1 OVERVIEW
Bladder cancer (BC) is globally recognized as the ninth most common malignancy, presenting significant public health challenges and underscoring the necessity for standardized diagnostic and therapeutic protocols, particularly in China, where the disease prevalence is notable. BC treatment strategies are tailored according to the cancer stage, specific pathology, and the overall health of the patient, and it falls into three main categories: non-muscle-invasive bladder cancer (NMIBC), muscle-invasive bladder cancer (MIBC), and metastatic BC.
In preceding sections of the guideline, we have explored BC screening, diagnosis, clinical presentation, the histopathology and staging of urinary tract tumors[
1], and the treatment of NMIBC[
2]. This part of the guideline specifically dwells on MIBC and metastatic BC treatment.
For MIBC, a combination of neoadjuvant chemotherapy and radical cystectomy constitutes the standard care regimen. Patients with locally advanced MIBC may benefit from an integrated approach involving both systemic and local therapy to enhance outcomes, and the necessity for adjuvant chemotherapy or radiotherapy is determined by postoperative pathological findings.
When addressing metastatic BC, systemic treatment, including chemotherapy and immunotherapy, form the cornerstone of care, supplemented by palliative surgery and radiotherapy aimed at symptom management.
2 TREATMENT AND FOLLOW-UP OF MIBC PATIENTS
In recent years, significant progress has been made in the treatment of MIBC through the development of novel drugs and clinical studies. Consequently, the therapeutic strategy for MIBC has evolved into a multifaceted approach, offering a variety of treatment regimens that are meticulously tailored to the particular stages of MIBC.
The leading treatment principles for MIBC patients can be summarized as follows: neoadjuvant chemotherapy in combination with radical cystectomy is the standard treatment regimen for MIBC patients. For those with locally advanced MIBC, an amalgamation of systemic and local therapies is advocated to amplify treatment effectiveness. Meanwhile, the primary management for metastatic MIBC pivots on systemic treatments complemented by supportive care.
Preoperative systemic examinations are conducted to determine the clinical stage of the disease and the presence or absence of metastasis. Chief among the diagnostic tools are chest, abdomen, and pelvic computed tomography (CT)/CT urography or/and magnetic resonance imaging (MRI)/magnetic resonance urography examinations. Additional positron emission tomography-CT scans may be necessary in certain cases.
An array of treatment modalities for MIBC are in clinical use, including, but not limited to, neoadjuvant chemotherapy, radical cystectomy, partial cystectomy, postoperative adjuvant chemotherapy, and comprehensive bladder preservation treatments (Table 1).
2.1 Neoadjuvant therapy
Radical cystectomy is established as the standard intervention for patients with MIBC at the clinical stage of cT2 to T4aN0M0. Despite this, the 5-year overall survival rate hovers around 50%. To enhance treatment outcomes, the use of platinum-based neoadjuvant chemotherapy has been widely adopted. In addition, ongoing research is investigating the potential of neoadjuvant immunotherapy with immune checkpoint inhibitors. The impact of neoadjuvant therapy is notably significant for patients who, posttherapy, show no residual tumor (ypT0) or have a tumor downstaged to at least ypT2.
2.1.1 Neoadjuvant chemotherapy
For MIBC patients at the clinical stage of cT2-4aN0M0, the current recommendation is to employ platinum-based neoadjuvant chemotherapy in conjunction with radical cystectomy. When patients progress to the clinical stage of pT3 to pT4 or present with lymph node metastases, the administration of postoperative adjuvant chemotherapy is advised.
The use of carboplatin as a substitute for cisplatin is not endorsed for patients who are unable to tolerate platinum-based neoadjuvant chemotherapy, due to a scarcity of supporting clinical data. In such scenarios, proceeding with radical cystectomy without prior neoadjuvant therapy is the suggested course of action.
Multiple randomized trials and meta-analyses have shown that platinum-based neoadjuvant chemotherapy can significantly enhance the rate of complete tumor response and prolong the overall survival of MIBC patients. The data indicate a reduction in the risk of death by 10%–13% and an enhancement in the 5-year overall survival rate by 5%–8%. For patients at the clinical stage of cT3, the 5-year survival rate can experience an uplift of up to 11%.
The Southwest Oncology Group study involving 307 MIBC patients demonstrated that neoadjuvant MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin), followed by radical cystectomy, did not lead to an increase in treatment-related mortality. This approach yielded a median overall survival of 77 months, compared to 46 months in the surgery-only group of MIBC patients.
Another meta-analysis of 3005 patients found that platinum-based neoadjuvant chemotherapy significantly boosts the 5-year survival rate by 8% and tumor-specific survival rate by 9%.
The GETUG/AFU V05 trial, which compared the efficacy of ddMVAC with the gemcitabine and cisplatin (CG) regimen for neoadjuvant chemotherapy, found similar pathological response rates (ypT0N0) of 42% and 36%, respectively (p = 0.2).
Commonly used neoadjuvant chemotherapy regimens include
① Gemcitabine combined with cisplatin (GC regimen):
- Regimen 1: Gemcitabine 1000 mg/m2 intravenous infusion on Days 1 and 8, cisplatin 70 mg/m2 intravenous infusion on Day 2. One cycle is completed every 21 days.
- Regimen 2: Gemcitabine 1000 mg/m2 intravenous infusion on Days 1 and 8, cisplatin 70 mg/m2 intravenous infusion on either Day 1 or Day 2. One cycle is completed every 28 days.
Generally, neoadjuvant chemotherapy is administered for four cycles, each consisting of either 21 or 28 days. The 21-day regimen has a shorter treatment duration and may have better compliance with dosing.
② ddMVAC combined with growth factors for 3–4 cycles:
Recommended dosing: methotrexate 30 mg/m2, vinblastine 3 mg/m2, doxorubicin 30 mg/m2, cisplatin 70 mg/m2, administered intravenously on Day 1, repeated every 2 weeks. Given the requirement for hydration during chemotherapy, routine prophylactic use of granulocyte colony-stimulating factor (G-CSF) is recommended.
③ CMV (cisplatin, methotrexate, and vinblastine) regimen: CMV can be used as a first-line neoadjuvant chemotherapy regimen.
Methotrexate 30 mg/m2 and vinblastine 4mg/m2 are administered intravenously on Days 1 and 8, respectively. Cisplatin 100 mg/m2 is administered intravenously on Day 2. One cycle is completed every 3 weeks.
In a multicenter, randomized phase III clinical trial (BA06 30894), 976 patients were enrolled and followed up for an average of 8 years. The results showed that CMV neoadjuvant chemotherapy increased the 10-year survival rate from 30% to 36%. This increment corresponded to a 16% reduction in the risk of mortality (hazard ratio (HR): 0.84, p = 0.037).
The decision to proceed with neoadjuvant therapy is influenced by the potential for side effects and their implications for subsequent surgical procedures. Contemporary clinical data indicates that while neoadjuvant chemotherapy may induce certain adverse reactions such as gastrointestinal issues, anemia, and leukopenia, it does not lead to an increased incidence of severe postoperative complications (Grade 3-4). Furthermore, the likelihood of successfully completing surgery is comparable between patients who receive neoadjuvant chemotherapy and those who do not, reinforcing the viability of this preoperative intervention.
2.1.2 Neoadjuvant immunotherapy
Immune checkpoint inhibitors targeting (programmed death-1 [PD-1] or programmed death ligand-1 [PD-L1; B7 homolog 1]) have been used as a second-line treatment regimen for unresectable and metastatic MIBC patients, as well as a first-line treatment regimen for platinum-intolerant patients with PD-L1 positivity. Both types of treatment regimens have shown clinical benefits.
Phase II and III clinical trials examine their efficacy both as standalone treatments and in combination with other agents like chemotherapy or CTLA-4 inhibitors. These trials are yielding promising results that could redefine presurgical treatment protocols. Data from two Phase II trials have been particularly encouraging. In one trial, the use of pembrolizumab, an immune checkpoint inhibitor, resulted in a complete pathological response (pT0) in 42% of patients, while 54% achieved a pathological downstaging to less than pT2. Another trial with atezolizumab showed a complete pathological response rate of 31%. Despite these optimistic outcomes, it is important to note that immunotherapy has not yet received approval for use as a neoadjuvant treatment.
2.1.3 Principles for recommending neoadjuvant treatment in MIBC
For MIBC patients at the clinical stage of cT2-T4aN0M0, neoadjuvant chemotherapy followed by radical cystectomy is recommended. Neoadjuvant chemotherapy is not recommended for MIBC patients who cannot tolerate cisplatin. Currently, neoadjuvant immunotherapy is only taken into consideration in clinical trials.
2.2 Radical cystectomy
In the wake of neoadjuvant chemotherapy, radical cystectomy, with pelvic lymph node dissection, is the standard treatment regimen for MIBC. This multistep approach is critical in improving survival rates, preventing local recurrence and mitigating the risk of distant metastasis in MIBC patients.
2.2.1 Applicability indications for radical cystectomy
- MIBC T2-T4aN0-x at the clinical stage of M0 without distant metastasis.
- High-risk NMIBC patients: Bacillus Calmette-Guerin (BCG) treatment-resistant tumors; recurrent or multifocal T1G3 (high-grade) tumors; T1G3 (high-grade) tumors with concomitant carcinoma in situ (Tis); extensive papillary tumors that cannot be controlled by transurethral resection of bladder tumor (TURBt) and by bladder instillation therapy.
- NMIBC patients with recurrent postoperative tumors.
- BCs of nonurothelial histology, such as adenocarcinoma or squamous cell carcinoma.
- Urothelial carcinoma with adverse histological subtypes.
2.2.2 Indications for salvage (palliative) cystectomy
Used when nonsurgical treatments are ineffective or when there is tumor recurrence after bladder-sparing therapy; used as a palliative intervention for MIBC patients with urinary diversion, pain, or recurrent hematuria.
2.2.3 Contraindications for radical cystectomy
- BC with distant metastasis.
- Patients with severe bleeding tendencies.
- Patients with severe comorbidities (heart, lung, liver, brain, kidney diseases) or those who are unable to tolerate surgery.
2.2.4 Timing of radical cystectomy
For MIBC patients who do not receive neoadjuvant chemotherapy, it is recommended for them to receive radical cystectomy within 3 months after diagnosis.
2.2.5 Surgical extent
The conventional radical cystectomy procedure entails the surgical excision of the bladder, nearby fat tissue, distal ureters, and pelvic lymph nodes. For male patients, this surgery also typically includes the removal of the prostate and seminal vesicles. In female patients, the uterus, a portion of the anterior vagina, and the adnexa (ovaries and fallopian tubes) are often removed. When a tumor invades the urethra, female bladder neck, or male prostate, or if the intraoperative frozen section reveals positive margins, a complete urethrectomy becomes necessary.
Sexual-preserving techniques (SPC) are an option for MIBC patients who place a high value on maintaining sexual function, and these are feasible when the tumor is localized without involvement of the prostate, prostatic urethra, or bladder neck. In men, SPC methods may conserve the prostate, prostatic capsule, seminal vesicles, and neurovascular bundles, which can play a crucial role in sexual function. For patients opting for an orthotopic neobladder, preserving the innervation of the dominant urethra can improve postoperative urinary control. In female patients, SPC techniques may include the preservation of the uterus, vagina, ovaries, and their associated neurovascular bundles, provided that the tumor does not involve the anterior vaginal wall, cervix, or ovaries.
A comparative study between classic radical cystectomy and SPC techniques showed no significant differences in local recurrence, metastasis, disease-specific survival (DSS), and overall survival after a median follow-up of 3–5 years.
2.2.6 Pelvic lymph node dissection
Pelvic lymph node metastasis stands as a significant prognostic indicator in MIBC, often correlating with poorer outcomes. Pelvic lymph node dissection is performed in tandem with radical cystectomy and serves both as a therapeutic intervention and as a means of prognosis evaluation.
In patients with NMIBC, the risk of lymph node metastasis varies from 1% to 10%. For MIBC patients, this risk increases to over 24% and is closely linked to the depth of tumor invasion, with varying percentages associated with different tumor stages (pT2a: 9%–18%, pT2b: 22%–41%, pT3: 41%–50%, pT4: 41%–63%).
Pelvic lymph node dissection is an essential component of radical cystectomy.
(1) Two types of lymph node dissection: standard lymph node dissection and extended lymph node dissection.
(2) Scope of standard lymph node dissection: 92% of bladder lymphatic drainage is located below the level of the iliac vessels crossing. It includes the bifurcation of the common iliac vessels (proximal), genitofemoral nerve (lateral), obturator lymph nodes, internal and external iliac lymph nodes, and presacral lymph nodes.
(3) Scope of extended lymph node dissection: In addition to the standard lymph node dissection, it extends upward to the bifurcation of the abdominal aorta, including the medial aspect of the ureter at the iliac vessel crossing, the common iliac vessels, the distal abdominal aorta, and the perivascular lymphatic fat tissue surrounding the inferior vena cava and presacral lymph nodes. All lymphatic fat tissue within the bilateral dissection range should be removed.
Compared to standard lymph node dissection, extended lymph node dissection does not significantly impact overall or recurrence-free survival and may raise the risk of postoperative complications such as lymphocysts. Therefore, standard pelvic lymph node dissection remains the recommended practice for the majority of MIBC patients. Extended lymph node dissection can be considered for MIBC patients with suspected lymph node metastasis preoperatively or intraoperatively.
2.2.7 Surgical approach for radical cystectomy
Radical cystectomy can be performed through open surgery or laparoscopic surgery, which includes conventional laparoscopic surgery and robot-assisted laparoscopic surgery. Open surgery is considered the standard approach. Conventional laparoscopic surgery requires the surgeon to possess advanced technical skills. Its operative time, overall complication rate, positive surgical margins, and lymph node dissection efficacy are comparable to open surgery. However, it offers advantages, such as less blood loss, minimal collateral damage, lighter postoperative pain, and faster recovery. Robot-assisted laparoscopic surgery for radical cystectomy allows for even more precise surgical maneuvers and further minimizes blood loss. Fully laparoscopic radical cystectomy and urinary diversion techniques are currently being explored and are gaining maturity in their application. However, the equipment and techniques related to uniportal laparoscopic surgery still require improvement before they can be widely adopted.
2.2.8 Complications and survival rates of radical cystectomy
Radical cystectomy, a mainstay treatment for MIBC, is associated with significant risks. The perioperative complication rate ranges from 28% to 64%, while the perioperative mortality rate lies between 2.5% and 2.7%. The leading causes of perioperative death include cardiovascular events, sepsis, pulmonary embolism, liver failure, and major hemorrhage. The 5-year recurrence-free survival rate and overall survival rate are 68% and 66%, respectively, and at 10 years, 60% and 43%, respectively. For MIBC patients without pelvic lymph node metastasis, the 5- and 10-year overall survival rates range from 57% to 69% and 41% to 49%, respectively. The corresponding tumor-specific survival rates are 67% and 62%. In contrast, patients with pelvic lymph node metastasis have significantly lower survival rates: the 5- and 10-year overall survival rates range from 25% to 35% and 21% to 34%, respectively, with tumor-specific survival rates of 31% and 28%.
2.3 Partial cystectomy
Partial cystectomy is not the preferred surgical approach for most MIBC patients. It is typically reserved for specific circumstances. These indications include the presence of a solitary MIBC lesion located at the dome of the bladder (cT2) with sufficient surgical margins away from the bladder neck and trigone area, absence of associated Tis, tumors within bladder diverticula, and patients who are not suitable for radical cystectomy due to severe comorbidities. For those MIBC patients for whom partial cystectomy is indicated, preoperative platinum-based neoadjuvant chemotherapy is recommended. Additionally, pelvic lymph node dissection should be performed during the partial cystectomy. For patients who did not receive neoadjuvant chemotherapy before surgery, the decision to administer adjuvant chemotherapy or radiotherapy (in cases of local invasion, lymph node metastasis, positive surgical margins, pT3-4a) should be based on the postoperative pathological findings.
2.4 Urinary diversion surgery
Urinary diversion surgery should be performed concurrently with radical cystectomy. Currently, there is no standardized approach for urinary diversion, but various methods are available to choose from, including incontinent urinary diversion, continent urinary diversion, and intestinal bladder substitution (orthotopic neobladder). The primary objectives of urinary diversion are to preserve renal function and enhance the patient's quality of life post-surgery.
The choice of urinary diversion is personalized and should take into consideration various factors, such as the patient's age, comorbidities, life expectancy, prior surgeries, previous radiation treatments, and the surgeon's proficiency. It is critical to engage in comprehensive discussions with the patient to ensure they are well-informed about the benefits and drawbacks of each option, facilitating an informed decision that aligns with their preferences and medical needs.
With the popularization of laparoscopic techniques, both conventional laparoscopic surgery and robot-assisted laparoscopic surgery have been widely used for various urinary diversion procedures.
Traditionally, laparoscopic radical cystectomy was followed by extraperitoneal urinary diversion, which involved creating the urinary diversion externally through a separate incision. Recently, there has been a shift towards performing urinary diversion intracorporeally during laparoscopic or robot-assisted surgeries. This approach has been found to be comparable to extracorporeal diversion in terms of operative time, margin status, and survival outcomes. However, patients undergoing intracorporeal urinary diversion tend to experience more rapid recovery of bowel function postoperatively.
Urinary diversion surgery mainly includes the following types.
2.4.1 In situ neobladder surgery
In situ neobladder surgery has become one of the main methods for urinary diversion after radical cystectomy, as it does not require an abdominal stoma, which can significantly improve a patient's quality of life and self-image.
The construction of a neobladder using the terminal ileum is commonly achieved through various surgical techniques, including the Studer bladder, M-shaped ileal bladder, Xing's neobladder surgery, modified U-shaped neobladder, the Institute of Urology Peking University neobladder, and colonic neobladder without mesenteric attachment. However, the long-term effectiveness of these methods still requires ongoing observation and evaluation.
(1) In situ neobladder should meet the following criteria: Intact urethra and good external sphincter function; negative urethral margins during surgery; good renal function; and no significant intestinal abnormalities.
(2) Contraindications: Include high-dose preoperative radiotherapy, complex urethral strictures, inability to perform self-care, and tumor invasion of the bladder neck and urethra.
(3) Complications: Approximately 22% of patients experience complications, such as varying degrees of urinary incontinence and difficulty with urination. Some patients may require long-term catheterization or intermittent self-catheterization. Daytime and nighttime urinary incontinence occurs in approximately 8%–10% and 20%–30% of patients, respectively. Ureterointestinal anastomotic stricture occurs in 3%–18% of cases, where urinary retention is seen in 4%–12% of patients. Some individuals might face metabolic disorders as a consequence of the urinary diversion. Furthermore, there is a potential risk of postoperative urethral tumor recurrence, which is reported to be between 1.5% and 7%. In cases where there are multiple in-situ BCs or if the prostatic urethra was involved, the recurrence rate can increase to approximately 35%.
2.4.2 Ileal conduit surgery
Ileal conduit surgery is a classic, simple, safe, and effective technique for non-continent urinary diversion, and it is the preferred and most commonly used method for urinary diversion.
The most notable disadvantage of an ileal conduit is the necessity for a permanent stoma and the lifelong dependency on a urinary collection bag. Approximately 48% of patients may face early postoperative complications, such as urinary tract infections, pyelonephritis, and leakage or stenosis at the ureterointestinal anastomosis. Long-term complications include those related to the stoma, which affect about 24% of cases, as well as functional and structural changes in the upper urinary tract, seen in roughly 30% of patients. However, compared to other forms of intestinal urinary diversion like continent reservoirs or in situ neobladders, the ileal conduit typically has fewer long-term complications.
Patients with short bowel syndrome, inflammatory diseases of the small intestine, or extensive radiation exposure to the ileum are not suitable for this procedure. Colonic conduit surgery can be performed in cases where the ileum is not feasible for urinary diversion.
2.4.3 Ureterostomy
Ureterostomy is a simple and safe procedure that is suitable for patients with a short life expectancy, distant metastases, or palliative bladder removal. It may also be considered for patients who are unable to use the intestines for urinary diversion or those deemed medically unfit for surgery. The risk of stoma stenosis and retrograde urinary tract infection after a ureterostomy is higher compared to ileal conduit surgery.
2.4.4 Other urinary diversion methods—not recommended
(1) Percutaneous controllable urinary diversion: This method involves the reconstruction of a low-pressure urinary reservoir using the intestines, an antireflux ureteral anastomosis, and a controllable abdominal wall stoma for urine drainage. Patients need to intermittently self-catheterize for urination after the surgery. It necessitates the patient's intermittent self-catheterization to empty urine. Due to its high complication rate, this method has largely been abandoned in current practice.
(2) Anal sphincter control urinary diversion: This method utilizes the anal sphincter to control urine. It includes procedures such as urinary and fecal diversion, such as ureterosigmoidostomy, and urinary and fecal separation, such as rectal bladder procedures. These methods have fallen out of favor due to significant long-term complications.
Postoperative follow-up is essential regardless of the urinary diversion technique used. Regular monitoring is required to detect any complications such as obstruction of the upper urinary tract, infections, or stone formation. Timely intervention is crucial to prevent deterioration of renal function.
2.5 Comprehensive treatment for bladder preservation
When an MIBC patient cannot tolerate radical cystectomy or chooses not to undergo the procedure, a comprehensive treatment for bladder preservation can be considered. This approach may offer a better quality of life, maintain physical and sexual function, and preserve bowel function when compared to the outcomes following radical cystectomy.
This approach is suitable for patients with a solitary tumor, absence of lymph node metastasis, no widespread or multifocal Tis, and no hydronephrosis related to the tumor. It is also important that the patient has a normally functioning bladder prior to treatment.
The basic approach for comprehensive treatment of bladder preservation in MIBC patients involves maximal transurethral resection of the bladder tumor (concurrent transurethral resection of bladder tumor [cTURBt]) to remove all visible tumors and the use of adjuvant therapies such as postoperative radiotherapy and chemotherapy. Close follow-up is required after surgery, and salvage cystectomy may be performed when necessary.
2.5.1 Two surgical approaches for bladder preservation
- Maximal transurethral resection of the bladder tumor (complete TURBt or cTURBt).
- Partial cystectomy.
The 5-year overall survival rate for MIBC patients undergoing comprehensive treatment for bladder preservation ranges from 45% to 73%, and the 10-year overall survival rate ranges from 29% to 49%.
2.5.2 Other treatment methods for bladder preservation
(1) TURBt combined with radiotherapy and chemotherapy: Prospective data indicate that using any single modality—TURBt, radiotherapy, or chemotherapy alone—does not yield optimal results for bladder preservation. Currently, a trimodality therapy (TMT) or a multimodality treatment (MMT) approach that combines surgery with radiotherapy and chemotherapy is a widely adopted bladder preservation strategy. Chemotherapy regimens in the context of TMT often involve cisplatin and gemcitabine.
While there is a current lack of high-quality studies directly comparing the effectiveness of radical cystectomy with MMT, several studies and systematic reviews have suggested that there is no significant difference in DSS and overall survival between patients treated with TMT and those undergoing radical cystectomy. A systematic review consisting of 57 studies and 30 000 patients compared the efficacy of radical cystectomy and TMT. The findings suggested that TMT could offer extended 10-year overall survival and DSS, with no substantial difference from radical cystectomy outcomes. However, some retrospective studies have indicated superior survival rates for patients who underwent radical cystectomy compared to those receiving TMT or external radiotherapy.
A study from the Massachusetts General Hospital reported that for T2–T4a stage MIBC patients treated with cTURBt combined with radiotherapy and platinum-based chemotherapy, the complete response rate for T2 tumors was 79%, with around 22% of patients later requiring salvage cystectomy. The 5- and 10-year DSS rates were 64% and 59%, respectively, and the overall survival rates were 52% and 35%, respectively, figures that are comparable to those for radical cystectomy.
Another study indicated a 79% bladder preservation rate at 10 years, with overall survival, tumor-specific survival, and metastasis-free survival rates reaching 43.2%, 76.3%, and 79.2%, respectively.
Further, a prospective MMT study by the radiotherapy oncology group in the United States, which included 468 MIBC patients and had a follow-up period of 4.3 years, demonstrated a partial response in 69% of patients. The 5-year and 10-year tumor-specific survival rates were 71% and 65%, respectively, and the overall survival rates were 57% and 36%, respectively.
If an MIBC patient does not respond to TMT or MMT, early radical cystectomy is recommended.
(2) TURBt combined with chemotherapy: Neoadjuvant chemotherapy combined with cTURBt is a treatment option for certain patients. In a study with a follow-up period of 56 months, 44% of patients retained their bladder function, and the 5-year survival rate stood at 69%. The range of complete response rates varied from 8% to 26%. Among patients with more advanced disease (T3/4 stage), those who received platinum-based chemotherapy showed a complete response rate of 11% and a partial response rate of 34%. Following three cycles of chemotherapy, cystoscopy and biopsy are critical to evaluate the presence of residual cancer. If lesions are still present, a salvage radical cystectomy is recommended.
In a retrospective analysis involving 1538 MIBC patients, those who underwent TURBt combined with multidrug chemotherapy experienced 2- and 5-year overall survival rates of 49% and 32.9%, respectively. Specifically, for the cT2 group, the survival rates were 52.6% and 36.2%. Although the data showed that some patients can achieve long-term bladder preservation, routine use of this treatment is not recommended.
(3) TURBt combined with external radiotherapy: Postoperative adjuvant radiotherapy after TURBt is primarily used as an alternative treatment for patients who are not suitable for radical cystectomy or cannot tolerate chemotherapy. Comparative studies have suggested that the combination of TURBt with both radiotherapy and chemotherapy offers a better median survival time (70 months) than TURBt with adjuvant radiotherapy alone (28.5 months).
(4) Simple TURBt: Simple TURBt followed by intravesical BCG therapy is a treatment option for patients whose tumors are confined to the superficial muscle layer and who have negative resection margins at the tumor base. However, it is not recommended as a standalone treatment because 20% of patients with a negative tumor base biopsy (pT0 or pT1) will progress to MIBC and require radical cystectomy. The tumor-specific mortality rate in these cases has been reported at 47%. Therefore, TURBt is recommended as a means of bladder preservation for MIBC.
(5) Partial cystectomy combined with chemotherapy: Although partial cystectomy carries a risk of local tumor implantation, it is a suitable option for MIBC patients deemed medically unfit or do not consent to radical cystectomy. With partial cystectomy combined with chemotherapy or chemoradiation, MIBC patients have been reported to have a 5-year overall survival rate of 53.7% and a progression-free survival rate of 62.1%. Despite the inherent risk of local tumor recurrence associated with partial cystectomy, a significant proportion of patients, approximately 81.5%, were reported to maintain a good quality of life after the procedure, which underscores the role of partial cystectomy as a viable alternative in select cases.
2.6 Adjuvant chemotherapy for MIBC
The role of adjuvant chemotherapy following surgery for MIBC is a topic of ongoing investigation.
Multiple retrospective studies have shown that adjuvant chemotherapy after radical cystectomy can delay recurrence and extend overall survival, providing clinical benefits. A 2014 meta-analysis involving 945 patients who had MIBC suggested that adjuvant chemotherapy after surgery could reduce the risk of death by 23% (HR: 0.77, P = 0.049), indicating a benefit in tumor-specific and overall survival.
Additionally, a retrospective study in 2016 involving 5653 MIBC patients found that those who received adjuvant chemotherapy after radical cystectomy had a 5-year survival rate of 37%, compared to 29.1% for those who did not receive chemotherapy, showing a significant improvement in overall survival (HR: 0.70, 95% confidence interval [CI]: 0.06–0.76).
It is important to note the possibility of selection bias in the above retrospective studies, thus larger randomized controlled trials are necessary to definitively ascertain the benefits of adjuvant chemotherapy in this setting.
Based on current evidence, routine adjuvant chemotherapy for all MIBC patients is not universally recommended. For patients with a lower risk profile, such as those with postoperative pathology of ≤pT2, no lymph node metastasis, or no lymphovascular invasion, adjuvant chemotherapy is generally not advised. However, adjuvant chemotherapy, particularly cisplatin-based, is recommended for patients with a higher risk of recurrence, such as those with postoperative pathology of pT3/4 and/or pN+M0, especially if they have not received neoadjuvant chemotherapy before surgery. This approach can extend the overall survival of these patients. Carboplatin has not shown survival benefits in adjuvant or neoadjuvant chemotherapy and cannot be used as a substitute for cisplatin in adjuvant or neoadjuvant chemotherapy.
2.7 Postoperative adjuvant radiotherapy for MIBC
MIBC patients who have undergone radical cystectomy and pelvic lymph node dissection face a high risk of recurrence and metastasis, with poor prognosis and a 5-year survival rate of approximately 10%–50%. The role of postoperative adjuvant radiotherapy is to improve local control of the disease.
A randomized study that included 236 patients with pT3a to pT4a BC found that postoperative adjuvant radiotherapy improved the 5-year recurrence-free rate and local control when compared to surgery alone.
While concrete evidence is lacking to show a definitive extension of overall survival due to adjuvant radiotherapy, the consensus in the current medical practice is that it can improve local control and survival rates. It is considered a viable treatment option for patients with certain postoperative pathologies such as pT3/pT4N0-2, residual tumors, positive surgical margins, and specific histological types like squamous cell carcinoma, adenocarcinoma, carcinosarcoma, or small cell carcinoma, or in cases of palliative resection.
The postoperative radiotherapy field includes the bladder bed, pelvic lymph nodes, and possible residual tumor areas, with a dose range of 45–50.4 Gy. Depending on the tolerance of normal tissues, the dose can be increased to 54–60 Gy for the surrounding area of surgical margins and up to 66–70 Gy for residual tumor areas. For locally recurrent tumors, the radiotherapy dose is 66–74 Gy.
2.8 Postoperative adjuvant immunotherapy
Several randomized phase III trials are currently underway to evaluate the efficacy of immune checkpoint inhibitors (PD-1/PD-L1) as adjuvant therapy after surgery. These trials include drugs, such as atezolizumab, nivolumab, and pembrolizumab, among others, and have obtained preliminary results. However, the specific efficacy of these drugs as adjuvant therapy requires further validation through rigorous follow-up and larger-scale studies. At present, these drugs are exclusively utilized in clinical trials.
3 TREATMENT OF METASTATIC UROTHELIAL CARCINOMA OF THE BLADDER
Approximately 10%–15% of BC patients are initially diagnosed with metastatic disease. Following radical cystectomy, about half of the patients may experience recurrence or metastasis. Of these recurrences, 10%–30% are local, while the remainder are distant metastases.
Urothelial carcinoma of the urinary tract is generally sensitive to chemotherapeutic agents, such as platinum-based drugs, gemcitabine, doxorubicin, and paclitaxel. Combination chemotherapy regimens based on platinum agents is the most important and fundamental treatment method for patients with metastatic urothelial carcinoma of the bladder. The overall response rate can reach around 50%, and the median overall survival time is 9–15 months. For those patients who do recur after initial chemotherapy, the prognosis is less favorable, with a median survival time of 5–7 months.
3.1 Resection of oligometastases in patients with metastatic urothelial carcinoma of the bladder
Multiple studies have confirmed that the resection of oligometastases in patients with metastatic urothelial carcinoma of the bladder can provide clinical benefits, especially for patients who respond well to chemotherapy, have isolated metastases, and have lung or lymph node metastases.
The criteria for selecting patients for the resection of oligometastases typically include those with fewer than three metastatic sites, all contained within a single organ, each with a maximum diameter of less than 5 cm, and specifically without liver metastases.
For patients undergoing resection of pulmonary oligometastases from bladder urothelial carcinoma, the 3-year and 5-year overall survival rates are 59.8% and 46.5%, respectively. The survival rate significantly favors patients with a single metastasis, at 85.7% over 5 years, compared to a 20% survival rate for those with multiple metastases.
A meta-analysis showed that among 412 patients with metastatic BC, resection of oligometastases could lead to extended overall survival, with a 5-year overall survival rate between 28% and 72%. These rates are relatively better compared to those for patients who did not undergo surgery.
At present, it is important to acknowledge that the level of evidence for related studies is not yet well-established, and the surgical procedure itself is technically challenging. Thus, the selection of patients for such surgeries should be executed with careful consideration, evaluating the risks and benefits on a case-by-case basis.
3.2 The first-line treatment options for metastatic urothelial carcinoma of the bladder
The platinum-based combination chemotherapy regimen is the standard treatment for metastatic urothelial carcinoma of the bladder. It can be categorized into two types based on the tolerance level to cisplatin (Table 2).
3.2.1 Patients who can tolerate cisplatin (with a ZPS score of 0–1 or a glomerular filtration rate >50–60 mL/min)
The first-line treatment recommendation: Gemcitabine in combination with cisplatin; ddMVAC in combination with G-CSF.
The second-line treatment recommendation: Gemcitabine + paclitaxel + cisplatin.
After chemotherapy, patients may choose to receive maintenance treatment with avelumab.
(1) GC regimen (gemcitabine in combination with cisplatin):
The GC regimen is currently the standard first-line treatment regimen. Generally, it is administered for 4–6 cycles and has similar efficacy to the MVAC regimen but milder adverse reactions.
Recommended administration:
Regimen 1: Gemcitabine 1000 mg/m2 administered intravenously on Days 1 and 8, cisplatin 70 mg/m2 administered intravenously on Day 2. Each cycle lasts for 21 days.
Regimen 2: Gemcitabine 1000 mg/m2 administered intravenously on Days 1, 8, and 15, cisplatin 70mg/m2 administered intravenously on Days 1 or 2. Each cycle lasts for 28 days.
In a randomized controlled trial with 405 patients evaluating the efficacy of GC versus MVAC for the first-line treatment of advanced stage III urothelial carcinoma, both chemotherapy regimens showed comparable effectiveness. The study reported the following outcomes: The efficacy of both regimens was similar, with objective response rates of 49.4% and 45.7%, respectively, and median overall survival times of 14.0 and 15.2 months, respectively. Complete response rate for the GC group was 15%, and the partial response rate was 33%, with a median survival time extension of 13.8 months. The 5-year overall survival rates were 13.0% and 15.3% for the GC and MVAC groups, and the progression-free survival rates were 9.8% and 11.3%, respectively. Notably, the GC regimen was associated with relatively fewer adverse reactions compared to MVAC.
(2) The ddMVAC regimen: The response rate of the ddMVAC regimen is 46%, with a prolonged survival time of 14.8 months.
A study comparing the ddMVAC regimen and the traditional MVAC regimen for the first-line treatment of advanced stage III urothelial carcinoma found that the objective response rates were 62% and 50%, respectively. Median progression-free survival was longer for ddMVAC at 9.1 months versus 8.2 months for traditional MVAC. In addition, median overall survival was similar between the two regimens, with ddMVAC at 15.1 months and traditional MVAC at 14.9 months, indicating no significant difference. The ddMVAC regimen had higher chemotherapy drug dosages yet lower adverse reactions, better tolerability, better progression-free survival rates and objective response rates compared to the traditional MVAC regimen.
Further support for ddMVAC comes from another phase III randomized study with a median follow-up of 7.3 years. In this study, the ddMVAC group demonstrated a 24.6% patient survival rate, which was significantly higher than the 13.2% observed in the standard (28 days) MVAC group. Based on these outcomes, the ddMVAC regimen has gained wide acceptance as a replacement for the traditional MVAC regimen.
Recommended administration: Methotrexate 30 mg/m2, vinblastine 3 mg/m2, doxorubicin 30 mg/m2, cisplatin 70 mg/m2, administered intravenously on Day 1, repeated every 2 weeks. Hydration is required, and prophylactic use of G-CSF is recommended during chemotherapy.
(3) Paclitaxel + cisplatin + gemcitabine regimen (PCG regimen):
A randomized controlled study comparing the PCG regimen and the GC regimen for the first-line treatment of advanced Stage III urothelial carcinoma showed the following results: The objective response rates were 55.5% and 43.6%, respectively, the median progression-free survival times were 8.3 months and 7.6 months, respectively, and the median overall survival times were 15.8 months and 12.7 months, respectively. These results indicate that the PCG regimen not only offers a higher response rate but also shows a trend towards improved overall survival, all without an increase in adverse reactions. Consequently, the PCG regimen is considered one of the viable options for the first-line treatment of metastatic urothelial carcinoma.
Recommended administration:
Paclitaxel 80 mg/m2 administered intravenously on Days 1 and 8, cisplatin 70 mg/m2 administered intravenously on Days 1 or 2, gemcitabine 1000 mg/m2 administered intravenously on Days 1 and 8, with a 21-day cycle.
3.2.2 Patients who are unable to tolerate cisplatin (ZPS score of 2 or estimated glomerular filtration rate of 30–60 mL/min)
The first-line treatment option involves a combination of carboplatin and gemcitabine. Following chemotherapy, patients may opt for maintenance therapy with avelumab. Atezolizumab and pembrolizumab, both immunotherapy drugs, are suitable for patients with positive PD-L1 expression or those who cannot tolerate platinum-based chemotherapy.
The second-line treatment recommendations include the use of gemcitabine plus paclitaxel or gemcitabine monotherapy. In special cases, the combination of ifosfamide, adriamycin, and gemcitabine may be considered as an alternative treatment approach.
(1) Recommended administration for carboplatin combined with gemcitabine: Carboplatin is calculated according to the area under the concentration–time curve (ACU) = 4.5, administered intravenously on Day 1, gemcitabine 1000 mg/m2 administered intravenously on Days 1 and 8, with a 21-day cycle.
(2) Recommended administration for gemcitabine combined with paclitaxel: Gemcitabine 1000mg/m2 administered intravenously on Days 1 and 8, paclitaxel 80 mg/m2 administered intravenously on Days 1 and 8, with a 21-day cycle.
(3) Recommended administration for gemcitabine monotherapy:
① Gemcitabine 1000 mg/m2 administered intravenously on Days 1 and 8, with a 21-day cycle.
② Gemcitabine 1250 mg/m2 administered intravenously on Days 1, 8, and 15, with a 28-day cycle.
(4) Immunotherapy: Immunotherapy involves the use of antibodies targeting PD-1 or its ligand PD-L1 to block the PD-1/PD-L1 signaling pathway and leverage the body's immune system to target and destroy cancer cells, improving overall survival in patients. Immune checkpoint inhibitors, represented by PD-1/PD-L1 monoclonal antibodies, significantly improve the efficacy of second-line treatment for advanced urothelial carcinoma.
Currently, the Food and Drug Administration (FDA) has approved several immunotherapy drugs, including PD-L1 inhibitors, such as atezolizumab, durvalumab, avelumab, as well as PD-1 inhibitors such as pembrolizumab and nivolumab. These immunotherapy drugs are primarily used as second-line treatments for patients who have previously received platinum-based chemotherapy or for those who have shown disease progression within 12 months following treatment. Additionally, atezolizumab and pembrolizumab are approved as a first-line treatments for advanced urothelial carcinoma patients who are ineligible for platinum-based chemotherapy and have high PD-L1 expression.
① First-line immunotherapy for patients who can tolerate platinum-based chemotherapy: Recent phase III trials (IMvigor130 and KEYNOTE-361) investigated the use of immune checkpoint inhibitors combined with platinum-based chemotherapy as a first-line treatment for patients who can tolerate such chemotherapy. For patients with advanced or metastatic BC who can tolerate platinum-based chemotherapy, there were no statistically significant differences in progression-free survival or overall survival between the group receiving chemotherapy combined with pembrolizumab or atezolizumab and the group receiving platinum-based chemotherapy alone. No significant survival benefits were found with these combination approaches over chemotherapy alone.
Currently, immune checkpoint inhibitors in combination with chemotherapy, or using two different immunotherapy drugs together (IO-IO), is not recommended as a first-line treatment for advanced BC patients who can tolerate platinum-based chemotherapy.
② First-line immunotherapy for patients who cannot tolerate platinum-based chemotherapy: The KEYNOTE-052 Phase II clinical trial explored the efficacy of pembrolizumab as a first-line therapy for patients with advanced or metastatic urothelial carcinoma who were not candidates for platinum-based chemotherapy. In this trial, which enrolled 370 patients, pembrolizumab achieved an overall response rate of 24%. Complete remission was seen in 5% of patients, and partial remission in 19%. At the 6-month mark, the overall survival rate was reported to be 67%.
A Phase II clinical trial (IMvigor-210) evaluated the use of atezolizumab in a similar patient population. It enrolled 119 patients and reported an objective response rate of 23%, with 9% of the patients reaching complete remission. The median overall survival for participants was 15.9 months, and significant adverse events of Grade 3 or higher were observed in 16% of patients.
Recommendation: Atezolizumab and pembrolizumab can be used as first-line treatments for patients with advanced or metastatic urothelial carcinoma who cannot tolerate platinum-based chemotherapy and have positive PD-L1 expression.
3.3 Maintenance therapy after first-line chemotherapy for metastatic bladder urothelial carcinoma
For patients with metastatic bladder urothelial carcinoma, the median progression-free survival after first-line platinum-based chemotherapy is typically 6–9 months. Subsequent disease progression is common, and this is where immunotherapy has shown potential in delaying recurrence and extending survival.
Patients who have stable disease or an objective response after completing 4–6 cycles of first-line chemotherapy may be candidates for maintenance therapy. Patients are recommended to first participate in clinical trials of new drugs. Alternatively, avelumab or pembrolizumab can be considered for maintenance treatment based on current evidence from clinical studies.
3.3.1 Avelumab
A Phase III randomized controlled study (JAVELIN Bladder100 study) was conducted on patients with advanced urothelial carcinoma of the urinary tract. These patients who had stable disease after first-line chemotherapy. They were either treated with avelumab or supportive care. The results showed that the median overall survival time in the avelumab group was 21.4 months, significantly better than the 14.3 months in the supportive care group (HR: 0.69, p = 0.0005). Avelumab could significantly extend the progression-free survival of patients, which was 3.7 months compared to 2.0 months in the supportive care group. All groups of patients benefited from the treatment. 47.4% of patients experienced Grade 3 or higher adverse reactions, higher than the 25.2% in the control group.
Administration: Avelumab was administered at a dose of 10 mg/kg every 2 weeks.
3.3.2 Pembrolizumab
A Phase II randomized controlled study involved 108 patients who received pembrolizumab or a placebo as maintenance therapy after stable disease post-first-line chemotherapy. The study showed that pembrolizumab significantly prolonged progression-free survival time, which was 5.4 months compared to 3 months with the placebo. The objective response rates were 23% and 10%, respectively. The overall survival were 22 months and 18.7 months for the pembrolizumab and placebo groups, respectively, with no statistically significant difference.
Administration: Pembrolizumab was administered at a dose of 200 mg every 3 weeks.
3.4 Second-line treatment options for metastatic urothelial carcinoma of the bladder
Compared to traditional chemotherapy regimens, the current study shows that immunotherapy, primarily using immune checkpoint inhibitors (PD-1/PD-L1 monoclonal antibodies), can substantially enhance the effectiveness of second-line treatments for advanced urothelial carcinoma of the bladder. All patients with metastatic BC are recommended to actively engage in clinical trials for new medications, while immune checkpoint inhibitors should be considered as a priority second-line treatment option for patients with advanced urothelial carcinoma of the bladder (Tables 3 and 4).
3.4.1 Immunotherapy drugs
(1) Atezolizumab: This is used as a second-line treatment for advanced urothelial carcinoma of the bladder is unresponsive to initial therapies. Phase II trials have demonstrated a 23.1% objective response rate, a median progression-free survival time of 2.1 months, and a median overall survival time of 9.8 months. In China, atezolizumab has been sanctioned for use in patients with locally advanced or metastatic urothelial carcinoma exhibiting high PD-L1 expression after unsuccessful platinum-based chemotherapy.
Administration: Atezolizumab 200 mg per dose, administered every 3 weeks.
(2) Tepotinib: For patients with advanced urothelial carcinoma resistant to previous treatments, a Phase II study revealed an objective response rate of 25.2%, and a notably higher response rate of 39.6% in PD-L1 positive patients, with a median progression-free survival time of 2.3 months.
Administration: Tepotinib 3 mg/kg per dose, administered every 2 weeks.
(3) Pembrolizumab: A Phase III randomized study (KEYNOTE-045) comparing pembrolizumab to chemotherapy (paclitaxel, docetaxel, or vinflunine), in 542 patients with recurrent or progressing advanced bladder urothelial carcinoma after platinum-based chemotherapy, showed that the pembrolizumab significantly extended patient survival compared to that of the control group, with a median overall survival of 10.3 months versus 7.4 months (p = 0.002), and objective response rates of 21.1% and 11.4%, respectively. The incidence of adverse reactions in the pembrolizumab group was 15.0%, significantly lower than in the chemotherapy group (49.4%). Analysis of the study results with a 2-year follow-up showed that the median duration of sustained response was not reached in the pembrolizumab group, while it was 4.4 months in the chemotherapy group, with a lower incidence of adverse reactions (62% and 90.6%, respectively). Pembrolizumab can be used as a second-line treatment for patients with recurrent or progressing advanced bladder urothelial carcinoma after platinum-based chemotherapy.
Administration: Pembrolizumab 200 mg per dose, administered every 3 weeks.
(4) Atezolizumab: It is the first FDA-approved PD-L1 inhibitor. The Phase II IMvigor 210 study, which involved 310 patients with metastatic urothelial carcinoma of the bladder previously treated with platinum-based therapy, observed a 15% overall response rate in the treatment group—a figure notably higher than the 10% reported in the control group (p = 0.0058). With a median follow-up period of 11.7 months, an impressive 84% (38 out of 45) of patients maintained a positive response. Further analysis postdisease progression indicated that those continuing with atezolizumab treatment experienced longer overall survival (8.6 months) compared to those who underwent alternative treatments (6.8 months) or received no subsequent treatment (1.2 months).
The multicenter Phase III IMvigor211 randomized controlled trial compared atezolizumab against chemotherapy agents such as paclitaxel, docetaxel, or vinflunine in 931 patients with recurrent or progressing advanced bladder urothelial carcinoma postplatinum-based chemotherapy. After 17.3 months of median follow-up, the median overall survival did not significantly differ between the atezolizumab group (11.1 months) and the chemotherapy group (10.6 months) (p = 0.41). Objective response rates were similarly close, at 23% for atezolizumab and 22% for chemotherapy, with no significant disparity. Despite the lack of difference in overall survival, the atezolizumab group reported a notably lower incidence of Grade 3 or higher adverse events (20%) compared to the chemotherapy group (43%).
(5) Avelumab: In a Phase II study with 249 patients with metastatic urothelial carcinoma of the bladder who had previously received platinum-based chemotherapy and were either refractory, or who were unfit for platinum-based therapy, the objective response rate was 17%, with complete responses in 6% of cases and partial responses in 11%. The objective response rate was significantly higher in patients with PD-L1 expression ≥5% (24%) compared to those with PD-L1 expression <5% (13%). The median overall survival stood at 6.5 months, but was higher in PD-L1 positive patients at 8.2 months, compared to 6.2 months in PD-L1 negative patients. Furthermore, PD-L1 positive patients exhibited a longer progression-free survival (11.9 months) relative to their PD-L1-negative counterparts (6.4 months). Grade 3 adverse events were reported in 8% of the cases.
(6) Nivolumab: In the Checkmate 275 Phase II study involving 265 patients with metastatic urothelial carcinoma of the bladder who had previously undergone platinum-based therapy and subsequently experienced disease progression, nivolumab treatment yielded a 19.6% objective response rate, with a median overall survival of 8.74 months. Patients with PD-L1 expression ≥1% had a significantly longer median overall survival of 11.3 months compared to those with PD-L1 expression <1%, who had a median overall survival of 5.95 months. Analysis of the latest data with a minimum follow-up of 37.7 months showed an objective response rate of 25.6% (95% CI: 16.4%–36.8%) and a median duration of response of 30.5 months.
(7) Durvalumab: A Phase II study on durvalumab evaluated 191 patients with PD-L1 positive, locally advanced, or metastatic urothelial carcinoma of the bladder who were ineligible for surgery or had disease progression after chemotherapy. The objective response rate was 17.8% overall, with a higher rate of 27.6% in patients with high PD-L1 expression and only 5.1% in those with low or no expression. The median overall survival for all patients was 18.2 months, with a further increase to 20 months for those with high PD-L1 expression. The 1-year survival rate was reported to be 55%.
The latest Phase III clinical study results (DANUBE) comparing durvalumab to chemotherapy as first-line treatment for advanced urothelial carcinoma of the bladder did not reach the primary endpoint. Neither durvalumab alone nor in combination with tremelimumab extended overall survival compared to chemotherapy, and their respective response results were negative.
Immune-related adverse events (irAE) can occur with immune therapy, such as itching, fatigue, nausea, diarrhea, loss of appetite, rash, and fever. Despite these potential side effects, the treatments are generally well-tolerated, with a reported mortality rate of 0.64% related to irAEs.
3.4.2 Chemotherapy
Several studies have indicated that second-line chemotherapy agents like docetaxel, paclitaxel, albumin-bound paclitaxel, gemcitabine, and the combination of cisplatin plus gemcitabine may offer some benefit in treating advanced urothelial carcinoma of the bladder. Although these treatments have shown a certain level of efficacy, the response rates are generally modest, and the quality of evidence supporting their use is not robust. Further clinical study is needed to confirm the findings that so far exist.
3.4.3 Targeted therapy
Erdafitinib is an fibroblast growth factor receptor (FGFR) inhibitor that has been approved for the treatment of locally advanced or metastatic urothelial carcinoma in patients who have previously received platinum-based chemotherapy and have FGFR3 or FGFR2 gene mutations.
The BLC2001 study evaluated the efficacy of erdafitinib in 99 patients with advanced urothelial carcinoma and who had previously failed chemotherapy and had FGFR gene mutations. The objective response rate was 40% (95% CI: 31%–50%), including a complete response rate of 3% and a disease control rate of 79%. Additionally, the median progression-free survival was 5.5 months, and the median overall survival was 13.8 months.
The recommended dosage of erdafitinib is 10 mg once daily for the first 7 days, followed by a 1-week break, and this 14-day regimen should be repeated for 28 days.
3.5 Third-line treatment options for advanced or metastatic BC
The options for third-line treatment of advanced or metastatic BC have significantly increased with the emergence of new chemotherapy drugs, targeted therapies, and immune checkpoint inhibitors, showing some efficacy. It is recommended that patients in this category actively participate in clinical trials of relevant new drugs. For patients who have not received previous immunotherapy, priority is given to PD-1/PD-L1 monoclonal antibody immunotherapy. For patients for whom immunotherapy has failed and who have FGFR2/3 gene mutations, erdafitinib is a viable option with an objective response rate of 59% (Table 5).
The antibody-drug conjugate enfortumab vedotin (EV) consists of a monoclonal antibody targeting the tumor surface molecule nectin-4 and a microtubule-disrupting agent monomethyl auristatin E.
In the EV-201 study, EV was used to treat 125 patients with metastatic urothelial carcinoma who had previously received platinum-based chemotherapy or for whom PD-1/PD-L1 immune checkpoint inhibitors had failed. The objective response rate was 44%, with a complete response rate of 12%. The median progression-free survival was 5.8 months, and the median overall survival was 11.7 months. The duration of response was 7.6 months, and 54% of patients experienced Grade 3 or higher adverse reactions. EV has been approved in the United States for the treatment of metastatic urothelial carcinoma for which platinum-based chemotherapy or immunotherapy has failed.
Preliminary results from a Phase III randomized controlled trial comparing EV with monotherapy chemotherapy showed significant survival benefits. The combination of EV and pembrolizumab as first-line treatment for locally advanced or metastatic urothelial carcinoma patients who were intolerant to platinum resulted in an objective response rate of 73.3% and a complete response rate of 15.6%.
The recommended dosage of EV is 1.25 mg/kg, administered on Days 1, 8, and 15, with a 28-day treatment cycle.
3.6 Exploring new frontiers of immune checkpoint inhibitors
Currently, the prediction of whether patients will respond to immune therapy includes biomarkers such as the expression level of PD-L1, BC molecular subtypes, tumor mutation burden, gene signatures, Zubrod/ECOG/WHO performance status (ZPS) scores, and metastasis status.
Immune checkpoint inhibitors are mainly used for second-line and first-line treatment of advanced urothelial carcinoma. Numerous clinical trials are currently underway, including neoadjuvant immune therapy, adjuvant immune therapy, combination therapy with other drugs, and treatment for NMIBC patients. These approaches are still in the clinical study stage, and are expected to achieve significant response results.
4 RADIOTHERAPY FOR BC
Radiotherapy is one potential treatment method for BC patients, but its efficacy is lower than that of radical cystectomy combined with pelvic lymph node dissection. Radiotherapy is suitable for patients with MIBC who are unwilling or unable to tolerate radical cystectomy. It is one of the comprehensive treatment methods for bladder preservation (Table 6).
4.1 Preoperative radiotherapy for MIBC patients
For MIBC patients with T3-4 or N+ disease who have difficulties with surgical resection, preoperative concurrent chemoradiotherapy can shrink the tumor and facilitate surgery. Pathological downstaging occurs 4–6 weeks later, with a response rate ranging from 9% to 34%. The recommended radiation dose for preoperative chemoradiotherapy is generally 40–45 Gy over 4–5 weeks. Preoperative chemoradiotherapy or radiotherapy can achieve downstaging, but there is a lack of high-quality study evidence on whether it can reduce the local recurrence rate after radical cystectomy in MIBC patients or prolong overall survival. A meta-analysis showed no significant difference in the 5-year overall survival rate for MIBC patients receiving preoperative neoadjuvant radiotherapy.
Routine preoperative radiotherapy is currently not recommended.
4.2 Comprehensive treatment with bladder preservation
In the comprehensive treatment of MIBC patients with bladder preservation, the effectiveness of cTURBt combined with GC chemotherapy and radiotherapy is significantly better than that of radiotherapy alone. The 5-year overall survival rate is 48%, and the bladder preservation rate is approximately 70%. Data from the National Cancer Center show that MIBC patients who receive concurrent chemoradiotherapy have significantly better outcomes than those who receive radiotherapy alone, with 3-year overall survival rates of 64% and 30%, respectively.
Multidisciplinary comprehensive treatment with bladder preservation achieves a complete tumor response rate of approximately 60%–85%, a 5-year bladder preservation rate of 40%–80%, and a 5-year overall survival rate of 50%–60%. Therefore, it can be considered as an alternative option, in addition to radical cystectomy, for selected patients with localized MIBC.
4.3 Radical radiotherapy
Radical radiotherapy is suitable for MIBC patients who are intolerant or unwilling to undergo cystectomy. It is not recommended to use radiotherapy alone as a means of bladder preservation.
Image-guided intensity-modulated radiotherapy is recommended for MIBC patients. The target area includes the tumor region, bladder, partial urethra, and pelvic lymphatic drainage area. The recommended dose for radical radiotherapy is 60–66 Gy, with a fraction dose of 1.8–2.0 Gy. The entire course should not exceed 6–7 weeks. The radiation schedule is as follows:
① Completing a total dose of 50–55 Gy in 25–28 fractions (>4 weeks).
② Completing a total dose of 64–66 Gy in 32–33 fractions.
The local control rate of radiotherapy is approximately 30%–50%, the 5-year overall survival rate for MIBC patients is 40%–60%, the tumor-specific survival rate is 35%–40%, and the local recurrence rate is approximately 30%.
4.4 Palliative radiotherapy
Radiotherapy is one of the palliative treatment options for advanced BC patients to relieve symptoms. It is suitable for the treatment of recurrent disease after failed conservative treatment or bladder preservation, nonurothelial carcinoma, and locally advanced BC (cT4b, involving the pelvic or abdominal wall) with severe hematuria, pain, urinary difficulties, urinary obstruction, or fistula formation.
Palliative radiotherapy can relieve symptoms such as hematuria, pain, and bone metastasis caused by bladder tumors, improving the quality of life. It is effective in 90% of patients, with about 50% experiencing complete symptom relief and a 7-month extension in overall survival for 22% of patients.
Palliative radiotherapy generally uses a hypofractionated scheme, such as 30–35 Gy/10 fractions over 2 weeks or 30 Gy/5–6 fractions over 2–3 weeks. Adverse reactions to radiotherapy include radiation cystitis, urethritis, proctitis, enteritis, bone marrow suppression, and sexual dysfunction, with an overall incidence rate of 20%–60%. Severe complications occur in approximately 3%–5% of cases.
5 TREATMENT FOR INCURABLE BC
5.1 Treatment of cT4b stage BC with or without lymph node involvement
5.1.1 Treatment of cT4b stage BC
Chemotherapy or chemoradiotherapy is the primary treatment for patients with cT4bM0 disease. After chemotherapy or concurrent chemoradiotherapy, patients should be evaluated after 2–3 months. If complete response is achieved, consolidation chemotherapy, radical radiotherapy, or palliative bladder removal surgery can be considered. If tumor residue is still present, it is recommended to switch to a different chemotherapy regimen, continue chemotherapy, or consider palliative bladder removal surgery or radiotherapy, especially in cases of severe hematuria or severe ureteral obstruction with hydronephrosis.
5.1.2 Treatment of M1a stage BC
Systemic chemotherapy or concurrent chemoradiotherapy is recommended. For patients who achieve complete response, treatment options include bladder removal surgery, consolidation radiotherapy and chemotherapy, or close observation. For patients who achieve partial response, increasing the radiation dose, palliative bladder removal surgery, or referring to treatment methods for metastatic cancer can be considered. For patients with disease progression, systemic treatment for metastatic BC should be considered.
A study in the United States included 1783 patients with cN+ BC, with 1388 patients receiving chemotherapy alone and 395 patients receiving concurrent chemoradiotherapy. The results showed that the median overall survival time for patients receiving concurrent chemoradiotherapy was 19.0 months, significantly higher than the 13.8 months for those receiving chemotherapy alone (p < 0.001).
5.2 Treatment of pelvic multiple lymph node metastases in BC (cN2–3 stage)
Patients with cN2–3 stage BC have a poor prognosis. Treatment options include chemotherapy or concurrent chemoradiotherapy. The choice of subsequent treatment depends on the treatment response and the specific condition of the patient. If complete response is achieved, treatment options include palliative bladder removal, concurrent radiotherapy and chemotherapy, or close observation. If the partial response is achieved, treatment options include palliative bladder removal, concurrent radiotherapy and chemotherapy. For patients with disease progression, systemic treatment for metastatic BC should be followed.
5.3 Palliative bladder removal
For patients with locally advanced BC (T4b) and with surgery being not curative, palliative bladder removal and urinary diversion can be an effective treatment method, especially for patients with refractory hematuria. However, the surgical risk is high.
For patients with ureteral obstruction and renal failure caused by locally advanced BC, palliative bladder removal and ureteral stenting or permanent renal fistula construction can be chosen to relieve the obstruction and improve kidney function, with the use of chemotherapy.
5.4 Symptomatic treatment
Patients with incurable BC often experience problems such as pain, bleeding, urinary difficulties, and upper urinary tract obstruction. Symptomatic treatment is important.
5.4.1 Upper urinary tract obstruction
Preferred options include ureteral stents or nephrostomy to relieve the obstruction. If ureteral stent placement is difficult, urinary diversion (with or without palliative bladder removal) can also be effective.
5.4.2 Hematuria and pain
For patients with incurable BC presenting with hematuria, it is important to determine if the patient has any coagulation disorders or is taking anticoagulant medications. If the bleeding is not severe, continuous bladder irrigation can be performed. If irrigation is ineffective, intravesical instillation of 1% silver nitrate or 1%–2% alum solution can be used for hemostasis without the need for anesthesia. For patients who do not respond to continuous irrigation after a thorough evaluation, transurethral electrocoagulation or laser coagulation can be considered for hemostasis. In cases of large bladder tumors, radiotherapy can be chosen to achieve hemostasis and pain relief, with control rates of 59% for hemostasis and 73% for pain relief, respectively. If none of the above methods are effective in controlling bleeding, options such as bladder arterial embolization or bladder removal with urinary diversion can be considered.
5.5 Recurrence after bladder removal or radiotherapy
A total of 10%–50% of patients may experience local recurrence or metastasis after bladder removal surgery. Treatment options include chemotherapy, concurrent chemoradiotherapy, immune checkpoint inhibitors, or radiotherapy. Various treatment options can be combined for optimal therapeutic effects.
6 FOLLOW-UP
Patients who undergo radical cystectomy and urinary diversion for BC must undergo long-term follow-up to assess tumor recurrence, metastasis, and complications related to urinary diversion.
The risk of BC recurrence and metastasis after surgery is related to histological type and stage, with the highest occurrence rate in the first 24–36 months postsurgery and relatively lower rates thereafter.
Routine recommendations include annual examination, blood tests, chest X-ray, abdominal and pelvic ultrasound, CT, and/or MRI for patients with stage pT1. Patients with stage pT2 should undergo the same examinations every 6 months. Patients with stage pT3 tumors should undergo examinations every 3 months. For patients with stage pT2 to pT3 tumors, chest, abdomen, and pelvic CT scans should be performed every 6 months. Upper urinary tract imaging is valuable for ruling out ureteral strictures and upper urinary tract tumors.
7 BLADDER NONUROTHELIAL CARCINOMA
Bladder nonurothelial carcinoma mainly includes squamous cell carcinoma, adenocarcinoma, and neuroendocrine tumors (small cell carcinoma). The treatment principle is primarily radical cystectomy (Table 7).
7.1 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 females. It can be classified into nonschistosomiasis-associated squamous cell carcinoma and schistosomiasis-associated squamous cell carcinoma, with the former being more common in China.
Chronic inflammation caused by bacterial infection, foreign bodies, chronic lower urinary tract obstruction, bladder mucosal leukoplakia, long-term indwelling catheters, and other factors may be associated with the development of squamous cell carcinoma of the bladder.
Squamous cell carcinoma of the bladder often occurs in the trigone and sidewall of the bladder, and typically presents as ulceration and infiltration. Approximately 8% of squamous cell carcinomas of the bladder are diagnosed with metastasis.
Hematuria is the main clinical manifestation, with 93% of patients having urinary tract infections. Diagnosis is mainly based on cystoscopy and histopathological biopsy.
The leading treatment is surgical resection, although some patients may be treated with radiotherapy. Radical cystectomy has better efficacy than radiotherapy and is recommended, but partial cystectomy can be considered in select cases. Currently, there is a lack of evidence for the effectiveness of neoadjuvant or adjuvant chemotherapy before surgery.
For high-grade and advanced-stage patients, neoadjuvant radiotherapy followed by radical cystectomy is more effective than radical cystectomy alone and helps prevent pelvic recurrence. Postoperative radiotherapy is recommended for patients with positive surgical margins, while standalone radiotherapy is not recommended due to poor efficacy.
For some advanced or metastatic squamous cell carcinoma of the bladder patients, combination chemotherapy with paclitaxel, ifosfamide, and cisplatin can be considered, although the response rate is low.
The 5-year survival rate for squamous cell carcinoma of the bladder is approximately 25%, with non-muscle-invasive squamous cell carcinoma having a 33% survival rate, muscle-invasive carcinoma having a 28% survival rate, and metastatic squamous cell carcinoma having a 6% survival rate.
7.2 Adenocarcinoma
Adenocarcinoma accounts for approximately 1.5% of bladder malignancies. Bladder adenocarcinoma can be classified into three types based on the tissue of origin: Primary nonurachal adenocarcinoma, urachal adenocarcinoma, and metastatic adenocarcinoma. Diagnosis is mainly based on histopathological biopsy obtained through cystoscopy. Ultrasound, CT, and MRI can provide information on tumor size, extent of invasion, and clinical staging, especially for urachal adenocarcinoma. Currently, there is a lack of evidence regarding the effectiveness of neoadjuvant or adjuvant chemotherapy in bladder adenocarcinoma or urachal carcinoma. The leading treatment option is surgical resection, although radiotherapy may be considered for some patients.
7.2.1 Nonurachal adenocarcinoma
Nonurachal adenocarcinoma is associated with glandular metaplasia of the transitional epithelium. Long-term chronic irritation, obstruction, and bladder diverticulum, often accompanied by glandular cystitis, are common causes of metaplasia. The main symptoms of bladder adenocarcinoma are hematuria, dysuria, bladder irritability, and mucous urine. Primary bladder adenocarcinoma mostly occurs in the trigone area and lateral walls of the bladder, with rapid disease progression and most cases being MIBC.
Pathological types include papillary (intestinal type), mucinous type, signet ring cell type, nonspecific type, and mixed type. Signet ring cell adenocarcinoma has a poor prognosis. At the time of clinical presentation, most cases are already in the advanced stage, and radical cystectomy is recommended. Transurethral resection or partial cystectomy have poor efficacy. Postoperative adjuvant radiotherapy can enhance the tumor recurrence-free survival rate. Patients with advanced or metastatic bladder adenocarcinoma can choose chemotherapy, and a chemotherapy regimen based on 5-fluorouracil is recommended.
7.2.2 Urachal adenocarcinoma
Urachal adenocarcinoma is associated with urachal epithelial hyperplasia and metaplasia of the urachal lining, accounting for about 1/3 of bladder adenocarcinomas. Urachal adenocarcinoma occurs in the top anterior wall of the bladder and can invade the deep layers of the bladder wall, urachus, retroperitoneal space, and anterior abdominal wall. Urachal adenocarcinoma is often diagnosed at an advanced stage and carries a high risk of distant metastasis.
Clinical staging of urachal adenocarcinoma is generally done using the Sheldon staging scheme. Stage I: Tumor is confined to the urachal mucosa; Stage II: Local invasion is present beyond the mucosa but confined to the urachus; Stage III: There is local involvement of the bladder, abdominal wall, peritoneum, and other adjacent organs; Stage IV: Occurrence of local lymph node metastasis and distant metastasis.
The leading treatment option for urachal adenocarcinoma is surgery, including partial or radical cystectomy, along with pelvic lymph node dissection. Radiotherapy and chemotherapy have limited effectiveness.
Extended partial cystectomy involves the complete removal of the urachal mucosa, urachus, and bladder dome, including part of the rectus muscle, posterior sheath of the rectus muscle, peritoneum, and the arcuate line. Postoperative recurrence and metastasis are the main reasons for treatment failure, usually occurring within 2 years after surgery.
For patients with lymph node metastasis, chemotherapy regimens used for colorectal cancer can be considered, such as FOLFOX (oxaliplatin, folinic acid, and 5-fluorouracil) or GemFLP (5-fluorouracil, folinic acid, gemcitabine, and cisplatin) or ITP (paclitaxel, ifosfamide, and cisplatin) regimens.
Two studies from the United States have shown that negative surgical margins and lymph node involvement are important prognostic factors, with a 5-year overall survival rate of 40% and an average survival of 46 months. The average survival time is 10.8 years for Stages I/II and 1.3 years for Stages III/IV.
7.2.3 Metastatic adenocarcinoma
Metastatic adenocarcinoma is a common type of bladder adenocarcinoma, with primary lesions originating from the rectum, stomach, endometrium, breast, prostate, ovaries, and other sites. Treatment primarily focuses on managing the primary cancer through comprehensive treatment.
7.3 Bladder small cell carcinoma
Bladder small cell carcinoma is histologically similar to small cell carcinoma of the lung. Tumors are often found in the lateral walls and base of the bladder. Bladder small cell carcinoma tends to have larger tumor size, with an average of about 5 cm. It is highly invasive and prone to metastasis. Patients often present with infiltration of the deep muscle layer at the time of diagnosis.
The diagnosis of bladder small cell carcinoma includes cystoscopy and biopsy to confirm the pathology, as well as imaging examinations to determine the extent of invasion and presence of metastasis.
The treatment options generally involve a comprehensive treatment plan combining adjuvant chemotherapy or neoadjuvant chemotherapy with local treatment. For patients with bladder small cell carcinoma, the recommended neoadjuvant or adjuvant chemotherapy regimens are those used for small cell lung cancer. Patients who can tolerate cisplatin are recommended to receive cisplatin in combination with etoposide, while patients who cannot tolerate cisplatin are recommended to receive etoposide in combination with carboplatin. Radical cystectomy or radiotherapy is recommended for local treatment. Studies have shown that neoadjuvant chemotherapy combined with radical cystectomy significantly enhances survival rates. For patients with postoperative pathological staging of T3 or T4, adjuvant chemotherapy is recommended.
8 QUALITY OF LIFE IN BC PATIENTS
The exploration of health-related quality of life (HRQoL) is increasingly central in clinical oncology, serving not only to guide treatment selection but also to appraise treatment outcomes.
Evaluating the quality of life in BC patients necessitates a comprehensive look at their physical, emotional, and social well-being, in addition to any treatment-related complications such as urinary issues, urinary fistulas, skin conditions, and sexual dysfunction. Quality of life assessments are primarily conducted through the use of standardized questionnaires, with FACT, EORTC QLQ-C30, FACT-BL, and FACT-VCI being among the most prevalent tools employed in studies of BC patients.
To promote the quality of life for these individuals, it is crucial that physicians engage in comprehensive discussions with patients prior to treatment. These conversations should cover the spectrum of available treatment options and the potential complications associated with each, ensuring that patients are well-informed and able to make decisions that align with their personal values and quality-of-life considerations.
The end.
This English version was translated from the Chinese version, “Guidelines for Diagnosis and Treatment of Tumor and Blood Related Diseases (version 2022)” released by the General Office of the National Health Commission of the People's Republic of China. The copyright of the English version has been obtained. If there is any conflict in the information, the Chinese version shall prevail. See the Chinese version at the website of the National Health Commission of the People's Republic of China.
2024 The Authors. UroPrecision published by John Wiley & Sons Australia, Ltd on behalf of Higher Education Press.
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