If you were diagnosed with a type of brain cancer known as glioblastoma multiforma back in the 1950s, there wasn’t much doctors could do to fight it.
There still isn’t.
About 6,000 to 12,000 Americans per year come down with this disease, a relatively small number of cancer victims in comparison to the hundreds of thousands who develop breast cancer each year. But while this brain cancer is rare, it is hyper-aggressive. The typical glioblastoma multiforma patient back then only had six months to live; today, the median survival rate is a year.
Conventional treatments such as chemotherapy have little success in reaching every rootlet of this brain cancer. The human body’s natural defense mechanism, known as the blood-brain barrier, keeps most cancer-fighting drugs from reaching these sites deep in the brain. And doctors cannot afford to miss even a few of these cancer cells; if they do, this cancer comes back quickly. Chemotherapy typically buys “glio” patients only 15 extra days of life.
But with better knowledge of cancer and improved technology, a radiation treatment for glioblastoma multiforma that was largely neglected for decades in America may return. The treatment, known as boron-neutron capture therapy, may yet escape its Cold War heritage and a shaky start full of controversy. If it does, some of the credit may go to a newly developed optical fiber device that can monitor the exact amount of radiation delivered to a tumor in real time.
Known as a neutron-beam flux monitor, the device is made of small, flexible fibers that can be easily guided to the cancer site. “It could be implanted prior to irradiating the tumor. . . .It would be wonderful, absolutely wonderful,” said Jim Venhuizen, program manager of the boron neutron capture therapy research program at the Idaho National Engineering and Environmental Laboratory in Idaho Falls, Idaho. “It’s a totally different ball game now,” he said. “Up to now, you could only estimate the amount of radiation received by the tumor beforehand and then measure the actual dosage well afterward. You were kind of flying blind. You didn’t know if you were giving enough radiation for a long enough time, or if you had the correct orientation of the beam,” Venhuizen added.
His laboratory colleague, research scientist Yale Harker, explained that the key to the device lies in the optical fibers themselves, which are made of a new, lithium-doped cerium glass developed at Pacific Northwest National Laboratories in Richland, Wash. When a neutron strikes this sandwich, it collides with the lithium and releases an alpha particle and tritium, exciting the cerium atoms and causing them to produce a series of scintillation flashes which are then transferred to a photomultiplier tube to give a chain of electronic pulses that can be counted. This gives an indication of the number of neutrons delivered to the tumor, as the lithium has a similar neutron absorption cross section to the drugs used for the treatment.
The lack of such a monitor was one of a number of factors that helped doom previous attempts at this cancer-fighting technique. To understand why, you must go back to the early days of what was then called the Atomic Age, when the Eisenhower administration wanted to promote its “Atoms for Peace” initiative. In the spirit of the era, scientists turned to an avenue that sounded promising: fission.
The theory behind boron neutron capture therapy, as first suggested by neurosurgeon William Sweet of Massachusetts General Hospital, is relatively simple. Sweet, who oversaw the project, injected patients with a chemical compound, boric acid, which contained a non-radioactive isotope called boron-10. The idea was that the boric acid would easily slip past the blood-brain barrier and deliver the isotope to the tumor, where it would be taken up. (Healthy tissue would not absorb boron-10 as well.) In oncologists’ parlance, boron-10 was preferentially absorbed by the tumor.
Once the boron isotope was in the tumor, a beam of thermal neutrons was directed at the brain. These low-energy particles, containing just a few electron volts, would sail harmlessly past the healthy brain tissue to strike the nuclei of the boron-10 in the tumor. The boron-10 would then “capture” the neutrons and immediately break itself apart, or fission. Over 2.4 million electron volts would be released in the process, killing the tumor cell. Because of a quirk of this reaction, this energy can only travel 5 μ, or about the distance of one cell diameter, effectively preventing it from harming the surrounding healthy tissue. The remaining boron compound could then be cleared from the body without causing any harmful side effects.
In practice, however, the very first forms of boron neutron capture therapy were primitive, at least to modern eyes. First, one of the reactors used for nuclear research at Long Island’s Brookhaven National Laboratory was switched off, then blocks of radiation shielding were removed from the floor, a hole opened up in the roof, and a semi-conscious brain cancer patient lowered on a stretcher into the pit below. Then the reactor was switched back on and the patient exposed to high flux neutron beams for forty minutes. Afterward, the reactor was temporarily shut down again, and the patient hoisted out and taken back to the hospital.
Brookhaven was home to one of only two reactors used to conduct this type of medical research in America. (The other was at the Massachusetts Institute of Technology [MIT] in Cambridge, Mass.) Tour the green, leafy, campus-like setting of the Brookhaven facility in Upton, N.Y., today, and it is hard to conceive the physical and emotional trauma those first patients must have gone through. The reactor would hiss during the procedure, as 400-mph winds raced through the cooling channels that interlaced the graphite blocks in the reactor. “All the lights would go off while they were doing it,” said one Brookhaven employee in a phone interview recently. “Those treatments were a big event back then.” The public spectacle of the treatment must have been trying in itself; a 1951 Collier’s Magazine article ran an article on the radiation therapy headlined “Science Explodes an Atom in a Woman’s Brain.”
Unfortunately, the superheated publicity raised hopes that were soon dashed. While still called an elegant technology, there were many difficulties to practicing the treatment at the time: the boric acid that carried the boron-10 was not always preferentially taken up by the tumor; it was difficult to pinpoint the precise site of the tumor; and it was hard for the weak neutron particles to get past the human skull. And the lack of a real-time monitoring device meant that it was hard to determine whether the patient was receiving too much or too little radiation until well after the fact. There were some promising initial results, but after some patients suffered from radiation burns, boron neutron capture therapy gradually fell into disfavor in the United States by the late 1960s.
More recently, on October 16, 1999, a federal jury ordered Massachusetts General Hospital and the 89-year old Sweet to pay $8 million in damages to the families of two glioblastoma multiforma patients who died while undergoing the experimental procedure 38 years ago. (Claims against MIT were thrown out, on the grounds that their facility merely provided technical expertise in nuclear energy, not medical care.) According to the Boston Globe, jurors found that the hospital and Sweet were negligent and wrongfully caused the deaths, while rejecting the claim that they had failed to inform patients about the procedure and get their consent. Lawyers for the defense said that they would appeal, and ask the judge presiding over the trial to set aside the jury’s verdict.
Paradoxically, despite these enormous setbacks, interest in this radiation treatment has grown. Part of the reason for this is the success of overseas researchers, who continued to work in this area even while the United States cut back its program. Hiroshi Hatanaka, a Japanese scientist who studied under the US program, modified the approach, using a combination of conventional surgery to remove the bulk of the tumor and an eight-hour long BNCT radiation session to finish off the remaining cancer cells. Thirty percent of his glio patients survived over 5 years. (Only 10 percent of these cancer victims survived as long under standard photon therapies.) Although details of the Japanese program — the longest and most well-established boron neutron capture therapy treatment — have not been published in peer-reviewed journals, word of such results swelled interest in the approach here. By the mid-‘90s, American citizens with glioblastoma multiforma were flying to Japan to undergo Hatanaka’s $60,000 treatment.
Another part of the reason for the renewed interest here is improved technology. Computers operating at speeds that were only dreamed of in the ‘50s and ‘60s can model the exact position of a tumor in three-dimensions. An improved chemical compound, known as p-boronophenylalanine, has made it easier to ensure that boron-10 is preferentially absorbed by cancerous tissue. And a different type of neutron beam makes it easier for these particles to get past the formidable barrier of the human skull. As a result, in 1995, Phase 1 clinical trials on this technique began once again on humans in the United States.
In an ironic twist, the fibers of the monitor were originally created by researchers as part of a Cold War military program to detect plutonium smuggling. Recently declassified for civilian use, the new lithium-doped glass proved adept at picking up neutrons, regardless of whether they came from a pile of weapons-grade plutonium or the beam of a medical reactor. Recognizing its potential, project leader Mary Bliss and her colleagues at Pacific Northwest National Laboratories brought the fibers to the attention of the boron neutron capture therapy researchers, with the aid of the Department of Energy’s Office of Arms Control and Nonproliferation.
With the advent of a promising new boron delivery compound, new fibers and a new detector, researchers are hopeful that research on this brain cancer treatment can start to progress again in the United States. Though Harker cautions that the fiber optic neutron detector is still in the early stages of development, a reactor beam facility to test the effects of this radiation treatment on animals is already under construction at Washington State University in Pullman. His fiber optic device will be used to monitor the radiation dosages.
Only time will tell whether these latest technological developments will make this treatment an everyday event, or whether this elusive goal will continue to remain out of reach. As of press time, the program is under review, as the Department of Energy decides whether to continue studies on humans at Brookhaven or step back to experiments on animals and cell cultures. The optical fiber device continues to be tested in the Idaho laboratory, and can be used under either scenario.
Harker and his colleagues remain undaunted by the hard luck dogging boron neutron capture therapy. “There’s not many other options for these patients,” he said.
-- Dan Drollette
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