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Mike Cusnir, MD, discusses the role of Y-90 maintenance therapy in colorectal cancer and how it can supplement chemotherapy to prolong life and reduce adverse effects.
SIR-Spheres® Y-90 resin microspheres have revolutionized the frontline treatment of patients with metastatic colorectal cancer (mCRC) by extending progression-free survival (PFS), increasing chemotherapy tolerability, and helping minimize patient exposure to chemotherapy toxicities, according to Mike Cusnir, MD.
Y-90 resin is a potential maintenance therapy for patients with CRC and liver metastasis and is most effective in earlier lines of therapy, showing efficacy in patients whose disease has not spread to other organs. As another line of therapy in addition to chemotherapy, Y-90 resin improves resectability rates in patients who would otherwise have unresectable disease.
“More than anything, [the goal of maintenance therapy is] to extend the life of the chemotherapy regimens that we give. Getting patients temporized by giving them a treatment that keeps the disease controlled and in the liver is beneficial,” Cusnir said.
In an interview with OncLive®, Cusnir, chief of the Division of Hematology & Oncology and co-director of Gastrointestinal Malignancies at Mount Sinai Medical Center, discussed the role of Y-90 maintenance therapy in CRC and how it can supplement chemotherapy to prolong life and reduce adverse effects (AEs). Cusnir also highlighted how patients have tolerated Y-90 therapy, this treatment’s outpatient potential, and its benefits in patients with right-sided tumors.
Cusnir: Usually, chemotherapy is effective in all lines of CRC. We see chemotherapy being used in the adjuvant setting with curative intent. In advanced CRC, chemotherapy has a role in all levels. The problem is not where chemotherapy has a role. The problem is the toxicities chemotherapy can have and how we prevent these toxicities and spare patients from some of them, while still prolonging their life.
Usually with chemotherapy in CRC, patients tend to have an extremely good overall condition throughout their disease progression. However, when patients start to get some of the toxicities of chemotherapy, namely chemotherapy-associated steatohepatitis, in the long run, that impairs the possibility for them to have that type of treatment on a more prolonged status.
By getting Y-90 therapy and addressing the liver, which is the main disease site in most patients with advanced CRC, we might be able to give patients breaks from chemotherapy or intervals of systemic treatment, not counting some moderations, to possibly prolong their lives and give them the benefits of liver-directed therapies. Y-90 microspheres tend to have a role early in the maintenance setting, where we see maximum patient responses in their different disease statuses as they receive treatment.
We also see a role [for Y-90] in the refractory CRC setting. Many patients who come to see us for clinical trials and other treatments have never been treated with Y-90 microspheres, and their disease continues to be localized in the liver. We can also use Y-90 resin in these patients.
Maintenance therapy in CRC is a controversial topic. In terms of the clinical trials that have studied maintenance therapy, some have shown the benefits of a small amount of chemotherapy, mainly 5-fluorouracil maintenance, [while others have shown the benefits of] biologics, mostly with antiangiogenics. Even more recently, there’s been reports that some EGFR inhibitors appear to be beneficial in keeping patients on initial or subsequent lines of therapy for longer periods of time.
Obviously, we always want patients to be able to go for a complete resection that renders them tumor-free. Unfortunately, we can’t do that most of the time, so that’s why we’re trying to get maintenance therapy to be less toxic through systemic therapies, so we can give patients more benefits from their treatments.
The data is a mixed batch. The data on Y-90 microspheres in the front-line setting was not significant, although there were some subgroups, such as [patients with] right-sided tumors that tend to have a worse prognosis, that benefitted from Y-90 therapy in the frontline setting.
However, looking at the data on using Y-90 resin in subsequent lines of therapy, and even in the maintenance setting, and seeing when patients achieve a maximum response, is important. Many studies looked at large-volume centers. These studies have shown that the earlier that you treat patients, [the more effective the treatment is], namely because most of those times, those patients have liver-limited disease. If you wait, when the disease is much more widespread into other organs, addressing the liver in isolation may not be as beneficial as it is when you address it in earlier disease status.
Across several studies, we have seen data showing that the number of lines of therapy in patients with CRC correlates with survival. A patient who gets only a single line of therapy may survive somewhere around 15 to 18 months. Nowadays, however, with biologics as well, [patients have options for more lines of therapy].
However, patients with CRC who receive multiple lines of therapy are now usually surviving over 30 months. If we consider Y-90 resin, which is another line of therapy, we might continue to extend that survival. That’s been seen in some studies in which some patients were able to achieve PFS of 7 to 8 months after Y-90 microsphere liver-directed therapy.
You may not think 7 to 8 months of PFS sounds like much. However, when you consider that the median survival of 1 line of therapy is 10 to 15 months, this is an additional 50% improvement in frontline therapy. Y-90 therapy is also significant when you consider that the average patient with mCRC survives 30 months. If, out of those 30 months, we can deliver a 1- or 2-dose liver-directed therapy that spares them from systemic therapy for a while and buys them 7 to 8 months, it becomes very significant.
In my practice, I try to treat patients early, when they have liver-only disease. Once they achieve their maximum response from chemotherapy induction, I start withdrawing the chemotherapy and rapidly try to move to liver-directed therapy. Then, I can look at which patients would have been considered borderline resectable with the chemotherapy alone and try to make them resectable with Y-90 resin.
We’re always trying to get patients to be tumor free, if possible. The earlier I intervene and try to get patients to that point, the better. Even when I see that resection is not possible because of widespread disease in the liver, I still prefer to spare the liver parenchyma as much as possible by giving those patients Y-90 resin earlier.
I see many patients in a setting where I get referrals for clinical trials. Many patients who come in to see me for a third-line treatment or subsequent clinical trial may not have received any liver-directed therapies yet and have liver-only disease. Sometimes, before I offer them some other options, I tell them they will probably be able to receive Y-90 resin in the meantime until we decide on their clinical trial. This treatment can [limit the amount of toxicity] in the liver when the disease is more widespread.
[In terms of tolerance], many of the targeted agents we have now are not completely targeted to the point where they’re blocking the EGFR receptors and giving the patients terrible acne. Part of the reason why EGFR-directed maintenance therapy has been called into controversy is because it still gives patients several AEs. It makes no sense to do maintenance therapy with something that gives AEs.
However, with Y-90 resin, most of my patients are treated on an outpatient basis. Most of the time, they’re home on the same day as their treatment. They may have some fatigue, but it’s a minimal amount of AEs, and they’re back to their activities by the next day. Y-90 resin is extremely well tolerated. [There is always the possibility of] radiation-induced liver damage, as every patient we treat with anything could experience toxicity. However, the frequency of those AEs is so low with Y-90 resin that we administer it with absolute confidence. The possibility of radiation-induced liver damage is below 10%, which is even less than what we see with our standard cytotoxic drugs.
First, keep it in mind and use it. Second, this treatment brings many patients to a resectability level. There are some conflicting data to consider. [For instance, in the REsect study, a post-hoc analysis of the SIRFLOX frontline study [NCT00724503], the investigators initially saw an unimpressive number of responses. However, when the investigators were blinded and showed only the liver images, over 10% of the patients who were considered non-resectable at the beginning had become resectable.
Looking at the numbers for that 10%, instead of facing a 30-month median survival, those patients usually have over a 55-month median survival. Improving the lives of that 10% of the population by going to a full resectability rate is important.
Y-90 therapy is also important because it appears to be quite active in patients with worse prognoses. We tend to believe that right-sided CRC has an extremely poor prognosis compared with left-sided CRC. A post-hoc analysis of that patient population, where the data of right- vs left-sided tumors were evolving as all these studies were being done, shows that the biggest benefit of using liver-directed therapy was apparent in these patients with right-sided tumors. It’s important to consider that patients who are facing worse prognoses are the ones who require more interventions.
Colleagues want to know if Y-90 resin can be safely combined with chemotherapy, as well as when they should withhold chemotherapy, and when a patient would be able to receive biologics in combination with Y-90 treatment.
Y-90 resin and chemotherapy can be safely combined. Most interventional radiologists are concerned about using antiangiogenics close to the Y-90 injection site, partly because they want to avoid a pseudo aneurysm at the puncture site. [Although there is no concern regarding the liver with this combination], there’s still a slight risk of intestinal perforation when using antiangiogenics. Since one of the AEs of Y-90 resin could be abdominal pain, you don’t want to worry, not knowing whether your patients are experiencing toxicity from the Y-90 treatment, normal mild abdominal pain, or a much more serious effect such as a perforation from the antiangiogenic that’s unrelated to the Y-90 resin.
Overall, it is safe to combine Y-90 resin with near-standard doses of chemotherapy. Most of us who administer Y-90 therapy don’t combine it with standard doses, however. Instead, [we often give patients a break from chemotherapy and use Y-90 treatment as an opportunity to lead the patients into maintenance therapy].