Emerging Data Could Show True Benefit of Y-90 Radioembolization in Liver-Metastatic CRC

Andrew Kennedy, MD

The incorporation of selective internal radiation therapy (SIRT) with SIR-Spheres Y-90 resin microspheres into the treatment paradigm of liver-metastatic colorectal cancer (CRC) is showing interesting potential in this patient population, experts say.

One ongoing 2-arm study is evaluating the safety of the multikinase inhibitor regorafenib (Stivarga) before or following SIRT with Y-90 for the treatment of approximately 50 patients with refractory CRC with liver metastases (NCT02195011).

Y-90 has already shown encouraging findings in this area. Phase III findings of the SIRFLOX study demonstrated a significant increase in hepatic depth of response from treatment with SIRT with Y-90 versus standard frontline chemotherapy in patients with metastatic CRC.

Longer follow-up from 2 clinical trials related to SIRFLOX will likely be presented at the 2017 ASCO Annual Meeting, explains Andrew Kennedy, MD.

OncLive: Please provide an overview of your presentation on liver-metastatic CRC?

During the 2017 OncLive^® State of the Science Summit on Gastrointestinal Malignancies, Kennedy, physician-in-chief and radiation oncologist at Sarah Cannon Research Institute, spoke on the various approaches used in clinical practice to treat patients who have CRC with liver metastases. In an interview at the meeting, he discussed some of these methods and how the emerging Y-90 data could evolve the field further.Kennedy: The most success we’ve had for mCRC to the liver have been in those cases where surgery can be performed. Unfortunately, more than 80% of the patients who present with tumor in the liver with a colon or rectal cancer cannot have surgery. The other attempts to make the tumor liver-free have included ablating them—putting in a probe through the skin and heating the tumor up to kill it or freezing it—to radioactive approaches, which is using external-beam radiation therapy, called stereotactic body radiation therapy (SBRT), which is very effective. For tumors that are smaller, there is an over 80% control rate with either ablation with the heat probe, called radiofrequency ablation, or with SBRT.

We saw data with the SIRFLOX study last year with Y-90. What are your thoughts on that trial and the utility of Y-90?

In tumors that are more widespread in the liver, then we usually use something called intra-arterial therapy. The most successful one to date is a radioactive microsphere, and that is released into the liver arteries and those little spheres that are radioactive become embedded in the tumors permanently. The radiation doesn’t affect the whole liver, just the tumor that it’s embedded in.Using radioembolization, or Y-90 particularly, in CRC is very helpful in that we have very good level 1 data, both in first-line and in third-line patients. The promise of it is to protect the normal liver while radiating tumors that may not be responding to chemotherapy. It can treat multiple tumors in the liver at once, and it can be used even when patients are not feeling their best. Their performance status is lower.

The SIRFLOX study, which was in first-line patients with CRC, was the first to show that moderate chemotherapy with Y-90 at the same time was safe and efficacious. The primary endpoint, which was progression-free survival, was not met. That’s probably because they allow patients into the study who have bad disease outside of the liver.

What are the next steps with that study?

What it did show was that, in the liver, those tumors were very well controlled, and there were statistically much higher control rates than the patients who just had chemotherapy. So, in the area where the radiation was applied, it was very effective.Fortunately, there are 2 sister trials that were identical to SIRFLOX and they have closed and met their accrual. At the 2017 ASCO Annual Meeting in June, they will be presenting the combined data of all 3 studies for overall survival (OS). Right now, we are not sure whether adding Y-90 in the first-line setting is going to improve survival. We know it already controls the liver much better than chemotherapy alone, but there will be over 1100 patients in the cohort. It will have the power to tell us what the real answer is in first line.

What do you hope we can accomplish in this area of liver-metastatic CRC in the next 5 years?

Is there any other research in particular that you’re excited about?

In second- and third-line patients, that is really where the improvement is seen the most dramatically. Patients in these settings have very low response rates to multi-agent chemotherapy. It is probably because they have a lot of disease. By adding radiation earlier—not when everything else has failed—we’ve seen in small studies that the Y-90 is much more effective. The improvement in OS in second- and third- line patients has been significant over chemotherapy alone.In the next 5 years, the advances we would like to see are, on the 1 hand, patient selection. Conversely, can we refine our skills and our selection of agents to get better control in those who we are confident we are going to help? Rather than just adding 2 or 3 months of control, can we get 6 or 8 months of control by doing that procedure better?One of my interests in Y-90 therapy as a radiation oncologist is trying to refine and discover what the optimal radiation dose is for that metastatic lesion. We know that different tumors that metastasize to the liver have different radio sensitivities. What we haven’t known is what the right amount of radiation for a particular tumor is. That is an area of active research right now, and I suspect that it’s going to show us that we can reduce the amount of radiation we're delivering and get the same outcome.