Nonsurgical options for localized hepatocellular carcinoma

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Volume 10, Issue 4
October 2017
Pages 103–106

Review

John Ha M.D., Robert J. Wong M.D., M.S.

First published: 31 October 2017

First published: 31 October 2017 Full publication history

DOI: 10.1002/cld.662 View/save citation

Potential conflict of interest: Nothing to report.

Abstract

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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the United States. With its current trend, HCC is projected to become the third leading cause of cancer-related deaths in the United States by 2030.[1] Currently, more than 55% of HCC cases are diagnosed beyond localized disease, and the majority do not receive definitive curative therapies, such as surgical resection or liver transplantation.[1, 2] Curative therapies are mainly reserved for patients with localized disease or those within Milan criteria. However, many nonsurgical treatment options are still available to patients with unresectable, advanced stage HCC (Table 1). Although there are many options for locoregional or systemic therapies in the management of unresectable HCC, this review will focus specifically on transarterial radioembolization (TARE), radiofrequency (RFA)/microwave ablation (MWA), stereotactic body radiation therapy (SBRT), systemic therapy, and hospice/supportive medicine. It is important to note that the approach for HCC treatment is variable and dependent on many factors, such as medical expertise, performance status, tumor stage and location, and degree of liver dysfunction. Therefore, utilizing multidisciplinary teams may provide the best option for developing a treatment plan.

Table 1. Curative Versus Noncurative Therapies for HCC

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Transplanting Patients with HIV and Liver Cancer

Attention: Medical & Science Editors/Producers

Media Contact: Gregory Bologna
703-299-9766
gbologna@aasld.org
Press Room: November 7 – 11, 2014
Hynes Convention Center, Boston, MA
Telephone: 617-954-2977

Researcher: Heather Platt, MD
Email: hplatt@gmail.com
Phone: 732-485-9222 

For Immediate Release
Presented: Date Monday, November 10

Liver transplantation is a therapeutic option for selected patients with liver cancer with high 5-year survival rates of 75 – 80 percent. HIV-infected patients often do not have access to liver transplantation, and experience with HIV-infected patients with liver cancer undergoing liver transplantation is limited.

An international group of researchers at 43 centers in North and South America, Europe, and Australia retrospectively identified 135 HIV-positive patients with hepatocellular carcinoma (HCC) who underwent potentially curative treatment.  Twenty-seven patients who underwent orthotopic liver transplantation (OLT) were compared to 108 patients who underwent either radiofrequency ablation, surgical resection, or percutaneous ethanol injection.

Compared to the 108 patients undergoing other potentially curative therapy, the 27 patients undergoing OLT were younger, had higher Child-Turcotte-Pugh scores (used to assess liver function), and more often had multiple liver tumors, but were otherwise similar in disease etiology, frequency of alcohol abuse, and control of HIV infection.

Patients who had a liver transplantation had a significantly higher 5-year survival rate of 85 percent, compared to 52 percent for all other curative therapies combined. The 5-year survival rate of 85 percent was similar to 75 – 80 percent reported in HIV-negative patients with HCC undergoing OLT.

When asked about the results, Heather Platt, MD, principal investigator of the study said, "The primary point of this study is to show that HIV+ patients with HCC should be included in evaluation for OLT, as there does not seem to be any difference in survival when compared to HIV negative patients. Importantly, the survival data, while retrospective, does indicate a benefit compared to other curative interventions. "

Dr. Platt also addressed barriers to transplanting these patients. Dr. Platt said, "The main barriers include a center's experience and comfort with transplanting HIV+ patients. HIV+ patients are examined quite carefully for compliance and for anticipation of post-transplant complications. This requires a comprehensive, multidisciplinary transplant program including specialists in HIV care."

Abstract title:
Liver transplantation for HIV-infected patients with hepatocellular carcinoma (HCC)

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AASLD is the leading medical organization for advancing the science and practice of hepatology. Founded by physicians in 1950, AASLD's vision is to prevent and cure liver diseases. This year's Liver Meeting®, held in Washington, November 7-11, will bring together more than 9,000 researchers from 55 countries.

A pressroom will be available from November 7 at the annual meeting. For copies of abstracts and press releases, or to arrange researcher interviews, contact Gregory Bologna at 703-299-9766.

Press releases and all abstracts are available online at www.aasld.org.

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Largest ever genomic study of liver cancer identifies mutations that distinguish Asian and Western disease

Baylor College of Medicine News

Glenna Picton
713-798-4710
Houston, TX - Nov 7, 2014

The largest ever study of the genomes of liver tumors identified a mutation signature that contributes more to cases of the disease in Japanese males that in men of European ancestry, said an international consortium of researchers in a report online in the journal Nature Genetics.

“The novelty of this study involves associating mutation patterns with different ethnic groups,” said Dr. David Wheeler, professor in the Baylor College of Medicine Human Genome Sequencing Center and a corresponding author of the report. Researchers from the University of Tokyo, The National Cancer Center Research Institute and the National Cancer Center Hospital in Tokyo, Japan, were also colleagues on this work.

“Patients are subject to different environmental factors or they are genetically different,” said Wheeler, also a member of the NCI-designated Dan L. Duncan Cancer Center at Baylor. The profiles of the tumors were not associated with hepatitis B, hepatitis C or cirrhosis, which are known environmental factors associated with hepatocellular carcinoma (liver) cancers.

“Liver cancer occurs in males at two to five times the frequency of females,” he said.

Data from 503 liver cancer genomes derived from different populations identified 30 candidates as genes that drive the cancer and 11 cancer pathways. In addition, the collaboration of two large-scale genome projects analyzed the changes found in 608 liver cancer cases and in doing so, identified the mutational pattern associated in the disease in Japanese men, said Wheeler.

The study found more extensive mutation in the mTOR pathways than had been realized before, suggesting that drugs that inhibit that pathway might be useful. One such drug is everolimus, an anti-cancer drug used in treating kidney as well as some types of pancreatic, breast and brain cancers, might also be effective in liver cancer, said Wheeler. (The mTOR pathway is an intracellular pathway important in programmed cell death and, thus, cancer.)’

The study’s first authors include Yasushi Totoki of the Division of Cancer Genomics at the National Cancer Center Research Institute in Tokyo, Kenji Tatsuno of the Genome Science Division of the Research Center for Advanced Science and Technology at the University of Tokyo and Kyle R. Covington of the Human Genome Sequencing Center at Baylor College of Medicine. Research also took place at the National Cancer Center Hospital in Tokyo and Nihon University School of Medicine in Tokyo.

Corresponding authors include Wheeler, Dr. Hiroyuki Aburatani of the Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo and Dr. Tatsuhiro Shibata of the Division of Cancer Genomics, National Cancer Center Research Institute in Tokyo, Japan.

Funding came from Grants-in-Aid from the Ministry of Health, Labour and Welfare of Japan for the third-term Comprehensive 10-Year Strategy for Cancer Control, grants from the U.S. National Human Genome Research Institute ( 5U54HG003273) and National Cancer Institute (HHSN261201000053C), the Program for Promotion of Fundamental Studies in Health Sciences from the National Institute of Biomedical Innovation (NIBIO) and the National Cancer Center Research and Development Funds (23-A-8). The National Cancer Center Biobank is supported by the National Cancer Center Research and Development Fund, Japan. The supercomputing resource SHIROKANE was provided by the Human Genome Center at the University of Tokyo.

Source

Benefits of Screening for Liver Cancer Remain in Question

Provided by news@JAMA

By Jill Jin, MD, MPH on June 16, 2014

Screening for liver cancer in individuals with chronic liver disease may not be beneficial. Image: ©iStock.com/choja

The ultimate goal of cancer screening is to reduce one’s risk of cancer-related death. In the case of screening for liver cancer, the story is still evolving, but new studies continue to suggest that it may not achieve this goal.

Screening tests for different types of cancer have presented a mixed picture on the overall utility of screening. Some, such as Papanicolaou (Pap) smears to screen for cervical cancer, have clear value in detecting cervical cancers at a earlier, more treatable stages and improving long-term survival. Others, such as prostate-specific antigen (PSA) levels to screen for prostate cancer, are more in doubt, as studies indicate that the benefits of PSA testing are small at best, and the harms of unnecessary treatment can be significant.

A systematic review released today in the Annals of Internal Medicine about screening tests for liver cancer in high-risk individuals (those with liver cirrhosis or chronic hepatitis B infection) found that overall, the evidence is of low quality and offers no proof that screening these individuals offers any advantage in extending life or in decreasing mortality from the disease.

This review, funded by the US Department of Veterans Affairs, included 18 observational studies and 4 clinical trials that studied the issue. After a careful assessment of the methods and results of all the studies, the authors concluded that the 2 largest randomized clinical trials, both conducted in China, had “substantial methodological flaws” that threatened the validity of their results. One study showed that routine screening with liver ultrasound and alpha-fetoprotein testing was associated with reduced liver cancer mortality, but the other showed no effect. Furthermore, most of the patients in these 2 studies had chronic hepatitis B infection as the cause of the their chronic liver disease, whereas the majority of people in the United States with chronic liver disease have chronic hepatitis C infection or alcoholic liver disease.

The 18 observational studies included a wider range of geographic settings and more patients with hepatitis C infection; however, the results on mortality reduction resulting from screening were still mixed. Given the inherent bias present in observational studies, the authors state that these studies “do not contribute substantially to the strength of evidence.” Overall, the results did suggest that liver cancers diagnosed as a result of screening tended to be at an earlier stage than those diagnosed clinically in the absence of screening, but the “lead time bias” in these findings makes any true effects on mortality questionable. In other words, people may perceive they are living longer because of a longer period between diagnosis and death, but that longer period may simply be the result of earlier diagnosis and not of extending lifespan.

None of the studies examined the harms of screening, which can include psychological stress, needle-track “seeding” of cancer cells as a result of biopsy, and overdiagnosis, a concept that refers to finding very slow-growing tumors that never would have otherwise caused problems in a patient’s lifetime.

Current guidelines by the American Association of Liver Diseases recommend screening for liver cancer with ultrasound every 6 months for all individuals with cirrhosis, and for some individuals with chronic hepatitis B infection in the absence of cirrhosis. The US Preventive Services Task Force has not released official guidelines on the topic. The authors suggest that there are still major evidence gaps that need to be addressed before more solid guidelines can be created, but also recognize that conducting large-scale randomized trials in the United States or Europe that focus on this specific clinical question in this patient population may not be feasible.

Source

Immunotherapy could help tackle tough liver cancer

PUBLIC RELEASE DATE: 11-Apr-2014 Contact: Courtney Lock
Courtney.Lock@cohnwolfe.com
44-789-438-6422
European Association for the Study of the Liver

London, England, Friday 11 April 2014 Significant new data presented today at the International Liver Congress™ 2014 indicate that liver cancer (Hepatocellular Carcinoma (HCC)) may be treated by adoptive T-cell therapy.

This new therapeutic approach in the treatment of HCC could be very important as without treatment the 5 year survival rate is just 5%. Globally, HCC accounts for 746,000 deaths, and in the UK alone is responsible for over 4,000 deaths per year.

Glypican-3 (GPC3) is a tumour associated antigen expressed in up to 70% of HCC but not in healthy human tissue. Isolating GPC3-specific T-cell receptors and expressing them on patient's T-cells can help treat HCC, as these T cells can recognise and eliminate GPC3-postive HCC.

The study detected and expanded MHC-multimer-positive CD8+ T-cells specific for targeted GPC3 epitopes and grew T-cell clones. From these clones, the most specific and active T-cell receptor was isolated. When this T-cell receptor was expressed on donor T cells it conferred specificity for GPC3, the HCC-associated antigen. Thus, it enables HLA-A2+ patient's T cells to specifically kill GPC3+ HCC.

Systemic treatments for advanced stage HCC are constantly evolving and current approaches include drug treatment with sorafenib - yet the current standard of care still does not offer a strong enough prognosis for patients. Liver transplant is an option for only 10 -15% of HCC carriers diagnosed at an early stage and therefore the importance of other treatment options for patients is critical. This is a treatment gap that adoptive T-cell therapy could potentially fill.

Disclaimer: the data referenced in this alert is based on the submitted abstract. More recent data may be presented at the International Liver Congress™ 2014.

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Notes to Editors

About EASL

EASL is the leading European scientific society involved in promoting research and education in hepatology. EASL attracts the foremost hepatology experts and has an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

EASL's main focus on education and research is delivered through numerous events and initiatives, including:

• The International Liver CongressTM which is the main scientific and professional event in hepatology worldwide
• Meetings including Monothematic and Special conferences, Post Graduate courses and other endorsed meetings that take place throughout the year
• Clinical and Basic Schools of Hepatology, a series of events covering different aspects in the field of Hepatology
• Journal of Hepatology published monthly
• Organisation of a Mentorship program and Masterclass to support young investigators starting out on their career path
• Participation in a number of policy initiatives at European level

About The International Liver CongressTM 2014

The International Liver Congress™ 2014, the 49th annual meeting of the European Association for the study of the Liver, is being held at ExCel London from April 9 – 13, 2014. The congress annually attracts in excess of 9000 clinicians and scientists from around the world and provides an opportunity to hear the latest research, perspectives and treatments of liver disease from principal experts in the field.

For further information on the studies, or to request an interview, please do not hesitate to contact the EASL Press Office on:
Email: easlpressoffice@cohnwolfe.com

Helena Symeou +44 7976 562 430
Courtney Lock +44 7894 386 422

1. C.Dargel et al. T-CELL RE-DIRECTION AGAINST GLYPICAN-3 FOR IMMUNOTHERAPY OF HCC. Abstract presented at the International Liver CongressTM 2014

2. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F.GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet].Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr. Accessed 11.03.14

3. Liver Cancer Mortality Statistics http://www.cancerresearchuk.org/cancer-info/cancerstats/types/liver/mortality/uk-liver-cancer-mortality-statistics Accessed 11.03.14

4. Statistics and Outlook for Liver Cancer http://cancerhelp.cancerresearchuk.org/type/liver-cancer/treatment/statistics-and-outlook-for-liver-cancer. Accessed 11.03.14

Source

ProMetic's PBI-4050 Delivers New Positive Preclinical Results in Liver Fibrosis and Liver Cancer

LAVAL, QUEBEC, CANADA, - April 10, 2014 - ProMetic Life Sciences Inc. (TSX: PLI) (OTCQX: PFSCF), ("ProMetic" or the "Corporation") presented new pre-clinical data at the 2014 annual meeting of the European Association for the Study of the Liver ("EASL") currently being held in London, UK. The new data supports the claim that PBI-4050's anti-fibrotic activity could also address various liver conditions such as non-alcoholic steatohepatitis ("NASH"), a condition affecting 2% to 5% of Americans, as well as liver cancer.

PBI-4050's favorable effect in reducing the progression of fibrosis in the liver was demonstrated in a gold standard animal model where liver fibrosis is induced by chronic administration of carbon tetrachloride ("CCL₄"), a chemical which at high chronic doses, causes irreversible damages to the liver and kidneys.  Animals treated with PBI-4050 displayed a significant reduction of liver lesions as evidenced by histology and relevant biomarkers results. Following prolonged exposure to CCL₄, a significant number of the non-treated animals also developed hepatocellular carcinoma unlike those treated with PBI-4050.

"These results clearly indicate that PBI-4050's anti-fibrotic activity is at the core of the fibrosis regulation pathway in the liver", stated Dr. Lyne Gagnon, Head of Biology & Immunology at ProMetic.

Dr. John Moran, Chief Medical Officer at ProMetic stated "The progression from fibrosis to cirrhosis to hepatocellular carcinoma is well defined in humans. The positive effects observed with PBI-4050 in multiple challenging animal models bodes well for its potential use to treat various medical conditions involving and or leading to fibrosis." 

The presentation at the EASL annual conference is available on the ProMetic website at: http://www.prometic.com/en/therapeutics/conferences.php

More on NASH:         

Non-alcoholic steatohepatitis or NASH is a common, often "silent" liver disease. It resembles
alcoholic liver disease, but occurs in people who drink little or no alcohol. The major feature in NASH is fat in the liver, along with inflammation and damage. Most people with NASH feel well and are not aware that they have a liver problem. Nevertheless, NASH can be severe and can lead to cirrhosis, in which the liver is permanently damaged and scarred and no longer able to work properly. NASH affects 2 to 5 percent of Americans

More on Hepatocellular Carcinoma

Hepatic fibrosis is an outcome of many chronic liver diseases, including hepatitis B virus, hepatitis
C virus, alcoholic liver disease and non-alcoholic steatohepatitis. Liver fibrosis is characterized by the excess accumulation and alteration of extracellular matrix molecules, including collagen, in the tissue. Liver fibrosis can progress to liver cirrhosis, liver failure, portal hypertension and hepatocellular carcinoma. Liver transplantation is the only treatment available for patients with advanced stage of fibrosis.

About ProMetic Life Sciences Inc.

ProMetic Life Sciences Inc. (www.prometic.com) is a long established biopharmaceutical company with globally recognized expertise in bioseparations, plasma-derived therapeutics and small-molecule drug development.  ProMetic offers its state of the art technologies for large-scale purification of biologics, drug development, proteomics and the elimination of pathogens to a growing base of industry leaders and uses its own affinity technology that provides for highly efficient extraction and purification of therapeutic proteins from human plasma in order to develop best-in-class therapeutics and orphan drugs. ProMetic is also active in developing its own novel small-molecule therapeutic products targeting unmet medical needs in the field of fibrosis, cancer and autoimmune diseases/inflammation. Headquartered in Laval (Canada), ProMetic has R&D facilities in the UK, the U.S. and Canada, manufacturing facilities in the UK and business development activities in the U.S., Europe and Asia.

Forward Looking Statements

This press release contains forward-looking statements about ProMetic's objectives, strategies and businesses that involve risks and uncertainties. These statements are "forward-looking" because they are based on our current expectations about the markets we operate in and on various estimates and assumptions. Actual events or results may differ materially from those anticipated in these forward-looking statements if known or unknown risks affect our business, or if our estimates or assumptions turn out to be inaccurate. Such risks and assumptions include, but are not limited to, ProMetic's ability to develop, manufacture, and successfully commercialize value-added pharmaceutical products, the availability of funds and resources to pursue R&D projects, the successful and timely completion of clinical studies, the ability of ProMetic to take advantage of business opportunities in the pharmaceutical industry, uncertainties related to the regulatory process and general changes in economic conditions. You will find a more detailed assessment of the risks that could cause actual events or results to materially differ from our current expectations in ProMetic's Annual Information Form for the year ended December 31, 2013, under the heading "Risk and Uncertainties related to ProMetic's business".  As a result, we cannot guarantee that any forward-looking statement will materialize. We assume no obligation to update any forward-looking statement even if new information becomes available, as a result of future events or for any other reason, unless required by applicable securities laws and regulations.  All amounts are in Canadian dollars unless indicated otherwise.

Source

Screening for liver cancer in patients with cirrhosis

Provided by MedicalXpress

April 1, 2014

In a systematic review and meta-analysis of 47 studies with 15,158 patients, Amit Singal (University of Texas Southwestern Medical Center) and colleagues found that patients with cirrhosis who underwent surveillance (via liver ultrasound with or without measurement of serum alpha fetoprotein) for hepatocellular carcinoma (HCC) had cancers detected at an earlier stage, were more likely to receive curative instead of palliative treatment, and had longer survival. Across all the studies, the pooled 3-year survival rate was 50.8% among the 4735 patients who underwent HCC surveillance, compared to 27.9% among the 6115 patients without prior surveillance (p<0.001).

The finding of longer survival persisted after the authors limited their review to studies that took into account lead time bias. Lead time bias, as it applies to this study, is the time between when a disease would normally be diagnosed without screening and when the disease is diagnosed with screening. Detecting disease earlier through screening can sometimes appear to increase survival when instead it only prolongs the time the person has the diagnosis. However, in this case, studies that accounted for lead time bias statistically still found that screening increased survival. Among the 6 studies that adjusted for lead time bias, those who underwent HCC surveillance had 3-year survival rates of 39.7%, vs. 29.1% among those who did not (p<0.001).

The authors note that while screening for HCC in patients with hepatitis B virus (HBV) infection is supported by a large randomized trial, no such randomized trials exist for patients with cirrhosis. Therefore the authors systematically reviewed published research that evaluated whether screening was associated with improved patient outcomes. While guidelines of the American Association for the Study of Liver Diseases and European Association for the Study of the Liver recommend surveillance with ultrasound every 6 months in high-risk patients (which includes those with chronic HBV infection and/or cirrhosis), the authors note that studies have shown that surveillance in the US is performed in less than 20% of these patients nationally, with lower rates among primary care physicians than gastroenterologists/hepatologists (physicians who specialize in caring for patients with liver disease).

A limitation of the study is that the studies were quite heterogeneous, suggesting benefits of surveillance may not be uniform among all patients, and studies did not include functional status, an important factor in determining appropriate treatment.

The authors conclude, "the preponderance of data that consistently demonstrate benefits should provide sufficient rationale to recommend HCC surveillance, even in the absence of a randomized controlled trial among patients with cirrhosis."

More information: Singal AG, Pillai A, Tiro J (2014) Early Detection, Curative Treatment, and Survival Rates for Hepatocellular Carcinoma Surveillance in Patients with Cirrhosis: A Meta-analysis. PLoS Med 11(4): e1001624. DOI: 10.1371/journal.pmed.1001624

Provided by Public Library of Science

Source

Liver tumors: 3-D MRI scans better predict survival after chemo

03/25/2014

In a series of studies involving 140 American men and women with liver tumors, researchers at Johns Hopkins have used specialized 3-D MRI scans to precisely measure living and dying tumor tissue to quickly show whether highly toxic chemotherapy – delivered directly through a tumor’s blood supply – is working.

The investigators say their findings, to be presented March 22-27 in San Diego at the annual meeting of the Society of Interventional Radiology, are the first “proof of principle” that this technology can show tumors in three dimensions and accurately measure tumor viability and death. Early data was also presented at the Radiological Society of North America annual meeting, December 1-6 in Chicago.

They also say their results – in patients with either primary liver cancers or metastatic tumors from cancers originating elsewhere in the body -- are evidence that using this technology before and after treatment is a faster and better tool for predicting patient survival after chemotherapy targeted directly at tumors, called chemoembolization.

Unlike standard methods to assess tumor response after chemoembolization, which are based on two-dimensional images and tumor size, the Johns Hopkins-developed 3-D technology also distinguishes between dead and live tissue, giving an accurate assessment of tumor cell death.

The new technology builds on standard 2-D methods and uses computer analytics to evaluate the amount of so-called contrast dye absorbed by tumor tissue. The dye is injected into patients before their MRI scan to enhance image production. Researchers say live tissue will absorb more dye than dead tissue, affecting image brightness, which can also be measured for size and intensity.

“Our high-precision, 3-D images of tumors provide better information to patients about whether chemoembolization has started to kill their tumors so that physicians can make more well-informed treatment recommendations,” says Johns Hopkins interventional radiologist Jean-Francois Geschwind, M.D., the senior investigator on the studies.

Geschwind, a professor in the Russell H. Morgan Department of Radiology at the Johns Hopkins University School of Medicine and its Kimmel Cancer Center, says that knowing the true extent of a tumor’s response to chemoembolization is particularly important for patients with moderate to advanced stages of the disease, whose liver tumors might initially be too large or too numerous to surgically remove.

In the first study, researchers compared the standard imaging method and the newly developed technology in 17 Baltimore men and women with advanced liver cancer. All were treated with surgery or liver transplantation after chemoembolization. The research team used existing MR analysis techniques, as well as the new 3-D method to compare the radiologists’ analyses with pathologic review of tumor samples after therapy and surgical removal. The error margin of the new 3-D image analysis, they say, was low (at up to 10 percent) when predicting the amount of dead tumor tissue found by pathologists whereas the standard, 2-D method deviated by as much as 40 percent from actual values.

In a series of additional studies, Geschwind and his team used the standard and new imaging techniques to analyze the MRI scans of more than 300 liver tumors in some 123 other men and women, also from the Baltimore region. All patients were treated at The Johns Hopkins Hospital between 2003 and 2012, and each received pre- and post-chemoembolization MRI scans to assess the effects of therapy on the tumors.

Using the new 3-D method method, Geschwind’s team found that patients who responded well to therapy lived 19 months longer (an average of 42 months) than patients who did not respond well (average 23 month survival). Standard methods showed slightly less difference in survival (average 18 months longer) between patients who responded to therapy and those who did not respond.

Geschwind says the 3-D technology’s improved accuracy removes a lot of the guesswork that now goes into evaluating treatment outcomes. The new assessment takes seconds to perform, he adds, so radiologists can provide faster, almost instantaneous treatment advice.

Geschwind and his team plan further software refinements to the new approach before training more physicians to use it. He also has plans to study how it can affect treatment decisions, and whether these therapy choices help people live longer.

The software used in the MRI scans was developed at Johns Hopkins and at Philips Research North America, in Briarcliff Manor, N.Y. Philips, whose parent company is based in the Netherlands, manufactures some of the MRI devices used in the study.

Liver cancer kills nearly 20,000 Americans each year, and is much more prevalent outside the United States, where it is among the top-three causes of cancer death in the world. Experts cite the rising numbers of hepatitis C infections, which cause chronic liver inflammation and are a leading risk factor for liver cancer.

Funding support for this study was provided by the French Society of Radiology and Philips Research North America. Additional funding support was provided by the National Cancer Institute, and the National Center for Research Resources, both members of the National Institutes of Health (R01 CA160771, P30 CA006973, and UL1 RR 025005), and the Rolf W. Günther Foundation for Radiology and Radiological Sciences.

In addition to Geschwind, Johns Hopkins scientists involved in the study were Julius Chapiro, M.D., Rafael Duran, M.D., Laura Wood, M.D., Ph.D., Vania Tacher, M.D., Toby Charles Cornish, M.D., Ph.D., Nikhil Bhagat, M.D., Constantine Frangakis, Ph.D., Hooman Yarmohammadi, M.D., Michael Chao, M.Sc., Rongxin Chen, M.D., Ph.D., Zhijun Wang, M.D., Ph.D., and Vivek Charu, M.D., Ph.D. Additional research assistance was provided by MingDe Lin, Ph.D., a Philips biomedical engineer based at Johns Hopkins who has been collaborating with Geschwind for the past seven years on the new technology.

Abstracts described in this news release include:

SIR abstracts:

1830145 Quantitative 3-D Volumetric Assessment of Tumor Response after Intra-arterial Therapy of Colorectal Cancer Metastases to the Liver - a new surrogate marker for survival;
Scientific Session TACE IV, Wednesday 3/26 - 1:39 PM - 1:48 PM, Room 16 A

1859360 Uveal Melanoma Metastatic to the Liver: the Role of Quantitative and Functional MR Imaging in the Assessment of Early Tumor Response after TACE;
Scientific Session TACE I, Sunday 3/23 - 2:42 PM - Room 16 A

1831150 Radio-pathological correlation of 3-D-quantitative contrast-enhanced and functional MRI in HCC patients after TACE- do we see what we treat?
Scientific Session TACE II, Monday 3/24 - 9:03-9:12 AM - Room 16 A

RSNA abstract:

SSSC16-07 Volumetric Tumor assessment Predicts Survival in Patients Treated with Transarterial Chemoembolization for Hepatocellular Carcinoma

For additional information, go to:
http://www.sirmeeting.org/
http://www.hopkinsmedicine.org/vascular/staff/physicians/geschwind.html
http://www.hopkinsmedicine.org/vascular/procedures/chemoembolization/

Source

Bayer's Nexavar misses target in liver cancer trial

FRANKFURT Tue Mar 11, 2014 4:22am EDT

(Reuters) - Germany's Bayer said a final stage Phase III clinical trial of cancer drug Nexavar as an adjuvant therapy for liver cancer did not meet its main target.

Nexavar, or sorafenib, is made by Bayer and Onyx Pharmaceuticals, and is already approved to treat advanced kidney cancer and liver cancer that cannot be surgically removed.

Bayer is testing the drug, taken orally, as an additional treatment for liver cancer patients who had no detectable disease after surgery. It said on Tuesday that the trial did not meet its main goal of improving recurrence-free survival.

"We are disappointed that the trial did not meet its primary endpoint," said Joerg Moeller, member of the Bayer HealthCare Executive Committee. "However, we remain committed to exploring the full potential of sorafenib in all stages of liver cancer."

Bayer shares were down 0.3 percent in early trade, underperforming a 0.2 percent rise for German blue chips.

Liver cancer is the sixth most common cancer in the world with more than 780,000 cases diagnosed each year, Bayer said.

(Reporting by Victoria Bryan; Editing by Christoph Steitz and Mark Potter)

Source

Celsion Announces FDA Clearance of the OPTIMA Study - A Pivotal Phase III Trial of ThermoDox in Primary Liver Cancer

PRESS RELEASE

Feb. 24, 2014, 8:00 a.m. EST

--Study Developed in Consultation with Clinical Advisors, Statistical Experts and FDA --Compelling Survival Data Supports Development --Trial Advances Global Regulatory Strategy in Key Markets

LAWRENCEVILLE, N.J., Feb. 24, 2014 /PRNewswire/ -- Celsion Corporation CLSN -0.27% announced today that the U.S. Food and Drug Administration (FDA) has reviewed and provided clearance for the Company's planned pivotal, double-blind, placebo-controlled Phase III trial of ThermoDox®, its proprietary heat-activated liposomal encapsulation of doxorubicin in combination with radio frequency ablation (RFA) in primary liver cancer, also known as hepatocellular carcinoma (HCC). The trial design is based on a comprehensive analysis of data from the Company's Phase III HEAT Study, which demonstrated that treatment with ThermoDox resulted in a 55% improvement in overall survival in a substantial number of HCC patients that received an optimized RFA treatment.  Celsion expects to launch the study in the first half of 2014.

The Phase III trial, known as the OPTIMA Study, was designed with extensive input from globally recognized HCC researchers and clinicians, and after formal consultation with FDA. The OPTIMA Study is expected to enroll 550 patients globally, with up to 100 sites in the United States, Europe, China and Asia Pacific and will evaluate ThermoDox in combination with RFA, which will be standardized to a minimum of 45 minutes across all investigators and sites for treating lesions 3 to 7 centimeters, versus standardized RFA alone. The primary endpoint for the trial is overall survival (OS).  The statistical plan calls for two interim efficacy analyses by an independent Data Monitoring Committee (iDMC).

"ThermoDox appears to hold great promise as a first-line treatment when used in combination with  optimized RFA, for primary liver cancer, one of the most deadly and prevalent forms of cancer worldwide," stated Nicholas Borys, MD, Celsion's Chief Medical Officer. "Consistency of the retrospective data emerging from the HEAT Study over the past year has been remarkable, and underscores the potential of ThermoDox to extend survival in primary liver cancer patients. Now informed by critical insights from our HEAT Study, I am confident that the OPTIMA Study is robust, well-designed and well-supported by HCC researchers worldwide.  We look forward to initiation and timely completion of this important study."

As reported in January 2014, post-hoc data from the Company's  HEAT Study demonstrate that the patient subgroup in the ThermoDox arm whose RFA procedure lasted longer than 45 minutes (285 patients or 63% of single lesion patients), experienced a 55% improvement in overall survival, with a Hazard Ratio of 0.64 (95% CI 0.41 - 1.00) and a P-value = 0.0495. Median overall survival for this subgroup has not yet been reached. Celsion will continue to follow patients in the HEAT Study on a quarterly basis.

"FDA allowance of the Phase III OPTIMA Study represents a significant step forward in our global development strategy for ThermoDox and establishes a clear regulatory pathway that advances our goal of delivering a new treatment option to patients with this devastating and underserved disease," stated Michael H. Tardugno, Celsion's President and CEO. "In parallel with our efforts in the United States, we continue to advance discussions with regulators in other important global markets, including a recent positive meeting with China FDA (CFDA) and near-term plans to meet with European regulatory authorities."

In support of the Company's global regulatory efforts, Celsion recently met with CFDA to discuss the Phase III trial, including minimum patient enrollment requirements supporting ThermoDox's registration in China. Based on those discussions, Celsion is submitting an application for accelerated approval of the study in China. Celsion will expand its clinical site footprint in Europe and plans to meet with the European Medicines Agency (EMA) in the first half of 2014.

The HEAT Study and prior post-hoc analyses were presented at three medical conferences in 2013, including the World Conference on Interventional Oncology in May; the European Conference on Interventional Oncology in June and the International Liver Cancer Association Annual Conference in September.  Presentations were made by some of the most highly recognized liver cancer researchers and key HEAT Study investigators.  Quarterly overall survival data analyses have been conducted with the full support of these researchers and clinical investigators.

About Celsion Corporation

Celsion is dedicated to the development and commercialization of innovative cancer drugs, including tumor-targeting treatments using focused heat energy in combination with heat-activated liposomal drug technology.  Celsion has research, license or commercialization agreements with leading institutions, including the National Institutes of Health, Duke University Medical Center, University of Hong Kong, the University of Pisa, the UCLA Department of Medicine, the Kyungpook National University Hospital, the Beijing Cancer Hospital and the University of Oxford.  For more information on Celsion, visit our website: http://www.celsion.com .

Celsion wishes to inform readers that forward-looking statements in this release are made pursuant to the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995.  Readers are cautioned that such forward-looking statements involve risks and uncertainties including, without limitation, unforeseen changes in the course of research and development activities and in clinical trials; the uncertainties of and difficulties in analyzing interim clinical data, particularly in small subgroups; FDA and regulatory uncertainties and risks; the significant expense, time, and risk of failure of conducting clinical trials; HEAT Study data is subject to further verification and review by the HEAT Study Data Management Committee; the need for Celsion to evaluate its future development plans; possible acquisitions or licenses of other technologies, assets or businesses or the possible failure to make such acquisitions or licenses; possible actions by customers, suppliers, competitors, regulatory authorities; and other risks detailed from time to time in the Celsion's periodic reports and prospectuses filed with the Securities and Exchange Commission.  Celsion assumes no obligation to update or supplement forward-looking statements that become untrue because of subsequent events, new information or otherwise.

Celsion Investor Contact Jeffrey W. ChurchSr. Vice President and CFO609-482-2455jchurch@celsion.com

SOURCE Celsion Corporation

Source

Changing Hepatocellular Carcinoma Incidence and Liver Cancer Mortality Rates in the United States

Am J Gastroenterol. 2014 Feb 11. doi: 10.1038/ajg.2014.11. [Epub ahead of print]

Altekruse SF¹, Henley SJ², Cucinelli JE³, McGlynn KA⁴.

Abstract

OBJECTIVES:The objectives were to describe Surveillance, Epidemiology and End Results (SEER) hepatocellular carcinoma (HCC) incidence trends and the US liver cancer mortality trends by geography, age, race/ethnicity, and gender.METHODS:HCC incidence data from SEER 18 registries and liver cancer mortality data from the National Center for Health Statistics were analyzed. Rates and joinpoint trends were calculated by demographic subgroup. State-level liver cancer mortality rates and trends were mapped.RESULTS:HCC incidence rates in SEER registries did not significantly increase during 2007-2010; however, the US liver cancer mortality rates did increase. HCC incidence and liver cancer mortality rates increased among black, Hispanic, and white men aged 50+ years and decreased among 35-49-year-old men in all racial/ethnic groups including Asians/Pacific Islanders. Significantly increasing incidence and mortality rates among women were restricted to blacks, Hispanics, and whites aged 50+ years. Asian/Pacific Islander liver cancer mortality rates decreased during 2000-2010 with decreasing rates among women aged 50-64 years and men aged 35-49 years and stable rates in other groups. During 2006-2010, among individuals 50-64 years of age, blacks and Hispanics had higher incidence and mortality rates than Asians/Pacific Islanders. Liver cancer mortality rates were highest in Louisiana, Mississippi, Texas, and Washington, DC.CONCLUSIONS:Decreasing HCC incidence and liver cancer mortality rates among Asians/Pacific Islanders, men aged 35-49 years, and the nonsignificant increase in overall HCC incidence rates suggest that the peak of the epidemic may be near or have passed. Findings of geographic variation in mortality rates can inform control efforts.Am J Gastroenterol advance online publication, 11 February 2014; doi:10.1038/ajg.2014.11.

PMID: 24513805 [PubMed - as supplied by publisher]

Source

Prevention of hepatocellular carcinoma in chronic viral hepatitis B and C infection

World J Gastroenterol. 2013 December 21; 19(47): 8887-8894.

Published online 2013 December 21. doi: 10.3748/wjg.v19.i47.8887.

Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.

Tao Lu, Wai-Kay Seto, Ran-Xu Zhu, Ching-Lung Lai and Man-Fung Yuen.

Tao Lu, Wai-Kay Seto, Ran-Xu Zhu, Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, Guangdong Province, China

Wai-Kay Seto, Ching-Lung Lai, Man-Fung Yuen, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Author contributions: Lu T and Seto WK did the literature search and wrote the manuscript; Zhu RX did the literature search and reviewed the manuscript; Lai CL reviewed the manuscript; Yuen MF designed the manuscript topic, reviewed the manuscript and supervised the study.

Correspondence to: Man-Fung Yuen, MD, PhD, Professor, Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China. mfyuen@hkucc.hku.hk

Telephone: +86-852-22553984 Fax: +86-852-28725828

Received September 10, 2013; Revised October 26, 2013; Accepted November 12, 2013;

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with the majority of cases associated with persistent infection from hepatitis B virus (HBV) or hepatitis C virus (HCV). Natural history studies have identified risk factors associated with HCC development among chronic HBV and HCV infection. High-risk infected individuals can now be identified by the usage of risk predictive scores. Vaccination plays a central role in the prevention of HBV-related HCC. Treatment of chronic HBV infection, especially by nucleoside analogue therapy, could also reduce the risk of HBV-related HCC. Concerning HCV infection, besides the advocation of universal precautions to reduce the rate of infection, pegylated interferon and ribavirin could also reduce the risk of HCV-related HCC among those achieving a sustained virologic response. Recently there has been mounting evidence on the role of chemopreventive agents in reducing HBV- and HCV-related HCC. The continued advances in the understanding of the molecular pathogenesis of HCC would hold promise in preventing this highly lethal cancer.

Keywords: Hepatitis B virus, Hepatitis C virus, Hepatocellular carcinoma, Vaccination, Prevention

Core tip: Hepatocellular carcinoma (HCC), with the majority of cases associated with infection from hepatitis B virus (HBV) or hepatitis C virus (HCV), is the most common primary liver tumor. We introduced risk factors and risk predictive scores associated with HCC development among chronic HBV and HCV infection for its early diagnose and prevention. Vaccination plays a central role in the prevention of HBV-related HCC. Treatment of chronic HBV infection, especially by nucleoside analogue therapy, could reduce the risk of HBV-related HCC. Pegylated interferon and ribavirin could reduce the risk of HCV-related HCC. Chemopreventive agents in reducing HBV- and HCV-related HCC were also discussed.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the most common primary liver tumor, and represents the third leading cause of cancer death worldwide. It is the fifth most common cancer in men and seventh in women, accounting for 7% of all cancers[¹]. Hepatocarcinogenesis is a multistep process mainly associated with persistent infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)[²], which affects more than 350 and 170 million individuals respectively worldwide. HCC is highly prevalent in regions endemic for chronic HBV and HCV infection[³].

The incidence of HCC continues to increase worldwide, with a unique geographic, age, and sex distribution. The most important risk factor associated with HCC is liver cirrhosis, which is again predominantly caused by chronic HBV or HCV infection. Primary prevention in the form of HBV vaccination has led to a significant decrease in HBV-related HCC, and the antiviral therapy for chronic HBV and HCV infection also reduce the incidence of HBV- and HCV-related HCC[⁴].

China has one of the highest carrier rates of HBV in the world，reaching nearly 10% of the general population. The disease burden of HBV infection and HCC is also believed to be among the world’s largest, and that of HCV infection is likely to be substantial as well[⁵].

RISK PREDICTION

An important component of HCC prevention is the identification of high-risk HBV- and HCV-infected individuals, who will benefit from various chemopreventive therapies discussed below. Several natural history studies have identified important risk factors for HCC among patients with chronic hepatitis B (CHB) and chronic hepatitis C (CHC), with risk predictive scores also designed for practical usage.

Risk factors and prediction scores: CHB

A study evaluating the relationship between serum HBV DNA level and risk of HCC demonstrated that the incidence of HCC among CHB patients increased with serum HBV DNA level. Elevated serum HBV DNA level (≥ 2000 IU/mL) is a strong risk predictor of HCC independent of hepatitis B e antigen (HBeAg)-positivity, serum alanine aminotransferase levels, and liver cirrhosis[⁶]. Subsequent studies also showed patients with moderate levels of serum HBV DNA (60-2000 IU/mL), when compared to individuals not infected with HBV, still had a substantial increased risk of HCC and liver-related death[⁷].

Besides serum HBV DNA levels, other host- and viral-related factors could also predispose to HCC. A meta-analysis found HBeAg-positive non-cirrhotic patients, when compared to HBeAg-positive cirrhotic patients, had a significantly reduced HCC risk after antiviral therapy[⁸]. HBV genotype also plays a role; HBV genotype C is closely associated with HCC especially in cirrhotic patients aged > 50 years[⁹]. An observation study in Hong Kong also found genotype C HBV infection to be an independent risk factor for HCC development when compared with genotype B[¹⁰].

Several clinical scoring systems have been developed for the prediction of HCC in CHB, as depicted in Table 1. These scoring systems are based on the longitudinal follow-up of treatment-naïve CHB patients for 5 years or more. Two common parameters used are age and serum HBV DNA levels. Other parameters used include gender, serum alanine aminotransferase levels, serum albumin, HBeAg status, presence of cirrhosis and presence of core promoter mutations[^11-15]. Risk prediction is now also possible for CHB patients undergoing nucleoside analogue (NA) therapy. A recent study investigated the risk of HCC among a large population of CHB patients treated with entecavir. Older age and presence of cirrhosis were independently associated with HCC in the entire cohort; advanced age and hypoalbuminemia were associated with HCC in patients without cirrhosis. The risk scores accurately predict which patients with CHB treated with entecavir would have a higher chance of developing HCC[¹³].

Table 1 Risk factors and prediction scores for hepatitis B virus- and hepatitis C virus-related hepatocellular carcinoma

Risk factors	HBV-related HCC	HCV-related HCC
Increased age	√[11-15]	√[16]
Male gender	√[11,12,15]	√[16]
Increased serum HBV DNA levels	√[11,12,14,15]
Presence of cirrhosis	√[12-14]
Increased serum ALT concentration	√[11,15]
HBeAg positivity	√[11,15]
Presence of core promoter mutations	√[12]
Presence of virological remission after 24 mo	√[13]
Presence of hypoalbuminemia	√[13]
Decreased serum albumin	√[14]
Increased serum bilirubin	√[14]
HBV genotype C	√[15]
Presence of HBsAg	√[15]
Family history of HCC	√[15]
Presence of portal hypertension		√[16]
Presence of hepatic inflammation		√[16]
Increased iron storage levels		√[16]
Presence of sustained virological response		√[17]
Presence of complete viral suppression		√[17]

HBV: Hepatitis B virus; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; HBsAg: Hepatitis B surface antigen; ALT: Alanine aminotransferase.

 

Risk factors: CHC

When compared to CHB, fewer clinical scoring systems have been developed for the prediction of HCV-related HCC. These are as depicted in Table 1. The majority of HCV-related HCC develop in patients with established cirrhosis. In a study investigating prognostic risk factors for HCV-related HCC, among 913 patients followed up for at least 3 years, age, male sex, portal hypertension, hepatic inflammation, and iron storage were significant risk factors for HCV-related HCC[¹⁶]. In a meta-analysis involving HCV-infected persons, sustained virologic response (SVR) was associated with reduced risk for HCC[¹⁷]. Even transient virologic control among patients with subsequent relapse after treatment, was associated with a lower risk of the development of HCC[¹⁸].

Prediction of HCV-related HCC may be enhanced by the development of related markers. Signal transducer and activator of transcription 1 and phosphatase and tensin homolog are associated with early growth response protein 1 signaling, which potentially promotes angiogenesis, fibrogenesis, and tumorigenesis in HCV-related HCC. This approach has potential for the early diagnosis and possible prevention of HCC. The corresponding serum markers found can help to predict high-risk groups for HCC[¹⁹].

Host factors

HCC is more common in HBV carriers with a family history of HCC. In a study of 5238 HBV carriers (553 with HCC and 4685 without HCC), the risk of HCC was significantly higher in those with a family history of HCC, with a multivariate-adjusted rate ratio for HCC of 2.41 compared with HBV carriers without a family history[²⁰]. If the carriers had two or more affected family members, the risk was even higher with the ratio increased to 5.55. It is therefore recommended to begin surveillance in adults once a family history of HCC has been identified. A recently published study also included the presence of family history, besides traditional viral-related parameters as a component for risk prediction[¹⁵].

PREVENTION OF HBV-RELATED HCC

HBV infection is the major cause of HCC. Vaccination against HBV is instrumental in the prevention of HCC, and is recommended for all newborns and individuals who are at increased risk for infection. Studies in Taiwan, where universal HBV vaccination was introduced in 1984, have documented a significant decrease in the incidence of HCC in both children and adolescents after the introduction of HBV vaccination as discussed below[^21,22].

In patients already chronically infected with HBV, antiviral treatment could prevent disease progression to cirrhosis or HCC. Additionally, periodic surveillance using ultrasonography and serum α-fetoprotein every 3-6 mo for earlier detection of HCC is also important so that curative treatments (e.g., hepatic resection) can be offered[²³].

The antiviral interventions and chemopreventive methods to prevent

Table 2 Antiviral interventions for prevention of hepatitis B virus- and hepatitis C virus-related hepatocellular carcinoma

Antiviral interventions	HBV-related HCC	HCV-related HCC
IFN: IFN-α	+/-[28,29]	√[46]
Pegylated IFN		√[47]
NAs: Lamivudine	√[36]
Entecavir	√[37,38]
Ribavirin		√[47]
Vaccination	√[21,22]
Screening of blood product	√[27]	√[27]

HBV: Hepatitis B virus; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; IFN: Interferon; NA: Nucleotide analogs.

Table 3 Chemopreventive agents for hepatitis B virus- and hepatitis C virus-related hepatocellular carcinoma

Chemopreventive agents	HBV-related HCC	HCV-related HCC
Statins	√[42]
Antidiabetic medications	√[42]	√[42]
Aspirin	√[41,53]	√[53]
Propranolol		√[51]
FASN		√[52]
Dietory agents: Coffee	√[54]	√[54]
Vitamin E	√[54]	√[54]
Vitamin D		√[50]
Fish oil (n-3 PUFA)	√[55-57]	√[55-57]
Phytochemicals: Resveratrol	√[43]
EGb	√[44]

HBV: Hepatitis B virus; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; PUFA: Polyunsaturated fatty acid; FASN: Fatty acid synthase; EGb: Extract of ginkgo biloba leaf.

Vaccination

Vaccination plays a central role in HBV prevention strategies worldwide, and a decline in the incidence and prevalence of HBV infection following the introduction of universal HBV vaccination programs has been observed in many countries[²⁴]. Control and significant reduction in incidence of new HBV infections as well as HCC have been repeatedly reported in countries in East Asia and Africa[²⁵].

A study of the incidence of HCC in children in Taiwan from 1981 to 1994 showed that the average annual incidence of HCC in children 6-14 years of age declined from 0.70 per 100000 children (between 1981 and 1986), to 0.57 per 100000 (between 1986 and 1990), and to 0.36 per 100000 (between 1990 and 1994). The corresponding rates of mortality from HCC had also decreased. The incidence of HCC in children 6-9 years of age declined from 0.52 per 100000 (for those born between 1974 and 1984) to 0.13 per 100000 (for those born between 1984 and 1986). Since the institution of Taiwan’s program of universal HBV vaccination from 1984, the incidence of HCC in children has declined dramatically[²²]. The risk of developing HCC for vaccinated cohorts was statistically significantly associated with incomplete HBV vaccination. The prevention of HCC by HBV vaccination extends from childhood to early adulthood. Failure to prevent HCC results mostly from unsuccessful control of HBV infection by highly infectious mothers[²¹].

Antiviral therapy: Interferon and NAs

DNA integration of hepatitis viruses alters the function of critical genes, promoting malignant transformation of virus-infected liver cells[²⁶]. Treatment of CHB infection aims to control viral replication and prevent the development of complications. There are currently seven drugs available for the treatment of CHB, five NAs and two interferon (IFN)-based therapies. Long-term treatment with NA is often required, and the decision to treat is based on the clinical assessment including the phase of CHB infection and the presence and extent of liver damage[²⁴].

Concerning IFN therapy, a study involving 641 biopsy-proven CHB patients treated with IFN-α2b were followed up for a median period of 113 months. Although HCC occurred less frequently in biochemical responders than in non-responders, virologic response is not associated with decrease in HCC development. Poor biochemical response, as well as older age and a higher serum AFP level remain independent predisposing factors of HCC development in CHB patients treated with IFN-α[²⁷]. In addition, a study about the long-term effects of IFN-α in Chinese patients showed that IFN-α was of no long-term benefit in inducing HBeAg seroconversion or in the prevention of HCC and other cirrhosis-related complications[²⁸].

On the contrary, nearly all the studies showed that NA is able to reduce HCC[²⁹]. Many randomized controlled trials showed that lamivudine, one of the earliest oral NAs for antiviral therapy in HBV infection, can reduce disease progression in HBV-related cirrhosis and HCC[^29-34]. A recent study followed up 293 CHB patients without HCC who were treated with lamivudine for a mean duration of 67.6 mo. In cirrhotic patients, the attainment of maintained viral response (defined as HBV-DNA levels of < 4.0 log copies/mL) during lamivudine treatment was revealed to reduce the risk of HCC development. No significant reduction was observed in the non-cirrhotic group[³⁵].

Entecavir is a potent NA with high genetic barrier to resistance, and prolonged treatment results in regression of fibrosis, hence is currently recommended as first-line antiviral therapy for CHB. In a study of CHB patients with liver cirrhosis, entecavir therapy reduces the risks of hepatic complications, HCC, liver-related and all-cause mortality of CHB patients with liver cirrhosis in 5 years, particularly among those who had sustained viral suppression[³⁶]. In another multicentre cohort study, 372 entecavir-treated patients followed up for a mean duration of 114 mo were investigated. Clinical events were defined as development of HCC, hepatic decompensation or death. Virological response to entecavir (HBV DNA < 80 IU/mL) was associated with a lower probability of disease progression in patients with cirrhosis, suggesting that complete viral suppression is essential for NA treatment, especially in patients with cirrhosis[³⁷].

A meta-analysis investigating the effects of IFN or NA on the risk of developing HCC in CHB patients shows that, the reduction in HCC is more significant among patients with early cirrhosis than among non-cirrhotic patients. Five studies (n = 2289) compared patients treated by NA with control. The risk of HCC after treatment is reduced by 78%. HBeAg-positive patients have a more significant reduction in HCC risk with treatment. Patients without cirrhosis benefit more from NA than those with cirrhosis, although resistance to NA blunts the benefit of treatment[⁸].

In summary, while the evidence of the efficacy of IFN in preventing HBV-related HCC remains conflicting, there is a gradual accumulation of evidence supporting the positive effect of NA on reducing HBV-related HCC.

Chemoprevention

The observation that anti-platelet therapy inhibits or delays immune-mediated hepatocarcinogenesis suggests that platelets may be one of the key players in the pathogenesis of HBV-associated liver cancer and that immune-mediated necroinflammatory reactions may be an important cause of malignant transformation during chronic hepatitis[³⁸]. A prospective study on 300504 patients with chronic liver disease showed that aspirin users had statistically significant reduced risks of incidence of HCC and mortality due to chronic liver disease compared to those who did not use aspirin[³⁹]. Further studies are needed to confirm this finding and clarify its underlying mechanism.

A study concerning the association between the use of statins in HBV-infected patients and the risk of HCC shows that statin use may reduce the risk for HCC in HBV-infected patients in a dose-dependent manner[⁴⁰]. This may be related to the effect of statins in reducing fatty change in the liver, and requires future validation studies to confirm the findings.

There are also several investigational drugs which could have potential for chemoprevention against HBV-related HCC. Resveratrol is a natural polyphenol that has beneficial effects across various disease models. In an animal study investigating the efficacy of resveratrol against HBV-related HCC in HBV X protein (HBx) transgenic mice, resveratrol had a pleiotropic effect on HBx transgenic mice in terms of the down-regulation of lipogenesis, the promotion of transient liver regeneration, and the stimulation of antioxidant activity. Furthermore, at later precancerous stages, resveratrol delayed HBx-mediated hepatocarcinogenesis and reduced HCC incidence from 80% to 15%. The potential mechanisms for resveratrol on HCC prevention might be associated with its effects of stimulating the activity of Ampk and SirT1, and downregulating the expression of the lipogenic genes, Srebp1-c and peroxisome proliferator-activated receptor gamma. The decrease in Srebp1-c further downregulates the expression of its target genes, Acc and Fas[⁴¹]. Several other studies demonstrated resveratrol downregulates cyclin D1 as well as p38 MAP kinase, suppresses Akt and Pak1 expression and activity, and increases ERK activity, suggesting that growth inhibitory activity of resveratrol is associated with the downregulation of cell proliferation and survival pathways, and sensitization to apoptosis[⁴²]. Resveratrol also acts as an inhibitor for sirtuins. Overexpression of SIRT1 in cancer tissue has been demonstrated to promote mitotic entry of liver cells, cell growth and proliferation, and inhibit apoptosis related to the PTEN/PI3K/AKT signaling pathway[^43,44].

A study in China suggested that extract of Ginkgo Biloba leaf (EGb) could reduce the incidence of the HCC with HBV transgenic mice. The reason may be that EGb could reduce liver HBx, p53, Bcl-2 protein expression in HBV transgenic mice[⁴⁵]. These investigational products would need confirmation in human clinical trials in the future.

PREVENTION OF HCC RELATED TO HCV

With the commencement of successful vaccination programs against HBV, CHC is now emerging as an important cause of chronic liver diseases. The drive of carcinogenesis during HCV infection is thought to result from the interactions of viral proteins with host cell proteins. Thus, the induction of liver mutation phenotypes through the expression of HCV proteins provides a key mechanism for the development of HCV-associated HCC. With the emerging importance of CHC, mechanisms of HCV-associated hepatocellular carcinogenesis should be clarified to provide insight into advanced therapeutic and preventive approaches to decrease the incidence and mortality of HCC[⁴⁶].

Strategies aimed at eliminating the virus may provide opportunities for effective prevention of the development of HCC. The first step is to encourage universal precautions to reduce infections transmittedvia different modalities e.g., iatrogenic routes, sharing of intravenous needles etc and further implementation of universal screening of donated blood products. Concerning therapy for HCV, pegylated IFN plus ribavirin therapy is effective at reducing the risk of HCC in patients with CHC who achieve SVR.

The effects of antiviral therapy and chemopreventive measures in preventing HCC are mentioned in Tables 2and 3 respectively.

Antiviral therapy: IFN and ribavirin

Current strategies to reduce HCC incidence in CHC patients include prevention of cirrhosis development by avoiding metabolic, pharmacological, or social factors associated with accelerated progression of liver disease, or through virus eradication by IFN-based treatments. Moreover, a successful antiviral treatment has positive impact on the rate of HCC development in patients who are already cirrhotic[¹].

Combination of pegylated IFN and ribavirin therapy is recommended for antiviral therapy worldwide, and is effective in reducing the rate of recurrence of HCV-associated HCC after curative resection or transplantation[⁴⁷]. The pooling of data from the literature suggests a preventive effect of antiviral therapy on HCC development in patients with HCV-related cirrhosis, but the preventive effect is limited to those achieving SVR[⁴⁸]. However, some HCV mutations, such as the amino acid substitution M91L, are associated with treatment failure and a poor prognosis[⁴⁷].

There is a recent study of the effect of pegylated IFN and ribavirin treatment of CHC on the incidence of HCC. After a median observation period of 3.6 years, a significantly lower rate of HCC incidence was noted in patients achieving SVR when compared to non-virological responders. A similarly lower rate of HCC incidence was noted among cirrhotic patients achieving SVR (18.9%) when compared to cirrhotic non-virological responders (39.4%)[¹⁸].

A meta-analysis study has been performed recently with the data sources from MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science, and the Database of Abstracts of Reviews and Effectiveness from inception through 2012, to systematically review observational studies to determine the association between response to HCV therapy and development of HCC among persons at any stage of fibrosis and those with advanced liver disease. Among HCV-infected persons, there is moderate-quality evidence demonstrating SVR to be associated with reduced risk for HCC; SVR after treatment among HCV-infected persons at any stage of fibrosis is associated with reduced HCC[¹⁷].

Chemoprevention

Vitamin D insufficiency has been associated with the occurrence of various types of cancer. A recent study aimed to determine the relationship between genetic determinants of vitamin D serum levels and the risk of developing HCV-related HCC. The data suggest a relatively weak but functionally relevant role for vitamin D in the prevention of HCV-related hepatocarcinogenesis[⁴⁹].

Propranolol has antioxidant, anti-inflammatory, antiangiogenic properties and antitumoral effects and therefore is potentially active in the prevention of HCC. A retrospective long-term observational study suggests that propranolol treatment might decrease HCC occurrence in patients with HCV cirrhosis[⁵⁰]. These findings also need to be verified by prospective clinical trials.

Understanding the interplay between the viral and cellular components of the HCV replication complex could provide new insight for prevention of the progression of HCV-associated HCC. Fatty acid synthase (FASN) is found to interact with NS5B. FASN may thereby serve as a target for the treatment of HCV infection and the prevention of HCV-associated HCC progression[⁵¹]. Thus, understanding the molecular mechanisms, which are implicated in the development of HCC during the course of HCV infection, may help to design a general therapeutic protocol for the treatment and for its prevention.

PREVENTION OF HCC RELATED TO HBV AND HCV COINFECTION

HBV and HCV coinfection is not uncommon with an estimated 7-20 million infected individuals worldwide[⁵²]. A community-based prospective cohort study evaluating HCC development in HBV and HCV co-infected subjects found the hazard ratios (HRs) of HBV monoinfection, HCV monoinfection, and HBV/HCV coinfection were 17.1, 10.4 and 115.0, respectively. Different genotypes and multiplicative synergistic effect of HBV and HCV coinfection on HCC risk was observed. Infection with HCV genotype 1 (HR = 29.7) and mixed infection with genotype 1 and 2 (HR = 68.7) significantly elevated HCC risk, much higher than HBV infection. The effect of different HCV genotypes and the multiplicative synergistic effect of HBV/HCV coinfection on HCC risk underline the need for comprehensive identification of hepatitis infection status in order to prevent and control HCC[⁵³].

Pegylated interferon-alpha plus ribavirin should be recommended in patients with dominant HCV replication. However, HBV rebound may occur after elimination of HCV with anti-HBV treatment required. These therapeutic measures may contribute to the prevention of HCC this special group of patients[⁵²].

OTHER POTENTIAL CHEMOPREVENTIVE METHODS

The use of aspirin, but not nonsteroidal anti-inflammatory drugs, is associated with a decreased risk of HCC and death from chronic liver disease in the National Institutes of Health-AARP Diet and Health Study of patients between the ages of 50 and 71 years[³⁹]. However this study does not provide information on the HBV and HCV status of its participants, and would need confirmation by future studies specifically for the HBV- and HCV-infected population.

More recent data have suggested dietary factors, including increased intake of coffee[⁵⁴], unsaturated fatty acids and fish to be protective against HCC. Subjects with known HBV or HCV status, and subjects who were anti-HCV and/or hepatitis B surface antigen positive were analysed. Consumption of n-3 polyunsaturated fatty acid (PUFA)-rich fish or n-3 PUFAs, particularly eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid, appears to protect against the development of HCC, even among subjects with HBV and/or HCV infection[⁵⁵], probably through dampening the inflammation in the liver and decreasing formation of tumor necrosis factor (TNF)-α, and through simultaneously inhibition of COX-2 and beta-catenin[^56,57]. The findings also point to a potential anticancer role for the n-3 PUFA-derived lipid mediators 18-HEPE and 17-HDHA, which can down-regulate the important proinflammatory and pro-liferative factor TNF-α.

CONCLUSION

Clinical experts evaluated ten previously identified dimensions of HCC control: clinical education; risk assessment; HBV strategy; HCV strategy; life-style risk factors; national statistics; funding for screening; funding for treatment; political awareness; and public awareness. Of these strategies, the most significant needs in regional efforts to control HCC are political awareness, public awareness, and life-style risk factors[⁵⁸].

HCC is a challenging malignancy of global importance. As HCC is strongly associated with chronic viral hepatitis, prevention against the infection is crucial for prevention against HCC. Vaccination against HBV in the newborns and early childhood is highly effective to lower infection rates substantially. For HCV, universal precautions when dealing with human blood, education on high-risk behaviours and screening programs for blood donors can reduce infection rates. Although prevention and treatment of CHB and CHC have been improved within the last decades even in high-risk countries, further effective and sustainable reduction of these infections is still needed[²⁶].

Antiviral therapies for CHB and CHC, while important, can only reduce but not completely eliminate HCC. Improvement in identification of infected persons, accessibility of care and affordability of treatment are needed for antiviral therapy to have a major impact on the global incidence of HCC[⁵⁹]. Further advances in our understanding of the molecular pathogenesis of HCC hold promise in improving the diagnosis and treatment of this highly lethal cancer[⁴].

Footnotes

P- Reviewers: Chen Z, Vinciguerra M S- Editor: Gou SX L- Editor: A E- Editor: Ma S

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