Worldwide, there are more than 300,000 new cases of bladder cancer each year, which is the 7th most common tumor and the 8th most deadly tumor in the human body, and is a serious threat to human life safety. Evidence-based medicine has been fully recognized and implemented from the treatment guidelines in Europe and the United States as well as the formulation characteristics of China’s treatment guidelines. The essence of evidence-based medicine is to start from the subtle clinical symptoms, step by step, simple first, then complicated, early diagnosis and early intervention. The principles of diagnosis and treatment for oncological diseases should be prevention-oriented, early diagnosis and early treatment. Early diagnosis emphasizes early cystoscopic biopsy and second postoperative transurethral bladder tumor electrosurgical biopsy. The early treatment plan is a combination of surgical resection, bladder irrigation and radiotherapy.
I. Prevention issues
There are many causes of bladder cancer, and the occurrence of bladder cancer is a complex, multifactorial and multi-step pathological process, with both intrinsic genetic factors and extrinsic environmental factors. Two of the clearer risk factors are smoking and long-term exposure to industrial chemical products. Smoking is the most definite risk factor for bladder cancer, about 30% to 50% of bladder cancer is caused by smoking, and smoking can increase the risk rate of bladder cancer by 2 to 4 times, and the risk rate is proportional to the intensity and duration of smoking. Occupational factors are the first known risk factors for bladder cancer, and about 20% of bladder cancers are caused by occupational factors, including those involved in textiles, dye manufacturing, rubber chemistry, pharmaceutical and pesticide production, paint, leather, and aluminum, iron, and steel production. Epidemiological evidence suggests that chemical carcinogens are causative factors in bladder cancer, particularly aromatic amines such as 2-singing naphthylamine and 4-singing aminobiphenyl, which are widely present in tobacco and various chemical industries. Tobacco metabolites are excreted through urine, and the carcinogenic components in urine induce malignant transformation of bladder epithelial cells. Therefore, it is important to strengthen prevention in these source factors of tobacco and industrial chemical carcinogens to prevent malignant changes and reduce the incidence of bladder cancer. The malignant transformation of normal bladder epithelial cells begins with alterations in cellular DNA. Most current research in bladder cancer etiology focuses on genetic alterations. The study of oncogenes and oncogenes enriches the field of prevention as well as therapeutic entry points.
Early diagnosis of bladder cancer
Hematuria is the most common and early symptom of bladder cancer, especially recurrent painless hematuria, which can be manifested as either carnal hematuria or microscopic hematuria. Patients with bladder cancer also have urinary frequency, urinary urgency, urinary pain, i.e. bladder irritation sign and pelvic pain as the first manifestation, which is another common symptom of bladder cancer, often associated with diffuse carcinoma in situ or invasive bladder cancer, requiring active diagnostic cystoscopy and pathological biopsy. We emphasize that early cystoscopy and pathologic biopsy or diagnostic transurethral resection (TUR) should be performed for all patients considering bladder cancer. Random biopsy should be considered for suspected carcinoma in situ and positive urinary exfoliative cytology without clear mucosal abnormalities. For patients with muscle-infiltrating bladder cancer, pelvic CT/MRI and bone scan can be selected as needed to determine the extent and severity of the lesion. Diagnostic tools include both physical examination, routine urinalysis, ultrasonography, urine exfoliation cytology, intravenous pyelogram (IVU) and chest X-ray. Urine tumor marker testing is also one of the clinical options. Although tumor markers are more sensitive, their specificity is generally lower than that of urine exfoliative cytology, especially for low-grade bladder cancer. The use of a reasonable combination of multiple markers can complement each other to improve sensitivity and specificity, and may become a very effective noninvasive method for detecting bladder cancer, providing a strong basis for early diagnosis and postoperative follow-up.
The application of the above comprehensive methods of imaging, cytology and pathology is conducive to early clinical diagnosis, pathological grading and clinical staging of tumors, and provides sufficient evidence for early treatment.
Early treatment of bladder cancer
According to the clinical stage of bladder cancer, the treatment of bladder cancer is divided into two parts: non-muscle invasive bladder cancer and muscle invasive bladder cancer treatment. Non-muscle invasive bladder cancer or superficial bladder cancer accounts for 75% to 85% of all bladder cancers, of which Ta accounts for 70%, T1 accounts for 20% and Tis accounts for 10%. Transurethral electrical resection of bladder tumors (TUR sing BT) is the primary treatment for non-muscle invasive uroepithelial carcinoma of the bladder. Transurethral electrodesiccation has two purposes: first, to remove the entire tumor visible to the naked eye, and second, to remove tissue for pathological grading and staging. Transurethral electrodesiccation should completely remove the tumor until the normal bladder wall musculature is exposed. After tumor resection, basal tissue biopsy is recommended to facilitate pathologic staging and determination of the next treatment plan. Some reports have confirmed that performing another transurethral resection after 2-6 weeks after T1 stage bladder cancer can reduce the probability of postoperative recurrence and achieve early diagnosis and early treatment.
Early intrathecal drug infusion therapy for non-muscle invasive bladder cancer, for low-risk non-muscle invasive bladder uroepithelial carcinoma, only a single dose of immediate postoperative bladder infusion chemotherapy can be administered without maintenance bladder infusion therapy. For intermediate and high-risk non-muscle invasive uroepithelial carcinoma of the bladder, postoperative single-dose immediate bladder irrigation chemotherapy should be followed by follow-up chemotherapeutic agents or BCG maintenance irrigation therapy. For high-risk non-muscle-infiltrating bladder uroepithelial carcinoma, BCG bladder perfusion therapy is preferred and maintained for at least 1 year.
Another aspect of early and aggressive treatment of bladder cancer is demonstrated by the recommendation of immediate radical total cystectomy for non-muscle invasive bladder uroepithelial carcinoma that has failed to respond to bladder perfusion therapy, including tumor progression, multiple tumor recurrences, and stage Tis and T1G3 tumors that have failed to respond to TURBT and bladder perfusion therapy. The current modalities of radical cystectomy can be divided into open surgery and laparoscopic surgery. Compared to open surgery, laparoscopic surgery is characterized by less blood loss, less postoperative pain, and faster recovery. In recent years, robot-assisted laparoscopic radical cystectomy allows for more precise and rapid surgery with less bleeding.
Radical cystectomy with simultaneous lymph node dissection is preferred for muscle-infiltrating uroepithelial carcinoma of the bladder. The decision to perform urethrectomy can be made based on the specimen margin. Surgery to preserve the bladder in special cases must be carefully selected and should be supplemented with radiotherapy and chemotherapy, and closely followed up.
IV. Urinary diversion for radical total cystectomy
The urologist should fully communicate with the patient and obtain a consensus before deciding on the urinary diversion procedure, which should pay attention to protecting renal function and improving the patient’s quality of life. There is no standard treatment plan for urinary diversion. There are several options available, including uncontrolled urinary flow diversion, controlled urinary flow diversion, and bladder reconstruction.
In situ neocystectomy or bladder reconstruction has been used as the procedure of choice for urinary diversion by many treatment centers in the last 10 years due to the high quality of life of patients after surgery. The main advantage of this procedure is that it does not require an abdominal wall stoma and the patient can void urine by abdominal pressure or intermittent clean catheterization. Disadvantages are nocturnal incontinence and the need for intermittent self-catheterization. In situ neocystectomy is recommended using ileal for in situ neocystectomy. Preoperative biopsy of prostatic urethral tissue should be routinely performed in male patients and cystoscopic biopsy in females or intraoperative frozen section, and postoperative urethroscopy and urine exfoliation cytology should be performed periodically. Controlled urinary flow diversion is recommended with a controlled storage bladder. In the absence of an indication for in situ neocystectomy, a controlled urinary bladder is an option. The controlled urinary bladder must meet the principles of bowel decannulation into a high volume, low pressure bladder, anti-reflux and urinary control, and the ability to self-catheterize. Ileal cystotomy is recommended for uncontrolled urinary diversion. Ileal cystectomy is a simple, safe and effective procedure. The main disadvantage is the need for abdominal wall stoma and lifelong wearing of urinary collection bags.
V. Chemotherapy and radiotherapy are mainly used as adjuvant treatment for bladder cancer
Systemic chemotherapy is the standard treatment for metastatic bladder cancer. Chemotherapy should be combined with platinum-containing chemotherapy regimens, and MVAC and GC regimens are the first-line chemotherapy regimens. Chemotherapy or radiotherapy may be used as an elective alternative to radical surgery, but is less effective than radical surgery. Combined radiotherapy has the potential to improve the possibility of bladder preservation, but should be followed closely.
Follow-up of bladder cancer
The purpose of post-treatment follow-up for bladder cancer patients is to detect local recurrence and distant metastases as early as possible, and to start remedial treatment early if indicated and possible. The follow-up protocol for bladder cancer should be determined by the prognostic assessment and the treatment modality adopted (e.g., TURBT, cystectomy, urinary diversion modality, etc.). Cystoscopy is still the gold standard in the follow-up of non-muscle invasive bladder cancer, and urologists should help patients overcome their fears and undergo cystoscopy whenever possible. Pathologic biopsy should be performed if abnormalities are found. Ultrasound, urine cytology and IVU are also valuable in the follow-up of non-muscle invasive bladder cancer, but they cannot completely replace the status and role of cystoscopy. All patients with non-muscle invasive bladder cancer must undergo their first cystoscopy at 3 months postoperatively, but earlier is necessary if the surgical resection is incomplete, if there are implants at the site of trauma, or if the tumor is progressing rapidly. Subsequent follow-up should be determined by the risk of recurrence and progression of the tumor. In the event of patient recurrence, the post-treatment follow-up program must be restarted. Patients should have lifelong follow-up after radical cystectomy. Follow-up intervals: yearly in stage pT1, every 6 months in stage pT2 and every 3 months in stage pT3. The follow-up should include physical examination, blood biochemical examination, chest X-ray examination and ultrasound examination (including liver, kidney, retroperitoneum, etc.). For pT3 stage tumor patients, pelvic CT examination can be chosen every six months. Upper urinary tract imaging is optional to rule out the presence of ureteral strictures and upper urinary tract tumors. Follow-up of patients after urinary diversion is focused on surgery-related complications, metabolic complications, urinary tract infections, and secondary tumors.
VII. Diagnosis and treatment of non-urethral epithelial carcinoma of the bladder
Non-uroepithelial cell carcinoma of the bladder accounts for a relatively small proportion of malignant tumors in the bladder, but once diagnosed, it is often poorly treated. Non-uroepithelial cell carcinoma of the bladder includes squamous cell carcinoma, adenocarcinoma, small cell carcinoma, and mixed cell carcinoma. The principle of treatment for non-uroepithelial carcinoma of the bladder is to opt for radical cystectomy. Preoperative radiation therapy for high-grade, high-stage squamous cell carcinoma of the bladder may improve the prognosis. Expanded partial cystectomy is an option for umbilical ureteral adenocarcinoma of the bladder, and radical cystectomy for non-umbilical ureteral adenocarcinoma can be followed by adjuvant
After radical cystectomy for non-umbilical ureteral adenocarcinoma, adjuvant radiotherapy or (and) chemotherapy can be chosen. Small cell carcinoma of the bladder with pathological stage T3 or T4 can be treated with postoperative adjuvant chemotherapy. Because of the heterogeneous and unpredictable biological behavior of bladder cancer, clinical diagnosis and treatment are difficult. Currently, international emphasis is placed on early diagnosis, early TURBT combined with bladder perfusion therapy to prevent tumor progression and recurrence of non-muscle invasive bladder cancer, preservation of the bladder, long-term cystoscopic follow-up, and improvement of quality of life. For progressive uroepithelial bladder cancer, muscle layer invasive uroepithelial bladder cancer and non-epithelial cell bladder cancer, radical total laparoscopic cystectomy and in situ neo-cystectomy combined with neoadjuvant chemotherapy or radiotherapy are advocated to achieve eradication and cure. Also close postoperative follow-up is crucial.