Josep Llovet, MD, PhD: Do you want to talk a bit about the guidelines and how all these treatments have affected the guidelines? Do you want to start?

R. Kate Kelley, MD: Sure, with NCCN [National Comprehensive Cancer Network]? Here in the United States we turn to NCCN for clinical issues quite frequently, and it’s quite remarkable to see the changes that have happened, again as a marker of the times in HCC [hepatocellular carcinoma] in this dramatic landscape expansion. But as of early 2019—based on these randomized phase III data sets and promising immunotherapy, or provocative early phase II data sets in the advanced setting—for first-line we have lenvatinib as well as sorafenib as an option in the NCCN guidelines. And second line, we have regorafenib, cabozantinib, and ramucirumab for AFP [alpha-fetoprotein] high disease, and that’s a remarkable change compared with years past. Oh, and I should add, those are the level 1 evidence based on phase III trials, but I neglected to mention that pembrolizumab and nivolumab also are NCCN approved. The guideline included options in the advanced setting after progression on sorafenib.

Josep Llovet, MD, PhD: So I’ve been involved this year in the guidelines that have been released by EASL [European Association for the Study of the Liver] and by ESMO [European Society for Medical Oncology]. And certainly the 5 drugs we have with phase III data, all of them are endorsed by both guidelines. Also, checkpoint inhibitors with a less strong level of evidence because still the data are pending phase III. So nivolumab is pending the phase III in frontline, sorafenib-nivolumab and pembrolizumab are pending the phase III in second line, pembrolizumab versus placebo. But both are accepted, according to the guidelines.

One thing that is interesting, and I want to mention here, is that there was a lot of controversy among panelists about the role of internal radiation with Y-90 in advanced HCC and intermediate HCC. I have to say, it was a long discussion. Despite that, the 2 trials that are out there are negative against sorafenib. But there’s also a point of controversy that certainly was settled, particularly in advanced disease, that it is not recommended by EASL guidelines. But in intermediate disease, still it is in the field because there are phase II data suggesting that it may improve the patient’s survival but still not phase III data. Something that is interesting that the strong controversy was between systemic therapies and Y-90 in advanced disease.

R. Kate Kelley, MD: I think the SIRveNIB and SARAH data are examples of how difficult it is to study a device versus a systemic therapy. But in both cases, the intention-to-treat analyses were negative for superiority.

Arndt Vogel, MD, PhD: In respect to the EASL and ESMO guidelines, I think they are not really significant changes in respect to AFP. There was always the question whether we should use AFP as a screening parameter, and this is in most guidelines not really recommended. It might add a little bit to select patients who are at risk to develop HCC, but it’s a poor biomarker for screening. Therefore, there’s some discussion whether we should include it in our screening programs or not.

In respect to patients who have established diagnosis of AFP, it was always part of our workup, and we all have recommended before that AFP levels should be determined. It’s a good marker if it’s elevated to see whether a patient responds to therapy or it could also be a marker to detect recurrent disease if the marker was elevated before. So in respect to more advanced disease, patients who are in an established diagnosis of HCC, in our clinic AFP was always part of the diagnostic workup.

Masatoshi Kudo, MD, PhD: JSH guidelines will definitely be changed because of the success of REACH-2 trial. Our guideline is changed online as soon as it is approved. So presume the ramucirumab will be approved as a second-line agent with elevated AFP value. So definitely JSH [Japan Society of Hepatology] guidelines will be changed.

Transcript Edited for Clarity