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Survival outcomes according to NAC regimen
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PurposeTo compare the efficacy and safety of high dose-intensity combination of methotrexate, vinblastine, adriamycin and cisplatin (HD MVAC) with gemcitabine plus cisplatin (GC) as a neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) or locally advanced upper tract urothelial cancer (UTUC).Patients and methodsA retrospective a...
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Citations
... 4 Nevertheless, ddMVAC reported more frequent adverse events (AEs). 5,6 Immune checkpoint inhibitors (ICIs) monotherapy has been approved by the US Food and Drug Administration for treating advanced or metastatic urothelial cancer (UC) in patients who have failed chemotherapy or as first-line therapy for platinum-ineligible patients. [7][8][9][10][11][12][13] In addition, maintenance avelumab has also been approved for the treatment of metastatic UC after chemotherapy. ...
Background:
Neoadjuvant chemotherapy followed by radical cystectomy (RC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC). However, treatment outcomes are suboptimal. Camrelizumab, a PD-1 blockade, has shown benefits in several tumors. This study aimed to investigate the efficacy and safety of neoadjuvant camrelizumab in combination with gemcitabine plus cisplatin (GC) followed by RC for MIBC patients.
Methods:
This was a multi-center, single-arm study that enrolled MIBC patients with a clinical stage of T2-4aN0-1M0, and scheduled for RC. Patients received three 21-day cycles of camrelizumab 200 mg on day 1, gemcitabine 1000 mg/m2 on day 1 and 8, and cisplatin 70 mg/m2 on day 2, followed by RC. The primary endpoint was pathologic complete response (pCR, pT0N0).
Results:
From May 2020 to July 2021, 43 patients were enrolled and received study medications at nine centers in China. Three of them were deemed ineligible and excluded from efficacy analysis but included in safety analysis. In total 10 patients were unevaluable as they declined RC (two due to adverse events [AEs] and eight due to patient's willingness). Among 30 evaluable patients, 13 patients (43.3%) achieved pCR, and 16 patients (53.3%) achieved pathologic downstaging. No AEs leading to death were observed. The most common AEs were anemia (69.8%), decreased white blood cell count (65.1%), and nausea (65.1%). Immune-related AEs were all grade 1 or 2. Pathologic response was not correlated with PD-L1 expression status or tumor mutation burden. Individual genes as a biomarker for pathologic response were not identified.
Conclusions:
Neoadjuvant treatment with camrelizumab and GC regimen demonstrated preliminary anti-tumor activity for MIBC patients with manageable safety profiles. The study met its primary endpoint, and the following randomized trial is ongoing.
Introduction
This meta-analysis aims to evaluate the efficacy and safety of neoadjuvant PD-1 inhibitors or PD-L1 inhibitors [PD-(L)1 inhibitors] for muscle-invasive bladder carcinoma (MIBC).
Materials and methods
Four databases (Medline, Embase, Web of Science, and 21 CENTRAL) were searched for articles studying neoadjuvant PD-(L)1 inhibitors for MIBC. The search time period was from the establishment of each database to 21 July 2023. Meta-analyses of pCR, pPR, Grade≥ 3 irAEs rate, RFS, and OS were performed.
Results
In total, 22 studies were included for meta-analysis. The overall pooled pCR of neoadjuvant PD-(L)1 inhibitors was 0.36 (95%CI=0.30–0.42, p=0.00). In subgroup meta-analysis, the pooled PCR of PD-(L)1 inhibitors alone, PD-(L)1 inhibitors plus other ICI, and PD-(L)1 inhibitors plus chemotherapy was 0.27 (95%CI=0.19–0.35, p=0.1), 0.41 (95%CI=0.21–0.62, p=0.01), 0.43 (95%CI=0.35–0.50, p=0.06), respectively. The overall pooled pPR of neoadjuvant PD-(L)1 inhibitors was 0.53 (95%CI=0.46–0.60, p=0.00). In subgroup meta-analysis, the pooled pPR of PD-(L)1 inhibitors alone, PD-(L)1 inhibitors plus other ICI, and PD-(L)1 inhibitors plus chemotherapy was 0.36 (95%CI=0.22–0.51, p=0.01), 0.51 (95%CI=0.39–0.62, p=0.43), and 0.61 (95%CI=0.53–0.69, p=0.01), respectively. Kaplan–Meier curves for OS and RFS were reconstructed, but there was no significant difference among three groups in terms of OS or RFS. The pooled result of Grade≥ 3 irAEs rate for neoadjuvant PD-(L)1 inhibitors was 0.15 (95%CI=0.09–0.22, p=0.00%). In subgroup analysis, the pooled result of Grade≥ 3 irAEs rate for PD-(L)1 inhibitors alone, PD-(L)1 inhibitors plus other ICI, and PD-(L)1 inhibitors plus chemotherapy was 0.07 (95%CI=0.04–0.11, p=0.84), 0.31 (95%CI=0.16–0.47, p=0.06), and 0.17 (95%CI=0.06–0.31, I² = 71.27%, p=0.01), respectively.
Conclusion
Neoadjuvant PD-(L)1 inhibitors were feasible and safe for muscle invasive bladder cancer. Compared with PD-(L)1 inhibitors alone, PD-(L)1 inhibitors plus other ICI and PD-(L)1 inhibitors plus chemotherapy were associated with higher pCR and pPR, but higher Grade≥3 irAEs. Kaplan–Meier curves for OS and RFS indicated that neoadjuvant PD-(L)1 inhibitors had an acceptable long-term prognostic, but it was not possible to discern statistical differences between the three neoadjuvant subgroups.
Systematic review registration
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023452437, identifier PROSPERO (CRD42023452437).
Purpose:
While previous retrospective or phase II studies in Western populations showed that dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) as neoadjuvant chemotherapy (NAC) was beneficial, no studies have been reported in Asian populations. This prospective phase II study aimed to evaluate efficacy and safety of ddMVAC in Korean patients with muscle-invasive bladder cancer (MIBC) or locally advanced urothelial cancer (UC).
Materials and methods:
Patients with MIBC (cT2-4aN0M0) or locally advanced UC (cTanyN1-3M0) eligible for radical cystectomy (RC) were enrolled prospectively. The participants were treated with four cycles of ddMVAC with pegfilgrastim every 2 weeks. The primary endpoint was pathologic response rate (≤ypT1N0). Secondary endpoints were pathologic complete response (pCR, ypT0N0), relapse-free survival (RFS), overall survival (OS), and safety.
Results:
Among 24 patients enrolled between December 2019 and August 2021, 23 were evaluable (52%, cT2-4aN0; 48%, cTanyN1-3). Eighteen patients (78%) completed four cycles of ddMVAC, while remaining five patients experienced early discontinuation. Dose modification (91%) and dose delay (70%) occurred, and the dose intensity of ddMVAC was 79%. Nineteen patients underwent RC and four patients declined. Of 19 patients who underwent RC, eight patients (42%) achieved ≤ypT1N0. With a median follow-up of 22.8 months, the median RFS was 13.5 months (95% CI, not yet evaluable) and the median OS was 28.9 months (95% confidence interval, 19.9-37.9).
Conclusion:
Our study showed substantial efficacy and safety of ddMVAC, even in patients with locally advanced UC. The ddMVAC still should be a promising option as NAC in Asian patients with UC.
Purpose
Magnetic resonance imaging (MRI) has been applied to predict the neoadjuvant chemotherapy (NAC) response of bladder cancer at an early stage, but the performance remains poor. A tool for the selection of patients with muscle-invasive bladder cancer (MIBC) with high probability of benefitting from NAC is not yet available. We designed a prospective study to assess a quantitative MRI for predicting the early response of MIBC to NAC.
Methods
All individuals underwent a time-course MRI at pre-NAC, 24 hours after initial cisplatin medication (24h-NAC) and post-NAC. Chemosensitivity was evaluated according to pathological response. The transfer constant (Ktrans), plasma volume (Vp), extravascular extracellular space (Ve), and apparent diffusion coefficient (ADC) were quantitated based on dynamic contrast-enhanced and diffusion-weighted imaging. Quantitative RECIST criteria were constructed by modelling pre-NAC and 24h-NAC MRI measures, and then compared with conventional RECIST by using pre- and post-NAC MRI measures.
Results
In this pilot study, a total of 24 patients were enrolled into the study. Eight patients were pathologically confirmed to be NAC-responders. After a thorough evaluation of these parameters, different parameters showed good discrimination at different point in time. ROC curves showed quantitative MRI can predict the response to NAC, especially ADC_M (AUC = 0.859, P = 0.005) and ADC index (AUC = 0.844, P = 0.007) at pre-NAC timing and ADC_M (AUC = 0.816, P = 0.013) at 24h-NAC timing. Then, a qRECIST model was established for predicting NAC sensitivity, with AUC of 0.91, TP rate of 0.8, and accuracy of 0.75.
Conclusion
The diagnostic performance of mpMRI parameters for NAC response is excellent. The qRECIST derived between pre- and 24h NAC MRI could predict the early response of MIBC to NAC and help for candidate selection.
Simple Summary
Bladder cancer (BC) is a common cancer that causes high morbidity and mortality among affected patients. As a carcinogen-driven cancer, molecular oncology of BC has contributed to several fundamental concepts in cancer biology. Molecular insights into the divergent pathways for low- and high-grade BC development, heterogeneity in bladder tumors regarding recurrence and progression, genetic polymorphism, and the associated risk for developing BC among smokers, driver mutations, and molecular subtyping of muscle-invasive BC for prognostic predictions find commonality with other cancers and therefore, have advanced the field of molecular oncology. Similarly, research into lineage plasticity and tumor heterogeneity has revealed both challenges and opportunities in applying molecular approaches to patient care. The quest for finding a “PSA” for BC has contributed to novel technologies in the biomarker field. This review critically assesses and offers a perspective on the areas where molecular oncology could directly contribute to improving patient care.
Abstract
Within the last forty years, seminal contributions have been made in the areas of bladder cancer (BC) biology, driver genes, molecular profiling, biomarkers, and therapeutic targets for improving personalized patient care. This overview includes seminal discoveries and advances in the molecular oncology of BC. Starting with the concept of divergent molecular pathways for the development of low- and high-grade bladder tumors, field cancerization versus clonality of bladder tumors, cancer driver genes/mutations, genetic polymorphisms, and bacillus Calmette-Guérin (BCG) as an early form of immunotherapy are some of the conceptual contributions towards improving patient care. Although beginning with a promise of predicting prognosis and individualizing treatments, “-omic” approaches and molecular subtypes have revealed the importance of BC stem cells, lineage plasticity, and intra-tumor heterogeneity as the next frontiers for realizing individualized patient care. Along with urine as the optimal non-invasive liquid biopsy, BC is at the forefront of the biomarker field. If the goal is to reduce the number of cystoscopies but not to replace them for monitoring recurrence and asymptomatic microscopic hematuria, a BC marker may reach clinical acceptance. As advances in the molecular oncology of BC continue, the next twenty-five years should significantly advance personalized care for BC patients.
PURPOSE
The optimal perioperative chemotherapy regimen for patients with nonmetastatic muscle-invasive bladder cancer is not defined.
PATIENTS AND METHODS
Between February 2013 and March 2018, 500 patients were randomly assigned in 28 French centers and received either six cycles of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) once every 2 weeks or four cycles of gemcitabine and cisplatin (GC) once every 3 weeks before surgery (neoadjuvant group) or after surgery (adjuvant group). We report the primary end point of the GETUG-AFU V05 VESPER trial (ClinicalTrials.gov identifier: NCT01812369 ): progression-free survival (PFS) at 3 years. Secondary end points were time to progression and overall survival.
RESULTS
Four hundred thirty-seven patients (88%) received neoadjuvant chemotherapy; 60% of patients received the planned six cycles in the dd-MVAC arm, 84% received four cycles in the GC arm, and thereafter, 91% and 90% of patients underwent surgery, respectively. Organ-confined response (< ypT3N0) was observed more frequently in the dd-MVAC arm (77% v 63%, P = .001). In the adjuvant group, 40% of patients received six cycles in the dd-MVAC arm, and 81% of patients received four cycles in the GC arm. For all patients in the clinical trial, 3-year PFS was improved in the dd-MVAC arm, but the study did not meet its primary end point (3-year rate: 64% v 56%, hazard ratio [HR] = 0.77 [95% CI, 0.57 to 1.02], P = .066); nevertheless, the dd-MVAC arm was associated with a significantly longer time to progression (3-year rate: 69% v 58%, HR = 0.68 [95% CI, 0.50 to 0.93], P = .014). In the neoadjuvant group, PFS at 3 years was significantly higher in the dd-MVAC arm (66% v 56%, HR = 0.70 [95% CI, 0.51 to 0.96], P = .025).
CONCLUSION
In the VESPER trial, dd-MVAC improved 3-years PFS over GC. In the neoadjuvant group, a better bladder tumor local control and a significant improvement in 3-year PFS were observed in the dd-MVAC arm.
