Concomitant CIS on TURBT does not impact oncological outcomes in patients treated with neoadjuvant or induction chemotherapy followed by radical cystectomy

© Springer-Verlag GmbH Germany, part of Springer Nature 2018Background: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer improves all-cause and cancer specific survival. We aimed to evaluate whether the detection of carcinoma in situ (CIS) at the time of initial transurethral resection of bladder tumor (TURBT) has an oncological impact on the response to NAC prior to radical cystectomy. Patients and methods: Patients were identified retrospectively from 19 centers who received at least three cycles of NAC or induction chemotherapy for cT2-T4aN0-3M0 urothelial carcinoma of the bladder followed by radical cystectomy between 2000 and 2013. The primary and secondary outcomes were pathological response and overall survival, respectively. Multivariable analysis was performed to determine the independent predictive value of CIS on these outcomes. Results: Of 1213 patients included in the analysis, 21.8% had concomitant CIS. Baseline clinical and pathologic characteristics of the ‘CIS’ versus ‘no-CIS’ groups were similar. The pathological response did not differ between the two arms when response was defined as pT0N0 (17.9% with CIS vs 21.9% without CIS; p = 0.16) which may indicate that patients with CIS may be less sensitive to NAC or ≤ pT1N0 (42.8% with CIS vs 37.8% without CIS; p = 0.15). On Cox regression model for overall survival for the cN0 cohort, the presence of CIS was not associated with survival (HR 0.86 (95% CI 0.63–1.18; p = 0.35). The presence of LVI (HR 1.41, 95% CI 1.01–1.96; p = 0.04), hydronephrosis (HR 1.63, 95% CI 1.23–2.16; p = 0.001) and use of chemotherapy other than ddMVAC (HR 0.57, 95% CI 0.34–0.94; p = 0.03) were associated with shorter overall survival. For the whole cohort, the presence of CIS was also not associated with survival (HR 1.05 (95% CI 0.82–1.35; p = 0.70). Conclusion: In this multicenter, real-world cohort, CIS status at TURBT did not affect pathologic response to neoadjuvant or induction chemotherapy. This study is limited by its retrospective nature as well as variability in chemotherapy regimens and surveillance regimens.Peer reviewedFinal Accepted Versio

Neoadjuvant treatment for muscle-invasive bladder cancer: The past, the present, and the future

Background: Approximately half of patients who undergo radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) will succumb to metastatic disease. We summarize the evidence for neoadjuvant radiation (NAR), chemo (NAC), and immunotherapy (checkpoint inhibition) prior to RC for MIBC. Materials and methods: Data were obtained by a search of PubMed, ClinicalTrials.gov, and Cochrane databases for English language articles published from 1925 up to 2017. Results: NAC usage has increased over the last decade, while NAR is rarely administered. Although NAR results in downstaging, its impact on survival is inconclusive. Based on level I evidence, cisplatin-based NAC (CB-NAC) is considered standard of care in cT2–4aN0M0 MIBC. NAC results in a 6% absolute 10-year overall survival (OS) benefit. In-depth analyses of key randomized controlled trials showed that failure to correct for uniform staging, surgical variation, and patient selection compromises the ability to identify factors predictive of response to NAC. The benefit appears to be restricted to patients downstaged to ypT1N0 or less. In these patients, 5-year OS is 80% to 90%. Regarding a number needed to treat of 17, most patients with cT2–4aN0M0 MIBC will be exposed to toxicity without benefit. Possible approaches to reduce overtreatment are suggested in this article and include patient selection, the chosen NAC regimen, and emerging molecular data to predict responsiveness to NAC. Neoadjuvant immunotherapy with checkpoint inhibitors is a promising future perspective currently under investigation. Conclusions: Past studies on NAR show inconclusive results and NAR is rarely administered. Instead, CB-NAC is advised in eligible patients with cT2–4aN0M0 MIBC prior to RC. In the near future, predictive biomarkers will be the key to tailor the use of CB-NAC and reduce harm to nonresponders.</p

Neoadjuvant treatment for muscle-invasive bladder cancer: The past, the present, and the future

Background: Approximately half of patients who undergo radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) will succumb to metastatic disease. We summarize the evidence for neoadjuvant radiation (NAR), chemo (NAC), and immunotherapy (checkpoint inhibition) prior to RC for MIBC. Materials and methods: Data were obtained by a search of PubMed, ClinicalTrials.gov, and Cochrane databases for English language articles published from 1925 up to 2017. Results: NAC usage has increased over the last decade, while NAR is rarely administered. Although NAR results in downstaging, its impact on survival is inconclusive. Based on level I evidence, cisplatin-based NAC (CB-NAC) is considered standard of care in cT2–4aN0M0 MIBC. NAC results in a 6% absolute 10-year overall survival (OS) benefit. In-depth analyses of key randomized controlled trials showed that failure to correct for uniform staging, surgical variation, and patient selection compromises the ability to identify factors predictive of response to NAC. The benefit appears to be restricted to patients downstaged to ypT1N0 or less. In these patients, 5-year OS is 80% to 90%. Regarding a number needed to treat of 17, most patients with cT2–4aN0M0 MIBC will be exposed to toxicity without benefit. Possible approaches to reduce overtreatment are suggested in this article and include patient selection, the chosen NAC regimen, and emerging molecular data to predict responsiveness to NAC. Neoadjuvant immunotherapy with checkpoint inhibitors is a promising future perspective currently under investigation. Conclusions: Past studies on NAR show inconclusive results and NAR is rarely administered. Instead, CB-NAC is advised in eligible patients with cT2–4aN0M0 MIBC prior to RC. In the near future, predictive biomarkers will be the key to tailor the use of CB-NAC and reduce harm to nonresponders.</p

Intermediate-term survival of robot-assisted versus open radical cystectomy for muscle-invasive and high-risk non-muscle invasive bladder cancer in The Netherlands

BACKGROUND: Radical cystectomy with pelvic lymph node dissection is the recommended treatment in non-metastatic muscle-invasive bladder cancer (MIBC). In randomised trials, robot-assisted radical cystectomy (RARC) showed non-inferior short-term oncological outcomes compared with open radical cystectomy (ORC). Data on intermediate and long-term oncological outcomes of RARC are limited. OBJECTIVE: To assess the intermediate-term overall survival (OS) and recurrence-free survival (RFS) of patients with MIBC and high-risk non-MIBC (NMIBC) who underwent ORC versus RARC in clinical practice. METHODS AND MATERIALS: A nationwide retrospective study in 19 Dutch hospitals including patients with MIBC and high-risk NMIBC treated by ORC (n = 1086) or RARC (n = 386) between January 1, 2012 and December 31, 2015. Primary and secondary outcome measures were median OS and RFS, respectively. Survival outcomes were estimated using Kaplan-Meier curves. A multivariable Cox regression model was developed to adjust for possible confounders and to assess prognostic factors for survival including clinical variables, clinical and pathological disease stage, neoadjuvant therapy and surgical margin status. RESULTS: The median follow-up was 5.1 years (95% confidence interval ([95%CI] 5.0-5.2). The median OS after ORC was 5.0 years (95%CI 4.3-5.6) versus 5.8 years after RARC (95%CI 5.1-6.5). The median RFS was 3.8 years (95%CI 3.1-4.5) after ORC versus 5.0 years after RARC (95%CI 3.9-6.0). After multivariable adjustment, the hazard ratio for OS was 1.00 (95%CI 0.84-1.20) and for RFS 1.08 (95%CI 0.91-1.27) of ORC versus RARC. Patients who underwent ORC were older, had higher preoperative serum creatinine levels and more advanced clinical and pathological disease stage. CONCLUSION: ORC and RARC resulted in similar intermediate-term OS and RFS in a cohort of almost 1500 MIBC and high-risk NMIBC

Contemporary update on neoadjuvant therapy for bladder cancer.

Administration of neoadjuvant chemotherapy preceding radical cystectomy in patients with bladder cancer remains a matter of debate. Results of prospective, randomized studies have demonstrated an overall absolute survival benefit of 5% at 5 years, provided cisplatin-based combination regimens are used. Owing to the perception of a modest survival benefit, the medical community has been slow to adopt the use of neoadjuvant chemotherapy. Other reasons for the underuse of neoadjuvant chemotherapy range from patient ineligibility to fear of delaying potentially curative surgery in nonresponders. Instead, several institutions have adopted an individualized, risk-adapted approach, in which the decision to administer chemotherapy is based on clinical stage and patient comorbidity profile. The development of new cytotoxic and targeted therapies, in particular immune checkpoint inhibitors, warrants well-designed prospective studies to test their efficacy alone or in combination in the neoadjuvant setting. Moving forward, genomic characterization of muscle-invasive bladder cancer could offer information that aids clinicians in selecting the appropriate chemotherapy regimen. Following neoadjuvant therapy, every effort should be made to ensure optimal surgery, as surgical margins and the number of removed lymph nodes are prognostic factors; thus, radical cystectomy and a meticulous extended pelvic lymph node dissection should be performed by expert surgeons