Scheduling nab-paclitaxel combined with gemcitabine as first-line treatment for metastatic pancreatic adenocarcinoma.
Aged
Aged, 80 and over
Albumins
/ administration & dosage
Antineoplastic Combined Chemotherapy Protocols
/ administration & dosage
Carcinoma, Pancreatic Ductal
/ drug therapy
Deoxycytidine
/ administration & dosage
Drug Administration Schedule
Female
Humans
Male
Middle Aged
Paclitaxel
/ administration & dosage
Pancreatic Neoplasms
/ drug therapy
Progression-Free Survival
Gemcitabine
Pancreatic Neoplasms
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
29
10
2019
accepted:
01
04
2020
revised:
19
03
2020
pubmed:
1
5
2020
medline:
20
3
2021
entrez:
1
5
2020
Statut:
ppublish
Résumé
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. 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. 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). SEQ delivery of nabP+gemcitabine improved PFS and ORR, with manageable toxicity, but did not significantly improve OS. ISRCTN71070888; ClinialTrials.gov (NCT03529175).
Sections du résumé
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).
Identifiants
pubmed: 32350413
doi: 10.1038/s41416-020-0846-2
pii: 10.1038/s41416-020-0846-2
pmc: PMC7283477
doi:
Substances chimiques
130-nm albumin-bound paclitaxel
0
Albumins
0
Deoxycytidine
0W860991D6
Paclitaxel
P88XT4IS4D
Gemcitabine
0
Banques de données
ClinicalTrials.gov
['NCT03529175']
ISRCTN
['ISRCTN71070888']
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1760-1768Références
Malvezzi, M., Bertuccio, P., Levi, F., La Vecchia, C. & Negri, E. European cancer mortality predictions for the year 2014. Ann. Oncol. 25, 1650–1656 (2014).
doi: 10.1093/annonc/mdu138
Von Hoff, D. D., Ervin, T., Arena, F. P., Chiorean, E. G., Infante, J., Moore, M. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 369, 1691–1703 (2013).
doi: 10.1056/NEJMoa1304369
Goldstein, D., El-Maraghi, R. H., Hammel, P., Heinemann, V., Kunzmann, V., Sastre, J. et al. Nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. J. Natl Cancer Inst. 107, 3–10 (2015).
Von Hoff, D. D., Ramanathan, R. K., Borad, M. J., Laheru, D. A., Smith, L. S., Wood, T. E. et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J. Clin. Oncol. 29, 4548–4554 (2011).
doi: 10.1200/JCO.2011.36.5742
Alvarez, R., Musteanu, M., Garcia-garcia, E., Lopez-Casas, P. P., Megias, D., Guerra, C. et al. Stromal disrupting effects of nab-paclitaxel in pancreatic cancer. Br. J. Cancer 109, 926–933 (2013).
doi: 10.1038/bjc.2013.415
Frese, K. K., Neesse, A., Cook, N., Bapiro, T. E., Lolkema, M. P., Jodrell, D. I. et al. Nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov. 2, 260–269 (2012).
doi: 10.1158/2159-8290.CD-11-0242
Neesse, A., Frese, K. K., Chan, D. S., Bapiro, T. E., Howat, W. J., Richards, F. M. et al. SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice. Gut 63, 974–983 (2014).
doi: 10.1136/gutjnl-2013-305559
Olive, K. P., Jacobetz, M. A., Davidson, C. J., Gopinathan, A., McIntyre, D., Honess, D. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009).
doi: 10.1126/science.1171362
Jacobetz, M. A., Chan, D. S., Neesse, A., Bapiro, T. E., Cook, N., Frese, K. K. et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62, 112–120 (2013).
doi: 10.1136/gutjnl-2012-302529
Ciccolini, J. Dosage de l’activite Serique en Cytidine Desaminase (CDA). PhD thesis, Universite d’Aix-Marseille, (2009).
Osoba, D., Rodrigues, G., Myles, J., Zee, B. & Pater, J. Interpreting the significance of changes in health-related quality of life scores. J. Clin. Oncol. 16, 139–144 (1998).
doi: 10.1200/JCO.1998.16.1.139
Reni, M., Wan, Y., Solem, C., Whiting, S., Ji, X. & Botteman, M. Quality-adjusted survival with combination nab-paclitaxel+gemcitabine vs gemcitabine alone in metastatic pancreatic cancer: a Q-TWiST analysis. J. Med. Econ. 17, 338–346 (2014).
doi: 10.3111/13696998.2014.903122
Chiritescu, G., Dumon, K., Verslype, C., Houbiers, G., Peeters, M., Janssens, J. et al. Final results of a phase II quality of life (QOL) randomized, cross-over (CO) study with gemcitabine (Gem) and nab-paclitaxel (n-P) in locally advanced and metastatic pancreatic cancer. Ann. Oncol. 29(suppl_8), viii205–viii270 (2018).
Serdjebi, C., Seitz, J. F., Ciccolini, J. & Duluc, M. Rapid deaminator status is associated with poor clinical outcome in pancreatic cancer patients treated with a gemcitabine-based regimen. Pharmacogenomics 14, 1047–1051 (2013).
doi: 10.2217/pgs.13.93
Carrato, A., Falcone, A., Ducreux, M., Valle, J. W., Parnaby, A., Djazouli, K. et al. A systematic review of the burden of pancreatic cancer in Europe: Real-world impact on survival, quality of life and costs. J. Gastrointest. Cancer 46, 201–211 (2015).
doi: 10.1007/s12029-015-9724-1
Ciccolini, J., Dahan, L., Andre, N., Evrard, A., Duluc, M., Yang, A. B. et al. Cytidine deaminase residual activity in serum is a predictive marker of early severe toxicities in adults after gemcitabine-based chemotherapies. J. Clin. Oncol. 28, 160–165 (2010).
doi: 10.1200/JCO.2009.24.4491
Serdjebi, C., Gagniere, J., Desrame, J., Fein, F., Guimbaud, R., Francois, E. et al. FFCD-1004 clinical trial: impact of cytidine deaminase activity on clinical outcome in gemcitabine-monotherapy treated patients. PLoS ONE 10, e0135907 (2015).
doi: 10.1371/journal.pone.0135907
Zauri, M., Berridge, G., Thezenas, M.-L., Pugh, K., Goldin, R., Kessler, B. et al. CDA directs metabolism of epigenetic nucleosides revealing a therapeutic window in cancer. Nature 524, 114–118 (2015).
doi: 10.1038/nature14948
Tibaldi, C., Giovannetti, E., Vasile, E., Mey, V., Laan, A. C., Nannizzi, S. et al. Correlation of CDA, ERCC1, and XPD polymorphisms with response and survival in gemcitabine/cisplatin-treated advanced non-small-cell lung cancer patients. Clin. Cancer Res. 14, 1797–1803 (2008).
doi: 10.1158/1078-0432.CCR-07-1364
Yonemori, K., Ueno, H., Okusaka, T. et al. Severe drug toxicity associated with a single-nucleotide polymorphism of the cytidine deaminase gene in a Japanese cancer patient treated with gemcitabine plus cisplatin. Clin. Cancer Res. 11, 2620–2624 (2005).
doi: 10.1158/1078-0432.CCR-04-1497
Boyum, A., Lovhaug, D., Seeberg, E. & Nordlie, E. M. Identification of cytidine deaminase as an inhibitor of granulocyte-macrophage colony formation. Exp. Hematol. 22, 208–214 (1994).
pubmed: 7507861
Micozzi, D., Carpi, F. M., Pucciarelli, S., Polzonetti, V., Polidori, P., Vilar, S. et al. Human cytidine deaminase: a biochemical characterization of its naturally occurring variants. Int J. Biol. Macromol. 63, 64–74 (2014).
doi: 10.1016/j.ijbiomac.2013.10.029
Hessmann, E., Patzak, M. S., Klein, L., Chen, N., Kari, V., Ramu, I. et al. Fibroblast drug scavenging increases intratumoural gemcitabine accumulation in murine pancreas cancer. Gut 67, 497–507 (2018).
doi: 10.1136/gutjnl-2016-311954
Valkenburg, K. C., de Groot, A. E. & Pienta, K. J. Targeting the tumour stroma to improve cancer therapy. Nat. Rev. Clin. Oncol. 15, 366–381 (2018).
doi: 10.1038/s41571-018-0007-1
Hidalgo, M., Plaza, C., Musteanu, M., Illei, P., Brachmann, C. B., Heise, C. et al. SPARC expression did not predict efficacy of nab-paclitaxel plus gemcitabine or gemcitabine alone for metastatic pancreatic cancer in an exploratory analysis of the phase III MPACT trial. Clin. Cancer Res. 21, 4811–4818 (2015).
doi: 10.1158/1078-0432.CCR-14-3222