Upon Further RefleXion

The RefleXion X1 radiation treatment platform is the first to integrate PET/CT imaging with a medical linear accelerator. Using a PET signal identifying the tumor while also depicting its biology, RefleXion treats patients with unique biology-guided radiotherapy (BgRT). The UT Southwestern Department of Radiation Oncology is one of a handful of centers worldwide with this treatment capability.

BGRT technology delivers treatment capabilities that greatly complement existing treatment platforms in the department. Other treatment machines in the department, such as the Ethos (CT-based adaptive), Unity (MR-based adaptive), and other new adaptive treatment modalities, can image patients and utilize their anatomy to modify the treatment delivered on a specific day. MR also supplies some biological information about the tumor status. But in addition to measuring the tumor biological response, RefleXion can track tumor motion without any beacons or fiducial markers in real time, with tracking based on the signal from the tumor itself. It basically “reflects” the signal and shoots right back at the tumor with tumoricidal photons, allowing for a highly accurate and efficient treatment.

“It’s like the tumor lights its own tail on fire, allowing the system to keep track of its position for beam guidance at any moment,” says Bin Cai, Ph.D., Associate Professor of Radiation Oncology and Director of Advanced Physics Service. “So, this machine not only gives you biological response information about the ongoing success of therapy but also utilizes this same biological signal to drive the delivery with tracking.”

In 2021, Aurelie Garant, M.D., Associate Professor of Radiation Oncology and Director of the Brachytherapy Program, led an Investigational Device Exemption (IDE) trial to get the RefleXion technology approved by the Food and Drug Administration (FDA). The components of the trial included measuring the imaging accuracy of various aspects of the machine and verifying that it was safe to administer multiple administrations of intravenous radioisotopes, specifically a sugar-based isotope called F18 FDG.

The department aimed to ensure that with this technology the PET scan signal would not fade to the point where the tumor could not be detected at the end of radiotherapy. The trial ultimately led to FDA approval for RefleXion to treat FDG-guided therapy in the lung and bone, with other disease sites to follow. In combination with the hybrid technology, the trial highlighted a great collaboration between industry partners – the FDA and two large academic centers (UT Southwestern and Stanford University) – Dr. Garant says.

“When we first sat down and met with the FDA, we were asked to meet several standards of all three types of technologies, and it took a lot of people, especially at UT Southwestern, to succeed at this important task in a reasonable timeframe,” Dr. Garant recalls. “Fortunately, we found the way to accrue quickly to the trial and make this machine accessible to patients.”

Other notable contributors to the trial included UT Southwestern’s Orhan Oz, M.D., Ph.D., Professor of Radiology and Chief of the Nuclear Medicine Division; Tu Dan, M.D., Assistant Professor of Radiation Oncology; and Arnold Pompos, Ph.D., Professor of Radiation Oncology and Associate Vice Chair of Strategic Initiatives and Capital Investments.

PET scans are mostly performed with FDGs – sugar analogs – but they can also track other things related to metabolism or biomarkers, such as locations with low oxygen concentration or PSMA for prostate cancer. Another example is a PET tracer developed by Xiankai Sun, Ph.D., Professor of Radiology and Director of UT Southwestern’s Cyclotron and Radiochemistry Program, that targets PD-L1 expression within tissues, allowing improved immunotherapy personalization.

This is important for the Department of Radiation Oncology’s direction of personalized ultrafractionated stereotactic adaptive radiotherapy (PULSAR®), according to Robert Timmerman, M.D., Chair and Professor of Radiation Oncology. If functional aspects of tumors or the tumor microenvironment can be detected, this provides another way to assess the tumor’s biology and predict how each patient is responding, ultimately allowing personalization. Most currently used cancer therapy delivers an entire course without interruption, followed months later by an assessment of success or failure. With RefleXion, the therapy can be administered in real time, de-escalating treatment for those responding and intensifying for those with resistant tumors.

“We are trying to move into more biologically oriented therapy, which is the key to the personalization of therapy that is in our mission statement,” Dr. Timmerman says. “Biology changes not only with just time and evolution of the tumor, but if you perturb it by treatment such as a big dose of radiation, the biology is going to change more markedly, and you want to measure that change to see if it was good or bad. That’s why RefleXion is a tool well-suited for this novel strategy.”

In the past, tumor movement was dealt with by using a “motion envelope” larger than the tumor itself, where the tumor never strayed beyond. But this extra volume is made of normal tissues possibly injured by the potent treatment intended for the tumor. PET tracers move according to the movement of tumors and tissues they penetrate. There is hope that RefleXion will be able to overcome tumor motion and identify tumors that were undetectable by other imaging. This brings the potential to treat multiple tumors that move either unusually or often, thereby expanding radiotherapy indications.

The RefleXion offers another strategy for personalizing each patient’s therapy: It has great potential for providing a choice of the PET tracer to steer toward unseen tumors or tumors with unknown characteristics and changing therapy by intensifying, deintensifying, or dose painting. For example, FDG could potentially give a higher dose in the highest consumption of glucose, which would most likely be the most proliferative part of the tumor and could be located on a specific side of the tumor.

The hope is for the department to gain experience using this method with bone and lung indicators and to eventually expand to other sites of the body and find additional tracers that can give information not given from FDG, such as PSMA and hypoxia markers. There is also excitement for its potential as an adaptive machine.

“We think this machine could eventually be a really useful surrogate for guiding adaptation,” Dr. Timmerman says. “For example, if the FDG is high in the first treatment but is low by the second treatment, we might be justified in lowering the dose for the second treatment. Investments in platforms such as RefleXion show our commitment to end the common one-size-fits-all therapies used for cancer.”