HCC often develops among patients who have cirrhosis. It is estimated that approximately 60% of all patients with HCC have underlying cirrhosis . In some patients, cirrhosis associated with portal hypertension and thrombocytopenia makes systemic chemotherapy for HCC extremely difficult and contributes to the poor prognosis associated with HCC. Furthermore, there is no prospective controlled study suggesting that systemic chemotherapy prolongs survival in HCC patients when compared with best supportive care.
Single chemotherapeutic agents, which have demonstrated a consistent response rate of more than 10% are doxorubicin [4, 19], 5-FU and cisplatin [5, 6]. In a systematic review of clinical trials , the 1-year survival rate was superior for doxorubicin-containing regimen over non-doxorubicin-containing chemotherapy. In a study using PIAF regimen (cisplatin, doxorubicin, 5-FU and interferon alpha), 9 out of 50 HCC patients with PR were able to receive surgical resection resulting in pathologic CR in 4 patients . This indicates that aggressive systemic combination chemotherapy may result in CR for HCC patients. However, the PIAF regimen was associated with considerable toxicities with significant myelosuppression, which led to 2 treatment-related deaths. Triplet combination with ECF (epirubicin, cisplatin and 5-FU) was also evaluated in patients with HCC . ECF chemotherapy gave a modest response rate (15%) at the cost of considerable hematologic toxicity.
In an attempt to achieve better tolerability and effectiveness with doxorubicin-containing combination regimen, we substituted 5-FU with capecitabine, which is considered to be as effective and more tolerable than 5-FU [21–23]. Although capecitabine has not been compared to infusional 5-FU to prove similar efficacy, oral administration has the advantage of permitting convenient, patient-orientated therapy, providing the patient with a degree of independence and improved quality of life, while avoiding complications associated with intravenous drug administration. Furthermore, most patients prefer orally administered therapy to intravenous treatment . The presence of mild-to-moderate hepatic dysfunction had no clinically significant effect on the pharmacokinetics of capecitabine and its metabolites . These findings suggest that capecitabine may be useful for patients with HCC , including those with impaired hepatic function.
The combination of doxorubicin, cisplatin and capecitabine was well tolerated by patients with metastatic HCC. It should be kept in mind that the degree of cirrhosis was limited to Child-Pugh class A; none of the treated patients had class B or C cirrhosis. Using this triplet combination, we achieved an overall response rate of 24% and a median time to progression of 3.7 months. Forty percent of patients showed a significant reduction in serum AFP in this study. This observation should be interpreted with caution because it represents only a small group of patients with metastatic HCC in this phase II study and the majority of patients had good performance status and preserved hepatic function. As a result, grade 3 or 4 neutropenia occurred only in 14% of patients. This favorable toxicity profile achieved with triplet chemotherapy differed from results reported with other doxorubicin-based chemotherapy for HCC. Although it would be difficult to compare our data directly with the results of other studies, a survival benefit from our triplet combination in HCC seems unlikely, despite the acceptable response rate and favorable toxicity profile observed in our study. The response rate of our regimen is comparable to those found in most phase II studies of doxorubicin-based combination chemotherapy ranging from 13% to 26% [4–6, 19, 20]. Capecitabine monotherapy was also evaluated in a phase II study, resulting in a modest response rate and good tolerability . Recently, Yeo et al. have conducted a phase III study comparing single-agent doxorubicin with PIAF in patients with inoperable HCC . There was no significant difference in response rates and overall survival between doxorubicin and PIAF. To date, none of combination regimens has been recognized as a standard or superior to doxorubicin alone.
With few exceptions, it is generally conceived that systemic chemotherapy is relatively ineffective in HCC . HCC is resistant to chemotherapy because of the high mutational load it carries and the myriads of drug resistance mechanisms [27, 28]. This is in addition to the underlying liver dysfunction that imposes lower chemotherapy doses to mitigate toxicity. More recently, targeted therapeutics are being looked at aggressively in HCC. Several potential targets along the angiogenesis and the signal transduction pathway are evaluated in HCC. These include epidermal growth factor receptor, hepatocyte growth factor and its receptor c-met, and vascular endothelial growth factor . Bortezomib, considered as a potent and reversible inhibitor of the proteasome, was also evaluated in a phase I/II study . Interestingly, bortezomib attenuates certain pathways implicating in resistance to anthracyclines, and thus, a significant synergy between bortezomib and anthracyclines was observed . Our next step will be to combine doxorubicin with bortezomib and to investigate the relative place of the targeted therapy in the treatment of metastatic HCC.