Date Published: May 10, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Daniel A. Barocas, Denise R. Globe, Danielle C. Colayco, Ahunna Onyenwenyi, Amanda S. Bruno, Thomas J. Bramley, Rachel J. Spear.
Seventy percent of newly diagnosed bladder cancers are classified as non-muscle-invasive bladder cancer (NMIBC) and are often associated with high rates of recurrence that require lifelong surveillance. Currently available treatment options for NMIBC are associated with toxicities that limit their use, and actual practice patterns vary depending upon physician and patient characteristics. In addition, bladder cancer has a high economic and humanistic burden in the United States (US) population and has been cited as one of the most costly cancers to treat. An unmet need exists for new treatment options associated with fewer complications, better patient compliance, and decreased healthcare costs. Increased prevention of recurrence through greater adherence to evidence-based guidelines and the development of novel therapies could therefore result in substantial savings to the healthcare system.
Non-muscle-invasive bladder cancer (NMIBC), formerly known as superficial bladder cancer, is a common, heterogeneous disease associated with high rates of recurrence and that often requires lifelong surveillance [1–4]. Treatment options for NMIBC are limited, with initial management involving transurethral resection of the bladder tumor (TURBT), followed by adjuvant instillations of chemotherapy or immunotherapy to reduce recurrence rates and prevent disease progression . Commonly used current intravesical therapies include mitomycin C—a naturally occurring product of Streptomyces bacteria that has antibacterial and antitumor properties—and bacillus Calmette-Guérin (BCG), an attenuated mycobacterium that produces an inflammatory reaction in the bladder. Both of these therapies were introduced several decades ago and have been shown to reduce recurrence rates. Each of the intravesical therapy options has associated toxicities that can impair patient compliance, particularly so for BCG, which routinely causes irritative voiding symptoms, often causes fever and malaise, and in rare cases, results in systemic sepsis [5–9].
This qualitative review was conducted by applying a list of search terms to a database of the medical sciences (PubMed, published by the National Library of Medicine). The set of search terms included variations of “bladder cancer,” “NMIBC,” “BCG,” “mitomycin,” “intravesical therapy,” “cystectomy,” “epidemiology,” “risk factors,” “guidelines,” “efficacy,” “clinical burden,” “toxicity,” “diagnostic,” “health-related quality of life,” and “economic burden.” Articles were excluded if they were published in languages other than English. A total of 98 articles were identified, abstracted, and evaluated using the Oxford Center for Evidence-Based Medicine’s 2011 levels of evidence . The majority of those were then used in this paper to describe current treatment options, the clinical and economic burden of NMIBC, and unmet needs of NMIBC that exist today.
The bladder is a vessel that stores urine produced by the kidneys before excretion . The bladder itself is made up of several tissue layers. The first 2 layers include the urothelial and the lamina propria layers. The urothelial or mucosal layer makes contact with the bladder contents, while the lamina propria, or submucosal layer, connects the urothelial layer to the underlying smooth muscle . Bladder cancer is a common malignancy arising from the urothelial cells and is responsible for considerable morbidity and mortality . The most common symptom of bladder cancer is hematuria, which occurs in 80% to 90% of patients . Approximately 70% of newly diagnosed cases of bladder cancer are NMIBC, meaning that they are confined to the urothelial and lamina propria layers of the bladder [3, 4, 26, 29–32]. Among NMIBCs, around 70% present as Ta lesions (papillary tumor confined to the urothelium), 20% as T1 lesions (tumor invades the lamina propria), and 10% as carcinoma in situ (CIS) (flat, high-grade tumor confined to the urothelial layer) [4, 29].
Bladder cancer is one of the most commonly diagnosed malignancies in the USA, with an estimated 70,530 new cases diagnosed in 2010 . Its effect on mortality is also substantial, with a projected 14,680 deaths that same year . However, in terms of stage distribution, bladder cancer has a 5-year relative survival rate—which measures the survival of the cancer patients in comparison to the general population—of 97% for in situ, 71% for local, 35% for regional, and 5% for distant cases .
Important clinical outcomes in the natural history of NMIBC include recurrence and progression. Patients with NMIBC have a high risk for disease recurrence (i.e., tumors of the same stage and grade as primary tumor), or disease progression (i.e., a higher stage with muscle invasion or metastasis throughout the clinical course of treatment), even in those treated with TURBT and existing intravesical therapies [3, 6–8, 13, 14, 24, 32–45]. Nearly one-third of patients with NMIBC will have a recurrence of disease within 2 years, and patients often require routine monitoring and treatment for the rest of their lives [2, 15, 26, 31, 46, 51–56].
Considerations for appropriate treatment options in non-muscle-invasive disease must be made in conjunction with clearly defined goals—namely, to prevent disease recurrence and progression to muscle-invasive disease and to avoid the loss of the bladder . The standard initial treatment supported for NMIBC is TURBT, which can be performed on an outpatient basis with general anesthesia [13, 14, 16, 35, 57]. The most common side effects associated with TURBT are bleeding and infection . To prevent tumor recurrence, TURBT may be followed by an immediate postoperative instillation of chemotherapy (e.g., mitomycin C, epirubicin, and doxorubicin) and/or an adjuvant course of intravesical chemotherapy or immunotherapy (e.g., BCG). The typical adjuvant course consists of a 6-week induction (to induce remission) of intravesical chemotherapy given via a urethral catheter and left in the bladder for a specific amount of time, usually 1 to 2 hours [4, 7, 13]. In addition, a patient may go on to receive a maintenance regimen, typically consisting of 3 weekly instillations at 3, 6, 12, 18, 24, 30, and 36 months from start of induction .
Current treatment guidelines support the use of a single dose of adjuvant intravesical chemotherapy for low-risk patients with NMIBC because of its ability to reduce the risk of tumor recurrence [14, 16]. A meta-analysis of 7 randomized clinical trials found a 39% decreased odds of recurrence at a median follow-up of 3.4 years in patients who received a single postoperative instillation of chemotherapy versus patients receiving TURBT alone . In 2005, a review by an international consensus panel found that the risk of recurrence can be reduced by 50% at 2 years and by 15% or more at 5 years with a single dose of adjuvant intravesical chemotherapy . Accordingly, the panel recommended a single dose of intravesical chemotherapy, ideally within 6 hours, and no more than 24 hours after TURBT, with the exception of patients with a suspected bladder perforation .
Overall, bladder cancer is the ninth-most costly cancer in the US and was estimated to cost approximately $3.98 billion in 2010 . Assuming a 2% annual increase in direct medical costs in the initial and final phases of care, projected 2020 costs increase to $4.9 billion (in 2010 dollars) . Furthermore, because these cost estimates do not include other types of costs, such as lost productivity or patient suffering, the total economic burden of bladder cancer is considerably higher. Based exclusively on direct medical costs, however, bladder cancer is the most costly of all cancers in terms of lifetime per-patient treatment costs, which have been estimated to range from $96,000 to $187,000 per patient in 2001 US dollars . This high cost of bladder cancer is largely due to the disease’s high recurrence rate and low mortality rate and costs associated with disease surveillance [25, 26].
Treatment-associated complications not only contribute to the economic burden of bladder cancer but also increase patient impairment in physical health and worsened quality of life [78–80]. Quality of life affecting patient care and patient satisfaction with treatment options is becoming increasingly important by the medical community at large . While there are several quality of life instruments in bladder cancer, no predominant single index is used widely .
Bladder cancer is a heterogeneous, highly prevalent disease that accounts for significant morbidity and mortality in the USA [2, 3]. The high rates of recurrence and risk of disease progression in bladder cancer often require lifelong surveillance, making the disease both clinically and economically important . Further research is needed to quantify the humanistic burden of NMIBC using instruments validated in the appropriate patient populations.