Proton Beam Therapy: 3 Decades After Approval, Still Unanswered Questions About Where It Fits In

When a new medical technology comes along, it ushers in hope that treatment of a disease will improve and that patients will enjoy better health and longer lives. But the march of progress isn’t so sunny and simple these days. New technology also leaves in its wake nettlesome issues such as added cost and whether that cost is worth the benefit, insurance coverage and comparisons with existing technology. Proton beam radiation therapy as a cancer treatment isn’t new at all; the FDA approved it more than 30 years ago. But partly because it involves such a large capital expense, it is still dogged by issues that new technology stirs up. Insurers are being sued for not covering the therapy, and some facilities have struggled financially for lack of patients. A 2018 study of prior authorization for proton beam therapy found that 64% of patients were initially denied coverage and 32% denied after an appeal. Enrollment in clinical trials has often moved at a snail’s pace, partly because many potential participants elect not to participate because the proton beam therapy isn’t covered by their health plan.

Proponents of proton beam radiation therapy can point to some recent developments that put the technology’s situation in a more positive light. Researchers from The University of Texas MD Anderson Cancer Center in Houston reported results last year in the Journal of Clinical Oncology that showed the toxicity burden — a weighted sum of the side effects — among 145
patients with esophageal cancer was less for those treated with proton beam therapy than those treated with conventional photon therapy. An accompanying editorial noted that this was the first trial to report a positive primary end point for proton beam radiation in a head-to-head trial with conventional photon radiation. Facilities now are being designed so the investment can be in the tens of millions of dollars rather than more than $100 million.

Meanwhile, the Patient-Centered Outcomes Research Institute (PCORI), the nonprofit healthcare research organization funded by fees on insurers, is sponsoring the kind of proton-versus-photon randomized trials that may go a long way toward answering questions about proton beam therapy (although not necessarily in proton beam therapy’s favor). The COMPPARE study of localized prostate cancer and the RadComp study of breast cancer are recruiting patients. The RadComp trial, which has a target enrollment of 1,278, had enrolled 960 patients as of late March, according to Justin E. Bekelman, M.D., the principal investigator and a professor of radiation oncology at the University of Pennsylvania’s Perelman School of Medicine.

Photon versus proton

Radiation therapy damages the DNA of cancer cells so they can’t divide and proliferate. Radiation treatment is effective partly because the DNA of cancer cells is more susceptible to radiation’s effects. And radiation has been part of cancer treatment for more than a century.

Radiation is now increasingly used along with surgery and chemotherapy. A combined approach can increase the chances of preserving the part of the body that has been affected by cancer. For example, lumpectomies to treat breast cancer usually involve radiation treatment after the surgery.

Conventional radiation therapy uses photons, commonly known as X-rays, to damage the DNA of cancer. Photons penetrate tissue easily and therefore can reach internal organs. Proton beam radiation therapy, as the name suggests, uses protons instead of photons. Protons are the large, positively charged part of an atom’s nucleus.

Radiation therapy that uses photons has become increasingly precise. Intensity-modulated radiation therapy depends on computers to calibrate the radiation so it follows the shape of the tumor and limits the exposure of normal, healthy tissue. Even so, the penetrating power of photons means some of the radiation passes through the tumor. The chief selling point for proton therapy is that it gives off less scatter radiation and that the protons stop at the tumor and don’t exit.

“When we deliver the radiation treatment, we reduce the amount of radiation that goes outside of the target area that you’re treating,” says Curtiland Deville Jr., M.D., medical director of the Johns Hopkins Proton Therapy Center in Washington, D.C. “By doing so, we hopefully reduce the side effects related to the treatment or, alternatively, we can deliver more radiation dose to that target because there’s less dose going into the surrounding tissues.” Deville says proton therapy is an important radiation oncology tool for a comprehensive cancer program, particularly when it comes to pediatric cancer.

Gopal K. Bajaj, M.D., MBA, chair and medical director at Inova Schar Cancer Institute in Northern Virginia, says his health system decided to adopt proton therapy partly because it would help the five-hospital Inova system to compete. “When we were in the process of planning a cancer center of the future, we did a deep dive and evaluated the types of technologies that would be present in a cutting-edge, tertiary care, referral-type cancer center,” he says. “Proton therapy rose to the top as a technology that is truly a market differentiator that patients seek out. It can also serve as a nidus for the growth of other clinical programs.”

Other healthcare systems and hospitals have also heeded the call to build proton beam radiation centers. The National Association for Proton Therapy website lists a total of 38 centers: 34 members, two nonmembers and two members with centers under development — one at the University of Kansas Cancer in Kansas City and the other at the Huntsman Cancer Institute in Salt Lake City.

Proven but proven better?

The adoption of expensive medical technology by individual providers to compete for patients is one of the reasons that U.S. healthcare is the world’s most expensive on a per capita basis. Many experts see proton beam as a classic example of an American-style medical arms race. “There’s real harm in spending money on something that’s not better and is more expensive. That harm is a hospital not investing in something else that could improve its community or improve the health of more patients,” Shannon Brownlee, special adviser to the president of the Lown Institute, wrote in a recent blog post about proton beam therapy. The Lown Institute is a think tank in suburban Boston that researches low-value healthcare.

A 2014 assessment of proton beam therapy by the Institute for Clinical and Economic Review (ICER) was not a ringing endorsement. The Boston-based cost-effectiveness group determined that proton beam therapy was superior to surgery for ocular tumors and a safer treatment than photon radiation for pediatric cancers and brain and spinal tumors. But outside of that handful of conditions, the ICER reviewers found insufficient evidence of added benefit for proton beam therapy and also pointed out that it is usually priced two to three times higher than conventional photon therapy.

Seven years later, the ICER review is becoming dated. Still, many insurers have continued to deem proton beam radiation for many cancers as experimental and therefore not covered, although those denial of coverage decisions are getting challenged in court. Three cancer survivors have filed a class-action lawsuit in federal district court in Boston against UnitedHealthcare for refusing to cover proton beam radiation therapy. A class-action lawsuit also has been filed against Aetna in Florida.

Penn’s Bekelman says that many payers cover proton beam therapy for childhood cancers, chordomas, brain and spinal cord cancers and selected other indications where there is a consensus that it is medically necessary. But he also referenced the continuing debate about its added benefit for the more prevalent cancers, including breast, prostate, gastrointestinal and lung cancers. “Proton therapy is a proven treatment for cancer — there’s no doubt about it. Period,” says Bekelman. “However, what remains undefined is whether it is any better than what we currently use, which is photon-based treatment and, most commonly, intensity modulated radiation therapy. That is the debate. It is a proven treatment, but is it proven as better than what we usually do for the prevalent cancers? The answer is not yet.”

Bekelman says the long-lingering questions about proton beam radiation can be traced back, in part, to the FDA having different standards for approving devices than it does for drugs. In contrast to drugs, most devices are approved and come on the market without being evaluated in randomized clinical trials.

Fewer hospitalizations

Researchers are beginning to fill the void of evidence for proton beam therapy. The RadComp study led by Bekelman and the COMPPARE study of prostate cancer are PCORI “pragmatic trials” designed to answer high priority issues in real-world circumstances. Enrollment for these studies has been going at a decent clip relative to others for proton therapy. RadComp, which started in 2016, is scheduled to enroll its last patient next year, and the COMPPARE trial of prostate cancer, which started in 2018 and has an enrollment goal of 3,000, is scheduled to enroll its last patient in 2023. The RadComp website warns potential study participants that if their insurance doesn’t cover “a specific radiation treatment and you still want to participate, you will be responsible for paying for the radiation treatment you receive.”

Bekelman and others have called on equipment manufacturers to help fund research. “[Although] manufacturers do fund radiation-related research, there remains a gap in engagement across manufacturers, providers, insurers and funders on how to pay for proton therapy treatments as part of large definitive randomized trials of this technology,” he wrote in an email.

The results from the MD Anderson study of patients with esophageal cancer stand out because it was a gold-standard study: a prospective, randomized head-to-head trial. But there are other positive findings for proton beam therapy. Jennifer Maggiore, executive director of the National Association for Proton Therapy, says recent research is showing that proton beam radiation might produce savings in the bigger picture because it produces fewer harmful side effects: “In 2020, several key studies demonstrated the promise of proton therapy in making significant and clinically meaningful reductions in acute toxicity in patients.”

Bekelman is co-author of a retrospective study of 1,483 patients treated at Penn. The study, which was published in JAMA Oncology in 2019, compared 391 patients who were treated with proton radiation with 1,092 treated with conventional photon radiation. Lead author Brian Baumann, M.D., Bekelman and their co-researchers found that the patients treated with proton radiation were far less likely to have severe adverse events associated with unplanned hospitalizations than patients treated with photon radiation (11.5% versus 27.6%). There was a difference, but less of one, when it came to milder adverse events (74.2% of patients treated with proton beam versus 84.8% of patients treated with photon beam). Results from nonrandomized, retrospective studies such as this come with caution signs against overinterpretation and causal inference. Still, Baumann and his colleagues wrote in the conclusion of the study that the results “at least raise the tantalizing possibility” of cost savings from proton radiation despite the higher upfront price. “Value-based models must acknowledge these benefits and opportunities for long-term savings and promote new and innovative ways to treat cancer,” says Maggiore.

Maggiore acknowledges the expense and time it takes to develop a proton beam facility. Manufacturers have responded by developing single-room systems that are more affordable, she says, and insurers have expanded coverage in the past two years in recognition of the short- and long-term savings. But Bajaj at Inova mentions the difficulties of staffing and keeping costs in line. “Because there are a limited number of proton therapy centers in the country, competition is relatively high for a small and highly trained pool of physicians, physicists, therapists and other clinical staff. ”

However, Bajaj says, “if anything, we’ve established through published work over the last decade that there likely is an expanded role of proton therapy in the future of radiation oncology care. I think we’ll continue to see, with clinical evidence development and expansion across disease sites, that increasing numbers of patients will seek it out.”

Keith Loria, a frequent contributor to Managed Healthcare Executive®, is a freelance writer in the Washington, D.C., area.