The only proven potentially curative therapy for HCC remainssurgical, either hepatic resection or liver transplantation,and patients with single small HCC ( 5 cm) or up to three lesions3 cm should be referred for assessment for these treatment modalities. A variety of local therapies are avialble short of surgical resection. In regard to chemotherapy, palliative systemic therapy with doxorubicin (Adriamycin) has been considered a standard of therapy with response rates of 10 to 20 % with usually partial responses, but with no evidence for survival benefit. As doxorubicin is metabolized by the liver, the dose needs to be reduced or discontinued with rising bilirubin levels and liver dysfunction. Single agent 5-flurouracil, capecitabine or gemcitabine may be better tolerated in such a situation but still with low objective response rates. Combination chemotherapy regimens results in higher response rates but at increased toxicities and unproven survival benefits, and are not usually recommended.
Combination chemotherapy produces better results in HCC. Cisplatin (CDDP)-containing regimens such as epirubicin, 5-FU and CDDP produces a response rate of up to 25% a regimen comprising gemcitabine and CDDP produces a response rate of 21%. However, median survivals were still short. A National Cancer Centre clinical study is evaluating gemcitabine and CDDP. More recently, a French Phase II study reported 19% response rate and 48% stable disease to combination gemcitabine and oxaliplatin. One compelling Hong Kong study with CDDP, interferon-alpha (IFN- a ), doxorubicin, and infusional 5-FU (PIAF), a modification of an MD Anderson regimen, reported a response rate of 26% in advanced HCC and pathologic complete response in 44% of HCC patients who were able to undergo surgical resection following chemoimmunotherapy cytoreduction. The overall median survival was 8.9 months. It was also shown that normalization of tumour marker alphafetoprotein ( a FP) was predictive of pathologic complete remission in these HCC patients. This illustrates that radiological response evaluation may underestimate the true response. Toxicity was a problem in this intensive regimen with a 4% mortality and significant morbidity. Combinations of 5-FU with IFN- a have divergent results with one study reporting responses in 9 of 36 HCC patients. The role of single agent IFN- a against HCC may be related to its anti-angiogenesis mechanism, its ability to induce anti-tumour immunity or both, but clinical studies have again ranged from zero response rates to studies suggesting response rates better than doxorubicin with a survival benefit. Newer agents such as bevacizumab (Avastin), a monoclonal antibody against vascular endothelial growth factor (VEGF), or Thalidomide (an immune modifier or angiogenesis inhibitor) used alone or in combination with chemotherapy remain experimental. New combinations such as capecitabine and avastin (an antibody against vascular endothelial growth factor), the focus of an ongoing Asia-Pacific study, are promising, not least for its ability to produce low toxicity and potentially target this highly vascular tumour. However, they remain experimental and intriasl at this time.
A recent guideline states: “Systemic chemotherapy with standardagents has a poor responserate and should only be offered inthe context of trials ofnovel agents (evidence grade I, recommendationgrade A). “ NCCN only recommends chemotherapy in a context of clinical
S D Ryder Guidelines for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults Gut 2003;52:iii1
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