Proton beam therapy: Is it the future of radiation?
There is great enthusiasm for proton beam therapy, but it has not yet been proven better than existing treatments.
Proton beam therapy may be the next great leap forward in radiation oncology.
Supporters say the technology allows physicians to treat a broad spectrum of cancers with few adverse effects, while more precisely targeting tumor cells with higher doses of radiation. Detractors say proton beam therapy is hugely expensive and has not been shown to be superior to conventional radiation treatment.
With proton beam therapy, physicians use a cyclotron to accelerate protons and fire them directly into tumor cells with submillimeter precision. Because healthy tissue is largely spared, oncologists can, in theory, deliver much higher doses of radiation, while improving local control and reducing the risk for recurrence and morbidities.
Courtesy of Massachusetts General Hospital
Proton beam therapy can be used to treat any disease that can be treated with radiation, though it is most often associated with head and neck cancers, pediatric cancers and prostate cancer. The James M. Slater, M.D. Proton Treatment and Research Center at Loma Linda University Medical Center focuses on prostate, lung and brain cancer treatment. Physicians at the massive Hampton University Proton Therapy Institute under construction in Hampton, Va., plan to begin treating 2,000 patients annually for prostate, breast, lung and pediatric cancers in 2010.
Leonard Arzt is the executive director of National Association for Proton Therapy. The association is a nonprofit corporation that promotes the clinical benefits of proton beam radiation therapy for cancer patients.
Arzt has been a supporter of the therapy for 20 years. Proton beam therapy, he said, is simply superior to conventional radiotherapy.
“There are no drawbacks that I know of in terms of the modality itself,” Arzt said, speaking from his office in Silver Spring, Md. “It’s the best medically accepted radiation that can control cancer and do minimal to no harm to surrounding healthy cells, tissues or organs. It provides higher doses for better control.”
Anthony L. Zietman, MD, a professor of radiation oncology at Massachusetts General Hospital and the Francis H. Burr Proton Therapy Center, believes that proton beam therapy, however, can cause side effects.
“It’s a misconception,” he said. “I see a lot of patients with side effects. I wish I didn’t, but I do with all the therapies. There’s no such thing as the perfect therapy.”
Jerry M. Slater, MD, medical director at the Loma Linda’s proton clinic, does not go so far as Arzt, though he did say the side effects of proton beam are minimal.
“The published reports are out there showing there are always some morbidities, but we’re looking at making them less than we would have otherwise,” he told HemOnc Today.
The first use of proton therapy to attack tumor cells dates back to the 1950s, but the treatment began gaining in popularity in 1990 after Loma Linda opened the first hospital-based proton therapy center. Like all emerging therapies, proton beam therapy faces two important questions: Is it any better than current treatments? And if so, is it worth the price? Two articles published in The Journal of Clinical Oncology last year suggest the answers to both questions could be “no.”
As good or better?
Brada et al searched as far back as 1966 for publications on clinical applications of protons and found only two phase-3 trials. Both of those trials looked at prostate cancer patients and neither made a direct comparison between photons and protons.
Upon conducting a systemic analysis of those articles, they found that there was not enough evidence to conclude proton therapy was superior to conventional radiotherapy at treating chordomas and chondrosarcomas of the skull base, ocular tumors, prostate cancer, head and neck cancer, or a host of other cancers.
They went on to say that protons may in fact be a useful treatment, but the therapy requires more research, especially appropriately designed and powered clinical studies. Slater argued that proton beam has been proven safe and effective time and time again.
“It’s a well-known fact that there’s no other form of radiation that I can put into a patient, give the maximum dose to the target and [give] less to normal tissue with every single beam I use,” he said. “X-rays will never do that. There’s no other technology that will ever allow you to maximize every beam into the target. Protons can do that.”
Arzt said it was a well-established fact that there are few clinical trials evaluating proton beam therapy, but added that the lack of scientific evidence is not slowing the demand for the treatment.
“It’s true; there could be more studies out there to prove to the scientific community, if that’s what they’re looking for,” he said. “There is a lot of anecdotal evidence, there is a lot of experience, there are a lot of testimonials from patients.”
For some physicians, that lack of hard clinical evidence is a huge problem, but Cynthia Keppel, PhD, scientific and technical director at the Hampton University Proton Therapy Institute, among others, says that clinical trials will be informative but should not be necessary in this case. She compared the adoption of proton beam to the move from analog X-rays to digital or from hand-calculated treatment planning to computerized simulation codes.
“They didn’t have to go through a big multicenter trial,” she said. “The technological improvements were just so obviously better that, while they did have to be FDA approved, they were adopted immediately. There is a long history of that, from digital X-rays to treatment planning to new imaging devices. Proton therapy has taken this path. The fundamental proton dose deposition is so obviously an improvement on what’s done now that the devices have received FDA approval and we as a community have started treating.”
“All new approaches need clinical trials,” said Theodore Lawrence, MD, PhD, chair of radiation oncology at the University of Michigan Medical School and a member of the physician leadership group of the Particle Therapy Institute of Michigan. “We can discuss what kind of clinical trial, but all new approaches need to be rigorously evaluated in human beings.”
Lawrence said it is still unknown exactly how proton beams act in the body, and added that there is evidence suggesting that proton beam therapy has “as much as 4 mm of inaccuracy about where the beam actually stops.”
“I’m not against proton therapy,” he said. “I’m against blindly accepting a new, expensive therapy without rigorous testing. ... I don’t think we are incapable of testing new technology. I just think we have to have the will.”
Worth the cost?
Konski et al conducted a cost-benefit analysis of proton beam therapy and concluded that it would not be cost effective for most patients with adenocarcinoma of the prostate. The results, published in The Journal of Clinical Oncology, showed proton beam therapy only had a 49% chance of being cost-effective at 15 years for a 70-year-old patient. For a 60-year-old patient, the treatment had a 54% chance of being cost-effective at 15 years.
However, as Lawrence points out, that study is based on an as-yet-unproven assumption about proton beam therapy.
“He assumed you could give 10 Gy more with protons than you could with photons,” Lawrence said. “There’s no proof of that at all. There’s no proof you can give even one more Gy with protons than with photons.”
On the other hand, a 2005 study published in Cancer showed that protons had a lifetime cost savings of €23,600 and added 0.68 quality-adjusted life-years per patient for childhood medulloblastoma. The analysis found that reductions in IQ loss and growth hormone deficiency contributed to the greatest part of the cost savings and were the most important parameters for cost-effectiveness.
The experts who spoke with HemOnc Today felt that proton beam therapy was likely to have the most benefit for children with cancer. Children are much more radiosensitive than adults and are at far greater risk for secondary cancers and late effects.
Results of a study published in 2003 in the International Journal of Radiation Oncology-Biology-Physics showed that the dose to 90% of the cochlea was reduced from 101.2% of the prescribed posterior fossa boost dose from conventional X-rays to 2.4% for photons and 33.4% IMRT in a patient with pediatric medulloblastoma. Dose to 50% of the heart volume was reduced from 72.2% for conventional X-rays to 0.5% for protons compared with 29.5% for IMRT.
Other studies have shown proton therapy provides better target coverage with excellent sparing of orbital bone compared with IMRT or 3D-conformal radiotherapy for retinoblastoma, and that protons were superior at treating pediatric orbital rhabdomyosarcoma because of reduced exposure to orbital structures, the pituitary gland and the brain.
In a 2007 review published in Cancer, Greco and Wolden concluded that doses of 70 Gy or higher could possibly control unresectable osteosarcoma and non-rhabdomyosarcoma soft-tissue sarcomas and that protons were the “most feasible means” to achieve that level of radiation.
Mody et al reported the results a 25-year follow-up on survivors of childhood acute lymphoblastic leukemia in Blood earlier this year. The researchers found that, compared with their siblings, survivors suffered more multiple chronic medical conditions and more severe or life-threatening chronic medical conditions. Survivors were also more likely to report functional impairment, activity limitations and poorer mental and physical health. Survivors were also less likely to marry, graduate from college or have a job or health insurance.
Rajen Mody, MD, an assistant professor in the department of pediatrics and communicable diseases at University of Michigan Medical School and one of that study’s co-authors, told HemOnc Today in June that only the survivors who had undergone radiotherapy or relapsed suffered those late effects. He added that those negative outcomes were a direct result of radiation delivered to the cranial-spinal axis.
Proton beam therapy may be able to spare survivors of childhood cancers a lifetime of suffering.
“Young children are incredibly sensitive to radiation. If irradiated early in life, they may experience a lot of growth and development problems,” Mody said. “They are also at a high risk for developing treatment-induced cancers down the line. If radiation is deemed absolutely necessary for treatment during early years, newer modalities like proton beam therapy should be studied to see if they cause fewer long-term side effects.”
It takes a colossal, hugely expensive set-up to deliver proton beam therapy, and one of the chief arguments against the procedure is its massive cost. The University of Florida Proton Therapy Institute opened in 2006 at a cost of $125 million. It is a three-story, approximately 98,000-square-foot building housing a 220-ton cyclotron, three gantry-fitted treatment rooms, a fixed-beam room, a milling shop for the fabrication of patient-specific devices, an anesthesia and infusion suite and a patient library.
Hampton’s facility, or HUPTI, is slated to cost $225 million, and the university deems it will be the world’s largest free-standing proton therapy institute. Keppel said the expense was well-justified.
“The university has made a focused effort to expand cancer research,” she said. “The proton center represents the largest movement of the university in this direction, but it has been the university’s vision to look at cancer research.”
Keppel added that HUPTI is part of a larger investment that will put the school at the forefront of cancer research and treatment.
“It’s a new step. The university is ready to play a more prominent role on the national scene,” she said. “This project has already raised the visibility of the university and we hope to show the country and the world what we can do at Hampton.”
Hampton is an historically black university and Keppel hopes that minorities will be more willing to trust a historically black institution. She notes that there are devastatingly large minority health disparities associated with many types of cancers, most notably prostate cancer. The national death rate for black men is more than twice that of white men.
She added that although the cost for proton beam therapy will be greater than conventional radiotherapy for patients, it will still cost less than some forms of chemotherapy.
“It is more expensive than conventional radiotherapy, but it is not 10 or 100 times more expensive for the patient, even though putting up a center is 10 to 100 times more expensive for an institution willing to make this investment in improved health care.”
In a 2007 article published in Oncology Issues, Nancy Price Mendenhall, MD, medical director at The University of Florida Proton Therapy Institute, estimated that these centers can cost 10 times as much to build compared with a similarly sized conventional facility. She added that proton beam centers also face higher costs for treatment planning, quality assurance, machine operation and maintenance, though these centers are designed to last three times as long as conventional clinics.
In a 2003 study published in Clinical Oncology, Goiten and Jermann estimated the costs for proton beam therapy as 2.4 times that of conventional therapy, though the authors suggested that could drop to as low as 1.7 times higher as more facilities open. They estimated that if construction costs could be “forgiven” somehow, proton beam could cost 1.3 times as much as X-ray therapy.
Mendenhall wrote that if proton beam therapy lives up to its promise of lowering rates of toxicity and recurrence, the treatment could cost less than conventional radiotherapy over time. However, the initial outlays are huge and the treatment is at least somewhat more expensive to patients.
Arzt, however, points out that the cost is worth it for many patients.
“How can you put a price tag on quality of life? How can you put a price tag on outcomes?” he said. “How do you put a price tag on men who fear they’ll have to wear a diaper or be impotent? It’s hard to put a price tag on that.”
Slater argues that looking at current costs is short-sighted. All new therapies are expensive at the outset, but the cost drops over time.
“Ultimately you have to create something that can become efficient enough so that the costs are not exorbitant,” he said. “That’s directly the way proton therapy is going. The cost is, over time, going to become less and less for the patient. In the long term, some things we will be able to do will be cheaper than other forms of radiotherapy,” he said, adding that nothing is cheaper when it’s first developed.
Zietman, who uses proton beam in his clinical practice, said about 85% of patients who are treated at Francis H. Burr Proton Therapy Center have pediatric or brain cancers. Approximately 15% of patients are treated for prostate cancer compared with as much as 50% of patients at some centers. But, he adds, his facility is largely free of financial pressures because the proton beam center there is paid off.
His fear is that the only path to survival for a proton center coming online now is to see a lot of men with relatively easy to treat prostate cancers, and there is some question as to whether proton beam is the best treatment for that disease.
“If these centers were being established to treat children and brain tumors, I would have absolutely no problem with them,” Zietman said. “My problem is not with proton beam therapy and not with the good use of proton beam therapy. My problem is with the most common use of proton beam therapy, which is to treat prostate cancer.
“I worry that the new centers will have these financial pressures. The only business model that makes any sense is treating a lot of prostate cancer,” he said.
Construction costs could drop sooner rather than later. Still River Systems of Littleton, Mass., has announced plans to build more smaller proton beam clinics in St. Louis and Mandarin, Fla. The Siteman Cancer Center at Barnes-Jewish Hospital and Washington University has broken ground on The Kling Center, which it bills as what will be the world’s first miniature proton beam clinic. The $25 million project is expected to open next summer.
First Coast Oncology-Mandarin in Jacksonville, Fla., is planning to open a clinic at an estimated cost of $20 million to $35 million. The FDA, however, has not yet approved these compact systems.
Ultimately, careful science and fiscal sense are keystones for proton beam therapy moving forward. “Proton beam therapy can potentially be a good form of treatment in many clinical situations,” Mody said. “It needs to be prospectively studied, established carefully and used wisely.” – by Jason Harris
For more information:
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- Pollack A. Cancer fight goes nuclear, with heavy price tag. New York Times. Available at: http://www.nytimes.com/2007/12/26/health/25cnd-proton.html?_r=1&scp=5&sq=proton%20beam&st=cse&oref=slogin. Accessed November 7, 2008.
- Voiland A. The promise of proton-beam therapy. U.S. News & World Report. Available at: http://health.usnews.com/articles/health/cancer/2008/04/16/the-promise-of-proton-beam-therapy.html. Accessed November 4, 2008.
- Zietman A, DiSilvio M, Slater J, et al. Comparison of conventional-dose vs. high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: A randomized controlled trial. JAMA. 2005;294;1233-1239.