More than 3 decades after receiving FDA approval, proton beam radiation therapy has failed to find a footing as a go-to treatment for many cancers in the United States.

About three dozen proton therapy facilities are in operation nationwide — fewer than one per state — limiting accessibility in some regions.

Several other factors have limited proton therapy’s adoption, including cost concerns, technological advances in photon therapy, and a lack of comprehensive and comparable data to advance the science. In addition, reimbursement from insurers remains inconsistent.

“It is truly an injustice to the patient when they would benefit from this treatment but cannot get it,” J. Isabelle Choi, MD, clinical director and director of research at New York Proton Center, radiation oncologist at Memorial Sloan Kettering Cancer Center and chair of National Association for Proton Therapy’s physician advisory committee, told HemOnc Today. “It is up to all of us to come together, do the homework, do the legwork and continue to move things forward to improve access.”

Choi and other proponents of proton therapy are optimistic that larger studies underway or planned in breast cancer, liver cancer and other common malignancies could lead health insurers to expand coverage of this modality. In addition, more proton therapy centers are expected to open across the U.S. in the next 10 years, all of which could result in a substantial increase in research uptake.

“We have made a lot of progress over the last decade and even in the last few years,” Choi said. “Hopefully, with all of us coming together, we can keep improving the landscape for our patients who would stand to benefit.”

HemOnc Today spoke with radiation oncologists about the state of proton therapy, why access remains limited for many Americans, the potentially pivotal research underway, and how and when the landscape could change.

A ‘striking’ difference

The absence of proton therapy centers in many Midwestern states runs in contrast to what, judging from imaging data, may look like a clear-cut advantage compared with photon therapy.

For instance, imaging from a study by Baumann and colleagues published in JAMA Oncology showed the targeted area proton radiation touches in head and neck cancers, compared with the wider swath of radiation when a patient is treated with photons.

“It is quite striking,” Choi said of this and other such comparisons, with proton therapy better protecting normal tissues from unnecessary radiation. “Pictures speak a thousand words, especially in this scenario.”

One of the main differences between protons and photons is the former does not have an exit dose, so it does not deliver unnecessary radiation to organs on the other side of the tumor.

“Even though we have had dramatic advances in the technology of photon radiation over the last 10 to 15 years, the dose is still scattered throughout the area being treated, and that is almost unavoidable in a lot of these cases,” Timothy P. Kegelman, MD, PhD, chief resident in the department of radiation oncology at Perelman School of Medicine at the University of Pennsylvania, told HemOnc Today.

One of proton therapy’s most common uses is in pediatric cancer care. Children benefit most because their tissues are still developing and, thus, they are at greater risk for deformity or second cancers due to radiation.

Proton therapy also is used to treat some tumors in the brain, spine, liver, head and neck, as well as for patients who have a recurrence after prior radiation treatment, according to Ronald C. Chen, MD, MPH, FASCO, FASTRO, Joe and Jean Brandmeyer endowed chair and professor in the department of radiation oncology and associate director of health equity at University of Kansas Cancer Center.

The therapy has demonstrated safety benefits when used to treat tumors near critical organs, such as the heart.

Data presented by Kegelman and colleagues at last year’s American Society for Radiation Oncology Annual Meeting showed proton therapy could reduce risk for radiation-induced heart diseases compared with conventional photon therapy. In a retrospective trial of more than 200 patients, they found mini-strokes were significantly less common after median follow-up of 29 months among patients treated with protons vs. photons (1.2% vs. 8.2%). A lower proportion of patients in the proton therapy group experienced heart attacks (2.3% vs. 9%), although the difference did not reach statistical significance.

A study by Li and colleagues, published in JAMA Network Open in June, showed intensity-modulated proton therapy (IMPT) conferred a safety benefit compared with intensity-modulated radiotherapy among 77 patients with nonmetastatic nasopharyngeal carcinoma. Multivariable logistic regression analyses showed a lower likelihood of grade 2 or higher acute adverse events with IMPT vs. IMRT (OR = 0.15; 95% CI, 0.03-0.6). Researchers also reported “rare late complications and excellent oncologic outcomes, including 100% locoregional control at 2 years.”

Baumann and colleagues reported similar benefits in their retrospective, nonrandomized study that compared proton vs. photon therapy among 1,483 patients with locally advanced cancer undergoing concurrent chemoradiotherapy. Proton chemoradiotherapy was associated with significantly lower risks for adverse events (grade 3 or higher, RR = 0.31; 95% CI, 0.15-0.66; grade 2 or higher, RR = 0.78; 95% CI, 0.65-0.93) within 90 days, with similar DFS and OS.

Larger, phase 3 studies may yield more insights that shape the future of proton therapy, but evidence seems to be accumulating in its favor, Choi said.

“Essentially all the data we have thus far have shown the overall, cumulative toxicities are decreasing with proton therapy compared with photons, and we expect that with certain disease sites this will translate to a survival benefit,” Choi told HemOnc Today.

Cost and complexities

When examining proton beam therapy’s place in the radiation oncology landscape, it may be worth considering where it is widely used in practice: pediatric cancer care.

“We would not be introducing a technology in any form to a pediatric population of children if we didn’t know that it was at least as effective as a comparison modality and that it was in many cases going to be beneficial,” Choi said.

So, what has prevented proton beam therapy from being more widely used?

“Cost and complexity,” Helen A. Shih, MD, MS, MPH, FASTRO, associate professor of radiation oncology at Harvard Medical School, and medical director of the proton therapy program and chief of central nervous system and eye services in radiation oncology at Massachusetts General Hospital, told HemOnc Today.

“You can buy a regular, commercial radiation machine for about $2 million and spend maybe another million to get it set up the way you want it, so a $3 million investment,” Shih added. “[Costs vary widely for proton centers], but ours was $50 million. It’s all about that investment.”

Penn Medicine, which opened the Roberts Proton Therapy Center in Philadelphia in 2010, is continuing to invest in the modality. It soon will add centers in nearby Lancaster, Pennsylvania — a $48 million project — and Voorhees, New Jersey — an estimated $35 million project.

Meanwhile, The University of Texas MD Anderson Cancer Center is investing in development of a new proton therapy center equipped with dramatically more advanced imaging and treatment delivery capabilities than its existing 15-year-old proton center in Houston, according to Choi.

Although the number of proton therapy centers in the U.S. has increased over the past few years, profitability has not been guaranteed.

In 2018, The New York Times reported that although most of the nation’s proton centers were profitable, nearly a third of them had either lost money, defaulted on debt or had to overhaul finances.

Further, those who might benefit from proton therapy must consider whether it is covered by their insurance.

According to a local coverage determination, CMS considers proton beam therapy “medically reasonable and necessary” for unresectable benign or malignant central nervous system tumors; intraocular melanomas; pituitary neoplasms; chordomas and chondrosarcomas; advanced-stage and unresectable malignant lesions of the head and neck; malignant lesions of the paranasal sinus and other accessory sinuses; unresectable retroperitoneal sarcoma; and for any solid tumors in children.

United Healthcare covers proton beam therapy for patients aged younger than 19 years but limits all other coverage to localized, unresectable hepatocellular carcinoma (with documentation proving that the sparing of surrounding tissue cannot be achieved with standard radiation therapy techniques), intracranial arteriovenous malformations, ocular tumors and skull-based tumors. The insurer noted that it evaluates other requests on a case-by-case basis, and listed a dozen other common cancers — including lung, breast and gynecologic cancers — as those for which proton therapy “is unproven and not medically necessary due to insufficient evidence of efficacy.”

This underscores the importance of larger clinical trials. If researchers can enroll enough people on trials to study the efficacy of proton therapy in individual cancers, the results could lead to expanded coverage from insurers and, thus, more access for more patients.

“Insurers should look to support these trials,” David R. Grosshans, MD, PhD, associate professor in the department of radiation oncology at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “In the end, if proton therapy has fewer side effects and, in some diseases, may actually improve disease control, this would be cost effective in the long term.”

However, some studies that potentially could show these benefits have been unable to get off the ground as insurance coverage for proton therapy remains limited.

“A recent study [by Mohan and colleagues] on patients with glioblastoma randomly assigned to proton vs. photon showed over one-third of the patients could not receive proton therapy because of insurance denials,” Choi said.

Attitudes appear to be changing, Shih said.

“I think there’s enough buy-in there — and an increasing willingness and open-mindedness and leniency from insurers to cover it — that we’re slowly doing these studies and expanding proton therapy’s use,” Shih said.

Closing the gap

For decades, photon therapy has been much more commonly used in practice than protons. It also has matured more technologically.

The effect — as Grosshans and Radhe Mohan, PhD,FAAPM, FASTRO, of the department of radiation physics in the division of radiation oncology at The University of Texas MD Anderson Cancer Center, wrote in a January 2017 article published in Advance Drug Delivery Reviews — was photon therapy seemingly catching up to proton therapy.

“Many of the limitations of proton therapy and concerns about them have been known for several decades. However, even in the face of such limitations, the gap between protons and photons at that time was sufficiently large that protons could be assumed to be superior. That is no longer the case,” Grosshans and Mohan wrote. “Over the last 3 decades, photon therapy has advanced considerably. In particular, IMRT was introduced in mid-1990s and has continued to evolve steadily. In addition, there has been continued enhancement in ancillary imaging, treatment planning and delivery technologies. In contrast, proton therapy state-of-the-art had not advanced significantly from the 1980s through the middle of the last decade. Thus, the gap between photon therapy and proton therapy had essentially vanished.”

Although those words may seem almost damning for anyone feeling bullish about proton therapy, they were printed more than 4 years ago. Technology and modern medicine can move quicker than many anticipate.

“In 2021, I believe that proton therapy planning and delivery technologies have advanced to the point where they now match photon therapy planning and delivery technologies,” Chen said in an interview with HemOnc Today. “This means that we can now do meaningful clinical trials to determine the potential benefit of proton therapy in different cancers.”

Grosshans agreed — to a point.

“Proton therapy is rapidly advancing, including improved imaging, as well as newer treatment planning and delivery techniques,” Grosshans told HemOnc Today. “However, there remains room for improvement if we are to match and exceed modern photon therapy.”

Proton vs. photons also is a question that must be asked and answered in each individual cancer, according to experts with whom HemOnc Today spoke.

In a 2012 study published in JAMA, Chen and colleagues set out to determine the comparative morbidity and disease control of proton vs. photon for primary prostate cancer treatment. In a nonrandomized retrospective study, they concluded that proton therapy did not demonstrate a clinical benefit and wrote there were “no significant differences among patients treated with proton therapy vs. IMRT in morbidity or receipt of additional cancer therapy, except an association with increased gastrointestinal morbidity [among patients who received proton therapy].”

Chen put that study in context 9 years later.

“Compared with today, the technology available to plan and deliver proton therapy 10 years ago was quite crude,” Chen said. “[Although] the proton particle has certain advantages over photons, because the technology for treatment planning and delivery was much less developed 10 years ago, that limited potential benefit to patients. Today, the proton technology is much more developed and more accurate than before.

“Ongoing studies — such as the PARTIQoL and COMPPARE studies, the latter led by Nancy P. Mendenhall, MD, and me — are comparing patient outcomes of modern proton therapy vs. modern photon therapy,” Chen added. “These studies will provide crucial results to address this question.”

‘Commitment’ to produce data

Confidence in the future of proton therapy among those in the field may hinge on results of those trials and others currently underway or finalizing enrollment.

“If high-level clinical evidence becomes available, proton therapy may prove to be the superior treatment,” Grosshans said.

A randomized phase 3 trial by NRG Oncology and NCI is comparing OS among patients with stage II to stage IIIB non-small cell lung cancer who received chemotherapy plus photon vs. proton therapy. The trial is estimated to be completed by the end of 2023.

In addition, the pragmatic, randomized RadComp (Radiotherapy Comparative Effectiveness) clinical trial is investigating protons vs. photons in locally advanced breast cancer. Researchers seek to determine which modality is more effective for reducing major cardiovascular events, as well as the frequency and severity of radiation toxicity. Quality-of-life outcomes also will be assessed.

RadComp is the largest such randomized trial to date, enrolling just under 1,300 patients from 23 proton centers across the country, with researchers from New York Proton Center, Mayo Clinic, MD Anderson Cancer Center, Mass General and Penn Medicine among those involved. RadComp is set for primary completion in August 2022.

“The primary driving hypothesis of this study is that because proton therapy has the ability to dramatically decrease the dose of radiation to the heart compared with photons, incidence or rates of major cardiovascular events will be significantly reduced at 10 years for patients receiving proton therapy for breast cancer,” Choi said. “There is a tremendous commitment across the proton community to produce this high-level data so that we can improve access for patients.”

NRG Oncology also is recruiting for a phase 3 trial to compare OS among patients with HCC treated with protons vs. photons. Researchers additionally will assess PFS, local progression, differences in toxicity and quality of life; estimated primary completion is set for June 2024.

A separate randomized phase 2 study by NRG and NCI will investigate proton therapy vs. IMRT for preserving brain function among patients with IDH-mutant grade II or grade III glioma. Estimated primary completion is set for January 2025.

“We have many similar trials now across disease sites — such as head and neck, esophagus, liver, prostate, lung, you name it — because we know research is going to drive access,” Choi said.

The goal, experts said, is to gain as much information as possible through research to alleviate the barriers of access and availability that have held proton therapy back for decades.

“Right now, we are in the middle of a big moment of change in the field and in the landscape of proton therapy,” Choi said. “It might be happening more slowly than some of us would like, but it is still set in motion with the research that is ongoing. And I expect that the outcomes of the research that we’re doing and data we are accumulating are going to lead to a major shift in the way we practice medicine.”

Shih estimated that perhaps as many as “80 to 100” proton facilities could be operating in the next 2 decades across the country.

“Maybe we will plateau,” Shih said. “But, it’s similar to technology with cellphones, cars and computers — as time goes by and there’s investment in these technologies, they become better and faster, the bells and whistles improve, and the cost comes down. If protons were equal to a linear accelerator in cost, we’d all be doing protons. Why wouldn’t we want less unnecessary radiation everywhere beyond the treatment target? But, it’s that margin of benefit [and] cost-effectiveness ratio balance.”

Kegelman said he is optimistic research will reveal the indications for which proton therapy is the better option for certain patients.

“Hopefully down the road, we’ll be able to disseminate that information more clearly to patients and other clinicians and say, ‘for these particular scenarios, it’s generally better to get proton therapy and it should be discussed as an option and offered to patients who can get it.’”

• References:
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• Chung CS, et al. Int J Radiat Oncol Biol Phys. 2013;doi:10.1016/j.ijrobp.2013.04.030.
• CMS.gov. Medicare coverage database. Local coverage determination (LCD): proton beam therapy. Available at: www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=36658&ver=15&Date=&DocID=L36658&bc=ggAAAAIAAAAA&. Accessed on June 30, 2021.
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For the first time, there are final results from a randomized controlled trial that compares the much-hyped proton-beam therapy with conventional radiotherapy.

But the data are disappointing.

Overall, the expensive therapy was as effective as conventional therapy for the treatment of lung cancer, but was no less toxic, according to results presented by lead author Zhongxing X. Liao, MD, from the M.D. Anderson Cancer Center in Houston, here at the American Society of Clinical Oncology 2016 Annual Meeting.

Proton therapy should remain experimental in this setting, said Martin Edelman, MD, from the University of Maryland Greenebaum Cancer Center in Baltimore, who discussed the study during a Highlights of the Day session.

“Radiation oncologists have the same obligation as medical oncologists,” Dr Edelman pointed out. “A technology, like a drug, should not be adopted until its benefits are demonstrated.”

He also criticized the use of proton therapy outside of clinical trials: “Given the costs, are we really choosing wisely with this approach?”

The study was conducted at M.D. Anderson and the Massachusetts General Hospital Cancer Center in Boston, which are two of the 11 proton centers currently operating in North America. However, 13 more centers are in development.
“Proton centers are springing up like mushrooms after a rainstorm. Or, one could say, metastasizing across the country,” said Dr Edelman. The centers are “almost unheard of” in other countries around the world, he reported.

Nevertheless, he congratulated the Boston and Houston radiation oncologists for conducting the challenging Bayesian study of 255 patients with locally advanced non-small-cell lung cancer (NSCLC).

The patients were assigned to receive either 3D proton therapy or standard intensity-modulated radiation therapy (IMRT).

Patient characteristics were well balanced in the two groups, but target volumes were larger in the proton therapy group than in the IMRT group (P =.071), and more patients in the proton therapy group received higher doses to tumors and had larger lung volumes receiving at least 30 to 80 Gy.

For patients with “larger” tumors, there were more 74 Gy doses delivered in the proton therapy group than in the IMRT group (75.4% vs 63.0%; P < .001).

The primary outcome — treatment failure — was defined as radiation pneumonitis of at least grade 3 or local recurrence within 12 months. There were no significant differences between the groups for these criteria, either alone or in combination.

No differences were found between IMRT and 3D proton therapy.
In fact, “no differences were found between IMRT and 3D proton therapy in treatment failure in this randomized trial,” Dr Liao and her colleagues report.

In addition, proton therapy did not outperform IMRT in terms of overall survival.

There has been an ongoing search for a way to increase the radiation dose in locally advanced lung cancer because about 30% of initial relapse in these patients is local/regional, Dr Edelman explained.

The current standard of care for locally advanced NSCLC — “established many years ago” — is concurrent chemoradiotherapy, he pointed out. At the time, data showed that platinum-based chemotherapy plus radiation 60 Gy was the “way to go.”

Then, in the landmark RTOG 0617 trial of conventional radiotherapy, it was shown that mortality was worse the high-dose group (74 Gy) than in the low-dose group (60 Gy), and the increase appeared to be related to irradiation of heart, he said.

IMRT allows radiation to be shaped to the irregular edges of tumor. “That’s our current modern approach,” which is “a vast advantage” over the older approaches, Dr Edelman noted.

“But there is still a great deal of scatter [with IMRT] to the adjacent structures, including the lungs and heart, and therefore there is a greater risk of cardiac damage, as well radiation pneumonitis,” he pointed out.

The question of whether doses to primary tumor/regional lymph nodes can be increased without damage to adjacent structures persists.

“The answer to this may be — perhaps — proton therapy,” Dr Edelman said.

Although mean doses to the lung and esophagus were equivalent with proton therapy and IMRT, Dr Liao’s team reported, there was a significant reduction in mean dose to the heart area with protons.

Still, this randomized clinical trial indicates that proton therapy does not improve treatment failure rates or overall survival.

An Observational Study, Considered and Dismissed

During the same session, results from another study on the treatment of NSCLC — comparing proton therapy with conventional photon therapy — were presented.

Madhusmita Behera, PhD, from the Winship Cancer Institute at Emory University in Atlanta, and her colleagues used the National Cancer Data Base to identify patients with NSCLC (any stage) who were treated from 2004 to 2012. They found about 140,000 patients treated with various forms of photon therapy and 346 patients treated with protons.

“Who got protons? To be very simple, rich white people,” Dr Edelman explained.

The researchers found “some advantage” with protons, but, Dr Edelman cautioned, “keep in mind the small numbers.”

The results are “interesting,” said Dr Edelman, but he promptly dismissed them in light of the higher standard of evidence provided by the prospective clinical trial results from Boston and Houston.