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March 2013 HCV Advocate

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In This Issue:

SVR = Cognitive Improvement
Alan Franciscus, Editor-in-Chief

HCV Snapshots
Lucinda K. Porter, RN

HealthWise: - The Weight of Hepatitis C
Lucinda K. Porter, RN


Liver Cancer in People with Hepatitis C: Part 2–HCC Treatment and Management
Liz Highleyman



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SVR = Cognitive Improvement
—Alan Franciscus, Editor-in-Chief

The staff at the HCV Advocate have written multiple articles on the relationship between the hepatitis C virus and difficulties with cognitive abilities in ourselves, those we love and the general HCV community at-large.  Two excellent articles come to mind—Lucinda Porter’s May 2010 HealthWise:  “Hepatitis C and Brain Fog”  and Dr. Chaim-David Mazoff’s January 2013 article “Brain Fog:  It Really Is All in Your Head.”  Both articles discuss serious problems that many people with hepatitis C experience.  We call it ‘Brain Fog’ which is a cute name, but from my own experience and others I talk with about it, it is anything but a cute or funny condition.  As one of my friends exclaimed:  “This is really scary stuff.”  I have to agree—nothing would be more frightening to me than losing the ability to think clearly, retain information and/or have difficulty with trying to work on multiple tasks (to name a few) that affect your everyday life.

We have written extensively on many ways to help work around memory problems in articles and fact sheets such as “Brain Fog Busters,” which work well to help us to hold it together; but we all want to feel as back to normal as possible.  Now, a study was released that offers hope that with successful HCV treatment cognitive functions affected by the hepatitis C virus can be improved. 

“Improvement of neurocognitive function in responders to an antiviral therapy for chronic hepatitis C,” by Michael R. Kraus and colleagues, released results from the largest study to date to address cognitive functioning pre- and post-HCV antiviral therapy.  The study included 168 HCV patients who were to receive HCV antiviral therapy (pegylated interferon plus ribavirin).  The study participants were recruited from three centers in Germany between 2005 and 2008.  Treatment duration was based on genotype:  genotype 2 and 3 patients were treated for 24 weeks and genotype 1 and 4 patients were treated for 48 weeks.  However, those genotype 1 patients who had a low viral load pre-treatment and who achieved a rapid virological response (undetectable HCV RNA at treatment week 4) were treated for only 24 weeks. 

In the current study the patients were tested for neurocognitive functioning before and after treatment (for at least 12 to 48 months afterwards).  The patients were tested using computer-assisted psychological tests in 4 domains:

  • Alertness:  the reaction time to visual stimulus (white crosses on black background)

  • Divide Attention:  paying attention to multiple tasks (visual and sound)

  • Vigilance:   measures the ability to sustain attention

  • Working memory:  testing short-term memory— numbers appear and disappear on a screen and the person must identify the number when it appears again

HCV Treatment Response:  sixty-nine percent of the patients in the study achieved a sustained virological response (SVR)—that was the combined response for all genotypes. 

Post Treatment Neurocognitive Improvement:  The people who achieved an SVR had significant improvements in neurocognitive performance in vigilance, divided attention (optical) and working memory compared to their tests before being successfully treated.  The results were found to be statistically significant across the three domains (P<0.001). In the group that did not achieve an SVR there were no improvements in cognitive functioning, but neither was there any worsening of cognitive function.  

This study is important for a couple of reasons:

  • Since SVR resulted in improvements in cognitive functioning—those ‘brain fog’ issues people with hepatitis C have been complaining about are real; but we already knew that. 

  • Successful treatment can reverse some of the hepatitis C-related cognitive dysfunction—truly really good news.

The study authors very nicely summed up their findings with their conclusion:  “Successful eradication of HCV leads to a significant improvement of relevant aspects of attentional and neurocognitive performance, indicating that the neurocognitive impairment caused by chronic HCV infection is potentially reversible. This therefore suggests an added therapeutic benefit of antiviral treatment in HCV infection.  Improvement of neurocognitive function may he an additional treatment indication in patients with HCV.”

Source:
Improvement of neurocognitive function in responders to an antiviral therapy for chronic hepatitis C. Kraus MR, Schäfer A, Teuber G, Porst H, Paul K, Wollschläger S, Keicher C, Scheurlen M. Hepatology. 2013 Jan 8. doi: 10.1002/hep.26229. [Epub ahead of print]


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HCV Snapshots:
—Lucinda K. Porter, RN

Article: Interferon for Interferon-Nonresponding and Relapsing Patients with Chronic Hepatitis C – Koretz RL, et al. 
  Source: Cochrane Database of Systemic Reviews, January 2013; 368:34-44
Note: Be sure to read entire Snapshot before drawing conclusions.

This study began with the notion that although sustained virologic response (SVR) is the measure of successful treatment for people with chronic hepatitis C virus infection (HCV), there isn’t a great deal of research supporting this outcome as a gold standard. Further, patients who do not have an SVR are often candidates for retreatment.  Some patients may not be candidates for ribavirin or protease inhibitors. The goal of this study was to see whether interferon monotherapy is safe and effective when used for retreatment of HCV patients

The Bottom Line: Using data from seven clinical trials and 1676 patients who had severe liver damage, the researchers concluded that retreatment with peginterferon (PEG-IFN) does not offer any benefits to patients with serious liver disease, and may have increased risk of harm.

Editorial Comment: I am a fan of the Cochrane Reviews because they are evidence-based and unbiased. However, this study disturbs me because I have seen several headlines that distort the data. Example: “Interferon May be Harmful in Retreatment of Hepatitis C.” This makes me think that interferon could hurt me. The study isn’t saying this—it is saying interferon alone  (with no protease inhibitor or ribavirin) may be harmful.

Also, the study looked at patients with severe liver damage. The headline would be more accurate if it read, “ Interferon-monotherapy May be Harmful in Retreatment of Hepatitis C for Those with Severe Liver Damage.”

An even worse headline was, “Interferon Therapy for Hepatitis C Offers Little Benefit.” Granted, often the headlines are written by someone other than the journalist, but this is horrendous. Don’t draw conclusions from a headline.

 

Article: Hepatocellular Carcinoma Surveillance at 4- vs.12-Month Intervals for Patients With Chronic Viral Hepatitis: A Randomized Study in Community – Wang JH, et al.
  Source: American Journal of Gastroenterology Advanced online publication January 15, 2013

The purpose of this study was to compare liver cancer screening intervals among patients with viral hepatitis and low platelets (an indicator of cirrhosis). This study occurred in Taiwan, where 744 subjects were randomly assigned to liver cancer surveillance using ultrasound procedures every 4 months; 357 were screened every 12 months. In a 3-year period, the incidence of liver cancer was roughly the same in both groups.

The Bottom Line: The tumors were smaller in the 4-month surveillance group when seen by ultrasound. However, despite early detection, the four-year survival rate was the same for both groups.

Editorial Comment: In the U.S., ultrasound screening for liver cancer detection in hepatitis C patients is usually recommended every six months for HCV patients with cirrhosis and stage 3 fibrosis. Screening for hepatitis B patients occurs much earlier, without the presence of cirrhosis.

 

Article: Vitamin D for Your Patients with Chronic Hepatitis C? – Rahman A and Branch A
  Source: Journal of Hepatology January 2013 Volume 58, Issue 1, Pages 184-189
Although not technically a research article, this piece uses basic science for clinical application. 

The article begins by discussing vitamin D deficiency in patients with hepatitis C. There is growing evidence suggesting the vitamin D supplementation might protect against liver disease progression and help improve treatment response. There is insufficient research on this, including optimal vitamin D dosing. The authors recommend, “Until clinical data are available, 4000IU/day is a reasonable daily dose for patients with baseline 25(OH)D levels below 10ng/ml and 2000IU/day is an appropriate starting dose for patients with levels between 10 and 20ng/ml.”

The Bottom Line: Vitamin D may help to protect against progression of liver disease and improve response to antiviral therapy in HCV patients.

Editorial Comment: Talk to your medical provider before taking large doses of vitamin supplements. Vitamin D levels can be measured by a simple blood test. Vitamin D levels tend to be lower in older adults and people of all ages who have limited sun exposure.

 

Article: Integrating Phylodynamics and Epidemiology to Estimate Transmission Diversity in Viral Epidemics – Magiorkinis G, et al.
  Source: PLOS Computational Biology January 2013 Volume 9, Issue 1

These so-called super-spreaders of hepatitis C were the subject of a study at Oxford in which researchers collected data from studies on four hepatitis C epidemics in Greece, as well as 100 genetic sequences from frozen plasma samples, and then used a mathematical model to estimate when and how the people in the studies were infected with hepatitis C.

This study used data and plasma samples collected from 943 patients during four hepatitis C epidemics in Greece from 1996 and 2006. Using genetic sequencing and a mathematical model, they estimated how long it took for HCV to spread to others. They found that HCV-positive intravenous drug users (IDUs) are likely to infect around 20 other people, and about half of these occur within the first two years after the original person contracts this virus.

The Bottom Line: This research identified patterns among IDUs that may help to prevent further HCV transmission. The researchers observed that people tended to transmit HCV to others early after acquiring HCV. This research may have huge benefits in the public health HCV-prevention arena.

Editorial Comment: When this research was published, the term, “Super-Spreaders” was used in the headlines and news articles.  The HCV Advocate feels strongly about not using this phrase, feeling that HCV and injection drug use are both highly stigmatized enough without adding the term, “Super-Spreaders” to the lexicon.


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HEALTHWISE: The Weight of Hepatitis C
—Lucinda K. Porter, RN

If I could gather up all of the hepatitis C (HCV) viral particles and put them on a scale, I wonder what they’d weigh. Sometimes HCV feels heavy, like it weighs a ton. During those heavy moments, I re-evaluate my HCV treatment decision, asking myself, “Treat now, or wait?” As someone who has been through treatment twice, I am anxious to be rid of HCV, but seasoned enough to know that I want my next attempt to be my last.

Treat now or wait is a popular topic, especially with many potential HCV treatments in the pipeline. (See Hepatitis C Treatments in Clinical Trials for current listings.) Reviewing articles on this debate, I was particularly drawn to the following:

  • Patients with HCV and F1 and F2 Fibrosis Stage: Treat Now or Wait? by Mitchell L. Shiffman and Yves Benhamou (Liver International Jan 2013; Volume 33, Supplement 1)

  • Therapeutic Algorithms for Chronic Hepatitis C in the DAA Era During the Current Economic Crisis: Whom To Treat? How To Treat? When To Treat? by Salvatore Petta and Antonio Craxi (BMC Infectious Diseases Nov 2012; Supplement 2)

  • The Waiting Game by Alan Franciscus (HCV Advocate Sep 2012)

Let’s start with a summary of these points of view. In the first article, Shiffman and Benhamou begin by pointing out that the current standard of care (SOC) for the majority of HCV patients (genotype 1) includes peginterferon (PEG-IFN), ribavirin (RBV) and either boceprevir or telaprevir. These combinations have challenging side effects. With interferon-free drugs in the pipeline, does it make sense for patients to wait?

Shiffman and Benhamou report that combination therapies with more tolerable side effects and fewer pills are in phase 3 clinical trials (simeprevir and faldeprevir). Although both use PEG-INF/RBV with similar efficacy rates, they have fewer side effects. Other drugs are just behind, such as the polymerase inhibitor, sofosbuvir. Sofosbuvir is being tested in interferon-free and PEG-IFN/RBV clinical trials.

Shiffman and Benhamou make the following points:

  • The argument for treating now: Current HCV treatments are effective, with cure rates around 70-75%, and in certain populations 80-90%. They do recommend aggressive side effect management for those who choose this option.

  • The argument to wait for future protease inhibitors, such as simeprevir and faldeprevir (used with PEG-IFN/RBV): With phase 2 clinical trials yielding 70-85% cure rates, more tolerable side effects (less anemia), and fewer pills, it may be worth waiting. Expected to be out late 2013 or 2014. Note: I don’t know what the cost will be, but I expect the cost to be high.

  • The argument to wait for future polymerase inhibitors, such as sofosbuvir. With PEG-IFN/RBV, the side effects are similar to those with just PEG-IFN/RBV. With cure rates hovering at 90% and treatment lengths of 12 to 24 weeks, this may be worth waiting for. Expected to be out mid to late 2014. Note: I don’t know what the cost will be, but I expect the cost to be high.

  • The argument to wait longer for interferon-free treatment: There are quite a few interferon-free therapies in phase 2 and 3 clinical trials. The results from previous studies are promising, but larger studies are needed. Among genotype 1 patients, the highest predictors of response rates are for IL28B genotype CC, genotype 1B, and those without cirrhosis, respectively.

  • With good treatment already for genotypes 2 and 3, Shiffman and Benhamou suggest that these patients would do well either way. They suggest that genotype 4 patients get treatment now. 

Shiffman and Benhamou discuss the reality that HCV is a progressive disease. The more liver damage, the less likely patients are to eliminate HCV. Many clinicians have been telling their patients to wait, and during that time, liver fibrosis increases and chances of responding to treatment decreases. 

Shiffman and Benhamou express concern that as we wait, we decrease our odds of being cured. They summarize with this:

  • Treat the following now: Non-black, low viral load, IL28B genotype CC, fibrosis 0-2, treatment-naïve, prior relapse, prior partial response 

  • Delay treatment for the following: Black, high viral load, IL28B genotype TT, fibrosis 3-4, prior null response, contraindication or intolerance to interferon

Their recommendations are substantially different from what many providers suggest, which is to treat patients with fibrosis 3-4 now and earlier stages can wait. Let’s see what Petta and Craxi recommend. 

Taking some of the same factors into consideration, Petta and  Craxi look at the issue from a different perspective. They note the scarcity of resources and the burden that HCV places on health care by the sheer volume of patients needing treatment during a time of economic crisis.  Although Petta and Craxi utilize a European healthcare system, their concerns are globally relevant.

Petta and Craxi use a creative approach. Looking at response rates for genotype 1 patients, they recommend using combination PEG/RBV without a third drug as first-line therapy in non-cirrhotic patients with IL28B CC genotype or in those who achieve RVR. Boceprevir or telaprevir would be used for the remaining patients who qualify. Note that this recommendation is an opinion, and not supported by the American Association for the Study of Liver Diseases HCV Practice Guidelines.  Although I am uncomfortable with their recommendations, their article opens up the discussion, allowing us to look outside the box.

Leaving that discussion aside, Petta and Craxi recommend that responder-relapsers and those with advanced disease (fibrosis 3-4) be treated now. Previous null responders and those with mild disease can wait. Everyone else falls in a gray area. In short, Petta/Craxi and Shiffman/Benhamou are completely opposite on the fibrosis stage. They are in agreement on delaying treatment for prior null responders and treating prior responder-relapsers now.

Let’s hear the opinion of a non-clinician—HCV advocate, Alan Franciscus. He begins his editorial by referring to a previous editorial (2010) in which he expressed, “the earlier, the better” approach. Alan then launches into a well-considered discussion, acknowledging the complexity of the decision. His bottom line:

  • The decision needs to made with a medical provider. (Let’s face it, Alan is conscientious.)

  • Consider treatment now: People who have factors that could increase HCV disease progression or lower chances of achieving a cure in the future. Examples: Fibrosis stage 2 or higher; older age, especially for those who were above age 40 at time of infection; presence of fatty liver disease; high viral load

  • Those who could delay treatment: Those with minimal liver damage (stage 0-1, maybe early stage 2). He points out that those who have less damage and who are younger are more likely to respond to current therapy.

In short, Alan’s opinion spans the other researchers’ recommendations. However, as an advocate, Alan touches on another area—what to do while waiting. He suggests looking ahead and “planning for the day when the newer treatments are available.  Investigate your medical insurance coverage, support and work-related issues.” He also recommends making changes that would increase your chances of being cured, such as improving fitness and nutrition.  Lifestyle changes are also helpful to those who don’t eliminate HCV.

Although it is helpful to have these perspectives, the decision to wait or seek treatment now is not entirely rational. I am influenced by how encumbered I feel by HCV. Lately I have felt more burdened, not because of HCV symptoms so much as by what I can only describe as the “ticking time bomb” syndrome. I just passed the twenty-fifth anniversary of having HCV, I am turning sixty this year, and recent liver biopsy results jumped to a higher level than I had anticipated.

You may wonder why I would want to wait, knowing that current triple therapies have fabulous success rates, particularly for someone such as myself who was a responder-relapser to PEG-IFN/RBV. There are many factors, but the bottom line is cost. Because of HCV, I am uninsurable and my HIPAA policy basically covers catastrophic costs.  HCV treatment is way beyond my budget. In the meantime, I am looking for a clinical trial or waiting for better insurance under the Affordable Care Act, whichever comes first. 

In the meantime, it is Alan’s words about what to do while waiting that resonate most with me. Waiting is not a passive act—it is an opportunity to prepare myself for both the present and the future. Like an athlete preparing for a race or a soldier preparing to do battle, I too want to be at my best for this next event.

Lucinda K. Porter, RN, author of Free from Hepatitis C is a long-time contributor to the HCV Advocate. Her blog is http://lucindaporterrn.com

Further Information:


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Liver Cancer in People with Hepatitis C: Part 2–HCC Treatment and Management
—Liz Highleyman

Over years or decades, chronic hepatitis B or C can lead to advanced liver disease including cirrhosis and hepatocellular carcinoma (HCC), a type of primary liver cancer. While HCC remains among the most difficult-to-treat cancers, there have been some encouraging developments in recent years.

This article discusses treatment options for HCC, focusing on targeted molecular therapy. Part 1, in the February 2013 HCV Advocate, looked at HCC risk factors, screening, and hepatitis B and C treatment for preventing liver cancer.

Types of Treatment
Liver cancer is not easy to detect since people typically do not show symptoms during early stages. Often diagnosed at advanced stages, HCC is difficult to treat and survival is generally measured in months.

HCC is classified as localized resectable (single tumors that can be surgically removed), localized unresectable (cancer that cannot be removed due to liver damage or other reasons), or advanced (cancer that has metastasized or spread throughout the liver or to other parts of the body).

The five broad HCC treatment approaches involve surgically removing tumors (resection), liver transplantation, local therapies that destroy cancerous tissue, traditional systemic chemotherapy, and targeted molecular agents. Both the extent of cancer and an individual’s liver function and overall health determine appropriate treatment options; often a combination approach is most beneficial.

Surgical resection and liver transplantation are considered potentially curative. Non-curative therapies can slow diseases progression and prolong survival. Chemoembolization is considered standard-of-care for intermediate non-resectable liver cancer, while the targeted molecular drug sorafenib is the standard for advanced HCC.

Resection and Transplantation
People with small (<5 cm) localized tumors and mild-to-moderate liver damage making up approximately 15% of HCC patientsmay be eligible for resection, or surgical removal. Because the liver can regenerate itself, a large segment or even an entire lobe can be safely removed (partial hepatectomy). Tumor removal offers the best odds of a cure, with five-year survival rates up to about 70%. Malignant cells may be left behind, however, and recurrence is common.

People with small tumors and little or no metastasis may be eligible for a liver transplant. Transplantation has a high rate of success, with an overall five-year survival rate of around 75%. But hepatitis C patients do not fare as well as people receiving liver transplants for other reasons, and opportunities for transplantation are limited by high cost and the shortage of suitable donor organs.

Localized Therapies
About one-third of people with HCC, who have cancer that is confined to the liver but not fully resectable, may be candidates for localized or regional ablation therapies that shrink or destroy tumors in place. Methods include burning, freezing, chemical poisoning, and radiation.

Radiofrequency ablation (RFA) uses an electrical current to superheat tumors; similar methods use microwaves or lasers. Freezing, or cryosurgery, applies liquid nitrogen to tumors. Poisoning uses toxic substances to destroy cancer cells.

Percutaneous ethanol injection involves injecting ethyl alcohol into a tumor through the skin; acetic acid (concentrated vinegar) or heated saline solution may also be used.

Transarterial chemoembolization, or TACE, uses a catheter to deliver chemicals into the hepatic artery supplying tumors; TACE agents include cisplatin (Platinol), doxorubicin (Adriamycin or Doxil), or zinostatin stimalamer, administered with lipiodol (iodized poppyseed oil) or via drug-emitting beads.

Radioembolization is a similar technique using small particles containing yttrium-90 or other radioactive isotopes (SIR-Spheres or TheraSpheres).

Embolization interferes with blood flow to tumors and enables longer, more focused exposure of cancer cells to drugs or radiation, while sparing nearby healthy tissue which can rely on circulation from the portal vein.

Systemic Chemotherapy
Traditional systemic chemotherapy using cytotoxic agents such as cisplatin, doxorubicin, docetaxel (Taxotere), or fluorouracil (5-FU or Efudex) generally does not work very well–or for very long–against HCC. These agents are administered via intravenous infusion and can have severe side effects that may be particularly difficult for patients with advanced liver disease.

To date, randomized clinical trials of systemic chemotherapy have not shown significantly improved survival for people with advanced HCC. Newer agents of this type–including gemcitabine (Gemzar) and oxaliplatin (Eloxatin)–continue to be studied, especially in combination with targeted agents.

Targeted Molecular Therapy
Targeted molecular therapy, which interferes with specific biochemical processes that play a role in cancer development, is a major focus of recent research. Many targeted agents are kinase inhibitors that disrupt chemical signaling pathways, often by binding to receptors for molecules that promote tumor growth.

Anti-angiogenesis agents that interfere with blood vessel development are particularly relevant because HCC is a highly vascular cancer that requires an extensive blood supply.

Some promising targets include epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), serine/threonine protein kinases, and the hepatocyte growth factor receptor known as MET or c-MET.

Sorafenib (Nexavar) is a multi-targeted inhibitor–active against VEGFR, PDGFR, and some serine/threonine kinases–that interferes with both blood vessel and tumor growth. In 2007 the U.S. Food and Drug Administration (FDA) approved sorafenib as a treatment for unresectable HCC, and it is currently the only approved drug for this indication.

The Phase 3 SHARP trial compared 400 mg twice-daily oral sorafenib vs placebo in 602 patients with advanced HCC (mostly due to HCV or alcohol). Participants who were randomly assigned to receive sorafenib experienced slower cancer progression. Median survival was significantly longer in the sorafenib group than in the placebo group (10.7 vs 7.9 months), with a 31% relative reduction in mortality.

However, only 2% of sorafenib recipients experienced partial response (none had complete response), and response may be temporary because HCC can develop drug resistance. In addition, most sorafenib recipients experience treatment-related adverse events–including dermatological reactions affecting the hands and feet–underlining the need for more effective and better-tolerated therapies.

Brivanib (formerly BMS-582664) is another multi-kinase inhibitor that interferes with VEGFR and FGFR. Although it showed evidence of efficacy in Phase 2 studies, its promise has not been confirmed in later trials.

The Phase 3 BRISK-PS trial, presented by Joseph Llovet from Mt. Sinai School of Medicine at the 2012 EASL International Liver Congress, compared 800 mg once-daily oral brivanib vs placebo in 395 people with advanced HCC (mostly due to HBV or HCV) who were unable to take or progressed despite using sorafenib.

Brivanib did not significantly lengthen survival compared with placebo overall (9.4 vs 8.2 months) or for any patient subgroup. But researchers did see improvement in secondary endpoints indicating anti-tumor activity. Brivanib recipients had half the rate of disease progression (22% vs 44%), significantly longer time to progression (4.2 vs 2.7 months), and were six times more likely to experience partial response (12% vs 2%). Similar proportions of patients experienced serious adverse events in both the brivanib and placebo arms (63% vs 57%).

Another Phase 3 trial, BRISK-FL, compared the safety and efficacy of brivanib vs the standard-of-care sorafenib. As Phillip Johnson from the University of Birmingham reported at the 2012 AASLD Liver Meeting, the study enrolled 1155 participants with advanced HCC with no prior systemic treatment. They were randomly assigned to receive 800 mg once-daily brivanib or 400 mg twice-daily sorafenib.

Overall median survival was 9.5 months in the brivanib arm vs 9.9 months in the sorafenib arm, and median time to progression was 4.2 vs 4.1 months, neither difference being statistically significant. However, more brivanib recipients achieved partial response (12% vs 8%) while more sorafenib recipients experienced disease progression (16% vs 24%). Both brivanib and sorafenib were difficult to tolerate, with more than half of patients experiencing serious adverse events; quality of life declined in both arms, but significantly more so with brivanib.

Another study, presented at AASLD 2012 by Ivan Borbath from Cliniques Universitaires Saint-Luc in Brussels, evaluated tivantinib (formerly ARQ 197), a selective tyrosine kinase inhibitor of MET. In this Phase 2 trial, 107 patients with unresectable HCC were randomly assigned to receive 240 or 360 mg twice-daily oral tivantinib or placebo, but the higher dose was reduced after some participants developed neutropenia.

Overall survival (6.6 months with tivantinib vs 6.2 months with placebo) and median time to progression did not differ significantly. But benefits were greater for patients with high MET expression. Within this subgroup, overall survival was 7.2 months with tivantinib vs 3.8 months with placebo, while time to progression was 2.7 vs 1.4 months. Frequency of adverse events was similar, except tivantinib recipients were more likely to experience blood cell deficiencies.

Other oral targeted molecular agents that have been evaluated for HCC treatment include the dual VEGFR/PDGFR inhibitors linifanib (ABT-869), pazopanib (Votrient), and sunitinib (Sutent), the VEGFR/MET inhibitor cabozantinib (Cometriq), and the EGFR inhibitors erlotinib (Tarceva), gefitinib (Iressa), and lapatinib (Tykerb). Monoclonal antibody targeted inhibitors include bevacizumab (Avastin), cetuximab (Erbitux), and ramucirumab (IMC-1121B). Many of these drugs are already FDA-approved for other types of cancer, meaning clinicians are allowed prescribe them off-label for liver cancer.

While several of these agents have demonstrated some promise in early trials, improvements in survival and partial response rates have been small, and some have had safety issues.

As with brivanib, the Phase 3 SUN 1170 trial found that sunitinib demonstrated anti-tumor activity but did not work as well as sorafenib and was associated with more adverse events, leading to early cancellation of the study. Likewise, a Phase 3 trial of linifanib vs sorafenib showed similar overall survival, but linifanib was not as safe and the study was terminated prematurely.

Most trials to date have looked at targeted molecular agents in people with advanced liver cancer that is not suitable for surgical resection. Some recent research is investigating whether drugs such as sorafenib or combination regimens might work better if started at earlier stages.

Other Experimental Approaches
Given how difficult HCC is to treat, researchers have explored a wide range of other potential therapies. Among these are

  • immune-modifying agents such as interferons and interleukins;
  • hormonal therapies; the vitamin A analog peretinoin;
  • and a genetically engineered poxvirus dubbed JX-594 designed to destroy cancer cells.

HMG-CoA reductase inhibitors, better known as statins, are usually used to manage high cholesterol but also have anti-inflammatory effects and may slow cancer progression.

The mTOR inhibitors everolimus and sirolimus, usually used as immunosuppressants to prevent organ rejection, also inhibit angiogenesis.

Combination Therapy
As with many diseases, combination therapy for liver cancer may be more effective than single treatments–though not surprisingly combination approaches can also increase adverse effects. Common combinations include surgical resection followed by chemotherapy or radiation, traditional systemic drugs plus targeted molecular agents, and combinations of targeted drugs that inhibit different kinases. In some cases ablation, chemotherapy, or radiation may shrink tumors enough to allow successful resection or keep people alive long enough to receive a transplant.

More is not always better, however. The SEARCH trial, presented by Andrew Zhu at the 2012 European Society for Medical Oncology Congress, tested 400 mg twice-daily sorafenib plus either 150 mg once-daily erlotinib or placebo in 720 patients with advanced HCC. Participants taking combination therapy had more side effects but there were no significant differences in overall survival or time to progression.

Looking to the Future
HCC is likely to remain difficult to treat for the foreseeable future, but prospects are improving. Liver cancer prevention has also improved with widespread hepatitis B vaccination and development of direct-acting antiviral agents for hepatitis C.

Treatment for HCC is much more successful if tumors are detected early. People with advanced liver fibrosis or cirrhosis–and, according to some experts, individuals with chronic HBV or HCV infection even without extensive liver injury–should undergo regular liver cancer screening.

In an overview of liver cancer research at EASL 2012, Jordi Bruix from the University of Barcelona stated that sorafenib had “changed the view of liver cancer as an impossible cancer to treat.”

That view should become increasingly optimistic with the development of new targeted agents, use of combination therapy, and genetic profiling that enables individually tailored treatment.

References

  • Borbath, I. et al. Randomized Controlled Phase 2 Study (RCT) with Tivantinib in pre-treated hepatocellular carcinoma (HCC): Efficacy, Safety, and MET-analysis. 63rd Annual Meeting of the American Association for the Study of Liver Diseases. Boston, November 9-13, 2012. Abstract 114.
  • Cabrera, R. Systemic Targeted Therapy Beyond Sorafenib. Clinical Liver Disease 1(6):212-. December 2012.
  • Cheng, A. et al. Phase III Trial of Sunitinib (Su) versus Sorafenib (So) in Advanced Hepatocellular Carcinoma (HCC). 2011 American Society of Clinical Oncology Annual Meeting. Chicago, June 3-7, 2011. Abstract 4000.
  • Fang, P. et al. Efficacy and Safety of Bevacizumab for the Treatment of Advanced Hepatocellular Carcinoma: A Systematic Review of Phase II Trials. PLoS One 7(12):e49717. December 19, 2012.
  • Heo, J. et al. Sequential Therapy With JX-594, A Targeted Oncolytic Poxvirus, Followed by Sorafenib in Hepatocellular Carcinoma: Preclinical and Clinical Demonstration of Combination Efficacy. Molecular Therapy 19(6):1170-1179. June 2011.
  • Johnson, S. et al. Brivanib (BRI) versus Sorafenib (SOR) as First-line Therapy in Patients with Unresectable, Advanced Hepatocellular Carcinoma (HCC): Results from the Phase 3 BRISK-FL Study. 63rd Annual Meeting of the American Association for the Study of Liver Diseases. Boston, November 9-13, 2012. Abstract LB-6.
  • Llovet, J. et al. Brivanib versus Placebo in Patients with Advanced Hepatocellular Carcinoma (HCC) Who Failed or Were Intolerant to Sorafenib: Results from the Phase 3 BRISK-PS Study. 47th International Liver Congress. Barcelona, April 18-22, 2012. Abstract 1398.
  • Llovet, J. et al. Sorafenib in Advanced Hepatocellular Carcinoma. New England Journal of Medicine 359(4):378-390. July 24, 2008.
  • Villanueva, A. et al. Medical Therapies for Hepatocellular Carcinoma: a Critical View of the Evidence. Nature Reviews - Gastroenterology & Hepatology 10(1):34-42. January 2013.
  • Zhu, A. et al. SEARCH: A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Sorafenib Plus Erlotinib in Patients with Hepatocellular Carcinoma (HCC). 37th European Society for Medical Oncology Congress. Vienna, September28-October 2, 2012. Abstract LBA2.



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2013 Hepatitis C Support Project

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