Mark Yarchoan, MD

 Going back to our patient, a 60-year-old man who is Asian has hepatitis B and a tumor in multiple sites. The question is, how can we treat the patient? Dr Salem, you’ve got the story. Teach us.

 If you think about what this patient received, he received 1 of the major arterial therapies, the locoregional therapies or chemoembolization, which involves accessing the hepatic artery via the groin or the risk, placing a catheter and injecting various combinations of chemotherapeutics. That’s still a little controversial. The idea is that you instill a high dose of chemotherapy and slow down the blood flow by injecting some particles, effectively causing ischemic necrosis, chemical necrosis, etc, as a mode of treatment. It’s the gold standard for BCLC [Barcelona Clinic Liver Cancer] B disease. This person had C disease, but it was based only on performance status, so I can understand why chemoembolization was performed. Effectively, it’s a method of trying to control the disease, get a response, and maybe even downstage in some settings and, obviously, prolong life.

Perfect. Along that line, Dr Salem, I’m going to put on the screen the FDA approval of TARE [transarterial radioembolization]. Tell us a little more about that.

 As I was mentioning, chemoembolization is in the family of the arterial LRTs [locoregional therapies]. In the family is gland embolization and also radioembolization. I used to say that’s a relative newcomer, but I don’t think it’s a newcomer anymore; it’s been around for about 15 years. The technical principle is the same: you access the hepatic artery. But in this case, instead of injecting some chemotherapeutic or particle that will starve the tumor, you’re injecting a very high-dose radiotherapy. That basically means that the activity and the dose you can give in that area is very localized. It’s focused, it’s surgically precise, and it’s very well tolerated because you’re effectively radiating a very small portion of the liver where the tumor is held within that vascular territory. The biggest advantage, if you think about TARE over chemoembolization, is probably the adverse event profile. It’s very well tolerated, it’s done on an outpatient basis, and the response rate is very high. The quality of life is clearly 1 reason why the development of TARE was advocated.

 That’s very important information. I especially like that you brought up this last point because we all have to remember that the approval for procedural interventions is totally different from the approval for therapeutics. As Dr Salem just discussed, it’s about the safety component, or at least the effectiveness of it. It’s not necessarily required to have a randomization or a comparison. That’s what differs from what we do in systemic therapy, which we’re going to talk about in a second. Before we go there, we’ll go to Dr Yarchoan. Mark, have you seen any change in regard to the use of TARE with this approval, compared with TACE [transarterial chemoembolization], which has been the standard for more than 20 years?

 As a medical oncologist, I often defer decisions about best local therapy to others at our multidisciplinary tumor board. It’s wonderful to have this option; clearly some end points appear to be better with TARE. It’s important to remember that the LEGACY study was not a randomized study; it showed very nice local control rates. It did seem like patients did better if they went on to surgery, which suggests that maybe the pathologic response rates are not perfect with this modality. But we’re seeing more use of TARE, and it’s great to have this option.

 Thanks so much for that, Mark. Dr Singal, I have a question for you as well. Within the context of TARE and TACE, especially TARE, please tell us about the hepatology concerns and perspective. Of course, you can add what you like.

 There are a couple of things that I’d add. As we had said, TARE has been around for a long time. Even though the approval just happened, you’ve seen use of TARE in many academic centers for years. As Mark was saying, you see some increase. I don’t think it went from 5% to 50%. It’s worth putting in perspective that this has been a long road. We point to the LEGACY study, but LEGACY was the straw that broke the camel’s back in terms of getting this through the door. It wasn’t just 1 study. It wasn’t like SHARP, and it wasn’t like IMbrave150 in terms of it being 1 trial and then it happens. There have been years of investigation showing that TARE is safe and effective, and much was led by Riad in the Northwestern group. You’ve seen slow adoption of this over many years. To Riad’s point, this is because of longer time to progression and better tolerance but also a higher safety profile.

Compared with chemoembolization, where you see postembolization syndrome, you can see the LFTs [liver function tests] increase in many patients. With TARE, you can be highly selective. You can do a radiation segmentectomy. You can do this very safely. From a hepatologic standpoint, you can do this with less degradation in liver function over time if done in an expert and selective manner. From a hepatology perspective, in well-selected patients, when done by experts, it’s a very well tolerated therapy. It’s important not to expand use to a broad selection of patients just because it’s well tolerated in general. If patients are a Child-Pugh B9, have uncontrolled ascites, uncontrolled encephalopathy, a large shunt fraction, etc, then they shouldn’t undergo radioembolization. Patient selection is important. This is a very helpful therapy for us to have in our armamentarium, but it’s not like it went from 5% to 50%. This has been increasingly adopted over time.

Videos

Expert perspectives on the role of transarterial radioembolization in unresectable hepatocellular carcinoma following FDA approval.

Case 1: Role of TARE in Unresectable Hepatocellular Carcinoma

™ presentation titled “Hepatocellular Carcinoma Treatment Advances.” It’s a 

®. My name is Ghassan Abou-Alfa. I’m from Memorial Sloan Kettering Cancer Center, and I’m delighted and honored to be with great panelists. Dr Riad Salem from Northwestern University, maybe you could say a word or 2.

 Thanks, Ghassan. I’m the chief of interventional radiology and the vice chair of image-guided therapy at Northwestern Medicine in Chicago, Illinois. I’ve been here for about 20 years, and my area of research is hepatocellular carcinoma [HCC].

Great, thank you so much. It’s great having you aboard. Dr Amit Singal?

 Thanks, Ghassan. I’m excited to be here. I’m a medical director of our liver cancer program and the chief of hepatology at UT [The University of Texas] Southwestern Medical Center in Dallas, Texas. I’ve been here for 10 years. Like Riad, my area of clinical and research interest is hepatocellular carcinoma.

 That’s excellent. It’s good to see you again, Dr Singal. Now that we have a great doctor from Chicago and a great doctor from Dallas, we need somebody from the East Coast. Dr Yarchoan?

 Thank you so much, Ghassan. It’s a pleasure to be here. I’m Mark Yarchoan, and I’m a medical oncologist at Johns Hopkins Medicine in Baltimore, Maryland, focused on hepatocellular carcinoma and immunotherapy in particular.

Thank you again, Mark. It’s great seeing you all. We’ll be focusing on the treatment of advances in hepatocellular carcinoma. In today’s presentation, my colleagues and I will review clinical cases, discuss approaches of treating patients with hepatocellular carcinoma, and share our perspectives on key clinical trials that may impact our decisions. We’ll start with the first case of unresectable hepatocellular carcinoma. This patient is a 60-year-old Asian man with a history of chronic hepatitis B. He was treated for hepatitis B about 7 years ago, and he presents with a concern of abdominal pain to his gastroenterologist—a right upper quadrant pain. His performance status is 1. The work-up included an MRI and a large liver lesion. At 12 cm, it’s abutting the major blood vessels with multiple small lesions around it. A biopsy confirmed HCC [hepatocellular carcinoma], and the tumor was deemed unresectable after a surgical evaluation. As such, the patient was recommended to go on a chemoembolization, and that was given 3 times. There’s a lot of information that was presented. I’d like to touch on key points. I’ll start with Dr Singal. As a hepatologist, that biopsy story: yes or no? What are your thoughts?

 Ghassan, as you know, hepatocellular carcinoma has been an interesting cancer. It’s 1 of the few that we’ve been able to diagnose radiographically in many at-risk patients, including patients with cirrhosis and select patients with hepatitis B. If somebody has arterial phase hyperenhancement or delayed-phase washout, that’s typically classified as a LI-RADS [Liver Imaging Reporting and Data System] LR-5, and it can be called HCC with a 95% to 97% positive predictive value. Interestingly, those criteria have not been as well validated in patients with chronic hepatitis B. There are fewer data in chronic hepatitis B and only in select patient populations.

As far as we can tell, he’s noncirrhotic. In a noncirrhotic setting, and without the details of his chronic hepatitis B, some of these patients deserve biopsy to confirm the diagnosis. In general, we’re going back and forth on this whole biopsy question. Five years ago, I was firmly in the camp that we shouldn’t do routine biopsies in some of these patients, but now we’re seeing that some of these patients have mixed tumors. Some of these patients have cholangiocarcinoma that we didn’t recognize previously. The field is reassessing the role of biopsy in these patients. In this case in particular, we probably would have done a biopsy, given that he was noncirrhotic.

 a lot with the treatment of hepatocellular carcinoma. Do you have any mechanism of how you diagnose cirrhosis? Is it more about what you hear or are told? Is it a bit of a guesstimate?

 These cases often come through our liver multidisciplinary clinic. All of us approach these cases a little differently. Normally, it’s a clinical gestalt for us. What are the laboratory values? Is there clear evidence of cirrhosis on the skin? More and more, as Amit said, we’re erring on the side of biopsy, especially when, like this, there’s no clear evidence of cirrhosis. I agree with that recommendation.

 I second what you said, Mark. There’s no firm way of diagnosing cirrhosis. At the same time, we just mentioned hepatitis B, which can cause hepatocellular carcinoma without cirrhosis per se. As such, a biopsy would be a necessity. At the same time, I’ll add to what Dr Singal mentioned in regard to LI-RADS. LI-RADS is a great language for doctors to talk to one another, but it’s not 100% operatory diagnostic. As we heard, there’s no full validation for it. That’s why a biopsy would probably be deemed necessary. Before we move on to treatment, where we’re going to need a lot of help from Dr Salem as an interventional radiologist, what’s the recommendation for screening for patients with hepatitis B in regard to HCC. Dr Singal?

 Ghassan, when you look at this story, the patient presented symptomatically and was found to have a large tumor. This highlights that because he was not receiving screening, this tumor was unfortunately found at a large stage. When somebody has hepatitis B, they can develop HCC in the absence of cirrhosis. When you combine with other risk factors, this can happen at a relatively early age. If you have vertical transmission—which can happen in high-risk countries, many in Asia, Africa—the recommendation is to screen men starting at age 40 in the setting of chronic hepatitis B and women at age 50. This is because the male sex is an independent risk factor for HCC.

If somebody has a family history of HCC, you start screening early as well, and this screening should be done using an abdominal ultrasound with a blood-based tumor biomarker called alpha-fetoprotein [AFP]. When you use these 2 in combination, they should be done semiannually. If it’s done in an expert center, you can find the vast majority of HCC at an early stage. There are select patients with obesity, with significant liver nodularity, for whom ultrasound doesn’t work as well and you may need to consider alternative imaging modalities, such as MRI. For a majority of patients, particularly in chronic hepatitis B, where the liver is often less nodular, we do an ultrasound and AFP every 6 months in these high-risk individuals.

Thanks so much. I’ll summarize what we’ve heard so far because it’s very important. No. 1 is that a biopsy is a necessity because we’re dealing with localized disease, because we’re unclear about the cirrhotic component, and because of the relative limitation of LI-RADS. No. 2 is that the screening that’s best understood at this point is an ultrasound and then AFP on an every-6-months basis. Despite that, the risk factors are the same. They’re probably applied the same to the 2 sexes. Men, because of a genetic makeup, are more prone to HCC. That’s why we probably see more of the disease in that situation.

Sharing the first patient case of unresectable hepatocellular carcinoma, experts consider optimal screening and diagnosis practices in this setting.

Case 1: A 60-Year-Old With Unresectable Hepatocellular Carcinoma

During a Targeted Oncology Case-Based Roundtable event, Mark Yarchoan, MD, an assistant professor of oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, moderates a discussion about a 77-year-old woman with Child Pugh B and C hepatocellular carcinoma (HCC). 

According to the NCCN [National Comprehensive Cancer Network] guidelines, atezolizumab [Tecentriq] plus bevacizumab [Avastin] is the preferred first-line therapy regimen.

 Sorafenib [Nexavar] and lenvatinib [Lenvima] are both supported by category 1 data, and nivolumab [Opdivo] and FOLFOX [folinic acid, fluorouracil, and oxaliplatin] may be useful in select cases.

As an overview, the treatment landscape in HCC [hepa-tocellular carcinoma] has changed rapidly over the last couple of years. When I started treating this disease, sorafenib was the only approved therapy. Since then, we have gone from 1 to 9 therapies over 4 years. It is remarkable. Virtually every single trial we have is either a comparison with sorafenib or testing a new drug in sorafenib-treated patients. The biggest recent develop-ment is the positive IMbrave150 study [NCT03434379], which assessed the combination of atezolizumab plus bevacizumab.

 This combination had better results than sorafenib in terms of OS [overall survival] as well as some secondary end points. There are also a couple of trials of other therapies vs sorafenib that did not show superiority with regards to OS but showed some benefits with regard to secondary end points. These include the trials with lenvatinib, which had better PFS [progression-free survival] and ORR [objective response rate] than sorafenib. Then there was the trial with nivolumab, which is a technically negative study but I think is still useful as a front-line therapy in select cases.

What proportion of your patients with advanced HCC receive tyrosine kinase inhibitor (TKI) monotherapy as their first-line systemic therapy?

YARCHOAN: I would say that it is in the 11% to 25% range. This includes patients who have a history of transplant and probably should not get PD-L1 therapy, patients with active autoimmune disease, patients who need procedures where the use of bevacizumab is going to be problematic, and patients with a recent bleed or those for whom you are particularly worried about bleeding. These categories add up to quite a few patients. So there is a select group of patients who cannot get atezolizumab plus bevacizumab and for whom TKI monotherapy is an appropriate choice.

What is the evidence for the use of sorafenib for HCC?

YARCHOAN: Sorafenib was the first therapy to show a survival benefit in HCC. This is based on the SHARP [NCT00105443] and Asia-Pacific [NCT00492752] trials.

The SHARP study, a multicenter, phase 3 trial, was the definitive study in the United States.

 Sorafenib is a static drug; it does not tend to cause responses, but it did translate to an OS benefit

There was a survival benefit of almost 3 months with the sorafenib [10.7 months with sorafenib vs 7.9 months with placebo (HR, 0.69; P < .001)] but no significant difference in time to symptomatic progression [4.1 months vs 4.9 months; P = .77].

 The response rate was in the single digits. However, this was a very important landmark study because it was the first to show an OS benefit.

What is the evidence for the use of lenvatinib for HCC?

YARCHOAN:Much more recently, lenvatinib was the second therapy to be approved for frontline HCC treatment.

This approval was based on the phase 3 REFLECT study [NCT01761266]. This was a global study that was randomized against sorafenib and was set up as a noninferiority study. That means they were not trying to prove that lenvatinib was better; rather, that it was noninferior. There were multiple secondary end points such as PFS and ORR, and the study had standard enrollment criteria, and patients with unresectable disease, either BCLC stage B or not candidates for TACE [transarterial chemoembolization] or stage C.

The trial met its primary end point of demonstrating noninferiority.

 The median OS was similar for the lenvatinib and sorafenib arms [13.6 months vs 12.3 months, respectively (HR, 0.92; 95% CI, 079-1.06)]. There was a trend toward better survival in the lenvatinib arm, especially in patients with more aggressive disease, those with higher AFP levels, and other subgroups that have particularly aggressive biology.

Compared with sorafenib, lenvatinib did have better results in certain secondary end points. For example, PFS was basically double [7.4 months vs 3.7 months (HR, 0.66; 95% CI, 0.57-0.77; P < .0001)], and the ORR was 24% compared with 9% for sorafenib. So lenvatinib is clearly an active agent for HCC and some patients can get partial responses. I think it is worth noting that sorafenib performed well in this study. This is something we [have] observed with every single study since 2007. All studies used sorafenib as the control group, and sorafenib does a little bit better each time. For example, in this study the OS was 12 months, which is significantly better than the OS in the original SHARP study. The lenvatinib benefit was consistent in all subgroups. The poststudy systemic therapy was also similar between the 2 arms. However, PFS was a little longer in the lenvatinib arm; the patients switched over to secondary therapy less often and later than those on the sorafenib arm.

Since these drugs are both multitargeted TKIs, many of the AEs [adverse events] overlap.

 The thing to keep in mind with lenvatinib is that it tends to cause less hand-foot syndrome than sorafenib, which is a real plus. On the other hand, it does seem to cause a bit more hypertension than sorafenib does, probably due to more potent inhibition of VEGF.

How would you compare sorafenib and lenvatinib?

 Both sorafenib and lenvatinib are reason-able choices in the front-line setting. The sorafenib label says that it should be started at 400 mg twice a day.

However, many of us start it at 200 mg and work our way up. Lenvatinib is dosed by weight.8 So we start at 12 mg for patients who are over 60 kg and 8 mg for patients who weigh less than 60 kg. Lenvatinib comes in 4-mg tablets, which makes it easy to adjust the dose. We usually adjust the dose down by 4 mg per dose reduction, up to 3 dose reductions. I have had patients who seemed to be benefiting even from 4 mg. This is a potent drug and many patients require dose reductions, and that is OK. I do not think you should be nervous about going down on the dose. 

For patients with a Child-Pugh score B, I feel more comfortable with sorafenib because there are prospective data for sorafenib in that subgroup, while there are none for lenvatinib. Additionally, the REFLECT trial showed a little bit of an association with hepatic encephalopathy for lenvatinib.

I have a question regarding the etiology of cirrhosis. In the subset analysis for those with alcoholic cirrhosis there are impressive data with lenvatinib, while for those with hepatitis B and C there are good data with sorafenib but not so strong with lenvatinib. What do you think about that? Similarly, what are the data for dealing with cirrhosis due to the NASH [nonalcoholic steatohepatitis] type of hepatitis? This is important because it is going to become more prevalent as hepatitis B and C become a thing of the past. What is your opinion about this?

 The data suggest that sorafenib may be better for hepatitis C. But I do not think that difference is so striking in the clinical practice.

 All phase 3 trials in HCC break down the results based on the different etiologies. However, I am still not totally convinced that we should be changing our practice patterns that much based on etiology. In my experience, patients with hepatitis B usually have a little bit less cirrhosis and can often tolerate more intensive therapy. But aside from that, I don’t often change my management based on etiology because I do not think there is strong enough evidence to do so.

Another question I have is about something that was a hot topic many years ago. Say you discover a new hepatitis B or C infection during the work-up; do you hold up on treating it because it could lead to some kind of immune response that would interfere with the HCC?

That is a great question. There were some data, mostly from Spain, that showed that if you treat the hepatitis C, even if at the time of transplant, that the cancer might recur.

 So they suggested that the hepatitis C was some kind of neoantigen or antigen for the immune system to control the cancer. I have to say that story has not really panned out with subsequent data. It does not seem like the hepatitis C itself is an important antigen for controlling HCC because it is not only in the tumor but also in the tissues around it. So I do not get nervous about treating hepatitis C. That being said, the reason to treat hepatitis C is to prevent cirrhosis, to prevent HCC. So once they have HCC, I also do not know if it is necessary to treat the virus itself. I am not sure that there is a clear answer at this point. But I would not be nervous about treating the hepatitis C; I think it is a reasonable thing to do.

On the topic of etiology, liver cancer is now projected to be the number 3 cause of cancer deaths in the United States by 2040.

 There is a misconception that this problem is going away because we have drugs for hepatitis B and C. I think this NASH epidemic is translating into many more cases of HCC. Additionally, alcohol consumption has also increased, and that may be driving part of the epidemic that we are seeing.

I am always a little bit puzzled with NASH cirrhosis because of the lipid metabolites. Sometimes patients say that they don’t drink or only drink socially. However, I think that over several decades the alcohol has a role in NASH development.

The way patients are being referred to my practice is very interesting. A lot of the patients [with HCC] that I treat come from interventional radiologists who are holding them too long, or the patients feel that the treatment is not working and they want to see an oncologist. [However,] I still have a trickle from gastrointestinal doctors.

 I think this discussion of when patients should transition from interventional radiology to medical oncology is very interesting. It’s a controversial thing that every single practice and every group needs to deal with. We all have seen these patients who get repeated TACE until there is no liver left. It seems like it is becoming more often that the patients are the ones requesting to see a medical oncologist. So it seems that the patients are driving the referrals.

1. NCCN. Clinical Practice Guidelines in Oncology. Hepatobiliary cancers, version 3.2021. Accessed August 10, 2021. https://bit.ly/3iVa7pC

2. Finn RS, Qin S, Ikeda M, et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745

3. Llovet JM, Ricci S, Mazzaferro V, et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390. doi:10.1056/NEJMoa0708857

4. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25-34. doi:10.1016/S1470-2045(08)70285-7

5. Cheng AL, Finn RS, Qin S, et al. Phase III trial of lenvatinib (LEN) vs sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocel-lular carcinoma (uHCC). J Clin Oncol. 2017;35(suppl 15):4001. doi:10.1200/JCO.2017.35.15_suppl.4001

6. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treat-ment 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

7. Nexavar. Prescribing information. Bayer HealthCare Pharmaceuticals Inc; 2018. Accessed August 18, 2021. https://bit.ly/2W3NSF5

8. Lenvima. Prescribing information. Eisai Inc; 2021. Accessed August 18, 2021. https://bit.ly/2W0qQyK

9. Vinaixa C, Rubín A, Aguilera V, Berenguer M. Recurrence of hepatitis C after liver transplantation. Ann Gastroenterol. 2013;26(4):304-313.

10. Rahib L, Wehner M, Matrisian LM, Nead KT. Projection of cancer inci-dence and death to 2040 in the US: impact of cancer screening and a changing demographic. J Clin Oncol. 2020;38(suppl 15):1566. doi:10.1200/JCO.2020.38.15_suppl.1566

Articles

During a Targeted Oncology Case-Based Roundtable event, Mark Yarchoan, MD,  moderates a discussion about a 77-year-old woman with Child Pugh B and C hepatocellular carcinoma. 

Yarchoan Compares Lenvatinib and Sorafenib for Child Pugh B and C Hepatocellular Carcinoma

Mark Yarchoan, MD, medical oncologist, John Hopkins Medicine, explains his method for sequencing available treatment options for patients with hepatocellular carcinoma (HCC).

There is no correct answer to the question of what the best second-line treatment is for HCC. This is because more data are needed on most of the available agents. Previously, many of these drugs were studied when the only first-line drug available was sorafenib (Nexavar).

Immunotherapy will continue to play some role in the treatment of HCC because there is a group of patients who respond well to antiPD-1 therapy and some can have disease control for years. The majority of patients, however, do not respond to anti&ndash;PD-1 therapy, so it should only be considered for patients who progress on first-line therapy and are reluctant to take another tyrosine kinase inhibitor because of toxicity.

Mark Yarchoan, MD, explains his method for sequencing available treatment options for patients with hepatocellular carcinoma.<br />
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Mark Yarchoan, MD | Authors

Articles

Case 1: Role of TARE in Unresectable Hepatocellular Carcinoma

Case 1: A 60-Year-Old With Unresectable Hepatocellular Carcinoma

Yarchoan Compares Lenvatinib and Sorafenib for Child Pugh B and C Hepatocellular Carcinoma

Yarchoan Discusses Sequencing Treatment Options for Patients With HCC