Megan+Kohn

** Introduction **
Hepatocellular carcinoma ranks in the top five of the most common causes of cancer related death worldwide. Moreover, the incidence of this malignancy in the United States has increased threefold over the past twenty years. Unlike a number of other diseases, the underlying causes of liver cancer are well known, which should make it easy to screen for and potentially prevent, but the lack of access to healthcare in the United States and elsewhere has hampered this effort. There exist a litany of treatment options for hepatocellular carcinoma, as well; however, the five year survival rate in the United States is less than 20%. The underlying molecular mechanics of hepatocellular carcinoma are under vigorous study, but due to the complexity of its pathogenesis to date, only one form of molecular therapy is known to show some effectiveness at treating this cancer. By shadowing a patient named Peter Goodwin, much can be learned about hepatocellular carcinoma, including how it is diagnosed, treated, and hopefully ultimately defeated.

** Diagnosis and Etiology of Hepatocellular Carcinoma ** “It looks like my twenties have finally caught up to me, huh?” mutters Goodwin sarcastically after his physician explained to him the results of the liver CT scan. Peter Goodwin, a 53-year old Caucasian male who has lived in California his whole life, works as a truck driver for Western Express Trucking Company. A few weeks ago, Goodwin thought he was finally living on “easy street:" he had obtained affordable California health insurance, witnessed his son’s high school graduation, and celebrated his birthday drinking a few beers and watching basketball with his family and friends. Physically, he felt fine. True, he was fifty pounds overweight, but he reassured himself that most men his age had at least a slight gut. Unfortunately, Goodwin was brought down to earth, rather abruptly, after his first appointment with his new primary care doctor.

As with every new patient, his physician performed a physical, probed into Goodwin’s family medical history, and ordered routine blood tests. Other than being obese, with a body mass index (BMI) of 30, his physician felt that this new patient was in reasonably good health. Cancer did not run in his family, but Goodwin mentioned that his father was an alcoholic. Goodwin’s bloodwork revealed a few abnormalities frequently found in overweight Americans: mildly elevated fasting blood sugar levels and high cholesterol. It also uncovered a more disconcerting discovery, a low platelet count of 80 x 10^3/microliter (a normal platelet count is 150-450 x 10^3/microliter) raising a concern that Goodwin might have an underlying liver disease. As a result, his doctor ordered additional tests, which divulged a more ominous condition: Goodwin was positive for hepatitis C.

Goodwin’s physician, after obtaining additional history, is able to determine the source of his hepatitis C infection. He subsequently develops a treatment plan and recommends that Goodwin undergo testing to determine the extent of his liver disease. With further prodding, Goodwin admits to intravenous drug use in his early twenties and states he shared needles with others. However, he insists that he has been drug free for over thirty years. Goodwin’s doctor urges him to exercise, to watch his diet, and to lose weight. Most importantly, the physician stresses the absolute avoidance of alcohol because obesity and alcohol usage magnify the damaging effects of the hepatitis C virus on the liver. Ultimately, a fibroscan, also called ultrasound-based elastography, demonstrates that Goodwin has an early stage of cirrhosis. This imaging procedure determines the extent of liver fibrosis and cirrhosis and is noninvasive, unlike a liver biopsy. To further delineate the severity of Goodwin’s liver disease, an upper endoscopy was performed and showed small esophageal varices, a common complication of cirrhosis. Esophageal varices are enlarged dilated veins that lie close to the inner surface of the esophagus and are prone to ulceration and severe bleeding. Even more ominous, his ultrasound displayed a three centimeter mass in his liver. Subsequently, a liver CT scan confirmed the presence of hepatocellular carcinoma. Goodwin, although originally oblivious, is battling cancer.



Hepatocellular carcinoma is a cancer of the liver often linked to chronic liver disease and cirrhosis. Cirrhosis is a buildup of scar tissue in the liver. In most circumstances, scarring is a normal component of the body’s healing process, but in the case of the liver, exposure to toxins, for example from excessive alcohol consumption, can damage the organ, leading to fibrosis. Continued liver damage will produce diffuse fibrosis and attempts by the liver to regenerate lead to nodular formations. Ultimately, the normal liver architecture is destroyed, and it no longer functions properly; this condition is called cirrhosis. 75 to 85 percent of hepatocellular carcinomas occur in conjunction with cirrhosis.



Hepatocellular carcinoma is one of the most prevalent cancers worldwide and common factors associated with its development are aflatoxin B1 exposure and, as noted previously, cirrhosis stemming from any cause including excessive ongoing alcohol consumption and non-alcoholic steatohepatitis (NASH). Exposure to aflatoxin B1, which is produced by the fungus [|//Aspergillus flavus//] and found in grains, rice, and peanuts, is a source of hepatocellular carcinoma particularly in areas of Africa. Mozambique has the highest incidence of hepatocellular carcinoma in the world—143.7 cases out of 1 00,000 persons per year—and this is felt to be due to the ingestion of foods stored without refrigeration under hot humid conditions, where the molds producing aflatoxin flourish. While alcohol abuse is common worldwide, it is particularly prevalent in Europe and the United States and excessive a lcohol use can lead to cirrhosis and ultimately hepatocellular carcinoma. Moreover, wealthy countries such as the United States have seen an explosion in obesity, which in turn has led to an increase in the development of NASH—fat deposits in the liver due to obesity—and this may have damaging effects on the liver progressing to cirrhosis as well.

Another source of this cancer is chronic hepatitis B infection with or without cirrhosis. Hepatitis B is endemic in Eastern Asia and sub-Saharan Africa. Worldwide, there are an estimated 250 million hepatitis B carriers. Hepatitis B can be spread by exposure to blood or body fluids from infected individuals, and this can occur as a result of intravenous drug use involving the sharing of needles. Prior to the early 1970’s, the decade in which tests were first developed to screen blood donors for chronic hepatitis B, it was possible to contract the infection from blood transfusions. However, the more common mode of viral infection from hepatitis B is through sexual intercourse and perinatal transmission. Immunization against hepatitis B began over 20 years ago, but in developing countries, especially those in sub-Saharan Africa, hepatitis B vaccination is a not a common practice because it is prohibitively expensive, and the incidence of hepatocellular carcinoma in these regions is quite high as a result.

Hepatitis C associated with cirrhosis is another leading cause of hepatocellular carcinoma, and according to //UpToDate// “in 2005, more than 185 million people worldwide had hepatitis C infection.” As with hepatitis B, hepatitis C in the past was frequently acquired from blood transfusion. In 1992, screening tests for hepatitis C were developed, greatly decreasing the risk of blood transfusion related hepatitis C. However, most cases of hepatitis C in the United States are the result of needle sharing and intravenous drug abuse, as in the case of Peter Goodwin. Since it takes about thirty years to develop hepatocellular carcinoma from hepatitis C, many people were initially exposed to the virus during the 1960’s and 1970’s. Of note, 30 to 50 percent of patients in the United States diagnosed with hepatocellular carcinoma are infected with hepatitis C and hepatocellular carcinoma associated with hepatitis C is currently one of the fastest rising causes of cancer related death in the United States.

As with all cancers, treatment and prognosis for hepatocellular carcinoma is determined by a number of factors including the size of the tumor at the time of diagnosis, but with liver cancer, the severity of the underlying liver disease must also be taken into consideration. Since hepatocellular carcinoma most frequently occurs with cirrhosis, patients with hepatocellular carcinoma frequently have not one, but two potentially life threatening conditions. Therefore, the severity of the underlying cirrhosis has implications in regard to treatment options for the cancer. The median survival following diagnosis of this cancer is approximately 6 to 20 months, and the five year overall survival rate for patients diagnosed with any stage of liver cancer is about 15%. However, a patient’s chance of survival in increased to between 50 and 70%, if the hepatocellular carcinoma is diagnosed and treated at an early stage.

Peter Goodwin, like many patients with hepatitis B and C, was not aware that he had chronic liver disease and that it was putting him at risk for developing liver cancer. Even though he lacked symptoms, he was fortunate that he did have at least one sign of liver disease—a low platelet count. This can be due to the impact of the hepatitis C on the bone marrow, which may lead to decreased platelet production. Also, patients with liver disease often have an enlarged spleen which sequesters platelets, removing them from the blood circulation. It was serendipitous that the doctor noticed the low platelet count which lead to the cascade of tests resulting in the eventual discovery of his hepatocellular carcinoma. If his physical exam had been conducted later or his platelet count had been normal, it is possible his cancer would have been larger or his cirrhosis more severe at the time of diagnosis.

On the other hand, Peter Goodwin’s case illustrates the struggles of those who lack health insurance, specifically because his cancer potentially could have been prevented. Although Goodwin’s hepatitis C infection may be attributed to his previous risky behavior (his intravenous drug abuse in his youth), Goodwin’s cirrhosis could have been avoided if his liver disease had been detected earlier. If he had access to health insurance and healthcare at an earlier age, prompt detection of the virus might have been possible for Goodwin and others like him. Currently, since individuals who have hepatitis C often are asymptomatic, the U.S. Preventive Services Task Force, strongly recommends that all individuals who were born between 1945 and 1965 be screened for its presence. Although, a prior knowledge of the presence of hepatitis C does not necessarily prevent cirrhosis and hepatocellular carcinoma, patients who are diagnosed with hepatitis C are strongly advised to exercise, lose weight, and abstain from drinking alcohol. If Goodwin had followed these entreaties at an earlier age, his chances of developing cirrhosis would have sharply declined. Without cirrhosis, Goodwin would not have developed hepatocellular carcinoma. Also, antiviral therapy for hepatitis C has been available dating back to the late 1980’s. Initially these treatments had limited effectiveness and multiple side effects, but therapy for this infection has progressively improved over time. Currently there is antiviral medication for hepatitis C that can completely eliminate the virus and cure the disease. However, treatment for the virus from the beginning has been extremely expensive, and therefore not an option for the uninsured. Unfortunately for Goodwin, his prior lack of access to basic healthcare services contributed to his contraction of hepatocellular carcinoma.

At this juncture, Goodwin’s primary care doctor refers him to an oncologist, who assumes responsibility for Goodwin’s ongoing cancer therapy. While Goodwin is still finding it hard to believe he really has cancer, he slowly realizes that he is starting a new chapter in his life; one that will be marked by frequent and ongoing appointments with healthcare professionals. At times, he feels depressed and scared, as he contemplates the possibility that he might die from this disease. At other moments, he feels optimistic, reassuring himself that he is relatively young and strong. He vows to win this battle and is eager to move forward with treatment. Goodwin, ready to embark as soon as possible on this scary and uncertain journey, requests that he be seen by the oncologist at the earliest opportunity.

** The Molecular Maze of Hepatocellular Carcinoma ** Hepatocellular carcinoma, like many other neoplasms, results from a multistep process leading to genetic anomalies: a progression of mutating blows is required to initiate the cancer, but the set of mutations may differ drastically from patient to patient. While a handful of mutated genes are deemed to be associated with hepatocellular carcinoma, it is often difficult to deduce whether each correlated mutation is a driver mutation or a passenger mutation. In other words, it is felt that some of the genetic mutations seen in the setting of hepatocellular carcinoma may not actually trigger the disease, but instead are affiliated in some way with the cancer inducers. Nevertheless, the genes associated with hepatocellular carcinoma illustrate numerous cancer hallmarks including sustaining cell proliferation, resisting cell death, activating invasion and metastasis, reactivating telomerase, and establishing a micro tumor environment. Hopefully, with further research, scientists will be able to deduce the exact genetic mechanisms underlying this cancer and use these discoveries to develop targeted therapies to treat patients with hepatocellular carcinoma, like Peter Goodwin.

Proliferation is a key component of all cancers including hepatocellular carcinoma. The hepatocyte growth factor receptor c-Met is often overexpressed in patients with hepatocellular carcinoma, and this increased frequency is likely involved with the proliferation and growth of liver tumors. The receptor c-Met triggers the signaling pathway Ras/Raf/MEK/ERK which consists of a chain of protein kinases that are activated via phosphorylation. Activation of this pathway allows for the transcription of important proteins that are involved in cell division or proliferation. In the presence of increased c-Met, growth factors are more likely to bind to the c-Met receptor, thereby maintaining the activation of the pathway and encouraging the cell to continue to proliferate. Furthermore, hepatocellular carcinoma is also strongly associated with the over-activation of the Wnt/β catenin pathway. Wnt pathways play a role in the expression of genes that are critical for cell growth including cytoskeleton development. It appears that dysregulation of this pathway is due to a mutation of CTNNB1 (gene that encodes for β-catenin) or AXIN1 genes. Ordinarily, AXIN1 genes code for a protein that functions as a negative regulator by inhibiting the Wnt signaling pathway and inducing apoptosis. Not surprisingly, mutations in AX1N1 problematically and unintentionally design a cell that is invincible: it can never die and it will never stop burgeoning. Abnormalities in the Wnt/β catenin pathway are especially pronounced in patients with hepatitis C related hepatocellular carcinoma, occurring in up to 30% of the cases. Unfortunately, thus far, it has been difficult to find pharmaceuticals that effectively target the Wnt/β catenin pathway. However, there are several therapeutic agents currently being tested in drug trials that target the c-Met pathway.

Normal cells are collectivists who care about the overall health of the cellular community; therefore, they are willing to risk death in order sustain the constitution of the body, and they do this through the use of factors such as tumor suppressor genes. On the other hand, cancer cells lack this essential team player mentality—instead they play to win and to be the victor. Patients with hepatocellular carcinoma often have a mutation in the tumor suppressor gene TP53, which, in its normal capacity, halts the cell cycle in the presence of DNA damage and activates DNA repair or even apoptosis (programmed cell death), if the genetic damage is extensive. Peter Goodwin may have obtained the TP53 mutation due to his hepatitis C infection, since mutations in TP53 are often caused by aflatoxin exposure, hepatitis B, and hepatitis C. According to Nishida and Goel, nitric acid, which is induced by inflammatory cytokines such as TNF-alpha and IFN-gamma in chronic hepatitis C virus infections, causes mutations in cancer related genes including TP53. The gene TP53 normally functions as a repairman for the cell: if DNA damage occurs due to ionizing radiation, for example, TP53 will halt the cell cycle and allow for proteins to repair the genetic injury. Conversely, if a mutation occurs in TP53, the repair mechanism is no longer available to fix the genetic error, and this injury potentially could promote the survival and proliferation of the cancer cell. Notably, 20.8% of patients with hepatocellular carcinoma show a mutation in TP53. Furthermore, MDM2 (murine double minute 2), which regulates TP53 through a negative feedback loop, is overexpressed in some hepatocellular carcinomas, promoting the ubiquitination or inactivation of TP53. Studies evaluating mutations affecting the MDM2 and TP53 genes suggest that these mutations do not usually occur in the same tumor. Whether the mutation directly affects TP53 or indirectly affects it through MDM2, once functional TP53 is compromised, the cell will not undergo programmed cell death.

Invasion and metastasis are other key defining components of cancer. Hepatocellular carcinoma is epithelial in origin, and employs epithelial-to-mesenchymal transition (EMT) to invade other areas of the body incognito. Transcription factors, such as Snail, Slug, and Twist, regulate the EMT process. In hepatocellular carcinoma, an overexpression of Snail contributes to the continual activation of EMT, which allows the cancer to enter the extracellular space, lymph nodes, and blood stream, thereby giving it the ability to traverse the body. Matrix metalloproteinases (MMP) assist in the invasion process by breaking down impediments, such as the extracellular matrix, that inhibit mobility. The increased transcription of MMP-9 and MMP-2 in hepatocellular carcinoma patients most likely allows the cancer to invade and metastasize at a faster rate. MMP-9 and MMP-2, in turn, seem to be associated with a targeting protein called Xenopus kinesin-like protein 2 (TPX2). This protein regulates spindle formation and controls microtubule branching and nucleation. The TPX2 gene displays increased expression in hepatocellular cancer cells as well as in many other carcinomas. Several studies have shown that a knockdown of TPX2 reduces cancer cell invasion and leads to decreased expression of the MMP’s. In a study conducted by Huang et al., patients found to be positive for TPX2 expression were more likely to have tumors with vascular invasion and cancers associated with a shorter length of survival. As a result, it is thought that TPX2 could serve as a prognostic marker for hepatocellular cancer patients in the future.

Epigenetic alterations in hepatocellular carcinoma may also contribute to invasion and metastasis. Epigenetic mutations do not alter genetic information, but instead change chromatin structure or regulate gene transcription through methylation and histone modification. In hepatocellular carcinoma, hyper-methylation of CpG islands—repeated cytosine and guanine base pair sequences at DNA promoter regions—are associated with decreases in the transcription of the CDH1 gene that codes for E-cadherin. E-cadherin is an essential protein that detects other E-cadherin proteins on adjacent cells and prevents uncontrolled cell growth and proliferation. In other words, it acts as a tumor suppressor. The CDH1 gene that codes for E-cadeherin is hyper-methylated in 49% of patients with hepatocellular carcinoma. Another cell adhesion molecule called dihydropyrimidinase-like 3 (DPYSL3) is down regulated in many hepatocellular carcinoma patients due to hyper-methylation of its promoter region as well. DPYSL3 is expressed in normal tissues including the brain, retina, and liver. In several studies, patients with reoccurring metastatic hepatocellular carcinoma display lower levels of DPYSL3. In vitro experiments reveal that a knockout of DPYSL3 causes invasion and metastasis. Hyper-methylation of these genes occurs not only in hepatocellular carcinoma, but also in premalignant conditions associated with this cancer, including cirrhosis and hepatitis B and C, which suggests that hyper-methylation may play a role in the origin of the cancer.

Cancer cell lines are immortal, and one way they are able to evade death is through the reactivation of the telomerase enzyme. In patients with hepatocellular carcinoma, the enzyme sirtuin (SIRT1) is often overexpressed. SIRT1 is involved in numerous metabolic processes as well as tumorigenesis. Since, SIRT1 is directly linked to the transcription of telomerase (TERT), as SIRT1 levels rise, TERT levels ascend simultaneously. Data from studies reveal that SIRT1 controls histone modification and methylation of the TERT promoter, thereby regulating the expression of the enzyme. Telomerase adds additional telomere sequences (junk sequences) to the ends of chromosomes enabling endless cell division. Normally cell division is limited due to the erosion of telomere ends and the eventual deletion of important genes with each cycle of DNA replication. The reactivation of telomerase due to the over-expression of the TERT gene allows for the development of hepatocellular carcinoma. Conversely, depletion of SIRT1 inhibits proliferation of hepatocellular cancer cells due to cell aging and apoptosis. Developing drugs to target SIRT1 pathways may prove to be another means with which to control hepatocellular carcinoma growth and spread.

Hepatocellular carcinoma thrives in an inflammatory microenvironment; an environment essential for sustaining angiogenesis and proliferation of the cells making up the tumor. Hepatic cancer arises in the setting of liver damage and regeneration, which involves inflammation. This inflammatory microenvironment consists of stromal fibroblasts, endothelial cells, and infiltrating immune cells including T and B cell lymphocytes and macrophages. Immune cells, in particular, produce cytokines, which can encourage or prevent tumor growth. One of the most common cells found in the liver cancer microenvironment is the CD4+ T helper lymphocyte. This lymphocyte produces two cytokines labeled as Th1 cytokine and Th2 cytokine. Increased levels of Th1 cytokines and decreased levels of Th2 cytokines, in the setting of hepatocellular carcinoma, are associated with a poor prognosis. Tumor associated macrophages (TAM) are another subset of immune cells found in the hepatocellular carcinoma microenvironment. TAMs produce tumor-promoting growth factors, cytokines, and chemokines and these too encourage cancer growth and proliferation. High levels of TAM have also been associated with a poor prognosis in hepatocellular carcinoma patients.

A number of inhibitors targeting molecular pathways known to be important in the development of hepatocellular carcinoma are currently undergoing clinical trials. At this time, however, the only chemotherapeutic agent approved for use in the treatment of hepatocellular carcinoma is the multi-kinase inhibitor Sorafenib.

** Treatment and Prevention of Hepatocellular Carcinoma ** There are a variety of treatment options for hepatocellular carcinoma. However, most of the targets explored in the discussion on the molecular basis of hepatocellular carcinoma have yet to be exploited. The only systemic chemotherapeutic agent proven to be effective against hepatocellular carcinoma, to date, is Sorafenib, and it is reserved for use in patients that have failed other therapies or have no other options for treatment available to them at the time of diagnosis, due to the advanced stage of their cancer. Most patients are treated with more conventional therapies, and one of these is liver transplantation, which offers the best chance for a cure of the disease.

Hepatocellular carcinoma cells display high levels of heterogeneity and as a result of this diversity, it has been very difficult to target hepatocellular carcinoma with drug therapy. Currently Sorafenib is the only molecular agent known to effectively treat liver cancer. It is used in patients who have intermediate or advanced stage hepatocellular carcinoma. Germano, et al. states that Sorafenib is “a novel signal transduction inhibitor that blocks tumor cell proliferation by targeting the Raf/MEK/ERK signaling pathway and exerts an antiangiogenic effect by targeting the tyrosine kinases of vascular endothelial growth factor receptor VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor PDGFR-beta.” Therefore, Sorafenib acts on the Ras/Raf/MEK/ERK pathway, mentioned during the discussion on the molecular basis of hepatocellular carcinoma, which is activated by c-Met and is involved in transcription of important proteins that participate in cell division and proliferation. Conversely, VEGF receptors play a role in hepatocellular carcinoma by triggering angiogenesis or the formation of blood vessels around a tumor; angiogenesis ensures that nutrients and oxygen are available to the cancer. Sorafenib, by blocking the effects of Ras/Raf/MEK/ERK and VEGFR, helps to decrease cell viability and trigger apoptosis. Two randomized phase III placebo-controlled studies showed a median survival of 10.7 months with Sorafenib compared to 7.9 months with the placebo. This equates to a 37% increase in overall survival. Of note, Goodwin’s cancer has been diagnosed at an early stage, and he is not a candidate for treatment with Sorafenib.

In all forms of cancer, staging of the disease is very important, since the treatment offered to a given patient depends on the stage of the cancer. The Barcelona Clinic Liver Classification system is the staging schemata most frequently used to delineate treatment options and assess prognosis for patients with liver cancer. It takes into consideration the number and size of cancer nodules, cancer symptoms, and liver function. Liver function is determined by another classification system called Child-Pugh. Patients with early-stage hepatocellular carcinoma, BCLC 0 or BCLC A, normally display a single, solitary tumor in the absence of vascular invasion, and treatments for this stage include surgical resection, radio-frequency ablation, and transplantation. Patients are considered to have intermediate-stage hepatocellular carcinoma (BCLC B) when they have mild cirrhosis and no symptoms due to the cancer, but have more than three lesions or a single lesion larger than 5 cm. Similar to BCLC A, BCLC B also lacks the presence of vascular invasion or extrahepatic spread. The principle treatment recommended for this stage is trans-arterial chemoembolization (TACE). Patients with vascular invasion are classified at the BCLC C stage and are treated with Sorafenib. Finally, patients with metastasis have BCLC D stage, do not benefit from any of the treatment options already mentioned, and have 1 year survival rate of 10%.

During his initial visit with his oncologist, the stage of his cancer, his treatment options, and his prognosis are revealed to Peter Goodwin. In his case, he has a three centimeter mass located at the periphery of his liver, and he has mild liver cirrhosis at the time of diagnosis. Ultimately, this places him in a Child-Pugh A cirrhosis category with early stage BCLC A hepatocellular carcinoma. Given the stage of his cancer Goodwin is offered the treatment choices of either radio-frequency ablation or liver transplantation. He is not a good candidate for surgical resection despite the early stage of his cancer, because he has underlying cirrhosis with portal hypertension. Portal hypertension is an elevation in the blood pressure present in the portal vein, which is a major source of blood flow to the liver, and it is caused by scarring and nodule formation seen with cirrhosis, which creates resistance to blood flowing through the liver. Portal hypertension lead to the formation of esophageal varices that were seen on the upper endoscopy Goodwin received to determine the severity of his liver disease.



Surgical resection and radio-frequency ablation are treatments offered to patients with early stage BCLC 0 or BCLC A hepatocellular carcinoma. Resection involves the removal of small portions of the liver. This treatment is normally reserved for patients with tumors 3 cm or less in size, who have preserved liver function without portal hypertension, since removal of a portion of a cirrhotic liver increases the risk of liver failure. Radio-frequency ablation (RFA) is the best treatment option for patients ineligible to receive surgical resection or transplantation, perhaps due to underlying cirrhosis or because their tumors may be too large at the time of diagnosis, and it involves the use of electrodes. Using ablation procedures, it is possible to fully remove a tumor 2 centimeters in size with tumor-free margins, similar to those attained with surgery. Studies comparing ablation with surgical resection have shown no significant differences in overall or recurrence free survival, with both procedures having 5 year survival rates around 70%. Unfortunately both also have recurrence rates at 5 years as high as 70% as well. The reason for the high recurrence rate is due to the fact that following surgical resection and RFA, chronic liver disease still persists, and this is the source of hepatocellular carcinoma to begin with.

The best chance for cure of hepatocellular carcinoma is liver transplantation, since it not only eliminates hepatocellular carcinoma, but also expunges the underlying cirrhosis. Unfortunately, the majority of patients have advanced disease at the time of diagnosis and are not eligible for transplant. In order to qualify for liver transplantation, patients must meet a set of guidelines called the Milan criteria which include: one tumor less than five centimeters in size or up to three lesions less than three centimeters in diameter, no vascular invasion, and no extrahepatic spread. A major problem exists in regards to liver transplantation, however: there is a large demand for livers and a limited supply of donors. In order to deal with this, liver transplant lists are used to allocate the organs, and the primary way in which this is done is through the use of the Model for End-Stage Liver Disease (MELD) criteria. This criteria uses a scoring system which includes the use of total bilirubin values (the higher the bilirubin, the worse the liver function), creatinine levels (a measure of kidney function), and INR (a measure of clotting function) to determine the severity of the patient’s liver disease. These criteria predict the mortality risk for patients with hepatic dysfunction, but they were not developed to predict the risk of death in patients with both hepatic dysfunction and liver cancer. Therefore, patients with hepatocellular carcinoma are assigned additional MELD points, and as a result, may qualify for an available liver before someone who has cirrhosis without hepatocellular carcinoma. Even with this advantage, however, many patients have tumor growth and progression while waiting for a liver, and ultimately have to drop off the eligibility list due to increase in tumor size or metastasis. However, in patients fortunate enough to receive liver transplantation for hepatocellular carcinoma, at 5 years, the overall survival rate is 75%, and the rate of cancer recurrence is less than 15%.

After discussing the various forms of treatment for hepatocellular carcinoma with his oncologist, Peter Goodwin decides to pursue liver transplantation. He meets the Milan criteria for a liver transplant, since he has a solitary tumor that is less than 5 centimeters in diameter. In addition, in order to qualify for liver transplant, Goodwin must refrain from drinking alcohol for six months before he is placed on the transplant list and must remain alcohol free for good. Once he receives his liver transplantation, he will need to continue immunosuppressive medication to prevent liver rejection for the rest of his life.

A number of controversies surround liver transplantation for hepatocellular carcinoma. Normally, in order for a patient to become eligible for a liver transplant, his tumor must be greater than two centimeters in diameter. A moral dilemma emanates from this strict limitation: if the patient has a tumor one centimeter in size, is it better to pursue an alternative treatment method or should a patient wait until the tumor grows larger in order to reach eligibility? In most cancers, the earlier the treatment, the better the prognosis. Even so, if the patient decides to receive treatment through resection or radiofrequency ablation, he will no longer qualify for a liver transplant since cancer will no longer be present. Furthermore, even if a patient is placed on a liver transplant list, he is not guaranteed a liver. With the lack of donors, it can take months or even years for a patient to finally reach the top of the list and receive an organ. Unfortunately, this interim allows the cancer to continue to grow, and it is not uncommon for patients to start with a tumor two centimeters in size, only to be dropped from the transplant list after their tumor grows to six centimeters. Schlachterman, et al. estimates that the risk of a patient being dropped from a liver transplant list due to disease progression approaches 25% at 1 year.

For patients that have intermediate stage BCLC B hepatocellular carcinoma, trans-arterial chemoembolization or TACE is the recommended form of treatment. Patients with a large single nodule (ideally less than 5 cm) or those with multifocal hepatocellular carcinomas without evidence of vascular invasion or metastasis, who have preserved liver function, normally receive TACE. TACE involves the injection of chemotherapy drugs into the hepatic artery. Radiologists use CT scans to pinpoint the exact location to inject the chemotherapeutic regimen, normally doxorubicin or cisplatin. The chemotherapy injection is followed by the addition of embolizing particles to promote artery blockage. TACE exposes the tumor to cytotoxic agents, but also obstructs the hepatic artery which supplies nutrients to the carcinoma. The average median survival of patients receiving trans-arterial chemoembolization is about sixteen to twenty months.

While Peter Goodwin waits for a compatible liver to become available, much to his dismay, his tumor does show evidence of growth, causing him many sleepless nights, and ultimately his physician recommends that he undergo a treatment modality called “downstaging.” TACE is most commonly used to downstage or decrease the size of the tumor and prevent cancer progression, so that the tumor size continues to meet the Milan criteria in patients waiting for transplant. This practice is particularly prevalent in the United States, where waiting time on the transplant list frequently exceeds 6 months. Ultimately, Goodwin is one of the lucky few to receive a new liver, when after 13 months, he moves to the top of the transplant list and a compatible liver becomes available.

Unfortunately, the majority of hepatocellular carcinomas are discovered at an advanced stage, which is why the overall survival rate at 5 years for this cancer is only about 15%. At the time of diagnosis most patients do not qualify for surgical procedures due to tumor size, tumor number, and poor underlying liver function and must settle for palliative therapy, which can include RFA, TACE, and chemotherapy with Sorafenib. Strategies designed to decrease the mortality associated with hepatocellular carcinoma should focus on prevention and early detection, and since the underlying causes of liver cancer are known, it is imperative that immunization, screening, and treatment for hepatitis be offered to those at risk for the disease. As mentioned previously all people born between 1945 and 1965 should be screened for hepatitis C. Patients born in areas of the world known to be endemic for hepatitis B (such as Southeast Asia) should undergo testing as well. All patients found to be carriers of these viruses should be offered treatment, since effective therapy for both hepatitis B and C now exists. Immunization against hepatitis B should be strongly encouraged worldwide. Finally, those patients known to have chronic liver disease or cirrhosis should receive a screening ultrasound of their liver every 6 months, in an attempt to identify tumors when they first crop up and are still at a curable stage.

** Conclusion ** Treatment of hepatocellular carcinoma requires a multi-disciplinary approach involving surgeons, oncologists, gastroenterologists, and interventional radiologists, and the choices that must be made by clinicians and patients can at times seem overwhelming. Despite the availability of a myriad of treatments for liver cancer, the reality is that most of these are not options for patients with advanced disease at the time of diagnosis, and the prognosis for this population remains bleak. Moreover, the only treatment option that offers a chance for a cure is liver transplantation, but the shortage of organs for transplant makes choosing this treatment route risky as well. The other forms of treatment are frequently associated with recurrent disease and high mortality rates. This reinforces the importance of immunizing against and treating those who have viral hepatitis, promoting healthy life styles to prevent obesity and development of non-alcoholic steatohepatitis, and discouraging the excessive use of alcohol. However, the real hope for the future in regard to treatment of early and advanced disease involves the targeting of molecular pathways involved in the development and progression of hepatocellular carcinoma, and Sorafenib represents the first step forward in the use of molecular therapy.

//** Aperçu **// // Your past bad behavior, specifically intravenous drug abuse, was a leading force to your contraction of hepatocellular carcinoma, but do not berate yourself too much! How could you have known that cancer was the future consequence of your past indiscretions? Fortunately, you have been given a second chance as a liver transplant recipient, and you must do everything in your power to protect your new liver. Stay conscientious: meticulously take your immunosuppressive medications, diligently schedule your future doctor appointments, stringently avoid alcohol, and rigidly exercise. Most of all, forget the past and focus on the present. Live each day as if it is your last and be thankful for the gift of life you have received. //