Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder

INTRODUCTION — 

Bladder cancer is the most common malignancy involving the urinary system. Urothelial (transitional cell) carcinoma is the predominant histologic type, particularly in the United States and Europe, where it accounts for 90 percent of all bladder cancers. In other areas of the world, non-urothelial carcinomas are more frequent. (See "Epidemiology and risk factors of urothelial carcinoma of the bladder", section on 'Epidemiology'.)

The role of adjuvant chemotherapy, adjuvant immunotherapy, and adjuvant radiation in patients with locoregionally advanced muscle-invasive urothelial carcinoma of the bladder will be reviewed here. The following topics related to the management of urothelial carcinoma are discussed separately:

●(See "Radical cystectomy".)

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

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

●(See "Malignancies of the renal pelvis and ureter".)

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

DECISIONS REGARDING ADJUVANT THERAPY — 

Management is complex for patients with muscle-invasive urothelial carcinoma of the bladder who are treated with cystectomy and found to be at high risk for recurrence based on pathologic staging. For such patients, the selection of adjuvant therapy is based upon whether neoadjuvant chemotherapy was previously received or not prior to radical cystectomy, among other clinical factors. Neoadjuvant chemotherapy followed by radical cystectomy remains the preferred approach since it is associated with improved overall survival (OS), but some patients may still be at high risk for recurrence after cystectomy. Other patients may receive initial treatment with radical cystectomy rather than neoadjuvant chemotherapy, and adjuvant therapy may be reserved for those at high risk for recurrence. Enrollment in clinical trials is encouraged, where available.

Prior neoadjuvant chemotherapy — For patients previously treated with neoadjuvant cisplatin-based chemotherapy and high-risk pathologic features at cystectomy (persistent muscle-invasive [ypT2-T4a] or nodal disease), we suggest one year of adjuvant immunotherapy with either nivolumab or pembrolizumab rather than observation (algorithm 1). In separate randomized trials, adjuvant nivolumab confers both a disease-free survival (DFS) and a trend towards an OS advantage [1,2], and adjuvant pembrolizumab confers a DFS advantage [3].

Select patients who received neoadjuvant cisplatin-based combination chemotherapy may have high-risk pathologic features at cystectomy. Such high-risk characteristics for this specific patient population are defined as persistent muscle-invasive disease (pathologic T2 to T4a disease (table 1)) and/or pathologic node involvement at cystectomy. These patients may have chemotherapy-refractory tumors and appear to benefit from adjuvant immunotherapy.

Adjuvant nivolumab — The efficacy of adjuvant nivolumab was demonstrated in an international, placebo-controlled phase III trial (CheckMate 274) of 709 patients with muscle-invasive urothelial carcinoma of the urinary bladder or upper urinary tract who underwent radical cystectomy and had high-risk disease on postoperative pathology [1]. Patients either received neoadjuvant cisplatin-based chemotherapy and had persistent muscle-invasive or nodal disease or did not receive neoadjuvant chemotherapy, had extravesical extension or nodal involvement at surgery, and were ineligible for (or declined) adjuvant cisplatin-based chemotherapy. (See 'Ineligible for cisplatin-based chemotherapy' below.)

Patients were randomly assigned to either nivolumab at 240 mg intravenously every two weeks or placebo for up to one year. Results were as follows:

●Intention to treat population – At a median follow-up of approximately 20 months, compared with placebo, adjuvant nivolumab improved DFS, the primary endpoint (median 21 versus 11 months, 63 versus 47 percent at one year, hazard ratio [HR] 0.70, 98% CI 0.55-0.90), nonurothelial tract recurrence-free survival (NUTRFS; 65 versus 51 percent at one year, HR 0.72, 95% CI 0.59-0.89), and distant metastasis-free survival (median 41 versus 30 months, 83 versus 70 percent at six months, HR 0.75, 95% CI 0.59-0.94) [1]. These data continued to be confirmed with extended follow-up [2].

At a preplanned interim analysis (median follow-up of 36 months), adjuvant nivolumab showed a trend towards an improved OS over placebo (median 70 versus 50 months, three-year OS 66 versus 58 percent, HR 0.76, 95% CI 0.61-0.96) [2]. Follow-up of OS is ongoing, as the prespecified statistical significance boundary was not met at the time of this analysis.

●Prior neoadjuvant cisplatin-based chemotherapy – In the subset of 308 patients who received previous neoadjuvant cisplatin-based therapy and the above high-risk pathologic features at cystectomy, adjuvant nivolumab improved DFS over placebo (HR 0.52, 95% CI 0.38-0.71) [1]. These data continued to be confirmed with extended follow-up [2].

At a preplanned interim subset analysis of the patients previously treated with neoadjuvant therapy (median follow-up of 36 months), adjuvant nivolumab also showed a trend towards improved OS over placebo (HR 0.71, 95% CI 0.51-0.99) [2]. Follow-up of OS is ongoing, as the prespecified statistical boundary was not met at the time of this analysis.

●Programmed cell death ligand 1 (PD-L1) positive tumors (≥1 percent) – In the subset of patients with PD-L1 positive tumors (≥1 percent), compared with placebo, adjuvant nivolumab improved DFS (67 versus 46 percent at one year, HR 0.55, 99% CI 0.35-0.85), NUTRFS (69 versus 47 percent at one year, HR 0.55, 95% CI 0.39-0.79), and distant metastasis-free survival (79 versus 66 percent at six months, HR 0.61, 95% CI 0.42-0.90) [1]. These data continued to be confirmed with extended follow-up [2].

At a preplanned interim subset analysis of this population (median follow-up of 36 months), adjuvant nivolumab also showed a trend towards improved OS over placebo (median not reached for both arms, three-year OS 71 versus 57 percent, HR 0.56, 95% CI 0.36-0.86) [2]. Follow-up of OS is ongoing, as the prespecified statistical significance boundary was not met at the time of this analysis.

The most common grade ≥3 nivolumab-related toxicities included elevated lipase (5 percent), elevated amylase (4 percent), and diarrhea, colitis, and pneumonitis (<1 percent each) [1]. Health-related quality of life was also similar between the two treatment arms, with no significant deterioration over time noted in those receiving nivolumab [4].

Based on these data, the US Food and Drug Administration (FDA) granted regulatory approval for adjuvant nivolumab in patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical resection of disease [5]. High risk of recurrence is defined as muscle-invasive (ypT2-T4a) and/or node-positive disease for patients who received neoadjuvant cisplatin, or extravesicular extension (pT3-T4a) and/or node-positive disease for patients who did not receive neoadjuvant cisplatin and who were also either ineligible for or refused adjuvant cisplatin.

Adjuvant pembrolizumab — The efficacy of adjuvant pembrolizumab was demonstrated in an open-label phase III trial (AMBASSADOR; KEYNOTE-123) of 702 patients with muscle-invasive urothelial carcinoma of the bladder, upper urinary tract, or urethra who underwent surgical resection (radical cystectomy, nephrectomy, nephroureterectomy, or ureterectomy) and had high-risk disease on postoperative pathology [3]. Prior to surgery, patients previously received neoadjuvant cisplatin-based chemotherapy and had persistent muscle-invasive (pT2 or greater), nodal disease, or positive surgical margins or did not receive neoadjuvant chemotherapy and had extravesicular extension (pT3 or greater), nodal disease, or positive surgical margins and were ineligible for (or declined) adjuvant cisplatin-based therapy.

Patients were randomly assigned to either adjuvant pembrolizumab at 200 mg every three weeks for one year or observation. At a median follow-up of 45 months, pembrolizumab improved DFS relative to observation (median 30 versus 14 months, HR 0.73, 95% CI 0.59-0.90) [3]. At a median follow-up of 37 months, OS was similar between the two treatment arms (median 51 versus 56 months, HR 0.98, 95% CI 0.76-1.26) with ongoing follow-up. Grade ≥3 toxicity rates for pembrolizumab versus observation were 48 and 32 percent, respectively; no new safety signals were identified for pembrolizumab.

Of note, the trial was closed early at 95 percent of full accrual due to the approval of adjuvant nivolumab. Patients withdrew from the trial in both treatment arms, and 21 percent of patients on observation subsequently received an immune checkpoint inhibitor.

Ineligible for immunotherapy — Patients who are ineligible for immunotherapy may be enrolled in clinical trials. In very select cases, some may also be candidates for adjuvant radiation therapy (RT). These options may be offered after a discussion with the patient on the limited available data for adjuvant chemotherapy in this setting [6-8]. (See 'Experimental options' below and 'Decisions regarding adjuvant radiation' below.)

No prior neoadjuvant chemotherapy — For patients not previously treated with neoadjuvant chemotherapy who are found to have high-risk disease at cystectomy (table 1), we recommend adjuvant systemic therapy rather than observation. High-risk characteristics for this patient population include tumor that extends beyond the muscle (pathologic T3 or T4 disease (table 1)) and/or pathologic node involvement [9].

Selection of adjuvant therapy is based on the patient's eligibility for cisplatin (algorithm 1). (See 'Definition of cisplatin eligibility' below.)

●For patients who are eligible for cisplatin-based therapy (table 2), we suggest a cisplatin-based combination regimen rather than other systemic regimens. (See 'Eligible for cisplatin-based chemotherapy' below.)

●For patients who are ineligible for (or decline) cisplatin-based therapy, adjuvant immunotherapy (nivolumab or pembrolizumab for one year) is an acceptable alternative. (See 'Ineligible for cisplatin-based chemotherapy' below.)

Definition of cisplatin eligibility — For patients not previously treated with neoadjuvant chemotherapy prior to cystectomy, the preferred choice of regimen for adjuvant therapy is cisplatin-based combination chemotherapy (algorithm 1). Patients with indications for adjuvant chemotherapy should be evaluated for eligibility to receive such regimens, which have the most efficacy in this setting. (See 'Eligible for cisplatin-based chemotherapy' below.)

Given that cisplatin-based therapy is the standard of care and that kidney dysfunction and systemic comorbidities increase with age, the following criteria are used to select patients for adjuvant therapy [10]. Patients who meet all these criteria are deemed eligible for cisplatin-based combination chemotherapy (table 2). These are published criteria used to define cisplatin eligibility in clinical trials for metastatic patients [10]. (see "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract", section on 'Defining eligibility for systemic therapy'):

●World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status <2 (table 3) or Karnofsky performance status (KPS) >70 (table 4)

●No significant hearing loss or hearing loss less than grade 2

●Peripheral neuropathy less than grade 2

●No clinical evidence of New York Heart Association (NYHA) class III or worse congestive heart failure (table 5)

●Creatinine clearance ≥60 mL/minute

However, for patients receiving adjuvant chemotherapy, clinicians may adjust some of these criteria based on particular patient situations. For example, a patient may have some degree of hearing loss, but still be offered cisplatin-based adjuvant chemotherapy because they otherwise meet all other criteria for cisplatin eligibility. Additionally, some (but not all) UpToDate experts offer patients with borderline kidney dysfunction (creatinine clearance between 50 and 60) the option to split the dose of cisplatin over two days, extrapolating from trials of neoadjuvant chemotherapy (table 6) [11].

Of note, if the impairment in kidney function is due to kidney/urinary tract obstruction and/or hydronephrosis, the obstruction should be addressed, and the creatinine clearance should be rechecked before a final therapeutic decision is made. (See "Clinical manifestations and diagnosis of urinary tract obstruction (UTO) and hydronephrosis".)

Eligible for cisplatin-based chemotherapy

Adjuvant cisplatin-based chemotherapy — For patients with no prior neoadjuvant chemotherapy and pathologic extravesical extension (pT3-T4a disease) or nodal involvement at cystectomy who are eligible for cisplatin-based combination chemotherapy (table 2), we suggest a cisplatin-based combination regimen rather than other systemic regimens. Our preferred regimens include:

●Three to four cycles of dose-dense MVAC with growth factor support (table 7)

●Four cycles of gemcitabine plus cisplatin (GC) (table 6)

Either of these regimens is appropriate for most patients. Some clinicians prefer a GC regimen over dose-dense MVAC because GC has a lesser toxicity profile that is easier to manage during treatment. For example, compared with GC, dose-dense MVAC is associated with higher rates of neutropenia, neutropenic fever and sepsis, mucositis, and alopecia [12]. However, others dose-dense prefer MVAC over GC for fit patients, extrapolating from data in the neoadjuvant setting, which suggests a survival benefit for dose-dense MVAC. (See "Neoadjuvant therapy for localized muscle-invasive urothelial carcinoma of the bladder", section on 'Neoadjuvant therapy'.)

The rationale for these regimens is based on meta-analyses of randomized trials that demonstrated a survival advantage for adjuvant chemotherapy in patients following cystectomy, which included all of these regimens [13,14]. In one randomized trial, patients treated with either MVAC or GC demonstrated a median PFS of approximately three years [15]. (See 'Rationale for adjuvant chemotherapy' below.)

However, all these regimens have not been compared directly in randomized trials, and other regimens outside of MVAC, dose-dense MVAC, and GC have not been tested in larger, contemporary adjuvant trials. (See 'Rationale for adjuvant chemotherapy' below.)

The approach to adjuvant therapy in patients with urothelial carcinoma of the upper urinary tract is discussed separately. (See "Malignancies of the renal pelvis and ureter", section on 'Adjuvant platinum-based chemotherapy'.)

Rationale for adjuvant chemotherapy — We offer adjuvant cisplatin-based chemotherapy to patients with muscle-invasive bladder cancer who are eligible for cisplatin, did not receive neoadjuvant treatment, but were found at the time of surgery to have high-risk disease. Such patients have a poor prognosis after surgery without adjuvant systemic therapy, and most available data suggest that adjuvant cisplatin-based chemotherapy delays recurrences and improves OS.

Neoadjuvant chemotherapy remains the preferred approach for patients with muscle-invasive urothelial bladder cancer because it is associated with a survival advantage. In addition, approximately 30 percent of patients treated with radical cystectomy experience postoperative complications or slow recovery that preclude them from receiving adjuvant chemotherapy [16]. (See "Neoadjuvant therapy for localized muscle-invasive urothelial carcinoma of the bladder".)

However, some patients who do not undergo neoadjuvant therapy may have evidence of high-risk disease at cystectomy and are at risk for worse outcomes. For example, the five-year recurrence-free survival rates for patients with invasion beyond the bladder muscle (eg, T3 or T4 disease) and those with lymph node involvement are approximately 40 and 35 percent, respectively, and the five-year OS rates range from 10 to 40 percent [9]. In comparison, for patients with muscle-invasive bladder cancer with pT2 disease, cystectomy alone is associated with an overall cure rate that can be as high as 80 percent [17].

Most studies, but not all [15,18], suggest that adjuvant cisplatin-based chemotherapy delays recurrences and improve OS [10,13,14,19-23]. A meta-analysis from the Advanced Bladder Cancer (ABC) collaboration group included 10 randomized trials with 1183 patients with muscle-invasive bladder who did not receive neoadjuvant chemotherapy [14]. At a median follow-up of six years, the addition of adjuvant cisplatin-based chemotherapy to radical cystectomy improved OS (HR 0.82, 95% CI 0.70-0.96), which translated to a 6 percent absolute improvement in five-year OS. Similar OS results were seen after adjustment for age, sex, and pathologic tumor, and pathologic nodal stage (HR 0.77, 95% CI 0.65-0.92), which translated to a 9 percent absolute improvement in five-year OS. Adjuvant cisplatin-based chemotherapy also improved recurrence-free survival (HR 0.71, 95% CI 0.60-0.83). Limitations of this meta-analysis were the inclusion of some trials that were not fully accrued or terminated early (either for benefit or futility). In addition, approximately one-third of participants did not receive all planned cycles of chemotherapy.

Timing of administration — We suggest initiating adjuvant chemotherapy as soon as surgical recovery permits, typically around six to eight weeks postoperatively, and no later than three months after radical cystectomy. This approach is supported by randomized data (European Organisation for Research and Treatment of Cancer [EORTC] 30994) evaluating the use of adjuvant chemotherapy within 90 days of surgery [15]. Although observational studies have evaluated the initiation of chemotherapy beyond three months [24], the data are of low quality, and this is not an accepted approach in clinical practice. When choosing the appropriate time to initiate adjuvant chemotherapy, the clinician must take into account postoperative recovery in addition to other clinical factors. (See 'Eligible for cisplatin-based chemotherapy' above.)

Ineligible for cisplatin-based chemotherapy — For patients who did not receive neoadjuvant chemotherapy, have pathologic extravesical extension (pT3-T4a disease) or nodal involvement at cystectomy, and are ineligible for (or decline) adjuvant cisplatin-based chemotherapy, we suggest one year of adjuvant immunotherapy with either nivolumab or pembrolizumab. In separate randomized phase III trials (CheckMate-274 [1,2] and AMBASSADOR/KEYNOTE-123 [3], respectively) that included this patient population, both adjuvant nivolumab and adjuvant pembrolizumab improved DFS. However, these studies were not powered to evaluate this specific patient subgroup. Further details of these studies are discussed separately. (See 'Adjuvant nivolumab' above and 'Adjuvant pembrolizumab' above.)

Patients who are ineligible for immunotherapy may be enrolled in clinical trials. Select patients may be candidates for adjuvant RT. (See 'Experimental options' below and 'Decisions regarding adjuvant radiation' below.)

We do not use non-cisplatin-based chemotherapy as adjuvant therapy. In randomized trials and single-arm studies, multiple chemotherapy options (eg, single-agent cisplatin [25], carboplatin [26], and non-cisplatin regimens such as gemcitabine [27,28]) have been evaluated, but none has demonstrated a disease-specific or OS advantage in the adjuvant setting relative to observation or historical controls.

DECISIONS REGARDING ADJUVANT RADIATION

Patient selection and approach — For patients with positive soft tissue surgical margins after cystectomy, some UpToDate contributors offer adjuvant radiation therapy (RT), as these patients are at higher risk for locoregional recurrence (LRR) [29-31]. Additionally, in select cases of patients with high-risk pathologic features (eg, T3 to T4 disease or positive nodes at cystectomy), some UpToDate experts also offer adjuvant RT, but this is not a uniform practice [32,33].The decision to administer RT should be made in a multidisciplinary setting with input from radiation oncology, medical oncology, and urology.

Rationale for adjuvant radiation therapy — Adjuvant RT has been investigated to reduce risk of LRR in patients treated with cystectomy. Although the risk of LRR (ie, intrapelvic recurrences) is <10 percent in patients with organ-confined, node-negative disease, risk factors such as pT3-4 disease, positive lymph nodes and/or limited pelvic lymph node dissection, and positive surgical margins are associated with higher rates of LRR [31,34].

●Adjuvant RT alone – In one randomized trial, the addition of RT to cystectomy improved both disease-free survival (DFS) and local control [32]. In this trial conducted in Egypt of 236 patients treated with cystectomy alone, five-year DFS rates with adjuvant RT versus no RT were 44 versus 25 percent, and five-year local control rates were 93 versus 50 percent [32]. However, results of this trial are challenging to interpret because the majority of tumors were of squamous (rather than urothelial) histology, patients did not receive chemotherapy, and RT regimens differed from those typically used in the United States.

In another phase II trial of adjuvant RT in 72 patients with high-risk muscle-invasive bladder cancer treated with radical cystectomy, two-year local relapse-free survival and overall survival (OS) were 83 and 52 percent, respectively [35].

●Sequential RT and chemotherapy – In a randomized phase II trial, the addition of sequential adjuvant RT to adjuvant chemotherapy improved recurrence-free survival (RFS) [36]. One hundred twenty patients treated with cystectomy alone with at least one high-risk pathologic factor (≥pT3b disease, grade 3 histology, or positive nodes) were randomized to either four cycles of adjuvant chemotherapy or to a "sandwich" regimen of sequential chemotherapy and radiation [36]. The addition of RT to chemotherapy improved two-year locoregional RFS (96 versus 69 percent). While the study demonstrated a trend towards improved DFS (68 versus 56 percent) and OS (71 versus 60 percent) with the addition of RT to chemotherapy, the trial was not powered to address these endpoints. Similar to the previously described trial [32], approximately half the patients had tumors with squamous histology.

In addition to these randomized trials, limited retrospective studies have associated adjuvant RT with improved survival in patients with positive surgical margins, pT4 disease, or positive nodes, although these data should be interpreted with caution given the risk of selection bias [29,30].

Adjuvant radiation therapy dosing and technique — Common adjuvant RT regimens typically involve 45 to 50.4 Gy delivered in 1.8 to 2.0 Gy/day fractions over 4 to 5.5 weeks to the pelvic lymph nodes with or without inclusion of the cystectomy bed [37].

Intensity-modulated radiation therapy (IMRT) is increasingly used in the treatment of bladder cancer and can decrease the risk of late gastrointestinal toxicity by substantially reducing radiation dose to normal tissues [36,38].

Timing of adjuvant radiation therapy — For patients with an appropriate Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (table 4) and recovery after cystectomy, adjuvant RT is initiated approximately 8 to 12 weeks postoperatively. Adjuvant RT can be delivered before or after adjuvant chemotherapy in patients who may be eligible for both.

Bladder reconstruction and adjuvant radiation therapy — Most patients who have undergone radical cystectomy can safely receive adjuvant RT, although there are no established guidelines for the use of RT based on type of bladder reconstruction.

●Urostomy or Indiana pouch – Patients with urostomy (figure 1) or Indiana pouches (figure 2) can be good candidates for RT, as these reconstructions displace much of the urinary system above the radiation field. In one randomized trial of 120 patients with locally advanced bladder cancer who underwent radical cystectomy and adjuvant chemotherapy, late grade 3 gastrointestinal toxicity rates were higher with the addition of adjuvant RT, although such rates were generally low (6.7 versus 2.2 percent) [36].

●Orthotopic neobladder – Although none of the patients in the above study underwent neobladder reconstruction [36], some patients with an orthotopic neobladder and urethral anastomosis (figure 3) may still be candidates for RT, as the bowel used to create the neobladder can typically tolerate lower adjuvant doses of RT. Although there are limited data regarding safety of adjuvant RT after neobladder reconstruction, one study suggested low rates of acute genitourinary toxicity, with no patients experiencing neobladder leak, perforation, or fistula [39].

SPECIAL CONSIDERATIONS

Older or frail adults — Urothelial cancer predominantly occurs in older or medically frail adults, with a median age at diagnosis of 73 [40]. Advanced age is not a contraindication to treatment, and therefore, fit older patients are generally offered a similar treatment approach to adjuvant therapy as younger patients. (See 'Decisions regarding adjuvant therapy' above.)

By contrast, older patients who are medically frail and have a poor performance status are at high risk for toxicity from adjuvant platinum-based chemotherapy. These patients have also typically been excluded from clinical trials on adjuvant chemotherapy and adjuvant immunotherapy. For such patients, we suggest observation following surgical treatment rather than administering adjuvant systemic therapy (including single-agent or carboplatin-based chemotherapy). (See "Overview of the management of bladder cancer in older adults", section on 'Medically frail patients'.)

The impact of performance status on outcome was demonstrated in a series of 381 patients (30 percent over 70 years of age) that assessed treatment outcomes after platinum-based combination chemotherapy [41]. Among patients 70 years or older, a performance status ≥2 was significantly associated with an increased risk of death (hazard ratio [HR] for mortality 2.5).

EXPERIMENTAL OPTIONS

Postoperative ctDNA — Studies are evaluating the use of postoperative circulating tumor DNA (ctDNA) to select (or forego) adjuvant therapy following cystectomy. Further prospective data are necessary prior to the integration of this approach into routine clinical practice.

In a phase III trial (Imvigor010), the use of adjuvant atezolizumab did not improve disease-free survival (DFS) compared with observation; differences in trial design might explain the lack of positive data with atezolizumab [42]. A post-hoc analysis suggested that adjuvant atezolizumab may improve overall survival (OS) among patients with a positive ctDNA test following cystectomy [43,44]. Based on these data, a double-blind phase III trial (IMvigor011) is ongoing to compare adjuvant atezolizumab versus placebo in patients with muscle-invasive bladder cancer, high-risk disease following cystectomy, and a positive postoperative ctDNA test [45]. The study also included a nonrandomized cohort of 171 patients with high-risk disease following cystectomy and negative serial postoperative ctDNA testing who underwent radiographic surveillance [46]. In preliminary results, at a median follow-up of 16 months, one-year DFS and OS for this surveillance cohort were 92 were 100 percent, respectively [46].

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".)

SUMMARY AND RECOMMENDATIONS

●Neoadjuvant versus adjuvant chemotherapy for resected muscle-invasive bladder cancer – For patients with muscle-invasive bladder cancer who elect radical cystectomy, neoadjuvant chemotherapy prior to cystectomy is the standard of care, as this approach is associated with a survival advantage in randomized trials (algorithm 2). However, some clinicians and patients opt for initial treatment with definitive surgery, reserving the option of adjuvant treatment for those at high risk for recurrence based on pathologic staging. (See 'Introduction' above and "Neoadjuvant therapy for localized muscle-invasive urothelial carcinoma of the bladder".)

●Patients with prior neoadjuvant chemotherapy – For patients previously treated with neoadjuvant chemotherapy and high-risk pathologic features at cystectomy (persistent muscle-invasive [ypT2-T4a] or nodal disease), we suggest one year of adjuvant immunotherapy with either nivolumab or pembrolizumab rather than observation (algorithm 1) (Grade 2B). (See 'Prior neoadjuvant chemotherapy' above.)

●Patients without prior neoadjuvant chemotherapy – For patients not previously treated with neoadjuvant chemotherapy who are found to have high-risk disease at cystectomy (ie, pT3 to T4 and/or node-positive disease), we recommend adjuvant systemic therapy (Grade 1B). (See 'No prior neoadjuvant chemotherapy' above and 'Rationale for adjuvant chemotherapy' above.)

•Eligible for cisplatin – For patients who are eligible for cisplatin-based therapy (table 2), we suggest a cisplatin-based combination regimen rather than other systemic regimens (Grade 2C). Our preferred regimens include dose-dense MVAC (table 7) or gemcitabine plus cisplatin (GC) (table 6). We typically initiate treatment six to eight weeks postoperatively. (See 'Eligible for cisplatin-based chemotherapy' above and 'Timing of administration' above.)

•Ineligible for cisplatin – For patients who are ineligible for (or decline) cisplatin-based therapy, we suggest one year of adjuvant immunotherapy with either nivolumab or pembrolizumab (Grade 2B). (See 'Ineligible for cisplatin-based chemotherapy' above.)

●Decisions regarding adjuvant radiation therapy (RT) – For patients with positive soft tissue surgical margins after cystectomy, some UpToDate contributors offer adjuvant RT, as these patients are at higher risk for locoregional recurrences. The decision to administer RT should be made in a multidisciplinary setting with input from radiation oncology, medical oncology, and urology. (See 'Decisions regarding adjuvant radiation' above.)