Riad Salem MD, discusses previous data with TheraSphere™ Yttrium-90 in metastatic colorectal cancer, the potential role of this modality in the second-line setting, and future research directions.
The safety and effectiveness of TheraSphere™ Yttrium-90 (Y-90) Glass Microspheres is under examination in patients with colorectal cancer with metastases in the liver who are scheduled to receive second-line chemotherapy as part of the ongoing EPOCH trial (NCT01483027).1
“With EPOCH, we sought to investigate the role of Y-90 in the second-line setting. Y-90 does not have a role in the first-line setting for metastatic CRC, and it now has a decreasing role in the salvage setting, given the competitive landscape,” study investigator Riad Salem MD, said. “The second-line space was a prime area to see whether we could prolong progression-free survival [PFS], as well as hepatic PFS, and see whether we could either delay other types of treatments or add to standard-of-care treatment.”
In an interview with OncLive®, Salem, the vice chair for Image Guided Therapy, Department of Radiology; chief of Vascular and Interventional Radiology in the Department of Radiology; and professor of Radiology (Vascular and Interventional Radiology), Medicine (Hematology and Oncology), and Surgery (Organ Transplantation) at the Northwestern University Feinberg School of Medicine, discussed previous data with Y-90 in metastatic CRC, the potential role of this modality in the second-line setting, and future research directions.
Salem: Historically, Y-90 has been used in the salvage setting [for patients with CRC] after [progression on] chemotherapy. Several phase 2 trials have looked at the safety and efficacy [of the agent], and those showed approximately response rates of 30% to 40% in the salvage setting, and a median overall survival [OS] of 12 to 14 months, depending on the amount of chemotherapy that [the patient] had been exposed to. Clearly, [we are seeing] that there has been more chemotherapy applied, given the new agents that have come out, and as such, a progressively longer delay in when Y-90 is initiated in this patient population. That OS has now dropped in the salvage setting.
Some level I studies were performed, including the SIRFLOX [NCT00724503] and the phase 3 FOXFIREGlobal [NCT01721954] studies, which looked at Y-90 in the first-line setting. Those studies did not find that adding Y-90 [to chemotherapy] in the first-line setting improved OS. As such, currently, Y-90 is reserved for the salvage setting, [for use] when no other options or clinical trials [are available for] patients who have liver-dominant disease and preserved liver function.
In the salvage setting, most [studies] have [used] off-trial-type designs. A phase 1 trial [NCT00858429] [was done in patients with] metastatic disease to the liver, which includes CRC. That trial [utilized] a dose-escalation concept of Y-90, as well as a full dose of capecitabine, to see whether we could combine a radiosensitizer with standard-of-care therapy for metastatic disease. We were able to treat and get up to 170 Gy without any dose-limiting toxicities. As I mentioned before, [there have also been] the SIRFLOX and FOXFIREGlobal studies in the first-line setting that examined if Y-90 added to standard-of-care chemotherapy would improve OS. Again, those studies did not show an [improvement], and put to bed the idea that Y-90 would be [an option] to consider in that setting.
Those studies have led us to question whether [Y-90 would be beneficial in] the second-line setting. The first-line setting is a very competitive space; many agents work quite well and [improve OS]. However, once [a patient] progresses, the response rate drops, PFS drops, OS drops, and the number of agents available to use is reduced significantly. The question remains: What could we do in the second-line setting to improve the results of standard-of-care chemotherapies, prolong PFS, and provide patient benefit?
[In terms of the] patient population we wanted to study, the first and most important characteristic was that they had to have progressed on first-line chemotherapy, with a regimen that included irinotecan or oxaliplatin. From there, it tends to be dealer's choice. We tend to switch and go to [the other option we did not use in] the second line. We wanted to have patients who were able to tolerate their first-line therapy, and therefore, would be good candidates for second-line chemotherapy.
We also wanted a patient population who had liver-dominant disease. What we did not want to do is have outcomes that were confounded by significant extrahepatic metastases. We wanted liver metastases only, although patients were allowed 1 or 2 small lesions that were deemed to be benign, or very slow-growing metastases.
In terms of the end points, if we look at the guidelines for CRC, all the research suggests [utilizing] an imaging end point in the second-line setting. [As such, we chose] PFS, and we also added hepatic PFS as an end point to EPOCH. We wanted to see whether we could delay the progression of the disease by adding Y-90 to the standard-of-care second-line chemotherapy.
OS, in general, is not used as an end point in the second-line setting, because of the confounding effect of post-progression treatments. When a patient progresses, they crossover. They can crossover to Y-90, or they can crossover to other agents, and that is something we cannot control. It is not like patients receive a treatment and once they progress, they do not receive anything else. Because the landscape is so busy, and so active with so many treatments, patients then go on to a different clinical trial or a different treatment, and that is why OS is not the primary end point, but rather a secondary exploratory end point.
All we know right now is that in the first-line setting, Y-90 does not have a role in CRC. We will wait to see what the results from the EPOCH trial show in terms of [the agent] playing a role in the second-line setting. In the third-line setting there is a minor role for Y-90, but the advent of immunotherapies in that space and other treatments has reduced the use of Y-90 in the salvage setting. However, right now, the salvage setting is where Y-90 sits in CRC. Again, we will see what the results from the EPOCH trial will show, and hopefully [we will see] a benefit.
It is an exciting time to continue to investigate the role of Y-90 in various cancers. Now that we have solidified the use of Y-90 in hepatocellular carcinoma, we are now [examining] Y-90 in colon cancer, brain tumors, and in prostate cancer. [Y-90] is a very effective method of delivering radiotherapy, [and] it allows [us to] provide a very focal, high radiotherapeutic dose to a small area of the body that we inject through the artery. We see very low adverse effect profile with a very high, ablative radiotherapy dose.
Now that the technical aspects have been resolved in their entirety, it is a very exciting time to be dealing with Y-90, and we look forward to working on other types of applications with [this approach]. Y-90 as a technology is very exciting given its versatility and its ability to be injected in multiple areas in the body with very high ablative radiotherapy.
CAUTION: In the US, Therasphere is under and investigational device exemption for treatment of patients with metastatic colorectal cancer. The safety and effectiveness for this treatment has not been established.