Unresectable Hepatocellular Carcinoma: A Modest Improvement in the Bleak Prognos
Unresectable Hepatocellular Carcinoma: A Modest Improvement in the Bleak Prognosis?
ABSTRACT & COMMENTARY
Although hepatocellular carcinoma is one of the most common malignancies worldwide, it is less common in the United States. Tumors of the liver and biliary tree occur in about 20,000 people each year in the United States, and 16,000 people die each year from this form of cancer. However, the majority of these are tumors of the gall bladder and bile ducts. Hepatocellular carcinoma occurs in about 5000 people each year. The appropriate management of patients with liver cancer is controversial. The rare case that presents with disease localized to one hepatic lobe may be approached by hepatic lobectomy, with good results in the absence of underlying cirrhosis. However, the vast majority of patients present with disease widely disseminated throughout the liver and often the liver not involved with tumor is cirrhotic. Systemic chemotherapy, intrahepatic injection of ethanol, arterial embolization or chemoembolization, intra-arterial chemotherapy, radioimmunotherapy, and liver transplantation are all advocated for these patients in different centers.
Liver transplantation has a defined cure rate based upon stage: 75% for stage I, 60% for stage II, 40% for stage III, and 10% for stage IV. This approach is clearly superior to surgical resection in the presence of cirrhosis. For those who are not candidates for liver transplantation or in whom no donor is available, other approaches must be employed. Systemic chemotherapy is not effective. Various studies have evaluated different intrahepatic and intra-arterial approaches, but no consensus has emerged.
Johns Hopkins Oncology Center has been one of the major institutions evaluating treatment approaches to hepatocellular carcinoma. A recent report summarizes the results of three sequential studies in patients with unresectable hepatocellular carcinoma, two of which were done in conjunction with the Radiation Therapy Oncology Group. However, even in the cooperative group studies, the majority of patients were treated at Johns Hopkins Oncology Center.
RTOG 83-19 involved administration of doxorubicin (15 mg IV) and 5-fluorouracil (500 mg IV) given on the same days as fractions 1, 3, 5, and 7 of a total of seven fractions of external beam radiation therapy to the liver (3 Gy fractions, 21 Gy total dose). Four to six weeks after completion of radiation therapy, patients were randomly assigned to receive either systemic chemotherapy with doxorubicin and 5-fluorouracil every three weeks or chemotherapy plus 131I conjugated polyclonal antiferritin antibody. The rationale for antiferritin antibody is controversial and, as it turns out, irrelevant. One hundred eighty-three patients entered this study.
After this study, Johns Hopkins conducted a pilot study in 62 patients consisting of cisplatin (50 mg/m2 IV) on the first day of external beam radiation therapy, followed 4-6 weeks later by the same dose of cisplatin administered intra-arterially into the hepatic artery every 4-6 weeks until disease progression. RTOG 88-23 used the same induction regimen, but the intra-arterial cisplatin was given either alone or together with the iodinated polyclonal antiferritin antibodies. Thirty-five patients entered RTOG 88-23. This analysis was restricted to patients with elevated serum levels of alpha-fetoprotein.
Although the comparisons were not randomized, concurrent, and head-to-head, prognostic factors were well balanced. Groups receiving the radioactive antibodies had no apparent benefit in tumor control, but suffered significantly greater toxicity than those not receiving antibodies. The one-year and two-year survival rates for patients treated with cisplatin chemotherapy were 37% and 9%, respectively; those for patients treated with doxorubicin and 5-fluorouracil were 17% and 4%, respectively. Cisplatin was significantly more effective (P < 0.0001). The advantage for cisplatin was present in both good risk and poor risk patients (risk was determined by assessing performance status, presence of ascites, and elevations in transaminase, alkaline phosphatase, and bilirubin-abnormalities in 3 or more factors defines poor risk).1 (Abrams RA, et al. Cancer J Sci Am 1998;4:178-184.)
COMMENTARY
Certainly the best strategy for hepatocellular carcinoma is prevention. Persons at risk should be vaccinated against hepatitis B and C. Those chronically infected with these viruses should be treated with antiviral therapy. If disease cannot be prevented, outcome may be improved by instituting efforts at early detection in risk groups such as those with a history of blood transfusion, prior jaundice or hepatitis, intravenous drug abuse, and those with a family history of hepatoma. Screening efforts include twice yearly monitoring with hepatic ultrasound, liver function tests, and serum levels of alpha-fetoprotein. Another putative tumor marker is des-g-carboxy prothrombin protein induced by vitamin K abnormality (so-called PIKVA-2), but this can also be elevated in patients with vitamin K deficiency, chronic active hepatitis, cirrhosis, or metastatic tumors to the liver.2,3
Patients diagnosed early (stage I) appear to have a 70% or greater chance of being cured by surgical resection or percutaneous injection of tumor with ethanol. Patients with stage II disease have a 40-65% chance at five-year survival (2-year survival and 5-year survival are quite comparable in most series). Ethanol injection is less successful in masses greater than 5 cm in diameter. The outcome of these treatments is poorer in the presence of underlying cirrhosis and it is in patients with cirrhosis that liver transplantation offers the greatest benefits (see above).
If patients are not diagnosed early, the outlook for long-term survival declines significantly. Patients with poor prognostic factors may have a somewhat better outcome with liver transplantation, but this may be a consequence of patient selection. This effort to use systemic cisplatin as a radiosensitizer and follow it with intra-arterial cisplatin is well tolerated and appears to offer a modest benefit over doxorubicin and 5-fluorouracil. How the results compare to other intra-arterial and intrahepatic treatments is difficult to discern. On occasion, response to chemotherapy or chemoembolization therapy can induce sufficient tumor regression to permit resection. The true frequency of such responses remains unclear. Chemotherapy followed by liver transplantation for those with favorable responses may be a reasonable approach.
References
1. Stillwagon GB, et al. Int J Radiat Oncol Biol Phys 1991;20:65-71.
2. Liebman HA, et al. N Engl J Med 1984;310:1427-1430.
3. Sakon M, et al. Am J Gastroenterol 1991;86:339-345.
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