Accelerator for Boron Neutron Capture Therapy Proposed by Lab

June 21, 1996

By Lynn Yarris, LCYarris@LBL.gov

A proposal by Berkeley Lab researchers, if successful, offers hope for victims of one of the deadliest of all forms of cancer. The proposal calls for the construction of a unique room-sized accelerator that would be used in an experimental medical procedure aimed at treating a type of brain tumor called a "glio-blastoma multiforme." The procedure is known as boron neutron capture therapy (BNCT).

Glioblastoma multiforme afflicts approximately 12,500 people in the United States every year. The disease is always fatal, usually within six months of onset. Surgery and conventional radiation therapies may prolong life for as much as a year but do not stop the spread of tumors throughout the brain. Experiments in the U.S. in the early 1960s involving BNCT, and subsequent work in Japan, have tantalized researchers with hints that successful treatment of glioblastoma multiforme is possible. However, many critical questions need to be answered.

The idea behind BNCT is straightforward. A tumor-seeking compound containing boron-10, a non-radioactive isotope, is introduced into the brain and given time to accumulate in the tumor. The tumor is then exposed to a beam of neutrons, which are "captured" or absorbed by the boron-10. Capturing neutrons causes the boron nuclei to break apart, resulting in the emission of alpha radiation and lithium nuclei. Both alpha-particles and lithium are high in energy but short in range, which means they destroy the malignant cells in which boron-10 is imbedded without hurting the adjacent healthy cells.

Scientists have known about the ability of boron-10 to capture neutrons since the 1930s and use it as a radiation shield in geiger counters. In the 1960s, collaborative BNCT experiments were conducted by researchers at Brookhaven National Laboratory (BNL) and the Massachusetts Institute of Technology (MIT) on 69 patients diagnosed to be in the advanced stages of brain cancer. Despite treatments, all of the patients died. However, autopsies revealed that the tumors had been destroyed.

"At that time, researchers did not understand that you must have four times more boron-10 in the tumor than in the surrounding healthy tissue for BNCT to work," says Bill Chu, a Life Sciences Division (LSD) physicist working with the Ion Beam Technology Group in the Accelerator and Fusion Research Division (AFRD). "Otherwise, there is too much damage to the normal tissue for any therapeutic gain."

Subsequent BNCT experiments in Japan in which miraculous results were reported (though not always believed) have encouraged a revival of the research effort in the U.S and Europe. One of the chief issues to be resolved is finding the best way to generate the neutrons that the boron-10 captures. Following the path of the earlier experiments, researchers at BNL and MIT are using a nuclear reactor as their source of neutrons. This begs the question, how many hospitals are willing to install a nuclear reactor on their premises?

Berkeley Lab researchers, led by LSD's Chu, in partnership with medical researchers at major West Coast institutes, have proposed what should be a much more acceptable alternative.

"We want to build a high-current electrostatic quadrupole (ESQ) accelerator which would be used in a science-based BNCT facility at Berkeley Lab," says Chu. "We would use components from the SuperHILAC and the technology developed in the Lab's fusion energy program."

According to Chu, using a compact (about three meters in length) ESQ accelerator for BNCT rather than a nuclear reactor is not only more realistic, it also offers many technical and economic advantages. From the technical standpoint, an ESQ accelerator produces more "epithermal neutrons" (neutrons in the one to 10,000 electron volt energy range) at energies that are ideal for BNCT, especially for the treatment of deep-seated tumors.

"Furthermore, the ESQ accelerators generate epithermal neutrons at lower energies than those produced in nuclear fission processes," says Chu. "This makes it easier to reduce the harmful higher-energy components of the epithermal neutron beam."

Another technical issue is the type of boronated compound that is introduced into the brain. Researchers using a reactor for their neutron source have been approved to work with two compounds that were developed in the late 1950s and are not viewed as ideal. Recently, Professor Stephen Kahl, at UC San Francisco, developed a compound called "boronated porphyrin" or BOPP, which has shown enormous promise in various animal studies. For any such compound to be effective, it is crucial for it to be able to get past the blood barrier that encases and protects the brain. It is also crucial that the compound concentrates in tumors and rapidly clears from healthy brain cells and the blood system.

"In animal studies (mice and dogs), the ratio of BOPP in tumors and healthy cells was greater than 100 to one, and it cleared sufficiently fast from the blood," says Kahl. "BOPP is also better than 30-percent boron by weight and highly water soluble, which should make it safer and more effective than the old compounds."

A BNCT facility at Berkeley Lab with its ESQ-accelerator would be established specifically to test BOPP and other new boronated compounds as they are discovered. It could also be used to test compounds that concentrate in other types of tumors, such as melanoma, sarcoma, head, neck, and pancreas tumors.

To make sure that the Berkeley Lab's BNCT is a valuable resource for the medical community as well as an important scientific tool, Chu has worked with Dr. Ted Phillips, Chair of Radiation Oncology at UCSF, to organize an interdisciplinary group called the West Coast Neutron Capture Therapy Association. Joining Berkeley Lab and UCSF as member institutes of this association are UC Berkeley and UC Davis, Stanford University, Loma Linda University, and the University of Washington.

Here at Berkeley Lab, the BNCT project team has been able to draw from a wide and diverse talent pool. In addition to Chu, the list of involved Lab researchers includes, from AFRD, Darren Bleuel, Rick Gough, Joe Kwan, Ka-Ngo Leung, John Staples, Bob Stevenson, and Simon Yu; from LSD, Javed Afzal, Ellie Blakely, Tom Budinger, Dan Callahan, Bernhard Ludewigt, and Scott Taylor; from Engineering Division, Matt Hoff, Craig Peters, Lou Reginato, and Rajinder Singh; and from the Environmental Health and Safety Division, Rick Donahue.

The proposed ESQ-accelerator at Berkeley Lab would be an upgraded version of the Adam injector that served the SuperHILAC so well. With the accelerator technology for the most part proven, and portions of the hardware available through re-cycling, the cost of constructing a patient-ready BNCT facility at Berkeley is estimated at $4 million. This is substantially less than the cost of converting a nuclear reactor for medical use. Once up and running, operational costs for an accelerator-based facility would also be lower than those for a reactor-based system.

"There is also the matter of disposing of a nuclear reactor when it has reached the end of its useful life," says Chu. "This is not a problem for ESQ accelerators."

Chu estimates it would take approximately 2.5 years to complete Berkeley Lab's BNCT facility, which means that if started next year, clinical trials on patients could be underway by 1999. AFRD will be receiving $300,000 for the preliminary proposal work for this year. A peer review will be held this summer before a final decision on full funding is made.