Liver Metastatic Disease: The Dangers of Data Misinterpretation

In this Q&A, Daniel Sze, MD, PhD, discusses the results of SIRFLOX, FOXFIRE, and FOXFIRE Global trials and how continued investigations in this area, as well as in immunotherapy, may impact the field. Dr. Sze is a Professor of Radiology at Stanford University Medical Center in California, and he will be presenting at the Symposium on Clinical Interventional Oncology, which takes place February 3-4, 2018 in Hollywood, Florida.

What do you see as the significant studies thus far in 2017 for metastatic liver disease?

The combined survival results from SIRFLOX, FOXFIRE, and FOXFIRE Global were significant. Those were all prospective randomized trials looking at the addition of radioembolization to standard systemic chemotherapy for first-line treatment of metastatic colorectal cancer. It was probably the largest interventional oncology trial ever performed, but unfortunately it did not reach its primary endpoint. As a result, the press has covered it as a negative trial, and that perception has led to decreased enthusiasm from colleagues outside of interventional radiology.

However, the results should be put in perspective. The trials only examined first-line therapy, and we have good evidence that there is still utility for radioembolization for later lines of therapy. In addition, researchers are conducting subset analyses within the SIRFLOX/FOXFIRE data, and these have already indicated that certain subsets of patients benefit from the addition of radioembolization to first-line therapy. In particular, analysis has revealed that patients with right-sided rather than left-sided colon cancer have a pronounced, statistically significant benefit from the additional first-line radioembolization. In the months to come, more data will be released that will guide us in our clinical decision making.

There is also continuation of ongoing work in a variety of areas, including the application of immunotherapy to metastatic disease of different cell types. We had expected immunotherapy drugs to work on everyone with metastatic disease, but we can now do pathological analysis to help predict who could actually benefit from treatment. For example, microsatellite instability tests are being used to predict whether someone can expect benefit from immunotherapy. These types of predictive tests are important for a number of reasons—immunotherapy is very expensive, and immunotherapy can have severe or even fatal toxicities. It makes sense to personalize treatment and only give these treatments to patients who are most likely to benefit from them.

Based on these studies, have you made any changes to your practice?

I have not, but I’m sure there are some people who have made changes. Regarding the SIRFLOX/FOXFIRE results, most interventionalists never had an established first-line radioembolization practice for metastatic colorectal cancer. Most of us are still treating patients after they failed at least one and sometimes multiple lines of chemotherapy.

From that point of view, my practice hasn’t changed. However, our plans to grow the practice in the direction of earlier utilization in the sequence of treatments have been influenced by the trial results. We were hoping there would be more evidence for first-line radioembolization, but it looks like we have to be more discerning about who can be recommended for that treatment.

There is a danger that misinterpretation of the SIRFLOX/FOXFIRE data may result in decreased utilization of salvage radioembolization. Referring physicians may see the negative results of the SIRFLOX/FOXFIRE trials as applying across-the-board, even if many patients could potentially still benefit from later-line radioembolization.
What could interventional oncologists do to lessen that perception and explain the benefits for salvage therapy?

It’s the same information that’s been out for many years. Interventional oncologists have to be at the table when there is multidisciplinary discussion of how to treat patients.

What would you advise for continued investigation?

Clearly there is still reason to continue investigation. This is not the last word.

Distinguishing the biology of right-sided vs left-sided colon cancer is just a start. We should also look at other biomarkers that might predict who should be offered first-line therapy. We also have a huge opportunity to evaluate dosimetry in the SIRFLOX/FOXFIRE patients retrospectively and to replace the older, unscientific methods with new optimized protocols.

Are you anticipating interesting data from any other ongoing studies?

Both the BTG and Sirtex companies have started registries to gather real-world data. These are not randomized and controlled, but they can at least build a larger collective database to show actual results of treating patients.

Is your institution participating in any studies you’re excited about?

In the whole oncology community, the biggest excitement is around various flavors of immunotherapy. There have been many years of excitement of how to combine locoregional therapy with immunotherapy, and there are ongoing efforts in that area. For example, BTG and the Society of Interventional Oncology (SIO) have teamed up to sponsor grants, and the first round has already been awarded. The interventional oncology community (what we call “IO”) is definitely seeking to establish a role within the immuno-oncology world (what the rest of the oncology community calls “IO”).

Are most people optimistic or pessimistic about the potential of combining locoregional therapy with immunotherapy?

Everyone is optimistic but there are so little data right now that it’s a lot of promise and very little reality. There are anecdotal reports of people trying combination therapies outside of clinical trials, but that’s not going to have a major impact on the actual utilization. We clearly need to produce rigorous data.