The Metastatic Colorectal Cancer Liver Metastases Outcomes After Radio Embolization (MORE) Study Results: An Interview With Andrew S. Kennedy, MD, FACRO

Researchers involved in the MORE (Metastatic colorectal cancer liver metastases Outcomes after Radio Embolization) study released new findings at the American Society of Clinical Oncology’s 2014 Gastrointestinal Cancers Symposium (ASCOGI) confirming that standard laboratory tests are a valuable tool for predicting patient outcomes prior to selective internal radiation therapy (SIRT). The findings were released by MORE lead investigator Andrew S. Kennedy, MD, FACRO, director of radiation oncology research at the Sarah Cannon Research Institute, Nashville, Tennessee. Interventional Oncology 360 spoke with Dr. Kennedy after the results were presented.

Q: Could you give us a brief overview of the MORE study?

A: The MORE study is a retrospective collection of data on selective internal radiation therapy that I and my coauthor initiated a few years ago because we saw that although many of us had been using it for a number of years, there wasn’t a large collection of data, from the United States in particular. We chose to conduct the study because felt the type of patients that we were seeing are probably a little different from the type of patients they may see in Germany or the United Kingdom because there are different approved drugs in those countries and because patients are exposed to different things. 

This is an investigative study to attempt to answer a few basic questions, and what we’ve presented at the ASCOGI was just one of the four main points that we pulled out of that database so far. I invited the top 15 centers in the United States to participate in this review. Eleven of the 15 agreed, the other four were unable to participate. The intent was to identify every patient with colorectal cancer who was treated with Yttrium-90 resin spheres and make their records available to an independent auditor that would collect the data. 

The aim of this method was to eliminate some of the biases that come from retrospective reviews. Retrospective review is not as clean and as powerful as a prospective study, but there was no likelihood that the manufacturer was going to fund a prospective trial for a disease for which they already had an indication. So this was an attempt to learn what we could from what has been done so far and I’m pleased to say that the 11 institutions made all of their records available to the independent auditor who went there and collected the data. Also, in another attempt improve the quality of the analysis, we didn’t rely on radiology reports or the individual centers for information on who responded on X-rays and who didn’t; instead we were able to have a third-party professional radiology trials group, based in Germany, read every single one of the more than 2,000 scans and come up with an independent assessment on who responded and who didn’t. We tried our best to make it as robust and as helpful as possible. Out of all of the patients, 606 met our criteria. 

We presented the initial study at the ASCO annual meeting earlier in 2013 and we presented a different analysis at CIRSE in Barcelona in September, and the fourth of the four-set analyses at ASCOGI. The most recent information we presented was an attempt to describe what would be useful to know before we treat the patient to optimize a response. What we think we determined was that patients that have low hemoglobin might benefit from having that brought up to a normal level prior to receiving radioembolization. This has not been tested formally but this is the hypothesis coming out of the MORE study. We know from patients receiving external beam radiation that it is a well proven fact that hemoglobin should be at 10 or above to optimize external beam radiation. It’s our hypothesis that MORE data suggests that the same could be true when treating the liver with Yttrium-90.

Q: The recommendations coming out of the study are to do research on whether hemoglobin levels can affect outcome?

A: A prospective study to verify whether hemoglobin levels can affect outcome would be an excellent study, and that’s the hypothesis that we’re generating out of this portion of the MORE study. We believe that treating patients with a hemoglobin of 10 is beneficial, just like with external beam radiation. Our hope is that teams that don’t have a radiation oncologist will think about this and consider transfusion or erythropoietin or some other maneuver. Sometimes patients receiving a lot of chemotherapy can have hemoglobin in the 8 range, so while radiation oncologists might know this better than most, we want to make it more of a topic of conversation on those other teams. My personal belief is that it will certainly help, but we need to prove that prospectively.

Q: So this could help any interventional oncology and clinician considering treating a patient with SIRT.

A: Correct. What they could do if this is new to them is ask their radiation oncologist or ask their medical oncologist what their thoughts are. When we are treating with combined chemotherapy and radiation, generally medical oncologists will do their best to keep hemoglobin at a 10 or above. Sometimes a radiation oncologist will call a medical oncologist to say a patient’s hemoglobin has fallen, and the medical oncologist will then give the patient a transfusion. That’s the kind of interaction that we’re used to that we want to make the interventional team well aware of because it’s probably not something that they’ve seen before.

Q: This was the most recent data that you presented at the GI symposium. Can you describe the other data that came out of CIRSE and the ASCO meeting?

A: At CIRSE we highlighted that patients who are age 70 and older which we term as elderly did not have a worse outcome than patients younger than 70 and they tolerated treatment just as well as the younger patient. Also, in the very elderly, those greater than 75 years old, that held true. 

Readers may be aware that often, patients older than 70 are not included in chemotherapy trials for colorectal cancer. There’s a belief that has been well documented that older patients can’t tolerate a full dose of chemotherapy and there’s a bias against treating them aggressively. The medical oncology literature is showing that that’s really not the case, so a shift is occurring in medical oncology. We examined this for the CIRSE presentation with our MORE data and showed that advanced age did not mean that older patients shouldn’t get the treatment nor did it mean that they had worse complications or outcomes. At the ASCO annual meeting we presented imaging data from our analysis showing how well patients respond when we strictly apply the RECIST criteria. There was also an adverse event presentation on the summary of all the acute and late side effects out of this group of patients as according to the CDC. 

Q: And you also are working on a model to help improve dosage planning for SIRT?

A: Predictive modeling for SIRT is a side research project. It’s not clinical; it’s preclinical. I’ve been looking for a number of years for ways that we could either improve the calculation dose in the liver — make that more refined or predict how many microspheres we can put into a given tumor. Either way we’re going to come up with a better schedule for how to treat these tumors. In external beam radiation we have some tools that allow us to correlate the size of the tumor and the location of the tumor with the best approach to it. We don’t have those same tools with internal radiation microspheres. 

This predictive modeling exercise uses mathematical modeling to predict the blood vessel branching pattern and the number of blood vessels that would be around a given tumor. Prior to this we had done a fair amount of work on predicting blood flow through the catheter or around the catheter that the interventionist had put in the liver. After a few centimeters beyond the catheter we encountered limitations in our ability to calculate. Now we’ve gone in the other direction: we’ve gone from the tumor toward the catheter. Now we’ve linked the two data sets that we were creating and we now can, with some confidence using these fractal mathematics, introduce at least a valid mathematical representation of what the blood vessels would be like if we could leave the catheter like the microsphere and travel all the way to the tumor. 

The potential result of this mathematical modeling would be to do some further testing and then see if it could be helpful in refining how many spheres we’re delivering and conversely if the spheres are fixed, how much activity needs to be adjusted. We don’t know those answers yet, but now we have a tool to start testing it. It’s primarily liver that we can apply it in right now, although the model would work for any organ.

I have not used it yet in a patient. We still need to build some more pieces to make it applicable to a patient. Right now we have the rudimentary equations and calculating power down. It is very computer-intensive but now that we think we’ve got that worked out, we can start introducing patients into it. I’m hopeful that it will work.

Q: Is there anything else about the MORE study or the modeling technique that you’d like interventional oncology clinicians to know?

A: There will be four manuscripts coming out of the MORE experience in the near future that will further explain these data. The posters and the abstracts can show only a small portion of what we will describe in the manuscript.

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Disclosure: The author has completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The author reports grants and honoraria from Sarah Cannon Research Institute.

Suggested citation: Ford J. The Metastatic Colorectal Cancer Liver Metastases Outcomes after Radio Embolization (MORE) study results: an interview with Andrew S. Kennedy, MD, FACRO. Intervent Oncol 360. 2014;2(3):E11-E14.