With average fractionation, a single dose is. Efficacy of Fractionated Radiation Therapy for Cancer

UNCONVENTIONAL DOSE FRACTIONATION

A.V. Boyko, Chernichenko A.V., S.L. Darialova, Meshcheryakova I.A., S.A. Ter-Harutyunyants
MNIOI them. P.A. Herzen, Moscow

The use of ionizing radiation in the clinic is based on differences in the radiosensitivity of the tumor and normal tissues, called the radiotherapy interval. Under the influence of ionizing radiation on biological objects, alternative processes arise: damage and restoration. Thanks to fundamental radiobiological research, it turned out that during irradiation in tissue culture, the degree of radiation damage and restoration of the tumor and normal tissues are equivalent. But the situation changes dramatically when a tumor in the patient's body is irradiated. Primary damage remains the same, but recovery is not the same. Normal tissues, due to stable neurohumoral connections with the host organism, restore radiation damage faster and more completely than a tumor due to its inherent autonomy. Using these differences and managing them, it is possible to achieve total destruction of the tumor, while preserving normal tissues.

Unconventional dose fractionation seems to us to be one of the most attractive ways to control radiosensitivity. With an adequately selected dose splitting option, without any additional costs, a significant increase in tumor damage can be achieved while protecting surrounding tissues.

When discussing the problems of non-traditional dose fractionation, the concept of "traditional" radiotherapy regimens should be defined. In different countries of the world, the evolution of radiotherapy has led to the emergence of different, but have become "traditional" dose fractionation regimens for these countries. For example, according to the Manchester School, a course of radical radiation treatment consists of 16 fractions and is carried out over 3 weeks, while in the USA 35-40 fractions are delivered within 7-8 weeks. In Russia, in cases of radical treatment, fractionation of 1.8–2 Gy once a day, 5 times a week, up to total doses, which are determined by the morphological structure of the tumor and the tolerance of normal tissues located in the irradiation zone (usually within 60–70 Gr).

Dose-limiting factors in clinical practice are either acute radiation reactions or delayed post-radiation damage, which largely depend on the nature of fractionation. Clinical observations of patients treated in traditional regimens have allowed radiation therapists to establish the expected relationship between the severity of acute and delayed reactions (in other words, the intensity of acute reactions correlates with the likelihood of developing delayed damage to normal tissues). Apparently, the most important consequence of the development of non-traditional dose fractionation regimens, which has numerous clinical confirmations, is the fact that the expected probability of the occurrence of radiation damage described above is no longer correct: delayed effects are more sensitive to changes in the single focal dose delivered per fraction, and acute reactions are more sensitive to fluctuations in the level of the total dose.

So, the tolerance of normal tissues is determined by dose-dependent parameters (total dose, total duration of treatment, single dose per fraction, number of fractions). The last two parameters determine the level of dose accumulation. The intensity of acute reactions developing in the epithelium and other normal tissues, whose structure includes stem, maturing and functional cells (for example, bone marrow), reflects the balance between the level of cell death under the influence of ionizing radiation and the level of regeneration of surviving stem cells. This equilibrium primarily depends on the level of dose accumulation. The severity of acute reactions also determines the level of dose administered per fraction (in terms of 1 Gy, large fractions have a greater damaging effect than small ones).

After reaching the maximum of acute reactions (for example, the development of wet or confluent mucosal epithelitis), further death of stem cells cannot lead to an increase in the intensity of acute reactions and manifests itself only in an increase in the healing time. And only if the number of surviving stem cells is not enough for tissue repopulation, then acute reactions can turn into radiation damage (9).

Radiation damage develops in tissues characterized by a slow change in the cell population, such as, for example, mature connective tissue and parenchymal cells of various organs. Due to the fact that in such tissues cellular depletion does not appear before the end of the standard course of treatment, regeneration is impossible during the latter. Thus, in contrast to acute radiation reactions, the level of dose accumulation and the total duration of treatment do not significantly affect the severity of late injuries. At the same time, late damage depends mainly on the total dose, dose per fraction, and the interval between fractions, especially in cases where fractions are delivered in a short period of time.

From the point of view of the antitumor effect, a continuous course of irradiation is more effective. However, this is not always possible due to the development of acute radiation reactions. At the same time, it became known that tumor tissue hypoxia is associated with insufficient vascularization of the latter, and it was proposed to take a break in treatment for reoxygenation and restoration of normal tissues after a certain dose (critical for the development of acute radiation reactions) was given. An unfavorable moment of the break is the risk of repopulation of tumor cells that have retained viability, therefore, when using a split course, no increase in the radiotherapy interval is observed. The first report that, compared with a continuous course of treatment, split gives worse results in the absence of adjustment of a single focal and total dose to compensate for a treatment break was published by Million et Zimmerman in 1975 (7). More recently, Budhina et al (1980) have calculated that the dose required to compensate for the interruption is approximately 0.5 Gy per day (3). A more recent report by Overgaard et al (1988) states that in order to achieve an equal degree of radical treatment, a 3-week break in therapy for laryngeal cancer requires an increase in ROD by 0.11-0.12 Gy (i.e. 0, 5-0.6 Gy per day) (8). It was shown in the work that when the ROD value is 2 Gy, in order to reduce the fraction of surviving clonogenic cells, the number of clonogenic cells doubles 4-6 times over a 3-week break, while their doubling time approaches 3.5-5 days. The most detailed analysis of the dose equivalent for regeneration during fractionated radiotherapy was performed by Withers et al and Maciejewski et al (13, 6). Studies show that after varying delays in fractionated radiotherapy, surviving clonogenic cells develop such high repopulation rates that each additional day of treatment requires an increase of approximately 0.6 Gy to compensate for them. This value of the dose equivalent of repopulation in the course of radiation therapy is close to that obtained in the analysis of the split course. However, a split course improves treatment tolerance, especially in cases where acute radiation reactions preclude a continuous course.

Subsequently, the interval was reduced to 10-14 days, because. repopulation of surviving clonal cells begins at the beginning of the 3rd week.

The impetus for the development of a "universal modifier" - non-traditional fractionation modes - was the data obtained in the study of a specific HBO radiosensitizer. Back in the 1960s, it was shown that the use of large fractions in radiation therapy under HBOT conditions is more effective than classical fractionation, even in control groups in air (2). Undoubtedly, these data contributed to the development and introduction into practice of non-traditional fractionation regimes. Today there are a huge number of such options. Here are some of them.

Hypofractionation: larger, compared to the classical mode, fractions (4-5 Gy) are used, the total number of fractions is reduced.

Hyperfractionation implies the use of small, in comparison with the "classic", single focal doses (1-1.2 Gy), summed up several times a day. The total number of factions has been increased.

Continuous accelerated hyperfractionation as a variant of hyperfractionation: the fractions are closer to the classical ones (1.5-2 Gy), but are supplied several times a day, which reduces the total treatment time.

Dynamic fractionation: dose splitting mode, in which the summing up of coarse fractions alternates with classical fractionation or summing up doses of less than 2 Gy several times a day, etc.

The construction of all schemes of unconventional fractionation is based on information about the differences in the rate and completeness of the recovery of radiation damage in various tumors and normal tissues and the degree of their reoxygenation.

Thus, tumors characterized by a rapid growth rate, a high proliferative pool, and pronounced radiosensitivity require larger single doses. An example is the method of treatment of patients with small cell lung cancer (SCLC), developed at the MNIOI. P.A. Herzen (1).

With this localization of the tumor, 7 methods of non-traditional dose fractionation have been developed and studied in a comparative aspect. The most effective of them was the method of daily dose splitting. Taking into account the cellular kinetics of this tumor, irradiation was carried out daily with enlarged fractions of 3.6 Gy with daily splitting into three portions of 1.2 Gy, delivered at intervals of 4-5 hours. For 13 treatment days, SOD is 46.8 Gy, equivalent to 62 Gy. Of 537 patients, complete resorption of the tumor in the loco-regional zone was 53-56% versus 27% with classical fractionation. Of these, 23.6% with a localized form survived the 5-year milestone.

The technique of multiple splitting of the daily dose (classical or enlarged) with an interval of 4-6 hours is increasingly being used. Due to the faster and more complete recovery of normal tissues using this technique, it is possible to increase the dose in the tumor by 10-15% without increasing the risk of damage to normal tissues.

This has been confirmed in numerous randomized studies of leading clinics in the world. Several works devoted to the study of non-small cell lung cancer (NSCLC) can serve as an example.

The RTOG 83-11 study (Phase II) examined a hyperfractionation regimen comparing different levels of SOD (62 Gy; 64.8 Gy; 69.6 Gy; 74.4 Gy and 79.2 Gy) delivered in fractions of 1.2 Gr twice a day. The highest survival rate of patients was noted with SOD 69.6 Gy. Therefore, in phase III clinical trials, a fractionation regimen with SOD 69.6 Gy (RTOG 88-08) was studied. The study included 490 patients with locally advanced NSCLC, who were randomized as follows: group 1 - 1.2 Gy twice a day up to SOD 69.6 Gy and group 2 - 2 Gy daily up to SOD 60 Gy. However, the long-term results were lower than expected: the median survival and 5-year life expectancy in the groups was 12.2 months, 6% and 11.4 months, 5%, respectively.

FuXL et al. (1997) investigated a hyperfractionation regimen of 1.1 Gy 3 times a day at 4 hour intervals up to a SOD of 74.3 Gy. 1-, 2-, and 3-year survival rates were 72%, 47%, and 28% in the hyperfractionated RT group and 60%, 18%, and 6% in the classic dose fractionation group (4) . At the same time, "acute" esophagitis in the study group was observed significantly more often (87%) compared with the control group (44%). At the same time, there was no increase in the frequency and severity of late radiation complications.

The randomized study by Saunders NI et al (563 patients) compared two groups of patients (10). Continuous accelerated fractionation (1.5 Gy 3 times a day for 12 days up to SOD 54 Gy) and classical radiation therapy up to SOD 66 Gy. Patients treated with the hyperfractionation regimen had a significant improvement in 2-year survival rates (29%) compared to the standard regimen (20%). In the work, no increase in the frequency of late radiation injuries was noted either. At the same time, in the study group, severe esophagitis was observed more often than with classical fractionation (19% and 3%, respectively), although they were noted mainly after the end of treatment.

Another direction of research is the method of differentiated irradiation of the primary tumor in the locoregional zone according to the "field in the field" principle, in which a larger dose is applied to the primary tumor than to regional zones over the same period of time. Uitterhoeve AL et al (2000) in the study EORTC 08912 to increase the dose to 66 Gy added 0.75 Gy daily (boost - volume). 1 and 2 year survival rates were 53% and 40% with satisfactory tolerability (12).

Sun LM et al (2000) added an additional daily local dose of 0.7 Gy to the tumor, which allowed, along with a reduction in the total treatment time, to achieve tumor responses in 69.8% of cases compared to 48.1% when using the classical fractionation regimen ( eleven). King et al (1996) used an accelerated hyperfractionation regimen combined with an increase in focal dose to 73.6 Gy (boost) (5). The median survival was 15.3 months; among 18 NSCLC patients who underwent follow-up bronchoscopic examination, histologically confirmed local control was about 71% at follow-up periods of up to 2 years.

With independent radiation therapy and combined treatment, various options for dynamic dose fractionation, developed at the MNII named after M.I. P.A. Herzen. They turned out to be more effective than classical fractionation and monotonous summing up of coarse fractions when using isoeffective doses not only in squamous cell and adenogenic cancer (lung, esophagus, rectum, stomach, gynecological cancer), but also in soft tissue sarcomas.

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

Thus, in gastric cancer, traditionally considered as a radioresistant model of malignant tumors, the use of preoperative irradiation according to the dynamic fractionation scheme made it possible to increase the 3-year survival rate of patients up to 78% compared with 47-55% with surgical treatment or combined with the use of classical and intensive concentrated mode of irradiation. At the same time, radiation pathomorphosis of III-IV degree was noted in 40% of patients.

In case of soft tissue sarcomas, the use of radiation therapy in addition to surgery using the original scheme of dynamic fractionation made it possible to reduce the frequency of local recurrences from 40.5% to 18.7% with an increase in 5-year survival from 56% to 65%. A significant increase in the degree of radiation pathomorphosis was noted (III-IV degree of radiation pathomorphosis in 57% versus 26%), and these indicators correlated with the frequency of local relapses (2% versus 18%).

Today, domestic and world science suggests using various options for non-traditional dose fractionation. To a certain extent, this diversity is explained by the fact that taking into account the repair of sublethal and potentially lethal damage in cells, repopulation, oxygenation and reoxygenation, progression through the phases of the cell cycle, i.e. the main factors that determine the response of the tumor to radiation, for individual prediction in the clinic is almost impossible. So far, we have only group features for selecting a dose fractionation regimen. This approach in most clinical situations, with reasonable indications, reveals the advantages of non-traditional fractionation over the classical one.

Thus, it can be concluded that non-traditional dose fractionation makes it possible to simultaneously influence the degree of radiation damage to the tumor and normal tissues in an alternative way, while significantly improving the results of radiation treatment while preserving normal tissues. Prospects for the development of NFD are associated with the search for closer correlations between irradiation regimens and the biological characteristics of the tumor.

Bibliography:

1. Boyko A.V., Trakhtenberg A.Kh. Radiation and surgical methods in the complex therapy of patients with a localized form of small cell lung cancer. In the book: "Lung Cancer". - M., 1992, pp. 141-150.

2. Darialova S.L. Hyperbaric oxygenation in radiation treatment of patients with malignant tumors. Chapter in the book: "hyperbaric oxygenation", M., 1986.

3. Budhina M, Skrk J, Smid L, et al: Tumor cell repopulating in the rest interval of split-course radiation treatment. Stralentherapie 156:402, 1980

4. Fu XL, Jiang GL, Wang LJ, Qian H, Fu S, Yie M, Kong FM, Zhao S, He SQ, Liu TF Hyperfractionated accelerated radiation therapy for non-small cell lung cancer: clinical phase I/II trial. //Int J Radiat Oncol Biol Phys; 39(3):545-52 1997

5. King SC, Acker JC, Kussin PS, et al. High-dose hyperfractionated accelerated radiotherapy using a concurrent boost for the treatment of nonsmall cell lung cancer: unusual toxicity and promising early results. //Int J Radiat Oncol Biol Phys. 1996;36:593-599.

6. Maciejewski B, Withers H, Taylor J, et al: Dose fractionation and regeneration in radiotherapy for cancer of the oral cavity and oropharynx: Tumor dose-response and repopulating. Int J Radiat Oncol Biol Phys 13:41, 1987

7. Million RR, Zimmerman RC: Evaluation of the University of Florida split-course technique for various head and neck squamous cell carcinomas. Cancer 35:1533, 1975

8. Overgaard J, Hjelm-Hansen M, Johansen L, et al: Comparison of conventional and split-course radiotherapy as primary treatment in carcinoma of the larynx. Acta Oncol 27:147, 1988

9. Peters LJ, Ang KK, Thames HD: Accelerated fractionation in the radiation treatment of head and neck cancer: A critical comparison of different strategies. Acta Oncol 27:185, 1988

10. Saunders MI, Dische S, Barrett A, et al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomized multicentre trial. CHART Steering Committee. //lancet. 1997;350:161-165.

11. Sun LM, Leung SW, Wang CJ, Chen HC, Fang FM, Huang EY, Hsu HC, Yeh SA, Hsiung CY, Huang DT Concomitant boost radiation therapy for inoperable non-small-cell lung cancer: preliminary report of a prospective randomized study. //Int J Radiat Oncol Biol Phys; 47(2):413-8 2000

12. Uitterhoeve AL, Belderbos JS, Koolen MG, van der Vaart PJ, Rodrigus PT, Benraadt J, Koning CC, Gonzalez Gonzalez D, Bartelink H Toxicity of high-dose radiotherapy combined with daily cisplatin in non-small cell lung cancer: results of the EORTC 08912 phase I/II study. European Organization for Research and Treatment of Cancer. //Eur J Cancer; 36(5):592-600 2000

13. Withers RH, Taylor J, Maciejewski B: The hazard of accelerated tumor clonogen repopulating during radiotherapy. Acta Oncol 27:131, 1988

The radiobiological principles of radiotherapy dose fractionation are outlined, and the effect 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.

Dose Fractionation, radiation therapy

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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 y-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.

In systemic radionuclide therapy, radiopharmaceuticals (RP) are used, which are administered orally to the patient, compounds that are tropic to a specific 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 is carried out in order to cure the patient using radical doses and volumes of irradiation of the primary tumor and areas of lymphogenous metastasis.

Palliative treatment, 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 is 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, iso-effective doses are used for squamous cell and adenogenous cancer of the lung, esophagus, rectum, stomach, gynecological tumors, soft tissue sarcomas. 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 of radiation exposure is a process in which various methods lead to an increase in tissue damage under the influence of radiation. Radio protection - actions aimed at reducing the damaging effect of ionizing radiation.

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

Oxygenobarotherapy is 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 SL. Darialova, was especially effective in radiation therapy of undifferentiated tumors of the head and neck.

Regional tourniquet hypoxia is a method of irradiating patients with malignant tumors of the extremities under the conditions of applying a pneumatic tourniquet to them. The method is based on the fact that when a tourniquet is applied, p0 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 is a method in which, before and during an irradiation session, the patient breathes a hypoxic gas mixture (HGM) containing 10% oxygen and 90% nitrogen (HHS-10) or with a decrease in oxygen content 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 RCRC RAMS with the rationale 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, while their almost complete absence 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", "PRI-MUS and + I" for microwave (UHF) hyperthermia with various sensors for heating the tumor from the outside or with the introduction of the sensor into the cavity (see Fig. 20, 21 on color 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 acceptor compounds (EAS) are chemicals that can mimic 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 dimethyl sulfoxide (DMSO) solution, 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 antitumor antibiotic actinomycin D also weakens the 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 methods of treatment - a combination in various sequences of surgery, 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.

The goals of the preoperative course of irradiation are to reduce the tumor to expand the boundaries of operability, especially in large tumors, to suppress the proliferative activity of tumor cells, to reduce concomitant inflammation, and to influence the pathways 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 is 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 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 ways of regional metastasis, as well as of the entire organ, can significantly improve the results of treatment. You should strive to start postoperative irradiation no later than 3-4 weeks after surgery.

During 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 systemic radiation therapy is used - total and subtotal irradiation with a palliative or symptomatic purpose in the generalization of the process. Systemic radiation therapy makes it possible to achieve regression of lesions in patients with resistance to chemotherapy drugs.

TECHNICAL SUPPORT OF RADIOTHERAPY

5.1. DEVICES FOR EXTERNAL BEAM THERAPY

5.1.1. X-ray therapy devices

X-ray therapy devices for remote radiation therapy are divided into devices for long-distance and close-range (close-focus) radiation therapy. In Russia, long-range irradiation is carried out on devices such as "RUM-17", "X-ray TA-D", in which X-ray radiation is generated by a voltage on the X-ray tube from 100 to 250 kV. The devices have a set of additional filters made of copper and aluminum, the combination of which, at different voltages on the tube, allows you to individually obtain the required radiation quality for different depths of the pathological focus, characterized by a half-attenuation layer. These X-ray devices are used to treat non-tumor diseases. Close-focus X-ray therapy is carried out on devices such as RUM-7, X-ray-TA, which generate low-energy radiation from 10 to 60 kV. Used to treat superficial malignant tumors.

The main devices for remote irradiation are gamma therapeutic units of various designs (“Agat-R”, “Agat-S”, “Rocus-M”, “Rocus-AM”) and electron accelerators that generate bremsstrahlung, or photon, radiation with energies from 4 to 20 MeV and electron beams of different energies. Neutron beams are generated on cyclotrons, protons are accelerated to high energies (50-1000 MeV) on synchrophasotrons and synchrotrons.

5.1.2. Gamma therapy devices

As radionuclide radiation sources for remote gamma therapy, 60 Co and l 36 Cs are most often used. The half-life of 60 Co is 5.271 years. The daughter nuclide 60 Ni is stable.

The source is placed inside the radiation head of the gamma apparatus, which creates a reliable protection in the non-operating state. The source has the shape of a cylinder with a diameter and a height of 1-2 cm.

poured from stainless steel, the active part of the source is placed inside in the form of a set of disks. The radiation head ensures the release, formation and orientation of the γ-radiation beam in the operating mode. The devices create a significant dose rate at a distance of tens of centimeters from the source. Absorption of radiation outside a given field is provided by a diaphragm of a special design. There are devices for static

whom and mobile exposure. In the settlement 22. In the last case, a gamma-therapeutic radiation source, a device for remote irradiation of a patient, or both simultaneously in the process of irradiation move relative to each other according to a given and controlled program. Remote devices are static (for example, Agat- C"), rotational ("Agat-R", "Agat-R1", "Agat-R2" - sector and circular irradiation) and convergent ("Rokus-M", the source simultaneously participates in two coordinated circular motions in mutually perpendicular planes ) (Fig. 22).

In Russia (St. Petersburg), for example, a gamma-therapeutic rotary-convergent computerized complex "Rokus-AM" is produced. When working on this complex, it is possible to perform rotational irradiation with the radiation head moving within 0-^360° with an open shutter and stopping at specified positions along the rotation axis with a minimum interval of 10°; use the possibility of convergence; carry out sector swing with two or more centers, as well as apply the scanning method of irradiation with continuous longitudinal movement of the treatment table with the possibility of moving the radiation head in the sector along the axis of eccentricity. The necessary programs are provided: dose distribution in the irradiated patient with optimization of the irradiation plan and printout of the task for calculating the irradiation parameters. With the help of the system program, the processes of irradiation, control, and ensuring the safety of the session are controlled. The shape of the fields created by the device is rectangular; limits of changing the size of the field from 2.0x2.0 mm to 220 x 260 mm.

5.1.3. Particle accelerators

A particle accelerator is a physical facility in which, with the help of electric and magnetic fields, directed beams of electrons, protons, ions and other charged particles with an energy much higher than thermal energy are obtained. In the process of acceleration, the particle velocities increase. The basic scheme of particle acceleration provides for three stages: 1) beam formation and injection; 2) beam acceleration; and 3) beam extraction onto the target or collision of colliding beams in the accelerator itself.

Beam formation and injection. The initial element of any accelerator is an injector, which has a source of a directed flow of low-energy particles (electrons, protons, or other ions), as well as high-voltage electrodes and magnets that extract the beam from the source and form it.

The source forms a particle beam, which is characterized by the average initial energy, the beam current, its transverse dimensions, and the average angular divergence. An indicator of the quality of the injected beam is its emittance, that is, the product of the beam radius and its angular divergence. The lower the emittance, the higher the quality of the final beam of high energy particles. By analogy with optics, the particle current divided by the emittance (which corresponds to the particle density divided by the angular divergence) is called the beam brightness.

Beam acceleration. The beam is formed in the chambers or injected into one or several chambers of the accelerator, in which the electric field increases the speed and hence the energy of the particles.

Depending on the method of particle acceleration and the trajectory of their movement, the installations are divided into linear accelerators, cyclic accelerators, microtrons. In linear accelerators, particles are accelerated in a waveguide using a high-frequency electromagnetic field and move in a straight line; in cyclic accelerators, electrons are accelerated in a constant orbit with the help of an increasing magnetic field, and the particles move along circular orbits; in microtrons, acceleration occurs in a spiral orbit.

Linear accelerators, betatrons and microtrons operate in two modes: in the mode of electron beam extraction with an energy range of 5-25 MeV and in the mode of generating X-ray bremsstrahlung with an energy range of 4-30 MeV.

Cyclic accelerators also include synchrotrons and synchrocyclotrons, which produce beams of protons and other heavy nuclear particles in the energy range of 100-1000 MeV. Proton beams have been obtained and used in large physical centers. For remote neutron therapy, medical channels of cyclotrons and nuclear reactors are used.

The electron beam exits the vacuum window of the accelerator through the collimator. In addition to this collimator, there is another collimator directly next to the patient's body, the so-called applicator. It consists of a set of low atomic number diaphragms to reduce the occurrence of bremsstrahlung. The applicators are available in various sizes to accommodate and limit the irradiation field.

High-energy electrons are less scattered in air than photon radiation, however, they require additional means to equalize the beam intensity in its cross section. These include, for example, leveling and scattering foils made of tantalum and profiled aluminum, which are placed behind the primary collimator.

Bremsstrahlung is generated when fast electrons decelerate in a target made of a material with a high atomic number. The photon beam is formed by a collimator located directly behind the target and a diaphragm that limits the irradiation field. The average photon energy is maximum in the forward direction. Equalizing filters are installed, since the dose rate in the beam cross section is inhomogeneous.

At present, linear accelerators with multileaf collimators have been created for carrying out conformal irradiation (see Fig. 23 on the color inset). Conformal irradiation is carried out with the control of the position of collimators and various blocks using computer control when creating curly fields of complex configuration. Conformal radiation exposure requires the mandatory use of three-dimensional exposure planning (see Fig. 24 on the color inset). The presence of a multi-leaf collimator with movable narrow lobes makes it possible to block part of the radiation beam and form the required irradiation field, and the position of the lobes changes under computer control. In modern setups, the shape of the field can be continuously adjusted, that is, the position of the petals can be changed during beam rotation in order to maintain the irradiated volume. With the help of these accelerators, it became possible to create the maximum dose drop at the border of the tumor and the surrounding healthy tissue.

Further developments have made it possible to produce accelerators for modern irradiation with modulated intensity. Intensively modulated irradiation is an irradiation in which it is possible to create not only a radiation field of any required shape, but also to carry out irradiation with different intensities during the same session. Further improvements have enabled image-corrected radiotherapy. Special linear accelerators have been created in which high-precision irradiation is planned, while the radiation exposure is controlled and corrected during the session by performing fluoroscopy, radiography and volumetric computed tomography on a cone beam. All diagnostic structures are built into the linear accelerator.

Due to the constantly controlled position of the patient on the treatment table of the linear electron accelerator and control over the shift of the iso-dose distribution on the monitor screen, the risk of errors associated with the movement of the tumor during respiration and the constantly occurring displacement of a number of organs is reduced.

In Russia, various types of accelerators are used to irradiate patients. The domestic linear accelerator LUER-20 (NI-IFA, St. Petersburg) is characterized by the boundary energy of bremsstrahlung 6 and 18 MB and electrons 6-22 MeV. NIIFA, under license from Philips, produces linear accelerators SL-75-5MT, which are equipped with dosimetric equipment and a planning computer system. There are accelerators PRIMUS (Siemens), multi-leaf LUE Clinac (Varian), etc. (see Fig. 25 on the color insert).

Installations for hadron therapy. The first medical proton beam in the Soviet Union with the parameters necessary for radiation therapy was created

given at the suggestion of V.P. Dzhelepov at the 680 MeV Phasotron at the Joint Institute for Nuclear Research in 1967. Clinical studies were carried out by specialists from the Institute of Experimental and Clinical Oncology of the USSR Academy of Medical Sciences. At the end of 1985, the Laboratory of Nuclear Problems of JINR completed the creation of a six-cabin clinical-physical complex, which includes: three proton channels for medical purposes for irradiating deep-seated tumors with wide and narrow proton beams of various energies (from 100 to 660 MeV); l-meson channel for medical purposes for obtaining and using in radiation therapy intense beams of negative l-mesons with energies from 30 to 80 MeV; channel of ultrafast neutrons for medical purposes (average energy of neutrons in the beam is about 350 MeV) for irradiation of large resistant tumors.

The Central Research Institute of X-Ray Radiology and the St. Petersburg Institute of Nuclear Physics (PNPI) RAS developed and implemented the method of proton stereotaxic therapy using a narrow beam of high-energy protons (1000 MeV) in combination with a rotational irradiation technique at the synchrocyclotron (see Fig. 26 in color). inset). The advantage of this method of irradiation "throughout" is the possibility of a clear localization of the irradiation zone inside the object subjected to proton therapy. In this case, sharp boundaries of irradiation and a high ratio of the radiation dose at the center of irradiation to the dose on the surface of the irradiated object are provided. The method is used in the treatment of various diseases of the brain.

In Russia, research centers in Obninsk, Tomsk and Snezhinsk are conducting clinical trials of fast neutron therapy. In Obninsk, within the framework of cooperation between the Institute of Physics and Energy and the Medical Radiological Research Center of the Russian Academy of Medical Sciences (MRRC RAMS) until 2002. a horizontal beam of a 6 MW reactor with an average neutron energy of about 1.0 MeV was used. At present, the clinical use of the small-sized neutron generator ING-14 has begun.

In Tomsk, at the U-120 cyclotron of the Research Institute of Nuclear Physics, employees of the Research Institute of Oncology use fast neutrons with an average energy of 6.3 MeV. Since 1999, neutron therapy has been carried out at the Russian Nuclear Center in Snezhinsk using the NG-12 neutron generator, which produces a neutron beam of 12-14 MeV.

5.2. DEVICES FOR CONTACT BEAM THERAPY

For contact radiation therapy, brachytherapy, there is a series of hose devices of various designs that allow you to automatically place sources near the tumor and carry out its targeted irradiation: devices of the Agat-V, Agat-VZ, Agat-VU, Agam series with sources of γ-radiation 60 Co (or 137 Cs, l 92 lr), "Microselectron" (Nucletron) with a source of 192 1r, "Selectron" with a source of 137 Cs, "Anet-V" with a source of mixed gamma-neutron radiation 252 Cf ( see Fig. 27 on color insert).

These are devices with semi-automatic multi-position static irradiation by one source moving according to a given program inside the endostat. For example, the gamma-therapeutic intracavitary multi-purpose apparatus "Agam" with a set of rigid (gynecological, urological, dental) and flexible (gastrointestinal) endostats in two applications - in a protective radiological ward and a canyon.

Closed radioactive preparations are used, radionuclides placed in applicators that are injected into cavities. Applicators can be in the form of a rubber tube or special metal or plastic ones (see fig. 28 on the color insert). There is a special radiotherapy technique to ensure the automated supply of the source to the endostats and their automatic return to a special storage container at the end of the irradiation session.

The set of Agat-VU apparatus includes small-diameter metrastats - 0.5 cm, which not only simplifies the method of introducing endostats, but also allows you to quite accurately form the dose distribution in accordance with the shape and size of the tumor. In devices of the Agat-VU type, three small-sized sources of high activity of 60 Co can discretely move with a step of 1 cm along trajectories each 20 cm long. The use of small-sized sources becomes important for small volumes and complex deformities of the uterine cavity, as it allows avoiding complications, such as perforation in invasive forms of cancer.

The advantages of using l 37 Cs gamma therapeutic apparatus "Selectron" with an average dose rate (MDR - Middle Dose Rate) include a longer half-life than that of 60 Co, which allows irradiation under conditions of an almost constant radiation dose rate. It is also essential to expand the possibilities of wide variation in the spatial dose distribution due to the presence of a large number of emitters of a spherical or small-sized linear shape (0.5 cm) and the possibility of alternating active emitters and inactive simulators. In the apparatus, linear sources are moved step by step in the range of absorbed dose rates of 2.53-3.51 Gy/h.

Intracavitary radiation therapy using mixed gamma-neutron radiation 252 Cf on the device "Anet-V" high dose rate (HDR - High Dose Rate) has expanded the range of applications, including for the treatment of radioresistant tumors. Completion of the apparatus "Anet-V" with three-channel type metrastats using the principle of discrete movement of three sources of radionuclide 252 Cf allows the formation of total isodose distributions by using one (with unequal exposure time of the emitter in certain positions), two, three or more trajectories of movement of radiation sources in accordance with with the actual length and shape of the uterine cavity and cervical canal. As the tumor regresses under the influence of radiation therapy and the length of the uterine cavity and cervical canal decreases, there is a correction (reduction in the length of the radiating lines), which helps to reduce the radiation exposure to the surrounding normal organs.

The presence of a computer-aided planning system for contact therapy makes it possible to carry out clinical and dosimetric analysis for each specific situation with the choice of dose distribution that most fully corresponds to the shape and extent of the primary focus, which makes it possible to reduce the intensity of radiation exposure to surrounding organs.

The choice of the mode of fractionation of single total focal doses when using sources of medium (MDR) and high (HDR) activity is mainly

The first task is to bring to the tumor optimal

total dose. The optimum is considered to be the level at which the

the highest percentage of cure is expected with an acceptable percentage of radiation

damage to normal tissues.

On practice optimum- is the total dose that cures

more than 90% of patients with tumors of this localization and histological structure

tours and damage to normal tissues occur in no more than 5% of patients

nyh(Fig. rv.l). The significance of localization is not emphasized by chance: after all,

lying complication strife! In the treatment of tumors in the region of the spine

even 5% of radiation myelitis is unacceptable, and with larynx irradiation - even 5 № necrosis of her cartilage. Based on many years of experimental and clinical

some studies have established exemplary effective absorbed doses. Microscopic aggregates of tumor cells in the area of ​​subclinical tumor spread can be eliminated by irradiation at a dose of 45-50 Gr in the form of separate fractions for 5 weeks. Approximately the same volume and rhythm of irradiations are necessary for the destruction of radiosensitive tumors such as malignant lymphomas. For the destruction of squamous cell carcinoma cells and ad-

nocarcinoma dose required 65-70 Gr within 7-8 weeks, and radioresistant tumors - sarcomas of bones and soft tissues - over 70 Gr for about the same period. In the case of combined treatment of squamous cell carcinoma or adenocarcinoma, radiation dose is limited to 40-45 Gy for 4-5 weeks, followed by surgical removal of the tumor remnant. When choosing a dose, not only the histological structure of the tumor, but also the characteristics of its growth are taken into account. Fast growing neoplasms

sensitive to ionizing radiation than slowly growing ones. Exophytic tumors are more radiosensitive than endophytic, infiltrating surrounding tissues. The effectiveness of the biological action of different ionizing radiation is not the same. The above doses are for "standard" radiation. Behind The standard accepts the action of X-ray radiation with a boundary energy of 200 keV and with an average linear energy loss of 3 keV/μm.

The relative biological effectiveness of such radiation (RBE) at-

nita for I. Approximately the same RBE differs for gamma radiation and a beam of fast electrons. The RBE of heavy charged particles and fast neutrons is much higher - about 10. Accounting for this factor, unfortunately, is quite difficult, since the RBE of different photons and particles is not the same for different tissues and doses per fraction. The biological effect of radiation is determined not only by the value of the total dose, but and the time during which it is absorbed. By selecting the optimal dose-time ratio in each case, you can achieve the maximum possible effect. This principle is implemented by splitting the total dose into separate fractions (single doses). At fractionated irradiation tumor cells are irradiated at different stages of growth and reproduction, i.e. during periods of different radioactivity. It uses the ability of healthy tissues to more fully restore their structure and function than it does in a tumor. Therefore, the second task is to choose the right fractionation regimen. It is necessary to determine a single dose, the number of fractions, the interval between them and, accordingly, the total duration.

the effectiveness of radiation therapy. The most widespread in practice is classical fine fractionation mode. The tumor is irradiated at a dose of 1.8-2 Gy 5 times a week.

divide until the intended total dose is reached. The total duration of treatment is about 1.5 months. The mode is applicable for the treatment of most tumors with high and moderate radiosensitivity. coarse fractionation increase the daily dose to 3-4 Gy, and irradiation is performed 3-4 times a week. This mode is preferable for radioresistant tumors, as well as for neoplasms, whose cells have a high potential to restore sublethal damage. However, with coarse fractionation, more often than

with small, radiation complications are observed, especially in the long-term period.

In order to increase the effectiveness of the treatment of rapidly proliferating tumors, multiple fractionation: dose exposure 2 Gy is carried out 2 times a day with an interval of at least 4-5 hours. The total dose is reduced by 10-15%, and the duration of the course - by 1-3 weeks. Tumor cells, especially those in a state of hypoxia, do not have time to recover from sublethal and potentially lethal injuries. Coarse fractionation is used, for example, in the treatment of lymphomas, small cell lung cancer, tumor metastases in the cervical lymphatic

some nodes. With slowly growing neoplasms, the mode is used hyper-

fractionation: the daily radiation dose of 2.4 Gy is divided into 2 fractions

1.2 Gr. Therefore, irradiation is carried out 2 times a day, but daily

the dose is somewhat higher than with fine fractionation. Beam reactions

tions are not pronounced, despite an increase in the total dose by 15-

25%. A special option is the so-called split course of radiation. After summing up to the tumor half of the total dose (usually about 30 Gy) take a break for 2-4 weeks. During this time, healthy tissue cells recover better than tumor cells. In addition, due to the reduction of the tumor, the oxygenation of its cells increases. interstitial radiation exposure, when implanted into the tumor

yut radioactive sources, use continuous mode of irradiation in

within a few days or weeks. The advantage of __________ this mode is

exposure to radiation at all stages of the cell cycle. After all, it is known that cells are most sensitive to radiation in the mitosis phase and somewhat less in the synthesis phase, and in the resting phase and at the beginning of the postsynthetic period, the radiosensitivity of the cell is minimal. remote fractionated irradiation also tried to

use the unequal sensitivity of cells in different phases of the cycle. For this, the patient was injected with chemicals (5-fluorouracil vincristine), which artificially delayed cells in the synthesis phase. Such an artificial accumulation in the tissue of cells that are in the same phase of the cell cycle is called cycle synchronization. Thus, many options for splitting the total dose are used, and they must be compared based on quantitative indicators. To assess the biological effectiveness of different fractionation regimens, F. Ellis proposed concept nominal standard dose (NSD). NSD- is the total dose for a full course of radiation at which there is no significant damage to normal connective tissue. Also proposed and can be obtained from special tables are factors such as cumulative radiation effect (CRE) and time-dose ratio- fractionation (WDF), for each irradiation session and for the entire irradiation course.

• 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 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.