Characteristics of the study sample stratified by time to cystectomy are displayed in Table 1. We identified 441 subjects with stage II TCC of the bladder who underwent radical cystectomy between 1992 and 2001. Most subjects were male, white, and married. Charlson indices ranged from 0 to 5, with 93% of subjects having comorbidity indices of 0 or 1. Time from diagnosis to radical cystectomy ranged from 4 to 52 weeks. Eighty-nine percent of subjects underwent definitive surgical extirpation within 24 weeks of diagnosis, of whom 73% underwent cystectomy within 12 weeks. The demographic characteristics of the sample did not vary by time to cystectomy. However, although not statistically significant, nonwhites and unmarried individuals trended toward longer time to cystectomy. Over the study period, 279 subjects (63.3%) died, most often from bladder cancer (136 [30.8%] subjects a median 16.0 months after diagnosis) or cardiovascular disease.
A delay of more than 12 weeks between diagnosis and radical cystectomy for TCC of the urinary bladder significantly compromises patient survival. This adverse impact affects both disease-specific and overall survival and is exacerbated by increasing time from diagnosis to cystectomy. Our findings corroborate prior single-institution series that identified a 12-week cutoff as conferring an increased risk of pathologic upstaging and mortality.7-10
Common reasons for delays in definitive treatment of muscle-invasive bladder cancer patients include extra time for medical clearance, given the preponderance of comorbid disease in this population, the need for transfer to centers equipped to manage the burden of care for cystectomy patients, and time required to overcome patient reluctance to undergo surgery that radically affects their voiding function and, potentially, their body image. Radical cystectomy with urinary diversion is a uniquely morbid operation. Complication rates after radical cystectomy range from 28% to 37% in studies derived from analysis of nationally representative datasets.11, 12 Many of these complications are medical and relate to the high prevalence of smoking history, vascular disease, coronary artery disease, and chronic pulmonary disease in bladder cancer patients. These conditions are likely more prevalent among elderly bladder cancer patients, explaining their underuse of aggressive therapy.13 These circumstances necessitate preoperative optimization of patients' medical condition to reduce these risks.
Given the operative time, length of inpatient stay, extensive care required during the convalescent period, and poor reimbursement for the procedure and postoperative care, many providers refer patients with indications for a cystectomy to higher volume centers. The 1990s witnessed a marked urbanization of radical cystectomy, as these patients were regionalized in an ad hoc manner to urban, high-volume, academic facilities.14 High-volume cystectomy centers have better perioperative mortality outcomes; incorporation of processes of care such as rates of continent urinary diversion enhances differences in clinical outcomes between high- and low-volume centers.15, 16 Although regionalization of radical cystectomy for bladder cancer to high-volume centers may be associated with improved perioperative outcomes, the incumbent delay required for such a transfer of care may worsen patients' long-term survival.
Our analysis is strengthened by the study sample and data source used. Differential referral patterns may bias the association between a delay in cystectomy and pathologic and survival outcomes at tertiary referral centers. Patient populations at these centers may not be generalizable to the average patient with muscle-invasive bladder cancer. In contrast, our study uses nationally representative data that include patients treated at academic and community institutions, by providers with various degrees of surgical volume. Similarly, referrals in our sample should reflect community patterns that may differ from those seen exclusively at tertiary referral centers. We restricted our sample to those with stage II TCC to eliminate equivocal treatment algorithms as a source of delays in cystectomy. Those with more advanced locoregional disease may suffer postponements related to the consideration of alternative treatments such as chemotherapy that could potentially bias our results. Similarly, the study period, with patients treated in an era that preceded more earnest consideration of neoadjuvant chemotherapy before cystectomy, favors the results of our study.
Our study is limited by the use of claims data to study procedural specifics and survival outcomes. We attempted to create an algorithm to measure time from diagnosis to cystectomy; however, we could not precisely determine, in the context of multiple TURBTs before cystectomy, the biopsy that confirmed muscle invasion. Among the small proportion of subjects who underwent multiple resections before cystectomy, many may have had reoperations for symptoms such as refractory hematuria. Re-resection is uncommon and likely not indicated for patients with pathologically confirmed muscle invasion, thus our algorithm for determining time to cystectomy is intuitively valid. Also, our staging algorithm involved identification of the initial diagnosis of bladder cancer. In the majority of cases, this stage classification is derived from the initial TURBT, with no account for upstaging at the time of cystectomy. Furthermore, we could not identify upstaging as an outcome in our sample, which may have further validated the adverse impact of a delay in cystectomy.
Determination of cause-specific survival from claims or registry data is often confounded by submission or coding errors, limiting analysis of disease-specific survival in this population. A selection bias may have further confounded the analysis. This may explain the crossing of the survival curves in Figure 1. To sustain a delay in cystectomy beyond 24 weeks, subjects had to survive those 6 months; that the survival curve for these subjects eventually dropped below all other time lapse categories may represent deaths from bladder cancer exclusively. We cannot account for subjects delayed beyond 24 weeks who eventually received no cancer-directed care. Contemporary management of invasive bladder cancer mandates consideration of neoadjuvant chemotherapy based upon randomized controlled trials demonstrating some survival benefit.17 We specifically excluded subjects who received chemotherapy before cystectomy, and our results do not apply to patients appropriately selected for neoadjuvant chemotherapy. The impact of chemotherapy on optimal pathways of care that include radical cystectomy has yet to be clearly delineated. Importantly, these results should not be interpreted as an indictment of neoadjuvant chemotherapy because of the resultant impact on time to cystectomy. Finally, our analysis focused on Medicare beneficiaries, which may limit generalizability of our results. However, most patients with newly diagnosed bladder cancer are between the ages of 60 and 79 years and thus are of Medicare age.18
We sought to determine the impact of delays between the diagnosis of muscle-invasive bladder cancer and definitive extirpative treatment with radical cystectomy. We could not adjust for delays in care between symptomatic presentation and eventual diagnosis, which may be a more critical determinant of cancer-specific outcome than delays between diagnosis and cystectomy. Patients with hematuria may receive treatment with antibiotics before referral for further evaluation. For muscle-invasive cancers, the prolongation of time to evaluation engendered by this inappropriate management may be more condemning than their management once diagnosed.
Despite these limitations, these results demonstrate the detrimental impact of a delay beyond 12 weeks between diagnosis of muscle-invasive bladder cancer and definitive treatment with radical cystectomy. Delaying cystectomy for patients with muscle-invasive TCC of the bladder beyond 12 weeks confers worse disease-specific and overall survival. Prompt treatment remains fundamental to the management of stage II bladder cancer; those processes that expedite care in this population should be disseminated to minimize the magnitude of the cohort delayed beyond 12 weeks.