Key points

Introduction

In 2014, approximately 74,690 patients in the United States will be diagnosed with bladder cancer and approximately 15,580 patients will succumb to the disease. Most patients will present with clinically localized disease. At initial presentation, muscle-invasive bladder cancer (MIBC) is present in approximately 30% of patients; approximately 8% to 10% of patients will have radiographic evidence of metastatic disease. MIBC is potentially curable, particularly with combined modality approaches. The fact that most patients do not have radiographic evidence of metastatic disease at the time of diagnosis affords a window of opportunity to eradicate local and micrometastatic disease. Unfortunately, even with the current approaches to curative-intent therapy for MIBC, approximately 50% of patients will still develop clinical evidence of distant metastasis and ultimately succumb to their disease in a median time of 14 months.

Novel therapeutic options for the management of bladder cancer have significantly lagged behind other malignancies. For example, since 1995, there has only been one new US Food and Drug Administration–approved therapy for the treatment of bladder cancer, an intravesical treatment of non–muscle-invasive disease. Although progress in the treatment of cancer should not be measured by drug approvals alone, this does provide at least one measurable metric of the state of the science. There are multiple potential reasons for this historical lack of progress, including a relatively poor understanding of disease biology, inadequate funding for research, and lack of investigator/industry interest in the disease.

An important, but commonly overlooked, contributor to the lack of progress for the treatment of bladder cancer is the disconnect between the efficacy and the effectiveness of the gold standard treatments for the disease. The typical patient with bladder cancer often poorly resembles the patients enrolled on prospective clinical trials or included in single-center series from large academic medical centers. Acknowledging this gap, while simultaneously increasing our understanding of the pathogenesis of the disease, may ultimately lead to more effective treatments that can be safely applied to a larger proportion of patients with the disease.

Introduction

In 2014, approximately 74,690 patients in the United States will be diagnosed with bladder cancer and approximately 15,580 patients will succumb to the disease. Most patients will present with clinically localized disease. At initial presentation, muscle-invasive bladder cancer (MIBC) is present in approximately 30% of patients; approximately 8% to 10% of patients will have radiographic evidence of metastatic disease. MIBC is potentially curable, particularly with combined modality approaches. The fact that most patients do not have radiographic evidence of metastatic disease at the time of diagnosis affords a window of opportunity to eradicate local and micrometastatic disease. Unfortunately, even with the current approaches to curative-intent therapy for MIBC, approximately 50% of patients will still develop clinical evidence of distant metastasis and ultimately succumb to their disease in a median time of 14 months.

Novel therapeutic options for the management of bladder cancer have significantly lagged behind other malignancies. For example, since 1995, there has only been one new US Food and Drug Administration–approved therapy for the treatment of bladder cancer, an intravesical treatment of non–muscle-invasive disease. Although progress in the treatment of cancer should not be measured by drug approvals alone, this does provide at least one measurable metric of the state of the science. There are multiple potential reasons for this historical lack of progress, including a relatively poor understanding of disease biology, inadequate funding for research, and lack of investigator/industry interest in the disease.

An important, but commonly overlooked, contributor to the lack of progress for the treatment of bladder cancer is the disconnect between the efficacy and the effectiveness of the gold standard treatments for the disease. The typical patient with bladder cancer often poorly resembles the patients enrolled on prospective clinical trials or included in single-center series from large academic medical centers. Acknowledging this gap, while simultaneously increasing our understanding of the pathogenesis of the disease, may ultimately lead to more effective treatments that can be safely applied to a larger proportion of patients with the disease.

Neoadjuvant chemotherapy and radical cystectomy: a gold standard?

Although radical cystectomy with pelvic lymph node dissection is a mainstay of treatment of MIBC, several studies have demonstrated improved survival with cisplatin-based combination chemotherapy administered preoperatively. Two randomized trials and a meta-analysis have demonstrated an improvement in survival with neoadjuvant cisplatin-based chemotherapy before radical cystectomy in patients with MIBC. The Southwestern Oncology Group (SWOG 8710) trial randomized patients with MIBC to 3 cycles of neoadjuvant methotrexate, vinblastine, doxorubicin plus cisplatin (MVAC) followed by radical cystectomy versus cystectomy alone. The neoadjuvant chemotherapy arm demonstrated a median survival of 77 months versus 46 months with surgery alone ( P = .06, 2-sided stratified log-rank test). Patients achieving a complete pathologic response fared best with an 85% survival rate at 5 years. Long-term data from a randomized trial of neoadjuvant cisplatin, methotrexate and vinblastine (CMV), followed by local therapy (either surgery or radiation) versus local therapy alone also demonstrated a survival benefit with the use of neoadjuvant chemotherapy (hazard ratio [HR]: 0.84; 95% confidence interval [CI], 0.72 to 0.99; P = .037) ( Table 1 ). The benefit achieved with neoadjuvant cisplatin-based chemotherapy has been further supported by a meta-analysis of 3005 patients, demonstrating a 5% absolute improvement in survival at 5 years (HR: 0.86; 95% CI, 0.77–0.95; P = .003). Although several randomized trials have explored the use of adjuvant chemotherapy for bladder cancer, these studies have generally been flawed, underpowered, and/or prematurely terminated, yielding mixed results.

The gap between evidence and practice

Though radical cystectomy with neoadjuvant cisplatin-based chemotherapy is the gold standard for treatment of MIBC, both of these treatments have been shown to be vastly underused in population-based studies. In an analysis of Surveillance, Epidemiology, and End Results–Medicare data, Gore and colleagues demonstrated that among 3262 patients aged 66 years and older with MIBC, only 21% underwent radical cystectomy. Similar results have been demonstrated in analyses using data from the National Cancer Database (NCDB), which represents data from greater than 70% of bladder cancer diagnoses in the United States. In an analysis of more than 28,000 patients from the NCDB, Gray and colleagues found that only 52.5% of patients with MIBC received aggressive therapy, defined as cystectomy, radiation, or chemoradiation. The use of aggressive therapy significantly decreased with advancing patient age (odds ratio: 0.34 for 81–90 years of age vs ≤50 years of age; P <.001).

As radical cystectomy is a major operation, with the potential for both treatment-related morbidity and mortality, the underutilization of this modality with advancing patient age is perhaps not surprising. Still, narrowing the gap between evidence and effectiveness requires establishing uniform definitions of cystectomy ineligibility, approaches to prehabilitate patients that are borderline cystectomy candidates, shared decision-making tools for choosing among the available curative local therapies (cystectomy vs radiation or chemoradiation), and standard-of-care regimens for patients who are neither candidates for cystectomy nor cisplatin-based concurrent chemoradiation.

Population-based analyses have also explored patterns of perioperative chemotherapy use for patients with MIBC and have begun to explore barriers to utilization. An analysis of an NCDB dataset of more than 7000 patients with MIBC identified that only 1.2% of patients received neoadjuvant chemotherapy and 10.4% received adjuvant chemotherapy. Feifer and colleagues, in collaboration with the Bladder Cancer Advocacy Network Muscle Invasive Bladder Cancer Quality of Care Consortium, performed a 2-phase evaluation of neoadjuvant chemotherapy use among a group of academic enters. In phase 1 of their study, they retrospectively evaluated 4972 patients and identified that neoadjuvant chemotherapy was administered in 12.4% of patients. A prospective phase 2 portion was subsequently initiated to define the precise reasons for the poor utilization of neoadjuvant chemotherapy, with the results pending. Booth and colleagues explored the use of perioperative chemotherapy for MIBC using the Ontario Cancer Registry and reported that 4% of patients received neoadjuvant chemotherapy from 1994 to 2008. Notably, this group reported that only 18% (520 of 2944) of patients in the cohort were seen by a medical oncologist before cystectomy and that 25% of patients referred to a medical oncologist received neoadjuvant chemotherapy. There was marked geographic variation in medical oncology referral rates before cystectomy (5%–40%).

Decreased enthusiasm for the use of neoadjuvant chemotherapy, particularly in older patients, may be related, at least in part, to concerns regarding the toxicities associated with the regimens used in the neoadjuvant randomized trials, MVAC and CMV. In the metastatic setting, gemcitabine plus cisplatin (GC) has largely supplanted MVAC as standard first-line therapy based on a phase III trial demonstrating similar efficacy albeit lesser toxicity. These results have been extrapolated to the neoadjuvant setting and even included in the National Comprehensive Cancer Network’s guidelines, in the absence of level I evidence, highlighting a pragmatic attempt by the oncology community to bridge the gap between efficacy and effectiveness. Retrospective studies have demonstrated similar complete pathologic rates comparing MVAC and GC, providing some support for this practice. There are no randomized trials establishing the efficacy of perioperative carboplatin-based therapy for patients with MIBC and even scant prospective phase II data, leaving the large population of cisplatin-ineligible patients without a standard perioperative systemic therapy option.

As outlined earlier, barriers to the utilization of neoadjuvant chemotherapy for MIBC exist at the system-, physician-, and patient-levels. Comprehensively identifying and addressing each of these barriers, while simultaneously developing more effective and less toxic systemic therapies, are critical to optimizing the likelihood of cure of all patients with MIBC.