This case that we have is a 77-year-old gentleman with hepatocellular carcinoma and extrahepatic involvement. He has a history of alcohol use and is still drinking 3 to 4 alcoholic drinks a day. He presented to his primary care doctor with abdominal pain and a 10-pound weight loss.

He has some fatigue, but his performance status is normal, and he&rsquo;s got good liver function with no decompensation, as well as Child-Pugh A cirrhosis. On imaging, he was found to have hepatocellular carcinoma in his liver, a 4.5-cm lesion with arterial enhancement, portal venous washout, and a pseudocapsule with a LI-RADS [Liver Imaging Reporting and Data System] 5 lesion. He also has what looks like a metastatic lesion to his iliac crest. His chest CT was clear. His weight was 72 kilos, so he had  BCLC-C [Barcelona Clinic Liver Cancer-stage C] hepatocellular carcinoma. He was started on lenvatinib [Lenvima] at 12 mg a day. During the initial period of his treatment, he experienced increased weight loss and was sent to nutritional therapy to help with his appetite. He did have a partial response at 16 weeks of imaging. Unfortunately, after 8 months of treatment, the therapy was discontinued because he had progressive disease.

This is a standard presentation for patients with HCC. Unfortunately, a lot of patients who have underlying cirrhosis, especially those who aren&rsquo;t decompensated, may not know they have cirrhosis and liver disease, and instead present symptoms of liver cancer. By the time they&rsquo;re diagnosed with symptoms, they already have advanced disease, like this gentlemen with metastatic disease. He does have excellent liver function, so that gives us some options because he&rsquo;s able to tolerate the systemic treatments that are available.

When I&rsquo;m seeing a patient for the first time with liver cancer, usually the initial imaging studies were done in an emergency room or through their primary care doctor. They may not have had multiphase imaging for the arterial, portal venous, and washout phases of the liver. Oftentimes we do more advanced imaging, so that we can identify all of the different pieces in the liver that they may have because you can have lesions in the liver that are hidden on just a single-phase imaging. We then do some metastatic workup; I typically do a chest CT and a nuclear medicine bone scan initially. Sometimes we&rsquo;ll do a PET scan, although they are not as sensitive for HCC, so this is not a standard imaging test that we&rsquo;ll do.

With patients who have advanced liver cancer and metastatic liver cancer, I tell them liver cancer is different from other cancers because, especially in the United States, over 90% of these diseases occur in people who have underlying liver disease. When we&rsquo;re thinking about the prognosis and treatment options, we have to take into account the cancer and underlying liver disease. The fact that this patient has a Child-Pugh A cirrhosis with no decompensation gives him a plus as far as his prognosis; however, he unfortunately had advanced disease with metastatic lesions. Without any treatment, his survival is probably around 6 to 12 months.

Approaching a Case of Unresectable HCC with Extrahepatic Involvement

The initial treatments that we think about for liver cancer are curative treatments, which would be resection, transplant, or potential ablation in the small tumors less than 2 cm. When we think about the eligibility for resection, the big thing to consider is the underlying disease and whether the liver with cirrhosis is going to be able to tolerate a resection. That has to do with the liver function as well as portal hypertension, as well as how much of the liver will need to be resected  and the volume of remnant. This patient is not a candidate because he has metastatic disease. If he did not have metastatic disease, we could potentially look at whether he would have portal hypertension, an elevation of his bilirubin, the location of the tumor, and whether resection would be an option.

For transplantation we need to see if they are within the Milan criteria: the initial liver cancer rules that we use to follow transplantation. These criteria state that the tumor must be up to 5 cm, or 3 tumors, or fewer than 3 cm without vascular invasion or extrahepatic spread. Because he has extrahepatic spread, he is not a candidate for transplant. He has only one 4.5-cm tumor, so if he did not have the extrahepatic setting, he could potentially have been a candidate. We&rsquo;ll also take patients who don&rsquo;t have metastatic disease or extrahepatic spread, but they&rsquo;re outside the Milan criteria. We&rsquo;ll treat them to try what we call &ldquo;downstaging,&rdquo; to bring them within the Milan criteria, by shrinking, ablating, or TACEing [transarterial chemoembolization] the tumors.

Multidisciplinary teams are important with the management of liver cancer. We&rsquo;re taking care of a cancer, but we also are taking care of underlying liver disease. We have to involve our surgeons, radiologists, and radiation oncologists to determine resectability or transplantability. It&rsquo;s important to interact with all of these different specialists. The best way to do this is to have a multidisciplinary tumor board every week that considers the cases as a group. Any initial treatment that we have for a new presentation or recurrence, is brought to our multidisciplinary tumor board. The data have shown that patients who are offered multidisciplinary approaches have a better overall survival, availability of treatment, and response to therapies.

When we&rsquo;re thinking about frontline treatment for metastatic liver cancer, we have several systemic treatments available. Many would consider doing a local regional therapy with some systemic treatment, but given the patients&rsquo; lack of disease in the liver and metastases, systemic treatment with some kind of oral chemotherapy is the way to go. Our options include lenvatinib [Lenvima] or sorafenib [Nexavar]. Immunotherapy [I-O] may be an option in the future, but right now it&rsquo;s approved for only second-line treatment. Lenvatinib is a good option for this patient because he&rsquo;s symptomatic; it has a better response rate, meaning the tumor has a better likelihood of shrinking in these patients. For those patients who present to me with symptoms such as pain or discomfort in the abdomen, I try to offer them lenvatinib as a front-line treatment because of these effects.

Unresectable HCC: Considerations for Resection and Frontline Therapy

The REFLECT trial was the phase III open-label trial of lenvatinib [Lenvima] versus sorafenib [Nexavar] for front-line therapy of advanced HCCeither metastatic disease or vascular invasion. It enrolled patients with good performance status, an ECOG [Eastern Cooperative Oncology Group] score of 0 to 2, and good Child-Pugh status&mdash;meaning Child-Pugh A&mdash;into an open-label randomization of lenvatinib or sorafenib. It was powered as a noninferiority trial with secondary endpoints of overall response rates [ORRs], overall survival [OS], and progression-free survival [PFS].

This was a positive trial, meaning the lenvatinib was proven to be noninferior to sorafenib as far as OS, which, in patients in the lenvatinib group, was 13.6 months and, in the sorafenib, 12.3 months, with a hazard ratio of 0.92. Statistically, these 2 therapies were equivalent or noninferior for the OS with these patients. It&rsquo;s important to realize that the sorafenib group did have a longer OS compared with, say, the SHARP trial or the Asia-Pacific trial, at which sorafenib was initially approved as a first-line therapy. The inclusion criteria for the RELFECT trial was very different: patients who had main portal vein invasion were excluded from the trial. They also excluded patients that had a tumor burden of greater than 50% in the liver. This means that patients with advanced liver cancer were excluded from the REFLECT trial, which accounts for the OS being potentially longer compared with registration trials. It is also important to understand that, even though the OS was the same, lenvatinib was shown to have a better ORR compared with sorafenib.

So lenvatinib&rsquo;s overall response rate was 24.1% compared with sorafenib, for which the overall response rate was 9%. This was modified by the RECIST criteria, which is the criteria that we use generally for patients with liver cancer, as opposed to other cancers, which use the RECIST 1.1. The progression-free survival and time to progression was also better with lenvatinib as compared with sorafenib. So lenvatinib&rsquo;s progression-free survival was 7.4 months compared with sorafenib, for which it was 3.7, and the time to progression was 8.9 months compared with 3.7 months. And these were both statistically significant. So overall survival was equivalent. However, response rates, progression-free survival, and time to progression all were better with lenvatinib.

The REFLECT trial then led to FDA approval for lenvatinib for first-line treatment of advanced HCC, a change in the standard of care that has existed for the past 10 years. Lenvatinib is a good option for patients who again are symptomatic or need stabilization for longer periods of time. There&rsquo;s also some discussion that potentially, with the ORR of lenvatinib, that patients will benefit with tumor shrinkage to the point where they may be able to undergo local regional therapy or surgical treatments.

We have to remember that lenvatinib did have more hypertension side effects than sorafenib, in the REFLECT trial, and that patients who already have poorly controlled hypertension may have cause to use sorafenib over lenvatinib. But that&rsquo;s the only exception.

In the REFLECT trial, the sorafenib-treated patients did have a longer OS of 12.3 months compared with what we expected from the SHARP trial, which was 10.7 months. This is probably because the patients in the REFELCT trial, again, were not allowed to have a main portal vein invasion in addition to not being allowed to have more than 50% of their liver involved. These 2 criteria were not part of the inclusion criteria for the SHARP trial. The patients with SHARP actually exhibited more advanced liver cancer, which perhaps caused the change in the median survival between those 2 trials.

Reviewing Lenvatinib Data for Treatment in mHCC

The 2 groups of lenvatinib [Lenvima] versus sorafenib [Nexavar] in the REFLECT trial were not stratified by AFP [alpha-fetoprotein] level. They were also not stratified by their underlying cause of liver disease. The patients in the lenvatinib group did have a slightly higher AFP than the patients in the sorafenib group. This may actually have resulted in a favorable imbalance in the positive for sorafenib. Additionally, hepatitis C patients were more frequent in the sorafenib group as compared with the lenvatinib group. This may have given a benefit to sorafenib. The reason for this discussion is that we recall, in the SHARP trial, when they broke out a subgroup of patients who were treated with sorafenib and had hepatitis C, had quite a longer median survival. In the SHARP trial, the overall survival [OS] in the subgroup was 10.7 months. In the hepatitis Ctreated population with sorafenib, there may have been a longer OS than would have been seen in patients who were stratified for that risk factor.

We have to remember toxicity profiles with these medications. We know that tyrosine kinase inhibitors have toxicities; that&rsquo;s what we have to deal with regarding our patients. In the REFLECT trial, we saw more hypertension in the lenvatinib group of 42% compared with 30% in the sorafenib group; however, lenvatinib also had less hand-foot-skin reaction as compared with sorafenib. The lenvatinib group had 27% hand-foot-skin reaction compared with 52% in the sorafenib group. This was notable when we think about the grade 3 and 4 hand-foot-skin reaction, which is so particularly painful for our patients. In the lenvatinib group, only 3% of them had grade 3 to 4 hand-foot-skin reaction, compared with 11% of the sorafenib group. We also have to remember that lenvatinib has a higher rate of proteinuria. 25% of the patients on lenvatinib had some element of proteinuria, compare with 11% of the sorafenib patients. For our patients who are being treated with lenvatinib, we need to monitor their urine proteins and address that if it becomes an issue. The lenvatinib-treated group did have a higher rate of treatment-related, treatment-emergent adverse events57% versus 49% for sorafenib.

Serious adverse effects [SAE] were also higher in lenvatinib43% versus 30% with sorafenib. However, part of these higher rates of adverse events may have been accounted for because the lenvatinib-treated arm had a longer treatment of duration. The treatment of duration for lenvatinib was 5.7 months and in sorafenib was 3.7 months. So as the patients are treated longer, we expect to see more serious adverse events.

There&rsquo;s not a lot of data for lenvatinib in patients with decompensated liver function as of yet. The REFLECT trial included predominantly Child-Pugh A patients. There were a few patients with Child-Pugh B who got into the trial, but again, it was really geared toward the Child-Pugh A patient. We now have 10 years of experience with sorafenib in conjunction with decompensated liver function. We know those patients need a dose reduction in many cases. They may not tolerate it at all and consequently have adverse side effects. We need to gain more experience with lenvatinib treating our decompensated patients. At this point, I would be cautious using lenvatinib for our decompensated patients until we get more data and experience.

Balancing Efficacy With Toxicity Among the Agents for HCC

Lenvatinib [Lenvima] dosing is either 2 or 3 pills a day. We want to remember to tell the patients to take them all at once; it doesn&rsquo;t matter whether that is in the morning or night. I let patients choose. It can be with or without food, which makes dosing a bit easier for our patients.

When I&rsquo;m deciding what to use for first-line HCC, lenvatinib or sorafenib [Nexavar], I think about the side effects the patients will be able to tolerate, like high blood pressure, hand-foot-skin reaction, diarrhea, and proteinuria. I also think about the underlying liver function. I want to make sure that whatever I&rsquo;m treating them with, they&rsquo;re going to be able to tolerate it. I also consider their symptoms. Patients who have a lot of pain from their cancer and receive a response from lenvatinib, it would certainly be beneficial to use that treatment and alleviate their symptoms.

The patient in our case has alcoholic liver disease and is continuing to drink 3 to 4 drinks a day. Many of these patients that come in don&rsquo;t want to quit drinking; however, I do counsel them that it is in their best interest to quit. The reason, again, is these patients have underlying liver disease, and if it worsens, it&rsquo;s going to limit our cancer treatment options; it will affect their overall survival [OS]. At this point, quitting alcohol is the most important thing they can do to stay functional and allow us to treat this cancer. The other thing I remember is that many of these patients have been drinking for years, so I ask them carefully about symptoms of alcohol withdrawal in the past. If they exhibited those symptoms, I try to get them in with an addiction specialist, so that we can safely get them off alcohol without tremors, seizures, or life-threatening reactions.

The patient&rsquo;s cirrhosis is Child-Pugh A, but we do have to be careful to take his liver disease and monitor him for issues that are going to make his liver disease worse and limit his cancer treatment. If he has low platelets, fewer than 150, and if he has signs of portal hypertension, we can get a FibroScan or transient elastography; we don&rsquo;t need to do an endoscopy. However, most patients with cirrhosis need to have an upper endoscopy to screen for varices. This is very important because as their liver disease and cancer progress, this will put them at risk for variceal bleeding. We need to know whether they have varices to be able to put them on beta-blockers for primary prophylaxis.

Additionally, many patients with liver disease are not well nourished and may develop muscle wasting. We know that with liver disease and cancer, muscle wasting is a bad prognostic indicator. We can prevent muscle wasting by improving his protein intake and exercise, which will increase his OS. I discuss a lot with them: small frequent meals, making sure they&rsquo;re getting enough protein1.2 to 1.5 g per [kg] daily, including a bedtime snack with protein to maintain muscle mass.

The other thing we want to watch for are decompensations, like development of ascites that may require diuretics or development of hepatic encephalopathy, which may affect their thinking, clarity, and sleep. These people usually present and come in, saying they have insomnia, which is related to encephalopathy. We need to treat to maintain their quality of life and keep them out of the hospital.

This patient, unfortunately, did have progression on lenvatinib after 8 months, and had to stop therapy. For those patients, we then think about doing second-line therapy. Now we have a few treatment options for second line: the immunotherapy [I-O] nivolumab [Bavencio], is currently being approved for second-line treatment in patients with advanced HCC. It was predominantly studied in patients after sorafenib, but it doesn&rsquo;t require sorafenib as part of its approval. Pembrolizumab [Opdivo], another I-O, has already been submitted to the FDA for approval for second-line treatment.

For patients that failed sorafenib, regorafenib [Stivarga] is an option. Regorafenib was studied in patients who tolerated sorafenib at half dose at least400 mg per day for 20 to 28 days. We also have cabozantinib [Cabometyx] as a second-line option and, in some patients, could even work third line. We actually have several treatment options that we can offer.

Unfortunately, many patients with advanced HCC, by the time they&rsquo;ve progressed on first line or are intolerant, have a worsening performance of their liver function, which many preclude them from being able to tolerate second-line treatment. It seems that only 50% to 60% of patients with advanced HCC make it to second-line treatment because of progression.

We&rsquo;re in an exciting time for systemic treatment in HCC right now. It&rsquo;s amazing to think that until 11 years ago, we had no systemic treatment options, and thereafter, only one. Now we have a myriad of options, and we&rsquo;re trying to figure out what the best first-line and second-line treatment options are for patients. We&rsquo;re also looking at various sequence therapiesthat&rsquo;s a big discussion going on. There&rsquo;s also a multitude of studies ongoing about combination treatment&mdash;tyrosine kinase inhibitors with I-O, which could offer better OS and overall response rate. We really have changed what we&rsquo;ve been able to offer our patients with HCC. It&rsquo;s amazing that we now have systemic treatment, keeping people with metastatic disease alive for 15, 20, 26 months, or longer.

Unresectable HCC with Extrahepatic Involvement

Approaching a Case of Unresectable HCC with Extrahepatic Involvement

Unresectable HCC: Considerations for Resection and Frontline Therapy

Reviewing Lenvatinib Data for Treatment in mHCC

Balancing Efficacy With Toxicity Among the Agents for HCC

Patient Factors in Choosing Optimal Agents in HCC Therapy