Chemotherapy for bladder cancer is considered one of the main treatment methods. Drug treatment of abnormal cellular structures with antitumor drugs is used both to improve surgical performance and to relieve the painful symptoms of this disease if surgery is impossible. And although this technique has a large number of negative consequences, without it the complete destruction of malignant neoplasms is difficult.

Antitumor treatment consists of introducing various toxic substances into the human body that can effectively destroy cells that have undergone a mutation process, which stops their further growth and suppresses their activity. antitumor drugs are prescribed to each cancer patient individually. This therapy consists of several courses, since a single administration of drugs is not capable of providing the desired therapeutic effect.

Worth knowing! Currently, a new and quite promising method is being used for antitumor drug treatment of bladder cancer, giving leading oncologists hope of achieving almost complete cure for malignant neoplasms in the future. This technique, which is an alternative to standard conventional treatment, is called targeted therapy. During its implementation, the drug introduced into the body of a cancer patient has a targeted effect on certain tumor structures and processes characteristic of them, thereby slowing down the growth and aggression of the tumor.

Harms and benefits of chemotherapy treatment

This type of therapeutic effect, which has a large number of undeniable advantages, very often threatens patients with negative and often irreparable consequences.

Chemotherapy for bladder cancer is characterized by the following advantages, for which it is often preferred in clinical oncological practice:

• abnormal cells are often completely destroyed thanks to this method of treatment;
• chemistry allows you to effectively control the development of the oncological process, since all chemotherapy drugs slow down the growth of mutated cellular structures. This allows specialists to monitor their spread and promptly destroy secondary malignant foci;
• drug antitumor treatment helps alleviate the painful symptoms that accompany it, as it reduces the size of the malignant neoplasm, and it ceases to put pressure on muscle structures and nerve endings;
• this method of therapy can be used not only as the main method of treatment, but also in combination with surgery and radiation.

The above advantages of chemistry, with the help of which any type of cancer is eliminated, indicate that systemic, endolymphatic and local or, as it is called, intravesical chemotherapy occupy one of the main places in the fight against bladder cancer. To get a chance to prolong their life or completely recover from this oncological pathology with the help of chemistry, many people pay a lot of money. Although, as statistics show, positive results are often illusory. Often, treatment with highly toxic drugs prolongs life by only a few months, and in some cases even brings death closer due to the fact that it promotes increased growth of metastases. The greatest harm that this procedure can cause to the human body is that chemotherapy drugs destroy healthy cells that are in the mitosis (division) phase, along with malignant ones that are always dividing. The most harmful effects of anticancer drugs are on the digestive and reproductive systems, as well as on the bone marrow, which is directly involved in the production of red blood cells. Often this effect of chemistry turns out to be fatal for a person.

Important! Despite the fact that many have heard about the dangers of chemistry, you should not categorically refuse this type of treatment. Often, only chemotherapy drugs for bladder cancer, despite multiple adverse reactions, can prolong a person’s life while maintaining its quality. It should be strictly remembered that the benefits of chemistry are directly dependent on how accurately the doctor’s recommendations are followed, who, in the process of selecting a course and regimen of antitumor treatment, took into account the characteristics of the human body, his age, as well as the stage of development and nature of the cancer.

Preparation and administration of chemotherapy

A diagnosis of oncology indicates that the body’s immune forces are very much depleted, and the physical condition of the body is at one of the stages of decay. At this time, chemotherapy, the main components of which are biological or synthetic poisons and cytotoxic agents, wears out the body’s resources even more, so before starting the treatment course, cancer patients require special preparation. First of all, it is necessary to take vacation or sick leave during chemotherapy, which will allow you to reduce physical activity as much as possible.

Secondly, it is imperative to follow the following recommendations of a specialist:

• undergo a mandatory course of treatment for diseases accompanying the pathological condition;
• cleanse the body of toxins that accumulate in it as a result. This will help achieve maximum effect from taking anticancer drugs;
• ensure protection of the urinary system, liver and gastrointestinal tract with the help of medications recommended by the attending physician;
• communicate with a psychologist and people who have undergone chemistry, which will allow you to prepare mentally.

The first procedure of antitumor drug treatment is carried out in an inpatient setting, under the supervision of a leading oncologist. This allows the doctor to track the effects of chemotherapy drugs and, if necessary, replace them with analogues. In the future, in case of bladder cancer, outpatient systemic chemotherapy is most often allowed. The patient takes oral medications at home, and comes to the clinic to perform intramuscular or intravenous injections, undergo regular blood tests and undergo an examination. In cases where a large number of courses of drug treatment are planned, a special catheter is installed in the patient’s vein. It allows you to avoid additional injury and accidental infection.

Schemes and courses

After an accurate diagnosis has been made and established, the specialist selects a more appropriate treatment protocol for the patient in each specific case using chemotherapy. It consists of prescribing a specific regimen for taking individually selected medications. For bladder cancer, modern medicine uses antitumor drugs such as VM-26, Ftorafur, Diiodobenzotef, Mitomycin C,. Their doses are selected depending on the main characteristics of the malignant neoplasm and the general condition of the person, and the name of the regimen consists of the first Latin letters of the drugs.

To most effectively destroy malignant tumors of the bladder, specialists usually prescribe a chemotherapy regimen, called MVAC in clinical practice.

This is a combination of four anticancer drugs administered in individual patient-specific cycles:

• M - Methotrexate.
• V – .
• A – Doxorubicin.
• C – Cisplatin.

But there are exceptions here. So, if there is a history of heart cancer, the use of Cisplatin is unacceptable in case of kidney pathologies. Most often, chemotherapy accompanies. In case of bladder cancer, this mutual effect of medications and radiation is most effective. Courses of therapy capable of destroying a tumor in the bladder are directly dependent on its location and the extent of the malignant process. Usually their number ranges from 3 to 6 with a mandatory rest interval of 2-4 weeks.

Rehabilitation: nutrition, possible diets

After a treatment course with the help of toxic cytostatics, a cancer patient necessarily needs to restore the body. Rehabilitation of a person who has undergone chemotherapy consists of raising his immunity. This is possible not only by taking certain vitamin complexes and medications, but also by maintaining a healthy lifestyle, as well as correction. The daily diet of a patient undergoing chemotherapy for bladder cancer should contain foods from four main food groups.

Moreover, it should be strictly maintained both during courses and in breaks between them:

1. Dairy. Products from this group are necessary for a person undergoing chemotherapy at least twice a day. Particular attention should be paid to fermented milk products enriched with bifidobacteria.
2. Fruit and vegetable. It includes both fresh and dry or cooked vegetables and fruits, as well as juices and fresh juices from them. They are eaten at least three times a day.
3. Bread and cereal. Any grains and seeds that are best consumed sprouted, cereals and baked goods.
4. Protein. It includes lean varieties of fish and meat, liver, eggs, legumes, and nuts.

From these products you can easily create a complete and tasty menu for every day. It must include vegetable and butter, as well as mayonnaise. This is necessary to increase the calorie content of food. In addition to this diet, microelements and a multivitamin complex are needed, which will be recommended by the attending physician. You should also strengthen your drinking regime with compotes and natural juices.

Dietary considerations during chemotherapy

Chemotherapy that destroys bladder tumors has an adverse effect on the gastrointestinal tract, which interferes with normal nutrition. At the same time, the general good condition of the cancer patient and, accordingly, increasing the susceptibility of his body to the effects of anticancer drugs depend on a correct and complete diet.

1. Food intended for a person with a tumor in the bladder should be freshly prepared and exclusively from fresh ingredients.
2. Only a balanced diet is acceptable. Sandwiches, fast food and snacks on the run are strictly prohibited.
3. Products must be selected based on the fact that they bear as little load as possible on the kidneys and liver, which are the target for the first blow of chemistry.
4. It is imperative to maintain a balance between the energy consumed by the patient and the energy supplied with food.
5. Semi-finished products, canned food, smoked foods, fatty, salty and spicy foods are subject to categorical exclusion from the diet.

Important! By following the correct diet, you can reduce the amount of tableted microelements, minerals and vitamins, which in some cases can be harmful. All this will enter the cancer patient’s body with products, which a professional nutritionist will help you choose in each specific case.

Complications and consequences of chemotherapy treatment for bladder cancer

Strong antitumor drugs can cause severe effects that are quite difficult to get rid of. Typically, patients undergoing chemotherapy suffer from many physiological complications.

In clinical practice, the following consequences of chemotherapy for bladder cancer are noted:

1. Risk of secondary infection. During chemotherapy, the production of leukocytes decreases and, as a result, the body's immune defense is weakened.
2. Unrelated occurrence of bleeding and hematomas. Thrombocytopenia, which accompanies antitumor treatment, provokes a decrease in blood clotting.
3. Nausea and vomiting. Their appearance is directly influenced by an increase in the level of toxins in the body of a person undergoing chemotherapy.
4. Chemotherapy provokes inhibition of sperm, which leads to a decrease in their number and damage to the genetic apparatus. As a consequence of this, the strong half of humanity develops infertility after a course of chemotherapy.
5. Chemotherapy ends in early menopause, which also provokes reproductive dysfunction.
6. Loss of appetite, resulting from atrophy of the sense of taste.
7. Alopecia (baldness). This negative consequence of chemistry lasts about six months after the end of the course, and then the hair begins to grow back.

It should be noted that intravesical chemotherapy for bladder cancer has exactly the same consequences, although they are much less pronounced in this case. In addition to them, this type of chemistry is accompanied by painful sensations and burning in the urethra. But, despite this, in no case should you refuse antitumor drug treatment, since all these negative phenomena disappear after completing the therapeutic course and adequate rehabilitation measures. It usually takes from 3 to 6 months to completely stop them.

Informative video

In intravesical therapy for bladder cancer, drugs are injected directly into the bladder through a catheter, rather than being injected into a vein or taken in tablet form. Immunotherapy and chemotherapy can be carried out using the method.

Intravesical chemotherapy. Single intravesical instillation of chemotherapy after TUR.

If the superficial tumor can be completely and safely removed during TUR without evidence of deep invasive growth, a single instillation can be prescribed after surgery. If you have multiple tumors, a single instillation is not prescribed, if the surgery involves deep layers of the bladder wall, there is a risk of bladder perforation, or post-operative bleeding is too severe.

A single instillation immediately after surgery destroys tumor cells floating in the TUR fluid and kills residual tumor cells at the site of removal. This reduces the risk of relapse. It is recommended to carry out instillations as early as possible, usually within several hours after TUR.

The drugs are injected directly into the bladder through a catheter, which is inserted during or after a TURBT. The main side effects of intravesical instillation are irritation and a burning sensation in the bladder, which disappear after a few days.

Additional intravesical chemotherapy after TUR.

Additional intravesical chemotherapy after surgery depends on the risk group. If you are at low risk of recurrence and progression, then a single instillation after TURBT is sufficient to reduce the risk of recurrence and is considered standard treatment. If you have an average-risk tumor, a single instillation may not be enough, so additional doses of chemotherapy may be required. The optimal number and frequency of instillations have not been determined.

Intravesical immunotherapy BCG (Bacillus Calmette-Guerin)

Bacillus Calmette-Guerin (BCG) is a strain of attenuated live bovine tubercle bacilli. For this reason, it is very important to tell your doctor about any history of tuberculosis, even if it was only suspected. You should tell us about any immunotherapies you have had in the past.

BCG activates the immune system, causing superficial inflammation in the bladder, which attracts and stimulates immune cells to destroy cancer cells. Treatment usually begins a few weeks after TUR and is given once a week for 6 weeks. Long-term “maintenance” BCG therapy is sometimes accomplished by extending therapy to 12-36 months. Studies have shown that BCG therapy reduces the risk of progression of all types of muscle-invasive tumors.

Toxicity of BCG

BCG treatment is known to have more side effects than intravesical chemotherapy. BCG can cause a burning sensation in the bladder and flu-like symptoms: fever, chills and fatigue. Rarely, BCG enters the circulatory system and spreading to other organs leads to a generalized infection (sepsis). In this case, a severe fever may occur that does not improve with medication. In such a situation, you need to contact your doctor, who will prescribe antibacterial drugs used to treat tuberculosis for several weeks.

Treatment of side effects of immunotherapy and chemotherapy

Side effects may be common, common, or uncommon. You need to tell your doctor about any symptoms you have. Try to describe your symptoms as accurately as possible. Notice how often they happen and how they affect your daily life. In some cases, temporarily interrupting treatment, changing the dose, or stopping treatment altogether may be considered.

Common Side Effects

Some common side effects include fatigue, nausea, diarrhea, high blood pressure, and changes in taste.

You may experience fatigue, i.e. feeling more tired than usual, feeling weak, less alert, and not feeling any better after sleep.

If you are experiencing fatigue, some methods may help:

• Write down the things that make you feel energized and give them priority throughout the day or week.
• Ask for help with household chores
• Short-term sleep of 1-1.5 hours is required several times during the day.
• Try to be as active as you can. A short walk every day is better than a long walk once a week.

During treatment, you may experience nausea and vomiting. You will be prescribed symptomatic treatment. It may also help:

• Eating less food but drinking plenty of fluids throughout the day.
• Eat more cold foods than hot ones. Hot foods cause nausea more often.

Another common side effect of treatment is diarrhea, which can lead to dehydration. Important:

• Drink more than usual.
• Avoid foods that you think make your diarrhea worse.
• Maintain good personal hygiene
• Consult your doctor for symptomatic therapy

Blood pressure may also increase, especially at the beginning of treatment. This is normal with this type of therapy. Blood pressure can be controlled with medications prescribed by your doctor. If you have dizziness or headache, you should tell your doctor.

Chemotherapy can cause changes in your sense of taste. You may feel disgusted by the foods you are used to. The best way to find out what kind of food you like is to try different things:

• Drink water before meals to neutralize taste receptors.
• If red meat seems weird, try white meat or fish, or vice versa.
• If hot food feels weird, try eating it cold or vice versa.
• Try using more or less spices
• Use a plastic fork and knife if there is a metallic taste.

This article reviews the published data regarding intravesical chemotherapy for superficial bladder cancer. The level of evidence is based on the sources of information: meta-analysis, systematic review, randomized and non-randomized controlled clinical trials, and uncontrolled studies or consensus documents.

The first step in the treatment of superficial papillary transitional cell carcinomas is transurethral resection, which allows you to accurately determine the stage and grading of the tumor. However, after TUR transitional cell carcinomas recur in 50%-80% of cases and progression of the tumor process is observed in 14% of cases. Therefore, adjuvant chemotherapy or immunotherapy is recommended. Immunotherapy with the BCG vaccine remains the most effective form of intravesical treatment in preventing recurrence and progression of superficial bladder cancer. However, the use of BCG can be accompanied by a significant number of side effects, including potentially fatal complications, such as BCG sepsis, infectious lesions of the lungs, liver, kidneys, and prostate gland. Intravesical chemotherapy does not have such disadvantages, but its effectiveness is insufficient, since the urothelium represents an almost impenetrable barrier to intravesically administered substances. Intravesical chemotherapy also reduces recurrence rates, but the effectiveness of available chemotherapy drugs in preventing tumor progression remains unproven. A. M. Kamat et al, in their review of the literature, reported relapse rates of 44%, 39%, 36%, and 39% with thiotepa, adriamycin, mitomycin C, and epirubicin, respectively. Despite almost identical effectiveness, the drugs differ in their toxicity and, accordingly, in the severity of side effects.

Therefore, research is aimed at increasing the effectiveness of intravesical chemotherapy. At the same time, various approaches to solving this problem are proposed. Some researchers aim to select the most optimal timing of instillations, others - to improve the pharmacokinetics of chemotherapy drugs by reducing their dilution, increasing stability or improving the absorption of drugs from the bladder mucosa. Some researchers are exploring the use of new chemotherapeutic agents or their combination. Suggested methods to avoid chemoresistance using modulating agents or testing in vitro for chemosensitivity to determine the most sensitive drug.

Instillation time

Research to determine the optimal time of instillation has been carried out since the beginning of the first experiments on the use of intravesical chemotherapy for bladder cancer. In the last few years, various clinical studies have proven the effectiveness of a single intravesical instillation immediately after TUR for any form of transitional cell carcinoma of the bladder. Even the least malignant bladder tumors, such as papillary urothelial neoplasms with low malignant potential, recur in 34% of cases within the first 2 years, 50% within 5 years, and 64% of cases within 5 years.- within 10 years. For these tumors, as well as other low-risk tumors, early single instillation can reduce the risk of recurrence by 39%. Early single dose chemotherapy is recommended by the European Urological Association (EUA) as the treatment of choice after TUR for low-risk tumors and as an initial step in the treatment of high-risk tumors. Meta-analysis conducted within EORTC (European Organization for Research and Treatment of Cancer) found no significant difference in effectiveness among different chemotherapy drugs. If bladder perforation is suspected, instillation should not be performed to avoid serious complications. Instillation time is also of great importance. In all studies, including the EORTC meta-analysis, instillations were administered within the first 24 hours. E. Kaasinen et al found that the risk of recurrence doubles if instillation is not carried out within 24 hours after TUR.

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 an early single instillation, to continue treatment for 4-8 weekly instillations.

The question of how long treatment should last remains controversial. Randomized study conducted EORTC showed that prescribing a maintenance course of chemotherapy for 1 year (one instillation per month) does not provide any advantages compared to a 6-month course of treatment if the patient received the first instillation immediately after TUR of the tumor. Based on 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-term treatment regimen. The latter may be recommended if early instillation of the chemotherapy drug was not carried out.

Improving the pharmacokinetics of drugs for intravesical administration

Dilution in residual urine or excessive diuresis during the exposure period, instability of major chemotherapeutic agents at low urinary pH values, inadequate exposure period, and limited penetration of drugs into the bladder wall are all factors that may contribute to the failure of intravesical chemotherapy. Several recommendations are proposed for implementation in clinical practice in order to increase drug delivery to tumor cells.

Preventing drug dilution. Particular attention should be paid to completely emptying the bladder before administering chemotherapy. Repositioning the catheter or changing the patient's position may further help with this.

It has been shown that limiting fluid intake 6 hours before each instillation reduces diuresis and prevents drug dilution by 20%. This simple technique is also recommended by the EUA protocol for superficial bladder cancer.

Oral administration of 0.2 mg of desmopressin 1 hour before each instillation is an even more effective method, increasing the intravesical concentration of the drug by an average of 38%. The potential clinical benefits of desmopressin may be somewhat limited by its side effects. However, it may be used to rule out heart failure or hyponatremia. Liquid intake should be limited 1 hour and 8 hours after desmopressin administration to avoid fluid retention in the body.

Alkalinization of urine. The stability of the drug, cellular uptake and penetration into the deep muscle layers of mitomycin C increases when urine is alkalinized using oral sodium bicarbonate. A dose of 1.5 g the night before, in the morning and 30 minutes before each instillation is sufficient to achieve optimal urine pH (>7).

Duration of exposure to chemotherapy drugs. Patients should be advised to retain the injected solution for 2 hours.

However, there are no studies indicating that this technique reduces the incidence of relapse, so the recommendation is based on indirect evidence gleaned from various sources.

Increased permeability of the bladder wall. In recent years, a number of devices have been developed to increase the permeability of drugs used for intravesical administration. Despite their relative novelty, their effectiveness has been proven in a number of studies.

Intravesical electrophoresis of chemotherapy drugs. The principle is based on the electrokinetic movement of charged (ionic) molecules in an electric field. Unlike passive diffusion of a drug, which depends on a concentration gradient, electrophoresis is much more effective and, above all, depends on the current strength and the amount of electricity supplied. Positive drug ions are introduced into the tissue by the anode, negative ions by the cathode. Transport of uncharged solutions is enhanced by two additional electrokinetic phenomena: electroosmosis - the transport of non-ionized molecules as hydration shells of ionized particles, and electroporation - increased tissue permeability under the influence of an electric field. Subsequently, a number of experimental studies have been carried out to support the concept of increasing the transport of drugs through the urothelium into the deeper layers of the bladder wall (detrusor) using drug electrophoresis. Thus, S. Di Stasi et al showed significantly increased rates of transfer of mitomycin C and oxybutynin into the viable bladder wall under the influence of electrophoresis. Laboratory studies using human bladder preparations have demonstrated that drug electrophoresis increases the transport of mitomycin C across the urothelium by 6-9 times compared to passive diffusion. In a study by R. Colombo et al on a model of marker tumors, the effectiveness of electrochemotherapy with mitomycin (20 minutes) was approximately equal to the effectiveness of intravesical instillation of mitomycin (2 hours) (the rate of complete regressions obtained in both groups was 40%). The relapse rate in responding patients was higher in the mitomycin instillation group (60%) than in the electrochemotherapy group (33%). Time to relapse was longer in the mitomycin electrochemotherapy group (mean 14.5 months versus 10 months).

In September 2003, the results of a phase III study comparing the effectiveness of BCG, mitomycin C electrophoresis and intravesical instillation of mitomycin C in the treatment of superficial bladder cancer with a poor prognosis were reported. The efficiency of mitomycin electrophoresis was approximately 2 times higher than that of passive diffusion of the chemotherapy drug. Thus, the overall effect after 3 and 6 months was, respectively, 53% and 58% for electrochemotherapy and 28% and 31% for intravesical chemotherapy with mitomycin. In contrast, the results of intravesical electrophoresis and BCG immunotherapy were similar: the complete response at 3 and 6 months was 56% and 64%, respectively, in the BCG group. Thus, it was concluded that for bladder cancer with a poor prognosis, electrochemotherapy is significantly more effective than passive diffusion of chemotherapy and comparable to BCG immunotherapy.

The method is well tolerated; the toxicity of intravesical electrochemotherapy does not differ significantly from conventional therapy. Systemic side effects and hematologic toxicity associated with possible absorption of the drug into the bloodstream were not observed in either studies using mitomycin C or doxorubicin. It has been shown in animals that carcinomatous areas of urothelium are 100 times more permeable to water and electrolytes than normal urothelium. It is likely that carcinomatous areas have less electrical resistance than normal urothelium and thus there is some specificity for drug delivery to these areas.

Application of local microwave hyperthermia. As is known from the literature, malignant cells are more sensitive to heat than normal cells. Hyperthermia causes inhibition of DNA, RNA and protein synthesis. These changes can be fatal to the cell if the repair mechanisms are not effective. Local hyperthermia (synergo) has shown a synergistic cell death effect when used in combination with chemotherapy to treat many solid tumors, including transitional cell carcinoma of the bladder. 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. Intravesical hyperthermia system ( synergo). Eur. Ur., 46, 1, 2004.

Patients tolerate combined chemotherapy and thermotherapy relatively well. Most side effects are localized, transient and cannot cause treatment interruption. During the procedure, patients usually note a slight urge to urinate and occasionally a burning sensation in the urethra. In some cases, prophylactic administration of anticholinergic drugs significantly reduces these symptoms. Several patients had a thermal reaction on the posterior wall of the bladder, which was asymptomatic and resolved without any intervention. The location of this thermal reaction corresponds to the location of the tip of the intravesical applicator, which provides the effect of microwave hyperthermia. The use of hyperthermia reduces the relapse rate to 14.3% one year after treatment, and after 2 years to 24.6%. No progression of stage or gradation was detected. According to A.G. Van Der Heiden et al when hyperthermia was used for prophylactic purposes in 15 of 24 patients with an average follow-up of 35.3 months, no relapses were detected. When this technique was used for ablation, 12 of 28 patients experienced complete tumor remission, 83.3% of whom remained tumor-free for an average of 20 months.

Dimethyl sulfoxide (DMSO) is widely used in the treatment of interstitial cystitis. DMSO , a solution with anti-inflammatory and bacteriostatic activity), causes analgesia and nerve blockade, cholinesterase inhibition, vasodilation and muscle relaxation. DMSO has the ability to penetrate tissue without causing significant damage. It is used to increase bladder absorption of chemotherapy drugs such as cisplatin, pirarubicin and doxorubicin.

Other methods are currently under investigation. In particular, we are talking about the use of bioadhesive microspheres with gelatinous material, which adhere to the bladder mucosa, facilitating the controlled release of the drug. A study was conducted using this new method of intravesical administration of the drug paclitaxel, in which high efficiency in ablation of poorly differentiated tumors was shown in animals.

New experimental drugs

In order to achieve maximum effectiveness of intravesical treatment A number of studies of new drugs have been carried out.

The anthracycline agent pirarubicin (tetrahydropyranyl-doxorubicin) is the only drug with proven effectiveness in preventing relapses after TUR. However, no published articles were found that compared it with other commonly used drugs (doxorubicin, mitomycin C, epirubicin, or adriamycin). Valrubicin, a semisynthetic derivative of Adriamycin, showed some benefit in patients with BCG-resistant CIS in a phase 1 and 2 clinical trial . Although there are no randomized trials, valrubicin is approved for use in the United States for the intravesical treatment of patients with BCG-resistant CIS.

Very high, histologically confirmed effectiveness in 67.4% of cases in the second phase of studies was shown by the use of 6 intravesical instillations of 4 mg of the drug apaziquone (EO9, EOquin). The drug is inactive, i.e. requires activation by cellular reductase enzymes to exhibit its cytotoxicity. Enzyme dioxythymidine diaphorase ( DTD ) plays a central role in EO9 activation, and about 40% of bladder tumors have higher activity DTD , compared with normal bladder tissue, which confirms the possibility of achieving selective toxicity against tumor cells. In preclinical studies, the concentration of EO9 required to achieve 50% cell death is 6-78 times less than mitomycin C, depending on the cancer cell line used.

Gemcitabine is a drug with a wide spectrum of antitumor activity. After entering the cell, it is phosphorylated into DNA and RNA, which in turn leads to inhibition of cell growth (43,44). When administered systemically, gemcitabine exhibits significant activity against invasive bladder cancer as monotherapy, with an efficacy of 27%-38%. In phase II clinical trials, intravesical instillation of gemcitabine for moderate-risk marker tumors led to complete tumor regression in 60% of cases.

Vinca alkaloid vinorelbine is used for non-small cell lung cancer, metastatic cancergland, prostate cancer, milk resistant to hormone therapy (in combination with small doses of GCS for oral administration). In phase I clinical trials, vinorelbine showed a pro-apoptotic effect in bladder cancer. Vinorelbine at the molecular level affects the dynamic equilibrium of tubulin in the microtubule apparatus of the cell, suppresses the polymerization of tubulin, binding predominantly to mitotic microtubules, and at higher concentrations also affects axonal microtubules. The drug blocks cell mitosis at the G2-M metaphase stage, causing cell death during interphase or during subsequent mitosis.

Meglumine gamma-linoleic acid is an essential fatty acid with cytostatic activity, which showed similar effectiveness compared to other intravesical drugs in phase I studies.

Suramin is an antitrypanosomal drug with antitumor properties that blocks the binding of epidermal growth factor (EGF) to its receptors (EGFr). In phase I studies, the feasibility of this treatment technique was confirmed due to its low systemic and local toxicity[ 51].

Among other techniques, studies are being carried out on photosensitive drugs that, when administered locally into the bladder, selectively accumulate in tumor cells. After intravesical administration of a light source, the cytotoxic effect of these drugs appears. Photodynamic therapy (PDT) has been successfully used for superficial bladder cancer that could not be cured with TUR, for primary CIS, and for BCG-resistant tumors. Photofrin was the first photosensitive drug used to treat superficial bladder cancer, but it had significant local and systemic side effects. In a study of 51 patients with stage Ta and/or T1 transitional cell carcinoma of the bladder, 41% had a complete response, while 39% had a partial response after one session of photodynamic therapy. For papillary transitional cell carcinoma, tumor size mattered: a complete response was observed only if the tumor diameter was less than 2 cm. In a multifocal, randomized study of 36 patients, preliminary data showed a reduction in tumor recurrence from 83% to 33% (50% improvement) using a single session of photodynamic therapy after complete TUR of a bladder tumor. The mean time to relapse increased from 3 to 13 months with single, adjuvant photodynamic therapy. Long-term data on the prevention of tumor relapses and progression after photodynamic therapy are not yet sufficient.

So R. Waidelich et al prescribed 5-aminolevulinic acid (5-ALA) orally. However, in 3 out of 5 patients with CIS and in 4 out of 19 patients with papillary tumors, no relapses were detected during 36 months of follow-up. Most patients experienced hemodynamic side effects, such as hypotension and tachycardia. These systemic side effects can be avoided by intravesical instillation of 5-ALA. A.P.Berger et al 31 patients were examined, 10 of whom had previously received BCG immunotherapy. The average follow-up period was 23.7 months; no recurrence of tumors was detected in 16 patients, including 4 out of 10 in whom BCG therapy was ineffective. Side effects included urinary tract infection and hematuria.

Figure 2. Mechanism of action of photodynamic therapy (Medscape)

The mechanism of action of photodynamic therapy (Fig. 2) includes: cytotoxic action caused by singlet oxygen and free radicals; damage to the vascular endothelium with thrombosis and hypoxia; intense local inflammation combined with an immune response. Consequently, PDT causes symptoms of cystitis (the so-called post-PDT syndrome): urinary frequency, urgency, nocturia, suprapubic pain and bladder spasm. The intensity and duration of symptoms is directly related to the dose of photodynamic therapy, the degree of detrusor damage from previous treatment, the intensity of acute inflammation, and the presence of carcinoma in situ (which increases Photofrin fixation). The most dangerous side effect of PDT is persistent bladder contracture, which was identified in various studies in 4%-24% of patients.

Sodium porfimer is another photosensitive instillation drug that has shown effectiveness in BCG-resistant CIS. Hypericin and the newly developed PAD-S31 have shown high efficiency in the destruction of bladder tumors in experimental animals. Despite all the research conducted on photodynamic therapy, human studies of these drugs are still limited to uncontrolled and non-randomized case series (level III evidence).

With proper patient selection and education, problems with skin photosensitivity are minimal. However, sun exposure should be avoided for 6 weeks after Photofrin injection. The introduction of new photosensitizers and the simplification of the WB-PDT laser will lead to increased use of photodynamic therapy in the treatment of bladder cancer.

Possible oral chemopreventive drugs such as tegafur, eflornithine difluoromethylornithine, tipifarnib, fenretinide, celecoxib, vitamins, fluoroquinolones (and other antibiotics) may be effective in vitro and in animal experiments. There are so far only phase I 3 randomized clinical trials in humans showing that long-term oral administration of tegafur (a precursor to 5-fluorouracil) after TUR prevents recurrence of superficial transitional cell carcinoma of the bladder. Oral chemopreventive drugs may be used in the future as an adjunct to intravesical chemotherapy, but it is not believed that they can completely replace instillations after TUR. In fact, synergistic interactions are possible because they have different mechanisms of action and methods of application. Although it seems unlikely that an orally administered drug would be as effective as a highly concentrated drug given directly to the tumor.

Combined use of drugs

Theoretically, one of the advantages of sequential use of chemotherapy and immunotherapy may be different mechanisms of action with enhanced antitumor effect. The second advantage is the increase in fibronectin activity against the background of the development of chemical cystitis, which may have a positive effect on the adhesion of BCG particles to the bladder wall. The main negative aspect of combining a chemotherapy drug with BCG is the possible increase in toxicity. In the study EORTC with marker tumors, sequential use of mitomyce C (4 instillations) and BCG (6 instillations) in patients with low-stage and graded tumors leads to complete tumor regression in 69% of cases. For CIS, the combination of intravesical chemo-immunotherapy is significantly more effective in terms of 24-month recurrence rate and disease-free interval.

Some researchers have proposed using experimental cytotoxic drugs to improve the effectiveness of conventional chemotherapy drugs. It is based on the concept of a synergistic effect of two drugs with different mechanisms of action. Tamoxifen, ciprofloxacin, gamma-linoleic acid, suramin have been studied in combination with intravesical drugs in several generations of cells and in animals (mice), with encouraging results. There is only one clinical trial of oral tegafur in combination with intravesical therapy after TURBT, which showed slightly better results compared with intravesical therapy alone. However, no statistics were demonstrated in this study. Although the combined use of drugs is an attractive approach, there is currently no evidence or documented research on this topic to recommend combinations of drugs for use at this time.

Modulating agents

Modulating agents are non-cytotoxic compounds that enhance the effects of certain chemotherapy drugs. Their emergence was facilitated by the identification of certain biochemical processes that were involved in the mechanisms of drug resistance development. The possibility of using pharmacological intervention to restore drug sensitivity has been explored. There are clinical, well-documented examples in oncology, such as the use of leucovorin in combination with 5-fluorouracil for colon, stomach, and breast cancer.

Verapamil, a calcium channel blocker, inhibits the activity of P-170 glycoprotein and is the most studied modulator in superficial bladder cancer. Glycoprotein P-170 acts as a membrane channel pump, causing the leakage of anthracyclines and other chemotherapeutic agents, making cells resistant to their effects. A large number of in vitro studies of colonies of bladder cancer cells, and in vivo in animal experiments have shown that verapamil attaches to resistant cells, blocks the P-170 glycoprotein, thereby improving the cytostatic effect of epirubicin, pirarubicin, thiotepa, adriamycin, peplomycin and mitomycin C Verapamil was also studied in humans, which showed significantly better results of the prophylactic use of a combination of verapamil with Adriamycin compared with Adriamycin alone after TUR (level I evidence) in a phase III randomized trial.. The study included 157 patients, average follow-up period- 38.5 months. In the group of patients receiving Adriamycin as monotherapy, the relapse rate was significantly higher. However, no significant differences were found in the ablative effect of the combination of adriamycin with verapamil compared with adriamycin monotherapy on marker tumors in a phase II clinical trial. Thus, there is sufficient evidence to support the addition of verapamil to adriamycin in the prevention of relapse after TUR. The optimal dose is 5 ampoules of verapamil (25 mg/10 ml saline) to adriamycin (50 mg/40 ml saline), to achieve a total volume of 50 ml. Verapamil is inexpensive, does not cause local side effects, cardiovascular disorders, because does not enter the systemic circulation.

Glycoprotein P-170 can also be inhibited by steroid hormones, estramustine, as demonstrated in in vitro experiments on colonies of bladder cancer cells. A second generation of P-170 inhibitors is being studied and includes drugs such as biricodar and valspodar. The latter has been extensively studied in clinical studies and has shown high toxicity and questionable effectiveness. A less toxic third generation of modulators, including drugs such as tariquidar, zosuquidar, laniquidar, and ONT-093, is currently being investigated in phase I and II studies.

Chemosensitivity tests. The choice of intravesical agent is usually based on ability or experience with the specific agent in clinical practice. However, failure of intravesical chemotherapy is mainly due to resistance to one or more drugs. Drug selection based on chemosensitive tests, as opposed to empirical therapy, is a new approach in research.

One could consider testing the drug against marker tumors as a model for an in vivo chemosensitive test used in patients, which is often done in phase II studies. Theoretically, instillation performed before TUR could evaluate the effectiveness of the drug in clinical practice. A positive response, as an indicator, is an incentive to continue further instillations after TUR. However, in this case, only one drug can be tested.

An in vitro study allows you to compare the effectiveness of different chemotherapy drugs by treating a primary culture of cells obtained from a biopsy with different chemotherapy drugs, and determine the cytotoxicity of each of them. Chemosensitivity tests have already been developed for cancers of the stomach, colon and rectum, esophagus, liver, pancreas, hematopoietic system, lung, ovary, breast, head and neck, brain, skin, bone, thymus, parathyroid, kidney, urinary bladder, testicles. Despite the limitations of in vitro testing and its questionable extrapolation to in vivo results, the benefit of chemosensitive testing has already been demonstrated in glioblastoma multiforme and other types of cancer.

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

In vitro chemosensitivity testing can be used to determine individual tumor sensitivity to several drugs before instillation. They could be routinely used in clinical practice to select the best drug for each patient and potentially reduce or delay relapse rates. These tests are expensive and time-consuming, but the cost-benefit analysis would be positive if ineffective instillations could be avoided. This would lead to fewer relapses, avoid surgery, and reduce complications. However, no study has yet shown evidence of the clinical effectiveness of chemosensitivity tests in superficial transitional cell carcinoma. Although a reduction in relapse rates is expected, it is too early to use chemosensitivity tests in clinical practice.

Conclusion

Level I evidence suggests early postoperative intravesical instillation for all superficial tumors (Grade A recommendation). Further treatment with 4- and 8-week courses is also recommended for intermediate-risk tumors (grade of recommendation A). Maintenance therapy for up to 6 months is likely to improve treatment effectiveness, although there is no convincing evidence for this (grade of recommendation C). Fluid intake should be limited and the urologist should ensure that the bladder is emptied before instillation (Grade of recommendation C). Oral desmopressin may be prescribed to avoid further excess dissolution of the chemotherapy drug (Grade of Recommendation C). Urine alkalinization with sodium bicarbonate is desirable to improve the effects of mitomycin C (GR: C). Verapamil can be instilled together with Adriamycin (grade of recommendation A) or with other chemotherapy drugs (grade of recommendation B) to increase their effectiveness. Local hyperthermia and EMDA are available techniques that can be implemented in every health care setting based on a cost-benefit analysis (Grade of Recommendation A).

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Intravesical chemotherapy after TUR of superficial bladder cancer

An analysis of the treatment results of 77 patients with non-muscle-invasive bladder cancer who underwent TUR and intravesical chemotherapy was carried out. Tumor relapse was determined after intravesical chemotherapy in 10.4% of patients with an average time range of 23.1 months. Tumor progression was observed in 6.5% of cases.

It was found that the use of immediate (within 6 hours) intravesical chemotherapy after TUR for non-muscle-invasive bladder cancer leads to a significant reduction in the number of relapses and the risk of progression of bladder tumors, and the use of cisplatin along with mitomycin for intravesical chemotherapy provides better results in comparison with doxorubicin .

Rice. 1. Tumor stage

Rice. 2. Tumor differentiation

Rice. 3. Tumor size

Rice. 4. Number of tumors

Rice. 5. Number of tumor recurrences

Introduction

Bladder cancer is the second most common malignant disease of the genitourinary system and the second most common cause of death among genitourinary tumors. Approximately 75% of new cases of bladder cancer in the USA and Europe are limited to the mucosa and/or lamina propria, while in Russia this figure is only 20–30%. Treatment of non-muscle-invasive bladder cancer poses significant challenges for physicians and patients. Up to 80% of patients with non-muscle-invasive bladder cancer require treatment with transurethral resection (TUR) with intravesical chemotherapy or immunotherapy. The risk of recurrence of non-muscle-invasive bladder cancer approaches 80%. The relative importance of clinical and pathological factors in the course of the tumor process depends on the type of adjuvant intravesical therapy.

Adjuvant intravesical BCG therapy reduces the risk of tumor recurrence by 30% compared to TUR alone and prolongs the time to disease progression. Most researchers are of the opinion that to reduce the risk of relapse and progression of non-muscle-invasive bladder cancer, it is necessary to carry out intravesical chemotherapy immediately after TUR of the bladder tumor. The risk of tumor recurrence is statistically significantly reduced (to 16–50%) compared to patients who did not receive intravesical chemotherapy (32–34%), progression was noted in 8–17% and 11–63% of cases, respectively. The effectiveness of intravesical chemotherapy after TURBT for non-muscle invasive bladder cancer remains controversial. In this regard, we analyzed the results of treatment in patients with non-muscle invasive bladder cancer who received intravesical chemotherapy after TUR of the bladder.

Materials and methods

The study included 77 patients with non-muscle-invasive bladder cancer who underwent TUR and intravesical chemotherapy from 2003 to 2008. All patients underwent TUR of bladder tumors using a standard technique to the deep muscle layer with immediate intravesical administration of chemotherapy after it. In 74% of cases, cisplatin was used at a dose of 50 mg with an exposure of 60 minutes, in 15.6% - mitomycin at a dose of 40 mg, in 10.4% - doxorubicin 50 mg with a similar exposure. The degree of differentiation was assessed according to the 1973 WHO classification. The pathological stage was established in accordance with the TNM system. The presence of carcinoma in situ (Tis) was defined as the presence of Tis in combination with other pathological categories or in monoform.

Observation of patients after TUR with intravesical chemotherapy was carried out in accordance with existing protocols for postoperative observation: ReTUR was performed within 4–6 weeks after primary treatment, control cystoscopies to exclude or confirm tumor recurrence and/or its progression were performed 3–4 times during the first year , every six months for the second year, and then annually. Statistical analysis was carried out using the Statistica 6.0 program. Differences in distributions across several gradations of characteristics were assessed using Fisher and chisquare tests using absolute frequency values ​​in the nonparametric statistics module. In addition, the comparison of alternative indicators, presented as percentages, was carried out using the Student's t-test - using the differentiation test in the descriptive statistics module. In all cases of comparison, the results of differences were considered statistically significant with an error probability of less than 5% (p Results

The average age of patients was 58 years (18–78 years), 88.7% of them were men. The median follow-up for patients was 29.2 months (6–72 months). The predominant stage was pT1 - 71 patients (92.2%). Tis in monoform was found in a single case (1.3%) (Fig. 1). Well-differentiated (G1) tumors dominated in the structure of all tumors and were found in 48 patients (62.3%), while moderately differentiated (G2) and poorly differentiated (G3) were found in 25 (32.5%) and 4 (5.2 %) cases, respectively (Fig. 2). The sizes of tumors and the number of tumors in the bladder are shown in Figures 3, 4. The sizes of tumors ranged from 1 to 6 cm, with tumors measuring 1–3 cm prevailing in 37 (48.1%) patients, while tumors > 3 cm were identified in 40 (51.9%) patients, tumors > 5 cm were removed in 11 (14.3%) patients.

There were no clinically significant complications after intravesical chemotherapy in patients, with the exception of pollakiuria, noted in 1 case. Tumor recurrence was determined using all 3 chemotherapy drugs in 8 patients (10.4%). Moreover, the development of relapse was detected significantly more often with intravesical instillation of doxorubicin - 4 cases (50% of cases with doxorubicin), while with the use of mitomycin and cisplatin, relapse was noted in 2 (16.6% and 3.5%) cases, respectively (p Faster the occurrence of tumor relapse occurred in the group of patients with intravesical instillations of doxorubicin, and a later relapse of bladder cancer occurred in the group with intravesical administration of cisplatin. The group of patients with the introduction of mitomycin occupies an intermediate position in the occurrence of tumor relapses. cases, relapses occurred when tumors were larger than 3 cm and the presence of moderate or low differentiation of tumors according to histological examination after TUR In addition, in 5 cases (6.5%) tumor progression was noted, requiring radical cystectomy, in 3 cases of which it was determined. Tis, both along with papillary tumor of the bladder and in mono form, which indicates the need to take this factor into account as a risk factor for the progression of bladder tumors.

Discussion

The standard treatment for non-muscle invasive bladder cancer remains TURBT of the bladder tumor with adjuvant intravesical chemotherapy. However, according to the latest data, only 4% of US urologists use direct administration of chemotherapy after TUR of the tumor, which indicates a decrease in the effectiveness of this therapy. According to recent studies, the risk of recurrence of bladder cancer with monotherapy with TUR is up to 75%, and tumor progression is observed in 11–63% of cases.

In our study, a significantly lower percentage of recurrent bladder cancer was noted after TUR with immediate intravesical chemotherapy - 10.4% with a median follow-up of 29 months. Moreover, relapse develops significantly less frequently with intravesical chemotherapy with cisplatin at a dose of 50 mg with exposure in the bladder for 60 minutes. The time to tumor recurrence is increased with the use of mitomycin and cisplatin compared with numerous studies evaluating the effectiveness of mitomycin and doxorubicin for intravesical chemotherapy. Tumor progression in the cohort of our patients was noted only in 6.5% of cases, while some foreign studies indicate that intravesical chemotherapy has no effect on reducing the progression of non-muscle-invasive bladder cancer.

Tumor relapse and progression depend on pathohistological characteristics: thus, the number of tumor relapses increases with large, moderately and poorly differentiated tumors, as well as in the presence of Tis. These factors are determining, according to some studies, for the development of relapse and progression of non-muscle-invasive bladder cancer. Thus, the use of intravesical chemotherapy leads to improved results of treatment of non-muscle-invasive bladder cancer, but continued study of specialized molecular and genetic markers that determine the effectiveness of the response to therapy is required.

The use of immediate (within 6 hours) intravesical chemotherapy after TUR for non-muscle-invasive bladder cancer leads to a significant reduction in the number of relapses and the risk of bladder tumor progression. The use of cisplatin along with mitomycin for intravesical chemotherapy provides better results compared to doxorubicin. To fully assess the effectiveness of intravesical chemotherapy and assess the prognosis of relapse and progression of bladder cancer, further retro- and prospective studies in numerous specialized centers are needed.

• KEY WORDS: oncourology, bladder cancer, chemotherapy, oncology, urology

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Chemotherapy for bladder cancer in Israel

Israeli clinics can offer the following in the treatment of bladder cancer:

1. Innovative methods of therapy, including gene therapy, immunotherapy, chemotherapy.
2. Minimally invasive laparoscopic and robotic surgical procedures.
3. Advanced reconstruction technologies.
4. Services of highly qualified and experienced surgeons.
5. Conformal 3D and IMRT radiation therapy.

Israeli researchers continue to study new combinations of chemotherapy drugs and their dosages to increase the speed of action, slow the progression of the disease and reduce side effects.

The medical service “TheBestMedic” offers services for organizing treatment in private and public clinics in Israel in the shortest possible time, with the best doctors, in the most comfortable conditions of stay in the country.

Let us consider in more detail how treatment with cytostatic agents is carried out for malignant tumors of the bladder.

Chemotherapy for bladder cancer, superficial forms

To reduce the risk of the disease returning after surgery, chemotherapy directly into the bladder or intravesical chemotherapy may be recommended.

This type of treatment destroys abnormal cells. When a cytostatic agent is injected into the bladder, the drug comes into direct contact with cancer cells located on the mucous membrane of the organ.

Intravesical chemotherapy is different from intravenous chemotherapy, which is sometimes used to treat invasive bladder cancer. Since the drug enters the organ, side effects such as nausea or hair loss do not develop. The cytostatic is not actually absorbed into the blood, so it rarely affects the rest of the body.

Intravesical chemotherapy for bladder cancer

Most patients receive one treatment after surgery. If there is a risk of recurrence, more procedures will usually be needed. When this probability is intermediate, a course of treatment is carried out once a week for approximately six weeks.

Intermediate risk means:

• Papillary cancer Ta, mushroom-like, grows only in the inner layer of the bladder wall. It is grade 1 (cancer cells grow slowly and are easily identified) or grade 2 (cancer cells grow faster and look more abnormal). The size of the tumor is more than 3 cm or there are several tumors, or they constantly return.

The T1 tumor has begun to grow into the layer of connective tissue under the mucous membrane, has grade 2, size less than 3 cm in diameter. Request a free call

How is intravesical chemotherapy performed for bladder cancer?

If chemotherapy is prescribed after surgery, it is performed several hours later.

When a large amount of blood is found in the urine, the procedure may be postponed until the next day. If additional treatment with cytostatics is necessary, it will be performed in the hospital outpatient department. After the therapy is completed, the patient will be discharged. The doctor will provide detailed information on preparation.

Your specialist may suggest limiting your fluid intake before chemotherapy for bladder cancer. A large amount of it can lead to an uncomfortable feeling of overcrowding in the organ, and a decrease in volume will help increase the concentration of the chemotherapy drug.

Patients taking diuretics will need to delay taking them until later after therapy. Also, the doctor must be warned about any other medications that the patient is taking, as well as about possible illness before treatment. Chemotherapy for bladder cancer will be delayed if the patient does not feel well or there is an infection in the urine.

During the procedure, the nurse will place a catheter in the bladder, through which fluid with chemotherapy will flow into the organ. The most commonly used are mitomycin-c, doxorubicin or epirubicin, and sometimes gemcitabine.

After the cytostatic is administered, the catheter is removed. It is recommended not to urinate for at least an hour. This may cause some discomfort, but it gives the chemotherapy time to start working. Sometimes the catheter is left in place and clamped to keep the medicine inside the organ. At this time, you can, for example, take a walk.

After the treatment is completed, you can visit the toilet. If the catheter is left in, the chemotherapy is drained before it is removed.

For six hours after treatment, you will need to take certain precautions to protect yourself and others from coming into contact with the cytotoxic agent:

1. If the patient is male, avoid splashing urine on the toilet seat. Flush the toilet twice.
2. Wash the skin in the genital area thoroughly with soap after urinating to remove any remaining drug.
3. Wash your hands thoroughly after using the toilet.

Drink at least 2-3 liters of fluid per day for 48 hours after each treatment session to eliminate the drug from the bladder. Calculate the cost of treatment

Potential Side Effects

The following side effects may result from inflammation of the bladder wall (cystitis):

• Frequent urination.
• Pain or burning during urination.
• Blood in urine.

The condition should improve within a day or two. Drinking plenty of fluids will relieve irritation. Taking painkillers may help.

Some patients sometimes develop a red rash on their arms and legs. If this happens, you must inform your doctor.

If the condition does not return to normal, or an elevated temperature occurs, or the smell or color of urine changes, you should immediately contact a specialist. Symptoms may indicate an infection in the urine.

Partner protection

You should use a condom during sex for the first 48 hours after chemotherapy for bladder cancer. This protects the partner from any drug that may be present in the semen or vaginal fluid.

Contraception

This treatment is a contraindication for pregnancy, since cytostatics can harm a developing baby. It is important to use effective contraception during therapy. This issue can be discussed with your doctor.

Chemotherapy for bladder cancer, invasive forms

Chemotherapy is a method that uses cytostatic drugs in the fight against malignant cells. For invasive cancer, it is given intravenously, and chemotherapy drugs circulate in the bloodstream, reaching pathological cells anywhere in the body.

Chemotherapy is prescribed:

1. Before surgery or radiation to reduce the volume of the tumor and reduce the likelihood of the disease returning.
2. At the same time as radiotherapy - the so-called chemoradiotherapy, to increase the effectiveness of treatment.
3. After surgery, if there is a high probability of the disease returning. However, it is not known how effective it is, so it is usually prescribed as part of a clinical trial.
4. As the primary treatment for metastatic cancer.

Combination drugs are usually given over several days.

The patient will receive cytotoxic drugs every few weeks for a number of months. The drugs gemcitabine and cisplatin are often used to treat this disease. The most commonly used combinations are methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) and cisplatin, methotrexate and vinblastine (CMV).

Chemotherapy for metastatic bladder cancer

Treatment with cytostatic agents is also prescribed when the tumor process has spread beyond the boundaries of the bladder and penetrated into other parts of the body. Chemotherapy can help shrink or slow the growth of the tumor and reduce symptoms of the disease. The type of treatment will depend on how the cancer has spread and how well the patient is physically. A combination of chemotherapy drugs or one cytostatic agent may be prescribed.

Many people are wary of this method due to the potential side effects, but these can be successfully controlled with medication.

Making decisions about treatment for metastatic cancer can be difficult. It is important to talk with your doctor about the advantages and disadvantages of therapy for your specific situation. Discussing with family and loved ones may be helpful. If a patient decides not to have chemotherapy for bladder cancer, other medications and ways to manage symptoms may be used. The doctor discusses these issues with the patient.

Innovative treatment methods

Microwave (therapeutic) hyperthermia and intravesical chemotherapy for bladder cancer are considered as one such treatment modality.

During the procedure, a probe inserted into the bladder directs heat to the mucous membrane of the organ. At the same time, the chemotherapy drug is administered orally. Research continues to elucidate the mechanism for increasing the effectiveness of cytostatic treatment under the influence of hyperthermia.

Intravesical chemotherapy with electrical stimulation

A number of studies suggest injecting the cytostatic mitomycin into the bladder along with electrical stimulation. Under the influence of an electric current, cells absorb more chemotherapy.

Possible side effects

Cytostatic drugs can cause certain undesirable effects, but they can be successfully controlled with medications.

1. Risk of infection. This type of treatment can reduce the bone marrow's production of white blood cells, making a person more prone to infection. This effect generally begins seven days after the start of therapy, and the body's resistance reaches its lowest point ten to fourteen days after treatment. The blood cell count then increases and usually returns to normal within twenty-one to twenty-eight days.
2. Hematomas or bleeding. Chemotherapy for bladder cancer can reduce the production of platelets, which help the blood clot. It is important to tell your doctor if you experience any bruising or bleeding for no reason - from the nose, gums, or skin rash.
3. Anemia. Anemia is caused by a decrease in the number of red blood cells, which will cause fatigue and shortness of breath. A blood transfusion may be needed if the red blood cell count becomes too low.
4. Vomiting and nausea. These symptoms may develop several hours after therapy and last up to a day. Doctors prescribe very effective antiemetic drugs to prevent or reduce these symptoms.
5. An inflammatory process in the oral cavity and small ulcers may occur. Drinking plenty of fluids and regular, gentle brushing with a soft toothbrush can help reduce the likelihood of this side effect. If any of these problems appear, the doctor will prescribe mouthwashes and medications that prevent or fight the infection.
6. Poor appetite. If the patient cannot taste food during treatment, you can try replacing some meals with nutritious drinks. Your doctor or hospital nutritionist may recommend them.
7. Hair loss. Certain cytotoxic drugs can cause hair loss. If this happens, there are many ways to hide it using hats, scarves or wigs. Hair will begin to grow again three to six months after therapy ends.
8. Feeling tired. Many patients feel tired during treatment, especially towards the end. An attempt should be made to balance periods of rest with light exercise, such as walking, for example, when the patient is able to do so.
9. Early menopause. In women who have not reached menopause, it may occur earlier due to treatment. Its symptoms include hot flashes and vaginal dryness. If this occurs, a doctor at the hospital will be able to advise on procedures that can help combat the signs of this phenomenon.

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Features of chemotherapy for superficial forms of bladder cancer

Intravesical chemotherapy (chemotherapy directly into the bladder) is given to patients with superficial bladder cancer (stage T1). Its purpose is to reduce the risk of disease relapse after TUR of the bladder. This procedure is usually performed in the adjuvant setting for individuals at moderate to high risk of disease recurrence. According to numerous studies, this can reduce the risk of relapse by 50%. The duration of treatment takes from 4 to 8 weeks.

The main drug of choice during intravesical chemotherapy is the antibiotic mitomycin with antitumor effect. The therapeutic dosage of mitomycin C diluted in 50 mg of distilled water is 40 mg.

Treatment with mitomycin C at an early stage of the disease makes it possible to reduce the likelihood of developing bladder cancer relapses by 15%. Thanks to the use of mitomycin C, it is possible to obtain results similar to those obtained by a course of preventive immunotherapy.

Also, other drugs (doxorubicin, gemcitabine, epirubicin, etc.) can be used to prevent recurrence of bladder cancer.

When a cytostatic is introduced into the bladder, the latter begins to interact with cancer cells located on the mucous membrane of the organ. This is different from the intravenous therapy that some hospitals use to treat invasive bladder cancer. Since the cytostatic penetrates into the organ without entering the bloodstream, the patient has no side effects such as hair loss or nausea.

Many patients undergo only one procedure after surgery. If there is a risk of relapse, there may be more procedures.

At an intermediate risk, that is, with mushroom-like papillary cancer Ta, progressing in the inner layer of the bladder wall, having grade 1 or 2 tumor development, with a size of more than 3 cm, a course of treatment is prescribed, once a week, for about two months.

Carrying out intravesical chemotherapy for bladder cancer

Chemotherapy is given a few hours after surgery if prescribed by the attending physician. The procedure can be postponed to another day if blood or infectious processes are found in the urine. If necessary, an additional course of treatment with cytostatics may be prescribed on an outpatient basis. After completing the course of therapy, the patient is discharged from the hospital. It may be necessary to limit water intake until the course of chemotherapy, since a large volume of excess fluid can cause discomfort or interfere with the concentration of the cytostatic drug.

Patients taking diuretics should reschedule their intake to later hours. The attending physician must be informed of all medications that the patient takes for one reason or another. The drug will go into the bladder through a catheter. After administration of the cytostatic, the catheter will be removed. It is advisable not to urinate for an hour after the procedure to allow the drug to take effect.

• wash your hands thoroughly after using the toilet;
• thoroughly wash the skin of the genitals with soap, removing all traces of the drug;
• drink at least 2-3 liters of fluid for two days after each chemotherapy procedure to remove any remaining drug from the bladder.

Possible side effects

The effect of the drug can cause cystitis, inflammation of the bladder wall (cystitis). Its symptoms are hematuria, frequent urination, pain when urinating.

However, the patient should feel better within 24 hours. In order to relieve irritation, it is recommended to drink plenty of liquid. Taking painkillers may also be helpful. In some cases, a red rash may appear on the extremities, it happens. You must immediately inform your doctor. You should also consult a doctor if your condition does not improve, if your body temperature rises, or if your urine changes smell or color, as these symptoms may indicate the development of infectious processes in the urine.

Showing concern for your partner

After chemotherapy, you can continue to be sexually active, but you will need to use a condom to protect your partner from the aggressive effects of the drug, which may be in the vaginal fluid or ejaculate.

Prevention

Intravesical chemotherapy is contraindicated during pregnancy, as the drugs pose a danger to the fetus. Therefore, during therapy it is necessary to use proven contraception. If you are unsure, it is better to discuss this issue with your doctor.

Chemotherapy for invasive bladder cancer

Chemotherapy is the fight against malignant cells using cytostatic drugs. For invasive forms of cancer, drugs are given intravenously, so the drug enters the bloodstream and can fight cancer cells anywhere in the body.

• Even before surgery or radiation, to reduce the size of the tumor and reduce the likelihood of relapse;
• Along with radiotherapy to increase the effectiveness of treatment;
• As the main treatment method for metastatic cancer;
• After surgery, if there is a possibility of relapse;

Patients are usually prescribed combinations

• methotrexate, cisplatin and vinblastine;
• methotrexate, cisplatin, vinblastine and doxorubicin.

The duration of such therapy takes several weeks in a row.

Chemotherapy for metastases in the bladder

A course of cytostatic therapy can be prescribed when the tumor has spread beyond the boundaries of the bladder and spread to other parts of the body. Using chemotherapy, you can reduce or slow down the growth of the tumor, making the manifestations of the disease less pronounced.

Treatment tactics are selected depending on the patient’s condition and the extent of the spread of cancer. Chemotherapy is known to cause a range of side effects, but these can be managed with other medications. The patient may decide to refuse chemotherapy and use alternative drugs. Doctors will definitely suggest all available treatment methods. The patient can also consult with his relatives and friends.

Modern methods of treatment

Therapeutic microwave hyperthermia is a method of treating malignant tumors, which involves the use of thermal effects on cancer cells. During the procedure, the affected areas of the body are treated with high temperatures, which can significantly increase the benefits of using radiotherapy, chemotherapy or radiotherapy.

Since high temperature affects healthy and cancerous cells differently, it is possible to differentiate the application of thermal energy. Due to the action of hyperthermia, low-quality tumor cells are destroyed, while healthy cells remain intact.

During the procedure, a probe is inserted into the bladder, through which heat is directed to the mucous membrane of the organ. At the same time, a chemical is injected inside.

Intravesical electrical stimulation

Some methods involve, in addition to introducing cytostatics into the bladder, using electrical stimulation. This allows cells to more actively absorb chemicals. As is known, cytostatics can in some cases cause complications, but this can be combated with the help of other medications. It is important to know that intravesical electrical stimulation, along with obvious advantages, also has side effects. Let's look at them in more detail.

Anemia

Anemia develops against the background of a decrease in the number of red blood cells, causing shortness of breath, fatigue, a broken and depressed state of the patient. If the number of red blood cells drops to a critical level, a blood transfusion will be necessary.

Possibility of infection

This type of treatment can reduce the production of white blood cells by the bone marrow, which opens the body to infection. Such manifestations occur approximately a week after the start of therapy, and the body’s resistance to diseases decreases to zero after just two weeks. After this, the number of blood cells increases and most often returns to normal within a month.

Feeling nauseous or vomiting

These symptoms may appear within a few hours and continue over the next 24 hours. However, doctors have very effective medications in their arsenal that can help reduce or even eliminate these symptoms.

Bleeding and hematomas

A course of chemotherapy for bladder cancer can cause a reduction in the production of platelets, which help the blood clot. The patient must notify his attending physician of all cases of bruising or bleeding of the gums, nose, etc.

Hair loss

Some groups of cytostatics can cause hair loss. Some male patients are not bothered by this at all. However, for those people who are sensitive to the state of their appearance, wigs or hairpieces can be recommended as a temporary measure. In most cases, hair begins to grow again after chemotherapy is completed.

Inflammation

Inflammation may develop in the oral cavity with the formation of small ulcerations of the mucous membrane. You can minimize the likelihood of their occurrence by drinking a significant amount of fluid during the day and taking daily care of your oral cavity. It is best to use a soft-bristled toothbrush for this purpose. If necessary, your doctor may prescribe medications to prevent the development of infection.

Decreased apatite and lethargy

The patient may experience a feeling of lethargy and indifference, expressed in loss of taste. In order for the body to receive all the necessary substances and microelements, it is necessary to replace the dishes excluded from the diet with their alternative in the form of nutritious drinks.

Feeling overwhelmed and tired

Many patients feel completely overwhelmed during the treatment process. In order to cope with these sensations, you need to try to alternate rest with physical activity such as gymnastics, if there are no contraindications to this.

Development of early menopause

In patients who, due to their age, have not yet entered menopause, it can be triggered by a course of chemotherapy. The main symptoms are the appearance of dryness in the vagina and periodic sensations of heat. In such a situation, consultation with a urogynecologist is necessary.

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Adjuvant chemotherapy and immunotherapy for bladder cancer

Despite the fact that a radical TUR, as a rule, makes it possible to completely remove superficial tumors of the bladder, nevertheless, they often (in 30-80% of cases) recur, and in some patients the disease progresses.

Based on the results of 24 randomized trials involving 4863 patients with superficial bladder tumors, the European Organization for Research and Treatment of Bladder Cancer in 2007 developed a method for prospectively assessing the risk of tumor recurrence and progression. The technique is based on a 6-point system for assessing several risk factors: number of tumors, maximum tumor size, history of relapse rate, stage of the disease, presence of CIS, degree of tumor differentiation. The sum of these points determines the risk of recurrence or progression of the disease in %.

System for calculating risk factors for recurrence and progression of superficial bladder tumors

Risk factor	Recurrence	Progression
Number of tumors
The only one
Tumor diameter
Previously noted recurrence
primary relapse
less than 1 relapse per year
more than 1 relapse per year
Disease stage
Degree of differentiation
Total points

Groups of superficial bladder tumors according to risk factors

• Low risk tumors:
  • the only ones;
  • highly differentiated;
  • size
• High risk tumors:
  • poorly differentiated;
  • multiple;
  • highly recurrent;
• Intermediate risk tumors:
  • Ta-T1;
  • moderately differentiated;
  • multiple;
  • >3 cm in size.

From the above data, the need for adjuvant chemotherapy or immunotherapy after TUR of the bladder in almost all patients with superficial cancer becomes clear.

The goals and putative mechanisms of local chemotherapy and immunotherapy are to prevent the implantation of cancer cells in the early stages after TUR. reducing the possibility of recurrence or progression of the disease and ablation of residual tumor tissue when it is not completely removed (“chemorejection”).

Intravesical chemotherapy

There are two schemes of intravesical chemotherapy after TUR of the bladder for superficial cancer: a single installation early after surgery (within the first 24 hours) and adjuvant multiple administrations of chemotherapy.

Single instillation early after surgery

For intravesical chemotherapy, mitomycin, epirubicin and doxorubicin are used with equal success. Intravesical administration of chemotherapy drugs is carried out using a urethral catheter. The drug is diluted in 30-50 ml of 0.9% sodium chloride solution (or distilled water) and injected into the bladder for 1-2 hours. The usual doses for mitomycin are 20-40 mg, for epirubicin - 50-80 mg. for doxorubicin 50 mg. In order to prevent dilution of the drug in urine, patients are sharply limited in fluid intake on the day of instillation. To ensure better contact of the chemotherapy drug with the mucous membrane of the bladder, it is recommended to frequently change body position before urinating.

When using mitomycin, one should take into account the possibility of an allergic reaction with redness of the skin of the palms and genitals (in 6% of patients), which can be easily prevented by thoroughly washing the hands and genitals immediately after the first urination after instillation of the drug. Serious local and even systemic complications usually occur with extravasation of the drug, so early installation (within 24 hours after TUR) is contraindicated if extra- or intraperitoneal perforation of the bladder is suspected, which can usually occur with aggressive TUR.

Due to the danger of systemic (hematogenous) spread, local chemotherapy and immunotherapy are also contraindicated for gross hematuria. A single installation of chemotherapy reduces the risk of relapse by 40-50%, on the basis of which it is carried out in almost all patients. A single administration of a chemotherapy drug at a later date reduces the effectiveness of the method by 2 times.

A decrease in the recurrence rate occurs within 2 years, which is of particular importance in patients with low cancer risk, for whom a single installation has become the main method of metaphylaxis. However, a single installation is not sufficient for average and, especially, high cancer risk, and such patients, due to the high probability of recurrence and progression of the disease, require additional adjuvant chemotherapy or immunotherapy.

Adjuvant multiple administrations of chemotherapy

Treatment of bladder cancer involves repeated intravesical administration of the same chemotherapy drugs. Chemotherapy is effective in reducing the risk of recurrence. but is not effective enough to prevent tumor progression. Data regarding the optimal duration and frequency of intravesical chemotherapy are conflicting. According to a randomized study

According to the European Organization for Research and Treatment of Bladder Cancer, monthly insertion for 12 months did not improve treatment outcomes compared with that for 6 months, provided that the first installation was carried out immediately after TURBT. According to other randomized trials. the relapse rate with a one-year course of treatment (19 installations) was lower compared to a 3-month course (9 installations) of epirubicin.

Intravesical immunotherapy

For patients with superficial bladder cancer with a high risk of recurrence and progression, the most effective method of metaphylaxis is intravesical immunotherapy with the BCG vaccine, the administration of which leads to a pronounced immune response: cytokine expression occurs in the urine and bladder wall (interferon γ, interleukin-2, etc.) . stimulation of cellular immune factors. This immune response activates cytotoxic mechanisms, which form the basis of the effectiveness of BCG in preventing recurrence and progression of the disease.

The BCG vaccine consists of weakened mycobacteria. It was developed as a vaccine for tuberculosis, but it also has antitumor activity. BCG vaccine is a lyophilized powder that is stored frozen. It is produced by various companies, but all manufacturers use a culture of mycobacteria. received from the Pasteur Institute in France.

The BCG vaccine is diluted in 50 ml of 0.9% sodium chloride solution and immediately injected into the bladder through the urethral catheter under the gravity of the solution. Adjuvant treatment for bladder cancer begins 2-4 weeks after TURBT (the time required for re-epithelialization) to reduce the risk of hematogenous spread of live bacteria. In case of traumatic catheterization, the instillation procedure is postponed for several days. After instillation, the patient should not urinate for 2 hours; it is necessary to frequently change body position for full interaction of the drug with the mucous membrane of the bladder (turns from one side to the other). On the day of instillation, you should stop taking fluids and diuretics to reduce dilution of the drug in urine.

Patients should be warned about the need to clean the toilet after urinating, although the risk of household contamination is considered hypothetical. Despite the advantages of BCG compared with adjuvant chemotherapy, it is generally accepted that immunotherapy is recommended only for patients at high risk of cancer. This is due to the likelihood of developing various, including serious, complications (cystitis, fever, prostatitis, orchitis, hepatitis, sepsis and even death). Due to the development of complications, adjuvant therapy often has to be stopped. That is why its use in patients with low cancer risk is not justified.

Main indications for prescribing the BCG vaccine:

• presence of residual tumor tissue after TUR;
• metaphylaxis of tumor recurrence in patients with high cancer risk.

Great importance is attached to the use of the BCG vaccine in patients with a high risk of disease progression, since it has been proven that only this drug can reduce the risk or delay tumor progression.

Absolute contraindications to BCG therapy:

• immunodeficiency (for example, while taking cytostatics);
• immediately after the TOUR;
• macrohematuria (risk of hematogenous generalization of infection, sepsis and death);
• traumatic catheterization.

Relative contraindications to BCG therapy:

• urinary tract infection;
• liver diseases that exclude the possibility of using isoniazid in case of tuberculous sepsis;
• history of tuberculosis;
• severe concomitant diseases.

The classic regimen of adjuvant BCG therapy was empirically developed by Morales more than 30 years ago (weekly installation for 6 weeks). However, it was later determined that a 6-week course of treatment was not enough. There are several options for this scheme: from 10 installations over 18 weeks to 30 installations over 3 years. Although the optimal generally accepted regimen for the use of BCG has not yet been developed, most experts agree that if it is well tolerated, the duration of treatment should be at least 1 year (after the first 6-week course, repeat 3-week courses are given after 3, 6 and 12 months) .

• If there is a low or average risk of recurrence and a very low risk of progression, it is necessary to carry out a single installation of the chemical drug.
• With a low or moderate risk of progression, regardless of the degree of risk of recurrence. after a single administration of a chemical drug, maintenance adjuvant intravesical chemotherapy (6-12 months) or immunotherapy (BCG for 1 year) is required.
• If the risk of progression is high, intravesical immunotherapy (BCG for at least 1 year) or immediate radical cystectomy is indicated.
• When choosing a particular therapy, it is necessary to evaluate possible complications.

Treatment of bladder cancer (stages T2, T3, T4)

Treatment of bladder cancer (stages T2, T3, T4) - systemic chemotherapy for bladder cancer.

When bladder cancer is diagnosed, approximately 15% of patients are also diagnosed with regional or distant metastases, and in almost half of patients, metastasis occurs after radical cystectomy or radiation therapy. Without additional treatment, the survival rate of such patients is insignificant.

The main chemotherapy drug for systemic chemotherapy is cisplatin, but in the form of monotherapy, treatment results are significantly inferior to those compared with the combined use of this drug with methotrexate, vinolastine and doxorubicin (MVAC). However, treatment of bladder cancer with MVAC is accompanied by severe toxicity (mortality during treatment is 3-4%).

In recent years, it has been proposed to use a new chemotherapy drug, gemcitabine, in combination with cisplatin, which has achieved results similar to MVAC with significantly less toxicity.

Combination chemotherapy is partially or completely effective in 40-70% of patients, which was the basis for its use in combination with istectomy or radiation therapy in neoadjuvant or adjuvant therapy.

Neoadjuvant combination chemotherapy is indicated for patients with stage T2-T4a before radical cystectomy or radiation treatment and is aimed at treating bladder cancer, possible micrometastases, and reducing the likelihood of recurrence. and in some patients, to preserve the bladder. Patients tolerate it more easily before the main treatment (cystectomy or radiation), but randomized studies have revealed its insignificant or no effectiveness. In some patients (small tumor, absence of hydronephrosis, papillary structure of the tumor, the possibility of complete visual removal of the tumor by TUR), in 40% of cases adjuvant chemotherapy in combination with radiation avoided cystectomy, but such a recommendation requires randomized studies.

Adjuvant systemic chemotherapy

Its various regimens (standard MVAC regimen, the same drugs in high doses, gemcitabine in combination with cisplatin) are being studied in a randomized trial by the European Organization for Research and Treatment of Bladder Cancer, which does not yet allow recommending one of its options.

The MVAC regimen for metastatic disease was effective in only > 15-20% of patients (prolonging life by only 13 months). Moreover, the results were better in patients with metastasis to regional lymph nodes compared to metastasis to distant organs. When the combination of MVAC was ineffective, a high effectiveness of replacing the regimen with gemcitabine and paclitaxel was revealed. As primary therapy, good results were obtained with the combination of cisplatin gemcitabine and paclitaxel.

In conclusion, it should be noted that systemic chemotherapy is not indicated for invasive bladder cancer without metastases. The optimal indications for its use can only be determined after completion of randomized trials.

In the structure of oncological pathology, bladder tumors account for about 4%, and among urological oncological diseases - approximately 40%. In recent years, there has been an increase in the incidence of bladder cancer. Thus, in 1998 in the Republic of Belarus this figure reached 10.8 per 100 thousand population, while in 1991 it was 7.7 per 100 thousand.

Transitional cell carcinoma of the bladder (TCBC) is the most typical histological type of cancer of this location. It should be noted that 75-85% of all newly detected bladder tumors are superficial, i.e. stage T a, T1 and Tis (carcinoma in situ, CIS) . Ta is a tumor limited to the epithelium; T1 - tumor invading the basement membrane, but not the muscle layer of the bladder; Tis carcinoma is a flat (non-papillary) intraepithelial tumor. Thus, with superficial bladder cancer, there is no invasion of the muscle layer by the tumor, regional and distant metastases practically do not occur, and local effects are quite sufficient for the treatment of such tumors. In most cases, the initial treatment for superficial SCC is transurethral resection (TUR) of the bladder. Depending on patient characteristics and length of follow-up, up to 80% of superficial tumors recur after TUR, and 2-50% progress to muscle-invasive tumors. Intravesical therapy is widely used to prevent recurrence and treat superficial bladder cancer. However, at present there is no consensus regarding the specific indications for this therapy, the optimal drug has not been selected, and there are conflicting views on the need for maintenance therapy.

To decide whether adjuvant intravesical therapy is necessary, the degree of malignancy of the tumor is of primary importance. Regardless of stage, grade 3 tumors relapse in 70% of cases, and the risk of progression within 3 years is 45%. For tumors T 1G3 progression rate reaches 52%, and the average time to progression is 12.7 years. During the first 5 years, progression of the tumor to invasive is observed in 35% of patients, in 16% - within 5 to 10 years after diagnosis, and in 12% - from 10 to 15 years. Cancer kills 25% of patients within the first 5 years and another 10% within 5-15 years. This unfavorable prognosis necessitates intravesical therapy in patients with poorly differentiated SCC, regardless of tumor stage.

Carcinoma in situ(CIS), as is known, is a very aggressive tumor with a high potential for invasive growth and metastasis. If concomitant CIS is detected, there is a high risk of disease progression. For example, in the presence of a tumor T 1G3 The presence of CIS significantly increases the risk of disease progression (65% at 5 years). Therefore, detection of even a small lesion of CIS in the bladder is considered an indication for intravesical therapy.

Stage T and low-grade tumors progress in 7% of patients within 7 years and can be treated with transurethral resection alone unless there are other risk factors for progression. However, multiple Ta tumors are a relative indication for intravesical therapy. Recurrent low-grade Ta tumors can be treated with repeat TURBT alone, but if recurrences are detected within the first 2 years after TURBT, intravesical therapy should be considered. In stage T1, tumor cells have access to blood and lymphatic vessels in the submucosal layer of the bladder. In this case, the progression rate reaches 30% or more, which necessitates intravesical therapy (Table 1, see the paper version of the journal).

Adjuvant intravesical therapy is also indicated in cases of positive urine cytology soon after TUR (meaning the presence of residual tumor in the bladder), frequent tumor recurrences, and concomitant urothelial dysplasia.

Cumulative data from 21 studies involving 3404 patients found that only 49% of patients did not experience relapse after a single TUR. It is concluded that intravesical therapy should be used exclusively in patients with a high risk of relapse or progression of the disease.

In other words, intravesical therapy should be prescribed to those patients who, based on tumor characteristics, have a higher risk of relapse after TUR (Table 2, see the paper version of the journal). For high-risk patients, the goal of treatment is to prevent tumor progression, thereby avoiding cystectomy and reducing the risk of death from SCC. When intravesical therapy is used in low-risk patients, the goal of treatment is to reduce the incidence of tumor recurrence, thereby improving patients' quality of life and reducing healthcare costs of treatment for recurrent tumors.

It is worth focusing on two main types of intravesical therapy with different mechanisms of action, indications, timing of administration and effectiveness - intravesical chemotherapy and immunotherapy.

Intravesical chemotherapy

As mentioned above, if the tumor belongs to the group with an unfavorable prognosis, then to prevent relapse and progression of the tumor to muscle-invasive after TUR, it is advisable to use intravesical therapy. When using intravesical chemotherapy, the first goal is quite achievable, while the second is doubtful.

Why do superficial bladder tumors recur? H. Akaza et al. suggest that there are four causes of relapse, which are not mutually exclusive: 1) implantation (“dispersal”) of tumor cells into the bladder epithelium during transurethral resection; 2) growth of accompanying microscopic tumors; 3) non-radicality of TOUR; 4) the appearance of new (“second primary”) bladder tumors.

An analysis of the results of treatment of 3614 patients participating in controlled trials of intravesical chemotherapy showed that over a 3-year period, the number of relapses was reduced by an average of 14% compared with surgical treatment. ThioTEP, doxorubicin hydrochloride, mitomycin C, epirubicin hydrochloride, and etoglucide, the most commonly used drugs, reduced short-term relapse rates by 17%, 16%, 12%, 12%, and 26%, respectively. Controlled comparative studies of different chemotherapy drugs have generally failed to demonstrate any significant differences in their effectiveness.

ThioTEF. This alkylating agent is the only intravesical chemotherapy agent approved by the FDA for the treatment of papillary SCC in the United States. Its use reduces the risk of tumor recurrence by an average of 16% (-5-41%). ThioTEF treatment results are comparable to newer and more expensive chemotherapy agents when the 367 patients in the Medical Research Council (MRC) trial who received low concentrations of the drug are removed from the pooled analysis.

Mitomycin C. Controlled studies have not revealed any superiority of the most expensive chemotherapeutic drug, mitomycin C, over other chemotherapeutic agents when administered intravesically. For T tumors a/T1, the rate of complete regressions when using mitomycin C is about 36%, and the rate of relapses is reduced by an average of 12% (1-42%). A single instillation of mitomycin C immediately after TUR significantly reduces the incidence of early tumor recurrence in superficial bladder cancer with a low risk of recurrence, but this effect decreases over time. Maintenance therapy does not improve treatment outcomes, and long courses are not superior to short courses of chemotherapy.

Doxorubicin- an anthracycline antibiotic with a wide antitumor spectrum of action. The number of relapses with its use decreases by an average of 16%. Doses ranging from 30 to 90 mg at a concentration of 1 mg/ml have been used without significant differences in effectiveness. The best results are observed when using a single early postoperative instillation of the drug; maintenance therapy does not improve them. In the work of A. Kamat et al. Oral quinolone antibiotics have been found to produce a synergistic effect when combined with intravesical doxorubicin.

Epirubicin. The epimer of doxorubicin - epirubicin in the form of a single intravesical instillation immediately after resection is able to reduce the rate of relapse of SCC by an average of 26% (60% with TUR alone and 34% with adjuvant treatment with epirubicin). As in other studies using chemotherapy drugs such as doxorubicin and ThioTEP, epirubicin maintenance did not provide additional benefit.

Etoglucid - a chemotherapy drug with an alkylating effect. K. Kurth et al. When comparing the effectiveness of ethoglucide and doxorubicin in a randomized trial, ethoglucide was found to be more effective when administered intravesically than doxorubicin or TUR alone. Compared with the control group, etoglucide reduced the relapse rate by 31%, doxorubicin - by only 13%.

Long-term results of intravesical chemotherapy. In a meta-analysis involving 2535 patients with stage T SCC a or T1 included in 6 randomized phase 3 intravesical chemotherapy trials (average follow-up of 7.7 years) was found to be statistically significant (P<0,01) снижение частоты рецидивов у 1629 пациентов, получавших тиоТЭФ, доксорубицин, эпирубицин, митомицин внутрипузырно или пиридоксина гидрохлорид внутрь, по сравнению с 906 пациентами, пролеченными только ТУР мочевого пузыря . Эти результаты демонстрируют долговременное снижение риска рецидива опухоли в среднем на 7%. Адъювантное лечение не влияло на частоту прогрессирования, сроки до появления отдаленных метастазов и выживаемость.

Indeed, while most studies demonstrate the benefit of chemotherapy in reducing relapse rates within the first 2 to 3 years, there is little evidence of long-term reduction in relapse rates and no evidence of a reduction in disease progression or mortality. In an analysis of the treatment results of 3899 patients with superficial SCC included in 22 randomized prospective controlled trials, D. Lamm et al. found that the disease progressed in 7.5% of patients treated with intravesical chemotherapy and in 6.9% after TUR.

H. Akaza et al. put forward a hypothesis to explain these observations. The authors believe that intravesical chemotherapy is effective against the dissemination of tumor cells during TUR of the primary tumor, as well as against residual microscopic foci of cancer or residual tumor after non-radical TUR, but does not prevent the subsequent appearance of new “primary” tumors, which, apparently, lead to to progression. This theory seems very plausible and highlights the need to find ways to prevent disease progression that accounts for mortality from superficial bladder cancer. The assumption of H. Akaza et al. that intravesical therapy is ineffective against “second primary” tumors is based on data reflecting the frequency of relapses at various times after TUR. While intravesical chemotherapy reduces the risk of relapse during the first 3 to 6 months after TURBT, as time after resection increases, the difference in relapse rates becomes less significant. The authors explain this by saying that intravesical chemotherapy may affect relapse due to implanted cells or microscopic tumors, but not the risk of “relapse” due to the appearance of a new tumor. Such tumors are diagnosed later after resection.

Although intravesical chemotherapy does not affect disease progression, instillation of TEF, mitomycin C, doxorubicin or epirubicin is recommended for patients with well- and moderately differentiated tumors and low stage (T a, grade 1-2), in which multiple tumors are detected upon initial treatment or have a high recurrence rate during the observation period. Intravesical chemotherapy will clearly benefit these patients, as this treatment may reduce the number of relapses or at least increase the time to relapse.

There is interest in the use of immediate adjuvant postoperative intravesical chemotherapy. This treatment method is based on the first mechanism of recurrence, namely the implantation, or “scattering,” of tumor cells during resection. The fact is that after TUR, areas without epithelial lining appear in the bladder, as a result of which the underlying tissues come into contact with the contents in the lumen of the bladder. The presence of such areas and desquamation of a large number of tumor cells during TUR can lead to implantation of tumor cells into the resection wound.

One of the most significant studies of immediate postoperative chemotherapy was a prospective randomized trial by H. Zincke et al., who compared immediate adjuvant administration of TEP (60 mg), doxorubicin (50 mg) and saline. Relapses were observed in only 30% of patients treated with TEF, in 32% of those treated with doxorubicin, and in 71% of patients in the control group. It follows that a 40% reduction in relapse rates is due to the prevention of tumor cell implantation. However, this seems highly unlikely. And it is absolutely incredible that after a single dose of ThioTEF, a microscopic or residual tumor can be cured. However, similar results were obtained in other clinical studies. For example, the European Organization for Research and Treatment of Cancer (EORTC) conducted a study of 431 patients that compared a single dose of epirubicin (80 mg) with water administration in a control group. The study demonstrated a significant benefit of immediate administration of epirubicin in reducing tumor recurrence. The review by P. Schellhammer raises the issue of combining immediate intravesical chemotherapy with an induction course of BCG immunotherapy 1-2 weeks after TUR and subsequent maintenance administration of BCG. It is assumed that such combined chemoimmunotherapy can significantly reduce the incidence of both tumor relapse and progression.

Intravesical immunotherapy

Immunotherapy for superficial bladder cancer became widespread after A. Morales et al. in 1976. published data on the effective intravesical use of the BCG vaccine. Subsequent studies have shown that intravesical BCG immunotherapy can reduce relapse rates and prevent the progression of SCC. This is considered to be the most effective intravesical treatment for superficial bladder cancer. BCG therapy is significantly superior to chemotherapy in reducing the incidence of disease progression. Controlled comparative studies have demonstrated the superiority of BCG over thioTEP, doxorubicin and mitomycin C. BCG immunotherapy reduces relapse rates by an average of 40%, compared with 14% with chemotherapy.

In a controlled prospective study of 94 patients, M. Melekos et al. demonstrated a reduction in relapse rates from 59% in the control group to 32% in the BCG treatment group. S. Krege et al. found relapses in 56 (46%) of 122 patients treated with TURBT alone, compared with 26 (25%) of 102 patients treated with intravesical BCG once a week for 6 weeks and then once a month for 4 months after TOUR.

H. Herr et al., assessing the results of treatment of 86 patients, found that the time until progression to a muscle-invasive tumor was significantly increased when treated with BCG. In this study, progression occurred in 35% of cases in the control group compared with 28% in the BCG group. In addition, with the use of BCG, mortality decreased from 37 to 12% (P< 0,01). Цистэктомия потребовалась 42% пациентов в контрольной группе и только 26% пациентов, пролеченных БЦЖ. У больных в группе БЦЖ среднее время до цистэктомии увеличилось с 8 до 24 мес .

Long-term follow-up studies have shown that the average reduction in tumor recurrence rate is 40% (from 60 to 20%), and the average progression rate with BCG is reduced from 28 to 14%. The South Western Oncology Group (SWOG) found that for patients with superficial tumors without concomitant CIS, the 5-year disease-free survival after doxorubicin treatment was 17% compared with 37% after BCG therapy (P=0.015).

A double-blind controlled study conducted by D. Lamm showed that using 40,000 IU vitamin A, 100 mg vitamin B 6, 2.0 g of vitamin C and 400 IU of vitamin E can further reduce the number of relapses by 40% in patients receiving BCG.

U. Nseyo and D. Lamm summarized the results of 6 clinical studies comparing TUR alone and TUR followed by intravesical BCG immunotherapy and found a significant advantage of BCG therapy in 5 of 6 studies. The one study that did not find superiority of BCG included only 77 patients, and the control group had a relatively low relapse rate of 42%.

BCG immunotherapy is highly effective in the treatment of CIS. In several studies involving more than 1500 patients, the rate of complete regression of CIS with BCG treatment averaged 70%. For comparison: the frequency of complete regressions during chemotherapy averages 38-50% for thioTEF, 48% for doxorubicin and 53% for mitomycin C. On average, less than 20% of patients who receive chemotherapy live without long-term relapse. In the SWOG study, patients with CIS had a 34% chance of complete regression with doxorubicin and 70% with BCG (P< 001) . Безрецидивная выживаемость в течение 5 лет составила 18% для доксорубицина и 45% для БЦЖ. В настоящее время БЦЖ считается препаратом выбора для лечения СIS, поскольку может повышать выживаемость больных и позволяет в ряде случаев избежать цистэктомии.

H. Akaza et al. 157 patients with superficial bladder cancer shared their experience of treating BCG. Complete regression rates reached 84.4% and 66.4% for 32 patients with CIS and 125 patients with T tumors a/T1 respectively. It is assumed that optimization of the BCG vaccine administration regimen can increase the rate of complete regressions to 87% and provide a long relapse-free period in 83% of patients. There is also evidence that the effectiveness of a single 6-week course of BCG can be significantly increased by using maintenance BCG (from 86% to 92%, P<0,04) . Следует помнить, что CIS - высокоагрессивный мультифокальный рак. Неэффективность 6-недельного курса БЦЖ должна рассматриваться как сигнал, предупреждающий о том, что больному требуется немедленное обследование для исключения мышечной инвазии или CIS уретры и верхних мочевых путей .

BCG is used to treat residual unresectable bladder cancer with an effectiveness of 35 to 84%. However, BCG therapy should not be considered as an alternative to surgical removal of a resectable tumor. For the treatment of muscle-invasive cancer, intravesical administration of BCG as monotherapy is not recommended. In a report of 13 patients with stage T SCC 2 or more treated with BCG, only one patient had neither local relapse nor metastases, 10 developed disseminated disease, 7 patients died from metastases.

Thus, the indication for intravesical BCG therapy is CIS or T tumors 1 and/or G3, which were completely or incompletely resected. BCG treatment is recommended for those patients in whom intravesical chemotherapy for well-differentiated low-stage tumors has been ineffective. Unlike chemotherapeutic agents, BCG cannot be administered immediately after tumor resection due to the potential for severe systemic infection.

The optimal dose of BCG has not been clearly established, but there are currently recommendations for two commercially available drugs - TheraCys-Connaught and TICE-ORGANON. Today, intravesical use of the BCG vaccine "Imuron" has become available. It is currently believed that intravesical BCG therapy requires at least 10 million living organisms to be effective. BCG treatment usually begins 2 weeks after TUR. After instillation, patients should keep the injected liquid for approximately 2 hours. To facilitate contact of the drug with the entire surface of the bladder, the patient is recommended to change body position at certain intervals. Excessive use of lubricants to lubricate the catheter during instillation may lead to a clinically significant decrease in the number of viable mycobacteria injected and poor contact of BCG with the bladder mucosa. Therefore, the use of catheters that do not require lubrication is of interest.

Maintenance therapy

One of the important ways to increase the effectiveness of intravesical BCG treatment is maintenance therapy. J. Witjes et al. published the results of their study of 104 patients with recurrent superficial SCC with a poor prognosis, in which patients received a 6-week course of intravesical instillation of BCG followed by follow-up, including urine cytology, cystoscopy, and bladder biopsy every 3 months. Of the 65 patients with an ineffective initial course of treatment, 57 were prescribed an additional 6-week course of therapy. A single 6-week course of BCG was successful in 36% of patients treated prophylactically, 37% of patients with CIS, and 41% of patients treated for residual tumor. The effectiveness for the entire population of patients receiving one 6-week course of BCG was 37.5%. A second 6-week course of BCG was successful in 65% of patients treated prophylactically, in 71% of patients with CIS, and in 40% of patients treated for residual tumor. The effectiveness of BCG for all 57 patients who received the second course was 59.6%. Of the 6 patients who refused the second 6-week course of BCG, 4 had relapses, and 3 of them had invasion into the muscle layer of the bladder.

W. Catalona et al. reported that 44% of 100 patients with superficial SCC experienced complete regression after one 6-week course of BCG, while the overall rate of complete regression increased to 63% after a second 6-week course of BCG. Thus, a single 6-week induction course of BCG in some cases does not provide optimal therapy for superficial bladder cancer.

Although two 6-week courses of BCG are better than one, the 6+6 regimen is not as effective as the 6+3 regimen proposed by D. Lamm in the SWOG study. In patients receiving a 6-week induction course of BCG followed by three weekly instillations of BCG at 3, 6 months and then every 6 months for 3 years, the relapse rate was significantly lower and the relapse-free period was longer than in patients receiving only an induction course . After only one three-week maintenance course of BCG instillations, 87% of patients with CIS had complete regression, 83% of patients with CIS or rapidly recurrent tumors T a/T1 SCC were without relapse.

During BCG therapy, a number of immunological changes are observed, such as infiltration of the bladder walls with mononuclear leukocytes (CD4+ and CD8+ lymphocytes, macrophages, B-lymphocytes) and an increase in the concentration of various cytokines in the urine (interleukin-1, -2, -6, -8, -10, tumor necrosis factor and interferon-γ). A study of the dependence of the effectiveness of BCG therapy on the level of cytokines in the urine showed the high prognostic significance of the latter. Thus, J. Fleischmann et al. identified the prognostic significance of interleukin-2 and/or interleukin-2 inhibitor levels in urine; F. Saint et al. demonstrated the predictive value of urinary interleukin-2 levels for tumor recurrence.

Urinary cytokine levels peak in most patients after the sixth BCG instillation, but in patients with prior induction therapy, cytokine levels peak after 3 weeks. A long course of weekly BCG instillations can suppress the immune response and significantly increase the toxicity of treatment. Unlike chemotherapy, in which increasing doses lead to increased cytotoxicity, the dose-response curve for BCG is bell-shaped. An overdose of BCG can reduce the antitumor effect and even stimulate tumor growth.

When discussing the best regimen for administering BCG, the toxicity of this treatment must be taken into account. In the SWOG study, toxic effects requiring treatment discontinuation, dose reduction, or isoniazid were observed in 26% of patients receiving maintenance therapy compared with 9% of patients receiving BCG induction alone (R< 0,0001) .

Thus, it seems rational to identify a subgroup of patients for whom maintenance BCG therapy is especially indicated. In patients with a good prognosis for cancer progression who are receiving BCG as second-line therapy because intravesical chemotherapy fails to prevent relapse, the high risk of toxicity from maintenance therapy does not justify its use. In this subgroup, it is likely appropriate to use either a 6-week induction course or a 6-week induction followed by three weekly instillations after 3 months. However, if the patient has CIS and/or a T tumor 1G3, maintenance therapy is necessary. This is especially true if no signs of significant toxicity were observed during the induction course.

Side effects of BCG therapy

BCG therapy can be complicated by side effects. Most of the symptoms accompanying BCG administration do not pose a threat to the patient's health, but there are also more serious complications that require immediate treatment. Cystitis is the most common side effect of BCG therapy and is observed in 90% of patients. Dysuria develops as a result of the inflammatory response to BCG therapy no earlier than after 3-4 instillations. Most often, the symptoms of cystitis disappear within 24 hours. Nonsteroidal anti-inflammatory and/or anticholinergic drugs can slightly reduce dysuria. However, if acute irritative symptoms continue for more than 72 hours, isoniazid can be prescribed. Treatment should be continued for 1-2 weeks or until the symptoms of cystitis subside. Some urologists recommend prescribing 300 mg of isoniazid the day before BCG instillation and for 3 days after it. BCG should not be administered until all side effects from the previous administration have stopped. This is especially important with the development of hematuria, which occurs in 20-35% of patients.

Other complications that are not life-threatening (20%) include general weakness, fatigue and drowsiness. Low-grade fever (less than 38°C) may occur in 10-15% of patients, but it usually resolves within 24 hours. It is important to distinguish these mild, short-lived side effects from more serious symptoms of a general infection.

Any patient with a body temperature greater than 39.5°C should be admitted to hospital and treated as for BCG sepsis. If treatment is not started on time, sepsis can lead to the death of the patient. Current recommendations for the treatment of BCG sepsis are isoniazid 300 mg, rifampicin 600 mg and prednisolone 40 mg per day. Treatment with prednisone continues until signs of sepsis are relieved (followed by a dose reduction over 1-2 weeks), isoniazid and rifampicin for 3-6 months. Patients with a history of BCG sepsis should no longer receive BCG.

Thus, intravesical chemotherapy reduces short-term relapse rates in superficial bladder cancer. However, there is no long-term reduction in relapse rates, and intravesical chemotherapy does not affect the rate of progression to muscle-invasive tumors. In addition, adjuvant intravesical chemotherapy does not affect survival. Intravesical chemotherapy may be recommended for patients with multiple or frequently recurrent well- and moderately differentiated Ta tumors.

Unlike chemotherapy, BCG immunotherapy, in addition to reducing the frequency of relapses, leads to a decrease in the incidence of tumor progression and increases the survival of patients with SCC. BCG immunotherapy is indicated for patients at high risk of recurrence and progression of superficial bladder cancer (CIS stage T 1, poorly differentiated tumors), as well as in cases of ineffectiveness of intravesical chemotherapy for highly and moderately differentiated tumors Ta.

The limited effectiveness of intravesical chemotherapy and the high toxicity of BCG necessitate the search for new approaches to the prevention of relapses and treatment of superficial bladder cancer. Such approaches include the use of new chemotherapeutic agents, as well as new immunological agents (interferon-α, interleukin-2, keyhole clam hemocyanin), electrophoretic delivery of chemotherapeutic agents, the use of photodynamic therapy and intravesical thermochemotherapy. Many of them have shown encouraging results, but more research is needed before introducing a new type of treatment into clinical practice.

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