Great, thank you very much for the opportunity to discuss the HCC practice guideline and guidance. I have no disclosures. And I would like to begin with thanks and appreciation to the co-authors of the ASLD guideline and companion guidance. Importantly, I'd like to note that this actually was an update of a previous guideline that was written in 2010 by Bruce and Sherman, and it took us, you know, only two people to write it, and now we have seven people to update it. At times when you have this large of a group, you know, you can struggle a little bit, like herding cats. That can be a risk, especially when you have so many different specialties involved. But I would like to identify that we do have participation from surgery, hepatology, and more importantly, radiology and oncology for this new update, which has actually been exceptionally valuable. And really, instead of herding cats, it was much more like working together as a team. So I was very lucky to be in that group. And of course, this is an important topic. Of course, this is the most common primary liver tumor. The incidence and the death rate of this is rising, now being the fifth most common cancer and second leading cause of cancer death worldwide. Of course, primarily occurring in the setting of cirrhosis, especially viral, but also importantly in the current era NASH. Specific to the United States, the situation is not quite as serious as in the rest of the world, but still a major issue with 42,000 new cases in 2019 and an estimated just over 31,000 deaths in 2019. So for the ASLD guideline, we utilized the GRADE format, which does require systematic reviews. And those were done on the key areas of surveillance, diagnosis, and treatment, specifically questions that would be faced, like what is the best method of surveillance? And once you've identified a lesion, how do you establish the diagnosis? And then once you've figured out that you've got HCC, then how is the best way to treat it according to the stage of the disease? So that's really how the new guideline was framed. And of course, you may or would have heard in the introduction, what is the GRADE format and what does that mean? And just to highlight it, because it is an important difference, the GRADE format is the recommended format by the National Academy of Medicine. And so these key questions on surveillance, diagnosis, and treatment for HCC that are faced by practitioners, we attempted to identify those key questions and then use systematic reviews whenever possible to answer those. And of course, for a systematic review, you need to have a randomized controlled trial or at least a comparative observational study. And then we could create a recommendation that was either strong, meaning the majority of the people should have this, or conditional, which means that the majority should have, but many will not. A recommendation of strong versus conditional is based not only on the quality of the evidence, but also consideration of other factors, such as the balance of benefit and harm and feasibility of obtaining the intervention. So for the guideline, we used the GRADE format with the systematic reviews, whereas in the guidance, we covered areas where we did not have sufficient data to follow that very rigorous standard that is required by the GRADE format. So we just had not necessarily relaxing how we were approaching it, but using a less constrained format, I would say. So with the first question being, should adults with cirrhosis undergo surveillance? And then if so, which test is best? Of course, there is only one actually randomized trial that was done on this specific question looking at surveillance versus no surveillance. This is in a different population group, hepatitis B carriers in China, but we were able to utilize an existing systematic review to summarize that surveillance does have a role and that it does improve survival. And so the recommendation for HCC surveillance is unchanged from the previous that patients should undergo surveillance, and that recommendation is strong. A difference in the previous guidance, which was around the use of ultrasound, uses ultrasound with or without AFP. And now we're recommending that it be with or without AFP as opposed to the previous, which only recommended ultrasound. The issue with that is there actually are no direct comparative studies between those two specific questions, ultrasound or ultrasound with AFP and ultrasound without AFP. But the majority of studies utilized in the systematic review used both. In fact, there are only four that did not. And after the publication, there's an additional study that is a systematic review highlighting the importance of AFP and ultrasound. The guidance covers the patient risk groups that are at highest risk and then the evidence that surrounds whether they should undergo surveillance. And so that is summarized in the guidance. And you can see it's all the traditional groups that we know about. And then discussing the role where surveillance benefit is unknown, and that is in younger hepatitis B carriers or hepatitis C with stage three fibrosis, and probably very importantly discussing NAFLD, and where we really can't make a comment about the benefit of surveillance in that group. We also discussed, you know, sort of the room for improvement around this topic of surveillance and what are the new things that are needed, certainly discussing other tumor markers or combinations such as the GALAD score. Also the possibility of circulating tumor DNA, which is highlighted here in this, which is using methylated DNA in plasma and showing that potentially this is a new strategy going forward of how we can improve surveillance so that we can identify patients at a curative stage. So once we've identified the patient with a lesion, how should we further characterize that lesion? Whether they have CT or MRI essentially is the question we tried to answer. We did perform a de novo systematic review to try to answer this because there was not an existing systematic review. And really their quality and certainty of the evidence to try to answer this question was low. So we really couldn't make a final conclusion. When we did pool the sensitivity, we found that it did favor the performance of MR as opposed to CT with a similar specificity. But there were a number of issues, most importantly surrounding cost and the ability of access to the technology, time, patient, issues like comfort that could impact that recommendation. And thus we really recommended that it would be with either CT or MRI. And then there is the creation of this diagnostic algorithm, which is quite complex. So I'm gonna give you a simple version of that same figure, but that same figure has some key details that I would refer you to. So essentially when you have a patient who has undergone ultrasound in their screening with or without AFP every six months, if the lesion is greater than one centimeter or they have a new AFP greater than 20, they should undergo CT or MR. And then if based on the findings of that cross-sectional imaging, you would proceed either to go back to screening every six months if it's benign. If it's indeterminate, then you could repeat the CT or MR within three to six months. If it's probable, which correlates with Lyrads 5, or excuse me, Lyrads 4, and these characteristics of this are discussed, then the patient could be considered in a multidisciplinary discussion whether they should potentially have a biopsy, potentially have a repeat image, or the image that they did not have opposite. And then, of course, the patient that has the diagnosis established by their cross-sectional image. So if the patient does have one of those indeterminate hepatic nodules, what should happen? Should they have a biopsy, repeat imaging, or alternative imaging? And I've just summarized that treatment strategy in the figure I showed you. We would not recommend one option over another, and really that it's critical to have that multidisciplinary discussion. But we would recommend against routine biopsy of every indeterminate nodule. So once we've established the diagnosis, now we're gonna move to the phase of treatment in the guidelines, and we're continuing, of course, to use the BCLC, and this is just an update of that same figure with the different BCLCC stages, and then with the treatment options at that stage, including the level of evidence for that treatment option. So to summarize each part of this figure, when we're talking about early stage, so this is BCLC0, should they undergo resection or local regional therapy? And according to the available evidence, which again, in the systematic review format, would recommend resection over ablation. The quality of this evidence is moderate, and the strength of this recommendation is conditional. But there are certainly key parts of this that you have to consider. If it's a small lesion, the benefit of surgery versus resection, I'm sorry, the benefit of surgery versus ablative therapies, you know, they're more equivalent in the lesions which are under two centimeters, but if you consider all classifications, the benefit would favor surgery. Certain patient preferences and other factors that need to be considered in making the recommendation. What about adults with cirrhosis who are successfully treated? Should they have adjuvant therapy? And this was also covered in the guidance, or in the guideline. And looking at the ideal therapy, we would recommend against the routine use of adjuvant therapy, considering the ideal therapy should really be not only aimed at the original tumor, so being anti-neoplastic, but also the idea that you are trying to prevent new tumors. So when a patient is treated, they could either recur in the treatment area, or because of the field effect of the underlying cirrhosis, they could develop a new tumor. So that's really what we're looking for. And so far, in multiple studies of serafinib, we have not seen a benefit. So to summarize this, in this figure from the STORM trial, no benefit of serafinib after resection or ablation. This is looking at DAA therapy, so this is a patient who has been treated with DAA therapy, now showing to have a reduced risk of new HCC, or of HCC, after treatment of their hepatitis C. And after the publication of this, additional evidence in the patient treated after HCC. So prevention of recurrence, that data is not covered in the guidance, because it came out after, but this is an important rule as well. Patients now to treat with stage A, what is the option for this patient group? And the Malone criteria, where Malone has now been established as an optimal treatment for this therapy, if a patient is not able to be resected, transplant is the ideal therapy for this patient population, if they are eligible for transplant. And in fact, in the United States now, HCC is the most common indication for being placed on the wait list, and also the most common reason to have a transplant. And that really stems from that early work on establishing specifically which patient can optimally benefit from transplant. Pushing that envelope from the patient that can optimally benefit from transplant, there have been numerous studies, including the most well-known from the group in UCSF, which has established the role of downstaging in a group of patients. If they are able to be downstaged within Malone, they can proceed to transplant. And I know you just heard about earlier today in the same room about those 10-year outcomes from a patient population, and showing still benefit out to 10 years. So this is benefit out to five years in one center, but you heard earlier about the same benefit. So based on that data, and this is a busy figure that is discussed at length in the guidance, but I wanted to call your attention to this aspect of the figure, which is really just the new things that have happened on this timeline. And this timeline is really walking through all the different things that have changed in terms of the use of transplant from a policy standpoint. So for HCC in the United States, there have, for HCC patient that needs to go to transplant in the United States, there have been a number of changes along that timeline, with the most recent summarized here on this slide, we have now adopted a national liver review board to look at cases where a patient would like to access transplant, as opposed to the regional review board system that we previously had. We've eliminated the idea that a patient would have a score that would go up every three months until it's high enough for them to access transplant. Now they have a fixed score, which is set at three below the median Meldat transplant for the area of distribution where the patient is listed. The patients still have a six-month waiting period that was adopted in 2016. And we now allow as a standard policy, based on that UCSF data, as a standard policy that the patient can actually present in beyond Milan as long as they are able to downstage to Milan. They have to be within UCSF downstaging criteria, they can't be beyond that for the standard, although even patients beyond UCSF could be reviewed by the NLRB and be considered. There is also a restriction. Patients must have an AFP less than 1,000 in order to qualify for a standard HCC exception. Previously there was no AFP restriction. So that's just a summary of the most recent changes, which are also discussed in the guidance. And another question that we tried to address, because this is one that actually people taking care of patients who are waitlisted face not uncommonly. So a patient who is listed on the waitlist waiting for a transplant, so they have an indication already for transplant, who now develop a new T1 lesion, should they be treated or should they not be treated? The issue with treating them is, of course, they're not going to then potentially qualify for that standard Meld exception. So can we answer that with any degree of evidence? Unfortunately, there were only, out of 87 studies identified, only two that really touched on this specific question. So it's very limited data. But looking at that data, it seems that it may be safe to observe patients with small lesions who are otherwise waiting for a transplant. But the strength of this evidence is very low, and thus this is a conditional recommendation and really an area where that's really important that we look at future research. So patients with T2 who are waiting for liver transplants, should they be bridged? Should they be treated with any kind of liver-directed therapy while they're waiting? This was a de novo systematic review, because there was nothing available. We were able to review only 18 comparative studies, there were no randomized trials. And thus the quality of this evidence is also very low, and the strength of this recommendation is conditional. But we do recommend, or we suggest, that bridging to therapy would decrease the progression of disease and subsequent dropout from the wait list. However, in looking at the data that was available at the time, we could not recommend one form of therapy over another. What about patients who are beyond Milan? And again, reviewing that same systematic review data that was collated, there is, again, very low quality, and the strength is conditional, but after successful downstaging, it does seem that the evidence would be in favor of proceeding to transplant. And this is systematic, or this is reviewed right here. So in terms of liver-directed therapies, of course, this is a continuously evolving field, almost impossible to keep on top of it, actually. But one important point, which I think is increasingly being recognized, is that response to treatment can serve as a biologic marker for selection for liver transplant with all of these different therapies. To highlight, though, that transplant can really only be available to a section of the patients, I told you earlier, 42,000 cases of HCC in the United States, and only 17,000 who underwent, or 1,700 who underwent transplant. So we're just getting to a fraction of these patients. Of course, not all of these patients are eligible for transplant, but of the patients, only 1,700 actually undergoing transplant. So if a patient is not able to be considered for transplant, a T2 or a T3, with no vascular involvement, but they're not a candidate for resection, and they cannot be considered for transplant for whatever reason, how is the best treatment for that patient? Looking at the factors of taste, or tear, or external beam, are we at a place that we can recommend one of these therapies over another? We tried hard to be able to do that, and we were not able to recommend one over another, but the strength of a recommendation to favor treatment versus no treatment is strong. The evidence for taste is moderate, whereas really for tear and radiation, I think these data are emerging and likely to become moderate quality or good quality evidence, but it's too early to conclude anything about that. So what about patients who are BCLC stage C? How should we be treating these patients who are non-resectable, who have vascular involvement, or metastatic disease, or both, with portal hypertension? Should they be treated, and if they should be treated, what should they be treated with? Systemic therapy, local regional therapy, or no therapy? And so the recommendation from this is definitely that systemic therapy over no therapy is recommended in patients with Childs A and well-selected Childs B with advanced HCC. It's not possible at this point in time to make a recommendation of systemic therapy over local regional therapy due to inadequate evidence, and this was also a de novo systematic review with the quality being evidence, or the quality of the evidence being moderate and the strength of the recommendation strong. So this is just showing you the data that would favor systemic therapy of serafinib versus no therapy. And then just to briefly summarize the new therapies that have just become available and that are summarized in, most importantly, in the guidance document after a long period of time where there were no new therapies, now sort of a pretty robust list of new therapies and showing you the summary of these new therapies. The SHARP trial is what I've already highlighted, as well as the Asia Pacific trial, but then additional trials that are reflected here with the treatment arm and the control group showing benefit. So the key takeaway for the guidance is that for adults with cirrhosis, surveillance is recommended every six months with ultrasound or ultrasound plus AFP. For diagnosis of lesions detected on surveillance, CT or MR is recommended. Resection is recommended for patients with early stage HCC who are eligible, though RFA is suitable for small lesions. Transplant with bridging or downstaging is recommended for early stage on resectable HCC. For those not eligible for resection or transplant with T2, T3 and no vascular involvement, TACE or TEAR or radiation is recommended. And for patients with advanced HCC, the ASLD recommends systemic therapy. Thank you very much. Thank you.

HCC practice guideline

surveillance methods

lesion characterization

treatment options

GRADE format

multidisciplinary approach