The article, Management of Hepatocellular Carcinoma, by Drs. Nakakura and Choti, is an excellent, comprehensive overview of the treatment modalities used for one of the most challenging cancers. The thoroughness of this review underscores the current frustration of the clinician in the management of this disease and the inadequacies of available therapies. The authors list more than 17 treatments for the various stages of this disease. However, if any one of the therapies mentioned offered cure to a majority of patients, there would be little need for more review articles or randomized controlled trials. There are few cancers that command such a vast array of differing therapies from so many different specialties.
No Successful Therapies
Most of the treatments mentioned in the article have been in use in some form for over 20 years. The authors note that any therapy a physician chooses should be properly assessed in prospective randomized clinical trials. The problem is not a lack of clinical trials but that none has resulted in therapies that are particularly successful. The reason for this is threefold.
First, the pathophysiology and biology of hepatocellular cancer (HCC) is unclear. No genetic predisposition or genetic defect associated with a specific causative environmental factor has been identified. There is a strong association with numerous hepatotoxins, but none have been shown to cause a specific reproducible genetic defect that results in HCC. Further investigation of the basic biology of this disease is necessary if we are to make a major therapeutic advance.
The second factor that has hindered the development of effective treatments is, as Nakakura and Choti indicate, the lack of randomized controlled prospective trials. This is due, in part, to the fact that there are few centers in the United States that have enough HCC patients to participate in large-scale studies. The worldwide incidence of this disease is alarmingly high, but in the United States, it is less common than breast, prostate, lung, and other gastrointestinal cancers. There would need to be a unique collaborative effort among multiple US centers in order to conduct a randomized controlled trial.
Impact of Hepatocellular Function
The third factor that impedes the development of novel therapies is the behavior of the tumor. Hepatocellular cancer grows rapidly. Because it involves a major organ that cannot be removed or replaced, if left untreated, it results in death from liver failure within 3 to 6 months. In addition, just as any tumor treatment depends to some degree on the stage at which it is discovered, staging of hepatocellular function is equally important because it determines the ability of the liver to tolerate therapy. The need to assess the level of organ function is not critical in the treatment of most cancers.
All available therapies for HCC have a dramatic impact on hepatic function, and most require intact hepatocellular function for the patient to survive. Intact hepatocellular function is essential for clearance and degradation of chemotherapeutic agents. Radiation therapy also has a significant impact on hepatic function, and surgical therapies result in the direct removal of parenchyma that immediately diminish hepatic function.
Hepatocellular cancer is frequently associated with impaired hepatic parenchymal function and cirrhosis, thus increasing the complexity of choosing an appropriate therapy. Both tumor and hepatocellular function should be simultaneously staged during the evaluation for therapy.
Considerations for Therapy
In the treatment of this disease, some therapies considered more effective from a cancer control standpoint cannot be implemented because of hepatic parenchymal disease, and other therapies considered superior from a hepatic function standpoint are less attractive as anticancer treatments. The management strategy outlined in Nakakura and Chotis review is reasonable, but most centers use the following five disease groupings to classify therapies: (1) early-stage disease with good hepatocellular function; (2) early-stage disease with poor hepatocellular function; (3) advanced local/regional disease with good hepatocellular function; (4) advanced local/regional disease with poor hepatocellular function; or (5) extrahepatic/systemic disease.
Standards of Care
Drs. Nakakura and Choti list many treatments, but there are only four widely accepted treatments that are considered standard of care. Many of the other treatments mentioned evolved from phase I or phase II trials, and should not be recommended as standard therapies.
The accepted therapies include hepatic resection, hepatic transplantation, percutaneous ethanol injection, or intra-arterial chemotherapies including chemoembolization. Patients should undergo hepatic resection if they have early-stage disease and good hepatic function. Patients with poor hepatic function and early disease should be considered for hepatic transplantation. Percutaneous ethanol injection can also be used in the case of poor hepatic function (Childs C).
Patients with advanced local disease (nodular variant or unresectable fibrolamellar) and good hepatic function should undergo intra-arterial chemotherapy or chemoembolization. Those with advanced local disease and poor hepatic function should undergo chemoembolization, whereas patients with systemic disease should be offered palliative care.
Many authors recommend that patients with stage IV advanced local/regional disease and poor hepatic function or systemic disease should be enrolled in phase I or phase II trials. Most surgical oncologists believe that appropriate phase I or phase II trials should be offered to patients at all stages of disease, if there is a significant opportunity for improved outcomes.
A Nonhierarchical Approach
Prospective randomized trials in HCC require multi-institutional cooperation and a multidisciplinary approach, as the current treatment paradigms involve cross-disciplinary evaluation and management. The latter emphasizes the need to abandon the traditional vertical paradigm of patient evaluation by primary care physicians, medical oncologists, radiation oncologists, and surgeons. A multidisciplinary team that comprises radiation oncologists, medical oncologists, surgical oncologists, and interventional radiologists should undertake the initial management of the patient with hepatocellular carcinoma, including the diagnostic evaluation of the hepatocellular mass.
A nonhierarchical approach to treatment is the single most important step toward significant advances in therapeutic outcomes. This approach obviates many delays in therapy that now occur as a result of evaluations that may take from 3 to 6 months and that significantly alter the patients chances for effective therapy and survival.
James V. Sitzmann, MD