Trimodality Bladder Preservation Therapy for Muscle-Invasive Bladder Cancer

Potentially curative treatments for patients with muscle-invasive bladder cancer (MIBC) are underused, especially in the elderly. Trimodality bladder preservation therapy, which includes a maximally safe transurethral resection of the bladder tumor, followed by concurrent chemoradiation, fulfills this currently unmet need. In multiple prospective clinical trials and large institutional series, trimodality therapy has demonstrated excellent 5-year overall survival rates of 48% to 65%, comparable to those reported in cystectomy studies. Approximately 75% to 80% of long-term survivors maintain their native bladders, which tend to function well and allow patients to maintain excellent quality of life. Salvage cystectomy for patients who develop a local invasive recurrence can be performed with acceptable operative complication rates, and results in excellent long-term disease control and survival outcomes. For patients with MIBC who are noncystectomy candidates, or select patients who are motivated to keep their native bladders, trimodality bladder preservation therapy is recognized by the International Consultation on Urological Diseases-European Association of Urology and the NCCN Clinical Practice Guidelines in Oncology for Bladder Cancer as an effective alternative to radical cystectomy, and should be considered. In the future, biomarkers may allow improved selection of patients for whom trimodality bladder preservation therapy is most likely to succeed.

Abstract

Potentially curative treatments for patients with muscle-invasive bladder cancer (MIBC) are underused, especially in the elderly. Trimodality bladder preservation therapy, which includes a maximally safe transurethral resection of the bladder tumor, followed by concurrent chemoradiation, fulfills this currently unmet need. In multiple prospective clinical trials and large institutional series, trimodality therapy has demonstrated excellent 5-year overall survival rates of 48% to 65%, comparable to those reported in cystectomy studies. Approximately 75% to 80% of long-term survivors maintain their native bladders, which tend to function well and allow patients to maintain excellent quality of life. Salvage cystectomy for patients who develop a local invasive recurrence can be performed with acceptable operative complication rates, and results in excellent long-term disease control and survival outcomes. For patients with MIBC who are noncystectomy candidates, or select patients who are motivated to keep their native bladders, trimodality bladder preservation therapy is recognized by the International Consultation on Urological Diseases-European Association of Urology and the NCCN Clinical Practice Guidelines in Oncology for Bladder Cancer as an effective alternative to radical cystectomy, and should be considered. In the future, biomarkers may allow improved selection of patients for whom trimodality bladder preservation therapy is most likely to succeed.

Bladder cancer is the sixth most common cancer in the United States, with approximately 73,510 patients diagnosed and 14,800 dying of the disease in 2012.1 When the cancer invades into or beyond the muscularis propria (muscle-invasive bladder cancer [MIBC], clinical stage ≥T2), it is life-threatening.1 Bladder cancer disproportionally affects the elderly, with median age at diagnosis 73 years.2 Because it is a smoking-related disease, a significant proportion of patients have comorbid illnesses, such as cardiovascular disease.3,4

Radical cystectomy is commonly considered a standard treatment for MIBC, and its efficacy and morbidity profile are well described.5 Radical cystectomy involves removal of the bladder with a lymph node dissection. In women, the uterus and part of the vagina are also commonly removed, and in men, the prostate and seminal vesicles.6 The risks of perioperative complications and mortality increase with age.7 In a series of 1142 patients who underwent cystectomy at a high-volume tertiary cancer center, 54% experienced grade 2 to 5 complications within 90 days of surgery, including bowel (eg, small bowel obstruction), infectious, wound, cardiac (eg, myocardial infarction), and thrombotic complications.8 Older age was significantly associated with increased complications. In a population-based study, Liberman et al9 reported a mortality rate within 90 days of cystectomy of 2% in patients aged 69 years or younger, 5.4% in those aged 70 to 79 years, and 9.2% those aged 80 years or older.

Possibly because of concerns about tolerability of surgery, elderly patients with this aggressive cancer are undertreated. A recent study using the National Cancer Database, which includes approximately 75% of patients with cancer in the United States, showed that the use of cystectomy for nonmetastatic MIBC decreases with patient age.2 Among patients aged 50 years and younger, 63% received cystectomy; this decreased to 55% for those aged 61 to 70 years, 45% for those aged 71 to 80 years, and 22% for those aged 81 to 90 years.2 For patients who are not cystectomy candidates, and those who are motivated to preserve their native bladders, an important need exists for an alternative treatment that is effective and tolerable to reduce the undertreatment of this disease. This article summarizes the literature on trimodality bladder preservation therapy, which includes a transurethral resection of bladder tumor (TURBT) followed by radiation therapy with concurrent chemotherapy.

Effectiveness of Trimodality Therapy for MIBC

In 1993, Kaufman et al10 reported results from one of the first prospective trials using modern trimodality therapy for MIBC. In this phase II trial, 53 patients at Massachusetts General Hospital with clinically staged T2-4,Nx disease underwent a TURBT with a maximally safe tumor resection, followed by 2 cycles of methotrexate/vinblastine/cisplatin chemotherapy, then radiation with concurrent cisplatin. Radiation treatment stopped at 40 Gy to allow cystoscopic evaluation. Patients with an incomplete tumor response and suitable for surgery underwent an immediate cystectomy, whereas the remainder received additional radiation to a total dose of 64.8 Gy. Patients with an intact bladder then underwent long-term cystoscopic surveillance. After a median follow-up of 48 months, the actuarial 5-year overall survival was 48% for the entire cohort and 58% among patients who completed the study treatments.

Subsequently, multiple prospective trials have confirmed these findings (Table 1). In most of the published trials, a course of initial chemoradiation therapy was given, followed by cystoscopic evaluation. Patients experiencing complete response then continued with chemoradiation, whereas those who did not underwent immediate cystectomy (Figure 1). Most trials have reported complete response rates of more than 70%; thus, fewer than 30% of patients for whom bladder preservation was attempted were unable to keep their native bladders and required immediate cystectomy. Five-year overall survival rates in published trials ranged from 48% to 65%. More recently, a pooled analysis was performed of 6 RTOG trials, and included 468 patients with a median age of 66 years at enrollment. After a median follow-up of 4.3 years (7.8 years among survivors), the 5-year overall survival rate was 57%, including 62% for patients with clinical T2 disease and 49% for those with T3-4 disease.11 Disease-specific survival was almost identical for patients younger than 75 years and those aged 75 and older,11,12 suggesting that trimodality therapy is similarly effective in younger and older patients. These high rates of complete response to chemoradiation therapy and 5-year overall survival have been consistently reported in large institutional series,12-14 including for the elderly when stratified by the age of 75 years.12 Minimal changes in the rates of invasive recurrences13,15 and disease-specific survival11,12 are seen beyond 5 years, demonstrating the long-term stability of disease control outcomes after trimodality therapy.

Some of the early trials included induction chemotherapy before concurrent chemoradiation. RTOG 8903, which randomized patients to receive or not receive 2 cycles of induction methotrexate/cisplatin/vinblastine chemotherapy before concurrent chemoradiation, demonstrated increased toxicity in patients receiving induction chemotherapy but no improved overall survival.16 Therefore, induction chemotherapy has not been part of more recent trials and is not recommended as part of standard trimodality therapy for MIBC.

Effective Radiosensitizing Chemotherapy Regimens

Most of the published trials have used cisplatin-based concurrent chemotherapy: cisplatin alone, cisplatin/5-FU, or cisplatin/paclitaxel (Table 1).The recently published BC2001 trial provides an alternative regimen for patients who are noncisplatin candidates either due to poor renal function or concerns about cisplatin tolerability.15,17 The primary hypothesis of this trial was that concurrent chemoradiation with 5-FU and mitomycin C was more effective than radiation alone, and the chemotherapeutic regimen was based on prior phase I and II trial data.18 The primary end point was locoregional disease-free survival. A total of 360 patients with MIBC and a median age of 72 years were randomized to receive either radiation therapy alone or radiation with concurrent 5-FU and mitomycin C.15 This regimen was well tolerated in this older patient group, with more than 95% of the patients randomized to the chemoradiation arm completing the radiation treatment, and approximately 80% completing chemotherapy. Five-year overall survival for patients in the chemoradiation therapy arm was 48%.

Table 1

Select Prospective Clinical Trials and Large Institutional Studies of Trimodality Bladder Preservation Therapy for Muscle-Invasive Bladder Cancer

Table 1

Another potential alternative is gemcitabine, which has been used in phase I19 and II20 studies. The effectiveness of gemcitabine versus cisplatin/5-FU is currently being compared in the randomized phase II trial RTOG 0712. Carboplatin has no proven effectiveness in this setting.5,13

Survival Outcomes of Trimodality Therapy Versus Immediate Radical Cystectomy

Definitive comparisons of patient outcomes from trimodality bladder-preservation therapy (with salvage cystectomy at recurrence) versus immediate cystectomy for MIBC are difficult because of the lack of a modern randomized trial comparing these treatment strategies. Differences in patient selection characteristics are seen among bladder preservation and cystectomy studies. The median age of patients in cystectomy studies is usually younger than among those in bladder preservation studies. For example, the median age of patients in the US Intergroup trial comparing cystectomy with or without neoadjuvant chemotherapy was 63 years,21 whereas that for BC2001 (radiation with/without concurrent chemotherapy) was 72 years.15 Furthermore, most cystectomy studies report pathologic staging, whereas bladder preservation studies can only report clinical staging. Clinical evaluations often result in understaging compared with pathologic staging with cystectomy. In 2 large studies, 19% to 35% of patients with clinically node-negative MIBC who underwent cystectomy were found to have positive nodes on surgical pathology.22,23 Therefore, results from studies using clinical versus pathologic staging cannot be directly compared.

Figure 1
Figure 1

Trimodality bladder-preservation treatment regimen. Split-course chemoradiation treatment is depicted, consistent with many published clinical trials that include an interim cystoscopic assessment of tumor status to allow immediate cystectomy for patients with an incomplete response. An alternative, which was used in the BC2001 trial15 and may be appropriate for noncystectomy candidates, is continuous-course chemoradiation treatment without an interim assessment.

Abbreviation: TURBT, transurethral resection of bladder tumor.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 8; 10.6004/jnccn.2013.0116

With these limitations in mind, based on published data, trimodality bladder preservation therapy seems to achieve long-term overall survival rates comparable to those reported for radical cystectomy. Table 2 summarizes results from cystectomy studies that have included patients with clinically staged MIBC.21,22,24,25 Five-year overall survival ranged from 43% to 59% overall, and 53% to 59% for those who received neoadjuvant chemotherapy.

Long-Term Morbidity, Bladder Function, and Quality of Life After Trimodality Therapy

Approximately 75% to 80% of long-term survivors after trimodality therapy preserve their native bladders.12-14,16,20,26-28 Severe long-term morbidity is uncommon (Table 3). Efstathiou et al29 reported a pooled analysis of 4 RTOG trials, including 157 patients who have survived for at least 2 years after treatment initiation. After a median follow-up of 5.4 years, approximately 7% of patients experienced long-term grade 3 toxicity, including 5.7% urinary and 1.9% gastrointestinal toxicity. Similarly low rates of toxicities were reported in other studies, all with long-term follow-up.13-15,30 Patients rarely (<1%) require a cystectomy because of bladder toxicity.

A phase II trial of 53 patients treated with radiation (63 Gy) with concurrent cisplatin/5-FU chemotherapy prospectively assessed quality of life.31 In the first year after treatment, urinary symptoms such as frequency, pain, and control improved compared with baseline, potentially because of tumor shrinkage and improved bladder function. Good urinary function was maintained up to 24 months after treatment; too few patients had long-term follow-up for meaningful conclusions of symptoms beyond this point. Overall quality of life as measured by the EORTC instrument (EORTC QLQ-C30) also improved from pretreatment through the follow-up period.

Table 2

Select Prospective Clinical Trials and Large Institutional Series of Radical Cystectomy for Muscle-Invasive Bladder Cancer

Table 2

In a single-institution study, Zietman et al32 evaluated long-term survivors after trimodality therapy who had their native bladders and were disease-free at a median of 6.3 years after treatment. Thirty-two patients underwent urodynamic studies, and 24 (75%) were judged to have normally functioning bladders. Furthermore, 48 survivors (median age, 68 years) completed quality-of-life questionnaires. Approximately 6% reported symptoms related to urinary flow, 15% reported urinary urgency, and 19% reported incontinence. Overall, 22% of patients reported bowel symptoms and 54% of men had erections sufficient for intercourse. Overall quality of life as measured by the Short Form-36 was high.

Table 3

Long-Term Grade 3 or Higher Morbidity After Trimodality Therapy for Muscle-Invasive Bladder Cancer

Table 3

These data suggest that trimodality therapy is well tolerated, with modest rates of significant long-term morbidity. In appropriately selected patients, a high probability exists for patients to preserve their native bladders, which tend to function well. Overall quality of life for long-term survivors after trimodality therapy is high. However, a potential downside is the need for long-term cystoscopic surveillance and a 20% to 25% chance of needing salvage cystectomy for local recurrence (see later discussion), not dissimilar to the need for surveillance in patients with noninvasive bladder cancer.

Effectiveness and Morbidity From Salvage Cystectomy

Trimodality therapy allows patients who do not experience a complete response to chemoradiation therapy to undergo an immediate cystectomy without significant delay. Incomplete response has been consistently found to be a poor prognostic factor, and likely indicates biologically aggressive disease that is unlikely curable. In multiple studies, long-term survival rates in patients who experience a complete response to chemoradiation therapy ranged from 62% to 79%, compared with 23% to 40% for those who do not.10,12-14,33

Trimodality therapy also allows for the use of salvage cystectomy when a patient develops an invasive local recurrence, thus reserving radical surgery for patients who need it. In one series, 42 patients after radiation-based bladder preservation therapy underwent radical cystectomy for an invasive local recurrence at a median of 26 months after the initial TURBT.13 Disease-specific survival rates at 5 and 10 years were 50% and 45%, respectively, from the time of cystectomy. Similar results were reported in 2 other studies,14,34 demonstrating the effectiveness of salvage cystectomy as a potentially curative treatment modality. However, radical cystectomy after radiation treatment may be associated with somewhat higher rates of complications. In the Massachusetts General Hospital experience of 91 patients who had a median age of 69 years, 50 underwent cystectomy for noncomplete response after chemoradiation therapy and 41 for invasive local recurrence.34 Tissue healing complications occurred in 12% of the former group and 35% of the latter. The overall 90-day complication rate was 69% (16% major complications) and mortality was 2.2%. These rates were slightly higher, although comparable to those reported from nonirradiated patients undergoing primary cystectomy at a large tertiary center.8

Ideal Candidates for Trimodality Bladder-Preservation Therapy

For patients with MIBC who are noncystectomy candidates, trimodality bladder preservation therapy offers a curative treatment regimen that is well tolerated in elderly patients, and therefore should be considered for all patients. However, for patients who are eligible for radical cystectomy but motivated to preserve their native bladders, careful patient selection based on pretreatment characteristics is important to maximize the probability of success: bladder preservation and long-term survival. The ideal candidates for trimodality therapy have the following characteristics:

  • No tumor-associated hydronephrosis: Hydronephrosis has been consistently found to be associated with a lower likelihood of complete response to chemoradiation therapy and bladder preservation,10,16 and worse overall survival.10,16,35,36 For example, in RTOG 8903, patients who had hydronephrosis, versus those who did not, had different rates of complete response (38% vs 64%; P=.02) and 5-year overall survival (33% vs 54%; P=.06).16

  • Visibly complete TURBT: Multiple studies have also found an association between a complete TURBT and achieving a complete response and bladder preservation,12-14,16 and overall survival.12-14,36 However, in the series from Massachusetts General Hospital, 57% of patients with a visibly incomplete TURBT still achieved a complete response to chemoradiation therapy. Therefore, the inability to obtain a visibly complete TURBT does not preclude successful bladder preservation in MIBC.

  • Tolerance of concurrent chemotherapy with radiation: The BC2001 trial has demonstrated, with level 1 evidence, that concurrent chemoradiation therapy is tolerable in an elderly patient population and improves patient outcomes compared with radiation alone.15 Two-year locoregional disease-free survival, the primary end point for the trial, was 67% in patients randomized to chemoradiation therapy and 54% for those who underwent radiation alone (P=.03). Concurrent chemoradiation also seemed to reduce salvage cystectomy rates (2-year rate, 11.4% vs 16.8% for radiation alone; P=.07) and improve overall survival (48% vs 35% for radiation alone; P=.16). However, the trial was not powered to fully detect differences in these secondary end points. In the retrospective series from Erlangen,13 multivariate analyses showed significantly different rates of complete response (P=.05) and borderline significant rates of 5-year overall survival (P=.06) among patients who received radiation alone (61% and 40%, respectively), radiation plus carboplatin (66% and 45%, respectively), radiation plus cisplatin (82% and 62%, respectively), and radiation plus cisplatin/5-FU (87% and 65%, respectively). Patients who received cisplatin-based concurrent chemotherapy seemed to have significantly better outcomes than those who received no chemotherapy or carboplatin.

In addition, whether patients with variant histologies (eg, sarcomatoid, micropapillary) experience similarly favorable outcomes is unknown because of the small numbers of these patients in published trials. Patients whose bladders have little capacity, whose tumors are palpable on examination under anesthesia (clinical T3b), and with extensive carcinoma in situ37 may not be ideal candidates for trimodality bladder preservation therapy. In patients with extensive carcinoma in situ, a complete resection of tumor is difficult to achieve with TURBT. The relative contraindications to radical cystectomy and trimodality therapy are summarized in Table 4.

Biomarkers Predicting Success for Bladder-Preservation Therapy

Data are emerging on the ability of biomarkers to predict patient outcomes after bladder-preservation radiotherapy for bladder cancer. In a study from the Leeds Cancer Center (United Kingdom), expression of several proteins potentially important in detection and repair of double-stranded DNA damage and cell cycle checkpoints were evaluated with immunohistochemistry in pretreatment tumor specimens, and correlated with patient outcomes.38 In a cohort of 86 patients treated with definitive radiation therapy, low tumor MRE11 expression was associated with worse cancer-specific survival compared with high expression (41% vs 69% at 3 years; P=.012). This finding was confirmed in a separate cohort of 93 patients who received radiation therapy, and importantly was not associated with outcomes in cystectomy patients.

Table 4

Relative Contraindications to Radical Cystectomy and Trimodality Therapy for Patients With Muscle-Invasive Bladder Cancer

Table 4

A more recent study of 148 patients treated with radiation therapy at Erlangen University Hospital has further validated this finding.39 On multivariate analysis, high MRE11 expression was associated with improved disease-specific survival (hazard ratio, 0.64; P=.005) in patients who underwent radiation but not those who underwent cystectomy. These results require prospective validation, and a trial is currently being planned by the RTOG working with the NCI Bladder Cancer Task Force. This work may enable biomarker information available at diagnosis to be used to individualize treatment decision-making and to help select patients mostly likely to experience a cure with trimodality bladder preservation therapy.

Discussion

Trimodality bladder-preservation therapy (Figure 1) addresses an important concern in MIBC: the undertreatment of this life-threatening disease, especially in the elderly. As recent population-based data have shown, the use of radical cystectomy for MIBC decreases dramatically with patient age, thus resulting in one-third to one-half of elderly patients with MIBC in the United States not receiving potentially curative treatment.2 Trimodality bladder-preservation therapy offers a curative-intent treatment option for patients who are medically inoperable because of age and comorbidities. Moreover, this treatment regimen offers an alternative to cystectomy for patients who are surgical candidates and want to preserve their native bladders. Results from multiple prospective trials and large institutional series have consistently shown that trimodality therapy—TURBT followed by concurrent chemoradiation—is well tolerated in elderly patients, and results in high rates of long-term overall survival. These results are comparable to those of modern cystectomy studies, even though clinical staging (used in all trimodality therapy studies) is known to understage a portion of patients compared with surgical staging. Approximately 75% to 80% of long-term survivors maintain their native bladders, and, in general, patients have excellent bladder function and quality of life. For cystectomy candidates, salvage cystectomy for patients who develop a local, invasive recurrence can be performed with acceptable operative complication rates, and results in excellent long-term disease control and survival.

Trimodality bladder-preservation therapy is endorsed by the recently published International Consultation on Urological Diseases-European Association of Urology6 and the NCCN Clinical Practice Guidelines in Oncology for Bladder Cancer5 as an effective alternative to immediate cystectomy for select patients with MIBC. For patients who are not eligible for cystectomy, trimodality therapy should be offered as a potentially curative treatment regimen. In addition, patients eligible for cystectomy but motivated to preserve their native bladders can be counseled regarding the evidence supporting this approach. Current and future research include trials that compare different radiosensitizing chemotherapy agents (RTOG 0712), using biomarkers such as MRE11 to help select patients most likely to succeed with bladder preservation treatment, and the use of this treatment approach for patients with T1 cancers for whom conservative management has failed (RTOG 0926).

Drs. Chen, Efstathiou, and Zietman have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article of their competitors. Dr. Shipley has disclosed that he owns stock in Pfizer Inc.

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Correspondence: Ronald C. Chen, MD, MPH, Department of Radiation Oncology, University of North Carolina at Chapel Hill, 101 Manning Drive, CB 7512, Chapel Hill, NC 27599-7512. E-mail: ronald_chen@med.unc.edu

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    Trimodality bladder-preservation treatment regimen. Split-course chemoradiation treatment is depicted, consistent with many published clinical trials that include an interim cystoscopic assessment of tumor status to allow immediate cystectomy for patients with an incomplete response. An alternative, which was used in the BC2001 trial15 and may be appropriate for noncystectomy candidates, is continuous-course chemoradiation treatment without an interim assessment.

    Abbreviation: TURBT, transurethral resection of bladder tumor.

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