Scheduling nab-paclitaxel combined with gemcitabine as first-line treatment for metastatic pancreatic adenocarcinoma
Open Access
- 30 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in British Journal of Cancer
- Vol. 122 (12), 1760-1768
- https://doi.org/10.1038/s41416-020-0846-2
Abstract
Background Nab-paclitaxel plus gemcitabine (nabP+gemcitabine) offers modest survival gains for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Sequential scheduling of nabP+gemcitabine in a PDAC mouse model improved efficacy; this hypothesis was tested in a clinical trial. Methods Patients with previously untreated metastatic PDAC were randomised to receive nabP+gemcitabine administered either concomitantly on the same day, or sequentially, with gemcitabine administered 24 h after nabP. The primary outcome measure was progression-free survival (PFS). Secondary outcome measures were objective response rate (ORR), overall survival (OS), safety, quality of life (QoL) and predictive biomarkers. Results In total, 71 patients received sequential (SEQ) and 75 concomitant (CON) treatment. Six-month PFS was 46% with SEQ and 32% with CON scheduling. Median PFS (5.6 versus 4.0 months, hazard ratio [HR] 0.67, 95% confidence interval [95% CI] 0.47–0.95, p = 0.022) and ORR (52% versus 31%, p = 0.023) favoured the SEQ arm; median OS was 10.2 versus 8.2 months (HR 0.93, 95% CI 0.65–1.33, p = 0.70). CTCAE Grade ≥3 neutropaenia incidence doubled with SEQ therapy but was not detrimental to QoL. Strongly positive tumour epithelial cytidine deaminase (CDA) expression favoured benefit from SEQ therapy (PFS HR 0.31, 95% CI 0.13–0.70). Conclusions SEQ delivery of nabP+gemcitabine improved PFS and ORR, with manageable toxicity, but did not significantly improve OS. Clinical trial registration ISRCTN71070888; ClinialTrials.gov (NCT03529175).Keywords
This publication has 23 references indexed in Scilit:
- Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus GemcitabineThe New England Journal of Medicine, 2013
- Human cytidine deaminase: A biochemical characterization of its naturally occurring variantsInternational Journal of Biological Macromolecules, 2013
- SPARC independent drug delivery and antitumour effects ofnab-paclitaxel in genetically engineered miceGut, 2013
- Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancerGut, 2012
- nab-Paclitaxel Potentiates Gemcitabine Activity by Reducing Cytidine Deaminase Levels in a Mouse Model of Pancreatic CancerCancer Discovery, 2012
- Gemcitabine Plusnab-Paclitaxel Is an Active Regimen in Patients With Advanced Pancreatic Cancer: A Phase I/II TrialJournal of Clinical Oncology, 2011
- Cytidine Deaminase Residual Activity in Serum Is a Predictive Marker of Early Severe Toxicities in Adults After Gemcitabine-Based ChemotherapiesJournal of Clinical Oncology, 2010
- Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic CancerScience, 2009
- Correlation of CDA, ERCC1, and XPD Polymorphisms with Response and Survival in Gemcitabine/Cisplatin–Treated Advanced Non–Small Cell Lung Cancer PatientsClinical Cancer Research, 2008
- Severe Drug Toxicity Associated with a Single-Nucleotide Polymorphism of the Cytidine Deaminase Gene in a Japanese Cancer Patient Treated with Gemcitabine plus CisplatinClinical Cancer Research, 2005