Neoadjuvant therapy for localized muscle-invasive urothelial carcinoma of the bladder

INTRODUCTION — Most patients with muscle-invasive urothelial bladder cancer are treated with neoadjuvant therapy followed by radical cystectomy. (See "Radical cystectomy".)

Some patients treated with neoadjuvant therapy and radical cystectomy who are still at high risk for disease recurrence may be candidates for adjuvant therapy. (See "Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder".)

The approach to neoadjuvant therapy followed by radical cystectomy for localized muscle-invasive urothelial bladder cancer is presented here. Bladder preservation treatment options for muscle-invasive urothelial bladder cancer and the management of advanced unresectable and metastatic urothelial bladder cancer are discussed separately.

●(See "Bladder preservation treatment options for muscle-invasive urothelial bladder cancer".)

●(See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract".)

PRETREATMENT EVALUATION — All patients with a pathologic diagnosis of urothelial cancer of the bladder (ie, bladder cancer) should undergo pretreatment evaluation to determine clinical disease stage, which in turn influences treatment options and prognosis. Clinical staging for bladder cancer is based upon the American Joint Committee on Cancer (AJCC) eighth edition tumor node metastasis staging system (table 1). (See "Clinical presentation, diagnosis, and staging of bladder cancer", section on 'Staging'.)

The pretreatment evaluation typically includes cystoscopy with transurethral resection of bladder tumor to confirm muscle-invasive (T2 or greater) (figure 1) disease and imaging studies to assess the extent of disease, including lymph node involvement and distant metastases. Further details on the diagnostic evaluation of bladder cancer are discussed separately. (See "Clinical presentation, diagnosis, and staging of bladder cancer", section on 'Initial evaluation'.)

NEOADJUVANT THERAPY — Selecting patients for neoadjuvant therapy is based on clinical disease stage as well as patient comorbidities and preferences.

Patient selection — For most patients with localized muscle-invasive urothelial bladder cancer (ie, T2-T4a, N0, M0) (figure 1 and table 1), we recommend neoadjuvant (ie, preoperative) cisplatin-based systemic therapy rather than upfront radical cystectomy, as this approach improves overall survival (OS). (See 'Rationale' below.)

Exceptions include the following groups:

●Ineligible for neoadjuvant cisplatin-based chemotherapy – Patients who are ineligible for neoadjuvant cisplatin-based chemotherapy (table 2) may be offered radical cystectomy followed by adjuvant therapy as indicated (algorithm 1). (See "Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder", section on 'No prior neoadjuvant chemotherapy'.)

●Ineligible for radical cystectomy – Patients who are ineligible for or wish to forego radical cystectomy (eg, to preserve their native bladder) may alternatively receive trimodality therapy (TMT) with maximal transurethral resection of bladder tumor followed by concurrent chemotherapy and radiation therapy (RT). (See "Bladder preservation treatment options for muscle-invasive urothelial bladder cancer", section on 'Patient selection'.)

Patients who complete neoadjuvant systemic therapy may subsequently be evaluated for radical cystectomy, based on their treatment response. (See 'Assessing response to neoadjuvant therapy' below.)

Rationale — In patients with localized muscle-invasive bladder cancer, the addition of neoadjuvant therapy to radical cystectomy improves OS and disease-free survival (DFS) [1-7].

As an example, a meta-analysis (Advanced Bladder Cancer [ABC] Collaboration) of 11 randomized clinical trials that included 3005 patients with localized muscle-invasive bladder cancer evaluated the addition of neoadjuvant platinum-based combination chemotherapy to local therapy (either radical cystectomy or curative-intent RT) [4,5]. Compared with local therapy alone, neoadjuvant platinum-based chemotherapy improved five-year OS (hazard ratio [HR] 0.86, 95% CI 0.77-0.95) and DFS (HR 0.78, 95% CI 0.71-0.86). This OS benefit of adding neoadjuvant chemotherapy to radical cystectomy for localized muscle-invasive bladder cancer (T2-T4a disease) was also confirmed in a subsequent meta-analysis [8].

Preferred neoadjuvant regimens

Selection of therapy — For most patients who are undergoing neoadjuvant (ie, preoperative) systemic therapy, have good Eastern Cooperative Oncology Group (ECOG) performance status (<2) (table 3), and are eligible for cisplatin-based therapy (table 2), we suggest either dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dose-dense MVAC (table 4)) or gemcitabine plus cisplatin (table 5), rather than other systemic regimens.

The optimal neoadjuvant regimen for muscle-invasive bladder cancer is not established. Selecting between dose-dense MVAC and gemcitabine plus cisplatin is based upon patient age, comorbidities, and preferences; treatment benefits and toxicity profiles; and the provider's clinical experience with administering each regimen. As an example, for medically fit, cisplatin-eligible patients (table 2), either regimen is appropriate. However, for older adults or those with significant comorbidities, gemcitabine plus cisplatin (using either standard dosing or a split dose of cisplatin (table 5)) may be preferred, since dose-dense MVAC may cause significant treatment-related toxicity and therefore may not be well-tolerated in these populations.

Observational studies initially suggested that neoadjuvant dose-dense MVAC was associated with improved OS compared with neoadjuvant gemcitabine plus cisplatin [9,10]. However, subsequent randomized trials demonstrated similar pathologic complete response (pCR) rates [11-14]. Randomized trials are also conflicting as to which regimen is superior for progression-free survival (PFS) and OS. One randomized phase II trial (SWOG S314) demonstrated similar OS benefit between the two regimens. By contrast, in a larger randomized phase III trial (GETUG/AFU V05 VESPER), dose-dense MVAC (administered either as neoadjuvant or adjuvant therapy) demonstrated a nonstatistically significant trend towards higher PFS and OS relative to gemcitabine plus cisplatin in the entire study population [12,15]. In a subgroup analysis of patients who received neoadjuvant therapy followed by radical cystectomy, dose-dense MVAC also improved PFS and OS over gemcitabine plus cisplatin [12,15]. Despite these PFS and OS benefits in patients treated with neoadjuvant dose-dense MVAC, this regimen is often associated with significant treatment-related toxicity (eg, anemia, nausea and vomiting, and generalized weakness). As a result, most patients were unable to complete all planned six cycles of dose-dense MVAC.

Dose-dense MVAC was compared with gemcitabine plus cisplatin in an open-label phase III trial (GETUG/AFU V05 VESPER) [11,12,15,16]. In this study, 500 patients with muscle-invasive bladder cancer were randomly assigned to either six cycles of dose-dense MVAC or four cycles of GC administered before or after radical cystectomy; 493 patients were included in the intention to treat population. Among the 437 patients (88 percent) with clinical T2 to T4a, node-negative disease treated with neoadjuvant chemotherapy, approximately 90 percent underwent cystectomy. The remaining 56 patients with pT3, pT4, or pathologic node positive disease (12 percent) received adjuvant therapy after cystectomy. The median patient age for both treatment arms was 63 years old, which is younger than that of the average real-world patient with bladder cancer (median 73 years old) [17,18]. Results for this trial were as follows [12,15]:

●Neoadjuvant therapy – Among the subgroup of 437 patients treated with neoadjuvant therapy, relative to gemcitabine plus cisplatin, dose-dense MVAC improved PFS (three-year PFS 66 versus 56 percent, HR 0.7, 95% CI 0.51-0.96 [12], five-year PFS 61 versus 52 percent, HR 0.74, 95% CI 0.55-0.99 [15]), improved OS (five-year OS 66 versus 57 percent, HR 0.71, 95% CI 0.52-0.97), and improved disease-specific survival (DSS; five-year DSS 76 versus 62 percent, HR 0.55, 95% CI 0.39-0.78) [15].

●All patients – For the entire study population, relative to gemcitabine plus cisplatin, dose-dense MVAC (administered in either the neoadjuvant or the adjuvant setting) demonstrated a nonstatistically significant trend towards higher PFS, the primary study endpoint (three-year PFS 64 versus 56 percent, HR 0.77, 95% CI 0.57-1.02 [12], five-year PFS 59 versus 51 percent, HR 0.78, 95% CI 0.59-1.02 [15]) and towards higher OS (five-year OS 64 versus 56 percent, HR 0.79, 95% CI 0.59-1.05) [15].

Dose-dense MVAC improved five-year disease-specific survival (DSS; 73 versus 60 percent, HR 0.61, 95% CI 0.45-0.84) relative to gemcitabine and cisplatin [15] and improved time to progression (69 versus 58 percent, HR 0.68, 95% CI 0.5-0.93) [12].

There was no significant difference in the pCR rate between the two chemotherapy regimens (42 versus 36 percent) [11]. However, dose-dense MVAC increased local control rates over gemcitabine plus cisplatin, including non-muscle-invasive (<ypT2pN0; 63 versus 49 percent) and organ-confined disease (<ypT3pN0; 77 versus 63 percent) [11,12].

●Adjuvant therapy – Data were inconclusive for those who received adjuvant therapy due to the very limited number of patients.

●Toxicity – Grade ≥3 toxicities were higher for dose-dense MVAC compared with gemcitabine plus cisplatin, including anemia (22 versus 8 percent), nausea and vomiting (10 versus 3 percent), and asthenia/generalized weakness (14 versus 4 percent) [11]. Only 60 percent of patients completed the planned six cycles of dose-dense MVAC due to toxicity [12]. Three deaths occurred among those treated with dose-dense MVAC due to sudden death, pulmonary embolism, and septic shock [11].

Dose-dense MVAC and gemcitabine plus cisplatin were also compared in a separate randomized phase II SWOG S1314 trial (Co-expression Extrapolation [COXEN]) of 237 patients with muscle-invasive bladder cancer. The median age of this patient population was 65 years old. Among the 167 evaluable patients, dose-dense MVAC had similar pCR rates (28 versus 30 percent), OS (HR 0.87, 95% CI 0.54-1.4), and event-free survival (HR 0.86, 95% CI 0.59-1.26) compared with gemcitabine plus cisplatin [13,14]. Further results of this trial from subgroup analyses based on gene expression profiling are discussed separately. (See 'Gene expression profiling' below.)

Dose-dense MVAC — Dose-dense MVAC is one of the preferred neoadjuvant regimens for localized muscle-invasive bladder cancer.

Dose-dense MVAC (table 4) is administered as methotrexate (30 mg/m² on day 1), vinblastine (3 mg/m² on day 2), doxorubicin (30 mg/m² on day 2), and cisplatin (70 mg/m² on day 2), with growth factor support every 14 days for four to six cycles.

Activity for neoadjuvant dose-dense MVAC was initially demonstrated in several nonrandomized phase II studies of patients with muscle-invasive bladder cancer [19,20]. The use of this regimen in the neoadjuvant (or preoperative) setting is further extrapolated from data in patients with advanced or metastatic urothelial carcinoma. In a randomized phase III trial (European Organisation for Research and Treatment of Cancer [EORTC] 30924) of 263 patients with advanced urothelial carcinoma, dose-dense MVAC demonstrated a nonstatistically significant trend towards higher OS compared with classic dosing of MVAC. Dose-dense MVAC also improved PFS, reduced toxicity, and shortened the total treatment duration compared with classic dosing of MVAC [21,22]. Further details of this study are discussed separately. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract", section on 'Dose-dense MVAC'.)

The efficacy of dose-dense MVAC versus gemcitabine plus cisplatin in the neoadjuvant setting is discussed separately. (See 'Selection of therapy' above.)

Gemcitabine plus cisplatin — Gemcitabine plus cisplatin is one of the preferred neoadjuvant regimens for muscle-invasive bladder cancer.

Neoadjuvant gemcitabine plus cisplatin (table 5) is administered as gemcitabine (1000 mg/m² on days 1, 8) plus cisplatin (70 mg/m² on day 1) every 21 days for a maximum of four cycles [23].

Patients with a creatinine clearance between 50 and 60 mL/minute may be offered gemcitabine (1000 mg/m² on days 1, 8) plus split-dose cisplatin (35 mg/m² on days 1, 8) every 21 days for a maximum of four cycles [24,25]. (See 'Patients with impaired kidney function' below.)

Prior to initiating neoadjuvant therapy, patients with kidney dysfunction should be evaluated for malignant obstruction of the ureters. Placement of a ureteral stent or a percutaneous nephrostomy tube can temporarily improve obstruction and the associated kidney dysfunction and may subsequently allow the administration of neoadjuvant gemcitabine and full-dose cisplatin. (See 'Patients with impaired kidney function' below.)

Activity for neoadjuvant gemcitabine plus cisplatin was initially demonstrated in observational studies [26] and initial clinical trials [24,25]. Similar to the way that MVAC regimens were initially introduced in the neoadjuvant setting, the use of gemcitabine plus cisplatin in the neoadjuvant setting is further extrapolated from data in metastatic bladder cancer. In a randomized phase III trial of 405 patients with metastatic urothelial carcinoma, gemcitabine plus cisplatin was similarly effective and less toxic compared with classic MVAC [27,28]. Further details of this study are discussed separately. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract", section on 'Gemcitabine plus cisplatin'.)

Data comparing gemcitabine plus cisplatin with dose-dense MVAC in the neoadjuvant setting are discussed separately. (See 'Selection of therapy' above.)

Neoadjuvant regimens not used

Carboplatin-based therapy — We do not administer neoadjuvant carboplatin-based therapy due to lack of a randomized trial in the neoadjuvant setting. In addition, most studies in patients with metastatic bladder cancer suggest that carboplatin is inferior to cisplatin.

Observational studies suggest similar activity for neoadjuvant carboplatin-based chemotherapy compared with cisplatin-based therapy [29]. However, prospective clinical trials in patients with advanced or metastatic urothelial carcinoma suggest that carboplatin is inferior to cisplatin [30-32] or have not directly compared it with cisplatin-based therapy [33]. As examples:

●In a randomized trial of 47 patients with inoperable advanced bladder cancer, the objective response rate with M-CAVI regimen (carboplatin, vinblastine, methotrexate) was lower than that of classic MVAC, a cisplatin-based regimen (39 versus 52 percent) [32].

●Similarly, in phase II trials of patients with advanced or metastatic bladder cancer, single-agent carboplatin has demonstrated low objective response rates (less than 15 percent) and limited OS [30,31].

Other regimens

●Classic MVAC – Classic MVAC (table 6) is no longer used as neoadjuvant therapy for muscle-invasive bladder cancer, since other regimens are available that are more effective and better tolerated [34].

The addition of neoadjuvant therapy with classic MVAC to radical cystectomy improved OS in a randomized trial (INT-0080) [1]. However, a subsequent randomized trial (EORTC 30924) demonstrated that dose-dense MVAC had similar OS benefit with less toxicity than classic MVAC in patients with metastatic disease [21]. (See 'Dose-dense MVAC' above.)

Additionally, observational studies have not demonstrated a difference in pCR rates between neoadjuvant classic MVAC and gemcitabine plus cisplatin [35,36], a regimen with less toxicity. (See 'Gemcitabine plus cisplatin' above.)

●CMV – Methotrexate, vinblastine, cisplatin, and leucovorin (CMV) is a less preferred neoadjuvant regimen for muscle-invasive bladder cancer.

In a randomized phase III trial, the addition of neoadjuvant CMV to local therapy (radical cystectomy or RT) improved OS at a median follow-up of eight years (HR 0.84, 95% CI 0.72-0.99) [6,7]. However, other better-tolerated regimens are available.

●No role for neoadjuvant radiation therapy (RT) – We do not use neoadjuvant RT as a single modality prior to radical cystectomy in patients with localized muscle-invasive bladder cancer.

Initial studies suggested that neoadjuvant RT alone could eradicate disease in a small proportion of patients undergoing cystectomy [37,38]. However, in subsequent randomized trials, the addition of neoadjuvant RT to radical cystectomy improved local control but failed to improve OS [39,40].

Timing — Neoadjuvant therapy should be initiated as soon as possible to avoid delays in curative intent therapy, typically within eight weeks of the diagnosis of bladder cancer [41,42]. In an observational study of 2227 patients with localized muscle-invasive bladder cancer, a delay in neoadjuvant therapy of eight weeks or more from diagnosis was associated with more advanced disease stage at radical cystectomy, including the development of positive lymph nodes [41].

SPECIAL POPULATIONS

Patients with impaired kidney function — Prior to initiating neoadjuvant therapy, patients with bladder cancer who present with impaired kidney function should be evaluated for a malignant obstruction of the ureters. Kidney tract obstruction is a commonly encountered problem among patients with bladder cancer, especially if the tumor is located adjacent to one or both ureteric orifices. Patients with an obstruction require intervention (ie, ureteral stent placement or a percutaneous nephrostomy tube) as an attempt to restore normal kidney function, which could then allow for the administration of standard doses of cisplatin. (See "Placement and management of indwelling ureteral stents" and "Percutaneous nephrostomy tubes".)

For patients with impaired kidney function who do not have malignant obstruction (or those with persistently impaired kidney function despite appropriate interventions for malignant obstruction), our approach is as follows:

●For those with creatinine clearance between 50 and 60 mL/min, we suggest neoadjuvant gemcitabine plus split-dose cisplatin (table 5) rather than gemcitabine plus full-dose cisplatin or other systemic regimens, based on limited data [24,25]. Intravenous hydration should also be administered. (See "Cisplatin nephrotoxicity", section on 'Intravenous saline'.)

We do not substitute neoadjuvant carboplatin for cisplatin, as data suggest that carboplatin is inferior to cisplatin. (See 'Carboplatin-based therapy' above.)

●Patients with creatinine clearance less than 50 mL/min are ineligible for neoadjuvant (or preoperative) cisplatin-based therapy (table 2). Such patients who are surgical candidates may be offered radical cystectomy followed by adjuvant therapy as indicated (algorithm 1). Further details are discussed separately. (See "Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder", section on 'No prior neoadjuvant chemotherapy'.)

Trimodality therapy (TMT) is an appropriate alternative for those who are not surgical candidates or decline radical cystectomy (eg, to preserve their native bladder). Further details are discussed separately. (See "Bladder preservation treatment options for muscle-invasive urothelial bladder cancer", section on 'Patient selection'.)

ASSESSING RESPONSE TO NEOADJUVANT THERAPY — Patients who complete neoadjuvant therapy are assessed for treatment response with a contrast-enhanced computed tomography (CT) of the chest, abdomen, and pelvis. Gadolinium-enhanced magnetic resonance imaging (MRI) of the abdomen and pelvis is an alternative for abdominal imaging in those who are unable to receive CT contrast agents. These imaging studies are also used to assess for the development of distant metastases. Patients with symptoms concerning for disease progression (eg, pain, persistent hematuria, worsening urinary symptoms) should receive restaging imaging studies sooner (ie, within two cycles of therapy).

●Patients with stable or improved locoregional disease and no evidence of metastatic disease may proceed to evaluation for radical cystectomy. Radical cystectomy is ideally performed no sooner than three weeks but no later than six weeks after neoadjuvant therapy is completed, if the patient has recovered from systemic therapy and their performance status permits surgery. This timing minimizes any surgical delays that could temper the clinical benefits of neoadjuvant therapy, including improved disease control and survival [43].

Further details on the surgical approach to radical cystectomy for bladder cancer are discussed separately. (See "Radical cystectomy".)

●Patients with progressive locoregional disease and no metastatic disease may be evaluated for immediate radical cystectomy upon recovery from neoadjuvant therapy. Trimodality therapy (TMT; radiation therapy [RT] with concurrent chemotherapy) is an appropriate alternative for patients with muscle-invasive bladder cancer. (See "Radical cystectomy" and "Bladder preservation treatment options for muscle-invasive urothelial bladder cancer".)

●Patients with progressive locoregional disease that cannot be controlled with local therapy (surgery or RT) or those with distant metastases should be offered systemic therapy. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract".)

We do not offer observation or less extensive surgical approaches after completion of neoadjuvant therapy. Although neoadjuvant therapy results in high clinical response rates, persistent disease can still be present, which can only be confirmed on the postoperative surgical specimen [44]. Patients who decline radical cystectomy in favor of observation or less intensive surgical therapies (eg, transurethral resection of bladder tumor or partial cystectomy) are also at higher risk for disease recurrence and inferior survival outcomes [45,46]. (See "Radical cystectomy", section on 'Prognostic factors for survival'.)

ADJUVANT THERAPY — Patients who complete neoadjuvant therapy plus radical cystectomy (or who are ineligible for neoadjuvant therapy) but are still at high risk for recurrence may be candidates for adjuvant therapy (algorithm 1). Further details are discussed separately. (See "Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder", section on 'Prior neoadjuvant chemotherapy'.)

PROGNOSIS — The addition of neoadjuvant chemotherapy to radical cystectomy improves overall survival (OS). (See 'Rationale' above.)

A pathologic complete response (pCR) following neoadjuvant chemotherapy is also associated with improved disease-free survival and OS [1,47]. As an example, in a phase III trial evaluating the addition of neoadjuvant classic MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) to radical cystectomy, patients with pCR had longer OS relative to those with residual disease on postoperative pathology (not reached versus four years) [1]. (See "Radical cystectomy", section on 'Prognostic factors for survival'.)

POSTTREATMENT SURVEILLANCE — For patients who have completed treatment for muscle-invasive bladder cancer, follow-up is essential to detect locoregional and metastatic disease. Posttreatment surveillance for bladder cancer is discussed in detail separately. (See "Overview of the initial approach and management of urothelial bladder cancer", section on 'Posttreatment surveillance'.)

INVESTIGATIONAL APPROACHES

Is there a role for neoadjuvant immunotherapy? — There is interest in investigating the use of checkpoint inhibitor immunotherapy as neoadjuvant therapy, given its efficacy in the treatment of metastatic urothelial cancer. Further randomized trials are necessary before incorporating neoadjuvant immunotherapy into routine clinical practice. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract".)

Most studies investigating neoadjuvant immunotherapy have been performed in patients who are ineligible for cisplatin-based chemotherapy (table 2) [48]. Complete pathologic response rates between approximately 30 to 40 percent have been reported in early phase I/II studies using neoadjuvant atezolizumab (ABACUS) [49,50], pembrolizumab (PURE-01) [51-53], the combination of durvalumab and tremelimumab [54], and nivolumab plus ipilimumab [55].

Pathologic complete response (pCR) rates have also been seen in patients receiving immunotherapy in combination with cisplatin-based chemotherapy prior to radical cystectomy [56,57]. As examples:

●Pembrolizumab plus gemcitabine and cisplatin – In a single-arm phase II trial, the addition of pembrolizumab to neoadjuvant gemcitabine plus split-dose cisplatin resulted in a pCR rate of 36 percent [56].

●Nivolumab plus gemcitabine and cisplatin – In preliminary results from a single-arm phase II trial (BLASST-1), the addition of nivolumab to neoadjuvant gemcitabine plus cisplatin resulted in a pCR rate of 50 percent [58].

●Durvalumab plus gemcitabine and cisplatin – In a single arm phase II trial (SAKK-06/17), the addition of perioperative (neoadjuvant and adjuvant) durvalumab to neoadjuvant gemcitabine plus cisplatin resulted in a pCR rate of 33 percent [59].

Gene expression profiling — Studies are investigating gene expression profiling to predict individual responsiveness to neoadjuvant chemotherapy. The role of gene expression profiling in the molecular prognostication of invasive bladder cancer remains experimental.

Studies may provide guidance on the implementation of personalized medicine in invasive bladder cancer. As examples:

●A randomized phase II trial (S1314) evaluated the utility of the Co-Expression Extrapolation (COXEN) biomarker [13,14,60]. COXEN is a panel of tumor-specific genes generated by a computer program to predict a pT0 rate in patients with localized muscle-invasive bladder cancer treated with a specific neoadjuvant cisplatin-based combination chemotherapy followed by cystectomy [13]. In this trial, COXEN scores for GC or dose-dense MVAC were not associated with improved overall survival (OS) within their respective treatment arms, although the COXEN-GC score was associated with improved OS among patients who received either regimen [14]. Further results of this study are discussed separately. (See 'Selection of therapy' above.)

●Bladder cancer can present with various molecular subtypes that are defined by gene expression profiling, including basal, luminal, and neuroendocrine-like, among others. (See "Molecular biology of bladder cancer", section on 'Subtypes defined by gene expression profiling'.)

Genomic bladder cancer classifier assays that report the molecular subtype of a bladder tumor are commercially available. Studies continue to evaluate the impact of these molecular subtypes on prognosis and selection of neoadjuvant therapy [60-63].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bladder cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic (see "Patient education: Bladder cancer treatment; muscle invasive cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Patient selection for neoadjuvant therapy – For most patients with localized muscle-invasive urothelial bladder cancer (T2-T4a, N0, M0) (figure 1 and table 1), we recommend neoadjuvant (ie, preoperative) cisplatin-based systemic therapy rather than upfront radical cystectomy (Grade 1B), as this approach improves overall survival (OS). (See 'Patient selection' above and 'Rationale' above.)

Exceptions include the following patient groups:

•Ineligible for neoadjuvant cisplatin-based therapy – Patients who are ineligible for neoadjuvant cisplatin-based therapy (table 2) may be offered radical cystectomy followed by adjuvant therapy as indicated (algorithm 1). (See "Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder", section on 'No prior neoadjuvant chemotherapy'.)

•Ineligible for radical cystectomy or desire bladder preservation – Patients who are ineligible for or wish to forego radical cystectomy (eg, to preserve their native bladder) may alternatively receive trimodality therapy (TMT) with maximal transurethral resection of bladder tumor followed by concurrent chemotherapy and radiation therapy (RT). (See "Bladder preservation treatment options for muscle-invasive urothelial bladder cancer", section on 'Patient selection'.)

●Approach to neoadjuvant therapy – For patients receiving neoadjuvant therapy, the optimal regimen is not established. Our approach is as follows:

•Selection of therapy – For most patients with good ECOG performance status (<2) (table 3) who are eligible for cisplatin-based therapy (table 2), we suggest either dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dose-dense MVAC (table 4)) or gemcitabine plus cisplatin (table 5), rather than other systemic regimens (Grade 2C). (See 'Selection of therapy' above.)

-Selection of therapy is based upon patient age, comorbidities, and preferences; treatment benefits and toxicity profiles; and provider's clinical experience with administering each regimen. For medically fit, cisplatin-eligible patients (table 2), either regimen is appropriate. However, for older adults or those with significant comorbidities, gemcitabine plus cisplatin (using either standard dosing or a split dose of cisplatin (table 5)) may be preferred since dose-dense MVAC may cause significant treatment-related toxicity and therefore may not be well-tolerated in these populations.

•Impaired kidney function – Prior to initiating neoadjuvant therapy, patients with bladder cancer who present with impaired kidney function should be evaluated for a malignant obstruction of the ureters. Patients with an obstruction require intervention (ie, ureteral stent placement or a percutaneous nephrostomy tube) as an attempt to restore normal kidney function. (See "Placement and management of indwelling ureteral stents" and "Percutaneous nephrostomy tubes".)

For patients with a creatinine clearance between 50 and 60 mL/min without malignant obstruction (or despite appropriate interventions for malignant obstruction), we suggest neoadjuvant gemcitabine plus split-dose cisplatin (table 5) rather than gemcitabine plus full-dose cisplatin or other systemic regimens (Grade 2C). (See 'Patients with impaired kidney function' above.)

●Assessing response to neoadjuvant therapy – Patients who complete neoadjuvant therapy are assessed for treatment response with a contrast-enhanced CT of the chest, abdomen, and pelvis. Gadolinium-enhanced MRI of the abdomen and pelvis is an alternative for abdominal imaging in those who are unable to receive CT contrast agents. Patients with symptoms concerning for disease progression should receive restaging imaging studies sooner (ie, within two cycles of therapy). (See 'Assessing response to neoadjuvant therapy' above.)

•Patients with stable or improved locoregional disease and no metastatic disease may proceed to evaluation for radical cystectomy. (See "Radical cystectomy".)

•Patients with progressive locoregional disease and no metastatic disease may be evaluated for immediate radical cystectomy upon recovery from neoadjuvant therapy. TMT (RT with concurrent chemotherapy) is an appropriate alternative for patients with muscle-invasive bladder cancer. (See "Radical cystectomy" and "Bladder preservation treatment options for muscle-invasive urothelial bladder cancer".)

•Patients with progressive locoregional disease that cannot be controlled with local therapy (surgery or RT) or those with distant metastases should be offered systemic therapy. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract".)

●Adjuvant therapy after neoadjuvant therapy and radical cystectomy – Patients who complete neoadjuvant therapy plus radical cystectomy but are still at high risk for recurrence may be candidates for adjuvant therapy (algorithm 1). Further details are discussed separately. (See 'Adjuvant therapy' above and "Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder", section on 'Prior neoadjuvant chemotherapy'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Derek Raghavan, MD, PhD, FACP, FASCO, and Phillip W Kantoff, MD, who contributed to earlier versions of this topic review.