With that in mind, it’s a good segue into our evolving role of TACE [transarterial chemoembolization] with systemic treatments. Is the whole BCLC [Barcelona Clinic Liver Cancer staging system] going to shift to the left, in that we’re going to offer patients systemic treatment earlier? Dan, how do you see the paradigm evolving that way and in your practice?

 That’s a great question, and I think there are multiple areas we have to consider. As our treatment armamentarium gets bigger and bigger, we need to determine whether combination strategies are the appropriate way, in terms of combining newer systemic therapies that we are seeing have impressive response rates in the advanced setting, and translating it into the BCLC stage B setting with TACE vs TACE. There are several ongoing trials looking at that combination.

Secondly, I think the other role is to say that it is time to take systemic treatment vs TACE. As you mentioned, TACE was done in an era when we didn’t have many systemic treatments. And as our systemic treatment options get better and better and the response rates get higher and higher, is it time to go up against TACE in that intermediate stage, and see whether there’s a benefit? There’s some rationale that systemic therapy can preserve liver function much better compared with TACE over time, so that might be beneficial for patients.

Finally, I think there’s the role of sequential therapy. As I mentioned before, there is this idea of whether incomplete TACE can induce hypoxia and increase angiogenesis, so is there a way to prime the tumor with systemic therapy so that patients can get additional benefit with TACE? I think that’s going to be very important.

Amit mentioned the study with Masatoshi Kudo, MD, PhD, that compares lenvatinib with TACE for those patients who have bulky tumors, and those are definitely patients who can benefit. In that trial, about 62% of patients in the lenvatinib arm, while there was tumor necrosis, went on to receive TACE, interestingly. The patients who had CRs [complete responses] were those patients who were primed with lenvatinib and then sequentially received TACE. There may be a role for that, to prime the liver tumor from an antiangiogenic perspective, and then treat it with TACE.

That’s an interesting idea that’s been around for some time. We know that TACE induces ischemia and embolizes the tumor, and ischemia is a very potent driver of 

 expression and secretion, and that was the rationale for looking at many VEGF inhibitors in liver cancer, especially in combination with TACE.

Josep, there have been 5, 6 TACE/systemic treatment studies to date. Most of them have concentrated on sorafenib, and then there was a study with brivanib, which never finished because the brivanib program was shut down eventually. At ASCO GI [the American Society of Clinical Oncology Gastrointestinal Cancers Symposium] this year and the year prior, we saw another study with sorafenib, the TACTICS study, which looked a little different than the others. Can you comment on this idea that Dan brought up about using VEGF receptor inhibitors, whether its sorafenib, lenvatinib, cabozantinib, regorafenib, ramucirumab, in this population?

 Yes. There are 2 issues here you are bringing up. One is when to introduce systemic therapies in patients in the intermediate stage, and the other question is should we do that in combination with TACE, or as a combination of systemic therapies, for instance, without TACE? To the first question, I would say that the trials as you know have all been negative. All the phase 3 trials, and there are not many, even fewer phase 2 trials, have been mostly negative. These trials are not providing enough robust data to establish that as a treatment of choice.

Therefore, what is going to change the role of systemic therapies is the introduction of immune therapies in the intermediate setting. The role of antiangiogenic agents will also be a stage to boost the immune response. It’s like what happened with bevacizumab, what happened with lenvatinib, as we already know, all these combinations are boosting immunity. Twenty percent, 25%, of patients may respond to a single agent, but certainly you are broadening that. This is amazing.

We are broadening the population, not only in terms of objective response, but in terms of disease control rate, up to 90% of the patients in advanced disease, with these combinations. So, this concept is what I think is going to switch the field of intermediate stage. In my view, enough attempts have been made for the combination of TACE with a single-agent antiangiogenic. It’s not flying, and I think that what’s going to fly is the testing of immune response.

The second question is what about all these patients who are not responding? There is a switch; there is a migration. Certainly, I think this is a critical point because when sorafenib was the only systemic therapy, there were no other locational efforts to, let’s say, educate physicians to treat the patients with systemic therapy upon progression with TACE, and these efforts never fly. Now without any effort, the physician is already convinced with the data that are out there, that upon progression with TACE, you have 3 lines of systemic therapy. You can start with atezolizumab-bevacizumab, and follow with sorafenib, or the other treatment options, you can use lenvatinib. The physician is now confident to treat patients who progress after TACE with systemic therapy, and this is growing.

Videos

An in-depth discussion about the role of TACE in combination with systemic therapies for the treatment of HCC.

TACE and Systemic Therapy in HCC

All of the phase 3 studies in advanced liver cancer are focusing mostly on this Barcelona Clinic Liver Cancer [BCLC] stage C population, which as Dr Llovet described, has extrahepatic spread, metastases, vascular invasion, or tumor-related symptoms. But most of the phase 3 studies have about 15% or 20% of patients who are BCLC stage B, which means they’re intermediate technically by staging, but they’ve either progressed on TACE [transarterial chemoembolization], as Dan mentioned, or they weren’t TACE candidates at presentation. It’s interesting to think about how these patients who are BCLC stage B do in the real world in some of these clinical trials with systemic treatment. Amit, you had some data at ASCO GI [the American Society of Clinical Oncology Gastrointestinal Cancers Symposium], and you’re familiar with the space. Can you comment about what is available for patients with BCLC stage B being treated with systemic treatment?

When we think of that intermediate stage, BCLC stage B, the first thing I typically do is look at those clinical trials. As you said, each of these clinical trials has about 15% to 20% of patients who are in that intermediate stage and still qualify for the clinical trial for any number of reasons, including TACE failure and large multifocal bilobar disease, who we would consider poor candidates for locoregional therapy.

When we look at those registration trials, we typically see that the effect of systemic therapy is fairly consistent in that intermediate stage. The most recent trial, the one with atezolizumab-bevacizumab in terms of the first-line standard of care for most patients in the unresectable stage, there was an interesting signal that people may have “overinterpreted” that subgroup analysis.

When we look of the subgroup analysis of the IMbrave150 trial, and you take a look at progression-free survival [PFS], that effect of atezolizumab-bevacizumab compared with sorafenib is consistent in terms of PFS, although when you look at the overall survival signal, the hazard ratio tends to be closer to 1. Some researchers interpreted those data to mean that atezolizumab-bevacizumab may not work as well in the intermediate stage.

We’re going to see as this plays out with longer data that were presented at ASCO GI, but I don’t think there’s any reason why systemic therapy would work any worse in the intermediate stage in terms of all of the considerations that we would have, all the options what we have.

Of course, the number of patients who were BCLC stage B that we see in those registration trials is limited, a relatively small group of patients, so we do want to see more real-world data. The real-world data that have been presented for systemic therapies, for example, in the frontline setting, sorafenib, lenvatinib, and I’m sure we’ll see atezolizumab-bevacizumab real-world data come out as well, all suggest these agents work equally well in the locoregional space as they do in the systemic space in terms of their efficacy.

As we’ve mentioned, the field is trying to define which patients in BCLC stage B are best or most appropriate for systemic therapy. Laura, you referenced the trial led by [Masatoshi] Kudo, [MD, PhD,] that compared lenvatinib with chemoembolization in patients with tumor burden beyond up-to-7 prognostic score. As a proof of concept, Dr Kudo and his colleagues demonstrated that those patients with larger tumor burden beyond the up-to-7 criteria, in a retrospective manner, did better with systemic therapy than locoregional therapy. The trial included relatively small numbers, 90 patients overall, but as both locoregional therapies and systemic therapies continue to evolve, these data are going to be more and more essential for defining which patients are the best candidates for systemic therapy.

You bring up an important point, because the phase 3 studies are not always powered to look at these smaller subgroups, but we often see a trend where the PFS and overall survival is very long for the intermediate group, as Josep commented earlier, and these patients go on to receive other treatments, which may make it more difficult to show an overall survival benefit for this group.

Daniel, at the Mayo Clinic, do you find yourself offering the BCLB stage B group systemic treatment, and what characteristics does that patient have?

As you mentioned, BCLC stage B is a wide range of true Bs and those who are closer to As. As Dr Li mentioned, some of these patients may be better candidates for systemic therapy, where they could be downstaged to get surgery. Some of the conflicting factors are whether these patients would be candidates for a liver transplant because the data are not emerging about the role of downstaging to potentially get these patients to a liver transplant. So there are some confounding factors as well.

Within BCLB stage B, there is a very gray area for who qualifies. And as you spoke at ASCO GI this year, we have to compare the role of systemic therapy with locoregional therapy, especially with a lot of these new emerging options that seem to have high response rates and durable responses that can provide an equal benefit and potentially be more efficacious for these patients classified as stage B.

Our armamentarium for systemic treatment has grown. We had sorafenib for a long time in the frontline setting, and then we had lenvatinib approved in the frontline setting based on noninferiority, but it does have a higher response rate and a higher effect on PFS compared with sorafenib. It has some adverse effect differences to consider, more hypertension, proteinuria with lenvatinib vs more hand-foot skin syndrome with sorafenib.

Then we had a slew of second-line therapies approved, which has markedly changed the landscape for patients. Starting these drugs earlier might offer patients more opportunities to see systemic treatment that can impact their survival. Recently the atezolizumab-bevacizumab data in the frontline setting are giving response rates that are comparable to locoregional treatment—not too far off—as far as objective response rates of 30% in the subset that has CRs [complete responses], and that’s in advanced disease. To your point Amit, maybe it is time to look at these drugs in earlier lines of treatment.

Amit G. Singal, MD, MS, leads a review of recent data around the outcomes of systemic therapy for patients with BCLC stage B HCC. 

Recent Findings in Systemic Therapy for Patients With BCLC Stage B HCC 

That’s a great segue to think about some of the practical considerations for using TACE [transarterial chemoembolization]. Laura, you’re a busy hepatologist at Northwestern University and play an active role in treating patients with liver cancer, as well as contributing to the intermediate space. What are you thinking about when considering a patient as a TACE candidate in practical terms?

Since the BCLC [Barcelona Clinic Liver Cancer staging system] started— it’s the 20-year anniversary, congratulations to Dr Llovet—there has been a lot of refining. Originally, you could have a Child-Pugh score of A/B. But now it has become clear that it is very important that the more the patient is doing well from a liver standpoint, the more you could expect them to tolerate TACE, and hence, have more of a response because you can deliver the treatment that you’re wanting to.

Dr Llovet brought up a couple of prognostic factors, the 6-and-12 score is one of them, the up-to-7 score is another. This is taking the tumor burden, which is defined by the largest lesion plus the number of lesions, so you get this linear equation. If you have 1 tumor that is 6 cm, and that’s the largest tumor, and you have 2 tumors, that would be 6 plus 2, which is 8. Up-to-7 has recently been defined as how you may start to think of patients who would deserve to go onto systemic therapy, or at least consider systemic therapy.

I would say as a transplant hepatologist though that some of those patients would be in the realm of consideration for downstaging in terms of upper limit. When we think of transplant, we don’t have a ceiling of anything and try to downstage, because the chances become less the more tumor burden you have.

I think you have to look at the patient overall, their age, their overall health, as to whether this patient will be a transplant candidate. Vincenzo Mazzaferro, MD, who was the grandfather of coming up with the Milan Criteria, recently published a randomized, controlled trial looking at transplant vs locoregional therapy and/or systemic therapy, which is remarkable that you can do this in this day and age. And not surprisingly, the overall survival was significantly improved at 5 years in patients who were transplanted.

You always have to consider the potential of downstaging, but we know there are patients, going back to your question, who are not going to be good TACE candidates. They’re either going to be refractory, have an infiltrative tumor, or they’re starting out with ALBI, which is the albumin plus bilirubin, and it’s also a linear equation, a 1, 2, 3. With these factors, we know that they probably won’t tolerate TACE well, and moving to systemic therapy earlier in those patients is becoming more of the thought process, as opposed to waiting.

You bring up some important points that are practical and speak to the point that hepatocellular carcinoma is a multidisciplinary disease, not only oncology and hepatology, but interventional radiology and surgery, such as hepatobiliary surgery and transplant. The criteria for transplant are somewhat fluid, especially in the United States. It is not so orthodox anymore that a patient gets assigned intermediate stage and stays there. Patients will migrate to become advanced eventually, and they may even migrate a little earlier, and there are opportunities for curative therapies for some of these patients.

Amit, when you see a patient and you’re considering TACE, how do you pay attention to their liver function? How does that impact your decision?

Laura started to talk about this to some degree in terms of when we consider somebody for chemoembolization or radioembolization, or any locoregional therapy. It is important that you consider the liver function, and we’ve gone beyond just considering the Child-Pugh score; many of our centers also add the ALBI score, which is adds value to the Child-Pugh score. We do this because whenever you treat with locoregional therapy, you’re trying to induce some degree of tumor response with the idea of either downstaging and/or improving survival. There’s also the concomitant risk of liver injury. Whenever we do a chemoembolization, radioembolization, SBRT [stereotactic body radiation therapy], etc, we have to watch the liver function carefully, because you can see patients who have deterioration, whether that’s new decompensation or increase in their bilirubin.

The stronger a patient’s liver comes in, the more likely they are to tolerate that chemoembolization or other locoregional therapy. This is a critical factor to consider as we go through this, and if you see a patient whose liver function gets worse—to your point of stage migration—that’s another consideration in terms of stopping locoregional therapy and switching to systemic therapy.

You bring up some important points. To put it in context historically, before the approval of sorafenib in 2007 and 2008, we didn’t have a proven systemic treatment. Josep led one of the pivotal studies that established TACE as a standard of care, but in a confined population anatomically, as well as liver function. And TACE and locoregional treatment expanded to fill the void over time, in that we didn’t have any systemic treatment, so TACE was used in patients who were probably not optimal candidates. Maybe they had vascular invasion, maybe they had progression after a TACE, and it was TACE beyond progression even, because we didn’t have anything else to offer these patients other than maybe clinical trials.

I remember back in the day offering patients octreotide because there were early data there, tamoxifen, eventually cytotoxic agents—capecitabine, doxorubicin—even though there weren’t data to support that. But we wanted to offer patients something or a clinical trial.

Dan, when you see a patient at your multidisciplinary program who had TACE, how do you assess response, and when do you decide TACE is no longer working?

I think it’s done, as you mentioned, in a multidisciplinary fashion. Usually, we would assess for a TACE response anywhere between 6 to 8 weeks post-TACE procedure, initially with imaging. How do you characterize response? You want to see that the tumor has died out and is not necessarily lighting up on the scan.

You want to assess whether you get clearage of that entire tumor or there’s residual enhancement. This is an important point because we know a lot of times with incomplete TACE, the tumor becomes a little more resistant moving forward. There are a lot of preclinical data to suggest that an incomplete TACE can lead to an increase in tumor hypoxia and ultimately rev up pathways involved in angiogenesis, which can be problematic in developing somewhat more resistant tumors.

How do you make that characterization of whether someone’s potentially TACE-refractory over time? I think there are a lot of different criteria in terms of whether you get an incomplete response, and not a complete response, where you’ve done the embolization. But also, whether new lesions show on that first scan afterward is suggestive of a somewhat refractory disease and may be an indication to transition to systemic therapy much earlier.

A panel of experts discuss practical considerations for TACE in patients with unresectable BCLC stage B HCC, as well as define TACE-refractoriness and what to do if a patient fails treatment.

Practical Considerations of TACE in HCC

® titled, “Redefining Treatment Approaches in Advanced Liver Cancer.” I’m Dr Richard Finn from the Geffen School of Medicine at UCLA [the University of California, Los Angeles]. I’m joined today by my friends and colleagues—a global multidisciplinary panel—Dr Daniel Ahn, from the Mayo Clinic in Phoenix, Arizona; Dr Laura Kulik from Northwestern University in Chicago; Dr Dan Li from City of Hope in Duarte, California; Dr Josep Llovet from Mount Sinai School of Medicine in New York; and Dr Amit Singal from UT [University of Texas] Southwestern Medical Center in Dallas.

Today, we are going to discuss key updates from the ASCO GI [American Society of Clinical Oncology Gastrointestinal Cancers Symposium] 2021 virtual meeting and review the rapidly evolving landscape for unresectable advanced hepatocellular carcinoma [HCC].

In our first topic we’ll be dealing with locoregional treatment and its evolving paradigm and use in the setting of systemic treatments that are highly active. To introduce the topic, I can’t think of anyone better than Dr Josep Llovet, one of the fathers of the BCLC [Barcelona Clinic Liver Cancer staging system], which had such a big impact, and Josep, you’ve made so many pivotal contributions. Thanks for joining us. Can you give us an overview of how locoregional treatment and systemic treatment fit within the BCLC?

Certainly. Thank you very much, Richard; thank you for this invitation. As you know, we have 5 stages in the BCLC system; very early stage, early stage, intermediate stage, advanced stage, and end-stage disease, which are defined by tumor burden according to the Child-Pugh system and ECOG performance status. My focus today will be on the intermediate stage of HCC. We have those patients with liver-only disease, an ECOG performance score of 0, and a Child-Pugh score of A and B. As you know for this patient, given the last 15 years, we have the same standard of care: transarterial chemoembolization [TACE]. The results from ongoing trials showed median survival between 26 and 30 months, progression-free survival around 7 to 10 months, and an objective response rate around 60%. This is to frame where we stand in terms of a standard of care. There has been a lot of discussion about heterogeneity of BCLC stage B. Patients with ALBI [albumin-bilirubin] grade 1, a subgroup of Child-Pugh A, mostly a Child-Pugh score of A5 with ALBI grade 1, 90% of these patients have a better outcome. Patients with AFP [alpha-fetoprotein] less than 400 µg/mL also have a better outcome. Patients with ECOG 0, certainly.

Now there have been discussions about tumor burden that we can further discuss. The beyond up-to-7 or the 6-and-12 prognostic scores are rules to define treatment responders and nonresponders. The rule in terms of management is that patients will be treated by TACE in the frontline setting. In the case that they receive 2 TACE treatments and do not achieve objective response, and have stable or certainly progressive disease, they will switch to systemic therapy. It is still controversial, but this will be the frame.

Certainly in the United States and other centers are also treating these patients with Y-90 [yttrium-90] radioembolization, and Dr Kulik surely will talk about that. Now there are trials, as you know, combining TACE with systemic therapy vs TACE alone, or even there are trials challenging TACE with systemic therapy alone, and we can discuss that later.

You brought up important prognostic points, that the staging in liver cancer and oncology in general is to prognosticate for our patients. And clearly there's a difference between that intermediate group and the advanced group, and as you commented, that’s based on performance status and tumor characteristics. That’s a very important prognosticator.

Josep, can you give us, for the practicing clinician, the tumor characteristics that differentiate BCLC stage B, which is intermediate, vs advanced, BCLC stage C?

 It is very simple. In BCLC B or intermediate stage, in principle, the disease is liver only. Whereas, if you have either vascular invasion or extrahepatic spread on one hand, or cancer-related symptoms, ECOG performance status of 1 or 2, then you are in BCLC C or advanced stage. This is mostly the distinction. For instance, 50% of patients with advanced stage HCC in the frontline setting will already have metastatic disease, and 20% will have portal vein invasion.

When you say vascular invasion, you get an MRI on a patient and it shows a tumor with a thrombus, let’s say macrovascular invasion or thrombus even within the liver, do we think about that differently than someone who has vascular invasion in the main portal vein?

When the BCLC staging system was established, segmental portal invasion, as you know there are 4 types. You probably are not going down to the details on the types of vascular invasion, 1, 2, 3, 4. But certainly segmental portal invasion within the liver is already considered, A), a prognostic factor of poor outcome, and B), a predictor of poor response to TACE. Therefore, these patients are considered at advanced stage of the disease.

Then we can discuss whether these patients might be suitable for a specific trial for advanced stage, and even there are good data with Y-90, for instance, with these patients. But certainly, any type of vascular invasion that you can detect by CT scan, MRI, or contrast-enhanced ultrasound is defined as advanced disease.

Richard S. Finn, MD, leads a panel of experts in a discussion around key updates from the 2021 ASCO GI virtual meeting, and a review of the rapidly evolving landscape for unresectable advanced hepatocellular carcinoma.

Josep M. Llovet, MD, PhD, Mount Sinai School of Medicine

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