Adjuvant Treatment of Residual Disease Following Neoadjuvant Chemotherapy and Radical Cystectomy for Muscle Invasive Bladder Cancer

2020 ◽  
Vol 6 (4) ◽  
pp. 525-535
Author(s):  
Markus Krebs ◽  
Ioannis Sokolakis ◽  
Roland Seiler ◽  
Siamak Daneshmand ◽  
Petros Grivas ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Clinical Trials ◽  
Neoadjuvant Chemotherapy ◽  
Radical Cystectomy ◽  
Adjuvant Treatment ◽  
Residual Disease ◽  
Treatment Options ◽  
Invasive Disease ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) has shown overall survival benefit for patients with muscle invasive bladder cancer (MIBC). In contrast, there is limited data for adjuvant treatment options in patients with residual muscle invasive disease after NAC followed by radical cystectomy (RC). OBJECTIVE: This systematic review aims to give an overview of studies examining adjuvant treatment options for patients with residual MIBC at RC despite NAC. METHODS: We systematically searched the PubMed database and Clinicaltrials.gov (end point August 2019) for publications and registered trials combining NAC, RC, and adjuvant treatment options. RESULTS: After removal of duplicates, 659 articles and registered trials were further analyzed. Finally, 10 studies and 7 registered clinical trials met inclusion criteria. While 5 publications did not further characterize NAC and adjuvant regimens, the remaining 5 studies reported mainly platinum-based regimens. Altogether, the selected studies showed conflicting results regarding the potential role of adjuvant treatment strategies in the setting of residual disease after NAC and RC. CONCLUSION: Although there is an urgent need for adjuvant treatment options for patients with MIBC after NAC and residual muscle invasive disease at RC, there has been very limited evidence available. Inclusion of such patients into ongoing adjuvant clinical trials is urgently needed; active surveillance is strongly recommended in the absence of trials.

scholarly journals Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort study

PLoS Medicine ◽  
2021 ◽  
Vol 18 (8) ◽  
pp. e1003732
Author(s):  
Pradeep S. Chauhan ◽  
Kevin Chen ◽  
Ramandeep K. Babbra ◽  
Wenjia Feng ◽  
Nadja Pejovic ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Radical Cystectomy ◽  
Residual Disease ◽  
Muscle Invasive Bladder Cancer ◽  
Curative Intent ◽  
Muscle Invasive ◽  
Bladder Sparing ◽  
Tumor Dna ◽  
Minimal Residual

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.

scholarly journals Efficient delivery of radical cystectomy after neoadjuvant chemotherapy for muscle-invasive bladder cancer

Cancer ◽  
2011 ◽  
Vol 118 (1) ◽  
pp. 44-53 ◽  
Author(s):  
Ajjai S. Alva ◽  
Christopher T. Tallman ◽  
Chang He ◽  
Maha H. Hussain ◽  
Khaled Hafez ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Radical Cystectomy ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Efficient Delivery ◽  
Muscle Invasive

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

BMC Urology ◽  
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.

scholarly journals Fewer tumour draining sentinel nodes in patients with progressing muscle invasive bladder cancer, after neoadjuvant chemotherapy and radical cystectomy

2019 ◽  
Vol 38 (9) ◽  
pp. 2207-2213
Author(s):  
Julia Alvaeus ◽  
Robert Rosenblatt ◽  
Markus Johansson ◽  
Farhood Alamdari ◽  
Tomasz Jakubczyk ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Radical Cystectomy ◽  
Progressive Disease ◽  
Clinical Staging ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Sentinel Nodes ◽  
Muscle Invasive ◽  
The Relationship

Abstract Purpose To examine the relationship between the number of tumour draining sentinel nodes (SNs) and pathoanatomical outcomes, in muscle-invasive bladder cancer (MIBC), in patients undergoing neoadjuvant chemotherapy (NAC) and radical cystectomy (RC). Materials and Methods In an ongoing prospective multicenter study, we included 230 patients with suspected urothelial MIBC from ten Swedish urological centers. All underwent TURb and clinical staging. From the cohort, 116 patients with urothelial MIBC; cT2-cT4aN0M0, underwent radical cystectomy (RC) and lymphadenectomy with SN-detection (SNd). 83 patients received cisplatin-based NAC and 33 were NAC-naïve. The number and locations of detected SNs and non-SNs were recorded for each patient. The NAC treated patients were categorized by pathoanatomical outcomes post-RC into three groups: complete responders (CR), stable disease (SD) and progressive disease (PD). Selected covariates with possible impact on SN-yield were tested in uni -and multivariate analyses for NAC-treated patients only. Results In NAC treated patients, the mean number of SNs was significantly higher in CR patients (3.3) and SD patients (3.6) compared with PD patients (1.4) (p = 0.034). In a linear multivariate regression model, the number of harvested nodes was the only independent variable that affected the number of SNs (p = 0.0004). Conclusions The number of tumor-draining SNs in NAC-treated patients was significantly lower in patients with progressive disease.

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