ROCHESTER, Minn. — As Mayo Clinic invests hundreds of millions of dollars into proton beams, the wait continues for decisive evidence that the treatments are superior to existing methods at reducing tissue damage following radiation of tumors.
The lack of highest-level trial data in support of the sophisticated cancer treatments underscores a persistent dichotomy in medicine today, one in which calls to "follow the data" rise alongside projects reflecting the intangible, enduring fascination with technology.
Otherwise known as demand.
Mayo cited the demand for proton beam therapy when it announced plans earlier this month to build a $200-million, 110,000-foot addition to its Robert O. Jacobson Building, a $188 million center launched in 2015.
When it opens in 2025, the expansion will increase capacity for the high-tech treatments on the Rochester campus by 50%, allowing the care of an extra 900 patients annually.
At six rooms, the Jacobson Building will become one of largest proton beam centers in the nation.
It will join a trio of planned or completed proton centers under the Mayo banner, an infrastructure stockpile that includes a $182 million structure in Phoenix, and a $233 million building in Jacksonville, Florida, slated for 2026.
The arsenal will give Mayo more proton resources than those currently held within the entire United Kingdom.
"Extensive research has proven that proton beam therapy is an effective therapy," said radiation department chair Dr. Nadia Laack in a statement earlier this month, "with the fewest side effects for patients with certain types of cancer."
Reached by email, Laack says studying protons with highest level methods known as randomized controlled trials would be like studying the effectiveness of parachutes — that the advantages of the therapy are so strong as to not require controlled study.
"We don’t have, nor will we ever have, a randomized controlled clinical trial to prove the benefit of proton therapy," she says. "It’s akin to offering a parachute to someone jumping out of an airplane ...."
"The average proton plan reduces radiation exposure to healthy tissues by the equivalent of 5 million dental X-rays, 50,000 mammograms, 5,000 chest CTs," Laack says. "To a radiation oncologist or a radiation physicist this is as clear as gravity is to a paratrooper."
It's become a common analogy to describe a medical intervention like a parachute.
Faced with calls for better evidence supporting a costly treatment, the argument is so widely proffered that in 2018 it earned its own rebuttal in the New England Journal of Medicine, a paper titled "Most medical practices are not parachutes."
It reported that nothing in medicine comes close to the effect size, in terms of benefits, of parachutes.
Are protons like parachutes? At $803 million in combined outlays by the nonprofit, Mayo has made a generational buy-in that the answer is yes, randomized evidence or not.
A silver bullet
Proton treatments act as the metaphorical silver bullet of lore, putative smart weapons capable of emptying their radioactive payload into a tumor before exiting the body, with the result being a sparing of radiation to nearby organs.
The treatments do not claim to kill tumors any better than conventional radiation, just that they protect neighboring tissues better, presumably to an extent that can be recorded or is appreciable to patients.
The question is whether the final part of that promise can be demonstrated through research that is carefully controlled.
A scientific consensus has designated protons to be advantageous for certain rare pediatric cancers of the brain and spine, reducing the risk of decades-delayed cancers in children.
But the treatments are predominantly used outside of pediatrics, for the higher-volume conditions including tumors of the breast, prostate, lung and esophageal region.
In these malignancies, the superiority of protons is contested through arguments that while protons reduce tissue damage, so do refinements in conventional radiation.
"With IMRT (intensity modulated radiation therapy) and other advanced techniques, this clearly reduces the exposure of normal organs (to radiation)," said Temple University cancer specialist Dr. Martin Edelman at a 2018 academic meeting.
"The problem is, the only evidence (for proton therapy) we have to date ... from a controlled trial comparing protons to photons ... at the end of the day, the outcomes were no better."
At the heart of the dispute is a lack of scientific evidence known as RCT, or randomized controlled trial data.
Though it is flawed in ways that remain underexplored, RCT data is widely considered the so-called "gold standard" within the medical literature due its ability to reduce researcher bias.
A controlled trial can separate what's plausible in medicine from what actually happens with a new treatment. With protons, the results to that question are often surprising.
In late 2019, a University of Pennsylvania and Johns Hopkins study of protons after prostate removal concluded there was no benefit to the patient over older methods like photons. An accompanying editorial depicted the enthusiasm over proton therapy for prostate cancer as "idolatry."
In a broader look at the question, a 2019 paper from the Institute of Cancer Research in London found that only eight of 219 studies of protons had been controlled trials, and that only one had compared it with older methods. That was a study of patients with lung cancer, the one cited by Edelman, and it found no benefit to protons over photons.
The UK researchers found the vast majority of proton studies were neither large, collaborative or carefully reported, and that half of the trials failed to declare a so-called "primary endpoint," a step considered essential in order to remove researcher bias.
"Our findings show that there is very limited level 1 evidence for the use of proton beam therapy," the authors concluded, "despite the steady increase of treatment uptake, across various tumor (locations) between 1979 and 2018."
"There is no question the reduction of radiation to healthy tissues is in society’s best interest," Laack says of the review, adding that the FDA approval process for proton therapy effectively bypassed a stage for RCT evidence. "As such, multiple countries with national health care systems ....have invested in proton facilities."
Mayo: cost of trials is factor
With a 10-year investment in protons totaling almost a billion dollars, Mayo says the production of randomized trials on protons has been limited by cost
"RCTs are very expensive," Laack says.
"For most new therapies, these are supported by pharmaceutical companies that are involved in developing the drug ... there are many possible cancers and indications and not enough vendors to fund all the possible trials that could demonstrate the value of protons for our patients."
Mayo researchers have contributed to more than 300 papers on the treatments, according to Laack. She says 12 of those papers are randomized controlled trials, but that they are concerned with which patients benefit most from protons, rather than whether protons are superior to photons.
Mayo currently has 10,459 patients enrolled in a registry that would allow comparisons of proton therapy patients to photon therapy, but that effort is not randomized. One reason is that it isn't easy to get cancer patients to accept randomization, Laack says, and the patient count is small enough to begin with.
Calling it "a chicken and egg" situation, Laack says the medical community will have to build more proton centers in order to get enough patients to one day study if the treatments have the highest level of evidence.
"We need more proton centers and more access to protons," she says, "if we are going to be able to run randomized clinical trials in a reasonable timeframe."
As the clinic moves more of its chips on the board in favor of protons, in other words, an answer to when the technology will demonstrate superiority according to the highest level research will have to wait.
In the meantime, Mayo is one of just a few medical centers in the country to have decided not to charge extra for the proton treatments.