RU2145239C1 - Method of treatment of patients with breast cancer - Google Patents

Abstract

FIELD: medicine, oncology. SUBSTANCE: invention relates to treatment of patients with breast cancer at preoperative stage. Invention proposes to administrate chemopreparations based on autoblood at increased course doses in combination with epithalamine based on autoblood by separate route for 4 weeks successively beginning from the 1st day. Vincristine and methotrexate are administrated once per a week up to 1, 2 course doses; fluoro-uracil is dosed 3 times per a week for each other day up to 1, 5 course doses and epithalamine is dosed at the dose 10 mg, 3 times per a week for each other day by drop intravenous route. In other days beginning from the second day epithalamine is administrated at the dose 10 mg by intramuscular route. Method ensures to use enhanced course doses of antitumor preparations at simultaneous improvement of tolerance of chemotherapy course and to correct immunohormonal status. EFFECT: enhanced effectiveness of treatment. 5 tbl, 3 ex

Description

 The invention relates to medicine, namely to oncology and can be used to treat a hormone-dependent disease - breast cancer in the preoperative period with cytotoxic drugs.

 A known method of treating breast cancer / see Antitumor chemotherapy. Edited by N. N. "Translatorova" 1996, p. 70 / by combinations of anticancer drugs CMFYP, including cyclophosphamide 2mg / kg orally or i.m. from 1-28 days, vincristine 0.025 mg / kg i.v. 1p / week, fluorouracil 12 mg / kg iv in 1 r / wk, methotrexate 0.75 mg / kg iv in 1 r / wk, prednisone 0.75 - 0.25 mg / kg orally for 3 weeks, then 10 mg for 1 week. The course of treatment is 4 weeks. Courses are repeated after 4 weeks.

 The disadvantages of the known method of treating breast cancer are the need to significantly reduce the standard single and course doses of cytostatics, forced interruptions in treatment due to side effects - hematotoxic, dyspeptic, etc., which does not allow observing the strategic principle of the maximum possible radicalism of chemotherapeutic treatment. In addition, the corticosteroids / prednisone / included in the scheme, although affecting lymphoid proliferation, have an immunosuppressive effect, which exacerbates immunosuppression during a course of chemotherapy and further weakens the immune system of the tumor carrier organism. The use of corticosteroids can lead to complications in the form of ulcerogenic effects on the gastrointestinal tract, hypertension, hyperglycemia, obesity, osteoporosis, impaired water-salt metabolism, etc., which leads to their wide range of contraindications for peptic ulcer and duodenal ulcer, arterial hypertension, renal failure, diabetes mellitus and other common concomitant pathology in patients with breast cancer. Meanwhile, other combinations of chemotherapeutic agents created on the basis of this scheme, but without corticosteroids / HP, CMF, CMFY, etc. / and currently quite common for the treatment of breast cancer, also do not allow courses in recommended doses due to toxic side effects. effects and comply with the planned regimes, negatively affect the immune system in patients, which ultimately affects the antitumor effectiveness.

A known method of treating cancer / Avt.svid. N 940379 from 05.15.80. IPC A 61 K 35/14, Aut. Sidorenko Yu.S., Katsman M.V. /, including intravenous administration of vincristine, fluorouracil, methotrexate, characterized in that 1/4 of the generally accepted course dose of the drug is dissolved in 50 ml of saline solution, mixed with 145-150 cm, autologous blood incubated at 36.5-37 ^o C for 25-30 minutes and drip iv administered to the patient.

 This method increases the tolerance of the generally accepted course dose of drugs, overcoming the toxic barrier inherent in systemic chemotherapy, but also has its drawbacks. His own limit of toxicity limits the dose of chemotherapy and lengthens the intervals between infusions, and general toxic manifestations occurring in a certain percentage of cases force interruption of autohemochemotherapy. The maximum treatment effect of this disease is possible when using the optimal dose of drugs, i.e. doses that have an antitumor effect without suppressing the body's defenses. However, this method does not allow the correction of the immunogormonal status of the body.

 Breast cancer is a hormone-dependent disease, which is accompanied by a violation of the interaction of the central / hormones of the hypothalamic-pituitary system / and peripheral hormones / adrenal glands, thyroid, genital, etc. /, as well as the development of immunosuppression and impaired regulation of immunopoiesis. In this regard, there is a need for correction of the endocrine and immune systems in the treatment of hormone-dependent tumors.

 The known "Method for the treatment of breast cancer" / see Prince "The use of epiphysis drugs in clinical practice", publishing house of Tomsk University, Tomsk, 1985. "Siberian branch of the All-Union Cardiology Scientific Center of the Academy of Medical Sciences of the USSR, pp. 97-121 /, which we selected as a prototype, including the introduction of epithalamine after radical mastectomy , chemotherapy or radiation therapy / persistent leukopenia /, as well as patients with inoperable forms of tumors or who have certain contraindications to all types of treatment, in order to reduce intoxication, improve blood counts, cellular immunity. These patients were treated only with epithalamine, daily, 10–20 mg intramuscularly, a course of treatment of 10–15 days, from 1 to 10 courses for 3-5 years with an interval of not more than 6 months. , a decrease in body temperature during fever, a decrease in intoxication. However, not all patients had a stable clinical condition. In some patients, symptoms of intoxication increased again after 2 weeks and the condition worsened. Not given are data on the assessment of immunological reactivity in terms of the functional activity of lymphocytes. In addition, the duration of treatment is one of the disadvantages. Comparison with the control group for an objective assessment of the effectiveness of treatment was not possible.

 The aim of the invention is the impact in the preoperative period of antitumor drugs in an increased course dose and at the same time improve the tolerability of the course of chemotherapy, as well as the correction of the immune and hormonal status and increase the effectiveness of treatment.

 This goal is achieved by the fact that in the preoperative period, chemotherapy is administered with increased course doses for autologous blood in combination with epithalamine on autologous blood, separately, sequentially for 4 weeks, starting from the first day, - vincristine and methotrexate 1 time per week to 1.2 course doses, fluorouracil 3 times a week every other day up to 2 course doses, cyclophosphamum 3 times a week every other day up to 1.5 course doses, epithalamin 10 mg 3 times a week every other day intravenously; on the remaining days, starting with the second, epithalamin 10 mg intramuscularly.

 The invention "A method for the treatment of breast cancer" is new, since it is not known from the level of medicine in the field of oncology in the preoperative treatment of breast cancer with cytostatic agents.

 The novelty of the invention lies in the fact that in the preoperative period, chemotherapeutic drugs are administered in increased course doses on autologous blood in combination with epithalamine on autologous blood, separately, sequentially, for 4 weeks starting from the first day, vincristine and methotrexate 1 time per week to 1, 2 course doses, fluorouracil 3 times a week every other day, up to 2 course doses, cyclophosphamide 3 times a week every other day, up to 1.5 course doses, epithalamine 10 mg 3 times a week every other day in / drip, on other days, starting from the second, epithalamin 10 mg in / . A known method of treating breast cancer using epithalamin prototype of the invention was not used in the preoperative period of patients. To improve the clinical condition of patients, repeated courses were required for a long time, and at the same time, the effect was unstable. With an improvement in cellular immunity, it was not possible to evaluate the immunological reactivity by indicators of the functional activity of lymphocytes.

 In order to overcome to a large extent these shortcomings, we have proposed a method that involves a combination of autohemoimmunological and autohemochemotherapeutic effects. The combination of autohemochemotherapy with the introduction of epithalamine on autologous blood allows you to change the biological response of the body to the tumor in such a way that it has a beneficial therapeutic effect and increases the body's ability to tolerate the damaging effects of cytostatics during antitumor therapy due to the inclusion of immunological and hormonal mechanisms. This allows the use of chemotherapy in an optimal dose, i.e. the dose that has the maximum antitumor effect without suppressing the body's defenses, which is especially important in the preoperative period. Acting through the hypothalamic - pituitary system, epithalamin also allows you to adjust the immunohormonal status of patients, contributing to changes in the tumor carrier that are favorable for antitumor treatment. The antitumor effect of epithalamin as an extract of the pineal gland indirectly through the endocrine system, as indicated by a number of researchers, cannot be ruled out.

 The invention has an inventive step, as for a specialist oncologist-chemotherapist does not explicitly follow from the level of medicine in the treatment of hormone-dependent tumors - breast cancer in the preoperative period.

 Successful treatment of hormone-dependent tumors requires an effect on the endocrine and immune systems. It has been established that extracts of the pineal gland have a significant antigonadotropic and immunostimulating effect. Considering that the main methods of treating breast tumors - surgical, radiation, chemotherapeutic - have an adverse effect on the immunological reactivity of the body, it is relevant to include agents that stimulate the immune system in the preoperative effect on the tumor.

 The combination of autohemochemotherapy with increased doses of cytostatics with the preparation of the cytomedine class pineal gland extract, which regulates the endocrine balance through modulation of the hypothalamic-pituitary system and also has an immunostimulating effect, allows one to achieve an antitumor effect without reducing the body's defenses.

 The proposed method for the treatment of breast cancer is original, non-obvious, does not explicitly follow from the level of medicine in this field of oncology - the treatment of hormone-dependent tumors, in particular breast cancer, neither in the CIS, nor in Russia, nor abroad.

 The invention is industrially suitable, as it can be used in healthcare for chemotherapy of breast cancer in various medical institutions, especially oncology, in the Oncology Research Institute, oncology dispensaries.

 A specific implementation of the method of treating breast cancer.

210 ml of blood from peripheral veins are taken from a patient with breast cancer in 2 bottles with the blood preservative Glyugitsir (70 ml in one, 140 ml in the other). Each antitumor chemotherapy drug is diluted in a separate syringe in 10 ml of saline, which is a total of 40 ml and injected into a vial with 140 ml of autologous blood. In a second bottle with 70 ml of autologous blood, 10 ml of epithalamin diluted ex tempore in 2 ml of saline solution is injected. Both vials are incubated at 36.5 - 37.0 ^o C for 30 minutes and injected iv drip sequentially / first a bottle with chemotherapeutic agents, then a bottle with epithalamine / 3 times a week. The combination is designed for 4 weeks and is administered in a regimen starting from the first day - vincristine 2 mg and methotrexate 60 mg once a week to 1.2 course doses, fluorouracil 500 or 750 mg per day 3 times a week every other day 2 course doses, cyclophosphamide 400 or 600 mg per day 3 times a week every other day up to 1.5 course doses, epithalamin 10 mg 3 times a week every other day in / drip; on the remaining days, starting with the second, epithalamin 10 mg IM.

 After drug administration, the patient’s general condition is monitored, laboratory control is carried out: a general blood test 2 times a week, a general urine test 2 times a week, an ECG, an immunogram and hormonal tests before and after treatment.

 An example of a specific implementation of the method of treating breast cancer.

Sick B-sky, and. b. 5192 / f, 48 years old, weight 67 kg. I entered the department 21 / V 1998 with complaints of serous discharge from the nipple of the right breast, the presence of education in it. When viewed at the border of the lower quadrants of the right mammary gland, the formation is up to 2.5 6 m. • 3 cm, dense, with fuzzy contours, limited displaced in relation to the surrounding tissues. The nipple and areola are infiltrated, hyperpigmented. The nipple is covered with crusts of a dark brown color, with a slight pressure on it, serous discharge is noted. In the right axillary region, the lymph node is up to 2.0 • 1.5 cm, dense, limitedly mobile. Cells of moderately differentiated cancer were cytologically detected. Ultrasound of the right mammary gland showed: at the border of the lower quadrants, the formation of reduced echo density of a heterogeneous internal echostructure with an uneven contour of 1.7 x 2.5 cm is located. Clinical diagnosis: cancer of the right breast / nodular form / with metastases to the axillary lymph nodes on the right / T ₂ N ₂ M ₀ / st. III.

From 27 / V to 24 / VI, a course of autohemochemotherapy was carried out according to the CMFY scheme with increased course doses with epithalamine administered to autologous blood. To do this, 210 ml of blood from the peripheral veins was taken from the patient in 2 bottles with the blood preservative Glyugitsir / in one - 70 ml, in the other - 140 ml /. Each cytostatic was diluted in 10 ml of saline and injected into a vial with 140 ml of autologous blood. In a second vial with 70 ml of autologous blood, 10 mg of epithalamin diluted ex tempore in 2 ml of saline was injected. Both vials were incubated at 36.5 - 37.0 ^o C for 30 minutes and were administered iv drip sequentially / first a vial of chemotherapy drugs, then a vial of epithalamine / 3 times a week. The combination was administered for 4 weeks, starting from the first day - vincristine 2 mg and methotrexate 60 mg once a week to 1.2 course doses, fluorouracil 500 mg on days 1 and 5 of each week and 750 mg in 3 day of each week up to 2 course doses, cyclophosphamide 400 mg on days 1 and 3 and 600 mg on day 5 of each week, up to 1.5 course doses, epithalamine 10 mg 3 times a week every other day in / drip; on the remaining days, starting with the second, epithalamin 10 mg IM.

 The treatment was tolerated satisfactorily, without adverse toxic reactions. In the second week of treatment, the discharge from the mammary gland stopped, the tumor began to decrease in size. Ultrasound data of the right breast showed a decrease in the size of the formation of 11 / VI to 1.5 • 2.4 cm; 18 / VI to 1.1 • 2.2 cm. Treatment results were evaluated 2 weeks after the course. The tumor was reduced in size by more than 2 times, became less dense and more mobile, the discharge from the nipple stopped. The axillary lymph node regressed completely. The control ultrasound of the right mammary gland from 3 / VII determined the formation sizes of 0.6 x 1.6 cm. We also compared the results of an immunological study before and 2 weeks after treatment (see table. 1).

 Thus, after treatment, there is a favorable immunological dynamics associated with an improvement in the quantitative and functional parameters of T and B cell immunity / an increase in the absolute and relative number of T lymphocytes, an increase in functional activity in RBTL with T and B mitogens /.

 Subsequently, the results obtained made it possible to perform a radical mastectomy according to Patty on the right. Histological examination revealed extensive fields of connective tissue with foci of necrosis, hyalinosis, dystrophically altered cells similar to cancerous.

 The results of the effectiveness of the treatment of patients with breast cancer of the proposed method.

 The proposed method for the treatment of breast cancer is tested in the conditions of RNII. From 01/98 to 06/98 in the preoperative period, 8 patients with locally advanced breast cancer, / T2-4N1-2 MO-1, where Mi metastases to the supraclavicular lymph nodes on the affected side / were treated by this method. In all patients, the tumor was verified cytologically.

 The control group was comparable with the main group by all the main criteria and consisted of 8 people who underwent autohemochemotherapy with the same chemotherapy, but without epithalamin, and of 8 people who underwent systemic chemotherapy according to the CMFYP scheme.

 As shown in the table. 2, toxic manifestations in patients of the control group were more frequent and more pronounced, which forced to interrupt the course of chemotherapy or to reduce the dose of cytostatics.

 The obtained results of assessing the immune status of patients indicate that the indicators of the functional activity of T and B lymphocytes in patients of various groups undergo multidirectional dynamics. So, in the control group in those who underwent both systemic and autohemochemotherapy without epithalamine, the number of PHA- and LPS-induced blasts does not differ from the initial one, and in patients who underwent autochemotherapy with epithalamine, it increases statistically significantly from 29.8 ± 1.15 up to 40.1 ± 1.9% and from 29.1 ± 1.1 to 37.8 ± 3.26%, respectively / p <0.05 /.

 As an example of the implementation of this method, we present immunograms of patients of various groups.

1. Patient B-sky, and. N 5192 / f, 48 years old, from the main group / autohemochemotherapy with epithalamine on autologous blood /, clinical diagnosis: cancer of the right breast with metastases to the axillary lymph nodes on the right / T ₂ N ₂ M ₀ /, Art. III.

 The immunogram is shown in example 1 / cm above / and demonstrates the favorable immunological dynamics of quantitative and functional indicators of T- and B-cell immunity units / increase in the absolute and relative number of T-lymphocytes, increase in functional activity in RBTL with T and B-mitogens / .

2. Patient B-va. 47 years old 2261 / f, control group / autohemochemotherapy without epithalamin /, clinical diagnosis: cancer of the left breast with metastases to the left axillary lymph nodes T ₂ N ₂ M ₀ /, Art. III.

 Thus, after treatment, pronounced changes in the immunogram do not occur. Most of the quantitative and functional indicators remain at the initial level, and for some their decrease is noted (the number of active T-lymphocytes, RBTL with Con A, etc.).

3. Patient M-va, 59 years old, and. 11039 / е, from the control group (systemic chemotherapy without epithalamin). Clinical diagnosis: breast cancer with metastases to the right axillary lymph nodes (T ₂ N ₂ M ₀ ), st. III gr. II.

 Thus, there is a sharp decrease in all quantitative and functional indicators of immunity after a course of systemic chemotherapy.

 So, the above examples illustrate the positive effect of epithalamine, used in the proposed scheme, on the immune status of patients with breast cancer, which is especially important in the preoperative period.

 The immediate results of the treatment of patients, presented in table 4, showed the high efficiency of this method, which allowed all patients to perform radical mastectomy according to Patty.

 Such a high efficiency of our proposed method was achieved due to the ability to comply with the strategic principle of chemotherapeutic radicalism: the possibility of administering chemotherapeutic drugs in elevated course doses in compliance with the regimen of administration of cytostatics with the maximum possible exclusion of toxic side effects and the simultaneous inclusion of immunological and other antitumor mechanisms.

 The technical and economic effectiveness of the “Method for the treatment of breast cancer” lies in the fact that the use of the method improves the clinical condition of patients by reducing the frequency and severity of adverse toxic reactions of the body to chemotherapy, allows the use of cytostatics in elevated course doses with simultaneous immuno-hormonal correction and to observe the planned regimes the introduction of chemotherapy, which increases antitumor efficacy and allows for surgical treatment in an adequate volume and at the optimum time.

Claims (1)

 A method of treating breast cancer, including autohemochemotherapy with intravenous drip administration of antitumor chemotherapy drugs, characterized in that in the preoperative period, chemotherapy drugs are administered in increased course doses on autologous blood in combination with epithalamine on autologous blood, separately, sequentially for 4 weeks starting from the first day - vincristine and methotrexate once a week up to 1.2 course doses, fluorouracil 3 times a week every other day up to 2 course doses, cyclophosphamum 3 times a week every other day up to 1.5 course doses, epithalamin 10 mg 3 times a week every other day intravenously, on other days, starting from the second, epithalamin 10 mg intramuscularly.

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