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Effect of neoadjuvant chemotherapy on locally advanced upper tract urothelial carcinoma: a pooled analysis.

ABSTRACT: Background:The outcome of neoadjuvant chemotherapy (NAC) has been established in bladder cancer but remains controversial in upper tract urothelial carcinoma (UTUC). In this work, we explored the therapeutic effect of NAC in patients with locally advanced UTUC. Methods:We conducted a literature search on articles published from 1995 up to April 2020 in PubMed/Medline, the Cochrane Library, Embase, Google Scholar. A total of 19 eligible studies with 6,283 patients were identified, from which the overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), disease-free survival (DFS), pathological complete response (pCR) rate and pathological partial response (pPR) rate were extracted. All analyses were conducted using Review Manager 5.3 and Stata statistical software (version 15). Results:In total, 6,283 UTUC patients were included from 19 eligible studies out of which 1,474 patients received NAC and subsequent radical nephroureterectomy (RNU), whereas 4,809 patients received RNU only. Compared with single RNU, patients with NAC and subsequent RNU exhibited longer OS, CSS, PFS, DFS by hazard ratio (HR) 2.14 [95% confidence interval (CI): 1.75-2.63; P<0.001], HR 2.07 (95% CI: 1.49-2.87; P<0.001), HR 2.00 (95% CI: 1.42-2.83; P<0.001), and HR 3.76 (95% CI: 2.16-6.56; P<0.001). pCR rate and pPR rate of NAC are 0.10 (0.07-0.13) and 0.40 (95% CI: 0.32-0.49, P <0.001) respectively. Conclusions:This work revealed that NAC and subsequent RNU provided better survival outcomes in patients with locally advanced UTUC when compared with single RNU.

SUBMITTER: Qiu D

PROVIDER: S-EPMC7658168 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Effect of neoadjuvant chemotherapy on locally advanced upper tract urothelial carcinoma: a pooled analysis.

Qiu Dongxu D Hu Jiao J He Tongchen T Li Huihuang H Hu Jian J Yi Zhenglin Z Chen Jinbo J Zu Xiongbing X

Translational andrology and urology 20201001 5

<h4>Background</h4>The outcome of neoadjuvant chemotherapy (NAC) has been established in bladder cancer but remains controversial in upper tract urothelial carcinoma (UTUC). In this work, we explored the therapeutic effect of NAC in patients with locally advanced UTUC.<h4>Methods</h4>We conducted a literature search on articles published from 1995 up to April 2020 in PubMed/Medline, the Cochrane Library, Embase, Google Scholar. A total of 19 eligible studies with 6,283 patients were identified, ...[more]

PMID: 33209672

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Project description:PurposeData supporting neoadjuvant chemotherapy of high grade upper tract urothelial carcinoma are scant. In this multi-institution, prospective, phase II trial we investigated pathological complete responses after neoadjuvant chemotherapy of high grade upper tract urothelial carcinoma.Materials and methodsPatients with high grade upper tract urothelial carcinoma in whom nephroureterectomy was planned were assigned to 4 neoadjuvant chemotherapy cycles of accelerated methotrexate, vinblastine, doxorubicin and cisplatin in those with baseline creatinine clearance greater than 50 ml per minute or gemcitabine and carboplatin in those with creatinine clearance 30 to 50 ml per minute or less. The study primary end point was a pathological complete response (ypT0N0). The accrual goal was 30 patients per arm. An 18% pathological complete response was considered worth further study while a 4% pathological complete response would not have justified pursuing this regimen. With 28 eligible patients per arm success was defined as 3 or more pathological complete responses (10.7%) in a given arm. Secondary end points included safety, renal function and oncologic outcomes.ResultsA total of 30 patients enrolled in the accelerated methotrexate, vinblastine, doxorubicin and cisplatin arm from 2015 to 2017. Six patients enrolled in the gemcitabine and carboplatin arm, which closed due to poor accrual. Of the 29 patients eligible for accelerated methotrexate, vinblastine, doxorubicin and cisplatin, including 23 men and 6 women with a median age of 65 years (range 40 to 84), 80% completed all planned treatments, 3 (10.3%) achieved ypT0N0 and 1 achieved ypT0Nx for a pathological complete response in 13.8% (90% CI 4.9-28.8). In 1 patient receiving accelerated methotrexate, vinblastine, doxorubicin and cisplatin nephroureterectomy was deferred due to grade 4 sepsis. The grade 3-4 toxicity rate was 23% in the accelerated methotrexate, vinblastine, doxorubicin and cisplatin arm with no grade 5 event.ConclusionsAccelerated methotrexate, vinblastine, doxorubicin and cisplatin neoadjuvant chemotherapy in patients with high grade upper tract urothelial carcinoma and creatinine clearance greater than 50 ml per minute was safe and demonstrated predefined activity with a 14% pathological complete response rate. Final pathological stage ypT1 or less in more than 60% of patients is encouraging. Together the results of this prospective trial support the use of neoadjuvant chemotherapy in eligible patients with high grade upper tract urothelial carcinoma.

Project description:Despite a similar histologic appearance, upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) tumors have distinct epidemiologic and clinicopathologic differences.To investigate whether the differences between UTUC and UCB result from intrinsic biological diversity.Tumor and germline DNA from patients with UTUC (n=83) and UCB (n=102) were analyzed using a custom next-generation sequencing assay to identify somatic mutations and copy number alterations in 300 cancer-associated genes.We described co-mutation patterns and copy number alterations in UTUC. We also compared mutation frequencies in high-grade UTUC (n=59) and high-grade UCB (n=102).Comparison of high-grade UTUC and UCB revealed significant differences in the prevalence of somatic alterations. Genes altered more commonly in high-grade UTUC included FGFR3 (35.6% vs 21.6%; p=0.065), HRAS (13.6% vs 1.0%; p=0.001), and CDKN2B (15.3% vs 3.9%; p=0.016). Genes less frequently mutated in high-grade UTUC included TP53 (25.4% vs 57.8%; p<0.001), RB1 (0.0% vs 18.6%; p<0.001), and ARID1A (13.6% vs 27.5%; p=0.050). Because our assay was restricted to genomic alterations in a targeted panel, rare mutations and epigenetic changes were not analyzed.High-grade UTUC tumors display a spectrum of genetic alterations similar to high-grade UCB. However, there were significant differences in the prevalence of several recurrently mutated genes including HRAS, TP53, and RB1. As relevant targeted inhibitors are being developed and tested, these results may have important implications for the site-specific management of patients with urothelial carcinoma.Comparison of next-generation sequencing of upper tract urothelial carcinoma (UTUC) with urothelial bladder cancer identified that similar mutations were present in both cancer types but at different frequencies, indicating a potential need for unique management strategies. UTUC tumors were found to have a high rate of mutations that could be targeted with novel therapies.

Project description:BackgroundUpper urinary tract urothelial carcinomas are relatively rare and have a cancer-specific survival rate of 20%-30%. The current gold standard treatment for nonmetastatic high-grade urinary tract urothelial carcinoma is radical nephroureterectomy with bladder cuff resection.ObjectiveThis study aimed to compare conditional cancer-specific survival between open radical nephroureterectomy and laparoscopic radical nephroureterectomy in patients with nonmetastatic stage pT3-4 or TxN(+) locally advanced urinary tract urothelial carcinoma from five tertiary centers.MethodsThe medical records of 723 patients were retrospectively reviewed. The patients had locally advanced and nodal staged tumors and had undergone open radical nephroureterectomy (n = 388) or laparoscopic radical nephroureterectomy (n = 260) at five tertiary Korean institutions from January 2000 and December 2012. To control for heterogenic baseline differences between the two modalities, propensity score matching and subgroup analysis were conducted. Conditional survival analysis was also conducted to determine survival outcome and to overcome differences in follow-up duration between the groups.ResultsDuring the median 50.8-month follow up, 255 deaths occurred. In univariate analysis, significant factors affecting cancer-specific survival (e.g., age, history of bladder cancer, American Society of Anesthesiologists score, pathological N stage, and presence of lymphovascular invasion and carcinoma in situ) differed in each subsequent year. The cancer-specific survival between patients treated with open radical nephroureterectomy and laparoscopic radical nephroureterectomy was not different between patients with and without a history of bladder cancer. After adjusting baseline differences between the two groups by using propensity score matching, both groups still had no significant differences in cancer-specific survival.ConclusionThe two surgical modalities showed no significant differences in the 5-year cancer-specific survival in patients with locally advanced urinary tract urothelial carcinoma.

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Effect of neoadjuvant chemotherapy on locally advanced upper tract urothelial carcinoma: a pooled analysis.

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Effect of neoadjuvant chemotherapy on locally advanced upper tract urothelial carcinoma: a pooled analysis.

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