19 November 2003�This fall, Siemens AG (Munich, Germany) announced that it had licensed technology to produce devices that fire carbon-12 (12C) ions at cancerous tumors in an attempt to kill them in one shot rather than in weeks of treatment with conventional radiation devices. Siemens says its aim is to bring the technique, whose first applications will likely be the treatment of hard-to-reach cancers near vital organs such as the brain or spinal cord, to hospitals within three years.
Researchers and clinicians have long known that high-energy particles are an ideal weapon for attacking cancerous cells because, when delivered in concentrated bursts, they overwhelm the built-in repair mechanisms of cells. Despite this knowledge, the effectiveness of such therapy was limited by the high cost, large size, and relative clumsiness of the tools at hand. But recent advances have now made it possible to pinpoint the placement of protons and ions of various elements, while strides are being made in the development of lasers that may turn these bank-busting behemoths into compact, inexpensive devices.
Hitting the bull�s-eye
Siemens� technique uses a particle accelerator to bring the 12C ions to energies as high as 300 MeV before magnets precisely beam them at the target. This is an improvement over traditional radiation therapy, in which photons or electrons are fired at a tumor, because the amount of energy with which the ions are fired can be fine-tuned, allowing clinicians to pinpoint the placement of a dose of radiation to within a millimeter. With this level of precision, a high-intensity dose can be trained on the malignant cells while sparing the surrounding healthy tissue.
Precision relates to particle energy in a fairly simple way. Because of their tremendous starting energy, the carbon ions are moving so rapidly when they first enter the body that there is very little interaction with the cells they pass on the way to the site of the tumor. Since most of the volume of a cell is empty space with subatomic particles such as electrons moving around rapidly, chances are good that a fast-moving ion can move through a cell without getting near enough to the its constituent parts to strip away some of its electrons. But as the ions lose energy, they slow down, extending the interaction time with nearby cells.
The ions� effect on these cells increases steadily until, in the instant before they come to a complete stop, the energy transfer between the accelerated particles and the surrounding cells is greatest. Giving the ions a relatively low starting energy, say 70 MeV, would target a tumor near the surface, such as in the eye. But a 200 MeV shot would hit deep-seated malignancies.
In traditional radiation therapy using X-rays or gamma rays, the opposite is true. The energy level of the photons (about 250 keV) or electrons (around 20 MeV) is so low that they immediately react with cells of the skin, fat, and any organs in the beam�s path. This dose distribution creates several disadvantages. By the time the beam reaches the tumor, most of the energy in the photons has been exhausted in damaging healthy tissue, leaving precious little for destroying the rapidly dividing cancer cells.
Also, some of the particles overshoot the tumor, irradiating healthy tissue behind it. To limit the damage inflicted on normal cells, the number of particles fired at the tumor has to be limited, increasing the odds that the cancerous cells will survive the series of barrages during the two or three dozen sessions in a round of radiation therapy.
Heavy ions beat standard radiation therapy for another reason. Because of their mass, they inflict far more damage on the cells with which they interact than, say, photons, which carry energy but have no mass. The difference in destructive power, known as radiobiological effectiveness, or RBE, is important. Although the self-repair mechanisms in cancerous cells are frequently not as efficient as a healthy cell�s, there is a period during a malignant cell�s life cycle when its resistance to traditional radiation therapy is far greater than normal.
Carbon ions, which create clusters of damage, especially to a cell�s DNA strands, eliminate this variability in effectiveness. According to Eros Pedroni, a physicist in the department of radiation medicine at the Paul Scherrer Institute of Physics (Villigen, Switzerland), the RBE of carbon ions is high enough so that, under the right circumstances, it will be a "one-hit, one-kill" treatment. Patients would need to go to the hospital only once or twice before the cancer is eliminated instead of 20 or 30 times.
But Pedroni cautions that heavy-ion therapy has not yet reached the point where there is enough clinical experience to say which cancers it should be used to attack or at what doses. Siemens and the research institutes with heavy-ion accelerators are working to identify the cases where patients can benefit from 12C therapy and to chart the effects of various dosages and energy levels.
Making it marketable
Quietly, patients around the world have been undergoing heavy-ion and proton therapy since 1954. But, for the most part, these people were participants in clinical research studies at the dozen or so facilities scattered across the globe that used existing particle accelerators that had been "repurposed" for the studies. Because these sites were originally designed for nonmedical particle experiments, some have been able to treat fewer than 100 patients in a decade.
The world�s first hospital-based proton therapy facility was opened at Loma Linda University Medical Center (Loma Linda, Calif.) in 1990. (While protons have about the same RBE as photons, they, like heavy ions, can be directed with great precision and transfer most of their energy to the target cells.) Treating about 1000 patients per year, Loma Linda outpaces the rest of the world, but other treatment centers of its ilk have been slow to materialize.
The Siemens effort, using technology developed by researchers at the German Institute for Heavy-Ion Research (GSI, Darmstadt), the German Cancer Research Center (Heidelberg), and Heidelberg University, aims to commercialize the production of the devices so each one won�t be a tremendously expensive, custom-made machine. The first heavy-ion facility dedicated to cancer therapy was at Japan�s National Institute of Radiological Sciences labs in Chiba, which began treatment in 1994. A few others have cropped up, but Siemens hopes to accelerate the use of heavy-ion treatmentfrom labs to hospitals.
Several obstacles must be overcome to get carbon and proton beams to market, however. Paul Scherrer�s Pedroni says that cost is a big factor. The beams require big, heavy accelerators that cost tens of millions of dollars. In fact, Siemens estimates that its first 12C systems will each carry a price tag of about 30 million (US $35 million). Pedroni told IEEE Spectrum that while the cost of heavy-ion treatment may be lower than for chemotherapy, it is higher than for X-ray and gamma-ray radiation by a factor of two. A round of heavy-ion therapy can easily total as much as $30 000.
Space is also an issue, because synchrotrons and cyclotrons, the devices used to accelerate the ions, can be as large as 20 meters on a side. Additional space is required for the power and control equipment as well as for the large gantries used to hold the patients in predetermined positions whose coordinates are matched with the position of the ion beam. Even hospitals for which the cost is not too great a hurdle often don�t have the space to allocate 500 or 600 square meters to such a device.
Researchers focused on proton therapy think they may soon have both problems licked. Teams at the Lawrence Livermore National Lab (Livermore, Calif.) and the University of Michigan (Ann Arbor) are working separately on inexpensive tabletop lasers that will provide high-energy ions for cancer treatment. The Michigan team made news in 1999 when they created a beam of protons by firing a 400-femtosecond (400 x 10-15 second) pulse at a 10-µm-thick piece of aluminum. The laser�s electromagnetic field ripped electrons from hydrogen atoms in water that had condensed on the back of the aluminum foil. The positively charged hydrogen nuclei were then dragged along by the electrons, accelerating them to an average energy level of 2 MeV.
Anatoly Maksimchuk, a research scientist at the University of Michigan�s Center for Ultrafast Optical Science, told Spectrum that by 2001, the team had accelerated protons to 15 MeV. He said that he and his colleagues are optimistic that, by spring 2004, they will have achieved 50 MeV. This improvement will come from increased laser power (to about 100 terawatts) and the tweaking of the target material (by coating it with a thin layer of ions). The ultimate goal, said Maksimchuk is, "a $2 million petawatt-class laser capable of producing a sufficient number of protons." Asked when that goal would be realized, he predicted, "We can expect a very reliable system that will fit on two tables [to be available at that price] in about five years."
Scott Wilks, a physicist at Lawrence Livermore, agreed with Maksimchuk�s assessment of petawatt lasers appearing in a few years, but told Spectrum , "I�d tend to be more conservative in extrapolating laser power to possible ion energies." Achieving energies exceeding 200 MeV from a tabletop device may take another decade, he said. As far as getting pinpoint radiation therapy in the hands of doctors everywhere, creating proton beams using tabletop lasers "is a huge step toward that goal. I see a few challenges that have to be addressed, but no showstoppers."