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Potentially Overestimated Efficacy of Nanoparticle Albumin-bound Paclitaxel compared with Solvent-based Paclitaxel in Breast Cancer: A Systemic Review and Meta-analysis.

ABSTRACT: Background: Nanoparticle albumin-bound paclitaxel (nab-PTX) has exhibited clinical efficacy in breast cancer treatment, but toxicities can be yielded more at the same time. We did this meta-analysis aiming to unambiguously compare nab-PTX with conventional solvent-based paclitaxel (sb-PTX) in breast cancer patients of all stages. Method: Pubmed, Embase and Cochrane Library were searched for head-to-head randomized controlled trials of nab-PTX and sb-PTX in breast cancer. Risk ratio (RR) with 95% confidence interval was used for dichotomous variables while Hazard ratio (HR) was used for time-to-event outcomes. Results: Our review finally included 9 studies with 3508 patients. Nab-PTX showed a benefit on objective response rate (ORR) (RR=1.22 [1.04-1.43], P=0.01) as well as non-inferiority compared with sb-PTX in disease control rate (DCR) (RR=1.01 [0.98-1.04], P=0.44), overall survival (OS) (HR=0.99 [0.93-1.05], P=0.81) and disease free survival/progression free survival (DFS/PFS) (HR=0.92 [0.81-1.05], P=0.21). However, when it comes to toxicities (fatigue, nausea or vomiting, peripheral sensory neuropathy and adverse event related discontinuation), results favored sb-PTX (RR=2.89 [1.07-7.8], 3.15 [1.78-5.59], 2.11 [1.32-3.37], 2.02 [1.61-2.53]; P<0.05). Patients with metastatic tumors or undergoing conventional schedule responses better to nab-PTX than the compared groups (RR of ORR in metastatic vs early or locally advanced patients: 1.46 [1.09-1.96] vs 1.01 [0.94-1.08]; conventional vs dose dense group: 1.59 [1.23-2.06] vs 1.01 [0.91-1.12]). Conclusions: Nab-PTX can improve ORR compared with paclitaxel and should be given priority to when aiming to reduce tumor load in breast cancer. Sb-PTX of dose dense schedule is recommended when toxicity of nab-PTX is hard to bear for breast cancer patients.

SUBMITTER: Li BX

PROVIDER: S-EPMC8317518 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNanoparticle albumin-bound paclitaxel (nab-PTX) has exhibited clinical efficacy in breast cancer treatment, but toxicities can be yielded more at the same time. We did this meta-analysis aiming to unambiguously compare nab-PTX with conventional solvent-based paclitaxel in breast cancer patients of all stages.MethodPubmed, EMBASE, Cochrane Library, Chinese Biomedical database, Chinese National Knowledge Infrastructure, Chinese Science and Technology Periodical database, and WangFang database were searched for head-to-head randomized controlled trials of nab-PTX and solvent-based paclitaxel in breast cancer. Other sources will also be searched like Google Scholar and gray literatures. Two researchers will independently search the database and extract data from the articles. Risk of bias will be assessed using the Cochrane Collaboration's tool. Objective tumor response rate, chemotherapy completion rate after 4 or 6 cycles, and toxicity will be primary outcomes. Disease control rate, overall survival, and progression-free survival/disease-free survival will be included in secondary outcomes. Risk ratio with 95% confidence interval was used for dichotomous variables while hazard ratio was used for time-to-event outcomes. The following 3 data sets will all be considered when synthesizing the data: intention-to-treat population, those who actually received taxanes treatment, and those who were actually assessed. All the analyses were done using Review Manager Software 5.3. Any disagreements in study selection, data collection, and analysis will be resolved by a third investigator.Results and conclusionThis study is aim to evaluate the efficacy and safety of nab-PTX compared with PTX in breast cancer treatment as well as to find the best dose or schedule and identify the benefit population. This meta-analysis could provide evidence for clinicians to make a better choice between nab-PTX and PTX in different specific contexts.Prospero registration numberCRD42019117912.

Project description:Purposenab-paclitaxel demonstrates improved clinical efficacy compared with conventional Cremophor EL (CrEL)-paclitaxel in multiple tumor types. This study explored the distinctions in drug distribution between nab-paclitaxel and CrEL-paclitaxel and the underlying mechanisms.MethodsUptake and transcytosis of paclitaxel were analyzed by vascular permeability assay across human endothelial cell monolayers. The tissue penetration of paclitaxel within tumors was evaluated by local injections into tumor xenografts and quantitative image analysis. The distribution profile of paclitaxel in solid-tumor patients was assessed using pharmacokinetic modeling and simulation.ResultsLive imaging demonstrated that albumin and paclitaxel were present in punctae in endothelial cells and could be observed in very close proximity, suggesting cotransport. Uptake and transport of albumin, nab-paclitaxel and paclitaxel were inhibited by clinically relevant CrEL concentrations. Further, nab-paclitaxel causes greater mitotic arrest in wider area within xenografted tumors than CrEL- or dimethyl sulfoxide-paclitaxel following local microinjection, demonstrating enhanced paclitaxel penetration and uptake by albumin within tumors. Modeling of paclitaxel distribution in patients with solid tumors indicated that nab-paclitaxel is more dependent upon transporter-mediated pathways for drug distribution into tissues than CrEL-paclitaxel. The percent dose delivered to tissue via transporter-mediated pathways is predicted to be constant with nab-paclitaxel but decrease with increasing CrEL-paclitaxel dose.ConclusionsCompared with CrEL-paclitaxel, nab-paclitaxel demonstrated more efficient transport across endothelial cells, greater penetration and cytotoxic induction in xenograft tumors, and enhanced extravascular distribution in patients that are attributed to carrier-mediated transport. These observations are consistent with the distinct clinical efficacy and toxicity profile of nab-paclitaxel.

Project description:ObjectivesPaclitaxel is a highly effective antitumor agent with notable adverse events, including hypersensitivity reactions, peripheral neuropathy, arthralgia, myalgias, and neutropenia. Solvent-based paclitaxel causes severe allergic, hypersensitivity, and anaphylactic reactions. Nanoparticle albumin-bound paclitaxel was recently developed and provides an advantage over solvent-based paclitaxel in avoiding solvent/surfactant-related adverse events. The aim of this study was to assess the adverse event profiles of solvent-based paclitaxel and nanoparticle albumin-bound paclitaxel formulations using data from the spontaneous adverse event reporting system of the US Food and Drug Administration Adverse Event Reporting System database.MethodsThis study relied on Medical Dictionary for Regulatory Activities preferred terms and standardized queries, and calculated the reporting ratio and reporting odds ratios of paclitaxel formulations.ResultsOf 8,867,135 reports recorded in the US Food and Drug Administration Adverse Event Reporting System database from January 2004 to December 2016, 3469 and 4447 adverse events corresponded to solvent-based paclitaxel and nanoparticle albumin-bound paclitaxel, respectively. Reporting odds ratios (95% confidence interval) for anaphylactic reaction (standardized MedDRA query code: 20000021) associated with the use of solvent-based paclitaxel and nanoparticle albumin-bound paclitaxel were 1.69 (1.56-1.84) and 0.75 (0.68-0.83), respectively. Reporting odds ratio signal for anaphylactic reaction was not detected for nanoparticle albumin-bound paclitaxel. Reporting odds ratios (95% confidence interval) for acute renal failure (standardized MedDRA query code: 20000003) associated with the use of solvent-based paclitaxel and nanoparticle albumin-bound paclitaxel were 0.75 (0.58-0.98) and 1.60 (1.37-1.89), respectively.ConclusionThis is the first study to evaluate the adverse event profile of nanoparticle albumin-bound paclitaxel using US Food and Drug Administration Adverse Event Reporting System data. Considering that the US Food and Drug Administration Adverse Event Reporting System database does not allow to infer causality or risk ranking, the different reporting frequencies of anaphylactic reaction and acute renal failure between solvent-based paclitaxel and nanoparticle albumin-bound paclitaxel must be further investigated via analytical observational research.

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Potentially Overestimated Efficacy of Nanoparticle Albumin-bound Paclitaxel compared with Solvent-based Paclitaxel in Breast Cancer: A Systemic Review and Meta-analysis.

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