Mitesh J. Borad, MD

Decisions in the Clinic: Treating Patients With Hepatocellular Carcinoma

Question

After a patient is diagnosed with hepatocellular carcinoma (HCC), what are the first treatment options you consider? What are the key patient factors that influence your decision making?

Answer

Patients with HCC, unlike some other patients with cancer, need a multidisciplinary approach when making decisions about initial treatment and prognostic communication. The spectrum of treatments that can be employed is quite wide. If eligible, the patient could be considered for curative procedures such as surgery or transplant. Discerning which patients may be suitable candidates for those treatments is not a trivial matter and is best done through proper engagement with colleagues in surgery and transplant, hepatology, and, of course, colleagues who are experts in local-regional therapies such as interventional radiologists or radiation oncologists.

It is important to determine whether a patient has curative potential or can be down-staged to get to curative potential, or if the patient clearly has advanced disease, the two extremes. Then you have local-regional therapies in the middle, if you’re not clearly going in 1 of those directions or the other. Determining which side of that spectrum the patient falls more toward, requires real time and multidisciplinary engagement.

In terms of patient factors to consider, we ask what is the extent of the patient’s disease — a single lesion or multiple lesions? Is there vessel involvement? Vascular invasion of the tumor? Is there metastatic spread outside of the liver?

What are the host factors of the patient? If there are potentially curative therapies on the anatomic level, could the patient undergo surgery? What is their age? What are their other medical conditions?

Do they have underlying liver disease? That fact can determine how much remnant a patient will have after resection. What is the volume of the remnant and the state of the liver?

These are some of the common factors. Etiology doesn’t play as big a role as of yet. One question people are wondering is, for patients with hepatitis C and resection, do you get rid of hepatitis C before or after the graft or transplant, so your new liver is not injured by the virus?

Question

What is the role of molecular profiling in HCC management? In what ways can it be useful to have a tissue diagnosis for patients?

Answer

I use molecular profiling on my end, but in the context of research. There are no approved [targeted] therapies per se for HCC, where you would use the molecular profiling to select patients for therapies.

I don’t think molecular profiling will necessarily preclude a patient from getting a particular therapy. Unlike other tumors, it is still an area where there needs to be a lot of development before people start to apply it to treatment and until research matures and more formal drug approvals come along.

Historically, HCC diagnosis has often been accomplished using imaging criteria in the context of relevant risk factors, such as chronic hepatitis B or C. However, with the advent of next generation sequencing-based genomic profiling, tissue samples may play the dual role of true diagnostic confirmation and therapeutic target identification, at least in the advanced disease setting. For patients being considered for transplant, biopsy may not be undertaken because of the concern for tumor seeding.

Question

What research from the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting did you find to be most relevant to treating patients with hepatocellular carcinoma?

Answer

Amongst the notable data presented were phase 2 data for the immune checkpoint inhibitor pembrolizumab, which was consistent with prior data using nivolumab with an approximately 20% response rate, with many of these responses being durable.¹ In a phase 3 study, ramucirumab, which is an antibody against VEGFR2, showed survival benefit in alpha-fetoprotein-high patients.² Lastly, a combination of atezolizumab with bevacizumab was one in which people saw some promise.³ This represents 1 of the first efforts combining an antiangiogenic agent with an immune checkpoint inhibitor. I envision a lot more activity using this concept with the various available agents from both categories.

Question

How might the data on agents like cabozantinib (eg, from the CELESTIAL trial), lenvatinib (REFLECT trial), and ramucirumab (REACH-2) change your decision making for patients?

Answer

I mentioned ramucirumab. Cabozantinib showed survival advantage in the second- and third-line and is another option in that space.⁴ Similarly, lenvatinib showed noninferiority to sorafenib, and provides another option in the first-line space.⁵ I don’t think these represent tremendous advantages, but they are certainly additional tools for physicians to use for these patients.

Question

Are there any ongoing clinical trials you would recommend for patients with advanced, unresectable HCC?

Answer

There is a wide array of studies of immune checkpoint inhibitors being conducted. Any of those studies would be highly pertinent for consideration.

We either refer patients to trials we’re conducting here at our institution or, if not, we certainly refer them to institutions where they can get access to these agents.

Immune effects in patients with HCC can include liver injuries because that’s the organ where the tumors reside and that is something for clinicians to keep in mind. Immune-related adverse effects (irAEs; such as endocrinopathies) are in the same range, no different from other cancers, and can be managed by holding the drugs or with steroids. The one concern is liver injury; it is important that we conserve carefully and manage appropriately. If injury occurs, it is difficult to continue administering those agents. I think it is a conundrum — if you get a response but you get toxicity, do you risk continuing the therapy or do you just stop after a certain number of doses.