Track and Treat
By Beth W. Orenstein
Radiology Today
Vol. 23 No. 4 P. 24

New real-time technology aims to make cancer and metastatic disease easier to ablate.

Cancer cells show up as bright spots on PET scans because they have a higher metabolic rate than normal cells. Radiation oncologists can combine PET and CT scans, which show the anatomy of the areas of concern, to treat tumors in cancer patients with external beam radiation. Currently, when a patient has tumors that may be treatable with a linear accelerator, the two scans are performed independently and combined using a computer for treatment planning. But what if PET could be used in real time to enable the external X-ray beam to lock onto the tumors? Wouldn’t the PET scan be able to better guide treatment and allow radiation oncologists to more precisely hit targets that are often moving due to patients’ breathing?

The idea for such a machine came to Sam Mazin, PhD, in 2007. Mazin, who specializes in electrical engineering, was doing work in medical imaging as a Stanford University postdoctoral student and attended a lecture by radiation physics professor Lei Xing, PhD. Xing talked about the difficulties associated with seeing tumors during cancer treatments.

“I am so glad I attended this lecture because it stimulated this idea in me—the concept of marrying PET with radiotherapy,” Mazin says. He is cofounder of RefleXion Medical Inc, based in Hayward, California. Ever since, Mazin and cofounder Akshay Nanduri have worked to bring their RefleXion X1 machine into clinical use.

In December 2021, the FDA granted RefleXion Medical a breakthrough device designation for its biology-guided radiotherapy (BgRT) system for use in treating lung tumors. The FDA’s Breakthrough Devices Program recognizes medical devices that meet certain criteria and hold the potential to provide more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions than what is currently available. Lung cancer is the most common cause of cancer-related death in the United States, according to the American Cancer Society. Additionally, a number of cancers that start elsewhere are likely to spread to the lungs, including breast, bladder, colon, kidney, ovarian, pancreatic, prostate, stomach, and melanoma.

“It’s important to understand where the RefleXion X1 machine fits into the field of radiotherapy,” says Terence Williams, MD, PhD, chair of radiation oncology at City of Hope in Duarte, California. City of Hope is involved in some of the early clinical trials with RefleXion. “Radiation oncology has been using PET for a long time to help define our targets when we plan radiation,” Williams says.

The current use of PET requires performing multiple sets of scans such as a CT simulation and a PET-CT. “Those scans are often done on two different days—sometimes the same day if you can coordinate it with nuclear medicine or radiology colleagues. Then, you fuse the imaging sets together for radiation planning, often after the patient goes home. Once the planning is complete, you bring the patient back for a series of treatments using the linear accelerator.” Conventional PET takes more effort than using CT imaging data alone to find the target, Williams says, “but it does provide more information to help the radiation oncologist devise a better radiation plan.”

The RefleXion X1 is the first system of its kind that enables radiation oncologists to perform PET imaging in real time, Williams says. “With it, PET/CT is married to the linear accelerator.” Mazin says his goal for the machine is to turn tumors into their own biological fiducials. “That’s the novel aspect of it: its ability to turn tumors into their biological beacons so that the machine can sense and track them in real time,” Mazin says.

Advantages of BgRT
The ability to deliver BgRT in real time has multiple advantages. First, it improves precision. Even when patients are fitted with molds and told not to move while the linear accelerator is aimed at their tumors, it is impossible for them to remain perfectly still, and even millimeters can make a difference in determining whether surrounding normal tissue is irradiated during a session. “When targeting tumors of the lungs and the upper abdomen, for example, the patient’s lungs are moving, heart is pumping, and the digestive system is moving,” Williams says. “You have to factor in this motion when doing radiation planning.”

However, with the RefleXion X1, the machine can detect FDG emissions with PET in milliseconds and shoot that radiation back at the target. “That enables us to improve the precision and accuracy of our treatment and enhance the workflow,” Williams says. The system pulls the motion out of the equation. “With this system, it is as if the patients’ tumors are telling the radiation targeting system, ‘Hey, here I am. Come get me,’ and within milliseconds they are targeted with therapeutic doses of radiation.”

BgRT will one day allow for more tumors to be treated in a single session. With current technology, the average single session treats one or two tumors per fraction, Mazin says. When guided by BgRT, treatments may be faster because they happen in real time and are targeted more precisely, so radiation oncologists can attempt to treat more metastatic disease in a session without concerns about delivering too much radiation to adjacent healthy tissue. BgRT is designed to be faster than conventional radiotherapy because “you don’t have to treat one nodule, move the center of the radiation to another spot (the isocenter), and then treat another nodule,” Williams says. “Theoretically, it’s going to speed up our treatment of multiple tumor nodules in the same session.”

Streamlined Treatment
RefleXion X1’s method of tumor detection and guidance helps streamline treatment, says David A. Clump II, MD, PhD, a radiation oncologist at UPMC Hillman Cancer Center, an assistant professor of radiation oncology at the University of Pittsburgh School of Medicine, and the medical director at the Mary Hillman Jennings Radiation Oncology Center, where a RefleXion X1 was installed in February. “It’s a really streamlined, efficient machine,” Clump says. With the new technology, radiation oncologists can treat three lesions in “a reasonable amount of time,” about an hour, Clump says. With BgRT, Clump anticipates being able to eventually treat five targets, and possibly as many as 10 targets, in roughly the same amount of time.

Traditionally, radiation is less likely to be given to those who have been treated with it previously. “The normal organs in the body remember the prior radiation dose, and that can be tricky,” Williams says. With BgRT, it may be possible to deliver more radiation to the same spot, due to better motion management and reduced margins. “It can be done in certain clinical scenarios,” he says. “In addition, if there is no overlap with prior radiation treatment, there is a high likelihood that the radiation oncologists would be able to treat that area again with higher doses of radiation with this system.”

According to Mazin, 600,000 patients die from metastatic disease annually. He believes the RefleXion X1 will unlock radiation therapy for many of these patients whose tumors have spread beyond their origins. “The challenge has been to be able to deliver radiation therapy to multiple sites in the body,” Mazin says. “You have an issue of complexity and of being able to repeat a process that can deliver safe and effective treatments to multiple sites. Current technology is serial in nature, where you go after one target and then go after the next. BgRT will one day be able to logistically treat more than one or two tumors in the body in a reasonable amount of time.”

BgRT gives those with metastatic disease the option of radiation therapy that they may not have had before, Mazin says. “We are starting where current technologies are ending because the potential for a closed feedback system, where not just one but multiple tumors are signaling their location simultaneously, can really solve this scalability problem for metastatic disease.” Clump notes that, because less radiation will be delivered to normal tissue, radiation oncologists will feel more comfortable treating multiple targets at once.

In addition, some research has shown that radiation can help make immunotherapy, which stimulates patients’ own immune systems to fight cancer, work better. “We are beginning to see studies that show radiation may help activate the immune system against the tumor in disease types,” Williams says. If that’s the case, then the new technology, which makes radiation therapy more precise and better able to treat metastatic disease, is potentially more useful, he says.

Mazin does not expect the side effects of BgRT radiation to be any greater than radiation from current technologies, but it is an area that still is being explored. “We believe we are closer to logistical limitations and the ability to safely deliver to multiple sites throughout the body, rather than encountering fundamental biological limitations,” he says.

Some Drawbacks
BgRT does have some disadvantages, however. One is that a bit more time is needed for planning before patients start radiation. “To see the tumor light up, we have to inject the radionuclide and make sure the radiotracer is present in the body for each of the treatments,” Williams says. That means it would not be feasible to treat a patient who needs 30 treatments, for example. “We can’t inject the radiotracer 30 times,” he says. The new technology is best utilized in situations where the number of treatments needed is five or fewer.

RefleXion X1 is not limited to just FDG, and new tracers are being developed which would make it useful for other cancers and biological features of tumors, Williams notes. For example, there are now FDA-approved prostate-specific membrane antigen imaging agents for prostate cancer, and Mazin says RefleXion already has programs underway to onboard these novel tracers. But FDG is a low-cost radiotracer—approximately $150 per dose. Other radiotracers can cost as much as $3,000 to $5,000 per dose. The high cost of some of these radiotracers could be a disadvantage. That’s another reason not to use the technology in patients who need an extended course of radiation sessions, Williams says.

In addition, some tracers have longer half-lives than others. The current half-life of FDG is 110 minutes, so the new technology requires patients to be injected before every session. In the future, Williams says, it may be possible to inject patients on a Monday with other radiotracers that have longer half-lives and bring them back for a second session on a Tuesday, rather than inject them with a radiotracer before the second session.

BgRT guided by FDG is not particularly useful for treating areas of the body such as the brain, which takes up a large amount of glucose and completely lights up on a PET scan. It also isn’t likely to be useful for treating kidneys or the bladder because radiotracers often concentrate in those organs, Williams says.

Making Adjustments
Like any technology, “there will be better applications than others,” Mazin says. “We are anticipating starting clinical studies in the lung. We’ve received breakthrough device designation from the FDA for lung cancer and lung tumors, and that’s significant. It’s not just lung cancer tumors, it’s lung tumors, which means these could be other cancers that metastasized to the lung.”

Learning to use BgRT will require some adjustments. “It’s not going to be as simple as installing a machine that is similar to the one you are currently utilizing,” Clump says. “It has separate planning software. At this point, it doesn’t have its own contouring component, so you will have to utilize traditional planning software within your department, with adaptations for biological guidance. Then it interfaces over to their planning software. The steps and workflow will be different and need adjustments compared to traditional treatment.”

Any radiation oncologist graduating today knows how to perform conventional PET-guided radiotherapy, Williams says; however, this “new technology will require some retraining on the part of radiation oncologists. The planning software is different because you are delivering treatment actively using the PET emission information. Some of the concepts are different too, and there are nuances to learn with BgRT.”

How long a single session lasts could depend on how many tumors are being treated and in which axial planes they lie. “Could we do five targets in 90 minutes?” Mazin asks. “It really depends on where the targets are. If two targets are in the same axial plane, they may be treated simultaneously. But we’re aiming for a state, which we think we’ll achieve relatively soon, where the number of targets is not the limiting factor, but rather the biological limits. We want this to be the first device that will really test the biological limits because we’ve overcome the logistical barriers.”

BgRT is limited by United States law to investigational use. Mazin says the company has completed one clinical study that was required by the FDA to apply for clearance to use BgRT in clinical settings. “We’re going to submit the application to the FDA quite soon,” he says. He can’t say whether or when it might be available because “it is always hard to predict the regulatory process.”

Also, Mazin doesn’t know what the new technology would cost centers. But, “we’ve designed the product so it would work solely with, for example, the economics around an academic center, but it would work with the economics of a community-based practice as well.”

Clump anticipates radiation oncologists would still use traditional diagnostic imaging to complement the planning process. “But the RefleXion X1 will be used to assist with guidance,” he says.

As with current radiotherapy, Clump expects patients to complete their treatment within a month of their initial consultation and have radiation delivered every other day over a two-week period. “It will be similar to what we do now, at least initially,” he says.

– Beth W. Orenstein of Northampton, Pennsylvania, is a freelance medical writer and regular contributor to Radiology Today.