Heather L. Van Epps, PhD

“I lit up like a Christmas tree,” says Heather McLean of the PET (positron emission tomography) scan that accompanied her 2008 diagnosis of stage 4 follicular lymphoma, a slow-growing type of non-Hodgkin lymphoma (NHL). PET scans, during which a radioactive sugar-like molecule called fluorodeoxyglucose is injected and taken up preferentially by active cancer cells, are used to determine how much cancer is present and where it’s located.

	The technique has proved its worth at the front and back ends of treatment. At diagnosis, PET scans provide a more accurate view of the extent of disease compared with CT (computed tomography) scans and detect a higher stage of disease in 20 to 40 percent of patients. In some cases, this warrants a more aggressive treatment approach, possibly offering a better shot at a cure. As an immediate follow-up to treatment, a PET scan can help to root out lingering disease and identify patients who might benefit from follow-up (consolidation) chemotherapy or radiation to kill the remaining cancer cells. A negative post-treatment PET scan predicts longer progression-free survival.

	Despite the lack of data to justify them, periodic surveillance PET scans during remission are performed frequently, says Bruce Cheson, head of hematology at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, D.C. Although surveillance scans are reasonably good at spotting relapses, they are not cost-effective, given that most relapses are heralded by a return of symptoms. One study showed that interim PET scans detected relapse before symptoms appeared in less than 2 percent of patients with diffuse large B-cell lymphoma.

	What’s also unclear is whether PET scan results can form the basis for modifying the course of treatment midway through. “So far, studies indicate that PET scans obtained partway through NHL treatment are not informative enough to allow you to customize your treatment for that individual patient,” says Brad Kahl, chairman of lymphoma research at the University of Wisconsin in Madison. There is some evidence that patients with early-stage Hodgkin lymphoma can benefit from treatment tweaks based on interim PET scan results, but so far this has not been the case for NHL. Thus, at this stage, interim PET scans are not recommended as part of routine treatment for NHL, although this is a topic of ongoing research.

	The use of Rituxan (rituximab) and chemotherapy combinations to treat B-cell lymphomas has also muddied the waters, with patients having more false-positive interim PET scan results. Why Rituxan treatment results in fluorodeoxyglucose uptake in the absence of active cancer cells is not entirely clear but seems to be associated with increased inflammation. A new approach to looking at PET scan results could help, as studies have suggested that measuring the difference in fluorodeoxyglucose uptake from one scan to the next decreased falsepositive rates compared with a positive versus negative assessment. Whether the benefits of interim PET scans in NHL will ever outweigh the risks remains to be seen.

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Despite the lack of data to justify them, periodic surveillance PET scans during remission are performed frequently.

What's in a Picture: Scans for Lymphoma Recurrence

“I couldn't understand what they were saying, but I knew something was wrong,” recalls Heather McLean of the technicians who performed an ultrasound of her abdomen in late 2008. She had been coping with stomach pain for five to six years, and when the pain escalated and she began to gain weight, her doctors suspected gallstones. What they found instead was an abdomen full of tumors. A later biopsy revealed stage 4 follicular lymphoma, a slow-growing type of non-Hodgkin lymphoma (NHL) that arises in immune cells called B cells.

	McLean’s cancer was widespread, and after a few months she began experiencing night sweats, one of the so-called “B symptoms” that is associated with more aggressive disease. She started treatment immediately with chemotherapy and Rituxan (rituximab), a targeted antibody drug that selectively eliminates those cancerous B cells. Five weeks later, she was not only in remission but was 25 pounds lighter after shedding the fluid accumulation caused by the cancer.

This past June, five years after remission, McLean’s cancer returned. Indeed, follicular lymphoma is characterized by good responses to treatment, but remissions become shorter with each relapse.

As Heather McLean considers the next move in her battle against follicular lymphoma, she remains optimistic. Photo by Mikelllouise Photography. 

Fortunately, there are multiple options for treating follicular lymphoma that has relapsed after initial therapy, although these are not curative. There are also several investigational drugs currently in clinical trials, which give patients like McLean new options for coping with relapses and living longer with their disease.

NHL is not one disease but a constellation of distinct cancers that arise in the body’s white blood cells—either antibody-producing B cells or infection-fighting T cells. These cancers are broadly divided into slow-growing and aggressive varieties, the most common of which is diffuse large B-cell lymphoma, an aggressive cancer that accounts for about a third of the more than 70,000 new NHL cases diagnosed yearly in the United States.

In the late 1990s, Rituxan revolutionized the treatment of B-cell NHL, curing more than half of patients with diffuse large B-cell lymphoma and substantially extending patient survival when combined with the go-to chemotherapy combination called CHOP, an acronym for cyclophosphamide, hydroxydaunorubicin (also known as doxorubicin or Adriamycin), Oncovin (a brand name for vincristine) and prednisone. But in the decade that followed, there was “radio silence,” says Hans-Guido Wendel, a cancer genetics expert at Memorial Sloan Kettering Cancer Center in New York, noting that Rituxan-CHOP (R-CHOP) remains the standard treatment for these patients today.

The problem with follicular lymphoma, Wendel says, is repeated recurrence and, subsequently, multiple cycles of treatment. Generally, only patients who have early-stage disease at the time of diagnosis can be cured.

“Every time, the tumor gets a little better as the patient’s bone marrow gets worse,” Wendel adds, referring to the cumulative toxicity and immune suppression that accompanies repeated chemotherapy. For these patients and the one-third of patients with diffuse large B-cell lymphoma who aren’t cured with R-CHOP or stem cell transplantation, new treatment options are sorely needed.

For patients with B-cell lymphomas whose disease has progressed after Rituxan-chemotherapy treatment, there are many options, but radioimmunotherapy drugs have proved effective in producing temporary, although sometimes longer, responses. These agents, including Zevalin (90Y-ibritumomab tiuxetan) and Bexxar (131I-tositumomab), combine antibody-based drugs (such as Rituxan) with a radioactive isotope to deliver a lethal hit of radiation directly to the cancer cells. Despite their success, these drugs are seldom used, says Bruce Cheson, head of hematology at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, D.C. He attributes the phenomenon to oncologists’ unfamiliarity with the agents, the necessity of referring patients to specialized radiation doctors or centers, and a small but real risk of secondary cancers. In fact, Bexxar’s maker stopped selling the drug in February due to waning sales.

Efforts to design new drugs, and to test existing ones in new settings, are based on an increasing knowledge of what makes these cancers tick. Scientists have already identified many so-called “signal transduction” pathways that are essential in order for normal B cells to grow, divide and survive, many of which are abnormally revved up in cancer cells. Agents that interfere with these pathways include Imbruvica (ibrutinib), Zydelig (idelalisib), everolimus, Torisel (temsirolimus), alisertib and ABT-199, among others, all of which have shown some activity against B-cell NHL and some of which are already approved by the U.S. Food and Drug Administration (FDA) for NHL or other cancers.

Zydelig was recently approved for patients with follicular lymphoma who experienced a disease relapse after two prior therapies. “[Zydelig] is a pill, which is attractive to patients, and it’s a pill that can work when chemotherapy won’t, which is pretty amazing,” says Brad Kahl, chairman of lymphoma research at the University of Wisconsin in Madison. Indeed, in the study that led to Zydelig’s FDA approval, a benefit was experienced by 54 percent of patients whose follicular lymphoma had not responded to, or had quickly relapsed after, Rituxan-chemotherapy. The drug is not currently an option for McLean, whose cancer initially responded to R-CHOP treatment, but it’s an option for subsequent relapses.

In early studies, participants with many types of B-cell NHL (including about half of those with relapsed follicular lymphoma and two-thirds of those with an aggressive form of B-cell NHL called mantle-cell lymphoma) benefitted from taking the oral drug Imbruvica, which received accelerated FDA approval for mantle cell lymphoma in 2013. Patients with mantle cell lymphoma tend to have shorter-lasting responses to R-CHOP and, until Imbruvica, they had fewer options when they experienced a relapse. Imbruvica was also recently approved for chronic lymphocytic leukemia, a first cousin to NHL.

Efforts are also being made to improve on the results that are possible with Rituxan by instead using different antibody-based drugs that target the same B-cell surface protein but kill the cell in somewhat different ways. These drugs, which include Arzerra (ofatumumab) and Gazyva (obinutuzumab), are being tested in various combinations, but Kahl isn’t sure that any of them will prove superior to Rituxan. Still others work the same way as Rituxan but bind to different B-cell surface proteins like CD19 (MEDI-551), CD22 (epratuzumab) or CD30 (Adcetris [brentuximab vedotin]).

Keeping track of these rapidly accumulating developments can be daunting for patients, particularly when they’re coping with the physical and emotional challenges of cancer treatment. McLean has done a lot of her own research and has kept meticulous records of every treatment, lab test and scan result along the way, something she suggests all patients do. She also joined a support group and was fortunate to befriend a woman who has the same diagnosis. “It’s important for people to find someone to walk with them through the journey, and also to be a detective for you, especially when you’re having a hard time doing things for yourself,” she says, joking that some days during her treatment she considered it an accomplishment to simply take a shower.

McLean is now considering a clinical trial with Imbruvica before undergoing another round of R-chemo with Treanda (bendamustine), an oral chemotherapy drug. Additional options on her list: a combination of Rituxan and the immunomodulatory drug Revlimid (lenalidomide)—a therapy known as R-squared&mdash;and stem cell transplantation.

Clinical trial results have shown that many investigational drugs work better in some types of NHL than in others, a fact that reflects the distinct biology of each NHL subtype. A more thorough understanding of the genetics underlying these cancers may eventually allow the choice of treatment to be tailored to the individual. “There are clinical trials that look at the activation of specific pathways to see if you can predict which patient will respond to which agent,” Cheson says, “but these trials are early in their gestation.”

Early studies have already revealed several tricks that B-cell lymphomas use to stay alive, one of which is expression of unusually high levels of a survival protein called Bcl2. “Most lymphoma cells make too much of this protein, and this sends a signal to the cell that says ‘don’t die,’” explains Kahl, who says he’s excited about ABT-199, a drug that targets Bcl2. Although the drug works only modestly well on its own, it’s now being tested in combination with other agents. “It’s sort of like a one-two punch,” Kahl says, with the ABT-199 crippling the cancer cells’ ability to survive and then chemotherapy or other targeted drugs coming in for the kill.

McLean wants to know the genetics lurking within her cancer cells, particularly after learning recently that two of her ancestors died of chronic lymphocytic leukemia. So far, genetic testing is performed only in the context of clinical studies, but McLean says she would jump at the chance to participate in one of these types of trials.

Regardless of whether the genetics of each patient’s cancer is understood, it’s becoming clear that the real power of these investigational drugs is in their combination, as many patients are learning through successful treatment.

“I thought, ‘if we’re going to battle this thing, let’s really battle it,’” 

	In early 2014, 67-year-old retired engineer Tom Ireland received a diagnosis of stage 4 mantle cell lymphoma, a type of NHL that typically arises in older patients and has an average overall survival rate of five to seven years. Ireland’s treatment options were limited (his age disqualified him from undergoing stem cell transplantation), but he was able to enter a clinical trial of Velcade (bortezomib)—a drug that prevents cells from ridding themselves of toxic protein waste&mdash;in combination with Rituxan and Treanda.

	But combining drugs, which alone are well tolerated, also increases their toxicity. “These agents should not be thrown together higgledy-piggledy,” Cheson says, “because you may get life-threatening or fatal occurrences.” Determining which drugs to combine, and how, means more research and clinical trials, and thus more patients willing to participate.

	Ireland was pleased when he was randomized to the most aggressive arm of his clinical trial, which involved taking a combination of all three drugs. “I thought, ‘if we’re going to battle this thing, let’s really battle it,’” Ireland says. Four months in, his tumors were virtually gone. And although he describes Velcade as a “real kick in the butt,” with side effects including constipation and nausea that worsened with every dose, he says he managed it relatively well.

Tom Ireland was diagnosed with lymphoma and received combination treatment in a clinical trial. Photo by Susan L. Toon.

	Ireland says he’s fortunate to have an oncologist who is savvy about the latest drugs and clinical trials, but many other patients aren’t as lucky. This is where nonprofit organizations, such as the Leukemia & Lymphoma Society and the Lymphoma Research Foundation, can help by identifying potentially relevant clinical trials that patients can then discuss with their oncologists. The groups also educate patients about their specific type of lymphoma and help them develop long-term cancer care plans. The LLS is currently helping Ireland navigate the billing morass involved with his clinical trial.

	Meanwhile, as McLean considers the next move in her battle against follicular lymphoma, she remains optimistic. And despite the uncertainly of wondering whether every twinge or pain has something to do with the cancer, she envisions a future in which NHL is treated as a chronic disease rather than a deadly cancer.

[What's in a Picture? Imaging for recurrence]

> Non-Hogkin lymphoma is a group of cancers, some slowgrowing and some aggressive, that affect white blood cells, compromising the body’s immune system.

> Follicular lymphoma, and in some cases diffuse large B-cell lymphoma, can be marked by repeated recurrences, so researchers aim to develop new drugs and test combination therapies. 

For patients with B-cell lymphomas, new treatments are providing more options.

B-Cell Lymphomas: A Long and Winding Road

Patients with advanced hepatocellular carcinoma (HCC) have poor survival odds and few treatment options. Nexavar (sorafenib), the only approved drug for this population, improves survival by about three months, illustrating the need for more and better options. Unfortunately, the bulk of recent phase 3 clinical trials in advanced HCC have proven no better than Nexavar at markedly improving patient survival.

These trials have included a variety of targeted drugs, including Sutent (sunitinib), which is approved to treat advanced kidney cancer, and investigational agents brivanib and linifanib. Chemotherapy regimens like FOLFOX (folinic acid, 5-FU [fluorouracil] and oxaliplatin), administered either as first-line treatment or after Nexavar stops working, are also being tested. Although it’s easy to simply conclude that nothing works against HCC, researchers need to learn more about its biology to develop better treatments.

Katie Kelley, an oncologist at the University of California, San Francisco, says it is very difficult to interpret the outcomes of these trials due to the inherent complexity of HCC as a cancer that almost always coexists with liver disease, such as cirrhosis or viral hepatitis. First, the early studies evaluating drug safety typically involved subjects who had intact liver function. Thus, the drug doses established by these studies could be much more toxic in patients with HCC who have impaired liver function, which makes it difficult to determine how well a drug works. The early studies also relied on tumor size as a standard of success, which is problematic for HCC, given that treatments such as Nexavar can prolong survival without measurably reducing the actual size of the lesion.

Kelley also points out that HCC is a mixed bag of cancers with diverse causes ranging from viral hepatitis to alcoholrelated cirrhosis, but many clinical trials lump all patients together. This heterogeneity could mask the benefits of a particular treatment in specific subsets of patients. Even with better patient stratification, it is difficult to perfectly match the treatment and control groups based on the cause and extent of disease.

Indeed, a phase 3 trial of Nexavar conducted on participants with advanced HCC in Asia resulted in uniformly lower survival rates and less of a survival benefit compared with a parallel study on participants in Europe and the Americas. Although the explanation is unclear, it’s important to consider that the prevailing cause of underlying liver disease in Asia is hepatitis B infection, while in the Western world it’s hepatitis C.

Thus, these completed trials might not have been for naught, as a closer look at the results according to the cause and extent of patients’ underlying liver disease might illuminate positive responses in particular subsets that were previously lost in the mix. And future studies that take these variables into careful consideration could produce more meaningful, and potentially more promising, results.

Researchers need to learn more about the biology of hepatocellular carcinoma to develop better treatments.

Researchers need to learn more about the biology of liver cancer to develop better treatments.

Finding the Positives in Negative Results

	“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.

	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&mdash;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.

[Read "Finding the Positives in Negative Results"]

	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.

Refined treatments and targeted drugs signal slow yet significant progress for liver cancer.

Heather L. Van Epps, PhD

What's in a Picture: Scans for Lymphoma Recurrence

B-Cell Lymphomas: A Long and Winding Road

Finding the Positives in Negative Results

Gradual Gains in Liver Cancer

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