment has been assessed in few prospective studies.
The median time to progression was 9. In another study Kudo et al[ ] did not find a difference in overall survival or time to progression benefit with TACE plus sorafenib combination compared with TACE plus placebo. Similar results were produced in another subgroup analysis of the START trial in Asia-Pacific region, without any un-expected side effects[ ].
The results of ongoing phase III trials will determine whether there is a role to implement this combination in clinical practice. The results of concurrent TACE and sorafenib in intermediate stage appear promising but at present it is difficult to recommend combination therapy. There are uncertainties regarding dose, frequency and duration of sorafenib when used in combination with TACE. Several on-going clinical trials are looking at the combination of radio-embolization and sorafenib in patients with HCC.
The patients were on sorafenib prior to yttrium treatment, which was resumed post- treatment. The overall survival of the patients was higher than the previously reported studies that only used sorafenib. Further prospective studies are being conducted to evaluate the combination of radiation therapy and sorafenib. Management of HCC depends on the tumor stage, liver function reserve, and patient performance status BCLC stage , and requires a multidisciplinary approach for optimal treatment.
LT and hepatic resection are the only curative options in early stage of disease. There have been significant advances in local ablative and trans-arterial therapies.
Drug-eluting beads have improved the efficacy and safety of conventional TACE. Radioembolization with use of resin or glass sphere appear promising. Molecular studies of HCC have identified aberrant activation of different signaling pathways, which represent key targets for novel molecular therapies. For patients with advanced disease, sorafenib is the only approved therapy, but novel targeted agents and their combinations are emerging.
National Center for Biotechnology Information , U. Journal List World J Gastroenterol v. World J Gastroenterol. Published online Apr Ali Raza and Gagan K Sood. Author information Article notes Copyright and License information Disclaimer. Author contributions: Raza A performed the data research and helped writing the manuscript; Sood GK designed the manuscript; performed the research; helped writing the manuscript and critically analyzed the manuscript.
All rights reserved. See letter " Hepatocellular carcinoma review: Current treatment, and evidence-based medicine " in volume 20 on page This article has been cited by other articles in PMC. Abstract Hepatocellular carcinoma HCC is the fifth most common tumor worldwide. Keywords: Hepatocellular carcinoma, Trans-arterial chemoembolization, Drug-eluting beads, Radiofrequency ablation, Liver transplantation, Chemotherapy, Sorafenib, Radioembolization.
RFA Surgical resection is currently considered the most curative strategy, but in the last decade highly satisfactory results have been obtained with local ablative therapies[ 36 ].
Table 1 Surgical resection vs radiofrequency ablation. Open in a separate window. TACE with drug-eluting beads The recent introduction of embolic microspheres that have the ability to actively sequester doxorubicin hydro-chloride from solution and release it in a controlled fashion has been shown to substantially diminish the amount of chemotherapeutic agent that reaches the systemic circulation, as compared with ethiodized oil-based regimens. Sorafenib Multiple cellular kinases are involved in the development and progression of the HCC by promoting angiogenesis, cellular differentiation, proliferation and survival.
Table 2 Phase III clinical trials of systemic targeted agents. Sorafenib and TACE combination As previously discussed, TACE works by blocking the hyper-vascular arterial blood supply of the tumor with the help of an embolic agent and injecting the chemotherapeutic drug.
Sorafenib and radio-embolization Several on-going clinical trials are looking at the combination of radio-embolization and sorafenib in patients with HCC. References 1. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Hepatocellular carcinoma.
Marrero JA. Clin Adv Hematol Oncol. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. J Hepatol. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. Mazzaferro V. Results of liver transplantation: with or without Milan criteria? Liver Transpl. Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience.
Taniguchi M. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. For more information regarding BMS clinical trial participation, please visit www. Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials. More Information. J Hepatol. Epub Jan J Clin Oncol. Epub Aug National Library of Medicine U. National Institutes of Health U. Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Liver Cancer. The study did not meet its primary overall survival objective based upon a non-inferiority statistical design.
Bristol-Myers Squibb and the lead investigators plan to present the findings of the study at an upcoming scientific meeting. Bristol-Myers Squibb is considering options for the ongoing brivanib development program. Ongoing clinical trials of brivanib, which include hepatocellular carcinoma as well as other tumor types, will continue at the present time. Additionally, Bristol-Myers Squibb shared the BRISK-FL results with the clinical trial investigators and will work with the investigators regarding the ongoing management of patients receiving study drug.
Bristol-Myers Squibb is studying a portfolio of compounds that aim to address unmet medical needs across the liver disease continuum, including hepatitis C, hepatitis B and liver cancer.
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