Why bladder perfusion chemotherapy after bladder cancer surgery? Why is BCG vaccine preferred?
Bladder tumors are multifocal, and by multifocal we mean two things. One meaning is manifested in spatial multiplicity; multiple tumors growing in the bladder at the same time. The other meaning is temporal multiplicity. A large number of clinical studies have confirmed that non-muscle invasive bladder cancer using transurethral bladder tumor electrosurgery has approximately 70-80% recurrence rate within 5 years without subsequent bladder perfusion therapy.
The main reasons for recurrence are.
1, primary tumor not excised.
2, intraoperative shedding of tumor cells for implantation.
3, derived from proliferation of pre-existing metastatic epithelium or atypical lesions.
4, continued irritation of the bladder epithelium by intra-urinary carcinogens. If correct bladder perfusion treatment is used, its recurrence rate can be reduced by half, generally to about 30%. Regular bladder perfusion chemotherapy after surgery can effectively prevent tumor recurrence and inhibit tumor progression to infiltration, and it is simple to operate and has few adverse effects, which is an important part of the treatment of non-primary invasive bladder uroepithelial carcinoma.
At present, there are two types of drugs for bladder cancer perfusion.
(1) chemotherapeutic agents: anthracyclines (e.g., famasin), mitomycin, and hydroxychalcone.
(2) Biological agents: including BCG (bacillus Calmette-Guerin, BCG), and interferon.
BCG is attenuated live Mycobacterium tuberculosis, and local infusion causes non-specific infection of bladder mucosa, which can encourage macrophages and lymphocytes to enter the lesion and destroy the normal growth environment of tumor, thus inhibiting the growth of tumor cells. In addition, the vaccine is absorbed into the blood stream through the bladder mucosa and drains into the local lymph nodes, stimulating the proliferation, differentiation and activation of reticuloendothelial cells and mobilizing a large number of immune cells to participate in the immune response. The clinical manifestations are bladder irritation signs, hematuria, and discharge of mucosal flakes. bcg enters the blood stream, causing fever, joint pain and lymph node enlargement in those allergic to tuberculosis bacilli, and tuberculosis infection of the lung and liver, which should be observed with special care.
BCG can induce non-specific immune response, cause Thl cell-mediated immune response and anti-tumor activity, thus reducing the risk of tumor progression and recurrence. From the current findings, BCG infusion is the most effective intravesical infusion therapy, which can effectively reduce recurrence and delay tumor progression.
Indications for BCG bladder infusion immunotherapy
The absolute indications for BCG bladder infusion immunotherapy include high-risk non-muscle invasive bladder cancer and bladder carcinoma in situ, and the relative indications are intermediate-risk non-muscle invasive bladder cancer. BCG achieves its therapeutic effect by inducing a local tumor-free immune response, and the exact mechanism of action is unclear. Compared with TUR surgery alone or TUR combined with postoperative bladder perfusion chemotherapy, postoperative BCG bladder perfusion immunotherapy after TUR combined with surgery prevents postoperative recurrence of non-muscle invasive bladder cancer and significantly reduces the risk of progression of intermediate-risk and high-risk tumors. Therefore, BCG bladder infusion immunotherapy is recommended for high-risk non-muscle invasive bladder cancer. The recurrence rate of intermediate-risk non-muscle invasive bladder cancer at 5 years after surgery is 42% to 65%, and the probability of tumor progression is 5% to 8%. For intermediate-risk non-muscle-invasive bladder cancer, bladder irrigation chemotherapy or immunotherapy is an option. Bladder perfusion chemotherapy is usually recommended, and some patients may be treated with BCG perfusion. BCG bladder perfusion does not alter the disease process in low-risk bladder cancer and has a high incidence of side effects, and immunotherapy with BCG bladder perfusion is not recommended. BCG should not be used in patients with immunodeficiency or impairment, in patients on immunosuppressive drugs, in patients with BCG allergy, and in patients with acute infectious diseases and severe chronic diseases.
Optimal course of BCG bladder infusion immunotherapy
The optimal duration of immunotherapy with BCG bladder infusion is currently inconclusive. BCG therapy is generally administered with 6 weeks of perfusion to induce an immune response, followed by 3 weeks of intensive perfusion to maintain a good immune response. BCG requires maintenance perfusion for more than 1 year to achieve clinical benefit and a 37% reduction in the probability of tumor progression. There are many regimens for maintenance perfusion therapy, ranging from 10 perfusions over 18 weeks to 27 perfusions over 3 years, but there is no evidence that any one regimen is significantly superior to the others.
BCG bladder perfusion dose
The optimal dose of BCG bladder perfusion immunotherapy is similarly inconclusive. The standard dose of BCG perfusion therapy is 81-150 mg and is recommended for the treatment of high-risk non-muscle invasive uroepithelial carcinoma of the bladder. Standard dose BCG treatment is more effective in case of multiple bladder tumors. For intermediate-risk non-muscle invasive bladder cancer, the use of 1/3 standard dose is recommended, which has the same efficacy as the full dose and significantly fewer side effects, but the incidence of serious systemic toxic reactions is not significantly reduced. The use of 1/6 standard dose affects the therapeutic efficacy and is not recommended. There is evidence that co-infusion of fibrinogen inhibitor and interferon can reduce BCG dosage and side effects without affecting the therapeutic effect.
BCG bladder perfusion process
1.Preparation for perfusion.
(1) Tuberculin skin test: confirm non-strong positive (suggesting non-tuberculosis active stage).
(2) Urine should be emptied before bladder perfusion, and make sure that no large amount of water, fluids or diuretics (such as hydrochlorothiazide) have been taken within the last 2 hours.
2) During perfusion: Keep your body relaxed during perfusion so that the urethral muscles are relaxed to facilitate the smooth entry of the catheter into the bladder. Patients with conditions such as urethral stricture can explain to the outpatient doctor in advance so that the appropriate size catheter can be replaced.
3.Lie flat after instillation and change the position appropriately, keeping it for a total of 2 hours, during which the position is changed (30 minutes each for supine, left lateral, right lateral and prone positions in that order), and the time can be shortened appropriately for patients with frequent urinary urgency and small bladder. If the patient has a history of urinary retention, it is recommended to retain the urethral catheter after instillation of BCG until the BCG instillation fluid is drained and then remove it.
Precautions after instillation
(1) Any medical devices contaminated with BCG drugs should be disposed of in a special medical waste bag, marked and properly disposed of according to the local hospital regulations.
(2) All urine disposal within 6 h after treatment should be noted: after urination, pour 2 cups of bleach solution in the toilet and keep it for 15-20 min before flushing the toilet, and the toilet should be flushed twice.
(3) Encourage patients to drink more water for 1 week after urination to excrete the residual drug, and avoid tea, coffee, alcohol and cola drinks to reduce bladder irritation.
(4) Advise patients to consult or seek medical advice if unintended adverse reactions occur.
(5) Fluoroquinolones, macrolides, tetracyclines and aminoglycoside antibiotics are prohibited because they can reduce the efficacy of BCG.
(6) Sexual life: Sexual life is prohibited within 48 h of BCG treatment, and condoms need to be used at other times.
(7) During the period of BCG infusion therapy, if you need to consult or use medication for other diseases, you should promptly inform the relevant attending physician.
(8) The rest of the post-perfusion precautions are the same as for chemical perfusion.
(9) Treatment after drug contamination or contamination: Once the drug has contaminated the skin, it should be rinsed locally with plenty of soap and water, then rinsed with water and reported to the hospital infection office. Do not use hand creams or emollients for topical application after washing the drug-stained skin, as this will increase the absorption of the drug. If the drug stains the eyes or mucous membranes, remove glasses or mask, flush with plenty of saline and report to the hospital infection office afterwards. If the drug stains clothing, the contaminated clothing should be removed quickly and the stained skin treated; contaminated clothing should be washed repeatedly with a dilute solution of hot bleach. For other forms of spills, the spill needs to be covered with an absorbable cloth and discarded.
Common Adverse Reactions to BCG Bladder Perfusion and How to Manage Them
Side effects of BCG bladder instillation therapy mainly include bladder irritation, hematuria and systemic flu-like symptoms. Rare side effects include tuberculous sepsis, prostatitis, epididymitis, and hepatitis. Systemic BCG reactions and allergic reactions are rare [68]. BCG instillation should not be performed in the presence of open bladder trauma or significant meatus hematuria.
Bladder irritation is the most common adverse reaction; BCG is a live bacterial preparation and causes local irritation after injection into the bladder, which is a normal phenomenon and the process of drug efficacy; therefore, drinking more water after urination by perfusion is encouraged to expel residual drugs from the body. Special attention is paid to the fact that the first urine excretion after perfusion contains a large amount of chemical drugs, so it is recommended that the first urination be performed in a hospital. The urine should be treated within 6 h after treatment: after urination, pour an appropriate amount of bleach solution into the toilet and keep it for 15-20 minutes before flushing the toilet.
Factors affecting the effectiveness of BCG infusion therapy and prevention of bladder cancer
1. The patient’s immune responsiveness. The stronger the patient’s immune response ability to Mycobacterium antigen, the more significant the therapeutic effect. BCG, unlike other anti-cancer drugs, is not a direct killer of cancer cells. Since BCG has the same antigen as the bladder tumor, BCG is used to treat bladder cancer by activating the mononuclear macrophage system in the patient’s body, increasing the cytotoxic effect of lymphocytes and producing anti-tumor antibodies, so that they can target and destroy the tumor tissue. Therefore, most of the patients who have positive tuberculin test have good response and therapeutic effect for the treatment of bladder cancer.
2.The number of live bacteria of BCG vaccine. It is found that BCG vaccine containing more than 7.5×108 live bacteria has better therapeutic effect, and preparations with less than this number have poorer therapeutic effect.
3, the number of times of medication. It is generally believed that the treatment effect is better for those who use the drug more than 8 times, and the treatment effect is worse for less than 8 times. Some patients are forced to stop the medication for various reasons, which is difficult to achieve the expected effect.
4.The type and size of tumor. BCG infusion is only effective for recurrence of superficial bladder cancer and treatment of residual cancer and carcinoma in situ, but not effective for bladder cancer infiltrating the muscular layer. The treatment is effective for those whose cancer is less than 0.5 cm in diameter. If the tumor size is too large, it will destroy the body’s immune ability and make the body lack sufficient immune active cells and affect the treatment effect. In addition, the tumor body is too large for BCG vaccine to be in close contact with the tumor extensively, resulting in part of the tumor tissue not getting the stimulating effect of inflammation and losing the effect of BCG vaccine to enhance immune function, which affects the therapeutic effect.