Adjuvant chemotherapy for residual disease after neoadjuvant chemotherapy for muscle invasive urothelial cancer (MIUC).

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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Treatment options for muscle-invasive urothelial cancer for patients who were not eligible for cystectomy or neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin

Cancer ◽

10.1002/cncr.23420 ◽

2008 ◽

Vol 112 (10) ◽

pp. 2181-2187 ◽

Cited By ~ 7

Author(s):

Celestia S. Higano ◽

Catherine M. Tangen ◽

Wael A. Sakr ◽

James Faulkner ◽

Saul E. Rivkin ◽

...

Keyword(s):

Neoadjuvant Chemotherapy ◽

Urothelial Cancer ◽

Treatment Options ◽

Muscle Invasive

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The effect of adjuvant chemotherapy for patients with adverse pathology after neoadjuvant chemotherapy for muscle invasive bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.367 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 367-367

Author(s):

William P. Parker ◽

Elizabeth B. Habermann ◽

Courtney N. Day ◽

Harras B. Zaid ◽

Igor Frank ◽

...

Keyword(s):

Bladder Cancer ◽

Adjuvant Chemotherapy ◽

Neoadjuvant Chemotherapy ◽

Locally Advanced ◽

Multivariable Analysis ◽

Invasive Bladder Cancer ◽

Rank Test ◽

Muscle Invasive Bladder Cancer ◽

Pathologic Stage ◽

Muscle Invasive

367 Background: While neoadjuvant chemotherapy (NAC) for muscle−invasive bladder cancer (MIBC) is recognized as the standard of care, the management of patients with locally advanced and/or nodal disease after NAC and radical cystectomy (RC) is not well defined. We sought to evaluate the association of adjuvant chemotherapy (AC) and overall survival (OS) among patients with adverse pathology after NAC and RC. Methods: The National Cancer Database was reviewed to identify patients with adverse pathology (pT3N0, pT4N0, or pTanyN1−3) at RC following NAC from 2006−2012. Patients were stratified by receipt of AC. Clinical and pathologic variables were abstracted. OS was the primary end−point and differences on the basis of AC were assessed by the Kaplan−Meier method and log−rank test. Multivariable Cox proportional hazards regression was used to assess the association of AC with OS controlling for age, sex, race, Charlson score, year of diagnosis, pathologic stage, and receipt of adjuvant radiotherapy. Results: Adverse pathology following NAC and RC was identified in 1,361 patients from 2006−2012, of whom 328 (24.1%) received AC. Staging was pT3N0 in 444 (32.6%), pT4N0 in 162 (11.9%), and pTanyN1−3 in 755 (55.5%). Median OS for the entire cohort was 22.9 months, which differed by pathologic stage: 34.6 months (pT3N0), 21.4 months (pT4N0), and 19.3 months (pTanyN1-3)(p < 0.01). No difference in OS was noted by receipt of AC in the overall cohort (median OS 24.6 months with AC vs 22.0 months without AC; p = 0.18), or when stratified by pathologic stage. On multivariable analysis, receipt of AC was not significantly associated with overall mortality (HR 0.86; 95%CI 0.74−1.01; p = 0.06) for all patients. When stratified by stage, AC was associated with a significantly decreased risk of mortality among patients with pT4N0 disease (HR 0.56; 95%CI 0.33−0.97; p = 0.04), but not pT3N0 or pTanyN1−3 (p > 0.05). Conclusions: Patients with adverse pathology at RC after NAC have a median OS of approximately 2 years. AC was not associated with improved survival, except in the subgroup with pT4N0 disease. Clinical trials with newer systemic therapies are warranted for patients in this setting.

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High-risk bladder cancer: improving outcomes with perioperative chemotherapy

Oncology Reviews ◽

10.4081/oncol.2008.103 ◽

2011 ◽

pp. 4-8

Author(s):

Daniel Y.C. Heng ◽

Jorge A. Garcia

Keyword(s):

Bladder Cancer ◽

High Risk ◽

Adjuvant Chemotherapy ◽

Neoadjuvant Chemotherapy ◽

Meta Analysis ◽

Standard Of Care ◽

Muscle Invasive Bladder Cancer ◽

Advantages And Disadvantages ◽

High Risk Disease ◽

Muscle Invasive

Despite treatment with radical cystectomy and pelvic lymph node dissection, muscle invasive bladder cancer has a relapse rate of 50%. Patients can develop regionally advanced or metastatic disease that ultimately leads to death. The addition of neoadjuvant or adjuvant chemotherapy to reduce the risk of relapse and death has been extensively studied over the past two decades. Two contemporary trials coupled with a recent meta-analysis evaluating neoadjuvant chemotherapy demonstrated a modest but real improvement in overall survival. This has made neoadjuvant chemotherapy a standard of care. Clinical trials evaluating adjuvant chemotherapy in patients with high-risk disease have been plagued with statistical flaws and have, therefore, been unable to define the survival impact of this approach. It is hoped that ongoing adjuvant trials that are powered to detect small but meaningful clinical differences will clarify the benefit of chemotherapy after cystectomy. Since there are theoretical advantages and disadvantages to each of these approaches, both are widely used in North America. The evidence behind each approach and potential future developments in this field will be described.

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Different responses to neoadjuvant chemotherapy in urothelial carcinoma molecular subtypes

10.1101/2021.05.11.21255912 ◽

2021 ◽

Author(s):

Gottfrid Sjödahl ◽

Johan Abrahamsson ◽

Karin Holmsten ◽

Carina Bernardo ◽

Gunilla Chebil ◽

...

Keyword(s):

Neoadjuvant Chemotherapy ◽

Urothelial Cancer ◽

Molecular Subtypes ◽

Treatment Approach ◽

Pathological Response ◽

Chemotherapy Response ◽

Muscle Invasive Bladder Cancer ◽

Gene Coding ◽

Differential Gene ◽

Muscle Invasive

For muscle-invasive bladder cancer (MIBC), there are no tissue biomarkers in clinical use that identify patients sensitive or resistant to neoadjuvant chemotherapy. The present study investigates how molecular subtypes impact pathological response and survival in 149 patients receiving preoperative cisplatin-based chemotherapy. Tumor classification was performed by transcriptomic profiling and by a 13-marker immunostaining panel. Furthermore, we explored differential gene expression and chemotherapy response beyond molecular subtypes. Tumors with Genomically Unstable (GU) and Urothelial-like (Uro) subtypes had higher proportions of pathological response and superior survival outcomes as compared to the Basal-Squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Based on our findings, we suggest that urothelial cancer of the luminal-like GU- and Uro-subtypes are more responsive to cisplatin-based chemotherapy. We also found the gene coding for osteopontin (SPP1) to display a subtype-dependent effect on chemotherapy response, confirmed at the protein level by immunohistochemistry. Combined analyses of second-generation, subtype-specific biomarkers may be an additional way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC.

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Neoadjuvant chemotherapy (NC) should be administered to fit patients with newly diagnosed, potentially resectable muscle-invasive urothelial cancer (MIUC) of the bladder – A 2013 CAGMO Consensus Statement and Call for a Streamlined Referral Process

Canadian Urological Association Journal ◽

10.5489/cuaj.1506 ◽

2013 ◽

Vol 7 (9-10) ◽

pp. 312 ◽

Cited By ~ 7

Author(s):

Jo-An Seah ◽

Srikala Sridhar ◽

Lori Wood ◽

Normand Blais ◽

Scott North ◽

...

Keyword(s):

Neoadjuvant Chemotherapy ◽

Patient Outcomes ◽

Urothelial Cancer ◽

Consensus Statement ◽

Urologic Oncology ◽

Canadian Association ◽

Medical Oncologists ◽

Cancer Of The Bladder ◽

Muscle Invasive ◽

Improve Patient

Neoadjuvant chemotherapy (NC) improves overall survival inpatients with resectable muscle-invasive urothelial cancer of the bladder (MIBC). However uptake of NC in Canada is disappointingly low. Following a detailed literature review and in consultation with urologic oncology, the Canadian Association of Genitourinary Medical Oncologists (CAGMO) has developed a consensus statement for the use of NC in MIBC. Our primary goal is to increase the uptake of NC for MIBC in Canada and improve patient outcomes.

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Pathologic Response Rates of Gemcitabine/Cisplatin versus Methotrexate/Vinblastine/Adriamycin/Cisplatin Neoadjuvant Chemotherapy for Muscle Invasive Urothelial Bladder Cancer

Advances in Urology ◽

10.1155/2013/317190 ◽

2013 ◽

Vol 2013 ◽

pp. 1-6 ◽

Cited By ~ 14

Author(s):

Franklin C. Lee ◽

William Harris ◽

Heather H. Cheng ◽

Jaideep Shenoi ◽

Song Zhao ◽

...

Keyword(s):

Bladder Cancer ◽

Neoadjuvant Chemotherapy ◽

Urothelial Cancer ◽

Response Rates ◽

Complete Response ◽

Pathologic Response ◽

Urothelial Bladder Cancer ◽

Urothelial Bladder ◽

Muscle Invasive ◽

Alternative Regimen

Objectives. To compare pathologic outcomes after treatment with gemcitabine and cisplatin (GC) versus methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) in the neoadjuvant setting.Methods. Data was retrospectively collected on 178 patients with T2-T4 bladder cancer who underwent radical cystectomy between 2003 and 2011. Outcomes of interest included those with complete response (pT0) and any response (≤pT1). Odds ratios were calculated using multivariate logistic regression.Results. Compared to those who did not receive neoadjuvant chemotherapy, there were more patients with complete response (28% versus 9%, OR 3.11 (95% CI: 1.45–6.64),P=0.03) and any response (52% versus 25%, OR 3.23 (95% CI: 1.21–8.64),P=0.01). Seventy-two patients received GC (n=41) or MVAC (n=31). CR was achieved in 29% and 22% of GC and MVAC patients, respectively (multivariate OR 0.39, 95% CI 0.10–1.58). Any response (≤pT1) was achieved in 56% of GC and 45% of MVAC patients (multivariate OR 0.45, 95% CI 0.12–1.71).Conclusions. We observed similar pathologic response rates for GC and MVAC neoadjuvant chemotherapy in this cohort of patients with muscle invasive urothelial cancer (MIBC). Our findings support the use of GC as an alternative regimen in the neoadjuvant setting.

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