Gradual Gains in Liver Cancer

“Every day of my life, I’m thankful for kidney stones,” says 50-year-old Kathy Dayton. It might seem like an odd sentiment until you learn that the imaging scan she received in February 2011 revealed not only a kidney stone but also stage 1 liver cancer. Because it was diagnosed early and her liver was functioning well, Dayton’s tumor could be surgically removed. Although the tumor returned a year later, today she is cancer-free. Primary liver cancer is a complex disease, and progress in treating it has been slow. Nexavar (sorafenib) remains the only approved drug for treating advanced forms of the disease, and its effects on survival are modest. Although it’s unlikely that liver cancer treatments will dramatically improve in the near future, the situation is gradually brightening with recent advances in diagnostics, radiation techniques and chemotherapy.

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause of cancer-related death worldwide, with more than 700,000 cases diagnosed each year.

Unlike many other types of cancer, its incidence has been rising for decades. Dayton’s road to HCC began in 1984, during her work as a dialysis nurse. She was stuck with a needle from a patient infected with the hepatitis C virus, and 10 years later, a blood test revealed that she had contracted the virus.

Over the years, Dayton hadn’t thought much about her hepatitis status because the levels of the virus in her system were very low and her liver was functioning well. So the HCC diagnosis came as something of a shock.

Unlike Dayton, the vast majority of patients who receive an HCC diagnosis have relatively poor liver function due to underlying disease, most often from viral hepatitis. Other factors thought to cause HCC include cirrhosis (scarring), which is primarily associated with chronic alcohol consumption, and nonalcoholic steatohepatitis (NASH), a condition associated with obesity. In fact, the obesity epidemic may help to explain the rising incidence that has been seen in individuals without hepatitis or a history of alcohol abuse.

With HCC, the best hope for a cure is with surgical removal of the tumor or, in some cases, liver transplantation, a procedure available only to patients who have localized disease and a limited number of small tumors. And because the demand for donor livers far outweighs the supply, patients like Dayton, who has well-preserved liver function, generally must wait behind patients who are critically ill.

Marilyn Townsend’s liver function was starting to decline in the summer of 2009, 18 years after she learned she had hepatitis C, which she most likely acquired after receiving contaminated blood in the era before blood banks routinely screened for the virus. An imaging scan revealed a single small tumor on her liver that was too close to a major blood vessel to be removed surgically, and because she was also in the early stages of cirrhosis, her name was added to the transplantion list. “They laid it on me all at once,” says Townsend, of her HCC diagnosis and the news that she would need a liver transplantation. She received a new liver after a three-month wait, and her scans have since shown no signs of HCC.

"They laid it on me all at once."

When localized to specific segments of the liver, early-stage HCC can also be potentially cured with local tumor ablation, an approach involving the direct delivery of tumor-destroying chemicals or extreme temperatures, although both techniques have approximately a 50 percent rate of recurrence. Dayton’s small tumor was removed a month after her diagnosis, keeping her cancer at bay for a year. Whether the most effective form of local ablation—heat-based radiofrequency ablation—can match the effectiveness of surgery is unclear.

Perhaps the best way to improve the sobering statistics associated with HCC is to catch and treat the disease early in a larger number of patients. This means keeping a close eye on those at high risk, particularly as symptoms of HCC, including pain, fatigue, weight loss and jaundice, often overlap with those of the underlying liver disease. Screening standards for high-risk patients, including those who have cirrhosis or viral hepatitis, now include annual or biannual liver ultrasounds and other routine tests to measure blood levels of alphafetoprotein (AFP), a protein produced by cancer cells that is increased in roughly 70 percent of patients with HCC.

Despite these advances, Mary Maluccio, a surgical oncologist at Indiana University Hospital in Indianapolis, thinks more should be done. “We have largely ignored the fact that if we diagnosed it early, we might have seen a plateau [in HCC incidence] just like we have with the other cancers,” she says.

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Diagnostic procedures for HCC have become more sophisticated and accurate in recent years, with new techniques, such as contrast-enhanced computed tomography and magnetic resonance imaging scans, better able to detect the characteristic features of HCC lesions. And studies are underway to improve upon current staging systems, which already consider multiple variables, including liver function, tumor characteristics and blood AFP levels, by including other factors, such as blood levels of VEGF and IGF-1, proteins that are altered in some cases of HCC.

Unfortunately, stories like Dayton’s and Townsend’s are more the exception than the rule in HCC. The majority of patients are not candidates for potentially curative treatments because their tumors are too large, their cancer too extensive, their livers too damaged to withstand the procedures or because there are simply no donor organs available. These patients are treated with palliative non-curative approaches, and less than half live beyond the three-year mark.

Fortunately, many of the recent strides in treating HCC have been in tumor-directed techniques. These treatments are generally not curative, but they may buy some time by delaying tumor growth. They take advantage of the unique anatomic structure of the blood supply to the liver. Normal liver tissue gets most of its blood supply from the portal vein, which not only carries oxygen and nutrients to the liver but also carries away the waste products that the liver normally removes from the blood. HCC, however, is nourished almost entirely by blood from the hepatic artery. “By directing the therapy into the artery, we selectively affect the tumor, without causing collateral damage to the surrounding liver tissue,” explains radiologist Anne Covey of Memorial Sloan Kettering Cancer Center in New York.

If you have someone with two 3-centimeter tumors, you have to keep them from growing or the patient will be out of the running for a liver transplant.

Many treatments take advantage of this route of entry to tumors, including embolization, in which small, beadlike particles are injected into a catheter that is placed in the portion of the artery that feeds the tumor. This impedes blood flow into the tumor, effectively starving it of oxygen and nutrients (bland embolization). The beads can also be added to chemotherapy drugs (drug-eluting beads) or radioactive particles (radioembolization), including the now widely used yttrium-90, to augment the anti-tumor effect.

Chemotherapy drugs can also be delivered in this way, typically followed by a gel-like substance or particles to prevent the drugs from getting washed away (chemoembolization). “Chemoembolization has been very popular but has more side effects, one of which is worsening liver function,” says Covey, whose own work suggests that it’s the physical blocking of the blood vessel that accounts for the effectiveness of chemoembolization rather than the chemotherapy drugs themselves.

Despite the fact that chemoembolization and radioembolization are on the rise, both Covey and Maluccio stress that there is no concrete evidence that they work better than bland embolization (without any drug), which is less expensive and also spares patients the side effects of chemotherapy or radiation. A combination of embolization and ablation might also be superior to either approach alone, as shown in one study of patients with large, inoperable tumors, but more research is required.

Dayton’s cancer returned a year after surgery, although she says she felt fine and her liver was still in good working order. But because the cancer had spread to her lungs, she didn’t qualify for a second surgery. Instead, Dayton’s liver tumor was treated with yttrium-90, from which she felt few side effects apart from some tiredness. She later underwent three Cyberknife procedures, a type of stereotactic body radiation therapy (SBRT), to treat the masses in her lungs. SBRT allows for radiation to be delivered more accurately and at higher doses with the help of computer modeling.

For decades, radiation has been used to treat HCC that can’t be treated with surgery, but whole-liver radiation is extremely toxic and provides only a minimal survival advantage. SBRT has been shown to control tumor growth in 90 percent of patients. Radiation can also be delivered by tethering radioisotopes to tumorhoming molecules. One such drug, iodine-131-labeled metuximab, improved survival when combined with chemoembolization based upon preliminary results from a small study of patients with advanced HCC. However, it is still very difficult to know if these therapies, which may induce temporary remissions or shrinkage, can extend survival.

These procedures are also widely used in patients awaiting liver transplantation. “If you have someone with two 3-centimeter tumors, you have to keep them from growing or the patient will be out of the running for a liver transplant,” Covey says. Townsend underwent two successful chemoembolizations as she awaited transplantation. In such a situation, when a long-term cure is possible, the stakes may be higher, but it’s still unknown if the chances of a cure can be improved with these procedures.

For those who receive a diagnosis of advanced disease where cure is not possible, the median survival ranges from approximately six to 11 months, even with Nexavar therapy. Since mid-2012, Dayton has taken the drug as maintenance therapy to prevent recurrence, although its effectiveness in this situation is unproven and the topic of an ongoing phase 3 trial. Dayton has had “every side effect under the sun,” that can be caused by this drug, including rash, diarrhea and mouth sores, but her cancer has not returned. Townsend also took Nexavar during her wait for liver transplantation, but the side effects she experienced were too severe to tolerate.

Unfortunately, using Nexavar as a single agent prolongs survival by only about three months. It might also be effective in combination with systemic doxorubicin, although how the combination stacks up to Nexavar alone awaits the results of further studies. Nexavar is a biologic therapy that inhibits a cellular growth signal called kinase. Several other kinase inhibitors have also been tested against HCC, but the results of these trials have been largely disappointing.

In an attempt to expand drug options for advanced HCC, many researchers are now focusing on tumor genetics in the hopes of finding key features of HCC tumors that could reveal new drug targets. This is a challenging undertaking in HCC patients, in whom biopsies are risky due to the possibilities of bleeding or spreading the cancer to other sites along the needle track (“seeding”), but some promising leads have emerged.

Increased expression of a cell receptor called MET, which drives tumor growth and survival in many cancer types, is seen in 20 to 50 percent of HCC tumors and is associated with decreased survival. In a phase 2 trial, the MET inhibitor tivantinib nearly doubled overall survival compared with a placebo in subjects with advanced disease, many of whom had previously been treated with Nexavar. It is now being tested in a phase 3 trial for participants who have cancer that has progressed on previous therapies.

If we could identify the 20 percent or so who will eventually develop cancer, we could try chemoprevention or antiviral treatment that might diminish that 20 percent down to 10 percent.”

Maluccio supports these genetic approaches but cautions that these studies have so far not justified the risks of routine biopsies in the study participants. “It’s not as if we have five or so drugs to choose from, where you would potentially change your drug choice based on the genetics of the tumors,” she says. Favoring a more front-end approach, Maluccio and others are searching for biomarkers in the blood of high-risk patients that might help identify those who will go on to develop cancer. “If we could identify the 20 percent or so who will eventually develop cancer, we could try chemoprevention or antiviral treatment that might diminish that 20 percent down to 10 percent.”

Townsend’s cancer has not returned, but her new liver is now infected with hepatitis C and is declining in function, a process she hopes will be curtailed by new antiviral drugs. For the rest of the HCC community, the hope is that the continued search for new therapies and improvements in diagnosis will allow more patients to join the ranks of HCC survivors like Dayton and Townsend.