Adjuvant chemo-and immunotherapy for bladder cancer

Treatment of bladder cancer (stage Ta, T1, Cis)

Adjuvant chemotherapy and immunotherapy

Despite the fact that radically performed TUR, as a rule, allows 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 4,863 patients with superficial bladder tumors, the European Organization for Research and Treatment of Bladder Cancer in 2007 developed a methodology for a prospective assessment of the risk of recurrence and progression of tumors. The methodology is based on a 6-point system for assessing several risk factors: the number of tumors, the maximum tumor size, the frequency of recurrence in the history, the stage of the disease, the presence of CIS, the degree of differentiation of the tumor. The sum of these scores is determined by the risk of recurrence or progression of the disease in%.

System for the calculation of risk factors for recurrence and progression of superficial tumors of the bladder

Factor risk	Recurrence	Progression
Number of tumors
The only	0	0
From 2 to 7	3	3
28	B	3
Tumor Diameter
<3 cm	0	0
23 centimeters	3	3
Previously reported recurrence
Primary relapse	0	0
Less than 1 relapse per year	2	2
More than 1 relapse per year	4	2
Stage of the disease
And	0	0
T1	1	4
CIS
No	0	0
There is	1	6th
Degree of differentiation
G1	0	0
G2	1	0
G3	2	5
Total points	0-17	0-23

[1], [2], [3],

Groups of superficial tumors of the urinary bladder in accordance with risk factors

• Tumors of small risk:
  • single;
  • And;
  • highly differentiated;
  • measuring <3 cm.
• Tumors of high risk:
  • T1;
  • low-differentiated;
  • multiple;
  • highly recurrent;
  • CIS.
• Tumors of intermediate risk:
  • Ta-T1;
  • medium-differentiated;
  • multiple;
  • measuring> 3 cm.

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

The goals and presumptive mechanisms of local chemo- and immunotherapy are to prevent the implantation of cancer cells in the early period after TUR. Decrease in the possibility of recurrence or progression of the disease and ablation of residual tumor tissue with incomplete removal ("hemirexia").

Intravesical chemotherapy

There are two schemes of intravesical chemotherapy after a bladder TUR for a superficial cancer: a one-time installation at an early time after the operation (within the first 24 hours) and an adjuvant multiple injection of a chemotherapy drug.

Single instillation at an early date after surgery

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

When using mitomycin, one should consider the possibility of an allergic reaction with redness of the skin of the palms and genitals (in 6% of patients), which can easily be prevented by careful washing of 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 in case of suspected out-or intraperitoneal perforation of the bladder, which can usually occur with aggressive TUR of the bladder.

Due to the danger of systemic (hematogenous) spreading, local chemo- and immunotherapy is contraindicated in macrohematuria. A single installation of a chemotherapy reduces the risk of recurrence by 40-50%, on the basis of which it is performed in almost all patients. A single injection of a chemotherapeutic agent at a later time reduces the effectiveness of the method by a factor of 2.

Reduction in the frequency of recurrence occurs within 2 years, which is of particular importance in patients with low oncological risk, for which a single installation has become the main method of metaphylaxis. However, a single-time installation is not sufficient for the average and, especially, high cancer risk, and such patients in connection with the high probability of recurrence and progression of the disease need additional adjuvant chemotherapy or immunotherapy.

Adjuvant multiple injection of a chemical

Treatment of bladder cancer consists of multiple intravesical administration of the same chemotherapy drugs. Chemotherapy is effective in reducing the risk of recurrence. But not effective enough to prevent the progression of the tumor. Data on the optimal duration and frequency of intravesical chemotherapy are contradictory. According to a randomized trial

Of the European Organization for Research and Treatment of Bladder Cancer, the monthly installation for 12 months did not improve the results of treatment compared to that for 6 months, provided that the first installation was performed immediately after TUR. According to other randomized studies. The frequency of recurrence with an annual course of treatment (19 installations) was lower compared to a 3-month course (9 instillations) of epirubicin.

[4], [5], [6], [7], [8], [9], [10], [11], [12]

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 BCG vaccine, the administration of which leads to a pronounced immune response: the expression of cytokines (interferon y, interleukin-2, etc.) occurs in the urine and the wall of the bladder . Stimulation of cellular immunity factors. This immune response activates the cytotoxic mechanisms that 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. The BCG vaccine is a lyophilized powder that is stored frozen. It is produced by various companies, but all manufacturers use the culture of mycobacteria. Received at 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 via the urethral catheter under the gravity of the solution. Adjuvant treatment of bladder cancer begins 2-4 weeks after TUR of the bladder (the time needed for re-epithelialization) to reduce the risk of hematogenous spread of living bacteria. In the case of traumatic catheterization, the instillation procedure is postponed for several days. After instillation for 2 hours, the patient should not urinate, it is often necessary to change the position of the body for a full interaction of the drug with the mucosa of the bladder (turning from one side to the other). On the day of instillation, you should stop taking fluids and diuretics to reduce the dilution of the drug with urine.

Patients should be warned about the need to wash the toilet after urinating, although the risk of household contamination is considered hypothetical. Despite the advantages of BCG in comparison with adjuvant chemotherapy, it is generally accepted that immunotherapy is recommended only for patients with high oncological risk. This is due to the likelihood of developing various, including serious, complications (cystitis, temperature rise, prostatitis, orchitis, hepatitis, sepsis and even death). Because of the development of complications, it is often necessary to stop adjuvant therapy. That is why its appointment to patients with low oncological risk is not justified.

The main indications for the BCG vaccine are:

• CIS;
• presence of residual tumor tissue after TUR;
• metaphylactics of tumor recurrence in patients with high oncological risk.

Great importance is attached to the use of BCG vaccine in patients at high risk of disease progression, as it is proved, only this drug is able to reduce the risk or stunt the progression of the tumor.

Absolute contraindications to BCG therapy:

• immunodeficiency (for example, against the background of taking cytotoxic drugs);
• immediately after TUR;
• macrohematuria (risk of hematogenous generalization of infection, sepsis and death);
• traumatic catheterization.

[13], [14], [15], [16], [17], [18], [19],

Relative contraindications to BCG therapy:

• urinary tract infection;
• liver diseases, excluding the possibility of using isoniazid in the case of tuberculosis sepsis;
• tuberculosis in the anamnesis;
• severe co-morbidities.

The classical scheme of adjuvant BCG therapy empirically developed Morales more than 30 years ago (weekly installation for 6 weeks). However, it was further established that a 6-week treatment course is not enough. There are several options for this scheme: from 10 installations for 18 weeks to 30 installations for 3 years. Although the most widely accepted BCG regimen 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 a first 6-week course, repeat 3-week courses at 3, 6 and 12 months) .

Recommendations for intravesical chemotherapy or BCG therapy

• If the risk of recurrence is low or medium and there is a very low risk of progression, it is necessary to perform a single installation of the drug.
• At a low or average risk of progression, regardless of the risk of recurrence. After a single injection of chimno-drug it is necessary to maintain adjuvant intravesical chemotherapy (6-12 months) or immunotherapy (BCG for 1 year).
• With a high risk of progression, 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 (stage T2, T3, T4)

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

Approximately 15% of patients with diagnosing bladder cancer also diagnose regional or distant metastases, and in almost half of the patients metastasis occurs after radical cystectomy or radiation therapy. Without additional treatment, the survival rate of such patients is negligible.

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

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

Combined chemotherapy in 40-70% of patients is partially or completely effective, which served as the basis for its use in combination with iystectomy or radiotherapy in the mode of neoadjuvant or adjuvant therapy.

Neoadjuvant combined chemotherapy It is shown in patients with stage T2-T4a before radical cystectomy or radiation treatment and is aimed at treating possible bladder cancer of possible micrometastases, reducing the likelihood of re-idiation. And in some patients to preserve the bladder. Patients carry it easier to the main treatment (cystectomy or radiation), however, randomized studies have revealed its insignificant effectiveness or lack thereof. In some patients (tumor of small size, lack of hydronephrosis, papillary structure of the tumor, possibility of complete visual removal of the tumor by TUR), adjuvant chemotherapy in combination with irradiation has allowed avoiding cystectomy in 40% of cases, however, randomized trials are needed for this recommendation.

Adjuvant systemic chemotherapy

Her various regimens (standard MVAC regimen, the same drugs in high doses, gemcitabine in combination with cisplatin) are at the stage of study in a randomized study by the European Organization for Research and Treatment of Bladder Cancer, which so far does not allow one of her options to be recommended.

The MVAC scheme with metastatic lesion was effective only> 15-20% of patients (prolongation of life only for 13 months). The results were better in patients with metastasis in regional lymph nodes compared with metastasis in distant organs. When the combination of MVAC was ineffective, a high efficiency of mode replacement with gemcitabine and paclitaxel was found. As a primary therapy, good results were obtained with the combination of cisplatinum gemcitabine and paclitaxel.

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

[20], [21], [22], [23], [24], [25],