Dataset Information

Circulating tumour cells to drive the use of neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer.

ABSTRACT:

Background

Guidelines recommend neoadjuvant chemotherapy (NAC) for the treatment of nonmetastatic muscle-invasive bladder cancer (MIBC). NAC is, however, underutilized in practice because of its associated limited overall survival (OS) benefit and significant treatment-related toxicity. We hypothesized that the absence of circulating tumour cells (CTCs) identifies MIBC patients with such a favourable prognosis that NAC may be withheld.

Patients and methods

The CirGuidance study was an open-label, multicentre trial that included patients with clinical stage T2-T4aN0-N1M0 MIBC, scheduled for radical cystectomy. CTC-negative patients (no CTCs detectable using the CELLSEARCH system) underwent radical surgery without NAC; CTC-positive patients (≥1 detectable CTCs) were advised to receive NAC, followed by radical surgery. The primary endpoint was the 2-year OS in the CTC-negative group with a prespecified criterion for trial success of ≥75% (95% confidence interval (CI) ±5%).

Results

A total of 273 patients were enrolled. Median age was 69 years; median follow-up was 36 months. The primary endpoint of 2-year OS in the CTC-negative group was 69.5% (N = 203; 95% CI 62.6%-75.5%). Two-year OS was 58.2% in the CTC-positive group (N = 70; 95% CI 45.5%-68.9%). CTC-positive patients had a higher rate of cancer-related mortality [hazard ratio (HR) 1.61, 95% CI 1.05-2.45, P = 0.03] and disease relapse (HR 1.87, 95% CI 1.28-2.73, P = 0.001) than CTC-negative patients. Explorative analyses suggested that CTC-positive patients who had received NAC (n = 22) survived longer than CTC-positive patients who had not (n = 48).

Conclusion

The absence of CTCs in MIBC patients was associated with improved cancer-related mortality and a lower risk of disease relapse after cystectomy; however, their absence alone does not justify to withhold NAC. Exploratory analyses suggested that CTC-positive MIBC patients might derive more benefit from NAC.

Trial registration

Netherlands Trial Register NL3954; https://www.trialregister.nl/trial/3954.

SUBMITTER: Beije N

PROVIDER: S-EPMC9058916 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Circulating tumour cells to drive the use of neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer.

Beije N N de Kruijff I E IE de Jong J J JJ Klaver S O SO de Vries P P Jacobs R A L RAL Somford D M DM Te Slaa E E van der Heijden A G AG Alfred Witjes J J Fossion L M C L LMCL Boevé E R ER van der Hoeven J J van Melick H H E HHE Wijburg C J CJ Bickerstaffe H H Martens J W M JWM de Wit R R Kraan J J Sleijfer S S Boormans J L JL

ESMO open 20220303 2

<h4>Background</h4>Guidelines recommend neoadjuvant chemotherapy (NAC) for the treatment of nonmetastatic muscle-invasive bladder cancer (MIBC). NAC is, however, underutilized in practice because of its associated limited overall survival (OS) benefit and significant treatment-related toxicity. We hypothesized that the absence of circulating tumour cells (CTCs) identifies MIBC patients with such a favourable prognosis that NAC may be withheld.<h4>Patients and methods</h4>The CirGuidance study wa ...[more]

PMID: 35248823

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Project description:BackgroundNeoadjuvant chemotherapy is underutilized in bladder cancer patients who undergo radical cystectomy. However, the quality of regimens used in this setting remains largely unknown.ObjectiveTo determine utilization treatment patterns and survival outcomes according to regimens administered.Design, setting, and patientsWe used the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database to identify patients diagnosed with clinical stage TII-IV bladder cancer from January 1, 2001 to December 31, 2011.Outcome measurements and statistical analysisTemporal trends were assessed using the Cochran-Armitage test. Multivariable logistic regression models were used to identify predictors for neoadjuvant chemotherapy use. Cox proportional hazards models were used to compare overall survival according to regimens administered.Results and limitationsOf 2738 patients treated with radical cystectomy, 344 (12.6%) received neoadjuvant chemotherapy. The agents most commonly used were gemcitabine (72.3%), cisplatin (55.2%), and carboplatin (31.1%). The regimens most commonly used were gemcitabine-cisplatin (45.3%), gemcitabine-carboplatin (24.1%), and methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC; 6.7%). Use of neoadjuvant chemotherapy more than tripled during the study period, from 5.7% in 2001 to 17.3% in 2011 (p<0.001). The quality of the regimen administered impacted survival outcomes, as M-VAC use was significantly associated with better overall survival among patients diagnosed with stage II bladder cancer (hazard ratio 0.24, 95% confidence interval 0.07-0.86; p=0.030]. Limitations include the limited ability of retrospective analysis to control for selection bias.ConclusionsNeoadjuvant chemotherapy was underused, and the quality of neoadjuvant chemotherapy regimens administered for bladder cancer was inconsistent with guideline recommendations. These findings are important when interpreting population-based data on the use of chemotherapy and extrapolating survival outcomes.Patient summaryIn a large population-based study, 12.6% of patients undergoing radical cystectomy for bladder cancer received neoadjuvant chemotherapy, half of whom received guideline-recommended regimens. The quality of the regimen impacted survival outcomes, as use of cisplatin-based chemotherapy was significantly associated with better overall survival among patients diagnosed with stage II bladder cancer. However, <1% of radical cystectomy patients received this regimen.

Project description:BackgroundBladder-sparing chemoradiation therapy is a definitive first-line treatment option for muscle-invasive bladder cancer. Randomized trials have demonstrated that the addition of neoadjuvant chemotherapy to radical cystectomy or radiation monotherapy results in a survival benefit. Whether neoadjuvant chemotherapy improves outcomes when used with definitive chemoradiation is unknown.Patients and methodsWe identified 2566 patients in the National Cancer Data Base with cT2-4N0M0 urothelial cell carcinoma of the bladder treated with definitive intent concurrent chemoradiation from 2004 to 2015. The exposure of interest was receipt of neoadjuvant chemotherapy versus those without neoadjuvant chemotherapy. The primary outcome was overall survival defined from the time of diagnosis. Kaplan-Meier and multivariable Cox proportional hazard analyses were used to compare survival between groups. Sensitivity analyses tested (1) an interaction term for clinical T stage and (2) defining survival from start of radiation (as opposed to time of diagnosis) to address potential leading time bias.ResultsWe identified 462 patients treated with neoadjuvant chemotherapy followed by chemoradiation and 2104 patients treated with chemoradiation alone. With a median follow-up of 6.2 years, we found no difference in survival between groups: 5-year or 10-year overall survival of 30.6% (95% confidence interval [CI], 28.4%-32.9%) in the neoadjuvant group versus 31.8% (95% CI, 27.0%-36.8%) in the standard chemoradiation therapy group and 13.3% (95% CI, 11.2%-15.5%) in the neoadjuvant group versus 13.0% (95% CI, 8.4%-18.7%) in the standard chemoradiation therapy group, respectively (log-rank P = .19). On multivariable analysis we found no association between receipt of neoadjuvant chemotherapy and overall survival (hazard ratio, 1.01; 95% CI, 0.88-1.15; P = .921). The sensitivity analyses did not identify any differential effect by clinical T stage nor by defining survival from start of radiation.ConclusionThese results do not support the routine addition of neoadjuvant chemotherapy to definitive chemoradiation for bladder cancer, and optimizing the chemotherapy sequencing and regimens for bladder-preserving approaches to muscle invasive bladder cancer should continue to be studied under prospective clinical trials.

Dataset Information

Circulating tumour cells to drive the use of neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer.

Background

Patients and methods

Results

Conclusion

Trial registration

Publications

Circulating tumour cells to drive the use of neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer.

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