From OncoLog, May 2008, Vol. 53, No. 5

Hepatocellular Carcinoma: New Standards in Therapy Emerging

by John LeBas

For decades, oncologists have been trying to turn the tide against hepatocellular carcinoma (HCC). It’s a daunting challenge. HCC is typically refractory to systemic chemotherapy, and the great majority of patients are not candidates for treatments that can potentially cure or slow the disease, such as surgery, radiation therapy, and nonsurgical ablation. Moreover, treatment can be made difficult by preexisting liver disease, which is very common in HCC patients.

The merging of these factors makes HCC an exceptionally lethal tumor type, with a median overall survival duration of less than 1 year for patients diagnosed with advanced disease. And the human toll is vast: HCC is the sixth most common cancer in the world and the third leading cause of cancer-related death, resulting in at least 500,000 deaths per year worldwide. While HCC is a relatively rare tumor in the United States, with about 18,000 new cases expected in 2008, the incidence has approximately doubled in the past 30 years.

Progress against HCC, which accounts for up to 90% of all liver cancers, has been slow, but that may be changing. Not only has recent research established sorafenib, a multi-kinase inhibitor, as the first-ever standard systemic therapy for advanced, unresectable HCC, but other agents are showing even better results in clinical trials. At the same time, advances in radiation therapy and nonsurgical ablation may make those already-proven approaches more effective in certain patients.

“For years, long-term survival or cure was considered possible only in a minority of HCC patients,” said Melanie Thomas, M.D., an assistant professor in The University of Texas M. D. Anderson Cancer Center’s Department of Gastrointestinal Medical Oncology. “While we’re still a long way off from curing HCC in the majority of patients, we are finally finding therapies that may enable long-term disease control for most.”

Understanding HCC

To appreciate the importance of recent advances in HCC, it helps to understand some of the etiologic and clinical variations that make the disease such a wily foe.

HCC usually develops in patients with liver damage caused by alcohol abuse, fatty liver disease, or, most commonly, chronic hepatitis infection. The vast majority of HCC cases occur outside the United States, particularly in Asia, which is home to about 80% of cases worldwide. The main cause of the disease in Asia is hepatitis B infection, primarily because of high rates of childbirth transmission. Children infected at birth are extremely likely to develop a chronic infection, and over time the virus causes cirrhotic changes that can lead to cancer.

The global incidence of hepatitis B is staggering—there are an estimated 350 million chronic infections, and up to 25% will lead to HCC. Fortunately, inroads have been made since the introduction of the hepatitis B vaccine, which has cut HCC incidence by half in some countries with robust vaccination efforts.

But the hepatitis B vaccine has had limited impact on HCC rates in the United States, where that strain of the virus causes very few HCC cases. Rather, 60% of U.S. cases of HCC arise from hepatitis C infection, which is becoming more common and for which no vaccine exists. Consequently, the incidence of HCC is increasing in the United States as well. “This is one of the few tumors that’s rapidly on the rise in the United States, and much of that rise is related to an increase in hepatitis C cases,” Dr. Thomas said. Even so, HCC is still considered an “orphan disease” in the United States—that is, the incidence is so low that there is little financial incentive for pharmaceutical companies to develop new therapies.

Treatment of HCC with the therapies that do exist often proves difficult for multiple intertwined reasons. Usually, the surrounding organ is already diseased by the time the tumor develops, increasing the risk of complications. “The worse the liver is, the worse the prognosis is,” Dr. Thomas explained. Since a diseased liver performs its metabolic detoxification functions poorly, a toxic chemotherapy is more likely to make the patient very sick.

Moreover, HCC is considered to be chemoresistant; historically, cytotoxic drugs have been minimally effective at killing this type of cancer cell, especially compared to their efficacy in chemosensitive cancers such as lymphoma or leukemia. In addition, the window for treatment is short; the underlying liver disease can progress faster than the cancer and often is what kills the patient.

Checkered history, promising future

The history of HCC therapy has been a story of limited and somewhat isolated successes. Surgical resection and liver transplant are the only curative options, and only for patients who present with a limited tumor burden and limited liver disease burden—perhaps 20% of all patients. Some success in controlling localized tumors has been achieved with cryotherapy, ablative therapies, radiation therapy, and chemoembolization. But systemic chemotherapies—the only real option for patients with advanced or metastatic disease—have largely yielded low response rates and virtually no survival benefit.

Finally, it was a biologic agent—not a cytotoxic chemotherapeutic agent—developed for another cancer type that bucked the negative trend in systemic therapy for HCC. This agent, sorafenib, was originally approved by the U.S. Food and Drug Administration (FDA) in 2005 for the treatment of renal cell carcinoma. But investigators desperate to find effective therapies for liver cancer also tested sorafenib against HCC, and encouraging results from early studies led to the phase III SHARP trial presented at the 2007 American Society of Clinical Oncology meeting.

The SHARP trial showed that sorafenib extended the overall survival of patients with advanced HCC by 44%, or nearly 3 months—the first agent to cause a significant increase. Approval of sorafenib for unresectable HCC was granted by the FDA in November 2007.

The SHARP trial has already made an important impact on the evolution of HCC therapy, Dr. Thomas said. Patients who are not eligible for other therapies finally have a systemic therapy option. Also, sorafenib provides a control arm for future clinical trials of other agents. And importantly, the SHARP trial has generated greater interest in HCC by proving that a biologic agent has activity in the disease.

This heightened interest has led investigators to launch clinical trials of other agents, with early results even more promising than those from sorafenib. Two of these agents are the targeted therapies bevacizumab (Avastin) and erlotinib (Tarceva), which have shown good results in other cancer types. Bevacizumab is an anti-angiogenic agent that is FDA-approved for the treatment of metastatic colorectal cancer and non–small cell lung cancer. Erlotinib targets epidermal growth factor receptors (EGFR) and is approved for the treatment of metastatic or locally advanced non–small cell lung cancer and pancreatic cancer.

Dr. Thomas began testing bevacizumab in HCC after reviewing the positive results of a trial of the drug in renal cell cancer. “I suspected bevacizumab would also work in HCC, since HCC and renal cell carcinoma are quite similar in that both tumors are highly vascular and both are very chemoresistant,” Dr. Thomas said. “So, we started a trial of bevacizumab in combination with erlotinib for HCC. Erlotinib was a rational choice in HCC because 80% of these cancers overexpress EGFR.”

The phase II trial, which has not yet been published, showed that the combination therapy prolonged progression-free survival in patients with advanced HCC by 50% compared to sorafenib—for a median progression-free survival interval of 9.75 months. Also significant, the investigators observed a 25% overall response rate, which is considered exceptionally high for clinical trials of agents in HCC. Based on these results, a phase III trial of bevacizumab and erlotinib is planned to open this summer at M. D. Anderson and seven other cancer centers in the United States.

“I am hopeful that bevacizumab and erlotinib will be the new standard for advanced HCC after this trial,” Dr. Thomas said. “We will also be seeing sorafenib tested in combination with other agents. I think that these therapeutic agents will eventually make HCC much more treatable for a wider population, as has happened with other historically difficult-to-treat cancer types such as renal cell carcinoma.”

M. D. Anderson is also participating in a multicenter phase II trial of brivanib (an inhibitor of vascular endothelial growth factor receptor 2) in HCC and is studying DHA-paclitaxel (a conjugate of paclitaxel and a natural fatty acid that enhances the drug’s ability to inhibit cell division and induce apoptosis) in a separate phase II trial.

Other novel approaches

For the minority of HCC patients whose tumors can be treated without systemic agents—namely, those with localized disease—groundbreaking work continues to refine the standards of care. Exciting results are being seen with proton therapy and an experimental type of thermal ablation that uses radio waves to heat carbon nanoparticles injected into tumors.

Proton therapy

Radiation therapy was once thought to have very limited application in HCC. The rationale was that the tumors were resistant to radiation and that the surrounding liver was too sensitive to tolerate an effective dose. Additionally, the risk of radiation-induced toxicity was considered high.

But over time, radiation oncologists came to understand that so long as the patient had no more than a solitary tumor with a few satellites and so long as a sufficient amount of healthy liver could be spared, effective doses of radiation could be given to the tumor-bearing tissue with a low risk of toxicity. Proton therapy, a relative newcomer in radiation therapy, appears to fit the bill perfectly.

“The best way to spare maximum healthy tissue is with a beam that has little scatter, concentrates its energy deposition within the tumor, and does not deposit its energy after it exits the tumor,” said Sunil Krishnan, M.D., an assistant professor in radiation oncology at M. D. Anderson. “That’s exactly what a proton beam does.”

The use of proton beams for HCC is still under study—M. D. Anderson’s Proton Therapy Center opened just last year—but initial results from investigators elsewhere are promising. In one study from Japan, a 5-year overall survival rate of 23% was seen in patients who were ineligible for other therapies and were treated with proton radiation. More impressive, the 5-year overall survival rate was 50% among patients who had a single tumor and preserved liver function and were treated with proton radiation. This result rivals what can be achieved with surgical resection and has helped propel further study on proton therapy for HCC. “We can also use photon beams to treat this tumor type, but we think that we can spare more good liver with proton therapy, which is especially important for a patient who has cirrhosis,” Dr. Krishnan said. M. D. Anderson is also running a phase I clinical trial in which the patient receives one cycle of bevacizumab prior to proton therapy, followed by two cycles administered concurrently with radiation.

Radiofrequency ablation

In traditional radiofrequency ablation, otherwise harmless radio wave energy is converted to heat via needle electrodes inserted into a tumor. The technique can be used to control localized liver cancers and some other tumor types. But incomplete ablation occurs in up to 40% of cases, and complications occur in 10% of patients because of damage to healthy tissue from the procedure. Thus, a more precise method is needed.

Recently, researchers collaborating at M. D. Anderson and Rice University reported that carbon nanotubes might offer such precision. In their study, nanotubes injected into rabbit tumors and heated with externally administered radio waves destroyed all tumor cells with minimal damage to healthy liver cells and no side effects. Results were published in the December 2007 issue of the journal Cancer.

“Our next step is to look at ways to more precisely target the nanotubes so they attach to, and are taken up by, cancer cells while avoiding normal tissue,” said Steven Curley, M.D., senior author of the nanotube study and a professor in the Department of Surgical Oncology at M. D. Anderson. He estimated that a clinical trial is at least 3 years away.

For more information, call Dr. Thomas at 713-792-2828, Dr. Krishnan at 713-563-2377, or Dr. Curley at 713-794-4957.

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