I. Treatment of non-muscle-invasive bladder cancer
Ta and T1 are both non-muscle-invasive bladder cancers, but their biological characteristics are significantly different. T1 is prone to tumor spread because of the abundance of blood vessels and lymphatic vessels in the lamina propria.
Certain factors are closely associated with the prognosis of non-muscle invasive bladder cancer. These include the number of tumors, the frequency of tumor recurrence, especially at 3 months postoperatively, tumor size, and tumor grade. The factors most associated with tumor progression include pathologic grading of the tumor and tumor stage. The prognosis of tumors at the bladder neck is poor. According to the risk of recurrence and prognosis, non-muscle invasive bladder cancer can be divided into three groups as follows.
1.Low-risk non-muscle invasive uroepithelial carcinoma of the bladder Solitary, Ta, G1 (low-grade uroepithelial carcinoma), diameter <75 px (Note: the above conditions must be present at the same time to be low-risk non-muscle invasive bladder cancer).
2.High-risk non-muscle invasive uroepithelial carcinoma of bladder Multiple or high recurrence, T1, G3 (high-grade uroepithelial carcinoma), Tis.
3.Intermediate risk non-muscle invasive uroepithelial carcinoma of the bladder Other than the above two categories, including multiple tumors, Ta ~ T1, G1 ~ G2 (low-grade uroepithelial carcinoma), diameter >75px, etc.
European bladder cancer guidelines classify non-muscle invasive uroepithelial carcinoma of the bladder as low, intermediate and high risk based on the tumor score of the EORTC scale (see section IX(ii), Prognostic factors for bladder cancer).
(i) Surgical treatment
1. Transurethral resection of bladder tumor Transurethral resection of bladder tumor (TUR-BT) is both an important diagnostic method and the main treatment for non-muscle invasive bladder cancer. The exact pathological grading and staging of bladder tumors are obtained with the help of pathological findings after the first TUR-BT. Transurethral resection of bladder tumors has two objectives: first, to remove the entire tumor visible to the naked eye, and second, to remove tissue for pathologic grading and staging.TUR-BT should completely remove the tumor until the normal bladder wall musculature is exposed. After tumor resection, basal tissue biopsy is recommended to facilitate pathological staging and determination of the next treatment plan. For incomplete tumor resection, no muscle layer in the specimen, high-grade tumor and stage T1 tumor, it is recommended to perform TUR-BT again 2~6 weeks after surgery, which can reduce the probability of recurrence after surgery.
2. Transurethral laser surgery Laser surgery can coagulate and vaporize, and its efficacy and recurrence rate are similar to those of transurethral surgery [13,14]. However, preoperative tumor biopsy is required for pathological diagnosis. Laser surgery is difficult for tumor staging and is generally suitable for papillary low-grade uroepithelial carcinoma, as well as uroepithelial carcinoma with a history of low-grade and low-stage disease.
3.Photodynamic therapy Photodynamic therapy (PDT) is a treatment method that combines laser and photosensitizer using cystoscopy. The tumor cells ingest the photosensitizer and then produce monomorphic oxygen under the action of laser, which causes the tumor cells to degenerate and necrosis. This therapy can be chosen for cases such as carcinoma in situ of bladder, control of bladder tumor bleeding, multiple recurrence of tumor, and intolerance of surgical treatment.
(II) Postoperative adjuvant therapy
1.Postoperative bladder perfusion chemotherapy TUR-BT will recur in 10%~67% of patients within 12 months after surgery and 24%~84% of patients within 5 years after surgery, which may be related to new tumor, tumor cell implantation or incomplete resection of the primary tumor. There are two peak periods of recurrence after TUR-BT for non-muscle invasive bladder cancer, 100-200 days postoperatively and 600 days postoperatively, respectively. The first peak of postoperative recurrence is associated with intraoperative tumor cell dissemination, and postoperative bladder perfusion therapy can greatly reduce recurrence due to tumor cell dissemination. Although TUR-BT theoretically allows complete resection of non-muscle-infiltrating bladder cancer, there is still a high probability of recurrence in clinical management and some cases progress to muscle-infiltrating bladder cancer. TUR-BT alone does not address the high recurrence and progression after surgery, and therefore adjuvant bladder perfusion therapy is recommended for all patients with non-muscle invasive bladder cancer after surgery.
(1) Immediate bladder perfusion chemotherapy after TUR-BT: Bladder perfusion chemotherapy with epirubicin, piribicin (THP) or mitomycin within 24 hours after TUR-BT can reduce the tumor recurrence rate by 39%, so it is recommended that all patients with non-muscle invasive bladder cancer have bladder perfusion chemotherapy within 24 hours after TUR-BT. Bladder irrigation chemotherapy immediately after TUR-BT is effective for both single and multiple bladder cancers. The probability of tumor recurrence after immediate postoperative perfusion for low-risk non-muscle invasive bladder cancer is low, so bladder perfusion therapy can not be continued after immediate perfusion.
(2) Early postoperative bladder perfusion chemotherapy and maintenance bladder perfusion chemotherapy: For intermediate-risk and high-risk non-muscle invasive bladder cancer, after immediate postoperative bladder perfusion therapy within 24 hours, it is recommended to continue bladder perfusion chemotherapy once a week for 4-8 weeks, followed by maintenance bladder perfusion chemotherapy once a month for 6-12 months. Studies have shown that maintenance perfusion therapy for non-muscle invasive bladder cancer does not continue to reduce the probability of tumor recurrence at more than 6 months, so postoperative maintenance bladder perfusion therapy for 6 months is recommended. However, some studies have found that epirubicin maintenance perfusion for 1 year reduces the probability of bladder tumor recurrence. In case of severe bladder irritation during instillation, instillation therapy should be delayed or stopped to avoid secondary bladder contracture. The side effects of bladder perfusion therapy are related to the drug dose and frequency of perfusion. Bladder perfusion therapy is mainly used to reduce the recurrence of bladder tumors and there is no evidence that it prevents tumor progression.
(3) Drugs for bladder perfusion chemotherapy: Commonly used drugs for bladder perfusion chemotherapy include epirubicin, mitomycin, pirarubicin, adriamycin, hydroxycamptothecin, etc. The pH of urine and the concentration of chemotherapeutic drugs are related to the effect of bladder infusion chemotherapy, and the drug concentration is more important than the drug quantity. Chemotherapeutic drugs should be instilled into the bladder through a catheter and retained for 0,5 to 2 hours (Note: the retention time in the bladder is based on the drug instructions). Do not drink large amounts of water before instillation to avoid dilution of the drug by urine. The usual dose of epirubicin is 50~80mg, mitomycin is 20~60mg, pirarubicin is 30mg, and hydroxycamptothecin is 10~20mg. Other chemotherapeutic drugs include gemcitabine, etc. The main side effect of bladder perfusion chemotherapy is chemical cystitis, the degree of which is related to the dose and frequency of perfusion. Immediate bladder perfusion after TUR-BT should be more aware of the side effects of the drug. Most of the side effects can improve on their own after stopping perfusion.
2.Postoperative bladder perfusion immunotherapy
（BCG is suitable for the treatment of high-risk non-muscle invasive bladder cancer and can prevent the progression of bladder tumors. BCG cannot change the course of low-risk non-muscle invasive bladder cancer, and because of the high incidence of side effects of BCG instillation, it is not suitable for the treatment of low-risk non-muscle invasive bladder cancer. low-risk non-muscle invasive bladder uroepithelial carcinoma, BCG perfusion is not recommended. For intermediate-risk non-muscle invasive uroepithelial carcinoma of bladder, the probability of tumor recurrence at 5 years after surgery is 42%-65%, while the probability of progression is 5%-8%. Therefore, the main purpose of bladder perfusion for intermediate-risk non-muscle invasive uroepithelial carcinoma of bladder is to prevent tumor recurrence, and bladder perfusion chemotherapy is generally recommended, and BCG perfusion therapy can also be used in some cases. Because of the traumatic nature of the postoperative bladder, BCG should be avoided for immediate postoperative perfusion therapy to avoid serious side effects. dose of BCG bladder perfusion: BCG therapy generally uses 6 weeks of perfusion to induce an immune response, plus 3 weeks of perfusion intensification to maintain a good immune response. when BCG perfusion is used to treat high-risk non-muscle invasive bladder uroepithelial carcinoma, the conventional dose (120~ 150 mg); when BCG is used to prevent recurrence of non-muscle-infiltrating bladder uroepithelial carcinoma, a low dose (60-75 mg) is generally used. It was found that the efficacy of 1/3 dose of BCG infusion for the treatment of intermediate-risk non-muscle invasive bladder uroepithelial carcinoma was the same as that of the full dose, with significantly lower side effects. There was no difference in efficacy between BCG strains.BCG perfusion is usually started 2 weeks after TUR-BT.BCG maintenance perfusion reduces the probability of bladder tumor progression by 37% [36]. Maintenance BCG instillation is required for 1 to 3 years (at least 1 year of maintenance instillation), therefore it is recommended to repeat BCG instillation at 3, 6, 12, 18, 24, and 36 months to maintain and intensify the efficacy [35,39].The main side effects of BCG bladder instillation are bladder irritation and systemic flu-like symptoms, and less common side effects include tuberculosis sepsis, prostatitis, epididymitis, and hepatitis. Therefore, BCG bladder instillation should not be performed in cases such as open trauma to the bladder after TUR-BT or in cases of meatus hematuria.
(2) Immunomodulators: Some immunomodulators can prevent recurrence of bladder tumor as well as chemotherapy drugs, including interferon, keyhole limpet hemocyanin (KLH), etc.
Perfusion therapy for recurrent tumors After recurrence of bladder tumors, TUR-BT therapy is generally recommended again. According to the postoperative grading and staging of TUR-BT, bladder perfusion therapy should be reintroduced according to the above protocol. For frequent recurrence and multiple recurrences, BCG perfusion therapy is recommended.
4.Treatment of bladder carcinoma in situ The treatment plan for bladder carcinoma in situ is to perform complete TUR-BT and postoperative BCG bladder irrigation treatment, which is performed once a week for 6 weeks. After 6 weeks of rest, cystoscopy and urinary exfoliation cytology were performed, and those with positive results underwent 1 more cycle of perfusion for a total of 6 weeks. Remission was achieved in an additional 15% of cases. After 6 weeks of rest, repeat cystoscopy and urinary exfoliative cytology, and if the results are still positive, radical cystectomy and radical urethrectomy are recommended. For cases in remission, 1 cycle of BCG instillation should be performed at months 3, 6, 12, 18, 24, 30 and 36 to prevent recurrence. 83% to 93% remission rate with BCG treatment and 11% to 21% death from the disease within 5 to 7 years. Ineffective and incomplete response tumor progression rates range from 33% to 67%. If there is no complete remission or tumor recurrence at 9 months of treatment, radical cystectomy is recommended .
5. Treatment of T1G3 bladder cancer T1G3 bladder cancer can preserve the bladder in 50% of cases by BCG infusion therapy or bladder infusion chemotherapy. It is recommended to perform TUR-BT first, and then perform TUR-BT again 2-6 weeks after surgery. For those without muscle infiltration, postoperative BCG instillation therapy or bladder instillation chemotherapy is performed. Radical cystectomy is recommended for cases in which 2 cycles of BCG perfusion therapy or 6 months of bladder perfusion chemotherapy are ineffective or recurrent.
To summarize.
1, TUR-BT procedure is the main treatment for non-muscle invasive uroepithelial carcinoma of the bladder.
2. For low-risk non-muscle invasive uroepithelial carcinoma of the bladder, only a single dose of immediate bladder perfusion chemotherapy can be administered after surgery.
3.For intermediate and high-risk non-muscle layer invasive uroepithelial carcinoma of bladder, after postoperative single-dose immediate bladder perfusion chemotherapy, follow-up chemotherapeutic drugs or BCG maintenance perfusion therapy should be administered.
4.For high-risk non-muscle invasive uroepithelial carcinoma of the bladder, BCG bladder perfusion therapy is preferred (at least 1 year maintenance).
5.For non-muscle invasive uroepithelial carcinoma of bladder that is not treated by bladder perfusion (such as tumor progression, multiple tumor recurrence, Tis and T1G3 tumors that are not treated by TUR-BT and bladder perfusion), then radical cystectomy is recommended.
II. Treatment of muscle-invasive bladder cancer
(A) Radical cystectomy
Radical cystectomy with pelvic lymph node dissection is the standard treatment for muscle invasive bladder cancer and is an effective treatment to improve the survival rate of patients with invasive bladder cancer and avoid local recurrence and distant metastasis. This procedure needs to be selected according to the pathological type, stage, grading of the tumor, the site of tumor occurrence, and the presence or absence of involvement of adjacent organs, combined with the patient’s general condition. The possibility of pelvic lymph node metastasis in patients with invasive bladder cancer is reported in the literature as 24%-43%. The extent of lymph node dissection can be decided according to the tumor extent, pathological type, depth of infiltration and patient condition.
1.Indications for radical cystectomy The basic surgical indications for radical cystectomy are T2-T4a, N0-X, M0 invasive bladder cancer, and other indications include T1G3 tumor of high-risk non-muscle invasive bladder cancer, Tis with ineffective BCG treatment, recurrent non-muscle invasive bladder cancer, extensive papillary lesions that cannot be controlled by TUR or endoluminal surgery alone, etc.; salvage total cystectomy The indications for salvage total cystectomy include ineffective non-surgical treatment, tumor recurrence after bladder preservation treatment, and non-uroepithelial bladder cancer.
The above surgical indications can be used independently or in combination. However, those with serious comorbidities (heart, lung, liver, brain, kidney, etc.) that cannot tolerate radical cystectomy should be excluded.
The scope of radical cystectomy includes the bladder and surrounding adipose tissue, the distal ureter, and pelvic lymph node dissection; men should include the prostate and seminal vesicles, and women should include the uterus and adnexa [9-11]. In recent years, some studies have questioned whether the prostate should be completely removed in men and whether the vagina and urethra should be removed in women. If the surgical urethral margins are positive and the primary tumor invades the urethra, the female bladder neck, or the male prostate, total urethrectomy should be considered. Some domestic scholars believe that if the tumor involves the prostate, bladder neck, triangle, or multiple tumors or carcinoma in situ, total urethrectomy should be performed. It has also been reported that the distal urethral cut edge should be sent for rapid pathological examination to clarify whether there is tumor involvement to decide whether urethrectomy should be performed at the same time. In younger male patients with normal sexual function, surgery with preservation of the sexual nerve and seminal vesicles may allow more than half of the patients to have unaffected sexual function, but close postoperative follow-up is required and the long-term outcome of patients needs to be further confirmed.
Current radical cystectomy approaches can be divided into open surgery and laparoscopic surgery. Compared with open surgery, laparoscopic surgery is characterized by less blood loss, less postoperative pain, and faster recovery, but the operative time is not significantly better than that of open surgery, and laparoscopic surgery requires higher operator skills. Recently, robot-assisted laparoscopic radical cystectomy allows for more precise and rapid surgery with reduced bleeding.
Lymph node dissection is not only a therapeutic tool, but also provides important information for prognostic determination. There are currently three main types of lymph node dissection: local lymph node dissection, conventional lymph node dissection, and expanded lymph node dissection. Local lymph node dissection only removes lymph nodes and fatty tissue within the foramen ovale; extended lymph node dissection covers: the aortic bifurcation and common iliac vessels (proximal), the genitofemoral nerve (lateral), the spinococaval vein and Cloquet’s lymph nodes (distal), the internal iliac vessels (posterior), including around the distal abdominal aorta, around the inferior vena cava, the foramen ovale, and the anterior sciatic and presacral lymph nodes on both sides, with dissection extending upward or even The lymph node dissection can be extended up to the level of the inferior mesenteric artery; the conventional lymph node dissection reaches the level of the common iliac vessel bifurcation, and the rest is the same as the extended dissection; more than 15 lymph nodes should be removed during lymph node dissection. It has been suggested that extended lymph node dissection is beneficial to patients and can improve the 5-year survival rate after surgery. The proportion of positive lymph nodes to intraoperative resected lymph nodes (lymph node density) may be one of the important prognostic indicators for patients at high risk of positive lymph nodes.
The current randomized controlled study showed that although preoperative radiotherapy for 4-6 weeks significantly reduced the stage of invasive bladder cancer, it did not significantly prolong the 5-year survival rate of patients.
3. Survival rates of radical cystectomy With improvements in surgical techniques and follow-up modalities, survival rates of patients with invasive bladder cancer have improved considerably. The perioperative mortality rate of radical cystectomy is 1,8% to 3,0%, and the main causes of death are cardiovascular complications, sepsis, pulmonary embolism, liver failure, and hemorrhage. The overall 5-year survival rate of patients is 54,5% to 68%, and the 10-year survival rate is 66%. If the lymph nodes were negative, the 5-year and 10-year survival rates were 89% and 78% for stage T2, 87% and 76% for stage T3a, 62% and 61% for stage T3b, and 50% and 45% for stage T4, respectively. In contrast, the 5- and 10-year survival rates for patients with positive lymph nodes were only 35% and 34%.
(ii) Bladder preservation therapy
For patients with invasive bladder cancer who are physically unable to tolerate radical cystectomy or unwilling to undergo radical cystectomy, bladder-preserving combination therapy can be considered. Given the high percentage of lymph node metastases in invasive bladder cancer, patients considered for bladder-preserving treatment need to be carefully selected and evaluated for the nature of the tumor and the depth of infiltration, and the correct bladder-preserving surgical approach should be selected, supplemented with postoperative radiation therapy and chemotherapy, and closely followed up after surgery.
There are two types of bladder preservation surgery for invasive bladder cancer: transurethral resection of bladder tumor (TUR-BT) and partial cystectomy. For most patients with bladder-preserving invasive bladder cancer, the tumor can be removed by the transurethral route. However, partial cystectomy should be considered for some patients: those with tumors located within the bladder diverticulum, around the ureteral opening or in the blind area of the transurethral surgical operation, those with severe urethral strictures and those who cannot tolerate a lithotomy position. Recently, it has been suggested that for patients with stage T2, a repeat TUR-BT within 4-6 weeks after the initial TUR-BT and combined with chemotherapy and radiotherapy can help preserve the bladder.
Since the ideal bladder preservation cannot be achieved with a single treatment, the current comprehensive treatment for bladder preservation is mostly a triple combination of surgery, chemotherapy and radiotherapy. The indications for the selection of this treatment regimen must be strictly controlled and the patient must have good compliance in order to obtain a better treatment outcome. Studies have shown that patients treated with TURBT followed by cisplatin-based chemotherapy regimens and radiation therapy can achieve a treatment efficiency of 60-80%. However, patients must be closely monitored and treatment regimens must be adjusted in a timely manner.
Overall survival rates for patients with invasive bladder cancer treated with bladder-sparing combination therapy ranged from 45% to 73% at 5 years and 29% to 49% at 10 years.
To summarize.
1.For muscle-infiltrating uroepithelial carcinoma of the bladder, radical cystectomy is preferred, and lymph node dissection is performed at the same time.
If the tumor invades the urethra, female bladder neck or male prostate, or if the surgical urethral margin is positive, total urethrectomy should be performed.
3.Surgery to preserve the bladder in special cases must be carefully selected and should be supplemented with radiotherapy and chemotherapy, and followed up closely.