Bladder cancer is one of the most common malignancies of the urinary system and is a disease that directly threatens patient survival. Non-muscle invasive bladder cancer (NMIBC) accounts for 70% of primary bladder tumors, including Ta, T1 and Tis. transurethral resection of bladder tumors and postoperative intravesical infusion chemotherapy are currently the main treatment modalities for NMIBC. Despite treatment, a significant proportion of patients still experience recurrence and progression. In recent years, some new treatments and perfusion methods have been applied in the clinic, which have opened up new ideas for the treatment of NMIBC.
Uroepithelial carcinoma may originate from any part of the urinary tract, but >90% of the cases occur in the bladder. Bladder cancer is one of the most common malignancies of the urinary tract. in 2010, there were approximately 70,000 (52,000 men and 14,000 women) patients with new bladder tumors in the United States. Bladder cancer can be divided into non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). NMIBC accounts for 70% of primary bladder tumors, with Ta accounting for 70%, T1 for 20%, and Tis for 10%. Transurethral bladder tumor electrosurgery and postoperative bladder perfusion chemotherapy play a crucial role in treating NMIBC and preventing its recurrence. Prevention of tumorigenesis, progression and metastasis is the key to reduce the recurrence and mortality of bladder cancer.
Surgical treatment
Transurethral bladder tumor resection
Transurethral resection of bladder tumors (TURBT) is both an important diagnostic and primary treatment for non-muscle invasive bladder cancer. The exact pathological staging and grading of bladder tumors are obtained with the help of pathological findings after the first TURBT. The greatest advantage of this procedure is that it preserves the bladder, and it is simple, less invasive, less complications, does not cause abdominal wall implantation metastasis, less painful for patients, quicker recovery, easily accepted by doctors and patients, and now it has become the gold standard for early diagnosis and treatment of NMIBC. Studies have confirmed that the 5-year survival rate and recurrence rate of TURBT are better than that of partial cystectomy. However, TURBT also has many shortcomings, such as high technical requirements for surgical operation, easy bleeding and bladder perforation during surgery, difficulty in removing tumors located in the neck and top of the bladder, and easy induction of the closed nerve reflex when cutting tumors located under the lateral wall of the bladder.
Therefore, the following points should be noted when applying TURBT for NMIBC.
1. because bladder perforation is likely to occur when resecting tumors on top of the bladder, when performing TURBT on multiple bladder tumors, other parts of the tumor should be treated first, and then resection of the top tumor should be performed after confirming the complete resection.
2.For larger bladder tumors, the base is not easily exposed, so when resecting, the tumor should be removed layer by layer starting from one side of the tumor, and once the base is revealed, the tumor should be removed from the base to avoid bleeding caused by excessive cutting on the surface of the tumor and affecting the visual field.
3.For tumor under the lateral wall of bladder, closed-hole nerve reflex is likely to occur during resection. The closed-hole nerve on the affected side should be blocked before performing electrodesiccation, and it should be avoided by first using electrocoagulation of bladder mucosa around the tumor, reducing the power of electrodesiccation, decreasing the amount of bladder irrigation fluid infusion, and tapping the switch rapidly.
4.Tumors located near the ureteral orifice may damage the ureteral orifice during surgery. Diuretics can be applied during surgery to diuretic and keep the ureteral orifice open for urination, and electrocoagulation should not be used as much as possible during cutting to avoid local scar formation after surgery and cause ureteral orifice stenosis.
5. For incomplete tumor resection, no muscle layer in the specimen, high-grade and T1 stage tumor, it is recommended to perform TURBT again 2-6 weeks after surgery, which can reduce the probability of postoperative recurrence. the overall complication rate of TURBT is 5. 1%-43%, and some data show that the chance of urinary tract infection after TURBT is as high as 24%, bleeding (2.8%-8%), bleeding requiring blood transfusion (0.9%-13 13%), bladder perforation (1.3%-5%); others are bladder contracture and incomplete tumor removal.
Transurethral laser surgery
Transurethral laser surgery has long been used as an alternative treatment for NMIBC. Laser treatment of superficial bladder tumors can be coagulation, excision, or vaporization, and its efficacy and recurrence rate are similar to those of TURBT surgery. Depending on the laser emitting medium, it can be divided into gas laser, solid laser, dye laser and semiconductor laser. Different wavelengths of laser have different tissue effects. In general, as the wavelength of laser increases, the vaporization effect of laser on tissue gradually decreases, while the coagulation effect gradually strengthens. After the laser is absorbed by tissues, it can rapidly convert light energy into heat energy, which can cause coagulation, necrosis and vaporization of tissues, and achieve the purpose of tumor treatment. Compared with TURBT, the main advantages of transurethral laser surgery are
1. shallow depth of tissue penetration, less thermal dispersion, slight damage to adjacent tissues, significant hemostatic effect, allowing the surgical operation to be performed in an almost bloodless field.
2. No electric current is generated during cutting and vaporization, which will not cause closed-hole nerve reflex and can effectively avoid bladder perforation, hemorrhage and other injuries.
3.When cutting the tumor, the lymphatic vessels and blood vessels around the tumor tip can be closed first to reduce the chance of tumor metastasis during the operation.
4.There is very little carbonized tissue after surgery, generally there is no obvious meatus hematuria after 2-3d, short time of indwelling catheter, no need of bladder irrigation, short hospitalization time.
5. Patients who are old and frail, have coagulation mechanism disorders, or have pacemakers can also tolerate the operation.
These advantages make laser a special superiority in the treatment of non-muscle invasive bladder tumors. Laser surgery, in which the tissue is mostly destroyed by vaporization, does not provide a complete surgical specimen for accurate pathologic staging and is costly, also carries the risk of bladder perforation, and is not recommended for primary or preoperative bladder tumors of unknown pathologic diagnosis, and is generally indicated for papillary low-grade uroepithelial carcinoma, as well as for more superficial and limited NMIBC and large mossy tumors <2 cm in diameter.
Photodynamic therapy
Photodynamic therapy (PDT) is a treatment that combines a laser with a photosensitizer using a cystoscope. The photosensitizer has a strong affinity for cancerous tissue. When the cancerous tissue ingests the photosensitizer, its photodynamic response is activated when it encounters the appropriate wavelength of visible light that can penetrate the tissue, producing monomorphic oxygen that kills the cancer cells and their vascular system. Theoretically, photodynamic therapy is a “targeted, cellular, microscopic killing effect” that is more suitable for bladder cancer that is clinically multicentric and highly recurrent. It is characterized by no contact with the tumor, simultaneous blocking of tumor-affiliated lymphatic vessels, low recurrence rate, and minimal patient pain, but larger tumors often require multi-field irradiation, long irradiation time, and waiting for tumor tissue necrosis to fall off before the effect can be seen after irradiation, a process that takes 1 to 2 weeks. It is often used clinically for in situ bladder cancer, control of bladder tumor bleeding, multiple tumor recurrence, and intolerance of surgical treatment.
Postoperative adjuvant therapy
The effect of surgery alone for non-muscle invasive bladder cancer is not ideal, and the recurrence rate is high. Its recurrence may be related to the following factors: incomplete resection of tumor during surgery; intraoperative tumor cell implantation; failure to remove carcinogenic factors, such as chemical carcinogens in urine; new tumors in the bladder caused by factors such as genetic susceptibility of patients. It is currently believed that TURBT alone cannot solve the problem of bladder cancer recurrence and disease progression after surgery, so all patients with non-muscle invasive bladder cancer should undergo adjuvant bladder perfusion therapy after surgery. The purpose of bladder perfusion is to prevent tumor recurrence, delay tumor progression, and destroy residual tumor and carcinoma in situ. Domestic and international studies have shown that intravesical bladder perfusion can reduce the recent recurrence rate of superficial bladder tumors by 15% to 20% and the long-term recurrence rate by about 6%.
Bladder perfusion has the following advantages.
1. anti-cancer drugs can act directly on cancer cells in the bladder for a long time and at high concentration.
2.It can kill the tumor cells left in the surgery, prevent their implantation and reduce the recurrence rate of tumor.
3.Can treat carcinoma in situ and precancerous lesions by infusing chemotherapeutic drugs.
4.Avoiding the adverse reactions and toxic effects of drugs brought by systemic administration.
5.Improves the survival rate and life quality of patients. The current perfusion therapy is mainly divided into two types: chemotherapeutic drug perfusion therapy and immune perfusion therapy.
Postoperative intravesical infusion chemotherapy
Postoperative intravesical perfusion chemotherapy can significantly reduce the recurrence rate of tumors. One study showed that the use of intravesical infusion chemotherapy alone after bladder tumor resection can reduce the recurrence rate by about 39%. Commonly used drugs for bladder infusion chemotherapy include thiotepa, adriamycins, mitomycin C, hydroxycamptothecin, gemcitabine, docetaxel, and so on. Their common feature is that they have large molecular weight and are not easily absorbed into the blood by the bladder mucosa. In vitro drug sensitivity tests have confirmed that the sensitivity of bladder tumors to different chemotherapeutic agents varies from patient to patient, but this result has not been clinically validated. The most commonly used drugs are piroplasin and mitomycin C. The methods of perfusion are divided into immediate postoperative bladder perfusion chemotherapy, early postoperative bladder perfusion chemotherapy and maintenance bladder perfusion chemotherapy.
The immediate bladder perfusion refers to the completion of a chemotherapy perfusion within 24 h after TURBT, in which time is very important, if the perfusion time > 24 h the chance of tumor recurrence will increase, but the perfusion should not be done when there is intraoperative bladder perforation or obvious postoperative hematuria, in order to avoid serious complications caused by chemotherapy drugs entering the abdominal cavity or entering the blood. bladder tumors. For low-risk NMIBC patients, the recurrence rate of tumors after immediate bladder perfusion chemotherapy is very low, so bladder perfusion therapy can not be continued after immediate perfusion.
2. maintenance perfusion, repeated perfusion is superior to single perfusion due to the specificity of chemotherapeutic drugs to the tumor cell cycle. Therefore, for patients with intermediate-risk and high-risk non-muscle invasive bladder cancer, continued bladder perfusion chemotherapy is recommended, except for immediate postoperative perfusion within 24 h. However, it is difficult to choose the timing of perfusion according to the tumor cell cycle, so weekly and monthly perfusion therapy should be performed. The current recommended perfusion is once a week for 4-8 weeks, and then once a month for 6-12 months. However, there is no unified conclusion on how long and how often maintenance perfusion therapy should last. Some studies have shown that maintenance perfusion for more than 6 months in non-muscle invasive bladder cancer does not continue to reduce the probability of tumor recurrence, so 6 months of postoperative maintenance perfusion is recommended; however, some studies have also found that 1 year of maintenance perfusion with piroplatin reduces the probability of bladder tumor recurrence. The effect of bladder perfusion is to some extent related to the pH of urine, the chemotherapeutic drug and its concentration, but too high a concentration can cause serious adverse effects, so it is not advocated to increase the concentration of the drug in pursuit of efficacy. Chemotherapy drugs must be injected into the bladder through the catheter, and direct injection through the urethra can cause urethral stricture. The retention time is usually 0.5-2 h. The main adverse reaction that occurs during infusion is chemical cystitis, which is manifested by some degree of hematuria and urinary frequency, urgency and pain. In most patients, symptoms can be relieved with symptomatic treatment. If symptoms are more severe, delaying or stopping perfusion therapy should be considered to avoid secondary bladder contracture. Although bladder perfusion chemotherapy is effective in reducing the recurrence rate of NMIBC, it does not reduce the rate of tumor progression, so it is better to use BCG perfusion immunotherapy for patients with high-risk NMIBC.
Postoperative bladder perfusion immunotherapy
Since 1976, when Morales et al. first applied BCG bladder instillation to prevent the recurrence of superficial bladder tumors, after more than 30 years of research, BCG has become the most effective drug in NMIBC instillation therapy and is currently the only biologic agent approved by the FDA that can be instilled into the bladder cavity to treat carcinoma in situ. BCG instillation not only reduces tumor recurrence, but also BCG is suitable for the treatment of high-risk non-muscle invasive bladder cancer, not only to reduce the recurrence rate but also to prevent tumor progression. Treatment with BCG-induced perfusion 6 weeks after TUR reduces tumor recurrence by 20% to 65%, with an average of 40%, and BCG maintenance perfusion reduces tumor recurrence by an additional 14% compared to induction perfusion. The recurrence rate of intermediate-risk non-muscle-infiltrating uroepithelial carcinoma of the bladder at 5 years after surgery is 42% to 65%, and the probability of progression is 5% to 8%; therefore, the main purpose of bladder perfusion for intermediate-risk non-muscle-infiltrating uroepithelial carcinoma of the bladder is to prevent tumor recurrence, and bladder perfusion chemotherapy is generally recommended, and BCG perfusion may also be used in some cases. The study by Shelley et al. also found that BCG showed superiority only in the treatment of high-grade tumors, with equal results in intermediate grades. BCG perfusion is not recommended for patients with low-risk non-muscle invasive bladder cancer because it does not alter the course of the disease and has a high incidence of adverse events. Induction perfusion is generally used once a week for 6 weeks to induce an immune response, followed by 3 weeks of intensive perfusion to maintain a good immune response. Maintenance perfusion, on the other hand, is a 1-week, 3-week immune booster treatment at months 3, 6, 12, 18, 24, 30, and 36 after induction perfusion treatment. The main side effects of BCG infusion are bladder irritation and systemic flu-like symptoms, with bladder irritation accounting for about 91% of cases. Agrawal et al. used 1/3 conventional dose of BCG to treat NMIBC and found that it was as effective as the conventional dose with significantly fewer side effects; Colombel et al. showed that the addition of of ofloxacin was effective in reducing the side effects of BCG without affecting its efficacy. Although BCG is one of the most effective biological agents known and maintaining BCG bladder perfusion therapy can reduce the probability of bladder tumor progression by 37%, there are still 30% to 45% of patients for whom BCG bladder perfusion therapy is ineffective, which, together with the effects of local and systemic adverse effects in the bladder, makes the clinical application of BCG somewhat limited. Other perfusion immunotherapies such as interferon, IL-2, tumor vaccines and monoclonal antibodies, immunogene therapy, and radioimmunotherapy have achieved many desirable results in in vitro and animal trials and are gradually moving toward clinical practice. As the most common malignant tumor of the urinary system, bladder cancer is receiving increasing attention for its high recurrence rate. The treatment goals of bladder cancer are to completely remove the primary focus, prevent local recurrence, progression and distant metastasis, and prolong the life span and improve the quality of life of patients. Although transurethral intracavitary bladder surgery supplemented with bladder irrigation therapy has greatly improved the treatment effect of bladder cancer, reduced the recurrence rate, prolonged patients’ life span and improved the quality of life. However, we must realize that the recurrence rate of bladder cancer is still very high and no matter what drugs and perfusion methods are used, the tumor cannot be completely removed. At present, new treatment methods like fluorescence cystoscopy, re-TUR, photodynamic therapy, thermochemical perfusion, targeted therapy, gene therapy, etc. have shown initial success in the treatment of NMIBC. It is believed that with the development of medicine, more and more patients with bladder cancer will be cured radically and retain their bladder.