Diabetic. Diet. Recipes. Sport. Popular treatment. Analyzes. Insulin. Complications
Study of efficiency and comparative assessment of adjuvant intravenous immunotherapy in intron A, adjuvant intravenous chemotherapy with mitomycin, adjuvant intravenous chemimmunotherapy with a combination of mitomycin and intron and after transurethral

Study of efficiency and comparative assessment of adjuvant intravenous immunotherapy in intron A, adjuvant intravenous chemotherapy with mitomycin, adjuvant intravenous chemimmunotherapy with a combination of mitomycin and intron and after transurethral

14.07.2020 Products

Research scheme

Introduction

The special problem is the treatment of surface tumors of the bladder, that is, tumors with invasion is not an deeper mucosa layer (Ta, T IS, T1 N0 m0). In recent years, a transurethral resection of the bladder (TOUR) has become the main method of treatment of the surface RMP (tour), practically witnessed other organ-powder methods operational treatment. However, the frequency of recurrences after the tour is extremely high (50-90%). The emergence of relapses is associated with the diffuse nature of neoplastic changes in the bladder mucosa, the plurality of tumor incidents, the presence of unseasonable CARCINOMA in situ foci, accompanying papillary tumors, the possibility of implantation of tumor cells during operation. In addition, the radical tour is sometimes impossible with multicenter growth of tumors, if there are in situ cancer sections. All of these factors make it seek additional treatments and ways to prevent RMP recurrence by applying various options for intravenous therapy.

Internal use of antitumor medicinal preparations It may be therapeutic when instillations are carried out in order to achieve the regression of residual after a tour of tumors and (or) of CARCINOMA in situ foci, and in cases where drugs are entered after a tour in the absence of visualized tumors and negative urine cytology. By the nature of the antitumor agent, intravenous therapy is divided into 2 groups: chemotherapy and immunotherapy. The ideal drug for intravenous treatment or prevention should possess 2 basic qualities: high antitumor efficacy with respect to transit-cellular RMP and minimal local and systemic side toxic effects, both sharp and chronic.

Until now, the most common method of inappropriate therapy with surface RMP is therapy with cytostatics. Intravenous chemotherapy is used since 1961, many different drugs were used as agents for instillations, but only 3 of them were detected reliable efficiency: Mitomycin, doxorubicin, thiophosphamide. The greatest use of B. clinical practice Found Mitomycin S. Traditionally, the drug is introduced weekly at a dose of 30 - 40 mg for 6 to 8 weeks, sometimes the main course is complemented by monthly instillations within 6 - 12 months. According to the majority of clinical studies, adjuvant intravenous chemotherapy with mitomycin with reliably reduces the number of relapses compared to the control group. The advantage of prophylactic chemotherapy with mitomycin C is 7 - 33% (at the frequency of recurrence after the tour). LAMM provides an analysis of 5 randomized studies comprising 859 patients with superficial RMP. The average frequency of recurrence in the group of patients receiving mitomycin instillation was 37%, while in the group of patients who were carried out only by the urinary bubble tour, recurrences were diagnosed in 52% of cases (the advantage of mitomycin C was an average of 15%). At the same time, most of the work shows that intravenous chemotherapy with mitomycin C does not lead to a decrease in the frequency of progression of the tumor process. In this regard, a number of authors propose to use the mode of one-time introduction of the drug in the early postoperative period And reports on equal effectiveness of this technique compared with traditional prolonged modes of internal chemotherapy in patients with a good or intermediate forecast (Solsona E., 1999).

Since the 70s, the possibility of conducting intravenous immunotherapy and immunoprophylaxis of surface RMP began to be studied. These experimental and clinical studies give reason to believe that immunologically active drugs can play an important role in the treatment of patients with this pathology, providing both direct and indirect effects both on tumor cells and on cells on different stages Tumor transformation, which is of great importance in preventive intravenous therapy.

From nonspecific immunomodulators the most studied drug is vaccine BCG.which was first applied in clinical practice in 1976 by Morales. Intravenous BCG therapy is effective method treatment and prevention of relapses of the surface RMP. But the BCG vaccine with intrapaulous use has a rather pronounced local and systemic toxicity, often leads to the development of adverse reactions and complications (cystitis, granuloma, fever). As a living vaccine, the BCG can lead to infection with tuberculosis of patient and medical personnel, there are cases of fatal outcomes after intravenous instillations of BCG. Intravel administration of the BCG vaccine is contraindicated in hematuria, cystitis, persistent after the previous instillation, reducing the tank of the bladder, the tuberculosis in the history. These disadvantages of BCG therapy force to look for more secure drugs for intravenous treatment and preventing the relapses of the surface RMP.

Currently, a number of recombinant and native immunologically applies for immunotherapy of malignant urinary tumors active drugs, such as interferon-alpha, interferon-beta, interferon-gamma, interleukin-2, interleukin-1, tumor necrosis factor, hemocyanin of mollusks of the "locking wells", Bropiminim, streptococcal extract OK-432, etc. wide spectrum Immunotherapeutic use is characterized by interferon-A2B (IFN-A2B). IFN-A2B is glycoprotein produced by leukocytes and macrophages. The antitumor effect of the IFN-A2B is due to its antiproliferative, antiviral effects, compositely stimulate NK cells (natural killers), T- and B-lymphocytes, phagocytosis.

The possibility and feasibility of the use of IFN-A2B for the treatment of RMM is shown in several experimental studies on cell cultures and animals. Most clinical studies are devoted to intravenous immunotherapy using IFN-A2B as an agent for preventing the recurrence of surface RMP. To study the preventive effectiveness of the IFN-A2B, most authors used weekly instillation regimen for 12 weeks with subsequent monthly instillations within 1 year.

In a randomized study of Portillo et al. IFN-A2B IFN-A2B intraprofilaxis was carried out in a group comprising 30 patients, as many patients were included in the control group. The dose of the drug amounted to 60 million meters. In all patients, prognostic adverse tumors were observed: T1G2-3 and recurrent T1G1. Recurps developed in 23.3% of cases in a group with IFN and in 36.6% of patients of the control group. At the same time, among the recurrent tumors, the progression (invasive growth in the muscular layer of the wall) was observed in 35.7% of cases in the control group and only in 8.3% of cases in the group of patients receiving IFN. The duration of the unqualified period was 11.5 months in a group with immunotherapy and 6.7 months in a group with a tour. During treatment, there were no local and general side Effects. The authors conclude the effectiveness of the intravenous use of the IFN-A2B to prevent the recurrence and progression of the surface tumors of the bladder and the safety of treatment. In another study of Spanish authors, including 26 patients and conducted in a similar mode, the dose of the drug amounted to 50 million meters. Recurrements were observed in 38% of cases, progression - by 3.8%, the duration of the risk-perid period was 25.7 months. The work of Hoeltl compares the preventive effect of the IFN-A2B in doses of 100 million IU and 10 million IU. In 44 patients with tumors Tu / T1G1 / G2, the efficiency in both dose regimes was the same, the average period before the development of the recurrence was 22.36 and 22.23 months, respectively. The possibility of achieving a good result with intravenous immunoprophylaxis using small doses of IFN-A2B is also shown in other works.
It should also be noted a decrease in the frequency of recurrence and an increase in the duration of the non-raised period during 2 courses of prolonged instillations of the IFN within 5 days.

In recent years, a number of studies on the new direction of intravenous therapy are published: combinations of IFN-A2B with cytostatics and BCG vaccine. Due to its low toxicity, the intrapaulous use of IFN can be successfully combined with other antitumor drugs, which reduces their dose and, accordingly adverse reactions and increase the effectiveness of treatment.

In the study of Engelmann et al., Comprising 66 patients, the effectiveness of monotherapy with mitomycin C (20 mg) and IFN A-2B (10 million IU), as well as combined therapy with two data, was studied. In the group of patients who received mitomycin with recurrences were diagnosed in 23% of cases, in a group received by IFN-A2B - in 18%, during combined recurrence therapy was not observed (the average observation period is 6.2 months). The identical effectiveness of IFN-A2B and Mitomycin C with preventive use is also shown in other work. In a randomized study of Finnish authors, a combination of 50 mg of epirubicin and 10 million IFN-A2B turned out to be substantially more efficient than the monotherapy with these drugs (81 patients, the observation periods is 20 months).

Purpose of the study.

The purpose of this study is to study the efficiency and comparative estimate of the four different methods of treatment of the surface of the bladder: the cloud of the bladder, followed by adjuvant intravenous immunotherapy of the Yuinton A, the tour of the bladder, followed by adjuvant intravenous chemotherapy with mitomycin, the urinary bubble tour, followed by adjuvant intravenous chemoimmunotherapy with mitomycin and intron And, the tour of the bladder followed by dynamic observation.

To achieve the goal set task:
Determine the frequency of recurrence in each group under study.
Determine the frequency of progression of the tumor process (the development of the inva of the muscular layer) in each studied group.
Determine the duration of the unqualified period in each studied group.
Assess the nature and degree of toxicity and side effects in each studied group.

Inclusion criteria.
Histologically verified adhesive bladder cancer.
The stage of the disease, which allows to include a patient in the study: 0 Stage (TA, TIS NXM0) and stage I stage (T1NXM0).
The absence of preceding and concomitant special treatment (chemotherapy, immunotherapy or radiation therapy).
Age - 17 - 75 years.
WHO status is less than 2.

Exception Criteria:
Previous and accompanying special treatment (chemotherapy, immunotherapy or radiation therapy). Under-17 or older than 75 years old.
Patients with an active infectious process or serious intercurrent diseases in the decompensation stage.
Patients who are not able to attend the medical institution involved in the protocol for test surveys.
WHO status is more than 2.

Information about drugs.
Recombinant Interferon Alpha-2B (intron a)


Description of the drug: Intron A - Sterile,
the stable form of highly purified IFN alpha-2b produced by the technique of recombinant DNA. The recombinant IFN ALPHA-2B is a water-soluble protein with a molecular weight of about 19.300 Dalton. The intron A is obtained from a clone E. coli, which by genetic engineering introduced plasmid with the IFN alpha-2B genome from human leukocyte.
The activity of intron A is measured in international units (IU). The drug is produced by Shering Play (USA) in each of the following dosages: 3 IU / vial, 5 IU / Vial, 10 Me \\ vial. Intron A contains 9 mg NaCl and 5 mg of human serum albumin. The drug is produced in a lyophilized injection form
Preparation of a solution: an intron solution for intravenous administration is prepared immediately before administration by adding 50.0 ml of 0.9% NaCl solution (saline). The resulting mixture must be shaken up to obtain a transparent solution.
Instructions for storage: The introne bottle A should be stored in the refrigerator or in the freezer at T from +2 to +8 C until the moment of use.
Stability: Intron A solution should be used immediately after cooking.

Mitomycin

Source of Acquisition: Medical Institutions, Pharmacy Network
Description of the drug: Mitomycin - antitumor antibiotic, isolated from the Streptomyces Caespitosus mushroom, structural consists of quinone, azridine and urethane. The substance is a crystal of a blue-violet color, a thermostable with a high melting point and is easily dissolved in organic solvents.
The drug is manufactured by Kova (Japan) - Mitomycin C - in each of the following dosages: 2 mg / bottle, 10 mg / bottle, 20 mg / bottle and Bristol-Myers Skwibb (USA) - Mutamicin - Dosage: 5 mg / bottle (Contains 10 mg of mannitol), 20 mg / vial (40 mg of mannitol) and 40 mg / bottle (80 mg of mannitol).
Preparation of a solution: a solution of mitomycin for intravenous administration is prepared immediately before administration by adding 50.0 ml of 0.9% NaCl solution (saline). The resulting mixture must be shaken until the solution is obtained.
Storage Instructions: Store at a temperature of 15-25 ° C in light-protected place.
Stability: Mitomycin solution should be used immediately after cooking.
Method of administration: intravenous instillations.

Treatment plan.
All patients will be registered in the data collection guiding center at the address: 125264 Moscow, 2nd Botkinsky passage, 3 MNII them. P.A. Herzen Rusakov I. G. Patients will be randomized into 4 groups in accordance with the criteria for inclusion.
Treatment begins with the fulfillment of all patients with a transurethral resection (tour) of the bladder. The criteria of a radically completed tour of the bladder are: 1. The absence of tumors in the bladder (including in biopsyts from the tumor bed). 2. Lack of tumor cells cytological examination urine (negative urine cytology).
Patients from the 1st group after performing the urinary bubble tour is carried out intravenous chemotherapy with mitomycin.
Mitomycin is administered intrapaulously at a dose of 40 mg (50.0 ml of PD. R-ra) on a catheter once in an early postoperative period (no later than 6 hours after the end of the operation) for 2 hours, after which the drug is evacuated from the urinary bubble cavity.

Patients 2 groups are conducted by intravenous immunotherapy by intron A.
Patients are held 5 courses of immunotherapy with an interval of 3 weeks. The duration of each course is 3 days. Motherwise dose The drug amounted to 6 million IU, the daily dose -12 million IU, the term dose - 36 million IU. The total dose of intron and for the entire period of treatment - 180 million IU. Half of the daily dose of the drug (6 million IU) dissolved EX Tempora in 50,
0 ml of sterile physiological solution is introduced along the catheter in a pre-empty bladder, followed by the holding of the solution in the urinary bubble cavity within 3 hours. Patients regularly change the position of the body during this time, after which the drug is excreted when urinating. It is further similar to the introduction and evacuation of the second half of the daily dose of Intron A. The beginning of the course is calculated from 1 day of intra-duty instillations of intron A. Instillations begin immediately after anemia of dysuric phenomena, but no later than after 14 days from the date of operation.
Treatment scheme:
Week 0 - Wearing Bubble Tour
Week 1 - 1 day - 12 million meters of intron and inoperative (in 2 receptions)
2 day - 12 million meters of intron and inoperative (in 2 receptions)
3 day - 12 million meters of intron and inoperative (in 2 receptions)
Week 2-3 - Break
Courses are repeated every 21 day for 3.5 months.
In the future, the patients with this group conducts observation.
Patients 3 groups after the cloud tour of the bladder are carried out intravenous chemoimmunotherapy with mitomycin and intron A.
The introduction of mitomycin and inton A is carried out in the same doses and according to the same schemes as in groups 1 and 2.
In the future, the patients with this group conducts observation.
Patients 4 groups produced a cloud of bladder, adjuvant intravenous therapy is not carried out. Dynamic observation of patients is carried out.

Examination of the patient before treatment.
Full history and examination of the patient, including the definition of general status, concomitant neonocheological diseases and treatment obtained by their occasion.
Laboratory studies include a general blood test with leukocyte formula and platelets, a common urine analysis, biochemical analysis blood, ECG.
Cystoscopy with tumor biopsy.
Ultrasound bladder and abdominal cavity.
Lung radiography.

Survey of the patient during treatment.

The nature of the study Groups with adjuvant intravenous therapy A group of dynamic observation
Inspection of the patient Every 3 months
General blood analysis Before the beginning of each course of treatment Every 3 months
Analysis of urine Before the beginning of each course of treatment Every 3 months
Cystoscopy Every 3 months Every 3 months
Cytological examination of urine Before the beginning of each course of treatment Every 3 months
Ultrasound urinary belly Every 3 months Every 3 months
Abdominal ultrasound Every 6 months Every 6 months
Light radiography Annually Annually

Any method of examination can be appointed unscheduled and additionally by decision of the attending physician.

Criteria for discontinuation of treatment.
Recurble tumor or the appearance of remote metastases.
Development of toxicity, defined as irreversible or IV degree.
Failure to comply with patients with the requirements of the protocol.
Failure to the patient from participation in the study.

Questions statistics.

Statistical processing of research results will be carried out in MNII them. P. A. Herzen using relevant statistical methods.

(Visited 11 Times, 1 Visits Today)

This article has a review of published data regarding intravenous chemotherapy of the surface cancer of the bladder. The degree of evidence is based on sources of information: meta-analysis, systemic overview, randomized and nerangerized controlled clinical studies, as well as uncontrolled studies or conciliation documents.

The first step in the treatment of surface papillary transient cell carcinomas is transuretral resection, which allows you to accurately determine the stage and gradation of the tumor. Nevertheless, after a tour, transitional cell carcinomas are recidening in 50% -80% of cases and in 14% of cases there is a progression of the tumor process. Therefore, it is recommended to carry out adjuvant chemotherapy or immunotherapy. Immunotherapy BCG vaccine remains the most effective form of intravenous treatment in the prevention of recurrence and progression of the surface cancer of the bladder. However, the use of BCG can be accompanied by a significant number of side effects, including potentially fatal complications, such as BCZH-sepsis, infectious lesions of lungs, liver, kidneys, prostatic gland. Such disadvantages are devoid of intravenous chemotherapy, but its effectiveness is insufficient, since the auxiliary is an almost impermeable barrier for intravenously introduced substances. Intravenous chemotherapy also reduces the recurrence rate, but the effectiveness of existing chemotherapeutic drugs in preventing tumor progression remains unproved.A. M. Kamat. eT Al In its reference review indicated the recurrence rate - 44%, 39%, 36% and 39% with the use of Tiotep, Adriamycin, Mitomycin C and Epirubicin, respectively. Despite almost similar effectiveness, the preparations differ in their toxicity and, accordingly, the severity of side effects.

Therefore, research is aimed at improving the effectiveness of intravenous chemotherapy. At the same time, various approaches to solving this problem are offered. Some researchers set the goal to choose the most optimal dates of the instillations, others - the improvement of the pharmacokinetics of chemotherapy by reducing their dilution, increase the stability or improve the absorption of the bladder mucosa drugs. Some researchers study the possibility of applying new chemotherapeutic agents or combined applications. The methods of avoiding chemoresistance with the use of modulating agents or testingin vitro. On chemochiness to establish the most sensitive drug.

Dates of instillation


Studies To determine the optimal instillation time are carried out since the beginning of the first experiments on the use of intravenous chemotherapy during bladder cancer. In the past few years, various clinical studies have been proved by the effectiveness of the use of single intravenous instillation directly after the tour with any form of the bladder transition-cell carcinoma. Even the least malignant tumors Urinary bubble, such as papillary urostic neoplasms with low malignant potential, in 34% of cases recur in the first 2 years, in 50% of cases - for 5 years and 64%- For 10 years. With such tumors, as well as with other low-risk tumors, early single instillation may reduce the risk of recurrence by 39%. An early single introduction of a chemotherapy is recommended by the European Urological Association (EUA) as a method of choice after a tour with low-risk tumors and as an initial stage of treatment of high-risk tumors. Meta-analysis carried out withinEORTC. (European Organization for the study and treatment of cancer) did not reveal a significant difference in efficiency among various chemotherapy preparations. If the bladder perforation is suspected, the instillation should not be carried out to avoid serious complications. Instillation time is also of great importance. In all studies, including a meta-analysis of Eourtc, instillations were carried out during the first 24h. E.Kaasinen et al. It was established that the risk of recurrence doubles if the instillation is not carried out within 24 hours after the tour.

The solitary tumors recur in 35.8% of cases during early single instillation, and in the case of multiple tumors, the recurrence rate reaches 65.2%. Therefore, it is recommended for multiple tumors and tumors of moderate and high risk in addition to early single instillation to continue treatment within 4-8 weekly instillations.

The question of how long the treatment should be carried out yet remains discountable. Randomized study conductedEORTC. It showed that the appointment of a supporting course of chemotherapy for 1 year (one instillation per month) does not give any advantages compared with a 6-month course of treatment, if the patient first instillation was made immediately after the tumor tour. According to the results of a systematic review of clinical studies, it can be concluded that a short intensive course during the first 3-4 months, subject to early instillation, can be as effective as a long treatment regimen. The latter can be recommended if there was no early instillation of the chemotherapy.

Improving the pharmacokinetics of drugs for intravenous administration


Dilution in residual urine or excessive diuresis during the exposure period, instability of basic chemotherapeutic agents at low urine pH, inadequate period of exposure and limited penetrability of drugs into the bladder wall - all of these factors can cause the ineffectiveness of intravenous chemotherapy. Several recommendations are proposed for introducing into clinical practice in order to increase the delivery of medication to tumor cells.

Prevent drug dilution. It is necessary to pay special attention to the complete emptying of the bladder before the introduction of chemotherapy. The repositioning of the catheter or the change of the patient's position can have additional help in this.

It is shown that the restriction of fluids for 6h to each instillation reduces diuresis and is 20% preventing drugs. This simple reception is also recommended by the EUA protocol on the surface of the urinary bubble.

Oral administration 0.2 mg Desmopressin for 1h to each instillation is an even more effective method that increases by an average of a 38% intravenous concentration of the drug. Potential clinical advantages of desmopressin can be somewhat limited by its side effects. However, it can be used with the exclusion of heart failure or hyponatremia. The intake of liquids should be limited in 1 h after 8h after the designation of the desmopressin, in order to avoid fluid delay in the body.

Urine sickness. The stability of the drug, cell absorption and penetration into deep muscle layers of mitomycin C increases when urine is observed by oral administration of sodium bicarbonate. The dose of 1.5g on the day before at night, in the morning and 30 minutes to each instillation is sufficient to achieve the optimal pH of urine (\u003e 7).

The duration of the exposure of chemotherapy. Patients should be recommended to hold the injected solution within 2 hours.

However, there are no research indicating that this reception reduces the recurrence frequency, so the recommendation is based on indirect evidence, drawn from various sources.

Improving the permeability of the wall of the bladder. In recent years, a number of devices have been developed to increase the permeability of drugs used for intravenous administration. Despite the relative novelty, their effectiveness has been proven by a number of research.

Internal Electrophoresis Chemotherapeutic Preparations. The principle is based on the electrokinetic movement of charged (ionic) molecules in the electric field. In contrast to the passive diffusion of the drug, depending on the concentration gradient, the electrophoresis is much more effective and, above all, depends on the strength of the current and the number of connected electricity. Positive medicinal ions are introduced into the tissue anode, negative - cathode. Transport of uncharged solutions is enhanced by two additional electricity phenomena: Electrosumes - transport of non-ionized molecules as shells of hydration of ionized particles, and electroporation - an increased permeability of tissues under the influence of an electric field. Subsequently, a number of experimental studies confirming the concept of increasing the transportation of drugs through the amendment in the deeper layers of the bladder wall (deproupor) with medicinal electrophoresis. Thus, S. di Stasi et al showed significantly increased mitomycin transfer rates and oxybutinin into the viable bladder wall under the influence of electrophoresis. Laboratory studies using human bladder preparations have demonstrated that the drug electrophoresis increases the transport of mitomycin C through the auxilia of 6-9 times compared with passive diffusion. In the study of R.Colombo et al on the marker tumor models, the efficacy of electrochemistry with mitomycin (20 minutes) was approximately equal to the effectiveness of intravenous instillations of mitomycin (2 hours) (the frequency of complete regressions, obtained in both groups amounted to 40%). The frequency of recurrences in patients responded to treatment was higher in a group of instillations of mitomycin (60%) than in the electrochemotherapy group (33%). Time before the recurrence appeared, there was more in the group of electrochemitherapy with mitomycin (on average 14.5 months against 10 months).

In September 2003, the results of the study of the III phase on compared efficiency BCG., electrophoresis of mitomycin C and intrauterine instillations of mitomycin C in the treatment of surface bladder cancer with an unfavorable outlook. The effectiveness of mitomycin electrophoresis is approximately 2 times superior with such a passive diffusion of the chemotherapy. Thus, the full effect after 3 and 6 months was, respectively, 53% and 58% for electrochemistry and 28% and 31% - for intrapaulic chemotherapy with mitomycin. On the contrary, the results of intravenous electro farms and immunotherapy BCG were similar: the full effect after 3 and 6 months was 56% and 64% in the BCG group. Thus, it was concluded that with a bladder cancer with an unfavorable outlook, electrochemistry of efficiency significantly exceeds the passive diffusion of the chemotherapy and comparable to the BCG immunotherapy.

There is a good portability of the method, the toxicity of intravenous electrochemistry is not significantly different from the usual. The systemic side effects and hematological toxicity associated with the possible absorption of the drug in the bloodstream were not observed both in studies using mitomycin C and when using doxorubicin. Animals have shown that carcinomatous areas of the package 100 times are 100 times more permeable for water and electrolytes than normal urobates. It is very likely that carcinomatous areas have less electrical resistance than normal aiming and, thus, some specificity is noted for the introduction of drugs in these areas.

The use of local microwave hyperthermia. As is known from literature, malignant cells are more sensitive to heat than normal cells. Hyperthermia causes inhibition of DNA synthesis, RNA and protein. These changes can be fatal for the cell if the recovery mechanisms are not effective. Local Hyperthermia (Synergo) showed the synergistic effect of cell death when used in combination with chemotherapy for the treatment of many solid tumors, including the bladder transition-cell carcinoma. At the same time, with the help of special microwave equipment and special catheters (Fig. 1), the temperature of the bladder walls is brought to 42 ° C.

Figure 1. System for intravenous hyperthermia (synergo). EUR. Ur., 46, 1, 2004.

Patients relatively tolerate combined chemical thermotherapy. Most side effects are localized, transient and cannot be the cause of treatment interruption. During the procedure, patients usually note the weak bearing at urination and occasionally a feeling of burning in the urethre. In some cases, the preventive purpose of anticholinergic drugs significantly reduces these symptoms. In several patients, a thermal reaction was revealed on the rear wall of the bladder, which proceeded asymptomatic and was resolved without any intervention. The location of this thermal reaction corresponds to the location of the tip of the intrapaulic applicator, which ensures the effect of microwave hyperthermia. The use of hyperthermia reduces the percentage of recurrence to 14.3% a year after treatment, and 2 years to 24.6%. The progression of stage or graduation was not detected. According to A.G. Van der Heiden.et al When using hyperthermia with a prophylactic target, 15 out of 24 patients with an average observation period of 35.3 months, there were no relapses. When using this method, with the aim of ablation in 12 patients from 28, a complete tumor remission was observed, 83.3% of which remained free from tumors for an average of 20 months.

Dimethyl sulfoxide widely used in the treatment of interstitial cystitis (DMSO. , The solution with anti-inflammatory and bacteriostatic activity) causes analgesia and nerves blockade, inhibition of cholinesterase, vasodilation and muscle relaxation. DMSO has the ability to penetrate the fabric without their substantial defeat. It is used to increase absorption bladder Such chemotherapeutic preparations as cisplatin, piraroindicin and doxorubicin.

Other methods are currently under study. In particular, we are talking about the use of bioadhesive microspheres with gelatin material, which adhere to the mucous bladder, contributing to the controlled release of the drug. A study was conducted using such a new method of intravenous administration of Paclitaxel, in which the animals show high efficiency in ablation of low-differentiated tumors.

New experimental drugs

In order to achieve maximum intravenous treatment efficacy a number of studies of new drugs were conducted.

Anthracycline Agent Pirarbitsin (Tetrahydropional-doxorubicin) is the only one drug With proven efficacy in the prevention of relapses after the tour. However, no published articles were found, in which a comparative characteristic was carried out with other frequently used drugs (doxorubicin, mitomycin C, epirubicin or adriamycin). Varubitsin, grasintetic derivative of adriamycin, revealed some advantage in patients with BCG-resistant CIS in the first and second phases of clinical research . Despite the absence of randomized studies of Warubicin approved for use in the United States for intravenous treatment of patients with BCG-resistant CIS.

Very high, histologically confirmed efficiency in 67.4% of cases in the second phase of studies showed the use of 6 intravenous instillations of 4 mg of the preparation of APAZIQUONE (EO9, EOQUIN). The drug is inactive, i.e. It needs activation by cell reductase enzymes to manifest their cytotoxicity. Enzyme dioxitimidine-diaphoraza (Dtd. ) Plays a central role in the activation of the EO9, and about 40% of the urinary bubble tumors have higher activityDtd. Compared to the normal cloth of the bladder, which confirms the possibility of achieving selective toxicity against tumor cells. In preclinical studies, the concentration of EO9 necessary to achieve 50% of cell death is 6-78 times less than that of mitomycin C, depending on the line of cancer cells used.

Hemcitabine - a preparation with a wide range of antitumor activity. After penetrating the cell, it is phosphorylated in DNA and RNA, which in turn leads to the suppression of cell growth (43.44). In the systemic purpose, gemcitabine exhibits significant activity against invasive bladder cancer as monotherapy, with an effectiveness of 27% -38%. In the II phase of clinical studies Inoperative instillations of hemcitabine during marker tumors middle degree Risk, in 60% of cases led to a complete tumor regression.

Alcoholoid Barwinka Vinorelbine is used in non-cellular lung cancer, metastatic cancerglands, prostate cancer, Material resistant to hormone therapy (in combination with small doses GKS for receiving inside). In the i-phase of clinical studies, Vinorlebin showed a pro-apoptotic effect with a bladder cancer. Molecular levels affect the dynamic equilibrium of the tubulin in the microtubule apparatus, suppresses the tubulin polymerization, binding mainly with mitotic microtubes, and in higher concentrations also has an effect on axonal microtubules. Preparation blocks mitosis of cells at the metafase stage G2-M, causing cell death. During the interphase or under the subsequent mitosis.

Meglumin Gamma Linoleic Acid is an indispensable fatty acid with cytostatic activity, which showed similar effectiveness in comparison with other intrapaulic drugs in the phase of studies.

Suramina is an antitripanosomal preparation with antitumor properties that blocks the binding of the epidermal growth factor (EGF) with its receptors (EGFR). In the phase of studies, the possibility of this treatment method was confirmed, due to its low systemic and local toxicity.[ 51].

Among other techniques are conducted studies of photosensitive drugs, which, with local administration in the bladder, selectively accumulate in tumor cells. After the intravenous administration of the light source, the cytotoxic effect of these drugs is manifested. Photodynamic therapy (PDT) is successfully used in surface bladder cancer, which could not be cured with a tour, with primary CIS, and in the case of BCG-resistant tumors. PhotoFrine was the first photosensitive drug used to treat surface bladder cancer, but he had strongly expressed side local and system effects. In a study that covered the 51 patient with the same and / or T1, the staging of transitional cellular cancer of the bladder, the full response was obtained in 41%, while 39% was detected a partial response after one session of photodynamic therapy. For papillary transient cell cancer, a tumor size was measured: the full response was observed only if the tumor diameter was less than 2 cm. In a multifocal, randomized study, which included 36 patients, preliminary data showed a decrease in tumor recurrences from 83% to 33% (improvement by 50%) when using one session of photodynamic therapy after a complete cloud tumor tour. The average recurrence time has increased from 3 to 13 months with single, adjuvant photodynamic therapy. There are not enough for remote data on the prevention of recurrence and progression of tumor after photodynamic therapy.

So R.Waidelich et al was prescribed 5-aminolevulinic acid (5-ALA) orally. At the same time, in 3 of 5 patients with CIS and 4 of 19 patients with papillary tumors during 36 months of observation of relapses were not detected. In most patients, hemodynamic side effects were noted, such as hypotension and tachycardia. These systemic side effects can be avoided by 5-ALA intra-duty instillations. A.P.Berger.et al 31 patients were examined, of which 10 previously conducted BCG immunotherapy. The average observation period was 23.7 months, in 16 patients recurrence of tumors were not identified, including 4 out of 10, in which BCG therapy turned out to be ineffective. The side effects were the infection of the urinary tract and hematuria.

Figure 2. Photodynamic therapy action mechanism (medcape)

The mechanism of action of photodynamic therapy (Fig. 2) includes: a cytotoxic effect caused by singlet oxygen and free radicals; damage to the endothelium of vessels with thrombosis and hypoxia; Intensive local inflammation in combination with an immune response. Consequently, PDT causes symptoms of cystitis (the so-called post-PDT syndrome): frequent urination, imperative urge to urination, niccountura, pain in the derivative area and the spasm of the bladder. The intensity and duration of symptoms directly depends on the dose of photodynamic therapy, the degree of damage to the detrier after the previous treatment, the intensity of acute inflammation and the presence of carcinoma in situ (which increases the capture of photofrin). The most dangerous side effect of the FDT is a steady bladder contracture, which was detected according to various studies in 4% -24% of patients.

Porphymer sodium is another photosensitive drug for instillation, which showed efficiency with CIS, resistant to BCG. Hypericin and recently developed PAD-S31 showed high efficiency in the destruction of the bladder tumors in experimental animals. Despite all studies conducted by photodynamic therapy, the study of these drugs in humans is still limited to an uncontrollable and non-radomized number of individual cases (III level of evidence).

With proper selection and training of patients, problems with photosensitivity of the skin are minimal. However, for 6 weeks after the injection of photoFrina, insolation should be avoided. The introduction of new photosensitizers and the simplification of the WB-PDT laser will lead to wider use of photodynamic therapy in the treatment of bladder cancer.

Possible oral chemorals, such as Tagafur, Eflornitin Diflouromethylornitin, Tipfarnib, Fenretinide, Cellotoxib, Vitamins, Fluoroquinolones (and other antibiotics) can be effective in vitro and in animal experiments. There is so far only the phase of 3 randomized clinical studies on people showing that the long-term oral use of Tegafur (5-fluorouracyl predecessor) after the tour, prevents the recurrence of the surface transition-cellular carcinoma of the bladder. Oral chemoral drugs may also be applied in the future as an addition to intra-peer chemotherapy, but it is not believed that they can completely replace the instillations after the tour. In fact, synergistic interaction is possible, because They have different mechanisms of action and methods of application. Although it seems unlikely that the orally used drug can be as effective as the highly concentrated drug with direct contact with the tumor.

Combined use of drugs

Theoretically, one of the advantages of consistent use of chemotherapy and immunotherapy can be various mechanisms of impact with the amplification of antitumor effect. The second advantage is the increase in fibronectin activity against the background of the development of chemical cystitis, which can positive impact On the grip of particles of BCG with the wall of the bladder. The main negative torque of the combination of the chemotherapeutic preparation with BCG is a possible increase in toxicity. In the studyEORTC. With marking tumors, the sequential use of a mitomycian C (4 instillations) and BCG (6 instillations) in patients with low stage tumors and gradation leads to full regression of the tumor in 69% of cases. With CIS, a combination of intravenous chemical immunotherapy is much more efficient in relation to the recurrence frequency for 24 months and the duration of the non-dedicated period.

Some researchers propose to apply experimental cytotoxic drugs to improve the efficiency of conventional chemotherapeutic drugs. The basis is the concept of the synergistic effect of two drugs with a different mechanism of action. Tamoxifen, ciprofloxacin, gamma-linoleic acid, Suramin were investigated in combination with intravical drugs on several generations of cells and animals (mice), with obtaining encouraging results. There is only one clinical study on the oral use of Tigufur in combination with intrapaulic therapy after a tour that showed some better results compared only with intrapaulic therapy. However, no statistical data was demonstrated in this study. Although the joint use of drugs is a fairly attractive approach, there are currently no evidence and documented studies on this topic in order to recommend combinations of drugs to use.

Modulating agents

Modulating agents are non-quotoxic compositions that enhance the effect of some chemotherapeutic drugs. Their appearance contributed to the identification of certain biochemical processes, which were involved in the mechanisms for the development of drug resistance. The possibility of using pharmacological intervention was studied to restore the sensitivity to drugs. There are clinical, well-documented examples in oncology, such as the use of leivojin in combination with a 5-fluorouracyl with a thick bowel cancer, stomach, breast.

Verapamil, calcium channel blocker, inhibits the activity of glycoprotein P-170 and is the most studied modulator with surface bladder cancer. Glycoprotein P-170 acts as a pump of membrane channels, causing leakage of anthracyclines and other chemotherapeutic agents, making cells resistant to their effects. A large amount of in vitro colonies of the bladder cancer cells, and in vivo in animal experiments showed that verapamil joins resistant cells, blocks glycoprotein R-170, thereby improving the cytostatic effect of epirubicin, piraroindicine, tiotepa, adriamycin, peplubicin, and mitomycin with . Verapamil was also studied in humans, which showed significantly better results of preventive use of a combination of verapamil with adriamycin compared with one adriamycin after the tour (I level of prognosis) in the III phase of randomized research. 157 patients participated in the study, the average observation period- 38.5 months. In the group of patients receiving adriamycin as a monotherapy, the frequency of relapses was significantly higher. However, no significant differences were found in the ablative effect of a combination of adriamycin with verapamil compared with adriamycin monotherapy for marker tumors in the II phase of a clinical study. Thus, there is a sufficient number of evidence in favor of additional use of verapamil to adriamycin in recurrence prevention after the tour. The optimal dose is 5 ampoules of verapamil (25mg / 10ml of physiological solution) to adriamycin (50mg / 40ml of the physiological solution), to achieve a total volume of 50ml. Verapamil inexpensive, does not cause local side phenomena, cardiovascular disorders, because Does not go into systemic bloodstream.

Glycoprotein P-170 can also be inhibited by steroid hormones, etramstin, which has been demonstrated in in vitro experiments on the colonies of the bladder cancer cells. The second generation of glycoprotein inhibitors P-170 is studied and includes drugs such as Byrique and Valfodar. The latter was carefully studied in clinical studies and showed high toxicity and dubious efficacy. The less toxic third generation of modulators, including drugs such as Tariquidar, Zosuquidar, Laniquidar, and Ont-093 are currently being investigated in the II and II phase of studies.

Tests for chemical sensitivity. The choice of intravenous drug is usually based on the ability or experience of circulation with a specific agent in clinical practice. However, inappropriate chemotherapy failures are mainly related to resistance to one or more drugs. Choosing a drug based on chemical sensitive tests, in contrast empirical therapyis a new approach in research.

It would be possible to consider the testing of the drug over marker tumors, as a sample of the chemical sensitive test in vivo, used on patients, which is often done in the II phase of studies. Theoretically, instillation performed to the tour could evaluate the effectiveness of the drug in clinical practice. A positive response as an indicator is an incentive to continue further instillations after the tour. However, in this case, only one drug can be tested.

In vitro research allows you to compare the effectiveness of different chemotherapy products by treating the primary culture of cells obtained in biopsy, various chemotherapy, and determine the cytotoxicity of each of them. Chemical Tests have already been developed for cancer of the stomach, thick and rectum, esophagus, liver, pancreas, a hematopoietic system, lungs, ovaries, breasts, heads and neck, brain, leather, bones, thymus, parachite gland, kidneys, urinary Bubble, eggs. Despite the limited tests in vitro and their dubious extrapolation on the results of in vivo, the benefit from the conduct of chemical sensitive tests has already been demonstrated during multiform glioblastomas and other types of cancer.

It has recently been studied that, together with unicellular mechanisms of resistance, such as the expression of glycoprotein P-170 MDR-1 gene, multicellular mechanisms are involved in drug resistance. As a result of adhesion cell-to-cell and cell-to-stroma, multicellular resistance can be demonstrated only in three-dimensional cultures. Tumor spheroids are reproduced in vitro not only single-cellular, but also multicellular mechanisms of resistance, becoming a more reliable model for determining the chemical sensitivity of drugs. Recently, a test for determining the chemical sensitivity for a bladder cancer based on the use of three-dimensional spheroid culture was carried out.

In vitro chemical sensitivity studies can be used to determine the individual sensitivity of the tumor to several drugs before instillation. They could routinely be used in clinical practice to choose a better preparation for each patient and potentially reduce the proportion of relapses or delay their appearance. These tests are expensive and time-consuming, but the cost of profitability would be positive if it was possible to avoid ineffective instillations. This would lead to a decrease in recurrence, preventing operational intervention and reduction of complications. However, so far no study showed evidence of the clinical efficacy of tests on chemical sensitivity at surface transitional cell carcinoma. Although the proportion of relapses is expected to reduce the tests on chemical sensitivity in clinical practice too early.

Conclusion

The level I evidence indicates the need for early postoperative intravenous instillation with all surface tumors (degree of recommendations a). A further treatment is also recommended for 4- and 8-week courses in the tumors of the intermediate degree of risk (degree of recommendations a). Supporting therapy for up to 6 months is likely to increase the effectiveness of treatment, although there are no convincing evidence of this (degree of recommendations from). The use of fluid should be limited, and the urologist should trace the bladder to be designed before instillation (degree of recommendations C). Oral application Desmopressin can be appointed in order to avoid further excessive dissolution of the chemotherapy (degree of recommendations C). Urine's leaning with sodium bicarbonate is desirable to improve the action of Mitomycin C (degree of recommendations C). Verapamil can be instilled together with adriamycin (degree of recommendations A) or with other chemotherapy preparations (degree of recommendations B) to increase their effectiveness. Local hyperthermia and EMDA are available methods that can be applied in each treatment institution based on the cost of cost profitability (degree of recommendations a).

Literaturebut

  1. Kurth K.h., Bouffioux C., Sylvester R., Van der Meijden A.P., Oosterlinck W., Brausi M .. The Eorthc Genitourinary Group. Treatment of Superficial Bladder Tumors: Achevements and Needs. EUR UROL. 2000; 37: 1-9.
  2. Bohle A., Jocham D., Bock P.R .. INTRAVESICAL BACILLUS CALMETTE-GUERIN VERSUS MITOMYCIN C FOR SUPERFICIAL BLADDER CANCER: A FORMAL META-ANALYSIS OF COMPARATIVE STUDIES ON RECURRENCE AND TOXICITY. J Urol. 2003; 169: 90-95.
  3. Bohle A., Bock P.R .. INTRAVESICAL BACILLE CALMETTE-GUERIN VERSUS MITOMYCIN C IN SUPERFICIAL BLADDER CANCER: Formal Meta-Analysis of Comparative Studies on Tumor Progression. Urology. 2004; 63: 682-686Discussion 6-7.
  4. Sylvester R.J., Van Der Meijden A., Lamm D.L .. IntraveSical Bacillus Calmette-Guerin Reduces The Risk of Progression in Patients with Superficial Bladder Cancer: A Meta-Analysis of the Published ReSults of Randomized Clinical Trials. J Urol. 2002; 168: 1964-1970.
  5. Pawinski A., Sylvester R., Kurth K.h. et al .. A Combined Analysis of European Organization for Research and Treatment of Cancer, And Medical Research Council Randomized Clinical Treatment of Stage Tat1 Bladder Cancer. European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group And The Medical Research Council Working Party on Superficial Bladder Cancer. J Urol. 1996; 156: 1934-1940, 40-1.
  6. van der Meijden A.P., Sylvester R., Oosterlinck W., et al .. Eau Guidelines on the Diagnosis and Treatment of Urothelial Carcinoma in Situ. EUR UROL. 2005; 48: 363-371.teruo M., Watanabe H., Kobayashi t. ABSORPTION OF ANTI-CANCER DRUGS THROUGH Bladder Epithelium. Urology, 27: 148, 1986.
  7. Kamat A.M., Lamm D.L .. INTRAVESICAL THERAPY FOR BLADDER CANCER. Urology. 2000; 55: 161-168.
  8. Fujii Y., Kawakami S., Koga F., Nemoto T., Kihara K .. Long-Term Outcome of Bladder Papillary Urothelial Neoplasms of Low Malignant Potential. BJU INT. 2003; 92: 559-562.
  9. Sylvester R.j., Oosterlinck W., Van der Meijden A.P .. A Single Immediate Postoperative InStillas of Chemotherapy Decreases The Risk of Recurrence in Patients with Stage Ta T1 Bladder Cancer: A Meta-Analysis of Published Results of Randomized Clinical Trials. J Urol. 2004; 171: 2186-2190quiz 435.
  10. Van der Meijden a.p.m., Bohle A., Oosterlinck W., et al. Guidelines on Non-Muscle Invasive Bladder Cancer: European Association of Urology; 2001.
  11. Kaasinen E., Rintala E., Hellstrom P., et al. FINNBLADDER GROUP. Factors Explaining Recurrence in Patients undergoing Chemoimmunotherapy Regimens for Frequently Recurring Superficial Bladder Carcinoma. EUR UROL 2002; 42: 167-174.
  12. Bouffioux C., Kurth K.h., Bono A., et al. European Organization for Research and Treatment of Cancer Genitourinary Group. Intravesical adjuvant chemotherapy for superficial transitional cell bladder carcinoma: results of two European Organization for Research and Treatment of Cancer randomized trials with mitomycin C and doxorubicin comparing early versus delayed instillations and short-term versus long-term treatment. J Urol. 1995; 153: 934-941.
  13. Sylvester R.j., Oosterlinck W., Witjes J.A. .. The Schedule and Duration of IntraveSical Chemotherapy in Patients with non-Muscle Invasive Bladder Cancer: A Systematic Review of the Published Results of Randomized Clinical Trials. EUR UROL 2008; 53: 709-719.
  14. Au J.L., Badalament R.A., WientJes M.G., et al. Methods to Improve Efficacy of IntraveSical Mitomycin C: Results of a Randomized Phase III Trial. J Natl Cancer Inst. 2001; 93: 597-604.
  15. Cliff A.M., Heatherwick B., Scotle J., Parr N.J. The Effect of Fasting Or Desmopressin Before Treatment On The Concentration of Mitomycin C During Intravestic Administration. BJU INT. 2000; 86: 644-647.
  16. Gasion Burgues J.P., Jimenez Cruz J.F. Improving Efficacy Of IntraveSical Chemotherapy. EUR UROL 2006; 50: 225-234.
  17. Stillwell G.K. Electric Stimulation and iontophoresis. In: Handbook of Physical Medicine and Rehabilitation, 2nd Ed. Edited by f.h. Rrussen. St. Louis: W.B. Saunders Co., Chapt. 14, 1971.
  18. ROLVEVICH A.I., Sukonko OG, Red S.A., Zhukovets A.G. Inspaudgment electrophoresis of doxorubicin with surface bladder cancer. The results of a prospective randomized study http://urobel.uroweb.ru/news/id-15.
  19. Brausi M., Campo B., Pizzocaro G., Rigatti P., Parma A., Mazza G., Vicini A., Stephen R.L. INTRAVESICAL ELECTROMOTIVE ADMINISTRATION OF DRUGS FOR TREATMENT OF SUPERFICIAL BLADDER CAN-CER: A Comparative Phase II Study. Urology 1998; 51: 506-509.
  20. GURPINAR T., Truong L.D., Wong H.Y., Griffith D.P. Electromotive Drug Administration to the Urinary Bladder: An An Animal Model and Preliminary Results. J. Urol. 1996; 156: 1496.
  21. Riedl C.R., Knoll M., Pflugeer H .. Detrusor Stimulation by IntraveSical Emda of Bethanechol. J. EndouroL., Suppl. 10: P7-236, 1996.
  22. Di Stasi S.M., Castagnola M., Vespasiani G., Giannantoni A., Cancrini A., Micali F., Stephen R.L. In Vitro Study of Passive VS Electromotive Mitomycin with Diffusion in Human Bladder Wall. Preliminary Results. J Urol 151: 447A, 1994.
  23. Colombo R., Brausi M., Da Pozzo L.F., Salonia A., Montorsi F., Scattoni V., Roscigno M., Rigatti P. Thermo-Chemotherapy and Electromotive Drug Administration of Mitomycin with in Superficial Bladder Cancer Eradication. A Pilot Study ON MARKER LESION. EUR. Urol. 2001. V. 39. P. 95-100.
  24. Di Stasi S., Giannantoni A., Stephen R., Navarra P .., Capelli G., Massoud R., Vespasiani G. INTRAVESICAL ELECTROMOTIVE MITOMYCIN C VERSUS PASSIVE TRANSPORT MITOMYCIN C FOR HIGH RISK SUPERFICIAL BLADDER CANCER: A PROSPECTIVE RANDOMIZED STUDY . J Urol. 2003. V. 170. 777-782.
  25. Giannantoni A., Di Stasi S.m., Chancellor M.B., Constantini E., Porena M .. New Frontiers in IntraveSical Therapies and Drug Delivery. EUR UROL 2006; Vol.50, Issue 6: 1183-1193.
  26. Hicks R.M., Ketterer in., Warren R.C .. The Ultrastructure and Chemistry of the Mammalian Urinary Bladder: A Structure with Low Permeability to Water and Ions. Phil. Trans. Roy. SOC. London Biol. Sci., 268: 23, 1974.
  27. Meyer J.L. The Clinical Efficacy of Localized Hyperthermia. Cancer RES 1984; 44: 4745-4751.
  28. Colombo R., Brausi M., Da Pozzo L. et al .. Thermo-Chemotherapy and Electromotive Drug Administration of Mitomycin C in Superficial Bladder Cancer Eradication A Pilot Study on Marker Lesion. EUR UROL. 2001; 39: 95-100.
  29. Di Stasi S.M., Giannantoni A., Stephen R.L. ET AL .. INTRAVESICAL ELECTROMOTIVE MITOMYCIN C VERSUS PASSIVE TRANSPORT MITOMYCIN C FOR HIGH RISK SUPERFICIAL BLADDER CANCER: A PROSPECTIVE RANDOMIZED STUDY. J Urol. 2003; 170: 777-782.
  30. Van der Heijden A.G., Kiemeney L.A., Gofrit O.N., et al. Preliminary European Results of Local Microwave Hyperthermia and Chemotherapy Treatment In Intermediate or High Risk Superficial Transitional Cell Carcinoma of The Bladder. EUR UROL. 2004; 46: 65-71Discussion 72.
  31. Colombo R., Da Pozzo L.F., Salonia A., et al. MultiCentric Study Comparing IntraveSical Chemotherapy Alone and With Local Microwave Hyperthermia for Prophylaxis of Recurrence of Superficial Transitional Cell Carcinoma. J clin oncol. 2003; 21: 4270-4276.
  32. Colombo R., Lev A., Da Pozzo L., Freschi M., Gallus G., Rigatti P .. A New Approach using Local Combined Microwave Hyperthermia and Chemotherapy in Superficial Transitional Bladder Carcinoma Treatment. J urol 1995; 153: 959-963.
  33. Melchior D., Packer C.S., Johnson T.C., Kaefer M .. Dimethyl Sulfoxide: Does It Change the Functional Properties of the Bladder Wall? J urol 2003; 170: 253-258.
  34. LU Z., YEH T.K., TSAI M., AU J.L., WientJes M.G .. PaclitaXEL-Loaded Gelatin Nanoparticles for IntraveSical Bladder Cancer Therapy. CLIN CANCER RES. 2004; 10: 7677 -7684.
  35. Eroglu M., Irmak S., ACAR A., Denkbas E.B .. Design and Evaluation of a Mucoadhesive Therapeutic Agent Delivery System for Postoperative Chemotherapy in Superficial Bladder Cancer. INT J Pharmacol. 2002; 235: 51-59.
  36. Le Visage C., Rioux-Leclercq N., Haller M., Breton P., Malavaud B., Leong K .. Efficacy of Paclitaxel Released from Bio-Adhesive Polymer MicroSpheres on Model Superficial Bladder Cancer. J Urol. 2004; 171: 1324-1329.
  37. Okamura K., ONO Y., Kinukawa T. et al. Randomized Study of Single Early Instillation Of (2? R) -4? -O-TetrahydropyRanyl-Doxorubicin for a Single Superficial Bladder Carcinoma. Cancer. 2002; 94: 2363-2368.
  38. Steinberg G., Bahnson R., Brosman S., Middleton R., Wajsman Z., Wehle M .. The Valrubicin Study Group. Efficacy and Safety of ValrubiCin for the Treatment of Bacillus Calmette-Guerin Refractory Carcinoma in Situ of the Bladder. J Urol. 2000; 163: 761 -67.
  39. HENDRICKSEN K., WITJES J.A. Treatment of Intermediate Risk Non-Muscle Invasive Blabber Cancer. EUR UROL 2007; Suppl. 6: 800-808.
  40. Witjes J.A. Management of BCG Failures In Superficial Bladder Cancer: A Review. EUR UROL 2006; 49: 790-797.
  41. Li D., Gan Y., Wientjes M.G., Badalament R.A., Au J.L .. Distribution of DT-Diaphorase and Reduced Nicotinamide Adenine Dinucleotide Phosphate: Cytochrome P450 Oxidoreductase in Bladder Tissues and Tumors. J urol 2001; 166: 2500-2505.
  42. Gontero P., Tizzani A .. IntraveSical Gemcitabine: State of the Art. EUR UROL 2007; Suppl. 6: 800-808.
  43. Witjes J.A., Van der Heijden A.G., VRIESEMA J.L., Peters G.J., Laan A., Schalken J.A. INTRAVESICAL GEMCITABINE: A Phase 1 and Pharmacokinoetic Study. EUR UROL. 2004; 45: 182-186.
  44. Palou J., Carcas A., Segarra J. et al. Phase I Pharmacokinoetic Study of A Single Intravesical Instillation of Gemcitabine Administered Immediately After Transurethral Resection Plus Multiple Random Biopsies in Patients with Superficial Bladder Cancer. J Urol. 2004; 172: 485-488.
  45. Serretta V., Galuffo A., Pavone C., Allegro R., Pavone-macaluso m. Gemcitabine in IntraveSical Treatment of Ta-T1 Transitional Cell Carcinoma of Bladder: Phase I-II Study On Marker Lesions. Urology. 2005; 65: 65-69.
  46. Gontero P., Casetta G., Maso G. et al. Phase II Study to Investigate The Ablative Efficacy of IntraveSical Administration of Gemcitabine In Intermediate Blidder Cancer (SBC). EUR UROL. 2004; 46: 339-343.
  47. Bonfil R.D., Gonzalez a.d., SiguelBoim D. et al. Immunohistochemical Analysis of Ki-67, P21Waf1 / CIP1 and Apoptosis in Marker Lesions from Patients Treated with Vinorelbine IntraveSical Therapy in a Preliminary Phase I Trial. BJU INT. 2001; 88: 425 -431.
  48. Bonfil R.D., RUSSO D.M., Binda M.M., Delgado F.m., Vincenti M .. Higher Antitumor Activity of Vinflunine Than Vinorelbine Against An Orthotopic Murine Model of Transitional Cell Carcinoma of the Bladder. Urol oncol. 2002; 7: 159-166.
  49. Harris N.M., Crook T.J., Dyer J.p. et al. INTRAVESICAL MEGLUMINE GAMMA-LINOLENIC ACID IN SUPERFICIAL BLADDER CANCER: AN EFFICACY STUDY. EUR UROL. 2002; 42: 39-42.
  50. Uchio E.M., Linehan W.M., Figg W.D., Walther M.M. A Phase I Study of IntraveSical Suramin for the Treatment of Superficial Transitional Cell Carcinoma of the Bladder. J Urol. 2003; 169: 357-360.
  51. Berger A.P., Steiner H., STENZL A., AKKAD T., BARTSCH G., HOLTL L .. PHOTODYNAMIC THERAPY WITH INTRAVESICAL INSTILLATION OF 5-AMINOLEVULINIC ACID FOR PATIENTS WITH RECURRENT SUPERFICIAL BLADDER CANCER: A SINGLE-CENTER STUDY. Urology. 2003; 61: 338-341.
  52. Waidelich R., Beyer W., Knuchel R. et al. Whole Bladder Photodynamic Therapy With 5-Aminolevulinic Acid using A White Light Source. Urology. 2003; 61: 332-337.
  53. NSEYO U.O., DEHAVEN J., Dougherty T.J. et al. Photodynamic Therapy (PDT) in The Treatment of Patients WITH Resistant Superficial Bladder Cancer: A Long-Term Experience. J Clin Laser Med Surg. 1998; 16: 61-68.
  54. Waidelich R., Stepp H., Baumgartner R., Weninger E., Hofstetter A., \u200b\u200bKreigmair M .. Clinical Experience With 5-Aminolevulinic Acid and Photodynamic Therapy for Refractory Superficial Bladder Cancer. J urol 2001; 165: 1904-1907.
  55. Lamm D., Colombel M., Persad R., Soloway M., Bohle A., Palou J., Witjes Ja, Araza H., Buckley R., Brausi M .. Clinical Practice Recommendations for the Management of Non-Muscle Invasive Bladder Cancer. EUR UROL 2008; Suppl. 7: 651-666.
  56. Rintala E., Jauhiainen K., Kaasinen E., Nurmi M., Alfthan O .. Alternating Mitomycin C and Bacillus Calmette-Guerin Instillation Prophylaxis for Recurrent Papillary (Stages Ta to T1) Superficial Bladder Cancer. FINNBLADDER GROUP. J urol 1996; 156 (1): 56-59.
  57. van der Heijden A.G., Witjes J.A. INTRAVESICAL CHEMOTHERAPY: AN UPDATE - NEW TRENDS AND PERSPECTIVES. EAU UPDATE SERIES 2003; Vol.1, No.2: 71-79.
  58. Witjes J.A., Caris C.T., Mungan N.A., Debruyne F.M., Witjes W.P ..Results of A Randomized Phase III Trial of Sequential IntraveSical Therapy with Mitomycin C and Bacillus Calmette-Guerin Versus Mitomycin C Alone in Patients with Superficial Bladder Cancer. J urol 1998; 160 (5): 1668-1671.
  59. Server Pastor G., Rigabert Montiel M., Banon Perez V. et al. Oral Tegafur Plus Mitomycin Versus IntraveSical Mitomycin Alone In The Prevention of Recurrence in Stage Ta Bladder Tumors. ACTAS UROL ESP. 2003; 27: 438-441.
  60. Naito S., Kotoh S., Omoto T. et al. The Kyushu University Urological Oncology Group. PROFHYLACTIC INTRAVESICAL INSTILATION CHEMOTHERAPY AGAINST RECURRENCE After A Transurethral Receection of Superficial Bladder Cancer: A Randomized Controlled Trial Of Doxorubicin Plus Verapamil Versus Doxorubicin Alone. Cancer Chemother Pharmacol. 1998; 42: 367 -372.
  61. Tsushima T., Ohmori H., Ohi Y. et al. INTRAVESICAL INSTILLATION CHEMOTHERAPY OF ADRIAMYCIN WITH OR WITHOUT VERAPAMIL FOR THE TREATMENT OF SUPERFICIAL BLADDER CANCER: THE FINAL RANTS OF A COLLABORATIVE RANDOMIZED TRIAL. Cancer Chemother Pharmacol. 1994; 35: S69-S75.
  62. Greenberg P.L., Lee S.J., Advani R. et al. Mitoxantrone, etoposide, and Cytarabine WITH OR WITHOUT OR REFRACTORY ACUTE MYELOID LEUKEMIA AND HIGH-RISK MYELODYSPLASTIC SYNDROME: A PHASE III TRIAL (E2995). J clin oncol. 2004; 22: 1078-1086.
  63. Thomas H., Coley H.M. Overcoming Multidrug Resistance In Cancer: An Update On The Clinical Strategy of Inhibiting P-Glycoprotein. Cancer Control. 2003; 10: 159-165.
  64. IWADATE Y., FUJIMOTO S., NAMBA H., YAMAURA A .. PROMISING SURVIVAL FOR PATIENTS WITH GLIOBLASTIMA MULTIFORME TREATED WITH INDIVIDUALED CHEMOTHERAPY BASED ON IN VITRO DRUG SENSITITIBY TESTING. Br j Cancer. 2003; 89: 1896-1900.
  65. Burgues J.P. A Chemosensitivity Test for Superficial Bladder Cancer Based On Three-Dimensional Culture of Tumour Spheroids From Biopsy Specimens: Ph.D. dissertation. University of Valencia MEDICAL SCHOOL; Valencia, Spain; 2005.
  66. Oddens J.R, Van der Meijden A.P.M., Sylvester R .. One Immediate Postoperative Instillation of Chemotherapy In Low Risk Ta, T1 Bladder Cancer Patients. Is IT Always Safe? EUR UROL. 2004; 46: 336-338.
  67. Manyak M.j, Ogan K .. Photodynamic Therapy for Refractory Superficial Bladder Cancer: Long-Term Clinical Outcomes of Single Treatment Using IntraveSical Diffusion Medium. J endouroL. 2003; 17: 633-639.
  68. Kamuhabwa A.A, Roskams T., D'Hallewin M.A., Baert L., Van Poppel H., De Witte P.a .. Whole Bladder Wall PhotoNamic Therapy of Transitional Cell Carcinoma Rat Bladder Tumors Using IntravestiCally Administered Hypericin. Int j Cancer. 2003; 107: 460-467.
  69. Asanuma H., Arai T., Morimoto Y. et al. Photodynamic Therapy with Pad-S31, A New Hydrophilic Chlorin Photosensitizer, In An Orthotopic Rat Bladder Tumor Model. J Urol. 2005; 174: 2016-2021.
  70. Nseyo U.O. Photodynamic therapy. In Lamm D.L., ED. The Urologic Clinics of North America, Philadelphia, PA: W.B. Saunders CO.; 1992; 19: 591-599.
  71. Nseyo U.O., Crawford E.D., Shumaker B. et al. Photodynamic Therapy AS An Alternative to Cystectomy in Refractory Carcinoma in Situ. Proceedings of the American Association of Cancer Research 86th Annual Meeting; 1995 March 18-22; Toronto, Canada: 36: A1856.

Red S.A., Sukonko OG, Polyakov S.L., Zhukovets A.G., Rolevich A.I ()

Introduction

Urinary bubble cancer - one of frequent diseasesWith which there are oncurologists. In the structure of the oncological morbidity of the bladder tumor, about 4% are, and among oncourological diseases - approximately 35%. The incidence of urinary bubble cancer increases. Thus, in 2002, the incidence of this pathology in the Republic of Belarus amounted to 10.5 per 100,000 population (3.1% of the total number of ill), while in 1991 it was 7.7 per 100,000 (2.8%, respectively ).

The most common histological type of bladder cancer is transit-weak. A distinctive feature of these tumors is that most of them (75-85% of all newly detected bladder tumors) refer to superficial, that is, in stage TA, T1 and TIS (in situ, CIS carcinoma). The tumor limited by the epithelium; T1 is an invasive own plate, but not a muscular bladder layer, in situ carcinoma - flat (not papillary) intraepithelial tumor. Thus, with the surface of the bladder, there is no invasion of the tumor into the muscle layer of the bladder. It is shown that with such a propagation of tumors, regional and remote metastases are practically not found, and local influences are quite sufficient for the treatment of such tumors. In most cases, the treatment of the surface cancer of the bladder starts with transurethral resection (tour). Depending on the characteristics of the group of patients and the duration of observation, up to 80% of surface tumors are recurred and 2-50% are progressing into a muscularly invasive tumor. To prevent recurrence and, less rare, the treatment of surface injection of the bladder is currently widely used intravenous therapy. There are two main types of intravenous therapy - chemotherapy and immunotherapy. These two types of treatment differ in mechanisms of action, in their effectiveness, the frequency of development of side effects and their severity. The most effective immunological preparation in the treatment of surface bladder cancer is the BCG vaccine. Despite the proven by numerous studies, the superiority of BCG over various chemotherapy preparations in preventing the recurrence of the surface cancer of the bladder, it is believed that due to the risk of developing heavy complications (BCZH-sepsis, infectious damage to the lungs, liver, kidney, prostate gland) BCG should be prescribed to patients with adverse The forecast regarding the relapse and progression of the tumor into the muscular and invasive cancer. The rest of the patients after the urinary bubble tour can be conducted a course of intravenous instillations of various chemotherapy products.

Intravenous chemotherapy

Intravenous chemotherapy is investigated from the 60s. Twentieth century. A large number of different studies were carried out to clarify the effectiveness of chemotherapy products administered intravenously in relation to a decrease in the frequency of the recurrence of the surface cancer of the bladder. Most of these studies had a relatively short observation period (1-3 years). Analysis of the results of treatment for 5192 patients who participated in controlled studies of intravenous chemotherapy showed that under the influence of adjuvant treatment in terms of 1 to 3 years, the number of relapses on average decreases by 14%. TiotEF, doxorubicin hydrochloride, hydrochloride mitomycin, epirubicin hydrochloride, and etoglucid - the most frequently used drugs - reduce the short-term frequency of relapses by an average of 17%, 16%, 12%, 12%, and 26%, respectively (Table 1). Controlled comparative studies of chemotherapy products for intravenous use as a whole failed to demonstrate any significant differences between individual agents.

Table 1.

A drug

Number of studies / Number of patients

Control (tour)

Tour + Chemotherapy

Difference in the number of relapses,%

Number of patients

Number. Recurrements (%)

Number of patients

Number. Recurrements (%)
TiotEF 11/1257 573 347 (61) 684 301 (44) 17
Doxorubicin 6/1446 495 271 (55) 951 374 (39) 16
Mitomycin C. 7/1505 683 327 (48) 822 294 (36) 12
Etoglucid 1/226 70 47 (67) 156 121 (41) 26
Epirubicin 5/758 354 182 (51) 404 156 (39) 12

In 2000-2001 A group of researchers from the United States under the leadership of M. HUNCHAREK published 2 meta-analysis, in which 1-, 2- and 3-year-old uniodic survival rate in groups with adjuvant intravenous chemotherapy and without it. Cumulative data from 11 randomized controlled studies with the participation of 3703 patients with the first revealed surface cancer of the bladder showed a decrease in the frequency of relapses when using administrative intravenous chemotherapy by 30% -80% for 1-3 years compared to only the tour.

Of all chemotherapists, Mitomycin C was the most efficient. Long-term treatment protocols (ie 2 years) were more effective than short instillation courses or single instillations.

Among patients treated about recurrent tumors, intravenous chemotherapy reduced the frequency of relapses by 38% in the first year of observation compared to only the tour, while on 2 and 3, the frequency of relapses decreased by 54% and 65%, respectively. Based on the specified data, it was concluded that the significant effect of intravenous chemotherapy on a non-raised period in patients with surface bladder cancer.

The long-term results of intravenous chemotherapy were studied in meta-analysis with the participation of 2535 patients with the stage of the type or T1 of the bladder cancer included in 6 randomized studies of intravenous chemotherapy of the third phase (median observation to determine the duration of the non-raised period was 4.6 years, time before the emergence of muscle invasion - 5.5 years and life expectancy - 7.8 years). As a result of the analysis of the data obtained, it was shown that in general, the adjoyant medicinal treatment (Tiotef, doxorubicin, epirubicin, metomicin intraubun or pyridoxine hydrochloride inside) improves rapid survival rate, in particular 8-year-old, by 8.2% (44.9% versus 36.7%, p<0,01). Наряду с этим, не было выявлено существенной разницы между группами в длительности времени до прогрессирования (появления мышечной инвазии и отдаленных метастазов), а также продолжительности жизни. . Не наблюдалось существенных различий и в частоте возникновения вторых опухолей, что позволяет сделать вывод об отсутствии канцерогенных эффектов от проведенного лечения. Результаты приведены в таблице 2.

Table 2.

Adjuvant treatment (%)

Without aduvante treatment (%)

Total (%)
Total number of patients 1629 (100) 906 (100) 2535 (100)
Recurry:
Yes 766 (47) 477 (53) 1243 (49)
Not 863 (53) 429 (47) 1292 (51)
Muscular invasion:
Yes 189 (12) 80 (9) 269 (11)
Not 1140 (88) 826 (91) 2266 (89)
Cystectomy
Yes 161 (10) 75 (8) 236 (9)
Not 1468 (90) 831 (92) 2299 (91)
Survival
Alive 1001 (61) 625 (69) 1626 (64)
Died 628 (39) 281 (31) 909 (36)

Indeed, while most studies show the advantage of chemotherapy with respect to reducing the number of relapses during the first 2-3 years, there is little data on a long-term reduction in the number of relapses, and a decrease in the frequency of disease progression, neither mortality. When analyzing the results of the treatment of 3899 patients with surface transit-cell bladder cancer included in 22 randomized prospective controlled studies, D. Lamm et al. It was found that the disease has progressed in 7.5% of patients who received intravenous chemotherapy, and 6.9% of the tour only treated.

While such results may question the necessity of using intravenous chemotherapy itself, in general it is believed that chemotherapy plays a certain role in the treatment of surface bladder cancer. Conducting intravenous chemotherapy brings apparent benefits, since this treatment can reduce the number of relapses or at least increase the non-raised period. Despite the fact that intrapaulous chemotherapy is not able to influence the progression of the disease, intrapaulic Tiotef instillations, Mitomycin C, doxorubicin or epirubicin is recommended to patients with high and moderately diffegenated tumors and the stage, in which multiple tumors are revealed during primary treatment, or there is a high recurrence frequency. During the observation period.

Thus, there is a need to increase the effectiveness of intravenous chemotherapy. The main ways of increasing such effectiveness are the search for new chemotherapeutic agents, the combined use of chemotherapy and immunotherapy, the use of modifying effects, such as hyperthermia, as well as the electrophoretic administration of chemotherapy drugs.

Inseveloped electrospheredherapy

The use of electrophoresis - the electrokinetic movement of charged (ionic) molecules in the electric field - to enhance the transport of medicinal substances into pathologically changed tissues has a long history in medicine. In contrast to the passive diffusion of the drug, depending on the concentration gradient, the electrophoresis is much more effective and, above all, depends on the strength of the current and the number of connected electricity. Positive medicinal ions are introduced into the tissue anode (positive electrode), negative - cathode (negative electrode). Transportation of uncharged solutions is enhanced by two additional electrokinetic phenomena - electricity - by transport of non-ionized molecules as shells of hydration of ionized particles, and electrofores - increased permeability of tissues under the influence of an electric field. To describe all these biophysical phenomena, the term "medicinal electrophoresis" was proposed.

Until recently, medicinal electrophoresis was primarily used to increase the penetration of drugs through the skin. Intra-band electrophoresis can expand the capabilities of drug electrophoresis, increasing the local drug concentrations without systemic side effects in the treatment of a number of diseases. Since the passive diffusion of intrapaulicly introduced substances into the bladder wall through the package is insignificant, the strengthening of this process can provide an opportunity to improve the results of drug therapy of the urinary bubble diseases.

In 1988, K. Thiel reported on the intrapaulous electrophoresis of a positively charged drug of professional-chromosomal toxin - to prevent the recurrence of the surface cancer of the bladder. This author described a specially designed intravenous anode and circular outer cathode. In the study of K. Thiel from 15 patients for 1 year of recurrence, 40% of patients were observed. Local or systemic toxicity has not been detected.

A number of experimental studies have been conducted confirming the concept of increasing the transportation of medicines through a lot of urobes in the deeper layers of the bladder wall (DETROR) with medicinal electrophoresis. So, S. di stasi et al. There was a significant increased rate of mitomycin with and oxybutinin to the viable wall bladder wall under the influence of electrophoresis. Laboratory studies using human bladder preparations have demonstrated that the drug electrophoresis increases the transport of mitomycin C through the auxilia of 6-9 times compared with passive diffusion. It was also shown on animals that carcinomatous areas of a package 100 times are 100 times more permeable for water and electrolytes than normal urobates. It is very likely that carcinomatous areas have less electrical resistance than normal aiming and, thus, some specificity is noted for the introduction of drugs in these areas.

In addition, several clinical studies have demonstrated that the intravenous electrophoresis of local anesthetics leads to the anesthesia of the bladder, sufficient to perform various endoscopic operations (transuretral resection of the bladder tumors, the urinary bubble ceride incidence, urinary bubble hydrogenation). The clinical and cystometric results of Betanehol drug electrophoresis (Bethanechol) significantly exceeded those after instillation of betanehola without electrophoresis. Lidocaine drug electrophoresis significantly reduced the pain associated with the subsequent intravenous administration of capsaicin for the treatment of interstitial cystitis, as well as actually eliminated spastic reductions in the bladder compared to the lidocaine's passive diffusion.

Data relative to the systemic absorption of medicines and blood levels in blood in the process of electrophoresis is not enough. In two studies, it was shown that the levels of lidocaine in the blood after drug electrophoresis were in the range from an undetectable up to about one-third of the therapeutic concentration. This suggests that during drug electrophoresis, the minimum, but clinically insignificant systemic administration of the drug may occur.

In several studies, the drug electrophoresis of mitomycin C can increase the efficiency of this cytotoxic preparation in the treatment of surface bladder cancer (Table 3). S. Riedl et al. We conducted 91 procedures of 22 patients with existing urinary bubble tumors with an unfavorable forecast and received 56.6% of complete regressions. Mitomycin C drug electrophoresis was well tolerated by patients, and the frequency of side effects was rather low (in 4.4% of patients a moderate pain reaction during treatment, in 14.3% of the symptoms of the lower urinary tract for less than 24 hours after electrophoresis and 2.2 % of patients for more than 24 hours). None of these side effects demanded the cessation of treatment.

In the study of M. Brausi et al. On the model of marker tumors, the efficacy of electrochemistry with mitomycin (20 minutes) was about equal to the effectiveness of intravenous instillations of mitomycin (2 hours) (the frequency of complete regressions, obtained in both groups amounted to 40%). The frequency of relapses in the patients responded to treatment was higher in the group of instillations of mitomycin (60%) than in the electrochemistry group (33%). Time before the recurrence appeared, there was more in the group of electrochemitherapy with mitomycin (on average 14.5 months against 10 months). Because of the small number of patients, certain conclusions are impossible. However, a decrease in recurrence frequency and a longer unidentified interval observed in a group of patients treated using electrochemotherapy can be explained by a large penetration of mitomycin deep into the bladder wall under the influence of electric current. Since electrophoresis increases militicine transport by 6-9 times compared with passive diffusion, the development of system side effects is possible. However, this study did not observe significant systemic effects or changes in blood test in two groups of patients.

R. Colombo et al. In its pilot study, a medicinal electrophoresis of mitomycin with 15 patients with surface bladder cancer was carried out. The treatment diagram was different from the study of M. Brausi et al. The fact that 4 electrophoresis sessions were carried out instead of 8. In the group of electrochemotherapy, 40% of full regressions were marked compared with 27.8% in the treatment of only mitomycin. Significant toxicity of therapy is not marked. Thus, the efficiency of electrophoresis of mitomycin did not decrease with a decrease in the number of procedures, while the effect of instillations of mitomycin decreased from 41.6% to 27.8% during 2 instillations compared with 8 in the study M. Brausi et al. . This study also demonstrates the efficiency of the electrophoresis of the chemotherapy compared to conventional instillations. A small number of patients did not allow to show the accuracy of differences in the effect of these treatment methods.

Table 3.

n INP / counter

Number of Sessions VPPEF

Type of research

PR in the VPPE group (%)

PR in counter group (%)

% of patients without recurrence
Thiel K., 1988 15/0 4 BUT – – 40% without recurrence for 1 year
Riedl C. et al., 1998 22/0 4 (1-9) BUT – – 56.6% without recurrence 4-26 months. (in Wed 14.1 months)
Brausi M. et al., 1998 15/13 8 M. 6/15 (40,0%) 5/12 (41,6%) No recurrence of 40% (VPEF) against 33% (control) after 7.6 and 6.0 months.
Colombo R. et al., 2001 15/36 4 M. 6/15 (40,0%) 10/36 (27,8%) –

Abbreviations: INPEF - INTERNAL ELECTORERS; PR - complete regression; A - adjuvant therapy after the tour; M - marker tumors.

Conclusion

Thus, in a few studies, intravenous electrochemistry showed a very encouraging effect. The absence of randomized controlled studies and a small amount of observations do not allow to come to any specific conclusion. However, preliminary data indicate the potential effectiveness of such an approach and the need for further studies of electrochemistry of bladder cancer.

LITERATURE

  1. Matveev B.P., Figurin K.M., Karyakin O.B. Bladder cancer. M., "Verdan", 2001, 244 p.
  2. Maker K.V., Vanagel S.A., Polyakov S.M., Savina I.I. Malignant neoplasms in Belarus, 1992-2001 / Edited by Ph.D. A.A.Gagakovich and prof. I.V. Zallytsky. - Minsk: Beltsmt, 2002. - 193 p.
  3. Kurth K.h. Natural History and Prognosis of "Untreated" and "Treated" SuperFicial Bladder Cancer: In Pagano F, Fair WR (EDS): Superficial Bladder Cancer. Oxford, Isis Medical Media, 1997. PP 42-56.
  4. Lamm D.L. Long-Term Results of IntraveSical Therapy for Superficial Bladder Cancer. Urol Clin North AM, 19: 573-580, 1992.
  5. Oosterlinck W., Lobel B., Jakse G., Malmstrom P.-U., Stockle M., Sternberg C. Guidelines on Bladder Cancer. EUROPEAN ASSOCIATION OF UROLOGY, 2002.
  6. Lamm D.L., Griffith J.g. INTRAVESICAL THERAPY: Does It Affect The Natural History Of Superficial Bladder Cancer? Semin urol. 1992; 10 (1): 39-44.
  7. HUNCHAREK M., GESCHWIND J.F., WITHERSPOON B., ET AL. INTRAVESICAL CHEMOTHERAPY PROPHYLAXIS IN PRIMARY SUPERFICIAL BLADDER CANCER: A META-ANALYSIS OF 3,703 PATIENTS FROM 11 RANDOMIZED TRIALS. J Clin Epidemiol 53: 676-680, 2000.
  8. Huncharek M., McGarry R., Kupelnick B. Impact of IntraveSical Chemotherapy on Recurrence Rate of Recurrent Superficial Transitional Cell Carcinoma of The Bladder: Results Of A Meta-Analysis. Anticancer RES 21 (1B): 765-769, 2001.
  9. Pawinski A., Sylvester R., Kurth K.h., et al. A Combined Analysis of EorthSis of Eourtc / Mrc Randomized Clinical Treatment of Stage Tat1 Bladder Cancer. J Urol. 1996; 156 (6): 1934-1940.
  10. Lamm D.L., Riggs D.R., TrayNelis C.L., et al. Apparent Failure of Current IntraveSical Chemotherapy Prophylaxis to Influence The Long-Term Course of Superficial Tcc of the Bladder. J Urol. 1995; 153 (5): 1444-1450.
  11. Stillwell G.K. Electric Stimulation and iontophoresis. In: Handbook of Physical Medicine and Rehabilitation, 2nd Ed. Edited by F. H. Rrussen. St. Louis: W. B. Saunders Co., Chapt. 14,1971
  12. TERUO M., WATANABE H., KOBAYASHI T. ABSORPTION OF ANTI-CANCER DRUGS THROUGH BLADDER EPITHELIUM. Urology, 27: 148, 1986.
  13. Hicks R.M., Ketterer V., Warren R.c. The Mammalian Urinary Blade of The Mammalian Urinary Bladder The Mammalian Bladder: A structure with Low Permeability to Water and Ions. Phil. Trans. Roy. SOC. London Biol. SCI., 268: 23, 1974
  14. Thiel K.H. Die Intravesikale Antineoplastische Lontophorese- Ein Unblutiges Verfahren Zur Therapie und RezidivProprophylaxe des Basenkarzinoms. In: Verhandlungsbericht Der Deutschen Gesellschaft Fur Urologie, 40. Tagung, Springer Veriag, 1988.
  15. Lugnani F., Mazza G., Cerull, N., Rossi C., Stephen R.L. Iontophoresis of Drugs In The Bladder Wall: Equipment and Preliminary Studies. ARTIF. ORG., 17: 8, 1993.
  16. Gurpinar T., Truong L.D., WONG H.Y., Griffith D.P. Electromotive Drug Administration to the Urinary Bladder: An An Animal Model and Preliminary Results. J. Urol., 156: 1496, 1996.
  17. Riedl C.R., Knoll M., Pfluger H. Detrusor Stimulation by IntraveSical Emda of Bethanechol. J. EndouroL., Suppl. 10: P7-236, 1996.
  18. Di Stasi S.m., Vespasiani G., Giannantoni A., Massoud R., Doici S., Micali F. Electromotive Delivery of Mitomycin C INTO HUMAN Bladder Wall. Cancer Res., 57: 875, 1997.
  19. Di Stasi S.m., Giannantoni A., Massoud R., Cortese C., Vespasiani G., Micali F. Electromotive Administration of Oxybutynin Into The Human Bladder Wall. J. Urol., 158: 228, 1997.
  20. Di Stasi S.M., Castagnola M., Vespasiani G., Giannantoni A., Cancrini A., Micali F., Stephen R.L. In Vitro Study of Passive VS Electromotive Mitomycin with Diffusion in Human Bladder Wall. Preliminary Results. J Urol 151: 447A, 1994.
  21. DASGUPTA P., FOWLER C.J., Hoverd P., Haslam C., Penberthy R., Shah J., Stephen R.L. Does electromotive Drug Administration (EMDA) with Lidocaine Before IntraveSical Capsaicin Confer Benefit? J. Urol., Part 2, 157: 186, Abstract 724, 1997.
  22. GURPINAR T., WONG H.Y., Griffith D.P. Electromotive Administration of IntraveSical Lidocaine in Patients with Interstital Cystitis. J. EndouroL., 10: 443, 1996.
  23. FontAnella U.a., Rossi C.A., Stephen R.L. Bladder and UreThral Anesthesia with Electromotive Drug Administration (EMDA): A technique for Invasive Endoscopic Procedures. Brit. J. Urol., 79: 414, 1997.
  24. Jewett M.A.S., Valiquette L., Katz J., Fradet Y., Redelmeier D.A., SAMPSON H.A. Electromotive Drug Administration (EMDA) of Lidocaine AS An Alternative Anesthesia for Transurethral Surgery. J. Urol., Part 2, 157: 273, Abstract 1059, 1997.
  25. FontAnella U.a., Rossi C.A., Stephen R.L. Iontophoretic Local Anesthesia for Bladder Dilatation In The Treatment of Interstitial Cystitis. Brit. J. Urol., 69: 662, 1992.
  26. SANT G.R., LAROCK D.R. Standard IntraveSical Therapies for Intersical Cystitis. Urol. CLIN. N. Amer., 21: 73, 1994.
  27. Huland H., Otto U. Mitomycin C Instillation to Prevent Revent Recurrence of Superficial Bladder Carcinoma. Results of a Controlled, Prospective Study In 58 Patients. EUR. Urol., 9: 84, 1983.
  28. Tolley D.A., Hargreave T.V., Smith P.h., Williams J.L., Grigor K.M., Parmar M.K.V., Freedman L.S., USCINSKA B.M. Effect of Intravesical MMC on Recurrence of Newly Diagnosed Superficial Bladder Cancer: Interim Report from The Medical Research Council Subgroup on Superficial Bladder Cancer. Brit. Med. J., 296: 1759, 1988.
  29. Riedl C.R., Knoll M., Plas E., Pfluger H. IntraveSical Electromotive Drug Administration Technique: Preliminary Results and Side Effects. J Urol 1998: 159: 1851-1856.
  30. Brausi M., Campo B., Pizzocaro G., Rigatti P., Parma A., Mazza G., Vicini A., Stephen R.L. INTRAVESICAL ELECTROMOTIVE ADMINISTRATION OF DRUGS FOR TREATMENT OF SUPERFICIAL BLADDER CANCER: A Comparative Phase II Study. Urology 1998: 51: 506-509.
  31. Colombo R., Brausi M., Da Pozzo L.F., Salonia A., Montorsi F., Scattoni V., Roscigno M., Rigatti P. Thermo-Chemotherapy and Electromotive Drug Administration of Mitomycin with in Superficial Bladder Cancer Eradication. A Pilot Study ON MARKER LESION. EUR. Urol 2001; 39: 95-100

This article has a review of published data regarding intravenous chemotherapy of the surface cancer of the bladder. The degree of evidence is based on sources of information: meta-analysis, systemic overview, randomized and nerangerized controlled clinical studies, as well as uncontrolled studies or conciliation documents.

The first step in the treatment of surface papillary transient cell carcinomas is transuretral resection, which allows you to accurately determine the stage and gradation of the tumor. Nevertheless, after a tour, transitional cell carcinomas are recidening in 50% -80% of cases and in 14% of cases there is a progression of the tumor process. Therefore, it is recommended to carry out adjuvant chemotherapy or immunotherapy. Immunotherapy BCG vaccine remains the most effective form of intravenous treatment in the prevention of recurrence and progression of the surface cancer of the bladder. However, the use of BCG can be accompanied by a significant number of side effects, including potentially fatal complications, such as BCZH-sepsis, infectious lesions of lungs, liver, kidney, prostate gland. Such disadvantages are devoid of intravenous chemotherapy, but its effectiveness is insufficient, since the auxiliary is an almost impermeable barrier for intravenously introduced substances. Intravenous chemotherapy also reduces the recurrence rate, but the effectiveness of existing chemotherapeutic drugs in preventing tumor progression remains unproved.A. M. Kamat. eT Al In its reference review indicated the recurrence rate - 44%, 39%, 36% and 39% with the use of Tiotep, Adriamycin, Mitomycin C and Epirubicin, respectively. Despite almost similar effectiveness, the preparations differ in their toxicity and, accordingly, the severity of side effects.

Therefore, research is aimed at improving the effectiveness of intravenous chemotherapy. At the same time, various approaches to solving this problem are offered. Some researchers set the goal to choose the most optimal dates of the instillations, others - the improvement of the pharmacokinetics of chemotherapy by reducing their dilution, increase the stability or improve the absorption of the bladder mucosa drugs. Some researchers study the possibility of applying new chemotherapeutic agents or combined applications. The methods of avoiding chemoresistance with the use of modulating agents or testingin vitro. On chemochiness to establish the most sensitive drug.

Dates of instillation


Studies To determine the optimal instillation time are carried out since the beginning of the first experiments on the use of intravenous chemotherapy during bladder cancer. In the past few years, various clinical studies have been proved by the effectiveness of the use of single intravenous instillation directly after the tour with any form of the bladder transition-cell carcinoma. Even the least malignant urinary bubble tumors, such as papillary urostic neoplasms with low malignant potential, in 34% of cases recur in the first 2 years, in 50% of cases - for 5 years and 64%- For 10 years. With such tumors, as well as with other low-risk tumors, early single instillation may reduce the risk of recurrence by 39%. An early single introduction of a chemotherapy is recommended by the European Urological Association (EUA) as a method of choice after a tour with low-risk tumors and as an initial stage of treatment of high-risk tumors. Meta-analysis carried out withinEORTC. (European Organization for the study and treatment of cancer) did not reveal a significant difference in efficiency among various chemotherapy preparations. If the bladder perforation is suspected, the instillation should not be carried out to avoid serious complications. Instillation time is also of great importance. In all studies, including a meta-analysis of Eourtc, instillations were carried out during the first 24h. E.Kaasinen et al. It was established that the risk of recurrence doubles if the instillation is not carried out within 24 hours after the tour.

The solitary tumors recur in 35.8% of cases during early single instillation, and in the case of multiple tumors, the recurrence rate reaches 65.2%. Therefore, it is recommended for multiple tumors and tumors of moderate and high risk in addition to early single instillation to continue treatment within 4-8 weekly instillations.

The question of how long the treatment should be carried out yet remains discountable. Randomized study conductedEORTC. It showed that the appointment of a supporting course of chemotherapy for 1 year (one instillation per month) does not give any advantages compared with a 6-month course of treatment, if the patient first instillation was made immediately after the tumor tour. According to the results of a systematic review of clinical studies, it can be concluded that a short intensive course during the first 3-4 months, subject to early instillation, can be as effective as a long treatment regimen. The latter can be recommended if there was no early instillation of the chemotherapy.

Improving the pharmacokinetics of drugs for intravenous administration


Dilution in residual urine or excessive diuresis during the exposure period, instability of basic chemotherapeutic agents at low urine pH, inadequate period of exposure and limited penetrability of drugs into the bladder wall - all of these factors can cause the ineffectiveness of intravenous chemotherapy. Several recommendations are proposed for introducing into clinical practice in order to increase the delivery of medication to tumor cells.

Prevent drug dilution. It is necessary to pay special attention to the complete emptying of the bladder before the introduction of chemotherapy. The repositioning of the catheter or the change of the patient's position can have additional help in this.

It is shown that the restriction of fluids for 6h to each instillation reduces diuresis and is 20% preventing drugs. This simple reception is also recommended by the EUA protocol on the surface of the urinary bubble.

Oral administration 0.2 mg Desmopressin for 1h to each instillation is an even more effective method that increases by an average of a 38% intravenous concentration of the drug. Potential clinical advantages of desmopressin can be somewhat limited by its side effects. However, it can be used with the exclusion of heart failure or hyponatremia. The intake of liquids should be limited in 1 h after 8h after the designation of the desmopressin, in order to avoid fluid delay in the body.

Urine sickness. The stability of the drug, cell absorption and penetration into deep muscle layers of mitomycin C increases when urine is observed by oral administration of sodium bicarbonate. The dose of 1.5g on the day before at night, in the morning and 30 minutes to each instillation is sufficient to achieve the optimal pH of urine (\u003e 7).

The duration of the exposure of chemotherapy. Patients should be recommended to hold the injected solution within 2 hours.

However, there are no research indicating that this reception reduces the recurrence frequency, so the recommendation is based on indirect evidence, drawn from various sources.

Improving the permeability of the wall of the bladder. In recent years, a number of devices have been developed to increase the permeability of drugs used for intravenous administration. Despite the relative novelty, their effectiveness has been proven by a number of research.

Internal Electrophoresis Chemotherapeutic Preparations. The principle is based on the electrokinetic movement of charged (ionic) molecules in the electric field. In contrast to the passive diffusion of the drug, depending on the concentration gradient, the electrophoresis is much more effective and, above all, depends on the strength of the current and the number of connected electricity. Positive medicinal ions are introduced into the tissue anode, negative - cathode. Transport of uncharged solutions is enhanced by two additional electricity phenomena: Electrosumes - transport of non-ionized molecules as shells of hydration of ionized particles, and electroporation - an increased permeability of tissues under the influence of an electric field. Subsequently, a number of experimental studies confirming the concept of increasing the transportation of drugs through the amendment in the deeper layers of the bladder wall (deproupor) with medicinal electrophoresis. Thus, S. di Stasi et al showed significantly increased mitomycin transfer rates and oxybutinin into the viable bladder wall under the influence of electrophoresis. Laboratory studies using human bladder preparations have demonstrated that the drug electrophoresis increases the transport of mitomycin C through the auxilia of 6-9 times compared with passive diffusion. In the study of R.Colombo et al on the marker tumor models, the efficacy of electrochemistry with mitomycin (20 minutes) was approximately equal to the effectiveness of intravenous instillations of mitomycin (2 hours) (the frequency of complete regressions, obtained in both groups amounted to 40%). The frequency of recurrences in patients responded to treatment was higher in a group of instillations of mitomycin (60%) than in the electrochemotherapy group (33%). Time before the recurrence appeared, there was more in the group of electrochemitherapy with mitomycin (on average 14.5 months against 10 months).

In September 2003, the results of a phase III study were reported on the comparison of the efficiency of BCG, electrophoresis of mitomycin C and intravenous instillations of mitomycin C in the treatment of surface bladder cancer with an unfavorable forecast. The effectiveness of mitomycin electrophoresis is approximately 2 times superior with such a passive diffusion of the chemotherapy. Thus, the full effect after 3 and 6 months was, respectively, 53% and 58% for electrochemistry and 28% and 31% - for intrapaulic chemotherapy with mitomycin. On the contrary, the results of intravenous electro farms and immunotherapy BCG were similar: the full effect after 3 and 6 months was 56% and 64% in the BCG group. Thus, it was concluded that with a bladder cancer with an unfavorable outlook, electrochemistry of efficiency significantly exceeds the passive diffusion of the chemotherapy and comparable to the BCG immunotherapy.

There is a good portability of the method, the toxicity of intravenous electrochemistry is not significantly different from the usual. The systemic side effects and hematological toxicity associated with the possible absorption of the drug in the bloodstream were not observed both in studies using mitomycin C and when using doxorubicin. Animals have shown that carcinomatous areas of the package 100 times are 100 times more permeable for water and electrolytes than normal urobates. It is very likely that carcinomatous areas have less electrical resistance than normal aiming and, thus, some specificity is noted for the introduction of drugs in these areas.

The use of local microwave hyperthermia. As is known from literature, malignant cells are more sensitive to heat than normal cells. Hyperthermia causes inhibition of DNA synthesis, RNA and protein. These changes can be fatal for the cell if the recovery mechanisms are not effective. Local Hyperthermia (Synergo) showed the synergistic effect of cell death when used in combination with chemotherapy for the treatment of many solid tumors, including the bladder transition-cell carcinoma. At the same time, with the help of special microwave equipment and special catheters (Fig. 1), the temperature of the bladder walls is brought to 42 ° C.

Figure 1. System for intravenous hyperthermia (synergo). EUR. Ur., 46, 1, 2004.

Patients relatively tolerate combined chemical thermotherapy. Most side effects are localized, transient and cannot be the cause of treatment interruption. During the procedure, patients usually note the weak bearing at urination and occasionally a feeling of burning in the urethre. In some cases, the preventive purpose of anticholinergic drugs significantly reduces these symptoms. In several patients, a thermal reaction was revealed on the rear wall of the bladder, which proceeded asymptomatic and was resolved without any intervention. The location of this thermal reaction corresponds to the location of the tip of the intrapaulic applicator, which ensures the effect of microwave hyperthermia. The use of hyperthermia reduces the percentage of recurrence to 14.3% a year after treatment, and 2 years to 24.6%. The progression of stage or graduation was not detected. According to A.G. Van der Heiden.et al When using hyperthermia with a prophylactic target, 15 out of 24 patients with an average observation period of 35.3 months, there were no relapses. When using this method, with the aim of ablation in 12 patients from 28, a complete tumor remission was observed, 83.3% of which remained free from tumors for an average of 20 months.

Dimethyl sulfoxide widely used in the treatment of interstitial cystitis (DMSO. , The solution with anti-inflammatory and bacteriostatic activity) causes analgesia and nerves blockade, inhibition of cholinesterase, vasodilation and muscle relaxation. DMSO has the ability to penetrate the fabric without their substantial defeat. It is used to increase the absorption by the urinary bubble of such chemotherapeutic drugs as cisplatin, piraroindicin and doxorubicin.

Other methods are currently under study. In particular, we are talking about the use of bioadhesive microspheres with gelatin material, which adhere to the mucous bladder, contributing to the controlled release of the drug. A study was conducted using such a new method of intravenous administration of Paclitaxel, in which the animals show high efficiency in ablation of low-differentiated tumors.

New experimental drugs

In order to achieve maximum intravenous treatment efficacy a number of studies of new drugs were conducted.

The anthracycline agent Pirarbitsin (Tetrahydropional-doxorubicin) is the only drug with proven effectiveness in the prevention of relapses after the tour. However, no published articles were found, in which a comparative characteristic was carried out with other frequently used drugs (doxorubicin, mitomycin C, epirubicin or adriamycin). Varubitsin, grasintetic derivative of adriamycin, revealed some advantage in patients with BCG-resistant CIS in the first and second phases of clinical research . Despite the absence of randomized studies of Warubicin approved for use in the United States for intravenous treatment of patients with BCG-resistant CIS.

Very high, histologically confirmed efficiency in 67.4% of cases in the second phase of studies showed the use of 6 intravenous instillations of 4 mg of the preparation of APAZIQUONE (EO9, EOQUIN). The drug is inactive, i.e. It needs activation by cell reductase enzymes to manifest their cytotoxicity. Enzyme dioxitimidine-diaphoraza (Dtd. ) Plays a central role in the activation of the EO9, and about 40% of the urinary bubble tumors have higher activityDtd. Compared to the normal cloth of the bladder, which confirms the possibility of achieving selective toxicity against tumor cells. In preclinical studies, the concentration of EO9 necessary to achieve 50% of cell death is 6-78 times less than that of mitomycin C, depending on the line of cancer cells used.

Hemcitabine - a preparation with a wide range of antitumor activity. After penetrating the cell, it is phosphorylated in DNA and RNA, which in turn leads to the suppression of cell growth (43.44). In the systemic purpose, gemcitabine exhibits significant activity against invasive bladder cancer as monotherapy, with an effectiveness of 27% -38%. In the II phase of clinical studies, hemcitabine intravenous instillations during the marker tumors of the average degree of risk, in 60% of cases led to the total regression of the tumor.

Alcoholoid Barwinka Vinorelbine is used in non-cellular lung cancer, metastatic cancerglands, prostate cancer, Material resistant to hormone therapy (in combination with small doses GKS for receiving inside). In the i-phase of clinical studies, Vinorlebin showed a pro-apoptotic effect with a bladder cancer. Molecular levels affect the dynamic equilibrium of the tubulin in the microtubule apparatus, suppresses the tubulin polymerization, binding mainly with mitotic microtubes, and in higher concentrations also has an effect on axonal microtubules. Preparation blocks mitosis of cells at the metafase stage G2-M, causing cell death. During the interphase or under the subsequent mitosis.

Meglumin Gamma Linoleic Acid is an indispensable fatty acid with cytostatic activity, which showed similar effectiveness in comparison with other intrapaulic drugs in the phase of studies.

Suramina is an antitripanosomal preparation with antitumor properties that blocks the binding of the epidermal growth factor (EGF) with its receptors (EGFR). In the phase of studies, the possibility of this treatment method was confirmed, due to its low systemic and local toxicity.[ 51].

Among other techniques are conducted studies of photosensitive drugs, which, with local administration in the bladder, selectively accumulate in tumor cells. After the intravenous administration of the light source, the cytotoxic effect of these drugs is manifested. Photodynamic therapy (PDT) is successfully used in surface bladder cancer, which could not be cured with a tour, with primary CIS, and in the case of BCG-resistant tumors. PhotoFrine was the first photosensitive drug used to treat surface bladder cancer, but he had strongly expressed side local and system effects. In a study that covered the 51 patient with the same and / or T1, the staging of transitional cellular cancer of the bladder, the full response was obtained in 41%, while 39% was detected a partial response after one session of photodynamic therapy. For papillary transient cell cancer, a tumor size was measured: the full response was observed only if the tumor diameter was less than 2 cm. In a multifocal, randomized study, which included 36 patients, preliminary data showed a decrease in tumor recurrences from 83% to 33% (improvement by 50%) when using one session of photodynamic therapy after a complete cloud tumor tour. The average recurrence time has increased from 3 to 13 months with single, adjuvant photodynamic therapy. There are not enough for remote data on the prevention of recurrence and progression of tumor after photodynamic therapy.

So R.Waidelich et al was prescribed 5-aminolevulinic acid (5-ALA) orally. At the same time, in 3 of 5 patients with CIS and 4 of 19 patients with papillary tumors during 36 months of observation of relapses were not detected. In most patients, hemodynamic side effects were noted, such as hypotension and tachycardia. These systemic side effects can be avoided by 5-ALA intra-duty instillations. A.P.Berger.et al 31 patients were examined, of which 10 previously conducted BCG immunotherapy. The average observation period was 23.7 months, in 16 patients recurrence of tumors were not identified, including 4 out of 10, in which BCG therapy turned out to be ineffective. The side effects were the infection of the urinary tract and hematuria.

Figure 2. Photodynamic therapy action mechanism (medcape)

The mechanism of action of photodynamic therapy (Fig. 2) includes: a cytotoxic effect caused by singlet oxygen and free radicals; damage to the endothelium of vessels with thrombosis and hypoxia; Intensive local inflammation in combination with an immune response. Consequently, PDT causes symptoms of cystitis (the so-called post-PDT syndrome): frequent urination, imperative urge to urination, niccountura, pain in the derivative area and the spasm of the bladder. The intensity and duration of symptoms directly depends on the dose of photodynamic therapy, the degree of damage to the detrier after the previous treatment, the intensity of acute inflammation and the presence of carcinoma in situ (which increases the capture of photofrin). The most dangerous side effect of the FDT is a steady bladder contracture, which was detected according to various studies in 4% -24% of patients.

Porphymer sodium is another photosensitive drug for instillation, which showed efficiency with CIS, resistant to BCG. Hypericin and recently developed PAD-S31 showed high efficiency in the destruction of the bladder tumors in experimental animals. Despite all studies conducted by photodynamic therapy, the study of these drugs in humans is still limited to an uncontrollable and non-radomized number of individual cases (III level of evidence).

With proper selection and training of patients, problems with photosensitivity of the skin are minimal. However, for 6 weeks after the injection of photoFrina, insolation should be avoided. The introduction of new photosensitizers and the simplification of the WB-PDT laser will lead to wider use of photodynamic therapy in the treatment of bladder cancer.

Possible oral chemorals, such as Tagafur, Eflornitin Diflouromethylornitin, Tipfarnib, Fenretinide, Cellotoxib, Vitamins, Fluoroquinolones (and other antibiotics) can be effective in vitro and in animal experiments. There is so far only the phase of 3 randomized clinical studies on people showing that the long-term oral use of Tegafur (5-fluorouracyl predecessor) after the tour, prevents the recurrence of the surface transition-cellular carcinoma of the bladder. Oral chemoral drugs may also be applied in the future as an addition to intra-peer chemotherapy, but it is not believed that they can completely replace the instillations after the tour. In fact, synergistic interaction is possible, because They have different mechanisms of action and methods of application. Although it seems unlikely that the orally used drug can be as effective as the highly concentrated drug with direct contact with the tumor.

Combined use of drugs

Theoretically, one of the advantages of consistent use of chemotherapy and immunotherapy can be various mechanisms of impact with the amplification of antitumor effect. The second advantage is to increase the activity of fibronectin against the background of the development of chemical cystitis, which can have a positive effect on the adhesion of particles of the BCG with the wall of the bladder. The main negative torque of the combination of the chemotherapeutic preparation with BCG is a possible increase in toxicity. In the studyEORTC. With marking tumors, the sequential use of a mitomycian C (4 instillations) and BCG (6 instillations) in patients with low stage tumors and gradation leads to full regression of the tumor in 69% of cases. With CIS, a combination of intravenous chemical immunotherapy is much more efficient in relation to the recurrence frequency for 24 months and the duration of the non-dedicated period.

Some researchers propose to apply experimental cytotoxic drugs to improve the efficiency of conventional chemotherapeutic drugs. The basis is the concept of the synergistic effect of two drugs with a different mechanism of action. Tamoxifen, ciprofloxacin, gamma-linoleic acid, Suramin were investigated in combination with intravical drugs on several generations of cells and animals (mice), with obtaining encouraging results. There is only one clinical study on the oral use of Tigufur in combination with intrapaulic therapy after a tour that showed some better results compared only with intrapaulic therapy. However, no statistical data was demonstrated in this study. Although the joint use of drugs is a fairly attractive approach, there are currently no evidence and documented studies on this topic in order to recommend combinations of drugs to use.

Modulating agents

Modulating agents are non-quotoxic compositions that enhance the effect of some chemotherapeutic drugs. Their appearance contributed to the identification of certain biochemical processes, which were involved in the mechanisms for the development of drug resistance. The possibility of using pharmacological intervention was studied to restore the sensitivity to drugs. There are clinical, well-documented examples in oncology, such as the use of leivojin in combination with a 5-fluorouracyl with a thick bowel cancer, stomach, breast.

Verapamil, calcium channel blocker, inhibits the activity of glycoprotein P-170 and is the most studied modulator with surface bladder cancer. Glycoprotein P-170 acts as a pump of membrane channels, causing leakage of anthracyclines and other chemotherapeutic agents, making cells resistant to their effects. A large amount of in vitro colonies of the bladder cancer cells, and in vivo in animal experiments showed that verapamil joins resistant cells, blocks glycoprotein R-170, thereby improving the cytostatic effect of epirubicin, piraroindicine, tiotepa, adriamycin, peplubicin, and mitomycin with . Verapamil was also studied in humans, which showed significantly better results of preventive use of a combination of verapamil with adriamycin compared with one adriamycin after the tour (I level of prognosis) in the III phase of randomized research. 157 patients participated in the study, the average observation period- 38.5 months. In the group of patients receiving adriamycin as a monotherapy, the frequency of relapses was significantly higher. However, no significant differences were found in the ablative effect of a combination of adriamycin with verapamil compared with adriamycin monotherapy for marker tumors in the II phase of a clinical study. Thus, there is a sufficient number of evidence in favor of additional use of verapamil to adriamycin in recurrence prevention after the tour. The optimal dose is 5 ampoules of verapamil (25mg / 10ml of physiological solution) to adriamycin (50mg / 40ml of the physiological solution), to achieve a total volume of 50ml. Verapamil inexpensive, does not cause local side effects, cardiovascular disorders, because Does not go into systemic bloodstream.

Glycoprotein P-170 can also be inhibited by steroid hormones, etramstin, which has been demonstrated in in vitro experiments on the colonies of the bladder cancer cells. The second generation of glycoprotein inhibitors P-170 is studied and includes drugs such as Byrique and Valfodar. The latter was carefully studied in clinical studies and showed high toxicity and dubious efficacy. The less toxic third generation of modulators, including drugs such as Tariquidar, Zosuquidar, Laniquidar, and Ont-093 are currently being investigated in the II and II phase of studies.

Tests for chemical sensitivity. The choice of intravenous drug is usually based on the ability or experience of circulation with a specific agent in clinical practice. However, inappropriate chemotherapy failures are mainly related to resistance to one or more drugs. The choice of drug based on chemical sensitive tests, as opposed to empirical therapy, is a new approach in research.

It would be possible to consider the testing of the drug over marker tumors, as a sample of the chemical sensitive test in vivo, used on patients, which is often done in the II phase of studies. Theoretically, instillation performed to the tour could evaluate the effectiveness of the drug in clinical practice. A positive response as an indicator is an incentive to continue further instillations after the tour. However, in this case, only one drug can be tested.

In vitro research allows you to compare the effectiveness of different chemotherapy products by treating the primary culture of cells obtained in biopsy, various chemotherapy, and determine the cytotoxicity of each of them. Chemical Tests have already been developed for cancer of the stomach, thick and rectum, esophagus, liver, pancreas, a hematopoietic system, lungs, ovaries, breasts, heads and neck, brain, leather, bones, thymus, parachite gland, kidneys, urinary Bubble, eggs. Despite the limited tests in vitro and their dubious extrapolation on the results of in vivo, the benefit from the conduct of chemical sensitive tests has already been demonstrated during multiform glioblastomas and other types of cancer.

It has recently been studied that, together with unicellular mechanisms of resistance, such as the expression of glycoprotein P-170 MDR-1 gene, multicellular mechanisms are involved in drug resistance. As a result of adhesion cell-to-cell and cell-to-stroma, multicellular resistance can be demonstrated only in three-dimensional cultures. Tumor spheroids are reproduced in vitro not only single-cellular, but also multicellular mechanisms of resistance, becoming a more reliable model for determining the chemical sensitivity of drugs. Recently, a test for determining the chemical sensitivity for a bladder cancer based on the use of three-dimensional spheroid culture was carried out.

In vitro chemical sensitivity studies can be used to determine the individual sensitivity of the tumor to several drugs before instillation. They could routinely be used in clinical practice to choose a better preparation for each patient and potentially reduce the proportion of relapses or delay their appearance. These tests are expensive and time-consuming, but the cost of profitability would be positive if it was possible to avoid ineffective instillations. This would lead to a decrease in recurrence, preventing operational intervention and reduction of complications. However, so far no study showed evidence of the clinical efficacy of tests on chemical sensitivity at surface transitional cell carcinoma. Although the proportion of relapses is expected to reduce the tests on chemical sensitivity in clinical practice too early.

Conclusion

The level I evidence indicates the need for early postoperative intravenous instillation with all surface tumors (degree of recommendations a). A further treatment is also recommended for 4- and 8-week courses in the tumors of the intermediate degree of risk (degree of recommendations a). Supporting therapy for up to 6 months is likely to increase the effectiveness of treatment, although there are no convincing evidence of this (degree of recommendations from). The use of fluid should be limited, and the urologist should trace the bladder to be designed before instillation (degree of recommendations C). Oral use of desmopressin can be appointed to avoid further excessive dissolution of the chemotherapy (degree of recommendations C). Urine's leaning with sodium bicarbonate is desirable to improve the action of Mitomycin C (degree of recommendations C). Verapamil can be instilled together with adriamycin (degree of recommendations A) or with other chemotherapy preparations (degree of recommendations B) to increase their effectiveness. Local hyperthermia and EMDA are available methods that can be applied in each treatment institution based on the cost of cost profitability (degree of recommendations a).

Literaturebut

  1. Kurth K.h., Bouffioux C., Sylvester R., Van der Meijden A.P., Oosterlinck W., Brausi M .. The Eorthc Genitourinary Group. Treatment of Superficial Bladder Tumors: Achevements and Needs. EUR UROL. 2000; 37: 1-9.
  2. Bohle A., Jocham D., Bock P.R .. INTRAVESICAL BACILLUS CALMETTE-GUERIN VERSUS MITOMYCIN C FOR SUPERFICIAL BLADDER CANCER: A FORMAL META-ANALYSIS OF COMPARATIVE STUDIES ON RECURRENCE AND TOXICITY. J Urol. 2003; 169: 90-95.
  3. Bohle A., Bock P.R .. INTRAVESICAL BACILLE CALMETTE-GUERIN VERSUS MITOMYCIN C IN SUPERFICIAL BLADDER CANCER: Formal Meta-Analysis of Comparative Studies on Tumor Progression. Urology. 2004; 63: 682-686Discussion 6-7.
  4. Sylvester R.J., Van Der Meijden A., Lamm D.L .. IntraveSical Bacillus Calmette-Guerin Reduces The Risk of Progression in Patients with Superficial Bladder Cancer: A Meta-Analysis of the Published ReSults of Randomized Clinical Trials. J Urol. 2002; 168: 1964-1970.
  5. Pawinski A., Sylvester R., Kurth K.h. et al .. A Combined Analysis of European Organization for Research and Treatment of Cancer, And Medical Research Council Randomized Clinical Treatment of Stage Tat1 Bladder Cancer. European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group And The Medical Research Council Working Party on Superficial Bladder Cancer. J Urol. 1996; 156: 1934-1940, 40-1.
  6. van der Meijden A.P., Sylvester R., Oosterlinck W., et al .. Eau Guidelines on the Diagnosis and Treatment of Urothelial Carcinoma in Situ. EUR UROL. 2005; 48: 363-371.teruo M., Watanabe H., Kobayashi t. ABSORPTION OF ANTI-CANCER DRUGS THROUGH Bladder Epithelium. Urology, 27: 148, 1986.
  7. Kamat A.M., Lamm D.L .. INTRAVESICAL THERAPY FOR BLADDER CANCER. Urology. 2000; 55: 161-168.
  8. Fujii Y., Kawakami S., Koga F., Nemoto T., Kihara K .. Long-Term Outcome of Bladder Papillary Urothelial Neoplasms of Low Malignant Potential. BJU INT. 2003; 92: 559-562.
  9. Sylvester R.j., Oosterlinck W., Van der Meijden A.P .. A Single Immediate Postoperative InStillas of Chemotherapy Decreases The Risk of Recurrence in Patients with Stage Ta T1 Bladder Cancer: A Meta-Analysis of Published Results of Randomized Clinical Trials. J Urol. 2004; 171: 2186-2190quiz 435.
  10. Van der Meijden a.p.m., Bohle A., Oosterlinck W., et al. Guidelines on Non-Muscle Invasive Bladder Cancer: European Association of Urology; 2001.
  11. Kaasinen E., Rintala E., Hellstrom P., et al. FINNBLADDER GROUP. Factors Explaining Recurrence in Patients undergoing Chemoimmunotherapy Regimens for Frequently Recurring Superficial Bladder Carcinoma. EUR UROL 2002; 42: 167-174.
  12. Bouffioux C., Kurth K.h., Bono A., et al. European Organization for Research and Treatment of Cancer Genitourinary Group. Intravesical adjuvant chemotherapy for superficial transitional cell bladder carcinoma: results of two European Organization for Research and Treatment of Cancer randomized trials with mitomycin C and doxorubicin comparing early versus delayed instillations and short-term versus long-term treatment. J Urol. 1995; 153: 934-941.
  13. Sylvester R.j., Oosterlinck W., Witjes J.A. .. The Schedule and Duration of IntraveSical Chemotherapy in Patients with non-Muscle Invasive Bladder Cancer: A Systematic Review of the Published Results of Randomized Clinical Trials. EUR UROL 2008; 53: 709-719.
  14. Au J.L., Badalament R.A., WientJes M.G., et al. Methods to Improve Efficacy of IntraveSical Mitomycin C: Results of a Randomized Phase III Trial. J Natl Cancer Inst. 2001; 93: 597-604.
  15. Cliff A.M., Heatherwick B., Scotle J., Parr N.J. The Effect of Fasting Or Desmopressin Before Treatment On The Concentration of Mitomycin C During Intravestic Administration. BJU INT. 2000; 86: 644-647.
  16. Gasion Burgues J.P., Jimenez Cruz J.F. Improving Efficacy Of IntraveSical Chemotherapy. EUR UROL 2006; 50: 225-234.
  17. Stillwell G.K. Electric Stimulation and iontophoresis. In: Handbook of Physical Medicine and Rehabilitation, 2nd Ed. Edited by f.h. Rrussen. St. Louis: W.B. Saunders Co., Chapt. 14, 1971.
  18. ROLVEVICH A.I., Sukonko OG, Red S.A., Zhukovets A.G. Inspaudgment electrophoresis of doxorubicin with surface bladder cancer. The results of a prospective randomized study http://urobel.uroweb.ru/news/id-15.
  19. Brausi M., Campo B., Pizzocaro G., Rigatti P., Parma A., Mazza G., Vicini A., Stephen R.L. INTRAVESICAL ELECTROMOTIVE ADMINISTRATION OF DRUGS FOR TREATMENT OF SUPERFICIAL BLADDER CAN-CER: A Comparative Phase II Study. Urology 1998; 51: 506-509.
  20. GURPINAR T., Truong L.D., Wong H.Y., Griffith D.P. Electromotive Drug Administration to the Urinary Bladder: An An Animal Model and Preliminary Results. J. Urol. 1996; 156: 1496.
  21. Riedl C.R., Knoll M., Pflugeer H .. Detrusor Stimulation by IntraveSical Emda of Bethanechol. J. EndouroL., Suppl. 10: P7-236, 1996.
  22. Di Stasi S.M., Castagnola M., Vespasiani G., Giannantoni A., Cancrini A., Micali F., Stephen R.L. In Vitro Study of Passive VS Electromotive Mitomycin with Diffusion in Human Bladder Wall. Preliminary Results. J Urol 151: 447A, 1994.
  23. Colombo R., Brausi M., Da Pozzo L.F., Salonia A., Montorsi F., Scattoni V., Roscigno M., Rigatti P. Thermo-Chemotherapy and Electromotive Drug Administration of Mitomycin with in Superficial Bladder Cancer Eradication. A Pilot Study ON MARKER LESION. EUR. Urol. 2001. V. 39. P. 95-100.
  24. Di Stasi S., Giannantoni A., Stephen R., Navarra P .., Capelli G., Massoud R., Vespasiani G. INTRAVESICAL ELECTROMOTIVE MITOMYCIN C VERSUS PASSIVE TRANSPORT MITOMYCIN C FOR HIGH RISK SUPERFICIAL BLADDER CANCER: A PROSPECTIVE RANDOMIZED STUDY . J Urol. 2003. V. 170. 777-782.
  25. Giannantoni A., Di Stasi S.m., Chancellor M.B., Constantini E., Porena M .. New Frontiers in IntraveSical Therapies and Drug Delivery. EUR UROL 2006; Vol.50, Issue 6: 1183-1193.
  26. Hicks R.M., Ketterer in., Warren R.C .. The Ultrastructure and Chemistry of the Mammalian Urinary Bladder: A Structure with Low Permeability to Water and Ions. Phil. Trans. Roy. SOC. London Biol. Sci., 268: 23, 1974.
  27. Meyer J.L. The Clinical Efficacy of Localized Hyperthermia. Cancer RES 1984; 44: 4745-4751.
  28. Colombo R., Brausi M., Da Pozzo L. et al .. Thermo-Chemotherapy and Electromotive Drug Administration of Mitomycin C in Superficial Bladder Cancer Eradication A Pilot Study on Marker Lesion. EUR UROL. 2001; 39: 95-100.
  29. Di Stasi S.M., Giannantoni A., Stephen R.L. ET AL .. INTRAVESICAL ELECTROMOTIVE MITOMYCIN C VERSUS PASSIVE TRANSPORT MITOMYCIN C FOR HIGH RISK SUPERFICIAL BLADDER CANCER: A PROSPECTIVE RANDOMIZED STUDY. J Urol. 2003; 170: 777-782.
  30. Van der Heijden A.G., Kiemeney L.A., Gofrit O.N., et al. Preliminary European Results of Local Microwave Hyperthermia and Chemotherapy Treatment In Intermediate or High Risk Superficial Transitional Cell Carcinoma of The Bladder. EUR UROL. 2004; 46: 65-71Discussion 72.
  31. Colombo R., Da Pozzo L.F., Salonia A., et al. MultiCentric Study Comparing IntraveSical Chemotherapy Alone and With Local Microwave Hyperthermia for Prophylaxis of Recurrence of Superficial Transitional Cell Carcinoma. J clin oncol. 2003; 21: 4270-4276.
  32. Colombo R., Lev A., Da Pozzo L., Freschi M., Gallus G., Rigatti P .. A New Approach using Local Combined Microwave Hyperthermia and Chemotherapy in Superficial Transitional Bladder Carcinoma Treatment. J urol 1995; 153: 959-963.
  33. Melchior D., Packer C.S., Johnson T.C., Kaefer M .. Dimethyl Sulfoxide: Does It Change the Functional Properties of the Bladder Wall? J urol 2003; 170: 253-258.
  34. LU Z., YEH T.K., TSAI M., AU J.L., WientJes M.G .. PaclitaXEL-Loaded Gelatin Nanoparticles for IntraveSical Bladder Cancer Therapy. CLIN CANCER RES. 2004; 10: 7677 -7684.
  35. Eroglu M., Irmak S., ACAR A., Denkbas E.B .. Design and Evaluation of a Mucoadhesive Therapeutic Agent Delivery System for Postoperative Chemotherapy in Superficial Bladder Cancer. INT J Pharmacol. 2002; 235: 51-59.
  36. Le Visage C., Rioux-Leclercq N., Haller M., Breton P., Malavaud B., Leong K .. Efficacy of Paclitaxel Released from Bio-Adhesive Polymer MicroSpheres on Model Superficial Bladder Cancer. J Urol. 2004; 171: 1324-1329.
  37. Okamura K., ONO Y., Kinukawa T. et al. Randomized Study of Single Early Instillation Of (2? R) -4? -O-TetrahydropyRanyl-Doxorubicin for a Single Superficial Bladder Carcinoma. Cancer. 2002; 94: 2363-2368.
  38. Steinberg G., Bahnson R., Brosman S., Middleton R., Wajsman Z., Wehle M .. The Valrubicin Study Group. Efficacy and Safety of ValrubiCin for the Treatment of Bacillus Calmette-Guerin Refractory Carcinoma in Situ of the Bladder. J Urol. 2000; 163: 761 -67.
  39. HENDRICKSEN K., WITJES J.A. Treatment of Intermediate Risk Non-Muscle Invasive Blabber Cancer. EUR UROL 2007; Suppl. 6: 800-808.
  40. Witjes J.A. Management of BCG Failures In Superficial Bladder Cancer: A Review. EUR UROL 2006; 49: 790-797.
  41. Li D., Gan Y., Wientjes M.G., Badalament R.A., Au J.L .. Distribution of DT-Diaphorase and Reduced Nicotinamide Adenine Dinucleotide Phosphate: Cytochrome P450 Oxidoreductase in Bladder Tissues and Tumors. J urol 2001; 166: 2500-2505.
  42. Gontero P., Tizzani A .. IntraveSical Gemcitabine: State of the Art. EUR UROL 2007; Suppl. 6: 800-808.
  43. Witjes J.A., Van der Heijden A.G., VRIESEMA J.L., Peters G.J., Laan A., Schalken J.A. INTRAVESICAL GEMCITABINE: A Phase 1 and Pharmacokinoetic Study. EUR UROL. 2004; 45: 182-186.
  44. Palou J., Carcas A., Segarra J. et al. Phase I Pharmacokinoetic Study of A Single Intravesical Instillation of Gemcitabine Administered Immediately After Transurethral Resection Plus Multiple Random Biopsies in Patients with Superficial Bladder Cancer. J Urol. 2004; 172: 485-488.
  45. Serretta V., Galuffo A., Pavone C., Allegro R., Pavone-macaluso m. Gemcitabine in IntraveSical Treatment of Ta-T1 Transitional Cell Carcinoma of Bladder: Phase I-II Study On Marker Lesions. Urology. 2005; 65: 65-69.
  46. Gontero P., Casetta G., Maso G. et al. Phase II Study to Investigate The Ablative Efficacy of IntraveSical Administration of Gemcitabine In Intermediate Blidder Cancer (SBC). EUR UROL. 2004; 46: 339-343.
  47. Bonfil R.D., Gonzalez a.d., SiguelBoim D. et al. Immunohistochemical Analysis of Ki-67, P21Waf1 / CIP1 and Apoptosis in Marker Lesions from Patients Treated with Vinorelbine IntraveSical Therapy in a Preliminary Phase I Trial. BJU INT. 2001; 88: 425 -431.
  48. Bonfil R.D., RUSSO D.M., Binda M.M., Delgado F.m., Vincenti M .. Higher Antitumor Activity of Vinflunine Than Vinorelbine Against An Orthotopic Murine Model of Transitional Cell Carcinoma of the Bladder. Urol oncol. 2002; 7: 159-166.
  49. Harris N.M., Crook T.J., Dyer J.p. et al. INTRAVESICAL MEGLUMINE GAMMA-LINOLENIC ACID IN SUPERFICIAL BLADDER CANCER: AN EFFICACY STUDY. EUR UROL. 2002; 42: 39-42.
  50. Uchio E.M., Linehan W.M., Figg W.D., Walther M.M. A Phase I Study of IntraveSical Suramin for the Treatment of Superficial Transitional Cell Carcinoma of the Bladder. J Urol. 2003; 169: 357-360.
  51. Berger A.P., Steiner H., STENZL A., AKKAD T., BARTSCH G., HOLTL L .. PHOTODYNAMIC THERAPY WITH INTRAVESICAL INSTILLATION OF 5-AMINOLEVULINIC ACID FOR PATIENTS WITH RECURRENT SUPERFICIAL BLADDER CANCER: A SINGLE-CENTER STUDY. Urology. 2003; 61: 338-341.
  52. Waidelich R., Beyer W., Knuchel R. et al. Whole Bladder Photodynamic Therapy With 5-Aminolevulinic Acid using A White Light Source. Urology. 2003; 61: 332-337.
  53. NSEYO U.O., DEHAVEN J., Dougherty T.J. et al. Photodynamic Therapy (PDT) in The Treatment of Patients WITH Resistant Superficial Bladder Cancer: A Long-Term Experience. J Clin Laser Med Surg. 1998; 16: 61-68.
  54. Waidelich R., Stepp H., Baumgartner R., Weninger E., Hofstetter A., \u200b\u200bKreigmair M .. Clinical Experience With 5-Aminolevulinic Acid and Photodynamic Therapy for Refractory Superficial Bladder Cancer. J urol 2001; 165: 1904-1907.
  55. Lamm D., Colombel M., Persad R., Soloway M., Bohle A., Palou J., Witjes Ja, Araza H., Buckley R., Brausi M .. Clinical Practice Recommendations for the Management of Non-Muscle Invasive Bladder Cancer. EUR UROL 2008; Suppl. 7: 651-666.
  56. Rintala E., Jauhiainen K., Kaasinen E., Nurmi M., Alfthan O .. Alternating Mitomycin C and Bacillus Calmette-Guerin Instillation Prophylaxis for Recurrent Papillary (Stages Ta to T1) Superficial Bladder Cancer. FINNBLADDER GROUP. J urol 1996; 156 (1): 56-59.
  57. van der Heijden A.G., Witjes J.A. INTRAVESICAL CHEMOTHERAPY: AN UPDATE - NEW TRENDS AND PERSPECTIVES. EAU UPDATE SERIES 2003; Vol.1, No.2: 71-79.
  58. Witjes J.A., Caris C.T., Mungan N.A., Debruyne F.M., Witjes W.P ..Results of A Randomized Phase III Trial of Sequential IntraveSical Therapy with Mitomycin C and Bacillus Calmette-Guerin Versus Mitomycin C Alone in Patients with Superficial Bladder Cancer. J urol 1998; 160 (5): 1668-1671.
  59. Server Pastor G., Rigabert Montiel M., Banon Perez V. et al. Oral Tegafur Plus Mitomycin Versus IntraveSical Mitomycin Alone In The Prevention of Recurrence in Stage Ta Bladder Tumors. ACTAS UROL ESP. 2003; 27: 438-441.
  60. Naito S., Kotoh S., Omoto T. et al. The Kyushu University Urological Oncology Group. PROFHYLACTIC INTRAVESICAL INSTILATION CHEMOTHERAPY AGAINST RECURRENCE After A Transurethral Receection of Superficial Bladder Cancer: A Randomized Controlled Trial Of Doxorubicin Plus Verapamil Versus Doxorubicin Alone. Cancer Chemother Pharmacol. 1998; 42: 367 -372.
  61. Tsushima T., Ohmori H., Ohi Y. et al. INTRAVESICAL INSTILLATION CHEMOTHERAPY OF ADRIAMYCIN WITH OR WITHOUT VERAPAMIL FOR THE TREATMENT OF SUPERFICIAL BLADDER CANCER: THE FINAL RANTS OF A COLLABORATIVE RANDOMIZED TRIAL. Cancer Chemother Pharmacol. 1994; 35: S69-S75.
  62. Greenberg P.L., Lee S.J., Advani R. et al. Mitoxantrone, etoposide, and Cytarabine WITH OR WITHOUT OR REFRACTORY ACUTE MYELOID LEUKEMIA AND HIGH-RISK MYELODYSPLASTIC SYNDROME: A PHASE III TRIAL (E2995). J clin oncol. 2004; 22: 1078-1086.
  63. Thomas H., Coley H.M. Overcoming Multidrug Resistance In Cancer: An Update On The Clinical Strategy of Inhibiting P-Glycoprotein. Cancer Control. 2003; 10: 159-165.
  64. IWADATE Y., FUJIMOTO S., NAMBA H., YAMAURA A .. PROMISING SURVIVAL FOR PATIENTS WITH GLIOBLASTIMA MULTIFORME TREATED WITH INDIVIDUALED CHEMOTHERAPY BASED ON IN VITRO DRUG SENSITITIBY TESTING. Br j Cancer. 2003; 89: 1896-1900.
  65. Burgues J.P. A Chemosensitivity Test for Superficial Bladder Cancer Based On Three-Dimensional Culture of Tumour Spheroids From Biopsy Specimens: Ph.D. dissertation. University of Valencia MEDICAL SCHOOL; Valencia, Spain; 2005.
  66. Oddens J.R, Van der Meijden A.P.M., Sylvester R .. One Immediate Postoperative Instillation of Chemotherapy In Low Risk Ta, T1 Bladder Cancer Patients. Is IT Always Safe? EUR UROL. 2004; 46: 336-338.
  67. Manyak M.j, Ogan K .. Photodynamic Therapy for Refractory Superficial Bladder Cancer: Long-Term Clinical Outcomes of Single Treatment Using IntraveSical Diffusion Medium. J endouroL. 2003; 17: 633-639.
  68. Kamuhabwa A.A, Roskams T., D'Hallewin M.A., Baert L., Van Poppel H., De Witte P.a .. Whole Bladder Wall PhotoNamic Therapy of Transitional Cell Carcinoma Rat Bladder Tumors Using IntravestiCally Administered Hypericin. Int j Cancer. 2003; 107: 460-467.
  69. Asanuma H., Arai T., Morimoto Y. et al. Photodynamic Therapy with Pad-S31, A New Hydrophilic Chlorin Photosensitizer, In An Orthotopic Rat Bladder Tumor Model. J Urol. 2005; 174: 2016-2021.
  70. Nseyo U.O. Photodynamic therapy. In Lamm D.L., ED. The Urologic Clinics of North America, Philadelphia, PA: W.B. Saunders CO.; 1992; 19: 591-599.
  71. Nseyo U.O., Crawford E.D., Shumaker B. et al. Photodynamic Therapy AS An Alternative to Cystectomy in Refractory Carcinoma in Situ. Proceedings of the American Association of Cancer Research 86th Annual Meeting; 1995 March 18-22; Toronto, Canada: 36: A1856.

Chemotherapy for bladder cancer is most often used in a complex with surgical treatment. This is due to the fact that malignant tumors of this body in 80% of cases are found on early stages, Therefore, they may be radical removal. The use of chemotherapy improves the results of treatment and increases survival.

Features of chemotherapy with bladder cancer

Chemotherapy with bladder tumors reduces the frequency of recurrences after surgical treatment and stops the progression of the disease.

In specialized centers, in most cases, preference is given to the combined treatment of bladder cancer. It combines surgical intervention (most often it is transurethral resection, or tour), chemotherapy and rauchery therapy. The effectiveness of treatment depends on the set of factors, among which early diagnosis, the stage of the disease, general state Patient, adequate therapy scheme and continuous monitoring for timely detection of relapses.

Types of chemotherapy

The following types of chemotherapy are used to treat bladder cancer:

  1. Intravenous. Used in surface tumors after a tour to prevent the occurrence of malignant foci in other parts of the organ. This treatment method is used when carcinoma is detected. The most common and efficient technique is the intravenous introduction of the BCZH-vaccine. It is applied by the course. The first dose is introduced immediately after the operation, the subsequent 6 sessions are conducted at intervals per week, and then supporting therapy is assigned for 1-3 years. The course allows you to significantly reduce the risk of relapses and improve the quality of life.
  2. Adjuvant therapy. It is conducted internally after radical removal of the tumor. To do this, a combination of 3-4 drugs are chosen, which are introduced in the early postoperative period, then 6-8 times weekly, and then in the form of supporting treatment for up to 3 years. Preparations of doxorubicin, mitomycin C, epirubicin, cisplatin, methotrexate are used.

The main criterion for choosing the drug is effectiveness and lower toxicity compared to others. It is believed that mitomycin, which relates to a group of antitumor antibiotics and directly affects the process of dividing malignant cells, gives the best results to prevent relapses. Cisplatin is often used to prevent tumor metastasis, especially after radical cystectomy.

  • Neoadjuvant therapy.It is assigned to the operation to reduce the volume of the tumor (its invasive forms that germinate into the muscular layer) and transfer it to the Operator state. This allows you to improve the forecast of surgical intervention and survival of patients. For such therapy, various combinations of chemotherapy are used.
    • Standard schemes for neoadjuvant chemotherapy are created, such as MVAC (methotrexate, vinblastine, doxorubicin, carboplatin), CMV (cisplatin, methotrexate, vinblastine), GC (hemcitabine, cisplatin). Unfortunately, they are sufficiently toxic, so permanent work is underway to find new, less toxic drugs that will give no less satisfactory results. However, the use of such treatment schemes before operational intervention quite often allows you to choose an organ-bearing operation, which further affects the quality of the life of patients.
    • A number of studies have proved the advantages of using neoadjuvant therapy: practically 2 times increased the survival of patients, the number of relapses increased.
  • Palliative therapy. It is prescribed for non-metering, in particular, the local strip of bladder cancer. Cisplatin, methotrexate, downtown, vinblastine, as well as hemcitabine in various combinations are used. Several clinical trials confirmed that in such a situation, the gemcitabine scheme + cisplatin is less toxic while maintaining efficiency. Such therapy reduces the size of the tumor and its toxic effect on the body, thus improving the quality of life of patients.

When carrying out chemotherapy in men and women, a tumor response for treatment is taken into account, after which the decision to continue the selected scheme or change it to more efficiently. The following answer options are possible:

  1. A complete answer is the disappearance of tumor formations within 4 weeks.
  2. A partial response is to reduce the total tumor sizes by 50% or more of the initial for 4 weeks.
  3. Stabilization - there is no progress of the disease, but at the same time dimensions decreased not so much as with a full or partial response.
  4. Progression is an increase in the existing tumor, the emergence of a new focus or complications directly related to the disease.

Analysis of the results of the use of chemotherapy showed that efficiency depends largely on the stage of the disease: the greater the prevalence of the tumor, the less expressed effect. Also affects the number of courses. With each re-exchange rate, the number of full and partial answers is growing. If there is no time for two courses for treatment, then chemotherapy is usually stopped.

Features and advantages of chemotherapy in the CM Clinic oncology center

Our oncology-urologists explore and adopt advanced foreign experience, international treatments. The scheme and dosage are selected for each patient with the attending physician. The diagnosis is taken into account, the overall condition, the presence of related diseases, the effectiveness of the drug, the response of the tumor for treatment and individual tolerance, as well as the recommendations of related specialists. Already proven domestic and foreign preparations with minimal toxicity are applied.

The treatment plan necessarily includes supporting and detoxification therapy. Further rehabilitation activities are held to restore organs and systems affected by chemotherapy. This is especially true of the hematopoietic system, gastrointestinal tract And the kidneys, since the bulk of side effects is associated with them.

Chemotherapy for bladder cancer in men and women is carried out in the CM Clinic oncology center after a thorough examination, studying the results of analyzes and instrumental research, setting and clarifying the diagnosis. Perhaps both independent appeal to the center and in the direction of other medical institutions.

The treatment is carried out outpatient, in a day hospital, and if necessary, with round-the-clock observation in the hospital department of oncurology. At the same time, a convenient schedule of visits, taking into account the treatment regimen and the wishes of the patient.

Also proposed further patient maintenance with regular consultations and control examinations.

Contraindications to chemotherapy

For chemotherapy with a bladder tumor there are a number of contraindications. These include:

  • Increased sensitivity to one of the preparations included in the treatment protocol.
  • Pronounced violations in the work of liver and kidneys, which are assessed by the results of preliminary analyzes.
  • Heavy chronic diseases.
  • Pregnancy.

In this case, another treatment method is selected, or chemotherapy is postponed until the state is improved (if possible).

Read also ...

Uranium - Planet of insights, intuition and astrology House Horoscope in Gemini

Uranium - Planet of insights, intuition and astrology House Horoscope in Gemini

Uranus in 1 house in a woman. First house. Articles from the rubric

Uranus in 1 house in a woman. First house. Articles from the rubric

What is dangerous agglutination of spermatozoa?

What is dangerous agglutination of spermatozoa?

Best on the site
1

Non-necrotic agnus: symptoms and treatment of necrosis Almonds The causative agent of ulcer necrotic angina
2

What signs of the zodiac are suitable for twins on a horoscope?
3

Who fits a woman twins on a horoscope
4

What names come to each other by date of birth - compatibility in numerology
5

Compatibility of male and female names in marriage and love
New
How to arrange a New Year's wallpaper?

How to arrange a New Year's wallpaper?

"Gas to what dream in a dream?
Who has some ears. The size of the ears. What are the big and small ears talk about. People with square shape ears

Who has some ears. The size of the ears. What are the big and small ears talk about. People with square shape ears
Meaning Aries Zodiac Sign

Meaning Aries Zodiac Sign
Sleep come in feces

Sleep come in feces
Interpretation of sleep: refrigerator

Interpretation of sleep: refrigerator
Horoscope for october for woman sign scales horoscope scale monkey for october

Horoscope for october for woman sign scales horoscope scale monkey for october
The happiest and unhappy men's names according to Astrologs & NBSP Successful Male Names

The happiest and unhappy men's names according to Astrologs & NBSP Successful Male Names

We recommend to read