U.S. Proton Therapy: Boom or Bust?
Proton therapy may be the cancer treatment of the future, but is it logistically practical in its current state?
When compared to conventional radiation therapy, which uses X-rays to irradiate tumors, proton therapy sounds incredibly promising. The favorable physics of proton beams allows for better control of where they deposit their energy, meaning cancer cells can be better targeted while surrounding healthy tissue is spared to a significantly greater degree. In theory, this could lead to longer survival, less toxicity, a lower risk of secondary tumors, and an increased quality of life as a result.
However, proton therapy in practice isn’t nearly as simple. The treatment approach has been mired in high facilities costs, a lack of randomized clinical trial evidence and a high rate of coverage denial by insurance companies. Yet many proponents still believe in the promise of protons, and despite their hefty price tag, the number of facilities in the U.S. keeps growing. Will the reality of proton therapy finally start to meet expectations?
A crash course in proton therapy
Harvard physicist Robert R. Wilson first recognized the potential of protons for cancer treatment in 1946. Less than a decade later, the first patient received proton therapy at the University of California, Berkeley with particles accelerated using a synchrocyclotron. This modified cyclotron could achieve greater proton energies by varying the frequency of the alternating electric field to compensate for relativistic effects as the particles approached the speed of light.
In conventional photon radiation therapy, a beam of X-rays passes straight through a person without stopping, which makes it difficult to deliver a curative dose without harming normal tissue along the way. Protons, on the other hand, slow down as they penetrate matter until their energy is depleted, and then they come to an abrupt stop. The unique depth-dose characteristics of protons mean they deposit their energy over a narrow range, and therefore can be tailored to precisely target the tumor, so that the surrounding healthy tissues and organs receive less radiation.
Due to its ability to limit unnecessary radiation exposure, proton therapy is considered to be the suitable treatment especially for cancers in children, since children are particularly susceptible to the late adverse effects of radiation. Proton therapy is also recommended for cancers arising in the sinonasal cavity and the base of skull to minimize damage to the nearby brainstem and optic structures. The technique also shows promise for brain tumors, esophageal cancer and breast cancer.
The price tag of making protons
Despite the physical properties of protons that indicate many more could benefit from the approach, fewer than 1 percent of people worldwide who are undergoing radiotherapy for cancer today are being treated with protons and heavier ions like carbon. The proportion of people receiving radiation from high-energy protons is increasing as more facilities open, but it still remains dwarfed by the number of people who receive conventional photon radiotherapy.
“Right now, we treat something like 15,000 patients per year with proton therapy, and that can be compared with 10 million patients treated with radiation therapy worldwide,” said Thomas Bortfeld, professor of radiation oncology and chief of the physics division at Massachusetts General Hospital. “That means only 0.1 percent of patients who receive radiation therapy receive protons as part of their treatment.”
The biggest hurdle? Cost. The price of building a proton center with a large particle accelerator and three or four treatment rooms hovers close to $150 to $200 million. Cost per treatment remains two to three times higher than that of conventional therapy with X-rays, and insurance companies often deny coverage. Most hospitals around the world don't offer proton therapy because they simply can't afford to build the equipment.
Due to its prohibitively expensive price tag, the first hospital-based proton therapy facility didn’t open until 1990 -- 35 years after Wilson’s discovery -- at the Loma Linda University Medical Center in California. Another decade would go by before more hospitals in the U.S. followed suit, such as Massachusetts General Hospital in Boston, the University of Texas MD Anderson Cancer Center in Houston, and the University of Florida Health in Jacksonville, which all installed proton therapy equipment in the early to mid-2000s.
The University of Florida Health Proton Therapy Institute -- the fifth proton therapy facility to open in the U.S. -- has treated more than 7,500 patients to date. The 98,000-square-foot center located in Jacksonville, Florida, was built with an initial investment of $125 million and recently announced a three-year, $39 million expansion project. It will add a 10,000-square-foot single room treatment system with a new particle accelerator and also upgrade the current equipment.
“MD Anderson started to build its proton therapy facility in 2003, and all of a sudden, there was a huge interest in building more facilities,” said Radhe Mohan, professor of radiation physics at the University of Texas MD Anderson Cancer Center.
Some centers experienced logistic hardships, such as construction delays, or they simply struggled to make a profit. In 2014, the Indiana University Proton Therapy Center in Bloomington closed down, and last year, the Scripps Proton Therapy Center in San Diego filed for bankruptcy only three years after opening.
“From my perspective, these are complicated facilities to operate, and you really do need a level of expertise above a traditional radiation therapy facility,” said Stuart Klein, executive director of the University of Florida Health Proton Therapy Institute. “There has been a tremendous amount of growth in proton therapy centers over time, and I think there are some players who got into the market that shouldn’t have. These facilities should be regional resources -- as in, there shouldn’t be one of these on every corner.”
Mohan believes that investors and institutions may have put the cart before the horse, and the field of proton therapy is fighting with the consequences as a result. Huge, expensive facilities were built before grasping the full complexity of proton therapy, he said, and the high cost of opening and running these facilities may have constrained the research and development necessary to maximize the clinical effectiveness of proton therapy.
Nevertheless, many experts including Mohan still believe in proton therapy and its many possibilities for cancer treatment. The hope is that the necessary clinical evidence supporting proton therapy for more indications will emerge in the near future so that insurance coverage improves, and then more people in need of treatment can have access to its benefits.
“I’m a huge proponent of protons, and I’m criticizing the way they are being used and not their potential,” said Mohan. “Our health care system drives us, and if you are going to build a $150 million facility, you need to recoup that. But still, I believe the most important thing is that we improve proton therapy to show its true clinical advantage.”
The next obstacle
Another major hurdle in the progression and adoption of the technology has been the lack of insurance coverage in the U.S. In 2012, a study of men with localized prostate cancer found that proton therapy didn't provide any additional benefit over intensity-modulated radiation therapy (IMRT) in terms of morbidity or receipt of additional cancer therapy. Given the high cost of treatment, insurers started to deny routine coverage.
“It has always been difficult to get paid by insurance companies for proton therapy, and in the last three or four years, it has gotten even harder,” said Klein. “There’s a lot of pushback considering the expense involved, and so I think a lot of effort is now being put into proving the efficacy of the treatment and the rationale of the investment into these facilities.”
Even for pediatric cancers, for which proton therapy is well-established, insurance companies will sometimes initially deny coverage. A 2017 study from the Roberts Proton Therapy Center at the University of Pennsylvania noted that 32 out of 287 proton therapy cases were initially denied. While 97 percent of those denials were overturned on appeal, not all families know that exists as an option, and appeals can take considerable time and effort. In 28 percent of cases, it took multiple rounds of appeal before coverage was finally approved.
The high frequency of insurance denial deters people from participating in clinical trials to prove efficacy -- the same trials that insurers say they require in order to approve coverage. For instance, up to 30 percent of eligible patients could not participate in a randomized, phase 3 clinical trial of proton therapy versus IMRT for prostate cancer due to denial of coverage. Although several studies to assess the technique are ongoing, the majority of clinical evidence supporting proton therapy still comes from early stage, nonrandomized trials.
While Medicare doesn’t have a national coverage policy for proton therapy, it is generally covered with a few limitations. A 2012 study reported that the median Medicare reimbursement for proton therapy for prostate cancer is $32,428 as compared to $18,575 for IMRT.
“We were being told early on that protons are so much better than photons, and we should not question their ability to produce better results. But we should have built a few facilities to experiment, evaluate and learn before building close to 30 facilities in the country,” Mohan said. “Unless we can show that the results are promising, insurance companies are not going to be paying, and facilities are not going to succeed.”
Future is getting brighter with protons
Despite all its obstacles, proton therapy as a treatment option continues to expand as new facilities continue to be built. The number of facilities in the U.S. has tripled in the past five years, bringing the total number of treatment centers to 27 nationwide. Ten more are currently under construction at institutions like Oklahoma University in Oklahoma City and Emory University in Atlanta.
A few years ago, Klein had to shift gears in terms of the patient population served by the facility. UF Health Proton Therapy Institute, like many other facilities, started out by mostly treating men with prostate cancer. Klein and his colleagues made a deliberate effort to treat other types of cancer, such as head and neck, brain, breast and sarcomas. Today, the institute is also the largest provider of pediatric proton therapy in the world.
While the institute's existing cyclotron accelerator feeds four treatment rooms, the expansion project will involve the construction of a single treatment room with its own smaller but dedicated accelerator -- a growing trend to bring down upfront costs.
“In the past, we had these football field-sized, multiroom facilities that would consist of three or four treatment rooms with a total price tag of over $100 million,” said Thomas Bortfeld. “With single-room facilities, even though the cost per treatment room is still $30 million, the jump from $5 to 10 million for a conventional radiation therapy treatment room to $30 million for proton therapy is perhaps more digestible for a smaller clinic.”
Bortfeld believes that the key to greater proton therapy accessibility for those patients who could benefit is making facilities smaller and cheaper with costs comparable to high-end X-ray systems. One way to save money is to replace existing, outdated linear accelerators used for conventional radiotherapy with proton therapy systems. For instance, Bortfeld and his colleagues at the Francis H. Burr Proton Therapy Center at Massachusetts General Hospital have recently converted two conventional treatment rooms into a single proton therapy area for $30 million. They will begin treating patients with this new miniaturized system in September.
However, $30 million is still about five times more than a top-end X-ray unit. The cost and size of accelerators for proton therapy have come down over the years, but the same hasn't happened for gantries -- the device that rotates the radiation delivery apparatus around the person undergoing treatment. Without technological improvements to bring the overall price tag down further, Bortfeld said, proton therapy could ultimately hit a ceiling in terms of growth.
There also need to be more studies that can prove the cost-effectiveness of the approach, according to Mohan -- an issue that has been under considerable debate over the last decade and a half due to the lack of patient data. Even proponents of proton therapy argue that this type of clear-cut evidence from randomized clinical trials is still needed to demonstrate its edge over conventional radiation therapy.
“Once we started using protons, there were some good results, but there has been no clear and obvious convincing advantage that could be overwhelmingly convincing,” said Mohan. “In theory, protons do have a clinical advantage -- we just have not adequately learned how to exploit it fully yet.”