Adjuvant chemotherapy and immunotherapy for bladder cancer

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

Adjuvant chemotherapy and immunotherapy

Despite the fact that radical TUR usually allows for the complete removal of superficial bladder tumors, they nevertheless often (in 30-80% of cases) recur, and in some patients the disease progresses.

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

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

Risk factor	Recurrence	Progression
Number of tumors
The only one	0	0
From 2 to 7	3	3
28	B	3
Tumor diameter
<3 cm	0	0
23 cm	3	3
Previously noted 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
Yes	0	0
T1	1	4
CIS
No	0	0
Eat	1	6
Degree of differentiation
G1	0	0
G2	1	0
G3	2	5
Total points	0-17	0-23

[ 1 ], [ 2 ], [ 3 ]

Groups of superficial bladder tumors according to risk factors

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

From the above data, it becomes clear that adjuvant chemo- or immunotherapy is necessary after TUR of the bladder in almost all patients with superficial cancer.

The goals and hypothetical mechanisms of local chemo- and immunotherapy are to prevent implantation of cancer cells early after TUR, reduce the possibility of recurrence or progression of the disease, and ablate residual tumor tissue if it is not completely removed (“hemireection”).

Intravesical chemotherapy

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

Single instillation in the early stages after surgery

Mitomycin, epirubicin and doxorubicin are used with equal success for intravesical chemotherapy. 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 with urine, patients sharply limit fluid intake on the day of instillation. For better contact of the chemotherapy drug with the mucous membrane of the bladder, it is recommended to frequently change body position before urination.

When using mitomycin, one should take into account the possibility of an allergic reaction with reddening of the skin of the palms and genitals (in 6% of patients), which can be easily prevented by careful washing of 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 instillation (within 24 hours after TUR) is contraindicated if extra- or intraperitoneal perforation of the bladder is suspected, which can usually occur with aggressive TUR of the bladder.

Due to the risk of systemic (hematogenous) spread, local chemotherapy and immunotherapy are also contraindicated in macrohematuria. A single instillation of a chemotherapy drug reduces the risk of recurrence 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.

The reduction in the recurrence rate occurs within 2 years, which is of particular importance in patients with low oncological risk, for whom a single installation has become the main method of metaphylaxis. However, a single installation is insufficient for patients with average and, especially, high oncological risk, and such patients, due to the high probability of recurrence and progression of the disease, require additional adjuvant chemo- or immunotherapy.

Adjuvant multiple chemotherapy administration

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 on the optimal duration and frequency of intravesical chemotherapy are controversial. According to a randomized trial

According to the European Organization for Research and Treatment of Bladder Cancer, monthly instillation for 12 months did not improve treatment outcomes compared with 6 months, provided that the first instillation was performed immediately after TUR. According to other randomized trials, the recurrence rate with a one-year course of treatment (19 instillations) was lower compared with 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 the BCG vaccine, the introduction of which leads to a pronounced immune response: cytokines (interferon y, interleukin-2, etc.) are expressed in the urine and bladder wall. Stimulation of cellular immunity 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. The BCG vaccine is a lyophilized powder that is stored frozen. It is produced by various companies, but all manufacturers use a mycobacterium culture obtained 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 through a urethral catheter under the force of gravity of the solution. Adjuvant treatment of bladder cancer begins 2-4 weeks after TUR of the bladder (the time required for re-epithelialization) to reduce the risk of hematogenous dissemination 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 (turning from one side to the other). On the day of instillation, fluid intake and diuretics should be stopped to reduce dilution of the drug in urine.

Patients should be warned about the need to wash the toilet after urination, although the risk of household contamination is considered hypothetical. Despite the advantages of BCG compared to adjuvant chemotherapy, it is generally recognized that immunotherapy is recommended only for patients with a high oncological risk. 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 discontinued. This is why its administration to patients with a low oncological risk is not justified.

The main indications for prescribing the BCG vaccine:

• CIS;
• presence of residual tumor tissue after TUR;
• metaphylaxis of tumor recurrence in patients with high oncological 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, due to taking cytostatics);
• 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 that preclude the use of isoniazid in case of tuberculous sepsis;
• history of tuberculosis;
• severe concomitant diseases.

The classic adjuvant BCG therapy regimen was empirically developed by Morales more than 30 years ago (weekly instillation for 6 weeks). However, it was later established that a 6-week course of treatment is insufficient. There are several variations of this regimen: from 10 instillations for 18 weeks to 30 instillations for 3 years. Although an optimal, generally 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 the first 6-week course, repeat 3-week courses are administered after 3, 6 and 12 months).

Recommendations for intravesical chemotherapy or BCG therapy

• In cases of low or moderate risk of recurrence and very low risk of progression, it is necessary to perform a single instillation of the chemical preparation.
• In case of low or moderate risk of progression, regardless of the degree of risk of relapse, after a single administration of the chemotherapy drug, maintenance adjuvant intravesical chemotherapy (6-12 months) or immunotherapy (BCG for 1 year) is necessary.
• In case of high risk of progression, intravesical immunotherapy (BCG for at least 1 year) or immediate radical cystectomy is indicated.
• When choosing one or another 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 of bladder cancer.

Approximately 15% of patients diagnosed with bladder cancer also have regional or distant metastases, and almost half of patients develop metastases after radical cystectomy or radiation therapy. Without additional treatment, these patients have poor survival rates.

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

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

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

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

Adjuvant systemic chemotherapy

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

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

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

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