The ACCLAIM Trial to Assess Microwave Ablation as the Standard of Care for Colorectal Liver Metastases

An Interview With Constantinos Sofocleous, MD, PhD, FSIR, FCIRSE

This podcast episode is part of the SIO Corner, a collaboration between IO Learning and the Society of Interventional Oncology. Our guest host is Dr Elena Violari, Interventional Radiologist and member of the SIO’s Publications Committee. Dr Violari invited Dr Constantinos Sofocleous, Interventional Radiologist and principal investigator of the ACCLAIM trial, to discuss the study’s origins and to provide an update on ACCLAIM, which recently enrolled its first patient.

This episode is also available on Spotify and Apple Podcasts!

Welcome to IOL Radio, the podcast for IO Learning, a digital publication that covers the latest advancements in interventional oncology. This podcast episode is part of the SIO Corner, a collaboration between IO Learning and the Society of Interventional Oncology. Our topic today is the ACCLAIM trial, which is the first international trial launched by the SIO, and is designed to Assess Microwave Ablation as the Standard of Care for Colorectal Liver Metastases. Our guest host is Dr Elena Violari, interventional radiologist and member of the SIO’s publication’s committee. She is joined by Dr Constantinos Sofocleous, Interventional Radiologist and principal investigator of ACCLAIM, to discuss the study’s origins and to provide an update on ACCLAIM, which recently enrolled its first patient.

Dr Elena Violari:

Hello everyone and welcome to the SIO Corner podcast. I'm your host, Elena Violari, and it is my honor to introduce our guest Dr. Constantinos Sofocleous. Dr. Sofocleous is a world renowned professor of radiology at Weill Cornell College of Medicine and Memorial Sloan Kettering Cancer Center. He's a founding member of the Society of Interventional Oncology. And throughout his career, he has been instrumental in advancing the field of interventional oncology. He has lectured nationally and internationally and published extensively on topics such as embolization, radioembolization, and ablation of liver tumors. His research interests lie in the assessment, validation, and development of biomarkers and surrogate imaging biomarkers, which can predict outcomes and help stratify patients undergoing image-guided locoregional therapies of tumors in general, and particularly in colon cancer metastasis.

Dr Sofocleous serves as the principal investigator of the ACCLAIM trial, which is the main topic of our discussion today. The ACCLAIM trial is the first international trial launched by the Society of Interventional Oncology, designed to impact guidelines with regards to the role of ablation as a treatment option for colorectal cancer liver metastasis, and is expected to raise the bar for the standard of care. On more of a personal note, I had the distinct pleasure of working with Dr. Sofocleous very early in my career, and his influence and mentorship was important in my decision to pursue interventional radiology. Welcome to the SIO Corner podcast, Dr. Sofocleous. Thank you for being here.

Dr Constantinos Sofocleous:

Thanks for inviting me, Elena, it's great to see you again. And thanks to the SIO for this initiative. It is a great pleasure to be with you today and I'm happy to discuss the ACCLAIM or anything else you want.

Dr Elena Violari:

Thank you. I want to start by asking you what inspired you to pursue interventional oncology and who were your mentors?

Dr Constantinos Sofocleous:

I was inspired to start interventional radiology when I was toward the end of my medical school career in Athens, Greece. I was doing a pediatric rotation at the time, and there was a little kid with a huge tumor that would go to the operating room and the surgeon was trying to figure out the vascularity and the vascular supply to that tumor and we had no way to do it. There was no interventional radiology at that time in Greece, and certainly there was no pediatric interventional radiology. Slowly, I started reading how we could do that and I came across arteriography and what was happening abroad and particularly in the United States as well as very developed Western European countries, especially France and Germany. I started getting very, very curious about interventional radiology.

I was determined to train in interventional radiology in another rotation, which was a little bit later. This was orthopedic rotation in the trauma hospital in Greece, again, where they were doing a replacement of a hip joint and they were using hammers and saws and it was very, very brutal. And I said, "It can't be so brutal in the 20th century, there must be a less brutal alternative to fix the human body." I think that was the seal on my determination to pursue interventional radiology as a career.

And then your second question, when did this become interventional oncology—I think much later, it was really towards the beginning of my first year as a faculty. It was in the very beginning of ablation knowledge. It was in the early 2000s at the time. I realized that we were doing this procedure to control tumors at the time, but we had no way to know at the end of the procedure whether the tumor was dead or alive. And really that triggered me and I started looking into how this treatment could have an immediate feedback. In interventional radiology, a lot of us are attracted because of the component of immediate gratification. And certainly when you're doing a balloon angioplasty, there is that feeling there is a stenosis and it's going away.

With cancer, maybe with embolization there is hypervascular tumor and you embolize and it's not there. You don't see it anymore. With ablation, it's much more indeterminate. Whether your ablation zone that may be looking great has killed the tumor or not. And that really intrigued me and made me think that this needs to be improved. And that's what started me thinking about interventional oncology and made me look into Sloan Memorial Kettering, where I have been for 20 years. And really all my work has been dedicated to how to know at the end of any interventional treatment that really your endpoint, the clinical endpoint you're striving for, has been achieved.

Dr Elena Violari:

That's a wonderful story, Dr. Sofocleous, and thank you for sharing that. Now, let's get to the topic that everyone is waiting to hear about. I was at the SIO meeting last month and it is what everyone is talking about and it's what everyone is so excited about. It's the ACCLAIM trial. Can you please give us a little background on this very important clinical trial and its early beginning?

Dr Constantinos Sofocleous:

Sure. The ACCLAIM trial was born out of a challenge between Professor Matt Callstrom, the now past president of the Society of Interventional Oncology, professor at Mayo Clinic, and professor of radiology and chairman, and Gigi Solbiati, a pioneer in ablation, and myself, and I think it was in an airport in one of the SIO meetings, pre-COVID, where for years people have heard me lecturing on the ablation with clear margins or a zero, I think I started that concept talking to colleagues like Steve Solomon and others to find a catchy name. What are we going to call ablation with margins? And I think the first time I mentioned it probably was 2007, and I think it was the CIRCE meeting in Athens that I mentioned it for the first time: do everything you can to have ablation with clear margins.

We were talking about that in an airport between Matt Callstrom and myself, and Gigi and I said, "We have over a thousand cases now combined between Italy and MSKCC—why don't we review them to further prove that this theory of the margin is absolutely true? And if we have a margin that is over a certain size, it really corresponds to the best tumor control. And our recurrences are certainly less than what we generally report and it actually may be comparable if not better than resection." And Matt Callstrom said, "I don't want to see another retrospective study. Forget about that. If you guys are going to do this, do a prospective trial." This was the challenge.

I think from that moment I went around and I talked to a lot of people and I came back to Matt and I said, "Okay, I'm going to start working on that idea and I'm going to need all of your support." And that's exactly what I did. We did it as a group, really, it was a group effort. So every single meeting we would get in a room, and we started with an initial protocol that we started at MSKCC and it was based on our prior work showing the value of the margin. I have here people who helped lot, like Maria Petri and Elena Kaye, who were very helpful with setting this protocol on the first draft. I circulated this protocol between everybody you can imagine that could have an impact in interventional oncology, from Philippe Pereira to Thomas Helmberger, and others (I apologize if I don't name everybody). Thierry de Baere, David Breen, Mike Soulen… it was a very long list of people involved with this. Every time we had a meeting, we would have a dedicated 1-hour meeting on the ACCLAIM protocol because I wanted to make sure that whatever protocol it was, everybody would comply. And I didn't want to have a protocol that then people would be like, "I didn't like that and I don't like that. I'm not going to do it because I do it this way." So everybody had a good time, long time with COVID. It became even longer to really give input on what was reasonable and not reasonable on the protocol.

And once we finalized the protocol, then we started presenting it to the sponsors and that's where we needed to be, as a group, believers and supporters of the idea we had and not break into smaller studies that "I'm going to do this here with this company and there with that company." And I think it was very critical to have the Society of Interventional Oncology buy in to this idea that we need to do a device-naïve study where the treatment of the target tumor is evaluated by an objective (or as objective as possible) way that was measurable, reproducible, and as much as possible, less dependent on the operator.

These were the guidelines and the principles that really led into defining what we're going to do with the ACCLAIM trial, which is really the final product that you see today where microwave ablation is used and it can be any microwave device. The only limitation is that it has to be either FDA or CMR clear. So any device in the market that is approved for clinical practice can be used in the ACCLAIM trial. You can treat up to 3 colorectal liver metastasis, none of which is supposed to be in larger in diameter than 2.5 cm. These are the eligibility criteria for the ACCLAIM trial. It is mandated that you assess the ablation zone, not simply with a contrast-enhanced CT to see that the ablation zone covers the target tumor, but to actually measure the ablation zone and assess it with stereotactic 3D with FDA clear or CMR relevant software, which are now available and really growing in numbers by the day.

That's how the ACCLAIM trial was born and we were very fortunate that eventually sponsors like Johnson & Johnson with Ethicon/NeuWave, Varian, and Boston Scientific, all 3 of them, really did the right thing, not to limit their support based on product, but really support us because it was a well-designed trial where they understood that it would promote interventional oncology in the future. Devices change, companies change, so establishing as much of an endpoint that can be reproduced 30 years from now with any device is the point and I think this is really the success of the ACCLAIM trial as a design.

Dr Elena Violari:

Thank you so much for sharing the story of how the ACCLAIM trial was born and for also sharing the background that sets the stage for this trial. What is the specific question, the specific research question that the trial is addressing?

Dr Constantinos Sofocleous:

So the trial’s primary aim is local progression-free survival at the site of a treated tumor and the trial is trying to prove the hypothesis that if the stereotactic margin assessed by a 3D software is over 5 mm, then the local progression-free survival will be 90% or higher. That may be a little bit ambitious for all of us who do this, but I think if we really do a 3D software assessment, we're going to be very close to that number.

Dr Elena Violari:

I think you briefly touched on it earlier, but let's discuss about the research design of ACCLAIM.

Dr Constantinos Sofocleous:

The design is really again to assess ablation, specifically microwave as a local cure. It is not a study to just see any tumor for any indication. It is a very specific indication for a tumor that possibly could be resected, but instead we are choosing microwave for whichever clinical reasons might exist. It's not changing the clinical decision-making process. Rather, the ACCLAIM trial is using clinical judgment that the standard of care and the guidelines support, which is that ablation can be used either with surgery or alone as a standard treatment for colorectal liver metastasis as long as you can eradicate all visible disease. That is in the guidelines that we have. That's the standard of care.

So ACCLAIM is using the standard of care but is going one step further to say, "We are treating as per standard of care, but we are raising the bar because we're not just saying that we're going to make the tumor not visible anymore, we actually want to make sure we have created a margin and we have proof for that and we have validation for that." So it is not just the judgment of the operator, but we have a freestanding mechanism where each operator, each side, is transmitting the real files obtained before and after the microwave ablation. So the ablation zone can be assessed by a freestanding software that is also approved by the FDA and is situated in Mayo Clinic.

And then we have an independent reader in the study, Dr Gigi Solbiati, who is not at a site that is enrolling trial participants, but acts as the reader and judge of everybody else’s results. He is assisted by Laura Crocetti, who is his backup, and they decide whether what the primary operator thought on the day of the ablation is correct or not. And the study allows for re-treatment, which we're going to capture if that's the case. If there is finally a judgment call that actually the margin was suboptimal (under 5 mm, that is). If there is a discrepancy between the primary side and the independent reader, then I come in as an adjudicator, as another vote to judge the margin.

It is really a pathway where the result is going to be not just reported but really assessed by others—almost like a peer review to make sure that the margin is indeed what it was intended to be. That's really the key methodology of the study.

Dr Elena Violari:

That's wonderful. How many patients will be participating and what are the major characteristics of the trial?

Dr Constantinos Sofocleous:

Sure. So to assess the local progression-free survival at 2 years, which is our goal, we have a statistician from MSKCC that is consulting on the study and he has been a colorectal liver metastasis expert statistician. His name is Mithat Gönen. He is originally from Turkey and has been with MSKCC probably longer than me, and I have known Mithat since 2002. But most importantly, Mithat is the statistician that actually described the clinical risk score, the clinical risk score for surgery, which is the most predictive tool we have to predict outcomes for liver resection for colorectal liver metastasis. So he's the same statistician and he knows that this disease very well. So he calculated for us, that for us to achieve a 90% local progression-free survival with a margin over 5 mm, we will need at least 325 events or we will need 325 ablation zones. Historically, we know that patients have approxiately 1.22-1.3 tumors eligible for ablation with curative intent. We therefore calculated that we will need roughly 275 patients to achieve that outcome. So, we are aiming for 275 patients, but really more accurately we are aiming for 325 measurable events.

Dr Elena Violari:

What are the primary and secondary endpoints of the ACCLAIM trial?

Dr Constantinos Sofocleous:

So the primary endpoint is the local progression-free survival at 2 years at the site of treatment. There is a very long list of secondary endpoints including stratification by margin. What is the difference if you had a 5 vs 10 mm margin, for example. Under 5 mm obviously is a failure for ACCLAIM and we're going to have to deal with that. Other secondary endpoints include overall survival, stratification by genetic markers, KRAS wild type, right-sided origin of the primary vs left, and all the known genetic factors that may impact local progression-free survival. Liver disease control is also one of the main secondary aims.

Dr Elena Violari:

Over the years, your talks and publications have emphasized how we can make ablation an effective treatment for local cure. In your opinion, what are the most important factors regarding the tumor characteristics, the ablation technique, and margin assessment that can achieve outcomes that can match surgical resection?

Dr Constantinos Sofocleous:

At MSKCC, we are doing much more than the ACCLAIM trial, which is really the baseline, and that's why I think it really should be standard of care. Personally, I don't think ACCLAIM answers a question that we don't know the answer to. We already know that margin counts. I would hope that most interventional radiologists, whether they're treating colorectal on the ACCLAIM or any other tumor for that matter, that they're going for local cure, have seen the evidence that supports that margin really matters and that's what makes the difference. So margin is definitely the most important.

In addition to that though, there are several other biomarkers including biopsies. We are actually biopsying tumors at Memorial and we are making sure that at the end of treatment there is no detectable viable disease where the tumor used to live. So we are using fusion and we are biopsying the area where the tumor used to be by using real-time PET. And we are also biopsying what is perceived visually or with 3D assessment as the minimal margin of each ablation zone. And I will tell you that that adds another layer of certainty that there would be no local failure.

Obviously that requires a lot of training of your pathologist and certain labs. So I think it's not quite there for being standard of care universally. I will tell you that at Memorial at this point, we consider that a standard of care. The detection of intact tumor cells is a very strong indicator that the patient is at risk for early local recurrence. So that's the next step I would say. But I think the ACCLAIM trial sets up at least the minimum bar much higher than where it is right now.

Dr Elena Violari:

Can you name a few previous trials that give us level one evidence in regard to the effectiveness of ablation for the treatment of colorectal cancer metastasis?

Dr Constantinos Sofocleous:

The best level 1 evidence is the Ruers trial. Ablation was used in combination with oxaliplatin-based chemotherapy for the treatment of initially unresectable actually liver metastasis. It was done by a surgeon in Amsterdam, Theodore Ruers. This was a classic example of an underpowered study where the initial results demonstrated no difference, at least in terms of overall survival on this population when it was first published in 2012. Ruers then did a very long follow-up that allowed him to assess 8-year survival in 2017, where the difference was dramatic with the ablation arm leaving almost 40% at 8 years out vs under 10% for the non-ablation arm treated only with chemotherapy. That is the strongest level 1 evidence we have to date.

I don't think we have any other strong, level 1 publication with randomization like that did at the time. I think that trial should be known to everybody, and we should probably advertise the Ruel trial more to the medical oncology society. I think what it tells us is that it's not acceptable to not consider ablation and keep treating patients with chemotherapy when ablation is an option. I think that's the main message of that trial.

Dr Elena Violari:

We know from prior studies that the outcomes of surgery or ablation in patients with colorectal liver mets are affected by the tumor biology as well, such as presence of KRAS mutation in patients with colorectal cancer. How will these patients be treated in the ACCLAIM trial? Will a different ablation margin goal be expected for high-risk patients or potentially early fall up in order to allow early sequential treatments?

Dr Constantinos Sofocleous:

That is a good question. We haven't mandated a higher treatment, but the data do support that tumors that have the KRAS mutation should be treated at least with a 10 mm margin rather than just 5 mm. This is based on data by Calandri and Odisio from the MD Anderson group. They publish repeatedly on that, and we also did here. The data all basically support the same finding that the KRAS mutation may carry some resistance to heat, and we don't know the mechanism yet, but certainly it seems that even a 10 mm margin where a non-mutant tumor basically has zero recurrence, a mutant tumor may have a recurrence of 17%. So it's certainly a different biology of disease.

Now, going to the ACCLAIM, the ACCLAIM has a mandate of a five mm at least. It does recognize that 10 mm is better. It's not like we're telling you "Don't do 10 mm," just to be fair, but we're saying "If you are under five, you're not technically successful for the ACCLAIM and you need to re-ablate," just making that sure, it's not... The ACCLAIM has not quite proven yet that 5 mm is enough. And a lot of the data, including ours and those from Austria and others who did 3D software assessments, unfortunately including ourselves, did not have enough patients to really stratify what is the difference in a 3D software over 10 mm vs over 5 mm, to be honest.

And I think that's a limitation. We're trying to address it. We're having some work done here assessing our ablation zones from 2 prospective trials that are NIH supported. So the data are pretty well controlled where we can see if there is a difference in recurrence between 10 mm and 5 mm margin of how significant that is. I don't have the data yet, so I cannot answer that yet. I do have some preliminary data that we presented at SIO regarding the assessment of the ablation zone in terms of time.

So one of the things with ACCLAIM that troubled us a little bit was the fact that historically all the data we're reading, including ours and others, were based on a post-ablation scan that really was usually between 4 to 8 weeks after ablation. It was not an intraoperative same-day assessment. And the question was, is the same-day assessment as accurate as the 4 to 8 week assessment? Do the post-surgical immediate changes impact the assessment of the ablation zone? And we had a couple publications along those lines. One was with Dr Vasiniotis in the International Journal of Hyperthermia, and recently one of my other research fellows presented at the SIO that really the assessment of the day of the procedure is certainly not inferior to the assessment of the four to eight weeks assessment in terms of predicting LTP.

So if you have a suboptimal margin intraoperatively, it is real, it's not going to get bigger margin 4 to 8 weeks later. So the sensitivity of the intraoperative assessment with software, and I can name at least the software that comes along with one of the devices of the study, and a lot of people are familiar, the ablation confirmation software comes with the Neuwave machine. That software has over 90% sensitivity in detecting suboptimal margins, and consequently LTP. And that's from a dataset that we did here and already published. So you can trust your intraoperative assessment.

Dr Elena Violari:

And that was actually my next question. Several studies have shown that if you stratify by margin, there's no difference in outcome between surgery and ablation and achieving local tumor control.

Dr Constantinos Sofocleous:

Correct.

Dr Elena Violari:

As you mentioned, margin is critical for an ablation to be effective. I was reading that there will be an FDA-approved, like you said, 3D software analysis to determine the five to 10 mm required margin. Can you discuss the software and how it will be integrated at other cancer centers participating in the trial?

Dr Constantinos Sofocleous:

Yes. We're going to see the outcome stratified by the measured margin, and that will be done from all sites at the end of this study. I'm not sure we're going to do an interim analysis when we have enough patients. That may not be a bad idea, but I haven't discussed it with Mithat Gönen (our statistician), and I don't know if that would impact the total number. I don't know if we're allowed to or not. We'll revisit that once we have a substantial number, whether this is allowed or not. But certainly that's something that we will definitely look to publish. No question.

One of the issues with all these softwares, as most of you may think, is that nobody knows exactly the standard error of a measurement. So when the machine says it's five mm, is it really 5 or could it be 3 to 7? We're working on that as well at least with the central software company where they have been very, very strict on what they want from us. And so for enrollment on the ACCLAIM, we are mandated to do an immediate pre-ablation contrast-enhanced CT at 1 mm cuts or as close to that as your machine allows you to go. And at the end of the ablation, the same scan, contrast-enhanced CT at the same slice thickness. And that's mandated from all sides so there is homogeneous imaging, at least on the day of the ablation for the assessment of the tumor in the ablation zone.

So I think that would answer some of these questions because for the first time, we're going to have a big number of cases done in exactly the same methodology in terms of the data put in in the computer that is doing the software analysis.

Dr Elena Violari:

Thank you for sharing that. Now, what will be some challenges that need to be overcome in order for this trial to be successful?

Dr Constantinos Sofocleous:

That's a good question. I wish I knew all the answers to that. I will tell you that one first challenge, it's really the transmission of data, especially with the new HIPPA regulations and all of that, we have to jump a lot of firewalls literally and be able to transmit this data in a fast manner so more than just one person can review the images and give feedback. And part of that is because the ACCLAIM, although that it does not mandate, certainly encourages re-treatment if the margin is suboptimal. And you have 30 days to retreat from the detection of a suboptimal outcome, whether this suboptimal outcome is on the day of the procedure or on the first post-ablation imaging. So these are some challenges that I'm sure we're going to have.

The other challenge, of course, is as always discrepancies on readings. The primary side says this, somebody says something else, and really where is the truth? And I think going to some challenges on that. Other than that, I think that the study is well-designed. So I do think if we do it, like we said we will, it will address the aims that we're going for.

Dr Elena Violari:

Acclaim seems to be a natural evolution of your research, Dr. Sofocleous, you've published extensively in the examination of tissue from ablated margin of malignant liver mets to predict outcomes and you proved through this work how important it is to standardize ablation practices and ablation zone assessments in order to achieve local tumor control that matches surgical resection. After the ACCLAIM trial, what do you envision are the next steps in this research? What questions are left to be answered and what are your future directions?

Dr Constantinos Sofocleous:

Certainly I'm very interested in the needle-less ablation modalities, and that's where I would like to see, there are a lot of new technologies where you don't need a needle and they deliver either ultrasound energy or other energies. I gave a lecture a couple of years ago as an invited keynote speaker in a radiation oncology meeting, and I closed the lecture of that meeting saying that "30 years from now, surgical oncology, interventional oncology or radiation oncology are all going to be radiation oncology, only that the energy is not going to be radiation, and I don't know what the energy is going to be. You can let your imagination go crazy, go wild. But I do think that if we are not in a position 30 years from now to do all of these ablated treatments without having to even put one needle, we will have failed.

So I think the trajectory is that this ground research that we are doing now with the 3D software validation, with biopsies and assessment of tissue biomarkers, genetics, and all of that, hopefully will translate through artificial intelligence models in some sort of totally bloodless equivalent having the same result or even better. That would be my hope for the humanity, that that's where the trajectory is in. And it's certainly way above my education and understanding of science to answer anymore than what I'm saying right now, is just letting my imagination go. I don't know how we're going to reach that point quite, but I do see the trajectory goes that way.

Dr Elena Violari:

Yeah, very exciting developments going on in the field of interventional oncology. We will all stay tuned as the ACCLAIM trial comes to fruition and readout. It's been a pleasure talking with you today, and thank you again for spending your time with us, sharing your expertise and knowledge time. Thank you so much.

Dr Constantinos Sofocleous:

Thank you very much, Elena. Thank you to SIO and thanks for having me. It's a pleasure. And hope we'll catch up soon. Stay well.

Dr Elena Violari:

Thank you.