Basic research. Radiation Therapy Methods Fractionation in Radiation Therapy

Radiation therapy, like surgery, is essentially a local treatment. Currently, radiation therapy is used in one form or another in more than 70% of patients with malignant neoplasms subject to special treatment. Based on the strategic objectives of helping cancer patients, radiation therapy can be used:

1. as an independent or main method of treatment;
2. in combination with surgery;
3. in combination with chemohormonotherapy;
4. as a multimodal therapy.

Radiation therapy as the main or independent method of antiblastoma treatment is used in the following cases:

• when it is preferable either cosmetically or functionally, and its long-term results are the same compared to those when using other methods of treating cancer patients;
• when it may be the only possible means of helping inoperable patients with malignant neoplasms, for whom surgery is a radical method of treatment.

Radiation therapy as an independent method of treatment can be carried out according to a radical program, used as a palliative and symptomatic means of helping patients.

Depending on the variant of the distribution of the radiation dose over time, there are modes of small, or ordinary, fractionation (single focal dose - ROD - 1.8-2.0 Gy 5 times a week), medium (GENERAL - 3-4 Gy), large ( ROD - 5 Gy or more) dose splitting. Of great interest are the courses of radiation therapy, which provide for additional splitting into 2 (or more) fractions of the daily dose with intervals between fractions of less than one day (multifractionation). There are the following types of multifractionation:

• accelerated (accelerated) fractionation - differs in a shorter duration of the course of radiation therapy compared to that with conventional fractionation; while the ROD remains standard or somewhat lower. Isoeffective SOD is reduced, with the total number of fractions either equal to that of conventional fractionation, or reduced by using 2-3 fractions daily;
• hyperfractionation - an increase in the number of fractions with a simultaneous significant decrease in the ROD. 2-3 fractions or more per day are brought in with a total course time equal to that of conventional fractionation. Isoeffective SOD, as a rule, increases. Usually use 2-3 fractions per day with an interval of 3-6 hours;

• multifractionation options that have features of both hyperfractionation and accelerated fractionation, and sometimes combined with conventional dose fractionation.

Depending on the presence of interruptions in irradiation, a continuous (through) course of radiation therapy is distinguished, in which a given absorbed dose in the target accumulates continuously; a split course of exposure consisting of two (or more) shorter courses separated by long scheduled intervals.

Dynamic course of irradiation - an irradiation course with a planned change in the fractionation scheme and / or the patient's irradiation plan.

It seems promising to conduct radiation therapy with the use of biological means of changing the radiation effect - radio-modifying agents. Radiomodifying agents are understood as physical and chemical factors that can change (increase or weaken) the radiosensitivity of cells, tissues and the body as a whole.

To enhance radiation damage to tumors, irradiation is used against the background of hyperbaric oxygenation (HO) of malignant cells. The method of radiation therapy based on the use of GO is called oxygen radiotherapy, or oxybaroradiotherapy - radiation therapy of tumors in conditions when the patient is in a special pressure chamber before and during the irradiation session, where an increased oxygen pressure (2-3 atm) is created. Due to a significant increase in RO 2 in blood serum (9-20 times), the difference between RO 2 in the capillaries of the tumor and its cells (oxygen gradient) increases, diffusion of 0 2 to tumor cells increases and, accordingly, their radiosensitivity increases.

In the practice of radiation therapy, preparations of certain classes, electron acceptor compounds (EACs), have found application, which can increase the radiosensitivity of hypoxic cells and do not affect the degree of radiation damage to normal oxygenated cells. In recent years, research has been conducted aimed at finding new highly effective and well-tolerated EAS, which will contribute to their widespread introduction into clinical practice.

To enhance the effect of radiation on tumor cells, small "sensitizing" doses of radiation (0.1 Gy, delivered 3-5 minutes before irradiation with the main dose), thermal effects (thermoradiotherapy) are also used, which have proven themselves in situations that are quite difficult for traditional radiation therapy (cancer of the lung, larynx, breast, rectum, melanoma, etc.).

To protect normal tissues from radiation, hypoxic hypoxia is used - inhalation of hypoxic gas mixtures containing 10 or 8% oxygen (GGS-10, GGS-8). Irradiation of patients, carried out under conditions of hypoxic hypoxia, is called hypoxic radiotherapy. When using hypoxic gas mixtures, the severity of radiation reactions of the skin, bone marrow, and intestines decreases, which is due, according to experimental data, to better protection from radiation of well-oxygenated normal cells.

Pharmacological radiation protection is provided by the use of radioprotectors, the most effective of which belong to two large classes of compounds: indolylalkylamines (serotonin, myxamine), mercaptoalkylamines (cystamine, gammaphos). The mechanism of action of indolylalkylamines is associated with the oxygen effect, namely, with the creation of tissue hypoxia, which occurs due to the induced spasm of peripheral vessels. Mercaptoalkylamines have a cellular concentration mechanism of action.

An important role in the radiosensitivity of biological tissues is played by bioantioxidants. The use of the antioxidant complex of vitamins A, C, E makes it possible to weaken the radiation reactions of normal tissues, which opens up the possibility of using intensely concentrated preoperative irradiation in cancericidal doses of tumors that are insensitive to radiation (cancer of the stomach, pancreas, colon), as well as the use of aggressive polychemotherapy regimens .

For irradiation of malignant tumors, corpuscular (beta particles, neutrons, protons, p-minus mesons) and photon (X-ray, gamma) radiation are used. Natural and artificial radioactive substances, elementary particle accelerators can be used as radiation sources. In clinical practice, mainly artificial radioactive isotopes are used, which are obtained in nuclear reactors, generators, and accelerators and compare favorably with natural radioactive elements in the monochromaticity of the emitted radiation spectrum, high specific activity, and low cost. The following radioactive isotopes are used in radiation therapy: radioactive cobalt - 60 Co, cesium - 137 Cs, iridium - 192 Ig, tantalum - 182 Ta, strontium - 90 Sr, thallium - 204 Tl, promethium - 147 Pm, iodine isotopes - 131 I, 125 I, 132 I, phosphorus - 32 P, etc. In modern domestic gamma-therapy installations, the source of radiation is 60 Co, in devices for contact radiation therapy - 60 Co, 137 Cs, 192 Ir.

Various types of ionizing radiation, depending on their physical properties and the characteristics of interaction with the irradiated environment, create a characteristic dose distribution in the body. The geometric distribution of the dose and the density of ionization created in tissues ultimately determine the relative biological effectiveness of radiation. These factors guide the clinic when choosing the type of radiation for irradiating specific tumors. So, in modern conditions for irradiation of superficially located small tumors, short-focus (close-range) X-ray therapy is widely used. The X-ray radiation generated by the tube at a voltage of 60-90 kV is completely absorbed on the surface of the body. At the same time, long-distance (deep) X-ray therapy is currently not used in oncological practice, which is associated with an unfavorable dose distribution of orthovoltage X-ray radiation (maximum radiation exposure to the skin, uneven absorption of radiation in tissues of different densities, pronounced lateral scattering, rapid dose drop in depth , high integral dose).

Gamma radiation of radioactive cobalt has a higher radiation energy (1.25 MeV), which leads to a more favorable spatial dose distribution in tissues: the maximum dose is shifted to a depth of 5 mm, resulting in a decrease in radiation exposure to the skin, less pronounced differences in radiation absorption in various tissues, lower integral dose compared to orthovoltage radiotherapy. The high penetrating power of this type of radiation makes it possible to widely use remote gamma therapy for irradiating deep-seated neoplasms.

High-energy bremsstrahlung generated by accelerators is obtained as a result of deceleration of fast electrons in the field of target nuclei made of gold or platinum. Due to the high penetrating power of bremsstrahlung, the maximum dose is shifted into the depths of the tissues, its location depends on the energy of the radiation, while a slow decrease in deep doses takes place. The radiation load on the skin of the input field is insignificant, but with an increase in the radiation energy, the dose to the skin of the output field may increase. Patients tolerate exposure to high-energy bremsstrahlung well due to its insignificant dispersion in the body and a low integral dose. High-energy bremsstrahlung (20-25 MeV) should be used to irradiate deep-seated pathological foci (cancer of the lung, esophagus, uterus, rectum, etc.).

Fast electrons generated by accelerators create a dose field in tissues that differs from dose fields when exposed to other types of ionizing radiation. The dose maximum is observed directly under the surface; the depth of the dose maximum is, on average, half or a third of the effective electron energy and increases with increasing radiation energy. At the end of the electron trajectory, the dose drops sharply to zero. However, the dose drop curve with increasing electron energy becomes more and more flat due to the background radiation. Electrons with energies up to 5 MeV are used to irradiate superficial neoplasms, with higher energy (7-15 MeV) - to affect tumors of medium depth.

The radiation dose distribution of the proton beam is characterized by the creation of an ionization maximum at the end of the particle path (Bragg peak) and a sharp drop in the dose to zero beyond the Bragg peak. This distribution of the dose of proton radiation in the tissues determined its use for irradiation of pituitary tumors.

For radiation therapy of malignant neoplasms, neutrons related to dense ionizing radiation can be used. Neutron therapy is carried out with remote beams obtained on accelerators, as well as in the form of contact irradiation on hose devices with a charge of radioactive californium 252 Cf. Neutrons are characterized by a high relative biological efficiency (RBE). The results of using neutrons depend to a lesser extent on the oxygen effect, the phase of the cell cycle, and the dose fractionation regimen compared to the use of traditional types of radiation, and therefore they can be used to treat relapses of radioresistant tumors.

Elementary particle accelerators are universal radiation sources that allow one to arbitrarily choose the type of radiation (electron beams, photons, protons, neutrons), regulate the radiation energy, as well as the size and shape of the irradiation fields using special multi-plate filters, and thereby individualize the program of radical radiation therapy for tumors of various localizations.

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1 BASIS OF RADIOTHERAPY DOSE FRACTIONING E.L. Slobina RSPC OMR them. N.N. Aleksandrova, Minsk Key words: dose fractionation, radiation therapy The radiobiological bases of radiation therapy dose fractionation are outlined, the influence of radiation therapy dose fractionation factors on the results of treatment of malignant tumors is analyzed. Data are presented on the use of various fractionation regimens in the treatment of tumors with a high proliferative potential. BASE OF DOSE FRACTIONATION OF RADIOTHERAPY E.L. Slobina Key words: dose fractionation, radiotherapy Radiobiological grounds of dose fractionation of radiotherapy were stated, the influence of dose fractionation factors of radiotherapy on the results of cancer treatment was analyzed. The application data of different schedules of dose fractionation, as well as treatment of tumors with high proliferative potential, were presented. One of the methods for improving the results of radiation therapy is the development of various modes of summing up the dose (fractionation). And the search for optimal dose fractionation regimens for each type of tumor is an active field of activity for radiation oncologists. In 1937 Coutard and Baclesse (France) reported treatment of laryngeal cancer with 30 small doses of X rays given 6 days a week for 6 weeks. This was the first report on the treatment of a deep tumor with the successful use of external irradiation and the first example of dose fractionation in the treatment of patients.

2 Most of the radiotherapy regimens in use today fall into several large dose regimen groups (fractionation) and are based on the use of the basic rules of radiobiology. The Fours Rules of Radiobiology were conceptualized by Withers H. R. (1975) and represent an attempt to understand the mechanisms of effects resulting from dose fractionation in both normal tissues and tumors: 1. The process of cell repair from sublethal and potentially lethal damage begins during the exposure itself and practically ends within 6 hours after exposure. In addition, the repair of sublethals is of particular importance when using low doses of radiation. Differences between the reparative potential of normal and tumor cells can increase when a large number of small doses are applied (i.e., the maximum increase in the difference is observed with an infinitely large number of fractions of infinitely small doses). 2. If we talk about cell repopulation, then it is absolutely certain that during radiation therapy, normal tissues and tumors "dramatically" diverge in their repopulation kinetics. Much attention is paid to this process, as well as to repair, in the development of fractionation regimens that make it possible to maximize the therapeutic interval. Here it is appropriate to speak of "accelerated repopulation", which means a faster multiplication of cells compared to multiplication before irradiation. The reserve for accelerated proliferation is a reduction in the duration of the cell cycle, a smaller exit of cells from the cycle into the phase

3 "plateau" or rest G0 and a decrease in the value of the cell loss factor, which in tumors can reach 95%. 3. As a result of irradiation, the cell population is enriched with cells that were in the radioresistant phases of the cycle during the session, which causes the process of desynchronization of the cell population. 4. The process of reoxygenation is specific for tumors, since there is initially a fraction of hypoxic cells. First of all, well-oxygenated and therefore more sensitive cells die during irradiation. As a result of this death, the total consumption of oxygen by the tumor decreases and thus its supply to previously hypoxic zones increases. Under fractionation conditions due to reoxygenation, one has to deal with a more radiosensitive tumor population than with a single radiation exposure. According to leading laboratories, in some tumors these processes increase by the end of the course of radiation therapy. Dose fractionation factors affecting the results of treatment are: 1. Dose per fraction (single focal dose). 2. Total dose (total focal dose) and number of fractions. 3. Total treatment time. 4. Interval between fractions. The influence of the dose value per fraction on the tissues exposed to radiation is explained quite well by Fowler J. using a linear-quadratic model. Each fraction is responsible for the same number of log deaths in a cell population. shoulder curve

4 survivability is restored in a time interval if it is at least 6 hours. A schematic representation of these processes is shown in Figure 1. Log 10 cell survival E D 1 D 2 D 4 D 8 D 70 ERD / BED = E / a Total dose (Gy) Figure 1 - Dependence of cell survival on the size and number of fractions Thus, the resulting curve of the logarithm of lethal outcomes in the cell population when the dose is multifractionated is a straight line along the chord connecting the beginning of exposure and the dose per fraction point on the cell survival curve when summing up one fraction. With an increase in the total dose, the survival curve becomes steeper for late reactions than for early ones, which was originally noted by Withers H.R. in animal experiments A schematic representation of these processes is shown in Figure 2.

5 Total dose (Gy) spinal cord (White) skin (Duglas 76) skin (Fowler 74) kidney kidney (Hopewell 77) colon (Caldwell 75) (Whither 79) spinal cord v.d.kogel 77) jejunum (Thames 80) testis (Thames 80) early effects late effects ROD (Gy) Figure 2 - Dependence of cell survival on the total dose, number of fractions and dose per fraction per fraction is explained by the fact that the dose response curves for critical cells in early responding tissues are less curved than in late responding ones. A schematic representation of these processes is shown in Figure 3. Damage Late reactions a/b=3gr Early reactions and tumors a/b=10gr D n1 D n2 D n1 D n2 Total dose doses per fraction The total dose (total focal dose) should be increased if the total treatment time (to achieve the desired effect) is increased

6 for two reasons: 1 - if small doses per fraction are used, then each of them has a smaller effect than a large dose per fraction; 2 - to compensate for proliferation in tumors and early reacting normal tissues. Many tumors proliferate as rapidly as early responding normal tissues. However, a large increase in the total dose requires an increase in the total treatment time. In addition, late complications have little or no time factor. This fact does not allow increasing the total dose sufficiently to suppress tumor proliferation if the total treatment time is long. An increase in total treatment time of one week indicates a reduction in local control of 6-25% for head and neck tumors. Thus, shortening of the total treatment time should be aimed at treating tumors that can be identified (by flow cytometry) as rapidly proliferating. According to Denecamp J. (1973), early responding tissues have a period of 24 weeks from the start of radiation therapy to the start of compensatory proliferation. This is equivalent to the renewal time of the cell population in humans (Figure 4). Additional dose required (Gy) ROD 3 Gy 130 cg/day J. Denekamp (1973) Time after 1st fraction

7 Figure 4 - Required additional dose to compensate for cell proliferation (J. Denekamp, ​​1973) Late responding normal tissues in which late radiation complications occur follow the same principles, but they do not have compensatory proliferation during the weeks of radiation therapy, and there is no dependence of the effect or total dose on the total time of treatment. A schematic representation of these processes is shown in Figure 5. Additional dose required (Gy) 0 10 Early reactions Late reactions Days after the start of irradiation Figure 5 - Additional dose required to compensate for cell proliferation in early and late responding tissues Many tumors proliferate during radiation therapy, often these processes are comparable to those occurring in early reacting normal tissues. Thus, reducing the total treatment time in radiotherapy leads to increased damage to rapidly proliferating normal tissues (acute, early reactions) (1); no increase in damage to late-reacting normal tissues (provided the dose per fraction is not increased) (2); increased damage to tumors (3).

8 Therapeutic benefit depends on the balance between (1) and (3) items; from a large total dose over a short total treatment time in order to avoid serious late complications (2) . Overgaard J. et al. (1988) have provided good examples of these principles. Figure 6 shows the reduction in local control when a 3-week break was introduced into a 6-week classical fractionation regimen. The tumor response is shown in two different curves showing proliferation in addition to the total time. The loss of local control at the same total dose (60 Gy) can reach %. Local control (%) weeks 60 Gy 57 Gy 72 Gy 68 Gy split course 10 weeks Total dose (Gy) J. Overgaard et al. (1988) Late edema (edema) is represented by a curve showing the independence of the effect from the total treatment time (Figure 7) .

9 Frequency of edema (%) Gy 68 Gy 72 Gy Total dose (Gy) Figure 7 - Frequency of swelling of the tissues of the larynx depending on the total dose. J. Overgaard et al. (1988) Thus, according to Fowler J. and Weldon H., it is necessary to keep the total treatment time short enough, and, in this regard, create new shorter treatment protocols for rapidly proliferating tumors. In terms of the effect of the interval between fractions, a multivariate analysis of RTOG studies conducted under the direction of K. Fu in 1995 showed that the interval between fractions is an independent prognostic factor for the development of serious late complications. It was shown that the cumulative rate of late radiation complications of the 3rd and 4th degrees increased from 12% at 2 years of follow-up to 20% at 5 years of follow-up in patients in whom the interval between treatment fractions was less than 4.5 hours, while at the same time, if the interval between fractions was more than 4.5 hours, the frequency of late radiation reactions did not increase and amounted to 7.3% for 2 years and 11.5% for 5 years. The same dependence was observed in all known studies where dose fractionation was carried out with an interval of less than 6 hours. The data of these studies are presented in Table 1.

10 The Golden Rules of Fractionation are defined and formulated by Withers H.R. (1980) : administer a total dose not exceeding the tolerable dose of late responding tissues; use as many fractions as possible; the dose per fraction should not exceed 2 Gy; the total time should be as short as possible; intervals between fractions should be at least 6 hours. Table 1 data from studies using dose fractionation at intervals of less than 6 hours. Source Observation period Localization EORTC HFO 22811, 1984 Van den Bogaert (1995) EORTC 22851, Horiot (1997) CHART, Dische (1997) RTOG 9003, Fu (2000) Cairo 3, Awwad (2002) IGR, Lusinchi Stage III/IV HFO +n/hl II IV OGSH+n/hl II IV OGSH OGSH OGSH 2001 II- IV III/ IV III/ IV Fractionation regimen Classical 67-72 Gy/6.5 weeks. Classic 72Gr/5wk split 66Gr/6.5wk 54Gy / 1.7 weeks Number of fractions per day ROD Classic 1 81.6 Gr / 7 weeks. 2 67.2 UAH / 6 weeks. Split 2 72 UAH / 6 weeks UAH / 6 weeks. 46.2Gy/2weeks postop Gr 1.6Gy 2Gy 1.6Gy 2Gy 1.5Gy 2Gy 1.2Gy 1.6Gy 1.8Gy+1.5Gy 2Gy 1.4Gy Number of patients Median obs. (months) Early responses % 67% % 55% 52% 59% % 16% (Gr 3+) Late responses 14% 39% 4% 14% р= % 28% 27% 37% 13% 42% 70Gy/5weeks . 3 0.9Gy % 77% (Gr 3+)

11 (2002) IGR, Dupuis (1996) GSS 1993 III/ IV GSS of head and neck tumors N/GL nasopharynx 62 Gy/3 weeks. 2 1.75 Gy 46-96% 48% CONCLUSION It should be noted that at the present stage of development of research, radiation therapy in a non-standard mode of fractionation is not fundamentally new. It has been proven that such radiation treatment options are highly likely to prevent the occurrence of local recurrences and do not adversely affect the long-term results of treatment. List of sources used: 1. Coutard, H. Röntgentherapie der Karzinome / H. Coutard // Strahlentherapie Vol. 58. P Withers, H.R. Biological basis for altered fractionation schemes / H.R. Withers // Cancer Vol. 55. P Wheldon, T.E. Mathematical models in cancer research / T.E. Wheldon // In: Mathematical models in cancer research. Ed. Adam Hilger. IOP Publishing Ltd. Bristol and Philadelphia p. 4. Clinical radiobiology / S.P. Yarmonenko, [et al.] // M: Medicine p. 5. Fractionation in radiotherapy / J. Fowler, // ASTRO Nov c. 6Fowler, J.F. Review article The linear-quadratic formula and progress in fractionated radiotherapy /J.F. Fowler // Brit. J. Radiol Vol. 62. P Withers, H.R. Biological basis for altered fractionation schemes /H.R. Withers // Cancer Vol. 55 P Fowler, J.F. The Radiobiology of brachytherapy / J.F. Fowler // in: Brachytherapy HDR and LDR. Ed. Martinez, Orton, Mold. Nucletron. Columbia P Denekamp, ​​J. Cell kinetics and radiation biology / J. Denekamp // Int. J. Radiat. Biol Vol. 49.P

12 10. Importance of overall treatment time for the outcome of radiotherapy of advanced head and neck carcinoma: dependency on tumor differentiation / O. Hansen, // Radiother. Oncol Vol. 43 P Fowler, J.F. Fractionation and therapeutic gain / J.F. Fowler // in: The Biological Basis of Radiotherapy. ed. G. G. Steel, G. E. Adams and A. Horwich. Elsevier, Amsterdam P Fowler, J.F. How worthwhile are short schedules in radiotherapy? / J.F. Fowler // Radiother. Oncol Vol. 18. P Fowler, J.F. Non standard fractionation in radiotherapy (editorial) / J.F. Fowler // Int. J. Radiat. oncol. Biol. Phys Vol. 10. P Fowler, J.F. Loss of local control with extended fractionation in radiotherapy / J.F. Fowler // In: International Congress of Radiation Oncology 1993 (ICRO "93). P Wheldon, T.E. Radiobiological rationale for the compensation of gaps in radiotherapy regimes by postgap acceleration of fractionation / T.E. Wheldon // Brit. J. Radiol Vol. 63. P Late effects of hyperfractionated radiotherapy for advanced head and neck cancer: long-term follow-up results of RTOG / Fu KK., // Int. J. Radiat. Oncol. Biol. Phys Vol. 32. P A radiation therapy oncology group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003 / Fu KK., Int. J. Radiat. Oncol. Biol. Phys Vol. 48. P A radiation therapy oncology group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: preliminary results of RTOG 9003 / Fu KK., // Int. J. Radiat. oncol. Biol. Phys Vol. 45 suppl. 3. P The EORTC randomized trial on three fractions per day and misonidasole (trial no) in advanced head and neck cancer: long-term results and side effects / W. van den Bogaert, // Radiother. Oncol Vol. 35. Accelerated fractionation (AF) compared to conventional fractionation (CF) improves locoregional control in the radiotherapy of advanced head and neck cancer: results of the EORTC randomized trial / J.-C. Horiot // Radiother. Oncol Vol. 44. P

13 21. Randomised multicentre trials of CHART vs conventional radiotherapy in head and neck and non-small-cell lung cancer: an interim report / M.I. Saunders, // Br. J. Cancer Vol. 73. P A randomized multicentre trial of CHART vs conventional radiotherapy in head and neck / M.I. Saunders // Radiother. Oncol Vol. 44. P The CHART regimen and morbidity / S. Dische, // Acta Oncol Vol. 38, 2. P Accelerated hyperfractionation (AHF) is superior to conventional fractionation (CF) in the postoperative irradiation of locally advanced head & neck cancer (HNC): influence of proliferation / H.K. Awwad, // Br. J. Cancer Vol. 86, 4. P Accelerated radiation therapy in the treatment of very advanced and inoperable head and neck cancers / A. Lusinchi, // Int. J. Radiat. oncol. Biol. Phys Vol. 29. P Radiotherapie accélérée: premiers résultats dans une série de carcinomes des voies aérodigestives supérieures localement très évolués / O. Dupuis, // Ann. Otolaryngol. Chir. Cervocofac Vol P A prospective randomized trial of hyperfractionated versus conventional once daily radiation for advanced squamous cell carcinomas of the pharynx and larynx / B.J. Cummings // Radiother. Oncol Vol. 40. S A randomized trial of accelerated versus conventional radiotherapy in head and neck cancer / S.M. Jackson, Radiother. Oncol Vol. 43. P Conventional radiotherapy as the primary treatment of squamous cell carcinoma (SCC) of the head and neck. A randomized multicenter study of 5 versus 6 fractions per week preliminary report from DAHANCA 6 and 7 trial / J. Overgaard, // Radiother. Oncol Vol. 40S Holsti, L.R. Dose escalation in accelerated hyperfractionation for advanced head and neck cancer / Holsti L.R. // In: International Congress of Radiation Oncology (ICRO "93). P Fractionation in radiotherapy / L. Moonen, // Cancer Treat. Reviews Vol. 20. P Randomized clinical trial of accelerated 7 days per week fractionation in radiotherapy for head and neck cancer Preliminary report on therapy toxicity / K. Skladowski, Radiother Oncol Vol 40 S40.

14 33. Withers, H.R. The EORTC hyperfractionation trial / H.R. Withers // Radiother. Oncol Vol. 25. P Treatment of patients with locally advanced larynx cancer using dynamic dose multifractionation / Slobina E.L., [et al.] / Slobina E.L., [and others] // In: Proceedings of the III Congress of Oncologists and Radiologists of the CIS, Minsk p. 350.

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• Introduction
• external beam radiation therapy
• Electronic therapy
• Brachytherapy
• Open sources of radiation
• Total body irradiation

Introduction

Radiation therapy is a method of treating malignant tumors with ionizing radiation. The most commonly used remote therapy is high-energy x-rays. This method of treatment has been developed over the past 100 years, it has been significantly improved. It is used in the treatment of more than 50% of cancer patients, it plays the most important role among non-surgical treatments for malignant tumors.

A brief excursion into history

1896 Discovery of X-rays.

1898 Discovery of radium.

1899 Successful treatment of skin cancer with x-rays. 1915 Treatment of a neck tumor with a radium implant.

1922 Cure of cancer of the larynx with X-ray therapy. 1928 The X-ray was adopted as the unit of radiation exposure. 1934 The principle of radiation dose fractionation was developed.

1950s. Teletherapy with radioactive cobalt (energy 1 MB).

1960s. Obtaining megavolt x-ray radiation using linear accelerators.

1990s. Three-dimensional planning of radiation therapy. When X-rays pass through living tissue, the absorption of their energy is accompanied by ionization of molecules and the appearance of fast electrons and free radicals. The most important biological effect of X-rays is DNA damage, in particular, the breaking of bonds between its two helical strands.

The biological effect of radiation therapy depends on the dose of radiation and the duration of therapy. Early clinical studies of the results of radiotherapy showed that relatively small doses of daily irradiation allow the use of a higher total dose, which, when applied to tissues at once, is unsafe. Fractionation of the radiation dose can significantly reduce the radiation load on normal tissues and achieve the death of tumor cells.

Fractionation is the division of the total dose for external beam radiation therapy into small (usually single) daily doses. It ensures the preservation of normal tissues and preferential damage to tumor cells and allows you to use a higher total dose without increasing the risk to the patient.

Radiobiology of normal tissue

The effect of radiation on tissues is usually mediated by one of the following two mechanisms:

• loss of mature functionally active cells as a result of apoptosis (programmed cell death, usually occurring within 24 hours after irradiation);
• loss of the ability of cells to divide

Usually these effects depend on the radiation dose: the higher it is, the more cells die. However, the radiosensitivity of different types of cells is not the same. Some cell types respond to irradiation predominantly by initiating apoptosis, such as hematopoietic cells and salivary gland cells. Most tissues or organs have a significant reserve of functionally active cells, so the loss of even a small part of these cells as a result of apoptosis is not clinically manifested. Typically, lost cells are replaced by progenitor or stem cell proliferation. These may be cells that survived after tissue irradiation or migrated into it from non-irradiated areas.

Radiosensitivity of normal tissues

• High: lymphocytes, germ cells
• Moderate: epithelial cells.
• Resistance, nerve cells, connective tissue cells.

In cases where a decrease in the number of cells occurs as a result of the loss of their ability to proliferate, the rate of renewal of the cells of the irradiated organ determines the time during which tissue damage appears and which can vary from several days to a year after irradiation. This served as the basis for dividing the effects of irradiation into early, or acute, and late. Changes that develop during the period of radiation therapy up to 8 weeks are considered acute. Such a division should be considered arbitrary.

Acute changes with radiation therapy

Acute changes affect mainly the skin, mucous membrane and hematopoietic system. Despite the fact that the loss of cells during irradiation initially occurs in part due to apoptosis, the main effect of irradiation is manifested in the loss of the reproductive ability of cells and the disruption of the replacement of dead cells. Therefore, the earliest changes appear in tissues characterized by an almost normal process of cell renewal.

The timing of the manifestation of the effect of irradiation also depends on the intensity of irradiation. After simultaneous irradiation of the abdomen at a dose of 10 Gy, the death and desquamation of the intestinal epithelium occurs within several days, while when this dose is fractionated with a daily dose of 2 Gy, this process is extended for several weeks.

The speed of recovery processes after acute changes depends on the degree of reduction in the number of stem cells.

Acute changes during radiation therapy:

• develop within B weeks after the start of radiation therapy;
• skin suffer. Gastrointestinal tract, bone marrow;
• the severity of changes depends on the total dose of radiation and the duration of radiation therapy;
• therapeutic doses are selected in such a way as to achieve complete restoration of normal tissues.

Late Changes After Radiation Therapy

Late changes occur mainly in tissues and organs, cells of which are characterized by slow proliferation (for example, lungs, kidneys, heart, liver and nerve cells), but are not limited to them. For example, in the skin, in addition to the acute reaction of the epidermis, later changes may develop after a few years.

The distinction between acute and late changes is important from a clinical point of view. Since acute changes also occur with traditional radiation therapy with dose fractionation (approximately 2 Gy per fraction 5 times a week), if necessary (development of an acute radiation reaction), it is possible to change the fractionation regimen, distributing the total dose over a longer period in order to save more stem cells. As a result of proliferation, the surviving stem cells will repopulate the tissue and restore its integrity. With a relatively short duration of radiation therapy, acute changes may occur after its completion. This does not allow for adjustment of the fractionation regimen based on the severity of the acute reaction. If intensive fractionation causes a decrease in the number of surviving stem cells below the level required for effective tissue repair, acute changes can become chronic.

According to the definition, late radiation reactions appear only after a long time after exposure, and acute changes do not always make it possible to predict chronic reactions. Although the total dose of radiation plays a leading role in the development of a late radiation reaction, an important place also belongs to the dose corresponding to one fraction.

Late changes after radiotherapy:

• lungs, kidneys, central nervous system (CNS), heart, connective tissue suffer;
• the severity of the changes depends on the total radiation dose and the radiation dose corresponding to one fraction;
• recovery does not always occur.

Radiation changes in individual tissues and organs

Skin: acute changes.

• Erythema, resembling a sunburn: appears in the 2-3rd week; patients note burning, itching, soreness.
• Desquamation: first note the dryness and desquamation of the epidermis; later weeping appears and the dermis is exposed; usually within 6 weeks after completion of radiation therapy, the skin heals, residual pigmentation fades within a few months.
• When the healing process is inhibited, ulceration occurs.

Skin: late changes.

• Atrophy.
• Fibrosis.
• Telangiectasia.

The mucous membrane of the oral cavity.

• Erythema.
• Painful ulcers.
• Ulcers usually heal within 4 weeks after radiation therapy.
• Dryness may occur (depending on the dose of radiation and the mass of salivary gland tissue exposed to radiation).

Gastrointestinal tract.

• Acute mucositis, which manifests itself after 1-4 weeks with symptoms of a lesion of the gastrointestinal tract that has been exposed to radiation.
• Esophagitis.
• Nausea and vomiting (involvement of 5-HT 3 receptors) - with irradiation of the stomach or small intestine.
• Diarrhea - with irradiation of the colon and distal small intestine.
• Tenesmus, secretion of mucus, bleeding - with irradiation of the rectum.
• Late changes - ulceration of the mucous membrane fibrosis, intestinal obstruction, necrosis.

central nervous system

• There is no acute radiation reaction.
• Late radiation reaction develops after 2-6 months and is manifested by symptoms caused by demyelination: brain - drowsiness; spinal cord - Lermitte's syndrome (shooting pain in the spine, radiating to the legs, sometimes provoked by flexion of the spine).
• 1-2 years after radiation therapy, necrosis may develop, leading to irreversible neurological disorders.

Lungs.

• Acute symptoms of airway obstruction are possible after a single exposure at a high dose (eg, 8 Gy).
• After 2-6 months, radiation pneumonitis develops: cough, dyspnea, reversible changes on chest radiographs; may improve with the appointment of glucocorticoid therapy.
• After 6-12 months, the development of irreversible pulmonary fibrosis of the kidneys is possible.
• There is no acute radiation reaction.
• The kidneys are characterized by a significant functional reserve, so a late radiation reaction can develop even after 10 years.
• Radiation nephropathy: proteinuria; arterial hypertension; kidney failure.

Heart.

• Pericarditis - after 6-24 months.
• After 2 years or more, the development of cardiomyopathy and conduction disturbances is possible.

Tolerance of normal tissues to repeated radiotherapy

Recent studies have shown that some tissues and organs have a pronounced ability to recover from subclinical radiation damage, which makes it possible, if necessary, to carry out repeated radiation therapy. Significant regeneration capabilities inherent in the CNS allow repeated irradiation of the same areas of the brain and spinal cord and achieve clinical improvement in the recurrence of tumors localized in or near critical zones.

Carcinogenesis

DNA damage caused by radiation therapy can lead to the development of a new malignant tumor. It can appear 5-30 years after irradiation. Leukemia usually develops after 6-8 years, solid tumors - after 10-30 years. Some organs are more prone to secondary cancer, especially if radiation therapy was given in childhood or adolescence.

• Secondary cancer induction is a rare but serious consequence of radiation exposure characterized by a long latent period.
• In cancer patients, the risk of induced cancer recurrence should always be weighed.

Repair of damaged DNA

For some DNA damage caused by radiation, repair is possible. When bringing to the tissues more than one fractional dose per day, the interval between fractions should be at least 6-8 hours, otherwise massive damage to normal tissues is possible. There are a number of hereditary defects in the DNA repair process, and some of them predispose to the development of cancer (for example, in ataxia-telangiectasia). Conventional radiation therapy used to treat tumors in these patients can cause severe reactions in normal tissues.

hypoxia

Hypoxia increases the radiosensitivity of cells by 2-3 times, and in many malignant tumors there are areas of hypoxia associated with impaired blood supply. Anemia enhances the effect of hypoxia. With fractionated radiation therapy, the reaction of the tumor to radiation can manifest itself in the reoxygenation of hypoxic areas, which can enhance its detrimental effect on tumor cells.

Fractionated Radiation Therapy

Target

To optimize remote radiation therapy, it is necessary to choose the most advantageous ratio of its following parameters:

• total radiation dose (Gy) to achieve the desired therapeutic effect;
• the number of fractions into which the total dose is distributed;
• the total duration of radiotherapy (defined by the number of fractions per week).

Linear quadratic model

When irradiated at doses accepted in clinical practice, the number of dead cells in tumor tissue and tissues with rapidly dividing cells is linearly dependent on the dose of ionizing radiation (the so-called linear, or α-component of the irradiation effect). In tissues with a minimal cell turnover rate, the effect of radiation is largely proportional to the square of the dose delivered (the quadratic, or β-component, of the effect of radiation).

An important consequence follows from the linear-quadratic model: with fractionated irradiation of the affected organ with small doses, changes in tissues with a low cell renewal rate (late-reacting tissues) will be minimal, in normal tissues with rapidly dividing cells, damage will be insignificant, and in tumor tissue it will be the greatest. .

Fractionation mode

Typically, the tumor is irradiated once a day from Monday to Friday. Fractionation is carried out mainly in two modes.

Short-term radiation therapy with large fractional doses:

• Advantages: a small number of irradiation sessions; saving resources; rapid tumor damage; lower probability of repopulation of tumor cells during the treatment period;
• Disadvantages: limited ability to increase the safe total dose of radiation; relatively high risk of late damage in normal tissues; reduced possibility of reoxygenation of tumor tissue.

Long-term radiation therapy with small fractional doses:

• Advantages: less pronounced acute radiation reactions (but a longer duration of treatment); less frequency and severity of late lesions in normal tissues; the possibility of maximizing the safe total dose; the possibility of maximum reoxygenation of the tumor tissue;
• Disadvantages: great burden for the patient; a high probability of repopulation of cells of a rapidly growing tumor during the treatment period; long duration of acute radiation reaction.

Radiosensitivity of tumors

For radiation therapy of some tumors, in particular lymphoma and seminoma, radiation in a total dose of 30-40 Gy is sufficient, which is approximately 2 times less than the total dose required for the treatment of many other tumors (60-70 Gy). Some tumors, including gliomas and sarcomas, may be resistant to the highest doses that can be safely delivered to them.

Tolerated doses for normal tissues

Some tissues are especially sensitive to radiation, so the doses applied to them must be relatively low in order to prevent late damage.

If the dose corresponding to one fraction is 2 Gy, then the tolerant doses for various organs will be as follows:

• testicles - 2 Gy;
• lens - 10 Gy;
• kidney - 20 Gy;
• light - 20 Gy;
• spinal cord - 50 Gy;
• brain - 60 Gr.

At doses higher than those indicated, the risk of acute radiation injury increases dramatically.

Intervals between factions

After radiation therapy, some of the damage caused by it is irreversible, but some is reversed. When irradiated with one fractional dose per day, the repair process until irradiation with the next fractional dose is almost completely completed. If more than one fractional dose per day is applied to the affected organ, then the interval between them should be at least 6 hours so that as many damaged normal tissues as possible can be restored.

Hyperfractionation

When summing up several fractional doses less than 2 Gy, the total radiation dose can be increased without increasing the risk of late damage in normal tissues. To avoid an increase in the total duration of radiation therapy, weekends should also be used or more than one fractional dose per day should be used.

According to one randomized controlled trial conducted in patients with small cell lung cancer, the CHART (Continuous Hyperfractionated Accelerated Radio Therapy) regimen, in which a total dose of 54 Gy was administered in fractional doses of 1.5 Gy 3 times a day for 12 consecutive days, was found to be more effective than the traditional scheme of radiation therapy with a total dose of 60 Gy divided into 30 fractions with a treatment duration of 6 weeks. There was no increase in the frequency of late lesions in normal tissues.

Optimal radiotherapy regimen

When choosing a radiotherapy regimen, they are guided by the clinical features of the disease in each case. Radiation therapy is generally divided into radical and palliative.

radical radiotherapy.

• Usually carried out with the maximum tolerated dose for the complete destruction of tumor cells.
• Lower doses are used to irradiate tumors characterized by high radiosensitivity, and to kill cells of a microscopic residual tumor with moderate radiosensitivity.
• Hyperfractionation in a total daily dose of up to 2 Gy minimizes the risk of late radiation damage.
• A severe acute toxic reaction is acceptable, given the expected increase in life expectancy.
• Typically, patients are able to undergo radiation sessions daily for several weeks.

Palliative radiotherapy.

• The purpose of such therapy is to quickly alleviate the patient's condition.
• Life expectancy does not change or increases slightly.
• The lowest doses and fractions to achieve the desired effect are preferred.
• Prolonged acute radiation damage to normal tissues should be avoided.
• Late radiation damage to normal tissues has no clinical significance.

external beam radiation therapy

Basic principles

Treatment with ionizing radiation generated by an external source is known as external beam radiation therapy.

Superficially located tumors can be treated with low voltage x-rays (80-300 kV). The electrons emitted by the heated cathode are accelerated in the x-ray tube and. hitting the tungsten anode, they cause X-ray bremsstrahlung. The dimensions of the radiation beam are selected using metal applicators of various sizes.

For deep-seated tumors, megavolt x-rays are used. One of the options for such radiation therapy involves the use of cobalt 60 Co as a radiation source, which emits γ-rays with an average energy of 1.25 MeV. To obtain a sufficiently high dose, a radiation source with an activity of approximately 350 TBq is needed.

However, linear accelerators are used much more often to obtain megavolt X-rays; in their waveguide, electrons are accelerated almost to the speed of light and directed to a thin, permeable target. The energy of the resulting X-ray bombardment ranges from 4 to 20 MB. Unlike 60 Co radiation, it is characterized by greater penetrating power, higher dose rate, and better collimation.

The design of some linear accelerators makes it possible to obtain electron beams of various energies (usually in the range of 4-20 MeV). With the help of X-ray radiation obtained in such installations, it is possible to evenly affect the skin and tissues located under it to the desired depth (depending on the energy of the rays), beyond which the dose decreases rapidly. Thus, the depth of exposure at an electron energy of 6 MeV is 1.5 cm, and at an energy of 20 MeV it reaches approximately 5.5 cm. Megavolt radiation is an effective alternative to kilovoltage radiation in the treatment of superficially located tumors.

The main disadvantages of low-voltage radiotherapy:

• high dose of radiation to the skin;
• relatively rapid decrease in dose as it penetrates deeper;
• higher dose absorbed by bones compared to soft tissues.

Features of megavolt radiotherapy:

• distribution of the maximum dose in the tissues located under the skin;
• relatively little damage to the skin;
• exponential relationship between absorbed dose reduction and penetration depth;
• a sharp decrease in the absorbed dose beyond the specified irradiation depth (penumbra zone, penumbra);
• the ability to change the shape of the beam using metal screens or multileaf collimators;
• the possibility of creating a dose gradient across the beam cross section using wedge-shaped metal filters;
• the possibility of irradiation in any direction;
• the possibility of bringing a larger dose to the tumor by cross-irradiation from 2-4 positions.

Radiotherapy planning

Preparation and implementation of external beam radiation therapy includes six main stages.

Beam dosimetry

Before starting the clinical use of linear accelerators, their dose distribution should be established. Given the characteristics of the absorption of high-energy radiation, dosimetry can be performed using small dosimeters with an ionization chamber placed in a tank of water. It is also important to measure the calibration factors (known as exit factors) that characterize the exposure time for a given absorption dose.

computer planning

For simple planning, you can use tables and graphs based on the results of beam dosimetry. But in most cases, computers with special software are used for dosimetric planning. The calculations are based on the results of beam dosimetry, but also depend on algorithms that take into account the attenuation and scattering of X-rays in tissues of different densities. These tissue density data are often obtained using CT performed in the position of the patient in which he will be in radiation therapy.

Target Definition

The most important step in radiotherapy planning is the definition of the target, i.e. volume of tissue to be irradiated. This volume includes the volume of the tumor (determined visually during clinical examination or by CT) and the volume of adjacent tissues, which may contain microscopic inclusions of tumor tissue. It is not easy to determine the optimal target boundary (planned target volume), which is associated with a change in the position of the patient, the movement of internal organs and the need to recalibrate the apparatus in connection with this. It is also important to determine the position of critical organs, i.e. organs characterized by low tolerance to radiation (for example, spinal cord, eyes, kidneys). All this information is entered into the computer along with CT scans that completely cover the affected area. In relatively uncomplicated cases, the volume of the target and the position of critical organs are determined clinically using conventional radiographs.

Dose planning

The goal of dose planning is to achieve a uniform distribution of the effective dose of radiation in the affected tissues so that the dose to critical organs does not exceed their tolerable dose.

The parameters that can be changed during irradiation are as follows:

• beam dimensions;
• beam direction;
• number of bundles;
• relative dose per beam (“weight” of the beam);
• dose distribution;
• use of compensators.

Treatment Verification

It is important to direct the beam correctly and not cause damage to critical organs. For this, radiography on a simulator is usually used before radiation therapy, it can also be performed in the treatment of megavoltage x-ray machines or electronic portal imaging devices.

Choice of radiotherapy regimen

The oncologist determines the total radiation dose and draws up a fractionation regimen. These parameters, together with the parameters of the beam configuration, fully characterize the planned radiation therapy. This information is entered into a computer verification system that controls the implementation of the treatment plan on a linear accelerator.

New in radiotherapy

3D planning

Perhaps the most significant development in the development of radiotherapy over the past 15 years has been the direct application of scanning methods of research (most often CT) for topometry and radiation planning.

Computed tomography planning has a number of significant advantages:

• the ability to more accurately determine the localization of the tumor and critical organs;
• more accurate dose calculation;
• true 3D planning capability to optimize treatment.

Conformal beam therapy and multileaf collimators

The goal of radiotherapy has always been to deliver a high dose of radiation to a clinical target. For this, irradiation with a rectangular beam was usually used with limited use of special blocks. Part of the normal tissue was inevitably irradiated with a high dose. By placing blocks of a certain shape, made of a special alloy, in the path of the beam and using the capabilities of modern linear accelerators, which have appeared due to the installation of multileaf collimators (MLC) on them. it is possible to achieve a more favorable distribution of the maximum radiation dose in the affected area, i.e. increase the level of conformity of radiation therapy.

The computer program provides such a sequence and amount of displacement of the petals in the collimator, which allows you to get the beam of the desired configuration.

By minimizing the volume of normal tissues receiving a high dose of radiation, it is possible to achieve a distribution of a high dose mainly in the tumor and avoid an increase in the risk of complications.

Dynamic and Intensity-Modulated Radiation Therapy

Using the standard method of radiation therapy, it is difficult to effectively influence the target, which has an irregular shape and is located near critical organs. In such cases, dynamic radiation therapy is used when the device rotates around the patient, continuously emitting X-rays, or the intensity of beams emitted from stationary points is modulated by changing the position of the collimator blades, or both methods are combined.

Electronic therapy

Despite the fact that electron radiation is equivalent to photon radiation in terms of radiobiological effect on normal tissues and tumors, in terms of physical characteristics, electron beams have some advantages over photon beams in the treatment of tumors located in certain anatomical regions. Unlike photons, electrons have a charge, so when they penetrate tissue, they often interact with it and, losing energy, cause certain consequences. Irradiation of tissue below a certain level is negligible. This makes it possible to irradiate a tissue volume to a depth of several centimeters from the skin surface without damaging the underlying critical structures.

Comparative Features of Electron and Photon Beam Therapy Electron Beam Therapy:

• limited depth of penetration into tissues;
• the radiation dose outside the useful beam is negligible;
• especially indicated for superficial tumors;
• eg skin cancer, head and neck tumors, breast cancer;
• the dose absorbed by normal tissues (eg, spinal cord, lung) underlying the target is negligible.

Photon beam therapy:

• high penetrating power of photon radiation, which allows treating deep-seated tumors;
• minimal skin damage;
• Beam features allow better matching with the geometry of the irradiated volume and facilitate cross-irradiation.

Generation of electron beams

Most radiotherapy centers are equipped with high-energy linear accelerators capable of generating both X-rays and electron beams.

Since electrons are subject to significant scattering when passing through air, a guide cone, or trimmer, is placed on the radiation head of the apparatus to collimate the electron beam near the surface of the skin. Further correction of the electron beam configuration can be done by attaching a lead or cerrobend diaphragm to the end of the cone, or by covering the normal skin around the affected area with lead rubber.

Dosimetric characteristics of electron beams

The impact of electron beams on a homogeneous tissue is described by the following dosimetric characteristics.

Dose versus penetration depth

The dose gradually increases to a maximum value, after which it sharply decreases to almost zero at a depth equal to the usual depth of penetration of electron radiation.

Absorbed dose and radiation flux energy

The typical penetration depth of an electron beam depends on the energy of the beam.

The surface dose, which is usually characterized as the dose at a depth of 0.5 mm, is much higher for an electron beam than for megavolt photon radiation, and ranges from 85% of the maximum dose at low energy levels (less than 10 MeV) to approximately 95% of the maximum dose at high energy level.

At accelerators capable of generating electron radiation, the radiation energy level varies from 6 to 15 MeV.

Beam profile and penumbra zone

The penumbra zone of the electron beam turns out to be somewhat larger than that of the photon beam. For an electron beam, the dose reduction to 90% of the central axial value occurs approximately 1 cm inward from the conditional geometric boundary of the irradiation field at a depth where the dose is maximum. For example, a beam with a cross section of 10x10 cm 2 has an effective irradiation field size of only Bx8 cm. The corresponding distance for the photon beam is only approximately 0.5 cm. Therefore, to irradiate the same target in the clinical dose range, it is necessary that the electron beam has a larger cross section. This feature of electron beams makes it problematic to pair photon and electron beams, since it is impossible to ensure dose uniformity at the boundary of irradiation fields at different depths.

Brachytherapy

Brachytherapy is a type of radiation therapy in which a radiation source is placed in the tumor itself (the amount of radiation) or near it.

Indications

Brachytherapy is performed in cases where it is possible to accurately determine the boundaries of the tumor, since the irradiation field is often selected for a relatively small volume of tissue, and leaving a part of the tumor outside the irradiation field carries a significant risk of recurrence at the border of the irradiated volume.

Brachytherapy is applied to tumors, the localization of which is convenient both for the introduction and optimal positioning of radiation sources, and for its removal.

Advantages

Increasing the radiation dose increases the efficiency of suppression of tumor growth, but at the same time increases the risk of damage to normal tissues. Brachytherapy allows you to bring a high dose of radiation to a small volume, limited mainly by the tumor, and increase the effectiveness of the impact on it.

Brachytherapy generally does not last long, usually 2-7 days. Continuous low-dose irradiation provides a difference in the rate of recovery and repopulation of normal and tumor tissues, and, consequently, a more pronounced destructive effect on tumor cells, which increases the effectiveness of treatment.

Cells that survive hypoxia are resistant to radiation therapy. Low-dose irradiation during brachytherapy promotes tissue reoxygenation and increases the radiosensitivity of tumor cells that were previously in a state of hypoxia.

The distribution of radiation dose in a tumor is often uneven. When planning radiation therapy, care should be taken to ensure that the tissues around the boundaries of the radiation volume receive the minimum dose. The tissue near the radiation source in the center of the tumor often receives twice the dose. Hypoxic tumor cells are located in avascular zones, sometimes in foci of necrosis in the center of the tumor. Therefore, a higher dose of irradiation of the central part of the tumor negates the radioresistance of the hypoxic cells located here.

With an irregular shape of the tumor, the rational positioning of radiation sources makes it possible to avoid damage to the normal critical structures and tissues located around it.

Flaws

Many of the radiation sources used in brachytherapy emit γ-rays, and medical personnel are exposed to radiation. Although the doses of radiation are small, this circumstance should be taken into account. The exposure of medical personnel can be reduced by using low activity radiation sources and their automated introduction.

Patients with large tumors are not suitable for brachytherapy. however, it can be used as an adjuvant treatment after external beam radiation therapy or chemotherapy when the size of the tumor becomes smaller.

The dose of radiation emitted by a source decreases in proportion to the square of the distance from it. Therefore, in order to irradiate the intended volume of tissue adequately, it is important to carefully calculate the position of the source. The spatial arrangement of the radiation source depends on the type of applicator, the location of the tumor, and what tissues surround it. Correct positioning of the source or applicators requires special skills and experience and is therefore not possible everywhere.

Structures surrounding the tumor, such as lymph nodes with obvious or microscopic metastases, are not subject to irradiation by implantable or cavity-injected radiation sources.

Varieties of brachytherapy

Intracavitary - a radioactive source is injected into any cavity located inside the patient's body.

Interstitial - a radioactive source is injected into tissues containing a tumor focus.

Surface - a radioactive source is placed on the surface of the body in the affected area.

The indications are:

• skin cancer;
• eye tumors.

Radiation sources can be entered manually and automatically. Manual insertion should be avoided whenever possible, as it exposes medical personnel to radiation hazards. The source is injected through injection needles, catheters or applicators, which are previously embedded in the tumor tissue. The installation of "cold" applicators is not associated with irradiation, so you can slowly choose the optimal geometry of the irradiation source.

Automated introduction of radiation sources is carried out using devices, such as "Selectron", commonly used in the treatment of cervical cancer and endometrial cancer. This method consists in the computerized delivery of stainless steel pellets, containing, for example, cesium in glasses, from a leaded container into applicators inserted into the uterine or vaginal cavity. This completely eliminates the exposure of the operating room and medical personnel.

Some automated injection devices work with high-intensity radiation sources, such as Microselectron (iridium) or Cathetron (cobalt), the treatment procedure takes up to 40 minutes. In low dose brachytherapy, the radiation source must be left in the tissues for many hours.

In brachytherapy, most radiation sources are removed after exposure to the calculated dose has been achieved. However, there are also permanent sources, they are injected into the tumor in the form of granules and after their exhaustion they are no longer removed.

Radionuclides

Sources of y-radiation

Radium has been used as a source of y-radiation in brachytherapy for many years. It is currently out of use. The main source of y-radiation is the gaseous daughter product of the decay of radium, radon. Radium tubes and needles must be sealed and checked for leakage frequently. The γ-rays emitted by them have a relatively high energy (on average 830 keV), and a rather thick lead shield is needed to protect against them. During the radioactive decay of cesium, gaseous daughter products are not formed, its half-life is 30 years, and the energy of y-radiation is 660 keV. Cesium has largely replaced radium, especially in gynecological oncology.

Iridium is produced in the form of soft wire. It has a number of advantages over traditional radium or cesium needles for interstitial brachytherapy. A thin wire (0.3 mm in diameter) can be inserted into a flexible nylon tube or hollow needle previously inserted into the tumor. A thicker hairpin-shaped wire can be directly inserted into the tumor using a suitable sheath. In the US, iridium is also available for use in the form of pellets encapsulated in a thin plastic shell. Iridium emits γ-rays with an energy of 330 keV, and a 2-cm-thick lead screen makes it possible to reliably protect medical personnel from them. The main drawback of iridium is its relatively short half-life (74 days), which requires a fresh implant to be used in each case.

The isotope of iodine, which has a half-life of 59.6 days, is used as a permanent implant in prostate cancer. The γ-rays it emits are of low energy and, since the radiation emitted from patients after implantation of this source is negligible, patients can be discharged early.

Sources of β-radiation

Plates that emit β-rays are mainly used in the treatment of patients with eye tumors. Plates are made of strontium or ruthenium, rhodium.

dosimetry

The radioactive material is implanted into tissues in accordance with the radiation dose distribution law, which depends on the system used. In Europe, the classic Parker-Paterson and Quimby implant systems have been largely superseded by the Paris system, particularly suited to iridium wire implants. In dosimetric planning, a wire with the same linear radiation intensity is used, radiation sources are placed in parallel, straight, on equidistant lines. To compensate for the "non-intersecting" ends of the wire, take 20-30% longer than necessary for the treatment of the tumor. In a bulk implant, the sources in the cross section are located at the vertices of equilateral triangles or squares.

The dose to be delivered to the tumor is calculated manually using graphs, such as Oxford charts, or on a computer. First, the basic dose is calculated (the average value of the minimum doses of radiation sources). The therapeutic dose (eg, 65 Gy for 7 days) is selected based on the standard (85% of the basic dose).

The normalization point when calculating the prescribed radiation dose for surface and in some cases intracavitary brachytherapy is located at a distance of 0.5-1 cm from the applicator. However, intracavitary brachytherapy in patients with cancer of the cervix or endometrium has some features. Most often, the Manchester method is used in the treatment of these patients, according to which the normalization point is located 2 cm above the internal os of the uterus and 2 cm away from the uterine cavity (the so-called point A) . The calculated dose at this point makes it possible to judge the risk of radiation damage to the ureter, bladder, rectum and other pelvic organs.

Development prospects

To calculate the doses delivered to the tumor and partially absorbed by normal tissues and critical organs, complex methods of three-dimensional dosimetric planning based on the use of CT or MRI are increasingly used. To characterize the dose of irradiation, only physical concepts are used, while the biological effect of irradiation on various tissues is characterized by a biologically effective dose.

With fractionated administration of high-activity sources in patients with cancer of the cervix and uterine body, complications occur less frequently than with manual administration of low-activity radiation sources. Instead of continuous irradiation with low activity implants, one can resort to intermittent irradiation with high activity implants and thereby optimize the radiation dose distribution, making it more uniform throughout the irradiation volume.

Intraoperative radiotherapy

The most important problem of radiation therapy is to bring the highest possible dose of radiation to the tumor so as to avoid radiation damage to normal tissues. To solve this problem, a number of approaches have been developed, including intraoperative radiotherapy (IORT). It consists in the surgical excision of the tissues affected by the tumor and a single remote irradiation with orthovoltage x-rays or electron beams. Intraoperative radiation therapy is characterized by a low rate of complications.

However, it has a number of disadvantages:

• the need for additional equipment in the operating room;
• the need to comply with protective measures for medical personnel (since, unlike a diagnostic X-ray examination, the patient is irradiated in therapeutic doses);
• the need for the presence of an oncoradiologist in the operating room;
• radiobiological effect of a single high dose of radiation on normal tissues adjacent to the tumor.

Although the long-term effects of IORT are not well understood, animal data suggest that the risk of adverse long-term effects of a single dose of up to 30 Gy of radiation is negligible if normal tissues with high radiosensitivity (large nerve trunks, blood vessels, spinal cord, small intestine) are protected. from radiation exposure. The threshold dose of radiation damage to the nerves is 20-25 Gy, and the latent period of clinical manifestations after irradiation ranges from 6 to 9 months.

Another danger to be considered is tumor induction. A number of studies in dogs have shown a high incidence of sarcomas after IORT compared with other types of radiotherapy. In addition, planning IORT is difficult because the radiologist does not have accurate information regarding the amount of tissue to be irradiated prior to surgery.

The use of intraoperative radiation therapy for selected tumors

Rectal cancer. May be useful for both primary and recurrent cancers.

Cancer of the stomach and esophagus. Doses up to 20 Gy appear to be safe.

bile duct cancer. Possibly justified with minimal residual disease, but impractical with an unresectable tumor.

Pancreas cancer. Despite the use of IORT, its positive effect on the outcome of treatment has not been proven.

Tumors of the head and neck.

• According to individual centers, IORT is a safe method, well tolerated and with encouraging results.
• IORT is warranted for minimal residual disease or recurrent tumor.

brain tumors. The results are unsatisfactory.

Conclusion

Intraoperative radiotherapy, its use limits the unresolved nature of some technical and logistical aspects. Further increase in the conformity of external beam radiation therapy eliminates the benefits of IORT. In addition, conformal radiotherapy is more reproducible and free from the shortcomings of IORT regarding dosimetric planning and fractionation. The use of IORT is still limited to a small number of specialized centers.

Open sources of radiation

Achievements of nuclear medicine in oncology are used for the following purposes:

• clarification of the localization of the primary tumor;
• detection of metastases;
• monitoring the effectiveness of treatment and detection of tumor recurrence;
• targeted radiation therapy.

radioactive labels

Radiopharmaceuticals (RPs) consist of a ligand and an associated radionuclide that emits γ rays. The distribution of radiopharmaceuticals in oncological diseases may deviate from the normal. Such biochemical and physiological changes in tumors cannot be detected using CT or MRI. Scintigraphy is a method that allows you to track the distribution of radiopharmaceuticals in the body. Although it does not provide an opportunity to judge anatomical details, nevertheless, all these three methods complement each other.

Several radiopharmaceuticals are used in diagnostics and for therapeutic purposes. For example, iodine radionuclides are selectively taken up by active thyroid tissue. Other examples of radiopharmaceuticals are thallium and gallium. There is no ideal radionuclide for scintigraphy, but technetium has many advantages over others.

Scintigraphy

A γ-camera is usually used for scintigraphy. With a stationary γ-camera, plenary and whole-body images can be obtained within a few minutes.

Positron emission tomography

PET uses radionuclides that emit positrons. This is a quantitative method that allows you to get layered images of organs. The use of fluorodeoxyglucose labeled with 18 F makes it possible to judge the utilization of glucose, and with the help of water labeled with 15 O, it is possible to study cerebral blood flow. Positron emission tomography makes it possible to differentiate the primary tumor from metastases and evaluate tumor viability, tumor cell turnover, and metabolic changes in response to therapy.

Application in diagnostics and in the long-term period

Bone scintigraphy

Bone scintigraphy is usually performed 2-4 hours after injection of 550 MBq of 99Tc-labeled methylene diphosphonate (99Tc-medronate) or hydroxymethylene diphosphonate (99Tc-oxidronate). It allows you to get multiplanar images of bones and an image of the entire skeleton. In the absence of a reactive increase in osteoblastic activity, a bone tumor on scintigrams may look like a "cold" focus.

High sensitivity of bone scintigraphy (80-100%) in the diagnosis of metastases of breast cancer, prostate cancer, bronchogenic lung cancer, gastric cancer, osteogenic sarcoma, cervical cancer, Ewing's sarcoma, head and neck tumors, neuroblastoma and ovarian cancer. The sensitivity of this method is somewhat lower (approximately 75%) for melanoma, small cell lung cancer, lymphogranulomatosis, kidney cancer, rhabdomyosarcoma, multiple myeloma and bladder cancer.

Thyroid scintigraphy

Indications for thyroid scintigraphy in oncology are the following:

• study of a solitary or dominant node;
• control study in the long-term period after surgical resection of the thyroid gland for differentiated cancer.

Therapy with open sources of radiation

Targeted radiation therapy with radiopharmaceuticals, selectively absorbed by the tumor, has been around for about half a century. A rational pharmaceutical preparation used for targeted radiation therapy should have a high affinity for tumor tissue, a high focus/background ratio, and be retained in the tumor tissue for a long time. Radiopharmaceutical radiation should have a sufficiently high energy to provide a therapeutic effect, but be limited mainly to the boundaries of the tumor.

Treatment of differentiated thyroid cancer 131 I

This radionuclide makes it possible to destroy the tissue of the thyroid gland remaining after total thyroidectomy. It is also used to treat recurrent and metastatic cancer of this organ.

Treatment of tumors from neural crest derivatives 131 I-MIBG

Meta-iodobenzylguanidine labeled with 131 I (131 I-MIBG). successfully used in the treatment of tumors from derivatives of the neural crest. A week after the appointment of the radiopharmaceutical, you can perform a control scintigraphy. With pheochromocytoma, treatment gives a positive result in more than 50% of cases, with neuroblastoma - in 35%. Treatment with 131 I-MIBG also gives some effect in patients with paraganglioma and medullary thyroid cancer.

Radiopharmaceuticals that selectively accumulate in bones

The frequency of bone metastases in patients with breast, lung, or prostate cancer can be as high as 85%. Radiopharmaceuticals that selectively accumulate in bones are similar in their pharmacokinetics to calcium or phosphate.

The use of radionuclides, selectively accumulating in the bones, to eliminate pain in them began with 32 P-orthophosphate, which, although it turned out to be effective, was not widely used due to its toxic effect on the bone marrow. 89 Sr was the first patented radionuclide approved for systemic treatment of bone metastases in prostate cancer. After intravenous administration of 89 Sr in an amount equivalent to 150 MBq, it is selectively absorbed by the skeletal areas affected by metastases. This is due to reactive changes in the bone tissue surrounding the metastasis and an increase in its metabolic activity. Inhibition of bone marrow functions appears after about 6 weeks. After a single injection of 89 Sr in 75-80% of patients, the pain quickly subsides and the progression of metastases slows down. This effect lasts from 1 to 6 months.

Intracavitary therapy

The advantage of direct administration of radiopharmaceuticals into the pleural cavity, pericardial cavity, abdominal cavity, bladder, cerebrospinal fluid or cystic tumors is the direct effect of radiopharmaceuticals on tumor tissue and the absence of systemic complications. Typically, colloids and monoclonal antibodies are used for this purpose.

Monoclonal antibodies

When monoclonal antibodies were first used 20 years ago, many began to consider them a miracle cure for cancer. The task was to obtain specific antibodies to active tumor cells that carry a radionuclide that destroys these cells. However, the development of radioimmunotherapy is currently more problematic than successful, and its future is uncertain.

Total body irradiation

To improve the results of treatment of tumors sensitive to chemo- or radiotherapy, and eradication of stem cells remaining in the bone marrow, before transplantation of donor stem cells, an increase in doses of chemotherapy drugs and high-dose radiation is used.

Targets for whole body irradiation

Destruction of the remaining tumor cells.

Destruction of residual bone marrow to allow engraftment of donor bone marrow or donor stem cells.

Providing immunosuppression (especially when the donor and recipient are HLA incompatible).

Indications for high dose therapy

Other tumors

These include neuroblastoma.

Types of bone marrow transplant

Autotransplantation - stem cells are transplanted from blood or cryopreserved bone marrow obtained before high-dose irradiation.

Allotransplantation - bone marrow compatible or incompatible (but with one identical haplotype) for HLA obtained from related or unrelated donors is transplanted (registries of bone marrow donors have been created to select unrelated donors).

Screening of patients

The disease must be in remission.

There must be no serious impairment of the kidneys, heart, liver, and lungs in order for the patient to cope with the toxic effects of chemotherapy and whole-body radiation.

If the patient is receiving drugs that can cause toxic effects similar to those of whole-body irradiation, the organs most susceptible to these effects should be specifically investigated:

• CNS - in the treatment of asparaginase;
• kidneys - in the treatment of platinum preparations or ifosfamide;
• lungs - in the treatment of methotrexate or bleomycin;
• heart - in the treatment of cyclophosphamide or anthracyclines.

If necessary, additional treatment is prescribed to prevent or correct dysfunctions of organs that may be particularly affected by whole-body irradiation (for example, the central nervous system, testicles, mediastinal organs).

Preparation

An hour before exposure, the patient takes antiemetics, including serotonin reuptake blockers, and is given intravenous dexamethasone. For additional sedation, phenobarbital or diazepam can be given. In young children, if necessary, resort to general anesthesia with ketamine.

Methodology

The optimal energy level set on the linac is approximately 6 MB.

The patient lies on his back or on his side, or alternating position on his back and on his side under a screen made of organic glass (perspex), which provides skin irradiation with a full dose.

Irradiation is carried out from two opposite fields with the same duration in each position.

The table, together with the patient, is located at a distance greater than usual from the X-ray apparatus, so that the size of the irradiation field covers the entire body of the patient.

Dose distribution during whole body irradiation is uneven, which is due to the unequal irradiation in the anteroposterior and posteroanterior directions along the whole body, as well as the unequal density of organs (especially the lungs compared to other organs and tissues). Boluses or shielding of the lungs are used to more evenly distribute the dose, but the mode of irradiation described below at doses not exceeding the tolerance of normal tissues makes these measures redundant. The organ of greatest risk is the lungs.

Dose calculation

Dose distribution is measured using lithium fluoride crystal dosimeters. The dosimeter is applied to the skin in the area of ​​the apex and base of the lungs, mediastinum, abdomen and pelvis. The dose absorbed by tissues located in the midline is calculated as the average of the dosimetry results on the anterior and posterior surfaces of the body, or CT of the whole body is performed, and the computer calculates the dose absorbed by a particular organ or tissue.

Irradiation mode

adults. The optimal fractional doses are 13.2-14.4 Gy, depending on the prescribed dose at the normalization point. It is preferable to focus on the maximum tolerated dose for the lungs (14.4 Gy) and not exceed it, since the lungs are dose-limiting organs.

Children. Tolerance of children to radiation is somewhat higher than that of adults. According to the scheme recommended by the Medical Research Council (MRC), the total radiation dose is divided into 8 fractions of 1.8 Gy each with a treatment duration of 4 days. Other schemes of whole body irradiation are used, which also give satisfactory results.

Toxic manifestations

acute manifestations.

• Nausea and vomiting - usually appear approximately 6 hours after exposure to the first fractional dose.
• Swelling of the parotid salivary gland - develops in the first 24 days and then disappears on its own, although patients remain dry in the mouth for several months after that.
• Arterial hypotension.
• Fever controlled by glucocorticoids.
• Diarrhea - appears on the 5th day due to radiation gastroenteritis (mucositis).

Delayed toxicity.

• Pneumonitis, manifested by shortness of breath and characteristic changes on chest x-ray.
• Drowsiness due to transient demyelination. Appears at 6-8 weeks, accompanied by anorexia, in some cases also nausea, disappears within 7-10 days.

late toxicity.

• Cataract, the frequency of which does not exceed 20%. Typically, the incidence of this complication increases between 2 and 6 years after exposure, after which a plateau occurs.
• Hormonal changes leading to the development of azoospermia and amenorrhea, and subsequently - sterility. Very rarely, fertility is preserved and a normal pregnancy is possible without an increase in cases of congenital anomalies in the offspring.
• Hypothyroidism, which develops as a result of radiation damage to the thyroid gland, in combination with damage to the pituitary gland or without it.
• In children, growth hormone secretion may be impaired, which, combined with early closure of the epiphyseal growth zones associated with whole body irradiation, leads to growth arrest.
• Development of secondary tumors. The risk of this complication after irradiation of the whole body increases 5 times.
• Prolonged immunosuppression can lead to the development of malignant tumors of the lymphoid tissue.

Methods of radiation therapy are divided into external and internal, depending on the method of supplying ionizing radiation to the irradiated focus. The combination of methods is called combined radiation therapy.

External methods of irradiation- methods in which the source of radiation is outside the body. External methods include methods of remote irradiation at various installations using different distances from the radiation source to the irradiated focus.

External methods of irradiation include:

Remote γ-therapy;

Remote, or deep, radiotherapy;

High energy bremsstrahlung therapy;

Therapy with fast electrons;

Proton therapy, neutron and therapy with other accelerated particles;

Application method of irradiation;

Close-focus X-ray therapy (in the treatment of malignant skin tumors).

Remote radiation therapy can be carried out in static and mobile modes. In static irradiation, the radiation source is stationary in relation to the patient. Mobile methods of irradiation include rotational-pendulum or sector tangential, rotational-convergent and rotational irradiation with controlled speed. Irradiation can be carried out through one field or be multi-field - through two, three or more fields. In this case, variants of counter or cross fields, etc. are possible. Irradiation can be carried out with an open beam or using various forming devices - protective blocks, wedge-shaped and equalizing filters, lattice diaphragm.

With the application method of irradiation, for example, in ophthalmic practice, applicators containing radionuclides are applied to the pathological focus.

Close-focus X-ray therapy is used to treat malignant tumors of the skin, while the distance from the external anode to the tumor is several centimeters.

Internal methods of irradiation- methods in which radiation sources are introduced into tissues or cavities of the body, and also used in the form of a radiopharmaceutical drug introduced into the patient.

Internal methods of irradiation include:

intracavitary irradiation;

interstitial irradiation;

Systemic radionuclide therapy.

During brachytherapy, radiation sources are introduced into hollow organs with the help of special devices by the sequential introduction of an endostat and radiation sources (irradiation according to the afterloading principle). For the implementation of radiation therapy of tumors of different localizations, there are various endostats: metrocolpostates, metrastats, colpostates, proctostats, stomatates, esophagostats, bronchostats, cytostats. Enclosed sources of radiation, radionuclides enclosed in a filter shell, in most cases in the form of cylinders, needles, short rods or balls, enter the endostats.

In radiosurgical treatment with Gamma Knife and Cyber ​​Knife, targeted irradiation of small targets is carried out using special stereotaxic devices using precise optical guide systems for three-dimensional (three-dimensional - 3D) radiotherapy with multiple sources.

With systemic radionuclide therapy use radiopharmaceuticals (RFP), administered to the patient inside, compounds that are tropic to a particular tissue. For example, by introducing iodine radionuclide, malignant tumors of the thyroid gland and metastases are treated, with the introduction of osteotropic drugs, bone metastases are treated.

Types of radiation treatment. There are radical, palliative and symptomatic goals of radiation therapy. Radical radiation therapy carried out in order to cure the patient with the use of radical doses and volumes of irradiation of the primary tumor and areas of lymphogenous metastasis.

palliative care, aimed at prolonging the life of the patient by reducing the size of the tumor and metastases, is performed with smaller doses and volumes of radiation than with radical radiation therapy. In the process of palliative radiotherapy in some patients with a pronounced positive effect, it is possible to change the goal with an increase in total doses and volumes of exposure to radical ones.

symptomatic radiation therapy are carried out in order to relieve any painful symptoms associated with the development of a tumor (pain syndrome, signs of compression of blood vessels or organs, etc.), to improve the quality of life. Irradiation volumes and total doses depend on the treatment effect.

Radiation therapy is carried out with different distribution of the radiation dose over time. Currently used:

Single irradiation;

Fractionated, or fractional, irradiation;

continuous irradiation.

An example of a single exposure is proton hypophysectomy, when radiation therapy is performed in one session. Continuous irradiation occurs with interstitial, intracavitary and application methods of therapy.

Fractionated irradiation is the main method of dose adjustment in remote therapy. Irradiation is carried out in separate portions, or fractions. Various dose fractionation schemes are used:

Usual (classical) fine fractionation - 1.8-2.0 Gy per day 5 times a week; SOD (total focal dose) - 45-60 Gy, depending on the histological type of tumor and other factors;

Average fractionation - 4.0-5.0 Gy per day 3 times a week;

Large fractionation - 8.0-12.0 Gy per day 1-2 times a week;

Intensively concentrated irradiation - 4.0-5.0 Gy daily for 5 days, for example, as a preoperative irradiation;

Accelerated fractionation - irradiation 2-3 times a day with conventional fractions with a decrease in the total dose for the entire course of treatment;

Hyperfractionation, or multifractionation - splitting the daily dose into 2-3 fractions with a decrease in the dose per fraction to 1.0-1.5 Gy with an interval of 4-6 hours, while the duration of the course may not change, but the total dose, as a rule, increases ;

Dynamic fractionation - irradiation with different fractionation schemes at individual stages of treatment;

Split-courses - an irradiation regimen with a long break for 2-4 weeks in the middle of the course or after reaching a certain dose;

Low-dose variant of total body photon irradiation - from 0.1-0.2 Gy to 1-2 Gy in total;

High-dose variant of total body photon irradiation from 1-2 Gy to 7-8 Gy in total;

Low-dose variant of subtotal photon irradiation of the body from 1-1.5 Gy to 5-6 Gy in total;

High-dose variant of subtotal photon irradiation of the body from 1-3 Gy to 18-20 Gy in total;

Electronic total or subtotal irradiation of the skin in various modes in case of its tumor lesion.

The size of the dose per fraction is more important than the total time of the course of treatment. Large fractions are more effective than small fractions. Enlargement of fractions with a decrease in their number requires a decrease in the total dose, if the total course time does not change.

Various options for dynamic dose fractionation are well developed at the P. A. Herzen Moscow Research Institute of Optics. The proposed options turned out to be much more effective than classical fractionation or summing up equal coarse fractions. When conducting independent radiation therapy or in terms of combined treatment, isoeffective doses are used for squamous cell and adenogenic cancer of the lung, esophagus, rectum, stomach, gynecological tumors, sarcomas

soft tissues. Dynamic fractionation significantly increased the efficiency of irradiation by increasing SOD without enhancing the radiation reactions of normal tissues.

It is recommended to reduce the value of the interval during the split course to 10-14 days, since the repopulation of surviving clonal cells appears at the beginning of the 3rd week. However, a split course improves tolerability of treatment, especially in cases where acute radiation reactions prevent a continuous course. Studies show that surviving clonogenic cells develop such high repopulation rates that each additional day of rest requires an increase of approximately 0.6 Gy to compensate.

When conducting radiation therapy, methods of modifying the radiosensitivity of malignant tumors are used. radiosensitization radiation exposure - a process in which various methods lead to an increase in tissue damage under the influence of radiation. Radioprotection- actions aimed at reducing the damaging effect of ionizing radiation.

oxygen therapy- a method of tumor oxygenation during irradiation using pure oxygen for breathing at normal pressure.

Oxygen barotherapy- a method of tumor oxygenation during irradiation using pure oxygen for breathing in special pressure chambers under pressure up to 3-4 atm.

The use of the oxygen effect in oxygen barotherapy, according to S. L. Daryalova, was especially effective in radiation therapy of undifferentiated tumors of the head and neck.

Regional tourniquet hypoxia- a method of irradiation of patients with malignant tumors of the extremities under the conditions of imposing a pneumatic tourniquet on them. The method is based on the fact that when a tourniquet is applied, pO 2 in normal tissues drops almost to zero in the first minutes, while oxygen tension in the tumor remains significant for some time. This makes it possible to increase the single and total doses of radiation without increasing the frequency of radiation damage to normal tissues.

Hypoxic hypoxia- a method in which, before and during the irradiation session, the patient breathes a gaseous hypoxic mixture (HGM) containing 10% oxygen and 90% nitrogen (HHS-10) or when the oxygen content decreases to 8% (HHS-8). It is believed that there are so-called acute hypoxic cells in the tumor. The mechanism of the appearance of such cells includes a periodic, lasting tens of minutes, a sharp decrease - up to termination - of blood flow in some of the capillaries, which is due, among other factors, to increased pressure of a rapidly growing tumor. Such acute hypoxic cells are radioresistant; if they are present at the time of the irradiation session, they "escape" from radiation exposure. This method is used at the Russian Cancer Research Center of the Russian Academy of Medical Sciences with the justification that artificial hypoxia reduces the value of the pre-existing "negative" therapeutic interval, which is determined by the presence of hypoxic radioresistant cells in the tumor with their almost complete absence.

twii in normal tissues. The method is necessary to protect normal tissues highly sensitive to radiation therapy, located near the irradiated tumor.

Local and general thermotherapy. The method is based on an additional destructive effect on tumor cells. The method is substantiated by the overheating of the tumor, which occurs due to reduced blood flow compared to normal tissues and the slowing down of heat removal as a result. The mechanisms of the radiosensitizing effect of hyperthermia include blocking the repair enzymes of irradiated macromolecules (DNA, RNA, proteins). With a combination of temperature exposure and irradiation, synchronization of the mitotic cycle is observed: under the influence of high temperature, a large number of cells simultaneously enter the G2 phase, which is most sensitive to irradiation. The most commonly used local hyperthermia. There are devices "YAKHTA-3", "YAKHTA-4", "PRIMUS U + R" for microwave (UHF) hyperthermia with various sensors for heating the tumor from the outside or with the introduction of a sensor into the cavity, see Fig. rice. 20, 21 on col. inset). For example, a rectal probe is used to heat a prostate tumor. With microwave hyperthermia with a wavelength of 915 MHz, the temperature in the prostate gland is automatically maintained within 43-44 ° C for 40-60 minutes. Irradiation follows immediately after the hyperthermia session. There is a possibility for simultaneous radiation therapy and hyperthermia (Gamma Met, England). Currently, it is believed that, according to the criterion of complete regression of the tumor, the effectiveness of thermoradiation therapy is one and a half to two times higher than with radiation therapy alone.

Artificial hyperglycemia leads to a decrease in intracellular pH in tumor tissues to 6.0 and below, with a very slight decrease in this indicator in most normal tissues. In addition, hyperglycemia under hypoxic conditions inhibits the processes of post-radiation recovery. It is considered optimal to conduct irradiation, hyperthermia and hyperglycemia simultaneously or sequentially.

Electron Withdrawing Compounds (EAC)- chemicals capable of imitating the action of oxygen (its electron affinity) and selectively sensitize hypoxic cells. The most commonly used EAS are metronidazole and misonidazole, especially when applied locally in a solution of dimethyl sulfoxide (DMSO), which makes it possible to significantly improve the results of radiation treatment when creating high concentrations of drugs in some tumors.

To change the radiosensitivity of tissues, drugs that are not associated with the oxygen effect, such as inhibitors of DNA repair, are also used. These drugs include 5-fluorouracil, halogenated analogs of purine and pyrimidine bases. As a sensitizer, an inhibitor of DNA synthesis, oxyurea, with antitumor activity, is used. The use of the antitumor antibiotic actinomycin D also leads to a weakening of post-radiation recovery. DNA synthesis inhibitors can be used to temporarily

artificial synchronization of tumor cell division for the purpose of their subsequent irradiation in the most radiosensitive phases of the mitotic cycle. Certain hopes are pinned on the use of tumor necrosis factor.

The use of several agents that change the sensitivity of tumor and normal tissues to radiation is called polyradiomodification.

Combined treatments- a combination in various sequences of surgical intervention, radiation therapy and chemotherapy. In combined treatment, radiation therapy is carried out in the form of pre- or postoperative irradiation, in some cases intraoperative irradiation is used.

Goals preoperative course of radiation are the reduction of the tumor to expand the boundaries of operability, especially in large tumors, the suppression of the proliferative activity of tumor cells, the reduction of concomitant inflammation, the impact on the path of regional metastasis. Preoperative irradiation leads to a decrease in the number of relapses and the occurrence of metastases. Preoperative irradiation is a complex task in terms of addressing issues of dose levels, fractionation methods, and appointment of the timing of the operation. To cause serious damage to tumor cells, it is necessary to apply high tumoricidal doses, which increases the risk of postoperative complications, since healthy tissues enter the irradiation zone. At the same time, the operation should be carried out shortly after the end of irradiation, since the surviving cells may begin to multiply - this will be a clone of viable radioresistant cells.

Since the advantages of preoperative irradiation in certain clinical situations have been proven to increase patient survival rates and reduce the number of relapses, it is necessary to strictly follow the principles of such treatment. Currently, preoperative irradiation is carried out in coarse fractions with daily dose splitting, dynamic fractionation schemes are used, which makes it possible to carry out preoperative irradiation in a short time with an intense effect on the tumor with relative sparing of the surrounding tissues. The operation is prescribed 3-5 days after intensely concentrated irradiation, 14 days after irradiation using a dynamic fractionation scheme. If preoperative irradiation is carried out according to the classical scheme at a dose of 40 Gy, it is necessary to prescribe an operation 21-28 days after the radiation reactions subside.

Postoperative irradiation are carried out as an additional effect on the remnants of the tumor after non-radical operations, as well as to destroy subclinical foci and possible metastases in regional lymph nodes. In those cases where surgery is the first stage of antitumor treatment, even with radical removal of the tumor, irradiation of the bed of the removed tumor and the pathways of regional meta-

stasis, as well as the whole organ can significantly improve the results of treatment. You should strive to start postoperative irradiation no later than 3-4 weeks after surgery.

At intraoperative irradiation a patient under anesthesia is subjected to a single intense radiation exposure through an open surgical field. The use of such irradiation, in which healthy tissues are simply mechanically moved away from the zone of intended irradiation, makes it possible to increase the selectivity of radiation exposure in locally advanced neoplasms. Taking into account the biological effectiveness, the summing up of single doses from 15 to 40 Gy is equivalent to 60 Gy or more with classical fractionation. Back in 1994, at the V International Symposium in Lyon, when discussing the problems associated with intraoperative irradiation, recommendations were made to use 20 Gy as the maximum dose to reduce the risk of radiation damage and the possibility of further external irradiation if necessary.

Radiation therapy is most often used as an effect on the pathological focus (tumor) and areas of regional metastasis. Sometimes used systemic radiation therapy- total and subtotal irradiation for palliative or symptomatic purposes during the generalization of the process. Systemic radiation therapy makes it possible to achieve regression of lesions in patients with resistance to chemotherapy drugs.

Fractionation is the division of the total dose of radiation into several smaller fractions. It is known that the desired effect of irradiation can be obtained by dividing the total dose into daily fractions while reducing toxicity. In terms of clinical medicine, this means that fractionated radiotherapy achieves a higher level of tumor control and a clear reduction in toxicity to normal tissue compared to single high-dose irradiation. Standard fractionation involves 5 exposures per week once a day at 200 cGy. The total dose depends on the mass (occult, microscopic or macroscopic) and the histological structure of the tumor and is often determined empirically.

There are two methods of fractionation - hyperfractionation and accelerated. In hyperfractionation, the standard dose is divided into smaller than usual fractions given twice a day; the total duration of treatment (in weeks) remains almost the same. The meaning of this effect is that: 1) the toxicity of late-reacting tissues, which are usually more sensitive to the size of the fraction, is reduced; 2) the total dose increases, which increases the likelihood of tumor destruction. The total dose for accelerated fractionation is slightly less than or equal to the standard, but the treatment period is shorter. This allows you to suppress the possibility of tumor recovery during treatment. With accelerated fractionation, two or more exposures per day are prescribed, the fractions are usually smaller than the standard ones.

Irradiation is often carried out under conditions of hyperthermia. Hyperthermia is the clinical use of heating tumor tissue to temperatures above 42.5°C, which kills cells by enhancing the cytotoxic effects of chemotherapy and radiotherapy. The properties of hyperthermia are: 1) effectiveness against cell populations with hypoxic, acidic environment and depleted food resources, 2) activity against cells in the S-phase of the proliferative cycle that are resistant to radiation therapy. It is assumed that hyperthermia affects the cell membrane and intracellular structures, including the components of the cytoplasm and the nucleus. The supply of energy to the tissue is achieved by microwave, ultrasonic and radio frequency devices. The use of hyperthermia is associated with the difficulties of uniform heating of large or deeply located tumors and an accurate assessment of the distribution of heat.

Palliative versus Radical Radiation The goal of palliative therapy is to relieve symptoms that impair function or comfort, or put them at risk for the foreseeable future. Palliative care regimens are distinguished by increased daily fractions (>200 cGy, more commonly 250-400 cGy), shortened total treatment time (several weeks), and reduced total dose (2000-4000 cGy). An increase in the fractional dose is accompanied by an increase in the risk of toxicity to late responding tissues, but this is balanced by a shortening of the required time in patients with limited chances of survival.