Transarterial chemoembolization (TACE) using lipiodol‐based regimens, including the administration of an anticancer‐in‐oil emulsion followed by embolic agents, is widely used in the treatment of ...hepatocellular carcinoma (HCC). This approach has been supported by meta‐analyses of randomized, controlled trials (RCTs) performed more than a decade ago. We performed a systematic review to understand current efficacy and safety data of lipiodol TACE in treatment of HCC. A search of the literature published between January 1, 1980 and June 30, 2013 was performed using MEDLINE and EMBASE databases. All potentially relevant publications were reviewed and articles were selected based on predefined inclusion and exclusion criteria. Of a total of 1,564 articles reviewed, 101 articles, including a total of 10,108 patients treated with lipiodol TACE, were selected for the efficacy analysis. Objective response rate was 52.5% (95% confidence interval CI: 43.6‐61.5). Overall survival (OS) was 70.3% at 1 year, 51.8% at 2 years, 40.4% at 3 years, and 32.4% at 5 years. Median OS was 19.4 months (95% CI: 16.2‐22.6). A total of 217 articles presenting precise description on numbers of adverse events (AEs) were selected for the safety review: In these studies, a total of 21,461 AEs were reported in 15,351 patients. Liver enzyme abnormalities were the most commonly observed AE, followed by the symptoms associated with postembolization syndrome. Overall mortality rate was 0.6% and the most common cause of death was related to acute liver insufficiency. Conclusions: In a systematic literature review, survival figures of HCC patients undergoing lipiodol TACE appear to be in line with those reported in previous RCTs, and no new or unexpected safety concerns were identified. (Hepatology 2016;64:106–116)
Altered energy metabolism is a biochemical fingerprint of cancer cells that represents one of the "hallmarks of cancer". This metabolic phenotype is characterized by preferential dependence on ...glycolysis (the process of conversion of glucose into pyruvate followed by lactate production) for energy production in an oxygen-independent manner. Although glycolysis is less efficient than oxidative phosphorylation in the net yield of adenosine triphosphate (ATP), cancer cells adapt to this mathematical disadvantage by increased glucose up-take, which in turn facilitates a higher rate of glycolysis. Apart from providing cellular energy, the metabolic intermediates of glycolysis also play a pivotal role in macromolecular biosynthesis, thus conferring selective advantage to cancer cells under diminished nutrient supply. Accumulating data also indicate that intracellular ATP is a critical determinant of chemoresistance. Under hypoxic conditions where glycolysis remains the predominant energy producing pathway sensitizing cancer cells would require intracellular depletion of ATP by inhibition of glycolysis. Together, the oncogenic regulation of glycolysis and multifaceted roles of glycolytic components underscore the biological significance of tumor glycolysis. Thus targeting glycolysis remains attractive for therapeutic intervention. Several preclinical investigations have indeed demonstrated the effectiveness of this therapeutic approach thereby supporting its scientific rationale. Recent reviews have provided a wealth of information on the biochemical targets of glycolysis and their inhibitors. The objective of this review is to present the most recent research on the cancer-specific role of glycolytic enzymes including their non-glycolytic functions in order to explore the potential for therapeutic opportunities. Further, we discuss the translational potential of emerging drug candidates in light of technical advances in treatment modalities such as image-guided targeted delivery of cancer therapeutics.
To review the current management, outline recent advances and address controversies in the management of hepatocellular carcinoma (HCC).
The treatment of HCC is multidisciplinary involving ...hepatologists, surgeons, medical oncologists, radiation oncologists, radiologists, interventional radiologists, and other disciplines. Each of these disciplines brings its unique perspective and differing opinions that add to controversies in the management of HCC.
A focused literature review was performed to identify recent studies on the management of HCC and thereby summarize relevant information on the various therapeutic modalities and controversies involved in the treatment of HCC.
The main treatment algorithms continue to rely on hepatic resection or transplantation with controversies involving patients harboring early stage disease and borderline hepatic function. The other treatment strategies include locoregional therapies, radiation, and systemic therapy used alone or in combination with other treatment modalities. Recent advances in locoregional therapies, radiation, and systemic therapies have provided better therapeutic options with curative intent potential for some locoregional therapies. Further refinements in combination therapies such as algorithms consisting of locoregional therapies and systemic or radiation therapies are likely to add additional options and improve survival.
The management of HCC has witnessed significant strides with advances in existing options and introduction of several new treatment modalities of various combinations. Further refinements in these treatment options combined with enrollment in clinical trials are essential to improve the management and outcomes of patients with HCC.
PURPOSE To evaluate safety and efficacy of combined transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEB) and sorafenib in patients with advanced hepatocellular carcinoma (HCC). ...PATIENTS AND METHODS A prospective single-center phase II study was undertaken involving patients with unresectable HCC. The protocol involved sorafenib 400 mg twice per day combined with DEB-TACE. Safety and response were assessed. Results DEB-TACE in combination with sorafenib was successfully administered in 35 patients: mean age, 63 years; Child's A, 89%; Barcelona Clinic Liver Cancer stage C, 64%; Eastern Cooperative Oncology Group performance status of 0 and 1, 46% and 54%, respectively; and mean index tumor size, 7.7 cm (standard deviation, ± 4.2 cm). Patients underwent 128 cycles of therapy (sorafenib plus DEB-TACE, 60 cycles; sorafenib alone, 68 cycles). Median number of cycles per patient was two (range, one to five cycles); median number of days treated with sorafenib was 71 (range, 4 to 620 days). The most common toxicities during cycle one were fatigue (94%), anorexia (67%), alterations in liver enzymes (64%), and dermatologic adverse effects (48%). Although most patients experienced at least one grade 3 to 4 toxicity, most toxicities were minor (grade 1 to 2, 83% v grade 3 to 4, 17%). Toxicity during cycle two was decreased. Over the course of the study, there were 40 sorafenib dose interruptions and 25 sorafenib dose reductions. Sorafenib plus DEB-TACE was associated with a disease control rate of 95% (Response Evaluation Criteria in Solid Tumors Group)/100% (European Association for the Study of the Liver EASL), with an objective response of 58% (EASL). CONCLUSION The combination of sorafenib and DEB-TACE in patients with unresectable HCC is well tolerated and safe, with most toxicities related to sorafenib. Toxicity is manageable with dose adjustment of sorafenib. Preliminary efficacy data are promising.
The purpose of this article is to present in a concise manner an overview of the most widely used locoregional transcatheter and ablative therapies for solid malignancies. An extensive MEDLINE search ...was performed for this review. Therapies used for liver cancer were emphasized because these therapies are used most commonly in the liver. Applications in pulmonary, renal, and bone tumors were also discussed. These approaches were divided into catheter-based therapies (such as transcatheter arterial chemoembolization, bland embolization, and the most recent transcatheter arterial approach with drug-eluting microspheres), ablative therapies (such as chemical ethanol or acetic acid injection), and thermal ablative therapies (such as radiofrequency ablation, laser induced thermotherapy, microwave ablation, cryoablation, and extracorporeal high-intensity focused ultrasound ablation). A brief description of each technique and analysis of available data was reported for all therapies. Locoregional transcatheter and ablative therapies continue to be used mostly for palliation, but have also been used with curative intent. A growing body of evidence suggests clear survival benefit, excellent results regarding local tumor control, and improved quality of life. Clinical trials are underway to validate these results. Image-guided transcatheter and ablative approaches currently play an important role in the management of patients with various types of cancer-a role that is likely to grow even more given the technological advances in imaging, image-guidance systems, catheters, ablative tools, and drug delivery systems. As a result, the outcomes of patients with cancer undoubtedly will improve.
Hepatocellular carcinoma (HCC) presents with a high burden of disease in East Asian countries. Intermediate‐stage HCC as defined by the Barcelona Clinic Liver Cancer (BCLC) staging system poses a ...clinical challenge as it includes a heterogeneous population of patients that can vary widely in terms of tumour burden, liver function and disease aetiology. Intermediate HCC patients often have unsatisfactory clinical outcomes with repeated transarterial chemoembolization (TACE, due to non‐response of the target tumour or the development of further metastasis indicating progressive disease. In September 2011, an Expert Panel Opinion on Interventions in Hepatocellular Carcinoma (EPOIHCC) was convened in HK in an attempt to provide a consensus on the practice of TACE. To that end, current clinical practice throughout Asia was reviewed in detail including safety and efficacy data on TACE alone as well as in combination with targeted systemic therapies. This review summarises the evidence discussed at the meeting and provides expert recommendation regarding the available therapeutic options for unresectable intermediate stage HCC. A key consensus of the Expert Panel was that in order to improve patient outcomes and long‐term survival, the possibility of using TACE in combination with targeted agents given systemically should be explored. While the currently available clinical data is promising, the expected completion of several pivotal phase II and III RCTs will provide further evidence in support of the rationale for combination therapy regimens.
Background
Many patients with intrahepatic cholangiocarcinoma (ICC) present with advanced and inoperable disease. Data on the safety and efficacy of intra-arterial therapy (IAT) for ICC are limited.
...Methods
Between 1992 and 2012, a total of 198 patients with advanced ICC treated with IAT were retrospectively identified from the databases of five major hepatobiliary institutions. Data on clinicopathological factors, morbidity, response rates, and overall survival were collected and analyzed.
Results
Median patient age was 61 years. Median tumor size was 8.1 cm, and 47.5 % patients had a solitary lesion. IAT consisted of conventional transarterial chemoembolization (cTACE) (64.7 %), drug-eluting beads (DEB) (5.6 %), bland embolization (TAE) (6.6 %), or yttrium-90 radioembolization (23.2 %). Median number of IAT sessions was 2 (range 1–8). The median time between IAT sessions was 48 days. The periprocedural morbidity was 29.8 %; most complications were minor (
n
= 43); however, 16 patients had a grade 3–4 complication. Assessment of tumor response revealed complete or partial response in 25.5 % patients, while 61.5 % had stable disease; 13.0 % had progressive disease. Median overall survival was 13.2 months and did not differ on the basis of the type of IAT (cTACE, 13.4 months vs. DEB 10.5 months vs. TAE, 14.3 months vs. yttrium-90, 11.3 months;
P
= 0.46). IAT response on modified response evaluation criteria in solid tumors (mRECIST; hazard ratio for complete–partial response 0.49, 95 % confidence interval 0.30–0.81;
P
< 0.001) was independently associated with better survival.
Conclusions
IAT for ICC was safe and led to stable disease or partial to complete response in up to three-quarters of patients. Among patients with an IAT response, overall survival was prolonged. The role of IAT therapy for ICC warrants further prospective evaluation in clinical trials.
In the fight against cancer, new drug delivery systems are attractive to improve drug targeting of tumors, maximize drug potency, and minimize systemic toxicity. We studied a new drug delivery system ...comprising microspheres, with unique properties allowing delivery of large amounts of drugs to tumors for a prolonged time, thereby decreasing plasma levels. Liver tumors, unlike nontumorous liver, draw most of their blood supply from the hepatic artery. Exploiting this property, we delivered drug-eluting microspheres/beads (DEB) loaded with doxorubicin, intra-arterially, in an animal model of liver cancer (Vx-2).
The purpose of our study was to determine the pharmacokinetics and tumor-killing efficacy of DEB.
Our results show that plasma concentration of doxorubicin was minimal in the animals treated with DEB at all time points (0.009-0.05 micromol/L), suggesting high tumor retention of doxorubicin. This was significantly lower (70-85% decrease in plasma concentration) than control animals treated with doxorubicin intra-arterially. Within the tumor, doxorubicin concentration peaked at 3 days (413.5 nmol/g), remaining high to 7 days (116.7 nmol/g) before declining at 14 days (41.76 nmol/g), indicating continuous doxorubicin elution from beads. In control animals, peak tumor concentration of doxorubicin was 0.09 nmol/g. Tumor necrosis (approaching 100%) was greatest at 7 days, with minimal adverse local side effects reflected in liver function tests results. The plasma concentration of doxorubicinol (doxorubicin main metabolite) was minimal.
Our results support the concept of DEBs as an effective way to deliver drugs to tumor. This new technology may prove to be a useful weapon against liver cancer.
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