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Journal of Clinical Oncology, Vol 23, No 13 (May 1), 2005: pp. 2892-2899 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.196
Hepatocellular Carcinoma: The Need for ProgressThe University of Texas M.D. Anderson Cancer Center, Houston, TX
Massachusetts General Hospital, Dana-Farber/Partners Cancer Care, Harvard Medical School, Boston, MA Hepatocellular carcinoma (HCC) is a malignancy of worldwide significance and has become increasingly important in the United States. HCC is currently the fifth most common solid tumor worldwide and the fourth leading cause of cancer-related death.1 Eighty percent of new cases occur in developing countries, but the incidence is increasing in economically developed regions, including Japan, Western Europe, and the United States.2,3 The worldwide distribution of HCC and its associated etiologies is summarized in Table 1. Liver cirrhosis is the seventh leading cause of death in the world and the 10th most common cause of death in the United States, and is acknowledged as a premalignant condition for developing HCC.4,5 In the United States, hepatitis C virus (HCV), alcohol use, and nonalcoholic fatty liver disease are the most common causes of cirrhosis.4,6-8 Approximately 18,000 new cases of HCC are projected to occur in the United States in 2005,9 however, the incidence of HCC has doubled during the period from 1975 to 1995 and continued to rise through 1998.10 This trend is expected to continue because of the estimated 4,000,000 hepatitis C–seropositive individuals in the United States and the known latency of HCC development from the initial HCV infection, which may take two to three decades.11 It is also known that nonalcoholic fatty liver disease–associated cirrhosis is increasing in the United States.12-14 Clearly, HCC represents a looming epidemic for which the medical oncology community is largely unprepared.
Many excellent reviews summarize the status of treatment options for this disease.15-20 Table 2 lists the principal treatment modalities available. Despite the many treatment options, the prognosis of HCC remains dismal. A majority (70% to 85%) of patients present with advanced or unresectable disease. Even for those patients who undergo resection, the recurrence rates can be as high as 50% at 2 years.49-51 In 1997, a meta-analysis evaluated the results of 37 randomized clinical trials of systemic and regional chemotherapy in 2,803 HCC patients and concluded that nonsurgical therapies were ineffective or minimally effective at best.48 Most published studies of systemic chemotherapy report response rates of 0% to 25%, and systemic chemotherapy has never been shown to prolong survival in patients with HCC.
The majority of HCC occurs in patients with liver cirrhosis and consequent hepatic dysfunction, which complicates safe administration of systemic therapy and poses a challenge to conducting clinical trials in this patient population. Hepatocellular carcinoma is a heterogeneous disease in terms of etiology and underlying associations as well as biologic and clinical behavior. The underlying liver dysfunction, aggressive nature of the disease, lack of general consensus regarding treatment, and lower incidence in the United States contribute to the challenges of studying and developing effective systemic therapies for HCC. In an effort to identify the perceived obstacles to more productive clinical research in HCC, a planning meeting was held in San Francisco in January 2004, concurrent with the first annual American Society of Clinical Oncology (ASCO) gastrointestinal (GI) Cancers Symposium, jointly sponsored with the American Gastroenterological Association, American Society for Therapeutic Radiology and Oncology, and Society for Surgical Oncology. The outcome of this session was identification by the participants (including medical and surgical oncologists, diagnostic and interventional radiologists, and gastroenterologists from throughout the United States, Asia, Canada, and Europe) of what were believed to be the key impediments to productive HCC research. This review briefly summarizes the biology of HCC as it relates to the development of new treatment options, and lists the key challenges identified by the participants at the ASCO GI Cancers Symposium HCC Meeting that must be met to advance clinical research in this important malignancy. HCC BIOLOGY: KEY MOLECULAR AND GENETIC ABERRATIONS HCC develops commonly, but not exclusively, in a setting of liver cell injury, which leads to inflammation, hepatocyte regeneration, liver matrix remodeling, fibrosis, and ultimately, cirrhosis. The vast majority of HCC worldwide (80%) is attributed to hepatitis B virus (HBV) and HCV, but other risk factors include alcohol abuse, hemochromatosis, fatty liver disease, androgenic steroid use, and other metabolic disorders. The mechanisms by which these varied etiologies lead to cirrhosis and HCC are not well understood. Hepatic carcinogenesis is likely due to both direct effects of the underlying liver insult, and indirectly to hepatocyte inflammation and regeneration. An estimated 60% to 80% of HCC arises in the setting of cirrhosis, but a moderate number of patients do not have cirrhosis in the background. Nearly every carcinogenic pathway is altered to some degree in HCC. Changes in hepatocyte growth factor expression, somatic mutations, protease and matrix metalloproteinase overexpression, and oncogene expression are seen in hepatic inflammation and chronic hepatitis and, in general, become more extensive as liver injury progresses through fibrosis, cirrhosis, and dysplastic foci and nodules to overt HCC. Because of the heterogeneity of the underlying etiologies, it is a challenge to provide a clear and consistent portrait of the principal molecular abnormalities in this disease. There are several excellent reviews (Table 3) of the most common and important molecular aberrations in hepatocellular carcinoma. Identification of key molecular targets and pathways involved in hepatocarcinogenesis has significant therapeutic implications: the arrival of many molecularly targeted agents in the clinic provides the rationale and opportunity for study of these agents in HCC.
CURRENT TRENDS IN MANAGEMENT OF HCC
At present, liver transplantation is considered the only curative treatment option for HCC. The current 1- and 5-year survival rates for HCC patients undergoing orthotopic liver transplantation are 77.0% and 61.1%, respectively. The 5-year survival rate has steadily improved from 25.3% in 1987 to 61.1% during the most recent period studied (1996 to 2001).108 These authors attribute this improvement to the incorporation of the Milan criteria as guidelines for patient selection at most United States liver transplantation centers. These criteria, as published by Mazzaferro et al,109 suggest that the long-term survival after HCC liver transplantation is highest in HCC patients with either a single lesion Liver-directed therapies include a variety of techniques to ablate individual tumors and are common practice in many centers. A significant body of literature has developed as a result of the extensive use of radiofrequency ablation, percutaneous ethanol injection, cryoablation, intrahepatic iodine-131–lipiodol administration, and transarterial hepatic artery embolization or chemoembolization in treating individual HCC lesions. Statistically significant evidence of improvement in survival as a result of liver-directed therapies, as demonstrated in prospective controlled trials, is scarce. However, two recently published studies in which HCC patients were randomly assigned to receive repeated transarterial hepatic artery embolization versus supportive care demonstrated modest survival improvement seen in patient groups who had small tumor burdens, good performance status, and preserved liver function.113,114 A majority (> 80%) of patients diagnosed with HCC have advanced disease at presentation, and based on the number, size, and location of lesions, and the severity of underlying cirrhosis, are not candidates for transplantation, surgical resection, or liver-directed therapies. At present, systemic chemotherapy is quite ineffective in HCC, as evidenced by low response rates and no demonstrated survival benefit (Table 2). Hepatocellular carcinomas are inherently chemotherapy-resistant tumors115 and are known to express the multidrug-resistant gene MDR-1.116,117 Few well-controlled randomized chemotherapy trials have been published in HCC. The ability to conduct controlled clinical trials of systemic regimens in HCC patients has been hampered by many factors, including the multiple comorbidities of cirrhosis, the advanced nature of HCC at presentation, rapid disease progression in many instances, and the distribution of patients primarily in developing nations, where multidisciplinary treatment of HCC may not be available. CHALLENGES TO PROGRESS IN THE DEVELOPMENT OF EFFECTIVE THERAPEUTICS FOR HCC The biologic heterogeneity and multiple etiologies of HCC result in an incomplete understanding of the key molecular changes that lead to HCC development. Developing a clearer picture of the most prominent and relevant molecular abnormalities is fundamental to developing effective therapeutic options, and should be a priority of those involved in basic and translational research. Few patients with HCC qualify for traditional clinical trials because of their compromised hepatic function. Liver cirrhosis that leads to portal hypertension may result in hypersplenism with platelet sequestration, thrombocytopenia, esophagogastric varices and GI bleeding, hepatic encephalopathy, hypotension, and hypoalbuminemia that may result in differential drug binding and altered pharmacokinetics. In patients with chronic HBV infection, their disease can be reactivated when treated with immunosuppressive chemotherapy, further complicating their medical management and clinical trial participation. The vast majority of HCC patients live in developing nations in Asia and Africa, where providing basic health care remains a challenge, and sophisticated, multidisciplinary cancer treatment is uncommon. In the United States, a comparatively small number of patients are spread among numerous institutions. Collaboration among interested institutions is essential, although it is recognized that collaboration can be cumbersome, time consuming, and costly. Many patients undergo surgical resection, tumor ablation, and regional therapies, yet these approaches have high tumor recurrence rates. Few large, controlled trials of adjuvant systemic therapy have been performed to determine whether adjuvant therapy is of benefit to these patients. There is an acute need for randomized trials, particularly in cirrhotic patients whose entire liver is at risk of recurrent as well as second primary tumors. Although liver transplantation offers a small number of patients a relatively high likelihood of long-term cure, is it the best and highest use of available medical resources? This option is costly and medical resource intensive, and siphons off the best HCC patients from a pool of patients with good performance status and low tumor burden who would otherwise be candidates for systemic therapy clinical trials. The patients on the waiting list tend to be the star athletes (ie, those with the smallest volume of disease at the time of listing), yet a majority of them will never receive a new liver. These patients represent a potential and important source of patients for clinical trials. Conversely, the ethical question remains: when liver transplantation offers patients the only chance for cure, would participation in some other therapy jeopardize their waiting list status and potential long-term outcome? The variety of disease etiologies and broad range of liver dysfunction seen in HCC patients confound designing and interpreting results from standard phase I, II, and III clinical trials. In typical phase II trial designs, with response rate as the primary end point, it is difficult to identify the significant interpatient variability that exists in HCC patients due to the heterogeneous nature of the disease. Few malignancies are cured by chemotherapy. More realistic goals for clinical trials in HCC patients may include prolonged survival, symptom palliation, and improved or maintained quality of life. Assessment of clinical benefit response should be incorporated into HCC clinical trial design. PRIORITIES FOR HCC RESEARCH Numerous challenges must be met in developing effective therapeutic options for HCC patients. First and foremost, HCC is a disease that requires multidisciplinary care, and patients will benefit from clinical care that integrates the expertise of surgical oncology, diagnostic and interventional radiology, gastroenterology, hepatology, radiation oncology, and medical oncology. Collaboration among the various medical disciplines remains essential in the care of complicated HCC patients. Substantial worldwide research efforts have focused on liver-directed treatment options. Data from a number of trials are beginning to emerge and show that these therapies can improve survival in HCC, but generally in highly selected patients with preserved liver function and small tumor burdens. Although progress in these areas is encouraging, it must be remembered that the vast majority of HCC patients present with unresectable disease and are not candidates for liver-directed therapies. Given the preponderance of HCC patients present with advanced disease, and because the incidence of HCC is increasing, there will be an ever-increasing demand for effective systemic therapies. Thus, the medical oncology community needs to become more active in advocating for broad, rational research into systemic chemotherapy options for these patients. Priorities for the future include the formation of a group that focuses efforts, resources, and attention on HCC, such as existing and highly productive working groups for sarcoma, brain tumors, leukemia, and other less-common tumors. The goals of such a group would include the following points. First, an HCC clinical research network should be established that fosters national and international collaborations to focus research effort and resources on HCC. An ASCO HCC Working Group, which integrates all of the important medical disciplines, could be a focal point for this effort. Second, all of the medical disciplines involved in the care of HCC patients must advocate for more basic, translational, and clinical research in both treatment and prevention of HCC. Medical oncologists, in particular, need to make HCC a research priority and actively develop clinical trials of systemic therapies for these patients to expand their treatment options. Working cooperatively with other medical specialties, particularly liver transplantation programs, offers a rich resource for both patients and for tissue for research programs. There are numerous potential clinical trial opportunities for HCC patients awaiting liver transplantation; for example, a trial could evaluate whether regional chemoembolization or other neoadjuvant therapy changes the histologic response rate in the liver explant and improves long-term survival. Third, advocating for clinical trial designs that account for variability in underlying HCC etiology and the wide spectrum of liver dysfunction seen is essential. End points such as time to progression and survival may be more informative in this patient population. Clinical trial designs should include stratification of patients according to one of the many clinical prognostic scoring systems (eg, Childs Pugh, Cancer of the Liver Italian Programme118) and stratification by disease etiology (for example, HBV related, HCV related, or other) to better identify those patients who may truly benefit from systemic therapy. Fourth, clinical trials in HCC should also include quality-of-life assessments because improvement in quality of life, particularly for the many patients with advanced disease in whom tumor response or prolonged survival may not be achievable, is beneficial. Fifth, response rates of traditional cytotoxic chemotherapy agents are low across all studies in HCC and there is no consensus regarding the standard chemotherapy regimen for this disease. A thorough, critical review of existing preclinical research on the efficacy of cytotoxic chemotherapy in HCC should be performed to provide a rational basis for identifying those agents that should be studied in future trials. For example, doxorubicin is commonly used as a control arm, yet it is a drug that is particularly susceptible to cellular efflux pumps, which may account for the low response rates seen with this agent. Clinical trial designs that include a placebo-controlled arm should be considered the gold standard in HCC, particularly in evaluating newer targeted therapies; it is recognized that many clinicians may object to such designs. Sixth, because of the chemotherapy-resistant nature of HCC, attention should shift to focus on translational work that identifies the most important and relevant molecular abnormalities, followed by clinical evaluation of existing molecularly targeted agents in HCC. Seventh, identifying the most appropriate imaging modality for assessing treatment response in HCC is challenging. HCC presents radiographically as a spectrum, from large dominant hypervascular masses to diffuse, infiltrative, poorly visualized lesions. Novel but practical imaging modalities for following HCC responses, particularly to novel biologic therapies, must be developed. This is particularly important in HCC, where the use of routine liver biopsy to conduct correlative studies is risky and likely unethical. Finally, it has been a challenge traditionally to interest the pharmaceutical industry in supporting clinical trials in less common diseases, and although HCC is extremely common worldwide, it is considered an orphan disease in the United States. Some of the most productive medical research in recent years has been fueled by the efforts of organized patient advocacy groups. Hepatocellular carcinoma offers a rich opportunity for the oncology community to develop a working partnership with advocacy groups such as The American Liver Foundation. Such partnerships can leverage their influence with pharmaceutical companies and cancer regulatory agencies to call their attention to the acute need for progress in developing effective therapies for our patients with HCC. Note: The is original work by the authors that is based on published literature and the consensus views of participants in a Hepatocellular Carcinoma (HCC) Meeting held concurrently with the First Annual American Society of Clinical Oncology GI Cancers Symposium, San Francisco, CA, January 22-24, 2004. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
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5 cm or three lesions 
