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Preclinical NCT Studies

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Preclinical Neutron Capture Therapy Studies at the MEPhI IRT Nuclear Reactor

Tech Area / Field

  • BIO-RAD/Radiobiology/Biotechnology
  • MED-RAD/Radiomedicine/Medicine
  • FIR-EXP/Experiments/Fission Reactors

Status
8 Project completed

Registration date
02.08.2000

Completion date
12.08.2005

Senior Project Manager
Novozhilov V V

Leading Institute
MIFI, Russia, Moscow

Supporting institutes

  • Cancer Research Center / Institute of Experimental Diagnostics and Therapy of Tumors, Russia, Moscow\nState Research Center – Institute of Biophysics, Russia, Moscow

Collaborators

  • Massachusetts Institute of Technology (MIT) / Nuclear Engineering Department, USA, MA, Cambridge

Project summary

There are many different forms of oncological diseases, for which the available methods of treatment are ineffective. According to the data of American clinicians, a combination of surgery and irradiation of the tumor results in healing of approximately 45% of patients; chemotherapy results in healing of ~5% of patients. Hundreds million dollars have been spent to improve the methods of chemotherapy, immunotherapy and radiotherapy of cancer. However, still about half of the patients die from this disease.

An increase in therapeutic efficiency can be reached with a method which is capable to provide a selective lesion of tumor, saving adjacent critical, normal tissue. Neutron Capture Therapy (NCT) is a method that meets the specified requirements. The main point of the method is simple. Compound containing boron, gadolinium or other element with a significant capture cross-section for thermal neutrons, is administered to the tumor. Under subsequent neutron irradiation, the neutron capture results in prompt secondary radiation originating in the tumor, which damages the tumor cells.

In 1993 a group of scientists from the Institute of Biophysics and MEPhI (the authors of this project), with support from the Institute of Diagnostics of Germany (Berlin), started studies on the efficiency of Gd-containing compound Magnevist (production of Schering AG, Berlin) in the neutron capture therapy. Magnevist is used as a contrast agent in the NMR-diagnostics of brain tumors, i.e. it is tumorotropic. As a result of studies at the IRT MEPhI nuclear reactor, the drug concentrations and irradiation time were selected so that in 80% of tumor-carrying rats (Enson sarcoma) with the drug, the full tumor resorption was observed. The first experiments on irradiation were carried out at a low level of the thermal neutron flux (~108 n/cm2×s), backgrounded with significant concomitant gamma-radiation of the beam (1.2 cGy/s), which is parasitic for the method of neutron capture therapy, as it can damage healthy tissues. The encouraging results stimulated the development of researches on NCT for other tumors with new compounds. Currently, the NCT is mostly applied to treat brain tumors and melanoma.

In 1995-1998, on the horizontal tube of the IRT MEPhI reactor, experimental studies were conducted in a cell culture and in small tumor-carrying laboratory animals (rats with S-45 sarcoma and mice with B-16 melanoma) for the study of the neutron capture therapy efficiency. The research showed complete tumor resorption in at least 60% of animals, and in the C-45 sarcoma cells suspension this effect made 100%.

During the last 10-15 years, new possibilities for the NCT have opened owing to the results on NCT of malignant melanoma obtained by Professor Mishima (Japan) . Malignant melanoma is a skin cancer, from which over 4000 patients die every year in the USA only. The rates of growth for this disease are rather high. Malignant melanoma is a highly lethal disease, and it is resistant to the existing methods of treatment. The NCT treatment for melanoma is effective at a level of 80-90% with five year survivors.

The NCT can be expected to be an effective method of treatment for many other types of cancer, such as cancer of colon, rectum, prostate, mamma, lungs, etc.

For the successful application of NCT it is necessary to have:

1. Thermal neutron beam with flux density ~ 109 n/cm2×s. For deeply seated tumors it is necessary to use an epithermal neutron beam with energy of ~10 keV. Therefore, the NCT technology is developed almost in all countries where research reactors are available.

2. Boron and/or Gadolinium-containing compound of certain tumorotropy, in order to provide 10В isotope concentration of 35-40 µg per gram of tumor, and for the 157Gd isotope - 800 µg per gram of tumor.

Main objectives of the proposed project:

· Development and implementation of an irradiation base for the neutron capture therapy at the IRT MEPhI nuclear reactor

Currently one of the main problems is the creation of medical base in Moscow for the application of new radiation technologies for radiotherapy of malignant tumors, and stepwise application of the NCT methods in the clinical practice for the rise of treatment efficiency for malignant neoplasm, which are not curable or poorly curable by conventional methods. For these purposes an irradiation facility will be created at the tangential tube of the MEPhI reactor.

The radiation source for the purposes of NCT for malignant neoplasm should meet certain strict requirements. Most of those are as follows:

1. Maximum thermal or epithermal neutron flux density (over 109 n/cm2×s) in the irradiation position with minimum contribution of concomitant radiation.

2. Minimum radiation dose outside of the beam in the irradiation box in order to decrease the effect of radiation on healthy organs.

3. Small geometrical size of the irradiation field at an even distribution of power through the radiating area, which requires to collimate the irradiation beam.

To a great extent, the specified requirements can be met with an appropriate optimization of the radiation field characteristics by means of intra-tube devices (scatterers, collimators, filters etc.).

In the course of work, an irradiation base with biological protection and movable system providing fixing of radiation detectors, phantoms and laboratory animals, will be created at the MEPhI nuclear reactor.

All of these will allow to increase the thermal neutron flux in the beam up to 109 n/cm2×s, and to reduce the gamma dose rate down to 0.1 cGy/s. Such characteristics will provide acceptable time limits for the local irradiation of the patient to achieve the integral thermal neutron fluence of ~1013 n/cm2 (such fluence is considered to be sufficient to achieve therapeutic success at an optimal content of 10В and/or 157Gd in tumor). Thus, it is reasonable to assume, that the neutron-physical support of the neutron capture therapy method for malignant melanoma at the IRT MEPhI reactor will meet the modern requirements.

For the implementation of the set goal it is necessary to develop an automated system of dosimetric support of irradiation, and a system to determine boron and/or gadolinium concentration in tumor (in vivo).

· Preclinical trials of neutron capture therapy of malignant melanoma in large laboratory animals

During implementation of the Project it is supposed to carry out a complex of studies on the most promising boron- and gadolinium-containing compounds in a cell culture (including tumor cell suspensions) in small laboratory animals in order to start preclinical trials of the neutron capture therapy method in large laboratory animals (dogs) with spontaneous malignant melanoma. A distinctive feature of these trials will be the use of boron- and gadolinium-containing compounds (foreign researchers in the USA, Europe and Japan mainly use boron compounds). Our researches and researches of Y. Mishima (Japan) have shown the synergism of 10B and 157Gd containing compounds. The nature of this phenomenon is unknown, therefore our task is to research this phenomenon, and apply it to increase the efficiency of the neutron capture therapy for malignant tumors.

Basing on the studies in small and large tumor-carrying (melanoma) laboratory animals it is supposed to formulate final requirements to the application of the new radiation technology on the basis of neutron capture therapy method and to present appropriate documents to the Ministry of Health of Russian Federation to get a permission for clinical trials.

Future clinical trials of the method of neutron capture therapy in humans are expected to prove the possibility to increase the efficiency of treatment for this type of cancer compared to the existing methods.

Conversion of the reactor into a therapeutic neutron source will become possible owing to the implementation of the present project supported by the ISTC.

Development and implementation of the new radiation technology for the treatment of malignant tumors with the method of neutron capture therapy in Russia will allow to admit patients from other countries and, first of all, CIS countries. The estimated treatment cost for one patient with application of this technology (according to the data of Japanese medical centres) is $50,000 USD. To our estimation, the cost of such treatment in Russia will be at least five times lower. Therefore its commercial use is possible, especially it is concerned with the know-how on the usage of compounds we synthesised, containing the neutron capture agents.

This project is an example, how the achievements in the field of nuclear and technical physics and appropriate intellectual potential of the experts in this area will be used in the field of medicine to solve the problem of struggle with the most dangerous oncological diseases.

Implementation of the Project will allow the scientists of Russia to become participants of the international scientific community for neutron capture therapy.


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