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Emerging Therapies for HCC Management

What are some unmet needs in liver cancer? We have a lot of treatment options that have come up. Just like the questions that were raised previously—how do we sequence the prime therapies? Do we use sorafenib first because second-line options are for sorafenib failures? Do we use lenvatinib? Do we use checkpoint inhibitors in second-line setting or do you continue TKIs [tyrosine kinase inhibitors]?— that sequencing question becomes important. How we sequence currently effective liver cancer patients is 1 crucial question we have.

The second area of unmet need for my patient population is that most of the studies are done in Child-Pugh A patient populations. These are patients with good liver function, and I have seen in my practice about 30% to 40% of my patients actually are Child-Pugh B and C patients. Unfortunately, there are not many studies, except for nivolumab in Child-Pugh B7 patients. All other studies are done in Child-Pugh A5 and A6 patient populations.

Another unmet need is how we can manage those patients with poor liver functions and those Child-Pugh B patients. For Child-Pugh C we discuss hospice and palliative care, but in people with moderate liver dysfunction, how do we manage those patients? Some critical unmet needs are: Do we need to conduct clinical trials in patients with Child-Pugh or liver dysfunction? How do we sequence currently effective agents? How do we do clinical trials in other pathways and things? There is a lot of science and a lot of progress that still needs to be made in patients with liver cancer.

We are conducting a lot of clinical trials of adding immune checkpoint inhibitors in the earlier setting. For a patient after resection, we are looking at checkpoint inhibitors to see if those are effective in high-risk patient populations. We are also doing clinical trials looking at checkpoint inhibitors after a locoregional therapy, like after TACE [transarterial chemoembolization].

Those data will be emerging and trying to use systemic therapies earlier on in the adjuvant setting as well as in the locally advanced setting. But we also have to answer questions for patients with poor liver reserve. How do we manage those patients?

 Most patients usually have poorly differentiated HCC. For those patients, we usually use the CT or Gd-EOB-DTPA [gadolinium–ethoxybenzyl-diethylenetriamine pentaacetic acid]–enhanced MRI scans to find differentiating factors. In that case, we performed a PET CT. PET CT is useful to diagnose poorly differentiated or invasive HCC, and the lenvatinib is very effective for poorly differentiated HCC. We use lenvatinib, which has good tolerability for poorly differentiated HCC, PET-positive HCC. Of course, lenvatinib is not perfect, so the very aggressive tumor is for those HCCs. We need another combination trial—a combination strategy like PD-L1 antibody plus anti-VEGF agent.

It’s diluting a lot along those lines. The problem in hepatocellular carcinoma patients is that the underlying cirrhosis is typically, over time, deteriorating. It is not just the tumor defining treatment options; it’s mostly liver function. We probably see only the sequence of 1 to the other line. This is what has been demonstrated by observational trials, that roughly a quarter only makes it from 1 line to the other.

 It was quite striking to see, from the CheckMate 459 trial, that around half of patients, after first line, went on to receive a second-line regimen. Likewise, from the KEYNOTE-240 trial in the second line, nearly half of patients went on to receive a third-line regimen. This is telling us that a subset of patients across lines of therapy are doing quite well and are able to try multiple approaches and to determine which is the most effective for their cancer. In some cases, this will allow us to perceive a third-line therapy, and I would add this is not an insubstantial number. This is a meaningful proportion of patients who will go on to receive third-line therapies.

That means that we need to better identify how to sequence therapies, particularly with the rapid changes in the frontline setting. We need to do our best using pooled analyses and retrospective analyses of patients who have received downstream therapies on clinical trials, as well as large real-world databases to the extent that they exist, to define the optimal approach in the later-line space. Ideally, we will have prospective trials to help guide choice of therapy. However, it will certainly take a long time and certainly won’t be feasible for every possible clinical question that we face. Therefore, it’s important to perform pooled and retrospective analyses, as well as look to the real-world data sets when available.

In the United States the checkpoint inhibitor monotherapies are approved: nivolumab and pembrolizumab. But in Japan, those 2 are not approved. We are waiting for atezolizumab-plus-bevacizumab approval. The IMbrave150 trial was positive and was published in the

 recently. It will be approved in Japan maybe this year.

The first-line option will be the atezolizumab-bevacizumab combination therapy. After that, we select the multikinase inhibitor, like sorafenib or lenvatinib, because there is a report that the PD-1 antibody binds to a CD8-positive T cell for more than 20 months. That means that even though progressive disease after immunotherapy is changing, switching to the multikinase-targeted agent like lenvatinib and sorafenib provided the very favorable situation that lenvatinib or sorafenib will kill the tumor cell and will change the tumor microenvironment, from tumor suppressive to tumor permissive. In that sense, for 20 months, there is that multikinase inhibitor, which provides the same situation with the combination therapy as immunotherapy plus TKI. Sequencing is similar after immunotherapy. In front line, maybe atezolizumab-bevacizumab therapy, then a first-line agent like lenvatinib, sorafenib, then ramucirumab or regorafenib or cabozantinib. Lenvatinib can also be used, as I said, third line and fourth line. It provides good response.

 My first hope is that we can identify a biomarker of response to immune checkpoint inhibition as monotherapy. There’s a reproducible number of patients who have deep and durable benefit from drugs like nivolumab, pembrolizumab, and even atezolizumab if we look at the phase 1b studies leading to the atezolizumab-bevacizumab regimen. Using immune checkpoint inhibitors as monotherapy, about 15% to 20% of patients can achieve a robust immune response. I hope there is a way to identify those patients, because it will help guide treatment sequencing, whether patients need an up-front combination or whether they could have this deep and durable benefit from a monotherapy, PD-1 or PD-L1 inhibitor, alone.

What that biomarker will be remains elusive right now. There is certainly a trend in many of these studies toward improved outcomes with higher PD-L1 expression on tumor, but not 1 study has shown a significant result, owing in part to small sample sizes and underpowering with respect to the biomarker question. This is because of small sample or perhaps an overall negative study end point.

There are other potential candidate biomarkers, such as immune infiltration or immune class gene signatures. Those are more complicated to scale as a biomarker across the larger population. We can look to data from other tumor types. It may be possible, at least based on the reproducible proportion of patients with a very clear-cut benefit. I hope there will be a monotherapy biomarker in the future.

Beyond a biomarker to define that population of patients likely to benefit from monotherapy, I see the treatment landscape evolving to include nuanced choice of combination regimens in front line, according to patient factors, tumor factors, and maybe a biomarker. Hopefully we will be able to develop wise approaches to choice of therapy in the second and third line using pooled and retrospective analyses to guide the sequence of therapy downstream.

Metastatic HCC Unmet Needs

What do we have as evidence? The only I/O agent that has been convincing in demonstrating benefit was atezolizumab in combination with bevacizumab in first line. That’s what we have. The monotherapy has not made it into a significant analysis, nivolumab in first line and pembrolizumab in second line, but there are other substances still around. As for the question about monotherapy, whether it’s first or second line, the door is not yet closed.

The objective response rates that we have been seeing in both first and second line are very convincing. If you benefit from I/O therapy, then the likelihood that this is a deep and a durable response is very good, and that can be an aim to go for. If you ask a group of experts if you—not as a physician but as a patient—were suffering from HCC, what would you personally want to get as first-line treatment? Most people will tell you they will get started with an I/O. But it is not really evidence based and has not been thoroughly compared. Once we have atezolizumab and bevacizumab approved, it will be in first line. Then it is very clear it is making a lot of sense to continue not with another I/O but with another I/O in combination or plainly a TKI [tyrosine kinase inhibitor].

For all targeted agents and all immunotherapy, the targeted patients are Child-Pugh A so far. But the CheckMate040 cohort 5 is patients with Child-Pugh B. In that patient subgroup, the response is 6 of 20 sorafenib-treatment patients. In other words, a 12% response rate, which is not bad in Child-Pugh B patients.

The tolerability is similar to Child-Pugh A patients in the CheckMate040 cohort; this is also similar, 55%. This is good information. There is no systemic therapy, no indication for any targeted therapy or immunotherapy for patients with a Child-Pugh B patient. But the CheckMate040 cohort 5 clearly showed Child-Pugh B patients also have a survival benefit and with similar adverse events.

 Immunotherapy-related toxicities can range from mild and almost trivial in some cases to impactful and life threatening and emergent. The spectrum of severity is quite dramatic and really requires immediate attention to detail and close follow-up, even for what seems to be a mild toxicity at the outset, because of its potential to represent something much more serious. Some toxicities, like dry skin, dry eyes, itching, and mild rashes, are managed conservatively quite well with moisturizers, sometimes topical steroids, eye drops for dry eyes, and things like that.

Other adverse effects can be much more elusive to determine the etiology but also quite dangerous. A patient who calls in with a complaint of new fatigue may have quite simply mild new fatigue from therapy. But that should also raise the index of suspicion for something more alarming, such as new onset endocrinopathy, which could be type 1 diabetes, adrenal insufficiency, or hypopituitarism from hypophysitis, which is inflammation of the pituitary gland. Any new, vague symptom that prompts a patient to reach out does have the potential to be something quite alarming.

Our practice in the clinic is generally to obtain a panel of laboratory tests, including a random cortisol test if there is concern for something as vague, but potentially serious and life threatening, as adrenal insufficiency, liver function, glucose, electrolytes, renal function[;7a comprehensive metabolic panel. We also do some endocrine surveillance in patients with vague or ill-defined symptoms and arrange for an in-person or a video visit, particularly in the era of COVID-19, where we may have restricted our in-person visits in some locations, to lay eyes on the patient and discuss in person their symptoms within a short period of time.

In severe immune-related toxicity, patients will require immunosuppressive therapy, such as high-dose steroids, which can even require inpatient hospitalization depending on the severity of the inflammation. Colitis or enteritis may require IV [intravenous] fluids or inpatient endoscopy evaluation or liver biopsy if it’s a hepatic adverse event. Depending on the results of the initial evaluation, a patient will require downstream treatment, and the treatment itself may require pretty intensive monitoring in the case of, for example, high-dose steroids or immunosuppressive regimens beyond steroids.

I/O Second-Line Treatment

Ramucirumab has been tested in 2 phase 3 trials: REACH and REACH2. It started with the REACH trial, assessing the efficacy and safety of ramucirumab in second line following sorafenib in a nonselect group of patients, and here it did not reach statistical significance. There was a trend, and in a subgroup analysis, it became apparent that among those patients with high alpha-fetoprotein [AFP]—

 meaning above 400 ng/mL—there was an improved overall survival compared with placebo.

This was then taken by Eli Lilly and Company as rationale to go into a select group of patients in the second line, and it was indeed required or the inclusion criteria included patients with AFP above 400 ng/mL. This was a positive trial, with a hazard ratio of 0.71. It’s not a dramatic absolute difference; it was a little more than 1 month. But in the pooled analysis, where all the patients positive for high AFP from the REACH trial combined with the REACH2 trial were assessed, it was coming down to a difference of about 3 months absolute number, which we have gotten used to more or less with respect to other therapies.

What sticks out here in terms of assessment of ramucirumab is very good tolerability. Although it’s an infusional regime, it requires the patient to come into the hospital, but that’s basically the only burden which ramucirumab is imposing. It was indeed, in clinical practice, very well tolerated. We do see those adverse effects, which we have been seeing in past use of antiangiogenic agents, such as hypertension, proteinuria. But overall it’s very simple: Patients on ramucirumab tolerate the therapy quite well.

What is relevant to point out is that we’ve always been asking for a biomarker-based therapy. Indeed, the ramucirumab trial REACH2 is the first 1 where we had gotten rid of the all-comer inclusion, which was basing inclusion on the biomarker.

The results of the REACH trial, as we talk about second-line treatment with respect to our situation, are quite comparable. All these trials were in the range of roughly 0.7, meaning a 30% reduction of the likelihood to die. That is, in fact, comparable to regorafenib and cabozantinib.

 The REACH and REACH2 trials are very important, both as a clinical option for patient care, but also as a model for the directions we’d like to go in hepatocellular carcinoma [HCC] by establishing the first biomarker-defined patient population for a drug. In the REACH trial, the overall population did not achieve a statistically significant benefit from ramucirumab, but the subgroup analysis for patients with elevated alpha-fetoprotein across a range of levels, with a cut point of 400 ng/mL, determined to be the optimal cut point, did show a significant benefit from ramucirumab. That prompted the development of the first successful biomarker-enriched and biomarker-selected trial of REACH2.

REACH2 required alpha-fetoprotein greater than 400 ng/mL for eligibility and, as we know, determined a statistically significant survival benefit and secondary end point benefit for ramucirumab in the high alpha-fetoprotein population over placebo. There is biological rationale for this. We know that alpha-fetoprotein expression is higher in patients with HCC tumors dependent on VEGF pathway signaling and angiogenesis. Thus, there is rationale for the drug having a disproportionate benefit in patients with high AFP and dependency on VEGF. On the other hand, how to place ramucirumab in the expanding treatment landscape will, I think, require additional studies in the future.

REACH and REACH2 Trial Overview

Ramucirumab is a very good agent because it’s a monoclonal antibody. Adverse events are very few, and the tolerability is very good. Relative dose intensity is 98% globally and also in Japan. Japan has a large elderly population. The average age of HCC [hepatocellular carcinoma] patients is more than 70 years old, 75 or so. Even in Japanese patients, that tolerability of ramucirumab is 98%, similar to global patients.

We prefer a dosing of greater than 400 mg, and we prefer to use the ramucirumab, even after lenvatinib or sorafenib. In sequential therapy, the first-line agent is very strong. Sometimes there are more adverse events with sorafenib than the sorafenib and lenvatinib. But ramucirumab has very few adverse events, and quality of life is very good.

Regarding sequential therapy, there was another subanalysis clearly showing that ramucirumab does not impair liver function. We prefer to use ramucirumab as a second-line agent, then patients can tolerate very well for a while and can rest. Then if the peak progress of disease appears, we change to the third-line agent. So we prefer ramucirumab.

 The role for ramucirumab after first-line bevacizumab-containing regimen is not clear, noting that both of them target the VEGF pathway, with ramucirumab as a VEGF receptor 2–targeted monoclonal antibody and bevacizumab as a VEGF-targeted monoclonal antibody. There is precedent for using the 2 drugs both in a disease such as colorectal cancer, but we don’t know the efficacy of the sequence in hepatocellular carcinoma. My inclination in the second-line setting after atezolizumab plus bevacizumab would be a multikinase inhibitor, such as cabozantinib, bearing in mind that it was established in the CELESTIAL trial after a more permissive first- or second-line population, including third-line patients after a variety of first- and/or second-line regimens. But ramucirumab certainly will continue to play a role in patients with high alpha-fetoprotein, particularly those who have exhausted other options.

The REACH-2 study has shown that ramucirumab is an effective agent in patients with refractory HCC. For many of these TKIs [tyrosine kinase inhibitors], the major reason this works is by blocking the VEGF receptor pathway, and we know that ramucirumab is a monoclonal antibody that blocks VEGF receptor 2 pathways. Antigenesis is important in liver cancer and is basically the mechanism how it’s spread. One advantage of ramucirumab is that it’s given as a parenteral, so the patient doesn’t have to take any pills either every day or twice a day. Another thing is that the toxicity for ramucirumab is a lot easier compared with some of the TKIs. We think the oral agents are more beneficial and have fewer adverse effects. But some of these TKIs, which are multikinase blockade—like regorafenib and cabozantinib—have toxicities like hand-foot syndrome and fatigue.

My clinical experience has been that ramucirumab is a little easier to tolerate than some of the TKIs. But every patient is different, so you have to really look at how the patient did well in their first-line setting. Some people want to take oral agents. Some people like to come to the infusion center and see the nurses. They like the parenteral infusion and they don’t like swallowing their medications, or they have co-pay issues and the parenteral option is better.

With the coronavirus pandemic, a lot of patients don’t want to come to the hospital and the cancer centers, so perhaps the TKIs or oral agents might be better than the parenteral infusions.

Second-Line Therapy: Monoclonal Antibody

We will, in many countries, at least in those where IMbrave150 results in approval and reimbursement, take over ATEZO-BEVA [atezolizumab-bevacizumab] as first-line therapy, and that requires a new assessment of the other therapeutic options in second and third lines. We will not have the chance to have sufficiently large trials for all these sequences to get an evidence base for the different lines of therapy. One of the rationales to make a decision of what treatment to choose is the specific spectrum of patients who had been treated in the available trial. It can be the adverse-effect profile, and of course it can be the rationale, the mode of action. For example, I would consider it useful to have in 1 line I/O [immuno-oncology]–based therapy and in another line a TKI [tyrosine kinase inhibitor]–based therapy to offer patients the chance to get these different modes of action as an individual patient.

 Our data for agents in the second line are really predicated on the receipt of first-line sorafenib so far. For example, when we think of regorafenib, that approval was based on the phase 3 RESORCE trial, which required patients to have received sorafenib for 20 of 28 preceding days, at a dosage of at least 400 mg total per day. I just had to understand how to use regorafenib if patients didn’t receive first-line sorafenib. For now, that is a predicament, and it will be interesting to see if there will be future second-line studies on the horizon to better characterize response, toxicity, and overall benefit in a different sequence of receipt.

We know that for antiangiogenic agents in other tumor types, that continuation beyond progression of a first antiangiogenic agent has shown benefit, and in HCC [hepatocellular carcinoma] that has been the case as well. For example, with drugs like cabozantinib, there has been benefit after first-line sorafenib, as well as any second-line other agent. We know that cabozantinib achieved benefit in a population that included third-line patients. I think it is intuitive to continue the use of cabozantinib after a combination regimen based on the way the CELESTIAL second-line trial was conducted in the population it included.

As we start looking at downstream immunotherapies after a first-line PD-L1 inhibitor in the case of atezolizumab plus bevacizumab, for example, that’s where we really don’t understand enough about the mechanism of the primary resistance as well as acquired or secondary resistance to immune checkpoint inhibition in HCC. It will be very important to try to perform studies in the second- and third-line space, along with translational end points, to try to understand which patients are likely to respond to a different immune checkpoint inhibitor approach versus an antiangiogenic approach in the second or third line.

It’s important here to add what a landmark this is, to be discussing later-line therapies as a reality in this disease. A decade ago, we didn’t think second-line therapy was a reality, and now we have not only a handful of second-line agents but also the likelihood of third-line studies on the horizon.

We do have clearly defined labels for those substances. Sorafenib was first line, and it was very clear regorafenib was approved in the second line following sorafenib. It was actually required that sorafenib had been tolerated for some period of time and approved for patients in the second line following sorafenib. Of course, this does not mean that second-line cabozantinib after ATEZO [atezolizumab] plus BEVA [bevacizumab] does not work, but we have to accept we have neither the evidence nor the label for it. That is an interesting discussion, and it is probably very country specific whether these substances are accepted or not. For example, in Spain, we have very limited second-line options today, even though the evidence is there. You can tell that different countries here come down to different decisions.

The agent used after sorafenib was lenvatinib. After lenvatinib, unfortunately, cabozantinib is not approved in Japan because Japan did not join the phase 3 trial. But currently the phase 2 trial finished and was successful. We will soon see cabozantinib available in Japan as well. But at the present, we have 2 secondary agents, regorafenib and ramucirumab. After regorafenib, we usually introduce sorafenib first. If the patient is tolerable to sorafenib for more than 20 days at 400 mg, we introduce regorafenib. After lenvatinib, if the AFP [alpha-fetoprotein] is greater than 400 mg, we use ramucirumab as a second-line agent after lenvatinib. After sorafenib, of course, we use the regorafenib or the ramucirumab if the dose is greater than 400 mg. In Japan, as a secondary agent after sorafenib, lenvatinib is also effective. As a third line after regular after regorafenib, lenvatinib is also useful. So we can use lenvatinib as a second-line or third-line agent after sorafenib

What are some clinical parameters I use in deciding what drug I would use? I have given you so many treatment options. One of the things I factor in is how well did the patient do on their first-line treatment, whether it’s lenvatinib or sorafenib? If the patient did very well on their first-line treatment options, then using another TKI agent would be an effective way. That means regorafenib or cabozantinib. If the patient didn’t do very well on their first-line treatments, they progressed rapidly within 3 or 4 months on their first-line treatment options, then I would personally use immunotherapy like nivolumab or nivo-ipi [nivolumab-ipilimumab] combination or pembrolizumab in my second-line setting. Then you can use both of these options as third-line treatment options in the future.

For patients whose alpha-fetoprotein is above 400 mg, we have another option, ramucirumab, which is a biomarker-based therapy that can be used in HCC patients. I would look at first how did the patients do in their first- and second-line settings, what are their alpha-fetoprotein level, and then what are the toxicities they have. If the patients did very well without many toxicities, then using another TKI might be a reasonable option. If the patient had a lot of adverse effects, like hand-foot syndrome, hypertension, fatigue, weakness, and weight loss in their first-line treatment options, then I would want to change the mechanism of action and go with checkpoint inhibitors in my second-line setting. I would factor in all those things.

It’s a nice problem because now we have so many options. A few years ago I would have told you that you have not many treatment options for liver cancer. We were just using different doses of sorafenib in managing those patients.

Second-Line Sequencing After IMbrave150 Regimen

Looking at refractory treatment options for hepatocellular cancer, just 3 years ago we didn't have any second-line treatment options for liver cancer. But over the last 3 years, large phase 3 trials have shown that there are good second-line treatment options for liver cancer.

I’m going to begin chronologically, in 2017, with regorafenib, which was approved after patients who failed sorafenib. This was based on a resource study showing that regorafenib is effective in patients with refractory HCC [hepatocellular carcinoma] who failed sorafenib. They showed an overall survival of 10 points, 6 months compared with about 8 months in the placebo group. The hazard ratio here was 0.63. Regorafenib is an NCCN [National Comprehensive Cancer Center]–approved indication in the second-line treatment of liver cancer.

Another TKI [tyrosine kinase inhibitor], cabozantinib, which looked at both the VEGF receptor as well as MEK and AXL pathway, has also shown to be an effective agent in refractory hepatocellular cancer. It was a large study comparing cabozantinib with placebo, and overall survival in cabozantinib was almost 10.2 months compared with 8 months in the placebo group. Here the hazard ratio was 0.76, and the PFS [progression-free survival] improved from 2 months to 5.2 months as well. Both regorafenib and cabozantinib are approved agents, and these are category 1 recommendations from NCCN in the treatment of refractory hepatocellular cancer.

However, I told you about lenvatinib and sorafenib in the first-line treatment of liver cancer. If you have actually gotten lenvatinib, you might consider sorafenib as a second-line treatment option. And if you got sorafenib, lenvatinib could be an option in the second-line setting. However, there are currently no studies conducted in those settings, so both of these options are recommended by the NCCN but not category 1 recommendations.

Now there are other monoclonal antibodies and immune checkpoint inhibitors that were approved in the second-line setting. One of these drugs is ramucirumab based on the REACH-2 clinical trials. In the previous REACH trial, ramucirumab was effective but was not clinically significant. But when they looked at alpha-fetoprotein, which is an important biomarker for liver cancer, they noted that people with alpha-fetoprotein above 400 ng/mL benefited from ramucirumab. In the REACH-2 study they looked at patients with alpha-fetoprotein above 400 ng/mL, and ramucirumab was an effective agent in this patient population.

Now both nivolumab and pembrolizumab are approved agents after sorafenib failure, so these are immune checkpoint inhibitors. Just last week we heard that nivolumab-and-ipilimumab combination was a fast track by the FDA for approval in the refractory HCC patients.

Nowadays we have so many options—regorafenib, cabozantinib, other TKIs, ramucirumab, nivolumab, and pembrolizumab—in our treatment for refractory HCC. But the NCCN category 1 recommendations are regorafenib, cabozantinib, and ramucirumab. One of the caveats here is that these are for patients who have failed on sorafenib, so people who progressed on sorafenib. If you use lenvatinib as your first-line treatment because this drug has shown to improve PFS and overall survival—and about 75% of the community oncologists and academic clinicians use lenvatinib as a first-line treatment—then what you do in the second-line setting is really not evidence based. These are based on your clinical experience and how you use the current data available.

R/R HCC: Second-Line Options

Regarding the PD-L1 plus CTLA4 procedure, the rationale is that CTLA4 can recruit the dendritic cells and activate T cells efficiently in the lymph nodes in the priming phase. The activated T cells infiltrate the tumor. At the tumor, the CTLA4 regular 3T cells, there is also expressed CTLA4. CTLA4 inhibits the regular 3T cell, so microenvironment is changed to chroma-immunosuppressive. At the same time PD-L1 blocks the PD-1/PD-L1 axis. In other words, tumor invasion activates T-cell effect. I think it’s a rationale of such combination.

Some recent development is combination therapy in the frontline treatment for liver cancer. There are emerging data from different clinical trials. One of them is the HIMALAYA study, which looked at nivolumab and tremelimumab combination. It’s just like the nivolumab-ipilimumab combination looking at anti–PD-1 plus a CTLA4 antibody, trying to see if those have a superior clinical outcome compared with just a single-agent PD-1 or CTLA blockade.

The phase 3 trial in the HIMALAYA study was completed, and we are eagerly awaiting the results. The recent results has been the combination of atezolizumab with Avastin, which showed that there was a definite clinical superiority when you do these types of combinations.

Now we were a part of the LEAP-002 study, which was looking at lenvatinib and pembrolizumab combinations. I have seen some patients of mine doing very well on this combination, having good clinical response to this treatment. I think the future will be the combination strategy looking at different TKIs [tyrosine kinase inhibitors] plus immune checkpoint inhibitors, and there are currently multiple studies going on. The COSMIC-312 study with cabozantinib and the atezolizumab study, LEAP-002, just completed its clinical trial core, so in the next 6 to 12 months we’ll be seeing a lot of combination strategies for the treatment of liver cancer. If these are positive, the first-line treatment from TKIs would be changed to combination strategies.

Frontline I/O: Clinical Trial Overviews

 It’s indeed now getting a bit crowded. There have been many signals pursued in phase 3 trials. The story started basically with the CheckMate040, and there were several cohorts. Among those cohorts was the IPI-NIVO combination, ipilimumab and nivolumab, 2 immuno-oncology [I/O] agents tackling CTLA4 and PD-1. The early data for this combination are looking very promising.

A similar concept is the combination of durvalumab and tremelimumab. In fact, we have just seen the abstracts for ASCO [American Society of Clinical Oncology Annual Meeting], showing further data on the DURVAL-plus-TREME [durvalumab, tremelimumab] combination. These data look quite promising, I have to say. Then we have the different combinations of checkpoint inhibitors plus TKIs [tyrosine kinase inhibitors]. Here, we probably have to pay attention to toxicity. That was 1 of the observations when we combined lenvatinib plus pembrolizumab. Relevant objective responses were in the range of 40%, but also quite relevant was toxicity. There were some fatalities, and that needs to be watched. But apparently, this is among the combinations that are working. Cabozantinib is combined with I/O agents, and there are other smaller trials ongoing. Indeed, we have in the palliative setting quite a few combinations. It’s actually going beyond that. There are also adjuvant treatments using combinations. So we expect a lot of new data in the next years.

There are 2 general categories of I/O combinations that we’re examining right now, and both are quite promising. The first are the combinations like IMbrave150 of an antiangiogenic agent with a checkpoint inhibitor. Other examples on the horizon, beyond the ATEZO-BEV [atezolizumab-bevacizumab] combo, are the combination of pembrolizumab plus lenvatinib in the LEAP-002 trial. That’s based on phase 1b data from a large 100-patient cohort being presented at the ASCO 2020 Annual Meeting. The combination of pembrolizumab with lenvatinib has shown quite high objective response rates by both RECIST 1.1 as well as modified RECIST. In the phase 1b context, that has been matched by disease-control rates and the longer-than-expected progression-free survival. Of course, the phase 1b data need to be validated and verified in the phase 3 context, so it will be quite interesting to see the results of LEAP-002.

Along those same lines in the antiangiogenic immunotherapy combination category, there’s also the COSMIC-312 trial combining cabozantinib with atezolizumab. That’s an ongoing study whose results will also be quite interesting, bearing in mind that cabozantinib is another tyrosine kinase inhibitor with antiangiogenic properties. But beyond being an antiangiogenic agent, it also has some immunomodulatory activity in reducing or inhibiting some of the immunosuppressive cells in the tumor microenvironment, like tumor-associated macrophages and myeloid-derived suppressor cells.

Beyond the antiangiogenic immunotherapy combinations, there are also the dual immune checkpoint inhibitor combinations on the horizon, and 1 of those trials to watch for is the HIMALAYA trial. The HIMALAYA trial studies the combination of the PD-L1 inhibitor durvalumab with the CTLA4 inhibitor tremelimumab, and it has already completed accrual. Hopefully, we can look to results in the not-too-distant future. The HIMALAYA regimen is based on phase 2 data in the second line from the combination of durvalumab plus tremelimumab in a study called Study 22, which is being presented at this year’s ASCO and as an oral abstract. In the phase 2 second-line context, the combination showed that a novel approach to CTLA4 combination of a single higher priming dose of tremelimumab given just once at the beginning of the regimen, combined with a continued monthly durvalumab backbone, had the highest objective response rate of that combination. It was also matched by the longest median overall survival.

Also, in the dual immune checkpoint inhibitor space is the combination of nivolumab plus ipilimumab. There’s a phase 3 trial of this regimen called CheckMate 9DW, and it also follows up on phase 2 data from the second-line space from the CheckMate040 cohort of nivolumab plus ipilimumab, which showed high objective responses and prolonged overall survival for the combination of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, given together for 4 doses, followed by nivolumab every 2 weeks as monotherapy. In fact, based on the phase 2 second-line data, the FDA has granted an approval for nivolumab plus ipilimumab in the postsorafenib population.

When we look ahead on the horizon, we see a host of new combinations that may become available if any of these phase 3 trials achieves their primary end point. The clinical implications are that we will have a dramatically expanded landscape in the first-line setting and a new opportunity to really choose a regimen according to patients’ clinical factors, such as bleeding risk in the case of atezolizumab plus bevacizumab, or other comorbidity profiles. Then we will also have an obligation to really do a whole new range of subgroup analyses on the individual trial data themselves, as well as potentially combined or pooled analyses across studies to try to understand whether the clinical biomarkers or clinical risk factors that identify patients more likely to benefit from 1 approach to another.

Frontline Therapy: Promising I/O Combinations

We have long been waiting for immunotherapy entering the stage in advanced-stage hepatocellular carcinoma. With IMbrave150, we indeed have the first clinical trial combining atezolizumab, an immuno-oncological agent, and bevacizumab, an antiangiogenic agent. It has been very clear that both overall survival and progression-free survival are improved, with very favorable hazard ratios of 0.58 and 0.59. Here we have a clear improvement of overall survival and, in fact, had additional significant objective response rate in the range of almost 30%, depending on how you are looking at it.

This was a major step forward in terms of efficacy, but also patient-reported outcomes were analyzed and gave clear data on the quality of life and physical functioning. It demonstrated that of all these aspects, there is a long maintenance of quality of life and the other aspects over time during treatment, particularly much longer in comparison with sorafenib. We have an efficacious new therapy improving outcome over what has been the standard in the past. This is the accepted discussion among all experts. I would say that this will become the next first line upon approval. There might be regulatory in different countries, but that will replace sorafenib as the first-line standard.

This is then having quite interesting sequelae, in that we do not have all the evidence for further-line therapies. Is then what used to be first line the new second line? And is the old second line the new third line? Or do we use those substances with a given rationale? For example, do you start with an I/O [immuno-oncology] therapy and continue with the TKI [tyrosine kinase inhibitor]? That is an open question. At this time it’s only expert opinion, but it is among the issues that needs to be clarified in the near future.

The combination of atezolizumab and bevacizumab is not only efficacious but also well tolerated, and it results in a maintained quality of life. The way this assessment was performed was by starting with a given number, for example, quality of life or role functioning, and then checking when this was deteriorating over time. Here it took up to a year for certain parameters to get worse in the treated group with the combo of ATEZO [atezolizumab] and BEVA [bevacizumab]. It was much shorter for sorafenib, meaning you are getting successfully treated but also maintaining your quality of life.

This is very relevant for the patient, and in the future I believe the aspect of patient-reported outcomes in general will play an increasingly important role, because it makes a lot of sense if you have a limited life span and we are still talking about a palliative situation. Then the quality of life for the remaining time you have is playing a really important role. Good for the patient.

It’s an interesting aspect, the rationale for the combination of an antioncogenic agent and an immuno-oncology agent. What have we learned? We have learned from the single-agent therapy that we do see in a percentage, between 10% and 20% or so, objective responses. But apparently the majority of the patients are not benefiting enough to get positive data in what has been produced as a phase 3 trial so far. We are looking for an appropriate combination partner improving and fostering the I/O impact. Apparently bevacizumab, which is tackling the VEGF ligand, not only is impacting angiogenesis—this is what it was produced for—but apparently has an immunomodulatory quality. It acts on the immune cells, antigen-presenting cells, and other cells, it seems, in combination with the I/O. Is this an additive effect? Is this synergy? This is something that needs to be investigated further. But it tells us a story, in the combination, we are able to move I/O therapy into the systemic therapy of HCC [hepatocellular carcinoma].

The atezolizumab-plus-bevacizumab data from the IMbrave150 trial has really become the new de facto standard of care in the first line for fit patients. By that I mean patients who really met the eligibility criteria for that phase 3 trial. In a patient who has Child-Pugh class A liver function, with no evidence of esophageal or gastric varices on a recent endoscopy, who is not at high risk for bleeding on an endoscopy—no patients on anticoagulation or is otherwise a high risk for bleeding—we really should consider atezolizumab plus bevacizumab as a first-line standard. Those criteria are very important to keep in mind, particularly that of the endoscopy. We know that bevacizumab as monotherapy has a substantial bleeding risk in patients with Child-Pugh class B liver function and in patients who have had incompletely treated esophagogastric variceal disease. In patients who haven’t had a recent endoscopy or who have high-risk findings on an endoscopy, it is not validated as a safe or effective therapy to date.

Phase 3 IMbrave150 Trial

The REFLECT trial is a global phase 3 noninferiority trial comparing the efficacy and safety of lenvatinib and sorafenib. Results were positive: Overall survival was at 95% confidence intervals; upper limit was 1.06, which was smaller than predefined noninferiority margin of 1.08. So the noninferiority was proven. But regarding the efficacy, such as response rate and the PFS [progression-free survival], the PFS is much longer in lenvatinib arm, which is 7.4 months, and the sorafenib arm was 3.7 months; the difference was, of course, significant.

An objective response rate in lenvatinib was 40.6%. In the sorafenib arm, objective response was 12.4 months. Response rate and the PFS are much better, and tumor effect was superior in lenvatinib. Regarding how to select an agent, we prefer lenvatinib for intermediate-stage HCC [hepatocellular carcinoma] with a high tumor burden because we can achieve the response, as I said, and follow TACE [transarterial chemoembolization]. We can achieve, at times, complete response.

For advanced-stage HCC, of course, there are several reports with systemic therapy. That report said the objective response in RECIST correlates with overall survival. That means the agent with the high objective response provides survival benefit for even more patients. We prefer to use the lenvatinib first. But in the REFLECT trial, there are different profiles of adverse events in the sorafenib arm: Hand-foot skin reaction, diarrhea, and alopecia are more frequently seen.

But in the lenvatinib arm, hypertension, hypothyroidism, or proteinuria are more frequent. Additionally, in the lenvatinib arm, fatigue is more frequent. In elderly patients or patients with uncontrollable hypertension or patients with liver and renal dysfunction, maybe we prefer to use sorafenib first. The younger populations will tolerate well, and we, therefore, might select lenvatinib.

What are treatment options for first-line therapy? Sorafenib has been available for the last 13, 14 years, and that was the only option for patients with unresectable liver cancer. There were a lot of clinical trials conducted because sorafenib is a multikinase inhibitor, and we all thought that by using different multikinase inhibitors and VEGF inhibitors, we can improve the clinical outcome in patients with unresectable HCC. However, many of these prior phase 3 clinical trials have failed to demonstrate a clear-cut overall survival improvement, but actually they were inferior to sorafenib.

Recently there was a study conducted using lenvatinib versus sorafenib. This was the REFLECT clinical trial, a noninferiority, large phase 3 international study that enrolled 954 patients. The primary end point was overall survival because there were no other treatment options in this patient population. It had 2 kinds of end points. The first was overall survival. Because there were so many failures in the past, there was also an assessment to look at a noninferiority study. It means that the drug is as good as sorafenib.

The study has shown that lenvatinib had overall survival of 13.6 months, and sorafenib had 12.3 months. However, the hazard ratio here was 0.92 There was a numerical improvement in overall survival with lenvatinib, but the confidence interval crossed 1; therefore, lenvatinib was not superior to sorafenib, but lenvatinib is as good as sorafenib.

However, the secondary end point of the study includes progression-free survival as well as overall response rate was superior in the lenvatinib arm. The PFS was 7.3 months versus 3.7 months, and 41% response rate for lenvatinib was pretty impressive for a tyrosine kinase inhibitor, and 12% for sorafenib. In my clinic patient, I usually see a patient who has good performance status, who is relatively well. I would use lenvatinib in those patient populations. If I see a frail patient whose liver function is not very good or a Child-Pugh B, which is not the best-case scenario, I would think of using sorafenib in those patients because lenvatinib is not well studied in patients with poor liver function.

Frontline Decision Factors for Metastatic Disease

HCC Treatment Algorithm: Asia and Europe

Transitioning From Locoregional to Systemic Therapy

 Hepatocellular cancer [HCC] diagnosis is mainly done with different imaging modalities. I have mentioned previously that ultrasound is used as a screening methodology, but in the diagnosis of liver cancer we use either contrast-enhanced CT [computed tomography] scan or cheaper-phase CT scan, or MRI [magnetic resonance imaging] in diagnosing those patients. Usually in the background of patients who have underlying liver disease or cirrhosis, when you have a liver mass that’s arterially enhanced and washes out, this is a typical diagnostic for liver cancer.

In light of underlying liver disease, we usually mention alpha-fetoprotein as a prognostic marker in patients with liver cancer. Usually I assess for serum albumin levels, serum PT [prothrombin time] or INR [internalized normalized ratio] levels, as well as bilirubin. By assessing those things, I’ll be able to calculate the Child-Pugh score, which shows you the severity of liver cirrhosis. With those 3 levels of findings as well as 2 clinical parameters, which are presence and absence of ascites and hepatic encephalopathy, you would be able to calculate the Child-Pugh score. This is important because in liver cancer, you’re dealing with not just liver cancer itself but underlying liver disease. You’re fighting 2 fronts, the cancer as well as the liver disease. This is important in managing hepatocellular cancer.

Moving on to the second question, alpha-fetoprotein is a glycoprotein that is usually excreted during the gestational period between the yolk sac and the liver. Usually this is an area where there’s a lot of inflammation going on and alpha-fetoprotein is generated. It is also a tumor marker for hepatocellular cancer as well as in some yolk sac cancer or teratoma and other things. Usually, about 400 ng/mL of alpha-fetoprotein is diagnostic in the background of our liver lesion for patients with hepatocellular cancer, and increased levels of alpha-fetoprotein have been correlated with increased risk of angiogenesis and metastases and tumor burden, so high alpha-fetoprotein is usually correlated with poor prognosis.

Basically, we use both MELD [model for end-stage liver disease] score and Child-Pugh score in assessing liver disease. The MELD score is model for end-stage liver disease, and usually a patient’s MELD score is calculated based on serum bilirubin, creatinine, and PT [prothrombin time] and INR [international normalized ratio]. The reason the MELD score is used is that the 3-month overall survival on mortality associated with liver disease is strictly correlated with the MELD score. Because of this, United Network for Organ Sharing has adapted using the MELD score to prioritize who can get liver transplant.

I personally use the Child-Pugh score because I’m not a transplant physician, so I use the Child-Pugh score A, B, and C in guiding my management for systemic therapies. For patients who are young, who have good performance status, and who meet the Milan criteria—which is a single lesion less than 5 cm and 3 lesions less than 3 cm—we have to consider liver transplant because this is a way of procuring those patients.

The standard assessment is either CT or MRI assessment. You are checking hypervascular lesions, and you’re asking for the late washout of hypervascularization. If you see these hallmark pictures, the diagnosis is safe. CT is not considered to be evidence based; therefore, the guideline recommendations do not include PET [positron emission tomography] or CT in the diagnostic armamentarium.

When do we do liver biopsy? Because people with liver cancers have underlying liver disease, they have coagulopathy. In the past, we wanted to avoid doing the liver biopsy because you don’t want to do a liver biopsy and cause either peritoneal spread or bleeding problems associated with liver biopsy. Usually most oncologists want to treat when there are biopsy results. The only exception is the liver cancer, where we can diagnose patients with underlying liver disease. Hepatic lesions enhance arterially and wash out on a delayed phase, and we have more than 95% chance of diagnosing liver cancer without a biopsy. However, because we are not doing a lot of liver biopsies, we don’t have the tissue to do genetic studies and clinical trials that can correlate with these genomic findings.

Over the last few years, most of the medical oncologists and hepatologists have been thinking maybe we should do more liver biopsies so we have more samples, so we can study this genomic alteration in liver cancer, and so we can come up with better treatments in the future. In general, we might not need it. But for the improvement in the future of science as well as improving scientific knowledge, we actually should be doing more liver biopsies. Nowadays, interventional radiologists do the liver biopsies without many other complications. So it’s pretty safe to do liver biopsies.

In Asia, it’s not much different from in the United States. The surveillance too is ultrasound and AP [arterial perfusion]. Then if there is a suspicious lesion of HCC in an Asian country, most patients receive CT scans, which will confirm HCC. The difference between Japan and United States may be the frequency of EOB [ethoxybenzyl] MRI use—gadoxetic acid MRI. That is a very sensitive and specific tool for detecting smaller lesions less than 1 cm, and the accuracy is much better. As I said before, The Japan Society of Hepatology guidelines recommend EOB MRI should be used as a diagnostic tool. That’s a big difference between Japan and United States.

The standards are pretty similar. Again, CT and MRI are the standard diagnostic procedures. In Europe, this is influenced by the fact that the ultrasound is typically in the hands of hepatologists and not radiologists. Also playing a role, particularly in dedicated centers, is CEUS, contrast-enhanced ultrasound. It is indeed used by some centers and can be helpful in individual patients; for example, in those patients who, because of a close personality, cannot use MRI assessment, and ultrasound might be more appropriate. It’s quite clear that CT and MRT [magnetic resonance tomography] are typically giving a more panoramic picture, and this is the standard in most cases. Ultrasound in Europe, however, plays a little more prominent role than it does in the United States. Particularly contrast-enhanced ultrasound, which virtually does not exist in the United States.

HCC Diagnosis and Prognosis

The history goes in a way that until 2002, when we had the definition of TACE [trans-arterial chemoembolization] as a successful treatment, we basically had surgery. That was transplantation, resection, and not much else. Then interventional radiologists entered the field, and medical oncologists and hepatologists did not play a major role. This changed in 2007 when we, for the first time, defined a center of care in systemic therapy. Ever since, systemic therapies have been evolving. Particularly in the last 6 months, we have seen a dramatic improvement in systemic therapeutic options, meaning that medical oncologists and hepatologists—those in charge for systemic therapy—are playing a much more important role compared with 20 years ago. That is something that is currently changing.

Of course, if you want to offer the patient the best of all worlds, then you need to integrate all the different specialties and subspecialties in the multidisciplinary team assessment. Surgeons, interventional radiologists, oncologists, and hepatologists should be on those teams, adding to the choice and the optimal treatment decision.

It is handled differently in Germany. For example, MDTs [multidisciplinary teams] are mandatory. You are required to get reimbursement and, for example, the specific certificates as a liver cancer center—to have MDT regular meetings, and that needs to be documented. It’s actually required that more than 95% of your patients are seen in these MDTs. This is not the case in all European countries, so it’s quite variable. The other issue, what needs to be addressed in terms of the quality and the relevance of MDTs, is that it always depends on who is sitting there and how is the balance. If there is a dominating subspecialty—for example, radiologists—then it might not result in the best choice in all means, because dominance in these settings is not really what is best for the patient. You need to have a balanced view with respect to all the involved subspecialties.

 The role of medical oncologists in the treatment of liver cancer has been evolving rapidly over the last 5 years. This is because of the increasing options in the treatment of systemic therapy in liver cancer. Just 3 or 4 years ago, we didn’t have a lot of treatment options except for sorafenib, which has been around for the last 10 years, but because nowadays we have so many tyrosine kinase inhibitors, immunotherapy treatment options, and monoclonal antibodies like ramucirumab, medical oncologists are becoming a more integral part of the multidisciplinary team that cares for liver cancer patients.

Most multidisciplinary cancer teams comprise a diverse group of physicians, including gastroenterologists, hepatologists, liver surgeons, liver transplant surgeons, interventional radiologists, radiation oncologists, and medical oncologists. Our interventional radiologists are involved in the locoregional therapy, while surgical oncologists are involved in local resection and liver transplant.

Because of available systemic options, including immunotherapeutic agents and different tyrosine kinase inhibitors, medical oncologists are getting involved both early on in the adjuvant clinical trials treatment as well as in the more advanced liver cancer patients. Many of the studies have shown that when you have multiple groups of subspecialists taking care of liver cancer, those patients’ clinical outcome improves with the multidisciplinary treatment approach.

Regarding HCC [hepatocellular carcinoma], mainly the hepatologists treat HCC. Most medical oncologists also do, and some oncologists treat HCC because, in general, the oncologist is familiar with the systemic therapy and adverse-event management. However, in HCC, there are many liver-specific adverse events, such as hepatic encephalopathy or bleeding or some very strict evaluation of liver function using the ALBI [albumin-bilirubin] score. It’s slightly difficult for medical oncologists. In Japan, hepatologists typically treat HCC.

How important is the multidisciplinary team, and how different is it in Asia and Japan? In Asia, most HCC cases have big or multiple tumors at time of detection. But in Japan many lesions are small and in fewer regions, since nationwide surveillance is established. The multidisciplinary team in Japan consists of a surgeon, a hepatologist, and an interventional radiologist, because 65% of the initially detected cases are early stage disease, and 30% are intermediate. Only 5% have advanced-stage disease, so medical oncologists rarely attend the multidisciplinary team. In Asian countries, more patients with advanced-stage disease are interventional, so of course the surgeons and interventional radiologists and oncologists will attend that multidisciplinary team to discuss how to pay for the treatment.

The Evolving Role of Medical Oncologists and Hepatologists

In Europe we basically follow the recommendations of the European Association for the Study of the Liver, and they have been recently updated, in 2018. Here we recommend the performance of ultrasound twice a year, every 6 months. This is an interesting aspect in terms of differences worldwide. In Asia, the addition of alpha-fetoprotein assessment is more or less mandatory. In the United States it’s optional, and in Europe it’s not recommended, so there are discrepancies as well to both. In the real world, I would say most physicians indeed include alpha-fetoprotein testing to the armamentarium and add it to ultrasound.

The problem is that if we watch what results we get, then we realize we, in most countries in Europe, detect early-stage cancer in only about 25% or so, telling us that we are not adhering very well to screening programs. Otherwise we would be much better. The best example here is Japan. They are very successful. They detect the vast majority of their patients in early stage and demonstrate that screening programs can be effective. But in Europe overall, it’s safe to say that in many countries patients are just neglected. Cirrhotics are not regularly screened, although the recommendations are very clear.

 What are the typical current screening procedures in the United States for liver cancer? In patients who are high risk, these are people with hepatitis C and cirrhosis and people with chronic hepatitis B infection are at risk of developing liver cancer. In those high-risk patients, what we usually recommend is doing ultrasound every 6 months to assess fine and liver nodules or liver cancer. We also add alpha-fetoprotein as 1 of the tumor markers in assessing those patients.

Now we have to understand that ultrasound is operator dependent. Therefore, in institutions where you cannot have very reliable ultrasound technicians and you can’t do the procedure in a good way, we recommend doing either a CT [computed tomography] scan or MRI [magnetic resonance imaging].

At-risk populations in Asia are those with hepatitis B virus cirrhosis, and it occurs mostly in Japan. But I see it as it cirrhosis and at risk for HCC [hepatocellular carcinoma]. Screening procedure in Asia mostly using ultrasound and AP [arterial perfusion] every 6 months. But in Japan, more intensive surveillance is performed, like ultrasound plus 3 tumor markers—AP plus APL2 and APL3 [arterial pseudolesions]—are measured every 3 to 4 months. Plus, for cirrhotic patients, every 6 to 12 months, an EOB [ethoxybenzyl] MRI is recommended. So it’s more extensively performed in Japan.

HCC Global Screening Programs for At-Risk Populations

 What are the etiology risk factors in the development of hepatocellular cancer? We all know that hepatocellular cancer or liver cancer is caused by a chronic irritation or inflammations. Usually the most common causes of this irritation or inflammations are viral hepatitis, like hepatitis B and C, because these are the viral infections that can cause chronic infection. Other etiologies could be alcohol irritation—people who drink a lot of alcohol—and recently there’s the incidence of NASH, which is nonalcoholic steatohepatitis, which is also associated with obesity.

There are some rare causes that can cause liver damage, and these are altered immune problems, genetic problems like alpha-1 antitrypsin deficiency, hemochromatosis, and some aflatoxin exposures, but the most common reasons are viral hepatitis, alcohol, and NASH.

Concerning the global trends in incidence and prevalence of hepatocellular carcinoma, we see in most countries a rise in incidence and in prevalence. There are some countries—for example, Japan would be 1—where there has been a decline. This is related to successful treatment of hepatitis C virus and the resulting cirrhotic complications in these countries. But for most countries, we indeed see a rising incidence. This is, for the most part, explained by the increasing incidence in NASH and nonalcoholic fatty liver disease, and in the resulting complications from NASH cirrhosis. Problem here is that we increasingly see noncirrhotic patients with NASH developing hepatocellular carcinoma.

We still see most patients with the viral hepatitis C, followed by hepatitis B patients. In many European countries, alcoholic liver disease is a main contributor as well. Recently as we saw an increase in what has been, in the past, considered to be cryptogenic cirrhosis. We had no explanation, and then we learned that this is basically a fatty liver disease and NASHs in these days, increasingly contributing to hepatocellular carcinoma.

Minsig Choi, MD, Stony Brook University Hospital

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