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Recent Research Publications

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Recent Research Publications

Aitelhaj M, Lkhoyaali S, Rais G, et al.
First line chemotherapy plus trastuzumab in metastatic breast cancer HER2 positive - Observational institutional study.
Pan Afr Med J. 2016; 24:324 [PubMed] Free Access to Full Article Related Publications
Breast cancer is the most common malignant disease and among the most frequent causes of cancer mortality in females worldwide. Metastatic breast cancer (MBC) is conventionally considered to be incurable. In first-line treatment of HER-2 positive MBC, randomized trials have demonstrated that trastuzumab when combined with chemotherapy significantly improves progression free survival and overall survival. To evaluate survival and toxicity of chemotherapy with Trastuzumab as first line therapy of human epithermal growth factor receptor 2 positive metastatic breast cancer, in Moroccan population. It is a phase IV observational institutional monocentric study. Including patients with metastatic breast cancer HER2 positive, as first-line chemotherapy combined with Trastuzumab from March 2009 until March 2010. Primary end point: progression free survival, secondary end point response rate and overall survival. A total of 20 patients were enrolled between March 2009 and March 2010. The lung was the first metastatic site in 60% of the cases, followed by bone, liver, nodes, skin and brain. All patients received chemotherapy with Trastuzumab: 9 of them with Docetaxel, 8 with vinorelbine, and 3 with capecitabine. The progression free survival was estimated by the Kaplan-Meier method, from the date of first cycle to the date of progression or at the last consultation, and the median was 12.8 months. Trastuzumab based chemotherapy was generally well tolerated; 5 patients (25%) presented cardiotoxicity. The results of this study join the literature and show the benefit of Trastuzumab to chemotherapy in first line metastatic breast cancer HER-2 positive.

Lange R, Heine RT, van Wieringen WN, et al.
Cytotoxic Effects of the Therapeutic Radionuclide Rhenium-188 Combined with Taxanes in Human Prostate Carcinoma Cell Lines.
Cancer Biother Radiopharm. 2017; 32(1):16-23 [PubMed] Related Publications
OBJECTIVE: Rhenium-188-HEDP is an effective radiopharmaceutical for the treatment of painful bone metastases from prostate cancer. The effectiveness of the β-radiation emitted by (188)Re might be enhanced by combination with chemotherapy, using the radiosensitization concept. Therefore, the authors investigated the combined treatment of the taxanes, docetaxel and cabazitaxel, with (188)Re in prostate carcinoma cell lines.
MATERIALS AND METHODS: The cytotoxic effects of single and combined treatment with taxanes and (188)Re were investigated in three human prostate carcinoma cell lines (PC-3, DU 145, and LNCaP), using the colony-forming assay. The half maximal effective concentration (EC50) of all individual agents was determined. The combined treatment was studied at 0.25, 0.5, 1, 2, and 4 times the EC50 of each agent. The interaction was investigated with a regression model.
RESULTS: The survival curves showed dose-dependent cell growth inhibition for both the taxanes and (188)Re. The regression model showed a good capability of explaining the data. It proved additivity in all combination experiments and confirmed a general trend to a slight subadditive effect.
CONCLUSIONS: This proof-of-mechanism study exploring radiosensitization by combining (188)Re and taxanes showed no synergism, but significant additivity. This encourages the design of in vivo studies. Future research should explore the potential added value of concomitant treatment of bone metastases with chemotherapy and (188)Re-HEDP.

Fu ZZ, Li K, Peng Y, et al.
Efficacy and toxicity of different concurrent chemoradiotherapy regimens in the treatment of advanced cervical cancer: A network meta-analysis.
Medicine (Baltimore). 2017; 96(2):e5853 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: The aim of this study was to compare the efficacy and toxicity of different concurrent chemoradiotherapy (CCRT) regimens in the treatment of advanced cervical cancer (CC) by adopting a network meta-analysis.
METHODS: We searched PubMed and Cochrane Library from the inception of these databases to September 2016, and all cohort studies (CSs) related to different CCRT regimens in the treatment of CC were included. A network analysis was adopted to compare the combination of direct and indirect evidence, to analyze the odds ratio (OR), and to draw a surface under the cumulative ranking curve of the efficacy and toxicity of different CCRT regimens for CC. Cluster analyses were used to group each category based on similar treatment regimens.
RESULTS: Nineteen CSs were enrolled in this network meta-analysis, including 12 CCRT regimens (radiotherapy [RT], CCRT [cisplatin], CCRT [vinorelbine], CCRT [paclitaxel], CCRT [hydroxyurea], CCRT [cisplatin + FU], CCRT [cisplatin + gemcitabine], CCRT [cisplatin + docetaxel], CCRT [cisplatin + paclitaxel], CCRT [cisplatin + amifostine], CCRT [cisplatin + FU + hydroxyurea], and CCRT [cisplatin + vincristine + bleomycin]). The results of the network meta-analysis showed that regarding efficacy, the overall response rate of CCRT (cisplatin + docetaxel) was higher than RT, and the 5-year overall survival (OS) rate of CCRT (cisplatin + FU + hydroxyurea) was relatively higher than CCRT (hydroxyurea). As for toxicity, CCRT (cisplatin) had a lower incidence of leukopenia than CCRT (hydroxyurea), CCRT (cisplatin + FU) and CCRT (cisplatin + paclitaxel), and the incidences of diarrhea and vomiting in CCRT (cisplatin) were lower than those in CCRT (cisplatin + gemcitabine). Additionally, the cluster analysis showed that CCRT (cisplatin) had relatively lower incidences of both hematotoxicity and gastrointestinal toxicity, and CCRT (paclitaxel) had lower gastrointestinal toxicity than other regimens.
CONCLUSION: Our study demonstrated that CCRT (cisplatin + docetaxel) might be the best choice of CCRT regimens in the treatment of CC, and the 5-year OS rate of CCRT (cisplatin + FU + hydroxyurea) might be the highest among these different regimens. CCRT (cisplatin) might have the lowest toxicity among all the CCRT regimens.

Qu CP, Sun GX, Yang SQ, et al.
Toxicities of different first-line chemotherapy regimens in the treatment of advanced ovarian cancer: A network meta-analysis.
Medicine (Baltimore). 2017; 96(2):e5797 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ovarian cancer (OC) is the 5th leading cause of cancer-related deaths around the world, and several chemotherapy regimens have been applied in the treatment of OC. We aim to compare toxicities of different chemotherapy regimens in the treatment of advanced ovarian cancer (AOC) using network meta-analysis.
METHODS: Literature research in Cochrane Library, PubMed, and EMBASE was performed up to November 2015. Eligible randomized controlled trials (RCTs) of different chemotherapy regimens were included. Network meta-analysis combined direct and indirect evidence to assess pooled odds ratios (ORs) and draw the surface under the cumulative ranking (SUCRA) curves.
RESULTS: Thirteen eligible RCTs were included in this network meta-analysis, including 8 chemotherapy regimens (paclitaxel + carboplatin [PC], pegylated liposomal doxorubicin [PLD] + carboplatin, carboplatin, gemcitabine + carboplatin, paclitaxel, PC + epirubicin, PC + topotecan, docetaxel + carboplatin). Gemcitabine + carboplatin regimen exerted higher incidence of anemia when compared with carboplatin and paclitaxel regimens. The incidence of febrile neutropenia of gemcitabine + carboplatin regimen was higher than that of PC, PLD + carboplatin, carboplatin, and PC + topotecan regimens. Topotecan PC + epirubicin regimen had a higher toxicity, comparing with PC, PLD + carboplatin, and PC + topotecan regimens. As for thrombocytopenia, gemcitabine + carboplatin chemotherapy regimen produced an obviously higher toxicity than PC and carboplatin. As for nausea, PLD + carboplatin chemotherapy regimen had a significantly higher toxicity than that of carboplatin chemotherapy regimen. Moreover, when compared with PC and carboplatin chemotherapy regimens, the toxicity of PC + epirubicin was greatly higher to patients with AOC.
CONCLUSION: The nonhematologic toxicity of PLD + carboplatin regimen was higher than other regimens, which was clinically significant for the treatment of AOC.

Garcia JR, Pérez C, Bassa P, et al.
18F-FDG PET/CT in the Staging and Management of Breast Cancer: Value in Disease Outcome and Planning Therapy.
Clin Nucl Med. 2017; 42(3):191-192 [PubMed] Related Publications
In hormone receptor-positive locally advanced breast cancer, endocrine therapy becomes an integral part of the therapeutic strategy. There are now significant numbers of available hormonal directed compounds, including selective aromatase and mTOR inhibitors, which allow an important therapeutic advance in these patients. Sequential F-FDG PET/CT studies provided essential information regarding response to different treatments, including targeted therapies, and adverse therapeutic effects that helped to better define the right moment to implement each therapeutic approach.

Zhao T, Jin Y, Mao G, et al.
CYFRA 21-1 is an early predictor of chemotherapeutic effectiveness in advanced nonsmall cell lung cancer: An observational study.
Medicine (Baltimore). 2016; 95(52):e5748 [PubMed] Free Access to Full Article Related Publications
Serum cytokeratin 19 fragment (CYFRA21-1) has been found to be a useful prognostic marker in lung cancer. Previous studies have revealed that change in CYFRA21-1 synchronously predicted therapeutic effectiveness in advanced nonsmall cell lung cancer (NSCLC) after the second cycle of chemotherapy. The objective of this study was to investigate the early predictive value of percentage change in serum CYFRA21-1 from pretreatment to completion of the first cycle of chemotherapy for chemotherapeutic effectiveness in advanced NSCLC patients.Ninety-seven advanced NSCLC patients with elevated serum CYFRA21-1 level (≥3.8 μg/L), who received 2 platinum-containing drugs, were included in this retrospective study. Serum CYFRA21-1 had been assayed before and after the first cycle of chemotherapy. To evaluate the effectiveness of chemotherapy, patients were allocated to disease control (DC) and progressive disease groups. The percentage changes of serum CYFRA21-1 concentration before and after first-cycle chemotherapy that occurred in each group were evaluated for their ability to predict achievement of radiologic DC, that is, to predict therapeutic effectiveness.The percentage change of serum CYFRA21-1 and the prevalence of ≥5% weight loss were higher in patients with progressive disease than in those with DC. The differences in other clinical and pathological variables including age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, cigarette smoking, histological type, gross type, clinical stage, and chemotherapy regimens of the 2 groups were not significant. Both multiple generalized linear model analysis and linear trend tests indicated that the percentage change of serum CYFRA21-1 concentration was independently and negatively linked to the effectiveness of chemotherapy for NSCLC (P < 0.01). The area under the receiver-operating characteristic curve of the percentage change in prediction of DC was 0.84 and the optimal cut-off value was17.5% (P < 0.001).The percentage change of serum CYFRA21-1 after completing the first cycle of chemotherapy was predictive of treatment effects and might be helpful in making early decisions to change chemotherapy regimens in patients with advanced NSCLC.

Wang C, Yu X, Wang W
A meta-analysis of efficacy and safety of antibodies targeting PD-1/PD-L1 in treatment of advanced nonsmall cell lung cancer.
Medicine (Baltimore). 2016; 95(52):e5539 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Nonsmall cell lung cancer (NSCLC)-patients treated with standard chemotherapy experienced progression rapidly. A novel therapy based on programed death 1 (PD-1)/programed death ligand 1 (PD-L1) inhibitors showed an increasing potential in several malignancies including advanced NSCLC.
OBJECTIVES: This article is a meta-analysis aiming to systematically evaluate the efficacy and safety profiles of PD-1/PD-L1 agents in patients with NSCLC.
DATA SOURCES: Data were collected from eligible studies searched from PubMed, ScienceDirect, and Web of Science.
SYNTHESIS METHODS: Pooled hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) was estimated to assess the efficacy of PD-1/PD-L1 inhibitors versus docetaxel, pooled odds ratio (OR) was calculated for objective response rate (ORR). The overall frequency was estimated for 1-year OS, 1-year progression-free survival, and ORR. A subgroup analysis among NSCLC patients tested with different epidermal growth factor receptor (EGFR) status was also performed to figure out the relationship between EGFR status and efficacy of PD-1/PD-L1 therapies. OR for occurrence of any grade and grade 3 to 5 treatment-related adverse effect was calculated for evaluating the safety of PD-1/PD-L1 therapies.
RESULTS: Nine studies were included in this analysis. The pooled HRs for OS and PFS were 0.68 (95% confidence interval [CI] 0.61-0.75) and 0.83 (95% CI 0.75-0.91), respectively, the pooled OR for ORR was 1.83 (95% CI 1.41-2.36), indicating a significant improvement in OS, PFS, and ORR. In the results of subgroup analysis, the HR for OS in NSCLC patients was 1.05 (95% CI 0.69-1.59) in patients with mutant EGFR and 0.66 (95% CI 0.57-0.77) in patients with wild-type EGFR status. OR for occurrence was 0.36 (95% CI 0.28-0.46) in any grade treatment-related adverse effect and 0.18 (95% CI 0.14-0.22) in grade 3 to 5 treatment-related adverse effect, suggesting a superior safety profile of PD-1/PD-L1 inhibitors.
CONCLUSION: The PD-1/PD-L1 therapy significantly prolonged the OS and improved the ORR, simultaneously lowering the treatment-related adverse effect events versus docetaxel.

Sun P, Zhang N, Hua H, et al.
Low density lipoprotein peptide conjugated submicron emulsions for combating prostate cancer.
Biomed Pharmacother. 2017; 86:612-619 [PubMed] Related Publications
Submicron emulsions (SEs) is an advanced formulation that possesses good biocompatibility, high loading of hydrophobic drugs, and good stability through autoclave sterilization. To enhance tumor targeting and tumor cell uptake, SEs could be modified with positive charge and targeting moieties. In the present study, three formulations were prepared: Docetaxel-loaded SEs (DocSEs), cationic DocSEs (DocCSEs), and low density lipoprotein receptor (LDLR) targeted peptide-RLT (CEKLKEAFRLTRKRGLKLA) modified DocCSEs (RLT-DocCSEs). The optimized RLT-DocCSEs showed a particle size 182.2±10nm, a zeta potential 39.62±2.41mV, and a loading efficiency of Docetaxel (Doc) 98%. RLT-DocCSEs demonstrated sustained release in 96h and was stable for two months at 4°C. Compared to DocSEs and DocCSEs, RLT-DocCSEs caused significantly more PC-3 cell inhibition and cell apoptosis. RLT-DocCSEs also showed more cellular uptake and slower cellular elimination than that of DocSEs and DocCSEs. The present study indicated RLT-DocCSEs could be a potential formulation for injection of anti-cancer therapeutics with increased tumor targeting and anti-tumor efficacy.

Cortinovis D, Gregorc V, Migliorino MR, et al.
New perspectives in the second-line treatment of non squamous NSCLC patients: Results from a large Italian Lung Cancer Working Group.
Crit Rev Oncol Hematol. 2017; 109:35-41 [PubMed] Related Publications
Lung cancer is still considered a big killer among cancer diseases, due to high incidence and mortality rates. The newer frontiers of therapeutic development regard the discovery of oncogene driven tumours: however, the majority of NSCLC patients are wild type and they cannot be treated with targeted based agents. The recent positive results obtained with immunotherapy and with the combination of angiogenesis inhibitors and docetaxel, changed the therapeutic scenario of the second line therapy of non squamous NSCLC without actionable mutations. A major issue is currently the lack of predictive biomarkers that could help the oncologists in the choice of the best second-line treatment. Aim of this project was to define an optimal therapeutic pathway for patients with non-squamous NSCLC, through a working group of a large number of Italian lung cancer oncologists. Panellists have identified and discussed the more significant criteria in the second-line setting for a therapeutic decision between the combination of angiogenesis inhibitors plus chemotherapy or immunotherapy. Finally, they expressed their preference on each criterion, building a proposal of a decision-making tree for a second-line treatment of non-squamous NSCLC.

An N, Zhang Y, Niu H, et al.
EGFR-TKIs versus taxanes agents in therapy for nonsmall-cell lung cancer patients: A PRISMA-compliant systematic review with meta-analysis and meta-regression.
Medicine (Baltimore). 2016; 95(50):e5601 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Currently, the nonsmall-cell lung cancer (NSCLC) is a worldwide disease, which has very poor influence on life quality, whereas the therapeutic effects of drugs for it are not satisfactory. The aim of our PRISMA-compliant systematic review and meta-analysis was to compare the efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) with Taxanes in patients with lung tumors.
METHODS: We collected randomized controlled trials (RCTs) of EGFR-TKIs (gefitinib, erlotinib) versus Taxanes (docetaxel, paclitaxel) for the treatment of NSCLC by searching PubMed, EMbase, and the Cochrane library databases until April, 2016. The extracted data on progression-free survival (PFS), progression-free survival rate (PFSR), overall survival (OS), overall survival rate (OSR), objective response rate (ORR), disease control rate (DCR), quality of life (QoL), and adverse event rates (AEs) were pooled. Disease-relevant outcomes were evaluated using RevMan 5.3.5 software and STATA 13.0 software.
RESULTS: We systematically searched 26 RCTs involving 11,676 patients. The results showed that EGFR-TKIs could significantly prolong PFS (hazard ratio [HR] = 0.78, 95% confidence interval [CI]: 0.66-0.92) and PFSR (risk ratio [RR] = 2.10, 95% CI: 1.17-3.77), and improve ORR (RR = 1.62, 95% CI: 1.38-1.91) and QoL. EGFR-TKIs had similar therapeutic effects to taxanes with respect to OS (HR = 1.00, 95% CI: 0.95-1.05) and OSR (RR = 1.03, 95% CI: 0.94-1.14). Furthermore, there were no significant differences between them in DCR (RR = 0.95, 95% CI: 0.88-1.03). Finally, EGFR-TKIs were superior to taxanes in most of all grades or grade ≥3 AEs.
CONCLUSION: In the efficacy and safety evaluation, EGFR-TKIs had an advantage in the treatment of NSCLC, especially for patients with EGFR mutation-positive. The project was prospectively registered with PROSPERO database of systematic reviews, with number CRD42016038700.

Cicero G, De Luca R, Dorangricchia P, et al.
Cabazitaxel in Metastatic Castration-Resistant Prostate Cancer Patients Progressing after Docetaxel: A Prospective Single-Center Study.
Oncology. 2017; 92(2):94-100 [PubMed] Related Publications
PURPOSE: The present study aims to evaluate the efficacy of cabazitaxel in combination with prednisone treatment in Italian patients affected by hormone-refractory metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel plus prednisone.
METHODS: Thirty patients with mCRPC were enrolled between June 2013 and January 2016 (the last follow-up was in January 2016). Cabazitaxel was used according to the summary of product characteristics and administered at a dose of 25 mg/m2 every 3 weeks plus oral prednisone at a dose of 5-mg tablets twice a day continuously. The reduction in serum prostate-specific antigen (PSA) was the primary endpoint while reducing pain, safety, progression-free survival, response rate and overall survival (OS) were secondary endpoints.
RESULTS: Cabazitaxel was well tolerated, showing a manageable toxicity profile, associated with a modest objective response rate and a good reduction in PSA levels. Only 12 patients (40%) had a partial response, 10 patients (33%) showed stabilization of disease and 8 (27%) experienced disease progression. The median OS was 14.8 months (95% CI: 11.6-19.8). The linear regression analysis revealed that PSA response was an important predictor of OS, showing a positive correlation with OS (β = 0.377, p < 0.01).
CONCLUSIONS: Three-week treatment with cabazitaxel was found to be valid and was a well-tolerated treatment option for patients with mCRPC after a first-line docetaxel treatment.

Gridelli C, Chella A, Valmadre G, et al.
Second-line Erlotinib or Intermittent Erlotinib plus Docetaxel in Male Ex-smokers with Squamous NSCLC: The TALISMAN Randomized Trial.
Anticancer Res. 2016; 36(12):6535-6540 [PubMed] Related Publications
BACKGROUND/AIM: The TArceva and docetaxeL In former-Smokers MAle patients with recurrent non-small cell lung cancer (TALISMAN) phase II, open-label randomized trial evaluates the combination of erlotinib with docetaxel in the second-line therapy of ex-smoker males with advanced squamous non-small cell lung cancer (NSCLC).
PATIENTS AND METHODS: Patients received erlotinib 150 mg/day (arm A; n=36) or docetaxel 75 mg/m(2) on day 1 of each 3-week cycle and erlotinib 150 mg/day on days 2-16 of each cycle (arm B; n=38). The primary end-point was progression-free rate (PFR) at 6 months.
RESULTS: The study was prematurely interrupted due to slow enrolment. Three (8.3%) patients in arm A and 3 (8.1%) in arm B remained progression-free at 6 months. Median progression-free survival (PFS) was 2.3 months in arm A and 2.8 months in arm B. Median overall survival (OS) was 5.6 and 8.9 months, respectively. Overall, 77.8% of patients in arm A and 89.2% in arm B experienced treatment-related adverse events (AEs).
CONCLUSION: Results do not support further investigation of the combination of erlotinib and docetaxel in this setting.

Joensuu T, Joensuu G, Kairemo K, et al.
Multimodal Primary Treatment of Metastatic Prostate Cancer with Androgen Deprivation and Radiation.
Anticancer Res. 2016; 36(12):6439-6447 [PubMed] Related Publications
AIM: We combined anti-androgen therapy with radiotherapy in a first-line setting for metastatic prostate cancer aiming to cause maximal cancer-cell death to delay the emergence of castration-resistant disease.
MATERIALS AND METHODS: In this non-randomized retrospective series of 46 patients, the initial median prostate-specific antigen (PSA) was 98.5 μg/l (range=6.7-15,500), median Gleason score 9 and most men had at least T3N1M1 disease. All patients received luteinizing hormone releasing hormone analog or degarelix with bicalutamide. If PSA remained above 1 μg/l, docetaxel was initiated. At PSA nadir, all patients received radical radiotherapy of the prostate.
RESULTS: The median follow-up time was 4.38 years (range=0.36-11.24). Most radiotherapy-related adverse events were grade 1 and transient. There were no grade 4 events. Overall survival (OS) at 5 years was 81.3%.
CONCLUSION: The feasibility and safety of aggressive multimodality treatment were good resulting in an excellent median OS of 8.35 years.

Tiainen L, Tanner M, Lahdenperä O, et al.
Bevacizumab Combined with Docetaxel or Paclitaxel as First-line Treatment of HER2-negative Metastatic Breast Cancer.
Anticancer Res. 2016; 36(12):6431-6438 [PubMed] Related Publications
AIM: The study evaluated the efficacy of bevacizumab combined with a taxane-based treatment for advanced breast cancer.
PATIENTS AND METHODS: In this non-randomized phase II study 65 patients received 10 mg/kg bevacizumab i.v. (days 1 and 15, q4w) plus either 50 mg/m(2) docetaxel (days 1 and 15, q4w) or 90 mg/m(2) paclitaxel (days 1,8 and 15, q4w) i.v. until disease progression, maximal response, unacceptable toxicity or the withdrawal of consent. Patients without progression continued bevacizumab at 15 mg/kg i.v. (q3w) alone, or with endocrine therapy. (NCT00979641).
RESULTS: Progression-free survival was 11.3 months (95% confidence interval=9.7-16.0 months) and overall survival was 35.1 months (95% confidence interval=22.2-50.3 months). More than half of the patients (62%) responded at least partially. Bevacizumab-related serious adverse events occurred in 10.8% patients and one patient died because of gastrointestinal perforation.
CONCLUSION: Treating advanced breast cancer with a bevacizumab-containing regimen as the first-line cytotoxic treatment resulted in excellent response rates and long survival.

Rugo HS, Barve A, Waller CF, et al.
Effect of a Proposed Trastuzumab Biosimilar Compared With Trastuzumab on Overall Response Rate in Patients With ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Randomized Clinical Trial.
JAMA. 2017; 317(1):37-47 [PubMed] Related Publications
Importance: Treatment with the anti-ERBB2 humanized monoclonal antibody trastuzumab and chemotherapy significantly improves outcome in patients with ERBB2 (HER2)-positive metastatic breast cancer; a clinically effective biosimilar may help increase access to this therapy.
Objective: To compare the overall response rate and assess the safety of a proposed trastuzumab biosimilar plus a taxane or trastuzumab plus a taxane in patients without prior treatment for ERBB2-positive metastatic breast cancer.
Design, Setting, and Participants: Multicenter, double-blind, randomized, parallel-group, phase 3 equivalence study in patients with metastatic breast cancer. From December 2012 to August 2015, 500 patients were randomized 1:1 to receive a proposed biosimilar or trastuzumab plus a taxane. Chemotherapy was administered for at least 24 weeks followed by antibody alone until unacceptable toxic effects or disease progression occurred.
Interventions: Proposed biosimilar (n = 230) or trastuzumab (n = 228) with a taxane.
Main Outcomes and Measures: The primary outcome was week 24 overall response rate (ORR) defined as complete or partial response. Equivalence boundaries were 0.81 to 1.24 with a 90% CI for ORR ratio (proposed biosimilar/trastuzumab) and -15% to 15% with a 95% CI for ORR difference. Secondary outcome measures included time to tumor progression, progression-free and overall survival at week 48, and adverse events.
Results: Among 500 women randomized, the intention-to-treat population included 458 women (mean [SD] age, 53.6 [11.11] years) and the safety population included 493 women. The ORR was 69.6% (95% CI, 63.62%-75.51%) for the proposed biosimilar vs 64.0% (95% CI, 57.81%-70.26%) for trastuzumab. The ORR ratio (1.09; 90% CI, 0.974-1.211) and ORR difference (5.53; 95% CI, -3.08 to 14.04) were within the equivalence boundaries. At week 48, there was no statistically significant difference with the proposed biosimilar vs trastuzumab for time to tumor progression (41.3% vs 43.0%; -1.7%; 95% CI, -11.1% to 6.9%), progression-free survival (44.3% vs 44.7%; -0.4%; 95% CI, -9.4% to 8.7%), or overall survival (89.1% vs 85.1%; 4.0%; 95% CI, -2.1% to 10.3%). In the proposed biosimilar and trastuzumab groups, 239 (98.6%) and 233 (94.7%) had at least 1 adverse event, the most common including neutropenia (57.5% vs 53.3%), peripheral neuropathy (23.1% vs 24.8%), and diarrhea (20.6% vs 20.7%).
Conclusions and Relevance: Among women with ERBB2-positive metastatic breast cancer receiving taxanes, the use of a proposed trastuzumab biosimilar compared with trastuzumab resulted in an equivalent overall response rate at 24 weeks. Further study is needed to assess safety and long-term clinical outcome.
Trial Registration: clinicaltrials.gov Identifier: NCT02472964; EudraCT Identifier: 2011-001965-42.

Yang F, Luo LJ, Zhang L, et al.
MiR-346 promotes the biological function of breast cancer cells by targeting SRCIN1 and reduces chemosensitivity to docetaxel.
Gene. 2017; 600:21-28 [PubMed] Related Publications
MicroRNAs (miRNAs) are a class of highly conserved small noncoding RNAs that play pivotal roles at the post-transcriptional level in the biological function of various cancers, including breast cancer. In our study, miR-346 mimic, inhibitor, negative control or si-SRCIN1 were transfected into MCF-7 and MCF-7/Doc cells, respectively. Quantitative real time PCR (qRT-PCR) was used to measure miR-346 and SRCIN1 mRNA expressions and western blot was used to detect the expression of SRCIN1 in protein level. CCK-8 and colony formation were employed to verify cell viability and proliferation. Flow cytometry showed the apoptosis. Transwell was performed to detect migration and invasion. The luciferase reporter assay data showed the target correlation of miR-346 and SRCIN1. Firstly, we found that the expression of miR-346 was higher in breast cancer tissues than in their paired corresponding non-cancerous tissues and there was significant inversed correlation between miR-346 and SRCIN1. Overexpression of miR-346 promoted cell proliferation, colony formation, migration and invasion, and reduced apoptosis, sensitivity to Docetaxel (Doc). SRCIN1 was identified as a direct target of miR-346, whose silencing promoted cell proliferation and the IC50 of Doc. Moreover, SRCIN1 silencing reduced the effect of miR-346 down-expression. Taken together, miR-346 may function as an oncogenic miRNA and mediate chemosensitivity to docetaxel through targeting SRCIN1 in breast cancer, targeted modulation of miR-346 expression may became a potential strategy for the treatment.

Pfeiffer P, Qvortrup C, Krogh M, et al.
S-1 in combination with docetaxel and oxaliplatin in patients with advanced gastro-esophageal adenocarcinoma: two parallel phase 1/2a studies.
Acta Oncol. 2017; 56(1):46-51 [PubMed] Related Publications
BACKGROUND: Docetaxel in combination with cisplatin and 5-fluorouracil (5-FU) is one of several standard chemotherapy regimens for patients with advanced gastro-esophageal adenocarcinoma (aGEA) in Europe. To enable outpatient treatment, we evaluated the maximum tolerated dose (MTD), recommended dose (RD), dose limiting toxicity (DLT) and safety of docetaxel in combination with oxaliplatin (O) and S-1 (DOS) in Caucasian patients with aGEA.
METHODS: We present final results of two parallel phase 1/2a studies (3 + 3 design). Escalating doses of docetaxel and S-1 with fixed dose O were given for 18 weeks every second week (DOS2w) or every third week (DOS3w) followed by S-1 maintenance therapy.
RESULTS: Thirty-four patients (18 in DOS2w and 16 in DOS3w) were enrolled between October 2013 and June 2015. Median age was 65 years (range 49-78). DLT was most often febrile neutropenia. Most common severe non-hematological adverse events were diarrhea (9%) and fatigue (6%). The RD of DOS3w was: docetaxel 50 mg/m(2), O 100 mg/m(2) and S-1 25 mg/m(2) twice daily and of DOS2w was: docetaxel 40 mg/m(2), O 70 mg/m(2) and S-1 35 mg/m(2) twice daily. Overall, response rate was 56%; median progression-free survival was 9.1 months; and median overall survival was 13.2 months in 34 patients.
CONCLUSIONS: At the RD, DOS2w and DOS3w showed an acceptable safety profile in patients with aGEA. Clinical trials ID: NCT-01928524 and EudraCT 2012-005187-10.

Shiraishi O, Yamasaki M, Makino T, et al.
Feasibility of Preoperative Chemotherapy with Docetaxel, Cisplatin, and 5-Fluorouracil versus Adriamycin, Cisplatin, and 5-Fluorouracil for Resectable Advanced Esophageal Cancer.
Oncology. 2017; 92(2):101-108 [PubMed] Related Publications
BACKGROUND: Neoadjuvant chemotherapy for resectable advanced esophageal squamous cell carcinoma (ESCC) requires reassessment. We have conducted a trial aiming at the comparison between DCF and ACF concerning perioperative adverse events.
METHODS: Patients were randomly assigned to receive either DCF [docetaxel 70 mg/m2, cisplatin 70 mg/m2 on day 1, and 5-fluorouracil (5-FU) 700 mg/m2 for 5 days] every 3 weeks or ACF (adriamycin 35 mg/m2, cisplatin 70 mg/m2 on day 1, and 5-FU 700 mg/m2 for 7 days) every 4 weeks. Each group consisted of 81 patients. Two cycles of preoperative chemotherapy were planned, after which patients underwent subtotal esophagectomy via a right thoracotomy with lymphadenectomy. Chemotherapy- and surgery-related adverse effects were assessed.
RESULTS: Grade 3-4 neutropenia and febrile neutropenia occurred in 90 and 39% of patients, respectively, in the DCF group compared with 69 and 17% of patients, respectively, in the ACF group (p < 0.01). Perioperative complications did not differ significantly between the groups. The overall response rates of DCF and ACF were 61 and 40%, respectively, while the histopathological complete responses were 15 and 3%, respectively (p < 0.01).
CONCLUSION: The DCF and ACF regimens were found to be equally feasible in patients with resectable advanced ESCC; however, DCF delivered an antitumor effect and therefore potentially improved the long-term outcomes.

Foukakis T, von Minckwitz G, Bengtsson NO, et al.
Effect of Tailored Dose-Dense Chemotherapy vs Standard 3-Weekly Adjuvant Chemotherapy on Recurrence-Free Survival Among Women With High-Risk Early Breast Cancer: A Randomized Clinical Trial.
JAMA. 2016; 316(18):1888-1896 [PubMed] Related Publications
Importance: Standard dosing of chemotherapy based on body surface area results in marked interpatient variation in pharmacokinetics, toxic effects, and efficacy. Whether tailored dosing can improve outcomes is unknown, as is the role of dose-dense adjuvant chemotherapy.
Objective: To determine whether tailored dose-dense adjuvant chemotherapy improves the outcomes of early breast cancer compared with a standard 3-weekly chemotherapy schedule.
Design, Setting, and Participants: A randomized, open-label, phase 3 trial of women aged 65 years and younger who had surgery for nonmetastatic node-positive or high-risk node-negative breast cancer at 86 sites in Sweden, Germany, and Austria between February 20, 2007, and September 14, 2011.
Interventions: Patients were randomized 1:1 either to 4 cycles of leukocyte nadir-based tailored and dose-dense adjuvant epirubicin and cyclophosphamide every 2 weeks followed by 4 cycles of tailored dose-dense docetaxel every 2 weeks, or to standard-interval chemotherapy with 3 cycles of fluorouracil and epirubicin-cyclophosphamide every 3 weeks followed by 3 cycles of docetaxel every 3 weeks.
Main Outcomes and Measures: The primary end point was breast cancer recurrence-free survival (BCRFS). Secondary end points included 5-year event-free survival (EFS), distant disease-free survival (DDFS), overall survival (OS), and rates of grade 3 or 4 toxic effects.
Results: Among 2017 randomized patients (1006 in the tailored dose-dense group and 1011 in the control group; median [IQR] age, 51 [45-58] years; 80% with hormone receptor-positive tumors; 97% with node-positive disease), 2000 received study treatment (≥1 cycle of chemotherapy; 1001 in the tailored dose-dense group and 999 in the control group). After a median follow-up of 5.3 years (IQR, 4.5-6.1 years), 269 BCRFS events were reported, 118 in the tailored dose-dense group and 151 in the control group (HR, 0.79; 95% CI, 0.61-1.01; log-rank P = .06; 5-year BCRFS, 88.7% vs 85.0%). The tailored dose-dense group had significantly better EFS than the control group (HR, 0.79; 95% CI, 0.63-0.99; P = .04; 5-year EFS, 86.7% vs 82.1%). The groups did not differ in OS (HR, 0.77; 95% CI, 0.57-1.05; P = .09; 5-year OS, 92.1% vs 90.2%) or DDFS (HR, 0.83; 95% CI, 0.64-1.08; P = .17; 5-year DDFS, 89.4% vs 86.7%). Grade 3 or 4 nonhematologic toxic effects occurred in 527 (52.6%) in the tailored dose-dense group and 366 (36.6%) in the control group.
Conclusions and Relevance: Among women with high-risk early breast cancer, the use of tailored dose-dense chemotherapy compared with standard adjuvant chemotherapy did not result in a statistically significant improvement in breast cancer recurrence-free survival. Nonhematologic toxic effects were more frequent in the tailored dose-dense group.
Trial Registration: clinicaltrials.gov Identifier: NCT00798070; isrctn.org Identifier: ISRCTN39017665.

Uemura H, Matsubara N, Kimura G, et al.
Patient preferences for treatment of castration-resistant prostate cancer in Japan: a discrete-choice experiment.
BMC Urol. 2016; 16(1):63 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Up to a fifth of patients diagnosed with prostate cancer (PC) will develop castration-resistant prostate cancer (CRPC), which has been associated with a poor prognosis. The aim of this study was to consider the patient perspective as part of the overall treatment decision-making process for CRPC, given that an alignment between patient preference and prescribing has been shown to benefit patient outcomes. This study examines preferences of patients with CRPC in Japan for treatment features associated with treatments like RA-223, abiraterone, and docetaxel and to examine the extent to which treatment preferences may vary between symptomatic and asymptomatic patients.
METHODS: A two-phase research approach was implemented. In Phase 1, N = 8 patients with CRPC were recruited from a single hospital to complete a qualitative interview to provide feedback on the draft survey. In Phase 2, N = 134 patients with CRPC were recruited from five hospitals to complete a paper survey. The survey included 6 treatment choice questions, each asking patients to choose between two hypothetical treatments for their CRPC. Each treatment alternative was defined by the following attributes: length of overall survival (OS), time to a symptomatic skeletal event (SSE), method of administration, reduction in the risk of bone pain, treatment-associated risk of fatigue and lost work days. A hierarchical Bayesian logistic regression was used to estimate relative preference weights for each attribute level and mean relative importance.
RESULTS: A total of N = 133 patients with CRPC completed the survey and were included in the final analysis. Patients had a mean age of 75.4 years (SD = 7.4) and had been diagnosed with PC a mean of 6.5 years prior (SD = 4.4). Over the attribute levels shown, fatigue (relative importance [RI] = 24.9 %, 95 % CI: 24.7 %, 25.1 %) was the most important attribute, followed by reduction in the risk of bone pain (RI = 23.2 %, 95 % CI: 23.0 %, 23.5 %), and OS (RI = 19.2 %, 95 % CI: 19.0 %, 19.4 %). Although symptomatic patients placed significantly more importance on delaying an SSE (p < .05), no other preference differences were observed.
CONCLUSIONS: CRPC patients were more concerned about reduced quality of life from side effects of treatment rather than extension of survival, which may have implications for shared decision-making between patients and physicians.

Asaka S, Shimakawa T, Yamaguchi K, et al.
The Influence of Neoadjuvant Chemotherapy with Docetaxel, Nedaplatin and 5-Fluorouracil After Esophagectomy.
Anticancer Res. 2016; 36(11):6165-6171 [PubMed] Related Publications
BACKGROUND: Neoadjuvant chemotherapy (NAC) with docetaxel, nedaplatin and 5-fluorouracil (5-FU) in esophageal cancer may adversely affect the postoperative clinical course following esophagectomy.
PATIENTS AND METHODS: We investigated the perioperative white blood cell count (WBC), C-reactive protein (CRP), serum albumin, body temperature (BT), heart rate (HR), respiratory rate (RR), water balance, partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FiO2) ratio, postoperative complications and systemic inflammatory response syndrome (SIRS) in patients who underwent NAC or surgery alone (SA group).
RESULTS: In the NAC group, the preoperative WBC (p=0.015) and postoperative day (POD) 3 BT (p=0.049), as well as RR (p=0.037) were lower, whereas the POD 2 PaO2/FiO2 ratio was higher (p=0.047), compared to the SA group. No differences in the incidence of postoperative complications and SIRS were observed between the groups.
CONCLUSION: NAC using docetaxel, nedaplatin and 5-fluorouracil was tolerated and feasible in esophageal cancer.

Kato H, Furuya Y, Miyazawa Y, et al.
Consequences of an Early PSA Response to Enzalutamide Treatment for Japanese Patients with Metastatic Castration-resistant Prostate Cancer.
Anticancer Res. 2016; 36(11):6141-6149 [PubMed] Related Publications
BACKGROUND/AIM: Recent studies have shown that an early prostate-specific antigen (PSA) response to androgen receptor (AR)-targeting agents in metastatic castration-resistant prostate cancer (mCRPC) is associated with a better prognosis. We analyzed early PSA response to enzalutamide and oncological outcomes to study their prognostic significance in the Japanese population.
PATIENTS AND METHODS: Fifty-one patients with mCRPC (26 of pre-docetaxel and 25 of post-docetaxel status) were treated with enzalutamide. The PSA progression-free survival (PFS), radiographic PFS (rPFS) and overall survival (OS) were assessed. The association of rPFS and OS in patients with an early PSA response at 4 weeks after commencement of enzalutamide was studied.
RESULTS: Early PSA responses were significantly associated with a longer rPFS (median of 47.9 vs. 20.1 weeks, p<0.001, in patients exhibiting a 50% PSA response; median of 40.9 vs. 20.1 weeks, p=0.016, in patients exhibiting a 30% PSA response). OS was also significantly associated with an early PSA response (p=0.002 for patients exhibiting a 50% PSA response, p=0.003 for patients exhibiting a 30% PSA response). Multivariate analysis showed that the predictors of a 50% PSA response were an interval to mCRPC and a docetaxel treatment history, while the predictor of a 30% PSA response was a docetaxel treatment history. Furthermore, a 50% PSA response was independently prognostic of rPFS.
CONCLUSION: An early PSA response to enzalutamide was significantly associated with a longer rPFS and OS. This information will aid in the management of patients treated with enzalutamide.

Liguigli W, Tomasello G, Toppo L, et al.
Safety and efficacy of dose-dense chemotherapy with TCF regimen in elderly patients with locally advanced or metastatic gastric cancer.
Tumori. 2017; 103(1):93-100 [PubMed] Related Publications
PURPOSE: To evaluate the efficacy and safety of dose-dense TCF in elderly (≥65 years) compared to younger patients.
METHODS: Safety and efficacy data relative to 119 consecutive patients with locally advanced or metastatic gastric cancer treated at our institution and enrolled in different phase II trials were retrospectively collected. All patients were treatment-naive and received docetaxel 70 mg/m2 day 1, cisplatin 60 mg/m2 day 1, l-folinic acid 100 mg/m2 days 1-2, followed by 5-fluorouracil 400 mg/m2 bolus days 1-2, and then 600 mg/m2 as a 22-hour continuous infusion days 1-2, every 14 days, plus pegfilgrastim 6 mg on day 3. Sixty patients (50%) aged ≥65 years received the same schedule with a dose reduction by 30%.
RESULTS: A total of 86% of patients were evaluable for response and all for toxicity. In patients aged ≥65 years, we observed an overall response rate of 51%. Median overall survival was 11.2 (95% confidence interval [CI] 7.3-15.1) and 11.8 months (95% CI 9.2-16.2) in elderly and younger patients, respectively. In the elderly patients, the most frequent grade 3-4 toxicities were neutropenia (13%), leukopenia (7%), thrombocytopenia (18%), anemia (3%), and febrile neutropenia (8%); in the younger patients, neutropenia (56%), leucopenia (31%), thrombocytopenia (22%), anemia (15%), and febrile neutropenia (15%).
CONCLUSIONS: Elderly patients can be safely treated with a dose-dense TCF regimen with a 30% dose reduction achieving similar efficacy results as younger patients with lesser toxicity.

Matsuoka A, Mitsuma A, Maeda O, et al.
Quantitative assessment of chemotherapy-induced peripheral neurotoxicity using a point-of-care nerve conduction device.
Cancer Sci. 2016; 107(10):1453-1457 [PubMed] Free Access to Full Article Related Publications
Chemotherapy-induced peripheral neurotoxicity (CIPN) seriously impairs patients' quality of life cumulatively and dose-dependently. Because assessment of CIPN usually depends on patients' subjective evaluation of symptoms, objective and quantitative measures are needed. We evaluated a point-of-care nerve conduction device (POCD), previously validated for the assessment of diabetic peripheral neuropathy. Sensory nerve action potential (SNAP) amplitude and sensory nerve conduction velocity (SNCV) of the sural nerve were measured using a portable, automated POCD (DPNCheck; NeuroMetrix Inc., Waltham, MA, USA) in patients with a clinical diagnosis of CIPN of grade 1 or higher. We compared SNAP and SNCV among patients with different grades of CIPN according to the Common Terminology Criteria for Adverse Events. A total of 50 patients (22 men, 28 women; median age, 64 years; grade 1/2/3, 21/18/11) were evaluated. Anticancer drugs responsible for CIPN were cisplatin in five patients, oxaliplatin in 15, carboplatin in 5, paclitaxel in 16, docetaxel in 14, nab-paclitaxel in 7, vincristine in 6, and bortezomib in 3. Unadjusted SNAP was 8.45 ± 3.67 μV (mean ± SD) in patients with grade 1 CIPN, 5.42 ± 2.68 μV with grade 2, and 2.45 ± 1.52 μV with grade 3. Unadjusted SNCV was 49.71 ± 4.77 m/s in patients with grade 1 CIPN, 48.78 ± 6.33 m/s with grade 2, and 44.14 ± 7.31 m/s with grade 3. The adjusted SNAP after controlling for age significantly differed between each CTCAE grade (P < 0.001, ancova). The adjusted SNCV after controlling for age and height also differed significantly (P = 0.027). Differences in the severity of CIPN could be detected objectively and quantitatively using this POCD.

Akladios C, Baldauf JJ, Marchal F, et al.
Does the Number of Neoadjuvant Chemotherapy Cycles before Interval Debulking Surgery Influence Survival in Advanced Ovarian Cancer?
Oncology. 2016; 91(6):331-340 [PubMed] Related Publications
OBJECTIVE: To evaluate the overall survival (OS) of patients with initially inoperable advanced ovarian cancer, tubal carcinoma, or primary peritoneal carcinoma of stages III or IV undergoing neoadjuvant chemotherapy (NAC) followed by cytoreductive surgery, according to the number of cycles performed.
METHODS: This retrospective study was conducted in three main oncology centres in the east of France, reviewing the charts of all patients who underwent NAC between January 1, 1998 and October 31, 2012. We performed an OS analysis using multivariate Cox regression models adjusted for potential confounders. We also analysed progression-free survival (PFS) as well as chemotherapy- and surgery-related morbidity.
RESULTS: Of the 204 patients included, 75 (36.8%) underwent ≤4 NAC cycles and 129 (63.2%) ≥5 NAC cycles. Characteristic data were similar in the two groups. Five-year OS was 35.0 and 25.8%, respectively. This difference was non-significant [HR = 1.06 (0.70-1.59), p = 0.79]. We also found no differences in PFS or morbidity between the two groups.
CONCLUSIONS: The number of NAC cycles does not seem to play a role in the OS of patients with advanced ovarian cancer. Further evidence and prospective data are needed to assess the value of a high/low number of NAC cycles among these patients.

Zhang Y, Huang Y, Jin Z, et al.
A convenient and effective strategy for the enrichment of tumor-initiating cell properties in prostate cancer cells.
Tumour Biol. 2016; 37(9):11973-11981 [PubMed] Related Publications
Stem-like prostate cancer (PrCa) cells, also called PrCa stem cells (PrCSCs) or PrCa tumor-initiating cells (PrTICs), are considered to be involved in the mediation of tumor metastasis and may be responsible for the poor prognosis of PrCa patients. Currently, the methods for PrTIC sorting are mainly based on cell surface marker or side population (SP). However, the rarity of these sorted cells limits the investigation of the molecular mechanisms and therapeutic strategies targeting PrTICs. For PrTIC enrichment, we induced cancer stem cell (CSC) properties in PrCa cells by transducing three defined factors (OCT3/4, SOX2, and KLF4), followed by culture with conventional serum-containing medium. The CSC properties in the transduced cells were evaluated by proliferation, cell cycle, SP assay, drug sensitivity technology, in vivo tumorigenicity, and molecular marker analysis of PrCSCs compared with parental cells and spheroids. After culture with serum-containing medium for 8 days, the PrCa cells transduced with the three factors showed significantly enhanced CSC properties in terms of marker gene expression, sphere formation, chemoresistance to docetaxel, and tumorigenicity. The percentage of CD133(+)/CD44(+) cells was ninefold higher in the transduced cell population than in the adherent PC3 cell population (2.25 ± 0.62 vs. 0.25 ± 0.12 %, respectively), and the SP increased to 1.22 ± 0.18 % in the transduced cell population, but was undetectable in the adherent population. This method can be used to obtain abundant PrTIC material and enables a complete understanding of PrTIC biology and development of novel therapeutic agents targeting PrTICs.

Tamura T, Hirata T, Tabata M, et al.
A Phase I Trial of 100 mg/m2 Docetaxel in Patients with Advanced or Recurrent Breast Cancer.
Acta Med Okayama. 2016; 70(5):425-427 [PubMed] Related Publications
Docetaxel is a standard treatment for patients with advanced or recurrent breast cancer. The recommended dose is 60 to 100 mg/m2. Previous study have shown that the tumor response rates of patients who received docetaxel monotherapy at doses of 60, 75, and 100 mg/m2 were 22.1% , 23.3% , and 36.0% , respectively, and there was a significant relationship between the dose and response. In Europe and the United States, docetaxel is approved at a dose of 100 mg/m2, and Japanese guidelines also recommend a dose of 100 mg/m2. However, the approved dose in Japan is up to 75 mg/m2. We have launched a phase I trial evaluating 100 mg/m2 docetaxel in patients with advanced or relapsed breast cancer. The major eligibility criteria are as follows: age 20 years, pathologically diagnosed breast cancer, recurrent or advanced breast cancer, a good performance status, and HER2 [human epidermal growth factor receptor 2] negative. The primary endpoint is demonstrated safety of 100 mg/m2 docetaxel. This study will clarify whether 100mg/m2 docetaxel can be administrated safely in Japanese patients with advanced or recurrent breast cancer.

Ai J, Li W, Zeng R, et al.
Blockage of SSRP1/Ets-1/Pim-3 signalling enhances chemosensitivity of nasopharyngeal carcinoma to docetaxel in vitro.
Biomed Pharmacother. 2016; 83:1022-1031 [PubMed] Related Publications
Nasopharyngeal carcinoma (NPC) is a rare cancer in most parts of the world, but is prevalent in South China area. Besides, therapeutic outcome is still unsatisfactory for patients with refractory and relapsed NPC, even though receiving a second line of docetaxel-based chemotherapy. These reasons require a better understanding of mechanisms underlying the carcinogenesis, malignancy and chemoresistance. In the basis of our previous finding of SSRP1 over-expression in NPC cell lines, this study continuously discovered up-regulated Ets-1, phosphor-Ets-1 and Pim-3 in NPC tissues with immunohistochemistry assay and revealed a close correlation of these up-regulated proteins with NPC proliferation and invasion. Using gene-silencing technology followed by western blot and immunocytochemistry detections, SSRP1 was found to facilitate the translocation of phosphor-Ets-1 from cytoplasm to cell nucleus, but have marginal effect on Ets-1 expression and phosphorylation. Pim-3 was positively regulated by Ets-1. In NPC HNE-1 cells, all SSRP1, Ets-1 and Pim-3 knockdown diminished the cell proliferation, enhanced the apoptosis, as well as inhibited the autophagy, invasion and clonogenicity in the presence or absence of docetaxel at IC25. Exposure of HNE-1 cells to docetaxel (IC25) alone had modest effect on cell proliferation and autophagy, and was not as effective as docetaxel treatment after knockdown of SSRP1, Ets-1 or Pim-3 on induction of the apoptosis and on inhibition of the invasion and clonogenicity. Our data indicate that SSRP1/Ets-1/Pim-3 signalling is tightly associated with the proliferation, apoptosis, autophagy, invasion and clonogenicity of NPC cells, and blockage of this signalling facilitates chemosensitivity of the cells to docetaxel.

Yamada Y, Matsubara N, Tabata KI, et al.
Abiraterone acetate after progression with enzalutamide in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer: a multi-center retrospective analysis.
BMC Res Notes. 2016; 9(1):471 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Both abiraterone acetate (AA) and enzalutamide are promising agents for patients with pre- and post-chemotherapy metastatic castration-resistant prostate cancer (mCRPC). Several retrospective analysis suggested clinical cross-resistance between these agents in patients previously treated with docetaxel. However, data on the antitumor activity of AA as a second androgen receptor-targeting new agent after the failure of enzalutamide in chemotherapy-naive mCRPC patients is unavailable.
METHODS: Patients with chemotherapy-naïve mCRPC who were treated with AA after disease progression with enzalutamide, were retrospectively reviewed at five institutions. Primary outcome measure was the rate of any prostate-specific antigen (PSA) decline. Secondary outcome measures were progression-free survival (PFS) and overall survival (OS) with subsequent AA treatment. We also performed correlation analysis between previous PSA response, PFS duration to enzalutamide and subsequent PSA response, PFS duration to AA.
RESULTS: A total of 14 patients were identified. Any PSA declines and PSA decline ≥50 % with AA treatment, were observed in 36 and 7 % of patients, respectively. Median PFS with initial enzalutamide was 5.0 months (95 % CI 3.7-6.4 months), and for subsequent AA treatment was 3.4 months (95 % CI 0.8-6.0 months). Median OS from initiation of AA was 9.1 months (95 % CI 5.6-12.5 months). No significant correlations were observed between these PSA responses (Pearson r = -0.67, p = 0.82) and PFS duration (Kendall tau r = 0.33, p = 0.87).
CONCLUSIONS: The PSA decline with subsequent AA treatment in chemotherapy-naive mCRPC patients after a failure of enzalutamide was modest, however, the PFS and OS with subsequent AA treatment were comparable to those of enzalutamide previously reported as a second androgen receptor-targeting new agent after AA failure. The PSA response and PFS duration to previous enzalutamide treatment did not predict those of subsequent AA treatment.

Dinh JA, Baker D, Chahal M
Therapy Update for Metastatic Castration-Resistant Prostate Cancer.
Consult Pharm. 2016; 31(10):581-592 [PubMed] Related Publications
OBJECTIVE: To provide an overview of the efficacy, tolerability, drug interactions, dosing, and administration issues associated with enzalutamide, abiraterone, and radium-223 for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).
DATA SOURCES: MEDLINE and Web of Science were used to search for relevant articles using a key-word search (enzalutamide, abiraterone, radium-223, and phase 3). No restriction was placed on the date of publication.
STUDY SELECTION/DATA EXTRACTION: Located articles were reviewed and selected based on their relevance to the treatment of mCRPC. Articles were selected if they focused on double-blind, randomized controlled, phase 3 studies conducted in humans and published in English. Other resources were used for the information pertaining to the drug's mechanism of action, administration, drug interactions, and adverse effects. Data extraction for the clinical application (e.g., efficacy, adverse reactions, and monitoring) was obtained from the identified clinical trials and the drug's approved labeling by one of the authors and validated by a second author.
DATA SUMMARY: Abiraterone, enzalutamide, and radium-223 have been shown to improve radiographic progression-free survival and overall survival before or after treatment with docetaxel. Abiraterone and enzalutamide has been able to delay time to the initiation of docetaxel. Major adverse effects vary with these medications. Enzalutamide-based therapy was associated with increased risk of seizures. Abiraterone-based therapy was associated with increased mineralocorticoid excess. Radium-223-based therapy was associated with increased risk of myelosuppression.
CONCLUSION: In clinical trials, abiraterone, enzalutamide, and radium-223 improved the radiographic progression-free survival and overall survival in patients with mCRPC compared with placebo. Each drug has unique adverse effects requiring monitoring of routine laboratory tests and for severe associated symptoms. To better define the role of these drugs in the treatment of mCRPC, clinical trials designed to directly compare these drugs' survival rate is necessary.

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