Impact of Anatomic Changes and SBRT Type/Dose in Pancreatic Cancer

Michael D. Chuong, MD, FACRO

Multiple studies of patients with pancreatic cancer have demonstrated the utility of magnetic resonance imaging (MRI)-guided stereotactic body radiation (SBRT). But a multi-institutional study presented during the American Society for Therapeutic Radiology and Oncology (ASTRO) is the first to compare MR-guided SBRT with computed tomography (CT)-guided SBRT in this patient population, according to Michael D. Chuong, MD, FACRO.

Based on the location of the pancreas and the organs surrounding it, radiotherapy is difficult to administer to patients with pancreatic cancer, explained Chuong, medical director of Proton Therapy and Photon Therapy in the Department of Radiation Oncology, Miami Cancer Institute, in an interview with Targeted Oncology™.

“Not surprisingly, what we found was that the internal anatomy changes on a day-to-day basis. In the vast majority of the treatment days that we looked at, almost 90% of all of the treatment days, across the CT vs the MRI-guided treatment plans, we found very large number of violations in terms of the dose that would have been delivered to the intestine or the stomach,” said Chuong. “For example, across most of the treatment days, if we weren't able to adapt the treatment, the doses to the stomach into the intestines would have been exceeding what the safe parameters would have been. If patients were treated with something like that, there would be a very high chance that we would cause major toxicities, like bleeding, ulceration, or perforation, which could potentially lead to death.”

This research, according to Chuong, provides essential information around the safety of the more traditional SBRT techniques. Further, it suggests that dosing of SBRT should vary based on the location of the target area at the time of treatment.

In an interview with Targeted Oncology™ following the ASTRO Annual Meeting, Chuong, discussed the research in detail as well as other studies which endorsed MR-guided SBRT.

TARGETED ONCOLOGY: What is the current role of MRI-guided SBRT in pancreatic cancer?

Chuong: Just taking a big picture view of how pancreas cancer is treated with radiotherapy, SBRT is a technique that's been used for many years in treating pancreas cancers, typically over 5 treatments. The standard of care today remains delivery of SBRT with moderate doses, but not especially high radiation dose. The challenges with delivering much higher radiation doses, which we would expect, would be a higher chance of killing the cancer and killing more cancer cells and providing better long-term outcomes, is the fact that these tumors are in a very difficult location within the abdomen. These tumors are many times touching the stomach and the intestines,so delivering a very high dose to the tumor has always been a difficult proposition because there is a high chance of causing major toxicities. For example, you could put a hole in the stomach or cause perforation or cause bleeding. Prior clinical trials attempting to deliver very high dose SBRT for these tumors has confirmed just that. They have shown that it is not safe to deliver very high or what we call ablative radiation dose with standard radiation devices that typically use CT scans for targeting purposes. The advent of something called MRI-guided radiation therapy a little bit more than 5 years ago has changed the paradigm in how pancreas cancers and other difficult cancers are treated and allows for significantly higher doses of radiation.

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Using MRI guidance really overcomes the main challenges with standard radiation machines, including the following issues. One is that MRI scans inherently provide much better imaging of the abdomen, much better clarity in terms of the tumor, and where that lies in relationship to the intestines on any given day. The ability to target tumors is much better with MRI. Number 2 is with standard radiation machines using CT scans, there is not an ability to image the tumor. During the treatment delivery, all imaging is done before the treatment. There's no imaging during the treatment itself with standard devices. With MRI-guided radiation, there's a real time MRI scan being acquired throughout the entire treatment. As the tumor moves when the patient breathes, for example, we can see that in real time, we can see the intestines contracting, we can see the heart beating, the lungs expanding, and all of that is seen in real time. Not only that, but as the tumor moves, if it moves out of the correct position where the treatment is being delivered, the system that we have will automatically stop treating, and when the tumor comes back to the right area, it will automatically resume treatment. That is an unparalleled ability to enhance safety.

Finally, is what's called adaptive radiotherapy. With the patient lying in the treatment machine, we can identify changes in the patient's internal anatomy from day to day. For example, maybe the stomach is much fuller, and it's closer to the tumor than it was on previous days. With standard radiation devices, there is not an ability to modify the treatment on any given day, so that the high dose is carved out of the stomach if it's closer to the tumor. That is something that we can easily do with MRI-guided radiation using what's called adaptive radiotherapy, so we can adapt the treatment or modify the treatment and sculpt the high-dose radiation out of the stomach or the intestines while still delivering exceptionally high dose to the to the tumor.

All these capabilities have allowed us to deliver more than twice, if not more, radiation to the tumor, which has led to excellent outcomes in terms of being able to control these tumors long-term and potentially even eradicate these tumors without surgery. We think this may be helping to prolong patient survival. This is an approach that we have helped pioneer internationally, treating patients over the last 5 and a half years or so. This is starting to influence how SBRT is delivered and the perspective on how SBRT should be delivered in terms of ablative radiation dose worldwide.

What other radiotherapy modalities are being used to treat these patients with pancreatic cancer?

The most common type of radiation would be to have what we would call a non-ablative dose. As I mentioned before, this is more of a moderate radiation dose, using a variety of different treatment approaches as well as a variety of different what's called fractionation schedules or numbers of treatments. I think the important concept would be that at the end of the day, the radiation dose is about the same across the board, whether patients are treated with a CyberKnife device or a TrueBeam device, which is a standard linear accelerator. In a lot of cases, patients are treated with an advanced type of radiation called proton therapy, just because of the limitations that I mentioned before. There is also a certain level of technical ability to ensure that the high dose is only going to the tumor and not to the intestines or the stomach nearby. There are many other ways to deliver radiation outside of MRI-guided radiation, but they almost all are constrained by technical challenges that lead to significant dose-escalation.

Can you discuss the important research around MRI-guided radiotherapy in pancreatic cancer?

With the MRI-guided data that we and a few select other centers have published, we have made some early, large steps forward in terms of showing the feasibility. We have shown that it is feasible to, number 1, deliver this type of ablative dose safely. I would say, 1 of the most important clinical trials in the pancreas cancer space in recent years is one called the SMART trial [NCT03621644]. The SMART trial is a multicenter trial that we were 1 of the largest centers in. But that is a trial that was published last year that confirmed prospectively that the high-dose radiation that we're delivering in 5 days utilizing the MRI-guided technique, is safe, and in fact, showed no definite major toxicities related to the treatment for patients who had inoperable pancreas cancer. It's just the beginning, I think of many more trials to come.

We are very proud to be one of the lead centers for the upcoming international phase 3 LAP-ABLATE trial [NCT05585554], which is aiming to show that this type of ablative radiation effect does prolong survival and help patients live longer, who have inoperable pancreas cancers. What we're studying is whether patients who get chemotherapy alone or chemotherapy followed by this ablative type of MRI-guided radiation longer or not. There is much more to come in the next few years with that trial and others that are exploring the space of ablative radiation therapy.I think there's a lot of reasons to be excited and optimistic that this, in fact, is helping patients we see it on a day-to-day basis. I'm optimistic that the clinical trials data will help them from that.

New research around ablative 5-fraction CT vs MR-guided pancreatic SBRT was presented at ASTRO. What can you tell us about this study?

The study that we performed was aimed at quantifying the benefits of the online adaptive radiation that I mentioned previously. Again, the adaptive radiation treatment approach is 1 where each day prior to that treatment delivery, we can modify the radiation doses to account for any changes inside the patient's body from the prior day.Of course, our insides are not concrete. Our intestines are always moving in digesting food, and our stomach is filling and emptying. So, when accounting for those changes on a day-to-day basis, it would be incredibly important to make sure that we are not delivering excessively high doses of radiation to the intestines, and that we account for those changes.

There really has not been any quantitation, or quantitative evaluation of what is the benefit of being able to adapt treatment plans and modify treatment plans on a day-to-day basis. What we did was we took patients who were treated here at our center with MRI-guided radiation therapy and we performed a planning study in which we retrospectively replanned some of these treatments, assuming that that the patients were treated with a standard CT-based our CT-guided linear accelerator, which is the what patients would be treated on as a standard of care if the center didn't have an MRI-guided device. We looked at what distributions would look like vs if we treated a patient with a CT-guided approach where adaptive radiation is not something that is routinely available, and where you can't modify the radiation dose or sculpt the radiation dose out of the bowel. So, what would the differences be if you could adapt with MRI-guided radiation versus if you couldn't, with CT-guided radiation? Also, how would that look in terms of the dose to the tumor, and then the dose to the intestines in the stomach nearby and other organs.

Can you explain the findings from the study?

Not surprisingly, what we found was that the internal anatomy changes on a day-to-day basis. In the vast majority of the treatment days that we looked at, almost 90% of all of the treatment days, across the CT vs the MRI-guided treatment plans, we found a very large number of violations in terms of the dose that would have been delivered to the intestine or the stomach. For example, across most of the treatment days, if we weren't able to adapt the treatment, the doses to the stomach into the intestines would have been exceeding what the safe parameters would have been. If patients were treated with something like that, there would be a very high chance that we would cause major toxicities, like bleeding, ulceration, or perforation, which could potentially lead to death.

Because we were able to adapt the treatment, the doses to those organs ultimately were modified so that they were safe before they were delivered. But with the CT-guided radiation treatment approach, we quantified and demonstrated that those doses would be unsafe, delivered with such a device because you could not adapt treatment with those plans.

There are multiple conclusions to draw from this study. One, the near internal anatomy is always changing, 2, the doses to the organs near the tumor, especially the stomach, and the bowel, would exceed the safe limit,and then, 3 is if you can adapt the treatment, you can get those doses to be within a safe range and still deliver a very high dose to the tumor. We're proud that it’s the first study to do a comprehensive evaluation between these 2 different approaches.

_REFERENCE:

_{Chuong M, Kaiser A, Hall, M, et al. Ablative 5-fraction CT- versus MR-guided pancreatic SBRT: dosimetric effects of interfraction anatomic change. Presented at: 2023 American Society for Therapeutic Radiology and Oncology Annual Meeting; October 1-4; San Diego, CA. 2632}