Neoadjuvant treatment options for muscle-invasive urothelial bladder cancer

INTRODUCTION — Worldwide, bladder cancer accounts for almost 600,000 new cases and over 200,000 deaths [1]. In developed areas of the world, such as North America and Western Europe, these bladder cancers are predominantly urothelial carcinoma. (See "Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder", section on 'Epidemiology'.)

The preferred management of patients with muscle-invasive bladder cancer consists of a multimodal approach comprising neoadjuvant chemotherapy followed by radical cystectomy. In appropriately selected patients who are not candidates for radical cystectomy or who prefer to retain their native bladder, a combined-modality approach of maximal transurethral resection of bladder tumor (TURBT) followed by concurrent chemoradiotherapy is an alternative.

This topic discusses neoadjuvant chemotherapy followed by radical cystectomy for muscle-invasive urothelial bladder cancer. Other treatment approaches to urothelial bladder cancer are discussed separately.

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

●(See "Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder".)

●(See "Radical cystectomy".)

●(See "Treatment of primary non-muscle invasive urothelial bladder cancer".)

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

OVERVIEW OF TREATMENT APPROACH — All patients must be clinically staged prior to initiation of treatment for bladder cancer. This typically includes computed tomography (CT) of the chest, abdomen, and pelvis, and cystoscopy with transurethral resection of bladder tumor (TURBT). The diagnosis and staging of urothelial carcinoma is covered separately. (See "Clinical presentation, diagnosis, and staging of bladder cancer", section on 'Initial evaluation'.)

Radical cystectomy with bilateral pelvic lymphadenectomy remains the standard of care for patients with muscle-invasive bladder cancer. However, the high relapse rates following cystectomy alone for patients with muscle-invasive bladder cancer have led to the use of neoadjuvant treatment [2].

●For most patients with muscle-invasive bladder cancer who will undergo a radical cystectomy, cisplatin-based neoadjuvant chemotherapy is indicated. The use of neoadjuvant chemotherapy improves survival in this population. (See 'Neoadjuvant chemotherapy' below.)

•Therapy should be initiated expeditiously in appropriate candidates. In an observational study of over 2200 patients from the National Cancer Database, a delay in neoadjuvant chemotherapy of ≥8 weeks from diagnosis was associated with upstaging [3]. It also suggested that radical cystectomy should be performed within 7 months of initial diagnosis, for optimal results. However, it should be noted that delay was also associated with African American race, Medicaid insurance, and academic facilities (which may have reflected their safety-net roles), and it is possible that there were other confounding variables that were not identified prospectively.

●For select patients with muscle-invasive bladder cancer who are not candidates for radical cystectomy or who desire preservation of their native bladder, radiation therapy (RT) plus concurrent chemotherapy is indicated rather than chemotherapy or RT as a single-modality treatment. (See "Bladder preservation treatment options for muscle-invasive urothelial bladder cancer", section on 'Patient selection'.)

NEOADJUVANT CHEMOTHERAPY — For patients undergoing neoadjuvant chemotherapy, cisplatin-based combination regimens should be used. The most commonly used neoadjuvant regimens are dose-dense MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin (table 1)) and gemcitabine plus cisplatin. Further data are needed to establish the optimal regimen. (See 'Choice of chemotherapy regimens' below.)

The administration of neoadjuvant cisplatin-based chemotherapy has consistently demonstrated a survival benefit when given prior to surgery [4,5]. This was demonstrated in a meta-analysis of 11 randomized trials that compared cisplatin-based neoadjuvant chemotherapy plus local therapy with local therapy alone [4]. Compared with local therapy alone, neoadjuvant cisplatin-based combination chemotherapy resulted in:

●An improvement in overall survival (five-year overall survival 50 versus 45 percent, hazard ratio [HR] 0.87, 95% CI 0.78-0.98).

●A lower risk of recurrence (HR for recurrence 0.81, 95% CI 0.74-0.9). This translated into an absolute disease-free survival (DFS) benefit of 7 percent.

Choice of chemotherapy regimens — There is no established ideal neoadjuvant chemotherapy regimen. Further follow-up of survival in a randomized trial comparing the most frequently used regimens (dose-dense MVAC and gemcitabine plus cisplatin [GC]) are necessary to help guide this decision [6,7].

In the absence of a definitive standard of care, we prefer dose-dense MVAC in young patients with good performance status and no comorbidities, as this approach shortens the time from diagnosis to surgery. In older patients and those unable to tolerate this combination due to medical comorbidities, GC is a reasonable alternative.

The most commonly employed regimens administered in the neoadjuvant setting are:

●Dose-dense MVAC – Methotrexate (30 mg/m² on day 1), vinblastine (3 mg/m² on day 2), doxorubicin (30 mg/m² on day 2), cisplatin (70 mg/m² on day 2), filgrastim (240 mcg/m² subcutaneously on days 4 to 10), repeated every 14 days, if toxicity permits, for three to six cycles (table 1).

●GC – Gemcitabine (1000 mg/m² on days 1, 8) plus cisplatin (70 mg/m² on day 1) given every 21 days for a maximum of four cycles (table 2) [8]. (See 'GC' below.)

•Patients with a creatinine clearance between 50 and 60 mL/min may be offered an alternative regimen of gemcitabine (1000 mg/m² on days 1, 8) plus split-dose cisplatin (35 mg/m² on days 1, 8) given every 21 days for a maximum of four cycles [9,10].

Regimens that are less commonly used in the neoadjuvant setting are:

●CMV – Methotrexate (30 mg/m²) and vinblastine (4 mg/m²) on days 1 and 8 plus cisplatin (100 mg/m² on day 2), with leucovorin (15 mg every six hours for four doses) on days 2 and 9, repeated every 28 days for three cycles [11]. (See 'CMV' below.)

●Classic MVAC – Methotrexate (30 mg/m² on days 1, 15, and 22), vinblastine (3 mg/m² on days 2, 15, and 22), doxorubicin (30 mg/m² on day 2), and cisplatin (70 mg/m² on day 2) administered every 28 days for three cycles (table 3) [12].

However, classic MVAC is no longer recommended as neoadjuvant chemotherapy by the NCCN [13]. (See 'MVAC' below.)

Data comparing these regimens come from randomized trials and observational studies [6,7,14-18].

Dose-dense MVAC was compared with GC in an open-label phase III trial (GETUG/AFU V05 VESPER) of 493 patients with non-metastatic muscle-invasive bladder cancer [6,7,19]. In this study, patients were randomly assigned to either six cycles of dose-dense MVAC or four cycles of GC administered before or after radical cystectomy. 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 (12 percent) received adjuvant therapy after cystectomy.

At median follow-up of 40 months, results were as follows [7]:

●All patients – For the entire study population, compared with GC, dose-dense MVAC had similar three-year progression-free survival (PFS; 64 versus 56 percent, HR 0.77, 95% CI 0.57-1.02) and improved time to progression (TTP; 69 versus 58 percent, HR 0.68, 95% CI 0.50-0.93). Overall survival data are immature. Data were inconclusive for those who received adjuvant therapy due to the limited number of patients.

●Neoadjuvant therapy – Among the subgroup treated with neoadjuvant therapy, dose-dense MVAC improved three-year PFS compared with GC (66 versus 56 percent, HR 0.70, 95% CI 0.51-0.96) [7]. There was no difference in the pathologic complete response (pCR) rate between the two chemotherapy regimens (42 versus 36 percent) [6]. However, dose-dense MVAC increased local control rates over GC, including non-muscle invasive (<ypT2pN0; 63 versus 49 percent) and organ-confined disease (<ypT3pN0; 77 versus 63 percent) [6,7].

●Toxicity – Grade ≥3 toxicity was higher for dose-dense MVAC compared with GC, including gastrointestinal toxicities and asthenia [6]. Only 60 percent of patients completed the planned six cycles of dose-dense MVAC due to toxicity [7].

In a separate randomized phase II SWOG S1314 trial (Co-expression Extrapolation [COXEN]) of 237 patients with muscle-invasive bladder cancer, pCR rates were also similar for dose-dense MVAC compared with GC (28 versus 30 percent) [16]. In preliminary results, OS and PFS were also similar for dose-dense MVAC compared with GC [20]. (See 'Gene expression profiling' below.)

Observational studies have not identified a substantive difference in pCR rates between neoadjuvant classic dosing of MVAC and GC [14,15]. As an example, one observational study from 19 centers in North America and Europe evaluated 935 patients treated with neoadjuvant chemotherapy for muscle-invasive (T2 to T4a), clinically node-negative (N0) bladder cancer [15]. Chemotherapy consisted of GC in 64 percent of cases, MVAC in 20 percent, and other regimens in 15 percent. The rate of pCR was similar between those treated with GC and MVAC (approximately 24 percent for each group). While the pCR rates for MVAC in this study are lower than that seen in randomized studies, such as the INT-0800 trial (38 percent) and the GETUG/AFU V05 VESPER trial (42 percent), this likely reflects selection bias and variations in staging/diagnostic work-up in the underlying patient populations.

MVAC — Classic MVAC is the best-studied regimen for neoadjuvant chemotherapy. Dose-dense MVAC regimens have been studied in an effort to further improve upon survival results.

Classic MVAC — The benefit and toxicity of MVAC was most conclusively demonstrated in the INT-0080 trial, which enrolled 307 patients with T2 to T4a bladder cancer and randomly assigned patients to three 28-day cycles of MVAC prior to radical cystectomy or surgery alone [12].

Compared with surgery alone, neoadjuvant MVAC resulted in:

●A statistically significant increase in the pCR rate (38 versus 15 percent)

●A trend toward improvement in overall survival (median, 77 versus 46 months, five-year survival rate 57 versus 43 percent)

●A high rate of serious (grade 3/4) hematologic or gastrointestinal toxicity, including neutropenia (57 percent), stomatitis (10 percent), and nausea and vomiting (6 percent)

Dose-dense MVAC — Data suggest that dose-dense MVAC is active when administered in the neoadjuvant setting for patients with muscle-invasive bladder cancer. Given the shortened time to surgery with the use of this modified regimen, we believe this represents one option with a reasonable treatment schedule.

Two single-arm phase II studies suggest that this dose-dense MVAC is feasible in the neoadjuvant setting [21,22]. In both, eligible patients had clinical stage T2 to T4 muscle-invasive bladder cancer; patients with a single lymph node up to 2 cm in greatest dimension on imaging (clinical N1) were also allowed to participate.

●One phase II trial included 39 patients (43 percent with N1 disease) who were treated with four cycles of dose-dense MVAC treatment [21]. Overall, 95 percent completed all four cycles of treatment. The pathologic response rate was 49 percent (19 of 39 patients), with a pCR in 10 patients. At a median follow-up of 24 months, the disease-free rate at one year was higher among those who achieved a pathologic response (89 versus 67 percent among those without one; HR 2.6, 95% CI 0.8-8.1).

●A second phase II trial included 40 evaluable patients (7 percent with N1 disease) who were treated with three cycles of accelerated MVAC therapy [22]. The pCR rate was 38 percent, and another six patients (14 percent) were downstaged to non-muscle invasive disease at the time of cystectomy. A pathologic response to neoadjuvant MVAC therapy was associated with significant prolongation of both disease-free and overall survival.

Data comparing neoadjuvant dose-dense MVAC versus GC are discussed above. (See 'Choice of chemotherapy regimens' above.)

Increasing the dose intensity of MVAC by administering treatment every two weeks with granulocyte colony-stimulating factor (G-CSF) support has been extensively evaluated in patients with metastatic or advanced urothelial cancer. In the European Organisation for Research and Treatment of Cancer (EORTC) 30924 trial of patients with locally advanced or metastatic urothelial carcinoma, this approach increased progression-free survival, but it did not result in a statistically significant difference in overall survival, although it suggested that toxicity was less severe [23]. Subsequent follow-up from that trial found that the overall survival rate at five years was 21.8 percent with dose-dense MVAC versus 13.5 percent with classic MVAC [24]. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract", section on 'MVAC'.)

Classic MVAC versus dose-dense MVAC — Dose-dense MVAC may be favored over classic MVAC due to the reduced toxicity reported for dose-dense MVAC in the metastatic setting, as described in the European Organisation for Research and Treatment of Cancer (EORTC) randomized trial. Additionally, classic MVAC is no longer recommended as neoadjuvant chemotherapy by the NCCN [13]. (See 'MVAC' above.)

GC — The combination of gemcitabine plus cisplatin (GC) is an option for neoadjuvant treatment of muscle-invasive bladder cancer (table 2). In patients with metastatic urothelial cancer, GC has similar efficacy and less toxicity compared with MVAC. However, a nonsignificant trend toward greater activity was observed with MVAC. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract", section on 'Gemcitabine plus cisplatin'.)

Data comparing neoadjuvant GC with dose-dense MVAC are discussed above. (See 'Choice of chemotherapy regimens' above.)

CMV — Neoadjuvant CMV was evaluated in a phase III study involving 976 patients with high-grade T2-T4aN0-NXM0 bladder cancer who were randomly assigned to three cycles of CMV or no chemotherapy. All patients were then managed according to each institution's choice (ie, radical cystectomy or radiation therapy) [11]. Neoadjuvant treatment with CMV resulted in a pCR rate of 33 percent. With a median follow-up of eight years, neoadjuvant CMV was associated with a reduction in the risk of death compared with local treatment alone (HR 0.84, 95% CI 0.72-0.99) [25]. This corresponds with an absolute improvement in overall survival at 10 years of 6 percent (30 to 36 percent).

Patients with kidney function impairment — For patients with kidney function impairment (creatinine clearance between 50 and 60 mL/min) may be offered gemcitabine plus split-dose cisplatin (table 2) [9,10]. (See 'Choice of chemotherapy regimens' above.)

Studies have also evaluated replacing cisplatin with carboplatin in patients with kidney function impairment [26]. However, there are no randomized data supporting the use of carboplatin for the treatment of bladder cancer in the neoadjuvant setting.

Patients with bladder cancer who present with kidney function impairment should be evaluated for a renal tract obstruction. Renal 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. All patients with an obstruction should undergo ureteral stent placement or a percutaneous nephrostomy 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".)

Despite promising preclinical evidence to support the activity of carboplatin for urothelial cancer [27], randomized data suggest that carboplatin is inferior to cisplatin [28-31]. For example, in a randomized phase II trial conducted by the Eastern Cooperative Oncology Group (ECOG), single-agent carboplatin resulted in a low response rate with a median overall survival of only five months [29]. In a separate randomized trial of 47 patients with advanced bladder cancer, compared with MVAC (a cisplatin-based regimen), the M-CAVI regimen (carboplatin, vinblastine, methotrexate) had lower objective response rates [32]. Subsequent trials evaluated carboplatin as a single agent [30], in combination with paclitaxel [33], and in combination with gemcitabine [26]. Such combinations (particularly carboplatin plus gemcitabine) appear to have substantial anti-tumor activity against urothelial malignancies [33] but are not considered to be optimal therapies in patients eligible for cisplatin-based chemotherapy.

Thromboembolic complications — Patients with cancer are at increased risk for thromboembolic events. A meta-analysis of bladder cancer patients found that the one-year risk was elevated approximately fivefold compared with the general population [34]. Currently, guidelines recommend prophylaxis for cancer patients who undergo pelvic or abdominal surgery. (See "Risk and prevention of venous thromboembolism in adults with cancer".)

The risk may be further elevated in patients who undergo preoperative neoadjuvant chemotherapy [35]. In a retrospective multicenter analysis of 761 patients treated with neoadjuvant chemotherapy followed by radical cystectomy, the overall incidence of thromboembolic events (primarily deep venous thrombosis and pulmonary embolism) was 13.8 percent; in 58 percent of cases, the thromboembolic event occurred during neoadjuvant chemotherapy and prior to radical cystectomy.

Additional prospective evaluation is required to determine if prophylaxis is beneficial during neoadjuvant chemotherapy.

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 [36]. Complete pathologic response rates between approximately 30 to 40 percent have been reported in early phase I/II studies using neoadjuvant atezolizumab (ABACUS) [37,38], pembrolizumab (PURE-01) [39-41], the combination of durvalumab and tremelimumab [42], and nivolumab plus ipilimumab [43].

Pathologic complete response rates have also been seen in patients receiving immunotherapy in combination with cisplatin-based chemotherapy prior to radical cystectomy [44,45]. As an example, in nonrandomized phase II trial, the addition of pembrolizumab to neoadjuvant gemcitabine plus split-dose cisplatin resulted in a complete pathologic response rate of 36 percent [44]. In preliminary results from a separate phase II trial (BLASST-1), the addition of nivolumab to neoadjuvant gemcitabine plus cisplatin resulted in a complete pathologic response rate of 50 percent [46].

IS THERE A ROLE FOR NEOADJUVANT RADIATION THERAPY? — Neoadjuvant radiation should not be used in patients with muscle-invasive bladder cancer prior to radical cystectomy.

As a single modality, preoperative radiation therapy (RT) can eradicate disease in a small proportion of patients undergoing cystectomy [47,48]. However, subsequent randomized trials demonstrated that while preoperative RT can improve local control, it has no impact on survival when compared with cystectomy alone [49,50].

ADJUVANT THERAPY — Although neoadjuvant chemotherapy is associated with a significant survival advantage, not all patients with muscle-invasive bladder cancer who undergo radical cystectomy are treated with neoadjuvant chemotherapy. In such patients, the approach to adjuvant systemic therapy is discussed separately. (See "Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder".)

RADICAL CYSTECTOMY — At the completion of neoadjuvant chemotherapy, patients should proceed with radical cystectomy regardless of the clinical response, unless there is the development of biopsy-proven metastatic disease. Although neoadjuvant chemotherapy results in a high response rate, the presence of persistent disease can only be assessed by cystectomy. (See "Radical cystectomy".)

When feasible, our approach is to reassess the extent of disease with computed tomography (CT) scan after two doses of neoadjuvant chemotherapy to ensure adequate response to cytotoxic treatment prior to continuing. If the tumor has progressed, cystectomy should be discussed with the patient, unless distant metastases have developed, in which case the patient should be treated for metastatic disease. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract".)

The risk of residual disease despite a clinical complete response was illustrated by the Southwest Oncology Group (SWOG) trial S0219, in which 77 patients with T2 to T4a bladder cancer were treated with three cycles of paclitaxel, carboplatin, and gemcitabine, followed by restaging [51]. Following chemotherapy, 34 patients (46 percent) had a clinical complete response, ten of whom underwent an immediate cystectomy. Of these ten, six had persistent tumor in the cystectomy specimen.

Although it might be possible to identify patients who may not require cystectomy at the end of neoadjuvant chemotherapy, the data to support a tailored postneoadjuvant surgical approach are limited. In one study of 104 patients with T2 to T4aNx urothelial cancer, all of whom received three courses of neoadjuvant MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin), all patients underwent clinical restaging at the end of treatment and selective surgical treatment was performed [52]. The main results were:

●Of those who underwent transurethral resection of bladder tumor (TURBT) only (n = 49), 37 had a pathologic complete response (pCR). The five-year survival rate for the group was 67 percent.

●Of those who underwent partial cystectomy for a residual monofocal lesion after chemotherapy (n = 13), five patients recurred (two with superficial and three with locally invasive disease). The five-year survival rate was 69 percent.

●Of those who underwent radical cystectomy for persistent disease at the end of neoadjuvant treatment (n = 39), 14 developed metastatic disease. The five-year survival rate was 46 percent.

The outcome for those who do not undergo immediate radical cystectomy was studied in a retrospective series of 48 patients who had a clinical complete response to neoadjuvant platinum-based chemotherapy [53]. Seven patients underwent immediate radical cystectomy, while 41 elected bladder preservation with close surveillance. Of these 41 patients, 19 relapsed (46 percent), with a median time to recurrence of 5.4 months. The five-year rates of cancer-specific survival, disease-free survival, and cystectomy-free survival were 87, 58, and 79 percent, respectively. It is important to note that case selection bias may have been an important determinant of outcome in this study.

Given these findings, we and others consider bladder preservation inferior to radical cystectomy when attempting to render patients treated with neoadjuvant therapy disease free.

PROGNOSIS — Pathologic complete response (pCR) following neoadjuvant chemotherapy is associated with improved disease-free and overall survival. As an example, in the Southwest Oncology Group trial of MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) plus cystectomy versus cystectomy alone, the median survival of patients with a pCR was not reached among those treated with MVAC prior to cystectomy [12]. For those with residual disease, median survival was four years. (See "Radical cystectomy", section on 'Prognostic factors for survival'.)

In addition, the prognostic impact of chemotherapy (whether administered before or after surgery) is likely complicated by factors beyond the use of this treatment modality, including the following:

●The prognosis of any given patient may depend as much on where a patient was treated as what treatment they received. For example, in one study, the outcome of patients with T2a or T2b urothelial cancer treated with surgery alone at one center was better than what has been previously reported in other series that used combined-modality treatment [54]. However, this was a single-center study, and it is not clear whether there was an impact from occult case selection bias, despite the very large number of cases reported. It has repeatedly been established that high case volume is associated with better outcomes, suggesting benefits from referral to centers of excellence.

●The staging of bladder cancer by the American Joint Committee on Cancer (AJCC) has evolved over the years, and thus, it becomes difficult to compare between older and more contemporary clinical trials. This illustrates the importance of randomized trials in preference to historical comparisons.

POSTTREATMENT SURVEILLANCE AND TREATMENT — For patients who have completed treatment for muscle-invasive bladder cancer, follow-up is essential for detection of a recurrence (in the case of partial cystectomy or bladder preservation) or a second primary urothelial tumor along the urogenital tract. Posttreatment surveillance depends on whether cystectomy or bladder preservation was performed. This is discussed in detail separately (see "Overview of the initial approach and management of urothelial bladder cancer", section on 'Posttreatment surveillance'). In summary:

Patients who were treated with cystectomy should be evaluated every three months for the first year, every six months for the second and third years, and then annually to year 5. After this, evaluations should be guided by clinical findings. The evaluation typically consists of lab work (ie, urine cytology, liver and renal function tests, and electrolytes) and imaging with computed tomography (CT) of the chest, abdomen, and pelvis.

INVESTIGATIONAL APPROACHES

p53 status for risk-directed clinical trials — Mutations in the tumor suppressor gene, p53 have been evaluated as a way to select patients for treatment. However, we recommend against routine study of p53 expression prior to neoadjuvant therapy outside an investigational setting.

Despite promising early data that had begun to influence clinical practice, the association between p53 mutations and a poor prognosis in bladder cancer has not been consistently demonstrated [55-61]. As an example, in one study involving 243 patients who underwent cystectomy for pTa to pT4B disease, the presence of p53-altered immunoreactivity compared with p53 wild-type was associated with a significantly higher risk of both disease recurrence and death [55]. Recurrence rates for tumors with and without detectable p53 immunoreactivity were 62 versus 7 percent for pT1 tumors, 56 versus 12 percent for pT2 tumors, and 80 versus 11 percent for pT3 tumors. However, other studies failed to confirm the prognostic significance of p53 mutation, and currently its role remains uncertain in view of the inconsistent and conflicting published data. Although there are occasional reports of nonrandomized trials that claim utility of p53 profiling, we believe that there is still no routine place for this outside the context of a clinical trial or investigative protocol.

One adjuvant trial attempted to select bladder cancer patients with pathologic organ-confined tumors positive for mutant p53 and randomly assign treatment with observation or adjuvant chemotherapy with MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin). However, this trial was closed at interim analysis due to futility and is reported as a negative trial [60]. This trial is discussed separately. (See "Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder", section on 'Patients eligible for cisplatin-based chemotherapy'.)

Gene expression profiling — The use of individual patient gene expression patterns to predict individual responsiveness to neoadjuvant chemotherapy is an area of active investigation [62,63]. The role of gene expression profiling in the molecular prognostication of invasive bladder cancer remains experimental.

●Several important clinical trials may provide guidance on the implementation of personalized medicine in invasive bladder cancer. As an example, a randomized phase II trial (S1314) evaluated the utility of the Co-Expression Extrapolation (COXEN) biomarker. 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 chemotherapy followed by cystectomy [16]. In preliminary results from this trial, COXEN scores for GC or MVAC were not associated with improved OS within their respective treatment arms, although the COXEN-GC score was associated with improved OS among patients who received either regimen [20].

●In one study, whole transcriptome profiling was performed on transurethral resection specimens from 343 patients with muscle-invasive bladder cancer prior to treatment with neoadjuvant chemotherapy. Molecular subtyping appeared to have an impact on the selection of patients who benefit from neoadjuvant chemotherapy. These data also suggested that patients with basal tumors should be prioritized for neoadjuvant chemotherapy [64].

●An emerging area of focus is the impact of mutations of DNA repair genes (eg, BRCA1, BRCA2, ATM, ERCC2, RB1, FANCC [65,66]), which may correlate with response to chemotherapy.

●Another important innovation has been the demonstration of the importance of programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression in advanced bladder cancer [67]. Data suggest that PD-L1 expression after neoadjuvant chemotherapy is associated with prolonged survival [68], and this biomarker remains under investigation.

Further data on neoadjuvant immunotherapy for bladder cancer are discussed above. (See 'Is there a role for neoadjuvant immunotherapy?' above.)

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

●Treatment approach – Radical cystectomy and bilateral pelvic lymphadenectomy remain the standard of care for patients with muscle-invasive bladder cancer. For patients with T2 to T4a bladder cancer (figure 1 and table 4) for whom a radical cystectomy is planned, we recommend neoadjuvant chemotherapy prior to cystectomy over surgery alone (Grade 1A). (See 'Neoadjuvant chemotherapy' above.)

●Selection of neoadjuvant chemotherapy regimen – For patients receiving neoadjuvant chemotherapy, the optimal regimen is not established.

•The most commonly used treatment options are dose-dense MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin (table 1)) and gemcitabine plus cisplatin (GC (table 2)).

•For most patients with good performance status, we suggest dose-dense MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) over GC (Grade 2C). However, for older patients and those unable to tolerate dose-dense MVAC due to medical comorbidities, GC (table 2) is a reasonable alternative. (See 'Choice of chemotherapy regimens' above.)

●Radical cystectomy after neoadjuvant chemotherapy – At the completion of neoadjuvant chemotherapy, all patients should proceed with radical cystectomy, even if they have had a complete response to neoadjuvant therapy. Although it may eventually be possible to identify patients who may not require cystectomy at the end of neoadjuvant chemotherapy, the data to support a tailored postneoadjuvant surgical approach are limited. We and others consider bladder preservation inferior to radical cystectomy when attempting to achieve cure. (See 'Radical cystectomy' above.)

●Alternatives to cystectomy – Bladder-sparing therapy may be considered a reasonable alternative to radical surgery in patients who are deemed unfit for cystectomy as well as for those seeking an alternative to radical cystectomy. (See "Bladder preservation treatment options for muscle-invasive urothelial bladder cancer".)

●Posttreatment surveillance – For patients who have completed treatment for muscle-invasive bladder cancer, careful and structured follow-up is essential for detection of a recurrence (in the case of partial cystectomy or bladder preservation) or a second primary urothelial malignancy in the urogenital tract. (See 'Posttreatment surveillance and treatment' above.)

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.