Version May 2024
INTRODUCTION — Bladder cancer is the most common malignancy of the urinary system, with over 80,000 new cases and approximately 17,000 deaths in the United States annually [1]. Worldwide, bladder cancer accounts for approximately 600,000 new cases and over 200,000 deaths [2]. In developed areas of the world, such as North America and Western Europe, these bladder cancers are predominantly urothelial.
Nearly 70 percent of new bladder cancer diagnoses are early stage (ie, Ta, Tis, and T1 disease (table 1)) and have not yet invaded the muscular layer of the bladder wall. These patients are often managed with transurethral resection of bladder tumor (TURBT) with or without adjuvant intravesical therapy. The remaining 30 percent of patients have muscle-invasive bladder cancer, including cancer involving the muscularis propria (T2), perivesical tissue (T3), or adjacent pelvic organs/structures (T4).
Radical cystectomy remains the cornerstone of curative treatment for muscle-invasive urothelial bladder cancer. Radical cystectomy involves removal of the bladder (in combination with removal of the uterus/ovaries/fallopian tubes and possibly a portion of the vagina in women and the prostate and seminal vesicles in men), pelvic lymph node dissection, and reconstruction of the urinary tract. The morbidity and long-term outcomes of cystectomy are well documented [3].
Because of the high risk of distant failure in muscle-invasive bladder cancer, systemic chemotherapy either before or after radical cystectomy is often administered to improve outcomes. For most patients with muscle-invasive bladder cancer who will undergo a radical cystectomy, cisplatin-based neoadjuvant chemotherapy is indicated, as this approach improves survival in this population. Modern series of patients managed with radical cystectomy have a five-year pelvic control rate of nearly 80 percent and five-year overall survival rates ranging from 40 to 60 percent [4,5].
Modern oncologic therapies are increasingly driven toward organ preservation and maximizing functional outcomes while maintaining treatment efficacy. Trimodality therapy (TMT) incorporating maximal TURBT followed by radiation therapy (RT) with concurrent radiosensitizing chemotherapy can be a comparably effective regimen to preserve a functioning bladder in well-selected patients with muscle-invasive bladder cancer who are either poor candidates for radical cystectomy or patients who are motivated to maintain their native bladder. This combined-modality approach utilizing TURBT followed by RT with concurrent chemotherapy is often referred to as trimodality therapy.
This topic discusses TMT for muscle-invasive bladder cancer. An overview of the approach to the treatment of bladder cancer is presented separately. (See "Overview of the initial approach and management of urothelial bladder cancer".)
Topics related to other specific aspects of bladder cancer management include:
●(See "Radical cystectomy".)
●(See "Neoadjuvant treatment options for muscle-invasive urothelial bladder cancer".)
●(See "Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder".)
●(See "Treatment of primary non-muscle invasive urothelial bladder cancer".)
●(See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract".)
PRETREATMENT EVALUATION — All patients must be clinically staged prior to pursuing definitive treatment. Briefly, patients should undergo cystoscopy with transurethral resection of bladder tumor (TURBT) along with an examination under anesthesia to assess the local extent of disease. Imaging studies are needed to rule out disseminated disease in the chest, abdomen, and pelvis. Because urothelial carcinoma can be multifocal, upper tract urothelial carcinoma of the ureters or renal pelvis should be ruled out as well. The diagnosis and staging of bladder cancer is discussed separately. (See "Clinical presentation, diagnosis, and staging of bladder cancer".)
Magnetic resonance imaging (MRI) of the bladder is a promising modality to assess the local extent of disease and has proven more useful in distinguishing non-muscle-invasive from invasive disease [6] and in assessing for perivesical disease extension [7-13]. Advanced MRI with nanoparticle lymphangiography may also prove more useful at detecting pelvic nodal metastases [9,12]. If obtained, bladder MRI should be performed before TURBT, as it may be difficult to distinguish between tumor and postsurgical change. More accurate bladder-specific imaging with MRI may also assist with radiation treatment planning in those patients who choose bladder-preserving, combined-modality therapy to better delineate tumor boost volumes. MRI technology is evolving, and further studies are necessary.
OVERVIEW OF TREATMENT APPROACH — Radical cystectomy with neoadjuvant cisplatin-based chemotherapy is the standard approach for the treatment of muscle-invasive urothelial bladder cancer. For patients who are not candidates for radical cystectomy or who desire preservation of their native bladder, trimodality therapy (TMT) incorporating maximal transurethral resection of bladder tumor (TURBT) followed by radiation therapy (RT) with concurrent chemotherapy is an appropriate alternative [14].
There have been no completed definitive, randomized trials that compare bladder-preserving TMT with radical cystectomy. The Selective Bladder Preservation Against Radical Excision (SPARE) trial was a randomized phase III study (with a built-in pilot feasibility study) initiated in the United Kingdom comparing radical cystectomy versus RT (with or without chemotherapy) in muscle-invasive bladder cancer [15]. However, this trial was closed due to poor accrual.
Observational data comparing TMT with radical cystectomy are conflicting for the optimal treatment approach. Most studies suggest similar or improved overall survival (OS) for TMT relative to radical cystectomy [16-19], while other studies suggest worse OS outcomes [20]. As an example, in one meta-analysis of eight observational studies that included 9000 patients with muscle-invasive bladder cancer, 5- and 10-year OS were similar between TMT and radical cystectomy [16]. In another retrospective analysis of 722 patients with advanced muscle-invasive bladder cancer, TMT was associated with improved five-year OS relative to radical cystectomy (66 versus 73 percent, HR 0.70, 95% CI 0.53-0.92) [18]. By contrast, in a retrospective study of approximately 18,000 evaluable patients with muscle-invasive bladder cancer, TMT was associated with a lower five-year OS relative to radical cystectomy (30 versus 40 percent) [20]. However, approximately 20 percent of the patients treated with TMT had node-positive disease, and there is limited information on the chemotherapy regimens used.
Other approaches that have been used to preserve a functioning bladder include TURBT alone [21], TURBT followed by interstitial brachytherapy [22], partial cystectomy [23], and radiation with intra-arterial chemotherapy [24]. However, none of these have an established role in muscle-invasive bladder cancer.
PATIENT SELECTION — Bladder-preserving, trimodality therapy (TMT) is an appropriate treatment strategy for selected patients with muscle-invasive urothelial bladder cancer who are not surgical candidates due to medical comorbidities and for those who desire to retain their native bladder.
Even among patients with minimal medical comorbidities, radical cystectomy is associated with a treatment-related mortality risk of 1 to 2 percent [3], with an increasing risk in patients with more severe comorbidities. Furthermore, urothelial carcinoma is a disease of the older population, and the median age at diagnosis is 73 years [25]. The 90-day perioperative mortality rates for patients ≤69, 70 to 79, and ≥80 years old have been reported to be as high as 2, 5, and 9 percent, respectively, in a population-based study [26]. Furthermore, cigarette smoking is an etiologic factor for bladder cancer, and many patients have one or more tobacco-related comorbidities that increase the risk of perioperative mortality.
Although there are no absolute criteria for identifying candidates for bladder-preserving TMT, important factors include:
●Urothelial histology – Prospective studies evaluating the use of TMT have been performed exclusively in patients with urothelial histology and thus cannot be generalized to patients with less common histologies (squamous cell carcinoma, adenocarcinoma, micropapillary). In addition, nonurothelial carcinoma histologies may respond less favorably to chemotherapy and radiation therapy (RT) [27].
Although TMT has been used primarily for patients with pure urothelial bladder cancer, this approach appears to have a similar level of activity for those with variant urothelial pathology (eg, elements of squamous or glandular differentiation) [28]. However, because of the limited number of patients in some of the histologic variants, definitive equivalence cannot be established.
●Maximal TURBT – A visibly complete transurethral resection of bladder tumor (TURBT) is associated with a higher complete response rate after chemoradiation, decreased rates of salvage cystectomy, and improved overall survival (OS) [29-33]. Although complete resection is optimal, a complete response was achieved in 57 percent of patients with a visibly incomplete TURBT in a single-institution series [29]. Similarly, over one-third of patients in the randomized Bladder Cancer 2001 (BC2001) trial had a biopsy only or an incomplete TURBT, and a similar proportion had a residual mass at time of treatment; despite this, the locoregional disease-free survival (DFS) was over 80 percent with chemoradiation [34].
●Clinical T2 to T4a disease – Increasing tumor (T) stage is associated with decreased rates of complete response after chemoradiation (table 1). This was illustrated by a single-institution series of 348 patients, in which clinical T2 disease had a complete response rate of 81 percent compared with 64 percent in clinical T3 to T4 disease [29]. Although patients with clinical T2 to T3a disease may be more favorable candidates for TMT, the large institutional experiences, Radiation Therapy Oncology Group (RTOG) prospective studies, and BC2001 trial used clinical T4a disease (ie, disease extension into the prostatic stroma in men or uterus/vagina in women) as the upper limit of clinical T stage acceptable for TMT.
●Absence of tumor-associated hydronephrosis – Patients with tumor-associated hydronephrosis are less likely to achieve a complete remission to chemoradiation (64 percent in patients without hydronephrosis versus 38 percent in patients with hydronephrosis) [33]. A large retrospective series of 348 patients treated at the Massachusetts General Hospital also suggests that patients with tumor-associated hydronephrosis (n = 58) fare worse with regard to OS and disease-specific survival (DSS) outcomes.
●Kidney function – Adequate kidney function is necessary to receive cisplatin-based concurrent chemotherapy. However, the combination of fluorouracil and mitomycin or single-agent gemcitabine represent reasonable alternative concurrent chemotherapy regimens for patients with compromised kidney function.
●Absence of extensive CIS – In a single-institution experience of 40 patients, extensive carcinoma in situ (CIS) was associated with a trend toward a higher bladder tumor recurrence rate compared with those without CIS (40 versus 6 percent) [35]. Furthermore, in a systemic review of bladder preservation in muscle-invasive bladder cancer, extensive CIS was found to be associated with a higher risk of local recurrence in patients treated with RT alone, although the association was less clear with TMT [36].
●Unifocal tumors <6 cm in maximum diameter.
●Good bladder function and capacity (ie, a bladder worth sparing).
Advanced age is not a contraindication for a combined-modality approach. While older patients are more likely to have significant comorbidities, a bladder preservation approach is appropriate in this population given its generally good tolerability. In an analysis from a large single-institution experience, there was no difference in DSS for older adult patients (≥75 years) treated with a bladder preservation approach compared with a younger cohort [29,37]. Similarly, the RTOG pooled analysis showed no difference with respect to rates of complete response, DSS, or bladder-intact DSS in patients ≥75 years [38].
There may be some patients whose medical comorbidities or other patient factors make them poor candidates for chemotherapy in combination with RT. In this setting, TURBT followed by radiation alone is a reasonable treatment strategy. RT was used as bladder-sparing monotherapy for several decades in patients unfit for radical cystectomy [34,39-41], and there exists a group of patients with durable disease control with radiation alone (34 percent locoregional DFS at five years in the BC2001 study [34]).
However, for patients who are candidates for bladder preservation and reasonable candidates for radiosensitizing chemotherapy, we recommend chemoradiation (CRT) over RT alone, as this approach improves locoregional disease control over RT alone [42]. Multiple chemosensitizing chemotherapy regimens are available that are well-tolerated. (See 'Chemoradiation versus radiation monotherapy' below and 'Chemotherapy' below.)
New biomarkers may represent a promising strategy for identifying patients appropriate for bladder-preserving TMT. For example, MRE11 is a protein involved in detecting double-stranded DNA breaks along with RAD50-NBS1. A study analyzing pretreatment tumor specimens from patients receiving RT for their bladder cancer demonstrated that high MRE11 expression is associated with improved cancer-specific survival compared with radical cystectomy patients. This finding was validated in another cohort of patients, wherein elevated MRE11 expression was associated with improved cancer-specific survival in patients receiving TMT but not in those managed with radical cystectomy [43-45]. Gene expression profiling studies have also suggested that higher immune infiltration is associated with improved DSS after TMT, whereas higher stromal infiltration is associated with shorter DSS after neoadjuvant chemotherapy and radical cystectomy [46]. Further studies are needed to prospectively validate such biomarkers.
TURBT — The goal of transurethral resection of bladder tumor (TURBT) is to define the depth of tumor invasion and to maximally resect all visible tumors in a safe manner. Site-directed bladder mapping biopsies should be performed to identify carcinoma in situ (CIS) remote from the primary tumor [47]. Several technical maneuvers can be employed to assist in maximally safe TURBT, including use of paralytics for lateral bladder wall tumors to mitigate an obturator reflex and avoiding bladder overdistension while resecting to decrease the risk of perforation. The depth of resection can often be safely extended through the detrusor muscle and into the perivesical adipose tissue by an experienced urologist if this is required to perform a visually complete TURBT. A bimanual examination under anesthesia (EUA) should be performed both before and after TURBT. A palpable three-dimensional mass on EUA prior to or after a maximal TURBT indicates locally advanced (T3 to T4) disease.
TURBT with EUA requires special consideration if performed postinduction (ie, after 40 to 45 Gy radiation therapy with induction chemotherapy) or after consolidation (ie, after completion of the entire course of chemoradiation) chemoradiation. Often the previous resection site has significant fibrosis. A cold-cup biopsy of the previous tumor site is frequently inadequate, and the previous resection site needs to be reresected with a resectoscope with the goal of obtaining detrusor muscle to assess for residual invasive cancer.
CONCURRENT CHEMORADIATION
Efficacy of chemoradiation — Data supporting the use of chemoradiation come from a pooled analysis of Radiation Therapy Oncology Group (RTOG) studies [38], a large British randomized trial comparing chemoradiation versus radiation therapy (RT) without chemotherapy [34], and several single-institution series [29,31].
RTOG pooled analysis — A pooled analysis of six NRG/RTOG studies demonstrated the efficacy of chemoradiation as part of a bladder-preserving trimodality therapy (TMT) approach [38]. These studies employed variable radiation doses and schedules, as well as different concurrent cisplatin-based chemotherapy regimens. This analysis included 468 patients with clinical T2 to T4a tumors; patients were excluded if they had evidence of biopsy-proven nodal or metastatic disease. At median follow-up of over four years among all patients, the main results included the following:
●The complete response rate following chemoradiation was 69 percent.
●The 5- and 10-year disease-specific survival (DSS) rates were 71 and 65 percent, respectively. The 5- and 10-year rates of muscle-invasive local failure were 13 and 14 percent, respectively; the 5- and 10-year rates of non-muscle-invasive recurrence were 31 and 36 percent, respectively; and the 5- and 10-year rates of distant metastases were 31 and 35 percent, respectively.
●The 5- and 10-year overall survival (OS) rates were 57 and 36 percent, respectively. However, most deaths were not attributable to bladder cancer, which was the cause of death in only 24 percent of patients who had died by year 5.
●Of the 205 patients alive at five years, 80 percent had an intact bladder.
Large single-institution experiences — Data from several single-institution retrospective series support the use of a bladder-preserving TMT (including chemoradiation) as an alternative to radical cystectomy.
Concurrent chemoradiation was associated with improved DSS and lower rates of salvage radical cystectomy when data from one study cohort was compared over two subsequent treatment eras. In an observational study of 475 patients with cT2-T4a muscle-invasive bladder cancer (of whom 90 percent had cT2 to T3a disease) were treated at the Massachusetts General Hospital between 1986 and 2013 on various institutional and RTOG protocols [29,48]. All patients underwent transurethral resection of bladder tumor (TURBT) and concurrent chemoradiation to 64 to 65 Gy with concurrent (largely cisplatin-based) chemotherapy; some patients also received neoadjuvant chemotherapy and/or adjuvant chemotherapy. Salvage radical cystectomy was recommended for those patients who did not have a complete response and for those with recurrent muscle-invasive disease.
With a median follow-up of approximately seven years for surviving patients, the main results include the following:
●The complete response rate following chemoradiation was 75 percent for all patients and 83 percent for patients with cT2 disease.
●The 5- and 10-year OS rates were 57 and 39 percent, respectively; for T2 disease, the 5- and 10-year OS rates were 65 and 46 percent, respectively. The 5- and 10-year DSS rates were 66 and 59 percent, respectively; for T2 disease, the 5- and 10-year DSS rates were 74 and 66 percent, respectively.
●Five-year rates of non-muscle-invasive (ie, clinical Ta, Tis, or T1), muscle-invasive, regional nodal, and distant failures were 26, 16, 12, and 32 percent, respectively, and the 10-year rates were 26, 18, 14, and 35 percent, respectively.
●The risk of salvage cystectomy was 29 percent at five years. Radical cystectomy was performed in 129 patients: 65 for less than a complete response to chemoradiation and 64 for invasive tumors identified during posttreatment surveillance. One patient required cystectomy for treatment-related toxicity. In more contemporary studies (2005 to 2013), the rate of salvage cystectomy decreased to 16 percent.
●In multivariable analysis, clinical tumor (T) stage and complete response and presence of tumor-associated CIS were associated with improved OS and DSS.
●When evaluating the cohort over treatment eras, rates of CR improved from 66 to 88 percent, and five-year DSS improved from 60 to 84 percent between the eras of 1986 to 1995 to 2005 to 2013, while the five-year risk of salvage radical cystectomy rate decreased from 42 to 16 percent.
In another observational study, 415 patients with high-risk cT1 or cT2 to T4 bladder cancer were treated at the University of Erlangen between 1982 and 2000 with radiation (n = 126) or chemoradiation (n = 302) after TURBT using either cisplatin or carboplatin-based chemotherapy [31]. The median bladder radiation dose was 54 Gy (range, 45 to 69.4 Gy). With a median follow-up of five years, the main results include:
●The complete response rate at restaging TURBT following RT or chemoradiation was 72 percent for all patients. For patients receiving RT alone, the complete response rate was 61 percent, and rates for those receiving chemotherapy with carboplatin, cisplatin, or fluorouracil (FU)/cisplatin were 66, 82, and 87 percent, respectively.
●Among patients experiencing a complete response, 65 percent were continuously free of local recurrence, 14 percent had a noninvasive or cT1 recurrence, 11 percent had a muscle-invasive recurrence, and 3 percent had a pelvic recurrence.
●The 5- and 10-year OS rates were 51 and 31 percent, respectively. The 5- and 10-year DSS rates were 56 and 42 percent, respectively.
●Twenty percent of patients underwent a salvage cystectomy for invasive residual or recurrent tumor. The 5- and 10-year DSS rates for patients requiring a salvage cystectomy for an invasive relapse were 50 and 45 percent, respectively.
●In multivariable analysis, chemoradiation was associated with improved OS and complete response rates compared with radiation alone.
Chemoradiation versus radiation monotherapy — The Bladder Cancer 2001 (BC2001) study was a multicenter randomized phase III trial that enrolled 360 patients with muscle-invasive bladder cancer [34,42]. All patients underwent TURBT, followed by randomization to either RT alone or RT with concurrent chemotherapy using FU and mitomycin. At a median follow-up of 10 years, the addition of concurrent chemotherapy to RT resulted in the following [42]:
●Improved locoregional disease control (five-year locoregional recurrence-free rates of 63 versus 49 percent; hazard ratio [HR] 0.61, 95% CI 0.43-0.86).
●A non-statistically significant trend towards higher DFS (five-year DFS 45 versus 34 percent, HR 0.78, 95% CI 0.60-1.02) and OS (five-year OS 49 versus 37 percent, HR 0.88, 95% CI 0.69-1.13).
●Reduced rate of cystectomy at five years (14 versus 22 percent, HR 0.54, 95% CI 0.31-0.95). Overall, 81 percent of cystectomies were performed for disease recurrence.
●Higher grade 3 or 4 toxicity rates during treatment (36 versus 28 percent) [34] but with lower grade 3 or 4 late toxicity rates in extended follow-up (9 versus 17 percent) [42].
A second, smaller randomized trial conducted by the National Cancer Institute of Canada randomly assigned patients to concurrent cisplatin with RT or RT alone [49]. There was a statistically significant decrease in the incidence of first recurrence in the pelvis (15 of 51 versus 25 of 48) with the addition of cisplatin. The trial failed to demonstrate an improvement in OS but was not adequately powered for that endpoint.
Radiation therapy technique — Conformal three-dimensional RT techniques replaced the two-dimensional approaches that were used in initial studies. More advanced techniques, including intensity-modulated radiation therapy (IMRT), are now widely used whenever possible. These highly conformal techniques allow more accurate delivery of the required high dose of radiation to the tumor and adjacent areas at risk while minimizing dose to normal surrounding structures. (See "Radiation therapy techniques in cancer treatment".)
The dose, frequency of treatment, fields, and restaging paradigms have not been standardized, and there are significant differences between centers. An adequate dose of radiation is required to eradicate all tumor and to treat adjacent areas of bladder that are at high risk for local recurrence. At the same time, careful attention is required to minimize the dose of radiation to adjacent normal tissues that are more radiosensitive (colon, rectum, small intestine, hips, and normal bladder) and are at risk for significant toxicity.
●One approach is to cover pelvic lymph nodes in addition to the bladder. This treatment entails delivering 40 to 45 Gy to the entire bladder, prostatic or proximal urethra, and the adjacent lymph node basin in the pelvis. An additional boost to 10 to 15 Gy is then given to the entire bladder, and a further 10 Gy is given to the tumor, for a total tumor dose of 64 to 65 Gy.
●In patients who are candidates for cystectomy, an alternative approach, known as "split-course chemoradiation" may be offered. In this approach, a restaging cystoscopy with repeat TURBT and biopsies may be obtained following the initial 40 to 45 Gy of radiation (induction course), and if a patient has a complete response or has only Ta or Tis residual disease that can be managed intravesically, consolidation concurrent chemoradiation is continued to the total dose of 64 to 65 Gy (algorithm 1). We most commonly administer a continuous course of chemoradiation to full dose without treatment break, although there are limited data demonstrating superiority of this approach over split-course chemoradiation.
●Another approach is to treat the bladder without a pelvic nodal field to full dose (64 Gy conventionally fractionated or 55 Gy with moderate hypofractionation).
●Moderately hypofractionated regimen may be a reasonable alternative to conventional fractionation. A meta-analysis of individual patient data from two randomized phase III trials in the UK suggested that a hypofractionated schedule of 55 Gy in 20 fractions is noninferior to conventional fractionation (64 Gy in 32 fractions) with regard to invasive locoregional control and toxicity [50]. These studies, however, did not include pelvic nodal fields. Additionally, data also suggest increased dose-limiting toxicity for hypofractionation in combination with checkpoint inhibitor immunotherapy on trial [51,52].
●Whether RT is optimally delivered on a twice-per-day or once-a-day schedule has not been resolved in randomized trials. Most commonly, the authors now use a once-a-day schedule. Previous RTOG protocols utilized a twice-a-day schedule, but this can be logistically challenging for some patients.
Salvage cystectomy is indicated for patients who do not have complete response to this combined-modality approach or who develop an invasive recurrence during follow-up cystoscopic surveillance.
Chemotherapy
Concurrent chemotherapy regimen
Selection of therapy — For patients receiving concurrent chemoradiation, the optimal radiosensitizing chemotherapy regimen is not established, as many of these regimens have not been directly compared in randomized trials. Selection of chemotherapy is based upon patient performance status and comorbidities, kidney function, and provider experience.
●For medically fit patients with adequate kidney function, preferred options include cisplatin-based regimens, FU plus mitomycin, and low-dose biweekly gemcitabine. (See 'Cisplatin-based chemotherapy' below and 'FU plus mitomycin' below and 'Low-dose biweekly gemcitabine' below.)
●For patients with impaired kidney function, FU plus mitomycin and low-dose biweekly gemcitabine are appropriate alternatives to cisplatin-based regimens. (See 'FU plus mitomycin' below and 'Low-dose biweekly gemcitabine' below.)
Cisplatin-based chemotherapy — For patients with adequate kidney function, options include cisplatin monotherapy (eg, 100 mg/m2 every two to three weeks [33,49] or 35 to 40 mg/m2 weekly, extrapolating from data in cervical cancer [53,54]). Cisplatin monotherapy is the best-studied regimen with daily RT. In a randomized trial of 99 patients with muscle-invasive bladder cancer, the addition of concurrent cisplatin (100 mg/m2 at two-week intervals for three cycles) to RT reduced the pelvic relapse rate (HR 0.50, 95% CI 0.29-0.86) but failed to improve OS [49].
Other combination cisplatin-based options include cisplatin plus FU [55] or cisplatin plus paclitaxel.
FU plus mitomycin — Mitomycin C is administered at 12 mg/m2 on day 1, and 5-FU at 500 mg/m2 per day as a continuous infusion during RT fractions one to five (during week 1) and RT fractions 16 to 20 (during week 4) [34,56]. Adequate venous access is also necessary for continuous infusion of FU. (See "Central venous access: Device and site selection in adults".)
Supporting data for FU plus mitomycin as part of chemoradiation for muscle-invasive bladder cancer are discussed separately. (See 'Chemoradiation versus radiation monotherapy' above.)
Low-dose biweekly gemcitabine — Low-dose biweekly gemcitabine (27 mg/m2 twice per week with daily RT) is an effective regimen with less toxicity relative to combination cisplatin-based therapy [55,57-59].
In a randomized phase II trial, 77 patients with muscle-invasive bladder cancer were treated with either low-dose biweekly gemcitabine (27 mg/m2 twice per week) with once-daily RT or cisplatin plus FU with twice-daily RT [55]. Treatment was reassessed after 40 Gy of RT; those with a complete response received additional RT to 64 Gy, while those without a complete response were treated with radical cystectomy. At median follow-up of five years, among the 66 patients eligible for evaluation, a distant metastasis rate of less than 25 percent at three years was similar between the two treatment arms (84 versus 78 percent). Grade 3 and 4 toxicity rates were lower for low-dose biweekly gemcitabine relative to cisplatin plus FU (55 versus 64 percent). Furthermore, this study also supported administering RT once daily as an alternative to twice-daily administration.
Other regimens — Other options include single-agent paclitaxel [60], weekly carboplatin plus paclitaxel (extrapolating from data in esophageal cancer [61]), single-agent FU, and single-agent capecitabine. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", section on 'Concurrent chemoradiotherapy'.)
We do not offer carboplatin monotherapy in this setting, as data suggest lower complete response rates compared with cisplatin-based regimens [31].
Is there a role for neoadjuvant or adjuvant chemotherapy? — Whether the use of neoadjuvant or adjuvant chemotherapy has a role in conjunction with concurrent chemoradiation as part of a bladder preservation regimen is not established, as there are limited high-quality data for either approach.
Concurrent chemotherapy is thought to act by sensitizing tumor cells to the effects of radiation. By contrast, the addition of neoadjuvant or adjuvant chemotherapy, given at systemic therapy doses, is intended to eradicate distant micrometastases that are not treated by the RT and thus improve DFS and OS.
The interest in neoadjuvant or adjuvant chemotherapy as part of a combined-modality bladder preservation approach has been extrapolated from the data in patients undergoing radical cystectomy. Cisplatin-based combination chemotherapy prior to radical cystectomy for muscle-invasive bladder cancer improves DFS and OS compared with radical cystectomy alone. The role of adjuvant cisplatin-based chemotherapy following cystectomy is less well established but is an option for selected patients. (See "Neoadjuvant treatment options for muscle-invasive urothelial bladder cancer" and "Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder".)
●In the RTOG 89-03 trial, 123 patients were randomly assigned to two cycles of neoadjuvant cisplatin, methotrexate, and vinblastine (CMV) chemotherapy prior to concurrent chemoradiation or to concurrent chemoradiation without neoadjuvant chemotherapy [33]. The addition of neoadjuvant chemotherapy to concurrent chemoradiation did not improve OS or the rate of distant metastases. There were four treatment-related deaths in the arm that received CMV (with three deaths due to neutropenic sepsis) and one in the control arm. Though supportive care has improved in the years since, these deaths highlight the potential risks associated with chemotherapy.
●In the BA06 30894 trial, 976 patients were treated with either cystectomy or curative-intent RT [62]. Patients were randomly assigned to either three cycles of CMV or no neoadjuvant chemotherapy. The trial included 403 patients who were treated with RT without cystectomy. In this subset, there was a 20 percent decrease in the risk of death with neoadjuvant CMV (HR 0.80, 95% CI 0.63-1.02). These patients did not receive chemotherapy concurrent with RT to the bladder. It is not known whether the apparent benefit would be maintained in patients treated with modern combined-modality bladder sparing (eg, more aggressive TURBT plus chemotherapy concurrent with RT).
●The British BC2001 study allowed but did not require neoadjuvant chemotherapy prior to curative-intent radiation or chemoradiation [34,63]. Neoadjuvant chemotherapy was given in 33 percent of the participants overall. The benefit from concurrent chemoradiation compared with RT alone was similar in those who received neoadjuvant chemotherapy (HR 0.62, 95% CI 0.35-1.13) and in those who did not receive neoadjuvant chemotherapy (HR 0.71, 95% CI 0.46-1.10). No comparison was possible concerning the effectiveness of neoadjuvant chemotherapy. Further details of this study are discussed separately. (See 'Chemoradiation versus radiation monotherapy' above.)
●The role of adjuvant chemotherapy after combined-modality, bladder-sparing therapy has not been examined in a prospective controlled study. Several RTOG studies have mandated treatment with adjuvant chemotherapy [64-66], but the absence of a control arm precludes assessment of its efficacy.
Cisplatin-based combination chemotherapy regimens (eg, methotrexate, vinblastine, doxorubicin, cyclophosphamide; gemcitabine/cisplatin; CMV) can be considered in the neoadjuvant or adjuvant setting if it is a well-informed decision that acknowledges the uncertainty of benefit or if it is being done in the context of a prospective clinical study.
Chemotherapy for disease metastatic to regional nodes — The role of TMT in the management of bladder cancer metastatic to regional lymph nodes has not been studied. In such cases, it is important from prognostic and management standpoints to establish the presence and location of metastatic disease (ie, imaging to verify absence of distant metastases, consideration of node biopsy). Such patients should be offered initial systemic therapy for metastatic disease. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract".)
Patients who receive systemic therapy and have radiographic resolution of metastatic lymphadenopathy may be evaluated for subsequent consolidative local therapy, although data are limited for this approach.
IS THERE A ROLE FOR IMMUNOTHERAPY? — Initial studies suggest that combining checkpoint inhibitor immunotherapy with chemoradiation is safe in muscle-invasive urothelial carcinoma [67,68]. However, further randomized trials are necessary to investigate the addition of immunotherapy to bladder-sparing trimodality therapy (TMT) in patients with muscle-invasive urothelial bladder cancer (including those with node-negative or node-positive disease) before incorporating this approach into routine clinical practice.
Immunotherapy also has efficacy in metastatic bladder cancer. These data are discussed separately. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract".)
POSTTREATMENT SURVEILLANCE AND TREATMENT — Patients require close surveillance after bladder-preserving, combined-modality therapy.
The first two to three cystoscopies with transurethral resection of bladder tumor (TURBT) after completion of treatment should be performed in the operating room. If these initial cystoscopies with TURBT do not identify recurrent disease, the patient can then be transitioned to office cystoscopies and urine cytology, which should be performed every three months for the first two years, every six months for years 2 to 5, and then yearly thereafter.
Long-term bladder surveillance is critical since 20 percent of de novo non-muscle-invasive bladder cancers occur after 10 years [7]. Computed tomography scans of the chest/abdomen/pelvis are performed every three months for years 1 and 2, every six months for years 3 through 5, and then yearly thereafter.
MANAGEMENT OF BLADDER RECURRENCES
General approach — Important factors in selecting appropriate therapy for patients with bladder recurrences after bladder-preserving, trimodality therapy (TMT) include the patient's overall health, time to recurrence, frequency of recurrence, and voiding symptoms, as well as the tumor size, pathologic stage, and pathologic grade at recurrence.
●Salvage cystectomy is indicated for patients who fail to have a complete response to TMT, as well as for patients with a muscle-invasive bladder cancer recurrence at any point.
●In patients who had a complete response to TMT, non-muscle-invasive bladder cancer recurrences have an equivalent overall survival (OS) compared with those who remain disease free [69-71]. These data, however, are retrospective, and there is significant heterogeneity in non-muscle-invasive recurrences; thus, the judgment of the treating clinicians is integral in deciding which patients can avoid cystectomy. Clinicians should continue long-term surveillance of these patients, as they would for patients with primary non-muscle invasive disease. (See "Treatment of primary non-muscle invasive urothelial bladder cancer", section on 'Posttreatment surveillance'.)
Low-grade and noninvasive recurrences can be treated with transurethral resection of bladder tumor (TURBT) along with adjuvant intravesical therapy such as Bacillus Calmette-Guérin (BCG) or mitomycin. Non-muscle-invasive bladder cancers with risk factors for progression such as high-grade, carcinoma in situ (CIS), or T1 disease can be managed with cystectomy or TURBT with BCG based on clinical judgment.
The efficacy of intravesical BCG following bladder-preserving TMT is similar to chemoradiation-naïve patients, as 59 percent of patients with Ta grade 2/3, CIS, or T1 disease treated with intravesical BCG had no further recurrences [71]. Further, intravesical therapy after TMT is well tolerated by patients, with 68 percent of patients in this setting completing induction BCG without a stop in therapy or significant toxicity. Thus, non-muscle-invasive bladder cancer recurrences following TMT can be managed with intravesical BCG with reasonable efficacy and tolerability. However, salvage cystectomy should be considered in patients with aggressive tumors, such as extensive high-grade/CIS or T1 disease, and in patients with non-muscle-invasive bladder cancer refractory to intravesical therapy.
Salvage cystectomy — Salvage cystectomy is indicated in patients who are cystectomy candidates and who failed to achieve a complete response after bladder-preserving TMT, those with muscle-invasive recurrence at any point, those with aggressive non-muscle-invasive bladder cancer recurrences (especially T1), and those with non-muscle-invasive bladder cancer refractory to intravesical therapy.
Post-TMT salvage cystectomy has an acceptable 90-day major complication (≥Clavien grade 3) rate of 16 percent and 90-day mortality rate of 2 percent, which is similar to published series for radical cystectomy without antecedent radiation therapy (RT) [72]. Early complications (<90 days) are most commonly cardiovascular and/or hematologic in nature, while delayed complications were related to wound complications, uretero-enteric anastomotic strictures, and stoma stenosis [72,73]. The risks of rectal injury (3 percent) and colostomy (1 percent) are rare in experienced centers [72].
Observational data generally suggest similar survival outcomes for patients who fail TMT and require salvage cystectomy compared with those who were treated with upfront cystectomy [18,72,74]. In a retrospective study, the five-year cancer-specific survival of patients who underwent salvage cystectomy following TMT was equivalent to those who underwent TMT and did not require salvage cystectomy (85 versus 84 percent) [18]. In another observational study, 265 patients who underwent radical cystectomy for cT1 to T4 bladder cancer were treated with either salvage cystectomy after TMT; primary cystectomy; or primary cystectomy with prior history of non-TMT abdominal or pelvic radiotherapy [74]. At median follow-up of 66 months, salvage cystectomy for intravesical recurrence after TMT had an intraoperative and early complication rate similar to primary cystectomy, but was associated with a higher risk of overall and major late complications. Notably, there was no difference in DSS or OS between the treatment groups.
There are several important technical aspects regarding salvage cystectomy.
●Although orthotopic neobladders are an option [75], most surgeons perform nonorthotopic diversions in this setting due to concerns about radiation-induced impaired bowel healing, urethra-neobladder anastomotic stricture, and incontinence. (See "Urinary diversion and reconstruction following cystectomy".)
●When performing any type of diversion, special care must be taken to ensure that the segment of bowel selected has been spared apparent injury from radiation. If an ileal conduit is planned, often selecting more proximal ileum can avoid using a segment of bowel that lays closer to the pelvic radiation field. If the ileum is unsuitable, then a transverse colon conduit can be created.
●Due to the potential need to use large bowel and the rare risk of rectal injury, all salvage cystectomy patients should have a preoperative mechanical bowel preparation. If there is a reasonable likelihood that large intestine will be needed for the urinary diversion, patients should have a recent colonoscopy prior to surgery.
QUALITY OF LIFE STUDIES — The primary objective of a trimodality therapy (TMT) is bladder preservation, and bladder preservation has merit only if the preserved bladder and other pelvic organs function at acceptable levels after treatment. Patients should expect some degree of urinary-irritative symptoms and bowel symptoms during treatment.
Overall, the available evidence supports the conclusion that the patients' native bladders function well, and late pelvic toxicity remains acceptable after combined-modality, bladder-preservation therapy.
●A pooled analysis of four prospective Radiation Therapy Oncology Group (RTOG) trials evaluated 157 patients who underwent bladder-preserving TMT and survived at least two years with their bladder intact [76]. With a median follow-up of 5.4 years, 6 percent of patients experienced late (≥180 days after start of consolidation therapy) grade ≥3 genitourinary toxicity, and 2 percent experienced grade ≥3 gastrointestinal toxicity. There were no grade 4 toxicities and no treatment-related deaths. Only one patient had persistent grade 3 genitourinary toxicity after TMT, and <1 percent of patients required cystectomy due to treatment-related toxicity.
●A patient-reported quality of life and urodynamics study of long-term survivors of bladder-preserving TMT showed that 75 percent of patients had normally functioning bladders [77]. Six percent of patients reported difficulty with urinary flow, 15 percent with urinary urgency, 19 percent with incontinence, and 22 percent with bowel symptoms. Among men, 36 percent reported normal erections, and another 18 percent noted weaker erections that were still sufficient for intercourse.
●A study of 226 long-term survivors with muscle-invasive bladder cancer compared patient-reported quality of life in patients treated with TMT versus radical cystectomy [78]. In multivariable analysis, patients who received TMT had significantly better general health-related quality of life than patients who had a radical cystectomy. TMT also had better bowel quality of life and equivalent urinary quality of life compared with radical cystectomy.
However, the patient's baseline urinary function before treatment is an important consideration, since patients with very poor baseline urinary function may not have a "bladder worth sparing."
Several patient advocacy groups serve as good resources to help support quality of life during and after treatment. For example, the Bladder Cancer Advocacy Network (BCAN) is a large community of advocates, bladder cancer survivors, and medical and research professionals that offers funding to advance research for bladder cancer as well as resources for patient education and support [79].
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 5th to 6th 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 10th to 12th 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.)
●Basics topics (see "Patient education: Bladder cancer (The Basics)")
●Beyond the Basics topics (see "Patient education: Bladder cancer diagnosis and staging (Beyond the Basics)" and "Patient education: Bladder cancer treatment; muscle invasive cancer (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Indications for bladder-preserving trimodality therapy – Bladder-preserving, trimodality therapy (TMT) integrates maximal transurethral resection of bladder tumor (TURBT) followed by concurrent chemotherapy and radiation therapy (RT) for patients with muscle-invasive bladder who are medically unfit for radical cystectomy or who have a desire to preserve the native bladder (algorithm 1). (See 'Overview of treatment approach' above.)
●Patient selection – Key factors important in patient selection include urothelial histology, the ability to achieve a complete tumor resection at TURBT, clinical stage T2 to T4a disease, lack of extensive carcinoma in situ (CIS), and the absence of hydronephrosis. (See 'Patient selection' above.)
●Treatment approach to TMT – For patients who are candidates for bladder preservation, we recommend concurrent chemoradiation rather than RT alone following maximal TURBT (Grade 1B). (See 'Efficacy of chemoradiation' above and 'Concurrent chemotherapy regimen' above.)
●Selection of concurrent chemotherapy regimen - For patients receiving concurrent chemoradiation, selection of a chemotherapy regimen to administer concurrently with RT is based upon patient performance status and comorbidities, kidney function, and provider experience. (See 'Concurrent chemotherapy regimen' above.)
•For medically fit patients with adequate kidney function, options include cisplatin-based regimens, fluorouracil (FU) plus mitomycin, and low-dose biweekly gemcitabine.
•For patients with impaired kidney function, FU plus mitomycin and low-dose biweekly gemcitabine are appropriate alternatives to cisplatin-based regimens.
●Posttreatment surveillance – Careful posttreatment surveillance is essential for the detection of recurrence or a second primary urothelial malignancy in the urogenital tract. (See 'Posttreatment surveillance and treatment' above.)
●Indications for salvage cystectomy – For patients who fail to achieve a complete response or who develop an invasive recurrence after TMT, a salvage radical cystectomy is indicated and is associated with reasonable surgical outcomes. (See 'Salvage cystectomy' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Nicholas Giacalone, MD, who contributed to an earlier version of this topic review.
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