New cancer clinical trials are encouraging


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Sarah H. Wright
Email: shwright@mit.edu
Phone: 617-258-5400
MIT News Office

CAMBRIDGE, Mass.--Researchers from the Massachusetts Institute of Technology and the Beth Israel Deaconess Medical Center have begun clinical trials of a new type of brain cancer therapy. The experimental form of radiation therapy is called boron neutron capture therapy, or BNCT.

BNCT has shown promising results in the ongoing FDA-approved phase-I clinical trials. To date, eleven patients suffering from glioblastoma multiforme, a highly malignant form of brain tumor, or brain metastases from melanoma, a malignant form of skin cancer that can spread throughout the body including the brain, have been given BNCT. Five patients with metastatic melanoma have also been given BNCT in a phase-I trial.

"The promise of BNCT is the selective irradiation of tumor cells in a way that is not achievable using current forms of conventional radiation. So far, our expectations have been met with respect to the scientific goals of the clinical trials, and two patients with melanoma have had complete regression of this disease, a very encouraging beginning," said Paul M. Busse, M.D. Ph.D., Associate Chairman, Joint Center for Radiation Therapy and Assistant Professor at Harvard Medical School, one of the principal investigators of the BNCT project and director of the clinical aspects of the research.

The research team has been directed by Robert G. Zamenhof, Ph.D., a radiological physicist at the Beth Israel Deaconess Medical Center and an Associate Professor of Radiology at the Harvard Medical School, and by Otto K. Harling, Ph.D., a Professor of Nuclear Engineering at MIT.

If in the future BNCT proves successful in controlling highly malignant brain tumors and peripheral melanoma it could be applicable to many other types of cancer which are at present not easily controlled by conventional therapeutic techniques.

The BNCT Protocol

Patients are first infused intravenously with a special drug which is tagged with a non-radioactive isotope called boron-10. The boron-10-tagged drug concentrates preferentially in tumor cells, where it lies in wait. The patients are then exposed to a specially designed beam of "epithermal neutrons" at the MIT research reactor in Cambridge. When the beam is turned on it passes through a "collimator" in the ceiling of the medical irradiation room and then passes through the patient's scalp and skull into the brain. When the brain is exposed to the epithermal neutrons, the boron-10 atoms absorb, or "capture," the neutrons that pass close by. Once they have captured a neutron the boron-10 atoms become unstable and immediately release highly energetic subatomic particles called alpha particles which travel only short distances.

The success of BNCT relies on both the ability of the boron-10 atoms in the tumor cells to capture neutrons followed by the alpha particles' brief, precise, and hopefully deadly targeting of the tumor cells' nuclei -- the most critical structures within the tumor cells. Because of the alpha particles' very short range, researchers expect that if alpha particles start their flight inside a tumor cell, they will mostly damage the tumor cell and not the nearby normal brain cells.

Before a judgment can be made regarding the efficacy of BNCT for brain tumors, the phase-I study must be completed so that the maximum possible safe level of radiation can be established. This is because in BNCT as in conventional forms of radiotherapy, the best therapeutic results are obtained when the patient is irradiated to a dose which is close to the tolerance level for their healthy tissue. However, even at lower radiation doses that have so far been delivered, tumor responses have been observed.

An interdisciplinary team of scientists and engineers from Harvard and MIT and previously Tufts-New England Medical Center devoted years of intense research effort to develop this experimental therapy to the stage where these clinical trials could be initiated.

All three principal investigators work closely together to coordinate the clinical trials as well as ongoing research in various aspects of neutron capture therapy.

The MIT-Harvard research team is also conducting a separately approved phase-I BNCT protocol on metastatic melanoma in the extremities. Researchers from the Tufts-New England Medical Center and the Boston Medical Center have also participated in the early stages of this melanoma study. Five patients have undergone the irradiation and no significant treatment toxicity has been observed so far.

Despite the phase-I nature of the protocol, clear indications of tumor shrinkage have been observed in several of the melanoma subjects, with complete regression of tumor in two cases.

Phase-I trials are aimed primarily at determining the safety of a new therapeutic technique and involve a process of gradual dose increase to determine the maximum safe dose of radiation that can be delivered.

The clinical researchers carefully follow the BNCT patients by periodic MRI scans and physical evaluations to detect the point in the dose escalation where the brain or other healthy tissue just starts to show some reversible reaction to the radiation.

Phase-II clinical studies include more patients and are designed to determine the benefits of the experimental treatment at the dose levels established in the phase-I trials. The Harvard-MIT researchers hope to complete Phase-I and to launch Phase-II studies in about six to twelve months.

The MIT scientists and engineers have started to construct a much more intense and higher-quality epithermal neutron beam. Called a "fission-converter beam," it should make the phase-II studies much easier for the patients and the BNCT more effective.

"This new neutron facility promises to be the best of its kind in the world and it should make the treatment more effective and greatly enhance patient comfort," stated Dr. Otto Harling.

"Not only is this an exciting project in view of the good that it may eventually do for victims of brain or other cancers, but it has brought together in a unique way the support of the US Department of Energy, the awesome resources of the MIT Research Reactor, and the collaboration of physicists, engineers, physicians, chemists, computer specialists, and nurses," commented Dr. Zamenhof.

"And our research has provided excellent education and training for a number of bright young graduate students. One could not wish for a more simulating project," commented Professor Harling.

Financial support for this research has been provided primarily by the US Department of Energy. Additional support has been provided by the Herbert M. Karol Cancer Foundation, American Medical Response Ambulance Co., Fallon Ambulance Co. and the parent institutions of the principal researchers.

Individuals interested in these phase I protocols can contact Dr. Paul Busse at the Beth Israel Deaconess Medical Center (617-632-8510), Dr. Robert Zamenhof also at BIDMC (617-667-0175) or Professor Otto Harling at MIT (617-253-4201).


Topics: Health sciences and technology, Nuclear science and engineering, Biology

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