Guidelines for the Treatment of Bladder Cancer (2022 Edition)

Bladder Cancer Treatment Guidelines

(2022 Edition)

I. Overview

Bladder cancer is one of the most common malignant tumors of the urinary tract. Worldwide, the incidence of bladder cancer ranks 9th among malignant tumors and 7th among malignant tumors in men.

(9.5/10 million) for women and 10 places later (2.410/100 million); the mortality rate is the highest for malignant tumors 13th place, with mortality rates of (3.2/100 million for men and (0.9/100 million).

There are geographic, racial, and gender differences in bladder cancer. It can occur in all age groups, with a high incidence at 50 to 70 years of age, and the incidence in men is 3 to 4 fold that in women.

According to data released by the 2019 National Tumor Registry:the incidence rate of bladder cancer in China in 2015 was 5.80/100 million, ranking as the No. 100,000 of systemic malignant tumors. family:Times New Roman”>13th place, and the incidence rate of men is 8.83 per 100,000 million, ranking 7th Roman”>7th place. The female prevalence rate was 2.61 per 100 million, ranking 17 . The mortality rate of bladder cancer in China in 2015 was 2.37 per 100 million, ranking 13th and the mortality rate for men was 3.56 per 100,000, ranking 11th place. The female mortality rate was 1.11/100 million, ranking 16th .

The incidence and mortality rates of bladder cancer are higher in urban areas than in rural areas at all ages. The incidence of bladder cancer in urban areas was 6.77 per 100,000 million in 2015 (male ). “font-family:Times New Roman”>10.36/100 million; female 3.04/100 million) and the incidence rate in rural areas was 3.04/100 million). family:Times New Roman”>4.55/100 million (male 6.89/100 million; female 2.06/100 million). The bladder cancer mortality rate in urban areas in 2015 was

2.69/100 million (men 4.01/100 million; female 1.31/100 million), rural deaths

The rate was 1.95/10 million (male 3.00/100 million; female 0.85/100 million). Patients with the same stage of bladder cancer had a better prognosis in men than in women.

Bladder cancer is one of the malignant tumors that seriously threaten people’s health, and standardized diagnosis and treatment is important to improve the diagnosis and treatment of bladder cancer in China.

II. Screening and Diagnosis

(A) Risk factors for bladder cancer.

The development of bladder cancer is a complex, multifactorial, multistep pathological process, the specific pathogenesis of which has not been elucidated, and both intrinsic genetic and extrinsic environmental factors play an important role.

Extrinsic factors

Smoking and long-term exposure to industrial chemicals are the two major extrinsic risk factors for bladder cancer and are the most certain risk factors for bladder cancer, with about 50% of bladder cancer patients having a high risk of bladder cancer. 50% of bladder cancer patients have a history of smoking, and the risk of bladder cancer increases 2 to 3 times in smokers, with the risk rate proportional to the intensity and duration of smoking. There is an association with the aromatic amine compound 4-aminobiphenyl, which is contained in cigarette smoke. The effect of smoking on the recurrence and progression of bladder cancer is unclear.

Long-term occupational exposure to industrial chemical products is another important category of risk factors. Approximately 20% of bladder cancer patients develop bladder cancer related to occupations such as textiles, dye manufacturing, rubber chemistry, pharmaceutical and pesticide production, paint, leather, and aluminum and steel production, where long-term exposure to aromatic amines, polycyclic aromatic hydrocarbons and chlorinated hydrocarbons, β-naphthylamine, 4-aminobiphenyl, etc.

Other causative factors include long-term chronic inflammatory irritation in the bladder (bacteria, blood

suckers, human papillomavirus infection, etc.), long-term foreign body irritation (indwelling catheters, stones) are strongly associated with squamous cell carcinoma and adenocarcinoma of the bladder.

Previous chemotherapy with cyclophosphamide, abuse of finasteride and history of pelvic radiotherapy, and pioglitazone for diabetes mellitus can increase the risk of bladder cancer. High intake of fat, cholesterol, fried foods and red meat, chronic consumption of arsenic-rich and chlorinated water, coffee, artificial sweeteners, and hair coloring may increase the risk of bladder cancer.

Intrinsic factors (genetic abnormalities)

The development of bladder cancer is associated with genetic and genetic abnormalities, and those with a family history have a significantly increased risk of developing bladder cancer 2. The mechanism needs to be further investigated.

Normal bladder cell malignancy begins with cellular DNA alterations, and chemical carcinogens are the major extrinsic bladder cancer Chemical carcinogens are the main external pathogenic factors in bladder cancer, including aromatic compounds such as 2-naphthylamine, 4-aminobiphenyl, etc., which are found in tobacco and various chemical These carcinogens are metabolized in the urine and cause malignant changes in the bladder epithelium.

Oncogenes associated with bladder cancer include HER-2, HRAS , BCL-2 , FGFR3, C-myc, MDM2, MSH2 and others. Another molecular mechanism is the inactivation of protein repressor genes encoding proteins that regulate cell growth, DNA repair or apoptosis, so that DNA >damaged cells from undergoing apoptosis, resulting in uncontrolled cell growth. Such as P53, RB, P21 and other oncogenes of 17, 13 and 9 chromosome deletions or heterozygous losses have been associated with the development of bladder cancer.

Uroepithelial tumors are temporally and spatially polycentric, and upper urinary tract urothelial carcinoma

History is an important risk factor for uroepithelial carcinoma of the bladder, and the risk of bladder cancer in such patients is approximately 15% to 50%.

(ii) Clinical presentation.

The clinical diagnosis is based on the patient’s history, symptoms, and signs, combined with laboratory tests, imaging, urine cytology and urinary tumor markers, and cystoscopy. Cystoscopy is the most important test, and cystoscopic biopsy pathology is the gold standard for the diagnosis of bladder cancer. Upper urinary tract imaging excludes the possibility of combined renal pelvis or / and ureteral tumors.

Symptoms caused by local growth of the primary tumor itself

Hematuria is the most common clinical manifestation of bladder cancer patients, with about 80%-90% of patients having intermittent, painless full The first symptom is flesh-eye hematuria. The color of the urine may vary from light red to dark brown, mostly washed out, and may form clots. Some patients have initial hematuria, suggesting a bladder neck lesion, and terminal hematuria, suggesting a lesion in the bladder trigone, bladder neck, or posterior urethra. A small number of patients have only microscopic hematuria.

The severity, duration, and amount of hematuria are not consistent with the malignancy, stage, size, number, or morphology of the tumor. In some patients, bladder cancer is discovered inadvertently during physical examination or examination for other diseases.

About 10% of patients with bladder cancer have signs of bladder irritation, which manifest as urinary frequency, urgency, and painful urination. This suggests that the patient may have carcinoma in situ, muscle-infiltrating uroepithelial carcinoma, squamous cell carcinoma, or adenocarcinoma.

Symptoms caused by primary tumor invading adjacent organs and structures

Other symptoms including back pain due to ureteral obstruction, lower limb edema, bone pain, urinary retention, and weight loss are all advanced symptoms.

(iii) Physical examination.

Patients with bladder cancer generally have no clinical signs, and for early stage patients (e.g. Ta, T1 stage) have limited diagnostic value. Palpation of a pelvic mass is suggestive of a locally advanced tumor.

(iv) Adjunctive tests.

Laboratory tests

General laboratory tests: Before treatment, patients need routine laboratory tests to The patient’s general condition and suitability for appropriate therapeutic measures should be known. (1) routine blood tests; (2) liver and kidney function and other necessary biochemical and immunological tests; and (3) blood clotting tests.
Urine cytology and tumor markers: Urine tests include urine exfoliative cytology and urine tumor markers.

1) Urine cytology: Urine cytology is one of the most important methods for the diagnosis of bladder cancer and postoperative follow-up, and the detection of cancer cells in urine is one of the qualitative diagnoses of pyel cancer, ureteral cancer, and bladder cancer. Urine specimens should be collected as fresh as possible by spontaneous urination or by bladder irrigation to improve the diagnostic yield. Continuous urine retention for 3 days is recommended, followed by centrifugation and fixation. The sensitivity of urine exfoliative cytology is 13%-75% and the specificity is 85%-100%. The sensitivity was positively correlated with tumor grade, with a positive rate of 84% for high-grade tumors (including carcinoma in situ); G1 and low grade tumors had a sensitivity of 16%.

The assessment of urine cytology results is influenced by low shedding of cells, urinary tract infection, stones or bladder irrigation treatment. Specificity exceeds 90%. The presence of suspicious cancer cells in the urine requires multiple tests to avoid false-positive results. The urine cytology must be performed at the same time as cystoscopy and imaging to reduce the rate of missed diagnoses.

Flow cytometry is a simple and objective technique for urine cytology. The principle is to stain the chromatin of urinary exfoliated cells with DNA specific fluorophore and analyze the DNA ploidy with analysis software to objectively reflect the cellularity. The ploidy was analyzed to objectively reflect the cell proliferation status. Tumor cells proliferate vigorously and are polyploid. Generally, diploidy represents low malignancy and triploidy to tetraploidy are highly malignant tumors. The sensitivity and specificity of flow cytometric analysis for the diagnosis of bladder cancer are related to the degree of differentiation and stage of the tumor. It is not a substitute for routine urine cytology.

② Urinary bladder tumor markers: There are several relatively mature urinary bladder tumor marker techniques, including nuclear matrix protein 22 (NMP22), bladder tumor antigen-related (BTAstat), and BTAtrak), immuno-–cytology, fibrinogen degradation products and urinary fluorescence In situ hybridization (fluorescence in situ hybridization, FISH), etc.

Other tests include telomerase, survivin, microsatellite analysis, and cytokeratin, which have high sensitivity but lower specificity than urine cytology.

The FISH technique has high sensitivity and specificity, but is less specific than urine cytology. The specificity of urine specimens from patients with a history of bladder inflammation, stones, radiation therapy, etc. is low. FISH has a high positive prediction for uroepithelial cancer in our population.

value.

Because of the high sensitivity but low specificity of urine tumor marker testing, clinically

Not yet widely used, there are no urinary tumor markers that can replace cystoscopy and urine cytology.

Imaging

Imaging includes ultrasonography, CT and CT urethrography (computed tomography urography, CTU ), M RI and magnetic resonance urography

(magnetic resonance urography, MRU), intravenous urography

(intravenous urography, IVU), chest X ray or chest CT etc. The main purpose is to understand the degree and extent of bladder lesions, thoracoabdominal pelvic organs, abdominal

posterior and pelvic lymph nodes and upper urinary tract, which can help determine the clinical staging of bladder cancer.

Ultrasound: Ultrasound is the most common and basic test to diagnose bladder cancer. It can also examine the kidneys, ureters, prostate, pelvic and retroperitoneal lymph nodes, and other organs.

Ultrasound can be performed in three ways: transabdominal, transrectal, and transurethral.

The sensitivity of transabdominal ultrasonography for the diagnosis of bladder cancer is 63% to 98%, and the specificity is 99%. The kidneys, ureters, and other organs of the abdomen can be examined simultaneously.

Transrectal ultrasound can clearly visualize the bladder triangle, bladder neck, and prostate, and can determine the depth of tumor infiltration better than transabdominal ultrasound, for patients with poor bladder filling.

Transurethral ultrasonography requires surface anesthesia of the urethra, and although the images are clear and the accuracy of tumor staging is high, it is invasive. The results of this study are not widely available.

Color Doppler ultrasonography can show the blood flow signal at the base of the tumor, but the tumor blood flow sign is of limited value in determining tumor staging and grading.

Ultrasound imaging can improve the detection rate of bladder cancer and assess the depth of bladder tumor invasion. Ultrasound cannot accurately diagnose carcinoma in situ of the bladder.

Sonographic findings: abnormal, confined protrusions in the bladder wall that do not move with the body; or irregularities in the surface of the bladder wall with disruption of the bladder wall hierarchy; or strong or mixed echogenic nodules or masses that are papillary or cauliflower-shaped, with or without a tip; tumors may be solitary or multiple. The tumor may be solitary or multiple. Color Doppler can show blood flow signals within or around the tumor.

CT. “font-family:Arial”>Examinations:CT Examinations (plain scan+enhanced scan) is valuable in diagnosing and assessing the extent of bladder tumor infiltration and can detect smaller tumors (1 to 5 mm). If cystoscopy reveals a broad-based, non-tipped tumor with high malignancy and possible muscle infiltration, CTis recommended to determine the extent of tumor infiltration, whether the tumor is adjacent to an organ or distant. CT to determine the extent of tumor infiltration, adjacent organ invasion or distant metastasis.

CT is not good for in situ bladder cancer and ureter; it is difficult to accurately differentiate non-muscle invasive bladder cancer (Ta, T1) and T2 to T3a stage bladder cancer, it is difficult to determine the nature of the enlarged lymph nodes.

Muscle-invasive bladder cancer (muscle-invasive bladder cancer , muscle-invasive bladder cancer.

MIBC) patients with MIBC =”font-family:Times New Roman”>The accuracy of CT examination was 54.9%, with about 39% had low staging and 6.1% had high staging. Patients with a history of prior tumor surgery may have elevated staging due to local inflammatory response.

CTU: It is recommended that patients with multiple bladder tumors, high-risk tumors, and bladder triangle tumors undergo CTU. style=”font-family:Times New Roman”>CTU examination. CTU provides information on the status of the upper urinary tract, peripheral lymph nodes and adjacent organs and has largely replaced traditional IVU examination.

CT images show a localized thickening of the bladder wall or a mass protruding into the lumen. The mass has a variety of shapes, often papillary, cauliflower, and irregular. The outer edges are smooth, but may appear rough when the tumor invades outside the wall. In larger masses, sandy calcifications are common at the inner edge, and large superficial tumors may show bladder contour deformation. Plain scan of the mass CT values 30 to 40HU, which shows inhomogeneous and significant enhancement after enhancement. The tumor grows outside the wall and shows indistinct bladder contours, loss of peri-vesical fat layer, and involvement of adjacent tissues and organs, which may show enlarged pelvic or retroperitoneal gonads.

Multiparameter Multiparameter MRI:MRI MRI =”font-family:Arial”>Examinations have good soft tissue resolution and can diagnose and stage tumors. MRI is able to show whether the tumor has spread to the peri-vesical fat, lymph node metastases, and bone metastases, and can assess the invasion of adjacent organs. The test can also assess the invasion of adjacent organs.

Bladder tumor T1 weighted images are of low to moderate signal intensity similar to bladder wall images, above low signal in urine, below high signal in bladder. lower than the high signal peri-bladder fat. T2 weighted images have high signal in the urine, low signal in the normal detrusor muscle, and moderate signal in most bladder tumors.

sign. The presence of interruptions in the low-signal detrusor muscle suggests muscle layer infiltration. Diffusion-weighted imaging (diffusion weighted imaging, DWI) is valuable for assessing whether the tumor is invading surrounding tissue is valuable.

Dynamically enhanced MRI is more accurate than MRI in showing the presence of myxoid infiltration. style=”font-family:Times New Roman”>CT or non-enhanced MRI; for <T3a tumor with better accuracy than CT examination, and the display of lymph nodes with CT is similar. Multiparametric MRI is valuable in assessing the invasion of the muscular layer in bladder cancer, with a sensitivity of 90% to 94% and a specificity of 90% to 94% . span>, and specificity 87%-95%. High field strength (3.0T) and DWI can improve the sensitivity and specificity of the diagnosis. MRI is more sensitive than CT in evaluating bone metastases and is even better than nuclear bone scan.

MRU examination: MRU displays the entire urinary tract, showing the site and cause of upper urinary tract obstruction and the presence of upper urinary tract tumors. MRU is particularly useful in patients with contrast allergy or renal insufficiency, IVU without visualization of the kidney and with pelvic ureteral effusion patients.

VUVU:IVUThe purpose of the test is to show if there is an accompanying upper urinary tract tumor. Because of the low positive rate of IVU tests to diagnose upper urinary tract tumors, the risk of missing the diagnosis is high, especially in small upper urinary tract tumors or when urinary tract fluid is not visualized The diagnosis is more likely to be missed. CTU, MRU examinations for clearer images have now replacedIVU =”font-family:Arial”>examination.

(5)X radiographs or chest CT examinations: frontal and lateral X radiographs of the chest are The patient is routinely examined before and after surgery for the presence of pulmonary metastases and to determine clinical staging.

Chest CT examination is a more sensitive test for lung metastases. Preoperative chest CT is recommended for patients with nodules in the lungs or MIBC for total cystectomy to clarify the presence of pulmonary metastases. .

Pulmonary metastases on chest X radiographs and chest CT film shows single, multiple, or a large number of diffusely distributed round nodular lesions.

Total Body Bone Imaging: Total Body Bone Imaging is the most commonly used method to detect bone metastases with high sensitivity. It can assess the presence of bone metastases to clarify the tumor stage, and can be performed earlier than Xray films. font-family:Times New Roman”>3 to 6 months to detect bone metastases.

Bone scans are not routinely performed in patients with bladder cancer, but are recommended when patients present with bone pain or elevated serum alkaline phosphatase and are suspected to be at risk for bone metastases.

Bone metastases from bladder cancer are osteolytic, most often showing abnormal radioactive concentrations, and rarely showing radioactive sparseness and defects. The spine is the common site of bone metastases, followed by the pelvis, ribs, skull, and the proximal ends of the femur and humerus. The specificity of bone imaging for bone metastases is not high, especially for benign and malignant identification of single or sporadic lesions, which requires CT or MRI Check to confirm.
) positron emission computed tomography (positron emission tomography-computed tomography (PET-CT): tracer fluorodeoxyglucose (fluorodeoxyglucose,FDG) is excreted to the bladder via the kidneys, affecting Smaller tumors in the bladder and lymph nodes in the peri-cystal region can be visualized at a high cost.PET-CT examinations are not usually performed as a routine test.

New tracers commonly used today include choline, methionine, and acetic acid. Carbon -11

(11C)– choline and 11C- acetic acid is not excreted via the urinary tract and can show both bladder tumors and lymph node metastases. The accuracy of PET-CT diagnosis of lymph node metastasis is better than that of CT and CT and MRI for preoperative staging of MIBC patients, metastasis in advanced patients, and outcome evaluation. PET-CT cannot yet replace MRI and bone scan in the diagnosis of bone metastases.

Endoscopy and other examinations

Cystoscopy and biopsy: Cystoscopy and biopsy are the most reliable methods to diagnose bladder cancer and one of the main tools for postoperative recurrence monitoring.

Cystoscopy includes both plain rigid cystoscopy and flexible cystoscopy, and painless cystoscopy is routinely recommended. If available, a flexible cystoscopy is recommended, which is less invasive, has no blind spots, and is relatively comfortable compared with rigid cystoscopy.

Cystoscopy can identify the number, size, morphology (papillary or broad-based), location, growth pattern, and abnormalities of the surrounding bladder mucosa of bladder tumors, and can biopsy tumors and suspicious lesions to identify the type of pathology.

When urine cytology is positive or the bladder mucosa is abnormal, selective biopsy is recommended to clarify the diagnosis and understand the extent of the tumor. When urine cytology is positive and bladder mucosa is normal, random biopsy should be considered when in situ cancer is suspected.

In situ cancer, multiple cancers, or tumors located in the bladder triangle or bladder neck increase the risk of concomitant urethral prostate cancer, and a urethral biopsy of the prostate is recommended for definitive pathology. In the case of positive urine cells or abnormalities in the urethral mucosa of the prostate, a biopsy of this area is recommended.

Biopsy.

Biopsy is not currently recommended for non-muscle-invasive bladder cancer (non-muscle-invasive bladder cancer, NMIBC) of the normal bladder mucosa for routine random or selective biopsy (less likely to find carcinoma in situ than 2%).

Cystoscopy has the potential to cause complications such as urogenital infections, urethral and bladder bleeding, urethral injury, and urethral stricture.

1) Fluorescence cystoscopy: Fluorescence cystoscopy is performed by instilling into the bladder a photosensitizer such as 5-amino ketone valeric acid (5- aminolevulinic acid, ALA), hexyl aminolevulinate (hexyl aminolevulinate, HAL), and pirarubicin, which produce fluorescent substances The fluorescence produced is highly selective and accumulates in the new bladder mucosa, which shows red fluorescence at the lesion site under laser excitation, contrasting with the blue fluorescence of normal bladder mucosa. .

Fluoroscopy is recommended when in situ bladder cancer is suspected or when urine cytology is positive and the mucosa is normal on plain cystoscopy.

Meta analysis 12 randomized controlled studies with a total of 2258 cases of NMIBC The use of fluoroscopic cystoscopy-guided surgery significantly reduced the postoperative recurrence rate, prolonged the time interval to first recurrence, extended recurrence-free survival, and improved tumor detection compared with conventional surgery, but did not significantly reduce the risk of progression to MIBC.

The disadvantage of fluorescence cystoscopy is that the specificity for diagnosing bladder cancer is 63%, which is lower than that of plain cystoscopy (81%) than that of plain cystoscopy (81%). Relative low specificity is associated with inflammation, recent bladder tumor electrosurgery

and bladder perfusion therapy, etc., leading to false positives.

②Narrow band imaging (narrow band imaging, NBI) cystoscopy: NBI is based on the principle of filtering out the broadband spectrum of red, blue, and green emitted by ordinary endoscopic light sources and selecting NBI. span style=”font-family:Times New Roman”>415nm, 540nm narrow-band light. Compared with traditional white light mode endoscopy, it shows the microscopic structures of bladder mucosa and submucosal vessels more clearly and in a more stereoscopic manner, which helps to detect and diagnose microscopic lesions at an early stage, improve the detection rate of bladder cancer in situ, and reduce the recurrence rate after surgery.

NBI cystoscopy has better sensitivity, specificity, and accuracy than plain cystoscopy for the diagnosis of bladder cancer in situ. . Tumors that could only be detected by NBI cystoscopy but not by plain cystoscopy accounted for 17.1%, 42% of patients with positive urine cytology and negative plain cystoscopy had bladder tumors detected by NBI cystoscopy.

Compared with white-light electrosurgery, NBI guided bladder tumor electrosurgery reduces

Postoperative recurrence rate in patients with NMIBC .

Diagnostic transurethral resection of bladder tumor (transurethral resection of bladder tumours,TURBt): If imaging reveals a tumor-like lesion in the bladder, cystoscopy can be omitted and diagnostic cystoscopy performed directly TURBt. The purpose is to remove the tumor and to clarify the pathologic diagnosis and the grading and staging of the tumor, and the base of the electrosurgical specimen should include the muscular layer of the bladder wall.
Ureteroscopy: for bladder cancer Patients with suspected upper urinary tract lesions, CTU or or MRU examination still cannot clearly diagnose the patient, ureteroscopy and biopsy can be chosen to clarify the diagnosis.

Recommended clinical diagnostic methods for bladder cancer: see Table 1.

Table 1: Recommendations for clinical diagnostic methods for bladder cancer.

Recommendations for clinical diagnostic methods for bladder cancer: Recommendation grade

History, symptoms, signs, ultrasound, CT and CT and MRI examinations Highly recommended

Cystoscopy, pathologic biopsy or diagnostic TURBt in suspected patients Highly recommended

Suspicious carcinoma in situ with positive urine cytology and normal mucosa Consider random biopsy Optional

Suspicious carcinoma in situ can be selected for fluoroscopic cystoscopy or NBI Cystoscopy Recommended

MIBC Bone scan for suspected bone metastases Recommended

Urine cytology for adjuvant examination and post-operative follow-up in suspected patients Recommended

FISH test for intolerant cystoscopy and urine with atypical cells Recommended

(v) Differential diagnosis.

Hematuria is one of the common clinical symptoms in urinary and male genital diseases. Hematuria due to bladder cancer needs to be differentiated from patients with urinary stones, inflammation, tuberculosis, malformation, trauma, prostate enlargement, and glomerular disease. It should be differentiated from other tumors such as umbilical ureteral cancer, prostate cancer and pelvic tumors, cervical cancer, colorectal cancer invading the bladder, and benign bladder lesions such as adenocystitis.

Ureteral carcinoma

Tumors of the apical region of the bladder need to be differentiated from ureteral carcinoma of the umbilicus. The main body of the tumor is located outside or in the bladder wall. If the tumor invades the bladder wall inward into the bladder cavity, it will secrete mucus, resulting in a mucus-like substance in the urine.

quality.

By cystoscopy and biopsy pathology and pelvic imaging

Differential diagnosis. The cystoscopy revealed a broad-based mass at the top of the bladder with intact or ruptured surface mucosa. Imaging suggests that the main body of the tumor is located lateral to the bladder wall.

Prostate cancer invading the bladder or prostate enlargement

Patients often have symptoms of difficulty urinating, and ultrasonography, MRI or CT scan may be mistaken for a tumor in the bladder triangle. Serum prostate-specific antigen, rectal examinations, MRI examinations can help in the differential diagnosis, and cystoscopy can clarify the origin of the tumor.

Tumor invasion of the bladder by other pelvic organs

Commonly, cervical cancer and colorectal cancer invade the bladder. The patient has symptoms or signs of the primary disease. Identification relies on history, imaging, or colonoscopy.

Adenocystitis

Patients present with frequent, urgent, or painless hematuria, and imaging reveals a large swelling near the neck of the bladder. Cystoscopy: The lesion was mainly located in the triangle and bladder neck, and the ureteral orifice was not visible. The morphology of the lesion is diverse and multicentric, often follicular, papillary, or lobulated, and the mass is nearly transparent without internal vascularity; biopsy is required to define the pathology.

Intrusive papilloma

Mostly solitary tumors in and around the triangle, mostly with elongated tips and a smooth surface mucosa.

III.

(i) Histological type.

Currently, the recommended histological type is 2004 WHO classification criteria for tumors of the urinary tract system. Bladder cancer includes uroepithelial (migratory cell), squamous and glandular cell carcinomas, ureteral carcinomas, Mullerian duct malignancies, neuroendocrine tumors (e.g., small cell carcinomas), mesenchymal tumors, mixed carcinomas, sarcomatoid carcinomas, and metastatic carcinomas. Among them, uroepithelial carcinoma of the bladder is the most common, accounting for 90% of bladder cancer, and squamous cell carcinoma of the bladder accounts for 3%-7%; adenocarcinoma of the bladder accounts for <2%. This guideline focuses on the diagnosis and treatment of uroepithelial carcinoma of the bladder.

2016 WHO updated the pathological types of uroepithelial tumors of the bladder, which are divided into two main categories, invasive uroepithelial carcinoma and non-invasive uroepithelial tumors. Invasive uroepithelial carcinoma is subdivided into different variant subtypes, and the different variant subtypes are closely related to patient prognosis. In addition to making the primary pathologic diagnosis, the pathologist needs to determine whether the various variant subtypes are combined (Table 2).

Table 2 2016 Edition WHO Pathological Types of Uroepithelial Tumors and variant subtypes

Infiltrative uroepithelial neoplasm Non-infiltrative uroepithelial neoplasm

Infiltrating uroepithelial carcinoma Uroepithelial carcinoma in situ

Invasive uroepithelial carcinoma with different differentiation Non-invasive papillary uroepithelial carcinoma, low grade uroepithelial carcinoma with partial squamous differentiation Non-invasive papillary uroepithelial carcinoma, high grade

Uroepithelial carcinoma with partial and / or glandular differentiation Urothelial epithelial papillary tumor

Uroepithelial carcinoma with partial trophoblastic differentiation Low malignant potential papillary uroepithelial tumor Uroepithelial carcinoma with partial Müllerian differentiation Involuted uroepithelial papillary tumor

Infiltrative uroepithelial carcinoma variant subtype Uroepithelial hyperplasia of undetermined malignant potential Micropapillary uroepithelial carcinoma Uroepithelial heterogeneous hyperplasia

Microcystic uroepithelial carcinoma

Nested variant of uroepithelial carcinoma (including large nests) Lymphangioepithelioma-like carcinoma

Plasmacytoid-like carcinoma/ Indolent cell carcinoma/Diffuse giant cell variant carcinoma

Undifferentiated carcinoma

Sarcomatoid carcinoma of clear cell carcinoma

Lipid-rich carcinoma

Carcinoma in situ of the bladder

In situ carcinoma of the bladder, also known as flat carcinoma, is a high-grade, non-muscle invasive carcinoma that is often multifocal in nature. It is easily confused by cystoscopy with inflammatory changes in the bladder and requires biopsy to confirm the diagnosis.

Other pathological manifestations of bladder cancer

The presence of vascular lymphovascular infiltration in cancer specimens is significantly associated with higher pathologic stage; uroepithelial subtypes such as micropapillary, sarcomatoid, and plasma cell carcinoma have a poor prognosis.

(b) Histologic grading of bladder cancer.

The malignancy of bladder cancer is graded (Grade, G, G, G, G). Roman”>G) indicates that grading is closely related to the risk of recurrence and invasion. The current method of WHO grading (WHO 1973, WHO 1973, WHO 1973) is used.

WHO 2004). The 2016 edition of the pathological diagnostic criteria for bladder cancer still recommends the 2004

version of the grading method.

1973 WHO grading criteria classify bladder cancer into highly differentiated, moderately differentiated and poorly differentiated 3 grades according to the degree of differentiation of the cancer cells, using G1, 2, 3 or GI, II, III indicates .

The WHO 2004/2016 year classification criteria classify uroepithelial tumors as having low malignant potential Papillary urothelial neoplasms of low malignant potential, papillary urothelial neoplasms of low malignant potential, PUNLMP), low-grade papillary urothelial neoplasms, and high-grade papillary urothelial neoplasms. The 2004 grading criteria are recommended. See Table 3.

Table 3 WHO 1973 and 2004 Bladder cancer grading system

Papillary tumors

WHO 1973 Grading

Uroepithelial carcinoma Grade 1 well differentiated

Uroepithelial carcinoma Grade 2 Moderately differentiated

Uroepithelial carcinoma Grade 3 Poorly differentiated

WHO 2004 Grade (papilloma)

Papillary uroepithelial neoplasm of low malignant potentialPapillary uroepithelial carcinoma of low grade

High-grade papillary uroepithelial carcinoma

WHO 1973 and WHO 2004 bladder tumor grading methods are two different grading

system that does not correspond exactly. There was no significant difference between the two grading methods in predicting patient progression to relapse. The 2004 version of the grading method is currently used.

(iii) Pathology report of bladder cancer.

It is important to standardize the process of sending and processing bladder cancer pathology specimens.

Pathology report of bladder tumor electrosurgery

It is necessary to include whether the specimen has a muscular layer, whether the tumor invades the muscular layer, whether it invades the lamina propria, whether there are blood vessels, lymphatic infiltration and carcinoma in situ.

Total bladder resection specimen

The type and stage of pathology should be included, including the urethra, ureteral margins, and whether the prostate gland is invaded in men. In females, the uterus and vagina should be included. The lymph nodes should be cleared and sent for examination.

Immunohistochemistry for bladder cancer

Immunohistochemistry is useful for identifying uroepithelial origin and distinguishing reactive hyperplasia from carcinoma in situ; it is also useful for the diagnosis of bladder spindle cell tumors and metastatic bladder cancer. 2013 ISUP Recommendations: Immunomarkers such as GATA3, CK7, CK20, P63 , HMWCK and CK5/6 help to clarify whether it is of uroepithelial origin; CD44 , CK20 , P53 help to identify reactive hyperplasia and carcinoma in situ; ALK1, SMA, desmin, P63 , P63, HMWCK and CK5/6 help to clarify the diagnosis of bladder spindle cell tumor and metastatic cancer, etc. The use of immunohistochemistry is valuable in the diagnosis, staging, and prognosis of bladder cancer, but further validation and research is needed.

(D) Staging of bladder cancer.

Staging of bladder cancer is evaluated based on the extent of primary tumor invasion, involvement of regional lymph nodes, and metastases to other sites. Using the International Union Against Cancer

(UICC) developed the TNM staging system. span>staging system, recommended for application 2017 Version 8 . See Table 4 for bladder cancer pathology and Table 5 for clinical staging.

The tumors were classified according to whether they infiltrated the bladder muscle as NMIBC and MIBC . NMIBC accounts for approximately 75% of bladder tumors, including Tis stage (carcinoma in situ, 5% to 10%), Ta phase (70%~75%) and T1 phase (20% to 25%), in which carcinoma in situ (Tis stage) is poorly differentiated and has a high risk of myxoid infiltration, which is a high-risk tumor. MIBC for patients with T2 stage and above.

Table 4 2017 Year UICC Bladder Cancer TNM Staging (Version 8)

Primary Tumor (T)

Tx Cannot evaluate primary tumor

T0 No evidence of primary tumor

Ta Non-invasive papillary carcinoma

Tis in situ carcinoma (“flat tumors“)

T1 Tumor invasion of subepithelial connective tissue

T2 Tumor invasion of muscle layer

T2a Tumor invasion of superficial muscular layer (medial 1/2) T2b Tumor invading deep muscle layer (lateral 1/2)

T3 Tumor invasion of peri-bladder tissue

T3a Microscopically visible tumor invading peri-vesical tissue T3b Visually visible tumor invading peri-vesical tissue (extra-vesical mass) T4 Tumor invading any of the following organs or tissues: prostate, seminal vesicles, uterus,
T4a tumor invading prostate, seminal vesicles, uterus or vagina T4b tumor invading pelvic or abdominal wall
N (regional lymph nodes)
Nx Regional lymph nodes could not be evaluated
N0 No regional lymph node metastasis
N1 Single lymph node metastasis in true pelvic cavity (closed foramen, internal iliac, external iliac and presacral lymph nodes)
N2 Multiple lymph node metastases in the true pelvic cavity (foramen ovale, internal iliac, external iliac, and presacral lymph nodes)
N3 Metastasis to common iliac lymph nodes
M (distant metastasis)
MX Unable to assess distant metastases
M0 No distant metastasis
M1 with distant metastases
M1a Non-regional lymph nodes
M1b Distant metastasis from other sites

Table 5 2017 AJCC bladder cancer staging mix
Staging TNM Status
0a
Ta
N0
M00is stage TisN0M0 stage I T1N0M0 stage II T2aN0M0T2bN0M0 stage III AT3aN0M0T3bN0M0T4aN0M0T1 to T4aN1M0 stage III BT1 to T4aN2-3M0 stage IV AT4b any NM0 any T any NM1a stage IV B any T any NM1b
(v) Molecular typing of bladder cancer (molecular/genomic testing).
In 2019, the Molecular Typing of Bladder Cancer Collaborative Group on MIBC molecular typing was divided into six types: luminal papillary (24%), luminal non-specific (8%), luminal unstable (8%), and luminal unstable (8%).
(8%), luminal indolent (15%), stromal enriched (15%), basal/squamous cell carcinoma (35%) and neuroendocrine (3%).
Molecular/genomic testing can be used in clinical trial studies of novel drugs to achieve greater precision and effectiveness. The most common clinically relevant genetic abnormalities include: CDKN2A (34%), FGFR3 (21%), PIK3CA (20%).
ERBB2 (17%); abnormal expression of PD1/PD-L1 gene, etc. The above genetic abnormalities may be associated with some of the drug treatment effects. For example, erdatinib is associated with abnormal FGFR3 or FGFR2 genes; the efficacy of atelelizumab or pablizumab is associated with PD-L1 expression level.
In addition, clinical and pathological staging, type and grade of pathology are closely related to the prognosis of patients. Some biomarkers have been found to have a predictive effect on patient prognosis. For example, defects in serum VEGF, circulating tumor cells, and DNA damage repair genes, including ERCC2, ATM, RB1, and FANCC, predict response to cisplatin-based neoadjuvant chemotherapy. Recently, FGFR3 mutations and gene fusions have been associated with response to fibroblast growth factor receptor (FGFR) inhibitors.
Molecular subtypes, immunogenic signatures, and matrix signatures may play an important role in predicting immunotherapeutic response. Although PD-L1 immunohistochemistry and TMB expression have predictive value in some cases and need to be investigated. Prospectively validated predictive molecular biomarkers will provide valuable data for clinical and pathological data and need to be validated in a large phase III randomized controlled trial (RCT).
A large phase III randomized controlled trial (RCT) is needed for validation.
Molecular typing of bladder cancer is currently used to determine prognosis and predict drug response, particularly to neoadjuvant chemotherapy, and to correlate with patient response to immunotherapy. It is still in the exploratory stage of research and its value needs to be confirmed by a large number of studies.
(vi) Recommendations for pathological diagnosis of bladder cancer: see Table 6.
Table 6 Histopathologic diagnostic recommendations for bladder cancer.
Recommendations for histopathologic diagnosis of bladder cancer: Recommendation grade

Using the 2017 version of TNM staging Highly recommended
Tissue grading using the 2004 WHO grading method is strongly recommended
Description of myelomeningocele and invasion is required for electrosurgical specimens Strongly recommend that total specimens include ureteral ureteral margins, prostate, vagina, and uterus involvement Strongly recommend that regional lymph node subdivision is recommended
The presence of vascular lymphatic infiltration and tissue subtypes should be recorded Strongly recommended
The presence of carcinoma in situ of the bladder should be recorded.
Intraoperative ureteral margin freezing is recommended for in situ neocystectomy Recommended for combined carcinoma in situ or staging ≥ T2, recommended Intraoperative ureteral resection margin freezing Optional
IV. Treatment of bladder cancer
Depending on the stage of bladder cancer, the type of pathology and the patient’s status, different treatment plans are selected.
Basic treatment for bladder cancer: The standard treatment for NMIBC is preferred
TURBt, and bladder perfusion treatment options are decided according to the risk of recurrence.
For MIBC, squamous cell carcinoma, adenocarcinoma, and umbilical ureteral carcinoma, radical total cystectomy is preferred, and partial cystectomy is an option for some patients. preoperative neoadjuvant chemotherapy is recommended for stage T2-4aN0M0 uroepithelial carcinoma of the bladder, and postoperative adjuvant chemotherapy and/or radiotherapy is determined based on pathology. Systemic chemotherapy is the main treatment for metastatic bladder cancer, and palliative surgery and radiotherapy can be used to relieve symptoms.
V. Treatment of NMIBC
(a) Risk classification of NMIBC.
NMIBC is a malignant tumor of the bladder confined to the mucosal layer (Ta) and the intrinsic layer (T1) of the bladder without infiltration of the muscular layer, including Ta, T1, and Tis stages. Although the Ta and T1 stages belong to NMIBC, their biological characteristics are significantly different.
Risk factors affecting the recurrence and progression of NMIBC include: number, size, stage, grade, frequency of recurrence, and the presence of carcinoma in situ (Tis).
Risk factors associated with recurrence include number of tumors (≥8) and frequency of recurrence (>1 time/year); risk factors associated with progression include stage (T1), grade (G3 or high-grade supra-urethral carcinoma)
(G3 or high-grade uroepithelial carcinoma) and the presence of Tis. depending on the risk of recurrence and prognosis, NMIBC was divided into 4 groups (Table 7).
Table 7 Risk grouping of NMIBC patients
Low-risk NMIBC Primary, solitary, TaG1 (low-grade uroepithelial carcinoma, PUNLMP), diameter
≤3 cm, no Tis (must have both of these conditions)
Intermediate-risk NMIBC All NMIBC patients not included in the low- and high-risk categories
High-risk NMIBC meeting any 1 of: G3 (or high-grade uroepithelial carcinoma), stage T1 tumor, Tis; also meeting: multiple, recurrent, and TaG1G2 (or low-grade uroepithelial carcinoma) >3 cm in diameter
Very high risk NMIBC meeting any 1 of: T1G3 (high grade uroepithelial carcinoma) with multiple, large, recurrent T1G3 (high-grade uroepithelial carcinoma); T1G3 (high-grade uroepithelial carcinoma) complicated by or invading urethral Tis in the prostate; uroepithelial carcinoma with poor histopathologic subtype; NMIBC that has failed BCG bladder irrigation therapy; lymphovascular invasion
(ii) Surgical treatment.
Patients with NMIBC were selected for surgery, bladder irrigation, and follow-up according to risk groups (Table 8).
TURBt

TURBt is both the standard treatment for NMIBC and an important diagnostic method. It is the treatment of choice for patients with NMIBC with the advantages of less trauma, less bleeding, and faster recovery.

TURBt aims to completely remove the bladder tumor down to the normal bladder wall muscle

layer. After tumor resection, it is recommended that the basal tissues be examined separately to facilitate accurate assessment of tumor tissue grading and pathologic staging and to guide the next treatment plan.

Complete resection of the tumor can be performed either in a fraction (including the tumor, the base of the bladder wall, and the margins of the resected area) or in a whole block (whole block resection with monopolar or bipolar electrodes, thulium laser, or holmium laser).

If the tumor is small (1cm), the tumor can be removed along with a portion of the bladder wall at its base for pathology. If the tumor is large, the tumor is excised in blocks, with the protruding part of the tumor removed first, followed by the basal part of the tumor, until the normal bladder wall muscle is exposed. The specimen should contain the muscular layer of the bladder and the basal tissue should be examined to determine the pathologic stage. Cautery is avoided during TURBt to minimize damage to specimen tissue.

Recurrent, small Ta/G1 tumors found during outpatient cystoscopy and treated with direct electrocautery are options of treatment.

For patients with multiple lesions or carcinoma in situ, NBI guided TURBt can improve tumor detection and reduce the risk of missed lesions, but whether it can improve overall patient outcomes remains to be proven.

NMIBCSecondary Electrocutting

Tumor remnants are one of the important causes of tumor recurrence after NMIBC electrodesiccation. Studies have shown that the rate of tumor residual after first TURBt procedure is 4% to 78%, which is related to tumor stage, size, number and physician technique. The first single tumor residual rate was 22% and the residual rate for multiple tumors was 45%. The diameter <3cm residual rate was 19

%, ≥3 cm residual rate was 42%. In patients with intermediate and high grade T1 stage bladder cancer, the tumor residual rate after initial electrosurgery was 33% to 55%, TaG3 stage was 41.4%.

There is a bias in pathological staging due to electrodesection technique and quality of the tumor specimens sent for examination. The study showed that about 1.3%-25% of patients with first electrosurgery at T1 stage were confirmed to have T1stage after second electrosurgery. span style=”font-family:Times New Roman”>MIBC; if the first electrosurgical specimen had no myelomeningocele component, the second electrosurgery revealed 45% as MIBC, and secondary electrosurgery corrected 9%of Roman”>to 49% of patients with pathological staging.

A multicenter retrospective study evaluating 2451 cases of BCG (Bacille Calmette-Guérin, BCG) infusion therapy of BCG family:Times New Roman”>T1G3/HG grade tumors (including 935 secondary resections), showed that secondary resection improved recurrence-free survival, progression-free survival, and survival time in patients without a muscle component in the initial resection specimen. The results showed that secondary resection improved recurrence-free survival, progression-free survival, and overall survival in patients without a muscle component in the initial resection specimen. It reduced the postoperative tumor recurrence rate from 63.24% in patients with T1 to 25.68% and the tumor progression rate decreased from 11.76% to 4.05%. The disease-free survival rate after secondary electrosurgery of high-grade T1 stage tumors at a follow-up of 10 years was 69.7% compared with 49.6% for those who underwent a single electrosurgery.

Secondaries can identify residual bladder tumor lesions, obtain more accurate pathologic staging, improve recurrence-free survival and patient prognosis, and improve treatment outcomes.

Indications for secondary electrosurgery include: ①First time Second time electrosurgery style=”font-family:Times New Roman”>TURBt is inadequate; (ii) the absence of myofibrotic tissue in the first electrosurgical specimen (except TaG1/low grade tumors and simple carcinoma in situ excluded); ③T1stage tumors; ④G3(high-grade) tumors. Excluding carcinoma in situ alone.
Timing of secondary electrosurgery: first time TURBt Long postoperative interval will affect the late perfusion chemotherapy, if the interval is too short, because of mucosal inflammatory swelling etc. with residual swelling

Difficulty in differentiating tumor lesions.

The current recommendation is to perform a second electrosurgery around 2 to 6 weeks after the first surgery, where the original tumor site needs to be resected again, to a depth to the deep muscle layer.

Surgical points: Resection of the original tumor base (including the surrounding mucosal inflammatory edema area), and the suspected tumor site in sequence. Excision to the deep muscle layer of the bladder is required. Biopsy of the base with biopsy forceps or electrodesiccated rings is recommended, and random biopsy is done if necessary.
Post-secondary electrodesiccation perfusion: recommended after secondary electrodesiccation 24 hours of immediate perfusion therapy. Intraoperative bladder perforation or severe sarcoid hematuria are not recommended. Bladder irrigation is recommended for high-risk NMIBC patients with no tumor remnants on pathology after secondary electrosurgery. style=”font-family:Times New Roman”>BCG or instillation of chemotherapeutic agents. If there is tumor residual after surgery, BCG bladder irrigation therapy or cystectomy is recommended; if the secondary electrosurgery pathological stage is span style=”font-family:Times New Roman”>MIBC, radical cystectomy is recommended.
- Laser resection of transurethral bladder tumor
Transurethral resection of the entire bladder tumor can obtain more bladder muscle tissue, improve the quality of the tumor specimen, and facilitate staging. The laser technique is more suitable for NMIBC block resection because of its good vaporization, precise tissue excision, and low probability of intraoperative bleeding and closed nerve reflexes.

The lasers currently used in clinical practice include the holmium, green, thulium, and

1470 semiconductor laser, etc.

The near-term outcomes of laser surgery for transurethral bladder tumors are similar to TURBt and evidence for long-term outcomes is lacking.

Partial cystectomy

The vast majority of NMIBC patients can be treated with TURBt resection. In a small number of patients with a single isolated tumor with adequate margins, a tumor in the bladder diverticulum, and no in situ cancer on random biopsy, partial cystectomy may be an option to reduce the risk of bladder perforation due to electrodesiccation. Partial cystectomy is recommended in conjunction with pelvic lymph node dissection, including at least the common iliac, internal iliac, external iliac, and foramen ovale lymph nodes. Postoperative bladder immunoperfusion or whole body adjuvant chemotherapy is recommended.

Radical cystectomy

For some high-risk NMIBC subgroup or very high-risk patients, if the following high-risk conditions are present: multiple and recurrent high-grade tumors, high-grade T1 stage tumors; high-grade tumors combined with carcinoma in situ, lymphovascular infiltration, micropapillary tumors or Radical cystectomy is recommended for patients who have failed BCG perfusion. Patients who do not undergo cystectomy may opt for simultaneous radiotherapy or TURBt+BCG bladder perfusion, with the advantages and disadvantages of the different treatment options being communicated and discussed with the patient.

table 8 Recommendations for surgical treatment of patients with NMIBC

NMIBC Recommendations for Surgical Treatment of Patients: Recommendation level TURBt is the primary treatment for patients with NMIBC Strongly recommended Cystoscopy with fluoroscopy or NBI is available to improve resection rates of Tis or microscopic lesions Recommended

If first TURBt is inadequate; electrosurgical specimens No myofibrotic tissue; recommended

(except for TaG1/ low-grade tumors and carcinoma in situ).

Stage T1 tumors; G3 ( high grade) tumors

Recommended secondary electrosurgery around 2 to 6 weeks after the initial procedure

Transurethral resection of the entire bladder tumor can be used as NMIBC treatment. Radical cystectomy is recommended for selected high-risk NMIBC subgroup or very high-risk patients Recommend fluoroscopy or NBI Cystoscopy to improve the diagnosis of carcinoma in situ or microscopic lesions Optional transurethral laser surgery is a treatment option for patients with NMIBC Optional

Small low-grade papillary tumors can be electrocautery in the outpatient setting Optional

(iii) bladder perfusion therapy after TURBt surgery.

NMIBC patients TURBt has a high recurrence rate after surgery, with a 5 year recurrence rate of 24% to 84%. Recurrence is associated with incomplete resection of the primary tumor, tumor cell implantation, or new tumors; some patients progress to MIBC. Therefore, postoperative adjuvant bladder perfusion therapy, including bladder perfusion chemotherapy and bladder perfusion immunotherapy, is recommended for all patients with NMIBC (Table 9, Table 10).

Bladder Perfusion chemotherapy (Table 9)
- Timing of Perfusion Therapy.

①TURBt immediate postoperative bladder perfusion chemotherapy: immediate postoperative perfusion chemotherapy can Kill intraoperatively disseminated or / and trauma residual tumor cells and significantly reduce recurrence rates in patients with NMIBC.

The study showed that 2844 cases of NMIBC patients with immediate postoperative instillation of mitomycin C , the recurrence rate was 27% compared with 36% in the control group; another phase III clinical study showed that the recurrence rate was 27% compared with Another phase III clinical study showed that immediate postoperative infusion of gemcitabine reduced the recurrence rate compared with the control group

34%.

The latest meta-analysis shows that 2278 examples of NMIBC patients with TURBt immediate postoperative bladder perfusion chemotherapy 5 year recurrence rate was reduced by 35% [risk ratio (hazard ratio< , HR) 0.65, P<0.001), but did not reduce the risk of patient progression and death.

Therefore, to prevent tumor cell implantation, immediate postoperative bladder irrigation is recommended for all NMIBC patients. chemotherapy, which should be completed as soon as possible within 24 hours after surgery

(ideally, perfusion should be completed within 6 hours postoperatively). Immediate perfusion is not recommended in case of intraoperative bladder perforation or severe postoperative meatus hematuria.

② Early postoperative and maintenance bladder perfusion chemotherapy: immediate postoperative perfusion in patients with intermediate risk high-risk NMIBC Maintenance perfusion chemotherapy or BCG infusion therapy is required after chemotherapy to reduce the rate of tumor recurrence. Bladder-perfusion chemotherapy lasting more than 1 year is not currently recommended.

Bladder perfusion regimens include: early induction perfusion: postoperative 4 to 8 weeks, weekly 1 times bladder perfusion; thereafter maintenance perfusion: monthly 1 times bladder perfusion; thereafter maintenance perfusion: monthly times bladder perfusion :Arial”>times, maintained for 6 to 12 months.

1) Low-risk NMIBC patients have a low rate of tumor recurrence after immediate postoperative perfusion, therefore immediate perfusion is not Maintenance bladder perfusion therapy is not recommended after immediate perfusion.

Two patients with intermediate-risk NMIBC are generally recommended to continue bladder irrigation chemotherapy after immediate postoperative bladder irrigation with weekly 1 times for a total of 8 weeks, followed by monthly 1 time for 10 months to prevent recurrence. Optional BCG infusion is also available.

③ For high-risk NMIBC patients, postoperative bladder instillation is recommended BCG to prevent recurrence and progression. If recurrence is resistant to BCG, postoperative maintenance bladder perfusion chemotherapy is an option.

At present, there is no evidence of a significant difference in efficacy between maintenance perfusion regimens using different chemotherapeutic agents, but it is not recommended 1 year or more of bladder-perfusion chemotherapy.

Choice of perfusion chemotherapy agents: commonly used perfusion chemotherapy agents include: mitomycin (dose 20-60mg), gemcitabine (at a dose of 1000mg), piricitabine (at a dose of 30 to 50mg), epirubicin (at a dose of 50-80mgper dose), epirubicin (at a dose of 50-80mg), doxorubicin (at a dose of 30-50mg), hydroxycamptothecin (at a dose of each time10~20mg), etc.

Chemotherapy drugs should be instilled into the bladder through a catheter and retained for 0.5 to 2 hours. The effect of bladder perfusion chemotherapy is related to the urine pH value, chemotherapeutic drug concentration and dose, and drug duration of action. Water abstinence for 6 hours before perfusion reduces the dilution of the drug by urine.

The main side effect of bladder irrigation chemotherapy is chemical cystitis, which is associated with the dose and frequency of irrigation and manifests as bladder irritation signs and granular hematuria, depending on the dose and frequency of irrigation. In mild cases, it may resolve on its own during intervals of perfusion, and drinking more water is sufficient. If severe bladder irritation occurs, delay or discontinue perfusion therapy; most side effects will improve on their own when perfusion is discontinued.

Table 9 Common bladder perfusion chemotherapy regimens for bladder cancer

=”border-bottom: solid black 0.5pt”>

Dose

td>

Medication		Medication	Solute and volume	Retention time (hours)
Melanomycin C	40mg	NS 40ml	2
Table Zoopithecine	< span style="font-family:Times New Roman; font-size:12pt">50mg	NS 40ml	1
Pyridoxine	40mg	< p style="text-align: right">GS 40ml	0.5
Hydroxycamptothecin	Hydroxycamptothecin	40mg	NS 40ml	2 >

Gemcitabine 1000mg NS 50ml 1

Note: NS, saline; GS, glucose injection.

Bladder perfusion immunotherapy

Bladder perfusion immunotherapy is primarily BCG bladder perfusion therapy, and others include biologic agents such as Pseudomonas aeruginosa, Streptococcus pyogenes, and red Nocardia agents.

BCG is a high-risk NMIBC patients TURBt the adjuvant of choice after surgery

TURBt.

The exact mechanism of action of BCG is unknown, and BCG is mediated by intravesical perfusion free

Immune agents induce a local immune response to directly kill tumor cells or induce a nonspecific immune response in the body, causing BCG prevented bladder tumor recurrence and controlled tumor progression, but had no clear efficacy on overall patient survival or tumor-specific survival.

BCG Bladder perfusion indications: including: intermediate-risk, high-risk NMIBC and bladder carcinoma in situ and low-risk non-muscle-infiltrating bladder is not recommended BCG infusion therapy. Compared to simple TURBt , TURBt postoperative combined BCG Bladder perfusion can pre

preventing NMIBC recurrence after surgery and significantly reducing the risk of intermediate-risk and high-risk tumor progression. Therefore, high-risk NMIBC patients are recommended for BCG bladder perfusion immunotherapy.

The recurrence rate in intermediate-risk NMIBC patients 5 years after surgery is 42% to 65% and a risk of tumor progression of 5% to 8%. Bladder perfusion chemotherapy is recommended for patients with intermediate-risk NMIBC.

Multicenter RCT confirmed that in intermediate-risk NMIBC patients, BCG infusion therapy was superior to chemotherapeutic agents in preventing tumor recurrence with relatively long-lasting efficacy and delaying tumor progression.

Spread, according to which some patients can choose BCG perfusion therapy with continuous perfusion for 1 year.

2015 Year EORTC analysis of 2 Phase III clinical studies of BCG perfusion treatment

1 to 3 years with follow-up 7.4 years, patients with T1G3 stage 5 years progressed to MIBC probability of

19.3%. High-risk patients were 45%. Compared with mitomycin infusion, high-risk patients receiving BCG infusion had a 32% lower risk of recurrence and a 32% lower rate of tumor progression. reduced by 27%. BCG maintenance therapy was more effective.

Patients with carcinoma in situ of the bladder with BCG infusion therapy had a complete remission rate of 72% to 93%, which is significantly higher than bladder perfusion chemotherapy (48%) and significantly reduces the tumor recurrence and progression rates. Postoperative BCG infusion therapy is recommended for patients with carcinoma in situ of the bladder.

BCG BCG Contraindications to bladder irrigation:TURBt within two weeks of surgery; active tuberculosis Patients with severe hematuria; post-traumatic catheterization; symptomatic urinary tract infections. Immunodeficient or compromised patients (e.g. AIDS patients, patients on immunosuppressive drugs or radiotherapy), BCG allergic patients, etc.
BCG Bladder perfusion protocol and dose:BCG The optimal regimen and duration of bladder perfusion therapy is inconclusive.

1) Time to start irrigation: Immediate BCG irrigation is prone to serious side effects, such as postoperative bladder trauma or visual hematuria. The immediate postoperative perfusion is contraindicated and is usually associated with serious side effects and risk of TB dissemination. Immediate postoperative instillation is contraindicated, and intravesical BCG infusion is usually started at least 2 to 4 weeks after surgery.

②Infusion regimen and dose: BCG treatment is usually started with weekly 1 treatment for a total of

6 infusions, called induction perfusion. Maintenance regimens are numerous, but there is no evidence to suggest

shows that any one regimen is clearly superior to the others.

Domestic BCG Bisergel recommended regimen: 6 After induction perfusion for 2 weeks 1

times, for a total of 3 intensive perfusions to maintain a good immune response, and monthly thereafter 1 visit per month thereafter.

sustained perfusion for a total of 10 times, 1 year for a total of 19 times.

The RCT study showed that the first 1 year 19 instillations in the BCG perfusion group of the 1 year recurrence-free survival rate was better than the first 1 year 15 th perfusionists.

BCG perfusion therapy is generally performed with 60-120 mg of BCG dissolved in 50-60 ml of saline by bladder instillation with each retention of 2 hours, the recommended full dose of domestic BCG is 120 mg. 1 dose for / weeks for 6 weeks of induction perfusion followed by maintenance of BCG perfusion for 1 to 3 years ( at least 1 year). The following years will be the first three years of the program (3, 6, 12, 18, 24, 36 months for maintenance perfusion at 1 time per week for a total of 3 times (for the first 1 year for a total of 15 times) to maintain and reinforce BCG efficacy. Full-dose BCG infusion is more effective than 1/3 dose BCG maintains perfusion better.

Patients with high-risk bladder cancer are recommended for 3 year of BCG bladder perfusion maintenance therapy is effective in preventing recurrence, and BCG maintenance perfusion is recommended for intermediate-risk patients family:Times New Roman”>1 year.

BCG Adverse reactions to intracavitary bladder instillation: the overall adverse reaction rate was 71.8% . Local adverse reactions were predominant, of which 1 to 2 grade adverse reactions were60.1%, with major adverse reactions including bladder irritation, hematuria and flu-like syndrome, fever, rare serious adverse reactions including tuberculosis septicaemia, granulomatous prostatitis, epididymitis, bladder contracture, tuberculosis pneumonia, arthralgia, and arthralgia. The most common serious adverse reactions include tuberculosis septicemia, granulomatous prostatitis, epididymitis, cyst contracture, tuberculosis pneumonia, arthralgia and / or arthritis, and allergic reactions. It can be relieved by discontinuing the drug and treating the symptoms.

BCG Types of bladder perfusion failure

①BCG Refractory: Receiving BCG After adequate treatment High-grade tumor found within 6 months or tumor in 1 cycle of BCG treatment after 3 months of graded stage progression .

② BCG Relapse: receive BCG after adequate treatment and maintenance of tumor-free status 6 months after high-grade tumor recurrence (last received BCG treatment within 6 to 9 months).

③ BCG No response: including BCG refractory and recurrent, when patients should opt for radical cystectomy. If surgery is not indicated, a combination of bladder preservation therapy is available.

Medium-risk patients treated with BCG with non-high-grade recurrence can repeat

BCG treatment or elective radical total cystectomy.

Pabrolizumab (immune checkpoint inhibitor)

A single-arm phase II clinical study (KEYNOTE-057) with pabolizumab for span style=”font-family:Times New Roman”>103 cases of previous BCG treatment failure, high risk, with carcinoma in situ, unable or not agreeing to radical cystectomy NMIBC patients. The results showed a 3 month complete remission rate of 38.8% [95% confidence interval (confidence interval, CI), 29.4% to 48.9%], last follow-up (median 14.0 months) was maintained at the last follow-up visit (median 14.0 months).

72.5% of complete remission. The complete remission rate in this study was 41% in 96 patients

(95% CI, 31% to 51%), with a median duration of remission of 16.2 months, 46% of complete remissions were maintained for at least 1 year. 12.6% of patients experienced grade ≥3 treatment-related adverse events, and immune-related adverse events accounted for 18.4%.

Other intravesical treatments

(1) Photodynamic therapy: Photodynamic therapy is the use of photosensitizers (including ALA, HAL) to be instilled into the bladder and the whole bladder is irradiated with laser through cystoscopy. The tumor cells ingest the photosensitizer and then produce monomorphic oxygen under the action of the laser, causing tumor cell degeneration and necrosis. The tumor recurrence and progression rates can be reduced, but the exact efficacy has yet to be confirmed in a multicenter clinical study with a large sample.

Indications: Patients with carcinoma in situ of the bladder, recurrent recurrence, intolerance to surgery, and failure of BCG perfusion therapy may be tried with photodynamic therapy.

(2) Thermal infusion therapy: The infusion chemotherapy drug is heated by a heating device, and the combination of heat and chemotherapy drug is used to improve the anti-tumor effect. For example, mitomycin infusion

(mitomycin C 20mg+ water for injection 50 ml) was heated to 42°C and maintained for 1 hour, which has some advantages over conventional perfusion chemotherapy advantage over conventional perfusion chemotherapy.

Table 10 Recommendations for bladder perfusion therapy in patients with NMIBC

Recommendations for bladder irrigation treatment in patients with NMIBC Recommendation grade low-risk patients Single immediate postoperative bladder irrigation chemotherapy only Recommended

After immediate postoperative instillation chemotherapy in medium- to high-risk patients, maintenance chemotherapy drugs or BCG infusion should be strongly recommended for high-risk patients BCG bladder perfusion for at least 1 year, preferably 3 years Highly recommended

(iv) Treatment of carcinoma in situ of the bladder.

In situ carcinoma of the bladder, although it is NMIBC, is usually poorly differentiated and highly malignant, with a higher risk of myxoid infiltration than Ta, T1 stage bladder cancer. Carcinoma in situ is often

with Ta, T1 stage bladder cancer, or T1 stage bladder cancer. /span>stage bladder cancer or MIBC concomitantly, are risk factors for poor prognosis.

The standard of care for carcinoma in situ is TURBt operation with postoperative adjuvant BCG bladder perfusion therapy. If the patient cannot tolerate BCG infusion, perfusion chemotherapy treatment is also an option.

Simple TURBt is not curative for carcinoma in situ, and compared to bladder perfusion chemotherapy, BCG irrigation for in situ cancer has a high complete remission rate (72% to 93%) compared with bladder irrigation chemotherapy (48%), significantly reducing the risk of tumor recurrence and progression. Approximately 10% to 20% of patients in complete remission eventually progress to MIBC, while those who do not are

66%.

BCG during treatment every every 3 to 4 months, and radical cystectomy is recommended if complete remission or tumor recurrence or progression is not achieved at 9 months of treatment. Radical cystectomy is recommended when in situ cancer is combined with MIBC.

(v) Treatment of recurrent tumors after TURBt.

NMIBC patients TURBt Patients who experience recurrence after bladder instillation chemotherapy after surgery are recommended to be treated with another TURBt treatment. Postoperatively, bladder perfusion chemotherapy can be replaced with re-bladder perfusion therapy, or BCG infusion can be chosen.

For recurrent and multiple recurrences, BCG perfusion therapy or radical cystectomy is recommended. For MIBC at follow-up; BCG infusion 3 months after high-grade NMIBC; 3 ~6 months when carcinoma in situ is detected; BCG within or after treatment with high

grade NMIBC patients considered to be BCG refractory bladder cancer, radical cystectomy is recommended for such patients.

(vi) Patients with positive urine cytology and negative cystoscopy and imaging are treated

Treatment.

TURBt Postoperative review revealed positive urine cytology, but cystoscopy and imaging

In patients with negative imaging, random cystoscopic biopsy, urine cytology, and imaging are recommended to determine whether there is a tumor in the upper urinary tract and, if necessary, ureteroscopy.

If the random biopsy pathology is neoplastic, BCG bladder perfusion therapy is recommended, with maintenance perfusion required if there is a complete response. If ineffective or in partial remission, total cystectomy, change of perfusion drugs or clinical trial drugs may be an option. If upper urinary tract tumor cells are positive along with positive ureteroscopy and imaging, treat as upper urinary tract tumor. If random biopsy and upper urinary tract examination are negative, periodic review is recommended.

(vii) Follow-up of patients with NMIBC.

Ultrasound is the most routine means of review. Cystoscopy is the preferred method of review for NMIBC patients. If suspicious bladder mucosal lesions are found, biopsy should be performed to clarify pathology. Urinary exfoliative cytology, CT/CTU or MRI/MRU are performed when necessary, but are not a complete substitute for cystoscopy.

Recommended for all NMIBC patients in the postoperative first cystoscopy at 3 months, or earlier if surgical resection is incomplete and tumor progression is rapid.

Low-risk patients undergo cystoscopy within 3 months after surgery, if the first cystoscopy

A negative test is recommended 1 year, followed by an annual 1

times until year 5.

High-risk patients are recommended for the first 2 years every 3 monthly for 1 urine cytology and cystoscopy

and every 3 years starting at 6 monthly 1 time and yearly 5 from year 5. span style=”font-family:Times New Roman”>1 time per year for life; for high-risk patients 1 time per year for upper urinary tract examination (CTU examinations).

Intermediate risk patients have a follow-up schedule in between, based on individual prognostic factors and general condition. In the event of relapse during follow-up, the post-treatment follow-up regimen is restarted as described above.

Random biopsy or fluoroscopic or NBI is recommended in patients with positive cytology and no bladder tumor during follow-up. span>Cystoscopy-guided biopsy and CT/CTU (to understand the upper urinary tract), urethral prostate biopsy.

VI. Treatment and follow-up of MIBC patients

In recent years, with the advancement of new drugs and clinical research, the treatment of MIBC patients has been gradually integrated. The treatment of patients with MIBC is gradually becoming more integrated, with different treatment options depending on the specific staging.

The general principle of treatment for patients with MIBC is that neoadjuvant chemotherapy combined with radical total cystectomy is the best way to treat patients with MIBC. span style=”font-family:Times New Roman”>the standard of care for patients with MIBC . Patients with locally progressive MIBC are treated with systemic systemic therapy in combination with local therapy to improve outcomes. Metastatic MIBC patients are treated with systemic systemic therapy combined with supportive therapy.

Preoperative systemic examination is performed to determine the clinical stage and the presence of metastases. Among them, thoracic, abdominal and pelvic CT/CTU or / and and MRI/MRU is the most important test for MIBC and, if necessary, for PET-CT when necessary.

Treatment options for patients with MIBC include: neoadjuvant chemotherapy, radical cystectomy, partial cystectomy, postoperative adjuvant chemotherapy, and bladder-preserving combination therapy

(Table 11).

(i) Neoadjuvant therapy.

Radical cystectomy is the clinical staging of cT2~T4aN0M0 of MIBC patients, but their 5 year overall survival rate is about 50%. To improve treatment outcomes, cisplatin-based combination neoadjuvant chemotherapy has been widely used, and neoadjuvant immunotherapy with immune checkpoint inhibitors is normally being explored. Neoadjuvant therapy has a significant impact on overall survival in patients who achieve ypT0 or at least ypT2

Neoadjuvant chemotherapy

cT2~4aN0M0 Phase MIBC patients, cisplatin-based neoadjuvant chemotherapy combined with radical cystectomy is recommended; postoperative adjuvant chemotherapy is recommended for patients with pT3~pT4 or lymph node metastases.

Carboplatin is not recommended instead of cisplatin for patients who cannot tolerate cisplatin-based combination neoadjuvant chemotherapy due to lack of clinical data, and direct radical cystectomy without neoadjuvant chemotherapy is recommended.

Multiple randomized trials and meta-analyses have shown that MIBC patients receiving cisplatin-based neoadjuvant chemotherapy span style=”font-family:Times New Roman”>10-13% and 5 years overall survival. span>year overall survival improved by 5% to 8% for cT3 patients 5 year survival rate can be improved up to 11%.

SWOG Study 307 Example MIBC patient with MVAC protocol neoadjuvant chemotherapy

Total cystectomy after treatment, with a median overall survival time of 77 months and a median overall survival time of 77 months for hand-only cystectomy.

in the surgery group was 46 months, with no increase in patient treatment-related mortality.

In another Meta meta-analysis, a total of 3005 patients, and found that MIBC patients receiving cisplatin-based neoadjuvant chemotherapy significantly improved patient 5 year survival rate

(8%) and tumor-specific survival ( 9%).

GETUG/AFU V05 Trial to investigate the MIBC patients using the ddMVAC

(dose dense methotrexate, vincristine, doxorubicin and cisplatin) with CG regimen neoadjuvant chemotherapy, both regimens had similar pathologic response rates (ypT0N0) of 42% and 36% (P=0.2).

(1) Commonly used neoadjuvant chemotherapy regimens include.

(1) Gemcitabine in combination with cisplatin (GC regimen).

Dosing regimen I: Gemcitabine 1000mg/m2 >1, 8 days intravenous, cisplatin 70 mg/m2 day 2 intravenous drip every 2days “font-family:Times New Roman”>21 days for 1 cycle.

Dosing regimen II: Gemcitabine 1000 mg/m2 >No. 1, 8 IV drip, cisplatin

70mg/m2 th . =”font-family:Times New Roman”>1 or day 2 intravenous drip every 28 days for 1 cycle.

General neoadjuvant chemotherapy 4 cycles, 21 day or 28 day cycles are available.

Accepted. Among them, the 21 day regimen is shorter and may have better dose adherence.

② ddMVAC (dose dense methotrexate, vincristine, doxorubicin, and cisplatin) in combination with growth factors, 3 to 4 cycles.

Recommended use: methotrexate 30 mg/m2, Vincristine 3mg/m2, Doxorubicin 3mg/m, Doxorubicin 30mg/m2, Cisplatin 70mg/m2, IV drip on day 1 , repeated every 2 weeks.

Requiring hydration, routine prophylactic application of granulocyte colony-stimulating factor during chemotherapy

(granulocyte colony stimulating factor, G-CSF).

③ CMV regimen (cisplatin, methotrexate, and vincristine):CMV is available for neoadjuvant chemotherapy in the first-line regimen.

Methotrexate 30mg/m2 , Vincristine 4mg/m2 , No. 1, 8 days intravenous drip, cisplatin 100mg/m2 day 2 intravenous doses every 3 weeks for 1 cycle.

A multicenter randomized phase III randomized clinical study (BA06 30894) enrolled a total of 1 cycles. span style=”font-family:Times New Roman”>976 cases with a mean follow-up of 8 years, and the results showed that CMV neoadjuvant chemotherapy can increase the patient 10 year survival rate from 30% Roman”>30% to 36%. The risk of death was reduced by 16% (HR 0.84, P=0.037).

Side effects and whether they interfere with surgery are important factors in the decision to use neoadjuvant therapy. Based on current clinical data, neoadjuvant chemotherapy mainly caused adverse effects including gastrointestinal reactions, anemia, and leukocyte reduction, and did not increase the rate of postoperative Grade 3-4 complications, and the completion rate of surgery was similar to that of the no-chemotherapy group.

Neoadjuvant immunotherapy

Immune checkpoint [Programmed death protein -1 (programmed death-1, PD – 1)/ programmed death protein ligand -1 (programmed death ligand-1, PD- L1; B7 homologue 1)] inhibitors have been used for second-line treatment of unresectable and metastatic MIBC patients and for first-line treatment of platinum intolerant and PD-L1 positive patients. positive patients with first-line therapy and clinical benefit.

Checkpoint inhibitors alone or in combination with chemotherapy or CTLA-4 checkpoints for neoadjuvant therapy.

Assisted immunotherapy for Phase II II /span>Phase II or Phase III clinical studies are gradually increasing and yielding preliminary results. The data from two of these Phase II trials are encouraging. Results from the Phase II trial with pablizumab showed that patients had complete pathological remission (pT0) of 42% and 54% of patients experienced pathological response (<pT2). The pathologic complete remission rate with atelelizumab treatment was 31%. Immunotherapy has not been approved in neoadjuvant therapy.

MIBC Recommended Principles of Neoadjuvant Therapy

cT2~4aN0M0 Phase MIBC patients, neoadjuvant chemotherapy in combination with radical cystectomy is recommended; neoadjuvant chemotherapy is not recommended for patients who cannot tolerate cisplatin. Neoadjuvant immunotherapy is only available as a clinical trial.

(ii) Radical cystectomy.

Radical cystectomy and pelvic lymph node dissection after neoadjuvant chemotherapy is the standard of care for MIBC. It is an effective treatment option to improve patient survival and avoid local recurrence and distant metastasis.

Indications for radical cystectomy
- without distant metastasesT2～4aN0~x,,M0 periodMIBC.

High-risk NMIBC patients:BCG treatment-naïve tumors; recurrent or multipleT1G3(high-grade) tumors; with carcinoma in situ (Tis) of T1G3(high-grade) tumors;TURBt and extensive papillary tumors that cannot be controlled by bladder irrigation therapy.
- Recurrent postoperative recurrence of NMIBC.
- Pathological types of non-uroepithelial carcinoma of the bladder such as adenocarcinoma and squamous carcinoma.
- Uroepithelial carcinoma with dysplastic histological subtypes.

Indications for salvage (palliative) cystectomy

Include: non-operative treatment failure, tumor failure after bladder preservation therapy or total recurrence, non-uroepithelial cancer (tumor insensitive to chemotherapy and radiotherapy). Also used as a palliative intervention, including patients with fistula formation, pain, and recurrent hematuria.

Contraindications to radical cystectomy
- Bladder cancer that has metastasized distantly.
- People with severe bleeding tendency.

Persons with severe comorbidities (heart, lung, liver, brain, kidney, etc.) and physical inability to tolerate the procedure.
- Start time of radical cystectomy
Patients with MIBC without neoadjuvant chemotherapy are recommended to undergo radical cystectomy within 3 months of diagnosis. span>within 3 months of diagnosis, radical cystectomy is recommended.
- Scope of surgical resection
The classical radical cystectomy includes the bladder and surrounding adipose tissue, the distal ureter, and pelvic lymph node dissection; the prostate and seminal vesicles in men and the uterus, part of the anterior vagina, and adnexa in women. If the tumor invades the urethra, the female bladder neck, or the male prostate, or if intraoperative freezing shows positive margins, total urethrectomy is required.

Sexual-preserving techniques SPC: Partial cystectomy for men with high sexual function requirements Men with high MIBC patients with limited tumor, prostate, prostatic urethra and bladder neck without tumor, may choose to preserve sexual function with

Cystectomy. In men, the choice of preserving the prostate, preserving the prostatic envelope or seminal vesicles (preserving the seminal vesicles, vas deferens, and neurovascular bundle), or simply preserving the neurovascular bundle technique can help improve urinary control and sexual function. In patients who choose to have a neobladder in situ, preservation of the autonomic nerves innervating the urethra can help improve postoperative urinary control.

Female patients with tumors that do not invade the anterior vaginal wall, cervix, or ovaries may choose to preserve the neurovascular bundle as well as the uterus, vagina, and ovaries.

A study of patients undergoing classical radical cystectomy versus radical cystectomy with the SPC technique In a comparative study with a median follow-up of 3 to 5 years, the time to local recurrence, metastasis, disease-specific survival (disease specific survival, DSS), and overall survival were not significantly different between the two groups.

Sexual function-preserving surgery should be performed to ensure radical tumor outcome, and regular postoperative follow-up is required.

Radical cystectomy with preservation of sexual function is not the standard procedure for MIBC, but may be considered for some patients with high demands on sexual function. style=”font-family:Times New Roman”>SPC.

Pelvic lymph node dissection

Pelvic lymph node dissection is both therapeutic and informative in assessing prognosis, and should be performed in conjunction with radical cystectomy.

The risk of lymph node metastasis in patients with NMIBC is 1% to 10%. The risk of lymphatic metastasis in patients with MIBC was 24% or more and correlated with the depth of tumor infiltration (pT2a 9% to 18%, pT2b 22% to 41%, pT3 41%~50%, pT4 41%~63%).

Pelvic lymph node dissection is an important component of radical cystectomy.

Lymph node dissection: two types of lymph node dissection, including standard lymph node dissection and expanded lymph node dissection.
Scope of standard lymph node dissection:92% of bladder lymphatic drainage is located below the plane of the ureter crossing the iliac vessels. At the bifurcation of the common iliac vessels (proximal), the genitofemoral nerve

(lateral), the spinous iliac vein and Cloquet lymph nodes (distal), and the internal iliac vessels (posterior), including the foramen occulta, internal and external iliac lymph nodes, and presacral lymph nodes.
Expanded lymph node dissection: expand upward from the standard lymph node dissection to the abdominal aortic bifurcation, including the iliac vessels The lymph node dissection should be expanded to include the medial iliac vessels, the common iliac vessels, the distal abdominal aorta and the lymphatic fatty tissue around the inferior vena cava, and the presacral lymph nodes. All lymphatic adipose tissue within the area of bilateral clearance should be removed.

Enlarged lymph node dissection does not improve overall survival and recurrence-free survival compared with standard lymph nodes, and postoperative lymphatic cysts increase. Standard pelvic lymph node dissection is recommended for most patients, with expanded lymph node dissection being an option for those with preoperative or intraoperative suspicion of lymph node metastasis.
- Surgical approach to radical cystectomy
There are two types of radical cystectomy: open surgery and laparoscopic surgery, which includes conventional laparoscopic surgery and robot-assisted laparoscopic surgery.

Open surgery is the classic surgical approach.

Conventional laparoscopic surgery requires high operator skill, operative time, overall complications, positive postoperative margins, and lymph node dissection compared with open surgery.

Similar to conventional laparoscopy, it has the advantages of less blood loss, less side effects, less postoperative pain, and faster recovery.

Completely laparoscopic radical total cystectomy and urinary diversion techniques are being explored and are becoming more sophisticated. The equipment and techniques associated with single-port laparoscopy need to be improved.

Complications and survival rates of radical cystectomy

Radical cystectomy is relatively risky, with a perioperative complication rate of approximately 28% to 64% and a perioperative The mortality rate is 2.5% to 2.7%, and the major causes of death include cardiovascular complications, sepsis, pulmonary embolism, liver failure, and hemorrhage.

The 5 year recurrence-free survival and overall survival rates were 68% and 66%, respectively; 10 60% and 43%, respectively, at >year. The 5 year and 10 year overall survival rates for those without pelvic lymph node metastases were 5 year and 10 year, respectively. -family:Times New Roman”>57% to 69% and 41% to 49%, respectively, and tumor-specific survival rates of 67% and 62% , respectively. The overall survival rates for those with pelvic lymph node metastases at 5 years and 10 years were 25% to 35% and 21% to 34% , respectively, and tumor-specific survival rates of 31% and

28%.

(iii) Partial cystectomy.

Partial cystectomy is not the preferred surgical procedure for MIBC patients.

Indications: solitary MIBC located at the top of the bladder (cT2); tumors away from the bladder neck and triangle with adequate surgical margins; no carcinoma in situ; tumors within the bladder diverticulum and patients with severe co-morbidities not suitable for total cystectomy.

Recommended preoperative platinum-based neoadjuvant chemotherapy, partial cystectomy

Concomitant pelvic lymph node dissection. In patients without preoperative neoadjuvant chemotherapy, the decision of adjuvant chemotherapy or adjuvant radiotherapy (peripheral tissue invasion, lymph node metastasis, positive cut margins, pT3~4a) was made based on postoperative pathological findings.

(iv) Uroflow diversion.

Urinary diversion surgery should be performed concurrently with radical cystectomy. There is no standard protocol for urinary diversion, and a variety of options are available, including uncontrolled urinary diversion, controlled urinary diversion, and bowel replacement bladder surgery. The ultimate treatment goal of urinary diversion is to preserve renal function and improve the patient’s quality of life.

Urinary diversion should be carefully selected based on the patient’s age, co-morbidities, life expectancy, history of previous pelvic and abdominal surgery or radiation therapy, the patient’s wishes, and the operator’s skill level. The patient should be informed of the advantages and disadvantages of different diversions, and the patient should choose the specific diversion option.

With the spread of laparoscopic techniques, conventional and robot-assisted laparoscopic procedures are widely used for many types of urethral diversions.

Urinary diversions were previously performed extraperitoneally through a small incision after laparoscopic cystectomy. Currently, laparoscopic or robot-assisted laparoscopic radical cystectomy plus intracorporeal urinary diversions are becoming more established. There are no significant differences in operative time, positive margin rates, or survival rates compared to extracorporeal urinary diversion, but patients recover quickly from postoperative bowel function.

The main types of urethral diversions include the following.

In situ neocystectomy

In-situ neocystectomy is one of the main options for urinary diversion after radical cystectomy because it does not require an abdominal wall stoma and maintains the patient’s quality of life and image.

Ileal neocysts made by end ileal detubation are preferred, such as the Studer bladder, M shaped ileal bladder, Xing’s neobladder, etc. Other procedures include modified U shaped neobladder, IUPU neobladder and other ileal neobladder construction modalities and debanded sigmoid neobladder, but long-term results remain to be seen. The ascending colon, cecum, and stomach have been used relatively infrequently. The postoperative 1 year daily urinary control rate can reach 87% to 96% and nighttime urinary control rates of 72% to 95%.

In situ neobladder should meet the following conditions: (1) intact urethra and good external sphincter function; (2) negative intraoperative urethral resection margin; (3) good renal (3) good kidney function; and (4) no significant intestinal lesions.
Contraindications include high-dose preoperative radiotherapy, complex urethral strictures, inability to care for oneself, and tumor invasion of the bladder neck and urethra.
Complications: approximately 22% of patients develop complications such as varying degrees of urinary incontinence and difficulty in urination, with some patients requiring long-term catheterization or intermittent self-catheterization. Daytime or nocturnal incontinence (about 8% to 10%, respectively, , 20% to 30%); uretero-intestinal anastomotic stenosis (3% to 18%); urinary retention (4% to 12%); metabolic diseases, etc. There is a risk of recurrence of urethral tumors (1.5% to 7%), and if multiple carcinomas in situ or invade the urethra of the prostate, the recurrence rate is about 35%.
- Ileal Channeling

Ileal access is a classic, simple, safe, and effective procedure for uncontrolled urinary diversion, and is the procedure of choice for uncontrolled urinary diversion and is one of the most commonly used. The ileal channel is a classic, safe, and effective uncontrolled urinary diversion procedure.

The main disadvantage is the need for an abdominal wall stoma and lifelong wear of a urinary collection bag.

Early postoperative complications are approximately 48% and include urinary tract infection, hydronephrosis, and uretero-ileal anastomosis leak or stricture. The major distant complications are stoma-related complications

(24%), functional and morphologic alterations of the upper urinary tract (30%). Of the various forms of bowel urinary diversion, ileal access has fewer long-term complications than controlled urinary bladder storage or in situ neobladder.

Patients with short bowel syndrome, inflammatory disease of the small bowel, or extensive radiation exposure to the ileum are not candidates for this procedure. Patients who are unable to use the ileum can be treated with colonic access.

Ureteral skin stoma

Ureteral skin ostomy is a simple and safe procedure.

It is indicated for people with short life expectancy, distant metastases, palliative cystectomy, bowel disease that prevents urinary diversion using the bowel, or a systemic state that does not tolerate the procedure.

The risk of stoma stricture and retrograde urinary tract infection is higher after ureterodermal stoma than after ileal access.

Other methods of urinary diversion are not currently recommended.
- Percutaneous controlled urinary diversion: low-pressure urinary storage reconstructed by bowel detubation

Capsule, anti-reflux ureteral anastomosis, and controlled urinary wall stoma, with intermittent postoperative self-catheterization. This procedure has a high complication rate and has been largely eliminated.

Use of the anal sphincter to control urine: (1) urinary-fecal colectomy, such as ureterosigmoid anastomosis; (2) urinary-fecal colectomy; and (3) urinary-fecal colectomy. (2) urinary-fecal diversion, such as rectal cystectomy. This is rarely done.

Regardless of the type of urinary diversion, postoperative follow-up should be performed periodically for upper urinary tract obstruction, infection, and stones, which should be addressed promptly to protect renal function.

(v) Comprehensive treatment with bladder preservation.

For patients with MIBC who are physically unable to tolerate radical cystectomy or who do not wish to undergo radical cystectomy, comprehensive treatment with bladder preservation is an option. treatment. Patients have better quality of life, physical status, sexual function, and bowel function than those with radical cystectomy.

For patients with a single tumor, no lymph node metastases, no extensive or multifocal carcinoma in situ, no tumor-associated hydronephrosis, and good bladder function prior to treatment.

The basic protocol for the comprehensive treatment of bladder preservation in patients with MIBC: by TURBt to maximize the visible tumor and combine it with a combination of postoperative adjuvant radiotherapy and adjuvant chemotherapy. The patient should be followed closely after surgery, and salvage cystectomy should be performed if necessary.
- Surgical options to preserve the bladder are 2 kinds
Maximal TURBt(complete TURBt, cTURBt) and bladder sections

resection.

MIBC patients treated with a bladder-preserving combination of 5 year overall survival rate was

45% to 73% and 10 year overall survival rates of 29% to 49%.

Current treatments for bladder preservation include the following

(1)TURBt combined with radiotherapy and chemotherapy. Prospective data studies have shown that optimal bladder preservation is difficult to achieve with TURBt, radiotherapy, or chemotherapy alone.

Currently, bladder preservation is mostly treated with a triple combination of surgery combined with radiotherapy and chemotherapy.

(Trimodality therapy, TMT) or multiple combination therapy (Mulitimodality Treatment, MMT). Chemotherapeutic agents are typically cisplatin and mitomycin C plus 5-fluorouracil regimens.

Studies comparing the effectiveness of radical cystectomy with MMT treatment are lacking in quality. conclusions, and data from prospective randomized controlled studies are lacking.

The current study concludes that the use of TMT and radical cystectomy 2 protocols in MIBC patients with DSS and overall survival time were not significantly different. A systematic review including 57 studies and 30 000 patients compared radical cystectomy and TMT efficacy, showing that patients treated with TMT were 10 year overall survival time and DSS improved, but radical cystectomy and TMT were not statistically different from each other. However, retrospective studies have shown that survival in patients undergoing radical cystectomy is significantly better than in patients undergoing external radiation therapy or TMT as compared to those undergoing 2. Roman”>2 options.

The Massachusetts General Hospital study cTURBt combined with radiotherapy and platinum-based chemotherapy in MMT regimen for T2 to 4a stage MIBC patient outcome: median

Follow-up 7.7 years, with a T2 phase complete remission rate of 79%, about 22% of patients required salvage cystectomy. The 5 year and 10 year disease-specific survival rates were 64% and 59%, respectively. The overall survival rates were 52% and 35%, respectively. The efficacy was similar to that of concurrent radical cystectomy.

Another similar study showed a 10 year bladder retention rate of 79%, with overall survival, tumor-specific survival, and metastasis-free survival rates of 43.2%, 76.3% and 79.2%, respectively.

An enrolled 468 cases from the US Radiotherapy Collaborative Group were MIBC patients in a prospective MMT study: follow-up 4.3 years, 69% patients in partial remission, 5 years, 5 years, 10 year tumor-specific survival rates of 71%, 71%, 65%, and overall survival rates of 57% and 36%, respectively.

If combination therapy is not sensitive, early radical cystectomy is recommended.

(2 ) TURBt combination chemotherapy: neoadjuvant chemotherapy combined with cTURBt is a treatment option for some patients with follow-up 56 months, 44% of patients retained their bladders, and 5 year survival rate was 69%. The pathological complete remission rate was 8% to 26%. Complete and partial remission rates for T3/4 stage patients treated with cisplatin-based chemotherapy were 11% and 34%. After 3 cycles of chemotherapy, cystoscopy and biopsy were used to re-evaluate for residual disease; if the disease was still present, salvage total cystectomy was recommended.

A recent study of 1538 cases of a retrospective analysis of MIBC patients treated with TURBt in combination with multidrug chemotherapy, patients 2 year and 5 year overall survival rates of 49% respectively and 32.9%, and the overall survival rates for the cT2 group were 52.6% and 36.2%, respectively. Although

the data suggest that long-term survival with bladder preservation can be achieved in some patients, it is not recommended for routine use.

TURBtCombined external radiation therapy:TURBt Adjuvant postoperative radiotherapy It is primarily indicated as an alternative for patients who are not candidates for radical cystectomy or who cannot tolerate chemotherapy. Studies have shown thatTURBt postoperative combined radiotherapy compared with adjuvant radiotherapy alone has a median survival time of 70 months, better than the latter’s 28.5 months, with better postoperative efficacy in combination with radiotherapy.
simply TURBt: some patients whose tumors are confined to the superficial muscular layer and who are negative for secondary electrodesis of the tumor base can be used, and postoperative procedures BCG bladder perfusion therapy. Because the basal biopsy was pT0 or or pT1 of patients with 20%will progress to MIBC and be forced to undergo total cystectomy, with tumor-specific mortality accounting for 47% and therefore not recommended alone,TURBt as MIBC means of bladder preservation.
Partial cystectomy combined with chemotherapy Although partial cystectomy carries the risk of local tumor implantation, it corresponds to a subset of patients with good compliance who are not suitable for or do not agree to cystectomy MIBC patients, partial cystectomy combined with chemotherapy can be one of the treatment options for MIBC patients.

Partial bladder resection combined with chemotherapy or radiotherapy in patients with MIBC 5 year overall survival rate was 53.7% and progression-free survival rate was 62.1% and about 81.5% successful bladder preservation with good quality of life.

(vi) Adjuvant chemotherapy after MIBC surgery.

The role of postoperative adjuvant chemotherapy in patients with MIBC is not fully defined.

Multiple retrospective studies have shown that adjuvant chemotherapy after total cystectomy delays recurrence and improves overall survival, providing clinical benefit. A Meta meta-analysis in 2014 945 patients with MIBC, showing that MIBC patients treated with postoperative adjuvant chemotherapy had a 23% lower risk of death (HR 0.77, P=0.049), improved tumor-specific survival time, and prolonged overall survival time.

A retrospective study in 2016 5653 cases of pT3~pT4 and /or Patients with total cystectomy with lymph node metastases, postoperatively 23% underwent adjuvant chemotherapy, showing that the adjuvant group 5 year The survival rate was 37% and the chemotherapy group was 29.1%, which prolonged the overall survival time

(HR 0.70, 95% CI 0.06 to 0.76).

There may be selective bias in the analysis of the results of these retrospective studies, and large randomized controlled studies are needed to confirm the survival benefit of adjuvant chemotherapy.

Therefore, based on the results of the current study, there is insufficient evidence for routine adjuvant chemotherapy in patients with MIBC after surgery. Patients with postoperative pathology of ≤pT2 and without lymph node metastasis or lymphovascular invasion are at lower risk and postoperative adjuvant chemotherapy is not recommended. Recommended postoperative pathology is pT3/4 and / or pN+M0), especially postoperative cisplatin-based adjuvant chemotherapy in MIBC patients who did not receive preoperative neoadjuvant chemotherapy and were at high risk of recurrence, improved overall patient survival time. Carboplatin has not shown a survival benefit in adjuvant or neoadjuvant chemotherapy and should not be used in place of cisplatin for adjuvant or neoadjuvant chemotherapy.

(vii) Postoperative adjuvant radiotherapy for MIBC.

pT3~4 stage Radical cystectomy and pelvic lymph node dissection in MIBC patients

The probability of recurrent metastases after radical cystectomy and pelvic lymph node dissection is high and the prognosis is poor, with a 5 year Survival rate is about

10%-50%, and postoperative adjuvant radiotherapy can improve local control rates.

A study of 236 cases of pT3a to pT4a A randomized study of patients with bladder cancer showed improved 5 year recurrence-free rates and local control in patients treated with postoperative adjuvant radiotherapy compared with surgery alone.

Although authoritative data demonstrating that postoperative adjuvant radiotherapy improves patient OS are lacking, it is currently believed that radical pathology after cystectomy or partial cystectomy is pT3/pT4N0 to 2, with residual tumor or cut margins In those with positive tumors or cut margins, pathology of squamous cell carcinoma, adenocarcinoma or carcinosarcoma, small cell carcinoma, and post-palliative resection, postoperative adjuvant pelvic radiotherapy can improve local control and survival and is a reasonable treatment option.

Postoperative radiotherapy includes the cystectomy bed, pelvic lymph nodes, and possible tumor residual areas at a dose range of 45 to 50.4 Gy; depending on the tolerance of normal tissues, the dose can be increased to 54-60 Gy for the extended area around the surgical margins and to 54-60 Gy for the residual tumor area, if necessary. family:Times New Roman”>66~70Gy. For local recurrent tumors, the dose of radiation therapy is 66 to 74 Gy.

(H) Postoperative adjuvant immunotherapy.

Multiple assessments of postoperative adjuvant therapy with immune checkpoint inhibitors (PD-1/PD-L1) Efficacy of The randomized Phase III trials, including atelelizumab, nabritumomab, or pablizumab, are ongoing and have yielded preliminary results, but the specific adjuvant efficacy of these agents requires further follow-up and is currently being used only for clinical participation.

Patients in the trial.

Table 11 Treatment recommendations for patients with MIBC bladder cancer

Bladder Cancer Chemotherapy Recommendations: Recommendation Grade

Neoadjuvant chemotherapy

T2～4aN0M0 preoperative cisplatin-based neoadjuvant combination chemotherapy Strongly recommend neoadjuvant chemotherapy with GC regimen or ddMVAC or CMV regimen Strongly recommend neoadjuvant chemotherapy for patients not suitable for cisplatin-based combination chemotherapy Optional

Surgical treatment

T2-4aN0M0 Preferred radical cystectomy style=”font-family:Times New Roman”>+ pelvic lymph node dissection Highly recommended for tumors invading the male urethral prostate and / or its distal end, female bladder neck and / or

its distal urethra, or a positive surgical urethrotomy margin, total urethrectomy Recommended for comprehensive bladder preservation treatment, with adequate risk communication, good compliance and close follow-up Recommended

TURBt, chemotherapy or concurrent radiotherapy are the main methods of bladder preservation. The main method of comprehensive bladder treatment strongly recommends urinary flow diversion approach requires detailed communication with the patient about the advantages and disadvantages of different procedures Recommended

In-situ neocystectomy and ileal cystectomy are the most commonly used urinary diversions in clinical practice Adjuvant chemotherapy

No neoadjuvant chemotherapy pT3~4 and / or pN+ recommended cisplatin-based chemotherapy Recommended

Adjuvant radiotherapy Optional

pT3~4N0-2, tumor remnants, positive cut margins, squamous carcinoma, adenocarcinoma or carcinosarcoma, small cell carcinoma, etc. Adjuvant immunotherapy Optional

Immune checkpoint inhibitors (PD-1/PD-L1), for patients in clinical trials only

VII. Treatment of metastatic urothelial carcinoma of the bladder

Patients with bladder cancer are diagnosed as about 10% to 15% having metastases, and radical bladder About 50% of patients undergoing radical bladder resection have recurrence or metastasis, with local recurrence accounting for 10% to 30% and the rest The majority are distant metastases.

Uroepithelial cancer cells are sensitive to chemotherapeutic agents such as platinum, gemcitabine, adriamycin, and paclitaxel, and platinum-based combination chemotherapy is the most important and essential treatment for patients with metastatic bladder uroepithelial cancer, with an overall response rate of up to 50%, with an overall survival time of 9-15 months, and a median survival time of 15 months if the patient relapses after chemotherapy. span style=”font-family:Times New Roman”>5 to 7 months.

(A) Resection of oligometastases in patients with metastatic urothelial carcinoma of the bladder.

Several studies have demonstrated the potential clinical benefit of metastasectomy in some patients with metastatic bladder urothelial carcinoma with oligometastases, especially in patients with good response to chemotherapy, solitary metastases, and pulmonary or lymph node metastases.

Oligometastasectomy is indicated for patients with metastases limited to a single organ; fewer than 3 metastases; and a maximum diameter of 5 cm; bladder cancer patients without liver metastases.

Patients with pulmonary oligometastases from urothelial carcinoma of the bladder resected at 3 years and 5 year overall survival rates of 59.8% and 46.5% respectively Roman”>46.5%, with an overall survival rate of 5 years for single metastases 85.7% and 85.7% for multiple metastases and 20% for those with multiple episodes.

A Meta meta-analysis showed that a total of 412 patients with metastatic bladder cancer, oligometastasectomy improved the overall survival time of patients compared with the non-operated group, with 5 year overall survival rate of 28% to 72%, an improvement relative to those for surgery.

The current level of evidence is low and the procedure is difficult, and the right patients must be carefully selected for this procedure.

(ii) First-line treatment options for metastatic urothelial carcinoma of the bladder.

Platinum-based combination chemotherapy regimens are the standard of care for metastatic uroepithelial carcinoma.

The following 2 categories are classified according to the degree of cisplatin tolerance (Table 12).

Patients who can tolerate cisplatin (patients ZPS score 0 to 1 or glomerular filtration rate

> 50~60 ml/min)

Preferred recommendation: gemcitabine in combination with cisplatin; ddMVAC in combination with G-CSF. Second: gemcitabine + paclitaxel + cisplatin is an option.

Patients may choose maintenance therapy with avelumab after chemotherapy.

GC regimen (gemcitabine in combination with cisplatin).

GC regimen is currently the most commonly used standard first-line clinical regimen with fewer adverse effects than MVAC regimen is less severe and has similar efficacy. Generally 4 to 6 cycles.

Recommended Use.

Dosing regimen I: Gemcitabine 1000 mg/m2 day 1, 8 day intravenous drip, cisplatin 70mg/m2 day 2 and cisplatin 2 >day intravenous drip, every 21 days for 1 cycle.

Dosing regimen 2: Gemcitabine 1000 mg/m2th 1, 8, 15 day intravenous drip, cisplatin 70mg/m2 On day 1 or day 2 of intravenous infusion every 28 days for 1 cycle.

A study using the GC regimen and the MVAC regimen for advanced uroepithelial carcinoma stage III

The randomized controlled study showed that 405 patients were enrolled. The efficacy of the two regimens was similar, with objective remission rates of 49.4% and 45.7%, respectively, and median overall survival times were

14.0 months and 15.2 months. The complete remission rate for the GC program was 15% and the partial remission rate was 33% and an extended survival time of 13.8 months. The 5 year overall survival rates for the two groups were 13.0% and 15.3%; progression-free survival rates were 9.8% and 11.3%, respectively. Roman”>11.3%. Adverse effects were relatively small in the GC treatment group.

ddMVAC Program:ddMVAC Program response rate of 46%, with an extended survival time of 14.8 months.

A program that uses ddMVAC and traditional digital digital digital digital digital

family:Times New Roman”>MVAC regimen for the first-line treatment of advanced uroepithelial carcinoma in a Phase III randomized controlled study showed that the objective remission rates in the two groups were 62% and 50%, respectively, with a median progression-free survival of 9.1 months and 8.2 months; median overall survival time was 15.1 months 14.9 months; no significant difference, but ddMVAC regimen had higher chemotherapy drug doses for the same duration However, the ddMVAC regimen was better than conventional MVAC in terms of progression-free survival time and objective remission rate with lower adverse effects and better tolerability.

Another similar Phase III randomized study comparing ddMVAC and standard (28 days) Efficacy of MVAC regimens with a median follow-up 7.3 years. The results showed that ddMVAC survived in 24.6% of patients in the treatment group, which was significantly better than the standard MVAC group (13.2%). Based on these findings, the ddMVAC program has now replaced the traditional MVAC program.

Recommended use: methotrexate 30mg/m2, vincristine 3mg/m2, Doxorubicin 30mg/m2, Doxorubicin 30mg/m2 =”font-size:10pt”>2, cisplatin 70mg/m2, p, p. span style=”font-family:Times New Roman”>1 day intravenous drip and repeated every 2 weeks.

Requires hydration and routine prophylactic application of G-CSF during chemotherapy.

Paclitaxel< +cisplatin+gemcitabine regimen (PCG programs)

A PCG program with GC regimen for the first-line treatment of advanced uroepithelial carcinoma Phase III in a randomized controlled study showed that the objective remission rates in the two groups were 55.5% and 43.6%, respectively, with a median progression-free survival time of 8.3 months and 7.6 months; median overall survival time was

15.8 months 12.7 months; the PCG regimen was more efficient; there was a tendency to improve overall survival time and no increase in adverse events. The PCG regimen is one of the first-line treatment options for metastatic uroepithelium.

Recommended Use: Paclitaxel 80 mg/m2 days 1, 8 intravenous, cisplatin

70mg/m2 th 1 day or 2 day intravenous drip, gemcitabine 1000mg/m2 th 1,

8th day intravenous drip every 21 days for 1 cycle.

Patients who cannot tolerate cisplatin (ZPS score 2 2 “font-family:Arial”>or glomerular filtration rate

30 to 60 ml/min)

Preferred: carboplatin in combination with gemcitabine; post-chemotherapy patients have the option of avelumab maintenance therapy. Atelelizumab or pablizumab, two immunotherapeutic agents for patients with positive PD-L1 expression or intolerance to platinum-based chemotherapy. Next recommendation: gemcitabine + paclitaxel; gemcitabine chemotherapy alone. Exceptional cases may be considered with isocyclophosphamide, adriamycin, and gemcitabine.

(1) Carboplatin in combination with gemcitabine, recommended use: Carboplatin at concentrations – time area under the concentration-time curve, area under the concentration-time curve, area under the concentration-time curve, area under the concentration-time curve. span style=”font-family:Times New Roman”>ACU)

=4.5 calculated on day 1day intravenous drip, gemcitabine 1000mg/m2 th 1, 8 days static

Pulse titration every 21 days for 1 cycle.

(2 ) Gemcitabine in combination with paclitaxel, recommended use: Gemcitabine 1000mg/m2 th 1, 1, 2. span style=”font-family:Times New Roman”>8th day intravenous drip, paclitaxel 80mg/m2 < day 1, 8 day intravenous drip every 21 days for 1 cycle.

(3 ) Gemcitabine monotherapy, recommended use: ① Gemcitabine 1000mg/m2 th 1, 1, 8 day intravenous drip every 21 day for 1 cycle. ② Gemcitabine 1250 mg/m2 th 1 cycle Roman”>1, 8, 15 day intravenous drip per 28 days for 1 cycle.

(4) Immunotherapy: Immunotherapy is applied to target PD-1 or its ligand PD- L1 by blocking PD-1/PD-L1 signaling pathway, using the body’s own immune system to kill cancer cells and improve overall patient survival time.

Immune checkpoint inhibitors represented by PD-1/PD-L1 monoclonal antibodies can significantly improve second-line outcomes in advanced urothelial carcinoma. epithelial cancer in the second line.

Currently, the FDA has approved immunologic drugs, including PD-L1 inhibitors: atelelizumab (atezolizumab), dulvalumab (durvalumab), avelumab (avelumab), etc. PD-1 inhibitors: pabrolizumab

(pembrolizumab), nabolutumab (nivolumab), and others.

Primarily for use in platinum-based combination chemotherapy treated with or progressing within 12 months after treatment Second-line therapy for patients with locally progressive or metastatic uroepithelial carcinoma. Atelelizumab and pablizumab can also be used as first-line therapy for patients with PD-L1 positive advanced uroepithelial carcinoma who are intolerant to platinum-based chemotherapy.

1) First-line immunotherapy in patients tolerant to platinum-based chemotherapy: newly announced 2 phase III trial results (IMvigor130) and the IMvigor130 study (IMvigor130). span>and KEYNOTE 361 studies) in patients with advanced or metastatic uroepithelial bladder cancer tolerant to platinum-based chemotherapy treated with immune checkpoint inhibitors in the first line. In patients with advanced or metastatic bladder cancer who tolerated platinum-based chemotherapy, there was no statistically significant survival benefit in terms of progression-free survival and overall survival time for chemotherapy combined with pablizumab or atelelizumab compared with platinum-based chemotherapy alone.

Immune-checkpoint inhibitors in combination with chemotherapy or IO-IO first-line therapy for patients with advanced bladder cancer who are tolerant to platinum-based chemotherapy are not recommended at this time. chemotherapy in patients with advanced bladder cancer.

②First-line immunotherapy in patients intolerant to platinum-based chemotherapy: a phase II clinical study

(KEYNOTE-052) to evaluate pabrolizumab as first-line therapy for patients with advanced or metastatic disease intolerant to platinum-based patients with advanced or metastatic uroepithelial carcinoma of the urothelium who could not tolerate chemotherapy; a total of 370 cases were enrolled, with an overall effective rate of 24% The total effective rate was 24%, 5% patients achieved complete remission and 19% achieved partial remission. The 6 month overall survival rate was 67%.

Phase II clinical study (IMvigor-210) to evaluate atelelizumab as first-line treatment for patients with locally advanced or metastatic uroepithelial cancer intolerant to platinum-based chemotherapy; a total of 119 cases were enrolled, with an objective remission rate of 23% and complete remission in 9% of patients; the median overall survival time was 15.9 months. The incidence of adverse reactions of Grade 3 and above was 16%.

Recommendation: atelelizumab and pablizumab for patients who are intolerant to platinum-based chemotherapy and PD-L1 first-line therapy for patients with advanced or metastatic uroepithelial carcinoma who are positive for expression

Treatment.

Table 12 First-line treatment for those with locally advanced or metastatic urothelial carcinoma of the bladder

Categories Recommended Treatment Options

Patients who can tolerate cisplatin Gemcitabine in combination with cisplatin, with the option of avelumab maintenance therapy after chemotherapy ddMVAC combined with G-CS, with the option of avelumab maintenance therapy after chemotherapy PCG regimen with avelumab maintenance option after chemotherapy

Patients who cannot tolerate cisplatin

Preferred regimen: carboplatin in combination with gemcitabine, with the option of avelumab maintenance therapy against atelelizumab after chemotherapy,PD-L1 positive expression or intolerance to platinum-based chemotherapy

Pabrolizumab, PD-L1 positive expression or Optional regimen for those who cannot tolerate platinum-based chemotherapy: gemcitabine + paclitaxel

Gicitabine monotherapy

Options: isocyclophosphamide, adriamycin, gemcitabine

(iii) Maintenance therapy after first-line chemotherapy for metastatic urothelial carcinoma of the bladder.

Median progression-free survival time with platinum-based chemotherapy for metastatic bladder urothelial carcinoma is 6 to 9 months, and patients will progress again. Immunotherapy delays recurrence and improves survival time.

Patients with advanced bladder cancer who have received first-line chemotherapy for 4 to 6 cycles and who have stable or objectively effective disease may choose maintenance therapy: patients are recommended to participate in new drug clinical studies first; secondly, avelumab can be chosen and pablizumab can be considered.

Avelumab: APhase IIIRandomized Controlled Study (JAVELIN Bladder

100 study) in patients with advanced uroepithelial carcinoma treated with first-line chemotherapy stabilized and received either avelumab or supportive therapy. The results showed that the median overall survival time for patients in the avelumab group was 21.4 months, which was significantly better than the supportive therapy-only group of 14.3 months

(HR 0.69, P=0.0005), which significantly improved patients’ progression-free survival time by 3.7 months and 3.7 months, respectively, and 2.0 months, with survival benefit in all subgroups of patients. 47.4% of patients experienced grade ≥3 adverse reactions, compared with 25.2%.

Administration: avelumab 10 mg/kg per 2 weekly dosing 1 times.

Pabrolizumab: onePhase IIRandomized Controlled Study108 Patients with advanced uroepithelial carcinoma who were stable after first-line chemotherapy received maintenance treatment with pabrolizumab and placebo. showed that pabrolizumab significantly prolonged progression-free survival by 5.4 months and months, respectively. style=”font-family:Times New Roman”>3 months. The objective remission rates were 23%or 10%. The total survival time was 22 months and 18.7 months, with no statistical difference.

Use: Pabrolizumab 200 mg per 3 weekly dosing 1 times.

(iv) Second-line treatment regimen for metastatic urothelial carcinoma of the bladder.

Immunotherapy based on immune checkpoint inhibitors (PD-1/PD-L1 monoclonal antibody) has been shown to significantly improve the efficiency of second-line therapy in patients with advanced urothelial carcinoma. All patients with metastatic urothelial carcinoma of the bladder are recommended to actively participate in clinical trials of new drugs, and immune checkpoint inhibitors are a priority second-line treatment option for patients (Table 13, Table 14).
- Immunotherapeutics

Tirelizumab: Tirelizumab for second-line treatment after treatment failure in advanced uroepithelial carcinoma, Phase II study results showed: Objective remission rate of 23.1% and a median progression-free survival time of 2.1 months and median overall survival time of

9.8 months. We have approved it for patients with locally advanced or metastatic PD-L1 highly expressed uroepithelial carcinoma who have failed prior platinum-based chemotherapy.

Use: Tirelizumab at 200 mg per 3 weekly dosing 1 times.
Treplexumab: A Treplexumab Treatment for Previously Treated Advanced uroepithelial carcinoma in a Phase IIstage study. Its objective effective rate was 25.2%, with PD-L1 positive patients had an objective remission rate of 39.6%, with a median progression-free survival time of 2.3 months .

Use: Treprolizumab at 3mg/kg per dose. Administer 1 times every 2 weeks.
) Pabrolizumab: onetime =”font-family:Times New Roman”>Phase IIIRandomized Study (KEYNOTE- 045), comparing the efficacy of pabrolizumab with chemotherapy (paclitaxel, docetaxel, vincristine), enrolled a total of 542 Patients with advanced urothelial carcinoma of the bladder who had recurrence or progression after prior platinum-based chemotherapy were enrolled. The results showed that pablizumab significantly improved patient survival compared to the control group, with overall survival times of 10.3 months and months, respectively. span>7.4 months (P=0.002), with objective remission rates of 21.1%and 11.4%. The incidence of adverse reactions in the pablizumab group was 15.0%, which was significantly better than the chemotherapy group

(49.4%). Analysis of the study results with a follow-up of 2 years showed that the pabrolizumab group

had a median duration of remission of 4.4 months compared with the chemotherapy group and a lower incidence of adverse events (62% and 90.6%) for second-line treatment in such patients.

Use: Pabrolizumab at 200mg per 200mg per span style=”font-family:Times New Roman”>3 weekly dosing 1 time.

Atelelizumab: Atelelizumab is FDA approval of the firstPD- L1inhibitor: Phase II The study (IMvigor 210) totaled 310 patients with metastatic uroepithelial carcinoma of the bladder previously treated with platinum, with an overall response rate in the treatment group of 15%, which was significantly higher than the control group 10%(P=0.0058), with a median follow-up 11.7 months, 84%(38/45). Analysis of outcomes after treatment progression showed that: compared with patients treated with other drugs (6.8 months) and no further treatment

(1.2 months) Patients who continued on atelelizumab had a longer overall survival time after progression compared to those who did not receive further treatment (8.6 months).

A multicenter Phase III randomized controlled study (IMvigor211) comparing the efficacy of atelelizumab with chemotherapy (paclitaxel, docetaxel, vincristine). A total of 931 patients with advanced urothelial carcinoma of the bladder who developed recurrence or progression after prior platinum-based chemotherapy. With a median follow-up of 17.3 months, the median overall survival time in the atelelizumab-treated group was 11.1 months, compared with the chemotherapy group (11.1 months). (10.6 months), which was not significantly different from the chemotherapy group (10.6 months)

(P=0.41). Objective remission rates were 23% and 22%, respectively, with no significant difference. Although there was no significant difference in overall survival time between the two groups, the incidence of adverse reactions in the Grade 3 and above in the atelelizumab-treated group was 20%, which was significantly lower than in the chemotherapy group (43%).
Avelumab (avelumab):IIPhase II study: total 249 patients with previous platinum-based drugs The objective remission rate of avelumab treatment was 17% in patients with metastatic urothelial carcinoma of the bladder who were previously treated with chemotherapy that was ineffective or unsuitable for platinum-based therapy. Of these, 6% were in complete remission,11%for partial remission. PD-L1 expressed positive (≥5%) objectively slow

Resolution rate (24%) was significantly better than PD-L1 expression-negative patients (13%). The median overall survival time was 6.5 months and PD-L1 expression-positive patients were 8.2 months and negative for

6.2 months. Progression-free survival was better in PD-L1 expression-positive than in negative (11.9 months and 6.4 months). Grade 3 adverse reactions 8%.

(6 ) Navulizumab: The 6 of Navulizumab family:Times New Roman”>Phase II study

(Checkmate 275):265 patients with metastatic uroepithelial carcinoma of the bladder who had progressed on prior platinum-based therapy, with an objective remission rate of 19.6% and median overall survival time in the treatment group 8.74 months, and the incidence of adverse reactions of Grade 3 and above was 18%. The median overall survival time for patients with PD-L1 expression ≥1% was 11.3 months, significantly better than PD-L1 expression rate <1% patients (5.95 months). Analyzing the most recent data, the minimum follow-up time 37.7 months, the objective remission rate with nabumab monotherapy was 25.6%(95% CI 16.4% to 36.8%), with a sustained remission The median time to

30.5 months.

(7) Dovalizumab: Phase II study analysis 191 cases of PD-L1 Patients positive for surgery or metastatic bladder uroepithelial carcinoma progressing after chemotherapy. The objective remission rate in patients treated with dulcolizumab was 17.8% and PD-L1 high expressers were 27.6%; and 5.1% for those with low or no expression. The median overall survival time was 18.2 months for all patients, PD-L1 high expressers were 20 months. 55% of patients survived at 1 year follow-up.

The latest Phase III clinical study ( DANUBE) results comparing the efficacy of dulvalizumab and chemotherapy for the first-line treatment of advanced uroepithelial carcinoma. The results show that the

The study did not meet the primary endpoint, and the results showed that dulcolizumab alone or in combination with tremelimumab was more effective than chemotherapy. Tremelimumab neither improved overall survival and the results were negative.

Immunotherapy can induce immune-related adverse events (immune-related adverse events, irAE), with common adverse reactions including pruritus, malaise, nausea, diarrhea, lack of appetite, rash, fever, etc., well-tolerated, lethal irAE incidence is 0.64%, which needs to be taken seriously.

Chemotherapy

There are multiple studies showing that docetaxel, paclitaxel, albumin paclitaxel, periflunomide, pemetrexed, gemcitabine + Paclitaxel and other chemotherapeutic agents were used in the second-line treatment of advanced uroepithelial carcinoma and achieved some efficacy, but none of the efficiency rates were high and the evidence grade was low, which needs to be confirmed by further clinical studies.

Targeted drug therapy

Eldatinib is a FGFR inhibitor that has been approved abroad for the presence of FGFR3 or FGFR2 mutations in patients with locally advanced or metastatic uroepithelial cancer who have failed platinum-based chemotherapy.

BLC2001 Study of erdatinib for 99 cases of advanced uroepithelial carcinoma patients with combined FGFR mutations who had failed previous chemotherapy. Their objective remission rate was 40%

(95% CI 31% to 50%), a complete remission rate of 3%, and a disease control rate of 79%, median progression-free survival of 5.5 months, and median overall survival of 13.8 months. Roman”>13.8 months.

Use: Eldatinib tablets: 10 mg each time, daily 1 times orally, and the first 1 to 7

day, followed by a break of 1 week and repeated after each 28 days for one cycle.

Table 13 Second-line treatment (failure of platinum-based chemotherapy) in patients with advanced or metastatic urothelial carcinoma of the bladder

Categories Treatment options

All patients are recommended to participate in clinical trial studies of new drugs

Preferred regimen Immune checkpoint inhibitor Pabrolizumab Alternative preferred regimen: Immune checkpoint inhibitor Naburizumab

Avelumab tirelizumab teraplizumab

FGFR inhibitors udatinib

Optional regimen: paclitaxel or docetaxel gemcitabine monotherapy

Optional regimen (applied based on prior drug therapy).

Isocyclophosphamide, Adriamycin, GemcitabineGemcitabine and Paclitaxel

Gicitabine vs. cisplatin

ddMVAC Joint G-CS

Vincristine or pemetrexed or albumin paclitaxel

Table 14 Advanced or metastatic Second-line treatment for those with urothelial carcinoma of the bladder

(Failure of immune checkpoint inhibitor therapy)

Categories Treatment options

All patients are recommended to participate in the clinical trial study of the new drug in patients who cannot tolerate cisplatin

Preferred regimen: gemcitabine + carboplatin-tolerant cisplatin Patients (no prior chemotherapy).

Preferred regimen: gemcitabine with cisplatin

ddMVAC in combination with G-CS

Optional regimen: eldatinib

Paclitaxel or docetaxel gemcitabine monotherapy

Options: isocyclophosphamide, adriamycin + gemcitabine gemcitabine and + Paclitaxel

(v) Third-line treatment options for metastatic bladder cancer (Table 15).

With the advent of new chemotherapeutic agents, targeted agents, and immune checkpoint inhibitors, there is a significant increase in the number of options available for third-line treatment of advanced bladder cancer, with some success. Active participation in clinical studies with these new agents is recommended for all patients. For patients with no prior immunotherapy, priority is given to immunotherapy with PD-1/PD-L1 monoclonal antibody. Patients who have failed immunotherapy in the presence of FGFR2/3 gene variants may choose erda

Tinib treatment with an objective efficiency of 59%.

The antibody-coupled drug Enfortumab Vedotin (EV) consists of a monoclonal antibody to the tumor surface molecule Nectin-4 with the microtubule-disrupting agent MMAE constitutes.

EV-201 Study EV treatment of 125 cases with prior cisplatin-based chemotherapy or PD- 1/ PD-L1 immune checkpoint inhibitor therapy failed in patients with metastatic uroepithelial carcinoma, the objective remission rate was 44% and the complete remission rate was 12%. Median progression-free survival was 5.8 months, median overall survival was 11.7 months, and duration of remission was 7.6 months, and 54% of patients experienced ≥3 grade compounding side effects. The US has approved EV for the treatment of metastatic uroepithelial carcinoma that has failed cisplatin chemotherapy or failed immunotherapy.

A study comparing EV with single-agent chemotherapy for Phase III RCT preliminary results showed a significant survival benefit. EV in combination with pablizumab as first-line therapy in patients with cisplatin-intolerant locally advanced / metastatic uroepithelial carcinoma The results: The objective remission rate was 73.3% and the complete remission rate was 15.6%.

Use: EV Injectable: 1.25 mg/kg, pp. 1, 8, 15 days, every 28 days is a cycle.

Table 15 Third-line treatment for people with advanced or metastatic urothelial carcinoma of the bladder

Categories Treatment options

All patients are recommended to participate in clinical trial studies of new drugs

Failed prior chemotherapy or immunotherapy: Preferred regimen Erdaﬁtinib (Erdaﬁtinib) /span>)

Enfortumab vedotin

Previously unimmunized (choice of immune checkpoint inhibitor) tirelizumab atelelizumab

Trepleximab Navulizumab Pabrolizumab Dulvalizumab Avelumab

Other options: paclitaxel or doxorubicin

Gemcitabine monotherapy

isocyclophosphamide, adriamycin, gemcitabine gemcitabine and paclitaxel

Gicitabine vs. cisplatin

ddMVAC Union G-CS

(vi) New exploration of immune checkpoint inhibitors.

Current biomarkers predicting whether patients are effective for immunotherapy include PD- L1 expression levels, the bladder cancer molecular typing, tumor mutational load, gene labeling, ZPS score, and metastatic tumor status.

Immune checkpoint inhibitors are mainly used in the second-line treatment of advanced uroepithelial carcinoma and

first-line therapy. A large number of clinical studies are currently underway, including neoadjuvant immunotherapy, adjuvant immunotherapy, combination therapy with other agents, and treatment of patients with NMIBC . It is still in the clinical research phase with the hope of achieving effective results.

VIII. Radiotherapy for bladder cancer

Radiotherapy is one of the treatment options for patients with bladder cancer, but radiotherapy alone is less effective than radical cystectomy combined with pelvic lymph node dissection. Radiotherapy is indicated for patients with MIBC who are unwilling or unable to tolerate radical cystectomy. Radiotherapy is one of the integrated bladder preservation treatments (Table 16).

(i) Preoperative radiotherapy in patients with MIBC.

T3 to 4 or N+ difficult to resect in patients with MIBC, preoperative concurrent chemotherapy Radiotherapy can reduce the size of the tumor and facilitate surgery. 4-6 weeks later, pathological regression up to

(9% to 34% ). The typical radiation dose of preoperative neoadjuvant radiotherapy for MIBC patients is

40~45Gy/4~5 weeks.

Preoperative chemoradiotherapy or radiotherapy has a downstaging effect, but does it reduce the radical cystectomy rate in patients with MIBC . There is a lack of high-quality research evidence on whether local recurrence rates after radical cystectomy in patients with MIBC prolong overall survival. A meta-analysis showed no significant difference in overall survival in MIBC patients treated with preoperative neoadjuvant radiotherapy 5 years.

Currently, conventional preoperative radiotherapy is not recommended.

(ii) Combined treatment with radiotherapy to preserve the bladder.

Integrated treatment of bladder preservation in patients with MIBC via cTURBt combined with GC regimen chemotherapy and radiotherapy was significantly more effective than radiotherapy alone. The 5 year overall survival rate was

48%, with a bladder retention rate of about 70%. Data from the National Cancer Center study showed that patients with MIBC were significantly better treated with concurrent chemoradiotherapy than with radiotherapy alone, with 3 The overall survival rates were 64% and 30%, respectively.

Integrated multidisciplinary bladder preservation therapy with complete tumor remission rate of approximately

60% to 85%, 5 year bladder preservation rate was 40% to 80% and 5 The >year overall survival rate was

50% to 60%. Therefore, for some patients with limited MIBC it can be one of the options in addition to radical cystectomy.

(iii) Radical radiotherapy.

Radical radiotherapy is indicated for patients with MIBC who do not tolerate or undergo cystectomy and is not recommended solely The use of radiotherapy as a means of comprehensive bladder preservation therapy.

Radiation therapy for patients with MIBC is recommended with image-guided intensity-modulated radiotherapy. The target area includes the tumor area, the bladder and part of the urethra, and the pelvic lymphatic drainage area. The recommended dose of radical radiotherapy is 60-66 Gy, with a fractionated dose of 1.8-2.0 Gy. The entire course of treatment will not exceed 6 to 7 weeks. The radiotherapy schedule is: ① 50 to 55Gy in 25 to 28 times (>4 weeks); ② 64~66Gy in 32 to 33 times to complete.

The local control rate of radiotherapy is approximately 30% to 50%, and MIBC patients with 5year overall survival was 40% to 60%, and tumor-specific survival was 60%. =”font-family:Times New Roman”>35% to 40%, and the local recurrence rate is about 30%. Roman”>30%.

(iv) Palliative radiotherapy.

Radiotherapy is one of the palliative treatments to relieve symptoms in patients with advanced bladder cancer. It is indicated for recurrence after conservative treatment has failed and bladder preservation treatment; non-uroepithelial cancer of

Treatment; locally advanced bladder cancer (cT4b, invading the pelvis or abdominal wall) combined with severe hematuria, pain, dyspareunia and urinary tract obstruction, fistula formation.

Palliative radiotherapy can improve the symptoms of hematuria, pain, and bone metastasis pain due to bladder tumors and improve the quality of life. It is effective in 90% of patients, with about 50% having complete relief of symptoms and 22% of patients had an extended overall survival time of 7 months.

Palliative radiotherapy is generally administered with a large split-dose regimen, which can be 30 to 35 Gy/10

times /2 weeks or 30Gy/5~6 times /2~3 week program.

Adverse effects of radiotherapy include radiation cystitis, urethritis, proctitis, small bowel inflammation, bone marrow suppression, and sexual function effects. The overall incidence is 20% to 60%. Severe complications are about 3% to 5% of the effects.

Table 16 Recommendations for radiotherapy in patients with bladder cancer

Recommendation for radiotherapy for bladder cancer patients Recommendation grade

Inoperable MIBC(cT3~4 and / or pN+ ), chemotherapy is an option , and

Combination therapy with simultaneous chemoradiotherapy is highly recommended

Inoperable MIBC(cT3~4 and / or pN+ ), simultaneous chemoradiotherapy downstaging is an option Recommended for single foci (cT2~3N0M0, ≤3cm >, no urinary tract obstruction, no in situ cancer and renal impairment, and

normal bladder volume), with the option of TURBt, chemotherapy, and synchronized chemoradiotherapy for combined treatment Recommended

positive margins, T4N±, pathology of squamous cell carcinoma after palliative resection , adenocarcinoma or carcinosarcoma, the

small cell carcinoma, postoperative radiotherapy or chemoradiotherapy Recommended

locally advanced with pain, hematuria, dyspareunia and bone pain, palliative radiotherapy or chemoradiotherapy Image guided intensity modulated radiotherapy is recommended Strongly recommended

9. Treatment of bladder cancer that cannot be cured

(a) Treatment of patients with stage cT4b with or without positive lymph nodes.

cT4b Stage bladder cancer treatment

Chemotherapy or radiotherapy combined with chemotherapy is the basic treatment for patients with cT4bM0 . . Patients are evaluated after 2 to 3 months of chemotherapy or concurrent chemoradiotherapy. If complete remission is achieved, consolidation chemotherapy or radical radiotherapy or palliative cystectomy can be continued; if tumor residual is still evaluated, it is recommended to change the chemotherapy regimen to continue chemotherapy, palliative cystectomy or radiotherapy. If severe hematuria or ureterorenal effusion is present, palliative cystectomy and urinary diversion may be indicated.

M1a Stage bladder cancer treatment

Systemic chemotherapy or synchronized chemoradiotherapy should be administered. Patients in complete remission may opt for cystectomy or consolidation radiotherapy or close follow-up. Patients in partial remission may be treated with further radiation dose increase or palliative cystectomy or refer to metastatic cancer treatment. Patients with tumor progression refer to the metastatic cancer treatment regimen.

(ii) Treatment of bladder cancer with multiple pelvic lymph node metastases (stage cN2 to 3).

Patients with stage cN2~3 bladder cancer have a poor prognosis and treatment includes chemotherapy or synchronized chemoradiotherapy. Subsequent treatment options are selected based on the outcome of the treatment, taking into account the patient’s specific status. If complete remission is assessed, palliative cystectomy, concurrent chemoradiotherapy, or follow-up may be chosen. If disease progresses, systemic treatment is required for metastatic bladder cancer.

A US study enrolled a total of 1783 cases cN+ bladder cancer patients, divided into chemotherapy-only

treatment group (1388 cases), and chemotherapy combined with radiotherapy group as 395 cases. The results showed that the median overall survival time was 19.0 months for patients who received concurrent chemoradiotherapy, which was significantly higher than that for patients who received chemoradiotherapy alone.

The chemotherapy group 13.8 months ( <0.001).

(iii) Palliative cystectomy.

For patients with surgically incurable locally advanced bladder cancer (T4b), often associated with bleeding, pain dyspareunia and urinary tract obstruction. In patients with bladder cancer with intractable hematuria, palliative cystectomy and urinary diversion are effective treatments if other treatments fail, but the risks of surgery are high.

For locally advanced bladder cancer leading to ureteral obstruction and uremia, palliative cystectomy and ureterostomy or permanent nephrostomy may be an option to relieve the obstruction, improve renal function, and utilize chemotherapy.

(iv) Symptomatic treatment.

Patients with incurable bladder cancer often have the following problems: pain, bleeding, dysuria, and upper urinary tract obstruction. Symptomatic treatment is important.

style=”margin-left: 55pt”>

Upper urinary tract obstruction

Intraureteral stenting is preferred; nephrostomy is effective in resolving upper urinary tract obstruction; if ureteral stenting is difficult to place, urinary diversion (with or without palliative cystectomy) is also an effective measure to relieve upper urinary tract obstruction.

style=”margin-left: 55pt”>

Bleeding and pain

For patients with incurable bladder cancer who present with hematuria, it is important to first determine if the patient has a coagulation disorder or if they are on anticoagulants. If the bleeding is not severe, the bladder can be

Continuous irrigation; if irrigation does not work, intravesical instillation of 1% silver nitrate or silver nitrate can be used. span style=”font-family:Times New Roman”>1% to 2% of Miniso to achieve hemostasis without anesthesia. Transurethral electrocoagulation or laser coagulation may be an option for hemostasis if continuous irrigation is not effective after systematic evaluation. For large bladder tumors, radiotherapy may be chosen to provide hemostasis and analgesia, with hemostasis and analgesia control rates of 59% and 73%, respectively. span>. If bleeding cannot be controlled by any of these methods, bladder artery embolization or cystectomy combined with urinary diversion may be an option.

(v) Recurrence after cystectomy or radiotherapy.

10%-50% of patients with cystectomy will have local recurrence or metastasis, and treatment options include The treatment options include chemotherapy, concurrent radiotherapy, immune checkpoint inhibitor therapy, or radiation therapy, and the different treatment options can be combined to achieve optimal outcomes.

X. Follow up

Patients with bladder cancer who undergo radical cystectomy and urinary diversion must be followed up over time to assess for tumor recurrence, metastasis, and complications associated with urinary diversion.

The risk of recurrence and metastasis after bladder cancer is related to the histopathological type and stage, with the highest incidence at 24 to 36 months postoperatively and a relatively low incidence thereafter. The incidence is highest and relatively low thereafter.

Routine recommendations: pT1 stage patients have annual examinations, blood biochemical tests, chest X-ray, abdominopelvic B ultrasound, CT and / or MRI exams; MRI exams =”font-family:Times New Roman”>pT2 stage patients 6 months for 1 of these examinations; pT3 stage tumor patients every 3 months style=”font-family:Times New Roman”>1 time. For patients with pT2 to pT3 stage tumors should have 1 thoracoabdominopelvic series every 6 months “font-family:Times New Roman”>CT examinations. Imaging of the upper urinary tract is important to rule out ureteral strictures and upper urinary

tract tumors are valuable.

XI. Non-urethral epithelial carcinoma of the bladder

Non-uroepithelial carcinoma of the bladder includes squamous cell carcinoma, adenocarcinoma, and neuroendocrine tumors (small cell carcinoma) of the bladder. The treatment principle is radical cystectomy (Table 17).

(i) Squamous cell carcinoma of the bladder.

Squamous cell carcinoma of the bladder accounts for approximately 2.5% of bladder malignancies. The incidence is slightly higher in women than in men. It can be divided into non-schistosomiasis squamous cell carcinoma of the bladder and schistosomiasis squamous cell carcinoma of the bladder, mainly the former in China.

Chronic inflammation caused by bacterial infection, foreign bodies, chronic lower urinary tract obstruction or bladder stones, bladder mucosal leukoplakia, and long-term indwelling catheters may be associated with the development of squamous cell carcinoma of the bladder.

Squamous cell carcinoma of the bladder most often occurs in the bladder triangle and lateral wall and is usually ulcerated and infiltrated, with about 8% of bladder cases. squamous cell carcinoma is already metastatic at the time of diagnosis.

Hematuria is the main clinical manifestation, and 93% of patients have urinary tract infection. Diagnosis relies primarily on cystoscopy and biopsy to clarify the type of pathology.

The primary treatment is surgical resection, with some patients having the option of radiotherapy. Radical cystectomy is recommended for patients with simple squamous cell carcinoma of the bladder; partial cystectomy is an option for some patients. Radical cystectomy is more effective than radiotherapy. There is a lack of evidence that preoperative neoadjuvant chemotherapy or adjuvant chemotherapy is effective.

Preoperative radiotherapy plus radical cystectomy in high-grade, highly staged patients is more effective than radiotherapy alone.

Radical cystectomy is more effective and helps prevent pelvic recurrence. Postoperative margin positive patients are treated with postoperative radiotherapy; radiotherapy alone is less effective and is not recommended alone.

Combination chemotherapy with paclitaxel, isocyclophosphamide, and cisplatin is an option for some patients with advanced or metastatic squamous cell carcinoma of the bladder, but is ineffective.

The 5 year survival rate for squamous cell carcinoma of the bladder is approximately 25%, with 33% for non-muscle-invasive squamous cell carcinoma and 28% and metastatic squamous cell carcinoma was 6%.

(ii) Adenocarcinoma.

Adenocarcinoma of the bladder accounts for approximately 1.5% of bladder malignancies. There are three types of bladder adenocarcinoma based on tissue origin: primary non-umbilical ureteral adenocarcinoma, umbilical ureteral adenocarcinoma, and metastatic adenocarcinoma. The diagnosis is based on cystoscopic biopsy pathology. Ultrasound, CT and MRI can reveal the size, extent of invasion, and clinical stage of the tumor, especially in the case of ureteral adenocarcinoma. The test can show the size, extent of invasion and clinical stage of the tumor, especially for the umbilical ureter. There is a lack of evidence that preoperative neoadjuvant chemotherapy or adjuvant chemotherapy is effective for patients with bladder or umbilical ureteral adenocarcinoma. The main treatment options are surgical resection and, in some patients, radiotherapy.

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Non-umbilical ureteral adenocarcinoma

Non-umbilical ureteral adenocarcinoma is associated with metastatic epithelial glandular metaplasia. Long-term chronic irritation, obstruction, and bladder ectasia are common causes of metaplasia, often with adenocystitis.

The main symptoms of bladder adenocarcinoma are hematuria, painful urination, bladder irritation, and mucinous urine. The primary bladder adenocarcinoma mostly occurs in the bladder triangle and the lateral wall of the bladder, and the lesions progress

Progression is rapid, mostly MIBC.

Pathologic types are classified as papillary (intestinal), mucinous, indolent, nonspecific, and mixed. Indolent cell adenocarcinoma has a poor prognosis.

Most are locally advanced at the time of clinical presentation, and radical cystectomy is recommended. Transurethral resection or partial cystectomy has poor outcome. Postoperative adjuvant radiotherapy can improve the recurrence-free survival rate. Chemotherapy is an option for patients with progressive and distant metastatic bladder cancer, and a 5-fluorouracil-based regimen is recommended.

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Adenocarcinoma of the umbilical ureter

Adenocarcinoma of the umbilical ureter is associated with epithelial hyperplasia of the umbilical ureter and glandular metaplasia of its underlying metastatic epithelium, which accounts for about 1/3 of adenocarcinomas of the bladder. . Ureteral adenocarcinoma occurs in the anterior wall at the top of the bladder and may infiltrate deep into the bladder wall, umbilicus, retropubic space, and anterior abdominal wall. Ureteral adenocarcinoma is highly staged at diagnosis and has a high risk of distant metastases.

Clinical staging of umbilical ureteral adenocarcinoma: generally using Sheldon staging: Stage I: Tumor is confined to Stage II: localized invasion through the mucosa but limited to the umbilical ureter; Stage III: localized involvement of the bladder, abdominal wall, Stage IV: local lymph node metastasis, distant metastasis.

Treatment of adenocarcinoma of the navel: Surgery is the primary treatment, including partial and radical cystectomy with extended cystectomy combined with pelvic lymph node dissection. Radiotherapy and chemotherapy are not effective.

Enlarged partial cystectomy: the entire parietal bladder, umbilical ureter, and umbilicus are removed, including part of the rectus abdominis muscle, posterior rectus abdominis sheath, peritoneum, and arch line. Postoperative

Recurrence and metastasis are the main causes of treatment failure and usually occur within 2 years postoperatively.

Patients with adenocarcinoma with lymph node metastasis may be referred to a colorectal chemotherapy regimen with FOLFOX (oxaliplatin, folinic acid and 5-fluorouracil) or GemFLP (5- fluorouracil, folinic acid, gemcitabine, and cisplatin) or ITP (paclitaxel, isocyclophosphamide, and cisplatin) regimens.

A US 2 studies have shown that negative surgical margins and metastatic lymph nodes are important prognostic factors. The 5 year overall survival rate was 40% and the mean survival 46 months. Of these, Phase I/II was 10.8 years and III/IV for 1.3 years.

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Metastatic adenocarcinoma

Metastatic adenocarcinoma is a common adenocarcinoma of the bladder with primary lesions in the rectum, stomach, endometrium, breast, prostate, and ovary. The treatment is a combination of treatment based on the primary lesion.

(iii) Small cell carcinoma of the bladder.

Histologically, it is similar to small cell carcinoma of the lung. The tumor is most often found on both sides of the bladder wall and at the base of the bladder. Small cell carcinoma of the bladder is large, averaging about 5 cm. It is highly invasive and easily metastasized. Patients often have deep muscle infiltration at the time of presentation.

The diagnosis of small cell carcinoma of the bladder includes: cystoscopy and biopsy to clarify pathology; imaging to clarify the extent of invasion and whether it has metastasized.

Treatment options are generally a combination of adjuvant chemotherapy or neoadjuvant chemotherapy combined with local therapy. The recommended neoadjuvant or adjuvant chemotherapy regimen for patients with small cell lung cancer of the bladder is to use the chemotherapy regimen for small cell lung cancer, and for patients who can tolerate cisplatin, to choose the cisplatin combination

combined with etoposide for patients who cannot tolerate cisplatin; etoposide combined with carboplatin for patients who cannot tolerate cisplatin. Radical cystectomy or radiotherapy is recommended for local treatment. Neoadjuvant chemotherapy combined with radical total cystectomy has been shown to significantly improve survival. Postoperative adjuvant chemotherapy is recommended for postoperative pathological stages T3 and T4.

Table 17 Recommendations for the treatment of patients with non-urothelial carcinoma of the bladder

Recommendations for chemotherapy of bladder cancer: Recommendation grade

Surgical Treatment

The principle of treatment for non-uroepithelial carcinoma of the bladder is to choose radical cystectomy Highly recommended preoperative radiotherapy for high-grade, high-stage squamous bladder cancer improves prognosis Recommended

elective extended partial cystectomy for umbilical ureteral adenocarcinoma + Pelvic lymph node dissection Highly recommended for non-umbilical ureteral adenocarcinoma Radical cystectomy with adjuvant radiotherapy or / and chemotherapy Optionally recommended T3 , T4 stage small cell carcinoma of the bladder with adjuvant chemotherapy after surgery Recommended

Adjuvant radiotherapy

Tumor remnants, positive cut margins, squamous carcinoma, adenocarcinoma or carcinosarcoma, small cell carcinoma, etc. Recommended

XII.

Health-related quality-of-life studies are now widely used in screening clinical treatments for oncology and evaluating treatment outcomes.

The quality of life assessment of patients with bladder cancer includes physical, emotional, and social activities as well as associated comorbidities (e.g., urinary problems, urinary fistula, skin problems, sexual function problems, etc.). Quality of life is primarily measured by scales. Current bladder cancer
span>, EORTC QLQ-

C30, FACT-BL and FACT-VCI.

Urologists need to give adequate attention to the quality of life associated with bladder cancer patients. The physician should have a thorough discussion with the patient about treatment options and their complications prior to treatment in order to achieve the best quality of life after treatment.

Attachments

Bladder Cancer Treatment Guidelines (2022 Edition) Development and Validation Expert Group

(in surname stroke order)

Group leader: Xing Nianzeng

Members: Wang Tie, Feng Xiaoli, Liu Yulin, Liu Min, Ji Zhigang, Li Xiao, Li Jiongming, Zhang Yong, Zhou Fangjian, Zhou Aiping, Xu Wanhai, Xu Tao, Gao Xianshu, Guan Kaopeng, Zhai Qing, Wei Qiang

Diagnosis and Treatment Guidelines