Oncology perspectives in the management of liver cancer

Hepatocellular carcinoma (HCC) is so prevalent that the many treatment options available require cross-speciality co-ordination and co-operation, from hepatologists and pharmacists, to radiologists and oncologists. The final speaker of the symposium was Professor Michel Ducreux, Paul Brousse University Hospital, Gustave Roussy Institute, Villejuif, France, who gave an oncological perspective on the treatment of HCC.

He began by stating that there are currently two main diseases affecting the liver; HCC and cirrhosis (present in 90% of liver disease cases). Both diseases independently influence the prognosis and possibilities of treatment which in turn determine their classification/s. There is currently a low level of proof for most of the treatments (very few Phase III trials) and this has lead to many different classifications, practices and recommendations across centres and countries. Despite good results in terms of the efficacy of local methods (resection by surgery or radiofrequency ablation), there are poor results when considering recurrence rates (Lencioni R et al. Radiology, 2005) (Figure 1). In addition, Ducreux also highlighted problems following resection, with disappointing results with modern pharmacological therapies and with no current standard adjuvant therapies.

By far the best option is liver transplation. However, due to the low number of suitable donors, patients must wait and this waiting period is increasing as the cases of HCC increase (Llovet JM. Hepatology 1999; 30:1434-40). Ducreux said that during this waiting period what is needed is adjunctive therapies to stop the spread of HCC. In patients with limited, non-complicated HCC chemoembolisation has demonstrated its efficacy with 30% five-year survival, however this only represents 10% of patients. In the case of extended metastatic disease, representing 40-50% of patients, five year survival is <10% with medical treatment (Llovet JM. et al. Lancet 2003; 362:1907-17).

Discussing chemotherapy in particular, he said that the evidence shows the response rate of systemic chemotherapy for HCC is <12% demonstrating very little efficacy (Figure 2).

For example, Ducreux cited Gish et al, EASL 2006 and a Phase III trial that compared nolatrexed (nolatrexed - 800mg/m2/d x 5d/3 weeks) versus doxorubicin (adriamycine - 60mg/m2/3 weeks). With a total of 446 patients (cirrhosis: 38%, Child-Pugh A score: 73%), the outcomes reveal that the objective response rate was 1.4% versus 4%, progression free survival was 12 versus ten weeks (not significant) and the overall survival was 20.7 versus 31 weeks (p=0.0055). In addition, there was more toxicity in the nolatrexed arm. Ducreux concluded that modern therapy for HCC is not a very effective treatment with very poor results.

He then compared the results from combined systematic chemotherapies. The outcomes of combining two, three, and sometimes four drugs were again unsatisfactory, with less than 20-25% response rate and no evidence of a benefit for the patient (Figure 3).

One such trial was Yeo et al, JNCI 2005, compared doxorubicin versus 5FU (fluorouracil) + Adria + cisplatin + interferon (PIAF schedule). The trial enrolled a total of 188 patients (Cirrhosis: 48%, Child-Pugh A: 80%) and reported an objective response rate of 10.5% versus 20.9% and a higher rate of toxic side effects in the arm PIAF including, Neutropenia: 82% versus 63% (p=0.003), Thrombocytopenia: 57% versus 24%, (p<0.001), Hypokaliemia: 7% versus 0%, (p=0.007).

Ducreux spoke a little about the future outlook for local chemotherapy in colorectal cancer. Twenty years ago, response rates for chemotherapy were very poor, however, the proof of concept was achieved when non active systemic drugs resulted in high response rates when administered in hepatic artery (5% of ORR IV versus 50% with intra-arterial hepatic [IAH] administration). Citing Boige et al. 2007 (V Boige et al. Ann Surg Oncol, 2007, 26 sept), a total of 44 patients were given IAH administration and reported a 62% (n=24) objective response rate after patients failed to respond to Folfiri (n=17), Folfiri + Folfox (n=12) or Folox treatment (n=12). Moreover, Ducreux commented that the same positive results were seen in the treatment of primary liver cancer with intra-arterial hepatic chemotherapy using non active drugs given intravenously (Lai, 2003; Ando, 2002) (Figure 4).

In considering the future of the medical treatment of HCC, he discussed sorafenib, as this drug targets both tumour-cell proliferation and angiogenesis (Wilhelm S et al. Cancer Res. 2004;64: 7099-7109) and the successful results of bevacizumab and a reported case of tumour growth control of 80% (Schwartz, ASCO 2006).

Conclusion
In conclusion, Ducreux said that in patients with limited, non-complicated HCC new treatments could yield improved results. With new randomised controlled trials, combining new drugs with IAH administration the response rates of extended metastatic disease should be improved, reflecting the improvements witnessed in colorectal cancer.