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March 3, 2022

Rohan Jeyarajah, MD, discusses what makes SIR-Spheres® Y-90 resin microspheres unique from other therapeutic approaches in the treatment of patients with metastatic colorectal cancer and liver metastases, and how it can best be leveraged in different clinical scenarios.

SIR-Spheres^® Y-90 resin microspheres has potential utilization in several different subsets of patients with metastatic colorectal cancer (CRC), according to Rohan Jeyarajah, MD, who added that in patients with liver-predominant disease, Y-90 resin represents an ideal maintenance therapy for patients looking to de-escalate chemotherapy.

SIR-Spheres^® Y-90 resin microspheres are tiny radioactive beads that are leveraged in selective internal radiation therapy; they are much smaller than the width of a human hair and contain the radioactive component yttrium-90 (Y-90).¹

The microspheres are injected into the tumors within the liver through the tumor’s main blood supply. They then stick within the small blood vessels that are in and around the tumor and proceed to emit high doses of radiation to the tumor cells to eliminate them.

“[We can use this product in patients who have] small tumors throughout the liver [where] we want to treat the whole liver,” Jeyarajah said. “[We can use this to] treat 1 side [of the liver] to cause growth of the other side [before we operate], which may give the patient a holiday [from] chemotherapy during that time. [We can also use it in terms of] margin accentuation, when I am going to take out [disease] that is very close to other structures. This is a phenomenal technology, and the resin beads are a phenomenal product that seems to work very well with minimal toxicity.”

In an interview with OncLive^®, Jeyarajah, a hepatopancreaticobiliary surgeon at Methodist Richardson Medical Center, discussed what makes SIR-Spheres^® Y-90 resin microspheres unique from other therapeutic approaches in the treatment of patients with metastatic CRC and liver metastases, and how it can best be leveraged in different clinical scenarios.

OncLive^®: In the context of CRC, could you provide some insight into what resin Y-90 is?

Jeyarajah: This is an amazing product. My major use [with] resin Y-90 [is] for [patients with] metastatic CRC. When we think about this, we think about radiation; however, this involves putting tiny radiation beads into the tumor through the arteries that supply the tumor. [The product is] being delivered from the inside, and because the blood supply is directed preferentially to the tumor than it is to the background liver, these tiny beads are pushed toward the tumor, rather than to background liver.

How is SIR-Spheres^® Y-90 resin typically administered?

Y-90 [is usually given as] two procedures to place the beads. The first is usually a mapping procedure. However, that is changing in that you can now do same day delivery. However, many still do mapping [in] a different sitting during which you would embolize vessels where you don’t want the beads to go, so that you don’t get toxicity from a gastrointestinal standpoint. You then calculate the dosing and order the beads. You can calibrate etc., and I’m not an interventional radiologist or nuclear medicine doctor, but you then deliver [the treatment]. The way that things are moving, this will probably be able to be done in the same setting if there’s no major shunt where beads are going elsewhere, like to the lungs.

[After we treat], we then watch. I would not retreat before a good 6 months [after the initial procedure], and I would only retreat if there was liver progression that we couldn’t treat in some other way.

For example, in the scenarios that I explained to you before, where there are multiple liver metastases, usually what we’ll see is that most things will regress or resolve, but [there may be] a couple of rogue lesions that we’ll have to treat again or ablate in those circumstances.

The choice of the next line of therapy for the liver with regard to non–chemotherapy options is going to be either to add resection, add ablation, or retreat with Y-90, with the understanding that there’s a little bit more toxicity as you retreat the liver with the radiation source. As opposed to chemotherapy, which is ongoing, Y-90 occurs [once], but the effect is ongoing, and then we would come in again with another manipulation if there was a reason to retreat the liver.

What disease features make a patient ideal for this therapy?

CRC is so common in our community. Some factors [are] environmental, and some are probably underlying genetic factors. [Regardless,] certainly in the West, CRC is a big tumor type. With that in mind, unfortunately, the reality is that approximately 50% of patients with CRC will develop metastases to their liver. What that means is, we are [trying to figure out] what to do [to treat] their liver disease. They all need chemotherapy—there is no question about that. The question for me, as a hepatobiliary surgeon, is whether I can take these lesions out, or whether I can take out the part of the liver that is affected.

When considering [this product], there are 3 buckets to put this into. [The first group is patients who] have tumor throughout the liver, multiple small lesions, [who we know] are going to be very difficult to cure and very difficult to treat surgically. We, of course, want to use chemotherapy [because we] know that [modality] prolongs life. However, when [disease is] scattered throughout the liver, Y-90 together with chemotherapy [may be able to produce] a response in these small lesions. We do know that chemotherapy alone does not make lesions completely go away; there are always viable tumor cells within even small lesions, so we need to add something else. Some other groups have used [tools] like hepatic artery infusion pumps, but I use Y-90 in a similar [way].

Group number 2 [comprises patients] who have 1 or several large lesions in 1 side of the liver, but the remaining part of the liver is not big enough for me to leave just this little piece of liver. In those patients, I tend to use Y-90 [on] the affected side [of the organ] and let the other side grow. This takes a little bit longer [to do]; in fact, we need to wait about 3 months before we can come in with liver resection. Most surgeons do not feel comfortable operating after Y-90, but there are plenty of data to support us being able to operate afterward.

[I believe this] is a great [option for] someone who has no other disease anywhere else, or even [someone who has] their primary [tumor] as the only site of disease. We can treat the liver, give them 3 months off of chemotherapy, better quality of life, maybe even take out the primary tumor during that time, and then come back and take out this large piece of liver.

Group number 3 is a little bit more challenging; this is where we are very close to important structures and do not believe that we can get a great margin on the tumor. We use this in the pancreas all the time, when we treat with neoadjuvant chemotherapy, because we are sterilizing in the very outer border. We know we cannot take out some of these structures, but we assume that our margin is better, so I use Y-90 in that respect.

In terms of the second scenario, you said that some are hesitant to operate after Y-90. Why is that?

The liver is a little bit firmer after any kind of radiation; whether it is from the outside or from the inside, the liver just becomes a little firmer. It is just a touch more technically challenging, because to manipulate the liver is a little bit more difficult. However, plenty of available data [suggest that] Y-90 followed by surgery is very safe unless you are doing an extended resection, where we are taking out 75% to 80% of the liver. I would not advocate [administering] Y-90 before that [kind of surgery] in those patients.

One of the papers that I am a co-author on looked at a pooled experience. Even in major hepatectomy, it was very safe to do surgery after Y-90. My feeling is, and the data would suggest, that in these very extended resections, I would be cautious in using Y-90.

From a liver standpoint, surgeons who do not [deal with the] liver on a frequent basis are always a little bit hesitant with liver. Don’t get me wrong, I deal with livers constantly, but it is an unforgiving organ. When things go wrong, they really go wrong. [I do believe that] someone who is frequently dealing with the liver should not be afraid to use Y-90 in the neoadjuvant [setting].

The term I really want to coin is ‘neoadjuvant Y-90’ because it takes away that stigma of thinking of Y-90 as palliative, [where] we are just trying to [use it to] extend life. No, I really believe that Y-90 can be used in the potentially curative circumstance, too.

Is there any ongoing or planned research to that end?

The phase 1 FOXFIRE Global trial [NCT01410760] and the phase 3 SIRFLOX trial [NCT00724503] did show disease-free benefit to Y-90 resin microspheres. I was in the group that looked at the CT images from the patients who were enrolled in FOXFIRE Global, and we published this finding in the RESECT trials.

Unfortunately, what was seen was that the investigators biased themselves against a beneficial response because many of these patients had terrible extrahepatic disease, meaning disease outside of the liver. It was not surprising that we were able to control liver disease well. However, there was so much extrahepatic disease that that effect was marred by overall tumor progression.

The corollary to that is that the liver is going to be your life-determining issue, and that is going to be the issue here for patients with metastatic CRC. We can control this very well. Research wise, FOXFIRE Global and SIRFLOX really were our best studies, and we do need to build on those.

What is the potential benefit of using Y-90 resin as maintenance therapy?

The data are all over the place with regard to the utility of maintenance therapy, but we generally think about maintenance as chemotherapy and using it in a de-escalated format so that we’re not using a cytotoxic agent as we would do with standard chemotherapy. For example, [this might mean that] a patient would get full-dose FOLFOX for a period, usually 12 cycles, and then if they have small volume disease, and we’re trying to treat them with quality of life [QOL] in mind, we [would] de-escalate to something like 5-flourouracil plus a biologic.

When I think about patients who have liver predominant disease, I think that algorithm can be changed to even more QOL-based treatment by treating the liver with Y-90, if that’s the main site of disease, and then taking patients off chemotherapy completely as long as they don’t have other sites of disease that need treatment.

I would not do this if the patient had retroperitoneal lymphadenopathy or if they had lung metastases that would need to be treated. Those patients will need some form of continuation of therapy. The term maintenance in this way would refer to controlling liver disease without toxicity or with minimal toxicity.

Could you discuss your anecdotal experience using SIR-Spheres® resin Y-90 as maintenance therapy? What are some common adverse effects? Have you seen improved QOL with the modality?

[QOL] is probably the main thing that we need to be thinking about. I am really impressed with the fact that apart from a little bit of fatigue for about 5 days post Y-90 implantation, patients are pretty much good to go. Even patients with some underlying liver disease for various reasons, whether it be chemotherapy-related or other factors, tend to tolerate [Y-90] very well.

Rarely you will see some ascites or fluid buildup in the abdomen. This is kind of a sporadic phenomenon that I don’t quite understand. I’ve had patients develop this as late as 6 months after treatment where it didn’t make any sense, and we just don’t know if this is [due to the combination of] chemotherapy plus Y-90, or whether it’s timing related or toxicity related, etc. Most of those patients have done well with diuretics, and usually this will resolve with time.

I have not seen fulminant hepatic failure or jaundice or any of those things. I feel like this is very user dependent. Choosing the right patients with preserved bilirubin and preserved platelets [is important], but I also think that [the toxicities that are seen has to do with] the treater too. I’m very lucky to partner with some great interventional radiologists that have had a lot of experience in this arena. Delivery is critical. You must calculate the treatment well, and you must deliver it well. Honestly, I have not seen problems with this.

Very rarely we can see bead leak, so resin microsphere leak into something like the GDA distribution, [creating] bowel-related issues. I’ve seen a couple of radiation-induced ulcers in the duodenum. Those are difficult to manage. I did have one patient that developed an obstruction, and I needed to do a gastrojejunostomy to bypass that. But considering the hundreds of patients that we’ve treated over the years; I can count the patients that have had issues with Y-90 on one hand.

What would you say to clinicians who would prefer to take a more aggressive treatment approach and reserve Y-90 for later lines of therapy?

The earlier we use Y-90, really the more lines of chemotherapy we can give these patients because they live longer. I would advocate sequencing Y-90 early when the liver is not completely hammered. You mentioned aggressive, and I’m aggressive on the surgical side. I think we all agree that if we can resect and if it makes oncologic sense, that would be the aim. We can use Y-90 to achieve that aim.

Being aggressive on the medical oncology side is also important. We do want to use all our best agents, but we also want to try to preserve QOL and be able to deliver these agents over a longer period. With the correct sequencing of therapy, we can achieve that and treat these patients for longer because they live longer and give them chemotherapy breaks and give them as little toxicity as possible by using novel agents when appropriate.

Is there anything you would like to emphasize to others who are not as familiar with this product?

[There are] 2 big aims: surgeons learning to use Y-90 to get to surgery, so [in the] neoadjuvant [setting]; and then, from the oncologist standpoint, I would consider Y-90 if there is liver-only disease that is not resectable. Maybe we could treat [these patients] with Y-90, get them off chemotherapy and give them better quality of life—even in the palliative circumstance.

The other thing I would like to note is that in patients with underlying liver disease—if they have fibrosis, cirrhosis, or significant liver injury—I have found that Y-90 has been a lot less toxic than transarterial chemoembolization or bland embolization. I tend to favor Y-90 quite a bit in these patients, because they do not tend to have that postembolic phenomenon.

In fact, if you look back, the reason that Y-90 was registered as radioembolization was not because it is an embolic phenomenon; it was [because of] FDA-related reasons, from my understanding. However, [Y-90] really causes very little of an embolic phenomenon. [Patients] do not get sick in the same way. [They experience] fatigue, and a little soreness, but I do not see the type of fever, terrible abdominal pain, and drop in liver function that I do with other modalities.

Is there anything else about the use of this product, or any of your own anecdotal experiences, that you would like to share?

One case stands out, where a patient showed up with what I call ‘shotgun liver.’ The whole liver was filled with tumor, small volume, and by using Y-90 effectively and then sequencing in colon resection, that gentleman lived 5 years. I really do believe that [this approach] was controlling his liver disease that was good [to see] in this case.

The other thing [I want to stress] is if surgeons would realize that it is still possible to operate after Y-90, it will be a huge [step] forward. Last, I will just [mention] our paper that we published, which looked at a consensus set of guidelines. I would really like the medical oncologists and the hepatobiliary surgeons in the group to look out for that.

The idea is that there are various [areas where] Y-90 fits into. We came up with this general algorithm, which I believe would resonate very well with medical oncologists [who are treating patients with] resectable, borderline resectable, and unresectable metastatic CRC. This really resonates with how we look at other tumors. In the esophagus, we look at this. In the pancreas, certainly these terms are used. The idea is that with resectable CRC liver metastases, we use Y-90 to make that resection safer and to get a better margin.

Similarly, with [those who have] borderline resectable [disease], we are trying to get them to resection. Then in the unresectable group, those patients are probably never going to come to surgery, but early use of resin microspheres does result in good control of the liver, a la hepatic artery infusion pump, and more time off chemotherapy with less toxicity.

The big thing is understanding the product. Resin microspheres are very safe. If you have had a bad experience, consider that it could have been patient related or delivery related. I have extreme comfort with this product with regard to using it with minimal toxicity. Thinking about the whole patient, this is something that needs to be in your armamentarium. It’s not for every patient.

I am always looking for a reason to try to resect, if possible, because that’s our best chance of a cure. But, in the right patient, using [Y-90] as a neoadjuvant approach to resection or as a definitive approach but not just palliatively in end-of-life care is really something to keep in mind.

Reference

1. About SIR-spheres microspheres. SIRTEX website. Accessed February 4, 2022. http://bit.ly/3glAt1S