Commentary (Fong): Management of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common solid organ tumor worldwide. In recent decades, diagnosis and treatment of this cancer has evolved significantly. The article by Drs. Nakakura and Choti summarizes many of the advances in this field, delineates the current evidence-based treatment options, and defines promising areas for future study.

Diagnosis and Staging

Several issues discussed in this article deserve emphasis. With regard to diagnosis, imaging modalities have improved tremendously over the past 2 decades, and staging can now be accomplished accurately by dynamic magnetic resonance imaging or computed tomography (CT). Hepatocellular carcinomas are vascular tumors that often become isodense with the liver after contrast injection. Therefore, noncontrast scans are an essential part of CT imaging for this disease.

The key point about diagnosis, however, is that the combination of a liver mass and an alpha-fetoprotein measurement greater than 500 ng/mL is diagnostic for HCC. Biopsy in that setting is unnecessary and potentially harmful.

As Nakakura and Choti point out, current staging for HCC is largely inadequate. While the TNM staging system does not take into account liver function status, the majority of patients with HCC have liver parenchymal dysfunction due to viral hepatitis, alcohol abuse, or other hepatic injury. The degree of liver dysfunction is a primary determinant of outcome, and a revision of the current staging system is necessary in order to incorporate liver function status into a clinically practical staging scale that predicts patient prognosis.

Surgical Therapies

Much improvement in outcome has been documented for the treatment of HCC. Less than a decade ago, a partial hepatectomy in patients with cirrhosis and HCC was associated with an operative mortality between 10% and 20%. Most recent series from major centers have demonstrated that partial hepatectomies are now associated with an operative mortality less than 5% and result in long-term survival in more than one-third of patients.[1,2]

This favorable change in outcome is the result of improvements in anesthesia, perioperative support, and surgical technique. It is also undoubtedly due to a change in surgical philosophy, whereby nonanatomic resections are accepted in cirrhotic patients-that is, wide surgical margins may be sacrificed in favor of preservation of functional parenchyma.

Parallel to this improvement in the safety of partial hepatectomies has been an improvement in the safety of liver transplantation.[3] Thus, it is not surprising that there is an ongoing debate as to whether patients would derive greater benefit from partial hepatectomy or total hepatectomy and liver transplantation. Direct comparisons of these two potentially curative treatment options are difficult, however. Transplantation is rarely offered to patients with more than three tumors, or with tumors larger than 5 cm, whereas tumors that are resected by partial hepatectomy are routinely larger than 5 cm.

Patients with poor hepatic functional status (Childs B or C) are rarely treated with partial hepatectomy; instead, they are often subjected to liver transplantation. In the few studies where only patients undergoing partial hepatectomy for tumors less than 5 cm are assessed, the long-term survival and disease-free survival are quite similar to those obtained with orthotopic liver transplantation.[1,4]

A recent study from the Barcelona Clinic Liver Cancer Group highlights another treatment issue. These data indicate that the waiting period for liver graft availability is a major determinant of poor comparative outcome in patients treated by liver transplantation.[5] Furthermore, with less than 4,000 liver grafts available for transplantation in the United States each year, only approximately 100 patients are receiving transplants for malignancies of any type in this country.[6]

Complementary Modalities

In reality, these two potentially curative treatment options should be considered complementary modalities for patients afflicted with HCC. Since most surgeons are reluctant to perform partial hepatectomy in patients with Childs B or C liver function status, the livers available for transplantation should be reserved for patients who also have severe liver failure. Patients with a relatively favorable liver function status should be considered for partial hepatectomy.

It remains unknown whether any benefit can be derived from transplantation for those who experience a recurrence after partial hepatectomy. Another emerging controversy centers on whether patients with HCC should receive transplants from living-related donors. In living-related transplantation, the right hepatic lobe is used as the graft; this can result in significant morbidity and possible mortality for the donor. It is, therefore, highly dubious that two lives should be placed at risk when the majority of patients are not cured of their HCC even after transplantation.

Ablative Therapies

The majority of patients presenting with HCC, however, are beyond reasonable surgical therapy, because this disease has a great propensity for intravascular and intrabiliary spread. Multifocal tumor is the rule and not the exception. The large functional reserve of the liver also means that tumors are often quite extensive by the time clinical symptoms appear.

Given that chemotherapy has had only marginal success in HCC, the ablative therapies mentioned in the review article by Nakakura and Choti are the therapies with the greatest promise. As the authors point out, however, there are few well-controlled trials of the various therapies. Although it is well accepted that most of these therapies will result in tumor shrinkage, whether they will prolong life or improve quality of life is still debated. It must also be acknowledged that ablation, even when incomplete, is in theory a sensible treatment for HCC, since these are generally slow-growing tumors with doubling times measured in months.

The lack of controlled trials is partly due to the fact that various ablative modalities are used for diverse patient subpopulations, as dictated by technical considerations. Ethanol injection or radiofrequency ablation can be performed percutaneously but cannot be used for tumors larger than 3 to 4 cm. Cryoablation usually requires open surgery, but can be used to treat tumors larger than 3 to 4 cm.

Therefore, at most centers, radiofrequency ablation or ethanol injection is used to treat the smallest tumors, cryotherapy is used to treat intermediate-size tumors, and embolization or conformal radiation is reserved for the treatment of the largest tumors. Large, uncontrolled trials of ethanol injection ablation demonstrating 5-year survival in one-third of patients with small HCC tumors support the opinion that such ablative therapies are useful.[7] It is, therefore, probably unethical to use “no therapy” as a control arm for any study of small HCC tumors.

Future Directions

The difficulties in setting up clinical trials notwithstanding, numerous potentially important trials should be undertaken. For example, a comparison of ethanol injection and radiofrequency ablation should be performed in patients with small HCC tumors who are awaiting transplantation and have tumor viability accessed at explant. Such a trial can address the issue of durability and completeness of ablation.

These ablations can also be compared to partial hepatectomy in patients with cirrhosis, a population in which resection is still associated with significant morbidity and mortality. Various forms of embolization, conformal radiation, and supportive care should also be evaluated in patients with large HCC tumors. The majority of patients with HCC are incurable at diagnosis, and it is imperative that evidence-based treatment strategies be devised to improve the outcomes of the approximately 1 million patients afflicted with HCC each year.

References:

1. Fong Y, Sun RL, Jarnagin W, et al: An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg 229(6):790-799, 1999.

2. Lai ECS, Fan ST, Chu KM, et al: Hepatic resection for hepatocellular carcinoma: An audit of 343 patients. Ann Surg 221:24-28, 1995.

3. Mazzaferro V, Regalia E, Doci R, et al: Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis [see comments]. N Engl J Med 334(11):693-699, 1996.

4. Livraghi T, Bolondi L, Buscarini L, et al: No treatment, resection, and ethanol injection in hepatocellular. J Hepatol 22:522-526, 1995.

5. Llovet JM, Fuster J, Bruix J: Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: Resection vs transplantation. Hepatology 30(6):1434-1440, 1999.

6. Transplant data. UNOS database, 1999.

7. Livraghi T, Giorgio A, Marin G, et al: Hepatocellular carcinoma and cirrhosis in 746 patients: Long-term results of percutaneous ethanol injection. Radiology 197:101-108, 1995.