Kim and Schwartz Break Down the Role of Radiation Segmentectomy With Y-90 in Early-Stage HCC


Edward Kim, MD, and Myron E. Schwartz, MD, discuss the background and findings of the RASER study, the role of radiation segmentectomy, and its potential to be combined with immunotherapy.

Edward Kim, MD

Edward Kim, MD

Retrospective studies have pointed to the benefits of radiation segmentectomy, a treatment that delivers yttrium-90 (Y-90) glass microspheres (TheraSphere) to a tumor in the liver, vs standard of care in patients with unresectable, very early– to early-stage hepatocellular carcinoma (HCC). Now, prospective data have further clarified the benefit of this method, according to Edward Kim, MD, and Myron E. Schwartz, MD.

Myron E. Schwartz, MD

Myron E. Schwartz, MD

Data from the single-center, single-arm RASER trial (NCT03248375) showed that among 29 evaluable patients, radiation segmentectomy with Y-90 achieved an initial objective response in 100% of patients. Specifically, the complete response (CR) rate was 83%, and 17% of patients had a partial response. Notably, 90% of patients experienced a sustained CR.1

“We developed [radiation segmentectomy] because there is a stage migration, and people were using chemoembolization. But chemoembolization on explant tissue historically has had about 50% correlation with pathologic necrosis,” Kim explained. “Radiation should be indiscriminate in terms of its destructive abilities. With chemoembolization, we don’t know if the drug matches a certain tumor type, but radiation in and of itself should be indiscriminate. With a high enough dose, we should be able to get destructive radiation into target tissue. We devised this protocol to go head-to-head with the ablation data to see if we can rival that type of data.”

In an interview with OncLive®, both Kim and Schwartz discussed the background and findings of the RASER study, the role of radiation segmentectomy, and its potential to be combined with immunotherapy. Kim is the director of Interventional Oncology, a professor of Diagnostic, Molecular, and Interventional Radiology, and a professor of Surgery at the Mount Sinai Medical Center. Schwartz is the director of Hepatobiliary Surgery and the Henry Kaufmann Professor of Surgery at the Recanati/Miller Transplantation Institute at Mount Sinai Medical Center.

OncLive®: What is the current standard of care for patients with unresectable HCC? What unmet needs exist for these patients?

Schwartz: Unresectable can mean more than 1 thing. It can mean either that the tumor is advanced in a way that it can’t technically be removed, or it can mean that the tumor, while it’s early, can’t be resected because it’s not safe. For the patients who are early stage and who are not resectable because of liver function, then liver transplantation is the standard of care. There’s a process of getting a patient to transplant that involves a variety of different modalities, chemoembolization, and microwave or radiofrequency ablation. We feel that radiation segmentectomy has a key role in this indication, as well.

When it comes to the tumors that are unresectable because they’re more advanced, then it depends on whether the tumor is confined to the liver, in which case local regional treatments, chemoembolization, or radioembolization [are used]. However, it is not radiation segmentectomy in the same way that’s presented in the RASER trial, but radiation [currently used includes] internal, external, or systemic therapy.

Now immunotherapy with the combination of durvalumab [Imfinzi] and bevacizumab [Avastin] has become a standard based on the [phase 3 EMERALD-2 trial (NCT03847428)], with data showing the combination had the best survival of any of the systemic combinations reported thus far.

Kim: I would agree with that sentiment. Unresectable HCC has a wide range of populations and can include, according to the BCLC [Barcelona Clinic Liver Cancer] guidelines, early stage all the way through the advanced stage. It is a big, heterogeneous population, and locoregional therapies can come into play in a certain subset. Systemic therapies come in to play in the advanced subset.

Could you expand on radiation segmentectomy and the mechanism of action of Y-90?

Kim: Radiation segmentectomy is a sub-selective injection of Yttrium-90, which is a radiation source and a beta emitter. The radiation only goes a short distance in soft tissue—about 3 millimeters—and is localized to where we inject our spheres that are embedded with Y-90. All the credit to our surgical colleagues, including Dr Schwartz, because radiation segmentectomy is similar in concept to an anatomic resection where we take a small, perfused area of the liver with radiation therapy.

I tell my patients that it’s similar to an anatomic resection, except we’re not removing tissue but just injecting a high dose of radiation spheres into the area and destroying it.

Schwartz: As far as the mechanism is concerned, it’s straightforward. It is similar in concept to resection. It has been an evolution in our practice in terms of where we use radiation segmentectomies, as it’s been proven to be effective, to the point where we are now starting to apply it in patients who might be resectable but are not the most ideal resection candidates due to an increase in confidence, based on the results of the RASER trial.

Similar to surgery, for which we undergo a 5-year residency and a 2-year fellowship, this is a technique that took a period of years to be developed to the point where it is as good as it is now. This is credited to Dr Kim, as it is a procedure that takes a high level of expertise on the part of the radiologist to do it reliably and consistently to the point where we can count on it as an alternative to something like resection.

What were the objectives of the RASER trial?

Kim: Dr Schwartz and I, along with other investigators, developed this protocol together because there was an unmet need. At that time, any patient that could go to surgical resection would go to surgical resection. But not everyone is resectable for one reason or another. The other gold standard is thermal ablation but it’s limited in its efficacy based on location, adverse effects, or inefficiency of the ablation, as well as the size of the lesion.

Schwartz: This technique, radioembolization, is not a new thing. It’s been around for 25 or 30 years, but it became popular over recent years, [now] using it the way that Dr Kim has. It is a versatile technique. This application [in the RASER trial] may be the best. It’s very impressive, now that it’s been developed to this level, how consistent the results are. Our liver cancer program relies on it a lot.

How was radiation segmentectomy evaluated in the target patient population of the trial?

Kim: The target population is [patients with] solitary lesions up to about 3 centimeters without any extra hepatic spread or vascular invasion, very early to early HCC with a Child-Pugh A score and excellent performance status. In terms of evaluating its efficacy, we performed a pre- and post-MRI, as well as quantified how much dose was delivered to the patient with a PET CT. This was the only prospective trial that evaluated post–Y-90 PET CT dosimetry. We had some very good metrics to quantify the amount of radiation and the targeting that was available for these patients. The goal was curative intent, though we rely on this heavily to bridge our patients to transplantation.

Schwartz: The patients were, in some cases, candidates for transplantation who needed to be bridged to transplant and in other cases, [older] patients who were not ideal candidates for resection. They all had normal liver function. That was part of the trial because we were setting this trial up to be a comparison with the trials of ablation and even to compare with the data on resection, which applies only to patients with normal liver function.

What was observed in terms of efficacy in the trial?

Kim: We had a primary end point of objective response, according to modified RECIST [criteria]. We found that out of the 29 patients that were enrolled in this study that a 100% objective response was achieved with an 83% CR rate, which is quite remarkable. With chemoembolization, and other transarterial-based therapy, it’s usually on the order of 55% to 70%, depending on which literature you cite. That was impressive.

Eight patients then went on to transplantation with explant tissue, and all 8 of those patients who had CR on imaging also had complete pathologic necrosis. There was a concordance between the radiologic-pathologic findings, and it was shown to be safe with mostly just grade 1 toxicities, such as fatigue and nausea, which is what we've found over the past decade when we perform this therapy.

Was there anything else notable regarding safety and toxicity?

Kim: It is important to note what has been reported before with radioembolization in multiple studies, which has just been nausea, some vomiting, and fatigue, though [we observed a] very low incidence of any type of toxicity, which were usually grade 1 events. [Patients] don’t get the pain or post-embolization syndrome that patients get with chemoembolization, as Y-90 is more reliant upon the radioembolization, or radiation, and not so much the blocking off of arteries.

Schwartz: This is one of the advantages, that it’s an ambulatory procedure. Patients can come and go home, and they don’t remain in the hospital. It’s very appealing from the patient’s perspective.

How does the study support the inclusion of the approach for early-stage HCC in BCLC guidelines?

Kim: It was incorporated into the BCLC guidelines in 2022, based off a multicenter retrospective analysis from the LEGACY study, but there was no prospective data for this technique. The RASER study validates the findings of the LEGACY study and the inclusion into the BCLC guidelines with the prospective phase 2 data. We are quite proud of validating that dataset prospectively.

Schwartz: There still may be a bit of work to do. If you look in the BCLC where radioembolization is placed in the intermediate-stage patients, [radiation segmentectomy] is not yet in the BCLC guidelines up against resection or microwave radiofrequency ablation as a treatment for early-stage disease. The RASER trial, in our minds, puts it there based on not just the trial, but our experience overall with this technique.

In order to get into guidelines, you need a trial of more than 29 patients. We are familiar with the guidelines, since the person who creates the BCLC is our director of research at Mount Sinai, Josep Llovet, MD. [Radiation segmentectomy] is increasingly accepted around the country. The RASER study has had a big impact, but it’s not listed in the BCLC as an alternative to resection, which in our minds it actually is.

Kim: It is listed in the early stage after resection and ablation if those are not feasible, but we’re potentially moving into the space where we could use it as an alternative to resection or ablation.

How does this add to what was observed in the retrospective LEGACY study?

Kim: It validates it with a prospective analysis of this data set. Moreover, we also have a pathology correlation, showing that high doses that were delivered to the target area resulted in complete pathological necrosis.

Dr Schwartz, what considerations do you have as a surgeon for the patient population, and how would this fit in with immunotherapy?

Schwartz: That is a big and interesting question. Radiation segmentectomy is a treatment that’s applied to early-stage tumors, and we use it. We’ve already talked about it in patients who are awaiting transplantation, who need their tumor controlled until they can get there, and in patients who are early stage and maybe not transplant candidates based on their age or other considerations but who are not optimal resection candidates. In patients who are optimal resection candidates, I tell them that we can remove this and that’s been the standard for years, but we have a treatment that we’ve been developing that has been tested and doesn’t involve surgery, and we explain what the data are.

Some of the patients who are candidates for resection, especially for tumors that are in locations that we can’t remove easily with a minimally invasive approach, we’ll choose the non-surgical treatment, radiation segmentectomy, recognizing that it may be a couple of percentage points less likelihood of complete destruction of the tumor. However, patients don’t have to have their belly cut open, and it’s often a reasonable trade off.

When it comes to the role of systemic therapy, systemic therapy is a treatment for what’s traditionally been applied in advanced disease. As it’s been showing its benefit, we’re starting to apply it in earlier-stage disease. We have trials open using immunotherapy prior to resection in the neoadjuvant setting to try to lower the incidence of recurrence of cancer.

The same concept applies with radioembolization because there is a lot of interest in the idea that radiation has the ability to affect the tumor in a way that it releases antigens and proteins from the tumor that may help the immune system recognize the tumor. So it may have a role together with immunotherapy.

Dr Kim has been working to get a trial open combining radioembolization and immunotherapy. The concept of radiation segmentectomy plus immunotherapy is analogous to our resection trials, but the bigger role may be in the patients with more advanced disease who have tumors in the liver that are advanced, which are indicated for systemic therapy but may be very nicely augmented by radioembolization.

Dr Kim, what role do you see Y-90 playing in combination with immunotherapy for patients with unresectable HCC?

Kim: Not within the context of the RASER study, but I agree with Dr Schwartz that outside of that patient population, we envision radioembolization playing a role in the various stages of the BCLC. In the advanced stage, especially in individuals with vascular invasion or a hypervascular tumor, we should be able to target and deposit the Y-90 spheres into the tumor and the tumor thrombus and cause destruction, as well as prevent progression.

We like to combine the therapies for an immunomodulatory effect, as Dr Schwartz has described, in conjunction with checkpoint inhibitors. When you look at the phase 3 IMbrave150 trial [NCT03434379], about patient 33% to 35% of patients had an objective response to the systemic therapy, and with radioembolization, achieving higher objective response rates, particularly with hypervascular tumors with vascular invasion, can potentially improve median OS, as objective response has been used as a surrogate for survival benefit.

Overall, we’re hoping to get higher objective response rates and improve upon atezolizumab [Tecentriq]/bevacizumab in the advanced population. We’re also interested in the potential downstaging population, especially individuals that have an aggressive tumor biology. Can we potentially downstage these patients with Y-90 to within UNOS T2 criteria, and then add adjuvant checkpoint inhibitors to give those patients a chance at a true curative therapy, which would be transplantation? We’re also investigating that potential role.

What should be the key takeaways for colleagues regarding what was observed with Y-90 in this trial?

Schwartz: The RASER trial advances what we’ve been seeing and doing at Mount Sinai. The idea that radiation segmentectomy is truly an ablative technique that is analogous to thermal ablation, and even resection and its ability to reliably destroy the tumor that’s being targeted. It needs to be considered among alternatives for patients. The choice of which one to use is based on technical issues, the location of a tumor, and the condition of the liver. However, it’s right there and should be advanced into the consideration for first-line treatment of early-stage tumors.

Kim: Ultimately, patients benefit from these data, which we've been using at Mount Sinai for almost a decade now. Patients have been benefiting because they have alternatives now, as not everyone’s a resection candidate. Ablation can be considered, but not everyone’s an ablation candidate. After that, oncologists didn’t have many options in terms of a curative intent treatment, but now they do. Ultimately, patients benefit with curative intent treatments for this subset of the population.

What is significant about this dataset vs other data sets that have previously read out in this space?

Kim: For this particular subset of patients with very early– to early-stage [disease] that were included in this study, none of the studies previously were prospective in their analysis of this data set. We had a 2-year follow up, which presented strong data that validate what we’ve been practicing for many years.

There have been retrospective studies, but those are always open to criticism, because of the retrospective nature. However, this is a prospective data set.

What are the next steps in the research for radiation segmentectomy and the use of Y-90?

Schwartz: Radioembolization got started in an interesting way. The companies that provide it have always been reluctant to do large-scale, randomized trials putting it up against other treatments. It has gotten to where it is based on retrospective data and now prospective data. The obvious answer would be a large, randomized trial, but I don’t believe that’s going to happen.

I believe that the evidence has been building, notwithstanding the absence of randomized trials, that this is an effective treatment, and companies are [now] looking to do a big phase 3 trial, putting radiation segmentectomy up against embolization. The different treatments that we have each have their application. Like Dr Kim said, there are some patients where the tumor is in a place that we can’t get via radiation or ablation. They each have a role.

Combining radiation with other modalities to try to increase the cure rate [could be the next step]. The trouble with HCC is whatever is done to the index tumor, there’s a greater than 50% recurrence rate over the first 5 years, because that’s the nature of the tumor. Patients also have a tendency to develop other tumors because they generally have underlying liver disease. The research has [shown] that the treatment of that tumor works, and [we have to] start looking at what we can do to maintain the response with immunotherapy and other modalities to try to cure not only the individual tumor that we were able to destroy, but to leave the patient free of cancer and able to live out their natural lifespan without HCC.

Kim: I agree with you. The easy answer that everyone gives is that we now need to expand to phase 3 studies, but that is not necessarily the realistic or correct answer. I don’t know if we need to go on to a phase 3 study, but I’d like to see the role of Y-90 expand and be validated in the roles of downstaging and in the intermediate stage, which is also a heterogeneous population similar to the advanced stage. The excitement is in combining [Y-90] with checkpoint inhibition, though not all patients respond to checkpoint inhibitors, and not everyone responds to radioembolization.

Radioembolization is a holdover for certain patients who may have good or aggressive tumor biology. We need to get at the core and to try to help those individuals across all their tumor biology types. We can’t forget that there’s also a competing cause of mortality, which is cirrhosis in this patient population.

Until we can reverse cirrhosis with medication, there will always be the role of transplantation, because we can treat the HCC. We have seen patients where we have treated their HCC and they responded well to local regional or systemic therapy, but then the cirrhosis may progress, decreasing their life expectancy. I’d like to see combination trials examine the role of radioembolization in combination with an agent that can treat underlying cirrhosis.


  1. Kim E, Sher A, Abboud G, et al. Radiation segmentectomy for curative intent of unresectable very early to early stage hepatocellular carcinoma (RASER): a single-centre, single-arm study. Lancet Gastroenterol Hepatol. 2022;S2468-1253(22)00091-7. doi:10.1016/S2468-1253(22)00091-7
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