Before I consider treating a patient with hepatocellular carcinoma (HCC) I would look at the leading etiology. HCC is caused by four major risk factors: hepatitis B; hepatitis C; alcoholic cirrhosis; and non-alcoholic steatohepatitis (NASH), a latter manifestation of non-alcoholic fatty liver disease (NAFLD) due to morbid obesity and diabetes. Insofar as I would treat HCC almost the same way regardless of etiology, understanding the etiology is critical, as each etiology has its particularity-for example, its association with cirrhosis. HCC that is caused by hepatitis B is less likely to be associated with cirrhosis, in contrast to all other risk factors.
I make sure to understand the extent of the cirrhosis, as it has important implications in regard to the choice of therapy. I generally use the Child-Pugh scoring system and assess its five parameters: bilirubin, albumin, and PT/INR levels and a clinical assessment of ascites and encephalopathy. The Child-Pugh scoring has its limitations, mainly the lack of any parameters related to the cancer itself.
Other scoring systems that I use are the Cancer of the Liver Italian Program (CLIP) for patients with hepatitis C and alcohol etiology, and the Chinese University Prognostic Index (CUPI) for patients with hepatitis B etiology, as the prognostic parameters have been shown to differ among etiologies.
Curative Therapies
For patients with Child-Pugh A and limited disease in the liver, I entrust my surgery colleagues on managing the patient. Radiofrequency ablation (RFA) can serve the purpose of locoregional control as an alternative option or for patients who may not be suited to surgery. In patients with more advanced cirrhosis, yet with limited cancer extent, I make sure to guide such patients for an evaluation at a liver transplantation program.
In select instances where the cancer may be large enough not to permit a surgical resection, I may work with my surgical colleagues on a conversion therapy plan, and I would consider use of a combination of cisplatin, interferon, doxorubicin, and fluorouracil (PIAF) aiming at reducing the tumor size before sending the patient to surgery.
In the setting of transplant, the local therapies described below may be applied to downsize the tumor and maintain eligibility on the transplant list.
There are no data to support giving patients with HCC any adjuvant therapy following surgery, RFA, or transplantation. Despite early efforts using systemic retinoid analogs and radioactive iodine intrahepatically, the standard of care following any loco-regional approach is observation.
The STORM study (NCT00692770) evaluated a possible role for sorafenib as an adjuvant therapy and although that study is now closed to accrual, I would not recommend sorafenib as an adjuvant treatment until the data of the STORM study are reported.
Locally Advanced Disease
I entrust patients with locally advanced HCC-i.e., disease that is not amenable to resection or transplantation and yet not metastatic-to my interventional radiology colleagues for consideration of local therapies. Local treatment approaches are some of the most developed and remain some of the most controversial treatment approaches in managing HCC.
Two studies have shown that chemoembolization helps improve median survival, although four other studies refute this notion. Work from MSKCC evaluating bland embolization to chemoembolization in a randomized Phase II study, demonstrates equivalency of the two approaches and bland embolization avoids some of the chemo-toxicity concerns.
I refrain from adding systemic sorafenib to embolization, in that while safety has been shown, there remains no evidence of any improvement in outcome.
Yttrium 90 radioembolization has gained interest as a treatment modality for locally advanced disease with portal vein involvement despite the lack of randomized studies.
Managing locally advanced disease can prove to be difficult, especially in view of differing opinions on the applicability of the different technologies available, and the paucity of phase III studies.
In deciding on a local therapeutic approach, I generally depend on the following considerations:
(1) Local therapies are not curative therapies;
(2) Despite the excellent local control, the focus should always be on survival-in other words, never push the envelope; local therapies cannot serve as surrogates for systemic therapies when the latter are indicated; and
(3) A multi-disciplinary group should always be engaged to discuss especially controversial situations.
Systemic Therapy
Some of the most important advances in the treatment of HCC in the last decade have been in systemic therapy. I use sorafenib as a standard of care for advanced HCC. Sorafenib is a multi-kinase inhibitor that has shown in two randomized placebo-controlled clinical trials an improvement in survival in patients with advanced HCC.
Certainly the addition of sorafenib remains a relatively small step towards the improvement of survival in advanced HCC, but it has undoubtedly opened the field to the many new biologic agents under development.
As an alternative to use of sorafenib as a standard of care, I make sure that all patients are considered for clinical trials, in the first- or second-line settings. Despite disappointing efforts that evaluated different anti-angiogenics in the first-line setting with agents including brivanib, linifanib, and sunitinib compared with sorafenib, there is a plethora of data about other emerging targets.
The first NCI-sponsored Phase III trial in HCC is ongoing, evaluating sorafenib and doxorubicin compared with sorafenib alone. This is a very important national effort that we strongly recommend that all contribute to and accrue patients on.
In the second-line setting, ongoing Phase III studies include evaluations of ramucirumab, everolimus, and ADI-PEG20, all compared with placebo. I would not recommend use of any commercially available therapy like everolimus outside of a clinical trial setting.
Like many colleagues, I continue to follow the evolving story on the role of c-met inhibitors in HCC. Two agents, cabozantinib and tivantinib, have shown an ability to improve survival in HCC in the second-line Phase II settings. It is unclear yet if this therapy is best limited to patients with c-met positive tumors only versus an unselected population.
Summary
Therapies for HCC continue to evolve rapidly. Managing a patient with HCC can be seen as challenging. I make sure to understand the etiology, evaluate the extent of disease and cirrhosis, and most critical, I involve all my colleagues in a very multidisciplinary way to evaluate the best plan of care for an individual patient.
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