Initial Treatment Approach in Hepatocellular Carcinoma

Ahmed Kaseb, MD:Our case was treated with transarterial chemoembolization, or what we callTACE, based on the treating team’s multidisciplinary decision at the time. If we calculate the Child-Pugh classification of this patient, he will fall under the category of class B because of a bilirubin of 3 mg/dL and mild ascites. This is a gray zone based on the fact that most of the randomized clinical trials, whether systemic or localized, focus on patients classified as Child-Pugh A. However, it reflects real-life scenarios where treating physicians in community settings are faced with patients with underlying liver disease, typically Child-Pugh B in a significant number of cases. So they proceeded with selective TACE for this patient based on the fact that it was a single tumor and the patient’s performance status was excellent.

Restaging at 1 month revealed that the patient did not have a good response to the TACE procedure, which is not totally unexpected in this very specific scenario for 2 main reasons. No. 1, the size of the tumor. That basically takes us back to 2002, when the TACE procedure was approved for HCC [hepatocellular carcinoma]. The 2 major studies that approved it were relying on a patient population with an average tumor size of 5 cm, based on 1 study, and 7 cm, based on another study. So beyond 7 cm, patients typically need more than 1 session of TACE. Additionally, patients with advanced liver disease, Child-Pugh B, in general, don’t respond very well because of their liver function status. So these 2 factors probably could have contributed to the lack of a good response in our patient.

The treating team decided to start systemic therapy in the form of lenvatinib at 12 mg daily. That leads to a very important question: When to start systemic therapy, and how to make the choice of which systemic therapy to use. In general, systemic therapy for HCC is indicated in the case of metastatic disease, or in the case of major vascular invasion on imaging—the portal venous system, for example, or hepatic veins; or in the case of a lack of response to localized therapies. So patients who are not candidates for surgical resection or transplant, who either did not respond to local therapy or were not local therapy candidates, can go on systemic therapy.

This patient followed this train of thought, and was started on lenvatinib at 12 mg daily. However, 3 months later, the patient did not respond based on imaging. The first big question is, which agent to start with. Currently, FDA-approved frontline therapies in HCC are limited to 2 drugs: sorafenib and lenvatinib. If you follow both studies that approved both agents, they had almost identical inclusion/exclusion criteria. And then, lenvatinib was approved based on a noninferiority study design against sorafenib.

In general, the decision to start patients on which agent is really dependent on the specific practice. There was a meta-analysis published in theJournal of Clinical Oncologya couple of years ago that looked into this question of sorafenib and looked into an old meta-analysis of all phase III studies of sorafenib. It was concluded that patients with hepatitis C benefitted the most from sorafenib. There is also a subset analysis of lenvatinib, a phase III study, against sorafenib that suggested a trend toward better benefit for hepatitis B patients on lenvatinib. The study was not powered enough to really answer that question. However, these trends led a lot of practices to tailor treatment based on a patient’s hepatitis status. For hepatitis C, for example, a lot of physicians start with sorafenib. For hepatitis B, a lot of physicians start with lenvatinib.

Also, one of the determinant factors is whether any response of the tumors to therapy would change their course of management. For example, if you look at the lenvatinib versus sorafenib study, the response rate was much higher on lenvatinib than sorafenib. In fact, the independent radiologic assessment with modified RECIST [Response Evaluation Criteria in Solid Tumors] showed up to a 40% response to lenvatinib. So if the patient responds, in terms of partial shrinkage of the tumor, it could change therapy decisions. Some physicians also start on lenvatinib.

However, we have to be careful in this era of strong antiangiogenic drugs, such as lenvatinib in the frontline and other drugs in the second-line, in terms of potential adverse events in patients with portal hypertension and large varices. In my practice, I always start with an upper endoscopy before initiating antiangiogenic therapy to make sure we evaluate the varices. If a patient is at risk for bleeding, we address that before we initiate therapy.

Transcript edited for clarity.

Case: A 65-year-old Man With Cirrhosis and HCC

A 65-year-old man with 10-year history of cirrhosis was seen for routine follow-up; referred for further lab and imaging studies based on enlarged lymph nodes and new-onset jaundice.

H & P

• PE: Yellowing of the skin and sclerae
• Social History: drinks 20+ alcoholic beverages/ week for the past 15 years
• ECOG: 0

Labs

• AFP: 550 IU/mL
• Child-Pugh B
  • Bilirubin: 3 mg/dL
  • Albumin: 3.5 g/dL
  • No hepatic encephalopathy
  • Grade 1 ascites

Imaging

• Multiphasic contrast MRI of the abdomen revealed an 8-cm encapsulated mass in the left hepatic lobe showing hypervascularity on arterial phase and washout on venous phase
• Further imaging of CAP revealed no metastasis
• Diagnosis: unresectable hepatocellular carcinoma

Treatment

• Underwent TACE; follow-up imaging at 1 month showed no response
• Started on lenvatinib 12 mg once daily; follow-up imaging at 3 months showed no response
• Received nivolumab 3 mg/kg every 2 weeks

Follow-up

• 3 months later; patient complained of increasing fatigue
• AFP; 600 IU/mL
• MRI showed disease progression in the liver, one new adrenal lesion