Liver cancer: Current mgm’t and future trends

The hallmarks of hepatocellular carcinoma (HCC) are that it is identified clinically at an advanced stage and usually together with cirrhosis. Surgical resection has been considered the optimal treatment approach, but only a small proportion of patients’ quality for surgery, and there is a high rate of recurrence. Approaches to prevent recurrence have included chemoembolization before and neoadjuvant therapy after surgery, neither of which has proven to be beneficial. Liver tansplantation has been successful in treating limited-stage HCC, affecting cure of both the tumor and underlying cirrhosis. However, only a minority of patients with HCC qualify for transplantation. Recently chemoembolization has been shown to prolong survival in selected patients who do not qualify for resection. Both doxorubicin and cisplatin are frequently used, but overall response rates are low, and neither seems to prolong survival. Prospective, randomized controlled trials using current therapies are needed to better define optimal management of this important tumor. Most needed, however, are new therapeutic agents that are effective against HCC, are noncytotoxic, and are tolerated by the atypical patient with underlying cirrhosis. Newly emerging agents with promise include 90Y microspheres, natiangiogenesis agents, inhibitors of growth factors and their receptors, and K vitamins.

Hepatocellular carcinoma (HCC) is the most common tumor that originates in the liver, and it has great heterogeneity with respect to tumor behavior and disease of the underlying liver. Although most types of cancer are sub classified on the basis of the TNM staging system or the extent of disease, HCC is not a uniform disease within any given current staging system. In addition, it is heterogeneous with regard to the severity of disease, and measurement of treatment outcomes in HCC related to the fact that 80 percent of patients with HCC have two diseases, each of which, independently, may cause death; namely the cancer and the underlying cirrhosis. Concomitant cirrhosis distinguishes HCC from all other types of cancer, and has been acknowledged in at least one staging system, but confounds and confuses the evaluation of different treatments.

HCC In The United States

The experience with HCC at the Liver Cancer Center of the University of Pittsburgh recently has been summarized. During the 15-year period, 1700 patients with HCC were evaluated. Seventy-five percent of patients had bilobar cancer, 72 percent had portal vein thrombosis, and 65 percent had three or more tumor masses in their livers. Thirty percent had HCV infection, 20 percent were infected with HBV, and 28 percent had alcohol-associated cirrhosis. Among those with HCV infection, more than 66 percent also had a history of alcoholism. Interestingly, 20 percent of the patients had no identifiable underlying liver disease. The male-to-female ratio was 2.5:1. The ages of the patients averaged 56 years and ranges from 6 months to 92 years. Twenty percent presented with end-stage liver disease and were not eligible for any form of treatment. The median survival in these untreatable patients was three months, in keeping with the known rate of survival of HCC.

Treatments For HCC

A high proportion of patients with HCC in the United States do not receive any therapy. The exact proportion is not known, but may be as high as 50 percent. There are several reasons for this low rate of therapy. Chronic liver disease is often silent, and many patients are unaware of having liver disease or being at risk for liver cancer. Furthermore, among those patients who are known to have liver disease, there are no guidelines or accepted approaches to regular surveillance. As a consequence, most patients with HCC rarely present with symptoms unless there is advanced-stage cancer. Because the cancers are large, they are often bilobar or have already invaded a major trunk of the portal vein, and hence are not respectable. Because of the late stage of presentation, many patients with HCC are not referred to a medical oncologist for either systemic chemotherapy reflects an atmosphere of nihilism over therapy for this tumor, and until recently, a lack of new and innovative therapies. Finally, contraindications to therapy may already be present (ascites, end-stage liver disease) and referral is considered unjustified.

Surgical Resection

Surgical resection of varying degrees and extent has been time-honored standard treatment for HCC. Recent series, particularly from Asia, suggest that in experienced hands, perioperative mortality can be less than 5 percent. Although recurrence rates after surgery have decreased and survival has increased over the last 20 years, most patients with TNM stage II still have only a 50 percent 5-year survival, death usually being caused by recurrent cancer.

Other Ablative Localized Treatments

An increasing array of other localized semi surgical treatments has become widely accepted for extremely localized tumors. These include percutaneous ethanol injection, radiofrequency ablation, cryotherapy, and newer forms of radio-wave therapy. These local ablative therapies seem to be similar in applicability, and results are highly dependent on clinician skills and choice of patients. Local ablative therapies are generally useful for patients with 1 or 2 tumor lesions with a maximum diameter of 3 cm.

Liver Transplantations

There were two hopes for liver transplantation in the management of patients with advanced HCC. The first was to remove the limitations that cirrhosis imposes on the surgeon to reset HCC. The second was to improve the ability of the surgeon to resect larger tumors. In the first category, liver transplantation has been gratifyingly successful, and HCCs that are confined to the liver can be surgically removed, whatever the degree or severity of the underlying cirrhosis. For the second, there continues to be a learning phase on how to use and extend the possibilities of liver transplantation for the management of advanced-stage HCC. In addition, the standards for acceptable of liver transplantation for HCC need to be continually reviewed and reconsidered. In other types of advanced cancer, a 50 percent 5-year survival rate is considered worthwhile, but in liver transplantation, a 50 percent 5 year survival is not. For most patients with advanced HCC, extension of life for three years would be considered meaningful if the quality of life were reasonable.

Hormonal Therapy

Almost 90 percent of newly diagnosed HCCs referred to the University of Pittsburgh were considered to be non-respectable and non transplantable as judged by the extent of the tumor. The management of such tumors is currently non surgical. The gender differences noted in HCC incidence rates have encouraged many investigators to examine tumor profiles for hormonal or growth factor receptors and, with or without this information, to embark on clinical trials of various hormonal modalities, including agents such as tamoxifen to inhibit estrogen actions (which is unlikely to be successful because this tumor predominantly occurs in male subjects) and anti-androgens such as leuprolide acetate and flutamide. Despite many trials, the overall results have been disappointing and survival has remained poor. Nevertheless, such approaches are attractive because the agents are in general non toxic, inexpensive, and easy to administer.

Chemotherapy

A huge number of randomized and non randomized clinical trials to evaluate the usefulness of single agents or combinations of agents of cytotoxic cancer chemotherapy have been published and recently reviewed. Overall, few published series have been able to show response rates in 20 percent of the patients (considered to be a lower limit of usefulness for most cancers), and very few claims have been made for prolonging survival. Some more recent combinations such as cisplatin, interferon, Adriamycin, and 5-fluorouracil are extremely toxic and yield response rates of only 20 percent, and show no survival advantage compared with supportive care alone.

New Medical Agents

Several new classes of non surgical therapy for HCC have begun to be evaluated systematically in the past 2 years. These include the following.

1. Antiangiogenesis agents, such as vascular endothelial growth factor (VEGF) antibody, Angiostatin, and endostatin; thalidomide, thrombosponding analogs; and interferon-The vascularity of HCC makes it an excellent candidate for the action of these agents.

2. Inhibitors of growth-factor signaling and cell-cycle enzymes, such as inhibitors of Kinase (Bay 43-9006), Cdks, tyrosine kinases, epidermal growth factor receptor antagonists (Iressa), P13 kinase and phosphatase and tensin (PTEN) pathways, mitogen activated protein (MAP) kinase pathway, and suramin.

3. Nonspecific growth inhibitory agents, including Sandostatin and arsenic trioxide and Activators of apoptosis.

4. Novel means of delivering localized radiation, such as Yttrium microscopheres, Theraspheres, and Sirsphres.

5. Specific antagonists of HCC tumor markers, such as vitamin K2 and the Cde 25-Antagonizing vitamin K analogs.

6. Anti-inflammatory agents that might interfere with the carcinogenic process, such as Cox-2 inhibitors (celecoxib, rofecoxib).

Conclusions

The largest impact on mortality from HCC will clearly come initially from primary prevention such as decreasing alcohol consumption, decreasing HCV infection through lifestyle changes, improving screening of blood donors, and vaccination against HBV. Next will be the benefit derived from earlier diagnosis leading to more effective therapy for more limited-stage disease. However, new therapies for HCC will continue to be needed. Multiple new therapies are now being evaluated, and combination of modalities clearly should be examined to improve the efficacy of treatment of most patients who continue to present with an advanced stage of their tumor.