RU2664597C1 - Method of combined treatment of patients with primarily operable and locally advanced inoperable breast cancer - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, oncology, and can be used for combined treatment of patients with primarily operable or locally advanced inoperable breast cancer. To do this, drug therapy, including courses of neoadjuvant combined polychemotherapy (NAPCP) according to the 4AC→4T scheme: doxorubicin 60 mg/m² + cyclophosphamide 600 mg/m² every 3 weeks, followed by 12 injections of paclitaxel 80 mg/m² weekly. Simultaneously with the drug therapy, 8 courses of high-intensity focused ultrasound therapy (VFUZT) with an average acoustic power of 300–600 W daily, with a break of 3 weeks. With a maximum tumor size of up to 30 mm, 3 sessions of VFVTT for 1 course are carried out. With a maximum tumor size of 31–40 mm – 4 sessions per 1 course. With a maximum tumor size of more than 40 mm – 5 sessions per 1 course.

EFFECT: method provides increase in effectiveness of NAPHT, maximum reduction in the volume of the tumor, while minimizing the risk of side effects – skin burns of I-II degree, development of high-intensity pain syndrome in treatment zone, translation of the locally advanced process into a localized one with the possibility of performing the next stage of treatment – radical surgery in a minimal amount.

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Description

The invention relates to medicine, namely to oncology, in particular to methods of combined treatment of patients who are primarily operable (clinical stage IIA-T2N0M0 with a triple negative biological subtype; IIB and IIIA) and locally advanced inoperable breast cancer (clinical stages IIIB, IIIC) .

Breast cancer (BC) is the most socially significant cancer of women around the world, characterized by the highest prevalence, late detection and high mortality (S.B. Shakhsuvaryan S.B., Krasnovskaya E.S., Vertash O.Yu. Breast cancer: classification, diagnosis, treatment, quantitative assessment of the degree of functional impairment in the implementation of medical and social examination medical and social problems of disability. 2016; 3: 47-63).

In 2015, the largest proportion of cancer patients - 18.3% - was formed by patients with malignant neoplasms of the mammary gland. The prevalence of breast cancer in 2015 amounted to 426.4 per 100 thousand people. Among patients with a newly established diagnosis, breast cancer at the I-II stages was detected in 69.5% of cases; at stage III - in 21.9%; at stage IV - in 8.1% of cases. The mortality rate of patients with breast cancer during the year since the diagnosis of malignant neoplasms in Russia in 2015 amounted to 6.6% of the number of patients first registered in the previous year (The status of cancer care for the population of Russia in 2015. Edited by Kaprin A .D., Starinsky V.V., Petrova G.V.M .: MNIII named after P.A. Herzen - a branch of the Federal State Budget-Funded Institution "Federal Medical and Research Center" of the Ministry of Health of Russia. 2016.236 p.).

The incidence of breast cancer increases with age, starting from 40 years, and reaches a peak in 60-65 years. The average 5-year survival rate for cancer patients of this location is 55%. For women aged 20-44, breast cancer is the main cause of death and disability (Denisov I.N., Shevkut G.V., Grushko I.P. Breast cancer. Clinical recommendations for general practitioners (family doctors). All-Russian public organization "Association of General Practitioners (Family Doctors) of the Russian Federation. Moscow-Rostov-on-Don. 2015. 32 p.).

An analysis of clinical observations indicates that the effectiveness of treatment for breast cancer patients depends mainly on the degree of prevalence of the tumor process at the start of treatment, and the fact of the presence of a metastatic lesion of a regional tumor of the lymph nodes is of decisive importance (Davydov M.I., Welsher L.Z. , Polyakov B.I. et al. Oncology: a modular workshop. Textbook. Moscow: GEOTAR-Media. 2009. 320 p.).

At present, neoadjuvant polychemotherapy (NAPCT) is recommended for patients with proven invasive primary operable breast cancer - clinical stages IIA (T2N0M0) IIB (T2N1M0, T3N0M0), IIIA (T3N1M0) and the presence of all criteria, with the exception of the size of the tumor organ, which confirms the size of the tumor node operations. This treatment may allow subsequently performing organ-preserving surgery, improving the prognosis if complete morphological regression is achieved in breast cancer patients with triple negative and HER2 positive (non-luminal) subtypes, assessing the effect of drug therapy and terminating it in case of failure.

Pharmaceutical treatment of patients with locally advanced inoperable breast cancer (clinical stages IIIB, IIIC - T0-2N2M0, T3N1-2M0, T4N0-2M0, Lyubaya N3M0) is carried out in order to reduce the size of the tumor and achieve an operable state (Bolotina L.V., Zakiryakhodjaev A.D., Malygin S.E., Medvedev S.V., Pak D.D., Petrovsky A.V., Portnoy S.M., Rozhkova N.I., Rasskazova E.A., Saribekyan E. .K., Stenina MB, Trofimova OP, Tyulyandin SA, Frolova MA, Khmelevsky EV Clinical recommendations for the prevention, diagnosis and treatment of patients with cancer ary gland. All-Russian Union of Public Associations "Russian Association of Oncologists". 2014. 51 pp.).

High Intensive Focused Ultrasound (HIFU therapy, HIFU ablation, ultrasound ablation) is a modern method of non-invasive local thermal ablation of tumors of various localization, used both for the purpose of radical treatment and palliative care for patients suffering from localized, locally distributed or generalized processes. The HIFU method is based on the propagation of mechanical waves with a frequency above 20,000 hertz by scattered beams through tissues with focusing in a given zone (focal point), in which a cascade of interconnected processes that cause local tissue necrosis occurs.

In addition to the direct thermal effect on proliferating cells, during HIFU ablation, the vessels in the affected area of the tumor are destroyed, which violates the interdependent vicious circle of tumor angiogenesis and prevents uncontrolled tumor growth (Liming Guan, Gang Xu. Damage effect of high- intensity focused ultrasound on breast cancer tissues and their vascularities. Guan and Xu World Journal of Surgical Oncology (2016) 14: 153).

Many authors also note the possibility of developing a local and systemic antitumor immune response of the body to antigens resulting from the decay of tumor tissue in the ablation zone (Renske J.E. van den Bijgaart, Dylan C. Eikelenboom, Martijn Hoogenboom, Jurgen J. Futterer, Martijn H den Brok, Gosse J. Thermal and mechanical high-intensity focused ultrasound: perspectives on tumor ablation, immune effects and combination strategies. Cancer Immunol Immunother. 2017; 66 (2): 247-258).

The effectiveness and safety of conducting high-intensity focused ultrasound therapy of localized operable breast cancer has been demonstrated in numerous studies. The morphological picture of local coagulation thermal necrosis in remote mammary gland preparations after ablation is observed in 70-100% of cases (Laura G. Merckel, Floor M. Knuttel, Roel Deckers, Thijsvan Dalen, Gerald Schubert, Nicky HGM Peters, TeunWeits5, Paul J. van Diest, Willem P. Th. M. Mali, Paul HHB Vaessen, Joost MHH van Gorp, Chrit TW Moonen, Lambertus W. Bartels, Maurice AAJ vanden Bosch. First clinical experience with a dedicated MRI-guided high-intensity focused ultrasound system for breast cancer ablation. Eur Radiol. 2016; 26: 4037-4046. Feng Wu, Zhi-Biao Wang, You-De Cao, Xue-Qiang Zhu, Hui Zhu, Wen-Zhi Chen, Jiang-Zhong Zou. "Wide local ablation "of localized breast cancer using high intensity focused ultrasound. Journal of Surgical Oncology. 2007; 96 (2): 130-136. Zhou YF. High intensity focused ultr asound in clinical tumor ablation. World J Clin Oncol. 2011; 2: 8-27). However, this method involves the treatment of local primary operable forms of breast cancer, which do not require systemic chemotherapy at the preoperative stage and are characterized by a more favorable prognosis for patients.

As the most common complications associated with HIFU therapy of malignant neoplasms of the mammary gland, they describe the development of pain in the treatment area (40.1%), swelling of the soft tissues of the breast on the affected side (16.8%), skin burns I-II degrees (4.2%) (Peek M.S., Ahmed M., Napoli A., ten Haken B., Ms Williams S., Usiskin SI, Pinder SE, van Hemelrijck M., Douek M. Systematic review of high intensity focused ultrasound ablation in the treatment of breast cancer. Br J Surg. 2015 Jul; 102 (8): 873-82).

The effectiveness of HIFU therapy in the treatment of locally advanced tumor process has been demonstrated in patients with borderline resectable pancreatic cancer. The study involved 30 patients with borderline resectable pancreatic cancer who underwent HIFU therapy at the first stage of combination treatment before surgery. When evaluating computed tomograms after HIFU therapy, destruction of the target areas was described in 28 patients and subsequently confirmed by the results of a planned morphological study of surgical material as coagulation necrosis. In 2 patients, there was no significant difference in perfusion of tumor foci with RCT. The overall effectiveness of ablation after HIFU therapy was 71.5%. Radical surgery was performed on 28 patients. All patients in the postoperative period received chemotherapy with gemcitabine. The resectability of borderline resectable malignant tumors of the pancreas after the HIFU therapy carried out in the first stage according to the above study was 93.3%. The frequency of operations in the volume of R0 was 92.7%, and the 1-year survival rate for this group of patients was 96.7% (Guojing Wang, Dinghua Zhou. Preoperative ultrasound ablation for borderline resectable pancreatic cancer: A report of 30 cases. Ultrasonics Sonochemistry. 2015 (27): 694-702). In this study, patients did not receive preoperative chemotherapy in parallel with local ultrasound exposure, which could increase treatment efficacy.

In 2012, Chinese scientists published a clinical case of achieving complete clinical and laboratory remission in a patient with locally advanced pancreatic cancer, 40 × 32 mm in size according to computed tomography, which underwent combined treatment: 6 courses of chemotherapy with gembitabin 1000 mg / m ² + capecitabine 800 mg / m ² and 27 sessions of HIFU therapy. The observation period was 22 months from the onset of the first symptoms of the disease. Each session of HIFU therapy was performed without analgesia and sedation for 60-90 minutes. The entire tumor volume was treated with 5 mm of surrounding normal tissue (Patrick Chi-Pan LAU, Shu Fan ZHENG, Wai Tat NG, Simon Chun-Ho YU Inoperable pancreatic adenocarcinoma rendered complete remission by high-intensity focused ultrasound concurrent with gemcitabine-capecitabine chemotherapy: Case report and topic review. Journal of Digestive Diseases. 2012; 13; 60-64).

This method involves the treatment of only the locally common form of pancreatic cancer, characterized by a deep location of the tumor in the patient’s body relative to the skin, significant scattering of ultrasound rays due to adjacent air-borne tubular structures (stomach, intestine), intensive heat removal by blood flow in large vessels of the hepatopancreatoduodenal zone. Despite this, the main complications of this treatment are skin burns of the I-II stage, sclerotic changes in the subcutaneous adipose tissue of the anterior abdominal wall, pancreatic pseudocyst formation, portal vein thrombosis (Xiong LL, Hwang JH, Huang XB et al. Early clinical experience using high intensity focused ultrasound for palliation of inoperable pancreatic cancer. JOP 2009; 10: 123-129; Orsi F, Zhang L, Arnone P et al. High-intensity focused ultrasound ablation: effective and safe therapy for solid tumors in difficult locations. AJR Am J Roentgenol 2010; 195: 245-252). Often patients with the described prevalence of the process at the time of treatment start have a weakened somatic state (ECOG 2-3), which leads to a decrease in tolerance and treatment efficiency and low survival rates.

The closest is the method of neoadjuvant combination chemotherapy in patients with locally advanced breast cancer with metastatic lesion of the regional lymph nodes (NSABP B-30 program), which demonstrated the efficacy of 4AC → 4T as the optimal regimen for NAPCT in this category of patients. It was shown that the sequential administration of doxorubicin and docetaxel (4AC → 4T) exceeds both simultaneous regimens (4AT and 4TAC) in terms of overall survival of patients.

Т.,

A., Jelic S., Gorbunova V., Mrsic-Krmpotic Z. et al. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. J. Clin. Oncol. 2001; 19:1707-15; Figgit D.P., Wiseman L.R. Docetaxel: an update of its use in advanced breast cancer. Drugs. 2000; 59(3):621-51).However, the number of objective tumor responses to treatment ranged only between 53-82% (Bontembal M., Creemers GJ, Braun HJ, de Boer AC, Janssen JT, Leys RB et al. Phase II to III study comparing doxorubicin and docetaxel with fluorouracil, doxorubicin and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer: results of the Dutch Community Setting Trial for the Clinical trial group of the Comprehensive Cancer Center. J. Clin. Oncol. 2005; 23: 7801-8; Jassem J. ,

T.,

A., Jelic S., Gorbunova V., Mrsic-Krmpotic Z. et al. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. J. Clin. Oncol. 2001; 19: 1707-15; Figgit DP, Wiseman LR Docetaxel: an update of its use in advanced breast cancer. Drugs 2000; 59 (3): 621-51).

The technical result of the invention is to increase the efficiency of NAPCT and achieve maximum reduction in the volume of the tumor focus (with minimizing the risk of developing such side effects of ablation methods as skin burns of the I-II degree, the development of a highly intense pain syndrome in the treatment area), which will ensure local transfer - a common process in a localized and will enable the next step to carry out radical surgical intervention in a minimal amount.

The specified technical result in the implementation of the invention is achieved due to the fact that, as in the known method, all patients are primarily operable (clinical stage IIA - T2N0M0 with a triple negative biological subtype; IIB and IIIA) and locally advanced inoperable breast cancer ( clinical stages IIIB, IIIC) conduct neoadjuvant combination chemotherapy according to the 4AC → 4T regimen: doxorubicin 60 mg / m ² + cyclophosphamide 600 mg / m ² every 3 weeks, then 12 paclitaxel 80 mg / m ² weekly.

A feature of the proposed method is that in parallel with the specific drug treatment according to the standard scheme, all patients undergo 8 courses of high-intensity focused ultrasound therapy of primary tumor formation of the mammary gland with an average acoustic power of 300-600 W daily, with a break of 3 weeks, with the following number Sessions per course:

- 3 sessions with a maximum size of the tumor focus up to 30 mm,

- 4 sessions with a maximum tumor size in the range of 31-40 mm,

- 5 sessions with focal formations of more than 40 mm maximum diameter.

Moreover, depending on the height of the plate with the emitters of the HIFU 2001 apparatus, when positioning the focal point in the target zone of ultrasound, ablation can be performed in two modes:

- in single-point mode with the number of pulses 5000-8000 per point when the plate with emitters is located during exposure at a height of less than 20 mm from zero (with a low spatial location of the tumor focus in the patient’s position lying on his stomach or on his side on the apparatus table - with a surface the location of the tumor in the large mammary gland with richly developed glandular tissue);

- in the zonal mode with a pulse frequency of 200-1000 per point when the plate with emitters is located at a height of 21 mm or more from zero.

The use of this invention will improve the efficiency of systemic specific drug therapy by reducing the tumor volume, activating the local and systemic antitumor immune response to antigens of necrotic tumor tissue, developing a moderate aseptic peritumoral inflammatory process, leading to an increase in blood flow around the tumor and intensification of metabolic processes in this zone, and therefore, improving drug delivery to malignancy neoplasm and increase the effectiveness of systemic chemotherapy.

The method is as follows.

All patients on the basis of a specialized department in a round-the-clock hospital mode are given neoadjuvant combined chemotherapy according to the 4AC → 4T regimen: doxorubicin 60 mg / m ² + cyclophosphamide 600 mg / m ² every 3 weeks, then 12 injections of paclitaxel 80 mg / m ² weekly. The next day after the administration of chemotherapy, provided the patient is in satisfactory condition and there is no need for correction of hematological abnormalities, patients undergo a course of high-intensity focused ultrasound therapy, for example, on a HIFU-2001 apparatus Shenzhen Huikang Medical Apparatus Co., LTD, China, 2015. Number of sessions per course local treatment is determined by the size of the tumor focus in the mammary gland:

3 sessions with a maximum size of the tumor focus up to 30 mm,

4 sessions with a maximum tumor size in the range of 31-40 mm,

5 sessions with focal formations of more than 40 mm maximum diameter.

Sessions are held daily. The course of treatment is repeated 1 time every 3 weeks.

Ultrasonic ablation is carried out in the patient’s position, lying on his stomach or on his side (for tumors located in the lateral quadrants of the mammary gland) on the table of the HIFU-2001 apparatus, with the obligatory condition of contact of the skin in the projection of the tumor focus with degassed water heated to 40 ° C. In order to fix the mammary glands and the tumor, as well as to achieve the optimal location of the target focus relative to the plate with emitters, all patients undergo a tight compression of the mammary glands with cling film to form a free “window” in the tumor projection. The procedure is carried out under ultrasound control (for example, on the Mindray DC-7 apparatus, 2015). Bringing the focus point of the emitters and selecting the exposure zone is carried out using a program (for example, HIFU-2001 Type High Intensity Focused Ultrasound Tumor Treatment System). Moreover, depending on the height of the plate with the emitters of the HIFU 2001 apparatus, when positioning the focal point in the target zone of ultrasound, ablation can be performed in two modes:

- in single-point mode with the number of pulses 5000-8000 per point when the plate with emitters is located during exposure at a height of less than 20 mm from zero (the minimum height of the plate with emitters provided by the device design) - with a low spatial location of the tumor focus in the patient’s position lying on his stomach or on his side on the apparatus table in case of superficial location of the tumor in the large mammary gland with richly developed glandular tissue);

- in the zonal mode with a pulse frequency of 200-1000 per point when the plate with emitters is located at a height of 21 mm or more from zero.

The number of exposure points is determined depending on the size of the tumor focus.

The duration of the ultrasonic pulse is 200 ms, the duration of the pause between pulses is 30-100 ms, the distance between the points of influence in the horizontal plane is 3-4 mm, along the vertical axis - 7-8 mm. The average acoustic power of the impact is 300-600 W (depending on the level of the patient's pain threshold), is adjusted during the procedure taking into account the patient's complaints. The total time of the procedure, taking into account the preparation of the patient, guidance, the ablation process itself, is 40-80 minutes. After the session, all patients undergo visual and palpation examinations of the breast on the affected side and a control diagnostic ultrasound examination of the ablation zone in order to timely detect the development of an excessive local inflammatory reaction of the skin and soft tissues of this area.

Clinical Examples

Clinical example No. 1

Patient E., 31 years old, with a clinical diagnosis: Cancer of the left breast IIIC Art. cT2N3M0; appealed to the Moscow Research Institute of Oncology named after P.A. Herzen - a branch of the federal state budget institution "National Medical Research Center of Radiology" of the Ministry of Health of the Russian Federation with complaints of palpable lesions in the left mammary gland. According to a comprehensive examination in the upper outer quadrant of the left mammary gland, a hypoechoic, hyperdense tumor formation with dimensions of 21 × 14 × 16 mm, irregular shape with a fuzzy contour, with an “path” of infiltration to the nipple, next to which there is an additional focal formation similar in structure, is determined (screening) up to 8 mm in size, between these nodes multiple malignant calcifications are determined. In the left supraclavicular region with the transition to the axillary, the secondarily changed lymph nodes are determined by the sizes: in the subclavian region - 16 × 9 mm, in the axillary - 21 × 14 mm, 12 × 8 mm, 11 × 7 mm. In a morphological study of a biopsy from a tumor of the left breast, an invasive cancer of the nonspecific type G3 of the breast with foci of necrosis and the presence of cancer emboli in the lumen of the lymphatic vessels. According to immunohistochemical studies - estrogen receptors-4 points, progesterone receptors-0 points, HER2 / neu 2+, Ki67-35%, FISH-positive reaction.

On the basis of the chemotherapy department, the patient underwent 4 courses of chemotherapy according to the AS regimen: doxorubicin 60 mg / m ² + cyclophosphamide 600 mg / m ² every 3 weeks and 12 injections of paclitaxel 80 mg / m ² weekly. The development of toxic effects of drug treatment was not observed.

In parallel with chemotherapy, the patient completed 8 courses (24 sessions) of high-intensity focused ultrasound therapy of a primary tumor of the left breast (3 sessions per 1 course daily, with breaks between courses of 3 weeks).

In order to fix the mammary glands and the tumor, as well as to achieve the optimal location of the target focus relative to the plate with emitters, before each session, the patient’s mammary glands were tightly compressed with cling film to form a free “window” in the tumor projection.

At the time of setting the focal point of ultrasound rays in the area of the tumor tissue during ultrasound marking on the HIFU 2001 device during the first treatment session, the height of the plate with emitters was 41 mm from zero.

All ablation sessions were performed in the zonal mode: the average number of pulses per point was 510 (200-1000 pulses), the duration of the ultrasonic pulse was 200 ms, the average pause time between pulses was 63.6 ms (50-100 ms), the distance between the points impacts in the horizontal plane - 3-4 mm, on the vertical axis - 7-8 mm, the average acoustic power of the impact - 499 W (400-600 W). The average session time was 45.4 minutes (43-66 minutes).

During the control ultrasound of the left breast at the end of the 8th course of HIFU therapy, a single tumor formation is poorly differentiated in the upper-outer quadrant, the echogenicity of which is increased, close to echogenicity with the surrounding normal tissue, 10 × 9 × 7 mm in size, in the subclavian region is determined one altered lymph node 12 × 7 mm in size; in the axillary, three lymph nodes 15 × 10 mm, 10 × 6 mm, 8 × 5 mm.

By the 2nd session of each ablation course, the patient noted the development of moderate pain in the area of influence, during examination and ultrasound, the development of moderate edema of the skin and subcutaneous fat in the area of acoustic access to the tumor was noted. These phenomena completely disappeared 18 days after the last procedure.

Clinical example No. 2

Patient K., 34 years old, with a clinical diagnosis: Cancer of the left breast IIB Art. CT3N0M0, Her2 / neu-positive, non-luminal subtype; appealed to the Moscow Research Institute of Oncology named after P.A. Herzen - a branch of the federal state budget institution "National Medical Research Center of Radiology" of the Ministry of Health of the Russian Federation with complaints of palpable lesions in the left mammary gland. According to the ultrasound of the mammary glands and regional zones: in the left mammary gland in the lower-outer quadrant, a multi-lobe hypo-inhomogeneous tumor formation with single blood flow loci and a wavy contour, 28 × 21 × 31 mm in size, without acoustic shadow, is located in the regional areas of lymph outflow - without pathological changes. In a morphological study of a biopsy from this formation, an invasive breast cancer without signs of G2 specificity of a solid-trabecular structure. According to immunohistochemical studies - estrogen receptors-0 points, progesterone receptors-0 points, HER2 / neu 3+, Ki67-25%.

On the basis of the chemotherapy department, the patient underwent 4 courses of chemotherapy according to the AS regimen (doxorubicin 60 mg / m ² + cyclophosphamide 600 mg / m ₂ every 3 weeks) and 12 injections of paclitaxel 80 mg / m ² weekly. Due to the patient's nausea during the 1st course of chemotherapy, the further administration of drugs took place against the background of the use of antiemetics.

In parallel with chemotherapy, the patient completed 8 courses (32 sessions) of high-intensity focused ultrasound therapy of the primary tumor of the left breast (4 sessions per 1 course daily, with breaks between courses of 3 weeks).

In order to fix the mammary glands and the tumor, as well as to achieve the optimal location of the target focus relative to the plate with emitters, before each session, the patient’s mammary glands were tightly compressed with cling film to form a free “window” in the tumor projection.

When performing ultrasound marking on the HIFU 2001 apparatus, a low spatial location of the breast tumor in the patient’s position on the abdomen was revealed due to its location in the front sections of the lower-outer quadrant, paraareolarly. When you set the focal point of ultrasound rays in the area of the tumor tissue, the height of the plate with emitters was 12 mm from zero. In this regard, tumor tissue was ablated in a single-point mode with an average number of pulses per point 5389 (5000-7000 pulses), an ultrasonic pulse duration of 200 ms, an average pause between pulses of 55 ms (30-100 ms), and average acoustic power exposure 346 watts (300-380 watts). The average session time was 48.3 minutes (40-55 minutes).

During the control ultrasound of the left mammary gland at the end of the 8th course of HIFU therapy, the hypoechoic tumor formation of irregular shape, 12 × 8 × 11 mm in size, is paraareolarly determined in the lower lateral quadrant of the left breast.

For each 3rd session of the ultrasound ablation course, the patient noted the development of minor pain in the area of exposure, stopped by the use of a non-steroidal anti-inflammatory drug. Upon examination and ultrasound, no clinically significant phenomena of the development of a local inflammatory reaction were noted. These phenomena completely disappeared 13 days after the last procedure.

The proposed number of sessions and three-week breaks between ablation courses made it possible to avoid the development of side effects such as skin burns of the I-II degree, which lead to disruption of the chemotherapy regimen by prolonging the interval between drug injections until the skin defect is completely epithelized, as well as the development of a highly intense pain in the treatment area, which leads to a decrease in the output power of the exposure during the procedure.

Thus, the use in clinical practice of the proposed method for conducting HIFU therapy has allowed for simultaneous drug treatment and repeated ablation procedures with maximum efficiency and tolerability, with a minimum likelihood of developing adverse reactions.

Claims (5)

1. A method for the combined treatment of patients with primarily operable or locally advanced inoperable breast cancer, comprising courses of neoadjuvant combination chemotherapy according to the 4AC → 4T regimen: doxorubicin 60 mg / m ² + cyclophosphamide 600 mg / m ² every 3 weeks, followed by 12 administrations of paclitaxel 80 mg / m ² weekly, characterized in that simultaneously with the drug therapy to patients spend 8 courses of high-intensity focused ultrasound therapy, with an average power of 300-600 watts acoustic daily with an interval of 3 is not ate, with the following number of sessions for the course: - 3 sessions with a maximum tumor size of up to 30 mm, - 4 sessions with a maximum tumor size of 31-40 mm, - 5 sessions with a maximum tumor size of more than 40 mm. 2. The method according to p. 1, characterized in that the local thermal effect is carried out at a height of less than 20 mm from a zero value, with a number of pulses 5000-8000 per point, or at a height of 21 mm or more from a zero value, with a pulse frequency of 200- 1000 to the point.