Docetaxel Group Research Articles

γ-Klotho is correlated with resistance to docetaxel in castration-resistant prostate cancer.

The Klotho (KL) gene was first identified as a potent aging suppressor. The KL family currently comprises of three proteins: α-Klotho (KLA), β-Klotho (KLB), and γ-Klotho (KLG). Many studies have shown that KLA and KLB participate in tumor progression or suppression, depending on the type of cancer; however, the relationship between KLG and prostate cancer has not yet been studied. Some studies have claimed that KL is correlated to sensitivity to chemotherapy. Here, we investigated the oncogenic potential of KLG in castration-resistant prostate cancer (CRPC). Immunohistochemical analysis using prostate biopsy specimens revealed that patients with high KLG expression in primary prostate cancer tissue had a significantly poor prognosis for overall survival. In addition, the prostate-specific antigen response rate after docetaxel (DTX) therapy in patients with high KLG expression was lower than that in patients with low KLG expression. To evaluate the potential of KLG as a therapeutic target in human prostate cancer, we generated a xenograft model of human CRPC cell line (PC-3) in male athymic mice. The animals were randomly divided into four groups as follows: i) control group (vehicle only); ii) DTX group (intraperitoneal administration); iii) small interfering RNA targeting KLG (KLG siRNA) group (intratumoral administration); and iv) a combination group (DTX plus KLG siRNA). After 3 weeks of treatment, the tumor weight and tumor Ki-67 labeling index were significantly lower in the KLG siRNA group and the combination group than in the control group. Sensitivity to DTX was increased upon treatment with KLG siRNA. These findings suggest that KLG expression in primary prostate cancer lesions is associated with resistance to DTX in CRPC and has potential as a diagnostic and therapeutic target for patients with CRPC.

Efficacy of chemotherapy and atezolizumab in patients with non-small-cell lung cancer receiving antibiotics and proton pump inhibitors: pooled post hoc analyses of the OAK and POPLAR trials

Preclinical data have shown that proton pump inhibitors (PPI) can modulate the microbiome, and single-arm studies suggested that antibiotics (ATB) may decrease the efficacy of immune checkpoint inhibitors (ICI), but randomized controlled trial data are lacking. This pooled analysis evaluated the effect of ATB and PPI on outcome in patients randomized between ICI and chemotherapy. This retrospective analysis used pooled data from the phase II POPLAR (NCT01903993) and phase III OAK (NCT02008227) trials, which included 1512 patients with previously treated non-small-cell lung cancer (NSCLC) randomly assigned to receive atezolizumab (n= 757) or docetaxel (n= 755). The main objective of this analysis was to assess the impact of ATB and PPI use on overall survival (OS) and progression-free survival (PFS). A total of 169 (22.3%) patients in the atezolizumab group and 202 (26.8%) in the docetaxel group received ATB, and 234 (30.9%) and 260 (34.4%), respectively, received PPI. Multivariate analysis in all patients revealed that ATB were associated with shorter OS [hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.04-1.39], as was PPI (HR 1.26, 95% CI 1.10-1.44). Within the atezolizumab population, OS was significantly shorter in patients who received ATB (8.5 versus 14.1 months, HR 1.32, 95% CI 1.06-1.63, P= 0.01) or PPI (9.6 versus 14.5 months, HR 1.45, 95% CI 1.20-1.75, P=0.0001). PPI use was associated with shorter PFS in the atezolizumab population (1.9 versus 2.8 months, HR 1.30, 95% CI 1.10-1.53, P= 0.001). There was no association between ATB and PPI use and PFS or OS within the docetaxel population. In this unplanned analysis from two randomized trials, data suggest that ATB or PPI use in patients with metastatic NSCLC is associated with poor outcome and may influence the efficacy of ICI.

The effects of docetaxel and/or captopril in expression of TGF-β1, MMP-1, CTGF, and PAI-1 as markers of anterior urethral stricture in an animal model.

Background:Treatment of urethral trauma is currently done after urethral stricture occurs. Stricture therapy after occurrence gives unsatisfactory success rates. Several genes, such as transforming growth factor beta 1 (TGF-β1), matrix metalloproteinase 1 (MMP-1), connective tissue growth factor (CTGF), and plasminogen activator inhibitor 1 (PAI-1), have a proven role in urethral stricture development. The purpose of this study was to assess the effect docetaxel and/or captopril on the RNA expression of those genes.Methods:The subjects of this research were 26 male New Zealand rabbits aged 230 ± 20 days weighing 4–5 kg that underwent urethral rupture by endoscopic resection under anesthetized conditions. Subjects were divided into five groups; control, stricture, captopril (captopril 0.05 mg/rabbit/day), docetaxel (docetaxel 0.1 mg/rabbit/day), and docetaxel-captopril (docetaxel 0.1 mg/rabbit/day and captopril 0.05 mg/rabbit/day). Each group consisted of 4–6 rabbits. Each rabbit received a water-soluble transurethral gel containing drug according to its group for 28 days. After the treatment period, rabbits were sacrificed with 200 mg Pentothal, and the corpus spongiosum was then prepared for real-time PCR examination.Results:TGF-β1 RNA expression in the stricture group was statistically different from that in the control, docetaxel and docetaxel-captopril groups (p = 0.016; p = 0.016; p = 0.004). The stricture group did not exhibit any statistical difference from the captopril group (p = 0.190). The control group did not show any statistically difference from the captopril, docetaxel, and docetaxel-captopril groups (p = 0.114; p = 0.190; p = 1.000). Docetaxel-captopril suppresses expression of TGF-β1 RNA most significantly. MMP-1 RNA expression showed no significant differences among groups (p = 0.827). The docetaxel group and stricture group pair was most significant (p = 0.247), compared with other pairs of stricture groups in MMP-1 RNA expression. CTGF RNA expression in the stricture group was statistically different from that of control, captopril, docetaxel, and docetaxel-captopril groups (p = 0.003; p = 0.019; p = 0.005; p = 0.005). The control group did not exhibit any statistically difference from the captopril, docetaxel, and docetaxel-captopril groups (p = 0.408; p = 0.709; p = 0.695). There was no statistical difference among treatment groups. Docetaxel and docetaxel-captopril groups suppress the most significant expression of CTGF RNA expression.PAI-1 RNA expression in the stricture group differed statistically significantly from the control and docetaxel groups (p = 0.044; p = 0.016). The stricture group did not show any statistically significant difference from the captopril and docetaxel-captopril groups (p = 0.763; p = 0.086). The control group did not exhibit any statistical difference with any of the treatment groups (p = 0.101; p = 0.637; p = 0.669).Conclusion:Docetaxel-captopril gel proved to be able to inhibit RNA expression of TGF-β1 and CTGF significantly. Captopril gel proved to be able to inhibit RNA expression of CTGF significantly. Docetaxel gel proved to be able to inhibit RNA expression of TGF-β1, CTGF, and PAI-1 significantly. There were no differences in MMP-1 expression among all study groups. Longer follow up after therapy discontinuation and greater sample size is needed to determine the therapeutic effect.

The Effects of Matrine in Combination with Docetaxel on Castration-Resistant (Androgen-Independent) Prostate Cancer.

BackgroundMatrine (MAT) exhibits higher efficacy of chemotherapy when it is combined with other chemotherapeutic drugs; however, the therapeutic efficacy of matrine in combination with docetaxel (DOC) for prostate cancer, or even androgen-independent prostate cancer, remains poorly understood and the underlying molecular mechanisms have not yet been clearly defined. In the present study, we investigated whether matrine combined with docetaxel can strengthen anti-cancer effect.MethodsIn this study, 7 groups were established, including (1) blank control group (cells). (2) 0.1 g/L MAT group, (3) 0.5 g/L MAT group, (4) 0.1 g/L MAT+ 50 μg/L DOC group, (5) 0.5 g/L MAT+ 50 μg/L DOC group, (6) 0.1 g/L MAT+ 100 μg/L DOC group, and (7) 0.5 g/L MAT+ 100 μg/L DOC group. MTS assay was performed to detect the anti-proliferative effects of each group on DU145 and PC-3 cells. At the same time, Transwell assay was performed to detect anti-migrative and anti-invasive effects of each group on DU145 and PC-3 cells. Biochemical colorimetric method and enzyme-linked immunosorbent assay were performed to detect the levels of LDH, IL-1β and IL-18 of each group on DU145 and PC-3 cells. Flow cytometry (FCM) assay was used to do the apoptosis analysis on DU145 and PC-3 cells of each group. At last, Western blot analysis was performed to investigate the expression levels of caspase1 in cells of each group. Statistical analyses were performed with SPSS 17.0 (SPSS Inc, USA) software, and one-way ANOVA and Fisher’s exact test was taken.ResultsMTS assay showed that matrine combined with docetaxel could inhibit both DU145 and PC-3 cells' proliferation in a dose- and time-dependent manner. Transwell assay showed that matrine combined with docetaxel could inhibit both DU145 and PC-3 cells' migration and invasion in a dose- and time-dependent manner. The levels of LDH, IL-1β and IL-18 of matrine combined with docetaxel-treated DU145 and PC-3 cells were significantly increased, compared with the untreated control cells. Flow cytometry, as well as Annexin-V/PI staining, showed a significant and dose-dependent increase in the number of early, as well as late-stage apoptotic cells in both DU145 and PC-3 cells compared with the untreated control cells. Western blot analysis showed that matrine combined with docetaxel treatment led to the expression of caspase1 in both DU145 and PC-3 cells.ConclusionIt may be more effective to use matrine in combination with docetaxel to treat androgen-resistant prostate cancer because matrine can help to affect proliferation, migration, invasion, apoptosis, metabolism, and have anti-inflammation effect on the tumor cells.

Risk factors of grade \u2265 2 radiation pneumonitis after gemcitabine induction chemotherapy for patients with non-small cell lung cancer

ObjectivesTo observe the risk factors affecting the occurrence of RP after gemcitabine-based induction chemotherapy.MethodsBetween January 2010 and December 2017, patients with NSCLC received gemcitabine or docetaxel chemotherapy, followed by radiotherapy at Zhejiang cancer hospital were enrolled in this study. Patients were treated with gemcitabine or docetaxel induction chemotherapy, followed by radiotherapy or concurrent chemoradiotherapy. Acute radiation pneumonitis was scored post chemoradiotherapy.ResultsOne hundred and eighty-four patients with NSCLC were included in the gemcitabine group and 144 in the docetaxel group. The gemcitabine group experienced a higher incidence of grade ≥ 2 RP, compared with docetaxel group (25.5% Vs. 13.2%, P = 0.005). The optimal cutoff values of lung V5, V20, V30 and MLD were set at 44% (AUC [area under the curve] = 0.593), 24% (AUC = 0.607), 14.2% (AUC = 0.622) and 1226 cGy (AUC = 0.626). On multivariate analysis, only lung V30 was identified as a predictor for grade ≥ 2 RP (P = 0.03). The grade ≥ 2 RP rate was only 9.4% for the low-risk group (Lung V5 ≤ 44%, V20 ≤ 24%, V30 ≤ 14.2%, and MLD ≤ 1226 cGy) in patients received gemcitabine induction chemotherapy.ConclusionsGemcitabine chemotherapy before thoracic radiotherapy in NSCLC patients was related to a higher incidence of grade ≥ 2 RP, compared with docetaxel chemotherapy. The Lung dose-volume variable V30 was the best predictor of grade ≥ 2 RP.

The efficacy and safety of docetaxel chemotherapy in the treatment of localised high-risk prostate cancer: a Meta-analysis

Objective The role of additional docetaxel chemotherapy in the treatment of localised high-risk prostate cancer (PCa) remains a controversy. This meta-analysis aimed to investigate the effect of additional docetaxel chemotherapy on localised high-risk PCa. Methods A computerized search was performed in Pubmed, Embase, Cochrane Library, Web of Science, CBM, CNKI, VIP and Wanfang Data to collect clinical controlled trails on localised high-risk PCa treated with docetaxel chemotherapy from the inception to April 2019. The Review Manager 5.3 software was used to perform meta-analysis of survival data and adverse events. Results Six literatures were enrolled, including 3 187 patients. Compared with the standard treatment (local treatment combined with endocrine therapy) group, the progression-free survival (PFS) was prolonged in the standard treatment plus docetaxel group, and the difference was statistically significant. [hazard ratio(HR)=0.75, 95%CI 0.65-0.86, P<0.01]. Patients in the standard treatment plus docetaxel group had longer overall survival (OS) and biochemical recurrence-free survival (BRFS) in comparison with standard treatment group, but the difference was not statistically significant (HR=0.843, 95%CI 0.68-1.01, P=0.06; HR=0.86, 95%CI 0.69-1.07, P=0.17). In terms of safety, the incidence of adverse reactions was increased in the standard treatment plus docetaxel group, including the incidence of grade ≥3 neutropenia (RR=44.14, 95%CI 19.15-101.71, P<0.01), the incidence of grade ≥3 febrile neutropenia (RR=13.4, 95%CI 7.93-22.65, P<0.01) and the incidence of grade ≥3 diarrhea (RR=13.43, 95%CI 3.21-56.16, P<0.01). Conclusions Additional docetaxel chemotherapy could significantly improve the PFS in localised high-risk PCa patients. OS and BRFS were prolonged, but the difference was not statistically significant. Key words: Prostatic neoplasms; High-risk; Docetaxel; Prognosis; Meta-analysis

Neutrophil-To-Lymphocyte Ratio Predicted Long-Term Chemotherapy Benefits In Stage IIIB-IV Non-Squamous Non-Small Cell Lung Cancer Patients Without Sensitive Mutations.

PurposeTo investigate the predictive capability of clinical parameters for long-term chemotherapy benefits among stage IIIB-IV non-squamous non-small cell lung cancer (NSCLC) patients without sensitive mutations.Patients and methodsWe investigated the clinical features of 206 stage IIIB-IV non-squamous NSCLC patients without sensitive mutations and assessed their predictive value for disease control rate (DCR) at 6 and 12 months post-treatment.ResultsSeventy-two patients received docetaxel and platinum-based chemotherapy while 134 received pemetrexed and platinum-based chemotherapy. The 6-month and 12-month DCR were 33 (45.8%) and 6 (8.3%) in the docetaxel group and 69 (51.5%) and 19 (14.2%) in the pemetrexed group, respectively. Univariate Cox regression revealed that age, sex, smoking history, adrenal gland metastasis, stage IV disease, neutrophil-to-lymphocyte ratio (NLR), and serum albumin were associated with unfavorable progression-free survival (PFS). Age, stage IV disease, and NLR were identified as independent predictors of PFS using multivariate analysis. NLR was the only parameter that could predict 3-month and 6-month DCRs. NLR and age were able to predict 12-month DCR, with NLR presenting a larger area under the curve. Kaplan–Meier curves demonstrated that patients with NLR > 2.231 displayed significantly reduced long-term disease control. The group with higher NLR had more male patients, lower ALB levels, and serum sodium levels as well as higher platelet counts.ConclusionNLR was an independent predictor of long-term chemotherapy benefits among non-squamous NSCLC patients without sensitive mutations. Patients with lower NLR were optimal candidates for chemotherapy. Patients with high NLR may receive alternative treatments or be included in clinical trials.

1910P - Radiomic signatures for identification of tumors sensitive to nivolumab or docetaxel in squamous non-small cell lung cancer (sqNSCLC)

BackgroundRadiomic signatures offer the potential to enhance clinical decision-making as on-treatment markers of efficacy to assess which patients (pts) should continue treatment. Using treatment-related radiomic signatures via quantitative, artificial intelligence (AI)-based analysis of computed tomography (CT) images, we evaluated early tumor changes in pts with sqNSCLC treated in 2 treatment groups: nivolumab (group A) or docetaxel (group B). MethodsData from pts with sqNSCLC were collected prospectively and analyzed retrospectively across 2 multicenter clinical trials (A, n=92 CheckMate 017 [NCT01642004], CheckMate 063 [NCT01721759]; B, n=50 CheckMate 017). For the current study, pts with a measurable lung lesion and baseline and on-treatment assessments (8 weeks) were randomized to training (T) or validation (V) datasets (A: 72T, 20V; B: 32T, 18V;). For each pt, the largest measurable lung tumor was segmented to extract 1,749 radiomic features. Pts were classified as treatment-sensitive or -resistant using median progression-free survival (PFS) calculated from pts included in this study (A, B). Using AI-based methodologies, up to 4 features were selected and combined to develop a signature score (range, 0-1) in the T datasets and applied to each pt in the V datasets to classify sensitivity to treatment. ResultsThe radiomics features associated with treatment sensitivity in the T datasets were a decrease in tumor volume (A, B), infiltration of tumor boundaries (A), or tumor spatial heterogeneity (A). The radiomic signatures predicted treatment sensitivity in the V dataset of each study group (AUC [95% CI]: A, 0.77 [0.55-1.00]; B, 0.67 [0.37-0.96]). ConclusionsAI-based CT imaging detected early changes in radiomic features from baseline to first on-treatment tumor assessment—decrease in tumor volume, tumor heterogeneity, and tumor infiltrativeness along boundaries—that were associated with sensitivity to treatment in pts with sqNSCLC, offering an approach that could guide clinical decision-making to continue or modify systemic therapies. Clinical trial identificationCheckMate 017 [NCT01642004] July 17, 2012 (first posted date) CheckMate 063 [NCT01721759] November 6, 2012 (first posted date). Legal entity responsible for the studyBristol-Myers Squibb and Columbia University Medical Center. FundingBristol-Myers Squibb. DisclosureM. Fronheiser: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. S. Du: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. W. Hayes: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. D.K. Leung: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. A. Roy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. L.H. Schwartz: Research grant / Funding (self), Member DSMB: Merck; Research grant / Funding (self), Member DSMB: Novartis; Research grant / Funding (self), Consultant endpoint analysis: Boehringer Ingelheim. All other authors have declared no conflicts of interest.

Overexpression of Mitochondrial Genes (Mitochondrial Transcription Factor A and Cytochrome c Oxidase Subunit 1) in Mouse Metaphase II Oocytes following Vitrification via Cryotop.

Background: Gamete cryopreservation is an inseparable part of assisted reproductive technology, and vitrification is an effective approach to the cryopreservation of oocytes. The aim of this study was to investigate vitrification effects on the expression levels of mitochondrial transcription factor A (Tfam) and mitochondrial-encoded cytochrome c oxidase subunit 1 (Cox1) in mouse metaphase II oocytes. Methods:Oocytes were selected by simple random sampling and distributed amongst five experimental groups (control [n=126], docetaxel [n=132], docetaxel+cryoprotectant agent [CPA] [n=134], docetaxel+vitrification [n=132], and vitrification [n=123]). After the warming process, the oocytes were fertilized and cultured into a 2-cell stage. Then, the effects of vitrification on the expression of the Tfam and Cox1 genes were determined via real-time reverse transcriptase polymerase chain reaction. Each group was compared with the control group. The data were analyzed with ANOVA using GraphPad and SPSS, version 21. Results:A significant decrease was observed in the fertilization rate of each group in comparison with the control group (P=0.001). The rate of 2-cell formation after in vitro fertilization was significantly lower in both vitrification groups (docetaxel+vitrification and vitrification) than in the non-vitrification groups (fresh control and docetaxel) and control group (P=0.001 and P=0.004). The expression level of Cox1 was significantly higher in the vitrification group than in the control group (P=0.01), while it was lower in the docetaxel group than that in the control group (P=0.04). The expression level of the Tfam gene was significantly high in the vitrification group (vitrification+docetaxel) and the non-vitrified group (docetaxel+CPA) in comparison with the control group (P=0.01). Conclusion:This study indicated that the vitrification of mouse MII oocytes increased the expression of the Tfam and Cox1 genes.

No survival benefit found after extended treatment with docetaxel for patients with castration-resistant prostate cancer.

Docetaxel (DOC) has been widely accepted as a therapeutic option for castration-resistant prostate cancer (CRPC). Evidence-based clinical guidelines have stipulated its use up to 10 cycles in most health care systems. There has been a paucity of information regarding potential benefits of its use over 10 cycles. The purpose of this study is to re-examine the rationale for the clinical guidelines concerning cycles of DOC in CRPC. Between July 2007 and July 2016, a total of 122 CRPC patients received at least five cycles of DOC at Jikei University and its affiliate hospitals. Doses of DOC (75 mg/m 2 ) were administered every 3 to 4 weeks. Clinical outcomes between patients receiving extended cycles of DOC (≥11 cycles, extended [ex]-DOC group) were compared to those receiving fewer (≤10 cycles, short-DOC group). A subgroup of patients who had discontinued DOC owing to adverse events, but whose disease did not progress, were also considered for comparison (adverse events [AE] group). Overall survival from the induction of DOC was the primary outcome measure. Univariate and multivariate analyses were conducted to analyze variables associated with overall survival. The ex- and short-DOC groups included 80 and 42 patients, respectively. Most baseline demographics did not differ between groups. However, in the short-DOC group more patients had received abiraterone acetate and/or enzalutamide before chemotherapy, age at DOC induction was younger, and lactate dehydrogenase at DOC induction was higher. Overall survival was significantly longer in the ex-DOC group compared to the short-DOC group (median, 53 and 27 months, respectively; P = .04). A subgroup of 22 patients in AE group was compared to compensate for potential bias. Overall survival from the induction of DOC was comparable between AE group and ex-DOC groups (median, 53 vs 53 months, respectively; P = 0.87). Univariate and multivariate analyses did not show any advantage of extended use of DOC on patient survival. The results of this study failed to show the survival benefit of extended use of DOC over 10 cycles in CRPC patients in the era of innovative drugs such as abiraterone acetate, enzalutamide, and cabazitaxel. Further prospective studies are required to confirm our findings.

Establishment of a non-small-cell lung cancer-liver metastasis patient-derived tumor xenograft model for the evaluation of patient-tailored chemotherapy.

In order to optimize patient-tailored chemotherapy, a non-small-cell lung cancer (NSCLC)-liver metastasis patient-derived tumor xenograft (PDTX) model is developed. Computed tomography (CT)-guided NSCLC percutaneous biopsy was subcutaneously inoculated into the flank of non-obese diabetic/severe combined immunodeficiency (NOD/SCID) female mice (PDTX F1) and allowed to reach 500 mm3 volume. Then, the tumors were re-transplanted into Balb/c nude mice and liver metastasis was confirmed (PDTX F2), which were further assigned into doxorubicin (DOX), docetaxel (DTX), and non-treatment control group. H&E staining and Keratin 20 (CK20) staining were applied to determine the consistency of PDTX models and primary tumors. Tumor growth curve, body weight, and the expression of p65 nuclear factor (NF)-κB and the secretion of interferon (IFN)-γ were investigated. The successive transplant procedure can induce the NSCLC-liver metastasis PDTX model, and morphological and structural characteristics of PDTX models (F2) were in accordance with primary tumors. DOX and DTX could delay tumor growth, activate the NF-κB pathway, and promote IFN-γ secretion in the PDTX models. The NSCLC-liver metastasis PDTX model is established and provides a powerful mean to assess chemotherapeutic efficacy.

Concurrent chemoradiotherapy with weekly docetaxel versus cisplatin in the treatment of locoregionally advanced nasopharyngeal carcinoma: a propensity score-matched analysis

BackgroundPromising efficacy and manageable toxicity of docetaxel-based concurrent chemoradiotherapy (CCRT) were reported in head and neck cancer. In addition, the effect of CCRT in combination with cisplatin and/or 5-fluorouracil on both locoregionally advanced and metastatic/recurrent nasopharyngeal carcinoma (NPC) was verified. However, CCRT with docetaxel for locoregionally advanced NPC are not well studied. This study aimed to compare effectiveness and toxicities of CCRT with weekly docetaxel versus tri-weekly cisplatin for locoregionally advanced NPC.MethodsClinical data of patients with locoregionally advanced NPC newly diagnosed between January 2010 and December 2014 receiving CCRT with either weekly docetaxel (15 mg/m2) or tri-weekly cisplatin (80–100 mg/m2) were reviewed. Propensity score matching at a 1:1 ratio was performed to balance baseline characteristics. Adverse events and survival were compared between the two groups.ResultsA total of 962 patients were included as the whole cohort, and 448 patients were matched and were regarded as the matched cohort. The median follow-up duration was 48 months for the whole cohort. The 3-year nodal recurrence-free survival rate was significantly increased for patients treated with docetaxel in both the whole (hazard ratio [HR] = 0.37, 95% confidence interval [CI] 0.19–0.72, P = 0.030) and matched cohorts (HR = 0.33, 95% CI 0.14–0.79, P = 0.023). However, no significant differences were observed in overall survival, local recurrence-free survival, and distant metastasis-free survival between the two groups in both cohorts. Significantly higher rates of grade 3 radiodermatitis (6.7% vs. 1.8%, P = 0.001), mucositis (74.5% vs. 37.9%, P < 0.001), and leucopenia (2.2% vs. 11.6%, P < 0.001) were observed in the docetaxel group, but any grade of renal injury (1.8% vs. 15.1%, P < 0.001), vomiting (18.8% vs. 88.3%, P < 0.001), and ALT elevation (19.2% vs. 31.3%, P = 0.027) were more common in the cisplatin group.ConclusionsCCRT with weekly low-dose docetaxel is an effective and tolerable therapeutic regimen for locally advanced NPC. It provides a survival benefit mainly by improving the control of regional lymph node metastases, especially for patients with low pretreatment EBV DNA levels.

Treatment with melatonin and selenium attenuates docetaxel-induced apoptosis and oxidative injury in kidney and testes of mice.

Docetaxel (DTX) has been used in cancer treatments for several decades, but it results in many adverse apoptotic effects through excessive production of reactive oxygen species (ROS) in some tissue including the kidney and testes. We aimed to investigate potential modulatory roles of melatonin (MEL) and selenium (Se) against DTX-induced apoptosis and oxidative injury in the testes and kidney of mice. Thirty-two mice were divided into four equal groups as control, DTX, DTX+MEL and DTX+Se. DTX group was treated with a single intraperitoneal dose of DTX. After DTX treatment, MEL and Se were administered to the mice in the DTX+MEL and DTX+Se groups for 7days respectively. Increased lipid peroxidation, ROS, apoptosis, caspase-3 and caspase-9 activities in the kidney and testes of the DTX group were diminished by treatment with MEL and Se. DTX-induced decreases in vitamin E (α- and γ-tocopherol), glutathione peroxidase and reduced glutathione levels in the kidney and testis were increased following MEL and Se treatments. In conclusion, our data show that MEL and Se can act as modulators against DTX-induced apoptosis and oxidative damage in the kidney and testis through up-regulation of glutathione and vitamin E and down-regulation of caspase pathways.

Addition of Docetaxel to Oral Fluoropyrimidine Improves Efficacy in Patients With Stage III Gastric Cancer: Interim Analysis of JACCRO GC-07, a Randomized Controlled Trial

PURPOSES-1 is a standard postoperative adjuvant chemotherapy for patients with stage II or III gastric cancer in Asia. Neoadjuvant or perioperative strategies dominate in Western countries, and docetaxel has recently shown significant survival benefits when combined with other standard regimens in advanced cancer and perioperative settings.PATIENTS AND METHODSThis randomized phase III study was designed to prove the superiority of postoperative S-1 plus docetaxel over S-1 alone for R0 resection of pathologic stage III gastric cancer. The sample size of 1,100 patients was necessary to detect a 7% increase in 3-year relapse-free survival as the primary end point (hazard ratio, 0.78; 2-sided α = .05; β = .2).RESULTSThe second interim analysis was conducted when the number of events reached 216 among 915 enrolled patients (median follow-up, 12.5 months). Analysis demonstrated the superiority of S-1 plus docetaxel (66%) to S-1 (50%) for 3-year relapse-free survival (hazard ratio, 0.632; 99.99% CI, 0.400 to 0.998; stratified log-rank test, P < .001), and enrollment was terminated as recommended by the independent data and safety monitoring committee. Incidences of grade 3 or greater adverse events, particularly neutropenia and leukopenia, were higher in the S-1 plus docetaxel group, but all events were manageable.CONCLUSIONAddition of docetaxel to S-1 is effective with few safety concerns in patients with stage III gastric cancer. The present findings may also be applicable in countries in which perioperative adjuvant chemotherapy or chemoradiation is not standard.

Effect of Taxane Plus Platinum Regimens vs Doxorubicin Plus Cisplatin as Adjuvant Chemotherapy for Endometrial Cancer at a High Risk of Progression

The efficacy of taxane plus platinum regimens has been demonstrated for advanced or recurrent endometrial cancer; however, it has not been assessed in postoperative adjuvant chemotherapy for endometrial cancer. To evaluate the clinical benefit of taxane plus platinum compared with standard doxorubicin plus cisplatin as postoperative adjuvant chemotherapy in endometrial cancer. In this multicenter, open-label, phase 3 randomized clinical trial, patients with endometrial cancer at high-risk stage I or II or stage III or IV that did not extend beyond the abdominal cavity and had 2 cm or greater residual tumor were included from 118 institutions in Japan from November 24, 2006, to January 7, 2011. Data was analyzed from March 15, 2017, to June 30, 2017. Eligible patients were randomly assigned (1:1:1) to receive 6 cycles of doxorubicin, 60 mg/m2, plus cisplatin, 50 mg/m2, on day 1; docetaxel, 70 mg/m2, plus cisplatin, 60 mg/m2, on day 1; or paclitaxel, 180 mg/m2, plus carboplatin (area under the curve, 6.0 mg/mL × min) on day 1 every 3 weeks. The primary end point was progression-free survival. Secondary end points were overall survival, occurrence of adverse events, tolerability, and status of lymph node dissection. Among 788 eligible patients, the median (SD) age was 59 (22-74) years; 263 patients were assigned to doxorubicin plus cisplatin treatment, 263 patients to docetaxel plus cisplatin treatment, and 262 patients to paclitaxel plus carboplatin treatment. The number of patients who did not complete 6 cycles was 53 (20.1%) for the doxorubicin plus cisplatin group, 45 (17.1%) for the docetaxel plus cisplatin group, and 63 (24.0%) for the paclitaxel plus carboplatin group. Tolerability of these regimens were not statistically different. After a median follow-up period of 7 years, there was no statistical difference of progression-free survival (doxorubicin plus cisplatin, 191; docetaxel plus cisplatin, 208; paclitaxel plus carboplatin, 187; P = .12) or overall survival (doxorubicin plus cisplatin, 217; docetaxel plus cisplatin, 223; paclitaxel plus carboplatin, 215; P = .67) among the 3 groups. The 5-year progression-free survival rate was 73.3% for the doxorubicin plus cisplatin group, 79.0% for the docetaxel plus cisplatin group, and 73.9% for the paclitaxel plus carboplatin group, while the 5-year overall survival rates were 82.7%, 88.1%, and 86.1%, respectively. There was no significant difference of survival among patients receiving doxorubicin plus cisplatin, docetaxel plus cisplatin, or paclitaxel plus carboplatin as postoperative adjuvant chemotherapy for endometrial cancer. Because each regimen showed adequate tolerability but different toxic effects, taxane plus platinum regimens may be a reasonable alternative to treatment with doxorubicin plus cisplatin. UMIN-CTR identifier: UMIN000000522.

Japanese subgroup analysis of a phase III study of S-1 versus docetaxel in non-small cell lung cancer patients after platinum-based treatment: EAST-LC

IntroductionThe East Asia S-1 Trial in Lung Cancer (EAST-LC) was a randomized phase III study conducted in East Asia that demonstrated the non-inferiority of S-1 to docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC). Here, we reported the results of the Japanese subgroup treated with docetaxel 60 mg/m2, the standard dosage in Japan.Patients and methodsPatients were randomized 1:1 to receive either S-1 or docetaxel. The primary endpoint was overall survival (OS); the secondary endpoints included progression-free survival (PFS), response rate (RR), quality of life (QOL), and safety.ResultsPatient characteristics in the Japanese subgroup (n = 724) were similar to those in the overall EAST-LC population. Median OS was 13.4 months in the S-1 group and 12.6 months in the docetaxel group. In pemetrexed-pretreated patients, OS with S-1 was similar to that with docetaxel. Median PFS was 2.9 and 3.0 months in the S-1 and docetaxel groups, respectively. RR was 9.4% and 10.3% in the S-1 and docetaxel groups, respectively. The QOL of patients treated with S-1 was better compared with that of patients treated with docetaxel. Decreased appetite and diarrhea were more common in the S-1 group, whereas the frequency of neutropenia and febrile neutropenia was markedly higher in the docetaxel group.ConclusionsThis Japanese subgroup analysis showed that S-1 had similar efficacy to docetaxel in patients with previously treated advanced NSCLC. These results are similar to those of the overall EAST-LC population.

Development of synthetic high-density lipoprotein-based ApoA-I mimetic peptide-loaded docetaxel as a drug delivery nanocarrier for breast cancer chemotherapy

In this study, a synthetic high-density lipoprotein (sHDL), peptide-based nanocarrier loaded with docetaxel (DTX) was constructed, against breast cancer. The thermodynamic and molecular dynamic analyses were conducted to examine the stability of nanoparticles synthesized from mimetic peptide 5 A and various types of phospholipids. Furthermore, the cellular uptake and in vivo fluorescence imaging analysis experiments, with scavenger receptor B-I (SR-BI) were carried out to examine the tumor-targeting ability of sHDL. The nanoparticles were investigated for their pharmacodynamic and cytotoxic effects to show their effectivity as anti-tumor agents. The results showed that the synthesized sHDL nanoparticles exhibited a high payload of DTX, sustained drug release properties, and excellent biocompatibility. Moreover, DTX-sHDL nanoparticles enhanced the uptake of DTX, increased the cytotoxicity against MCF-7 cells, and reduced the off-target side-effects to normal cells. Finally, experiments in 4T1 cell line-bearing mice indicate that inhibition of tumor growth by DTX-sHDL nanoparticles was superior to that of free DTX group. Thus, the sHDL nanoparticles are a promising drug delivery vehicle for improving the efficacy of anti-cancer drugs.

Atractylenolide III Enhances the Anti-Neoplastic Efficacy of Docetaxel in Gastric Cancer Cell by Inhibiting Fibroblast Growth Factor Receptors 1, -2, and -4 Expression.

Natural active components have been reported to serve as adjuvant medications in the clinical practice of cancer therapeutics. However, the antineoplastic roles of atractylenolide III (ATL) are rarely reported. In the present study, we assessed the functions of ATL combined with docetaxel in gastric cancer cells. Cell viability and cytotoxic activity were evaluated using CCK-8 and LDH-based cytotoxicity assays, respectively. Protein expression levels were measured by western blotting analysis. Annexin V-FITC/PI staining was used to evaluate cell apoptosis using flow cytometry. AGS and SGC-7901 cell viability was significantly inhibited in ATL combined with docetaxel group compared with docetaxel treatment alone. The levels of LDH, apoptosis rate, and the ratio of BAX to Bcl-2 were significantly elevated in combination treatment group compared to docetaxel treatment alone. Intriguingly, docetaxel combined with ATL resulted in a significant decrease in FGFR1, FGFR2, and FGFR4 protein expression compared with docetaxel treatment alone. Knockout of FGFR1, -2, and -4 exhibited a similar role of medications to inhibit growth and induce apoptosis in AGS and SGC-7901 cells. ATL and docetaxel treatment performed the synergistic effects on the inhibition of growth and induction of apoptosis in gastric cancer cells, and the underlying mechanism was mediated, at least partially, through the inhibition of FGFR1, -2, and -4.

Effects of Pemetrexed and Docetaxel Combined with Cisplatin in the Treatment of Non-Small Cell Lung Cancer

AbstractPurpose: To compare the clinical effects of pemetrexed and docetaxel combined with cisplatin in the treatment of patients with non-small cell lung cancer. Methods: A total of 58 patients with non-small cell lung cancer who were enrolled between January 2017 and January 2018 were enlisted into a randomized digital table. Twenty-nine patients who have received treatment with combined pemetrexed and cisplatin were assigned to the pemetrexed group whereas for the other 29 patients which were treated with docetaxel and cisplatin combined, were assigned to the docetaxel group to verify the calculated clinical treatment efficiency of the patients with non-small cell lung cancer, SVCAM-1 and alCAM-1 concentrations and to evaluate the quality of life scores of the patients after half a year as well as the incidences of adverse reactions following the treatments provided. Results: The differences in SVCAM-1 and alCAM-1 concentrations, and incidence of adverse reactions in patients with non-small cell lung cancer in the docetaxel group as compared with patients in the pemetrexed group after the treatments were statistically significant (P&lt;0.05) where the calculations were performed with data sets gathered from and between the two groups. Additionally, SVCAM-1 and alCAM-1 concentrations in patients in both pemetrexed group and docetaxel group demonstrated significant differences in concentrations before and after the treatments were provided, P&lt;0.05. The comparative studies of the effects of the treatments on the quality of life scores and clinical treatment efficiency between the two groups after half a year, P&gt;0.05, demonstrated no analytical significance. Conclusion: Both pemetrexed combined with cisplatin and docetaxel in combination with cisplatin as forms of treatments demonstrated significant effects in patients with non-small cell lung cancer. However, based on our study, it was found that the combined treatment involving pemetrexed and cisplatin can further reduce adverse reactions and thus, is worthy of clinical application.Â

Liposomal paclitaxel versus docetaxel in induction chemotherapy using Taxanes, cisplatin and 5-fluorouracil for locally advanced nasopharyngeal carcinoma

BackgroundWe wished to evaluate the efficacy and safety of liposomal paclitaxel and docetaxel for induction chemotherapy (IC) for nasopharyngeal carcinoma (NPC).MethodsA total of 1498 patients with newly-diagnosed NPC between 2009 and 2017 treated with IC plus concurrent chemotherapy were included in our observational study. Overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS) and grade-3–4 toxicities were compared between groups using propensity score matching (PSM).ResultsIn total, 767 patients were eligible for this study, with 104 (13.6%) and 663 (86.4%) receiving a liposomal paclitaxel-based and docetaxel-based taxanes, cisplatin and 5-fluorouracil (TPF) regimen, respectively. PSM identified 103 patients in the liposomal-paclitaxel group and 287 patients in the docetaxel group. There was no significant difference at 3 years for OS (92.2% vs. 93.9%, P = 0.942), PFS (82.6% vs. 81.7%, P = 0.394), LRFS (94.7% vs. 93.3%, P = 0.981) or DMFS (84.6% vs. 87.4%, P = 0.371) between the two groups after PSM. Significant interactions were not observed between the effect of chemotherapy regimen and sex, age, T stage, N stage, overall stage, or Epstein–Barr virus DNA level in the subgroup multivariate analysis. The prevalence of grade-3–4 leukopenia and neutropenia in the liposomal-paclitaxel group was significantly lower than that of the docetaxel group (P < 0.05 for all).ConclusionsCompared with docetaxel, liposomal paclitaxel has identical anti-tumor efficacy, but causes fewer and milder adverse reactions in IC for NPC.