Back in 2013, toxicologist Edward Calabrese and a colleague at the University of Massachusetts, Amherst, were combing over a cache of century-old data on low-dose radiation therapy, hunting for evidence on the scientific idea that small doses of certain poisons might actually be beneficial. They found small amounts of radiation were surprisingly successful in combating pneumonia. Again and again, doctors reported symptoms subsided within hours of a single X-ray.
Hardly anyone took notice. Calabrese’s ideas had sometimes been brushed off by his peers as too out-there, and the idea of low-dose radiation as therapy had long been dismissed in favor of more modern treatments. The paper only gained a smattering of citations.
That all changed when Covid-19 snowballed into a crisis, fueling fresh interest in anything that might ease the devastating cases of pneumonia in some patients. At least 52,000 of the more than 135,000 deaths due to Covid-19 in the U.S. have involved pneumonia, according to federal health data.
“Back in February, I started getting just dozens and dozens and dozens of emails from radiation oncologists —people who treat cancer patients with targeted radiation. And they had come across our paper and they thought that this might be a vehicle by which they could help suffering and dying Covid patients perhaps survive,” he said. “Clinical trials are now going on across the country.”
There are at least a dozen trials worldwide testing low-dose radiation therapy, or LDRT, as a treatment for pneumonia related to Covid-19, some spurred by the same historical data Calabrese and colleagues scoured years ago. The theory: Targeted radiation to the lungs will halt the out-of-control inflammation responsible for the devastating pneumonia that bookends the course of some Covid-19 patients.
But the revived interest in radiotherapy has sparked a debate among physicians and researchers, who are divided on whether the idea is even ready for test-driving in clinical trials. With little known about the way LDRT works on inflamed lungs, some experts say it might exacerbate respiratory damage, while introducing the additional risk of cancer. Others say patients participating in the trials may suffer by missing out on more promising treatments.
On the other side, though, are experts who say there’s a clear and urgent need for Covid-19 treatments that work, particularly for cases that become severe. Antibiotics can help treat cases of pneumonia from bacterial infections, but not those caused by viruses. Those experts argue compelling historical data gives LDRT a promising head start.
“It seems to be such an almost emotional topic,” said Dörthe Schaue, a radiation oncologist at UCLA, on the debate raging over LDRT. “You get two extremes on the spectrum and the truth is probably somewhere in the middle, where you have to consider all the pluses and minuses.”
The new wave of low-dose radiation trials are registered at academic centers and hospitals around the world, including in Italy, Spain, Iran, India, and the U.S. The studies are recruiting anywhere from five to 106 Covid-19 patients with pneumonia, and half require participants to be at least 40 years of age.
Arnab Chakravarti, chair of Ohio State’s radiation and oncology department, is spearheading two of the four LDRT trials in the U.S. The first trial, PREVENT, will enroll around 100 oxygen-dependent Covid-19 patients at up to 20 hospitals around the country. The second trial, VENTED, is limited to Ohio State, where it will recruit 24 critically-ill patients who require ventilator support. Unlike PREVENT, VENTED is open to participants as young as 18.
Chakravarti hypothesizes that LDRT will tamp down the unchecked inflammation that ultimately overwhelms the lungs of some Covid-19 patients. In these individuals, immune cells overreact to the virus and secrete a dangerous excess of proinflammatory cytokines, known as a “cytokine storm.”
“The severe illness and death that we see from Covid-19 pneumonia appear to be mostly due to the inflammatory response to the infection in the lung tissues,” said radiation oncologist David Kozono, who is launching a LDRT trial at Brigham and Women’s Hospital. “The idea is that low-dose lung radiation has the potential to reduce this inflammatory response.”
Some experts have theorized that small amounts of radiation might flip a switch on these immune cells so that they release soothing, anti-inflammatory cytokines instead, though this is just one among many proposed mechanisms.
“The history of the utilization of ultra-low-dose radiation for viral pneumonia actually dates back to the 1920s and ’30s and ’40s — just post the Spanish flu pandemic in 1918,” Chakravarti noted. He said literature from that era indicates that LDRT was effective in 75 to 90% of influenza-induced viral pneumonia cases, though the therapy “fell out of favor” after the development of antiviral therapies and vaccines.
Beyond historical data, Chakravarti said that his hypothesis is staked in recent evidence from an interim analysis of a clinical trial at Emory testing low-dose radiation in ten patients with Covid-19. All of the first five patients, averaging 90 years of age, were alive two weeks after treatment, and researchers reported three patients were weaned off oxygen within 24 hours of receiving radiation.
“So there is now accumulating data to support this type of approach not just in the setting of influenza viral pneumonia, but also in the setting of specifically Covid-19 based on the small but very promising study from Emory University,” he said.
The Emory researchers published updated data this month from 10 patients — including the initial five in the first study — in preprint paper, which found that LDRT was associated with a reduction in clinical recovery time from 12 to three days. A single patient died, while another suffered gastrointestinal acute toxicity. They are now recruiting for a 52-person trial.
Kozono, the Brigham and Women’s researcher, said the initial data from Emory was part of the reason they pushed to launch their own trial.
But not all radiation experts are convinced that findings from such a small study are worth running with just yet.
“It’s not thought-out. It’s not of value. I don’t take anything from these cases.”
Ralph Weichselbaum, radiation oncologist, UChicago Medicine
“No one’s going to be able to tell if it worked or not, unless it’s a huge trial. By that time there will be some other treatment like steroids, which is a lot less dangerous and makes a lot more sense and is a lot more scientifically based,” said Ralph Weichselbaum, a radiation oncologist at UChicago Medicine, referring to the initial five-person study. “It’s not thought-out. It’s not of value. I don’t take anything from these cases.”
A number of experts, incuding Weischselbaum and colleagues from Duke, Stanford, and the University of Nevada, Las Vegas, wrote a letter about LDRT recently in the Journal of Radiotherapy and Oncology, describing the risks of the treatment as “unacceptable” for future clinical trials — especially in the absence of clinical or preclinical evidence that meets today’s experimental standards.
But Mohammad Khan, a radiation oncologist leading the Emory trial, pushed back on those criticisms, citing another small study that supports the findings and arguing that Emory’s trial started out small to demonstrate safety and look for early signs of efficacy.
The idea, too, has won the backing of Calabrese and Gaurav Dhawan, the collaborator on the 2013 study. They and other experts penned a paper in May supporting the idea of testing LDRT to fight Covid-19, with caveats.
“Certainly, we do not endorse the use of RT for all COVID-19 patients; but we do offer its consideration for those patients who are most critical, and for whom other treatments options are unsuccessful or unavailable,” they wrote.
But with limited understanding of how LDRT interacts with the systemic inflammation seen in Covid-19, Weichselbaum said it’s possible that the therapy could put patients at risk of greater harm.
“Everything I know about pulmonary effects of radiation would make something like this worse, not better,” he said. In their paper, Weichselbaum and his colleagues also expressed concern that radiation could kill the immune cells that the body deploys to fight Covid-19, rendering it more susceptible to attack.
That and other risks make LDRT a “double-edged sword,” according to Fatemeh Ghahremani and Amirhosein Kefayat, physicians in Iran who authored a letter cautioning colleagues against conducting further clinical trials before learning more about its effects. They warned that radiation therapy has actually been demonstrated in some studies to increase the activation, transcription, and spread of some viruses — which could prove harmful for patients with Covid-19.
There is research to suggest LDRT can combat the hallmark inflammation in people with arthritis. But Ghahremani and Kefayat said the treatment’s success in managing local inflammation doesn’t mean it will be able to beat back the extensive, systemic inflammation that ravages the lungs of some Covid patients.
“Therefore, there is a high probability that the anti-inflammatory effect of LDRT may not be enough for inhibiting the Covid-19 cytokine storm,” they said in an email to STAT.
Experts said there are also still a number of unanswered questions about the cytokine storm itself. Among them: Why do only some patients experience it, and what role might age, gender, genetics, and weight play?
“In my mind, we don’t really know what we’re dealing with,” said Schaue, the UCLA radiation oncologist.
Schaue said there’s a need for carefully designed clinical trials that scrupulously record data about cytokine storms and the biological mechanisms at play. Other experts said so much is unknown that researchers launching clinical trials of LDRT for Covid-19 should pause their projects and conduct more animal testing first.
“In [our] opinion, the most ethical thing to do and conservative thing to do would have been to do this in some non human primates first,” Weichselbaum said.
Weichselbaum has another big ethical concern: Patients enrolled in radiation trials are being denied drugs “that might actually work in the long run.” With more than 1,200 clinical trials related to Covid-19 registered worldwide since January — and a limited number of eligible patients who live close enough to study centers to participate — researchers might have to compete for participants. The worry is that recruitment for a LDRT trial might snatch a patient away from a drug trial that is safer or more promising.
Kozono argued, however, that LDRT could prove faster-acting than the treatments currently being used, including the antiviral drug remdesivir.
There’s also concern among some experts that LDRT might increase a patient’s risk of cancer. Kozono said that of all the possible risks of radiation, cancer was his chief concern as he prepared to enroll nearly 50 patients in his clinical trial. Still, he said the study will use such a low dose of radiation that the risk of cancer remains low, particularly when compared to the risks of a severe case of Covid-19.
“When one thinks about this being relatively low risk — one in 10,000 chance [of cancer] per year — compared to the very immediate life threatening consequences that this infection can pose, it may be a reasonable treatment to offer to the sort of patients we are aiming to help — people who are hospitalized, who need to be on oxygen or on ventilators because of pneumonia from this virus,” he said.
Kozono added his study will include an extra cohort of patients who will receive LDRT in just one lung.
“Our idea is that radiation to one lung might be enough to help the patient breathe, while cutting the exposure to radiation effectively in half,” he said. He added that leaving one lung untreated might also allow the body to straddle the fine line between running a robust immune response and getting overwhelmed by inflammation.
In addition to the question of whether to treat one or both lungs, UCLA radiation oncologist William McBride said it is unclear when in the disease course physicians should administer LDRT.
“It’s quite a complex disease. You don’t really know when to give the radiation,” he said.
With so much still not known, McBride and other experts warn it is premature to champion LDRT over drugs currently in trial.
“It’s not that low-dose radiation won’t work. I think it has a reasonable chance at the moment,” he said. But, he emphasized, it has to be done thoughtfully.
“It’s not a slam dunk kind of therapy because of all these unknowns, and the speed with which the disease changes in the patient,” he added. “As a result, it’s quite hard to run a very tight clinical trial on itself and you need an awful lot of patients to prove it.”