Bladder Preservation Strategies (ie, Trimodality Therapy)
Selective bladder preservation strategies for MIBC have been promoted since the early 1990s and were primarily adopted from practices in the United Kingdom. Trimodality therapy has typically incorporated a complete transurethral resection, external beam radiation, and concurrent radiosensitizing chemotherapy. Patients are restaged at established intervals for evidence of response; those without complete response are encouraged to undergo RC, and the remaining patients continue on to receive consolidative radiotherapy. Radiation to the bladder and regional nodes is generally administered in 5 weekly fractions of 1.8–2.0 Gy up to a total dose of 50–55 Gy, followed by a small-volume boost to a total of 64 Gy. The most widely used cisplatin(Drug information on cisplatin) regimen is 70 mg/m2 every 3 weeks for a total of 3 courses, or 25 mg/m2 cisplatin on days 1–5 and 29–33 of radiotherapy.
The approach taken in the United States has been to preselect patients likely to do well with trimodality therapy and then further select according to these patients' response to induction chemoradiation. One of the key factors in the success of this approach is complete tumor removal by transurethral resection with the intent to remove all evidence of macroscopic disease and optimize the relationship between tumor volume and radiation dose required for sterilization. Evidence suggests that patients who are ideal candidates for trimodality therapy are those with a small (< 5 cm), solitary tumor, no associated carcinoma in situ, and a normally functioning bladder. The patient must be highly motivated to preserve a normal bladder and committed to lifelong surveillance and prompt treatment of new disease. Advanced stage, extravesical disease, large tumor size, and hydroureteronephrosis have been associated with reduced local control and survival.[67,68] Other inclusion criteria have typically included adequate renal function, a normal hemogram, and medical fitness for surgery.
The primary goal has been to maximize survival, with bladder preservation a secondary goal. In terms of the latter, quality of life is satisfactory in about 67% of patients. A third objective has been to study the tolerability of giving newer systemic chemotherapeutic regimens concurrently vs sequentially during treatment.
Outcomes with trimodality therapy
Early reports described a complete remission rate of 64% to 77%, with a little less than half of the patients able to retain a functional bladder and about one third of patients needing to undergo salvage cystectomy. Long-term outcomes typically involve 10-year disease-specific survival (DSS) rates of 40% to 60% and recurrence-free survival rates of about 65%, with almost 80% of survivors preserving their bladders.[71-74] Most recently, a phase II nonrandomized trial was reported that compared trimodality therapy to RC; the 5- and 10-year DSS rates did not significantly differ.
Toxicities of trimodality therapy
Toxicity with trimodality therapy is moderate; symptoms primarily involve the bladder (cystitis) and bowel (enteritis). Mild to moderate acute radiation cystitis with dysuria and urinary frequency (grades 1 and 2) is present in about half of patients, but the symptoms are usually self-limited. Acute bowel toxicity is present in less than 15% of patients. Neutropenia is nearly universal, and one third of patients may develop grade IV complications (mainly hematologic). Other complications include alopecia, vomiting, mucositis, and diarrhea; however, these are not typically a serious problem in those patients with good performance status. Potential long-term toxicities of trimodality therapy include hemorrhagic cystitis, lower urinary tract symptoms (including urgency and frequency), and loss of bladder function with diminished capacity and compliance. For some patients, these can be crippling and cause serious morbidity, potentially requiring surgical intervention.
Radiation Therapy Oncology Group (RTOG) trials
The first of many RTOG trials evaluating trimodality therapy for bladder cancer was completed in the early 1990s. Initially, patients were treated with induction radiotherapy (40 Gy) and concurrent cisplatin. Complete responders received consolidation radiation with an additional 24 Gy. Follow-up protocols have consecutively added combinations of chemotherapy, including MCV, cisplatin and fluorouracil(Drug information on fluorouracil) (5-FU), paclitaxel(Drug information on paclitaxel), and gemcitabine(Drug information on gemcitabine) with cisplatin.[76-79] Other protocols have further evaluated alterations in dose and fractionation of radiation delivered. Recently, the RTOG finished accruing for a randomized trial that is evaluating different protocols for both induction chemotherapy and adjuvant chemotherapy; results are pending.
Radiation therapy with protons, as opposed to photons, has been increasingly studied in multiple disease settings in recent years. Because of its unique properties, proton therapy can deliver highly conformal radiation, minimizing exposure of the surrounding structures. In particular, proton irradiation to the bladder potentially reduces the dose delivered to the small/large intestine and the normal bladder wall, with an increased dose delivered to the tumor. Unfortunately, there is limited literature evaluating the efficacy and toxicity of proton irradiation in this setting.
Interstitial radiation, as opposed to external-beam radiation, allows a higher dose of radiation to be delivered focally to a small area of the bladder, with relative sparing of surrounding normal tissues. For bladder cancer, it has been used to treat select patients with small, solitary, confined tumors. Survival rates have been reasonably comparable to the rates in surgical series, although inferior; recurrence rates have been as high as 17%.[81-83] There are regional differences in the way brachytherapy is administered. The Dutch irradiate the regional lymph nodes (approximately 28 Gy) and implant the tumor area with iridium after loading brachytherapy (40 Gy), whereas the French perform lymph node dissection and partial cystectomy, followed by source implantation into the post-cystectomy scar. Ultimately, brachytherapy fails to address the fact that urothelial cancer is a field defect malignancy with multifocal recurrences.
Investigators have studied the use of regional deep hyperthermia in bladder-sparing techniques and initially found a decrease in local recurrence and an increase in complete response rate.[84, 85] More recent investigations with quadrimodal therapy in a small cohort of 45 patients with either cT1 or cT2 disease found an 88% DSS rate and an 85% recurrence-free survival rate. Ninety-six percent of patients were able to retain their bladder at 3 years. Twenty-four percent of patients sustained chronic sequelae after treatment, and 80% were satisfied. Hyperthermia is believed to enhance radiation-induced DNA damage and drug cytotoxicity and may even lead to direct cell killing. Secondary effects include vascular damage and stimulation of the immune response.
More recently, proponents of bladder-sparing approaches have sought to identify markers of response to therapy. EGFR positivity seems to be a favorable prognostic factor and correlates with improved DSS and survival with an intact bladder. Conversely, HER2 overexpression correlates with reduced rates of complete response to chemoradiation. Immunohistochemical studies have shown that retinoblastoma (Rb) and bcl-2 expression are the strongest independent correlates of radiation response in MIBC.[88,89] The prognostic value of p53 expression has been well established,[90,91] and the level of apoptotic index has correlated to treatment response. However, another group found that cell cycle checkpoint proteins, such as p53 and p16, have no prognostic significance in patients with invasive bladder cancer. Lastly, the excision repair cross-complementing group 1 gene (ERCC1) is associated with resistance to cisplatin and radiation therapy. Therefore, it is a good predictor of efficacy in patients receiving chemoradiation. Furthermore, lack of ERCC1 expression may help select patients in whom trimodality therapy is more likely to result in a meaningful response.
There are many investigators searching to improve the trimodality approach to bladder cancer. The use of nanoparticles continues to be an avenue of avid investigation. For example, carbon and nicotinamide(Drug information on nicotinamide), sensitizers used to overcome tumor hypoxic radioresistance and tumor cell proliferation, have been examined in patients being treated with radiation for locally invasive bladder cancer. Others have sought to improve targeting accuracy by utilizing fiducial markers, real-time imaging guidance of radiation delivery, and newer intensity-modulated techniques. Finally, there is ongoing evaluation of chemotherapy administration, including regimen, dose, and schedule.
Trimodality therapy with selective bladder preservation for MIBC should be considered in appropriate patients. It is not necessarily designed to replace RC, but is rather a consolidative therapy for those who appear to have a favorable clinical course (good response to initial selection) and one that may be offered as a reasonable alternative to patients who are averse to undergoing RC and urinary diversion.
Contemporary staging and tumor evaluation for bladder cancer relies on cross-sectional images obtained by computed tomography (CT) and magnetic resonance imaging (MRI). Unfortunately, these modalities are limited in their ability to detect microscopic or small-volume extravesical tumor extension and lymph node metastases, leading to an unacceptably high rate of understaging.
A major improvement in the detection of bladder cancer came with the introduction of 64-slice multidetector CT, which provides higher spatial resolution. The sensitivity, specificity, and accuracy of multidetector CT are 85%, 94%, and 90%, respectively. However, despite the fact that multidetector CT provides greater diagnostic accuracy than a conventional CT urogram, it is still limited in its ability to detect lesions < 1 cm. Newer MRI analyses developed for other cancer models have been incorporated into the care of patients with bladder cancer. In particular, diffusion-weighted imaging provides greater accuracy of T stage for bladder tumors compared with T2 imaging alone.[99,100] Diffusion-weighted imaging and contrast-enhanced MRI with ultra-small superparamagnetic particles of iron oxide also improve the detection of nodal metastases in patients with urothelial carcinoma.
Positron-emission tomography (PET) is a nuclear medicine imaging technique that can be used to measure areas of increased metabolic activity, which is common in many types of malignant tissue. Radiolabeled fluorodeoxyglucose (FDG), an analog of glucose, is an imaging agent commonly used to measure regional glucose uptake. The utility of 18F-FDG-PET in bladder cancer is limited by urinary excretion of the radiotracer, causing increased background noise and making it difficult to distinguish areas of increased uptake. In MIBC, it has better sensitivity but worse specificity for the detection of primary tumors compared with conventional CT. A large prospective trial showed that PET findings not only improve diagnostic accuracy but also strongly correlate with survival outcomes. However, whether PET has the added benefit of detecting nodal metastases (compared with conventional CT alone) remains in question. 11C-acetate, which is not excreted in the urine, has been studied as an alternative agent for PET imaging, but there is a high false-positive rate in patients previously treated with intravesical bacille Calmette-Guérin because of inflammation or granulomatous infection. Finally, 11C-choline PET appears to have no advantage compared with 18F-FDG PET in the detection of metastatic bladder cancer.
Muscle-invasive bladder cancer is an aggressive and potentially lethal disease. Integration of multimodal therapies, improved surgical techniques, and utilization of targeted agents has tremendously improved outcomes. We expect even better results with further refinements in patient selection, based on detailed clinical and molecular assessments. The future lies in effective multidisciplinary collaboration and further investigation into the biology of urothelial tumors and host responses.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.