Journal of the National Cancer Institute Advance Access originally published online on October 28, 2008
JNCI Journal of the National Cancer Institute 2008 100(21):1496-1498; doi:10.1093/jnci/djn401
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© Oxford University Press 2008.
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Proton Therapy Use Incites Debate Over Clinical Trials
This is part of an occasional series that recalls some of the stories reported 10 years ago in the News section of the Journal.
Proton therapy is going through a period of enormous growth, with five centers now operational in the U.S. and seven more planned to open over the next 4 years. Compared with conventional radiation, which uses photons, proton treatments can, at least in theory, offer patients fewer side effects and a decreased chance of developing secondary cancers from radiation. But as this nascent field grows, a debate has arisen over whether randomized clinical trials comparing proton therapy with photon radiation are needed to clearly demonstrate proton therapy's benefits—and whether now is the appropriate time for such trials to begin.
Proton therapy differs from conventional radiation in several ways. In conventional radiation treatments, a linear accelerator fires photons at a tumor. These photons, which are delivered as high-energy x-rays, can damage the DNA of tumor cells and kill them. However, they also damage other cells in their path through the body. In proton therapy, hydrogen atoms are accelerated to a high speed, and protons are separated from the rest of the atom. Protons, which are positively charged particles, act differently in the body from photons—protons deliver most of their radiation in a sudden burst at a given point, rather than delivering it gradually over the course of the their path. Because protons may be able to deliver a lower radiation dose to nontarget tissue, doctors can administer higher doses of radiation and, ideally, kill tumor cells more effectively.
Massachusetts doctors ran the first proton therapy treatments in 1961 on one of Harvard University's particle accelerators when the machine (as large as three city blocks) was not in use for physics experiments. Though few patients were treated, the data suggested that the treatments were as effective as x-irradiation at killing cancer cells but had far fewer side effects. Consequently, the first hospital-based proton treatment center was built at Loma Linda University Medical Center in 1990. Today, there are proton therapy centers at Massachusetts General Hospital, the University of Texas M. D. Anderson Cancer Center, Indiana University, and the University of Florida at Jacksonville.
Over the last two decades, proton therapy has been used primarily to treat pediatric patients or patients with tumors that are relatively close to the surface of the body and are near critical body structures—such as cancers near the base of the skull or spinal column, or eye cancers. The key potential benefit of protons is that they release almost all of their energy at the point of their Bragg peak, the point at which the particles come to a rest. This method is different from that of photons, which deliver radiation both before and after they reach the tumor site. This approach makes protons potentially better suited to target tumors that lie dangerously close to other body structures. Earlier worries that proton beams may also produce damaging neutrons have been allayed by data that show that few neutrons are produced, and researchers are now focusing their efforts on advancing the precision of the technology.
Phase III Trials Debated
Throughout proton therapy's history, there have occasionally been calls for randomized controlled trials comparing it with conventional photon radiation, but during the spring of 2007, after the unveiling of plans for opening more proton centers, several scientists began to advance this position with increased fervor in several published reports. There is a general consensus in the field that proton therapy is unquestionably better than conventional radiation at treating tumors of the eye or near the spine, but for several common tumor sites, such as the prostate and the lung, there is a lack of evidence that protons are more effective at killing cancer cells.
Anthony Zietman, M.D., the chairman of radiation oncology at Massachusetts General Hospital in Boston, is calling for trials in prostate cancer. "There's an appetite for getting treatment with the new gizmo," he said, and that appetite combined with the commonness of prostate cancer means that the slew of new proton therapy centers set to open may turn into "prostate factories." In an article in Oncology, Zietman and colleagues wrote that protons are theoretically more effective than photons at killing cancer cells, but in reality it's difficult to localize the proton radiation dose at the tumor because the proton beam is far more influenced by small changes in organ position and other variables. "I have complete equipoise," he said, about whether protons or x-rays are better for treating prostate cancers. "On paper, the distribution of radiation doses does look excellent," he said, but "there is some reason to think that treating the prostate is not as razor sharp as we think."
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Protons, which damage DNA in a different way from photons, have long been thought to kill cells 10% more effectively than conventional radiation, says Radhe Mohan, Ph.D., chairman of the department of radiation physics at the University of Texas M. D. Anderson Cancer Center. Like Zietman, Mohan sees a need for trials. "In some situations, it's not unequivocally obvious that protons are going to be better." Mohan would like to see adaptive randomized trials that accrue more patients in the arm that seems to be more effective.
Perhaps protons are better only for certain subgroups of patients, and any trials should have the goal of ascertaining which patients respond best, says Allan Thornton, M.D., the medical director of Indiana University's Midwest Proton Radiotherapy Institute. For example, Thornton believes that protons are better than x-rays for treating low-grade prostate tumors and that trials aren’t needed for these tumor types. But for high-grade tumors, the choice is uncertain and trials would be informative.
But other researchers do not agree that trials are necessary and appropriate. Part of the problem, says Michael Goitein, Ph.D., a retired physicist from Harvard who worked on some of the first proton therapy treatments at Massachusetts General Hospital, is that protons let doctors deliver higher doses of radiation than photons do, and a trial comparing them, he says, would be "a dose study in disguise."
Herman Suit, M.D., former chief of radiation oncology at Massachusetts General Hospital, and colleagues, writing in Radiotherapy and Oncology, similarly criticized randomly assigning patients to receive photon treatments that, they write, have a known increased probability of causing radiation injuries and have no increase in controlling the tumor. The authors point to the previously published results of three phase III trials, all of which showed increased tumor control with the higher doses of radiation. One study (by Gragoudas and colleagues in 2000 published in the Archives of Ophthalmology) compared two proton dose levels, and two studies (one by Shipley and colleagues in 1995 published in the International Journal of Radiation Oncology, Biology, Physics and one by Zietman and colleagues published in JAMA in 2005) compared photon treatment alone and photon treatment given with a proton "boost" treatment, in which proton therapy is given to augment photon radiation. The studies showed increased tumor control with the higher dose, and the authors concluded that the available funds and effort should be dedicated to improving the technique by determining the effects of dose changes or combining radiation with different chemotherapeutic drugs rather than being used for clinical trials.
Jerry Slater, M.D., professor and chair of the department of radiation medicine at Loma Linda University, says that proton therapy is not even ready for randomized trials. "It's better to optimize the treatment first," he said. Proton therapy is evolving quickly right now, he says; at Loma Linda technical advances are allowing doctors to treat cancer at different sites, and forthcoming technology will give doctors an even better ability to shape the proton beam.
Future of Proton Therapy
As proton therapy continues to evolve, researchers will have to contend with the current shortcomings of the technique. So far, doctors have had difficulty treating organs that move within the body during treatment, such as the prostate, which can move depending on bowel and bladder contents. The lungs present a similar problem because they move and vary in their air volume from moment to moment. With photons, recent advances in intensity-modulated radiation therapy have improved the treatment, but the proton equivalent will require a new technology in the form of a scanned beam.
Currently, most proton beams are passively scattered, meaning that a beam of protons about 2 cm wide is targeted at a piece of Lucite, tungsten, or other material. When the beam strikes this material, the beam is scattered and made wide enough to cover the targeted tumor. In an actively scanned beam, magnets would move the beam around to cover the area of the tumor, while the beam itself does not change in width.
"Within 10 years’ time, we’ll only be using scanned beams," Goitein said, because the scanned beam will allow doctors to deliver a more uniform dose to the target through intensity-modulated beams, essentially giving increased precision. But Indiana University has a scanned beam and has been treating patients with it since 2007, and Thornton says that he's not sure whether it's an improvement. The best approach, he says, would be to develop something between scattered and scanned. "We want the advantages of scanning but without the difficulty and complexity of the scanned beam," he said. Most agree that a scanned beam would allow doctors to treat cancers in sites other than those that are treated today, such as more irregularly shaped tumors or larger tumors.
As the field grows, those working within it are trying to dispel misconceptions about proton therapy. "A lot of people think proton therapy is only for small tumors," said Thornton, who gives talks to medical oncologists about proton therapy treatments. Thornton also says that other physicians are often unaware that proton therapy can be given concurrently with chemotherapy. In photon radiation treatment, the bone marrow is often suppressed, and patients can become so sick that chemotherapy must be interrupted. But in proton radiation therapy, the dose is targeted much more closely to the tumor tissue, and the bone marrow is less affected, allowing patients to continue chemotherapy uninterrupted. Slater says that he works closely with surgical oncologists to increase awareness of the capabilities of proton therapy in treating tumors.
Some scientists, like Slater, point to the scanned beam technology on the horizon and the potential improvements to treatment that may accompany its implementation, and they say that this is further reason to postpone conducting randomized trials until the technique is better developed. They believe that the procedure should be optimized first, whereas those who disagree cite an urgency to conduct trials before proton therapy becomes a de facto standard of care—an argument that seems centered on different philosophies of the role of evidence-based medicine.
This technology is not new or experimental, but it is in rapid flux. The costs are coming down, and the many new centers opening will bring greater access for patients and more potential to gather data for researchers. "[The technology is] a 13-year-old; it's in a prepubescent stage," Thornton said, and it's poised to undergo a rapid maturation, perhaps with a few growing pains.
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