The Efficacy of Combined Cisplatin and Nanoparticle Albumin-Bound Paclitaxel in a Stage IV Pancreatic Squamous Cell Carcinoma Patient With a Somatic BRCA2 Mutation: A Case Report.
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SUBMITTER: Huang X
PROVIDER: S-EPMC8116796 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeGemcitabine and albumin-bound paclitaxel (ABP) exhibit synergistic antitumor efficacy, with ABP serving to increase the intratumoral gemcitabine concentration. Both drugs are active in squamous cell lung cancers (SQCLC) and are conventional partners for carboplatin. We hypothesized that combining gemcitabine and ABP would enhance the antitumor activity in patients with advanced SQCLCs.Patients and methodsThis was a Simon two-stage, open-label, single-arm, multicenter phase II study that enrolled patients between August 1, 2015 and June 1, 2018. We enrolled 37 patients with chemotherapy-naïve, PD-L1 low/unknown advanced stage IV SQCLC. Patients were administered weekly intravenous gemcitabine (1,000 mg/m2) plus ABP (100 mg/m2) in a 3-week on, 1-week off schedule during stage I and a 2-week on, 1-week off schedule in stage II. The primary endpoint was best objective response rate (ORR). Next-generation sequencing by MSK-IMPACT was used to calculate tumor mutation burden and genome doubling and assess somatic variants for correlations with efficacy.ResultsThirty-two patients were evaluable for response assessment. The study satisfied its primary endpoint, with confirmed partial responses in 18 of 32 patients and a complete response in 1 patient [ORR 59%; 95% confidence interval (CI), 42%-74%]. Median progression-free survival (PFS), a secondary endpoint, was 7.5 (95% CI, 6.7-10.5) months. There were no unexpected toxicities.ConclusionsGemcitabine plus ABP was a safe, tolerable, and effective first-line therapy for patients with chemotherapy-naïve SQCLCs, with an ORR and median PFS substantially higher than carboplatin doublet regimens and efficacy comparable with carboplatin plus taxane plus pembrolizumab.
| S-EPMC7169419 | biostudies-literature
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.
| S-EPMC4768222 | biostudies-literature
Project description:BackgroundThis phase I/II study aimed to determine the maximum tolerated dose (MTD) of nanoparticle albumin-bound paclitaxel (nab (®)-paclitaxel) plus cisplatin as treatment for metastatic nasopharyngeal carcinoma (NPC).MethodsPatients were enrolled into 1 of 3 dose cohorts, each with 21-day treatment cycles: 1) intravenous (IV) nab-paclitaxel 260 mg/m(2) on day 1; 2) IV nab-paclitaxel 140 mg/m(2) on days 1 and 8; 3) IV nab-paclitaxel 100 mg/m(2) on days 1, 8, and 15. All patients received IV cisplatin 75 mg/m(2) on day 1. Treatment continued for 4-6 cycles, or until progression or unacceptable toxicity. If more than one-third of the patients in a cohort experienced a dose-limiting toxicity (DLT), the dose used in the previous cohort would be designated the MTD. Secreted protein acidic and rich in cysteine (SPARC) expression was detected by immunohistochemistry staining.ResultsSixty-nine patients were enrolled, of whom 64 and 67 were eligible for efficacy and safety analysis, respectively. Two DLTs occurred in cohort 1 (grade 4 febrile neutropenia, grade 3 myalgia), none occurred in cohort 2, and 2 occurred in cohort 3 (both grade 3 fatigue). The MTD was not reached. Partial responses were achieved by 42 patients, 15 had stable disease, and 7 had progressive disease, giving an overall response rate of 66 %. Median progression-free survival was 9 months (95 % CI, 6-12 months). Grade ≥ 3 adverse events were mainly hematologic. There was no significant difference between the 3 cohorts with respect to efficacy or safety. Biomarker analyses indicated that stromal, rather than tumoral, SPARC may predict the response to nab-paclitaxel in NPC.ConclusionsOur findings suggest that nab-paclitaxel plus cisplatin is a highly active regimen with moderate toxicity for the treatment of metastatic NPC, which warrants further investigation in a phase III study.Trial registrationsClinicalTrials.gov ID: NCT01735409 . The trial was registered on November 20th, 2012.
| S-EPMC4944269 | biostudies-literature
Project description:PurposeThis study aimed to assess the effect of nanoparticle albumin-bound paclitaxel (nab-PTX) chemotherapy regimens in elderly patients (≥70 years old) with advanced squamous non-small-cell lung cancer (NSCLC).Patients and methodsThe clinical records of elderly patients aged ≥70 years with advanced squamous NSCLC were reviewed retrospectively. All of these patients received nab-PTX, with or without combination of chemotherapy in Shandong Cancer Hospital and Institute between 1 July 2012 and 30 June 2017. We analyzed the toxicity profiles, progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR).ResultsTotally, 52 elderly patients with squamous NSCLC were included in the analysis. For all patients, the ORR was 34.6%, the DCR was 80.8%, median PFS was 5.9 months (95% confidence interval [CI]: 4.0-7.8 months), and median OS was 14.3 months (95% CI: 11.0-17.8 months). Combination with chemotherapy significantly prolonged OS (19.3 vs 11.2 months, P = .016), despite a nonsignificant improvement in PFS (7.1 vs 4.2 months, P = .060) vs monotherapy. For patients who received nab-PTX as first-line treatment, the median PFS and OS were 6.7 months and 17.2 months, respectively, and the median OS in combination therapy subgroup was significantly higher than that in monotherapy group (20.3 vs 11.2 months, P = .013). Meanwhile, the median PFS and OS of patients with nab-PTX as second- or later-line treatment were 4.4 months and 13.3 months, respectively, but no survival benefit was achieved by the combination chemotherapy when compared with single-agent chemotherapy. Hematologic toxicities were the most common adverse events (AEs), which include grade 3 or 4 neutropenia (13.7%), thrombocytopenia (4.1%), and anemia (6.8%). The main nonhematologic toxicities were peripheral sensory neuropathy (39.7%), followed by anorexia and nausea/vomiting.ConclusionIn elderly advanced squamous NSCLC patients, the treatment of nab-PTX was effective and well tolerated.
| S-EPMC7013054 | biostudies-literature
Project description:Gastric cancer is the second common cause of cancer related death worldwide and lacks highly effective treatment for advanced disease. Nab-paclitaxel is a novel microtubule-inhibitory cytotoxic agent that has not been tested in gastric cancer as of yet. In this study, human gastric cancer cell lines AGS, NCI-N87 and SNU16 were studied. Nab-paclitaxel inhibited cell proliferation with an IC50 of 5 nM in SNU16, 23 nM in AGS and 49 nM in NCI-N87 cells after 72-hour treatment, which was lower than that of oxaliplatin (1.05 ?M to 1.51 ?M) and epirubicin (0.12 ?M to 0.25 ?M). Nab-paclitaxel treatment increased expression of the mitotic-spindle associated phospho-stathmin irrespective of the baseline total or phosphorylated stathmin level, and induced mitotic cell death as confirmed through increased expression of cleaved-PARP and caspase-3. After a two-week nab-paclitaxel, oxaliplatin or epirubicin treatment, the average in vivo local tumor growth inhibition rate was 77, 17.2 and 21.4 percent, respectively (p?=?0.002). Effects of therapy on tumoral proliferative and apoptotic indices corresponded with tumor growth inhibition data, while expression of phospho-stathmin also increased in tissues. There was an increase in median animal survival after nab-paclitaxel treatment (93 days) compared to controls (31 days, p?=?0.0007), oxaliplatin (40 days, p?=?0.0007) or to docetaxel therapy (81 days, p?=?0.0416). The strong antitumor activity of nab-paclitaxel in experimental gastric cancer supports such microtubule-inhibitory strategy for clinical application. Nab-paclitaxel benefits were observed independent from phosphorylated stathmin expression at baseline, putting into question the consideration of nab-paclitaxel use in gastric cancer based on this putative biomarker.
| S-EPMC3584019 | biostudies-literature
Project description:Hypovascularization in tumors such as liver metastases originating from breast and other organs correlates with poor chemotherapeutic response and higher mortality. Poor prognosis is linked to impaired transport of both low- and high-molecular weight drugs into the lesions and to high washout rate. Nanoparticle albumin-bound-paclitaxel (nAb-PTX) has demonstrated benefits in clinical trials when compared to paclitaxel and docetaxel. However, its therapeutic efficacy for breast cancer liver metastasis is disappointing. As macrophages are the most abundant cells in the liver tumor microenvironment, we design a multistage system employing macrophages to deliver drugs into hypovascularized metastatic lesions, and perform in vitro, in vivo, and in silico evaluation. The system encapsulates nAb-PTX into nanoporous biocompatible and biodegradable multistage vectors (MSV), thus promoting nAb-PTX retention in macrophages. We develop a 3D in vitro model to simulate clinically observed hypo-perfused tumor lesions surrounded by macrophages. This model enables evaluation of nAb-PTX and MSV-nab PTX efficacy as a function of transport barriers. Addition of macrophages to this system significantly increases MSV-nAb-PTX efficacy, revealing the role of macrophages in drug transport. In the in vivo model, a significant increase in macrophage number, as compared to unaffected liver, is observed in mice, confirming the in vitro findings. Further, a mathematical model linking drug release and retention from macrophages is implemented to project MSV-nAb-PTX efficacy in a clinical setting. Based on macrophage presence detected via liver tumor imaging and biopsy, the proposed experimental/computational approach could enable prediction of MSV-nab PTX performance to treat metastatic cancer in the liver.
| S-EPMC4919151 | biostudies-literature
Project description:The therapeutic goals in metastatic breast cancer (MBC) remain palliative in nature, aimed at controlling symptoms, improving or maintaining quality of life and prolonging survival. The advent of new drugs and new formulations of standard agents has led to better outcomes in patients with advanced or metastatic disease. These developments have also allowed a tailored therapeutic approach, in which the molecular biology of the tumour, the treatment history, and patient attitudes are taken into account in the decision-making process. Targeting drug delivery to the tumour is a promising mean of increasing the therapeutic index of highly active agents such as the taxanes, and nanoparticle albumin-bound paclitaxel (nab-paclitaxel), the first nanotechnology-based drug developed in cancer treatment, is one such advance. Data from randomized trials support the efficacy of single-agent nab-paclitaxel as first-line and further treatment lines in MBC at the registered 3-weekly schedule of 260 mg/m(2), but emerging evidence suggests its activity as a weekly regimen or combined with other agents in various clinical scenarios. Thus, nab-paclitaxel seems to offer flexibility in terms of dosing schedules, allowing physicians to tailor the dose according to different clinical situations. This paper reviews the clinical trial background for nab-paclitaxel in MBC, focusing on specific 'difficult-to-treat' patient populations, such as taxane-pretreated or elderly women, as well as those with triple-negative, HER2-positive and poor-prognostic-factors disease. Moving beyond evidence-based information, 'real life' available experiences are also discussed with the aim of providing an update for daily clinical practice.
| S-EPMC4872255 | biostudies-literature
Project description:Bevacizumab confers benefits in metastatic breast cancer but may be more effective as adjuvant therapy. We evaluated the cardiac safety of bevacizumab plus dose-dense doxorubicin-cyclophosphamide (ddAC) ? nanoparticle albumin-bound (nab)-paclitaxel in human epidermal growth factor receptor 2 normal early-stage breast cancer.Eighty patients with normal left ventricular ejection fraction (LVEF) were enrolled. Bevacizumab was administered for 1 year, concurrently with ddAC ? nab-paclitaxel then as a single agent. LVEF was evaluated at months 0, 2, 6, 9, and 18. This regimen was considered safe if fewer than three cardiac events or fewer than two deaths from left ventricular dysfunction occurred. Correlative studies of cardiac troponin (cTn) and plasma renin activity (PRA) were conducted.The median age was 48 years (range, 27-75 years), and baseline LVEF was 68% (53%-82%). After 39 months' median follow-up (5-45 months): median LVEF was 68% (53%-80%) at 2 months (n = 78), 64% (51%-77%) at 6 months (n = 66), 63% (48%-77%) at 9 months (n = 61), and 66% (42%-76%) at 18 months (n = 54). One patient developed symptomatic LV dysfunction at month 15. Common toxicities necessitating treatment discontinuation were hypertension (HTN, 4%), wound-healing complications (4%), and asymptomatic LVEF declines (4%). Neither cTn nor PRA predicted congestive heart failure (CHF) or HTN, respectively.Bevacizumab with ddAC ? nab-paclitaxel had a low rate of cardiac events; cTn and PRA levels are not predictive of CHF or HTN, respectively. The efficacy of bevacizumab as adjuvant treatment will be established in several ongoing phase III trials.
| S-EPMC4994894 | biostudies-literature
Project description:The aim of this sub-study is to explore the incidence of skin rash among advanced breast cancer(ABC) patients in a phase II trial treated with weekly nab-paclitaxel and cisplatin combination.Nab-paclitaxel(125 mg/m2) was administered on days 1, 8, 15, followed by cisplatin(75 mg/m2) on day 1 every 28 day cycle until disease progression, intolerable toxicities or the maximum of 6 cycles. Patients who received at least one injection of the study drug were included in this analysis of the incidence of skin rash among Chinese patients. Toxicity was graded using the CTCAE4.0 criteria. Statistical analysis was carried out by using SPSS 16.0 (SPSS Inc, Chicago, IL).Seventy three patients were enrolled and eligible for analysis. A total of 384 cycles were administered at the time of this analysis. Rash was presented in 27 patients (37.0%). The most common sites involved were face (14/27), neck (14/27), limbs (18/27) and frictional parts of the trunk (10/27). Macular and papular rash with pruritus commonly occurred 2 (95% CI: 1-7) days after the first day of chemotherapy. Only one patient developed Grade 3 skin toxicity with generalized erythroderma and disfigurement of the face requiring dose reduction. The rash gradually regressed 2 (95% CI: 1-10) days after antihistamines used, but pigmentation remained in 13/27 cases. The incidence rate of skin rash was significantly higher than what has been described for western patients (approximate 4%, P?<?0.0001).A higher rate of maculo-papular rash occurred in Chinese breast cancer patients treated with weekly nab-paclitaxel compared to western patients. The albumin component of nab-paclitaxel might be the cause of the skin disorder.NCT01149798.
| S-EPMC3658926 | biostudies-literature
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.
| S-EPMC7899816 | biostudies-literature