Stereotactic radiation therapy for gastric cancer. Stereotactic body radiation therapy (SBRT). Radiosurgery treatment using a medical linear accelerator

2
1MIBS-Medical Institute named after. Sergey Berezin, St. Petersburg; FSBEI HE Northwestern State Medical University named after. I. I. Mechnikov Ministry of Health of Russia, St. Petersburg
2 LLC "LDC MIBS", St. Petersburg
3 Federal State Budgetary Educational Institution of Higher Education St. Petersburg State University, St. Petersburg
4 Federal State Budgetary Institution “Russian Scientific Center of Radiology and Surgical Technologies named after. acad. A.M. Granova" of the Ministry of Health of Russia, St. Petersburg
5 LLC "LDC MIBS", St. Petersburg

Treatment of local and regional relapses of head and neck cancer remains an important problem in oncology due to the high frequency of their development after combined and complex treatment. Surgical treatment is not feasible in all cases, chemotherapy has low effectiveness, and re-irradiation using conventional techniques is characterized by low rates of local control, overall survival and a high risk of developing severe late radiation damage. Stereotactic radiation therapy in the hypofractionation mode has proven itself in the treatment of a number of primary tumors in the early stages (lung, prostate cancer), as well as palliative treatment for metastatic lesions of the lungs, liver, bones and lymph nodes. This type of radiation treatment is characterized by good tolerability and relatively high efficiency, however, there are currently no clear recommendations on the choice of fractionation regimen, total dose, and tolerable doses for normal tissues when stereotactic radiation therapy is used in previously irradiated areas. The review examines the use of stereotactic radiotherapy in the hypofractionation mode for the treatment of local and regional relapses of head and neck cancer in previously irradiated areas.

Keywords: head and neck cancer, re-irradiation, relapse, stereotactic radiation therapy, hypofractionation.
For quotation: Mikhailov A.V., Vorobiev N.A., Sokurenko V.P., Martynova N.I., Gutsalo Yu.V. Stereotactic radiation therapy in the hypofractionation mode in the treatment of recurrent head and neck tumors - state of the problem // Breast Cancer. Medical Review. 2018. No. 6. pp. 22-27

Hypofractionated stereotactic radiation therapy in the treatment of recurrent tumors of head and neck - state of the problem
A.V. Mikhailov 1,2, N.A.Vorobyov 1-3, V.P. Sokurenko 4, N.I. Martynova 1, Yu.V. Gutsalo 1

1 Medical Institute named after Berezin Sergey (MIBS), St. Petersburg
2 North-Western State Medical University named after I. I. Mechnikov, St. Petersburg
3 St. Petersburg State University, St. Petersburg
4 Russian Scientific Center Of Radiology And Surgical Technologies named after A. M. Granov, St. Petersburg

Treatment of local and regional relapses of head and neck cancer remains an important problem because of the high frequency of their development after combined and complex treatment. Surgical treatment is possible not in all cases, chemotherapy is characterized by low cure rates, and reirradiation with the use of conventional methods provides low rates of local control, overall survival and a high risk of developing severe late radiation toxicity. Hypofractionated stereotactic radiation therapy is effective in the treatment of primary tumors in the early stages (lung cancer, prostate cancer), as well as in the palliative treatment for metastatic tumors of the lungs, liver, bones and lymph nodes. This type of radiation treatment is characterized by good tolerability and relatively high efficacy, but there are currently no clear recommendations for choosing a fractionation regimen, prescription of a total dose, and tolerant doses for normal tissues in the case of stereotactic radiation therapy in previously irradiated regions. Current experience in hypofractonated stereotaxic radiation therapy for the treatment of local and regional recurrences of head and neck cancer in previously irradiated areas is presented in this review.

Key words: head and neck cancer, reirradiation, recurrence, stereotactic radiotherapy, hypofractionation.
For citation: Mikhailov A.V., Vorobyov N.A., Sokurenko V.P. yt al. Hypofractionated stereotactic radiation therapy in the treatment of recurrent tumors of head and neck - state of the problem // RMJ. Medical Review. 2018. No. 6. P. 22–27.

The review examines the use of stereotactic radiotherapy in the hypofractionation mode for the treatment of local and regional relapses of head and neck cancer in previously irradiated areas.


Introduction

After successful radical treatment of locally advanced forms of head and neck cancer, locoregional relapses develop in more than 30% of patients. The optimal treatment method for patients with recurrent head and neck cancer is surgery, which provides 36% two-year relapse-free and 39% five-year overall survival, however, no more than 20% of patients can be operated on due to pronounced post-radiation changes in the soft tissues of the neck, the proximity of the recurrent tumor to the great vessels and severe concomitant pathology.
Response to systemic treatment (chemotherapy, targeted therapy) is achieved in 15–25% of patients, and the median relapse-free and overall survival is
5.6 and 10.5 months. respectively .
Before the advent of high-precision radiation techniques, patients with unresectable recurrent head and neck tumors were subjected to repeat radiotherapy with conventional fractionation using two-dimensional and three-dimensional planning techniques, the total dose of which rarely exceeded 50 Gy. The main disadvantage of using repeated conventional radiotherapy is late radiation toxicity of grade III–IV, which develops in more than 30% of patients. According to literature data, after repeated conventional radiation therapy, competitive with chemotherapy, disease progression became the cause of death in 90% of patients. About 10% of patients died from treatment-related complications, and the overall five-year survival rate did not exceed 6%.
These disappointing data indicate the need to find new ways to treat this category of patients, and one of them is conformal radiation therapy techniques with total dose escalation to improve local control rates and overall survival without reducing the quality of life of patients.
Stereotactic radiation therapy (SRT) in the hypofractionation mode is a modern method of radiotherapy in which high doses of ionizing radiation (more than 3 Gy per fraction) are delivered to the target area in a small number of fractions (from 2 to 5). Treatment and the process of preparation for it are carried out using special fixing devices (headrests, masks made of thermoplastic material, vacuum mattresses), dosimetric planning methods of high conformity (IMRT - intensity modulated radiation therapy, VMAT - volumetric modulated arch therapy), with therapeutic control positions using X-ray imaging on modern linear accelerators, which allows for the required accuracy of irradiation.
The advantages of SLT in the hypofractionation mode include a shorter course of treatment compared to standard fractionation, a high biologically effective dose, and a smaller number of fractions, which increases the effectiveness of treatment by reducing the effect of the phenomenon of tumor repopulation and, in some cases, allows one to obtain satisfactory results when irradiating radioresistant tumors. This allows us to consider stereotactic radiation as one of the treatment methods for patients with recurrent head and neck cancer.

Hypofractionation in the primary treatment of patients with head and neck tumors

The use of high single doses has been studied since the 1980s. Thus, in 1982, Weissberg et al. published the results of a prospective study conducted at Yale University, where radiation therapy using high single doses has been used for palliative purposes in the treatment of malignant neoplasms of the head and neck since 1973. Patients were randomized into two groups. Patients of the first group were irradiated with a single dose of 2 Gy up to a total dose of 60–70 Gy for 6–7 weeks, patients of the second group were irradiated with 4 Gy up to a total dose of 44 Gy for 2–3 weeks. Treatment was carried out using bremsstrahlung radiation with a photon energy of 2–6 mV. The majority of patients (94% and 88% in the first and second groups, respectively) had T4 stage of the disease. Both groups had comparable tolerability and efficacy. Five-year disease-free survival was 10% in both groups.

The literature describes the “quad shot” technique (English: “four shots”), which was used for palliative purposes in patients with locally advanced disease in the head and neck area. The following fractionation regimen was used: 14 Gy in 4 fractions, 2 times per day with an interval
6 hours. This regimen was then repeated at 4-week intervals for the next two courses. At the same time, minimal toxicity and improved quality of life were noted. The objective response to radiation therapy was 53%, and in 23% of patients the process was stabilized. The median overall survival was 5.7 months, the median progression-free survival was 3.1 months.
The good tolerance of radiotherapy in the hypofractionated mode is also evidenced by the results published in 1990 by Ang et al. The work reported the safety and effectiveness of using a single dose of 5 Gy or higher in patients with head and neck melanoma. A single dose (6 Gy × 5 fractions) was selected based on the radiobiological characteristics of melanoma. These patients had high local control rates without any significant late radiation toxicity.
With the development of the technical capabilities of external beam radiation therapy, attempts have been made to use stereotactic radiation in a high single dose as a local supplement (boost) in patients with nasopharyngeal cancer after a course of radiation therapy in a standard fractionation mode up to a total dose of 66 Gy. After 4–6 weeks. After completing the course of irradiation in the conventional fractionation mode, a single dose of 7 to 15 Gy was administered to the nasopharynx area. According to the results of the study, good rates of local control were noted (100% three-year local control) against the background of satisfactory tolerability and an acceptable incidence of late radiation damage. The study included 45 patients; radiation toxicity manifested itself in the form of cranial nerve neuritis in 4 patients, post-radiation retinopathy in 1 patient, and asymptomatic radionecrosis in the temporal lobe in 3 patients.
Al-Mamgani et al. report the results of stereotactic hypofractionated irradiation as a local supplement after a course of external beam radiation therapy in the conventional fractionation mode in patients with squamous cell carcinoma of the oropharynx and oral cavity, who have traditionally been boosted using contact or interstitial brachytherapy. After reaching the total dose in the standard fractionation mode, local irradiation of the primary tumor was carried out in a single dose of 5.5 Gy up to a total dose of 16.5 Gy
(for 3 fractions). The 2-year local control, disease-free, and overall survival rates were 86%, 80%, and 82%, respectively. There were no interruptions in treatment; no early radiation toxicity of grade IV or higher was noted. Late radiation toxicity developed in 28% of patients during the two-year follow-up period. The authors concluded that stereotactic irradiation as a local adjunct is highly effective and safe in comparison with brachytherapy.
The positive experience of using SLT in the primary treatment of head and neck cancer according to the criteria of oncological effectiveness and safety laid the foundation for research into the use of this method in re-irradiation of patients with recurrent malignant tumors of the head and neck.

Repeated stereotactic irradiation in hypofractionation mode for recurrent head and neck cancer

The most dangerous complications of radiation therapy are irreversible damage to the central nervous system. The difficulty of irradiating the head and neck area lies in the proximity of critical structures such as the brain stem, spinal cord, optic nerves, cochlea, and auditory nerves to the irradiated volumes, damage to which leads to fatal consequences or significantly worsens the quality of life of patients. At the moment, there are no clear recommendations for the formation of radiotherapeutic volumes and dose prescriptions for repeated radiation therapy, and the issue of tolerable doses for normal tissues for repeated irradiation has not been finally resolved.
Many authors point to the importance of medical imaging tools in the formation of radiotherapeutic volumes. The significant role of positron-
emission computed tomography (PET, PET-CT) with glucose in determining the boundaries of a recurrent tumor against the background of post-radiation tissue changes. Deantonio et al. in their study showed that the macroscopic tumor volume (Gross Tumor Volume - GTV), formed according to PET data (GTV-PET), was less than GTV formed according to CT data (GTV-CT): 17.2 cm 3 versus 20 .0 cm 3, which was not statistically significant (p=0.2). However, the clinical volume of the target, formed on the basis of both imaging methods, was significantly larger than that determined only from computed tomography data, due to a more accurate determination of the boundaries of the recurrent tumor against the background of post-radiation changes in the surrounding tissues.
The choice of fractionation regimen and the prescription of total doses depend on the tolerable doses to the surrounding normal tissues and are based on knowledge of the radiobiology of tumors. During primary and repeated irradiation, single doses of 6–9 Gy are most often used, total doses are 30–54 Gy, the number of fractions varies from 2 to 7.

The largest oncology clinics in the USA, Europe and Japan have accumulated some experience in the use of SLT in the hypofractionation mode for repeated irradiation of the head and neck area. The International Consortium on Stereotactic Radiation Therapy summarized the experience of the world's leading oncology clinics; the results of this study were published in 2017. Data on the formation of radiotherapeutic volumes in various clinics are shown in Table 1.

It should be noted that there are a relatively small number of observations and significant differences in approaches to the formation of the irradiated volume among the centers that provided the data. In most cases, the margins for forming the clinical target volume (CTV) and the planned treatment volume (PTV) are small, from 1 to 3 mm, which is due to the high accuracy of dose delivery on the equipment used to implement radiation therapy. Some clinics prioritize tolerating normal tissue doses, while others prioritize dose coverage to the target.

Table 2 shows the data of the above clinics on the total dose prescribed, the fractionation regimen and the technical means of implementing radiation therapy. The most common are courses of radiation therapy, including from 5 to 6 radiation sessions with a total dose of 35–50 Gy, which is biologically equivalent to 48–100 Gy for the coefficient α/β = 10 Gy. In a number of centers, irradiation was carried out daily, in others - every other day or two days. It is important to note the differences in the approach to gradient planning. In centers that used CyberKnife systems, it was allowed to exceed the prescribed dose in the target by up to 135%, while in other clinics that carried out irradiation on linear accelerators with multileaf collimators, homogeneous coverage of the treatment volume was prescribed with a dose excess of no more than 10 -20%.

Table 3 shows the tolerant doses for normal tissues during re-irradiation in the hypofractionation mode, which were used in the clinics that took part in the survey study. These doses reflect generalized values ​​and are not recommendations. The decision remains with the attending physician, depending on the specific clinical situation, the dose received by a particular organ during primary irradiation, as well as the period of time elapsed between courses of radiation therapy.

Table 4 shows data on the incidence of late radiation complications presented by clinics that took part in summarizing the experience of repeated stereotactic irradiation.

With repeated irradiation, even if the maximum permissible doses discussed above are observed, there is an almost twofold increase in the incidence of complications such as osteoradionecrosis, dysphagia, and soft tissue necrosis. It should be noted that the incidence of fatal bleeding from the carotid artery, radiation ulcers, hemorrhagic mucositis and fistula formation does not differ significantly from that during primary irradiation. The authors agree that the risk of developing carotid artery bleeding does not depend on the volume of the tumor, response to treatment and the time interval between courses of radiation, but on the degree of coverage of the vessel wall by the tumor. A correlation was found between the incidence of bleeding and tumor coverage of more than 180° of the circumference of the vascular wall. Table 4 compares the incidence of late complications of radiation therapy in the hypofractionated mode for primary and repeated irradiation of the head and neck region.

Combination of repeated stereotactic irradiation in the hypofractionation mode for recurrent head and neck cancer with systemic treatment

One of the ways to overcome radioresistance of a recurrent tumor is the use of a systemic component simultaneously with local irradiation. Since effective classical cytostatics, as a rule, have already been used in the treatment of the primary tumor, targeted therapy becomes the method of choice. One of the most studied targeted drugs used in squamous cell carcinoma of the head and neck is cetuximab. Of particular note are randomized studies conducted by a team at the University of Pittsburgh Cancer Institute. In their study, Heron et al. patients were randomized into groups of SLT in a hypofractionated mode (n=35) and a combination of SLT with weekly administration of cetuximab (n=35). A complete response was obtained in 34.3% of patients who received SLT alone and in 45.7% of patients who received combination treatment with cetuximab. One- and two-year local control rates were 53.8% and 33.6% for patients treated with SLT alone, and 78.6% and 49.2%, respectively, for patients treated with combination therapy (p=0.009). One-year and two-year overall survival rates were 52.7% and 21.1% for patients treated with SLT alone and 66% and 53.5% for patients treated with combination therapy, respectively (p=0.31).
The results of this work were used as the rationale for opening a phase 2 study of re-irradiation of recurrent head and neck tumors with CRT competitive with cetuximab. In this study, 50 patients received cetuximab
(400 mg/m2 on day 7 and 240 mg/m2 on days 1 to 8) competitive with repeated SLT at a total dose of 40–44 Gy in 5 fractions. Median follow-up was 18 months. Among patients who survived to this follow-up period, one-year survival rate before local progression was 60%, locoregional - 37%, distant - 71%. The one-year overall survival rate for all patients included in the study was 40%. Treatment was well tolerated, with the incidence of late radiation complications of grade III or higher in 6% of patients. The authors concluded that it is possible to safely and effectively use this regimen for palliative treatment in patients with recurrent squamous cell carcinoma of the head and neck.

Conclusion

Today, hypofractionated stereotactic radiotherapy, either alone or in combination with systemic agents, appears to be an effective and relatively safe treatment for patients with recurrent head and neck cancer. Analysis of the experience gained to date in using this method reveals the heterogeneity of the studied groups of patients in approaches to the formation of radiation volumes, as well as the prescription of single and total doses, which dictates the need for further research into the influence of these parameters on the effectiveness of treatment, the frequency and nature of the observed complications.

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SBRT is an abbreviation of English words. They mean "stereotactic corporal (relating to the trunk - everything except the head) radiotherapy." A beam of ultra-powerful radioactive radiation focused precisely on the tumor allows, in one to five sessions, to irreversibly damage the DNA of tumor cells, causing their death. At the same time, the surrounding tissues and the entire body as a whole experience almost no negative influences. This is due to the technological features of the technique.

The need to calculate with maximum accuracy the direction and area of ​​influence of the radiation flow, its power, and to provide for tumor deviations associated with respiratory movements requires teamwork of specialists and sophisticated equipment. A radiation oncologist, a medical physicist, a dosimetrist, a radiologist, and a nurse participate in the treatment of each patient.

First, a four-dimensional CT or MRI is performed to image the tumor and accurately determine its location during the respiratory cycle, which is especially important when treating tumors of the lungs and abdominal cavity. Then, under the control of imaging techniques, radiopaque markers are injected into the tumor. This is done using a minimally invasive endoscopic or laparoscopic method.

The next stage is radiotherapy modeling. Individual fixing devices are prepared for each patient so that during the session the only possible movements are breathing. The tumor is re-analyzed in a four-dimensional image while the patient is in the fixation device.

At the third stage, during treatment planning, hundreds of thousands of radiation beam path options are evaluated using computer programs, achieving maximum compliance of the shape of their focus with the shape of the tumor and synchronizing them with its movement during breathing. Continuous irradiation or pulsed irradiation may be provided - only during inhalation or exhalation.

The final stage is the radiotherapy session itself. It is carried out using a linear accelerator. The patient is on an associated manipulation table. Numerous radioactive beams emanating from different angles individually have low power and cause virtually no harm on their way to the tumor. But in it they focus and have a powerful effect, destroying the DNA of tumor cells, the endothelium of the vessels that feed it and mutated stem cells. In tissues bordering the tumor, the beam power drops sharply. It is precisely to fully cover the entire tumor mass and prevent damage to adjacent healthy tissues that such careful planning of the procedure, down to fractions of a millimeter, is necessary.

Stereotactic radiotherapy SBRT is often effective for recurrent tumors, while classical radiotherapeutic methods are often ineffective in such cases. In addition, it is indicated if:

• the tumor is located in an area difficult to reach for surgical treatment
• The operation is not possible due to concomitant diseases or patient refusal
• the tumor is adjacent to vital anatomical structures
• when affecting a tumor, movements, such as breathing, cannot be excluded

The best effect from stereotactic radiation therapy SBRT is obtained in patients with primary and metastatic tumors that are not too numerous (no more than 3-5 foci) up to 5-6 cm in size. Most often these are tumors:

• lungs
• lymph nodes
• liver
• kidney
• prostate gland
• vertebrae and paravertebral tissues
• pancreas

Stereotactic radiotherapy SBRT is contraindicated if:

• there are general contraindications to radiotherapy - cancer cachexia, severe anemia, inhibition of leukocyte production, autoimmune disease, decompensation of severe diseases of internal organs - heart, lungs, liver, kidneys, serious complications of the tumor process (for example, bleeding)
• the tumor is radioresistant, that is, insensitive to X-ray radiation
• the tumor does not have clear boundaries and infiltrates (penetrates) the surrounding tissues. Due to the critical drop in the power of the radioactive beam at the border of the irradiated zone, in such cases it is impossible to ensure a full effect on tumor cells and preserve healthy structures in the border area

Typically, one to five sessions lasting 30-60 minutes are performed. The high power of the radioactive flux makes it possible to suppress the tumor focus in a short time, while traditional radiotherapy lasts several weeks or even months. The classical technique does not allow one-time exposure to high doses due to the pronounced overall negative effect of radiation on the body.

Benefits of SBRT Stereotactic Radiation Therapy:

• Highly effective radiotherapeutic technique, often not inferior to surgical methods
• Short course of treatment
• Minimal involvement of healthy tissue and minor side effects
• Can be used after an ineffective course of classical external irradiation
• Allows you to return to your normal lifestyle almost immediately and does not require long-term rehabilitation

It is known that the main methods of treating various malignant neoplasms are surgical, medicinal, radiation and their combination. In this case, surgery and radiation are considered methods of local impact on the tumor, and drug therapy (chemotherapy, targeted therapy, hormone therapy, immunotherapy) - systemic. The Association of Oncologists around the world is conducting various multicenter studies designed to answer the question: “Which method or combination of methods should be preferred in different clinical situations?” In general, all these studies have one goal - to increase the life expectancy of patients with cancer and improve its quality.

The patient should be informed by the attending physician about the various treatment options, including alternative treatments. For example, patients with early lung cancer with severe concomitant pathology and absolute contraindications to surgery, instead of surgical treatment, can be offered irradiation of the tumor (stereotactic radiation therapy), the so-called cancer treatment without surgery. Or, for example, for certain indications in patients with liver and prostate cancer. Stereotactic radiation therapy is actively and successfully used instead of surgery for brain tumors, thereby significantly reducing the risk of postoperative complications and accelerating the rehabilitation of patients after treatment. IN "OncoStop" center The decision to conduct radiation therapy (RT), either as an independent option or as part of a complex treatment, is made by a council of specialists.

Radiotherapy planned taking into account the following factors. Firstly, this is the main diagnosis, i.e. localization of the malignant tumor and the extent of its spread to surrounding tissues and distant organs. Secondly, this is the degree of malignancy, the presence of lymphovascular invasion and other prognostic and predictive factors, which are determined by morphological, immunohistochemical and molecular genetic studies. Thirdly, the presence of previous treatment and its effectiveness. And fourthly, this is, of course, the general condition of the patient, age, the presence and degree of correction of concomitant pathology and the patient’s life expectancy.

The effect of radiation therapy is based on ionizing irradiation of a certain area with a flow of particles that can damage the genetic apparatus (DNA) of the cell. This is especially pronounced in actively dividing cells, since they are most susceptible to damaging factors. The functions and vital activity of cancer cells are disrupted, which in turn stops their development, growth and division. Thus, as a result of radiotherapy, the malignant tumor decreases in size until it disappears completely. Unfortunately, healthy cells that are located on the periphery of the tumor can also enter the irradiation zone in different volumes (depending on the type of radiotherapy used), which subsequently affects the degree of their damage and the development of side effects. After treatment or in between irradiation sessions, healthy cells are able to repair their radiation damage, unlike tumor cells.

Treating cancer with tightly focused beams (such as stereotactic radiation therapy) helps avoid these unwanted effects. This technique is available at the radiation therapy center of the OncoStop project. Stereotactic radiotherapy is generally well tolerated by patients. However, when prescribing it, it is necessary to follow some lifestyle recommendations, as they can reduce the risk of side effects and improve the quality of life.

Types of radiation therapy

There are several classifications of radiation therapy. Depending on when radiotherapy is prescribed, it is divided into: neoadjuvant (before surgery), adjuvant (after surgery) and intraoperative. The goals of neoadjuvant irradiation are to reduce tumor size, achieve an operable state, and reduce the risk of metastasis through the vessels of the circulatory and lymphatic system to lymph nodes and distant organs (for example, in breast cancer, rectal cancer). Adjuvant radiation is aimed at minimizing the risk of local tumor recurrence (eg, breast cancer, malignant brain tumor, bone tumor). In each specific case, the advisability of prescribing radiotherapy is determined individually.

When choosing a method for delivering a radiation dose, the radiotherapist first evaluates the location of the tumor, its size, and the proximity of blood vessels, nerves, and critical organs. In this regard, there are 3 ways to administer the dose:

1. External beam radiation therapy uses an external radiation source (for example, a linear accelerator) that directs radiation beams to the tumor.
2. Contact (brachytherapy) - radioactive sources (for example, radioactive grains) are placed inside (for prostate cancer) or near the tumor.
3. Systemic radiation therapy - the patient receives radioactive drugs that are distributed throughout the systemic bloodstream and act on tumor foci.

Let's look at each of these types of radiotherapy in more detail.

1. EXTENSION RADIATION THERAPY

In external beam radiation therapy, one or more beams of ionizing radiation (generated by a linear accelerator) are directed at the tumor through the skin, which capture the tumor itself and nearby tissue, destroying cells within the main tumor volume and cells scattered near it. Irradiation with a linear accelerator is usually carried out 5 times a week, from Monday to Friday, for several weeks.

* Apparatus for external beam treatment: Varian TrueBeam linear accelerator

THREE-DIMENSIONAL CONFORMAL RADIATION THERAPY (3D-CRT)

As you know, each patient’s body is unique and tumors are also different in shape, size and location. With three-dimensional conformal radiation therapy, it is possible to take all these factors into account. As a result of using this technique, beam guidance becomes more accurate, and healthy tissue adjacent to the tumor receives less radiation and recovers faster.

BEAM INTENSITY MODULATION RADIATION THERAPY

Intensity-modulated radiation therapy (IMRT) is a special type of three-dimensional conformal radiation therapy that can further reduce the radiation dose to healthy tissue near the tumor by precisely tailoring the radiation beam to the shape of the tumor. Irradiation at a linear accelerator using IMRT allows each beam to be divided into many individual segments, with the radiation intensity within each segment being individually controlled.

IMAGING-GUIDED RADIATION THERAPY

Image-guided radiation therapy (IGRT) is also a conformal irradiation of the tumor, in which imaging techniques (for example, computed tomography, ultrasound or x-ray) are used daily to guide the beam, carried out directly in the canyon (a special room in which the treatment takes place) before each procedure. Because the tumor can move between linear accelerator irradiation sessions (for example, depending on the degree of filling of a hollow organ or due to respiratory movements), IGRT allows you to more accurately “target” the tumor, sparing surrounding healthy tissue. In some cases, doctors implant a small marker into the tumor or nearby tissue to better visualize the radiation target.

STEREOTAXIC RADIATION THERAPY

Stereotactic radiation therapy is a special treatment method that allows the delivery of a high dose of ionizing radiation with submillimeter precision, in contrast to classical radiation therapy (the methods described above). This allows you to effectively and safely irradiate tumors of various locations and sizes (even the smallest lesions), and protect surrounding healthy tissue from the damaging effects of radiation. In addition, stereotactic radiation therapy can be used for re-irradiation. The effect of therapy is assessed 2-3 months after its completion. All this time, the doctor actively monitors the patient’s health condition.

Fun fact: Stereotactic radiation therapy was first developed to treat brain tumors with a single dose of radiation, called stereotactic radiosurgery (SRS). In addition to oncological pathologies, radiosurgery can be used in the treatment of benign tumors (for example, meningioma, acoustic neuroma) and certain non-tumor neurological conditions (for example, trigeminal neuralgia, which is not amenable to conservative treatment methods). This irradiation technique is known to most people under the names “Gamma Knife”, “CyberKnife”.

* Installation for stereotactic radiosurgery of brain pathologies: Gamma Knife

Treatment of tumors outside the skull (extracranial locations) is called stereotactic body radiation therapy (SBRT), usually carried out in several sessions, used for cancer of the lung, liver, pancreas, prostate, kidney, spinal cord, and skeleton tumors. In general, the use of stereotactic radiation therapy in the treatment of various oncopathologies opens up new opportunities.

* Apparatus for stereotactic radiation therapy of tumors of any location: CyberKnife (Accuray CiberKnife)

Treatment using stereotactic radiation therapy using the modern robotic device CyberKnife is available at the Onkostop radiation therapy center.

PROTON RADIATION THERAPY.

Proton therapy is a special type of external beam radiation therapy that uses protons. The physical properties of the proton beam allow the radiotherapist to more effectively reduce the radiation dose in normal tissues close to the tumor. It has a narrow range of applications (for example, for brain tumors in children).

* Proton beam therapy device: Varian ProBeam

NEUTRON RADIATION THERAPY.

Neutron irradiation is also a special type of external beam radiation therapy that uses neutron radiation. Not widely used in clinical practice.

2. CONTACT RADIATION THERAPY (BRACYTHERAPY)

Contact RT involves temporary or permanent placement of radioactive sources inside the tumor or in close proximity to it. There are two main forms of brachytherapy - intracavitary and interstitial. In intracavitary radiation therapy, radioactive sources are placed in a space near the tumor, such as the cervix, vagina, or trachea. In interstitial treatment (for example, prostate cancer), radioactive sources are installed directly into the tissue (into the prostate gland). Another option for brachytherapy is the application form, when sources are placed on the surface of the skin in special individually adapted applicators (for example, for the treatment of skin cancer). Brachytherapy can be prescribed either alone or in combination with external irradiation.

Depending on the contact RT technique, ionizing radiation can be delivered at a high dose rate (HDR) or low dose rate (LDR). In high-dose rate brachytherapy, a radiation source is placed temporarily into the tumor through a (thin) tube called a catheter. Catheter placement is a surgical procedure that requires anesthesia. The course of treatment is usually implemented over a large number of sessions (fractions), 1-2 times a day or 1-2 times a week. With low-dose brachytherapy, radioactive sources can be installed into the tumor temporarily or permanently, which also requires surgery, anesthesia and a short hospital stay. Patients who have permanent sources installed are limited in their daily lives at first after irradiation, but over time they recover and return to their previous rhythm.

“Grain” with radioactive material implanted into the tumor during brachytherapy

SYSTEMIC RADIOTHERAPY

In some clinical cases, patients are prescribed systemic radiation therapy, in which radioactive drugs are injected into the bloodstream and then distributed throughout the body. They can be given by mouth (radioactive tablets) or through a vein (intravenous administration). For example, radioactive iodine capsules (I-131) are used to treat certain types of thyroid cancer. Intravenous administration of radioactive drugs is effective in the treatment of pain caused by the presence of bone metastases, for example, breast cancer.

Stages of therapy

There are several stages of radiation therapy: preparatory (pre-radiation), radiation and recovery (post-radiation). Let's look at each stage of therapy in more detail.

Preparatory stage

The preparatory stage begins with the primary radiotherapist consultations, who determines the feasibility of radiation therapy and selects the technique. The next step is tumor marking, radioactive dose calculation and planning, which involves a radiotherapist, a medical physicist and a radiographer. When planning radiation therapy, the area of ​​irradiation, single and total doses of radiation, the maximum ionizing radiation that falls on the tumor tissue and surrounding structures are determined, and the risk of side effects is assessed. If necessary, tumor marking is performed(i.e., special markers are implanted into it), which helps to further track it while breathing. In some cases, the boundaries of irradiation are marked with a special marker that cannot be erased from the skin until treatment is completed. If the markings have been erased as a result of careless handling or after hygiene procedures, they should be updated under the supervision of the attending physician. Before treatment, it is necessary to protect the skin from direct sunlight, do not use cosmetics, irritants, or antiseptics (iodine). In case of skin diseases and allergic manifestations, their correction is advisable. When planning to irradiate head and neck tumors, it is necessary to treat diseased teeth and diseases of the oral cavity (for example, stomatitis).

Radiation period

The irradiation process itself is complex and is carried out according to an individual treatment plan. It consists of fractions (sessions) of RT. The duration and schedule of irradiation fractions is individual in each case, and depends only on the plan that was drawn up by specialists. For example, with stereotactic radiosurgery, the treatment is one fraction, and with external beam radiotherapy, the course lasts from one to several weeks and is carried out over the course of a week for five consecutive days. This is followed by a two-day break to restore the skin after the irradiation. In some cases, the radiotherapist divides the daily dose into 2 sessions (morning and evening). The irradiation takes place painlessly in a special room - a canyon. Before treatment, detailed safety instructions are provided. During therapy, the patient must remain motionless in the canyon, breathe evenly and calmly, and two-way communication is maintained with the patient via a loudspeaker. The equipment may create specific noise during a treatment session, which is normal and should not frighten the patient.

*Canyon of the Radiation Therapy Center of the OncoStop project

Throughout the course of treatment, you must adhere to the following recommendations.

1. The diet should be balanced and enriched with vitamins and minerals.
2. You need to drink 1.5 - 2.5 liters. purified still water. You can drink fresh and canned juices, compotes and fruit drinks. Mineral water with a high salt content (Essentuki, Narzan, Mirgorodskaya) is taken only on the recommendation of a doctor and in the absence of contraindications. In some cases, these drinks help reduce the feeling of nausea.
3. Stop drinking alcoholic beverages and smoking.
4. Carefully monitor the condition of irradiated skin. Do not wear tight clothes, give preference to loose clothes made from natural fabrics (linen, calico, poplin, cotton).
5. It is better to keep the irradiation zones open; when going outside, they should be protected from sunlight and precipitation.
6. If redness, dryness, itching of the skin, or excessive sweating occur, do not self-medicate, but immediately inform your doctor.
7. Maintain a balanced daily routine (walk in the fresh air, light gymnastic exercises, sleep at least 8 hours a day).

Features of radiation therapy for tumors of various locations

For breast cancer Radiation therapy is used after organ-conserving surgery or after mastectomy according to indications (presence of metastatic regional lymph nodes, tumor cells in the margins of the surgical material, etc.). The external radiotherapy used in these cases aims to eliminate (destroy) possibly remaining tumor cells in the wound, thereby reducing the risk of local relapse. For locally advanced breast cancer, radiation may be prescribed before surgical treatment in order to achieve an operable condition. During treatment, women may be bothered by complaints such as fatigue, swelling and changes in the color of the skin of the breast (so-called “bronzing”). However, these symptoms usually disappear immediately or within 6 months after completion of radiation therapy.

In the treatment of rectal cancer Radiation therapy is actively used before surgery, since it can reduce the volume of surgery and reduce the risk of tumor metastasis in the future (during surgery and after it). The combination of radiation and chemotherapy leads to an increase in the effectiveness of therapy for this category of patients.

For cancer of the female genital organs Both external irradiation of the pelvic organs and brachytherapy are used. If at stage I of cervical cancer radiation therapy can be prescribed for certain indications, then at stages II, III, IVA, radiation together with chemotherapy is the standard of treatment for this cohort of patients.

Recovery (post-radiation) period

The post-radiation period begins immediately after the end of irradiation. In most cases, patients do not actively complain and feel relatively satisfactory. However, some patients may be bothered by side effects, which vary in severity in each case. If undesirable reactions occur, you should immediately consult a doctor.

The recovery period (rehabilitation) consists of maintaining a gentle daily regimen and good nutrition. The emotional mood of the patient, the help and friendly attitude of loved ones towards him, and correct adherence to the prescribed recommendations (control examination) are important.

Fatigue during irradiation is caused by an increased level of energy expenditure and is accompanied by various metabolic changes. Therefore, if the patient is actively working, then it is better for him to switch to light work or go on vacation to restore strength and health.

After completing a course of radiation therapy, you should regularly visit your doctor to monitor your health and evaluate the effectiveness of treatment. Dynamic observation is carried out by an oncologist in a district clinic, cancer clinic, or private clinic at the request of the patient. In the event of a deterioration in health, development of pain, or the appearance of any new complaints associated, for example, with dysfunction of the gastrointestinal tract, genitourinary system, cardiovascular and respiratory disorders, increased body temperature, you should consult a doctor without waiting next scheduled visit.

A special role is played by proper skin care, which is easily susceptible to the damaging effects of radiation (especially during external beam radiation therapy). It is necessary to frequently use a nourishing fatty cream, even in the absence of signs of inflammation and burns of the skin. During the period of irradiation and after it, you should not visit baths or baths, or use hard washcloths or scrubs. It is better to take a shower and use soft, nourishing and moisturizing cosmetics.

Many people believe that patients who have undergone radiation therapy may emit radiation themselves, so it is advisable for them to minimize interaction with others, especially pregnant women and children. However, this is a misconception. Irradiated patients do not pose a danger to others. You should not refuse intimate relationships for this reason. If the condition of the mucous membranes of the genital tract changes and unpleasant sensations occur, you should tell your doctor about it, he will tell you how to deal with it.

Some patients experience stress, and therefore it is necessary to properly organize their leisure time: cinema, theater, museums, exhibitions, concerts, meeting friends, walks in the fresh air and various social events of your choice.

Radiation reactions

All side effects can be divided into 2 types: general and local. Common side effects include fatigue, weakness, emotional changes, hair loss, deterioration of nails, decreased appetite, nausea and even vomiting (more common with irradiation of head and neck tumors), as well as changes in the bone marrow caused by irradiation of bone tissue. As a result, the main function of the bone marrow is disrupted - hematopoiesis, which is manifested by a decrease in the number of red blood cells, hemoglobin, leukocytes and platelets. It is very important to regularly take a clinical blood test in order to identify these changes and prescribe the appropriate medication correction in time or suspend the irradiation process until blood counts normalize. However, in most cases, after completing the course of radiation therapy, these symptoms go away on their own, without requiring any correction. Local complications of radiation therapy include:

Radiation damage to the skin, such as redness (it goes away over time, sometimes leaving behind pigmentation), dryness, itching, burning, peeling in the irradiation area. With proper care, the skin recovers within 1-2 months after radiation therapy. In some cases, with severe radiation damage, burns of varying severity develop, which can subsequently become infected.

Infectious complications, the risk of their occurrence increases with diabetes mellitus, the presence of concomitant skin pathology, with a high dose of radiation, and light skin type.

To avoid such complications, you must strictly follow the prescribed recommendations of your doctor and properly take care of your skin.

Radiation damage to the mucous membrane of the irradiated area. For example, when irradiating head and neck tumors, damage to the mucous membranes of the mouth, nose, and larynx is possible. In this regard, patients must follow some rules:

• give up smoking, alcohol, irritating (hot and spicy) foods;
• use a soft toothbrush and brush your teeth gently;
• rinse your mouth with chamomile decoction or other solutions (antiseptics) according to the recommendations of your doctor.

During radiation treatment of rectal tumors, there may be a tendency to constipation, blood in the stool, pain in the anus and abdomen, so it is important to follow a diet (exclude “fixing” foods).

During irradiation of the pelvic organs, patients may complain of urinary disorders (pain, burning, difficulty urinating).

Complications from the respiratory system: cough, difficulty breathing, pain and swelling of the skin of the chest wall. It can be observed during radiation therapy of tumors of the chest, lung, and mammary gland.

Any deterioration in well-being or the appearance of the above changes must be reported to the attending physician, who will prescribe appropriate accompanying treatment according to the identified disorders.

In general, radiation therapy is in most cases well tolerated by patients, and patients recover quickly after it. Irradiation is an important step in the complex treatment of malignant neoplasms, making it possible to influence the tumor with even greater efficiency, which in turn leads to an increase in the life expectancy of patients and an increase in its quality.

The specialists of the radiation therapy center of the OncoStop project successfully master all types of external beam radiation therapy, including stereotactic, and carefully care for the health of their patients.

TKACHEV S. I., MEDVEDEV S. V., ROMANOV D. S., BULYCHKIN P. V., YURIEVA T. V., GUTNIK R. A., YAZHGUNOVICH I. P., BERDNIK A. V., BYKOVA YU. B.

The emergence of innovative technical developments: three-dimensional planning, the use of a multi-leaf collimator, intensity-modeled radiation therapy, and more advanced fixation methods have significantly increased the ability to accurately deliver and escalate the dose of ionizing radiation to the selected volume. This has changed the understanding of the role of radiation therapy in the treatment of metastatic liver disease. Data from foreign authors indicate the possibility of achieving 95% of local control one year after stereotactic radiotherapy, 92% after two years (and 100% for tumors smaller than 3 cm) with the development of third-degree or higher radiation damage in only 2% of cases. In 2011, after the technical re-equipment of the Federal State Budgetary Institution Russian Research Center named after. N. N. Blokhin Russian Academy of Medical Sciences, the technique of local stereotactic radiosurgery (SBRS) began to be introduced in clinical practice for the treatment of patients with metastatic liver disease. The technique allows you to create a high dose of ionizing radiation locally in a metastatic tumor node and cause destruction of the tumor. This promising direction in the treatment of metastatic liver cancer has significantly expanded the possibilities of combination treatment. The article provides a review of the literature on the treatment of metastatic liver disease; we also publish the results of using stereotactic radiosurgery in thirty-five patients with metastatic liver disease and a clinical case of the successful use of this technique in a somatically burdened patient.

Key words: metastatic liver disease, stereotactic radiosurgery, local control.

Contact Information:

S. I. Tkachev, S. V. Medvedev, D. S. Romanov, P. V. Bulychkin, T. V. Yuryeva, R. A. Gutnik, I. P. Yazhgunovich, A. V. Berdnik, Yu. B. Bykova - Radiological Department, Department of Radiation Oncology (head - Prof. S.I. Tkachev) FSBI RORC named after. N. N. Blokhina, RAMS, Moscow. For correspondence: Romanov Denis Sergeevich, [email protected]

Introduction

During autopsy, metastatic foci in the liver are found in 30% of patients with cancer. For the treatment of patients with multiple metastatic liver lesions (more than three foci), systemic and/or regional drug therapy is preferred. In patients with limited liver damage, it is possible to use local treatment methods, such as: surgical resection, radiofrequency thermal ablation, chemoembolization, radioembolization, cryodestruction, ethanol administration,

microwave coagulation, laser thermal destruction, electrolysis of metastases. Each of these approaches has its own advantages and disadvantages, but only stereotactic radiation therapy can be used if there are contraindications to the use of the above methods.

For a long time, radiation therapy was considered an unpromising technique for the treatment of metastatic liver disease. The use of such a technique as total liver irradiation has not proven to be effective and safe, such as, for example, irradiation of the entire brain in the case of metastatic tumors.

OF MALIGNANT TUMOURS

damage to this organ. With the improvement of the scientific and technological base of radiation therapy: the emergence of new technologies for administering the dose of ionizing radiation, planning systems, verification of plans for external beam radiation therapy, visualization, fixation of patients, the development of radiobiology - radiation oncologists received a formidable weapon in the fight against metastatic liver damage - stereotactic radiosurgery of tumors of the specified organ.

Stereotactic radiosurgery

In the 90s of the last century, the first works appeared in foreign literature on the feasibility of performing local stereotactic body radiation surgery (SBRS) for single (up to 3 foci) liver metastases.

Due to the biological characteristics of metastatic liver damage in colon cancer, patients in this group are divided into a separate subgroup. The gold standard for local treatment of liver metastases, in particular colorectal cancer metastases, is liver resection. Several large studies demonstrate a fifty percent overall survival rate five years after surgery. Historically, it was considered possible to perform liver resection in situations where it was possible to completely remove a limited number of metastases with a negative resection margin of more than one centimeter and a liver volume remaining after surgery sufficient for adequate functioning of the organ (at least 30% of the total functional volume of the liver). If these criteria are followed, resection is possible in 30-40% of patients who require it. At the moment, it is possible to simultaneously remove more than seven metastases from the liver; it has been established that the width of the negative resection margin does not affect local control and patient survival. In large centers dealing with this problem, the risk of postoperative complications and mortality is reduced to minimal values. Moreover, repeated resections for recurrent cancer in the liver are quite safe

and provide similar survival benefits to first-time resection. Unfortunately, patients with synchronous bilobar, large, localized metastases that are inconvenient for surgical intervention and extrahepatic manifestations of the disease, those in whom resection will not leave the required 30% of the liver, patients over seventy years of age and with somatic complications are often considered unresectable, and following this logic, incurable. In addition, there are no randomized studies comparing the effect of resection versus conservative nonsurgical local therapy in resectable patients.

The emergence of innovative technical developments (three-dimensional planning, multi-leaf collimator, intensity modulated radiation therapy (IMRT), more advanced fixation methods), which significantly increased the possibility of accurately delivering ionizing radiation to the selected volume, and therefore delivering a higher dose to tumor volume, changed the understanding of the role of radiation therapy in the treatment of metastatic liver disease. A variant of high-precision radiation therapy, in which the ablative dose is delivered in 1-5 fractions, is called stereotactic radiotherapy. When used extracranially, this type of radiation therapy is called stereotactic body radiation surgery (SBRS). As defined by ASTRO, SBRS involves delivering large doses of ionizing radiation with high conformality and a sharp dose gradient in surrounding normal tissues in a small number of fractions (two to six) to tumors located outside the brain.

There are many publications regarding the use of SBRS for the treatment of malignant liver lesions, which show encouraging results. The earliest of them date back to 1994-1995. In this paper, the researchers report the first results of SBRT on 42 extracranial tumors.

in 31 patients. 23 patients underwent radiation therapy for liver metastases (14 patients) or hepatocellular carcinoma (9 patients). Most patients had single tumors in the liver, lungs and retroperitoneum. Their subclinical tumor volumes (CTV - clinical target volume) ranged from 2 to 622 cm3 (with a mean value of 78 cm3), and single focal doses (SOD) ranged from 7.7 to 30 Gy per fraction (with a mean value in 14.2 Gy), were supplied in 1-4 fractions. Researchers noted local control in 80% of cases during the subsequent life of patients, which lasted from 1.5 to 38 months. In addition, the disappearance or reduction in size of tumors was noted in fifty percent of cases. The median follow-up period was 10 months for patients with hepatocellular carcinoma (range 1 to 38 months) and 9 months for patients with liver metastases (range 1.5 to 23 months).

In 1998, the same research group reported experience with the use of stereotactic radiosurgery for the treatment of primary malignant and metastatic liver tumors, the SOD ranged from 15 to 45 Gy, delivered in 1-5 fractions. Fifty patients with 75 tumors were treated. Treatment volumes ranged from 2 to 732 cm3 (with a mean of 73 cm3). During follow-up with a mean of 12 months (values ​​ranged from 1.5 to 38 months), approximately 30% of cases showed stabilization, approximately 40% of tumors decreased in size and 32% completely regressed. Four (5.3%) tumors were interpreted as local failures. Unfortunately, the average life expectancy was only 13.4 months (with values ​​ranging from 1.5 to 39 months), with the predominant causes of death being progressive liver cirrhosis or extrahepatic progression of the underlying disease.

doses of 20 Gy (two fractions) or 15 Gy (three fractions). During follow-up periods from 13 to 101 months, local control of all recurrent tumors was achieved with complete regression of metastases in two cases. Only one patient experienced local progression of the disease in the form of damage to two lobes of the organ, which was preceded by extrahepatic spread of the disease. One patient subsequently died from non-oncological causes in the absence of signs of the underlying disease, two died from generalization of the malignant process, and one patient at the end of the study was in remission for 101 months after stereotactic radiosurgery.

Dawson et al. performed SBRT on 16 patients with hepatic metastases and 27 patients with primary hepatocellular carcinoma using 3D conformal radiotherapy at a median dose of 58.5 Gy (range 28.5 to 90 Gy) at 1.5 Gy per fraction twice daily. There was one case of grade III RILD and no treatment-related deaths. In a more recent study, Dawson et al. simulated the possibility of normal tissue complications for the development of RILD within 4 months after conformal radiotherapy for metastatic liver disease or intrahepatic hepatobiliary tumors. The study demonstrated a significant effect of volume and mean single focal dose on predicting the development of RILD in multivariate analyses. Other significant predisposing factors for the development of RILD were primary liver diseases (cholangiocarcinoma and hepatocellular carcinoma versus metastatic disease) and male gender. It was noted that these patients were also receiving concurrent local chemotherapy and the use of bromodeoxyuridine (versus fluorodeoxyuridine) was also associated with an increased risk of developing RILD. There were no cases of RILD development when an average total focal dose of less than 31 Gy was administered to the liver.

In 2001, Herfarth et al. conducted a study that examined the effectiveness

Possibilities of stereotactic radiosurgery in the treatment of patients with metastatic liver disease

effectiveness of SBRS use in 37 patients with 60 liver lesions. The absorbed dose was 26 Gy, and tumor sizes ranged from 1 to 132 cm3 with a mean of 10 cm3. All patients tolerated the treatment well, and SBRS did not result in any significant side effects. Eleven patients reported intermittent loss of appetite or mild nausea within one to three weeks after treatment. None of the treated patients developed clinically detectable radiation-induced liver disease. Following SBRS for 5.7 months (range, 1 to 26.1 months), fifty-four of fifty-five (98%) tumors responded to CT scans at 6 weeks (22 stable disease, 28 cases of partial response and 4 cases of complete response). The local positive effect was 81% within 18 months after treatment.

Wulf et al. reported the results of SBRS in five patients with primary liver cancer and 39 patients with 51 liver metastases, performed at the University of Wurzburg. Twenty-eight tumors were assigned to the so-called “low dose” group in three fractions of 10 Gy (27 patients) or four sessions of 7 Gy (1 patient). In addition, there was a so-called “high dose” group, in which patients received SBRS with single doses of 12-12.5 Gy in three fractions (19 patients) or 26 Gy in one fraction (9 patients). Median follow-up was 15 months (range 2 to 48 months) for primary liver cancer and 15 months (range 2 to 85 months) for patients with metastatic liver disease. In all cases of primary malignant liver disease, a positive effect was achieved, including true stabilization. Among fifty-one metastases, 9 cases of local recurrence were noted within a period of three to 19 months. There was a discriminative significant correlation between total radiation dose and local control rates (p=0.077) with local control rates of 86% and 58% at 12 and 24 months

in the “low dose” group versus 100% and 82% in the “high dose” group, respectively. There were no cases of RTOG-EORTC grade III or higher radiation injuries. In multivariate analysis, high versus low dose was the only significant predictor of local control rates (p=0.0089). Overall survival at one and two years among all patients was 72% and 32%, respectively. The authors conclude that SBRS for primary malignancies and metastatic liver tumors is an effective local treatment without significant complications for patients who are not eligible for surgery.

In a study by Hoyer et al. , the results of using SBRS in the treatment of colorectal cancer metastases are presented. Sixty-four patients with a total of 141 colorectal cancer metastases to the liver (44 patients) or lung (20 patients) received SBRS in three fractions of 15 Gy over five to eight days. Median follow-up was 4.3 years, and after two years local control rates were 86%. Radiation toxicity was moderate in most cases, however, there were three cases of serious adverse events and one death. The researchers concluded that SBRS for unresectable metastatic colorectal cancer was noninferior to other local metastasis ablation techniques.

Somewhat later, Schefter et al. reported preliminary results from a multicenter phase I trial of SBRS in patients with liver metastases. Patients had one to three liver metastases, with a maximum tumor diameter of less than six centimeters, and adequate liver function. Some patients received SBRS with a total dose of 36 Gy in three fractions. Another part of the patients received higher doses of radiation up to 60 Gy in three fractions. At least 700 milliliters of healthy liver tissue must have received a total dose of less than 15 Gy. Dose-limiting toxicity was selected as manifestations of acute radiation damage to the liver or intestines of the third degree or any manifestations of acute radiation damage.

Denia IV degree. No patient had dose-limiting radiation injuries, so the radiation dose was increased to 60 Gy in three fractions. Twelve of the 18 patients were alive at the time of the investigators' analysis, with a median of 7.1 months after entry into the protocol.

The study was continued in 2006 by Kavanagh et al. reported results from a phase I/II analysis of a prospective study of SBRS for the treatment of metastatic liver disease. In this case, the study included patients with no more than three tumors with a maximum diameter of less than six centimeters. The total focal dose was 60 Gy in three fractions over three to fourteen days. In 2006, interim results of SBRS were published in 36 patients: 18 from phase 1 and 18 from phase 2. Among 21 patients with follow-up ranging from six to 29 months, there was only one case of RTOG grade 3 radiation injury associated with SBRS, which occurred in the subcutaneous tissue. No cases of grade 4 radiation toxicity were recorded. The researchers noted that for 28 lesions over eighteen months, the benefit rate, including true stabilization, was 93%.

In 2009, Rusthoven et al. published the results of a multicenter (conducted between August 2003 and October 2007 at 7 institutions) phase I/II study of the use of SBRS in patients with metastatic liver disease. The study included patients with 1-3 liver metastases and a maximum size of individual nodes less than 6 cm. The initial level of bilirubin, albumin, prothrombin and aPTT, and liver enzyme activity were taken into account. Chemotherapy was not allowed for 14 days before or after SBRS. For 49 metastatic sites, local control rates were 95% (one year after SBRS) and 92% (two years after SBRS). In 2% of patients, radiation injuries of the third and higher degrees were detected with a median of 7.5 months after stereotactic radiosurgery. Two-year rates of positive local effect for metastases with a diameter of up to 3.0 cm were equal to

100%. This is the highest reported benefit rate, despite two-year survival rates of 30%. The authors conclude that stereotactic radiosurgery with a total dose of 60 Gy in three fractions is both safe and effective for treating patients with one to three liver metastases.

Van der Pool et al. in 2010 presented a study in which 20 patients with metastatic liver disease received SBRS doses ranging from 30 to 37.5 Gy in three fractions. One hundred percent rates of positive local effect were obtained one year after treatment. After two years, this rate had dropped to 74%, with a median survival of 34 months. Among radiation injuries, noteworthy was one case of rib fracture and 2 cases of grade III elevation of liver enzymes as long-term consequences of radiation therapy.

Also in 2010, the results of a prospective study by Goodman et al were published. , in which 26 patients with malignant liver tumors (19 of them with metastatic lesions) underwent SBRS in a single fraction of 18-30 Gy. Local response rates at 12 months were 77%. The two-year survival rate for patients with liver metastases was 49%.

In 2011, after technical re-equipment, at the Federal State Budgetary Institution Russian Cancer Research Center named after. N. N. Blokhin Russian Academy of Medical Sciences has introduced the technique of local stereotactic radiosurgery (SBRS) into clinical practice for the treatment of patients with metastatic liver disease. The technique allows you to create a high dose of ionizing radiation locally in a metastatic tumor node and cause destruction of the tumor. This promising direction in the treatment of metastatic liver cancer has significantly expanded the possibilities of combination treatment.

From August 2010 to July 2013 in the radiology department of the Federal State Budgetary Institution Russian Cancer Research Center named after. N. N. Blokhin, Russian Academy of Medical Sciences, SBRS was performed on thirty-five patients with liver metastases from tumors of various histological structures. A single focal dose varied from ten to twenty grays, radiosurgery was performed

Possibilities of stereotactic radiosurgery in the treatment of patients with metastatic liver disease

in three sessions over 5-7 days. Two patients did not provide follow-up data, and in two more cases local progression was recorded. In seven patients, complete regression of the tumor was noted, in thirteen - partial, and in eleven - stabilization of the treated lesions. In five patients, new metastatic lesions were subsequently identified in areas of the liver that were not treated. Median follow-up was 17 months. In none of the cases were there any early or late radiation injuries of degrees III-IV; the incidence of radiation injuries of degree II was 9%.

Conclusion

Only with the availability of modern equipment and technologies do prospects appear in the use of stereotactic radiosurgery in the treatment of patients with metastatic liver disease. This technology is a real alternative to other methods of local impact on metastatic formations. The data presented by foreign authors, as well as the experience of the radiological department of the Federal State Budgetary Institution Russian Cancer Research Center named after. N. N. Blokhin Russian Academy of Medical Sciences testifies to the high efficiency and safety of using this technology even in those patients who are denied other treatment methods.

Clinical case

Patient A. 65 years old. Sigmoid colon cancer, metastatic liver disease, T4N1M1, stage IV.

On 06/07/10, the patient underwent palliative resection of the sigmoid colon. 07/29/10 - left-sided hemihepatectomy, resection of the right lobe of the liver.

Histological examination revealed adenocarcinoma.

After the operation, 8 courses of chemotherapy were administered.

In August 2011, according to ultrasound data from 08/15/11, progression of the disease in the form of solitary metastasis in the remaining part of the liver was revealed.

By 11/17/11, 7 courses of chemotherapy were administered.

According to CT data from October 26, 2011, a formation of up to 2.7x2.5 cm is determined between the portal and right hepatic vein, in the VII segment the lesion is up to 0.9 cm (Fig. 1).

According to MRI data from 12/14/11, in the resection zone in segments S5-S8 there is a node up to 1.8 cm, closely adjacent to the portal vein. In segments S6-7, a node up to 0.5 cm is detected.

From 12/21/11 to 12/27/11, a course of stereotactic radiosurgery was conducted on both lesions in the liver using the IMRT technique, ROD 15 Gy, 3 times a week, SOD 45 Gy.

The patient was fixed using an individual vacuum mattress,

The irradiation program was verified using computed tomography technology in a conical beam on a linear accelerator table in the treatment position.

According to CT data dated May 15, 2012, a new lesion in S6 of the liver measuring up to 1.7 cm appeared. Two lesions subjected to stereotactic radiotherapy are not visualized (Fig. 2).

The patient subsequently received treatment in South Korea. In July 2012 and February 2013, radiofrequency

ablation of a lesion in S6 of the liver. The patient noted an increase in body temperature for a long time, and an abscess was detected at the site of metastasis in S6 of the liver. On August 21, 2013, a surgical intervention was performed: in areas of the liver accessible to visualization without signs of a malignant process, in the area of ​​the resected lesion in the S6 segment - tumor cells along the edge of the resection.

The patient is currently alive. According to the examination dated August 2013, no signs of the disease were found.

Literature

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Stereotactic radiosurgery (SRS) is a field of radiation therapy that involves the use of high-precision radiation. SRS was originally used to treat tumors and other pathological changes in the brain. Currently, radiosurgical techniques (called extracranial stereotactic radiotherapy, or stereotactic body radiotherapy) are used to treat malignant neoplasms of any location.

Despite its name, SRS is not a surgical procedure. The technique involves high-precision delivery of high-dose radiation to the tumor, bypassing healthy nearby tissues. This is what distinguishes SRS from standard radiation therapy.

When performing stereotactic radiosurgery, the following technologies are used:

• Three-dimensional visualization and localization techniques, which allows you to determine the exact coordinates of the tumor or target organ
• Devices for immobilization and careful positioning of the patient
• Highly focused beams of gamma rays or x-rays that converge on a tumor or other pathological formation
• Image-guided radiotherapy techniques, which involve tracking the position of the tumor throughout the entire radiation cycle, which increases the accuracy and efficiency of treatment

Three-dimensional imaging techniques such as CT, MRI and PET/CT are used to determine the location of a tumor or other pathological lesion in the body, as well as its exact size and shape. The resulting images are necessary for treatment planning, during which beams of rays approach the tumor from a variety of angles and planes, as well as careful positioning of the patient on the treatment table during each session.

As a rule, stereotactic radiosurgery is performed simultaneously. However, some experts recommend multiple sessions of radiation therapy, especially for large tumors larger than 3-4 cm in diameter. A similar technique with the appointment of 2-5 treatment sessions is called fractionated stereotactic radiotherapy.

SRS and extracranial stereotactic procedures are important alternatives to open surgical procedures, especially for patients who are unable to undergo surgery. In addition, stereotactic interventions are indicated for tumors that:

• Located in places hard to reach for the surgeon
• Located near vital organs
• Change their position during physiological movements, such as breathing

Radiosurgical procedures are used in the following cases:

• for the treatment of many brain tumors, including:
  • benign and malignant neoplasms
  • primary and metastatic lesions
  • single and multiple tumors
  • residual tumor foci after surgery
  • intracranial lesions and tumors of the base of the skull and orbit
• for the treatment of arteriovenous malformations (AVMs), which are collections of abnormally shaped or dilated blood vessels. AVMs disrupt the normal blood flow of nerve tissue and are prone to bleeding.
• For the treatment of other neurological conditions and diseases.

Extracranial stereotactic radiotherapy is currently used for malignant and benign tumors of small to medium size, including tumors in the following locations:

• Lungs
• Liver
• Abdomen
• Spine
• Prostate
• Head and neck

SRS is based on the same principle as other radiotherapy methods. In fact, the treatment does not eliminate the tumor, but only damages the DNA of the tumor cells. As a result, cells lose their ability to reproduce. After radiosurgery, the size of the tumor gradually decreases over 1.5-2 years. At the same time, malignant and metastatic foci decrease even faster, sometimes within 2-3 months. If SRS is used for arteriovenous malformation, then over several years there is a gradual thickening of the vessel wall and complete closure of its lumen.

What equipment is used when performing stereotactic radiosurgery?

There are three main methods of performing stereotactic radiosurgery, in each of which the source of radiation is one or another device:

• Gamma Knife: 192 or 201 beams of precisely focused gamma rays are used to irradiate the target organ. Gamma Knife is excellent for treating small to medium-sized intracranial lesions.
• Linear accelerators are devices that are widely used throughout the world and are used to deliver high-energy X-rays (photon beams). Suitable for treating large tumor lesions. The procedure can be performed once or in several stages, which is called fractionated stereotactic radiosurgery. The equipment is manufactured by various manufacturers who produce linear accelerators under different names: Novalis Tx™, XKnife™, CyberKnife®.
• Proton therapy, or heavy particle radiosurgery, is currently only performed in a few centers in North America, but the availability and popularity of the treatment continues to grow in recent years.

Which specialists are involved in stereotactic radiosurgery? Who operates the stereotactic radiosurgery equipment?

Stereotactic surgery requires a team approach. The care team includes a radiation oncologist, a medical physicist, a dosimetrist, a radiologist/radiology technician, and a radiology nurse.

• The team is led by a radiation oncologist and, in some cases, a neurosurgeon who oversees the treatment process. The doctor determines the boundaries of the area of ​​radiation exposure, selects the appropriate dose, evaluates the developed treatment plan and the results of the radiosurgical procedure.
• The results of the examination and the resulting images are assessed by a radiologist, which makes it possible to identify a pathological focus in the brain or other organs.
• A medical physicist, together with a dosimetrist, develops a treatment plan using special computer programs. The specialist calculates the radiation dose and determines the parameters of the beam of rays for the most complete impact on the pathological focus.
• The radiologist and/or radiologic technician is responsible for directly performing radiosurgery. The specialist helps the patient position himself on the treatment table and operates the equipment from a shielded room. The radiologist, who can communicate with the patient via microphone, monitors the procedure through an observation window or video equipment.
• The radiology nurse assists the patient during and after the procedure and monitors the patient's condition for side effects of treatment or other adverse events.
• In some cases, treatment involves a neurologist, neurosurgeon, or neuro-oncologist to help choose the most appropriate treatment for tumors or other brain lesions.

How are stereotactic radiosurgeries performed?

Radiosurgical treatment using the Gamma Knife system

Radiosurgery treatment using the system Gamma Knife consists of four stages: placing a fixing frame on the patient’s head, visualizing the position of the tumor, drawing up a treatment plan using a computer program, and the irradiation procedure itself.

At the beginning of the first stage, the nurse sets up an intravenous infusion system for drugs and contrast material. After this, the neurosurgeon anesthetizes the scalp at two points on the forehead and two points on the back of the head, and then, using special screws, fixes a special rectangular stereotactic frame to the skull. This prevents unwanted head movements during the procedure. In addition, a lightweight aluminum frame serves to direct the movement of gamma rays and focus them on the tumor.

During the second stage, magnetic resonance imaging is performed, which makes it possible to determine the exact position of the pathological area in relation to the fixing frame structure. In some cases, a computed tomography scan is performed instead of an MRI. When treating arteriovenous malformation, angiography is also prescribed.

During the next stage, which lasts about two hours, the patient rests. At this time, a team of treating doctors analyzes the obtained images and determines the exact location of the tumor or pathologically altered artery. Using special computer programs, a treatment plan is developed, the goal of which is optimal irradiation of the tumor and maximum protection of surrounding healthy tissue.

At the beginning of the last stage of treatment, the patient lies down on the couch, and the frame is fixed on his head. For convenience, the nurse or technologist offers the patient a pillow under his head or a special mattress made of soft material and covers him with a blanket.

Before treatment begins, the staff moves to the next room. The doctor monitors the patient and the progress of treatment using a camera installed in the treatment room. The patient can communicate with medical staff via a microphone mounted in the frame.

After all the preparations, the couch is placed inside the Gamma Knife machine, and the procedure begins. The treatment is completely painless, and the device itself does not make any sounds.

Depending on the Gamma Knife model and treatment plan, the procedure is carried out simultaneously or divided into several small sessions. The total duration of treatment is from 1 to 4 hours.

The end of the procedure is announced by a bell, after which the couch returns to its original position and the doctor removes the fixing frame from the patient’s head. In most cases, the patient can go home immediately after the procedure.

Radiosurgery treatment using a medical linear accelerator

Radiosurgical treatment using linear accelerator of charged particles proceeds in a similar way and also consists of four stages: installation of a fixing frame, visualization of the pathological focus, planning the procedure using a computer program and the irradiation itself.

Unlike the Gamma Knife, which remains motionless throughout the procedure, beams of rays enter the patient's body at different angles while continuously rotating a special device called a gantry around the couch. If a radiosurgical procedure is performed using the CyberKnife system, then a robotic arm rotates around the patient's couch under visual control.

Compared to the Gamma Knife, the linear accelerator creates a larger beam of rays, which allows for uniform irradiation of large pathological lesions. This property is used in fractionated radiosurgery or stereotactic radiotherapy using a movable fixation frame and is a great advantage when treating large tumors or neoplasms near vital anatomical structures.

Extracranial stereotactic radiotherapy (ESRT)

The ESRT course usually takes 1-2 weeks, during which 1 to 5 treatment sessions are carried out.

Before radiotherapy, fiducial marks are usually placed in or near the tumor. Depending on the location of the pathological formation, this procedure, during which from 1 to 5 marks are installed, takes place with the participation of a pulmonologist, gastroenterologist or radiologist. This stage is usually carried out on an outpatient basis. Not all patients require orientation marks.

At the second stage, radiotherapy simulation is carried out, during which the doctor selects the most appropriate way to direct the beam of rays relative to the position of the patient’s body. At the same time, immobilization and fixation devices are often used to accurately position the patient on the couch. Some devices immobilize the patient quite firmly, so the doctor should be notified in advance of the presence of claustrophobia.

After creating a personal fixation device, a CT scan is performed to obtain an image of the area that will be affected by radiation. CT scans are often “four-dimensional,” which means they create images of the target organ in motion, such as breathing. This is especially important for lung or liver tumors. After the scan is completed, the patient is allowed to return home.

The third stage of ESRT involves developing a treatment plan. At the same time, the radiation oncologist works in close collaboration with a medical physicist and dosimetrist, which makes it possible to bring the shape of the beam of rays as closely as possible to the parameters of the tumor. Radiotherapy planning may require MRI or PET/CT. Using special software, medical staff evaluate hundreds of thousands of different combinations of radiation beams to select the most appropriate parameters for a given case of disease.

Radiation delivery during ESRT is carried out using a medical linear accelerator. The session does not require any restrictions on food or liquid intake. However, many patients are prescribed anti-inflammatory or anti-anxiety medications before the procedure, as well as anti-nausea medications.

At the beginning of each session, the position of the body is fixed using a pre-made device, after which an x-ray is taken. Based on its results, the radiologist adjusts the patient’s position on the couch.

After this, the actual radiotherapy session is carried out. In some cases, additional radiography is required to monitor the position of the tumor during the session.

The session can last about one hour.

Is special preparation required from the patient for stereotactic radiosurgery?

Stereotactic radiosurgery and ESRT procedures are usually performed on an outpatient basis. However, short-term hospitalization may be required.

The doctor must notify the patient in advance of the need for a relative or friend to accompany the patient home.

You may need to stop eating and drinking 12 hours before your session. It is also important to ask your doctor about restrictions on taking medications.

The doctor must be informed of the following:

• About taking medications by mouth or insulin for diabetes.
• About the presence of allergic reactions to intravenously administered contrast materials, iodine or seafood.
• About the presence of an artificial pacemaker, heart valves, defibrillator, clips for cerebral aneurysms, implanted pumps or ports for chemotherapy, neurostimulators, eye or ear implants, as well as any stents, filters or coils.
• About the presence of claustrophobia.

What should you expect during stereotactic radiosurgery?

Radiosurgery treatment is similar to conventional X-ray examination, since X-ray radiation cannot be seen, felt or heard. An exception is radiotherapy for brain tumors, which can be accompanied by flashes of light even with the eyes closed. The radiosurgical treatment session itself is absolutely painless. It is important to tell your doctor if you experience pain or other discomfort, such as back pain or discomfort when applying a frame or other immobilization device.

When removing the fixing frame, there may be some bleeding, which can be stopped with a bandage. Sometimes headaches occur, which can be treated with medication.

In most cases, after completion of radiosurgical treatment or ESRT, you can return to your normal life within 1-2 days.

Side effects from radiation therapy result from both the direct effects of the radiation and damage to healthy cells and tissue near the tumor. The number and severity of adverse effects of RTVC depend on the type of radiation and the dose prescribed by the doctor, as well as on the location of the tumor itself in the body. You should talk to your doctor about any side effects that occur so that they can prescribe appropriate treatment.

Early side effects occur during or immediately after radiation therapy is stopped and usually resolve within a few weeks. Late side effects occur months or even years after radiotherapy.

Typical early side effects of radiotherapy include fatigue or tiredness and skin symptoms. The skin at the site of radiation exposure becomes sensitive and red, irritation or swelling appears. In addition, itching, dryness, peeling and blistering of the skin are possible.

Other early side effects are determined by the area of ​​the body that is affected by the radiation. These include:

• Hair loss in the area of ​​radiation
• Ulceration of the oral mucosa and difficulty swallowing
• Loss of appetite and digestive disorders
• Diarrhea
• Nausea and vomiting
• Headache
• Soreness and swelling
• Urinary disorders

Late side effects are quite rare and occur months or years after radiotherapy, but persist for a long time or forever. These include:

• Changes in the brain
• Changes in the spinal cord
• Changes in the lungs
• Changes in the kidneys
• Changes in the colon and rectum
• Infertility
• Changes in the joints
• Edema
• Changes in the oral cavity
• Secondary malignancy

Radiotherapy carries an extremely small risk of developing new malignant tumors. After treatment for cancer, it is very important to maintain regular check-ups with your oncologist, who will evaluate for signs of recurrence or the appearance of a new tumor.

Radiotherapy techniques such as ESRT allow radiation oncologists to maximize the harmful effects of radiation on a tumor, while minimizing the impact on healthy tissues and organs and limiting the risk of treatment side effects.

The CYBERKNIFE Center is located at the University Hospital of Munich "Grosshadern". It is here that since 2005, patients have been treated using the latest development in the field of medicine called CYBERKNIFE. This unique equipment is the safest and most effective of all methods for treating benign and malignant tumors.