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Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder

Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder
Literature review current through: Jan 2024.
This topic last updated: Dec 13, 2023.

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 (transitional cell) carcinoma of the bladder", section on 'Epidemiology'.)

The identification of active chemotherapy regimens in patients with metastatic urothelial carcinoma has resulted in the use of both neoadjuvant and adjuvant chemotherapy. Neoadjuvant chemotherapy is associated with a survival advantage for patients with locally advanced bladder cancer relative to no chemotherapy, but clinicians are not yet able to identify those patients most likely to benefit from treatment [1]. This raises the concern that some may be overtreated. As a result, some clinicians and patients opt for initial treatment with definitive surgery rather than neoadjuvant chemotherapy, reserving the option of adjuvant treatment for those at high risk for recurrence based on pathologic staging.

The role of adjuvant chemotherapy, adjuvant immunotherapy, and adjuvant radiation in patients with locally advanced urothelial carcinoma of the bladder will be reviewed here. Surgical approaches, the role of neoadjuvant chemotherapy, the use of bladder-sparing chemoradiotherapy in bladder cancer, and management of urothelial carcinomas of the upper urinary tract are discussed separately:

(See "Overview of the initial approach and management of urothelial bladder cancer".)

(See "Radical cystectomy".)

(See "Neoadjuvant treatment options for muscle-invasive urothelial bladder cancer".)

(See "Bladder preservation treatment options for muscle-invasive urothelial bladder cancer", section on 'Concurrent chemoradiation'.)

(See "Malignancies of the renal pelvis and ureter", section on 'Treatment of localized disease'.)

DECISIONS REGARDING ADJUVANT CHEMOTHERAPY

Patients who did not receive neoadjuvant chemotherapy

Patient selection — Patients with high-risk tumor features who did not receive neoadjuvant chemotherapy are appropriate candidates for adjuvant chemotherapy, as long as no contraindications to cisplatin are present (algorithm 1). 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 [1]. Patients with these tumor characteristics should be further evaluated for eligibility of adjuvant cisplatin-based combination chemotherapy. (See 'Choice of regimen' below.)

The approach to adjuvant therapy in those with high-risk pathologic features at cystectomy who have previously received neoadjuvant therapy is discussed below. (See 'Patients who received neoadjuvant chemotherapy' below.)

Rationale for adjuvant chemotherapy — The role of adjuvant chemotherapy in patients with muscle-invasive urothelial bladder cancer has not been established in fully accrued, adequately powered randomized trials [2]. Neoadjuvant chemotherapy remains the preferred approach for these patients because it is associated with a survival advantage, and approximately 30 percent of patients experience complications or slow recovery following radical cystectomy that preclude them from receiving adjuvant chemotherapy [3]. (See "Neoadjuvant treatment options for muscle-invasive urothelial bladder cancer".)

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 overall survival rate ranges from 10 to 40 percent [1]. 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 [4].

Although studies suggest that adjuvant chemotherapy is efficacious in such patients, as it may delay recurrences and improve survival, such data are controversial. Meta-analyses and observational studies suggest improved overall and progression-free survival (PFS) with adjuvant chemotherapy [5-12]. In one meta-analysis of nine randomized trials with 940 patients, the addition of adjuvant cisplatin-based chemotherapy to radical cystectomy improved overall survival (hazard ratio [HR] 0.77, 95% CI 0.59-0.99); it also improved disease-free survival (DFS) in the overall group (HR 0.66, 95% CI 0.45-0.91) and in those with positive nodal involvement (HR 0.39, 95% CI 0.28-0.54) [6]. However, this meta-analysis is not considered conclusive as it included trials with heterogeneous patient populations, poor accrual, and early termination. Additionally, the meta-analysis was unable to evaluate the benefits of adjuvant chemotherapy based on tumor (T) stage, due to insufficient information reported from the individual trials.

However, other studies, including one of the largest randomized trials, did not demonstrate an overall survival benefit with adjuvant chemotherapy [5,13]. As an example, in the randomized European Organisation for Research and Treatment of Cancer (EORTC) 30994 trial, among 284 patients who underwent radical cystectomy, those receiving adjuvant chemotherapy had improved five-year PFS (48 versus 32 percent; HR 0.54, 95% CI 0.40-0.73), but this did not translate to an overall survival benefit compared with those assigned to observation (five-year overall survival 54 versus 48 percent; HR 0.78, 95% CI 0.56-1.08). Additionally, in an exploratory analysis, adjuvant chemotherapy was associated with prolonged survival in patients with node-negative disease relative to those with node-positive disease, although the reasons to explain this finding are not readily apparent. It does raise the question of whether surgical factors (eg, extent of nodal dissection) may have impacted these outcomes.

Taking all the available data into account, the role of adjuvant therapy remains unresolved, and additional data are necessary. Nevertheless, given the benefits of chemotherapy in the neoadjuvant setting and the poor prognosis of some patients following surgical resection, we continue to offer adjuvant chemotherapy to those who did not receive neoadjuvant treatment but were found at the time of surgery to have high-risk disease, defined above (see 'Patients who did not receive neoadjuvant chemotherapy' above). In such cases, a risk-benefit discussion with the patient is needed, as some patients may reasonably opt to forego additional adjuvant chemotherapy or enroll in clinical trials. (See 'Experimental options' below.)

Choice of regimen

Definition of cisplatin eligibility — The preferred choice of regimen for adjuvant chemotherapy 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 'Patients eligible for cisplatin-based chemotherapy' below.)

Given that cisplatin-based therapy is the standard of care and that renal dysfunction and systemic comorbidities increase with age, the following criteria are used to select patients for adjuvant therapy [9]. 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 [9]. (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 renal 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) [14].

Of note, if the impairment in renal function is due to renal/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".)

Patients eligible for cisplatin-based chemotherapy — For patients with indications for adjuvant chemotherapy who are eligible for cisplatin-based combination chemotherapy (table 2), our preferred regimens include:

Three to four cycles of either MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin (table 7)) or high-dose MVAC with growth factor support (table 8)

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 MVAC because GC has a lesser toxicity profile that is easier to manage during treatment. For example, compared with GC, MVAC is associated with higher rates of neutropenia, neutropenic fever and sepsis, mucositis, and alopecia [15]. However, others prefer MVAC over GC for fit patients, extrapolating from data in the neoadjuvant setting, which suggests a survival benefit for MVAC. (See "Neoadjuvant treatment options for muscle-invasive urothelial bladder cancer", section on 'Neoadjuvant chemotherapy'.)

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 [6]. In one randomized trial, patients treated with either MVAC or GC demonstrated a median PFS of approximately three years [5]. However, all of 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' above.)

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'.)

Patients 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 nivolumab rather than observation. In a randomized phase III trial (CheckMate-274) that included this patient population, adjuvant nivolumab improved DFS over placebo [16]. However, this study was not powered to evaluate this specific patient subgroup. Further details of this study are discussed below. (See 'Adjuvant nivolumab' below.)

For patients who are ineligible for or do not meet the above indications for adjuvant immunotherapy, we do not suggest the use of non-cisplatin-based chemotherapy as adjuvant therapy. Select patients may be candidates for adjuvant radiation therapy (RT). Patients may also be observed or enrolled in clinical trials. (See 'Experimental options' below and 'Decisions regarding adjuvant radiation' below.)

In randomized trials and single-arm studies, multiple chemotherapy options (eg, single-agent cisplatin [17], carboplatin [18], and non-cisplatin regimens such as gemcitabine [19,20]) have been evaluated, but none has demonstrated a disease-specific or overall survival advantage in the adjuvant setting relative to observation or historical controls.

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 [5]. Although observational studies have evaluated the initiation of chemotherapy beyond three months [21], 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 'Patients eligible for cisplatin-based chemotherapy' above.)

Patients who received neoadjuvant chemotherapy

Patient selection — Select patients with high-risk tumor features who received neoadjuvant cisplatin-based combination chemotherapy are appropriate candidates for adjuvant immunotherapy. 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 — For patients who have previously received neoadjuvant cisplatin-based chemotherapy and had high-risk pathologic features at cystectomy (persistent muscle-invasive [ypT2-T4a] or nodal disease), we suggest one year of adjuvant nivolumab rather than observation (algorithm 1). Adjuvant nivolumab improves DFS among select patients with urothelial carcinoma of the bladder with high-risk pathologic features on radical cystectomy [16].

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 [16]. 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 'Patients ineligible for cisplatin-based chemotherapy' above.)

Patients were randomly assigned to either nivolumab at 240 mg intravenously every two weeks or placebo for up to one year. At median follow-up of approximately 20 months, compared with placebo, adjuvant nivolumab resulted in the following:

Intention to treat population – Improved DFS, the primary endpoint (median 21 versus 11 months, 63 versus 47 percent at one year, 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).

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 observation (HR 0.52, 95% CI 0.38-0.71).

PD-L1 positive tumors (≥1 percent) – 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).

Overall survival results are not mature and have not yet been reported.

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). Health-related quality of life was also similar between the two treatment arms, with no significant deterioration over time noted in those receiving nivolumab [22].

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 [23]. 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.

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

Ineligible for immunotherapy — For patients who are ineligible for or do not meet the above indications for adjuvant immunotherapy, either enrollment in clinical trials or observation are appropriate options. These options may be offered after a discussion with the patient on the limited available data for adjuvant chemotherapy in this setting [24-26]. In very select cases, some may also be candidates for adjuvant RT, which is discussed below. (See 'Experimental options' below and 'Decisions regarding adjuvant radiation' below.)

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) [27-29]. 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 [30,31].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 [29,32].

Adjuvant RT alone – In one randomized trial, the addition of RT to cystectomy improved both disease-free survival (DFS) and local control [30]. 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 [30]. 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 were 83 and 52 percent, respectively [33].

Sequential RT and chemotherapy – In a randomized phase II trial, the addition of sequential adjuvant RT to adjuvant chemotherapy improved recurrence-free survival (RFS) [34]. 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 [34]. 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 overall survival (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 [30], 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 [27,28].

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 [35].

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 [34,36].

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) [34].

Orthotopic neobladder – Although none of the patients in the above study underwent neobladder reconstruction [34], 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 [37].

SPECIAL CONSIDERATIONS

Older or frail adults — Urothelial cancer predominantly occurs in older or medically frail adults, with a median age at diagnosis of 73 [38]. 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 chemotherapy' 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 [39]. 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 — The following adjuvant immunotherapy regimens are being evaluated in clinical trials.

Atezolizumab – In a phase III trial (IMvigor010), the use of adjuvant atezolizumab did not improve DFS compared with observation [40]. Differences in trial design might explain the lack of positive data with atezolizumab. A post-hoc analysis suggests that adjuvant atezolizumab may improve survival among patients with a positive circulating tumor DNA (ctDNA) test following cystectomy [41], and further prospective data are necessary.

Pembrolizumab – Based on preliminary reports of an open-label phase III trial (AMBASSADOR; KEYNOTE-123) of 702 patients with localized muscle-invasive urothelial carcinoma and locally advanced urothelial carcinoma treated with surgery, adjuvant pembrolizumab improved disease-free survival compared with observation [42]. We await further results prior to the routine clinical use of adjuvant pembrolizumab in this population.

The approach to immunotherapy in patients with metastatic urothelial carcinoma is discussed separately. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract".)

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 treatment options for muscle-invasive urothelial bladder cancer".)

Patients without prior neoadjuvant chemotherapy – For patients not previously treated with neoadjuvant chemotherapy and with high-risk disease at cystectomy, we suggest adjuvant chemotherapy rather than observation (Grade 2C). High-risk features in this patient population include pathologic T3 to T4 disease and/or node-positive disease. However, given that data are controversial for the clinical benefits of this approach, some patients may alternatively choose observation or enrollment in clinical trials (algorithm 1). (See 'Patients who did not receive neoadjuvant chemotherapy' above.)

Patients eligible for adjuvant chemotherapy – For patients who are eligible for adjuvant chemotherapy (table 2), we suggest a cisplatin-based combination rather than single-agent cisplatin or a non-platinum-based regimen (Grade 2C). (See 'Patient selection' above and 'Choice of regimen' above.)

-Preferred cisplatin-based regimens – Our preferred regimens include MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin (table 7)), high-dose MVAC (table 8), or gemcitabine plus cisplatin (GC) (table 6). (See 'Patients eligible for cisplatin-based chemotherapy' above.)

-Timing of adjuvant chemotherapy – We typically initiate adjuvant chemotherapy around six to eight weeks postoperatively, and no later than three months after radical cystectomy. (See 'Timing of administration' above.)

Patients ineligible for cisplatin-based adjuvant chemotherapy – For patients not previously treated with neoadjuvant chemotherapy and high-risk disease at cystectomy (pathologic extravesical extension [pT3-pT4a] or nodal involvement) who are ineligible for (or decline) a cisplatin-based combination adjuvant therapy, we suggest one year of adjuvant nivolumab rather than observation (Grade 2C) (algorithm 1). For those who are ineligible for or do not meet the indications for adjuvant immunotherapy, we observe rather than using adjuvant non-cisplatin-based chemotherapy. (See 'Patients ineligible for cisplatin-based chemotherapy' above.)

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 nivolumab rather than observation (algorithm 1) (Grade 2B). (See 'Patients who received neoadjuvant chemotherapy' above and 'Adjuvant nivolumab' above.)

For patients who are ineligible for adjuvant immunotherapy, either enrollment in clinical trials or observation are appropriate options. (See 'Ineligible for immunotherapy' above and 'Experimental options' 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.)

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Topic 2966 Version 48.0

References

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