For patients receiving a diagnosis of liver cancer, the news can be daunting, especially when considering the low 5-year survival rates, particularly for distant metastases. However, new agents are now showing promise in combating liver cancer and extending the survival times of some patients. In addition, new research is suggesting that vitamin E may lower liver cancer risk and some individuals may be able to lower their risk of developing liver cancer by increasing their daily intake of vitamin E.
Research in Liver Cancer
A recently completed trial from Shanghai, China has found that adding cetuximab (Erbitux®, IMClone LLC) to standard chemotherapy may enable some patients with otherwise inoperable liver metastases due to colorectal cancer to have their metastases surgically removed.1
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The study, which was published online April 8, 2013 in the Journal of Clinical Oncology, showed the combination of cetuximab and chemotherapy extended the median overall survival for this patient population by 10 months compared with chemotherapy alone. This combination therapy is a standard treatment option for many patients with advanced colorectal cancer, but this is the first randomized study to explore its impact on inoperable liver metastases.
Other new agents are also showing promise for treating hepatocellular carcinoma (HCC) after patients have received sorafenib (Nexavar®, Onyx Pharmaceuticals) as first-line systemic treatment. Sorafenib is currently the only Food and Drug Administration–approved oral medication for use in advanced cases of HCC, which is the most common type of primary liver cancer.
“I think there is reason for optimism,” said William Harris, MD, Assistant Professor in the Division of Oncology at the University of Washington, Seattle, WA. “Overall trends over the last decade have shown improved survival rates. It is the combination of newer agents, better multi-disciplinary care, better selection of surgical candidates, and better selection for other therapy.”
Currently, Dr. Harris is helping to lead a multicenter, randomized, double-blind, phase 3 study of ramucirumab and best supportive care (BSC) versus placebo and BSC as second-line therapy in patients with HCC following first-line therapy with sorafenib. Ramucirumab is a fully human monoclonal antibody that is directed against the vascular endothelial growth factor receptor 2 (VEGFR2).
The American Liver Foundation reports that about 21,000 Americans are diagnosed with primary liver cancer every year, making it one of the few cancers on the rise in the United States. In addition, a report published in 2011 indicated that death rates increased for liver cancer in both men and women between 1990 and 1991 and in 2006.2 Individuals with cirrhosis, which can be caused by chronic alcoholism and hepatitis C, are at increased risk for liver cancer. These two factors are the leading causes of cirrhosis in the United States, according to the American Liver Foundation.
Hope in Vitamin E?
Greater efforts are now underway to identify individuals infected with hepatitis C and treatments for it have significantly improved over the past few of years. In addition, a new study has found that high consumption of vitamin E, whether through diet or vitamin supplements, may lower the risk of developing liver cancer.3
The researchers analyzed data from a total of 132,837 individuals in China who were enrolled in the Shanghai Women’s Health Study (SWHS) from 1997 to 2000 or the Shanghai Men’s Health Study (SMHS) from 2002 to 2006. Using validated food-frequency questionnaires and in-person interviews to gather data on study participants’ dietary habits, researchers compared liver cancer risk among individuals who had high intake of vitamin E compared to those with low intake.
The analysis included 267 liver cancer patients (118 women and 149 men) who were diagnosed between 2 years after study enrollment and an average of 10.9 (SWHS) or 5.5 (SMHS) years of follow-up. The study showed the intake of vitamin E from diet and vitamin E supplement use were both associated with a lower risk of liver cancer. In addition, this association was consistent even among those subjects with and without self-reported liver disease or a family history of liver cancer.
Better Understanding of the Disease and How to Combat It
It may now be possible to combat liver cancer in an entirely new way. A newly-published study revealed that liver cancer is armed with many tactics for evading immune responses. Researchers at Roswell Park Cancer Institute in Buffalo, NY published findings in the journal Cancer Research that help explain how advanced HCC evades the body’s natural anti-tumor responses.4 In a study involving 23 patients with advanced HCC, researchers measured multiple parameters of immune suppression simultaneously. They found that HCC patients accumulate an unusually high number and variety of immunosuppressive cells that impede immunotherapies and facilitate tumor growth.
“This gives us a first hope. There could be a treatment strategy based on these findings.” study investigator Yamin Thanavala, PhD, of the Department of Immunology at Roswell Park Cancer Institute, told ChemotherapyAdvisor.com.
Several experimental approaches are now trying to activate the body’s own immune response to fight advanced HCC. A multi-center clinical trial, known as TRAVERSE and sponsored by Jennerex Biotherapeutics, San Francisco, CA, is underway evaluating Pexa-Vec (JX-594) as a means of slowing the progression of HCC. Pexa-Vec is a genetically engineered virus that is used in the smallpox vaccine. During the 18-week trial, Pexa-Vec is given both intravenously and injected directly into the tumor.
Tony Reid, MD, PhD, a medical oncologist at the University of California San Diego and one of the clinical trial sites, said the goal of the trial is to determine if this approach can extend patients’ survival through its ability to selectively target and kill cancer cells, cut off the tumor’s blood supply, and activate the immune system to fight the cancer at the same time.
“I think there is reason for optimism for more than just one reason,” Dr. Reid said in an interview with ChemotherapyAdvisor.com. “There has been an explosion of new drugs that are tolerable in patients with cirrhosis.”
Dr, Reid noted better treatments for hepatitis B, hepatitis C, and cirrhosis may help curb the increasing numbers of patients being diagnosed with primary HCC. Dr. Reid said targeted therapies are now showing more promise than ever before for patients with advanced HCC and there are a record number of clinical trials underway.
“I do think the future of treatment for oncologists will be selecting target treatments based on the tumor biology,” said Dr. Reid. “Therapy will be directed on the pathology of the biopsy over the next 5 years.”
Michael Naughton, MD, who is a liver cancer expert at Washington University School of Medicine, St. Louis, MO, cautioned that there are many hurdles still to overcome. He said in general, the current treatment for advanced HCC is usually disappointing in a significant number of patients. Dr. Naughton said a large number of patients with advanced HCC are not getting to the goal of having surgery and that is disappointing. “We have made some progress,” Dr. Naughton told ChemotherapyAdvisor.com. “It is really the first baby step in the right direction.”
References
1. Ye LC, Liu TS, Ren L et al. Randomized Controlled Trial of Cetuximab Plus Chemotherapy for Patients With KRAS Wild-Type Unresectable Colorectal Liver-Limited Metastases. J Clin Oncol. 2013 Apr 8. [Epub ahead of print]
2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277–300.
3. Zhang W, Shu XO, Li H, et al. Vitamin intake and liver cancer risk: a report from two cohort studies in China. J Natl Cancer Inst. 2012 Aug 8;104(15):1173-81.
4. Kalathil S, Lugade AA, Miller A, et al. Higher Frequencies of GARP+CTLA-4+Foxp3+ T Regulatory Cells and Myeloid-Derived Suppressor Cells in Hepatocellular Carcinoma Patients Are Associated with Impaired T-Cell Functionality. Cancer Res. 2013 Apr 15;73(8):2435-44
