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For other articles and previous issues click here. November 28, 2005 Heavy
Hitter — Are Proton Beams Radiotherapy’s Next Generation? A description of a proton beam therapy (PBT) procedure reads like a plot summary of a Sci-Fi Channel show. Proton beams are directed, with deadly accuracy, at an intended target, destroying it with little or no collateral damage. However, in the real-world treatment scenario, the target is not a futuristic city, a cyborg army, or distant planet. With PBT, the target is cancer, and the collateral damage—or, more precisely, the lack of damage with this type of conformal radiation treatment—relates to surrounding tissue. Also, when you consider its history, PBT doesn’t seem so futuristic after all. Robert Rathbun Wilson, PhD, first proposed PBT back in 1946. In 1954, the first patient was treated with protons at the University of California, Berkeley. Over the next three decades, PBT activity remained in the realm of research, but in 1990, the first clinical proton facility, the Proton Treatment Center at the Loma Linda University Medical Center in California, began treating patients. More recently, PBT’s capabilities and potentials have generated increasing interest. PBT directs a highly focused beam at cancerous tumors with deadly accuracy. Unlike other radiation therapy treatments that have emerged in recent years, such as intensity-modulated radiation therapy (IMRT) or 3-D conformal radiation therapy (3D-CRT), it attacks tumors with protons instead of photons. A big advantage is that side effects are minimal compared with conventional radiation therapy, as the proton beam has little effect on the surrounding healthy tissue. Limited
Availability Due to increasing PBT interest, two more facilities will open within the next two years including the M.D. Anderson Cancer Center Proton Therapy Center in Houston and the Florida Proton Therapy Institute in the Shands Medical Center at the University of Florida at Jacksonville. In addition, initial planning has begun for several other centers. Nancy Mendenhall, MD, believes the spark in interest for PBT has a lot to do with developments in fields related to radiation oncology, particularly diagnostic imaging. “Exquisite 3-D imaging is now available,” says Mendenhall, chair of the department of radiation oncology at the University of Florida. “For instance, we can now fuse finely-detailed magnetic resonance imaging data with computed tomography data to determine the precise location and three-dimensional extent of the tumor. These diagnostic imaging advancements have made protons applicable to many more tumors.” Another factor, she says, is the emergence of computerized treatment planning software. “We can generate treatment plans using an infinite number of radiation beams, including beams that are dynamically modulated, to provide the very best radiation dose distribution for a patient,” Mendenhall says. Florida
Facility to Open Mendenhall is enthusiastic about PBT because she sees it as a way of improving patient outcomes. “Many outcomes for radiation oncology are excellent, but most have room for improvement, either in terms of better disease control or in complications and toxicity for the patient,” she says. PBT, she believes, could be a vehicle to drive those improvements. Advantageous
Energy Delivery In contrast to x-rays, a proton beam produces much less entrance dose and no exit dose to healthy tissues. The difference between protons and photons, Mendenhall indicates, is that protons have mass and x-rays don’t. Because of their mass, protons only travel a finite distance. How far they travel depends on their velocity—that is, how fast they are accelerated by the cyclotron. Therefore, protons can be better controlled. “You can program protons to go whatever depth in the tissue you want,” Mendenhall explains. “When they stop at that point, they give up all of their energy.” Further, because protons are relatively heavy, they don’t lose much energy in random collisions after they enter tissue. “They keep most of their energy until they come to the end of their path, which is determined by their acceleration, and then they give up all of their energy in a burst,” Mendenhall adds. That burst is called the Bragg Peak, where protons expend all their energy. In PBT, that burst is targeted to the tumor. Very little damage occurs to tissues and organs the protons pass by before reaching the target. No damage occurs to tissues and organs behind the tumor because the protons have expended their energy. So there is no exit dose to healthy tissues and much less entrance dose then with x-rays. Clinicians employing photon radiation therapy techniques are more limited by how much damage will be done to normal tissues, which frequently compromises the radiation dose to the tumor. But with PBT, clinicians utilize a radiation beam that deposits most of its energy right where they want, and the potential for more successful outcomes is two-fold: less toxicity to normal tissues and higher doses to tumors. The combination results in fewer side effects and better irradiation to tumor control. In this way, PBT may provide significant advantages over conventional x-rays for where there is room for improvement in the probability of either disease control or toxicity, particularly tumors in children or tumors located close to critical structures of the body. In looking at recent advancements in radiation therapy, Jerry D. Slater, MD, chair of the department of radiation medicine at Loma Linda University Medical Center, believes photon x-ray–based radiation therapy is nearing an end. “Considering where radiation therapy is going, in about 20 years it will no longer be x-ray–based,” he says. “In the history of radiation oncology, all of the advancements have been based on physics and dose distribution. With high-energy x-rays, 3D-CRT, and IMRT, we’re really just squeezing out the last bit of what we’re able to do with photon x-rays. Protons provide the next step up and will carry us into the upcoming decades.” Considerable
Cost “The cost of installation is enormous,” says Anthony L. Zietman, MD, a radiation oncologist at Massachusetts General Hospital, home of the Northeast Proton Therapy Center. “The price can range from $40 to $100 million dollars to equip a facility.” The ultimate price tag for M.D. Anderson’s new Proton Therapy Center will be approximately $125 million. The cost of the Florida Proton Therapy Institute is projected at $110 million. The Northeast Proton Therapy Center, which opened in 2001, is an 88,000-square-foot facility that cost $125 million to build. An inventory of its facilities and equipment help explain the high cost. The Northeast Proton Therapy Center has three PBT treatment rooms. Two of the rooms contain gantries that are three stories high and weigh 110 tons. Proton beams are generated by a cyclotron and accelerated by enormous magnets. Additional funding from the public or private sector is usually necessary to help cover the costs of new facilities. Construction of the Northeast Proton Therapy Center was jointly funded by the Massachusetts General Hospital and the National Cancer Institute. However, Slater, whose father James Slater, MD, pioneered PBT at Loma Linda, believes people are too fixated on the facility costs. He believes cost per patient is the more important consideration. “Medicare pays as much for IMRT as it does for some proton treatment,” he points out. “Certainly an IMRT machine is less expensive, but the real issue is being able to treat enough patients to push costs down per patient.” In 1990, Loma Linda’s Proton Treatment Center became the world’s first hospital-based proton treatment facility. Today, according to Slater, it treats 150 to 170 patients per day. “If I can run an operation and do proton therapy at relatively the same cost as photon therapy, and if you look at what I can do with proton therapy, it’s not an argument anymore,” says Slater. “In my opinion, cost is only an issue if outcomes are equivalent. When outcomes are significantly better, then you have to include that in the cost:benefit ratio. People don’t seem to understand that. They’re just looking at the $100 million investment.” One element that may divert attention away from the high investment is the increased applicability of PBT, which helps make it cost effective. Mendenhall believes the aforementioned developments in diagnostic imaging will increase its applicability. “Until we had the diagnostic imaging advances and the advances in treatment planning, as a discipline we weren’t ready for proton therapy,” she says. “But I think the advances have made proton therapy applicable to a large range of tumors.” Clinical
Applications Also, it’s very effective for treating some pediatric cancers and eye tumors. Zietman views it as the more desirable option for treating children with cancer. “Most childhood cancer can be cured, but children are very sensitive to radiation,” he says. “If the children treated live another 60 years, they face a risk of radiation-induced malignancy. So, for children, you want the most accurate form of radiation treatment, and proton therapy clearly benefits them.” Mendenhall says she would like to see PBT used in areas of radiation oncology that have room for improvement, either in tumor control or toxicity. As an example, she cites the treatment of brain tumors in children. “We’re not happy with our control rates or the toxicity we cause,” she says. “The brain tissue in children is very sensitive to even low doses of radiation. Radiation is necessary, but it almost always causes problems that show up sooner or later, including second malignancies.” Lung cancer is another potential improvement area. Mendenhall points out that control rate for most common carcinomas, even in the early stages, is only 30% to 50%. “So we have a huge opportunity to increase disease control,” she says. Mendenhall says the Florida Center also plans to target advanced pelvic tumors, whether they’re cervix or colorectal carcinomas. “We do well in early stages of those diseases but not in advanced stages,” Mendenhall adds. Other areas she believes PBT may help include prostate cancer, cancers in or around crucial structures such as the spinal cord, brain stem, optic nerves, and bone and soft tissue sarcomas. “Some of these sarcomas can be resected by the surgeon without causing much functional deficit,” Mendenhall says, “but others cannot be removed without causing major functional problems for the patient.” Comparative
Research Recently, Zietman was involved in a controlled study that demonstrated that encapsulated prostrate cancer treated with high-dose proton beam radiation, followed by conventional radiation therapy, resulted in lower prostate-specific antigen failure rates and better local control than in cancer treated with conventional doses of protons and x-rays. The study, published in the September 14 issue of The Journal of the American Medical Association, included colleagues at Massachusetts General Hospital, Loma Linda University Medical Center, and the American College of Radiology in Philadelphia. However, Zietman points out that the study wasn’t focused on proton beams. Rather, it was a study designed to compare radiation doses. In the published report, the authors wrote that even though the trial did validate the use of PBM, “it did not test whether [PBT] is more or less efficacious than other less expensive and more commonly available conformal techniques or, for that matter, than brachytherapy or surgery.” In the study, subjects from both low- and high-risk groups experienced benefits from high-dose therapy. Those receiving both high-dose PBT and x-rays had a 49% lower risk of biochemical failure at five years, compared with subjects receiving standard doses. Also, there were no differences in both the high- and low-dose groups as far as serious side effects on urinary or rectal function. “But the study didn’t answer the question as to what is the best way to give high radiation,” says Zietman. “Is it with protons, IMRT, or 3D-CRT? You can give high-dose radiation in all three ways.” In the meantime, the Northeast Proton Institute has developed a research program designed to improve current treatment techniques and develop new equipment. Zietman indicates that the Institute is particularly interested in determining whether PBT offers a significant advantage in prostate cancer treatment. For the past 20 years, the Proton Treatment Center at Loma Linda has been involved in significant research. Slater reports that the center is now studying the effects of protons on a molecular and sub-molecular level. Growing
Awareness — Dan Harvey
is a freelance writer based in Wilmington, Del., and frequent contributor
to Radiology Today.
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