Hitting the Target
Proton beam therapy eradicates cancer cells with less radiation spill-off. But do its benefits outweigh the cost?
The definition and properties of protons are taught in every basic physics and chemistry class. Yet, what most students never learn is that these positively charged subatomic particles are now being used by radiation oncologists to eradicate cancerous cells.
In 1948, Robert R. Wilson, PhD, scientist and member of the Manhattan Project group that developed the atomic bomb, first suggested using protons in radiation therapy in a procedure now called Proton Beam Therapy (PBT). Since that discovery, "The evolution of PBT has been relatively slow," explains Indra J. Das, PhD, FACR, vice chair, professor, and director of medical physics at the department of radiation oncology at the Indiana University School of Medicine in Indianapolis, who has been actively involved in creating a new ACR standard on proton beam radiation therapy. Use of this therapy didn't begin to surge until the 1970s and accelerated in the past 15 years with the development of hospital-based proton centers. "Now, close to 100,000 patients [have undergone PBT] since 1950," says Das. Today, ten PBT centers operate in the United States.
Despite its growing use, a great deal of controversy surrounds whether to use PBT or traditional X-ray radiation therapy. "There are a number of physical advantages [of PBT]," explains Mark W. McDonald, MD, assistant professor of radiation oncology at Indiana University School of Medicine, radiation oncologist at the Indiana University Health Proton Therapy Center in Indianapolis, and member of the ACR Appropriateness Criteria® Committee on head and neck cancer. "It has a biological effect equivalent to X-rays. However, with PBT, we can control where the radiation stops in the body, eliminating unnecessary radiation outside the targeted area. This allows for reduced dose to normal tissues and the opportunity to safely increase dose to tumors when necessary."
Refining the Toolkit
PBT provides better control over where the radiation is deposited, reducing dose to health cells, McDonald says. But what are the features in proton beams that make this possible? The first feature ties back to that basic definition learned in Physics and Chemistry 101: "Protons are charged particles," says Das. "They interact with tissue in very unique ways and produce ionization." In PBT, a particle accelerator is used to target the cancer site with a beam of protons. The process produces a very sharp, focused line of radiation damage made possible by the high mass of protons.
Because of its ability to minimize spill-off to noncancerous tissue areas, PBT is ideal for pediatric patients. "A primary use at our center has been on treatment of children, who are especially susceptible to the side effects of low and intermediate radiation," explains McDonald. "With PBT, we can reduce or eliminate radiation to healthy tissue and the subsequent risk of developing secondary tumors or other long-term consequences."
McDonald also sees PBT therapy as an attractive option for patients with brain tumors and certain head and neck cancers. "Part of this is because you can deliver a higher dose [of radiation with PBT] while still protecting critical structures like the visual apparatus, cochlea, and brainstem," he explains.
Despite its accepted use for certain patients or types of cancer, PBT has been criticized by some as being too costly. On Jan. 2, 2012, The New York Times published an op-ed, citing the dearth of evidence that PBT cures more people than traditional therapy or reduces side effects. "If the United States is ever going to control our health-care costs, we have to demand better evidence of effectiveness and stop handing out taxpayer dollars with no questions asked," the article stated.
The article also claims that health-care costs associated with PBT, including those required to build new treatment facilities, may outweigh the therapy's worth. "The main concern these days is that PBT is still more expensive than X-ray therapy," says McDonald, and those costs can be significant. According to Das, building a proton therapy facility with five treatment rooms can cost about $180 million, whereas the cost of five traditional X-ray therapy machines would be approximately 17.5 million for 5 linear accelerators — and the additional cost for a shielded radiation facility and clinic might add additional millions. One study estimated that the relative cost of protons was 2.4 times greater than that of protons.1 But for some cancer patients, the critical benefits of PBT might outweigh the dollars needed to support treatment facilities.
Considering the comparative cost, most stakeholders agree that more research is needed to evaluate the necessity of PBT in certain patients or disease sites. For example, should PBT be used in prostate cancer patients? According to Thomas F. DeLaney, MD, medical director of the Francis H. Burr Proton Therapy Center at Massachusetts General Hospital in Boston and member of the Radiation Oncology Therapy Group® (RTOG®) Advanced Technology Integration Committee, "The big question raised by The New York Times is the use of protons is general for patients with localized prostate cancer. You have to treat a large number of prostate cancer patients to save a life because screening identifies many patients with early stage disease with a long lead time before the disease produces mortality, and this often occurs in the setting of elderly patients who have many competing causes of mortality. Prostate cancer is often present in the elderly, and the additional low dose of radiation to the pelvis [from X-ray radiation therapy] may carry a small risk of radiation malignancies; these are very rare to begin with and often have a long latency period before they occur." Thus in this specific patient scenario, DeLaney wonders whether the cost/benefit ratio is large enough to justify the cost of PBT.
But addressing DeLaney's concern may not be as simple as securing funding and research sites. "It's hard to satisfy critics without clinical data," says Das. "For diseases like prostate or breast cancer, it takes 10-15 years to see the results."
Das adds that many critics complain of the lack of randomized controlled trials (RCT) for PBT. "The individuals claiming that there are no RCT are correct; some people are not interested in putting money into a center that costs as much as PBT without RCT."
Additionally, says McDonald, some of the tumors best treated by PBT are rare, such as chordomas, sinonasal tumors, and spine tumors and thus it's not uncommon to have little randomized data. "The hope is that we will continue to collect outcomes data, preferably in prospective trials that can be compared to historical controls," he adds. "That really is the highest level of evidence we're likely to get, given the extreme rarity of some of these cancers."
Doing the Research
But not everyone is ruling out RCT or other PBT clinical trials. Massachusetts General Hospital and the University of Pennsylvania are collaborating on a RCT to compare protons versus photons for early stage prostate cancer. RTOG also has been active in integrating proton beams into its assessment of cancer treatment and therapy. DeLaney says the group is working in conjunction with NCI and the Radiologic Physics Center "to initiate the process of credentialing centers for participation in multicenter cooperative group studies." The first step, he says, is to engage and credential interested centers for quality assurance reasons.
Additionally, RTOG now uses protons in many of its clinical trials. "Some patients undergoing proton therapy can receive 60-percent less radiation (i.e., integral dose) to normal tissue," DeLaney says. "So, at least a number of RTOG studies now allow PBT, including RTOG 0938 and RTOG 0815." The former is A Randomized Phase II Trial of Hypofractionated Radiotherapy for Favorable Risk Prostate Cancer-RTOG CCOP Study, while the latter is A Phase III Prospective Randomized Trial of Dose-Escalated Radiotherapy with or without Short-Term Androgen Deprivation Therapy for Patients with Intermediate-Risk Prostate Cancer.
DeLaney, as well as RTOG and the NCI, is also involved in the Proton Trials Consortium, a collaborative effort of all U.S. PBT centers. Members of the consortium have been discussing how to move forward on collaborative trials involving PBT and all participating centers. "We met to discuss how to broaden clinical trials," explains DeLaney. There are, in fact, already multiple ongoing single and multi-institutional studies, utilizing proton therapy in a variety of disease sites; these can be accessed at www.clinicaltrials.gov.
Despite the criticism and controversy surrounding PBT — especially concerning the lack of RCTs — McDonald believes the field has a bright future. "It's a very exciting part of radiation oncology and is becoming more widely available," he says. "We continue to communicate to patients and referring physicians the potential benefits so we can convey an understanding of why the expenses involved in treatment may be worthwhile for appropriate cases."
1. Goitein M, Jermann M. “The relative costs of proton and X-ray radiation therapy.” Clin Oncol 2003;15:S37–S50.
By Alyssa Martino