Does neoadjuvant chemotherapy diminish the sex disparity in bladder cancer survival after radical cystectomy?

Background The standard of care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy, which is typically preceded by neoadjuvant chemotherapy. However, the inability to assess minimal residual disease (MRD) noninvasively limits our ability to offer bladder-sparing treatment. Here, we sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis. Methods and findings We applied urine Cancer Personalized Profiling by Deep Sequencing (uCAPP-Seq), a targeted next-generation sequencing (NGS) method for detecting utDNA, to urine cell-free DNA (cfDNA) samples acquired between April 2019 and November 2020 on the day of curative-intent radical cystectomy from 42 patients with localized bladder cancer. The average age of patients was 69 years (range: 50 to 86), of whom 76% (32/42) were male, 64% (27/42) were smokers, and 76% (32/42) had a confirmed diagnosis of MIBC. Among MIBC patients, 59% (19/32) received neoadjuvant chemotherapy. utDNA variant calling was performed noninvasively without prior sequencing of tumor tissue. The overall utDNA level for each patient was represented by the non-silent mutation with the highest variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy adults. utDNA analysis revealed a median utDNA level of 0% in healthy adults and 2.4% in bladder cancer patients. When patients were classified as those who had residual disease detected in their surgical sample (n = 16) compared to those who achieved a pathologic complete response (pCR; n = 26), median utDNA levels were 4.3% vs. 0%, respectively (p = 0.002). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD detection was highly correlated with the absence of pCR (p < 0.001) with a sensitivity of 81% and specificity of 81%. Leave-one-out cross-validation applied to the prediction of pathologic response based on utDNA MRD detection in our cohort yielded a highly significant accuracy of 81% (p = 0.007). Moreover, utDNA MRD–positive patients exhibited significantly worse progression-free survival (PFS; HR = 7.4; 95% CI: 1.4–38.9; p = 0.02) compared to utDNA MRD–negative patients. Concordance between urine- and tumor-derived mutations, determined in 5 MIBC patients, was 85%. Tumor mutational burden (TMB) in utDNA MRD–positive patients was inferred from the number of non-silent mutations detected in urine cfDNA by applying a linear relationship derived from The Cancer Genome Atlas (TCGA) whole exome sequencing of 409 MIBC tumors. We suggest that about 58% of these patients with high inferred TMB might have been candidates for treatment with early immune checkpoint blockade. Study limitations included an analysis restricted only to single-nucleotide variants (SNVs), survival differences diminished by surgery, and a low number of DNA damage response (DRR) mutations detected after neoadjuvant chemotherapy at the MRD time point. Conclusions utDNA MRD detection prior to curative-intent radical cystectomy for bladder cancer correlated significantly with pathologic response, which may help select patients for bladder-sparing treatment. utDNA MRD detection also correlated significantly with PFS. Furthermore, utDNA can be used to noninvasively infer TMB, which could facilitate personalized immunotherapy for bladder cancer in the future.

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Impact of neoadjuvant chemotherapy on survival and recurrence patterns after robot‐assisted radical cystectomy for muscle‐invasive bladder cancer: Results from the International Robotic Cystectomy Consortium

International Journal of Urology ◽

10.1111/iju.14749 ◽

2021 ◽

Author(s):

Dharmesh Gopalakrishnan ◽

Ahmed S Elsayed ◽

Ahmed A Hussein ◽

Zhe Jing ◽

Qiang Li ◽

...

Keyword(s):

Bladder Cancer ◽

Neoadjuvant Chemotherapy ◽

Radical Cystectomy ◽

Invasive Bladder Cancer ◽

Robot Assisted ◽

Muscle Invasive Bladder Cancer ◽

Robotic Cystectomy ◽

Recurrence Patterns ◽

Muscle Invasive

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Meta-analysis of neoadjuvant chemotherapy compared to radical cystectomy alone in improving overall survival of muscle-invasive bladder cancer patients

BMC Urology ◽

10.1186/s12894-020-00733-z ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Agus Rizal A. H. Hamid ◽

Fanny Riana Ridwan ◽

Dyandra Parikesit ◽

Fina Widia ◽

Chaidir Arif Mochtar ◽

...

Keyword(s):

Overall Survival ◽

Bladder Cancer ◽

Neoadjuvant Chemotherapy ◽

Radical Cystectomy ◽

Meta Analysis ◽

Total Sample ◽

Invasive Bladder Cancer ◽

Forest Plot ◽

Muscle Invasive Bladder Cancer ◽

Muscle Invasive

Abstract Background Most patients with muscle-invasive bladder cancer (MIBC) developed metastasis within 2 years, even after radical cystectomy (RC). The recurrence rate of MIBC was more than 50% of the cases. A meta-analysis conducted by Yin et al. showed that neoadjuvant chemotherapy (NAC) + RC improves overall survival in MIBC compared with RC only. However, a new meta-analysis by Li et al. concluded that NAC + RC was not superior to RC only in improving overall survival. The inconsistencies of these studies required further comprehensive analysis to recommend NAC use in bladder cancer treatment. Therefore, this meta-analysis aims to analyze previous studies that compare the efficacy of NAC + RC versus RC only to improve overall survival of MIBC. Methods The articles were searched using Pubmed with keywords “muscle-invasive bladder cancer”, “neoadjuvant chemotherapy”, “cystectomy”, and “overall survival”. The articles that were published until June 2020 were screened. The overall survival outcome was analyzed as hazard ratio (HR) and presented in a forest plot. Result Seventeen studies were included in meta-analysis with a total sample of 13,391 patients, consist of 2890 received NAC followed by RC and 10,418 underwent RC only. Two studies used methotrexate/vinblastine/doxorubicin/cisplatin (MVAC), two studies used gemcitabine/cisplatin (GC), one study used Cisplatin-based regimen, one study used MVAC or GC, one study used gemcitabine/carboplatin (GCarbo) or GC or MVAC, one study used Cisplatin/Gemcitabine or MVAC, one study used Cisplatin only, one study used Cisplatin-based (GC, MVAC) or non-Cisplatin-based (combined paclitaxel/gemcitabine/carboplatin), one study used GC, MVAC, Carboplatin, or Gemcitabine/Nedaplatin (GN), and five studies did not mention the regimen The overall survival in the NAC + RC only group was significantly better than the RC only group (HR 0.82 [0.71–0.95], p = 0.009). Conclusion NAC + RC is recommended to improve overall survival in MIBC patients. A further study assessing side effects and quality of life regarding NAC + RC is needed to establish a strong recommendation regarding this therapy.

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Delaying radical cystectomy after neoadjuvant chemotherapy for muscle-invasive bladder cancer has a detrimental impact on survival outcomes: A single-center experience

European Urology Supplements ◽

10.1016/s1569-9056(18)33154-3 ◽

2018 ◽

Vol 17 (8) ◽

pp. 227

Author(s):

L. Boeri ◽

M. Soligo ◽

M. Colicchia ◽

A. Morlacco ◽

J. Karnes

Keyword(s):

Bladder Cancer ◽

Neoadjuvant Chemotherapy ◽

Radical Cystectomy ◽

Survival Outcomes ◽

Single Center ◽

Muscle Invasive Bladder Cancer ◽

Single Center Experience ◽

Impact On Survival ◽

Muscle Invasive ◽

Detrimental Impact

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Natural history of pT3-4 or node positive bladder cancer treated with radical cystectomy and no neoadjuvant chemotherapy in a contemporary North-American multi-institutional cohort

Canadian Urological Association Journal ◽

10.5489/cuaj.119 ◽

2012 ◽

Vol 6 (6) ◽

pp. 217 ◽

Cited By ~ 13

Author(s):

Nicholas E. Power ◽

Wassim Kassouf ◽

David Bell ◽

Armen Aprikian ◽

Yves Fradet ◽

...

Keyword(s):

Bladder Cancer ◽

High Risk ◽

Adjuvant Chemotherapy ◽

Neoadjuvant Chemotherapy ◽

Natural History ◽

Radical Cystectomy ◽

Node Positive ◽

Number Of Patients ◽

History Of ◽

Modern Era

Background: The present study documents the natural history and outcomes of high-risk bladder cancer after radical cystectomy (RC) in patients who did not receive neoadjuvant chemotherapy during a contemporary time period.Methods: We analyzed 1180 patients from 1993 to 2008 with >pT3N0 or pT0-4N+ bladder cancer who underwent RC ± standard (sLND) or extended (eLND) lymph node dissection from 8 Canadian centres.Results: Of the 1180 patients, 55% (n = 643) underwent sLND, 34% (n = 402) underwent ePLND and 11% did not undergo a formal LND. Of the total number of patients, 321 (27%) received adjuvant chemotherapy. The median follow-up was 2.1 years (range: 0.6 to 12.9). Overall 30-day mortality was 3.2%. Clinical and pathological stages T3-4 were present in 6.1% and 86.7% of the patients, respectively; this demonstrates a dramatic understaging. Overall survival (OS) at 2 and 5 years was 60% and 43%, respectively. Patients who received adjuvant chemotherapy hada 2- and 5-year disease-specific survival (DSS) of 72% and 57% versus 64% and 51% for those who did not (log-rank p = 0.0039). The 2- and 5-year OS for high-risk node-negative disease was 67%and 52%, respectively, whereas for node-positive patients, the OS was 52% and 32%, respectively (p < 0.001). The OS, DSS and RFS for patients with pN0 were significantly improved compared to those who did not undergo a LND (log-rank p = 0.0035, 0.0241 and 0.0383, respectively).Interpretation: This series suggests that bladder cancer outcomes inadvanced disease have improved in the modern era. The need for improved staging investigations, use of neoadjuvant chemotherapyand performance of complete LND is emphasized.

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