Hepatocellular carcinoma (HCC) is a relatively common malignancy worldwide, with approximately 750,000 new cases diagnosed in 2008.1 Surgical resection and/or liver transplantation are the best treatment options for patients with HCC; however, many patients are not candidates for these interventions based on their overall tumor burden and liver dysfunction. Nonsurgical treatment options for HCC include transarterial chemoembolization, radiofrequency ablation, and systemic chemotherapy.
Unfortunately, advanced HCC does not have many systemic chemotherapy options. Sorafenib is an oral tyrosine kinase inhibitor that works to inhibit the vascular endothelial growth factor receptor and Raf kinase pathways.2 In the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) clinical trial, sorafenib was shown to provide a benefit in both survival (10.7 months vs 7.9 months, respectively) and median time to radiologic progression (5.5 months vs 2.8 months, respectively) when compared with placebo.2
However, some patients with HCC who are treated with sorafenib may experience intolerable side effects from the drug, disease progression, or treatment failure. Therefore, a common dilemma for patients and clinicians is determining what alternative treatment options are available if sorafenib treatment is ineffective.
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At this time, there is a paucity of clinical trial data to support the use of other systemic chemotherapeutic agents such as doxorubicin, gemcitabine, or cisplatin in these patients.
Patients with HCC typically do not respond well to systemic chemotherapy based on their overall level of hepatic dysfunction and resulting inability to tolerate these medications. In addition, drug resistance genes are expressed at a relatively high level in patients with HCC, making the risk of these treatments outweigh the benefits.
RELATED: Gastrointestinal Toxicity of Sorafenib
In an effort to explore potential options for patients with HCC in whom sorafenib treatment is ineffective, Zhu et al recently published a clinical trial evaluating the use of everolimus in these patients.3 Everolimus is a mammalian target of rapamycin (mTOR) inhibitor, which has been approved for use in the United States in renal cell carcinoma, advanced breast cancer, pancreatic neuroendocrine tumors, and for the prevention of liver and kidney transplant rejection.4
The mTOR pathway has been implicated in the pathophysiology underlying HCC; therefore, it was hypothesized that everolimus may be a treatment option. The Everolimus for Liver Cancer Evaluation (EVOLVE-1) study included 546 adult patients with HCC who could not tolerate sorafenib or who had HCC progression during or after sorafenib treatment based on radiographic images. Patients received supportive care and either 7.5 mg of everolimus daily or placebo.
When everolimus was compared with placebo, there was no difference in medial overall survival (7.6 months vs 7.3 months, respectively) or median time to progression (3.0 months vs 2.6 months, respectively). Patients in the everolimus group experienced more adverse events compared with placebo in numerous categories including stomatitis, anemia, asthenia, decreased appetite, and hepatitis B reactivation.
RELATED: Gastrointestinal Cancers Resource Center
Sorafenib-refractory HCC continues to be a challenging disease state to treat, with many prior and current clinical trials failing to identify new treatment options. Future studies will continue to search for the next molecular pathway or biomarker that will prove useful in the development of systemic HCC medication.
References
- Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-90.
- Nexavar [prescribing information]. Wayne, NJ: Bayer Pharmaceuticals.
- Zhu AX, Kudo M, Assenat E, et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA. 2014;312(1):57-67.
- Afinitor [prescribing information]. Basel, Switzerland: Novartis Pharmaceuticals Corporation.
