Radical cystectomy is a standard treatment of nonmetastatic, muscle-invasive bladder cancer. Treatment with trimodality therapy consisting of maximal transurethral resection of the bladder tumor followed by concurrent chemotherapy and radiation has emerged as a method to preserve the native bladder in highly motivated patients. Several factors can affect the likelihood of long-term bladder preservation after trimodality therapy and therefore should be taken into account when selecting patients. New radiation techniques such as intensity modulated radiation therapy and image-guided radiation therapy may decrease the toxicity of radiotherapy in this setting. Novel chemotherapy regimens may improve response rates and minimize toxicity.
Key points
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Bladder preservation with maximal transurethral resection of the bladder tumor (TURBT), concurrent chemotherapy, and irradiation can result in approximately 75% of long-term survivors maintaining a functional bladder.
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The ideal patient for bladder preservation has a clinical T2 unifocal tumor, a visibly complete TURBT, no carcinoma in situ (CIS), and no tumor-related hydronephrosis, with good pretreatment bladder function.
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Participation in a bladder preservation approach requires a highly motivated patient who is a good candidate for irradiation and chemotherapy and is committed to long-term cystoscopic surveillance.
Introduction
An estimated 74,690 cases of urinary bladder cancer were diagnosed in the United States in 2014, of which 30% will be muscle invasive. The current standard of care for the treatment of muscle-invasive bladder cancer (MIBC) is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy (RC) with pelvic lymph node dissection. In appropriately selected patients, bladder preservation can be an effective alternative to RC. The term bladder preservation can include TURBT, limited surgery, chemotherapy, radiation therapy, or various combinations of one or more of these modalities; however, the best outcomes have consistently been seen with trimodality therapy (TMT) including maximal TURBT followed by concurrent chemoradiation. This review focuses on TMT for bladder preservation and does not detail other therapeutic combinations for bladder preservation.
Several prospective trials have been completed evaluating TMT as a means of bladder preservation. The purpose of these studies has been to define the rate of bladder preservation and survival with this approach and to improve the tolerability and efficacy of TMT regimens. This review provides an overview of modern TMT bladder-preservation strategies, focusing on important criteria for patient selection, the integration of novel radiation techniques, commonly used and new chemotherapies for TMT, and the role of chemoradiation for T1 disease.
Introduction
An estimated 74,690 cases of urinary bladder cancer were diagnosed in the United States in 2014, of which 30% will be muscle invasive. The current standard of care for the treatment of muscle-invasive bladder cancer (MIBC) is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy (RC) with pelvic lymph node dissection. In appropriately selected patients, bladder preservation can be an effective alternative to RC. The term bladder preservation can include TURBT, limited surgery, chemotherapy, radiation therapy, or various combinations of one or more of these modalities; however, the best outcomes have consistently been seen with trimodality therapy (TMT) including maximal TURBT followed by concurrent chemoradiation. This review focuses on TMT for bladder preservation and does not detail other therapeutic combinations for bladder preservation.
Several prospective trials have been completed evaluating TMT as a means of bladder preservation. The purpose of these studies has been to define the rate of bladder preservation and survival with this approach and to improve the tolerability and efficacy of TMT regimens. This review provides an overview of modern TMT bladder-preservation strategies, focusing on important criteria for patient selection, the integration of novel radiation techniques, commonly used and new chemotherapies for TMT, and the role of chemoradiation for T1 disease.
Discussion
Trimodality Therapy Treatment Approach
TMT includes the combination of maximal tumor debulking and concurrent chemoradiotherapy. The optimal radiation target volume, radiation fractionation, chemotherapy, and sequencing remain areas of active study. In general, the patient undergoes a maximal, preferably visually complete, TURBT, ideally with bladder mapping ( Fig. 1 ), followed by the delivery of cisplatin-based chemoradiotherapy to a dose of approximately 40 to 45 Gy. If no evidence of disease or minimal residual disease is noted at cystoscopic reassessment, the final consolidative phase of chemoradiotherapy is initiated. If progressive or unresponsive disease is found, therapy proceeds to RC. After completion of therapy, patients are closely surveilled with cystoscopy and urine cytology.
Patient Selection
Patient selection is a key component of bladder preservation ( Table 1 ). Most criteria used to select appropriate patients for TMT predict for a high rate of response or the ability to safely tolerate therapy. Factors predicting for increased rates of distant metastases are important for predicting overall survival (OS) after TMT.
| Preferred or Ideal | Less than Ideal | Relative Contraindications | Absolute Contraindications |
|---|---|---|---|
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A complete response (CR) to induction therapy with concurrent chemoradiation has typically been defined as negative results on urine cytologic analysis, as well as no visible tumor and negative results on biopsies at cystoscopy. Achieving a CR to induction therapy is required to avoid salvage cystectomy and has been associated with improved disease-free and overall survival after TMT. The CR rate for patients with T2-T4a disease treated with TMT is approximately 70%. Factors that may affect the likelihood of achieving a CR after TMT and should be considered when selecting patients include completeness of TURBT, tumor stage, hydronephrosis, multifocality and CIS, and baseline bladder function. It is important to consider that the rate of response to induction therapy may not always be known, as many recent trials, such as bladder cancer 2001 (BC2001) and Radiation Therapy Oncology Group (RTOG) 0926, do not include cystoscopic reassessment after induction. For these studies, careful patient selection becomes increasingly important as a full radiotherapy (RT) dose is delivered before response to therapy is assessed.
Completeness of transurethral resection of the bladder tumor
A pooled analysis of 314 patients treated on 6 RTOG trials found that a visibly complete TURBT was associated with a significantly higher rate of CR to TMT on multivariate analaysis. Similarly, the Erlangen series showed that completeness of resection after initial TURBT was an independent predictor of CR. Likewise, a series of 348 patients from Massachusetts General Hospital found that visibly complete TURBT was associated with higher CR rates (79% with visibly complete TURBT vs 57% without). Thus, a visibly complete TURBT is ideal. A less-than-complete TURBT is not an absolute contraindication to bladder preservation, as several trials have demonstrated acceptable CR rates without a visibly complete TURBT.
Tumor stage
Most TMT trials include patients with clinical T2-T4a disease. In RTOG 85-12, RTOG 88-02, RTOG 97-06, and the Erlangen series, tumor stage was not significantly associated with the rate of CR to TMT on multivariate analysis. A pooled analysis of 361 patients treated on RTOG trials confirmed that T stage did not predict for the likelihood of CR to TMT on multivariate analysis. In contrast, increasing T stage is reproducibly associated with reduced long-term survival after TMT.
In surgical series, the presence of prostate invasion by urothelial carcinoma is associated with a higher risk of lymph node metastases and reduced 5-year survival. The decrement in survival is greatest for patients with prostatic stromal invasion or extraprostatic invasion compared with patients with more limited mucosal involvement. Patients with prostatic stromal invasion are excluded from many trials of TMT for bladder preservation; however, prostatic urethral invasion is not generally an exclusion criterion if it is amenable to visibly complete resection.
Few data exist regarding the treatment of patients with involved lymph nodes with TMT. These patients have in some cases been included in RTOG trials of TMT if the lymph nodes are located below the bifurcation of the iliac vessels. The presence of lymph node involvement is a poor prognostic indicator in regards to OS, and in general, these patients are counseled to undergo neoadjuvant chemotherapy and RC.
Hydronephrosis
Tumor-related hydronephrosis has been an exclusion criterion for several trials of TMT. RTOG 89-03 found CR rates with and without hydronephrosis to be 38% and 64%, respectively. A series from the Massachusetts General Hospital found a CR rate of 52% in those with hydronephrosis and 77% in those without. Hydronephrosis not only predicts for a reduced likelihood of CR but also is a predictor for advanced stage and decreased survival. In RTOG 89-03, the 5-year OS for patients with and without hydronephrosis was 33% and 54%, respectively. Likewise, in RTOG 88-02, hydronephrosis was the only analyzed factor to be significantly associated with probability of distant metastases and death. Patients with tumor-related hydronephrosis are poor candidates for bladder preservation and are usually excluded from trials of TMT.
Multifocality and carcinoma in situ
Multiple tumors or multifocal disease has been suggested as a predictive factor for decreased response rates to TMT, and patients with these conditions are excluded from most trials of bladder preservation. Multifocality may not predict for lower rates of CR but is associated with a higher risk for local relapse. In general, TMT is not advocated in those with diffuse multifocal disease.
Similarly, the presence of extensive CIS before therapy has been associated with lower rates of CR to TMT and RT alone and higher rates of recurrence after TMT. A panel convened by the Société Internationale d’Urologie suggested that the presence of extensive CIS should be considered a relative and not absolute contraindication to TMT because the presence of CIS affects only the risk of recurrence after TMT and not survival.
Baseline bladder function
The rationale of bladder preservation therapy is to preserve a functional bladder. A subset of patients whose bladders are preserved with TMT may develop symptoms such as urgency and control problems. Therefore, baseline dysfunction in these areas should be considered when determining if a patient is a candidate for TMT.
Chemotherapy for Trimodality Therapy
Concurrent chemotherapy has been shown in randomized trials to improve local and regional control compared with RT alone. Although these trials did not demonstrate an OS advantage with the addition of concurrent chemotherapy, several large retrospective series have found concurrent chemotherapy to be associated with improved survival. Most bladder preservation trials using concurrent chemoradiation have used cisplatin-based chemotherapy regimens. Cisplatin-based combination regimens have been tested with the aim of improving response rates. The RTOG has evaluated cisplatin-based chemotherapy combinations including cisplatin with 5-fluorouracil (5-FU) (RTOG 9506) and paclitaxel with cisplatin (RTOG 9906). The RTOG 0233 trial compared paclitaxel with cisplatin with 5-FU with cisplatin with concurrent radiation in patients with mostly T2 disease (95%). Following TMT, patients received adjuvant gemcitabine, cisplatin, and paclitaxel. Both regimens showed similar rates of CR (62%–72%), 5-year OS (71%–75%), and 5-year survival with an intact bladder with moderate toxicity.
Candidates for TMT may have comorbidities that preclude the delivery of concurrent cisplatin, and several studies have evaluated alternative regimens. The BC2001 trial tested the use of 5-FU with mitomycin-C (MMC) concurrently with RT with excellent response rates and impressive tolerability. This regimen is particularly useful in those with renal dysfunction prohibiting the use of cisplatin. Gemcitabine is a potent radiation sensitizer and has shown activity in the setting of metastatic urothelial cancers. The use of 100 mg/m 2 weekly gemcitabine during RT as a component of TMT was tested in a recently completed phase II trial. The regimen resulted in an 88% cystoscopic response rate and a 3-year OS of 75%. Bowel toxicity resulted in 4 of 50 patients stopping chemotherapy and in 1 late bowel resection. There were 2 treatment-related deaths.
Single-institution phase I data supporting twice-weekly gemcitabine concurrent with RT as part of TMT are available. A study from the University of Michigan of TMT with RT delivered to a total dose of 60 Gy found the maximum tolerated dose of twice-weekly gemcitabine to be 27 mg/m 2 . Of the 23 patients treated in this trial, 21 obtained a CR. At a median follow-up of 43 months, 65% of patients were alive with no evidence of recurrence and intact bladders. Twice-weekly low-dose gemcitabine (27 mg/m 2 ) was compared with a regimen of twice-daily irradiation with 5-FU and cisplatin in the recently closed RTOG 0712 trial. Results for this trial are pending.
The target volume of radiation is an important consideration when comparing chemotherapy regimens for bladder cancer. Some trials testing alternative regimens have evaluated bladder only irradiation and have not included an initial pelvic irradiation field. Thus, toxicity for these chemotherapy regimens may be greater if extrapolated to a setting in which a pelvic field is included.
The use of neoadjuvant cisplatin-based chemotherapy in the setting of cystectomy has shown improvements in survival compared with cystectomy alone, likely through early treatment of micrometastatic disease. As distant failure remains a concern after bladder preservation, this approach has been tested in several trials of TMT. Unfortunately, neoadjuvant or adjuvant chemotherapy with TMT has not improved survival or bladder preservation rates. However, the data available are limited to older regimens, with only 2 cycles of chemotherapy delivered instead of the standard 3 to 4, and many of these studies were underpowered. As more effective chemotherapeutic regimens are developed, this strategy is likely to be further explored.
Targeted agents have been an area of interest in efforts to improve TMT outcomes. The epidermal growth factor receptor family of receptors has been of particular interest in this regard. HER2/Neu is overexpressed in bladder cancers, particularly in metastatic or lymph node–positive tumors, and overexpression may be correlated to worse outcomes after chemoradiotherapy. These findings suggest that targeting HER2/Neu in the context of TMT may provide a therapeutic opportunity. RTOG 0524 evaluated the addition of trastuzumab to paclitaxel and daily irradiation following TURBT in the treatment of noncystectomy candidates with MIBC. The study has been reported as an abstract and showed a favorable response rate but with an increase in hematologic toxicity and other adverse events.
Radiation Techniques
RT is a critical component of TMT. A range of doses of irradiation, fractionation schedules, sequences of treatment, and treatment volumes have been applied in the treatment of bladder cancer. Attempts to improve RT have been geared toward enhancing bladder preservation rates while minimizing the toxicity of therapy. Newer technologies, such as intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT), are being integrated into the clinic. The authors outline general concepts regarding RT field design and discuss current areas of research in RT technique.
The optimal volume of irradiation is one area of controversy. In most North American trials, treatment includes an initial course of RT to a total dose of 39.6 to 45 Gy directed at the pelvic lymph nodes below the bifurcation of the common iliac vessels, the prostate in men, and the whole bladder ( Figs. 2 and 3 ). A margin surrounding the bladder is included to account for daily variation in bladder filling, visceral organ motion, and setup error. To minimize the field size and to increase the reproducibility of daily treatment, patients are simulated and treated with an empty bladder (immediately postvoid) with a small amount of bladder contrast.
Related posts:
Multidisciplinary Care of the Urothelial Cancer Patient
Management of High Grade Bladder Cancer: A Multidisciplinary Approach
Radical Transurethral Resection Alone, Robotic or Partial Cystectomy, or Extended Lymphadenectomy
Potential Role for Targeted Therapy in Muscle-Invasive Bladder Cancer
Novel Biomarkers to Predict Response and Prognosis in Localized Bladder Cancer
Neoadjuvant Therapy in Muscle-Invasive Bladder Cancer
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