1. Report on the completion of theme 04-2-1035 -2001/2009 "Further Development of Methods and Instrumentation for Radiotherapy and Associated Diagnostics with the JINR Hadron Beams" and on new theme "Medical and Biological Researches with the JINR Hadron Beams" for the period 2010-2012 G.V. Mytsin

2. 2 The main aim of the researches is the realization of medical-biological and clinical investigations at the Medico-Technical Complex (MTC) based at the Phasotron of the Laboratory of Nuclear Problems, to study the effectiveness of hadron radiotherapy for treatment of various neoplasms, modernization of the equipment and devices and development of new methods of radiotherapy and associated diagnostics of cancer patients with medical hadron beams from the JINR Phasotron.

3. 3   Medical Radiological Research Centre of RAMS (Obninsk, Russia),   N.I.Vavilov Institute of General Genetics of RAS (Moscow),   Laboratory of Carcinogenesis OSC of RAMS (Moscow),   Institute of Biomedical Problems of RAS (Moscow),   Institute of Radiation Oncology (Prague, Czech Rep.),   Department of Radiation Dosimetry of the Nuclear Physics Institute (Prague, Czech Rep.),   Great Poland Cancer Centre (Poznan, Poland),   Nuclear Physics Institute (Krakow, Poland),   Institute of Atomic Energy (Otwock-Swierk, Poland),   Institute for Nuclear Research and Nuclear Energy (Sofia, Bulgaria),   University of Medicine and Pharmacy (Bucharest, Romania).

4. 4 Milestones of activity: 1967 – the beginning of the research on proton therapy; 1968 –1974 – first 84 patients treated with protons; 1975 –1986 – upgrading of accelerator and construction of a multi-room Medico-Technical Complex (MTC) for hadron therapy; 1987-1996 – treating of 40 patients with protons, mostly with uterine cervix cancer; 1999, December – inauguration of a radiological department of the Dubna hospital; 2000-2009 June - treating of 545 patients with different tumors, development of the technique for 3D conformal proton radiotherapy.

5. 5 A multi-room Medico-Technical Complex for radiothe- rapy with hadron beams from Phasotron of DLNP JINR.

6. 6 For the first time in Russia and Eastern Europe the technique of 3D conformal proton radiotherapy was realized and is used in radiotherapy sessions with the Phasotron beams. In this method the maximum of the proton beam dose distribution most precisely corresponds to the shape of the irradiated target. At the same time, the dose sharply decreases beyond the borders of the target that allows the irradiation of tumours seated closely to vital radiosensitive organs of the patient.

7. 7 Since 2000, 544 patients (including those from the JINR member states) with various neoplasms in the region of the head, neck and trunk underwent fractionated courses of proton radiotherapy, according to the schedule of research in the effectiveness of application of hadron beams in radiotherapy. The total number of single irradiations (fields) is approaching to 20,000.

8. 8 Results of the follow-up of patients testified that the developed technique of irradiation provides accurate dose delivery to the planned pathological volume. As an example, the figure presents a plan of proton radiotherapy of an intracranial tumour (centre) and images of magnetic-resonance tomography before irradiation (left) and 3 months after irradiation (right). Very good tumour control is observed.

9. 9 In collaboration with Great Poland Cancer Centre experiments have been done at the proton beam using radiochromic films and heterogeneous “Alderson phantom” simulating human ana- tomy to verify all techno- logical stages of prepa- ration and procedure of the patients therapeutic irradiation.

10. 10 Estimated dose distribution in irradiation of the “Alderson phantom” from six directions, with the distribution measured with radiochromic film imposed on it. Matching in the region of high isodoses (50-100 %) is within several mm.

11. 11 To reduce time spent for the verification of the patient’s position during proton therapy sessions, a digital X-ray equipment of Konica Minolta was purchased for extra budget and put into operation. First version of special software was created for that device.

12. 12 Studies in the field of radiation biology were continued in several ways: Determination of the relative biological effectiveness of the therapeutic proton beam in fractionated irradiation of fibroblast cells in conditions maximally approximated to those of patients’ irradiation in treatment sessions. Determination of the relative biological effectiveness of the therapeutic proton beam in fractionated irradiation of fibroblast cells in conditions maximally approximated to those of patients’ irradiation in treatment sessions. Radioprotective action of laser radiation on mice fibroblast cells at their combined irradiation with laser and gamma or proton radiation.Radioprotective action of laser radiation on mice fibroblast cells at their combined irradiation with laser and gamma or proton radiation. As prospects of application of “low-dose hypersensitivity” and “bystander effect” in radiotherapy, investigations of these effects on mice cells.As prospects of application of “low-dose hypersensitivity” and “bystander effect” in radiotherapy, investigations of these effects on mice cells. Two patents for the invention were obtained based on the results of these researches.Two patents for the invention were obtained based on the results of these researches.

13. 13 In collaboration with the Laboratory of Radiation Biology the researches on chromosomal damages in cells on the model of human blood lymphocytes at different stages of the cells cycle after the proton beam irradiation have been carried out.In collaboration with the Laboratory of Radiation Biology the researches on chromosomal damages in cells on the model of human blood lymphocytes at different stages of the cells cycle after the proton beam irradiation have been carried out.

14. 14 Group of molecular and radiation genetics continued researches on DNA mutation changes caused by different kinds of radiation in animal and human cells and the computer simulation of 2-D and 3-D genome macro architecture in the irradiated animal germ cells with the "position effect" of gene.

15. 15 To provide designing, construction, and "turn-key" delivery of the dedicated proton therapy centres and medical and diagnostic services JINR creates an innovation venture “Cyclone” in the frame of the Dubna Special Economic Zone. Since 2007 JINR together with “Cyclone” and Belgium firm IBA - the world lieder of the medical technique for the proton therapy - started construction of the dedicated medical cyclotron applied for the proton therapy. This cyclotron will have better parameters than IBA cyclotrons already installed in 7 hospital centres of proton therapy all over the world.

16. 16 The Federal program “Creation of federal high technology centres of medical radiology” is formed now in Russia at the leadership of Federal Medico-Biological Agency (FMBA). One of first four centres is planed to construct in Dubna.

17. 17

18. 18 The realization of the theme became an important achievement in the research on hadron therapy effectiveness for treatment of various neoplasms and development of new methods of radiotherapy of cancer patients with the medical hadron beams from the JINR Phasotron that was started as far as in 1967. New data have also been received during radiobiological and molecular radiation genetic researches.

19. 19 Proposal of New Theme "Medical and Biological Researches with the JINR Hadron Beams“ for the period 2010-2012 To continue clinical studies in proton therapy of various neoplasms at the JINR Phasotron beams.To continue clinical studies in proton therapy of various neoplasms at the JINR Phasotron beams. To develop equipment for conducting of dynamic conformal irradiation of deep seated targets with a wide proton beam.To develop equipment for conducting of dynamic conformal irradiation of deep seated targets with a wide proton beam. To continue research in the field of dosimetry and microdosimetry of therapeutic hadron beams and elaboration and upgrading of detectors for dosimetry of these beams.To continue research in the field of dosimetry and microdosimetry of therapeutic hadron beams and elaboration and upgrading of detectors for dosimetry of these beams. To study the prospects of using the effects of low-dose hypersensitivity and "bystander" effect in the radiation therapy with animals.To study the prospects of using the effects of low-dose hypersensitivity and "bystander" effect in the radiation therapy with animals. To continue fundamental investigations on the comparative mutagenesis at the DNA level in the gene- targets with different size and exon- intron structure as well after action of different quality radiation.To continue fundamental investigations on the comparative mutagenesis at the DNA level in the gene- targets with different size and exon- intron structure as well after action of different quality radiation.

20. Expenses for the theme implementation for the period 2010 - 2012 * - 40% of expenses for the electricity is covered by the Russian Federal Medico-Biological Agency. 20 №Units and systems of facilityResources needed 201020112012 1. 2. 3. 4. DLNP Phasotron* Materials Equipment Scientific visits 900 hrs 5,000 $ 10,000 $ 900 hrs 5,000 $ 10,000 $ 900 hrs 5,000 $ 10,000 $ Total25,000 $