RU2581946C2 - Method of treating bladder cancer - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology, and can be used for treating bladder cancer. For this purpose, at first day after transurethral resection of bladder intracystic introduction of 2,000 mg of gemcitabine dissolved in 50 ml of physiologic saline with concentration of 40 mg/ml is performed. Simultaneously exposed to projection of bladder scanning magnetic field with induction of 10 mTl, with signal frequency from 1 to 150 Hz, varying at rate of 1 Hz/s, exposure of 10 minutes, combined with constant magnetic field of 20 mTl. After completion of exposure to magnetic field exposure to magnetized chemopreparation solution is continued in patient lying on right side for 15 minutes, on his/her left side of 15 minutes, on stomach for 15 minutes, on back for 5 minutes. Complete exposure of chemopreparation is 60 minutes. Therapeutic course makes six procedures with one procedure a week.

EFFECT: method provides evident prolonged prevention effect as result of higher bioavailability of gemcitambine with exposure to magnetic field.

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Description

The invention relates to medicine, more specifically to oncology, and can be used in the treatment of bladder cancer.

According to the majority of foreign authors, 70-80% (in Russia - 30-50%) of newly diagnosed patients with bladder cancer (RMP) have no tumor invasion into the muscle layer (CIS, Ta, T1). Transurethral resection (TUR) is the first stage of treatment for RMP, but isolated TUR has low efficiency and the relapse rate is from 50% to 90%.

Currently, adjuvant intravesical chemotherapy has become widespread (A.K. Nosov, A.V. Vorobyov. Adjuvant therapy in oncology. Practical oncology. T. 8, No. 3, 2007. P. 140-146). One of the promising drugs for intravesical therapy for RMP is gemcitabine. This is an antitumor drug from the group of antimetabolites. According to studies with systemic use of gemcitabine in the bladder, it has the necessary effect, causing the death of tumor cells, and is characterized by a moderate level of toxicity to bladder tissue, with intravesical administration, its effectiveness and toxicity are similar to the level of effectiveness of BCG therapy (I.V. Seregin, V. M. Samoilenko. Gemcitabine in the treatment of bladder cancer without invasion of the muscular membrane. Bulletin of the Russian N. Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences, vol. 20, No. 4, 2009. P. 15-18). However, the use of gemcitabine does not solve the problem of preventing recurrence, and this urgent issue needs further development.

With all the variety of approaches to increasing the contact interaction of cytostatics with a tumor, the most popular modifier is local electromagnetic high-frequency (HF) hyperthermia. Special devices and treatment methods have been developed that allow for rapid and uniform heating of the malignant neoplasm to a critical temperature in order to increase the effectiveness of treatment due to more complete damage to cancer cells, reduce the risk of metastasis and relapse, and reduce the dose of chemotherapeutic exposure. This method, as a rule, involves several stages: local anesthesia, invasion of a conductive fluid, implantation of several electrodes, each group of which is supplied with RF energy, heating the neoplasm to 49 ° C (patent application RU 95101431/14, publ. 27.11.1996 A device for the treatment of malignant neoplasms and a method of treatment).

Indeed, this approach is justified in the treatment of locally advanced tumors of parenchymal organs, when surgical intervention is unacceptable. The method ensures the achievement of remission in severe cancer patients with stage 3-4 of the disease (patent application RU 95107493/14, publ. 08/27/1996, a Method for the treatment of tumors of parenchymal organs). The undoubted advantage of the method is the achievement of an equally effective effect of the chemotherapy drug not only on the tumor tissue, but also on the vascular walls, which reduces the likelihood of relapse. However, the complex structure and multi-stage method, the introduction of mechanical elements (catheters, iron particles, electrodes), heating are factors that cause pain and are not always easily tolerated by patients, especially in a weakened state.

With regard to bladder tumors, it is known that combining heating with high-frequency waves and an intravesical installation of a chemotherapy provides significant advantages over conventional adjuvant intravesical chemotherapy, preventing or reducing the risk of relapse or disease progression. So, there is a method of treating superficial malignant tumors of the bladder (patent RU No. 2422168, publ. 27.06.11, bull. No. 18). This method aims to selectively increase the heat sensitivity of the tumor. In this regard, conditions are created for heating the tissues of the bladder and a solution of a chemotherapy drug introduced into the bladder. Upon reaching a temperature of 40-43 ° C and maintaining it for an hour, the permeability of the tissues of the bladder for chemotherapy improves, the possibility of uniform heating of the tumor is provided, side effects and complications are reduced. At the same time, the technology requires a number of manipulations: installation of electrodes on the surface of the body in different places - sources of high-frequency waves, insertion of a main catheter into the bladder to administer the drug and an additional catheter with a temperature sensor that records and controls the temperature.

The development of chemotherapeutic approaches in combination with heating the tumor with rf waves substantially justifies its purpose, however, the situation with respect to blood flow in the bladder tumor, perifocal zone and healthy tissues is ambiguous, and we can talk about the relative “selectivity” of tumor overheating and the ablasticity of the effect .

The modification of local chemotherapy with non-thermal effects on the tumor is based on the use of electromagnetic coherent radiation of the optical frequency range - laser (patent RU No. 2405601, publ. 10.12.2010, bull. No. 34). Based on the fact that photodynamic therapy (PDT) of tumors in mono-mode does not have sufficient therapeutic activity and often does not relieve patients from relapses, the authors propose using a solution of the chemotherapy drug (CP) Mitomycin C as an optical medium for PDT with systemic administration of photosensitizers. An important role in the mechanism of the antitumor effect is PDT-induced increase in the desmosomal gaps of the tumor tissue, which ensures the transport of CP. The presence of a photosensitizer in tumor cells contributes to the concentration of CP in the tumor, rather than the normal mucosa, and increases the duration of exposure.

At the same time, the use of this method is limited by the possibility of developing phototoxicity, although it involves the use of special creams and glasses. The effectiveness of the very idea of laser exposure through an intravesical liquid optical medium is confirmed by examples of performance in which an annual relapse-free period was noted. However, the involvement of photosensitizers, catheters, fibrocystoscopes, laser fibers in the technology makes the procedure more invasive.

An object of the present invention is to provide a method for reducing the recurrence of bladder cancer by conducting adjuvant intravesical chemotherapy with gemcitabine in combination with non-invasive exposure to scanning and constant magnetic fields.

The technical result of the invention is the achievement of a pronounced prolonged anti-relapse effect in adjuvant intravesical chemotherapy of urothelial cancer.

The technical result is achieved by the fact that on the first day after transurethral resection of the urinary bladder, 2000 mg of gemcitabine dissolved in 50 ml of physiological solution of 40 mg / ml dissolved in 50 ml of physiological solution is administered via a urethral catheter with a 10 mT scanning magnetic field applied to the bladder projection area, signal frequency from 1 to 150 Hz, changing at a speed of 1 Hz / s, exposure time of 10 minutes, in combination with a constant magnetic field of 20 mT, after which the patient the ent independently continues the exposure of the magnetized solution of the chemotherapy drug, lying on the right side for 15 minutes, on the left side 15 minutes, on the stomach 15 minutes, on the back 5 minutes, the time of the full exposure of the chemotherapy drug is 60 minutes, after which the patient independently releases the bladder, all six treatments, one treatment per week.

The authors of the present invention found that a pronounced prolonged anti-relapse effect can be achieved with adjuvant intravesical chemotherapy of urothelial cancer using non-contact exposure to a scanning magnetic field (SC MP) and a constant magnetic field (PMF).

The method is as follows.

On the first day after transurethral resection (TUR) of the urinary bladder, 2000 mg of 40 mg / ml dissolved in 50 ml physiological solution of gemcitabine is injected through a urethral catheter with a 10 mT scanning magnetic field at the same time as the signal from 1 to 150 Hz, changing at a speed of 1 Hz / s, exposure time of 10 minutes, in combination with a constant magnetic field of 20 mT, after which the patient independently continues the exposure th magnetized solution chemotherapy, lying on his right side for 15 minutes, the left side 15 minutes on your stomach 15 minutes to 5 minutes back. The full exposure time of the chemotherapy drug is 60 minutes, after which the patient independently releases the bladder. In total, six procedures are performed, one procedure per week.

The indicated therapeutic result is due to the fact that a scanning magnetic disturbance by induction of 10 mT when changing the frequency from 1 to 150 Hz at a speed of 1 Hz / s in combination with PMF forms a dynamically complex field structure that hyperpolarizes the tumor cell membranes. Such a change in the membrane potential leads to an increase in the permeability of the membranes of tumor cells and, therefore, the bioavailability of the drug, as evidenced by an increase in the luminosity of live tumor cells of a bladder cancer biopsy specimen using the method of fluorescent probes (see Table 1, Fig. 1).

Visualization of the effect of enhancing the fluorescence of tumor cells and statistical indicators of the ratio of brightness without exposure and with effects on tumor cells indicated a 2.4-fold increase in the bioavailability of gemcitabine when exposed to a magnetic field. In experimental samples, it was possible to evaluate this effect also by mass cellular destruction, which was observed during combined exposure.

The invention "A method for the treatment of bladder cancer" is new, as it is unknown from the level of medicine, namely oncourology with electromagnetic influence on the permeability of gemcitabine solution through the membrane of tumor cells. The method is supported by in vitro studies of quantitative indicators of fluorescence of cancer cells obtained by TUR of a bladder tumor after incubation with gemcitabine and exposure to SC MP and PMF, indicating a 1.7-fold increase in the permeability of cytostatic to tumor cells.

The developed method has an inventive step, since it obviously does not follow for a specialist from a known level of development of oncourology, intravesical chemotherapy of bladder cancer. In well-known sources of information in Russia, the CIS countries and abroad, a similar method was not found.

We give examples of the method.

Example No. 1. Patient B., 35 years old. Complaints at admission: cramping during urination. Ultrasound from 02/05/13 - in the projection of the base of the bladder on the left is determined hyperechoic formation with sizes up to 25 mm.

Clinical diagnosis: T1N0M0 bladder cancer. Kl. gr 2.

02/13/2013 performed TUR of the bladder: performed video urethrocystoscopy. The volume of the bladder is 300 ml; the mouths of the ureters are typically located. On the right side wall of the bladder, 1.5 cm above the left mouth, an exophytic tumor up to 2.5 cm on a thin leg. Performed transurethral resection and vaporization of the tumor and the walls of the bladder. Hemostasis by coagulation. Macro drug - fragments of a bladder tumor - G.A. No. 8253-262 - G2 urothelial cancer with invasion of the subepithelial layer.

The patient determined therapeutic tactics: adjuvant intravesical chemotherapy with gemcitabine with SC MP and PMP, 6 procedures, one procedure once a week.

02/14/13, the Patient's condition is relatively satisfactory. Complaints about the presence of a urethral catheter. Hemodynamics is stable. Diuresis adequate about 1700 ml, no hematuria.

The patient started a course of intravesical adjuvant chemotherapy with SC MP and PMP. Intravesical 50 ml of a solution of gemcitabine at a concentration of 40 mg / ml was injected intravesically with simultaneous exposure to the area of the projection of the bladder with a scanning magnetic field in combination with a constant magnetic field from an inductor mounted in the center between the poles of a pair of inductors of the scanning magnetic field.

Physical parameters of the scanning MP:

Induction 10 mT

Signal frequency from 1 to 150 Hz, changing at a speed of 1 Hz / s

10 minutes exposure

Physical parameters of constant MP:

Induction 20 mT

10 minutes exposure

After the end of the magnetic action, the patient independently continues the exposure of the magnetized chemotherapy solution, lying on the right side for 15 minutes, on the left side for 15 minutes, on the stomach for 15 minutes and on the back for 5 minutes. The full exposure time of a chemotherapy drug is 60 minutes. 6 procedures were performed, one procedure per week.

Currently, the follow-up period is 16 months. According to a comprehensive examination, including ultrasound and urinalysis, no signs of relapse and progression were found.

Example No. 2. Patient M, 58 years old. Complaints upon admission: an admixture of blood in the urine, pain during urination - an ultrasound scan of 03/04/13 - kidney transplants are not expanded. In the bladder on the right side wall, a hyperechoic formation with dimensions of 12 × 14 mm is determined.

Clinical diagnosis: T1N0M0 bladder cancer. Kl. gr 2.

03/18/2013, performed TUR of the bladder: performed video urethrocystoscopy. The volume of the bladder is 250 ml; the mouths of the ureters are typically located. On the right side wall, 4 exophytic tumors are determined, one of which is 2 × 1.5 cm on a wide base, the others are 0.5-0.8 cm in size. A transurethral resection and vaporization of the tumors and bladder wall has been performed. Hemostasis by coagulation. Macro drug - fragments of a bladder tumor - G.A. No. 15043 -45 G3 urothelial cancer with foci of invasion of subepithelial, stromal tissue.

The treatment tactics was determined for the patient: adjuvant intravesical chemotherapy with gemcitabine with SC MP and PMP, 6 procedures, one procedure once a week.

03/21/13, the Patient's condition is relatively satisfactory. Complaints about the presence of a urethral catheter. Hemodynamics is stable. Diuresis adequate about 1400 ml, no hematuria.

The patient started a course of intravesical adjuvant chemotherapy with SC MP and PM. A 50 mg solution of gemcitabine was introduced intravesically at a concentration of 40 mg / ml with a simultaneous exposure to the area of the projection of the bladder with a scanning magnetic field in combination with a constant magnetic field from an inductor mounted in the center between the poles of a pair of inductors of a scanning magnetic field.

Physical parameters of the scanning MP:

Induction 10 mT

Signal frequency from 1 to 150 Hz, changing at a speed of 1 Hz / s

10 minutes exposure

Physical parameters of constant MP:

Induction 20 mT

10 minutes exposure

After the end of the magnetic exposure, the patient independently continued the exposure of the magnetized chemotherapy solution, lying on his right side for 15 minutes, on his left side for 15 minutes, on his stomach for 15 minutes and on his back for 5 minutes. The full exposure time of a chemotherapy drug is 60 minutes.

Currently, the follow-up period is 15 months. According to a comprehensive examination of signs of relapse and progression of the process was not detected.

This method treated 15 patients.

The invention is industrially applicable, as it can be repeatedly reproduced in research institutions of oncological profile, oncology departments and dispensaries providing surgical and drug treatment. The claimed method for the treatment of bladder cancer by intravesical chemotherapy in combination with SC MP and PMP has significant advantages and reinforces the criteria of patentability by signs:

1. An increase in the duration of the relapse-free period from 7 to 16 months (at the time of application).

2. Changes in intravital bioelectric properties of the membranes (membrane potential) of tumor cells of the bladder with the effect of magnetically induced hyperpolarization, evaluated by the method of voltage-dependent fluorescence probes: ANS and DSM, increased fluorescence of cells incubated with gemcitabine under the influence of SC MP and PMF (see table. 1, fig. 1).

3. The simplicity and accessibility of non-invasive manipulation of magnetization during intravesical chemotherapy of bladder cancer.

This "Method for the treatment of bladder cancer" is economical, available due to the availability of the necessary domestic magnetic therapy equipment on the market.

Claims (1)

A method of treating bladder cancer, including transurethral resection, intravesical chemotherapy, characterized in that on the first day after transurethral resection of the urinary bladder, 2000 mg of 40 mg / ml dissolved in 50 ml physiological solution of gemcitabine is administered via a urethral catheter with simultaneous exposure to the area of the projection of the bladder by a scanning magnetic field by induction of 10 mT, the signal frequency from 1 to 150 Hz, changing at a speed of 1 Hz / s, e at a dose of 10 minutes, in combination with a constant magnetic field of 20 mT, after which the patient independently continues the exposure of the magnetized solution of the chemotherapy drug, lying on the right side for 15 minutes, on the left side for 15 minutes, on the stomach for 15 minutes, on the back for 5 minutes, the time of full exposure chemotherapy is 60 minutes, after which the patient independently releases the bladder, a total of six procedures are performed, one procedure per week.

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