Treatment Of Hepatocellular Cancer Research Articles

Transarterial chemoembolization plus or minus intravenous bevacizumab in the treatment of hepatocellular cancer: A pilot study

BackgroundStimulation of vascular endothelial growth factor (VEGF) has been observed following transarterial chemoembolization (TACE) in hepatocellular cancer (HCC) and may contribute to tumor regrowth. This pilot study examined whether intravenous (IV) bevacizumab, a monoclonal antibody against VEGF, could inhibit neovessel formation after TACE.Methods30 subjects with HCC undergoing TACE at a single academic institution were randomized with a computer-generated allocation in a one to one ratio to either bevacizumab at a dose of 10 mg/kg IV every 14 days beginning 1 week prior to TACE (TACE-BEV arm) or observation (TACE-O arm). Angiography was performed with TACE at day 8, and again at weeks 10 and 14. Repeat TACE was performed at week 14 if indicated. TACE-BEV subjects were allowed to continue bevacizumab beyond week 16. TACE-O subjects were allowed to cross-over to bevacizumab at week 16 in the setting of progressive disease. The main outcome measure was a comparison of neovessel formation by serial angiography. Secondary outcome measures were progression free survival (PFS) at 16 weeks, overall survival (OS), bevacizumab safety, and an analysis of VEGF levels before and after TACE with and without bevacizumab.ResultsAmong the 30 subjects enrolled, 9 of 15 randomized to the TACE-O arm and 14 of 15 randomized to the TACE-BEV arm completed all 3 angiograms. At week 14, 3 of 9 (33%) TACE-O subjects and 2 of 14 (14%) TACE-BEV subjects demonstrated neovascularity. The PFS at 16 weeks was 0.19 in the TACE-O arm and 0.79 in the TACE-BEV arm (p = 0.021). The median OS was 61 months in the TACE-O arm and 49 months in the TACE-BEV arm (p = 0.21). No life-threatening bevacizumab-related toxicities were observed. There were no substantial differences in bevacizumab pharmacokinetics compared to historical controls. Bevacizumab attenuated the increase in VEGF observed post-TACE.ConclusionsIV bevacizumab was well tolerated in selected HCC subjects undergoing TACE, and appeared to diminish neovessel formation at week 14.Trial registrationClinicalTrials.gov NCT00049322.

Hepatobiliary Pancreatic Surgery at the Forefront

Emerging technology is driving advances in the surgical field at a rapid rate and hepatobiliary pancreatic (HPB) surgery is a prime example. In the last 20 years there has been a huge increase in HPB procedures and every major city in India now boasts of centers of excellence devoted to this subspecialty. This issue of the Indian Journal of Surgery with the special theme of GI Surgery is devoted to hepatobiliary pancreatic surgery. Topics have been chosen to reflect on technical advances and controversies. The issue contains matters of interest to all levels of surgeons. Every practicing surgeon must read the extremely balanced review article by A Behari and VK Kapoor, which dissects the controversy surrounding the need for surgery for asymptomatic gallstones. The article on pancreaticoduodenal injury by Atul Sharma provides a practical approach to tackling this challenging problem, that many general surgeons will encounter. Recent advances in surgical procedures for choledochal cyst, acute and chronic pancreatitis, portal hypertension, hilar cholangiocarcinoma and pancreatic cancer have all been dealt with in detail. Anil Sharma has written an excellent article on single incision HPB surgery. Liver transplantation have been exponentially increasing in India. This issue has two excellent reviews about the controversies surrounding transplanting for hepatocellular cancer which has been deftly dealt with by R Kakaodkar, and the all important issue of donor safety in living donor liver transplantation discussed by SK Mathur et al. Technological advances have led to complex radiological procedures for hepatocellular cancers. Kulkarni et al provide a comprehensive review on ablative and embolization treatment for hepatocellular cancer. It was ultrasonography that initially enabled accurate diagnosis of HPB morbid anatomy . Now, technology has advanced to be able to send an ultrasound probe into the gastrointestinal tract. The place of endoscopic ultrasound in GI surgery has been reviewed by Gouda and Gupta. Chandralekha Tampi provides an insight into the modern interpretation of HPB pathology and a balanced approach to the analysis of liver and pancreatic tumors; an article which must be read by all HPB surgeons. This volume starts with a thoughtful editorial by Professor Samiran Nundy, whose unstinting efforts established G I surgery as a separate speciality in North India, and deals with the direction for the future of GI surgery in our country. He makes an impassioned plea for a pragmatic approach in treating the middle class Indian and the need to publish Indian data in Indian journals rather than aping the protocols published in western literature. Now that the Indian Journal of Surgery is indexed in Pub Med Central, articles are visible worldwide through a PubMed search and we hope the readership of this journal will heed his advice. We hope to attract the best of our country’s surgical research in future.

Hepatic Arterial Infusion of Doxorubicin-Loaded Microsphere for Treatment of Hepatocellular Cancer: A Multi-Institutional Registry

Hepatic intra-arterial therapy for unresectable hepatocellular cancer (HCC) has been shown to improve overall survival, but can have significant toxicity. A recent prospective randomized controlled trial demonstrated superior response rates and significantly less morbidity and doxorubicin-related adverse events with drug-eluting beads with doxorubicin (DEBDOX) compared with conventional chemoembolization. The aim of this study was to confirm the efficacy of DEBDOX for the treatment of unresectable HCC. This open-label, multicenter, multinational single-arm study included 118 intermediate-staged HCC patients who were not candidates for transplantation or resection. Patients received DEBDOX at each treatment. Complications and response rates to treatment were analyzed. There were 118 patients who received a total of 186 DEBDOX treatments with a median total treatment dose of 75 mg (range 38 to 150 mg), and median overall total hepatic exposure of 150 mg (range 150 to 600 mg). Five lesions were targeted, with a median size of 5.3 cm (range 1.0 to 16.9 cm). Severe adverse events related to liver dysfunction were seen after 4% of treatments. Overall survival was a median of 14.2 months (range 5 to 30 months), with progression-free survival of 13 months and hepatic-specific progression-free survival of 16 months. Okuda class less than 1 at time of treatment, reduction of alpha-fetoprotein of 1,000 ng/mL at the first post-treatment evaluation, delivery of more than 200 mg doxorubicin, and less than 25% liver involvement were all predictors of favorable overall survival assessed by multivariable analyses. Hepatic intra-arterial injection of DEBDOX is safe and effective in the treatment of HCC, as demonstrated by a minimal complication rate and robust and durable tumor response.

The modernized treatment of hepatocellular cancer: time to think twice!

The field of hepatic oncology is rapidly changing due to the availability of a large diagnostic and therapeutic armamentarium. The popularization of several loco-regional treatments LRT) and the recent introduction in clinical practice of drugs such as tyrokinase inhibitors have changed the therapeutic algorithm of hepatocellular cancer (HCC). The role of surgery has been reduced markedly [1, 2]. This editorial aims at reminding surgical as well as medical communities that cure of liver cancer can only be obtained when resecting the tumor appropriately and that (long-term) results can be further improved when adhering to the classical oncologic paradigms.

Transarterial Chemoembolization for HCC in Patients With Extensive Liver Transplantation Waiting Times

The treatment of hepatocellular cancer (HCC) with transarterial chemoembolization (TACE) prior to orthotopic liver transplant (OLT) is of increasing importance due to the rise in HCC incidence and donor shortage. This single-center study examines 28 patients treated with TACE and 7 patients not treated with TACE, with HCC prior to OLT between 1999 and 2008. The overall 1- and 5-year survival of all transplanted patients with HCC was 94% (33 of 35) and 80% (28 of 35). There was no difference in survival (P = .99) between patients who underwent transplantation immediately (median 95 days) and patients who had significantly longer wait times (median 308 days) when treated with TACE. During extensive wait times for OLT, TACE can be used to keep patients with HCC on the waiting list by preventing tumor progression, with similar outcomes compared with those who underwent transplantation immediately.

Targeting Receptor Tyrosine Kinase Pathways in Hepatocellular Carcinoma

Hepatocellular cancer (HCC) is the fifth most common malignancy worldwide with 660,000 deaths annually. Studies of the molecular pathophysiology of HCC have shown that growth factors and their corresponding receptors are commonly overexpressed and/or dysregulated in HCC. Activation of these receptors and their downstream signaling pathways can lead to angiogenesis, cell proliferation, survival and metastasis of HCC. Hence, agents that specifically block their activation and signaling cascades would be valuable for treatment of HCC. Many small molecular tyrosine kinase inhibitors (TKIs) and antibodies have been tested in various phases of clinical trials. Although sorafenib has been shown to improve overall survival of patients with advanced HCC, the improvement is marginal and many patients eventually turn out to be refractory to this therapy. Thus, there is a pressing need to identify new drugs and effective treatments for this fatal disease. This review summarizes the pre-clinical and clinical data on the efficacy of the emerging tyrosine kinase inhibitors as well as the rationale for combination therapies for advanced HCC treatment. Understanding the mechanisms of action of these therapeutic agents and methods of combining these drugs may help to increase their efficacy, reduce toxicity, and improve overall survival and quality of life in patients with HCC.

Non-Invasive Radiofrequency-Induced Targeted Hyperthermia for the Treatment of Hepatocellular Carcinoma

Targeted biological therapies for hepatocellular cancer have shown minimal improvements in median survival. Multiple pathways to oncogenesis leading to rapid development of resistance to such therapies is a concern. Non-invasive radiofrequency field-induced targeted hyperthermia using nanoparticles is a radical departure from conventional modalities. In this paper we underscore the need for innovative strategies for the treatment of hepatocellular cancer, describe the central paradigm of targeted hyperthermia using non-invasive electromagnetic energy, review the process of characterization and modification of nanoparticles for the task, and summarize data from cell-based and animal-based models of hepatocellular cancer treated with non-invasive RF energy. Finally, future strategies and challenges in bringing this modality from bench to clinic are discussed.

Sorafenib and Radiation Therapy for the Treatment of Advanced Hepatocellular Carcinoma

Treatment options for advanced hepatocellular cancer (HCC) are limited. Sorafenib, an orally active multi-kinase inhibitor, is the only systemic agent with a survival benefit in randomized studies. However, the gain in survival is modest and new treatment strategies are needed. We report two cases of advanced HCC treated with a combination of sorafenib and radiation therapy. Impressive and sustained clinical and radiological responses were seen. Treatment was well-tolerated in both cases with no unexpected toxicities reported. There is sound rationale for the combination of sorafenib and radiation therapy for treatment of HCC. These two cases suggest both feasibility and efficacy of this combination, in selected patients. Prospective studies addressing this combination are ongoing.

Interventional radiological treatment of hepatocellular carcinoma

During the last years, interventional radiological treatment of hepatocellular cancer has changed dramatically. The percutaneous ethanol infiltration is partly replaced by thermoablative methods, mainly by radiofrequency ablation. Cooled-tip electrodes and volumetric therapy planning increased the treatment success. Embolisation beads made vessel occlusion more precise and predictable, while the development of the drug eluting beads led to the most effective way of chemoembolisation. The so called radioembolisation with Yttrium 90 isotopes filled into glass microbeads is slowly gaining acceptance worldwide. Thermoablation and embolisation or chemoembolisation are the main tools for downstaging tumors, or avoiding disease progression in liver transplant recipients on the waiting list. All of these therapeutic options have their well established places in well known and worldwide accepted protocols, such as the algorithm of the Barcelona group (BCLC). In the near future, further results can be expected from the combination of available treatments, including sorafenib medication.

Nonoperative therapies for combined modality treatment of hepatocellular cancer: expert consensus statement

Although surgical resection and liver transplantation are the only treatment modalities that enable prolonged survival in patients with hepatocellular carcinoma (HCC), the majority of HCC patients presents with advanced disease and do not undergo resective or ablative therapy. Transarterial chemoembolization (TACE) is indicated in intermediate/advanced stage unresectable HCC even in the setting of portal vein involvement (excluding main portal vein). Sorafenib has been shown to improve survival of patients with advanced HCC in two controlled randomized trials. Yttrium 90 is a safe microembolization treatment that can be used as an alternative to TACE in patients with advanced liver only disease or in case of portal vein thrombosis. External beam radiation can be helpful to provide local control in selected unresectable HCC. These different treatment modalities may be combined in the treatment strategy of HCC and also used as a bridge to resection or liver transplantation. Patients should undergo formal multidisciplinary evaluation prior to initiating any such treatment in order to individualize the best available options.

Nonoperative therapies for combined modality treatment of hepatocellular cancer: expert consensus conference

Nonoperative therapies for combined modality treatment of hepatocellular cancer: expert consensus conference

Surgical treatment of hepatocellular cancer: expert consensus conference

Surgical treatment of hepatocellular cancer: expert consensus conference

Abstract LB-110: CDK4 activation is a key step in ELF alteration and haploinsufficeny of cdk4 prevents HCC formation in elf+/− mice

Abstract Transforming growth factor (TGF-) is an important regulator of cell growth and the loss of TGF- signaling occurs early in carcinogenesis. Embryonic liver fodrin (ELF), an interaction protein of Smads, is involved in TGF- signaling. Significantly, elf+/− mice spontaneously developed the hepatocellular cancer (HCC) and lots of human HCC exhibited decreased or absent ELF expression. Here, we investigated how alteration of ELF led the deregulation of cell cycle progression and eventually formed the HCC. Up regulation of ELF expression led the decreased phosphorylation of Rb protein with the remarkable reduction of CDK4 than other CDKs and cyclins. Then, inhibition and downregulation of CDK4 by inhibitor and siRNA rescued the abnormality of G1/S transition and over-activation of Rb phosphorylation caused by infection of ELF shRNA in SNU475 HCC cell line. We further demonstrated the biochemical communications using immunoprecipitation that ELF interacted CDK4, and Smad3 in competitive way and TGF-ß-dependent manner. In addition, haploinsufficieny of cdk4 in elf+/− mice displayed the dramatic decrement of HCC formation than elf+/− mice with decreased Ki-67 and c-myc expressed hepatocyte in liver tissue. Thus, in response to ELF deficiency, the activation of CDK4 contributes to the phosphorylation of Rb protein, which leading to facilitated G1/S transition. Our data highlight CDK4 as an attractive target for pharmacologic inhibition and importance of elf+/− model to demonstrate pre-clinical efficacy in the treatment of HCC with ELF alteration. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-110.

Targeted therapy of hepatocellular cancer

Importance of the field: Hepatocellular cancer (HCC) is the fifth most common malignancy worldwide and third leading cause of cancer death. HCC is highly resistant to conventional systemic therapies, and prognosis for advanced HCC patients remains poor. However, identification of signaling pathways responsible for HCC growth and progression such as RAS/RAF/MEK/ERK or PI3K/AKT/mTOR has determined crucial molecular targets and led to development of novel promising targeted therapies.Areas covered in this review: This article presents molecular mechanisms responsible for development and progression of HCC and strategies aimed to block important molecules involved in signal transduction. It also reviews the clinical studies evaluating efficacy and safety of novel targeted approaches for treatment of this malignancy.What the reader will gain: Inhibition of molecular targets (ligands, membrane receptors and receptor-associated kinases) represents a promising strategy for treatment of HCC; in the case of sorafenib, this has already been demonstrated to significantly improve survival of advanced HCC patients. This article reviews novel therapeutic approaches that are based on combinations of different targeted agents with or without classic cytotoxic drugs.Take home message: Despite significant progress, advanced HCC remains an incurable disease, and the overall efficacy of recently approved targeted therapy (sorafenib) remains moderate. It is to be hoped that several ongoing clinical trials evaluating novel targeted approaches for treatment of HCC will lead to further improvement in the management of advanced disease.

New Pharmacological Developments in the Treatment of Hepatocellular Cancer

Hepatocellular carcinoma (HCC) is the most common primary liver neoplasm and fourth leading cause of cancer death worldwide. The survival for patients with advanced HCC is extremely poor. This is largely attributed to the lack of effective screening methods, advanced stage at presentation, limited utility of surgical intervention and ineffective medical therapy. Over the past 30 years, many conventional cytotoxic agents have been tested and have failed to confer a survival benefit. Recently, sorafenib, a multi-tyrosine kinase inhibitor, was approved by the US FDA as first-line therapy in HCC as the first agent demonstrating survival benefit in this disease. Although the survival benefit demonstrated by sorafenib is moderate, molecular targeted therapy has brought new hope in the management of HCC.

Radiosurgery in the Treatment of Unresectable Hepatocellular Cancer and as a Bridge to Transplantation

Radiosurgery in the Treatment of Unresectable Hepatocellular Cancer and as a Bridge to Transplantation

Traditional Chinese medicines in the treatment of hepatocellular cancers: a systematic review and meta-analysis

BackgroundLiver cancer is a common malignancy with a high mortality rate. Given the poor prognosis associated with this cancer, many patients seek additional therapies that may improve quality of life or survival. Several Traditional Chinese Medicines (TCM) have been evaluated in clinical trials, but little is known about them outside of China.MethodsWe searched independently and in duplicate 8 electronic databases, including 2 Chinese language databases, until February 2009. We included any randomized clinical trials (RCT) evaluating a TCM oral preparation for the treatment of hepatocellular cancers. We abstracted data on survival, tumor response, and performance scores. We conducted a random-effects meta-analysis and applied a meta-regression analysis.ResultsWe included 45 RCTs (n = 3,236). All studies employed an active control group. In general, the reporting of methodological issues was poor. We analyzed data from 37 trials reporting on complete response effects score (Relative Risk [RR] of 1.26 (95 CI, 1.04–1.52, P = 0.01, I2 = 0%, P = 0.99). Products containing ginseng, astragalus and mylabris had a larger treatment effect (OR 1.34, 95% CI, 1.04–1.71, P = 0.01) than the pooled broad estimate, also the case for astragalus-based treatments (OR 1.35, 95% CI, 1.001–1.80. P = 0.048). We examined survival rates and pooled 15 studies reporting on 6 month outcomes (RR 1.10, 95% CI, 1.04–1.15, P = < 0.0001, I2 = 0%, P = 0.60). This effect was consistent at other prospective dates, including 12 months (22 trials, RR 1.26, 95% CI, 1.17–1.36, P = < 0.0001, I2 = 7%, P = 0.36), 24 months (15 trials, 1.72, 95% CI, 1.40–2.03, P = < 0.0001, I2 = 0%, P = 0.75); and, at 36 months (8 trials, RR 2.40, 95% CI, 1.65–3.49, P = < 0.0001, I2 = 0%, P = 0.62).LimitationsAll included trials were conducted in China where emerging evidence suggests many RCTs are not, in fact, randomized. Publication bias may exist, favouring positive reports.ConclusionOur meta-analysis displays compelling evidence of effectiveness for hepatocellular cancers that should be evaluated in high-quality and transparent clinical trials.

Can hyperbaric oxygenation decrease doxorubicin hepatotoxicity and improve regeneration in the injured liver?

Portal vein embolization is used in the treatment of hepatocellular cancer, with the purpose of enhancing resectability. However, regeneration is restricted due to hepatocellular injury following chemotherapeutics (e.g. doxorubicin). The aim of this study was to investigate whether hyperbaric oxygenation (HBO) can alleviate the hepatotoxicity of chemotherapy and improve regeneration in the injured liver. Rats were allocated to four experimental groups. Group I rats were subjected to right portal vein ligation (RPVL); rats in groups II and III were administered doxorubicin prior to RPVL, with group III rats being additionally exposed to HBO sessions postoperatively; group IV rats was sham-operated. All rats were sacrificed on postoperative day 7, and liver injury was assessed by measuring alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Protein synthetic ability was determined based albumin levels and liver regeneration by the mitotic index (MI). The AST and ALT values of group II rats were significantly higher than those of group I, but not those of group III. Rats treated with doxorubicin and HBO (groups II and III) showed slightly but not significant differences in albumin levels than those subjected to only RPVL or sham-operated. The MI was significantly increased in groups I, II, and III, with the MI of group III rats significantly higher than those of group I rats. Based on our results, we conclude that HBO treatment has the potential to diminish doxorubicin-related hepatotoxicity and improve regeneration in the injured liver.

MTOR inhibitors for hepatocellular cancer: a forward-moving target

mTOR is a central regulator of cell growth and angiogenesis. The mTOR pathway is activated in 40–50% of patients with hepatocellular cancer (HCC). In different models (i.e., hepatoma cell lines and implanted HCC tumors in rats), mTOR inhibitors (mTORIs) were effective in reducing cell growth and tumor vascularity. Synergistic effects were observed for mTORIs and chemotherapeutic agents in these studies, while other combinations involving mTORIs and inhibitors of growth hormones and angiogenesis are awaiting further clinical testing. A number of mTORIs are already clinically available (e.g., sirolimus, temsirolimus and everolimus), sharing similiar pharmacokinetic parameters (except for absorption) and side effects. Clinical data are, as yet, only preliminary and are mainly derived from retrospective studies in patients who underwent liver transplantation for HCC. Those patients had received sirolimus thereafter for immunosuppression, and a much lower rate of tumor recurrence than with calcineurin inhibitors alone was noted. Current prospective trials for treatment of advanced HCC include mTORIs alone or in combination with either transarterial chemoembolization or other systemic drugs, and will be discussed in detail in this review.

Prospective, randomized, double-blind, multi-center, Phase III clinical study on transarterial chemoembolization (TACE) combined with Sorafenib®versus TACE plus placebo in patients with hepatocellular cancer before liver transplantation – HeiLivCa [ISRCTN24081794

BackgroundDisease progression of hepatocellular cancer (HCC) in patients eligible for liver transplantation (LTx) occurs in up to 50% of patients, resulting in withdrawal from the LTx waiting list. Transarterial chemoembolization (TACE) is used as bridging therapy with highly variable response rates. The oral multikinase inhibitor sorafenib significantly increases overall survival and time-to-progression in patients with advanced hepatocellular cancer.DesignThe HeiLivCa study is a double-blinded, controlled, prospective, randomized multi-centre phase III trial. Patients in study arm A will be treated with transarterial chemoembolization plus sorafenib 400 mg bid. Patients in study arm B will be treated with transarterial chemoembolization plus placebo. A total of 208 patients with histologically confirmed hepatocellular carcinoma or HCC diagnosed according to EASL criteria will be enrolled. An interim patients' analysis will be performed after 60 events. Evaluation of time-to-progression as primary endpoint (TTP) will be performed at 120 events. Secondary endpoints are number of patients reaching LTx, disease control rates, OS, progression free survival, quality of live, toxicity and safety.DiscussionAs TACE is the most widely used primary treatment of HCC before LTx and sorafenib is the only proven effective systemic treatment for advanced HCC there is a strong rational to combine both treatment modalities. This study is designed to reveal potential superiority of the combined TACE plus sorafenib treatment over TACE alone and explore a new neo-adjuvant treatment concept in HCC before LTx.