RU2560314C2 - Method of complex treatment and prevention of recurrences of muscular-non-invasive forms of urinary bladder cancer - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to oncology and oncological surgery, and can be used for complex endourethral treatment and prevention of recurrences of muscular non-invasive forms of urinary bladder cancer. For this purpose bilpolar transurethral resection of urinary bladder tumour in physiological solution is performed. After that, on 25-30 day once per week carried out is 1.5-2 month long induction course of intravesical immunotherapy with medicinal composition, which is prepared immediately before introduction into urinary bladder by mechanical mixing of 100-120 mg of BCG Imuron vaccine and 10 g of Tizol gel in 50 g of physiological solution. Time of exposure of medicinal composition in urinary bladder constitutes 30 minutes. 1 month after break in case of absence of tumour recurrence and satisfactory tolerance of treatment first course of supporting intravesical therapy with said medicinal composition is carried out once monthly with 12 month duration. When first course is completed, 1-month break is made. In case of absence of tumour recurrence and satisfactory tolerance of treatment second course of supporting intravesical therapy is carried out once monthly with 12 month duration.

EFFECT: method provides increase of recurrence-free period duration and improvement of patients' life quality with reduction of treatment toxicity and reduction of complications of performed drug therapy.

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Description

The invention relates to medicine, in particular to oncology, namely to oncourology, and can be used in the complex endourethral treatment of muscular non-invasive (Ta, T1, Tis) forms of bladder cancer (RMP), including a high risk of progression, and in the prevention of relapse after transurethral removal of tumors. The method can be used both in a hospital and in outpatient treatment.

Currently, the main method of treating patients with muscularly non-invasive bladder cancer (synonyms - non-muscularly invasive bladder cancer, superficial bladder cancer, bladder cancer without invasion of the muscle layer) is surgical treatment in the amount of transurethral resection (TUR).

Unfortunately, the results of only surgical treatment do not satisfy urologists: the frequency of relapses after transurethral resection (TUR) is extremely high and averages 80% [1, 2, 11]. In 20% of patients with non-invasive muscle cancer of the bladder (RMP), over time, there is a progression of the underlying disease, i.e. the appearance of invasive growth and / or an increase in the degree of tumor malignancy [1, 2, 11]. According to modern concepts, the treatment of muscle-non-invasive RMP consists of the steps of removing the tumor, preventing relapse and preventing the progression of the tumor [1, 3, 10, 12].

A known method of intravesical chemotherapy of muscle-non-invasive RMP in the adjuvant (postoperative) mode, when after transurethral removal of the tumor (TUR), antitumor chemotherapy drugs are introduced into the bladder [1]. Intravesical chemotherapy reduces the likelihood of relapse by 44%, 39%, 36% and 39% for ThioTEF, adriamycin, mitomycin C and epirubicin, respectively [4].

The disadvantages of this method include, that it does not affect the progression of the tumor process in patients with a high risk of disease progression.

In addition, the presence of damage to the wall of the bladder during transurethral resection is a contraindication for intravesical chemotherapy. And in the presence of extra-abdominal perforation of the bladder wall and extravasation of the drug (penetration into the general bloodstream), severe toxic reactions occur [5].

In the works of J. L. Au et al., 2001 [6], it was proved that the acidity of urine directly affects the stability of a chemotherapy drug, its absorption by cells, and also the penetration depth. In addition, the ideal chemotherapy drug for intravesical therapy should be lipophilic, easily penetrate urothelium and not enter the systemic circulation. However, most chemotherapeutic agents used are hydrophilic compounds.

The disadvantages of this method include the high cost of drugs.

A known method proposed in 1976 by A. Morales et al. [7], including the intravesical administration of BCG vaccine in a single dose of 100-120 mg once a week. The course of immunization consists of 6 weekly intravesical instillations and maintenance immunotherapy 100-120 mg once every 3 months up to 2 years.

Controlled comparative studies have demonstrated the superiority of intravesical BCG therapy over the administration of chemotherapy (thioTEF, or doxorubicin, or mitomycin C) [4]. Nine randomized trials [4] proved that complete tumor regression occurs in 51.0% of patients who received intraperitoneal chemotherapy with doxorubicin, and 68.1% of patients who received instillation of BCG vaccine.

However, despite the high antitumor efficacy, this method has disadvantages.

The disadvantages of this method include: severe dysuric phenomena and cystitis, the appearance of which is observed in 80% of patients; macrohematuria, which is observed in 40% of patients [1, 8], and as a result - the patient’s serious general condition, the impossibility of repeated courses of intravesical immunotherapy more often than after 3-4 weeks, hence the decrease in the effectiveness of treatment. Complications of this method of intravesical BCG therapy occur after 2-3 injections of the vaccine and begin 2-3 hours after instillation, last for 1-2 days and require additional treatment, and in some cases hospitalization of the patient. With an increase in the number of instillations, the severity of side effects increases. The appearance of macrohematuria increases the risk of BCG vaccine entering the general bloodstream, which leads to the development of systemic lesions. In 20% of patients, as a result of severe dysuria that does not pass by the time of the next instillation, treatment is interrupted or delayed. After treatment for urinary infection, BCG therapy can be continued, but with a dose reduction of 30%. With severe cystitis lasting more than 10 days, treatment is discontinued, fluoroquinolones are prescribed for 3-6 weeks; steroid hormones may be prescribed if symptoms persist for more than 2 weeks. 3-5% have local complications in the form of symptomatic granulomatous cystitis, prostatitis, epididymitis. In 40% of patients, the temperature of the body rises to 38.5 ° C on the day of instillation. It is proved that the most common complications of BCG therapy occur in elderly patients, and therefore maintenance therapy in this category of patients is carried out with limitations. Some complexity of the known method is the need for long-term retention of BCG vaccine in the lumen of the bladder, for 2 hours.

The closest analogue adopted for the prototype is a method of postoperative treatment of muscle-non-invasive bladder cancer ([9], patent RU 2443423, op. 27.02.2012), which includes adjuvant intravesical chemotherapy after transurethral resection of the bladder (TUR), previously diluted in an aqueous solution of Tolis. The essence of the method consists in instillations of a drug composition of: 40% aqueous solution of Tizol and a chemotherapeutic drug (doxorubicin 50 mg or mitomycin 40 mg) through a catheter installed in the bladder in patients with low-invasive muscular-non-invasive RMP (Ta, G1, primary, single, size <3 cm) and intermediate (Ta, T1, G1, G2, ≤1 relapse per year, the number of tumors from 2 to 7, size <3 cm), the risk of relapse and progression, in the following mode: a single instillation of a chemotherapy drug - cytostatic immediately immediately after surgical treatment of TUR conductive 6-week course of administration of chemotherapy with the frequency - 1 weekly.

However, this method has limitations. Despite the fact that the method increases the tolerance of antitumor chemotherapy drugs, the clinical efficacy of the method is specific only in patients with a low and intermediate risk of relapse (more favorable clinical forms of muscle-non-invasive RMP) and does not prevent the progression of a bladder tumor in patients with a high risk of progression (T1, G3 , multiple more than 8, ≥3 cm in size, often recurring tumors) and carcinoma in situ.

The disadvantages of the known prototype include the long retention time of the anticancer chemotherapy solution inside the bladder cavity - at least one hour, which causes significant discomfort in the patient, especially immediately after surgery. In the first hours, the patient has the problem of retaining urine with an antitumor drug in the bladder cavity as a result of postoperative pain, massive fluid perfusion by the kidneys and forced urine flow into the bladder.

A significant disadvantage of the prototype is the use of standard surgical treatment in patients with muscularly non-invasive (superficial) forms of bladder cancer - transurethral resection (TUR) of the bladder in monopolar mode, which is widely used in clinical practice in the Russian Federation. The disadvantages of monopolar surgery include: deep thermal damage to tissues, which makes it difficult to use this method in patients with a tumor of the bladder close to the mouth of the ureter or in the projection of the obturator nerve; the impossibility of using this method in patients with a pacemaker; with large tumors, which is associated with a limited time for the operation, due to the high risk of developing TUR syndrome.

These shortcomings reduce the effectiveness of the treatment of non-invasive muscle cancer of the bladder.

The problem to which the invention is directed is to increase the effectiveness of treatment of bladder cancer, reduce the toxicity of treatment, reduce the number of complications of drug therapy, reduce the frequency of recurrence and progression of bladder cancer, decrease the retention time of an antitumor drug in the bladder cavity without changing a single dose of the antitumor the drug, an increase in the duration of the relapse-free period and life expectancy, as well as improving the quality of life Know the patients.

To solve the problem in a method of complex endourethral treatment and prophylaxis of relapse of muscle-non-invasive forms of bladder cancer, including transurethral resection of a bladder tumor and subsequent intravesical therapy with an antitumor drug with addition of Tolys, according to the invention, a bipolar transurethral resection of the tumor in the physiological tumor is performed 0.9% NaCl), then on the 25-30th day, once a week, a 1.5-2-month induction course of intravesical immunotherapy with a drug composition containing the BCG vaccine Imuron vaccine and Tizol gel, and then 1 month after the induction course, in the absence of a relapse of the bladder tumor and satisfactory tolerance of treatment, the first course of maintenance intravesical therapy with the specified drug composition is carried out once a month for 12 months, at the end of a break for 1 month, then in the absence of relapse of a tumor of the bladder and satisfactory treatment tolerance, a second course of maintenance intravesical therapy with the indicated drug composition is carried out once a month for a period of 12 months, while the drug composition is prepared immediately before administration to the bladder by mechanical stirring of BCG Imuron vaccine 100-120 mg and Tizol gel 10 g in physiological saline 50 ml (0 , 9% NaCl) and the exposure time of the drug composition in the bladder is 30 minutes.

The BCG vaccine Imuron is used as an antitumor drug.

Distinctive techniques of the proposed method are that intravesical drug therapy is carried out after endourethral surgical treatment - bipolar transurethral resection of the bladder in physiological saline (0.9% NaCl). The fundamental difference between bipolar and monopolar electrical exposure is that the current does not pass through the patient’s entire body, but is limited by the distance between the electrodes (active and passive).

Bipolar transurethral resection of a bladder tumor in physiological saline (0.9% NaCl) does not cause deep thermal damage to tissues, therefore it can be used in patients with a bladder tumor located close to the mouth of the ureter and in the projection of the obturator nerve, with large tumors, as well as in patients with a pacemaker. In addition, bipolar transurethral resection of a bladder tumor in physiological saline does not cause the development of TUR syndrome. The distinctive advantages of bipolar transurethral resection of muscularly non-invasive RMP in physiological saline over monopolar transurethral resection are the reduction in the duration of surgery and the provision of better intraoperative hemostasis. The use of bipolar resection in physiological saline increases the radicalness of endourethral surgical treatment of muscularly non-invasive RMP.

Another distinguishing feature of the proposed method is that with intravesical drug therapy, a more effective antitumor drug is used - BCG vaccine Imuron. The BCG vaccine is a suspension of viable Calmette-Guerin bacilli, propagating intracellularly, they stimulate local immunity in which macrophages, T-lymphocytes and cytokines are involved. Despite the fact that the mechanism of the antitumor effect of the vaccine has not been fully studied, it has been proved that intravesical BCG therapy is most effective for superficial bladder tumors with a rather high risk of recurrence and progression compared with intravesical chemotherapy. BCG therapy after transurethral surgeries has a proper therapeutic effect in relation to muscular-non-invasive forms of RMP. BCG therapy has advantages over chemotherapy, as it reduces the rate of progression, which is explained by a deeper course of the inflammatory reaction to the introduction of an immunotherapy.

Unlike the prototype, the inventive method can be used in the treatment of carcinoma in situ, as well as an alternative to antitumor treatment of bladder cancer in patients poorly tolerating intravesical chemotherapy.

The combination of Imuron BCG vaccine and Tizol gel with intravesical adjuvant treatment of muscle-non-invasive bladder cancer reduces the rate of tumor recurrence in patients with a low, intermediate and high risk of relapse, and reduces the toxicity of the BCG Imuron vaccine. The bioadhesive properties of Tizol gel reduce the retention time of the BCG Imuron vaccine in the bladder cavity by up to 30 minutes, which helps to reduce the risk of severe general toxic and local complications without reducing the high antitumor efficacy of the vaccine. Thus, the claimed method is one of the possible ways to overcome the toxicity of intravesical immunotherapy with BCG vaccine Imuron without reducing a single dose of the main antitumor drug.

The Tizol gel used in the method is used as the main component by weight. Tizol gel, mixed with the main action antitumor drug - BCG Imuron vaccine, enhances its binding to the mucous membrane of the bladder, potentiates its permeability into the bladder wall to develop a local immune response, reduces the retention time of BCG vaccine Imuron in the bladder cavity, reduces the frequency of general toxic and local complications and improves the quality of life of patients. BCG vaccine and Tizol gel are biocompatible, which allows you to enter them into the bladder cavity together and is more effective than monotherapy with BCG vaccine.

The use of the bipolar transurethral resection of a muscle-non-invasive bladder tumor in physiological saline in the inventive method as compared with monopolar TUR helps to reduce: the duration of surgery, the frequency of surgical complications, the duration of postoperative catheterization of the bladder and the number of hospital days.

Technical and methodological aspects of the use of bipolar transurethral resection of muscularly non-invasive RMP in physiological saline as compared with monopolar TUR allow to achieve greater reliability and safety of endourethral surgery in most patients, increase the radicalness of surgical treatment: reduce the frequency of relapse, increase the duration of the relapse-free period and five-year survival.

The inventive method differs from the prototype also in that intravesical drug therapy is carried out on 25-30 days after surgery. During this period of time, the patient in the postoperative wound appears granulation shaft, preventing the massive entry of the drug into the blood. There is no macrohematuria. Conducting intravesical drug therapy for 25-30 days reduces the frequency of complications and helps to improve the quality of life of patients with bladder cancer.

The proposed scheme for carrying out intravesical immunotherapy with BCG vaccine Imuron with the addition of Toliz, in which on the 25-30th day a 1.5-2-month induction course of intravesical immunotherapy with the specified drug composition is carried out once a week and then 1 month after the induction course in the absence of recurrence of a bladder tumor and satisfactory tolerance of treatment, supportive intravesical therapy is carried out from two courses of the indicated medicinal composition odnra By taking monthly periods of 12 months each, with a 1-month interval between courses, preserving the exposure time of the drug composition in the bladder for 30 minutes, it is possible to reduce the retention time of BCG Imuron vaccine in the bladder cavity (from 2 hours to 30 minutes), which helps to reduce the risk of developing severe toxic and local complications without compromising the high antitumor efficacy of the vaccine; reducing the frequency of recurrence and progression of non-invasive muscle cancer of the bladder increases the disease-free survival and the duration of the disease-free period, and also improves the quality of life of patients.

In the scientific medical and patent literature analyzed by the authors, the set of essential features claimed in the invention was not found, therefore, the invention meets the “novelty” criterion.

During the search, no solutions were found that have features that match the distinguishing features of the claimed invention, these distinctive features for the specialist do not explicitly follow from the prior art, therefore, the claimed invention has the criterion of "inventive step"

This method has passed clinical trials at the SBEI HPE Irkutsk State Medical University and the SBEI IGMAPO of the Ministry of Health of Russia, Irkutsk. The invention "A method for the complex treatment and prevention of relapse of muscle-non-invasive forms of bladder cancer" is industrially applicable, as it can be used in healthcare, cancer research institutes, cancer dispensaries and other medical institutions involved in the treatment of bladder cancer.

Thus, this technical solution meets the criteria of the invention of "novelty", "inventive step" and "industrial applicability".

The method is as follows.

An operation is performed - bipolar transurethral resection (TURis) of a bladder tumor in physiological saline (0.9% NaCl) under spinal anesthesia using an OLYMPUS VES-40 Surg generator. Master The final stage of the oncological process is determined on the basis of the morphological study of the surgical material. On the 25-30th day in the conditions of a medical institution that complies with the sanitary and epidemiological rules of SP 3.3.2.1120-02, an intravesical immunotherapy is carried out with a drug composition containing an antitumor drug - BCG vaccine Imuron 100-120 g, Tizol gel 10 g, diluted in 50 ml of physiological saline (0.9% NaCl). During the procedure, under aseptic conditions, the bladder is catheterized with a thin Nelaton urethral catheter with a diameter of 12 Fr., freed from the urine and washed twice with physiological saline (0.9% NaCl) in order to maximize the removal of urine electrolytes and to control the absence of blood impurities in the wash fluid. After that, the BCG vaccine Imuron (100-120 mg), Tizol gel (10 g) and 50 ml of physiological saline (0.9% NaCl) are mixed in a disposable syringe. The finished drug composition in the form of a suspension after mechanical stirring is introduced through a catheter into the bladder. The drug composition is held in the bladder for 30 minutes. The patient is offered to change the position of the body for uniform contact of the vaccine with the walls of the bladder. After 30 minutes, the bladder is emptied into a container containing at least 500 ml of a disinfectant solution (5% chloramine). The recommended single dose of BCG Imuron vaccine is 100-120 mg. The introduction of the medicinal composition is carried out 1 time per week for 1.5-2 months. The total dose of BCG vaccine Imuron is 600-720 mg ÷ 800-960 mg. 4 weeks after the end of the main (induction) 1.5-2-month course, control fibrourethrocystoscopy is performed. Patients with no recurrence of a bladder tumor and satisfactory tolerance of treatment are transferred to maintenance therapy, consisting of two courses. The first course of maintenance therapy is that after 1 month break after the main (induction) course of immunotherapy, the drug composition of the BCG vaccine Imuron (120 mg) and Tizol gel (10 g), diluted in 50 ml of physiological saline (0.9) % NaCl) once a month for 12 months. At the end of the first course of maintenance therapy, a break is taken for 1 month and all patients undergo a follow-up examination, including: ultrasound examination of the kidneys, bladder; endoscopic examination of the bladder in order to determine the state of the walls of the organ and upper urinary tract. A biopsy is taken from the sites of focal hyperemia in the bladder. All patients undergo a cytological examination of urine. Patients with no recurrence of a bladder tumor and satisfactory tolerance of treatment are transferred to the second course of maintenance therapy. The second course of maintenance therapy with the indicated drug composition: BCG vaccine Imuron (120 mg) and Tizol gel (10 g) diluted with saline (50 ml) once a month for 12 months. A follow-up examination is carried out after the end of the course of treatment and every 3 months for 2 years, in the absence of relapse of a bladder tumor - annually.

The authors conducted clinical studies.

Example 1. In the period from 2004 to 2010 The study included 120 patients with muscular-non-invasive RMP who were being examined and treated at the Regional Oncology Center. Of these, 82 men and 38 women aged 41 to 82 years (average age was 56.6 ± 1.0). The criteria for selecting patients for the study were the presence of a histologically verified muscle-non-invasive transitional cell-mediated RMP with unfavorable (category T1, low differentiation - G3, multiple, often recurring tumors, cancer in situ) and intermediate (category Ta, high - G1 or medium - G2 degree of differentiation, multiple recurrent tumors with a diameter> 3 cm) prognosis, the absence of ureterohydronephrosis, distant or regional metastases, as well as informed consent of the patient in the treatment participation and participation in the study. Before inclusion in the protocol, patients underwent a standard examination. After performing a bipolar transurethral resection of a bladder tumor in physiological saline (TURis) under spinal anesthesia and obtaining a histological conclusion on the absence of muscle invasion and compliance with the inclusion criteria, randomization was performed. Patients were divided into 2 groups: the first control group (n = 60) - in which adjuvant intravesical drug therapy was used as instillations of a chemotherapeutic composition (doxorubicin 50 mg or mitomycin C 40 mg) and a 40% Tizol aqueous solution through a catheter placed in the bladder , within an hour after surgery, and the second main group (n = 60) - on the 30th day after TURis a 1.5-month induction course of intravesical instillations of the drug composition was prescribed - BCG vaccine Imuron 120 mg and Tizol gel 10 g in 50 ml physiological solution (0.9% NaCl) once a week.

Control examination of patients was carried out 3 months after surgery, then every 3 months during the first 2 years of observation, then every 6 months. During the follow-up examination, urine cytology, diagnostic urethrocystoscopy, ultrasound, chest x-ray, skeleton bone scintigraphy were performed to detect relapse and distant metastases. In case of recurrence and progression of the disease, appropriate treatment was carried out according to indications. Relapse that occurred during the first year of observation was recognized as early.

Patients with no recurrence of a bladder tumor and satisfactory tolerance of intravesical immunotherapy were transferred to the first course of maintenance therapy. The first course of maintenance therapy was that after 1 month break after the main (induction) course of immunotherapy, the drug composition of the BCG vaccine Imuron (120 mg) and Tizol gel (10 g) diluted in 50 ml of physiological saline (0.9 % NaCl) once a month for 12 months. At the end of the first course of maintenance therapy and a break for 1 month, the patients underwent a control examination. Patients with no recurrence of a bladder tumor and satisfactory tolerance of treatment were transferred to the second course of maintenance therapy. The second course of maintenance therapy with the indicated medicinal composition: BCG vaccine Imuron (120 mg) and Tizol gel (10 g) diluted with saline (50 ml) was administered 1 time per month for 12 months. A follow-up examination was carried out after completion of the course of treatment and every 3 months for the next 2 years, in the absence of relapse of a bladder tumor - annually.

The median follow-up for the entire cohort of patients was 30.9 months. During this period, relapses were detected in 26 (43.3%) patients in the first, in 8 (13.3%) - in the second group.

When assessing survival in the second group, the three-year disease-free survival was higher (78.5 ± 6.8%) than in the first (62.6 ± 6.3%), the differences were recognized as statistically insignificant (Dks = 0.43; p- value = 0.999), λ _emp = 0.43 <1.36 = λ _cr .

Progression was observed in 11 (9.7%) patients: in 9 (15.0%) in the first group and in 2 (7.0%) from the second group. There were no significant differences in survival before progression in the groups (p-value = 0.83). A full course of treatment was completed by 44 (73.3%) patients of the first group and 57 (95%) of the second group. The course of treatment was interrupted due to complications in 16 (26.6%) patients in the first group, in 3 (5.0%) patients in the second.

Of the systemic side effects, 2 cases of an allergic reaction in the first group were recorded. Hyperthermia> 38.5 ° C was observed in 5 (8.3%) patients of the first group and in 1 (1.7%) - of the second group. The development of pulmonary complications in the form of BCG pneumonitis was recorded in 1 (1.7%) patient in the second group. In this case, the appointment of long-term anti-TB therapy was required.

Among the local toxic manifestations of intravesical therapy, dysuric phenomena were noted in 11 (18.3%) patients of the first group and in 2 (3.3%) patients from the second group. Hematuria developed in 5 (8.3%) and 1 (1.7%) patients of the first and second groups, respectively. A comparison of the number of complications in the groups, taking into account the degree of toxicity and the total number of complications, showed statistically significant differences between the groups (p-value = 0.011 and p-value = 0.045, respectively). Comparison of the frequency of complications in the study groups showed that in the group using the drug composition: BCG vaccine + Tizol gel, fewer complications were observed, and this difference was statistically significant (p-value = 0.024). In addition, there was a statistically significant difference in the frequency of complications of the II-III degree of toxicity in favor of the second group compared with chemotherapy in combination with Tizol (p-value = 0.013).

Findings. Thus, the studies demonstrated that the main clinical advantages of intravesical adjuvant immunotherapy with the drug composition of BCG vaccine (Imuron) and Tizol gel used in the endourethral treatment of patients with muscle-non-invasive RMP over adjuvant intravesical drug chemotherapy for the majority of patients are: manifestations; a decrease in the rate of recurrence and progression of muscle-non-invasive bladder cancer, as well as an increase in three-year relapse-free survival.

Example 2. In the period from 2004 to 2011 The study included 95 patients who received treatment for transitional-cell muscle-non-invasive RMP: TaN0M0 - in 48 (50.5%), T1N0M0 - in 42 (44.2%) on the basis of the Regional Oncological Dispensary GBUZ g. Irkutsk The degree of G1 tumor differentiation was diagnosed in 18 (18.9%), G2 in 30 (31.6%), and G3 in 46 (48.4%) patients. The tumor size of the MP ranged from 3.5 cm to 6.3 cm.

In accordance with the inclusion criteria, randomization was performed, patients were divided into 2 groups. In group A (n = 45), patients received our proposed new method of immunotherapy with a combination of BCG vaccine and Tizol gel. On the 25-30th day after a bipolar transurethral resection (TURis) in physiological saline (0.9% NaCl) for muscular-non-invasive RMP (OLYMPUS VES-40 Surg. Master generator), intravesical immunotherapy was performed with a drug composition containing an antitumor drug - BCG vaccine Imuron 100-120 g, Tizol gel 10 g, diluted in 50 ml of physiological saline (0.9% NaCl). During the procedure, under aseptic conditions, the bladder was catheterized with a thin Nelaton urethral catheter with a diameter of 12 Fr., freed from the urine and washed twice with physiological saline (0.9% NaCl) in order to maximize the removal of urine electrolytes and to control the absence of blood impurities in the wash fluid. After that, the BCG vaccine Imuron (100-120 mg), Tizol gel (10 g) and 50 ml of physiological saline (0.9% NaCl) were mixed in a disposable syringe. The finished drug composition in the form of a suspension after mechanical stirring was introduced via a catheter into the bladder. The drug composition was suggested that the patient be kept in the cavity of the bladder for 30 minutes. For uniform contact of the vaccine with the walls of the bladder, the patient was asked to change the position of the body. After 30 minutes, the bladder was suggested to be emptied into a container containing at least 500 ml of a disinfectant solution (5% chloramine). The recommended single dose of BCG Imuron vaccine is 100-120 mg. The introduction of the medicinal composition is carried out 1 time per week for 1.5-2 months. The total dose of BCG Imuron vaccine was 600-720 mg ÷ 800-960 mg. 4 weeks after the end of the main (induction) 1.5-2-month course, control fibrourethrocystoscopy was performed. Patients with no bladder tumor recurrence and satisfactory tolerance of treatment were transferred to two-course maintenance therapy. The first course of maintenance therapy is that after 1 month break after the main (induction) course of immunotherapy, the drug composition of the BCG vaccine Imuron (120 mg) and Tizol gel (10 g) diluted in 50 ml of physiological saline (0.9 % NaCl) once a month for 12 months. At the end of the first course of maintenance therapy and a break for 1 month, the patients underwent a follow-up examination, including: ultrasound examination of the kidneys, bladder; endoscopic examination of the bladder in order to determine the state of the walls of the organ and upper urinary tract. A biopsy was taken from the sites of focal hyperemia in the bladder to exclude relapse. Patients with no recurrence of a bladder tumor and satisfactory tolerance of treatment are transferred to the second course of maintenance therapy. The second course of maintenance therapy with the indicated medicinal composition: BCG vaccine Imuron (120 mg) and Tizol gel (10 g) diluted with saline (50 ml) once a month for 12 months. A follow-up examination was carried out after completion of the course of treatment and every 3 months for 2 years, in the absence of a relapse of a bladder tumor - annually.

After a bipolar transurethral resection on days 25-30, patients from group B (n = 50) were given a standard 6-week induction course of intravesical instillations of 120 mg BCG vaccine (once a week) and a maintenance course: 12 intravesical instillations of BCG vaccine (120 mg ) 1 time per month with an interval of 4 weeks and then, after the next control examination, the following 12 instillations of 120 mg of BCG vaccine 1 time per month. The retention time of the vaccine in the MP cavity was 2 hours.

The age of 95 patients included in the study, including 59 (62.1%) men and 36 (37.9%) women, is represented by the following summary statistics: average 58.7; fashion many .; at least 40; 1st quartile 52 years old; median 60; 3-quartile 66; maximum 79 [95% (CI) 56.9-60.6].

The median follow-up was 36.8 months. A full course of treatment was completed by 44 (97.8%) patients from group A and 31 (62.0%) from group B.

The immediate and long-term results of treatment of patients with muscle-non-invasive RMP in the study groups using various adjuvant intravesical immunotherapy BCG vaccine methods were analyzed by comparing the frequency and nature of local and systemic side effects, treatment tolerance, the effect of instillations on the frequency of recurrence and progression of RMP, as well as 3 -year survival (general, adjusted, relapse-free and relapse-free adjusted).

Hematuria occurred much less frequently in group A - in 4 (8.9%) cases, in group B - in 16 (32.0%) cases. Comparison of the incidence of hematuria in the studied groups showed statistically significant differences between the groups (p (χ ² ) = 0.00001).

Systemic side effects of adjuvant intravesical immunotherapy with BCG vaccine in our study were much less common than local ones. After immunotherapy with BCG vaccine, we registered 57 different systemic complications in 38 (40.0%) patients, of which 15 (33.3%) patients from group A and 23 (46.0%) from group B (p ( χ ² ) = 0,0004).

Allergic reactions in the form of a skin rash were noted in 2 (2.1%) cases after the second and third instillations of BCG vaccine, which required the temporary administration of H ₂ histamine blockers. All allergic reactions arose in clinical comparison group B (4.0%).

The combination of BCG vaccine and Tizol gel showed a statistically significantly lower toxicity compared to monotherapy with BCG vaccine with respect to the incidence of local urogenital (group A - 28.9% and group B - 82.0%, p = 0.0012) and systemic complications (group A - 42.2% and group B - 76.0%, p = 0.042).

Criterion χ ² confirmed a statistically significant decrease in the frequency of recurrence (group A - 15.6% and group B - 42.0%, p = 0.0001) and progression of RMP (group A - not registered and group B -10.0%, p = 0.0023) when using BCG vaccine and Tizol gel compared with monotherapy with BCG vaccine.

Analysis of the effectiveness of the new method of adjuvant intravesical immunotherapy with BCG vaccine (Imuron) and Tizol gel provides a statistically significant improvement of 27.8% relapse-free (p _Log-Rank = 0.00759) and 26.2% - relapse-free adjusted (p _Log-Rank = 0.03420) survival (Figure 1 and 2). The most pronounced statistically significant tendency to improve 3-year survival (relapse-free and relapse-free corrected) is observed in muscle-non-invasive tumors with an invasion depth of T1N0M0 and a differentiation degree of G3: group A - 72.7% and group B - 20.0% (p _{Log -Rank} = 0.00644).

Thus, the use in the complex treatment of 45 patients with muscle-non-invasive RMP of intermediate and high risk of recurrence and progression of a new technique of adjuvant intravesical drug therapy with BCG vaccine (Imuron) and the titanium glycerol solvate complex - Tizol gel allowed us to achieve a statistically significant (p (χ ² ) = 0 , 0012) a 2.8-fold decrease in the rate of local complications (28.9%) compared with clinical comparison group B (82.0%), where a standard course of intravesical instillations of 120 mg BCG vaccine was used (They ron).

The administration of BCG vaccine (Imuron) and Tizol gel as adjuvant drug therapy resulted in a 2.7-fold decrease in the recurrence rate of muscle-non-invasive RMP by 2.7 times compared with the traditional method of BCG vaccine immunotherapy (group A - 15.6% and group B - 42.0%, p (χ ² ) = 0.0001).

The introduction into clinical practice of a new method of intravesical drug immunotherapy in combination with BCG vaccine and Tizol gel had a significant impact on the rate of relapse-free and relapse-free corrected 3-year survival probability of muscular-non-invasive RMP (Ta, T1).

An analysis of the effectiveness of the new method of adjuvant intravesical immunotherapy with BCG vaccine (Imuron) and Tizol gel, carried out in comparison with the results of using the traditional method of immunotherapy with BCG vaccine, revealed the following advantages of the method in a long three-year follow-up period:

- a statistically significant improvement of 27.8% relapse-free (group A - 77.8%, group B - 50.0%, p _Log-Rank = 0.00759) and 26.2% - relapse-free adjusted (group A - 82 , 2%, group B - 56.0%, p _Log-Rank = 0.03420) three-year survival;

- the most pronounced statistically significant tendency to improve 3-year survival (relapse-free and relapse-free adjusted) was observed in muscle-non-invasive tumors with a depth of invasion T1N0M0 and a degree of differentiation G3. This trend is observed throughout the entire period of dynamic observation, starting from the first year after completion of treatment.

Findings. Thus, the studies demonstrated that the main clinical advantages of intravesical adjuvant immunotherapy with the drug composition of BCG vaccine (Imuron) and Tizol gel used in the endourethral treatment of patients with muscle-non-invasive RMP over adjuvant intravesical drug chemotherapy for the majority of patients are: manifestations; a decrease in the rate of recurrence and progression of muscle-non-invasive bladder cancer, as well as an increase in three-year relapse-free survival.

The inventive method of complex endourethral treatment and prevention of relapse of non-invasive muscle cancer of the bladder allows you to obtain a significant clinical effect by conducting intensive treatment, achieving the maximum positive result with a minimum of complications, and the rate of recurrence and progression of bladder cancer in patients with low, intermediate and high risk of relapse, the toxicity of BCG Imuron vaccine is reduced.

The bioadhesive properties of Tizol gel reduce the retention time of the BCG Imuron vaccine in the bladder cavity to 30 minutes, which helps to reduce the risk of severe toxic complications without reducing the high antitumor efficacy of the vaccine.

The inventive method is one of the possible ways to overcome the toxicity of intravesical immunotherapy with BCG vaccine Imuron without reducing a single dose of the main antitumor drug.

A new not obvious effect of the application of the method is the absence of dysuric disorders and pain.

The method can be used in the treatment of patients with a high risk of progression of bladder cancer (T1, G3, multiple, often recurring tumors) and carcinoma in situ.

The method is an alternative to antitumor treatment of bladder cancer in patients poorly tolerating intravesical chemotherapy and having contraindications for radical cystectomy.

Thus, the achieved technical result of the proposed method is to reduce the duration of surgical intervention and provide better intraoperative hemostasis, reduce the number of postoperative complications, reduce the duration of the drainage of the bladder cavity with an urethral catheter and the number of days a patient spent on treatment in a hospital, reduce the retention time of an antitumor drug in the cavity of the bladder, which reduces the risk of developing severe toxic slozhneny without changing the high antitumor efficacy of BCG vaccine Imuron, decreasing the frequency and progression retsidirovaniya musculo-non-invasive bladder cancer, increasing the duration of disease-free interval and survival of three years, and also improves the quality of life of patients.

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Claims (1)

A method for complex endourethral treatment and prevention of relapse of muscularly non-invasive forms of bladder cancer, including transurethral resection of a bladder tumor, subsequent intravesical therapy with an antitumor drug with the addition of Toliz, characterized in that bipolar transurethral resection of a bladder tumor is performed in physiological bladder 0 (physiological bladder 0.9 % NaCl), then on the 25-30th day, once a week, they conduct a 1.5-2-month induction course of intravesical immunotherapy with a drug com with a dose containing an antitumor drug - BCG Imuron vaccine and Tizol gel, and then after 1 month break after an induction course in the absence of a relapse of a bladder tumor and satisfactory tolerance of treatment, the first course of maintenance intravesical therapy with the specified drug composition is carried out once a month for a period of 12 months, after which they do a break for 1 month, then in the absence of relapse of a bladder tumor and satisfactory tolerance of treatment, a second a maintenance course of intravesical therapy with the specified drug composition once a month for a period of 12 months, while the drug composition is prepared immediately before administration to the bladder by mechanical stirring of BCG vaccine Imuron 100-120 mg and Tizol gel 10 g in saline 50 ml (0.9% NaCl) and the exposure time of the drug composition in the bladder is 30 minutes.