© Oxford University Press 2006.
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Research Groups Promoting Proton Therapy "Lite"
For decades, the standard bearer of radiation treatment has been photons generated by an X-ray beam. Now, a mix of advanced physics and marketing is poised to promote proton therapy as the next move in radiation treatment.
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Two research teams of physics laboratories and cancer centers are creating clinical proton therapy units that they say can deliver protons to patients safely for a fraction of the $125 million price tag of current facilities. The new units could lower the barrier to offering proton therapy at midsized hospitals.
Proton therapy has been available for 40 years, but its use has been limited by the small number of facilities that offer it to cancer patients. Generating protons requires a building the size of a stadium to house the cyclotron and a staff of trained physicists to run it. The possibility of widespread availability of proton therapy could revolutionize how cancer patients receive radiation treatment. And with half of all cancer patients receiving some form of radiation therapy, the potential payoff for hospitals that offer protons could be huge. Proton therapy is Medicare reimbursable and is covered by private insurers for some forms of cancer.
But not everyone thinks that proton therapy is ready for widespread use. Although it has theoretical physical advantages, it hasn't been tested in head-to-head trials against X-rays, and a few doctors say that its potential side effects haven't been fully examined.
"There have never been any clinical trials to show that protons are as good as, never mind better than, X-rays with modern treatment," said Eric Hall, D.Phil., D.Sc., head of the center for radiological research at Columbia University Medical Center in New York.
But radiation oncologists familiar with proton therapy say that one reason for the paucity of data on proton therapy is that, until recently, it was used mainly for rare tumors such as ocular melanoma and chordomas. If proton therapy were more widely available, say its proponents, clinical trials would be more feasible.
The widespread availability of proton therapy "will make available to everyone [who needs radiation therapy] the chance to be treated with protons," said Ralph deVere White, M.D., director of UC Davis Cancer Center. For example, he said, widely available proton therapy would make it possible to use protons instead of X-rays in clinical trials testing the ability of new drug compounds to sensitize tumors to radiation treatment.
At a Hospital Near You
Until recently, proton therapy has been available at only three facilities in the United States—Massachusetts General Hospital in Boston; Loma Linda University Medical Center in Loma Linda, Calif.; and Indiana University in Bloomington—and a handful in Europe. Within the last year, two more facilities, Shands Cancer Center in Jacksonville, Fla., and the University of Texas M. D. Anderson Cancer Center in Houston, have come online.
But the real push for proton therapy is likely to come in the next couple of years as smaller, cheaper proton generating devices become available.
A collaboration between Lawrence Livermore National Laboratory and the UC Davis Cancer Center is adapting Cold War technology to deliver protons to patients. George Caporaso, Ph.D., beam research project leader at Lawrence Livermore, is spearheading a project that would use a compact linear accelerator first designed to test the U.S. nuclear stockpile to generate a proton beam.
What makes the project possible, Caporaso said, is a so-called dielectric wall accelerator that generates subatomic particles without the use of magnets. The research team's goal is to have a working prototype by the summer of 2007. The technology will allow the operator to vary the beam's intensity, size, and position, Caporaso said.
A second group, including physicists at the Massachusetts Institute of Technology's plasma science and fusion center and the startup company Still River Systems in Littleton, Mass., is developing a proton beam generator that would deliver protons to patients in a standard radiation oncology suite for 1/10 the cost of current systems, according to Still River Systems CEO Marc Buntaine.
Buntaine declined to describe the machine's specifics, citing proprietary concerns, but said that the company is on schedule to deliver its first device by mid-2008. The company is in discussions with several hospitals.
Are Protons Ready for Prime Time?
Few question the potential benefits of proton beam therapy. Protons have mass, whereas photons do not, and this physical property means that protons tend to penetrate tissues without being deflected as much as an X-ray beam. Their weight also makes it possible to control where they release their energy. As the energy of the protons increases, the beam penetrates more deeply. The proton delivers most of its ionizing radiation where it stops. This property is called the Bragg peak, and it allows radiation oncologists to more precisely target a tumor site. But the biggest advantage of protons over X-rays is that they deposit all their radiation inside the body and leave no exit trail of radiation. In theory, this precise control should allow radiation oncologists to deliver a larger radiation dose to tumors while sparing normal tissue and minimizing the total-body radiation dose.
However, some radiation oncologists question whether proton therapy is ready for widespread use. For one thing, there is scant medical literature comparing proton therapy to other forms of radiation therapy in a controlled clinical trial setting. The lack of direct evidence for its superiority has radiation oncologists debating the effectiveness of proton therapy compared to today's state-of-the-art photon radiation for treatment of common cancers.
Hall concedes that protons "should be better," but he objects to how the protons are delivered to patients. The beam generated by the cyclotron unit is about the width of a pencil. The problem is that most cancers aren't pencil sized, so a scattering foil is placed in the beam's path to spread the protons over a larger area. Hall said that proton treatment facilities should replace the scattering foil with an active scanning beam that would accomplish the same purpose without generating harmful neutrons.
"They just stick a scattering foil in the way to get the size beam that they want. Whenever protons lose energy they produce neutrons, so now they are scattering the patient with a total body dose of neutrons," said Hall, "and that I think is insanity."
A critical review by Hall in the International Journal of Radiation Oncology, Biology, Physics suggested that neutrons leaking from proton scattering devices could lead to excessive second cancers. This idea is generating ripples of discontent among doctors currently treating patients with proton therapy.
Carl Rossi, M.D., associate professor of radiation medicine at Loma Linda University, said that unpublished data on neutron scattering at the Loma Linda facility are 10 times lower than what Hall used for his analysis. Rossi said he is confident that patients are not being exposed to dangerous stray radiation and that technology now being developed to guide protons though an active scanning beam instead of a foil will be used mainly to treat large, irregularly shaped tumors. Also, proton therapy is being combined with advance computed tomography imaging, and for lung and internal organ cancers, matched to patients' breathing patterns to ensure that the radiation dose is delivered to the tumor site.
Testing in Clinical Trials
Rossi and his colleagues are one of the few groups to have published a phase III randomized clinical trial evaluating proton therapy. In a 2005 Journal of the American Medical Association paper they reported the results of a dose escalation study of 393 patients with localized prostate cancer. All patients received a 50.4 Gray (1 Gray = 100 rads) X-ray treatment, followed by a proton radiation dose to the tumor of either 19.8 Gy in the conventional treatment arm or 29.8 Gy in the high-dose arm. After 5 years, the number of patients who had no biochemical evidence of disease as measured by prostate-specific antigen levels was 61% for patients in the conventional-dose group and 80% for patients in the high-dose group. An accompanying editorial acknowledged the association of high-dose radiation with biochemical control but called for a long-term study to determine whether high dose translates into better long-term survival.
Long-term survival studies are in progress, but the results of the high-dose trial were encouraging enough to try further dose escalation, Rossi said. In a clinical trial now under way, Rossi and his team have enrolled 85 prostate cancer patients in a similar study combining conventional therapy with protons and will escalate the total radiation dose to 82 Gy. He sees the future of prostate cancer treatment in terms of greater radiation intensity delivered in a shorter time frame.
"In 5 years I may be treating at a higher dose based on the results of clinical trials, and I may be treating in a shorter time frame," he said.
Studies of proton therapy for other cancers, such as bladder and lung, have also combined protons with conventional therapies, making it difficult to isolate the contribution of proton beam therapy to treatment. A recent head-to-head comparison of photon versus proton therapy for choroid hemangiomas in Germany concluded that there was no discernible difference in outcome between the two forms of treatment.
"We don't know all the answers, and I think there is still a lot of evaluation that needs to happen," said David Wazer, M.D., radiation oncologist in chief at Tufts–New England Medical Center in Boston. "The evolution of radiation therapy in the last 15 years has been to become more conformal—that is, to wrap the radiation dose around the tumor and minimize the dose to normal tissue. The revolutionary technology has been intensity-modulated radiation therapy [IMRT]. What we've seen with IMRT is clear benefit at a variety of tumor sites. I see protons on that spectrum of continual improvement."
Working with conventional X-ray therapy, IMRT uses shielding "leaves" that permit or exclude radiation from reaching the patient. With computers, IMRT allows a radiation oncologist to customize the radiation distribution from dozens of points in a spiral, instead of from just a few points. These innovations have reduced the side effects from conventional radiation therapy, leading some to question whether protons are that much better. Yet many are eager to see how protons will perform when implemented on a large scale.
New Treatment Possibilities
Tufts–NEMC is among the first in line to get a Still River Systems proton therapy unit. Earlier this year it applied to the Massachusetts Department of Public Health for permission to install one of the units. Wazer said that he expects to hear from the state by December 2006.
Markus Fitzek, M.D., a radiation oncologist at Tufts–NEMC, worked at proton therapy facilities in Germany and England, as well as at Massachusetts General Hospital. He is eager for proton therapy to become more widely available and believes that it will find widespread use in cancers of the thorax, including some forms of lung cancer. Lung cancers have generally not been treated with protons previously because they require an energetic beam that can penetrate at least 15 cm. Until this year, such a beam existed at only two sites in the United States: Loma Linda and Massachusetts General.
"Lung cancer is the disease site that would make the greatest impact on public health," he said.
Wazer said that they are particularly interested in treating early-stage lung tumors that might otherwise be treated with surgery.
"Those are the sorts of differentiating applications that we are thinking very hard about," he said.
They also want to try using the proton therapy machine for lesions in the lung, liver, kidney, and paraspinal region, he said. "There are currently very innovative conventional photon techniques that we think could be markedly improved with a proton beam because of [its] dose advantages."
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