Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial.

Background: In LUX-Lung 7, the irreversible ErbB family blocker, afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus gefitinib in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data. Patients and methods: LUX-Lung 7 assessed afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naïve patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R). Primary OS analysis was planned after ∼213 OS events and ≥32-month follow-up. OS was analysed by a Cox proportional hazards model, stratified by EGFR mutation type and baseline brain metastases. Results: Two-hundred and twenty-six OS events had occurred at the data cut-off (8 April 2016). After a median follow-up of 42.6 months, median OS (afatinib versus gefitinib) was 27.9 versus 24.5 months [hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.66‒1.12, P = 0.2580]. Prespecified subgroup analyses showed similar OS trends (afatinib versus gefitinib) in patients with exon 19 deletion (30.7 versus 26.4 months; HR, 0.83, 95% CI 0.58‒1.17, P = 0.2841) and L858R (25.0 versus 21.2 months; HR 0.91, 95% CI 0.62‒1.36, P = 0.6585) mutations. Most patients (afatinib, 72.6%; gefitinib, 76.8%) had at least one subsequent systemic anti-cancer treatment following discontinuation of afatinib/gefitinib; 20 (13.7%) and 23 (15.2%) patients received a third-generation EGFR tyrosine kinase inhibitor. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib. Conclusion: In LUX-Lung 7, there was no significant difference in OS with afatinib versus gefitinib. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib. Clinicaltrials.gov identifier: NCT01466660.

Hydration-reduced lattice thermal conductivity of olivine in Earth's upper mantle.

Earth's water cycle enables the incorporation of water (hydration) in mantle minerals that can influence the physical properties of the mantle. Lattice thermal conductivity of mantle minerals is critical for controlling the temperature profile and dynamics of the mantle and subducting slabs. However, the effect of hydration on lattice thermal conductivity remains poorly understood and has often been assumed to be negligible. Here we have precisely measured the lattice thermal conductivity of hydrous San Carlos olivine (Mg0.9Fe0.1)2SiO4 (Fo90) up to 15 gigapascals using an ultrafast optical pump-probe technique. The thermal conductivity of hydrous Fo90 with ∼7,000 wt ppm water is significantly suppressed at pressures above ∼5 gigapascals, and is approximately 2 times smaller than the nominally anhydrous Fo90 at mantle transition zone pressures, demonstrating the critical influence of hydration on the lattice thermal conductivity of olivine in this region. Modeling the thermal structure of a subducting slab with our results shows that the hydration-reduced thermal conductivity in hydrated oceanic crust further decreases the temperature at the cold, dry center of the subducting slab. Therefore, the olivine-wadsleyite transformation rate in the slab with hydrated oceanic crust is much slower than that with dry oceanic crust after the slab sinks into the transition zone, extending the metastable olivine to a greater depth. The hydration-reduced thermal conductivity could enable hydrous minerals to survive in deeper mantle and enhance water transportation to the transition zone.

Gefitinib, cisplatin, and concurrent radiotherapy for locally advanced head and neck cancer: EGFR FISH, protein expression, and mutational status are not predictive biomarkers.

BACKGROUND: Gefitinib was demonstrated to be synergistic with cisplatin and radiotherapy (RT) in in vitro studies. Biomarkers predictive of response to gefitinib in squamous cell head and neck cancer is still lacking. METHODS: Thirty-one patients with locally advanced and easily accessible primary tumor sites for biopsies were recruited. Gefitinib was started 3 weeks before the start of cisplatin/concurrent radiotherapy (CTRT) and continued during the CTRT phase and thereafter for 4 months as consolidation phase. Two baselines and a repeat tumor sample were taken after 2 weeks of gefitinib alone to study its impact on tumor gene expression. Epidermal growth factor receptor (EGFR) protein expression, FISH and mutational status, and matrix metallopeptidase 11 (MMP11) protein expression were correlated with response and survival outcome. RESULTS: The overall response rate to gefitinib alone was 9.7%. The survival outcome is as follows: median disease free 1.3 years, median survival time 2.4 years, 3-year disease free 42.9%, and 3-year overall survival 48.4%. EGFR FISH, protein expression, and mutational status did not predict for response nor survival outcome of patients. Although MMP11 overexpression did not predict for response, it predicted significantly for a poorer survival outcome. CONCLUSIONS: Gefitinib can be combined safely with cisplatin/RT. More studies are needed to uncover predictive biomarkers of benefit to gefitinib.

A multicentre phase II gene expression profiling study of putative relationships between tumour biomarkers and clinical response with erlotinib in non-small-cell lung cancer.

BACKGROUND: Identification of appropriate markers for predicting clinical benefit with erlotinib in non-small-cell lung cancer (NSCLC) may be able to guide patient selection for treatment. This open-label, multicentre, phase II trial aimed to identify genes with potential use as biomarkers for clinical benefit from erlotinib therapy. METHODS: Adults with stage IIIb/IV NSCLC in whom one or more chemotherapy regimen had failed were treated with erlotinib (150 mg/day). Tumour biopsies were analysed using gene expression profiling with Affymetrix GeneChip microarrays. Differentially expressed genes were verified using quantitative RT-PCR (qRT-PCR). RESULTS: A total of 264 patients were enrolled in the study. Gene expression profiles found no statistically significant differentially expressed genes between patients with and without clinical benefit. In an exploratory analysis in responding versus nonresponding patients, three genes on chromosome 7 were expressed at higher levels in the responding group [epidermal growth factor receptor (EGFR), phosphoserine phosphatase (PSPH) and Rap guanine nucleotide exchange factor 5 (RAPGEF5)]. Independent quantification using qRT-PCR validated the association between EGFR and PSPH overexpression, but not RAPGEF5 overexpression, and clinical outcome. CONCLUSIONS: This study supports the use of erlotinib as an alternative to chemotherapy for patients with relapsed advanced NSCLC. Genetic amplification of the EGFR region of chromosome 7 may be associated with response to erlotinib therapy.

Seismological support for the metastable superplume model, sharp features, and phase changes within the lower mantle.

Recently, a metastable thermal-chemical convection model was proposed to explain the African Superplume. Its bulk tabular shape remains relatively stable while its interior undergoes significant stirring with low-velocity conduits along its edges and down-welling near the middle. Here, we perform a mapping of chemistry and temperature into P and S velocity variations and replace a seismically derived structure with this hybrid model. Synthetic seismogram sections generated for this 2D model are then compared directly with corresponding seismic observations of P (P, P(C)P, and PKP) and S (S, S(C)S, and SKS) phases. These results explain the anticorrelation between the bulk velocity and shear velocity and the sharpness and level of SKS travel time delays. In addition, we present evidence for the existence of a D" triplication (a putative phase change) beneath the down-welling structure.

Surgery and adjuvant radiotherapy vs concurrent chemoradiotherapy in stage III/IV nonmetastatic squamous cell head and neck cancer: a randomised comparison.

We compared concurrent combination chemotherapy and radiotherapy with surgery and adjuvant radiotherapy in patients with stage III/IV nonmetastatic squamous cell head and neck cancer. Patients with non-nasopharyngeal and nonsalivary resectable squamous cell head and neck cancer were randomised to receive either surgery followed by adjuvant radiotherapy (60 Gy over 30 fractions) or concurrent combination chemotherapy and radiotherapy (66 Gy in 33 fractions). Combination chemotherapy comprised two cycles of i.v. cisplatin 20 mg m(-2) day(-1) and i.v. 5-fluorouracil 1000 mg m(-2) day(-1), both to run over 96 h given on days 1 and 28 of the radiotherapy. A total of 119 patients were randomised. At a median follow-up of 6 years, there was no significant difference in the 3-year disease-free survival rate between the surgery and concurrent chemoradiotherapy (50 vs 40% respectively). The overall organ preservation rate or avoidance of surgery to primary site was 45%. Those with laryngeal/hypopharyngeal disease subsite had a higher organ-preservation rate than the rest (68 vs 30%). Combination chemotherapy and concurrent irradiation with salvage surgery was not superior to conventional surgery and postoperative radiotherapy for resectable advanced squamous cell head and neck cancer. However, this form of treatment schedule with a view to organ-preservation can be attempted especially for those with laryngeal/hypopharyngeal and possibly oropharyngeal disease subsites.

Gefitinib is more effective in never-smokers with non-small-cell lung cancer: experience among Asian patients.

We retrospectively analysed the results of patients with advanced non-small-cell lung cancer treated with gefitinib to derive clinical factors predictive of response and a favourable survival outcome. Patients were treated with gefitinib 250 mg per day and re-evaluated 4-8 weeks later with repeat CT scan and every 8 weeks thereafter to assess response and the duration of response. Pathology review by a histopathologist was conducted, in particular to confirm a recently published result of bronchioloalveolar carcinoma histology or its components as predictive of response to gefitinib. Logistic regression and Cox regression analytical methods were applied to determine factors that could predict for response and improved overall survival. A total of 110 patients were treated. The overall response rate was 32% partial responses (PRs). Only never-smoking status was predictive of response in the logistic regression analysis, adjusted OR=6.1, 95% CI=1.7, 21.5. The presence of a PR and good performance status were predictive of a favourable survival outcome from the Cox regression modelling. Responders had an adjusted HR of 3.0, 95% CI=1.5-5.8 compared to nonresponders, while patients with ECOG status 0-1 had an adjusted HR of 0.42, 95% CI=0.25-0.72, compared with patients with ECOG status 2-4. Bronchioloalveolar carcinoma or its components were distinctly absent on pathology review. In conclusions, Never-smoking status is an important clinical predictor of a favourable response to gefitinib.

Validation of a new prognostic index score for disseminated nasopharyngeal carcinoma.

Patients with metastatic nasopharyngeal carcinoma have variable survival outcomes. We previously designed a scoring system to better prognosticate these patients. Here, we report results on validation of this new prognostic index score in a separate cohort of patients. Clinical features and laboratory parameters were examined in 172 patients with univariate and multivariate analyses and a numerical score was derived for each independent prognostic variable. Significant independent prognostic variables and their scores assigned included poor performance status (score 5), haemoglobin < 12 g dl(-1) (score 4) and disease-free interval (DFI) (DFI < or = 6 months (score 10) or metastases at initial diagnosis (score 1)). Maximum score was 19 and patients stratified into three prognostic groups: good, 0-3; intermediate, 4-8; poor, > or = 9. When applied to a separate cohort of 120 patients, 59 patients were good, 43 intermediate and 18 poor prognosis, with median survivals of 19.6 (95% CI 16.1, 23.1), 14.3 (95% CI 12.3, 16.2) and 7.9 (95% CI 6.6, 9.2) months, respectively. (logrank test: P = 0.003). We have validated a new prognostic score with factors readily available in the clinics. This simple score will prove useful as a method to prognosticate and stratify patients as well as to promote consistent reporting among clinical trials.

Quick-FLIC: validation of a short questionnaire for assessing quality of life of cancer patients.

A practically useful measure of quality of life should be simple and quick to complete. A shortened Chinese version of the Functional Living Index - Cancer (FLIC) was recently proposed and was called Quick-FLIC. This study aims to assess the measurement properties of the Quick-FLIC. A total of 190 patients who received care from the National Cancer Centre of Singapore completed a questionnaire package at baseline. Patients filled in a retest questionnaire on average 2 weeks after baseline to assess test-retest reliability and responsiveness to change. The Quick-FLIC scores correlated well with the Functional Assessment of Chronic Therapy - General scores (r=0.78). Patients with different treatment status, performance status and self-rated health had significantly different Quick-FLIC scores in the expected directions (ANOVA; each P<0.001). Internal consistency (Cronbach's alpha=0.87) and 2-week test-retest reliability (intraclass correlation=0.81) were also satisfactory. The measure was responsive to changes in health status (P<0.001). The Quick-FLIC is a valid and reliable measure of health-related quality of life of cancer patients. The shortening of established health-related quality of life instruments should be considered in order to reduce the burden of having patients to answer lengthy questionnaires.

Sharp sides to the African superplume.

Beneath southern Africa is a large structure about 1200 kilometers across and extending obliquely 1500 kilometers upward from the core-mantle boundary with a shear velocity reduction of about 3%. Using a fortuitous set of SKS phases that travel along its eastern side, we show that the boundary of the anomaly appears to be sharp, with a width less than 50 kilometers, and is tilted outward from its center. Dynamic models that fit the seismic constraints have a dense chemical layer within an upwardly flowing thermal structure. The tilt suggests that the layer is dynamically unstable on geological time scales.

A Bayesian re-assessment of two Phase II trials of gemcitabine in metastatic nasopharyngeal cancer.

The Simon two-stage minimax design is a popular statistical design used in Phase II clinical trials. The analysis of the data arising from the design typically involves the use of frequentist statistics. This paper presents an alternative, Bayesian, approach to the design and analysis of Phase II clinical trials. In particular, we consider how a Bayesian approach could have affected the design, analysis and interpretation of two parallel Phase II trials of the National Cancer Centre Singapore, on the activity of gemcitabine in chemotherapy-naïve and in previously treated patients with metastatic nasopharyngeal carcinoma. We begin by explaining the Bayesian methodology and contrasting it with the frequentist approach. We then carry out a Bayesian analysis of the trial results. The conclusions drawn using the Bayesian approach were in general agreement with those obtained from the frequentist analysis. However they had the advantage of allowing for different and potentially more useful interpretations to be made regarding the trial results, as well as for the incorporation of external sources of information. In particular, using a Bayesian trial design, we were able to take into account the results of the parallel trial results when deciding whether to continue each trial beyond the interim stage.