DR LLOVET: Chemoembolization is the standard of care accepted, again, for the European and American guidelines for patients with multinodular tumors in the liver exceeding 6 centimeters in diameter, as long as the patient has well-preserved liver function and ECOG 0.

And because the patient still had well-preserved liver function, Child-Pugh A, and liver-only disease — so no extrahepatic spread, no metastases — and ECOG 0, well-preserved performance status, the first option for this patient is chemoembolization with doxorubicin. So we are performing the treatment time zero, 2 months, 6 months and 12 months, so generally it’s around 4 treatments per year. Sometimes, in some instances, you can even push that more and treat the patient even 5 times per year.

Overall, if we take all these areas reported in terms of chemoembolization, the median number of treatments applied to these patients is 3.5, because at one time point they present any contraindication for following with this treatment — for instance, contraindication can be that the patient progresses with extrahepatic metastases or with vascular invasion, or even that the tumors do not respond to therapy.

In this case we assessed the response with modified RECIST criteria, and the patient achieved partial response after 2 treatments, which is a very good indication of response and, therefore, we keep the patient ongoing with the treatment. But therefore, after the third therapy, the patient presents some signs of progression. And as you can see, early in 2016 the main nodule that was 4 centimeters was growing to 5 centimeters. There were also visible satellites by CT scan. And we identified branch portal vein invasion thrombosis.

So then here you have several signs of progression: growth of the main nodule, satellite surrounding — we define “satellite” as those tumors with a size below 2 centimeters in diameter within 2 centimeters of the edge of the main tumor — and also branch portal invasion, which is a bad sign of progression and is a predictor of prognosis. Then we check: What about all the other parameters, as I mentioned to you?

So certainly in terms of stage of the disease, we are in front of an advanced stage of the disease. The tumor has progressed, but what about liver function? Still the liver function was good: Child-Pugh A class, bilirubin 1.5, which is good. And ECOG performance moved from 0 to 1, which represents that the patient start feeling some pain related to the tumor. When we have cancer-related symptoms, as in this case, we consider this patient at advanced stage of the disease. So if you follow the case of this patient, in 2012 it was early, in 2014 with intermediate, and in 2016 he’s at advanced stage of the disease.

And then the question was, what is the ideal treatment for this patient? (A) continue chemoembolization despite progression, (B) sorafenib — that is, a multikinase inhibitor, systemic therapy, (C) internal radiation with yttrium-90, and (D) radiotherapy.

And then I went to dissect a bit with some granularity, how was the decision made in this patient, which was the rationale. If you want, I can walk you through the rationale.

DR LOVE: Yes. If you can talk about it, that’d be great.

DR LLOVET: Here, just to say that we’re following the American and European guidelines, the AASLD and the EASL guidelines. And there is universal consensus. This is the treatment schedule that we are following. It’s called the BCLC staging system. We are not using TNM in HCC because the TNM only takes into account one of the variables. It’s mostly tumor stage, but it’s not taking into account performance status or liver dysfunction.

In the high left you can see very early tumors or early tumors. In our case it was an early tumor at the beginning, single, with normal portal pressure and normal bilirubin. And therefore the patient was a candidate for resection. After the patient progressed, we had this patient at intermediate stage, multinodular with ECOG 0, and the treatment was chemoembolization. And after the patient progressed, we are now having a patient with portal invasion, branch portal invasion, ECOG performance 1. And then, as you can see in the treatment strategy, sorafenib was the ideal treatment.

But I’m explaining in this slide how we generated this classification in 1998. So at the beginning, the tumors, the liver cancer, hepatocellular carcinoma, was divided in resectable, in the left-hand side, or unresectable.

Then we took all the patients that were unresectable, and we analyzed this patient in the setting of a trial, testing a drug that was a vitamin D compound. And the trial was negative. Okay. But we realized that the outcomes of the patients called unresectable HCC were very different. As you can see in the left-hand side, the median survival of the patient, regardless of the treatment, placebo or seocalcitol, was around 16-month median survival. So these patients without treatment, the median survival is 16 months, whereas the patients in the right-hand side, the median survival was 6 months.

And which was the difference between patients? All of them are unresectable, but the patients in the left, they have liver-only disease, no vascular invasion or extrahepatic spread, ECOG 0 and well-preserved liver function, whereas the patients in the right have either vascular invasion, metastases or ECOG performance status 1 or 2. So then, that’s why we define these 2 stages.

As you can see here, what we formerly called unresectable HCC, in reality we have 3 subgroups of patients that, even without treatment, have different natural history. Patients at intermediate stage, natural history 16 months. Patients at advanced stage, natural history around 6 months. And then we have even another subset of patients at what we call end-stage disease, performance status ECOG 3/4 or Child-Pugh C — that means very advanced liver dysfunction — median survival of 3 months.

So now the standard classification of HCC no longer considers unresectable HCC as a group but defines 3 subtypes: BCLC B, intermediate; BCLC C, advanced; and BCLC D, terminal disease.

So then what are the treatments effective in HCC? If I have to choose one slide, I will choose this slide. In the left-hand side you have the levels of evidence that, in medicine, are very important. Level 1 means randomized studies or meta-analysis. Level 2 means Phase II studies. Level 3, retrospective studies. And in the lower axis you have level of recommendation: 1 is strong and 2 is weak.

And as you can see, in HCC we accept 5 treatments as treatments effective for the patients: sorafenib, chemoembolization, radiofrequency, resection and transplant, whereas all the other treatments that are out there, adjuvant therapies, radiation, chemotherapy and others, are not accepted at this point in guidelines.

Efficacy of sorafenib and integration of the recently FDA-approved multikinase inhibitor regorafenib into the treatment algorithm for advanced hepatocellular carcinoma (HCC)

Immune checkpoint inhibitors in the management of HCC: Biologic rationale and emerging data

Activity and tolerability of lenvatinib for patients with unresectable HCC

Management of local-regional disease