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Fast neutron therapy, which previously has demonstrated effective results, but along with a large number of complications, can again be considered a promising treatment method in the treatment of cancer. One of the ways of analyzing the relative biological efficiency and accurate biological dose of fast neutrons in body tissues is to improve the algorithms of computational biology and mathematical modeling. A high-performance computing code was written which allows to estimate in real-time mode the biological dose of the proton component from the action of neutron radiation with an energy of 14.8 MeV. A comparative analysis of the computing performance on various video cards was also performed., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

Proton therapy (PT) due to dosimetric characteristics (Bragg peak formation, sharp dose slowdown) is currently one of the most high-tech techniques of radiation therapy exceeding the standards of photon methods. In recent decades, PT has traditionally been used, primarily, for head and neck cancers (HNC) including skull base tumors. Regardless of the fact that recently PT application area has significantly expanded, HNC still remain a leading indication for proton radiation since PT's physic-dosimetric and radiobiological advantages enable to achieve the best treatment results in these tumors. The present review is devoted to PT usage in HNC treatment in the world and Russian medicine, the prospects for further technique development, the assessment of PT's radiobiological features, a physical and dosimetric comparison of protons photons distribution. The paper shows PT's capabilities in the treatment of skull base tumors, HNC (nasal cavity, paranasal sinuses, nasopharynx, oropharynx, and laryngopharynx, etc.), eye tumors, sialomas. The authors analyze the studies on repeated radiation and provide recent experimental data on favorable profile of proton radiation compared to the conventional radiation therapy. The review enables to conclude that currently PT is a dynamic radiation technique opening up new opportunities for improving therapy of oncology patients, especially those with HNC., Competing Interests: Conflicts of interest. The authors declare no conflicts of interest related to the present study.

The study is based on the results of treatment of 60 patients with locally advanced laryngeal cancer (T3-4N0-3M0) exposed to combined treatment: 31 with preoperative chemoradiothera-py, 29 thermochemoradiotherapy. Radiotherapy was performed in the hyperfractionated mode: “1 Gy +1 Gy” (every 4-5 hours) 5 times a week to 30-40 Gy in total. Local hyperthermia was performed 2 times a week before the second fraction of radiotherapy in 3-4 sessions. Eight-day courses of chemotherapy were administered in the beginning of radiotherapy by scheme: vincristine (1. 4 mg/m2 per 1day), cisplatin (20 mg/m2 2, 3, 4 days), bleomycetin (10 mg/m2 5, 6 days), cyclophosphamide (200 mg/m2 7, 8 days). Surgical treatment was performed through 2,5 3 weeks after completion of radiotherapy. Local hyperthermia intensified the course of radiation reaction on the mucous of the larynx but not significant influenced on healing of surgical wounds. Thermochemoradiotherapy compared with chemoradiotherapy raised local relapse-free survival from 75 to 93% (p = 0. 07), regional, for a group of patients with stage N1-3 from 33 to 70%, N1-2 from 40 to 78% (p = 0. 1), loco -regional from 67 to 87% (p = 0. 04). Our findings suggest the necessity for further research on the use of thermochemoradiotherapy in combined treatment of patients with locally advanced laryngeal cancer.

On November 23, 2015 in Protvino of the Moscow Region there was begun proton therapy using Russia's first medical therapeutic complex "Prometheus" produced by JSC "PRO- TOM" and certified to treat patients with head and neck tumors. The complex allows irradiating patients with active scanning beam. Energy of beam is 30-250MeV and maximum field size is 10 cm vertically and 40 cm horizontally. The manufacturer declared parameters were confirmed during preclinical stud- ies. By April 8, 2016 the successful proton therapy received 20 patients with complex "targets" mostly located, from the point of view of radiation tolerance, near the critical structures.

The combined treatment with preoperative chemoradiotherapy (CRT) was performed in 28 patients with locally advanced laryngeal cancer (T3-4N0-3M0). Radiation therapy (RT) was carried out according to the scheme "1 + 1 Gy" (interval 4-5 hours) 5 times a week till 30-40 Gy. RT was accompanied by simultaneous polychemotherapy: vincristine (1.4 mg/m² per day), cisplatin (20 mg/m²--2-4 days) bleomicetin (10 mg/ m²--5, 6 days), cyclophosphamide (200 mg/m²--7, 8 days). Surgical treatment was carried out in 2.5-3 weeks after CRT. CRT allowed conducting organ-saving surgery on the larynx in 11 (52%) of 21 patients with T3 of primary tumor. All other patients underwent laryngectomy at a different volume. Five-year disease-free survival for the whole group in total (T3-4) was 88%. Relapses of regional metastases (MTS) occurred in 7 of 9 patients including in 4 of 5 patients after lymphadenectomy. The overall survival of patients with T3N02 was 71%, with T4N0-3--20%. Thus we have developed a method of treatment allowing to achieve high local relapse-free survival in patients with locally advanced laryngeal cancer. However organ-saving effectiveness of preoperative CRT and its effect on regional MTS remain low, which requires further research in this direction.

This study presents the short-term outcomes of conformal external beam radiation therapy given in conjunction with hormone therapy to 110 patients with prostate cancer. We performed a comparative analysis of the rate and degree of radiation reactions and complications following delivery of a total dose of 70 Gy and 72-76 Gy to the tumor. In prostate cancer, a continuous course of dose-escalated conformal radiation therapy resulted in satisfactory tolerance and acceptable levels of late complications.

There were analyzed results of treatment of 58 patients with laryngeal cancer T3-4N0-3M0. Chemoradiotherapy (CRT) was carried out in 27 patients, thermochemoradiotherapy (TCRT)-in 31 patients. Radiotherapy (RT) was performed in hyperfractionated mode (1 Gy + 1 Gy with an interval of 4-5 hours) 5 times a week to CTD 52-60 Gy with a 2-week break after CTD 30-40 Gy. Local hyperthermia (LHT) was carried out 2 times a week before the second fraction of RT in an amount of 3-6 sessions. The first cycle of polychemotherapy was administered at the beginning of RT and the second one-after the break. The local control under the primary tumor category T3 after CRT was equal to 58% and after TCRT--88%, at T4--72% and 25%, respectively. Late radiation damage of the larynx in the form of mucosal edema and perichondritis after CRT was in 2 patients (7%) and after TCRT--in 3 patients (10%). Thus, TCRT for locally advanced laryngeal cancer allows obtaining a higher overall survival and a local control as compared to CRT and does not lead to a significant increase of frequency of perichondritis.

Long term results of treatment of patients with locally advanced breast carcinoma with the use of mixed photon-neutron therapy (PNT) are presented. Among 201 patients with locally advanced breast cancer receiving radiation therapy, in 95 of them it was implemented as a combination of photon and neutron radiation therapy and in 106--in the form of mega-volt photon therapy (PT). Comparative evaluation of the long-term results of treatment proved the superiority of PNT. The immediate effect after PNT in the form of complete and partial response of tumor was registered in 87.4%, and after PT--in 49% of cases. Five-year and ten-year survival rates without signs of disease after PNT were 58.1% and 29.5%, and after PT--36.4% and 7.4% respectively. Substantial differences in toxicity of techniques were not observed.

The analysis of the effectiveness of treatment was carried out in 257 patients with squamous cell carcinoma of the mucous membranes of the oral cavity and oropharynx. Two methods of irradiation were used in combination with concurrent polychemotherapy: standard radiotherapy (2 Gy 5 times a week) and radiotherapy in non-traditional modes of fractionation with uneven breaking of the daily dose into two fractions (1 Gy + 1.5 Gy or 1 Gy + 2 Gy with 4-hour intervals) to a focal dose of 60 Gy. Chemoradiotherapy with fractionated dose was more effective than standard chemoradiotherapy in frequency of objective tumor responses and regional metastases in the absence of increasing the number of early radiation reactions and late radiation damages. External beam radiotherapy in non-traditional modes of fractionation with simultaneous polychemotherapy exposure can significantly improve the results of the overall five-year survival compared with conventional fractionation technique--60.4 +/- 4.5%, 63.3 +/- 8.2% vs 27.6 +/- 10.2%, respectively.

The proton beam radiosurgery was performed to 65 patients with brain AVM since December, 2001 till February, 2012, in Joint Institute for Nuclear Research, Dubna, Russia. We have analyzed data for 56 patients. The follow up time varied from 24 to 109 months. The volumes of brain AVMs varied from 0.92 to 82 cc. The mean isocenter dose was 24.61 +/- 0.12 Gy E. The edge of the target was included in 70-90% isodose. The proton beam surgery was splitted in two similar doses and delivered in two consecutive days in vast majority of patients. Ten patients were missed for follow up due to some reasons. The radiosurgery was resulted in full obliteration of AVM in 23 from remaining 46 (50%) patients. There was full obliteration in 46.6% of patients with volume of AVM 10-24.9 cc; and this rate is significantly more than for photon radiosurgery of same size brain AVM. The partial obliteration was obtained in 21 patients. Only one patients suffered hemorrhage from partially obliterated AVM. We could not see any effect in 2 patients. There were delayed radiation toxicity in 5 patients in 12 months after treatment: in 4 patients, these reactions were assessed as 2 according to RTOG scale and were dissipated in 1 month after commencement of corticosteroid treatment. There was radiation necrosis in one patient, and it was relieved in 12 months after several courses of dehydration and corticosteroid therapy. So, proton beam therapy is effective and safe modality for treatment of inoperable brain AVM, especially of middle- and large size.

Thermochemoradiation therapy was performed in 31 patients with laryngeal cancer (T3-4N0-3M0). Radiotherapy was performed in 2 stages 1+1 Gy (every 4-5 hours), 5 times a week to SOD 52-60 Gy with a 2-week break after SOD 30-32 Gy. Local hyperthermia was carried out two times a week before the second fraction in an amount of radiation therapy sessions 3-6. In the days of local hyperthermia second fraction of radiotherapy increased to 3 Gy. Courses of chemotherapy were combined with radiation therapy and local hyperthermia at the beginning of each stage of treatment. For the whole group a complete response of the primary tumor was diagnosed in 25 (80.6%) patients, partial - in 6 (19.3%). Of the 12 patients with N1-3 complete regression of metastases occurred in 5 (41.7%), partial - also in 5 (41.7%). Five-year overall survival was 88.2% T3N0, T4N1 in 3 - 62.1%. Local control of the primary tumor in these terms in the group T3 was detected in 88.2%, in the group T4 - 77.8%, regional control of metastases with N1-3 - 33.3%. Late swelling of the mucous membrane of the larynx developed in 4 (12.9%) patients, perichondritis - in 3 (9.7%). Thermochemoradiation therapy of locally advanced cancer of the larynx provides a fairly good results comparable with those of the combined treatment.

This paper analyzes the results of combined treatment with preoperative thermochemoradiotherapy in 28 patients with locally advanced laryngeal cancer (T3-4N0-3M0). Radiation therapy (RT) 32 Gy was carried out 5 times a week with splitting the daily dose of radiation on the 2 factions (interval 4 hours) on a "1 Gy + 1 Gy," in the days of the local hyperthermia (LGT)--on a "1 Gy + 3 Gy". LGT in an amount of 3-4 sessions was performed two times a week before the 2nd fraction of RT. The course of polychemotherapy was administered concurrently with RT and LGT. In 2-3 weeks after completion of the course thermochemoradiotherapy patients were operated. Organ-saving operations were performed 10 (56%) of 18 patients with primary tumors categories T3 and 2 (20%) of 10 with T4. Postoperative wounds healed by first intention in 21 (75%) patients. The cumulative 5-year overall survival in the whole group (T3-4N0-3) was 89%, for patients without regional metastases (T3-4N0)--100%. Relapse-free survival time for those patients with a primary tumor T3 equaled 94%, T4--90%. Relapse metastases occurred in 20% of patients. Thus, preoperative thermochemoradiotherapy is a highly effective method of treatment for locally advanced cancer of the larynx and does not lead to the development of severe postoperative complications.

The objective of this study was to investigate in vivo the dose response of radiation induced chromosomal aberrations in human blood lymphocytes of lung cancer patients given non-uniform fractional exposures to high doses of therapeutic 60Co gamma-rays delivered synchronously with polychemotherapy. The chromosome aberration analysis was carried out in peripheral blood lymphocytes of 13 lung cancer patients who manifested II to IV developmental clinical stage. During the course of radiotherapy they received the accumulated tumor dose ranged 47.5 to 70 Gy. The yield ofdicentrics, centric rings and fragments was measured in the blood samples taken before treatment, after the first day and after the complete course of radiotherapy. Based on cytogenetic measurements of 3 patients, the average tumor dose after the first day was estimated to be 2.1 to 3.0 Gy given that the corresponding physical dose was (1.0 Gy + 1.5 Gy). The quotient of the individual dose estimated by the frequency of aberrations to the physical dose after the complete course of radiotherapy was calculated for all 13 patients. The mean quotient was shown to be equal to 93 +/- 9% ranged 50 to 154%.

The aim of this study was to evaluate the end results of the radiochemotherapy of 237 patients with squamous cell carcinoma of oral mucosa (locally advanced, stage III-IV, - 134; 56.4%, and metastases to regional lymph nodes of the neck - 91; 38.4%) carried out at the Center's Clinic. Interstitial neutron (252 californium) plus polychemotherapy was given to 26 (11%) (group 1); neutron + distant radio + polychemotherapy - 34 (14 %) (group 2); distant fractionated radiotherapy + polychemotherapy - 177 (75%) (group 3). Complete response was reported in 190 (80.2%); partial - 44 (18.6%) and stabilization - 3 (1.3%). Overall response was 98.8%; 5-year survival - 64.5 +/- 3.3%, irrespective of tumor site, grade and method of treatment. Concomitant modality proved highly effective, free from toxic and functional or cosmetic harm.

A modeling investigation was performed to choose moderator material and size for creating optimal epithermal neutron beams for BNCT based on a proton accelerator and the (7)Li(p,n)(7)Be reaction as a neutrons source. An optimal configuration is suggested for the beam shaping assembly made from polytetrafluoroethylene and magnesium fluorine to be placed on high current IPPE proton accelerator KG-2.5. Results of calculation were experimentally tested and are in good agreement with measurements.

The authors discuss the technological problems associated with the use of fast neutrons in radiotherapy of cancer patients and outline the approaches to the solution of these problems. The state of the art is assessed. Physical and radiobiological prerequisites for the use of fast reactors for radiotherapy of patients with malignant tumors are analyzed. Results of clinical use of BR-10 reactor at the Medical Radiology Research Center, Russian Academy of Medical Sciences, are presented. Experimental and clinical findings indicate that the results of radiotherapy may be appreciably improved if a novel perspective source of fast neutrons, a nuclear reactor, is used.

More than 250 patients, mainly with locally advanced tumors of the head, neck and breast were treated with a I MeV beam of fast neutrons emitted from a BR-10 reactor. The fast neutron contribution to the total dose of the radical component of complex gamma-neutron therapy was 20-40%. Said modality was shown to improve the results of treatment for laryngeal and breast tumors. The 5-year actuarial survival following complex gamma-neutron therapy for laryngeal cancer was 89.25, while in controls--65.2% (p < 0.005). The 5-year actuarial overall survival in breast cancer patients treated with fast neutrons was 66.5%: gamma-neutron therapy alone--46.0% (p < 0.05).

Studies of tumours and adjacent tissue were carried out in 29 patients with carcinoma of the larynx after preoperative irradiation with fast neurons at a total focal dose 5.6 Gy alone or in combination with gamma therapy. Pronounced pathomorphosis was established in all the cases, up to a full disappearance of the tumor in 2 patients, the degree of pathomorphosis did not depend on location, macroscopic form of growth, degree of dissemination. No changes were found in the wall of the larynx outside the tumor.

The results of multimodality treatment are analyzed in 56 patients with local breast cancer. Combined gamma-neutron therapy with the use of fast reactor neutrons enhances the efficiency of breast cancer treatment and does not increase the number of radiation reactions and complications. The three-year survival increased from 44 +/- 12 to 75 +/- 9%. The test reactors specifically adjusted may be useful for the radiation therapy of patients with various malignant neoplasms. Combined gamma-neutron therapy is more promising for this purpose than neutron therapy alone.

Since 1985 treatment of cancer patients on BR-10 reactor has been carried out in the Institute of Medical Radiology. Till May, 1989, 78 patients have received mixed gamma-neutron therapy and combined treatment (preoperative radiation therapy and surgery). Marked late local reactions (perichondritis) were observed only in three (7%) out of 42 patients treated with radical radiation therapy alone. 43 patients had a follow-up period of two years. Among them T2 tumors were registered in six (14%) cases, T3 in 28 (65%) cases, T4 in nine (21%) cases. Regional metastases were observed in 13 (30%) patients. 19 out of 27 patients (70%) treated with radical gamma-neutron therapy and 13 out of 16 patients (81%) treated with combined therapy using reactor fast neutrons as preoperative radiation therapy are alive two years without evidence of the disease.