Sequential Arm Research Articles

Validity Of The Ihealth-bp7 And Withings-bp800 Self-measurement Blood Pressure Monitors

Blood pressure (BP) control among treated people with hypertension remains poor. Home BP monitoring devices have led to their widespread adoption, and are now consistently utilized for the evaluation and management of hypertension. Classifying individual’s risk associated with BP should be monitored using accurate BP measurement devices. However, little is known about the validity of the newly developed iHealth-BP7 and Withings-BP800 devices. PURPOSE: The purpose of this study is to validate the wireless iHealth-BP7 and Withings-BP800 monitors according to the European Society of Hypertension (ESH) International Protocol revision 2010. METHODS: Data from 11 participants (31.6 ± 2.2 years) were initially examined according to the ESH International Protocol revision 2010 for the validation of BP measuring devices in adults. Participants were asked to sit and relax for 10-15 mins with legs uncrossed, and back supported prior to the test. In all participants, sequential left arm measurements were performed by two trained observers using a mercury sphygmomanometer and one supervisor using the device. Collected data were screened according to the ESH protocol for both systolic BP (SBP) and diastolic BP (DBP). ESH International Protocol requires 33 subjects, but currently only 11 subjects participated in this study. Thus, the adjusted criteria of the protocol were applied to establish the standard for the 11 subjects. RESULTS: The mean differences between the monitor and sphygmomanometer readings were -0.55±3.75 (SBP) and 0.54±3.62 (DBP) for iHealth-BP7 and 3.18±4.37 (SBP) and -0.35±5.42 (DBP) for Withings-BP800. The iHealth-BP7 monitor passed all of the modified requirements, however the Withings-BP800 did not meet the last phase of the modified criteria of the ESH international protocol. CONCLUSION: The iHealth-BP7 monitor is recommended as a valid home BP monitoring device, however the Withings-BP800 fails to meet the ESH criteria in this study potentially due to the small sample size. Since the ESH protocol requires 33 subjects, further study with additional participants is warranted to determine validation of both devices.

Abstract P1-12-02: Effect of using LHRH analog during chemotherapy (CT) on premature ovarian failure and prognosis in premenopausal patients with early-stage, hormone receptor-positive breast cancer: The primary analysis of a randomized controlled phase III trial

Abstract Background: Whether administration of LHRH analog during CT in premenopausal patients with early-stage, hormone receptor-positive disease would reduce CT-induced premature ovarian failure (POF) is still controversial. Moreover, whether LHRH analog would influence the prognosis of patients is unknown yet. This randomized study is to evaluate whether administration of LHRH analog during CT would reduce POF and effect the prognosis of breast cancer. Methods: This is arandomized, controlled phase III clinical trial. Premenopausal patients age <46 with stage I-IIIA, ER/PR-positive BC to be treated with CT were randomized into two arms. Concurrent arm received CT with goserelin (GN) 3.6 mg SQ starting 0-7 days prior to the first CT dose, and after CT, the researchers determined whether continuous GN to 2-5years or cessation. Sequential arm received CT without GN, and after CT, the researchers determined GN 2-5 years immediately or after restoration of ovarian function or bilateral ovariectomy. Neoadjuvant CT was allowed. Five-year tamoxifen after CT was administered to all patients. The primary endpoint is POF, defined as amenorrhea for the prior 12 months and post-menopausal FSH or not assessed after last CT dose or last GN dose. Other endpoints include efficacy of neoadjuvant CT and relapse-free survival (RFS), defined as time to the first of these events: loco-regional recurrence, contralateral breast cancer or distant metastasis. Results: Between 2/09 and 5/13, the trial has finished enrollment, 216 patients were enrolled. The median age were 37.5 in combined arm (n=108) and 39 in sequential arm (n=108), respectively. The median follow-up time was 27.4 months and 25.7 months, respectively. 15 patients and 21 patients received neoadjuvant CT, respectively. There were no significant difference in age, tumor stage and CT regimens (p>.05). The median cycles of GN were 25, respectively. 47% had complete primary endpoint data. POF rate were 5/42 (11.9%) in the combined arm and 16/60 (26.7%) in the sequential arm. POF rate (and post-menopausal FSH) rate were 1/42 (2.4%) in the combined arm and 8/60 (13.3%) in the sequential arm. In neoadjuvant CT subgroup, each has 1 patient achieved pathological complete remission, and there was no significant difference in objective clinical response. There were 9 patients in the combined arm and 3 patients in the sequential arm had occured RFS events (including 2 and 0 deaths, respectively, OR=3.18, 95%CI:0.84-12.09, P=.075). Conclusions:LHRH analog administration with CT might be associated with less POF and did not affect the efficacy of neoadjuvant CT, however, had no RFS benefit, it may need longer follow-up. We will conduct an interim analysis in November 2014. Clinicaltrials.gov Registry Number: NCT01712893. Citation Format: Jian-Wei Li, Guang-yu Liu, Ke-Da Yu, Ya-jie Ji, Miao Mo, Li Lei, Jiong Wu, Gen-hong Di, Yi-feng Hou, Zhen Hu, Can-ming Chen, Zhen-Zhou Shen, Zhi-Ming Shao. Effect of using LHRH analog during chemotherapy (CT) on premature ovarian failure and prognosis in premenopausal patients with early-stage, hormone receptor-positive breast cancer: The primary analysis of a randomized controlled phase III trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-12-02.

Antiangiogenic therapy in recurrent breast cancer with lymphangitic spread to the chest wall: A randomized phase II trial of bevacizumab with sequential or concurrent oral vinorelbine and capecitabine

ObjectivesTo assess efficacy of bevacizumab in combination with oral chemotherapy in patients with breast cancer with lymphangitic spread to the chest wall (LBC). To identify surrogate biomarkers of response to bevacizumab. Patients and methodsWe randomly assigned patients to receive bevacizumab plus either sequential or concurrent oral vinorelbine and capecitabine every 3 weeks. The primary endpoint was time to ultimate progression (TTP); the response rate and overall survival (OS) were secondary endpoints. We performed gene expression profiling on baseline tissue samples collected from triple negative LBC. We assessed circulating endothelial cells (CEC), circulating endothelial progenitors (CEP) and circulating pericyte progenitors (CPP). ResultsA total of 66 patients were enrolled. There was no difference in TTP (median TTP 5.3 vs. 4.8 months, p = 0.21) and in OS (median OS 15.8 vs 11.9 months; p = 0.25) when comparing concurrent vs sequential treatment, respectively. Response rate was 25% vs 28% in the concurrent vs sequential arm (p = 1.00), respectively. A set of 16 genes predictive of response to bevacizumab was identified. The counts of CEPs and viable CECs below the median value were associated with an improved overall survival: 26.6 vs 9.5 months for CEPs and 22.6 vs 11.0 months for viable CECs, respectively (p = 0.02). ConclusionsOral chemotherapy and bevacizumab (BEVIX) is an active regimen in patients with LBC. We support the importance of using LBC as a biological model for investigating angiogenesis inhibitors. CECs and CEPs biomarkers have been identified as predictive markers of outcome and warrant further investigation.

Prognostic Factors and Survival in Non-Small Cell Lung Cancer Patients Treated with Chemoradiotherapy.

BACKGROUND:According to the literature, performance status, stage-tumor dimension and nodal status, weight loss, were the most important prognostic factors for survival in patients with locally advanced non-small cell lung cancer.AIM:To evaluate the treatment results and the prognostic variables in our patients treated with sequential and concurrent chemoradiotherapy.MATERIAL AND METHODS:In the study 85 patients were randomly assigned to one of the two treatment arms. In the sequential arm, 45 patients had previously received sequential chemotherapy with 4 cycles of and etoposide followed by conformal radiotherapy (RT). In the second concurrent group, 40 patients received concomitant chemotherapy of cisplatine and etoposide and conformal RT, followed by two cycles of consolidation chemotherapy of carboplatine and etoposide. We described all phases of the conformal three dimensional (3-D) RT.RESULTS:From October 2005 to March 2008, 93 patients were enrolled. Eight patients were not eligible, seven had stage IV and one patient had pleural effusion. They were all initially considered to have stage IIIB disease. The median survival was 13 months for the patients in the sequential arm and 19 months for those in the concurrent treatment arm. The differences were statistically significant (log-rank test p=0.0039). The disease-free survival was 9 months in the sequential arm and 16 months in the concurrent treatment group. The differences were statistically significant (log-rank test p=0.0023). We found that the following prognostic factors significantly influenced the survival in lung cancer patients treated with conservative method: - age, p<0.05; - performant status, p<0.001; - weight loss, p<0.001; tumor dimension, p<0.05; and - nodal involvement, p<0.05.CONCLUSION:In our study, the dose-limiting toxicity, esophagitis was reduced by performing conformal radiotherapy. Conformal thoracic radiotherapy and new radiotherapy technics, such as respiratory gated radiotherapy, allow dose escalating and may probably improve survival and local control in lung cancer patients.

Comparison of Sequential Vs Alternating Administration of Bortezomib, Melphalan, Prednisone (VMP) and Lenalidomide Plus Dexamethasone (Rd) in Elderly Pts with Newly Diagnosed Multiple Myeloma (MM) Patients: GEM2010MAS65 Trial

Comparison of Sequential Vs Alternating Administration of Bortezomib, Melphalan, Prednisone (VMP) and Lenalidomide Plus Dexamethasone (Rd) in Elderly Pts with Newly Diagnosed Multiple Myeloma (MM) Patients: GEM2010MAS65 Trial

Cervical length screening: a randomized trial assessing the impact on visit length and patient attitudes.

The purpose of this study was to quantify the time required for transvaginal cervical length measurements during a second-trimester anatomy scan and to evaluate patient attitudes regarding cervical length assessment. Consenting women were randomly assigned to one of the following: (1) standard arm-cervix visualized, no prespecified cervical length measurement; (2) sequential arm-3 transabdominal cervical length measurements obtained, transvaginal sonography performed if images were inadequate or if any measurement was 3 cm or less; and (3) screening transvaginal sonography arm-3 transvaginal cervical length measurements obtained. Times were recorded for the entire examination and cervical length evaluation. Participants completed a questionnaire at the end of their visits. Sixty of 230 eligible women enrolled. Demographic characteristics were similar across groups except for body mass index, which was greater in the sequential arm than the screening arm (mean ± SD, 28.5 ± 7.75 versus 24.7 ± 3.89 kg/m(2); P = .03). There were no differences in total examination times between the 3 arms (24.8 ± 8.59 versus 27.8 ± 8.75 versus 28.5 ± 7.78 minutes; P= .39). There were no differences across groups in participant attitudes regarding examination discomfort or embarrassment. Performing screening transvaginal sonography to measure cervical length did not have a statistically significant impact on the amount of time for completion of the entire examination. Participants had positive responses regarding cervical length assessment by transabdominal and transvaginal sonography.

265PD - Ten-Year Safety and Efficacy Analyses of the Big 02-98 Phase III Trial with an Exploratory Analysis on the Role of Ki67 in Predicting Benefit of Adjuvant Docetaxel in Er Positive Patients

ABSTRACT Aim: The BIG 2-98 is a randomized phase III trial that tested the effect of adding docetaxel with anthracycline-based adjuvant chemotherapy (CT) in women with node-positive breast cancer (BC). here we present the 10 year safety and efficacy analyses and report an exploratory analysis of the predictive value of Ki67 for docetaxel efficacy. Methods: In total, 2,887 patients with node positive BC were randomly assigned to one of four treatments: (I) sequential control: doxorubicin (A, 75 mg/m2) × 4 → CMF; (II) concurrent control: AC × 4 → CMF; (III) A × 3 → docetaxel (T, 100 mg/m2) × 3 → CMF and (IV) : AT (50/75 mg/m2) × 4 → CMF. The primary objective was to evaluate the efficacy of docetaxel regardless of the schedule on disease free survival (DFS). Secondary objectives were toxicity, DFS between sequential arms and concurrent arms, and overall survival (OS). Ki67 expression was centrally evaluated by immunohistochemistry. Tumours with Ki67 ≥14% were considered to have a high proliferation index. Results: After a median follow-up 10.1 years (max 12.9 years) and 1,072 DFS events, docetaxel treatment did not improve DFS or OS compared to control arms (DFS: HR = 0.91, 95% CI = 0.81-1.04; P = 0.16; OS: HR = 0.88, 95% CI = 0.76-1.03; P = 0.11). Similar results were obtained in secondary comparisons where sequential docetaxel was compared with sequential control (DFS: HR = 0.86, 95% CI = 0.72-1.03, P = 0.1; OS: HR = 0.85, 95% CI = 0.68-1.06; P = 0.15) or with concurrent doxorubicin–docetaxel (DFS: HR = 0.88, 95% CI = 0.7-1.01; P = 0.09; OS: HR = 0.84, 95% CI = 0.7-1.01; P = 0.06). Worsening or development of treatment-related neurotoxicity following completion of adjuvant chemotherapy occurred in 1.6% and 1% of patients in the docetaxel and non-docetaxel-based regimens, respectively. Out of 1,492 patients with ER positive BC, central Ki67 evaluation was performed in 1,198 (80.2%), of whom 892 (74.4%) had Ki67 ≥ 14%. In a multivariate model, there was a trend for improved DFS and OS in patients with high Ki67 and treated with docetaxel (HR = 0.79,95% CI = 0.63-1.01; P = 0.05 and HR = 0.76,95% CI = 0.57-1.01; P = 0.06 respectively). Conclusions: At a median follow-up of 10 years, the DFS benefit previously demonstrated with docetaxel is no longer present in node-positive BC patients. However, an exploratory analysis suggested a benefit of docetaxel in patients with highly proliferative ER-positive BC. Disclosure: P. Francis: Travel support from Sanofi; J.P. Crown: Received research funding and speaking honoraria from Sanofi Aventis; M. Piccart: Board member: PharmaMar Consultant (honoraria) : Amgen, Astellas, AstraZeneca, Bayer, Eli Lilly, Invivis, MSD, Novartis, Pfizer, Roche-Genentech, sanofi Aventis, Symphogen, Synthon, Verastem Research grants to my Institute : most companies. All other authors have declared no conflicts of interest.

774P - Stride, a Randomized, Phase 2, Open-Label Study of Sipuleucel-T with Concurrent Vs Sequential Enzalutamide in Metastatic Castration-Resistant Prostate Cancer (Mcrpc)

ABSTRACT Aim: Multiple treatment options exist for patients (pts) with mCRPC, particularly in the setting of early metastasis. Sipuleucel-T, an autologous cellular immunotherapy, and enzalutamide, an androgen receptor inhibitor, are approved in the US and EU for treatment of mCRPC, but data are limited regarding use of these agents in combination. P12-2 (STRIDE; NCT01981122) is an ongoing, randomized, open-label, phase 2 study designed to evaluate concurrent vs sequential administration of sipuleucel-T and enzalutamide. Methods: Pts with asymptomatic or minimally symptomatic mCRPC are randomized 1:1 to receive sipuleucel-T with enzalutamide (160 mg QD for 52 wk) starting 2 wk before (concurrent arm [A]) or 10 wk after (sequential arm [B]) initiation of sipuleucel-T (3 infusions at 2-wk intervals). The primary endpoint is peripheral T cell immune response to PA2024, the immunizing antigen for sipuleucel-T. A secondary endpoint is time to recurrence of elevated serum PSA level. Results: As of April 7, 2014, 30 enrolled pts had completed sipuleucel-T infusions. At baseline, demographic and disease characteristics in arm A (n = 12) and arm B (n = 18) were generally comparable. Sipuleucel-T product parameters (antigen presenting cell [APC] activation, APC count, and total nucleated cell [TNC] count) did not differ significantly between the arms. A prime-boost effect on APCs was evident in both arms, as indicated by greater APC activation at infusions 2 and 3 than at infusion 1. The nature and incidences of adverse events (AEs) appeared to be similar between the arms and consistent with those previously reported with sipuleucel-T and enzalutamide. Overall, AEs occurred in 6 (50%) pts in arm A and 11 (61%) pts in arm B. Within 1 day of sipuleucel-T infusion, AEs occurred in 3 (25%) pts in arm A and 4 (22%) pts in arm B. No treatment-related grade ≥3 AEs were reported. Conclusions: Preliminary data suggest that sipuleucel-T potency, prime-boost, and safety are similar with and without concurrent enzalutamide. Data describing sipuleucel-T-induced peripheral immune responses with concurrent vs sequential enzalutamide will be presented at the meeting. Disclosure: D.P. Petrylak: Consultant or Advisory Role - Dendreon Corporation, Astellas - Self, compensated Corporate-sponsored Research - Dendreon Corporation, Astellas - Self, compensated; D.I. Quinn: Consultant, Honoraria: Dendreon, Medivation, Astellas, Pfizer, Bayer, Aveo, Algeta, Novartis, Amgen, Prometheus, Fresenius, Genentech, Jannsen-Self, compensated Sponsored research: Millenium, Sanofi-Aventis–Self Expert testimony: Medivation, Teva-Self; R. Dreicer: Consultant or Advisory Role: Medivation, Janssen, Dendreon, Roche, Millenium, Sanofi Aventis-Self, compensated Corporate-sponsored research: BIND, Progenics, Roche-Self; E.S. Antonarakis: Consultant or Advisory Role: Dendreon Corporation-Self, compensated Corporate-sponsored Research: Dendreon Corporation-Self; N.D. Shore: Consultant or Advisory Role: Algeta, Astellas, Bayer, Dendreon,Pfizer, Millenium, Janssen, Medivation, Sanofi-Self, compensated; J. Corman: Corporate-sponsored research: Dendreon Corporation-self R. Concepcion: Consultant or Advisory Role: Dendreon, Algeta, Bayer, MDxHealth, Cardinal Health,Chan Soon-Shiong Institute for Advanced Health-Self, compensated Corporate-sponsored Research: Janssen, Dendreon, Medivation, BNIT-Self; C.M. Pieczonka: Stock Ownership: Algeta-Self Consultant or Advisory Role: Dendreon-Self, compensated Honoraria: Dendreon, Astellas-Self; A.C. Stubbs: Employment: Dendreon Corporation-Self, compensated Stock Ownership: Dendreon Corporation-Self; N. Sheikh: Employment: Dendreon Corporation-Self, compensated Stock Ownership: Dendreon Corporation-Self; T. Devries: Employment: Dendreon Corporation Stock Ownership: Dendreon Corporation; A.S. Sandler: Employment: Dendreon Corporation Stock Ownership: Dendreon Corporation; C.G. Drake: Consultant or Advisory Role: Bristol Myers Squibb, Dendreon, Janssen, Pfizer, Roche-Self, compensated Corporate-sponsored Research: Aduro, Bristol Myers Squibb, Janssen-Self.

The influence of spatio-temporal structure on sequential eye and arm movements to remembered visual targets

The influence of spatio-temporal structure on sequential eye and arm movements to remembered visual targets

Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer.

Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m(2) day 1, LV 100 mg/m(2) as 2 h infusion and 5-FU 400 mg/m(2) as bolus, days 1 and 2 followed by 600 mg/m(2)/day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85-1.17; P = 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82-1.18; P = 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively. A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy. ClinicalTrials.gov Identifier: NCT01640782.

Predictive cytokine biomarkers for survival in patients with advanced pancreatic cancer randomized to sequential chemoimmunotherapy comprising gemcitabine and capecitabine (GemCap) followed by the telomerase vaccine GV1001 compared to concurrent chemoimmunotherapy in the TeloVac phase III trial.

4121 Background: The TeloVac trial randomized 1,062 patients with advanced pancreatic cancer to a control chemotherapy Arm1, using GemCap; sequential chemoimmunotherapy Arm 2, GemCap for 8 wks foll...

Improved survival in multidrug-resistant tuberculosis patients receiving integrated tuberculosis and antiretroviral treatment in the SAPiT Trial

The therapeutic effects of antiretroviral treatment (ART) in patients with multidrug-resistant tuberculosis (MDR-TB) and human immunodeficiency virus (HIV) infection have not been established. To assess therapeutic outcomes of integrating ART with treatment for MDR-TB. A subgroup of MDR-TB patients from a randomised controlled trial, the SAPiT (Starting Antiretroviral Therapy at Three Points in Tuberculosis) study, conducted in an out-patient clinic in Durban, South Africa, from 2008 to 2012. Clinical outcomes at 18 months were compared in patients randomised to receive ART within 12 weeks of initiating standard first-line anti-tuberculosis treatment with those who commenced ART after completing anti-tuberculosis treatment. Mycobacterium tuberculosis drug susceptibility results were available in 489 (76%) of 642 SAPiT patients: 23 had MDR-TB, 14 in the integrated treatment arm and 9 in the sequential treatment arm. At 18 months, the mortality rate was 11.9/100 person-years (py; 95%CI 1.4-42.8) in the combined integrated treatment arm and 56.0/100 py (95%CI 18.2-130.8) in the sequential treatment arm (hazard ratio adjusted for baseline CD4 count and whether MDR-TB treatment was initiated: 0.14; 95%CI 0.02-0.94, P = 0.04). Despite the small sample size, the 86% reduction in mortality due to early initiation of ART in MDR-TB patients was statistically significant.

Influence of Prognostic Factors on Survival in Locally Advanced Non-Small Cell Lung Cancer Patients Treated with Combination of Chemoradiotherapy

According to the literature, performance status, stage-tumor dimension and nodal status, weight loss, were the most important prognostic factors for survival in patients with locally advanced non-small cell lung cancer. To evaluate the treatment results and prognostic variables in our patients, study of 85 patients was randomly assigned to one of the two treatment arms. In the sequential arm, 45 patients had previously received sequential chemotherapy with 4 cycles of and etoposide followed by conformal radiotherapy (RT). In the second concurrent group, 40 patients received concomitant chemotherapy of cisplatine and etoposide and conformal RT, followed by two cycles of consolidation chemotherapy of carboplatine and etoposide. We described all phases of the conformal three dimensional (3-D) RT. From October 2005 to April 2008, 85 patients were enrolled. Eight patients were not eligible, seven had stage IV and one patient had pleural effusion. They were all initially considered to have stage IIIB disease. The median survival was 13 months for the patients in the sequential arm and 19 months for those in the concurrent treatment arm. The differences were statistically significant (log-rank test p=0.0039). The disease-free survival was 9 months in the sequential arm and 16 months in the concurrent treatment group. The differences were statistically significant (log-rank test p=0.0023). We found that the following prognostic factors significantly influenced the survival in lung cancer patients treated with conservative method: (1) age: p<0.05; (2) Performance status: p<0.001; (3) Weight loss: p<0.001; (4) Tumor dimension: p<0.05; (5) Nodal involvement: p<0.05 Conclusions: Given the higher toxicity in the concurrent-consolidation schedule, it should be reserved for patients younger than 70 years, having good performance status and minimal weight loss. Also we highly recommend precisely define the stage of disease and the prognostic factors in lung cancer patients for giving better treatment.

Combination versus sequential single agent chemotherapy for metastatic breast cancer

Combination chemotherapy can cause greater tumour cell kill if the drug dose is not compromised, while sequential single agent chemotherapy may allow for greater dose intensity and treatment time, potentially meaning greater benefit from each single agent. In addition, sequentially using single agents might cause less toxicity and impairment of quality of life, but it is not known whether this might compromise survival time. To assess the effect of combination chemotherapy compared to the same drugs given sequentially in women with metastatic breast cancer. We searched the Cochrane Breast Cancer Group Specialised Register, using the search terms "advanced breast cancer" and "chemotherapy", MEDLINE and EMBASE on 31 October 2013. The World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov were also searched (22 March 2012). Randomised controlled trials of combination chemotherapy compared to the same drugs used sequentially in women with metastatic breast cancer in the first-, second- or third-line setting. Two authors independently extracted data from published trials. Hazard ratios (HR) were derived from time-to-event outcomes where possible, and a fixed-effect model was used for meta-analysis. Response rates were analysed as dichotomous variables (risk ratios (RR)), and toxicity and quality of life data were extracted where available. Twelve trials reporting on nine treatment comparisons (2317 patients randomised) were identified. The majority of trials (10 trials) had an unclear or high risk of bias. Time-to-event data were collected for nine trials for overall survival and eight trials for progression-free survival. All 12 trials reported results for tumour response. In the 12 trials there were 1023 deaths in 2317 women randomised. There was no difference in overall survival, with an overall HR of 1.04 (95% confidence interval (CI) 0.93 to 1.16; P = 0.45), and no significant heterogeneity. This result was consistent in the four subgroups analysed (risk of bias, line of chemotherapy, type of schema of chemotherapy, and relative dose intensity). In particular, there was no difference in survival according to the type of schema of chemotherapy, that is whether chemotherapy was given on disease progression or after a set number of cycles. In the eight trials that reported progression-free survival, 678 women progressed out of the 886 women randomised. The combination arm had a higher risk of progression than the sequential arm (HR 1.16; 95% CI 1.03 to 1.31; P = 0.01) with no significant heterogeneity. This result was consistent in all subgroups. Overall tumour response rates were higher in the combination arm (RR 1.13; 95% CI 1.03 to 1.24; P = 0.008) but there was significant heterogeneity for this outcome across the trials. In the seven trials that reported treatment-related deaths, there was no significant difference between the two arms, although the CIs were very wide due to the small number of events (RR 1.53; 95% CI 0.71 to 3.29; P = 0.28). The risk of febrile neutropenia was higher in the combination arm (RR 1.32; 95% CI 1.06 to 1.65; P = 0.01). There was no statistically significant difference in the risk of neutropenia, nausea and vomiting, or treatment-related deaths. Overall quality of life showed no difference between the two groups, but only three trials reported this outcome. Sequential single agent chemotherapy has a positive effect on progression-free survival, whereas combination chemotherapy has a higher response rate and a higher risk of febrile neutropenia in metastatic breast cancer. There is no difference in overall survival time between these treatment strategies, both overall and in the subgroups analysed. In particular, there was no difference in survival according to the schema of chemotherapy (giving chemotherapy on disease progression or after a set number of cycles) or according to the line of chemotherapy (first-line versus second- or third-line). Generally this review supports the recommendations by international guidelines to use sequential monotherapy unless there is rapid disease progression.

Comparison Of Sequential Vs Alternating Administration Of Bortezomib, Melphalan and Prednisone (VMP) and Lenalidomide Plus Dexamethasone (Rd) In Elderly Patients With Newly Diagnosed Multiple Myeloma (MM) Patients: GEM2010MAS65 Trial

BackgroundVMP and Rd are two of the most efficient and widely accepted regimens in the treatment of elderly newly diagnosed MM patients. In order to further improve the outcome of elderly patients, one possibility would be to use regimens including all these drugs simultaneously, but this may result into high toxicity. Alternatively, the use of these regimens (VMP and Rd) in a sequential or alternating scheme could improve the treatment of elderly patients. We hypothesized the alternating scheme would minimize the emergence of resistant clones, and would reduce the cumulative toxicity. In order to test this hypothesis we decided to compare VMP and RD in a sequential vs an alternating scheme. Patients and methods241 patients were randomized to receive a sequential scheme consisting on 9 cycles of VMP followed by 9 cycles of Rd or the same regimens in an alternating approach (one cycle of VMP alternating with one Rd (half of the patients started by VMP and half by Rd) up to 18 cycles). VMP included the iv administration of bortezomib 1.3 mg/m2 twice weekly for 1 six-weeks cycle, followed by once weekly for 8 four-weeks cycles in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1–4 of each cycle. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly. Results121 patients were allocated to receive the sequential scheme and 120 the alternating regimen. Both arms were well balanced according to the baseline characteristics. 52% patients in the sequential arm and 55% in the alternating and had high risk cytogenetic abnormalities (t(4;14), t(14;16), del17p or 1q gains). After 9 cycles of treatment, in the sequential arm, 35 out of 66 (54%) achieved at least VGPR vs 51 out of 65 patients (78%) in the alternating arm (p=0.002), including sCR/CR rate of 28% vs 38% in the sequential and alternating arms, respectively (p=NS). Seven patients in each arm achieved immunophenotypic CR. Moreover, while four patients progressed in the sequential arm under treatment with VMP, no patients in the alternating scheme developed disease progression during the first 9 cycles,After a median follow up of 12 months, there was a trend for shorter TTP in the sequential as compared with the alternating scheme (18 m-TTP of 83% vs 89% (p=NS)). In terms of OS, 83% of patients in the sequential arm were alive at 18 m versus 93% in the alternating (p=NS). Patients who achieved sCR/CR had a significantly longer 18 m-TTP as compared with patients who didn't achieve it in both sequential (100% vs 71%; p=0.006) and alternating arms (100% vs 79%; p=0.006) and this translated into a significant benefit in OS. No differences were observed in overall response rates and CR rates in standard and high risk patients. The 18 m-TTP was similar in standard and high risk groups in both sequential (86% vs 81%) and alternating arms (84% vs 94%), noting that 94% of patients receiving the alternating scheme were progression-free at 18 months.Regarding hematologic toxicity, the frequency of G3-4 neutropenia was slightly lower in the sequential than in the alternating arm (16% and 23%) and the same trend was observed for G3-4 thrombocytopenia (16% vs 20%). Concerning non-hematologic toxicity, 5% and 4% of the patients in the sequential and alternating arms developed G3-4 infections, respectively; the rate of G3-4 skin rash was 4% in the sequential and 3% in the alternating arm; 4% of patients in the sequential arm developed G3-4 peripheral neuropathy and 3% in the sequential arm. The rate of grade 3-4 thrombotic events was 2% in both arms. Nevertheless, the detailed evaluation of the toxicity will be done at the completion of the trial when all patients will have received the same amount of drugs in either a sequential or an alternating scheme (at the present time, 42 patients in the sequential arm were not yet at risk for the development of lenalidomide-related side effects). ConclusionsThe administration of melphalan, bortezomib, lenalidomide and steroids in elderly MM patients in a sequential or alternating scheme is feasible. Although longer follow-up is necessary, the alternating scheme may be superior in terms of response rate and outcome, as result of the early exposure of the plasma cell to different agents. Toxicity profile is acceptable. Aparently both schemes of therapy seems to overcome the poor prognosis of high risk cytogenetic. Disclosures:Mateos:Janssen, Celgene: Honoraria. Off Label Use: Lenalidomide plus dexamethasone is not approved for newly diagnosed MM patients. Ocio:Onyx: Consultancy, Research Funding; Novartis: Consultancy; Array Biopharma: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding. San Miguel:Janssen, Celgene: Membership on an entity's Board of Directors or advisory committees.

Phenotypic and Genomic Analysis Of Multiple Myeloma (MM) Minimal Residual Disease (MRD) Clonal Plasma Cells (PCs)

MRD monitoring is emerging as a powerful prognostic biomarker in MM. In addition to its utility to redefine the depth of response achieved after therapy, the MRD clone represents, from a biological point of view, a very small fraction of tumor cells that are truly chemoresistant, potentially quiescent (not producing M-protein), and able to recapitulate the initial tumor burden at relapse. Thus, the MRD clone represents a unique model to understand chemoresistance (in otherwise serological responding patients) and the characteristics of eventual MM clonogenic cells; however, the MRD clone has never been characterized at the biological level. Here, we compared the immunophenotypic and genomic profiles of paired baseline vs MRD clonal PCs from a total of 40 newly-diagnosed elderly MM patients enrolled in the GEM2010 trial: sequential VMP (9 cycles) followed by Rd (9 cycles) vs alternating VMP with Rd (18 cycles). MRD monitoring was performed by multidimensional flow cytometry (MFC) at cycles 9 and 18.First, we focused on the immunophenotypic expression profiling (iPEP) of patient-paired baseline vs MRD clonal PCs through 23-color MFC, combining backbone markers for the identification of clonal PCs with additional integrins, adhesion, activation and maturation molecules. Our results show that the iPEP from MRD clonal PCs at cycle 9 differed from paired baseline tumor cells by significantly (P<.05) increased MFI of CD11c, CD29, CD44, CD49d CD49e, CD54, and CD138, indicating that among the initial tumor bulk, the few chemoresistant cells were those with stronger expression of integrin and adhesion molecules. This phenomenon was particularly evident in patients randomized to the sequential arm; in fact, only after VMP there was a specific selection of CD117+chemoresistant clonal PCs (P=.03). Moreover, MRD clonal PCs showed significantly increased MFI of CD28 (a pro-survival mediator through dendritic cell interaction) and HLADR.Using patient-specific aberrant phenotypes, we then sorted clonal PCs (purity ≥97%) by FACS for subsequent genomic studies. Patient-specific paired comparison of baseline vs MRD clonal PCs (n=11) genomic profile was performed by high density Cytoscan750K array. The pattern of copy number abnormalities (CNA; only those with minimum of 25 consecutive imbalanced markers/segment and minimum 100 Kb length were considered) significantly varied from baseline to the chemoresistant MRD PC clone (accounting for whole chromosome, chromosomal arm or interstitial imbalances). Individual patient analysis showed one case in which both PC clones showed exactly the same 25 CNA; a second case in which MRD cells showed +1p36.21, -9p23, -17q11.2 and +17q25.3 in addition to 10 CNAs already present at baseline; 4 cases in which MRD cells maintained initial chromosomal imbalances but lacked specific CNA (range: 1-34) present at diagnosis; and 5 patients in which MRD cells displayed none of the CNA (range: 7-20) detected at baseline. It should be noted that markedly subclonal heterogeneity was detected at diagnosis. Accordingly, in one out of the 5 latter cases baseline but not MRD clonal PCs had 1q+ and 13q- which were further confirmed by FISH (in 85% and 58% of clonal PCs, respectively); this suggests that MRD PCs were present at the baseline state as a minor sublclone with respect to the initial tumor bulk. On the other hand, copy number neutral loss of heterozygosity (larger than 3Mb) was slightly more frequent in MRD as compared to patient paired baseline clonal PCs (13 vs 8, respectively).Only in 5/40 patients sufficient RNA was extracted from baseline and paired MRD FACS-sorted clonal PCs to perform gene expression profiling (GEP; HumanGene 1.0ST). Although the numbers are small, it should be noted that GEP of baseline vs. patient-paired MRD clonal PCs mostly overlapped, with only 19 genes found to be down-regulated after chemotherapy (SAM Excel add-in with a FDR q-value<10-5). Interestingly, 4 of those genes were connected to the glucocorticoid receptor signaling pathway and receptor gene NR3C1, a mediator of glucocorticoids activity in MM cells.In summary, this integrated phenotypic and genomic analysis suggests that from the baseline MM tumor bulk, primarily chemoresistant MRD PCs may be those potentially closer to the BM niche (with initial increased expression of integrins and adhesion molecules), as well as a more ancestral subclone (with less CNA) in a significant proportion of patients. Disclosures:No relevant conflicts of interest to declare.

An international phase 3 trial in head and neck cancer: Quality of life and symptom results

The European Organization for Research and Treatment of Cancer (EORTC) 24954 phase 3 randomized clinical trial compared 2 schemes of combined chemotherapy for patients with resectable cancers of the hypopharynx and larynx: sequential induction chemotherapy and radiotherapy versus alternating chemoradiotherapy. The current study reports detailed effects of both treatment arms on health-related quality of life (HRQOL) and symptoms. A total of 450 patients aged 35 years to 76 years (World Health Organization performance status (WHO PS) ≤ 2) with untreated, resectable advanced squamous cell carcinoma of the larynx (tumor classification of T3-T4) or hypopharynx (tumor classification of T2-T3-T4) with regional lymph nodes in the neck classified as N0 to N2 with no metastases were randomized in this prospective phase 3 trial into either the sequential arm (control) or the alternating arm (experimental). QOL assessment was performed at randomization; at baseline; at 42 days; and at 6, 12, 24, 36, and 48 months. There were no observed differences with regard to the primary endpoint of Fatigue and secondary endpoint of Dyspnea. Significant differences were found in the secondary endpoints of Swallowing and Speech problems at 42 days after randomization in favor of patients in the sequential arm. Explanatory and sensitivity analysis revealed that the primary analysis favored the sequential arm, but the majority of differences in HRQOL did not exist at the end of treatment, and returned to baseline levels. In the current study, a trend toward worse scores was noted in the patients treated on the alternating chemoradiotherapy arm but very few differences reached the level of statistical significance. The HRQOL scores of the majority of patients returned to baseline after therapy.

Impact of c-MYC Protein Expression on Outcome of Patients with Early-Stage HER2+ Breast Cancer Treated with Adjuvant Trastuzumab NCCTG (Alliance) N9831

This study investigated the association between tumor MYC protein expression and disease-free survival (DFS) of patients randomized to receive chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) in the N9831 (Alliance) adjuvant HER2(+) trastuzumab breast cancer trial. This analysis included 1,736 patients randomized to Arms A, B, and C on N9831. Nuclear MYC protein expression was determined in tissue microarray sections containing three biopsies per patient or whole tissue sections using standard immunohistochemistry (clone 9E10). A tumor was considered positive for MYC protein overexpression (MYC(+)) if the nuclear 3+ staining percentage was more than 30%. Five hundred and seventy-four (33%) tumors were MYC(+). MYC(+) was associated with hormone receptor positivity (χ(2), P = 0.006), tumors 2 cm or more (χ(2), P = 0.02), and a higher rate of nodal positivity (χ(2), P < 0.001). HRs for DFS (median follow-up: 6.1 years) for Arm C versus A were 0.52 (P = 0.006) and 0.65 (P = 0.006) for patients with MYC(+) and MYC(-) tumors, respectively (P(interaction) = 0.40). For Arm B versus A, HRs for patients with MYC(+) and MYC(-) tumors were 0.79 (P = 0.21) and 0.74 (P = 0.04), respectively (P(interaction) = 0.71). For Arm C versus B, HRs for patients with MYC(+) and MYC(-) tumors were 0.56 (P = 0.02) and 0.89 (P = 0.49), respectively (P(interaction) = 0.17). Our data do not support an impact of tumor MYC protein expression on differential benefit from adjuvant trastuzumab.

Deterministic Sequencing of Exploration and Exploitation for Multi-Armed Bandit Problems

In the Multi-Armed Bandit (MAB) problem, there is a given set of arms with unknown reward models. At each time, a player selects one arm to play, aiming to maximize the total expected reward over a horizon of length T. An approach based on a Deterministic Sequencing of Exploration and Exploitation (DSEE) is developed for constructing sequential arm selection policies. It is shown that for all light-tailed reward distributions, DSEE achieves the optimal logarithmic order of the regret, where regret is defined as the total expected reward loss against the ideal case with known reward models. For heavy-tailed reward distributions, DSEE achieves O(T1/p) regret when the moments of the reward distributions exist up to the pth order for and O(T1/(1+p/2)) for p > 2. With the knowledge of an upper bound on a finite moment of the heavy-tailed reward distributions, DSEE offers the optimal logarithmic regret order. The proposed DSEE approach complements existing work on MAB by providing corresponding results for general reward distributions. Furthermore, with a clearly defined tunable parameter-the cardinality of the exploration sequence, the DSEE approach is easily extendable to variations of MAB, including MAB with various objectives, decentralized MAB with multiple players and incomplete reward observations under collisions, restless MAB with unknown dynamics, and combinatorial MAB with dependent arms that often arise in network optimization problems such as the shortest path, the minimum spanning tree, and the dominating set problems under unknown random weights.

Dorsal parietal area 5 encodes immediate reach in sequential arm movements.

To generate a coherent action sequence, it is essential to integrate all component movements beforehand, and such sequence-related information has been observed in numerous brain regions. However, this high-level sequential plan encompassing multiple motor elements in parallel ultimately must be decomposed into serial motor commands to be executed by the musculoskeletal system. In the present study, we recorded single-neuron activity from dorsal parietal area 5 (area 5d) while monkeys performed a double-reach task, and found that area 5d conveys the immediate upcoming reach, but not the subsequent movement, as opposed to the entire movement sequence being encoded as in other cortical sensorimotor areas. The elementary movement coded in area 5d suggests that unfolding of the motor sequence begins in the parietal-frontal cortex, instead of being exclusively implemented by downstream subcortical and spinal circuits.