Small cell carcinoma of the bladder

INTRODUCTION — 

Small cell carcinoma (SCC) of the bladder is an aggressive, poorly differentiated neuroendocrine neoplasm that is similar to small cell lung cancer in its clinical behavior, including a high likelihood of locally advanced disease at the time of diagnosis. In rare cases, SCC can also arise from the upper tract, such as the ureter and renal pelvis [1].

The clinical presentation, diagnosis, and treatment of SCC arising from the bladder or upper urinary tract will be reviewed here. Extrapulmonary SCC at other sites is discussed separately. (See "Extrapulmonary small cell cancer".)

EPIDEMIOLOGY

●Incidence – SCC of the bladder is a rare cancer, representing less than 1 percent of all bladder tumors [2,3]. For example, in the United States, approximately 500 new cases are diagnosed annually.

●Sex – Males are affected more commonly than females (76 versus 24 percent) [2,4,5].

●Age at diagnosis – The median age at diagnosis is 73 years, with older adults (age greater than 75 years) having a poorer prognosis [2,4,5].

●Risk factors – A past history of smoking has been associated with SCC of the bladder [6].

MOLECULAR PATHOGENESIS — 

SCC of the bladder is classified as a discrete histologic entity. The genetics of SCC of the bladder are also different from that of urothelial carcinoma, with a distinct molecular phenotype and involved pathways. Nevertheless, studies have indicated that SCC is derived from the same clonal population as urothelial carcinoma [7]. Although SCC of the bladder can present as a pure nonurothelial variant, it is frequently found in conjunction with other histologic forms of bladder cancer [6,8,9]. (See "Pathology of bladder neoplasms".)

Genetic and molecular findings that are specific to SCC of the bladder include:

●Deletion in chromosome 10q, 5q, 4q, and at 3p25-26, which encompasses the von Hippel-Lindau (VHL) tumor suppressor gene [10,11].

●Deletions at 10q, 4q, 5q, and 13q, with candidate genes including phosphatase and tensin homolog (PTEN) loss (10q23) and retinoblastoma (RB) loss (13q14) [11].

●Alterations in TP53 and RB1 in most cases, with co-occurring alteration for both in more than 70 percent of cases. Telomerase reverse transcriptase (TERT) promoter mutations are common, occurring in around 60 percent of cases in prior observational study [12,13].

●Fibroblast growth factor receptor (FGFR) alterations and translocations do not appear to be common in SCC.

●More common or higher expression of progestin receptor, c-kit, topoisomerase 2, tubulin 3, ribonucleotide reductase subunit M1, topoisomerase 1 [14], epidermal growth factor receptor (EGFR) [15], and somatostatin receptors [16]. Conversely, expression of nectin 4 expression is rarely detected in SCC of the bladder [17]. There is also decreased expression of inflammatory markers such as interferon gamma and canonical T-cell markers.

●Epigenetic alterations are noted to be important, with methylation silencing of the promoter for tumor suppressor genes including mut L homolog 1 (MLH1) and O-6-methylguanine deoxyribonucleic acid (DNA) methyltransferase (MGMT) [14].

CLINICAL PRESENTATION

Primary tumor — Most patients with SCC of the bladder (80 to 90 percent) present with a muscle-invasive primary tumor (T2 or greater; stage II or greater) (table 1) [18]. Symptoms related to the primary tumor for SCC of the bladder are similar to those seen with the primary tumor from urothelial carcinoma. Common symptoms include [19]:

●Hematuria (86 percent)

●Ureteral obstruction and acute kidney failure (13 percent)

●Dysuria and increased urinary frequency (29 percent)

SCC of the bladder can also be an incidental and concomitant diagnosis in patients with urothelial carcinoma. In one observational series of patients with a diagnosis of urothelial carcinoma undergoing surveillance cystoscopy, the incidental diagnosis rate for SCC of the bladder was 7 percent. SCC is also sometimes identified during comprehensive histopathologic evaluation of the surgical specimen from a patient being treated for urothelial carcinoma with radical cystectomy. (See 'Diagnosis' below.)

Metastatic disease — SCC of the bladder has a greater propensity to metastasize, regardless of tumor (T) stage [2,6,20,21]. Advanced or metastatic disease is seen in up to 80 percent of patients [22,23]. In an observational study of 642 patients with SCC of the bladder from the Surveillance, Epidemiology, and End Results (SEER) database, the stage at presentation was as follows [2]:

●Stage I – 12 percent

●Stage II – 32 percent

●Stage III – 14 percent

●Stage IV – 36 percent

●Unstaged – 6 percent

In advanced or metastatic SCC of the bladder, the most common areas of disease involvement include the regional lymph nodes (57 percent) followed by the distant visceral organs (28 to 50 percent) such as the lungs, bones, or liver. Brain metastases are much less common with SCC of the bladder (between 2 and 11 percent) than small cell lung cancer [5,21,24-29].

Paraneoplastic syndromes can also occur but are less common than with small cell lung cancer [30]. (See "Clinical manifestations of lung cancer", section on 'Paraneoplastic phenomena'.)

DIAGNOSTIC EVALUATION

Initial evaluation — The diagnostic evaluation for SCC of the bladder is the same as that for other bladder cancers. On cystoscopy, the most frequently involved sites in the bladder are the lateral wall or the bladder dome, but any area can be involved. (See "Clinical presentation, diagnosis, and staging of bladder cancer", section on 'Initial evaluation'.)

Diagnosis — The diagnosis of SCC of the bladder is generally made by histopathologic examination of a tissue specimen from a transurethral biopsy obtained during cystoscopy or resection of a tumor (eg, radical cystectomy). The pathology of SCC of the bladder is discussed separately. (See "Pathology of bladder neoplasms", section on 'Small cell carcinoma'.)

Imaging studies — Once the diagnosis of SCC of the bladder is confirmed, initial evaluation should also include staging imaging studies due to the high rate of metastatic disease.

●A contrast-enhanced computed tomography (CT) of the chest, abdomen, and pelvis should be obtained. A gadolinium-enhanced magnetic resonance imaging (MRI) of the abdomen and pelvis, in addition to appropriate chest imaging, is also an option or an appropriate alternative for those who are unable to receive CT contrast or require further imaging evaluation of radiographic findings on initial CT studies.

●A gadolinium-enhanced MRI of the brain is offered to patients with advanced disease (clinical T3b, node-positive), distant metastatic disease, or those with neurologic symptoms concerning for central nervous system involvement. (See "Epidemiology, clinical manifestations, and diagnosis of brain metastases", section on 'Clinical manifestations'.)

STAGING — 

SCC of the bladder is staged using the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) system that is used for other bladder cancers (table 1). (See "Clinical presentation, diagnosis, and staging of bladder cancer", section on 'Staging'.)

TREATMENT — 

The treatment approach to SCC of the bladder is based on disease stage. Patients should initiate therapy as soon as possible after the diagnosis is confirmed and staging studies are completed due to the aggressive nature and poor prognosis of this disease. (See 'Prognosis' below.)

Stage I, II, and III disease — For most patients with treatment-naïve SCC of the bladder that is stage I, II, or III (ie, disease localized to the bladder with or without lymph nodes, and no evidence of distant metastases), we suggest initial treatment with neoadjuvant (ie, preoperative) chemotherapy rather than upfront locoregional therapy to the bladder (ie, radical cystectomy or radiation therapy [RT]). (See 'Rationale' below.)

Patients who are treated with neoadjuvant chemotherapy and do not develop metastatic disease may subsequently be evaluated for consolidation therapy to the bladder (radical cystectomy or RT). (See 'Consolidation therapy to the bladder' below.)

Neoadjuvant chemotherapy

Rationale — In most patients with SCC of the bladder and stage I, II, and III disease, neoadjuvant chemotherapy is used to reduce local tumor burden prior to radical cystectomy as well as to systemically treat micrometastatic disease [31]. In addition, observational data comparing neoadjuvant chemotherapy followed by locoregional therapy to the bladder (either radical cystectomy or RT) suggest an overall survival (OS) advantage over locoregional therapy alone [5,20], although this has not been confirmed in prospective randomized trials. As examples:

●In one retrospective series, 95 patients with resectable (<cT4aN0M0) SCC of the bladder were treated either with neoadjuvant chemotherapy followed by radical cystectomy (48 patients) or initial radical cystectomy (47 patients, 21 of whom received subsequent adjuvant chemotherapy) [31]. The most frequently used neoadjuvant chemotherapy regimens were ifosfamide plus doxorubicin alternating with etoposide plus cisplatin (54 percent); etoposide plus cisplatin (15 percent); and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC; 10 percent).

•Neoadjuvant chemotherapy plus radical cystectomy was associated with a higher OS (median 160 versus 18 months) and five-year disease-specific survival (DSS; 79 versus 20 percent) compared with initial radical cystectomy with or without adjuvant chemotherapy.

•The rate of pathologic downstaging (≤ypT1N0) with neoadjuvant chemotherapy was 62 percent. Similar rates of pathologic downstaging with neoadjuvant platinum-based chemotherapy have been seen in other studies [32].

•In patients treated with initial cystectomy, the addition of adjuvant chemotherapy was not associated with improved OS (median 18 months either with or without adjuvant chemotherapy), suggesting that neoadjuvant systemic therapy might offer better systemic disease control by treating micrometastatic disease.

●In one retrospective study from the National Cancer Database of 625 patients with localized or locally advanced SCC of the bladder (18 percent with less than cT2 disease; 82 percent with cT2-4 disease), neoadjuvant chemotherapy plus cystectomy was associated with a higher three-year OS (53 percent) compared with radical cystectomy or bladder preservation therapy alone (38 percent and 23 percent, respectively) [20]. Another study also demonstrated similar clinical benefits for neoadjuvant chemotherapy [5].

●While stage I tumors are less common than stage II and III tumors, stage I tumors were also included in these and other studies evaluating neoadjuvant chemotherapy [33]. As an example, in an observational study of 30 patients with cT1N0 SCC of the bladder, most were treated with neoadjuvant chemotherapy (70 percent) and definitive local therapy (90 percent). Among those with cT1N0 SCC, neoadjuvant chemotherapy was associated with improved disease-free (hazard ratio [HR] 0.30) and overall survival (HR 0.32) [33].

Selection of neoadjuvant therapy — For most patients, we suggest neoadjuvant chemotherapy with cisplatin plus etoposide rather than other systemic agents. Patients who are ineligible for (or intolerant of) cisplatin-based therapy (table 2) may alternatively receive neoadjuvant chemotherapy with carboplatin plus etoposide. While doxorubicin plus ifosfamide alternating with cisplatin and etoposide is also an effective option, this regimen is not our preferred initial therapy since it is more complex to administer and difficult to tolerate.

The optimal number of cycles of neoadjuvant therapy is not established. For most patients, we typically offer at least four cycles of neoadjuvant platinum-etoposide chemotherapy. For those with high-risk pathologic features postsurgery (greater than ypT1 or N1-positive) and no other metastases to distant organs, we may offer up to six cycles of perioperative chemotherapy overall, provided the patient is tolerating treatment well [34]. (See 'Consolidation therapy to the bladder' below.)

Data suggest that neoadjuvant platinum plus etoposide can be successfully used to treat SCC of the bladder [5,31,32,34-37]. Most studies evaluated neoadjuvant cisplatin plus etoposide, extrapolating from data in limited-stage small cell lung cancer. (See "Limited-stage small cell lung cancer: Initial management".)

●In one retrospective study of 409 patients with SCC of the bladder, neoadjuvant chemotherapy was associated with improved OS (median 22 versus 9 months, HR 0.46, 95% CI 0.37-0.59) [5]. The most frequently used neoadjuvant regimens were carboplatin and etoposide (55 percent) and cisplatin plus etoposide (17 percent). Less frequently used regimens included platinum plus gemcitabine and other regimens.

●In one retrospective series of 95 patients with resectable SCC of the bladder, neoadjuvant chemotherapy was associated with improved five-year DSS [31]. Among the chemotherapy regimens used, most patients received cisplatin plus etoposide either with or without doxorubicin plus ifosfamide. (See 'Rationale' above.)

●A prospective phase II study included 18 patients with clinically localized SCC of the bladder who underwent neoadjuvant chemotherapy. Chemotherapy consisted of four cycles of doxorubicin plus ifosfamide alternating with the combination of cisplatin plus etoposide [34]. At cystectomy, 14 of 18 patients (78 percent) either had no evidence of residual disease or only carcinoma in situ. Median OS was 58 months, and 13 of the 18 patients are alive and disease-free. Grade 4 toxicities were seen in three patients (low neutrophil count, catheter-related infection, and pulmonary embolus). The most common grade 3 toxicities were transfusions (37 percent), neutropenic fever (23 percent), and non-neutropenic fever (17 percent). Two patients were unable to complete therapy due to toxicity and six patients required dose reductions. Similar efficacy was seen with this regimen in a retrospective study [31].

Consolidation therapy to the bladder — We monitor patients for disease progression using restaging imaging with a contrast-enhanced CT chest, abdomen, and pelvis every two to three cycles of neoadjuvant chemotherapy.

●For patients who are treated with neoadjuvant chemotherapy and have no evidence of distant metastatic disease, options for consolidation therapy include either radical cystectomy or definitive RT to the bladder. Since high-quality data comparing radical cystectomy to definitive RT are limited [5,24,36-40], selection of consolidation therapy is mainly based on patient performance status, comorbidities, and preferences. As an example, one retrospective study included a subset of 200 patients with bladder-confined SCC who were treated with neoadjuvant chemotherapy followed by either radical cystectomy or definitive RT alone. At a median follow-up of 15 months, OS was similar for both treatment arms (median 27 versus 30 months) [5].

●Patients who develop metastatic disease while on or shortly after neoadjuvant chemotherapy are not candidates for consolidation therapy to the bladder. Such patients are treated with systemic therapy directed at metastatic disease. (See 'Metastatic disease' below.)

Radical cystectomy has the benefit of completely removing residual disease, improving the chances of local disease control, and providing definitive pathologic staging. Radical cystectomy is performed once all cycles of neoadjuvant chemotherapy are completed and the patient has appropriately recovered. Further details are discussed separately. (See "Neoadjuvant therapy for localized muscle-invasive urothelial carcinoma of the bladder" and "Overview of the initial approach and management of urothelial bladder cancer", section on 'Radical cystectomy'.)

Definitive RT to the bladder is an equally appropriate option for consolidation therapy. This approach may be preferred in patients who may not be fit enough for radical cystectomy or those who prefer to preserve their native bladder. Data are limited for the optimal timing and integration of RT with cisplatin-based chemotherapy. In one retrospective study, 11 patients with locoregionally advanced SCC of the bladder were treated with transurethral bladder resection followed by chemotherapy and radiation [41]. The RT doses ranged between 45 and 65 Gy. RT was administered either as concurrent chemoradiation (CRT), with RT initiated prior to the second cycle of chemotherapy; induction chemotherapy followed by RT alone; or neoadjuvant chemotherapy followed by concurrent CRT. All patients received concurrent cisplatin-based chemotherapy, and the most frequently used regimen was cisplatin plus etoposide. At a median follow-up of 1.1 years, eight patients had a complete biopsy-proven response on cystoscopy. Three-year OS, distant-metastasis-free survival, and locoregional control rates were 24, 27, and 78 percent, respectively. No late genitourinary or gastrointestinal grade 3 toxicities occurred. (See "Bladder preservation treatment options for muscle-invasive urothelial bladder cancer".)

Despite data supporting the use of twice daily hyperfractionated RT with concurrent chemotherapy in limited-stage small cell lung cancer [42], there are no data supporting this approach in locoregionally advanced SCC of the bladder. (See "Limited-stage small cell lung cancer: Initial management".)

Indications for adjuvant therapy

●No prior neoadjuvant therapy – We suggest adjuvant (ie, postoperative) chemotherapy with cisplatin plus etoposide, administered for four to six cycles, for patients with localized SCC of the bladder who were initially treated with radical cystectomy alone and no prior neoadjuvant therapy, as limited observational data suggest an OS benefit with this approach. Patients who are ineligible for cisplatin (table 2) may receive four to six cycles of adjuvant carboplatin plus etoposide.

In observational studies, the addition of adjuvant chemotherapy to radical cystectomy is associated with improved OS [35,43]. In one retrospective study of 68 patients with SCC of the bladder were treated with cystectomy, patients treated with adjuvant chemotherapy had higher five-year OS compared with those who did not receive adjuvant chemotherapy (43 versus 20 percent) [43]. By contrast, cystectomy alone is associated with a poor prognosis and a relatively low cure rate, with five-year DSS ranging between 10 and 38 percent [6,20,21,31,35,43].

●Prior neoadjuvant therapy – Patients who receive neoadjuvant platinum plus etoposide chemotherapy followed by consolidation therapy (radical cystectomy or definitive RT) and have no disease progression do not require further systemic therapy. Such patients may proceed to posttreatment surveillance. (See "Overview of the initial approach and management of urothelial bladder cancer", section on 'Posttreatment surveillance (muscle-invasive bladder cancer)'.)

In patients with limited stage small cell lung cancer who are treated with concurrent CRT, the addition of consolidation durvalumab improved OS in a randomized trial (ADRIATIC) [44]. However, consolidation immunotherapy has not been specifically evaluated in locoregionally advanced SCC of the bladder and remains investigational for this population. (See "Limited-stage small cell lung cancer: Initial management", section on 'Consolidative durvalumab'.)

What is the role of prophylactic cranial irradiation? — For patients with locoregionally advanced SCC of the bladder, we do not routinely offer prophylactic cranial irradiation (PCI). Brain metastases are rare in with extrapulmonary SCC, including SCC of the bladder [5,25,26]. Limited data also do not show a significant benefit for PCI [45], which can also cause significant side effects. Further details are discussed separately. (See "Extrapulmonary small cell cancer", section on 'Treatment'.)

Metastatic disease

Initial therapy — For initial systemic therapy in most patients with metastatic SCC of the bladder, we suggest chemoimmunotherapy rather than chemotherapy or immunotherapy alone, extrapolating from data in extensive-stage small cell lung cancer. Further details are discussed separately. Doxorubicin plus ifosfamide alternating with cisplatin plus etoposide is also an alternative.

There are limited data on the initial management of metastatic SCC of the bladder due to the rarity of this disease [46]. As such, management is mainly extrapolated from data in treatment-naïve extensive-stage small cell lung cancer, which is treated with chemoimmunotherapy. Further details are discussed separately. (See "Extensive-stage small cell lung cancer: Initial management".)

One exception is alternating cycles of doxorubicin plus ifosfamide with cisplatin plus etoposide, a regimen that has been specifically evaluated in metastatic SCC of the bladder [34]. In a phase II trial, 12 patients with metastatic SCC of the bladder at presentation (five with only lymph node involvement and seven with involvement at other sites with or without lymph node disease) were treated with alternating regimens of doxorubicin plus ifosfamide and cisplatin plus etoposide [34]. Three patients had a complete response and underwent surgical consolidation. The median OS for this cohort was 13 months, but one patient remained disease-free for 28 months after the original treatment.

Second- and later-line therapy — For patients who progress on platinum-based therapy, we offer systemic therapy using the same approach for refractory and relapsed small cell lung cancer. Further details are discussed separately. (See "Treatment of refractory and relapsed small cell lung cancer".)

There are limited data on the management of treatment-refractory metastatic SCC of the bladder due to the rarity of this disease. As such, second- and later-line treatment is mainly extrapolated from data in extensive-stage small cell lung cancer. Regimens that have been studied in platinum-refractory metastatic SCC of the bladder include lurbinectedin, camptothecin, and topotecan [9,27,47]. For patients who progress on platinum-based chemotherapy but have not previously received immunotherapy, nivolumab plus ipilimumab [48], single-agent nivolumab, and single-agent pembrolizumab [49,50] may also be effective. However, the quality of studies in metastatic SCC of the bladder is limited due to small number of patients and/or the use of different regimens. Clinical trial enrollment is encouraged, where available.

Patients with brain metastases — For the rare patient with SCC of the bladder who presents with brain metastases, management of the brain metastases is similar to that of patients with extensive-stage small cell lung cancer. Patients with asymptomatic brain metastases may start initial systemic therapy, followed by RT to the brain metastases, whereas those with symptomatic brain metastases are managed with RT followed by systemic therapy. Further details are discussed separately. (See "Extensive-stage small cell lung cancer: Initial management", section on 'Patients who present with brain metastases'.)

PROGNOSIS — 

Patients with SCC of the bladder have a generally poor prognosis [2]. Median overall survival (OS) ranging between 4 and 23 months, and is longer for those with localized SCC (21 months) [4] and shorter for those with metastatic disease (7 to 13 months) [27,34]. The five-year OS ranges between 10 and 40 percent [23].

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

●General principles – Small cell carcinoma (SCC) of the bladder is a rare, aggressive, poorly differentiated neuroendocrine neoplasm that is similar to small cell lung cancer in its clinical behavior, including a high likelihood of locally advanced disease at the time of diagnosis. The prognosis is generally poor. (See 'Introduction' above and 'Epidemiology' above and 'Prognosis' above.)

●Clinical presentation

•Primary tumor – Most patients present with a muscle-invasive primary tumor (T2 or greater; stage II or greater). Common symptoms related to the primary tumor include hematuria, ureteral obstruction and acute kidney failure, dysuria, and increased urinary frequency. (See 'Primary tumor' above.)

•Metastatic disease – Advanced or metastatic disease is seen in up to 80 percent of patients. Common areas of disease involvement include the regional lymph nodes, lungs, bones, or liver. Brain metastases are much less common with SCC of the bladder than small cell lung cancer. (See 'Metastatic disease' above.)

●Diagnostic evaluation

•Diagnosis – The diagnosis of SCC of the bladder is generally made by histopathologic examination of a tissue specimen from a transurethral biopsy obtained during cystoscopy or resection of a tumor (eg, radical cystectomy).

•Imaging studies – Staging imaging is performed using a contrast-enhanced CT of the chest, abdomen, and pelvis. A gadolinium-enhanced MRI of the brain is obtained for those with advanced disease (clinical T3b, node-positive), distant metastatic disease, or those with neurologic symptoms. (See 'Diagnostic evaluation' above.)

●Staging – SCC of the bladder is staged using the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) system that is used for other bladder cancers (table 1). (See 'Staging' above.)

●Treatment of stage I, II, and III disease – For most patients with treatment-naïve, SCC of the bladder that is stage I, II, or III (ie, disease localized to the bladder with or without lymph nodes, and no evidence of distant metastases), we suggest initial treatment with neoadjuvant (ie, preoperative) chemotherapy rather than upfront locoregional therapy to the bladder (ie, radical cystectomy or radiation therapy [RT]) (Grade 2C). (See 'Stage I, II, and III disease' above.)

•Selection of neoadjuvant therapy – For most patients, we suggest neoadjuvant chemotherapy with cisplatin plus etoposide rather than other systemic agents (Grade 2C). Patients who are ineligible for (or intolerant of) cisplatin-based therapy (table 2) may alternatively receive neoadjuvant chemotherapy with carboplatin plus etoposide. While doxorubicin plus ifosfamide alternating with cisplatin and etoposide is also an effective option, this regimen is more complex to administer and difficult to tolerate. (See 'Selection of neoadjuvant therapy' above.)

For most patients, we typically offer a total of four cycles of neoadjuvant platinum-etoposide chemotherapy. For those with high-risk pathologic features postsurgery (greater than ypT1 or N1-positive) and no other metastases to distant organs, we may offer up to six cycles of perioperative chemotherapy overall, provided the patient is tolerating treatment well.

•Consolidation therapy to the bladder – For patients who are treated with neoadjuvant chemotherapy and have no evidence of distant metastatic disease, options for consolidation therapy include either radical cystectomy or definitive RT to the bladder. (See 'Consolidation therapy to the bladder' above.)

•Indications for adjuvant therapy – For patients with localized SCC of the bladder who were initially treated with radical cystectomy alone and no prior neoadjuvant therapy, we suggest adjuvant (ie, postoperative) cisplatin plus etoposide (Grade 2C), administered for four to six cycles, as limited observational data suggest an overall survival (OS) benefit with this approach. Patients who are ineligible for cisplatin may receive four to six cycles of adjuvant carboplatin plus etoposide. (See 'Indications for adjuvant therapy' above.)

Patients who receive neoadjuvant chemotherapy followed by consolidation therapy (radical cystectomy or definitive RT) and have no disease progression do not require further systemic therapy. Such patients may proceed to posttreatment surveillance. (See "Overview of the initial approach and management of urothelial bladder cancer", section on 'Posttreatment surveillance (muscle-invasive bladder cancer)'.)

•What is the role of PCI? – We do not routinely offer prophylactic cranial irradiation (PCI). Brain metastases are rare with SCC of the bladder, benefit from PCI is limited, and toxicity can be significant. (See "Extrapulmonary small cell cancer", section on 'Treatment'.)

●Treatment of metastatic disease – For initial systemic therapy in most patients with metastatic SCC of the bladder, we suggest chemoimmunotherapy rather than either chemotherapy or immunotherapy alone (Grade 2C), extrapolating from data in extensive-stage small cell lung cancer. (See "Extensive-stage small cell lung cancer: Initial management".)

Doxorubicin plus ifosfamide alternating with cisplatin plus etoposide is also an alternative. (See 'Initial therapy' above.)

ACKNOWLEDGMENTS — 

The UpToDate editorial staff acknowledges Tanya B Dorff, MD, Timothy Gilligan, MD, and David I Quinn, MBBS (Hons I), PhD, FRACP, FACP, who contributed to earlier versions of this topic review.