Liver-Directed and Systemic Therapy in HCC

Richard S. Finn, MD:Liver-directed therapies play a very big role in the management of patients with liver cancer. Certainly, patients who have early-stage disease or intermediate-stage disease do get liver-directed approaches, whether that be of radiofrequency or microwave ablation, which is percutaneous and is very effective for managing smaller tumors typically in a 3- to 4-cm range at most.

Chemoembolization, which is a transarterial approach, also called TACE, is a very effective way to managing multifocal tumors or larger tumors that are beyond resection or percutaneous ablation criteria. More recently, radioembolization, or Y90, is being looked at as a locoregional therapy for patients who would be candidates for chemoembolization or even patients refractory to chemoembolization.

There’s no doubt that these treatments play a key role, but it’s also recognizing the limitations of these treatments. Certainly, outcomes with any intervention are related to patient section. Certainly, patients have to be well compensated. Right? They can’t have significantly deteriorated liver function or they won’t tolerate these approaches. In this case specifically, I don’t have any real concerns about their liver function for getting a locoregional liver-directed therapy. However, there are several characteristics of this tumor that make it not a good tumor for local therapy. One, it has macrovascular invasion. We know that is a poor prognostic sign for efficacy and outcome with locoregional approaches. It is multifocal with several satellite lesions. In addition, it’s a very large infiltrative tumor. That’s a characteristic that typically does not do well with chemoembolization.

Radioembolization is still being worked out on where the most appropriate place for this therapy would be. Recent studies comparing radioembolization with systemic treatment for patients with more advanced tumors, possibly like the patient we have here, was a liver-confined disease but vascular invasion. This is a patient who we know gets a survival benefit from systemic treatment. And recent studies evaluating radioembolization versus systemic treatment with sorafenib have been negative, both the SARAH and SIRveNIB studies. So, I think the specific patient we have here is not someone who would benefit from locoregional therapy and is an appropriate candidate for systemic treatment.

So, this patient is an excellent candidate for systemic treatment. They have good performance status and they’re Child-Pugh A. The patient is not curable because of vascular invasion in the large tumor. The patient is not a good candidate for locoregional therapy because of the large tumor—it’s infiltrative nature, multifocality—but is a very good candidate for systemic approaches. A clinical trial, I think, would be the best option, if there was one available. Outside of a clinical trial, currently the standard treatment would be sorafenib. Sorafenib has been shown repeatedly in randomized studies to improve survival with a manageable side effect profile, especially in someone like this, and I think his high performance status in Child-Pugh A.

Recently, immunotherapy approaches have been shown to have some activity in liver cancer. The current USFDA label involves nivolumab in patients who have progressed on sorafenib. The use of MSI testing relates to the fact that PD-1—directed therapies have a fairly broad indication that is histology agnostic, but is based on patients who have tumor characteristics that have microsatellite instability that PD-1 drugs may be used.

The incidence of MSI in liver cancer is very low, probably around 5% of patients have MSI. The data of PD-1 inhibitors in MSI, HCC tumors specifically, are not a very large experience. Routinely, I do not check MSI status. Often, we don’t have tissue available to do that. I would say it’s not unreasonable to send it at some point for this patient. This patient did have a biopsy. It may open up a therapeutic opportunity later on, but I think overwhelmingly, the data for improving OS, or overall survival, right now are with the small molecule inhibitors.

Transcript edited for clarity.

February 2017

• A 59-year-old man with presented with RUQ pain and fatigue.
• PMH: Cirrhosis, HCV infection
• SH: lives alone, drinks alcohol daily (~15 drinks/week)
• ECOG, 0
• Laboratory findings:
  • AFP: 677 IU/mL
  • Platelets: 144,000 cells/mm³
  • INR, 1.7
  • Bilirubin: 1.8 mg/dL
  • Albumin: 3.9 g/dL
  • Hepatic encephalopathy: none
  • Ascites: mild
• Child-Pugh A
• Abdominal CT scan showed a large mass (8.6 cm) involving hepatic segments IV and VIII with portal vein infiltration, diffuse 1.0-cm to 1.5-cm nodules in the right hepatic lobe; 1.5-cm left portal vein thrombosis
• Surgical consult, unresectable based on tumor size and portal vein invasion
• Biopsy findings showed grade 3 hepatocellular carcinoma, marked fibrosis  
• The patient was treated with TACE; dynamic liver computed tomography at 1 month showed a partial response; repeat TACE showed no additional response
• The patient was started on sorafenib
• Imaging at 2 and 6 months showed a partial response with marked regression of the hepatic mass and smaller nodules.

February 2018

• The patient reports feeling fatigue, requiring rest during the day, but continues to work full-time
• CT of chest, abdomen, and pelvis showed new pulmonary nodules (2.0 cm and 3.1 cm) consistent with metastatic disease
• ECOG, 1
• He was started on regorafenib 160 mg daily
• After 2 weeks on therapy he developed grade 2 hand-foot syndrome which resolved after dose reduction to 120 mg daily
• After 3 months the patient has stable disease and improvement of symptoms