RU2338545C1 - Method of neoadjuvant chemotherapy of mammary gland cancer - Google Patents

Abstract

FIELD: medicine; oncology.

SUBSTANCE: from the first day of treatment centrifugate the autoblood obtained by vascular access in volume of 2400-2600 ml, 1600 ml of supernatant plasmas select in sterile vials, expose to filtrational detoxicating with use of filter F60S with rate of perfusion of 250-300 ml/minute. Then the obtained albuminous concentrate of autoplasma in volume 700-800 ml place in sterile vials in the equal portions corresponding to number of planned introductions of cytostatics under the scheme. Vials contain in a refrigeration cabinet at t-20°C. At carrying out of polychemotherapy by cytostatics under the scheme, an albuminous concentrate defreeze at t +4°C, each antitumoral preparation plant in 10 ml of a normal saline solution, enter into a vial with an albuminous concentrate, incubate at t +37.0°C within not less than 30 minutes and reinfuse them intravenously driply, spend 1-2 courses of neoadjunt treatment.

EFFECT: increase of efficiency of treatment at the expense of transfer of patients in an operable condition; reduction of the sizes of a tumour and lymphonoduses and depression of toxicity of spent polychemotherapy.

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Description

The invention relates to medicine, namely to oncology, and can be used in the treatment of patients with locally advanced breast cancer with metastases to the supraclavicular lymph nodes on the affected side.

The well-known "Method of neoadjuvant drug therapy for locally advanced breast cancer" (see M.R. Lichinitser, E. I. Zagrekova, L. G. Zhukova, V. D. Ermilova, M. I. Lukashina. “Russian Oncological journal "Russian Scientific Center named after N.N. Blokhin (dir. - Acad. N.N. Trepeznikov) RAMS, M., 5.2001, p.32, 33" Modern opportunities and problems of neoadjuvant drug therapy for locally advanced breast cancer " ) The essence of the method is as follows:

51 patients with locally advanced breast cancer (II-IA stage - 15, IIIB - 36) received neoadjuvant chemotherapy in the following modes:

1st - epirubicin 50 mg / m ² and cisplatin 60 mg / m ² intravenously 1 time in 3 weeks, fluorofur 400 mg 3 times a day by mouth daily, for a long time;

2nd - novantrone 10 mg / m ² and cisplatin 60 mg / m ² intravenously 1 time in 3 weeks, fluorofur 400 mg 3 times a day by mouth daily, for a long time;

3rd - Navelbinum 20 mg / m ² intravenously on the 1st and 8th days, novantrone 10 mg / m ² intravenously on the 1st day.

Intervals between courses 3 weeks, the number of courses 3-6.

Organ-preserving operations were performed in various modes in 18-65% of patients, which largely depended on the degree of tumor spread in the patients included in the study.

Complete and partial clinical regression of the tumor did not affect the long-term results of treatment. The effect achieved as a result of neoadjuvant chemotherapy was important only to reduce the volume of subsequent surgery.

It is possible to reduce the amount of subsequent surgery. However, rapid progress should be expected in the coming years.

A known method of treating patients with multiple myeloma (see A.K. Golenkov, V.I.Shabalin. Multiple myeloma, St. Petersburg, 1995 p.126), including polychemotherapy according to the scheme of the Central Testing Center (C) P, CSVKP, TsSVP, in which from 7 to 10 days of treatment, plasmapheresis is performed. The feasibility of combining chemotherapy and plasmapheresis is due to the reduction in the time to receive the effect of treatment, as well as the effect on immunocompetent cells. However, this method has drawbacks: it does not provide for autoplasma reinfusion, which does not allow the proteins to be replenished at the expense of their own and to use their modifying effect on chemotherapy during incubation. Unlike patients with myeloma, accompanied by hyperproteinemia, this approach is not pathogenetically justified in cancer patients with solid tumors. Moreover, the immunocorrecting properties of plasmapheresis are used only at the end of the course of treatment, however, the inclusion of immunological mechanisms, starting from the first day of treatment, is important to achieve its high efficiency. In addition, daily use of hardware plasmapheresis further increases the invasiveness of treatment.

A known method of treating breast cancer (see patent No. 2203687 publ. Bull. No. 13 of 05/10/2003.), We have chosen as a prototype, including intravenous drip of anticancer chemotherapy drugs pre-incubated with autoplasma, characterized in that, starting with the first day of treatment, continuous plasmapheresis is performed once a week, autoplasma is taken in an amount of 600-800 ml, divided into 6 equal parts, 3 of which are used for incubation at 137 ° C for 40 min with chemotherapeutic agents: vincristine 1 mg, methotrexate 30 mg fluorourac silt 750 mg, cyclophosphamide 800 mg in 1, 8 days of treatment, doxorubicin 30 mg in 1, 3, 5, 8, 10, 12 days of treatment, followed by intravenous drip reinfusion, and the other 3 are administered intravenously drip for detoxification, alternating with the infusion of chemotherapy and detoxification every other day.

A known method of treating breast cancer is used throughout the course of treatment using autoplasma for the introduction of chemotherapy, has a positive clinical effect. However, the presence in the plasma component of the blood of ballast substances, toxic substances, metabolites of exo- and endogenous origin, which also interact with albumin, predetermines a decrease in the binding activity of albumin to chemotherapy drugs.

The aim of the invention is to improve the quality of detoxification, processing of autoplasma, improve the effectiveness of treatment - increase the tumor morbidity of chemotherapy while minimizing its toxic effects.

This goal is achieved by the fact that from the first day of treatment autologous blood obtained in the volume of 2400-2600 ml is centrifuged, the supernatant plasma is taken into sterile bottles, the plasma extraction volume is 1600 ml, the autoplasma obtained is subjected to filtration detoxification with the Frezenius ADM apparatus using an F60S filter with perfusion rate of 250-300 ml / min, receive autoplasma protein concentrate with a volume of 700-800 ml, placed in sterile vials in portions equal to the volume and corresponding to the number of planned cytostatic administrations According to the scheme, the vials are refrigerated at t -20 ° C, during polychemotherapy autoplasma protein concentrate is thawed at t + 4 ° C, each antitumor preparation is diluted in 10 ml of physiological saline, injected into a vial with protein concentrate, incubated at t + 37.0 ° С for at least 30 minutes and reinfuse them intravenously, 1-2 courses of neoadjuvant treatment are carried out.

The method of neoadjuvant chemotherapy for breast cancer is new, as it is not known from the level of medicine in the field of chemotherapy for patients with breast cancer as a neoadjuvant component.

The novelty of the invention lies in the fact that for the first time in the treatment of patients with locally advanced breast cancer, the method of neoadjuvant chemotherapy with autoplasma protein concentrate was used.

When using autoplasma for chemotherapy, the main active principle is albumin, with which the prevailing amount of cytostatics interacts in the absence of the effect of competitive binding with blood cells, which is due to its physiological functions in the body and has been convincingly proved in experimental studies (Sidorenko Yu.S., 1996, 2000; Vladimirova L.Yu., 2000, 2001, 2005). At the same time, the presence in the plasma component of the blood of ballast substances, toxic substances, metabolites of exo- and endogenous origin, which also interact with albumin, determines a decrease in the binding activity of albumin to chemotherapy drugs. An important aspect is the development of a new high-tech method of processing, filtering autoplasma through hemofilters, which allows not only detoxifying it, but also obtaining the highest possible effective concentration of autoalbumin in a unit volume of plasma.

The complex treatment of patients with locally advanced breast cancer using neoadjuvant chemotherapy on protein concentrate autoplasma as a natural carrier of pharmacological drugs provides their "targeted" transport to target organs. This helps to increase the effectiveness of chemotherapy while minimizing its toxic effects on the body and the inclusion of adaptive regulation mechanisms of homeostatic systems.

The invention "Method for the Neoadjuvant Chemotherapy of Breast Cancer" is industrially applicable, as it can be used in healthcare, medical institutions of oncological profile, oncology dispensaries, cancer research institutes.

The method of neoadjuvant chemotherapy on protein autoplasma concentrate in the treatment of patients with locally advanced breast cancer is as follows.

To obtain autoplasmic protein concentrate, the patient is discretely sampled autologous blood in the amount of 2400-2600 ml in portions of 300-500 ml using Gemocon containers of the appropriate volume. Vascular access for autologous blood sampling is peripheral vein catheterization. The resulting blood is subjected to discrete gravitational plasmapheresis using the PC-6M apparatus. The modes of blood separation: speed (V) 2200 rpm, time (t) 17 min. The supernatant is collected in sterile vials and the cell pellet is reinfused. The plasma extraction volume is 1600 ml.

In order to replace the volume of plasma extraction, plasma-substituting (rheopolyglukin, refortan, etc.) and crystalloid solutions (5%, 10% glucose solutions, 0.9% sodium chloride solution, etc.) are introduced.

The resulting autoplasma is subjected to filtration detoxification with the Frezenius ADM apparatus using an F60S filter with a perfusion rate of 250-300 ml / min. The resulting autoplasmic protein concentrate with a volume of 700-800 ml is collected in sterile vials in portions equal to the volume. The number of servings corresponds to the number of cytostatic administrations planned during the course of PCT. Autoplasmic protein concentrate is stored in a refrigerator at t -20 ° C. Before administration, the autoplasma concentrate is thawed at t + 4 ° C. Each antitumor preparation is diluted in 10 ml of physiological saline, injected into a bottle with protein concentrate, incubated at t + 37.0 ° C for at least 30 minutes, and they are re-infused intravenously.

Neoadjuvant polychemotherapy is carried out according to the CMFA scheme:

25 mg methotrexate on 1.8 days;

500 mg 5-fluorouracil on days 1, 3, 5, 8, 10, 12;

200 mg cyclophosphamide on days 1, 3, 5, 8, 10, 12;

Doxorubicin 20 mg in 1, 3, 5, 8, 10, 12 days.

Patient A. 38 years old, and.b. No. 3276 / x turned to the RNII in March 2006 for cancer of the right breast with metastases to the axillary lymph nodes on the right, T4N2M0, st.IIIB, gr.IIa.

With a puncture biopsy No. 4059-60 of 03/03/06: moderately differentiated carcinoma.

Hospitalized for examination and treatment in the Department of HCG.

On examination: in the upper outer quadrant of the right mammary gland, a sedentary tumor up to 4.0-4.5 cm in diameter, with fuzzy contours, skin infiltration, strands to the areola and nipple. In the right axillary region, the lymph node is up to 2.5 cm in diameter, limitedly displaced.

On the mammogram of the right breast from 03.03.06: in the upper lateral quadrant of the right breast, a dense shadow formation of irregular star shape, 2.5 × 2.5 × 2.0 cm with multidirectional, connective tissue, radiant cords. Subaxillary metastatic lymph node, 3.0 * 3.5 cm with clear contours.

The local status of the patient corresponded to the inoperability of the tumor process, which did not allow for radical treatment in an adequate volume.

Conducted 2 courses of neoadjuvant chemotherapy (PCT) on protein autoplasma concentrate.

Course 1. March 7, 2006. In order to obtain autoplasmic protein concentrate in a patient with vascular access through a peripheral (ulnar) vein, autoblood was sampled discreetly in portions of 500 ml in an amount of 2400 ml using plastic containers "Gemokon" of the appropriate volume. We performed a discrete gravitational plasmapheresis using the RS-6M apparatus. The modes of blood separation were: speed (V) 2200 rpm, time (t) 17 min. The supernatant plasma was taken into sterile vials, and the cell pellet was reinfused. The volume of plasma extraction was 1600 ml.

In order to replace the volume of plasma extraction, plasma-replacing (reopoliglyukin, reftan) and crystalloid solutions (5%, 10% glucose solutions, 0.9% sodium chloride solution) were introduced.

The autoplasm obtained was subjected to filtration detoxification with a Frezenius ADM apparatus using a F60S filter with a perfusion rate of 250-300 ml / min. The resulting autoplasmic protein concentrate with a volume of 720 ml was collected in sterile vials in portions equal to the volume. Their number corresponded to the number of cytostatics administrations planned during the course of polychemotherapy - 6 servings. Autoplasmic protein concentrate was stored in a refrigerator at t -20 ° C. Before administration, the autoplasma concentrate was thawed at t + 4 ° C. Each antitumor preparation was diluted in 10 ml of physiological saline, introduced into a vial with protein concentrate, incubated at t + 37.0 ° C for at least 30 minutes, and they were re-infused intravenously.

March 9-21, 2006 - 1 course of neoadjuvant PCT on autoplasma protein concentrate according to the CMFA scheme. A total of 50 mg of methotrexate, 3000 mg of 5-fluorouracil, 1200 mg of cyclophosphamide, 130 mg of epirubicin were administered intravenously dropwise.

Moved without complications.

As a result of treatment, the tumor decreased to 3.5–4.0 cm in diameter, its contours became sharper, the displacement increased, the skin infiltration disappeared, the strands to the areola and the nipple became less pronounced. The lymph node in the right axillary region decreased to 1.5 in diameter, became mobile.

2 course from 13 to 25.04.06, similar to the 1st course.

Moved with moderate dyspeptic manifestations.

As a result of treatment, the tumor is 2.5 cm in diameter with clear contours, mobile, there is no skin infiltration, slightly expressed nipple heaviness. In the right axillary region, the lymph node is 1.5 cm in diameter with a pronounced dividing groove.

On the mammogram after treatment dated 05/11/06, the tumor in the upper lateral quadrant of the right mammary gland decreased to 2.0 * 1.5 * 1.0 cm, its structure became less dense compared to the initial local status, the cords were less pronounced. The right axillary lymph node fragmented into 2 components: 1.0 and 0.5 cm in diameter.

As a result of treatment according to WHO criteria, a partial regression of the tumor (76.0%) and metastatic lymph node (95.2%) was noted. The patient was transferred to an operable state.

The patient performed an operation on 05/12/06 - a radical mastectomy on the right, pT4N1M0, st.IIIB.

Macro drug: in the mammary gland after treatment, expressed drug pathomorphism, sclerosis, a tumor is not determined, in the axillary tissue 3 lymph nodes up to 1.5 cm metastatic in nature, in the subclavian and subscapular tissue, enlarged lymph nodes are not detected.

Histoanalysis No. 867088-98: in the mammary gland after chemotherapy, severe sclerosis, hyalinosis, single hyperchromic cells similar to tumor cells, lymph nodes in the axillary tissue (2) - duct cancer metastases.

In June 2006, postoperative remote gamma therapy (DHT) for postoperative scar and regional lymphatic drainage areas, SOD 36 Gy (40 isoGy).

Since July, adjuvant polychemotherapy has been carried out. Currently, 4 courses of adjuvant polychemotherapy on autoplasma have been performed.

As a result of the comprehensive treatment, the patient is in the III clinical group, she feels well, and has no complaints. Has 3 children, a housewife, performs all homework without restrictions.

In this way, 23 patients were treated. Partial tumor regression, according to WHO criteria, was observed in 69.0% of cases, stabilization - in 13.0% in the absence of tumor progression. Morphologically complete regression of the tumor was noted in 27.3% of cases, in 72.7% - partial regression. 48 courses of neoadjuvant chemotherapy with autoplasma protein concentrate were carried out, 34 courses (70.8%) were transferred to patients without complications. Side effects were noted in 29.2% of cases, manifested by gastrointestinal toxicity and hematological - in the form of grade II leukopenia in 12.8% of cases. This indicates a low toxicity of the method.

The technical and economic efficiency of the Method of neoadjuvant chemotherapy for breast cancer consists in the fact that conducting polychemotherapy on an autoplasma protein concentrate obtained by filtration detoxification improves the effectiveness of treatment: transferring patients from an inoperable to an operable state, reducing the size of the tumor and lymph nodes, reducing the toxicity of polychemotherapy , which reduces the additional cost of stopping complications that arise during treatment.

Claims (1)

A method of neoadjuvant chemotherapy for breast cancer, including intravenous drip administration of antitumor chemotherapy drugs, characterized in that from the first day of treatment, autologous blood obtained in the volume of 2400-2600 ml is centrifuged, 1600 ml of supernatant plasma is taken into sterile bottles, filtered using detoxification using F60S with a perfusion rate of 250-300 ml / min, obtaining a protein autoplasma concentrate with a volume of 700-800 ml, which is placed in sterile vials in equal portions, corresponding to According to the number of planned cytostatic administrations according to the scheme, the vials are kept in a refrigerator at t -20 ° С, during polychemotherapy with cytostatics according to the scheme, the protein concentrate is thawed at t + 4 ° C, each cytostatic is diluted in 10 ml of physiological saline, and introduced into a bottle with protein concentrate , incubated at t + 37.0 ° C for at least 30 minutes and reinfused them intravenously drip, spend 1-2 courses of treatment.