Original article
A delay ≥8 weeks to neoadjuvant chemotherapy before radical cystectomy increases the risk of upstaging

https://doi.org/10.1016/j.urolonc.2018.11.011Get rights and content

Highlights

  • NAC should be initiated within 8 weeks from diagnosis of MIBC to prevent upstaging.

  • Several socioeconomic factors associated with care delays were identified.

  • Time from diagnosis to surgery up to 7 months does not seem to affect OS after NAC.

Abstract

Objectives

To investigate delays to neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) and their effect on outcomes in a large national registry of patients with localized muscle invasive bladder cancer.

Patients and methods

Within the National Cancer Database (2004–2014), we identified 2,227 patients who underwent NAC and RC for cT2-T4aN0M0 urothelial carcinoma of the bladder. Times from diagnosis to treatments were tested for association with overall survival and pathologic outcomes, using Cox models, and restricted cubic splines regression.

Results

Median times from diagnosis to NAC and RC were 39 days (interquartile range: 26–56) and 155 days (interquartile range: 131–185), respectively. Time to NAC and time to RC were not associated with overall survival in the complete cohort, as well as in subgroups of responders and nonresponders to NAC. Overall, 916 patients (41%) were upstaged after RC, including 485 patients (22%) with positive lymph nodes. We identified delay to NAC ≥8 weeks as a significant cut-off point to predict the risk of upstaging in multivariable analysis (odds ratio: 1.27; 95% confidence interval: 1.02–1.59; P = 0.031). Black race, Medicaid insurance, and academic facilities were associated with a higher risk of delayed treatment.

Conclusion

After diagnosis of muscle invasive bladder cancer, NAC should be initiated as soon as possible and no more than 8 weeks to prevent upstaging. There is no evidence to support avoiding NAC due to concerns of delayed RC that was generated from surgery alone studies, as long as RC is performed within 7 months from initial diagnosis.

Introduction

Bladder cancer is the fifth most common cancer in the United States with an estimated incidence of 81,190 in 2018 [1]. Approximately 25% of new cases present as muscle invasive disease, which is associated with a higher risk of developing metastasis and death. Studies have suggested that a delay in radical cystectomy (RC) is associated with a decrease in overall survival (OS) [2], [3], [4], [5] and it is now recommended to perform radical surgery within 3 months from diagnosis [6]. However, after RC, the 5-year survival is only 50% [7]. In recent years, there has been a movement toward a multimodality treatment approach for patients with localized muscle invasive bladder cancer. Cisplatin-based neoadjuvant chemotherapy (NAC) in eligible patients is now recommended before RC, and is supported by large meta-analyses showing a 5% decrease in overall mortality [8]. Despite high level of evidence, the adoption of this strategy remains limited, with around 20% of patients effectively receiving NAC before RC in daily practice [9]. One of the hesitations in recommending NAC is that it may delay definitive therapy with RC, which may compromise patient outcomes [10]. However, it is unclear if the effect of delays on patient outcomes still holds true in the setting of NAC utilization. Care delays, care transitions, and access to cancer care are also becoming increasingly relevant in the debate over health care policy in the United States. In this study, we aimed to investigate in a large national registry of patients with bladder cancer, delays to NAC and RC and their effect on outcomes, using OS and pathological upstaging as primary endpoints.

Section snippets

Data source

The National Cancer Database (NCDB) is a nationwide, facility-based, comprehensive cancer registry, established in 1989, that currently captures approximately 70% of all newly diagnosed malignancies in the United States annually, comprising more than 34 million unique cancer cases [11]. The NCDB draws data from over 1,500 Commission on Cancer accredited facilities in the United States for initial diagnosis and/or first course of treatment administered. The database is a joint project of the

Time to NAC ± RC and OS

The characteristics of the 2,227 patients included are listed in Supplementary Table S1. Overall, 78% of the patients were cT2. Median time from diagnosis to initiation of NAC and from diagnosis to RC were 39 days (interquartile range [IQR]: 26–56) and 155 days (IQR: 131–185), respectively (Fig. 2). The median time between initiation of NAC and RC was 112 days (IQR: 92–137). With a median follow-up of 45.7 months (IQR: 31.0–65.5), the 2-year and 5-year OS rates were, respectively, 69% (95%

Discussion

In muscle invasive bladder cancer, delays of longer than 12 weeks to RC have been associated with pathologic upstaging [2], [15] and decreased survival [4], [5]. However, most of these studies were completed prior to the adoption of NAC. In this study, we explored if these effects continue to be significant in the setting of NAC. Using the NCDB, which represents the continuum of practice settings in the United States, our analysis showed that in patients who received NAC, time to RC up to 7

Conclusion

This report represents, to our knowledge, the first large observational cohort study evaluating the effect of time to treatments in patients receiving NAC + RC. We found that time from diagnosis to surgery up to 7 months does not seem to affect OS in patients treated with NAC. However, a delay ≥8 weeks to start NAC was significantly associated with a higher risk of upstaging and lymph node positivity on final pathology. Consequently, given the aggressiveness of the disease, we should expedite

Conflict of interest

None.

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  • Cited by (0)

    Funding: None.

    Disclaimer: The data used in the study are derived from a de-identified NCDB file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by the investigator.

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