I think these concepts are critical for the community physicians to have an understanding of, especially now that we not only have new front line, second line, but even drugs beyond that, third line, fourth line. And historically speaking, Katie, 10 years ago, who would have even thought we’d be having this discussion? And so it’s a very exciting time for liver cancer. With that in mind, I think we should delve into some of the data that are driving a lot of this excitement.

Historically speaking, before we had sorafenib’s approval in 2007/2008, as you’ve touched on, Katie, locoregional treatment filled a void, right? We had patients who had progression in the liver despite vascular invasion. Even patients who might have small extrahepatic disease would continue to get locoregional treatment. And the approval of sorafenib in 2008, which I think many people are familiar with now, that data, the SHARP study which showed a 31% decrease in the risk of death with sorafenib versus placebo. At that time, a placebo-controlled study could be done because no systemic treatment had been shown to improve survival. And we saw that for the first time, median survival was improved with a systemic drug with an adverse effect profile that is manageable, I would argue. VEGF adverse effects such as hypertension and proteinuria were not so severe with sorafenib, but more commonly, GI toxicity as well as hand-foot-skin syndrome were typically the dose-limiting toxicities. And we learned how to manage sorafenib, the full dose being 400 mg twice a day. And many of us have learned to dose adjust or use supportive care measures to keep patients on sorafenib.

The approval of sorafenib left us with a lot of unmet needs, I think. Specifically, we wanted something that did better than sorafenib. We needed something to do when sorafenib wasn’t working. We needed something when patients could not tolerate sorafenib, despite supportive care measures. I remember giving interviews in 2008 about what does the next 4, 5 years of liver cancer look like. And I said, "Sorafenib’s ushered in the golden age. We’re going to have so many new approvals.” I was off by about a decade. But we tried for a long time and had numerous negative studies. And this was not because of lack of trying. But I think our insight into how these drugs work and our expectations in clinical trial design just were not mature enough. Sometimes, you need to fail a few times to learn.

That changed in 2018 with the REFLECT study, which was the lenvatinib approval. We saw with lenvatinib that we had a new drug, a new option for liver cancer. When we looked at the survival data, it was noninferior, so it was no better and no worse, essentially, for its effect on overall survival. But it did delay progression. It did have a little different adverse effect profile as far as a lower incidence of hand-foot-skin syndrome, a higher incidence of hypertension. And it did have higher response rates. By RECIST, we saw response rates of around 18%, 19%. That was new, because sorafenib, while it improved survival, which all of us, I think, would agree is the most important end point in our liver cancer studies, it didn’t give us a high response rate. I think it was challenging for other physicians in the space to appreciate the importance of a drug that can improve survival but doesn’t necessarily shrink tumors.

Since that time, we’ve had a number of TKIs [tyrosine kinase inhibitors] approved, mostly in the second-line space, which we’ll talk about. Recently at ASCO [the American Society of Clinical Oncology annual meeting], we saw some interesting data with a novel TKI, donafenib. And this was the first time we saw a small molecule beat sorafenib. This study was done essentially in China, so its applicability to the Western population that we see, I think, is still lacking. But interestingly, this was one of the first TKIs that beat sorafenib and had a little more favorable adverse effect profile for TKIs.

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Tyrosine Kinase Inhibitors for Hepatocellular Carcinoma

Reena, we want to find liver cancer early because presumably it’s the most curable—resection, transplant, even radiofrequency ablation in small tumors. How do we think about the clinical aspect of liver cancer, specifically staging? Can you speak to Barcelona [Clinic Liver Cancer staging system]? Because I think that’s probably what people hear the most now. It’s used the most, the BCLC.

Yeah, that’s correct. Most commonly, we’ll use the Barcelona Clinic Liver Cancer staging system, or BCLC. And through the multidisciplinary liver tumor boards that I think most of us participate in on this panel, that’s really where we tend to link the staging with treatment options for patients. The advantage of BCLC being that it’s combining not just the tumor burden, but also the specific liver function as judged by the Child-Pugh status of the patient, knowing that most of these patients have a background of chronic liver disease or cirrhosis, and then also integrating the performance status, so all 3 parts, and then being able to further subdivide them into the options for treatment and prognosis.

 Probably the most common group of patients we see at presentation are patients with intermediate liver cancer. If anyone thinks otherwise, please let me know. Certainly, we see all stages. And hopefully, as we have earlier diagnosis, we’re seeing more patients with stage 0 or stage A, which is curable. But a lot of them are stage B, which are intermediate. These are patients who generally have well-compensated liver disease and multifocal tumor in the liver but do not have extrahepatic disease and do not have invasion to the vasculature. Historically, the standard of care for these patients has been locoregional treatment, such as chemoembolization and increasingly radioembolization with Y-90 [yttrium-90]. Some of these patients will be considered for transplant, they can be down-staged to transplant. I think this is a whole other discussion beyond the scope today, but I think highlights the point that these patients should be seen at a multidisciplinary program for an evaluation because of the importance of surgery and interventional radiology expertise. As compared to those patients who we’re talking about who are advanced, a lot of those patients would get systemic treatment, who have symptomatic disease, they have extrahepatic spread, or they have vascular invasion into the blood vessels of the liver. Certainly, a patient can stage-migrate. Someone with intermediate disease can progress beyond TACE [transarterial chemoembolization], or locoregional treatment, and become truly advanced, or even a patient who has [BCLC] stage B intermediate disease without vascular invasion or extrahepatic spread might be a patient for systemic treatment.

So Katie, all of us here see a lot of these patients, and we rattle these terms off pretty easily. But I think in clinical practice, as we have evolved into so many more treatment options, it’s going to be very important for the people in the trenches in the front line in the liver cancer space in oncology clinics, and hepatology clinics and GI [gastrointestinal] clinics, to have an understanding of this. Could you build out the multidisciplinary platform and stage migration and treatment decisions?



: I think this is a great area of discussion, and it’s important to reiterate the historical context here to remember that really, from 2007 until 2017, we had but 1 treatment available for systemic therapy, which was sorafenib. After that, there were clinical trials certainly, but very limited options for the majority of patients. That led to the evolution of locoregional therapy as the predominant mainstay of therapy for intermediate and sometimes even early advanced stages of HCC [hepatocellular carcinoma], and it’s really incumbent upon us now to reexamine the data, both for liver drug therapies, but also place it into context of the new systemic therapies. I think it’s important for us to remember that we do have limited prospective data for liver-directed therapies, particularly in the more advanced BCLC stage B space where the patients are having more than 3 to 5 lesions or getting more than 1 or 2 TACE procedures. Beyond those thresholds, we don’t have randomized trial data to confirm outcome benefit in large prospective trials. Likewise, we know from radioembolization trials that patients with more advanced stages of disease really do better with sorafenib, where there is no survival benefit to radioembolization in randomized trials compared to sorafenib in more advanced patients.

I think now that we have level 1 survival benefit in patients with unresectable, incurable HCC, including BCLC B or intermediate-stage patients, we need to be very careful about the use of locoregional therapies in patients who might have a survival benefit preferentially from systemic therapy. There are tools at our disposal to use, not all of them as well-validated as we may like, but for example, the prospective hepatic arterial embolization prognosis score that can help stratify patients according to their likelihood of benefit from TACE procedures, or patients who have already had a TACE procedure to look at toxicity and response such as the ART [Assessment for Retreatment with TACE] score. Those can help us potentially triage patients to switch over to systemic therapy, depending on their performance and their scoring. Now, all of this is complicated and absolutely enhances the importance of the multidisciplinary tumor board contexts, because these are complex decisions and lots of variables, including not only tumor response, but also liver function or deterioration thereof. I think that with this increase in options for systemic therapies, it requires us in medical oncology to become more present in the multidisciplinary tumor board setting to help guide and educate on the multiple therapies that we now have available.

You bring up some very important points. One of the concerns I think in continuing locoregional treatment beyond progression is that it could affect liver function. Amit, I know you’ve done some of these analyses. Continued locoregional treatment, while it’s very focused, very targeted, can you comment on its effect on the liver function over time?

Yes, what we see is that as Katie mentioned these scores, you can see that some people, when you go through locoregional therapy, you start to see basically off-target effects. You see some degree of injury to the background liver, and when you do this over and over again, just like any chronic injury, you can have deterioration of liver function. The most important reason that we have to consider this is because essentially, if somebody has worse liver function, then we may not be able to actually use these systemic therapies. I think that’s why we’re all becoming much more cognizant in terms of this appropriate time to transition and trying to maximize not only the benefit of locoregional therapy, but also maximizing the benefit and the availability of these systemic therapies.

Locoregional and Systemic Therapy for HCC

Reena, could you walk us through your patient who has an ultrasound in the background of chronic liver disease and has a nodule? How do we work that up?

Typically, for the majority of patients, the mainstay of diagnosis is going to be with dynamic multiphasic CT or MRI, preferably MR for purposes of sensitivity and specificity characteristics. We try to reserve doing a biopsy in, generally, under 10% of cases, if we see atypical features on the multiphasic imaging. That’s most commonly what we do. There are still areas, both from the imaging standpoint, as well as tissue diagnosis, where we have some limitations in diagnosis. One of the things that we certainly hear about as a diagnostic tool for a lot of other oncologic diagnoses is PET [positron emission tomography] scan and we tend to order this less frequently or rely on this less commonly for a diagnosis of HCC [hepatocellular carcinoma]. Much of that has been based on the lower sensitivity for detecting HCC generally felt to be inadequate to consistently rely on that for purposes of sensitivity of diagnosis. Some of the data that have come out have suggested that the level of differentiation of the tumor can be associated with characteristics of FDG [fluorodeoxyglucose] uptake. A more poorly differentiated HCC, for example, would be more likely to be PET-avid, and that may help in diagnosis of metastases in the future. There are also some data emerging looking at other tracers, radiotracers, that could expand on our utilization of PET scan in the future.

You bring up a great point that I think a lot of us in the cancer medicine research area are very sensitive to, certainly because of how it’s impacted other cancers we treat, and that is tissue. Here is a disease where you just said we only get tissue on less than 10% of patients historically because we can make the diagnosis noninvasively with CT or MRI, and that PET/CT doesn’t necessarily add much or actually might miss some tumors. So, if we don’t have tissue, how are we going to move to personalized medicine in liver cancer? Is there a role for these molecular testing modalities?

Certainly there’s a need for it, especially in this condition. One of the historic challenges of the molecular markers in testing in HCC has been the varied genetic profile. I think as more and more clinical-trial-based data have emerged, the hope is that we’ll be able to more reliably apply molecular targets, with the aim of precision medicine in mind for HCC as well. Historically, we’ve relied on AFP [alpha-fetoprotein]. I know Amit touched on AFP for screening purposes, and later on, we’ll talk about it more in terms of what we know in terms of AFP correlating with response to treatment. I think the goal is to expand the molecular targets and apply that to the individual patient and their treatment. There are more emerging data, though. I’m looking at some of these targets in HCC and circulating tumor DNA or doing liquid biopsies, all oncologic diagnoses, but applying that to HCC as well, and through that developing hopefully some reliable assays in the very near future that we can use both for screening and diagnostic purposes.

Anthony, how often do you end up sending NGS [next-generation sequencing] on your patients with liver cancer? Is that something you do at the get-go, like you might do in cholangiocarcinoma versus this disease?

: Certainly not. I think most of the NGS work that we do or others do is related to research. At this point, when we look at HCC, most of the targets that are altered in this disease appear to be not druggable, at the moment, at least. The more frequent alterations are not easily targetable with specific drugs. Now, this is changing gradually, as Reena mentioned. We do see targets such as 

, and others that are evolving. Many clinical trials are coming that are more tailored to specific alterations. So I think at this time, the clinical utility is limited, unless the patient has refractory disease and still has conserved liver function, where you may find an alteration that could be targeted, mostly in a clinical trial.

Katie, how about at UCSF [Helen Diller Family Comprehensive Cancer Center]? Do you biopsy everybody and send it for molecular testing?

 That’s a great question. I think particularly with the advent of more treatment options for both HCC as well as cholangiocarcinoma, our tolerance of a misdiagnosis or missing the most common alternate diagnosis of a biliary tract cancer is much lower. Even putting molecular profiling aside, we are tending to do biopsies for patients with advanced disease prior to systemic therapy much more frequently than before in patients who are fit for systemic therapy. Again, I agree with Anthony’s point that we don’t have a great established clinical target yet for NGS profiling in HCC, and I hope that will change with FGFR or 

 and other targets. I think it’s more that now that we do have multiple therapies, both for HCC and cholangiocarcinoma, we really don’t want to miss the alternate diagnosis.

Sure. There are a lot of exciting things in that diagnosis evolving over time.

Hepatocellular Carcinoma: Diagnostic Work-Up

You mention the word “surveillance.” Liver cancer is an interesting disease because like a lot of cancers, I guess it’s curable. But you commented on people who are at high risk. Should we be checking alpha-fetoprotein in these people? Is that how we identify this disease early, or any thoughts on that?

 With this identifiable target population and the vast difference in prognosis between early detection and advanced detection, despite advances in the advanced stage, it’s really important that we find this early so we can apply curative treatments, like you said. Surveillance is typically recommended using abdominal ultrasound with or without alpha-fetoprotein. The data suggest that alpha-fetoprotein actually does add something when you use it with ultrasound. Current recommendations, at least based on the data we have, suggest you should be using the two in combination every 6 months in any patient with cirrhosis.

 Reena, you’re a hepatologist, and you’re seeing these patients before necessarily the oncology community does. What about for patients who are obese from fatty liver disease and NASH [nonalcoholic steatohepatitis]? Is ultrasound the perfect test for them?

: That’s a great point, Rich. You’re absolutely right. In that patient population, we’re certainly challenged with the performance characteristics of ultrasound, in the obese male population, the growing fatty liver population, and any time a patient has ascites as well, these are limitations to the characteristics of ultrasound.

One of the things that I find frustrating, though I think I understand, is the US Preventive Services Task Force [USPSTF], they make the recommendations for screening, colonoscopy, mammogram. Still, screening for liver cancer is not something they’ve recommended. Reena or Amit, can you speak to the reason for that?

 Rich, the data for surveillance are good, but not optimal. What we have in the setting of cirrhosis is that we have many cohort studies, and largely retrospective cohort studies with limitations, like lead time and length time biases. When a randomized-controlled trial was attempted in the past, it actually failed to accrue and had to be shut down. I think without this level 1 data, the USPSTF has been reluctant to put forward a recommendation for HCC [hepatocellular carcinoma] surveillance. I think we’ve seen this in other cancers, where these recommendations are somewhat rushed out, then the USPSTF has to pull back. I think that given this controversy, for example, with prostate cancer screening, breast cancer screening in younger women, we’re finding that these organizations would rather have the data be there up front so they can make a recommendation, and everyone can feel truly confident that that is the right thing to do.

Surveillance for Hepatocellular Carcinoma

® titled, “Hepatocellular Carcinoma: Practical Implications of Emerging Data.” I’m Dr Richard Finn from the David Geffen School of Medicine at UCLA. I’m joined by an outstanding faculty today for a discussion, including Dr Bekaii-Saab, from the Mayo Clinic in Arizona; Dr Anthony El-Khoueiry, from USC Norris Comprehensive Cancer Center here in Los Angeles; Dr Katie Kelley from the University of California San Francisco Helen Diller Family Comprehensive Cancer Center; Dr Reena Salgia, from the Henry Ford Health System; and Dr Amit Singal, from the UT Southwestern Medical Center.

Today, we are discussing a number of topics regarding the use of systemic treatment in advanced liver cancer. We’ll discuss the latest research in the field, including from the ASCO [American Society of Clinical Oncology] 2020 virtual meeting, and the impact of recent clinical trials on making decisions around treatment selection.

Let’s get started with our first topic, early stage liver cancer. Amit, could you walk us through some of the epidemiologic factors in regard to the development of early liver cancer and how we can impact our patients?

Yes, I’m happy to, Rich. First, it’s exciting to be part of this great panel. As we know, HCC [hepatocellular carcinoma] is the fourth leading cause of cancer-related death worldwide, and we know that it’s not evenly spread across the world. The highest incidence and mortality rates are in East Asia and Africa, and this is driven by high rates of hepatitis B in those areas. In the United States, this is a cancer that’s gaining more attention because of the rapidly rising incidence and mortality rates. When you look at the last 15 years assessed by SEER [the Surveillance, Epidemiology, and End Results program], HCC has had one of the largest rises in incidence among all common cancers. It’s projected if this continues that HCC could become the third leading cause of cancer-related death here in the United States. One of the unique things about HCC is that we have an identifiable target population. It primarily develops in those patients with chronic liver disease, and over 90% occur in the setting of cirrhosis. This can happen from any host of chronic liver diseases, including viral hepatitis, like hepatitis B or hepatitis C. There is a certain proportion due to alcohol-related liver disease. And we’re finding more and more is related to what is now called metabolic-associated fatty liver disease, which is liver disease that happens in the setting of obesity and diabetes. As those become more common in the United States and worldwide, we’re seeing more HCC related to this etiology.

: We’ve heard a lot about the new advances in hepatitis C treatment, right? Is liver cancer going to go away now that we’ve cured hepatitis C?

: I wish that was the case. You’re right that when we treat viral hepatitis, we see a nice drop in the HCC incidence. But the first thing is that once you have cirrhosis, that doesn’t go away completely, you don’t eliminate that risk. Those patients still have an annual incidence rate above 1%, and therefore continue to need surveillance and need to be observed for the development of HCC. Even if we get rid of viral hepatitis, as I said, we still have large proportions that are related to alcohol and metabolic-associated fatty liver disease, and increases in those areas are likely largely offsetting any decreases in HCC-related viral hepatitis. I don’t think this is a disease that is going to go away anytime soon.

Amit Singal, MD, UT Southwestern Medical Center

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Tyrosine Kinase Inhibitors for Hepatocellular Carcinoma

Locoregional and Systemic Therapy for HCC

Hepatocellular Carcinoma: Diagnostic Work-Up

Surveillance for Hepatocellular Carcinoma

Incidence of Liver Cancer in the US