Hepatocellular Carcinoma (HCC) ( Liver Cancer )

Hepatocellular Carcinoma (HCC) ( Liver Cancer )

Hepatocellular carcinoma (HCC) or primary liver cancer often presents in the advanced stage. It is often discovered late, and the survival following diagnosis is often poor.  Although the mainstay of treatment is surgical operation, many patients are not suitable because of extensive tumour or poor liver function. Systemic therapy is the main treatment for these cases. In Asia, liver cancer is listed as one of the most common malignancies, in view of endemic hepatitis B and C. Advances and understanding of the disease, have led to the recent development of new systemic therapeutic options. Sorafenib Sorafenib (Nexavar) is an oral multi–kinase inhibitor, blocking the activity of VEGF receptors 1, 2, and 3, as well as PDGF receptor-β, braf, c-kit and FLT-3. These are targets that affect liver cancer growth and proliferation. It is the first targeted therapy to demonstrate overall survival benefit in advanced HCC, and was approved for use since 2007. Two phase III studies, the SHARP (Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol) trial and the Asia-Pacific trial (Efficacy and Safety of Sorafenib in Patients in the Asia-Pacific Region with Advanced Hepatocellular Carcinoma), showed that Sorafenib in patients with Child’s Pugh A (CP-A) good liver function had improvement in median survival compared to placebo. However, both studies did not show any improvement of symptoms or improved quality of life. Patients with impaired liver function (CP-B8 and above) were excluded from these studies. A post marketing study in such patients demonstrated an increase in treatment related toxicities, with difficulties in ascertaining benefit. Therefore, the use of Sorafenib in patients with impaired liver function is currently not strongly supported. Studies in the second-line setting, following disease progression on Sorafenib have been disappointing until recently. The phase III RESORCE (Regorafenib after Sorafenib in patients with Hepatocellular Carcinoma) trial found that patients taking Regorafenib, compared to placebo and best supportive care, had a better median overall survival. Regorafenib (Stivarga) is structurally similar to Sorafenib, but differs only by the addition of a fluorine atom in a centre phenyl ring. This difference results in a distinct biochemical profile, with higher potency. We would usually give Regorafenib continuously for 3 weeks, followed by 1 week of rest. Common side effects of both tyrosine kinase inhibitors include diarrhoea, hand-foot syndrome and fatigue. Regorafenib was approved for use by the United States FDA since April 2017. Anti-PD1 blockade with Nivolumab (Opdivo) showed a response rate of 19% and a disease control rate of 67%. More importantly, these responses were observed regardless of hepatitis infection status, and also demonstrated safety of its use. Sustained and durable response was also observed, including 2 complete responses and 7 partial responses in a small cohort of 39 patients. Based on this, the FDA has granted accelerated approval of Nivolumab in September 2017, for patients who have failed first line therapy with Sorafenib, or who are Sorafenib intolerant. Recently, the safety and efficacy of another PD1 inhibitor, Pembrolizumab (Keytruda) was also shown to have similar results as Nivolumab. The main difference is that Pembrolizumab is given in a 3 weekly dose frequency compared to Nivolumab. In March 2018, Nivolumab was approved for 4-weekly use at a dose of 480mg as well. Multiple phase II/III studies are now underway, exploring the combination of CTLA-4 and PD-L1 blockade, as well as the use of anti-PD1 antibodies with Sorafenib. Summary For the longest of times, Sorafenib had been the only approved option for advanced hepatocellular carcinoma. There are now 3 new options that are approved or in the midst of approval for use in the past year alone. Many are now available with our centre and using them has benefited many patients. With many more in the pipeline, we hope that the median survival for this lethal cancer can be meaningfully prolonged.