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Q&A| Kenneth Tanabe Works to Solve the Mysteries of Liver Cancer

While Progress Has Been Relatively Slow, This Noted Expert Sees Reasons for Hope
Jack McCain

Kenneth Kenji Tanabe, MD, is Chief of the Division of Surgical Oncology at the Massachusetts General Hospital (MGH), Deputy Clinical Director of the MGH Cancer Center, director of the MGH Liver Surgery Program, and a Professor of Surgery at Harvard Medical School. His clinical practice focuses on surgical management of patients with liver tumors and patients with melanoma, and he is a member of the melanoma committee of the National Comprehensive Cancer Network. His research laboratory, which has been continuously funded by the National Institutes of Health since 1993, focuses on prevention of hepatocellular carcinoma (HCC) and experimental gene therapy for liver tumors. He is the author or coauthor of more than 100 peer-reviewed scientific articles and 50 review articles and book chapters on melanoma and liver cancer. He received his medical degree from the University of California at San Diego and completed a residency at the Cornell University Medical Center and a fellowship at MD Anderson Hospital and Tumor Institute.

INTRODUCTION

P&T: How did your life and career evolve so that the treatment and prevention of HCC has become one of your chief professional interests?

KKT: When I joined the Massachusetts General Hospital in 1993, the hospital was in need of a liver surgeon. This field has been a constant challenge, as HCC is one of the deadliest cancers, and liver surgery is one of the most challenging operations. The limited efficacy of existing treatments provides a strong rationale to find strategies to prevent the formation of HCC.

Why is liver surgery so difficult?

First, the liver carries a very large amount of blood, and so the risk of bleeding during surgery is substantial—and bleeding can be fatal. Second, unlike other organs, the liver performs many functions that are difficult to replace. For example, dialysis can be implemented when the kidney fails. Similarly, when lungs fail we can provide respiratory function with a ventilator. Even when the heart isn’t working well we have devices and medications that effectively support cardiac function. But when the liver fails there are no substitute devices, so the tolerances are much smaller than with surgery on other organs.

What is the disease burden imposed by HCC, globally and in the United States?

Most patients are diagnosed at an advanced stage (Figure 1) and therefore are not curable, and the treatments are relatively ineffective. Even for patients diagnosed at an intermediate stage, the treatments are relatively ineffective. Only when HCC is detected at the earliest stages do patients have a reasonable likelihood of beating their cancer.

The big problem is that 70% of HCC occurs in patients with cirrhosis, and thus most HCC patients have two diseases—HCC and cirrhosis. So even if you cure a patient of an HCC, they stand a relatively high likelihood of developing additional, new HCCs within their cirrhotic liver. This elevated risk throughout the entire cirrhotic liver is known as a field defect. Cirrhosis and its complications account for 1 million deaths worldwide each year and $4 billion in medical costs in the United States alone. The most common cause of cirrhosis in the U.S. is chronic infection with hepatitis C virus (HCV). In the United States, the total cost from HCV infection is predicted to peak at $9.1 billion in 2024, with peak annual costs for decompensated cirrhosis ($4.2 billion) and HCC ($1.4 billion) predicted to occur in 2025.1

In the United States, HCC is the most rapidly increasing cause of cancer-related mortality. What factors have caused the annual mortality rate for HCC to rise while the annual mortality rates for most other major cancers have been falling?

Between 1975 and 2005 the incidence of HCC nearly tripled. This rise is partially attributable to an epidemic of HCV infection that occurred two to four decades earlier, recognizing that it is generally one to three decades after development of chronic HCV infection that the risk of HCC rises. It is also relevant to point out that adherence to screening guidelines is nowhere close to what it is for, say, breast cancer, and treatments for HCC are not nearly as effective as they are for other cancers, such as breast cancer or colon cancer.

What are the major risk factors for HCC in the United States?

Cirrhosis is the number-one risk factor, and the major causes of cirrhosis are hepatitis C, hepatitis B, and alcohol. Another risk factor that is growing very quickly is nonalcoholic fatty liver disease (NFLD), which is basically driven by obesity. There’s a higher prevalence of HCV in medically underserved populations, but people with HCV come from all walks of life. Obesity is really increasing as a cause of cirrhosis and NFLD, and that’s not just in indigent populations (Table 1).

What is the natural history of HCC?

“Natural history” means the course of disease left untreated. On the one hand, it is now more difficult to define the natural history of HCC because more and more patients undergo some form of treatment. On the other hand, we can still extrapolate from these observations to approximate natural history data because our treatments have only limited efficacy. We also obtain natural history data from watching the disease (in retrospect) up until it is diagnosed. The natural history of HCC is that it grows and then spreads within the liver. Most people die of liver failure because they start out with a compromised liver owing to cirrhosis, and then HCC grows to replace vital liver tissue. HCC also metastasizes to lymph node and bone, and sometimes to brain or lung, but in a large percentage of patients the metastasis occurs within the liver and leads to their demise.

SCREENING

Among the major guidelines, there is no consensus on screening for HCC, with respect to the use of ultrasound and alpha-fetoprotein (AFP). Does the high-sensitivity assay for AFP-L3 look promising?

The high-quality studies that have demonstrated cost-effectiveness of screening have been in hepatitis B virus (HBV) populations in other countries where HBV is endemic. Many experts have extrapolated from those studies to come to their conclusion that screening should be conducted in populations with cirrhosis from causes other than HBV (i.e., HCV, alcohol, or NFLD). The other issue is that in other countries, ultrasound is used extensively and it is often performed by physicians. In this country, ultrasound is performed by trained technicians and the acquired images are reviewed by physicians. It’s not entirely clear that ultrasound screening in the United States would be the equivalent of ultrasound screening elsewhere.

Work coming out of Japan with biomarkers such as AFP-L32 hasn’t gained a lot of traction here because of lack of specificity of this test, even when combined with AFP. Specificity becomes more important in a population that is not as enriched. Our incidence of HCC is substantially lower than that in Japan. Here, tests that lack specificity become extraordinarily expensive. In the United States, AFP-L3 is not yet ready for prime time.

With respect to cirrhosis and HCC, which patients are screened at MGH, and with what tools?

At Mass General, we tend to alternate ultrasound with MRI rather than going with only MRI, which of course would be more costly. It’s very difficult to show that MRI screening is cost-effective, because of the lower incidence of HCC here relative to other countries where HBV is endemic, and because of the higher cost of MRI relative to ultrasound.

What has led you to think that EGF genotype testing should become a routine service provided for patients with cirrhosis?

We published research3,4 showing that individuals with a particular genetic makeup of their epidermal growth factor (EGF) gene and cirrhosis have higher levels of this growth factor in their blood and in their livers. And we have shown that these individuals are at higher risk for developing HCC. We’re trying to get such testing incorporated into routine practice because we know the EGF genotype can discriminate among low-, intermediate-, and high-risk patients. We know that EGF genotypes can supplement clinical data—age, gender, smoking status, clinical values—in increasing the accuracy of risk prediction. But this test isn’t yet covered by insurance, so we’re still trying to figure out how to implement it.

DIAGNOSIS AND PROGNOSIS

How is HCC diagnosed? Which specialties are involved and what happens during the initial workup?

Some patients are detected by screening and some by an incidental finding, which occurs when someone undergoes an ultrasound, CT, or MRI scan for an unrelated reason. For example, a patient with a kidney stone may undergo a scan that also shows a liver mass, or a patient with a lung nodule may undergo CT of their chest that also shows a liver mass.

The initial evaluation is usually done by a primary care physician or a gastroenterologist/hepatologist, or both, but as soon as HCC is suspected the patient is typically referred to a subspecialist for treatment. At Mass General the subspecialists who are recipients of these referrals include transplant surgeons, surgical oncologists, interventional radiologists who perform radiofrequency ablation, interventional radiologists who perform transarterial chemoembolization (TACE), or medical oncologists who may administer chemotherapy. Until five or six years ago, the treatment recommendation may have been biased by the subspecialty to which you were referred. To prevent such biases and improve the quality of care, we developed a multidisciplinary clinic in which subspecialists from all these disciplines are represented to review cases and jointly decide the most appropriate treatment. Commonly, additional staging radiographs are needed (Figure 2), along with serology to determine HBV or HCV exposure and blood tests to determine the severity of any underlying cirrhosis.

Upon diagnosis, what indicates a poor prognosis and what indicates a relatively good prognosis?

Two factors simultaneously govern prognosis. One is the condition of the organ in which the cancer develops. This is unlike most other cancers. For example, the prognosis in breast cancer is determined by tumor-related factors (molecular aggressiveness, molecular genetics, etc.). The function of the remaining breast is completely irrelevant. With HCC, however, the condition of the surrounding cirrhotic liver significantly governs prognosis. For two people with the same tumor, the person with more advanced cirrhosis will have a shorter survival than the person with less advanced cirrhosis. To the extreme, there are some people with very advanced cirrhosis and a small early HCC whose tumor may not be treated at all because their longevity is defined by their rate of tumor progression.

How is liver function assessed?

One of the most common methods to assess liver function is the Child-Turcotte-Pugh (CTP) score, which is a modification of the original Child score that divides cirrhosis into three classes, A, B, and C. C represents the most advanced stage; B, intermediate; and A, the best. The CTP score is the summation of scores representing five parameters of liver function. The scoring system incorporates three laboratory tests, albumin, bilirubin, and INR (international normalized ratio, also known as the prothrombin test), and two clinical factors, ascites and encephalopathy (Table 2).

Do you use the Barcelona Clinic Liver Cancer (BCLC) staging system at MGH or some other staging system?

For the most part, the treatment decisions we make tend to be in line with the BCLC guide (Table 3), but we don’t strictly use BCLC as our guide. We use our own multidisciplinary team discussions, as just described, to assign treatment for each patient, and there are some patients who end up with recommendations that differ from the BCLC guide. For a patient with a single nodule in early stage A, sometimes we would recommend resection and sometimes we would recommend transplantation, and sometimes we might recommend ablation.

The five-year relative survival rate for patients with localized HCC at diagnosis is now 29% (Figure 3)—up from 9% in the mid-1970s. What is responsible for this improvement?

Because of substantially better imaging technology, what we now call “early disease” is much earlier compared with what was labeled “early disease” in the 1970s. In the 1970s, imaging would miss many tumors, whereas now we are able to detect tumors less than 1 cm in size. And tumors that were larger but radiographically indistinct based on 1970s technology can be seen much more clearly with newer imaging technology. Another major improvement has been in the arena of surgery. The safety of liver resections over recent decades has improved significantly. Better selection of patients appropriate for liver transplant has improved outcomes. The advent of better technologies for tumor ablation—namely, radiofrequency and microwave ablation—has enhanced survival and lessened treatment-related morbidity. And overall, matching of patients with appropriate treatments has improved.

TREATMENT

How is HCC treated today? What are the major changes in HCC treatment today compared with the treatment of, say, 20 years ago?

Most patients diagnosed with HCC are candidates for liver resection, liver transplantation, tumor ablation, chemoembolization, or systemic chemotherapy. As mentioned, major changes over recent decades are improvements in surgical techniques, advent of ablation technologies, and improved patient selection strategies. Resection is optimal for patients with a solitary tumor, preserved liver function, and absence of portal hypertension. Ablation is optimal for patients who are not healthy enough for resection because of comorbidities or because of more advanced cirrhosis. Ablation is most effective for tumors less than 3.5 cm in size and limited in number (e.g., no more than two or three). TACE is generally used for patients whose tumors are not amenable to resection or ablation. Transplant is reserved for HCC patients when they have a single tumor no larger than 5 cm in diameter, or if more than a single tumor, no more than three tumors and none larger than 3 cm in diameter. Radiation therapy via protons or photons is a relatively new option that is being explored in the context of clinical trials. Another relatively new development is the use of radiation particles administered internally via the hepatic artery.

What are the chief benefits and limitations of the treatments that, in theory, are curative (surgical resection, ablation, transplantation)?

The primary advantage of transplant is that it simultaneously removes the tumor and replaces the underlying cirrhotic liver with a normal liver. But transplants today still involve waiting for a donor graft, and the patient runs the risk of becoming ineligible for transplant because of cancer progression while waiting. Here in New England, where the wait times are a year and quarter to a year and a half, we need good “bridge” therapies—therapies that will control a tumor long enough until a transplant is available. At MGH the bridge for transplant we use most commonly is ablation. TACE is also used in some cases as a bridge therapy, and a newcomer is proton therapy. It’s in a clinical trial at Mass General (NCT00976898) for patients with unresectable liver tumors; Theodore S. Hong, MD, is the principal investigator.

The primary advantage of liver resection over transplant is that it is a much less complicated operation, does not require wait times for a donor graft, and does not involve lifelong immunosuppression with its attendant complications. The primary advantage of resection over ablation is greater certainty of tumor elimination, but with a greater complication rate than that associated with ablation. Three head-to-head comparisons of ablation and resection have been conducted.57 In two of these clinical trials no difference in survival was detected, whereas in the third clinical trial surgery provided survival statistics superior to ablation.

In the treatment of some tumors, such as breast cancer, adjuvant chemotherapy commonly follows surgery in patients at high risk for recurrence. Why isn’t adjuvant chemotherapy used after liver resection?

Theoretically it makes sense, and several chemotherapy agents have been tested in this setting. But so far, adjuvant chemotherapy with currently available agents after resection hasn’t been shown to be effective in any clinical trials. On one hand you might think that if a drug like sorafenib is shown to prolong survival in patients with advanced HCC, why wouldn’t it be effective in the adjuvant setting? But sorafenib was tested and found to be ineffective as an adjuvant despite its efficacy in advanced disease.

What promising drugs, if any, are in development for treatment of patients with HCC?

In HCC, there have been a lot of negative studies. HCC is in the stage where malignant melanoma was one or two decades ago, when there were a lot of promising phase 2 results that never seemed to pan out in phase 3. But now we have several targeted therapies for malignant melanoma. Everyone is waiting for the similar great breakthrough in HCC. JX594/TG6006 (Pexa-Vec) for HCC is an exciting agent because it’s a novel approach—it’s a live, oncolytic virus, so it’s different from targeted chemotherapy approaches.

PREVENTION

In cardiovascular disease, primary prevention is aimed at preventing the first event (e.g., myocardial infarction), and secondary prevention is aimed at preventing recurrence of that event. But in oncology, there are three levels of prevention. What are they and how do they apply to HCC?

Some oncologists think of primary prevention as preventing the establishment of a modifiable risk factor for a cancer, secondary prevention as addressing that risk factor once it has become established so that cancer does not emerge, and tertiary prevention as preventing the recurrence of cancer in a patient who has undergone successful treatment for the initial tumor. In HCC, primary prevention involves keeping people from getting a risk factor such as cirrhosis, for example via HBV vaccination; secondary prevention prevents people with a known risk factor (e.g., cirrhosis) from developing HCC; and tertiary prevention aims at preventing HCC from developing again in people who already have been successfully treated for HCC.8

There is speculation that delayed tumor recurrences after curative therapy may not represent metastasis of the original tumor but rather are new tumors arising from the cirrhotic liver.9 If this is true, wouldn’t it place a premium on preventing cirrhosis?

It places a premium on two things: first, using interventions that prevent HCC in patients known to have cirrhosis, as opposed to waiting for tumors to develop, and second, preventing the cirrhosis from occurring in the first place. Given that our current therapies for HCC are of limited efficacy, both steps are important.

If cirrhosis is irreversible, unlike fibrosis, should greater attention be paid to identifying patients with fibrosis who are at risk of progressing to cirrhosis and perhaps HCC?

Contrary to what’s considered gospel in many textbooks, there is increasing belief that one can reverse cirrhosis. Of recent, more and more animal studies show the ability to reverse cirrhosis. One of them is our work showing that, in animal models, erlotinib prevents HCC and reverses the process of cirrhosis.10 Focusing on patients with fibrosis to prevent them from getting to cirrhosis is key, and focusing on patients with cirrhosis to prevent them from getting HCC is also key.

Liver fibrosis conventionally has been assessed via biopsy. What are the limitations of that technique? Is there a better way to monitor patients with liver fibrosis?

One problem with biopsy is sample bias—samples can realistically be obtained from only one or two areas because of the risks associated with multiple biopsies throughout the whole liver. And biopsy provides information at a single point in time. Following the course of cirrhosis over time would require repetitive biopsies over time. To biopsy just one spot in the liver involves poking an organ with high pressures that will bleed easily. And biopsy is an invasive procedure. So noninvasive methods to assess the extent of fibrosis and cirrhosis are important to develop. We’ve been working with Peter Caravan, PhD, in the Martinos Center for Biomedical Imaging to use peptide probes that bind to collagen in hopes of being able to noninvasively and repetitively assess cirrhosis with MRI 11 (see Figure 4). Our early results suggest that this approach has much promise.

You are the principal investigator of a pilot study (Table 4) sponsored by the National Cancer Institute (NCT02273362) that began enrolling patients in November 2014 to study erlotinib in patients with cirrhosis. Please explain the goals of this study.

Our long-term goal is to see if erlotinib will slow the progression of cirrhosis or even reverse cirrhosis, as we have seen in animal models.10 In animal models, we used the oncology dose of erlotinib, but that dose is too high for people without cancer to tolerate for long periods. It’s one thing for cancer patients with terminal disease to take a drug with side effects because it will keep them alive longer, but if you were to give the same drug with the same set of side effects to people who are healthy and well and instruct them to take it because it will prevent their cirrhosis from getting worse, compliance would understandably be poor. So we need to figure out the lowest dose of erlotinib that’s effective, with the hope that such low doses are also associated with a tolerable side-effect profile.

We are now launching an early-phase clinical trial to develop an EGFR inhibitor for treatment of cirrhosis and prevention of HCC (NCT02273362). This trial is a dose-finding trial. We want to know the minimum dose at which erlotinib will shut down EGFR signaling in the liver. The only way to do that is to obtain a piece of the liver for baseline measurements, after which patients go onto erlotinib for a defined period of time. Following erlotinib administration, another piece of liver is obtained for analysis to compare with the baseline sample. If EGFR signaling has decreased between the first and second samples, we know the dose of erlotinib was effective.

It is a lot to ask of patients to undergo liver biopsy on two separate occasions solely for research purposes (i.e., perform a biopsy, then administer erlotinib for a period of time, and then perform a second liver biopsy). So we decided to study a patient population that’s already going to the operating room to have a piece of their liver removed. Nearly all these patients will have liver tumors—that’s the reason for the surgery, but that’s not our interest for this particular clinical trial. We’ll plan to perform a single liver biopsy well before the surgery, then administer the erlotinib during the week leading up to the operation, and then obtain more liver as a result of their scheduled operation.

Do drugs such as Sovaldi (Gilead Science’s sofosbuvir) and Harvoni (Gilead’s fixed-dose combination of sofosbuvir and ledipasvir) for treatment of chronic HCV have a role in prevention of HCC?

These drugs are going to have a big impact. They produce a sustained viral response, clearing virus. The peak of HCV health care costs from decompensated cirrhosis and HCC in the United States has been predicted to be around 2025. I would imagine that these drugs will change that. This would be an example of secondary prevention. Sustained viral response will prevent people with early HCV from getting cirrhosis, and that is expected to reduce HCC. In people with established cirrhosis and HCV, it remains to be seen whether sustained viral response will reduce the incidence of HCC.

What would you identify as the top priorities in the United States for the prevention and treatment of HCC?

Because HCC treatments are limited in efficacy, prevention is very important. Identification of individuals at risk for complications of cirrhosis also is extraordinarily important. We have a large cadre of people who don’t even know they have cirrhosis. If you don’t even know you have cirrhosis, you can’t participate in any prevention strategies for cirrhotics that prove to be effective. That’s why I really believe in two of these projects that I’m involved in, drug therapy to prevent HCC in cirrhotics, if not to reverse the process of cirrhosis, and noninvasive imaging to qualitatively if not quantitatively characterize the severity of cirrhosis.

GLOSSARY

Aflatoxin

toxic metabolite and potent carcinogen produced by fungi (Aspergillis parasiticus and A. flavus), normally found in soil and decaying vegetation but also in or on rice, wheat, corn, and peanuts, among other crops, before harvest or during storage. Chronic low-level exposure to aflatoxin is associated with an increased risk of liver cancer.

Allele

one of two or more versions of a gene; people inherit two alleles for each gene, one from each parent. If both alleles are the same, the person is homozygous for the gene; if the alleles differ, the person is heterozygous.

Alpha1-antitrypsin deficiency

inherited disorder resulting from mutation of SERPINA1 gene, which encodes alpha1-antitrypsin. This protein neutralizes neutrophil elastase, an anti-infective enzyme released by white blood cells. Insufficient levels of functional alpha1-antitrypsin lead to elevated levels of neutrophil elastase, resulting in damage to healthy lung and liver tissue; chronic obstructive pulmonary disease and cirrhosis may ensue.

Alpha-fetoprotein (AFP)

a protein normally made by immature liver cells in the fetus. One year after birth, AFP levels drop to normal adult levels. In adults, high blood levels of AFP (more than 500 ng/dL) suggest HCC, cancer of the ovaries or testes, or cancer that has metastasized to the liver. However, AFP is also elevated in patients who are pregnant or have cirrhosis or hepatitis flares. AFP is an inadequate assessor of early HCC because more than 80% of such patients present with AFP levels that are not elevated. A new high-sensitivity assay for AFP-L3 (Lens culinaris agglutin-reactive fraction of AFP) may be useful in some countries for predicting development of HCC,2 though not necessarily in the United States.

Ascites

fluid in the abdomen.

Bilirubin

protein produced by the liver when it breaks down old red blood cells. Hepatic damage is one cause of hyperbilirubinemia, a cause of jaundice.

Autoimmune hepatitis

inflammatory disorder of uncertain etiology. Risk factor for HCC.

Cirrhosis

disruption of functional units of the liver by scar tissue formed by liver fibrosis to the extent that blood flow is restricted and normal liver function is impaired. Scarring occurs as the liver attempts to repair injuries from viruses (e.g., hepatitis B, hepatitis C), chemicals (e.g., alcohol), or fat, among other causes. Generally thought to represent an irreversible injury. Important risk factor for hepatocellular carcinoma (HCC), the main cause of death in patients with cirrhosis.

EGF

epidermal growth factor. Protein that promotes cell growth and specialization. Made by many normal cells and some tumors.

EGFR

EGF receptor. A protein expressed on the cell surface of both normal and cancer cells, to which EGF binds, causing the cells to divide. In some tumor cells, signaling via EGFR plays a role in tumor cell survival and proliferation irrespective of EGFR mutation status. EGFR is found at abnormally high levels on many types of cancer cells, causing them to divide excessively if EGF is present. Erlotinib is an EGFR inhibitor.

Encephalopathy, hepatic

loss of brain function when the liver is unable to remove toxins, owing to cirrhosis, HCC, and other conditions. Clinical grades: 0, minimal (no abnormality detected); 1, mild (shortened attention span, mild euphoria/anxiety); 2, moderate (lethargy, apathy, inappropriate behavior); 3, severe (somnolence, semistupor, confusion); 4, coma.

Erlotinib (Tarceva, OSI Pharmaceuticals)

oral drug for treatment of patients with forms of non–small-cell lung cancer or pancreatic cancer. Blocks EGFR. Initial FDA approval in 2004. Erlotinib reversibly inhibits the kinase activity of EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor and thereby inhibiting further downstream signaling. Erlotinib binding affinity for EGFR exon 19 deletion or exon 21 (L858R) mutations is higher than its affinity for the wild-type receptor. Kenneth T. Tanabe, MD, is the principal investigator of a pilot study of erlotinib to prevent recurrence of HCC in patients with cirrhosis.

Fibrosis

the first stage of liver scarring that can result in cirrhosis, a more serious problem. Unlike cirrhosis, fibrosis may regress or even reverse to normal liver architecture if the underlying cause is addressed, but otherwise fibrosis will progress to cirrhosis.

Future liver remnant (FLR)

a preoperative assessment, performed with computed tomography (CT), to estimate postoperative liver function. In patients without cirrhosis, FLR of at least 20% is recommended; with cirrhosis, at least 30% to 40%.

Hepatic artery

the artery that supplies 30% of the blood volume and most of the oxygen to the liver. The balance is supplied by the portal vein.

Hepatocellular carcinoma (HCC)

the most common form of liver cancer in the U.S., responsible for about 80% of the 33,000 new cases of liver cancer that were expected to occur in the U.S. in 2014. About 90% of HCC cases occur in patients with cirrhosis.

Hereditary hemochromatosis

inherited disorder (mutations in HFE gene) resulting in accumulation of iron in liver and other organs.

Portal vein

the hepatic portal vein (not a true vein) conducts blood from the gastrointestinal tract and spleen to the liver, supplying about 70% of the liver’s blood. The remainder is supplied by the hepatic artery, which also is the main source of blood for HCC.

Prothrombin time, prolonged

prolonged prothrombin time (the time needed in a laboratory test for plasma to clot after the addition of tissue factor) is a finding in liver disease stemming from the liver’s inability to synthesize sufficient amounts of factor VII, a component of the coagulation cascade.

Sorafenib (Nexavar, Bayer Healthcare)

an oral inhibitor of multiple intracellular and cell-surface kinases approved by the FDA in 2007 for treatment of patients with unresectable HCC (initial approval in 2005 for advanced renal cell carcinoma). Currently considered the global standard of care and the only product approved for the first-line treatment of advanced HCC.

TACE (transcatheter arterial chemoembolization)

minimally invasive image-guided treatment that delivers chemotherapy (doxorubicin) directly to liver tumors, along with substances that physically block the blood vessels supplying the tumors.

TAE (transarterial embolization)

delivery of embolic particles without chemotherapy to HCC via a catheter in the hepatic arteries.

Wilson’s disease

inherited disorder resulting in accumulation of copper in liver and other organs.

Figures and Tables

Percentage of Cases of Liver and Intrahepatic Bile Duct Cancer by Stage at Diagnosis

In 2015, about 35,660 new cases of liver and intrahepatic bile duct cancer are predicted to occur in the United States, along with 24,550 deaths from these cancers, with about 70% of these new cases and deaths occurring in men. About 75% of these are expected to be hepatocellular carcinoma. Between 2007 and 2011, incidence of HCC increased by 3.4% per year for both sexes combined, and the death rate increased by 2.5% per year.12,13

Contrast-Enhanced MRI Examination Showing Arterially Enhancing Lesion in Dome of Liver

Five-Year Relative Survival Rates for U.S. Patients With Hepatocellular Carcinoma13

Noninvasive Staging of Liver Fibrosis Using Collagen-Enhanced MRI

The axial image on the left is a nonfibrotic mouse liver per the Ishak staging system for fibrosis and cirrhosis, where 0 = no fibrosis and 6 = probable or definite cirrhosis. The image on the right is a mouse liver with incomplete cirrhosis (Ishak score of 5). The false-color overlay depicts the extent of fibrosis as revealed by a gadolinium-based MRI probe that targets type 1 collagen. The probe (EP-3533) was utilized to noninvasively stage liver fibrosis induced with carbon tetrachloride in a mouse model.

Risk Factors for Hepatocellular Carcinoma

Common risk factors
  • Infection with hepatitis B virus
  • Infection with hepatitis C virus
  • Alcoholic liver disease
  • Nonalcoholic fatty liver disease
Less common risk factors
  • Alpha1-antitrypsin deficiency
  • Autoimmune hepatitis
  • Hereditary hemochromatosis
  • Wilson’s disease
  • Aflatoxin

Child-Turcotte-Pugh Scoring System to Determine Operative Risk via Assessment of Cirrhosis

Parameter 1 Point 2 Points 3 Points
Encephalopathy None Grade 1–2 Grade 3–4
Ascites None Slight Moderate
Albumin > 3.5 g/dL 2.8–3.5 g/dL < 2.8 g/dL
Prothrombin time prolonged 1–4 seconds 4–6 seconds > 6 seconds
Bilirubin < 2 mg/dL 2–3 mg/dL > 3 mg/dL
Bilirubin in primary biliary cirrhosis < 4 mg/dL 4–10 mg/dL > 10 mg/dL

Scoring

  • 5–6 points = Class A (good operative risk, because of early or no cirrhosis)
  • 7–9 points = Class B (moderate operative risk, because of moderate cirrhosis)
  • 10–15 points = Class C (poor operative risk, because of severe cirrhosis)

Median Overall Survival in HCC, by Treatment Appropriate for BCLC Stage14

BCLC Stage Typical Patient Population Treatment Median Overall Survival
Curative Treatments
Very early stage (0)
  • PS 0, Child A (Table 2)
  • Single nodule < 2 cm
  • Normal portal pressure
  • Normal bilirubin
Resection > 60 months (5-year survival, 40%–70%)
Early stage (A)
  • PS 0, Child A–B
  • Single or 3 nodules ≤ 3 cm
  • Increased portal pressure
  • Increased bilirubin
  • No associated diseases
Liver transplantation (CLT/LDLT)
Early stage (A)
  • PS 0, Child A–B
  • Single or 3 nodules ≤ 3 cm
  • Increased portal pressure
  • Increased bilirubin
  • Associated diseases
Radiofrequency ablation or, rarely, percutaneous ethanol injection
Noncurative Treatments
Intermediate stage (B)
  • PS 0, Child A–B
  • Multinodular
TACE or radioembolization 20 months
Advanced stage (C)
  • PS 1–2, Child A–B
  • Portal invasion
  • Regional lymph node involvement (N1)
  • Distant metastases (M1)
Sorafenib 11 months
Terminal stage (D)
  • PS > 2, Child C
Best supportive care < 3 months

BCLC = Barcelona Clinic Liver Cancer; CLT = cadaveric liver transplantation; HCC = hepatocellular carcinoma; LDLT = living donor liver transplantation; PS = Eastern Cooperative Oncology Group performance status (0, fully active; 1, restricted in physically strenuous activity but otherwise ambulatory and able to perform light or sedentary work; 2, ambulatory and capable of self-care but unable to work, up and about > 50% of waking hours; 3, capable of limited self-care, confined to bed or chair > 50% of waking hours; 4, completely disabled, incapable of self-care, totally confined to bed or chair); TACE = transcatheter arterial chemoembolization

Selected Ongoing Clinical Trials of Hepatocellular Carcinoma Prevention*

NCT ID Purpose Intervention Prevention Type Participants Estimated Start/Finish
NCT01798173 Identify environmental, metabolic, and nutritional factors of HCC in cirrhotic patients to better understand mechanisms of carcinogenesis Serum, plasma, DNA samples; CT scan or MRI Secondary, tertiary 1,200 cirrhotic patients with HCC versus cirrhotic patients without HCC June 2008/December 2013
NCT00913757 Identify HCC biomarkers for early diagnosis and prevention Questionnaire; blood and urine samples; samples of tumor and healthy tissue in selected patients undergoing surgery Secondary, tertiary 1,500 patients with HCC or at high risk for HCC because of fatty liver disease (alcohol-or nonalcohol-related) or chronic HCV or HBV May 2009/not specified
NCT01924624 Prevent HCC recurrence via postoperative adjuvant therapy Thalidomide Tertiary 140 patients undergoing surgical liver resection for HCC July 2013/December 2019
NCT02273362 Find lowest dose of erlotinib that blocks EGFR signaling (pilot study) Erlotinib Tertiary 65 cirrhotic patients with HCC scheduled for surgical liver resection November 2014/October 2016
NCT01835938 Phase 1 trial for treatment of chronic HCV infection Erlotinib Secondary 12 patients with chronic genotype 1b HCV infection May 2013/May 2015

*Primary prevention of cancer aims to prevent exposure to risk factors; secondary to prevent cancer development in patients with risk factors; tertiary to prevent recurrence of cancer in patients treated with curative intent.

HBV = hepatitis B virus; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; EGFR = epidermal growth factor receptor

Source: www.ClinicalTrials.gov, accessed November 2014

Author bio: 
The author is a freelance editor and medical writer living in Durham, Connecticut.

References

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