Targeting Cancer With Tyrosine Kinase Inhibition in Frontline HCC

Part 1: Selecting Systemic Therapy in HCC With Serious Comorbidities

During a live virtual event, Pierre Gholam, MD, discussed treatment options for a patient with hepatocellular carcinoma who had serious medical conditions including cirrhosis, Crohn's disease, and variceal bleeding.


A 77-year-old White woman presented to her primary care physician complaining of abdominal pain and fatigue.​ She had cirrhosis due to heavy alcohol use as well as Crohn’s disease controlled with infliximab. She had a history of variceal bleeding, with banding 2 months earlier. She had an ECOG performance status of 1.

A CT of her chest, abdomen, and pelvis with triphasic liver evaluation discovered a 4.5 cm LI-RADS 5 hepatic mass in the right lobe and metastasis in the lung. She had Child-Pugh class A and an alpha-fetoprotein level of 380 ng/mL.

A biopsy was obtained and confirmed the diagnosis of hepatocellular carcinoma (HCC). Considering the AJCC Stage IV disease and Child-Pugh A cirrhosis, what frontline therapy are you most likely to recommend for this patient?


  • How you would consider various factors in selecting frontline systemic therapy for this patient​, including age, cirrhosis, comorbidities, bleeding risk, Child-Pugh status, patient preference, and autoimmune disease?

PIERRE GHOLAM, MD: [Physicians may be concerned] about the diagnosis of Crohn’s disease, whether that was well-controlled or not, because they would to some extent tailor their therapy to that particular issue. Dr Karamlou, can you give us your thoughts on this?

KASRA KARAMLOU, MD: When you see a patient with hepatocellular carcinoma [HCC], their Child-Pugh status is very important, because I think the majority of the data we have for therapies are in that cohort of patients. Then their comorbidities, like autoimmune disease and presence of varices, will have an impact on your front-line therapy. If the patient had variceal bleeding recently, or has an autoimmune disease, regardless of what the NCCN recommendations are, you’re not going to treat them with bevacizumab [Avastin] plus atezolizumab [Tecentriq].

The etiology of the cirrhosis matters to some extent because I think there are data, at least for the immunotherapies, that certain patients with, for example, hepatitis B-related cirrhosis may do better.1

EVAN LANG, MD: For most patients, I try to use the best frontline therapy if possible. Of course, I agree that most indications for a lot of agents that we consider, those patients have to have a Child-Pugh A status. I look at some of the risk factors, the bleeding risk and for autoimmune disorder. I think most patients can tolerate the best possible treatment as frontline therapy.

In this case, I’ll worry about the Crohn’s disease even though it is under control. And the patient has varices, though it was banded about 2 months ago. So, those are the kind of factors that I would consider, and the Child-Pugh status and comorbidities. But my experience is that most patients can tolerate the best frontline therapy, and we [should] try to give the best treatment if possible.

GHOLAM: Dr Rhoades, what are your thoughts on [risk factors, including] oral versus intravenous [IV], convenience, and the COVID-19 pandemic? You could lump them together because this hearkens to whether the patient would rather just take oral therapy at home or come to an infusion center.

CHRIS RHOADES, MD: I tend to check for hepatitis B virus in all my patients if they haven’t been checked [already]. I’m concerned about reactivation with therapy, including immunotherapy. I am in a small community practice; less than 10% of my patients have HCC. But, if they have a prior liver transplant, I think immunotherapy is contraindicated in that situation.2

Regarding patient preference, that is a factor. The more advanced age, the more comorbid problems they have, and I would take their preference into account. COVID-19 pandemic, that’s an individual thing. I work in an area where our vaccination rate is extremely low, it’s about 36%....So, I tend to use the most aggressive treatment for response rate and survival, but I do take patient preference and safety/tolerability into account probably just about as equally.

GHOLAM: Dr Inoshita, oral versus IV; if you were to pick an oral agent, what would you typically use?

TSUYOSHI INOSHITA, MD: Tyrosine kinase inhibitors [TKI] are somewhat difficult for these patients, but we used to give sorafenib [Nexavar], which is tolerated OK. But, if you want to try something more efficacious, probably lenvatinib [Lenvima], or cabozantinib [Cabometyx], or something like that could be considered.

GHOLAM: Lenvatinib is FDA approved in the first line, [while] cabozantinib is [only] for the second line.3,4

INOSHITA: Yes, so if you are forced to use oral medication, probably lenvatinib. Or, if the patient has difficulty, maybe sorafenib.

TAREK SABAGH, MD: From my experience with HCC, [my choice would be based on survival outcomes]. Those patients, once they progress on first-line therapy, don’t do well. We have a dedicated liver cancer clinic with interventional radiology, surgical oncology, and medical oncology. The patients who have limited disease and end up getting local treatment with yttrium Y-90 or stereotactic body radiation therapy [are treated], but I have not seen a systemic therapy that affects survival for patients with metastatic disease. So my goal is [treatment with] response.

GHOLAM: That’s a very thoughtful way of thinking about it. When I started treating HCC a long time ago, I wasn’t entirely sure that that was a valid way of looking at it. But I see what you just said; I think response rates are meaningful and do factor in our decision to treat patients. So, I am very much in agreement with what you just said.

ARUN SENDILNATHAN, MD: I do want to add something for the bleeding risk. For patients with cirrhosis or hepatitis, I definitely look at their history of gastrointestinal [GI] bleeding if they have any history of varices. So, that is the reason for my decision of bevacizumab plus atezolizumab. This is a patient that never had any endoscopic workup in the past. I do send them to GI specialists to screen for varices, and then give them bevacizumab.

GHOLAM: Let me take this a step further. The process of variceal mitigation and eradication takes up to 2 months. Would you be willing to delay initiation of therapy while varices are mitigated or treated?

SENDILNATHAN: If they have a history of life-threatening bleeding requiring hospitalization, I would definitely want that to be taken care of before I give them the bevacizumab. But if they don’t have any evidence of life-threatening bleeding in the past, if their hemoglobin is stable with no clinical evidence of hematemesis, I would proceed.

GHOLAM: What if someone had a recent endoscopy that showed large varices, and an estimated risk of life-threatening bleeding in the next year of somewhere between 10% to 15%. Would you be satisfied with those odds?

SENDILNATHAN: We are fortunate that our GI specialist takes patients quickly. So, I have a couple of patients that he was able to take care of, and I was able to start those patients within 2 weeks.

KARAMLOU: [I believe] patients with varices were excluded from the [REFLECT] study [NCT01761266].5


1. Li B, Yan C, Zhu J, et al. Anti-PD-1/PD-L1 blockade immunotherapy employed in treating hepatitis B virus infection-related advanced hepatocellular carcinoma: a literature review. Front Immunol. 2020;11:1037. doi:10.3389/fimmu.2020.01037

2. NCCN. Clinical Practice Guidelines in Oncology. Hepatobiliary cancers, version 5.2021. Accessed March 4, 2022.

3. FDA approves lenvatinib for unresectable hepatocellular carcinoma. FDA. Published August 16, 2018. Accessed March 4, 2022.

4. FDA approves cabozantinib for hepatocellular carcinoma. FDA. Published January 14, 2019. Accessed March 4, 2022.

5. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173. doi:10.1016/S0140-6736(18)30207-1