NEWS

Can Increased Treatment of Hepatitis C Stem the Tide of Liver Cancer?

Renee Twombly

Reflecting concern at a projected fourfold increase in the prevalence of chronic hepatitis C infection in the next decade, a National Institutes of Health-sponsored advisory panel has recommended that previously ineligible patients receive the latest combination drug therapy designed to clear the virus from blood.

This recommendation and several others were the product of a consensus conference in June convened to update a 1997 report on the management of hepatitis C. The recommendations in the earlier statement excluded several patient groups because there was little information about the efficacy of treatment. But recent studies suggest more patients could be helped by the newer therapies now available. Nevertheless, experts question whether broader treatment efforts will ultimately have an effect on one of the most serious complications of infection—liver cancer.

Chronic Infection

More than four million Americans are infected with the blood-borne virus and most of them have a chronic, persistent infection that produces disease decades after exposure. Because researchers estimate that most hepatitis C infections were contracted in the 1960s and 1970s from injection drug use, high-risk sexual behaviors, and contaminated blood supplies, the health toll from these initial infections is just now beginning to mount, said the panel’s chairman, James Boyer, M.D., director of the Liver Center at Yale University.

"We are clearly in a period of epidemic proportions in the number of chronic cases," he said. That means, even given the panel’s recommendation that more people be treated, serious health effects produced by chronic infection are expected to quickly rise.

The latest treatment, a cocktail of pegylated (longer-acting) interferon and ribavirin, produces a sustained viral response compared with monotherapy or an earlier combination of standard interferon and ribavirin. Still, not all patients respond favorably or can tolerate the treatment’s side effects. For example, of the six different forms of hepatitis C virus (HCV), the most common one—genotype 1, accounting for three-fourths of all patients—is the most difficult to treat, even with the newer combination therapy. It is not known how many of these patients respond to therapy, but estimates range from as low as 20% to about 50%.

Boyer said the infection is already the leading cause of known liver disease in the United States, as well as the most common cause of cirrhosis and liver transplantation. Moreover, about one-third of primary liver cancer (hepatocellular carcinoma, or HCC) cases are caused by hepatitis C infection, and the incidence of the cancer is projected to skyrocket.

Unlike many other forms of cancer, the number of people who develop and die from primary liver cancer is increasing in the United States. In 2002, about 16,600 new cases will be diagnosed, and 14,100 people will die from the disease, according to the American Cancer Society. It is now the eighth most common cause of cancer death among men.

Data collected over the past decade show the increasingly significant role hepatitis C plays in incidence of a once rare cancer.

At the beginning of the 1990s, the virus accounted for 10% of all cases of HCC, but by the end of the decade, it was about one-third and rising, said Hashem El-Serag, M.D., an epidemiologist and gastroenterologist at the Houston Veteran Affairs Medical Center and Baylor College of Medicine.

Additionally, overall incidence of HCC has doubled in the last 20 years, from 1.4 cases to 3.0 cases per 100,000, said El-Serag, who has authored a number of studies on increasing threat posed by the cancer. Because there is a strong casual relationship between HCV and HCC, and because there is a large number of relatively young people who have been infected with HCV for several years, there may be a rapid increase in the number of liver cancer cases in the next one to two decades, said El-Serag.

"This is a very significant problem because we think cancer is the last complication of hepatitis C infection," agreed Kris Kowdley, M.D., a gastroenterologist at the University of Washington, Seattle. "There is likely to be an epidemic in hepatocellular carcinoma."

But the physicians disagree on whether the new hepatitis C consensus panel recommendations will stem the rising tide of liver cancer. Included in the panel’s recommendation is that patients in the first stage of cirrhosis—called compensated cirrhosis because the liver is still functioning—who were previously excluded from clinical trials testing the combination therapy, should now receive the treatment. (The majority of patients with cirrhosis have that form. Patients with later-stage "decompensated" cirrhosis may not be able to tolerate the treatment and should be referred to clinical trials until safety and efficacy data of treatment are established, the panel said.)

Cancer Development

Because cirrhosis represents the last stage of clinical progression of HCV infection before liver failure or cancer development, the idea that combination therapy should treat some patients effectively enough to prevent cancer makes sense, Boyer said.

Kowdley also said that, based on his clinical experience and research, he believes at least half of patients with cirrhosis will respond to therapy with pegylated interferon and ribavirin, if used at optimal doses. Because of the burgeoning liver transplant list, Kowdley said his clinic "has become more aggressive in treating patients with cirrhosis" and has been using the combination therapy on patients with compensated cirrhosis for about a year. "In cirrhosis patients, you can achieve a response that is able to make the greatest impact, and is likely to significantly change the projected increase in liver cancer," Kowdley said.

But others argue that, apart from a small Japanese study conducted 6 years ago using monotherapy and some data from European observational databases, no proof exists showing that hepatitis C treatment can prevent development of liver cancer. Although researchers do not know the mechanism by which HCV causes HCC, one theory is that a liver cell’s long-term and ongoing attempt to regenerate itself puts in motion genetic changes that result in cancer. Preventing that regeneration may not, thus, stop cancer development.

"Whether treatment of hepatitis C can actually impact liver cancer is not really known. Few studies actually state and make that case," said panel member Charles L. Shapiro, M.D., director of breast medical oncology at the Arthur G. James Cancer Hospital at Ohio State University. "A lot more research is required to understand the basic biology of the virus, including establishing cell cultures and animal models."

El-Serag said he does not think treatment "will make a dent" in the number of cancers that will develop from hepatitis C. "Given the profile of patients, the side effects, the current overall response, and the fact that only a small proportion of patients that actually do get treatment, I don’t think we will prevent an increase in the cancer over the next two decades."

Instead, El-Serag said the research community should "highlight primary liver cancer as a new problem. It is one of the few cancers that is on the rise, and is now presenting in younger people," he said. "As we see more of it, we should begin honing new skills in prevention, screening, diagnosis, and treatment."

The panel’s other recommendations included the following:

• Educate the American public on the transmission of HCV to better identify afflicted individuals.

• Develop reliable, reproducible, and efficient culture systems for propagating HCV and expand basic research in the pathogenic mechanisms underlying hepatic fibrosis.

• Promote the standardization and wide availability of diagnostic tests for HCV infection and its complications, leading to early diagnosis and the implementation of appropriate treatment practices.

The draft statement with the panel’s recommendations is available at http://consensus.nih.gov.


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