This is a classic scenario of a lady with, unfortunately, morbid obesity and nonalcoholic steatohepatitis that led to hepatocellular carcinoma. She is a Child-Pugh A, thankfully, and still has options that are available. Unfortunately, the tumor is rather large, but more importantly, it&rsquo;s really very close to blood vessels, deemed unresectable by an evaluation with the surgeon. And with the lack of metastatic disease, a local therapy might be appropriate over here.

This is a very classic scenario. We see it all the time, which is why chemoembolization, bland embolization, or some form of embolization would be totally appropriate. In that case, the patient did receive a chemoembolization with drug-eluting beads, which are now becoming more and more used in that domain. And it appears to be that she did rather very well. She obviously, the day after the intervention, had fevers, abdominal pain, and some elevation of the liver function tests, which are classic postembolization syndrome. She recovered from them, appropriately so. Within about 2 to 3 months, a certain CT scan did occur and it showed a very reasonable response to the embolization and the alpha-fetoprotein, if I heard, dropped from about 1500 to about 200. So, that&rsquo;s a great story! If anything, there was totally appropriate management and the patient did receive the appropriate care over here.

Management of HCC in Fatty Liver Disease

The important question though over here is, is there anything else that can be added? This is a classic question that we get all the time. What is the role of sorafenib, for example, after TACE or around TACE? Many studies have taken place, and all of them have been reported, mainly focusing on the combination of the sorafenib plus chemoembolization, ie, TACE in the setting of locally advanced disease. Among those, the one that&rsquo;s most recognized and reported at all times is the SPACE study, which was led by Dr. Riccardo Lencioni, our colleague from interventional radiology. There&rsquo;s the TACE II study from the UK, there&rsquo;s an ECOG 1208 study from the Corporate Groups here in the United States, and before that, there was a Japanese/Korean study.

As a very important example, and really a reference to that discussion, the SPACE study randomized patients to chemoembolization with sorafenib without any stopping of the sorafenib, ie, through and through. Patients continued taking the sorafenib and just the TACE in between. Unfortunately, there was no difference between patients who received that kind of intervention versus patients who received TACE alone without sorafenib. And any thoughts about sorafenib contributing to local therapy in the setting of TACE, unfortunately, did not pan out. As such, it is strongly recommended that the combination of TACE and sorafenib is not the right approach. If anything, if a patient has local disease, then by all means, local therapy like TACE is appropriate, but the combination is not really appropriate per se.

TACE, or transarterial chemoembolization, will depend really on the size of the tumor as well as the location of the tumor. In general, it would be nice to think that TACE will be applied once and to control all the disease. Sometimes, however, TACE is staged, ie, the interventional radiologist might plan more than 1 TACE based on how much they can cover of the tumor. However, nobody really has put any data in place, except our colleagues in Japan, in regard to how many TACE or how frequent they should be. This is really always a subject of contentious debate because people don&rsquo;t really realize what&rsquo;s necessary to do. And, if anything here, of course patient care comes first. In other words, the simplest scenarios, if there is a metastatic disease situation while on TACE, by all means, this is a time to go to systemic therapy. If we try TACE more than several times, let&rsquo;s say 3 or 4 times, and especially if there is a narrow sequence in between, ie, about 1 to 2 months in between, this is telling us that it&rsquo;s probably time to go to systemic therapy.

Locoregional Therapy in HCC

Another important factor in regard to the TACE, which even I would like to stress because this is a critical one, is patients with metastatic disease should not receive local therapy. There are exceptions to the rules for certain reasons, but, in general, they should not receive systemic therapy in the setting of metastatic disease. Because the argument that the disease is probably more responsible for outcome of patients, based on what&rsquo;s in the liver and not outside the liver, is not necessarily true. We have seen situations, unfortunately, where the disease can worsen outside the liver and can cause certain impact in regard to patient outcome, simply because there was no systemic therapy applied and it was all focused on local therapy. The fact that worrying about the disease in the liver is more important than anything else is not really the case. It&rsquo;s something to keep in mind.

Let&rsquo;s assume this patient had the same scenario but with 1 caveat or difference where the major blood vessel, let&rsquo;s say the portal vein, isn&rsquo;t involved with the cancerin other words, a tumor thrombus in the portal vein. TACE might not become a feasible option because, remember, TACE depends on the 2 blood flows that are available to the liver; ie, when we embolize on the arterial phase, we are dependent on the venous phase to allow the nourishment of the liver. And, as such, the venous part, which is a portal vein, is blocked. There&rsquo;s a jeopardy to the liver over here.

Another approach would be possibly Yttrium-90 or radioembolization. There are lots of data that have shown it to be effective in the setting of portal vein thrombosis. Obviously, systemic therapy could be another appropriate option. Which one versus which, there are data that will be coming out at some point in time that probably would help guide us better for an option of that nature.

Considerations in Advanced HCC

This patient has metastatic disease now to the lung. By all means, this is a time where the interventional radiologist should sit with the oncologist at the tumor board or pick up the phone and say, &ldquo;Maybe it&rsquo;s time to start talking about systemic therapy.&rdquo; And this patient by all means should go, again, on sorafenib as standard of care as a first-line of treatment or on a clinical trial if readily available at that time.

This patient appears to be that their bilirubin, which was totally normal at about 1.0, jumped about 1.8, which put them in a category of a high bilirubin that continues to 2.1. Their Child-Pugh score now is right on the edge between A and B, maybe a B7 if, let&rsquo;s say, the albumen is a little bit low as well. In that scenario, sorafenib is still appropriate, but there are data already published. The first author, Miller, from

a few years ago showed that for a bilirubin between 1.5 and 3 of the upper limit of normal, half the dose of the sorafenib will be appropriate. And this is where maybe a patient like this should be monitored very closely with bilirubin and other things, and still be given sorafenib with close monitoring. Close monitoring means that patients will be seen probably on a weekly basis, have their bilirubin checked, and be taught about any symptoms that will probably reflect on increased bilirubin like, for example, jaundice, change in the color of urine, yellow eyes, etc.

When sorafenib was first approved, there was a certain excitement that this was a pilljust give it to the patient and then check on them at a certain later point in time. A close follow-up is so critical for patients on sorafenib and probably is going to be the same for regorafenib patients. You&rsquo;ve got to make sure that you check on the patients on a regular basis. When we start therapy, I personally will probably give a call to the patient within 3 to 4 days. Anybody in the office can do that&mdash;the doctor or the nurse&mdash;checking to see how things are because hand-foot syndrome might be evolving at that time. And, within a week&rsquo;s time, patients should be seen in the clinic as well. It should not be underestimated how critical it is to closely follow up with those patients to avoid them from going to grade 3 toxicity, where options for them might be limited. And so, maximizing on the potential for the therapy by close monitoring and avoiding the worsening of the side effects is critical and of prime importance.

Considerations Following Locoregional Therapy in HCC

Management of HCC in Fatty Liver Disease

Locoregional Therapy in HCC

Considerations in Advanced HCC

Systemic Therapy Following TACE in Metastatic HCC