Prevention and Management of Bone Metastases in Lung Cancer: A Review

Abstract:Approximately 30 to 40% of patients with advanced lung cancer will develop bone metastases in the course of their disease, resulting in a significant negative impact on both morbidity and survival. Skeletal complications of bone metastases include pain, pathologic fractures, spinal cord compression, and hypercalcemia. Total medical care costs are greater among patients with bone metastases who develop skeletal complications. A randomized phase III trial of the third generation bisphosphonate zoledronic acid has shown clinical benefit in the management of a subgroup of patients with bone metastases from lung cancer. Zoledronic acid treatment was associated with a reduction in both the risk of, and time to, a skeletal-related event. One of the markers of bone resorption, N-telopeptide, is both prognositic for development of skeletal-related events and predictive for benefit from zoledronic acid. In preclinical models, bisphosphonates have also demonstrated antitumor activity and are therefore currently being evaluated in adjuvant trials. Inhibition of the receptor activator of nuclear factor kappa B ligand-RANK pathway can reduce osteoclast-mediated bone resorption, and trials comparing receptor activator of nuclear factor kappa B ligand inhibitors with bisphosphonates are ongoing, including patients with lung cancer. In this article, we review the management of bone metastases and hypercalcemia as well as potential future directions for bone directed therapies in patients with lung cancer

Exploiting the noise: improving biomarkers with ensembles of data analysis methodologies.

BackgroundThe advent of personalized medicine requires robust, reproducible biomarkers that indicate which treatment will maximize therapeutic benefit while minimizing side effects and costs. Numerous molecular signatures have been developed over the past decade to fill this need, but their validation and up-take into clinical settings has been poor. Here, we investigate the technical reasons underlying reported failures in biomarker validation for non-small cell lung cancer (NSCLC).MethodsWe evaluated two published prognostic multi-gene biomarkers for NSCLC in an independent 442-patient dataset. We then systematically assessed how technical factors influenced validation success.ResultsBoth biomarkers validated successfully (biomarker #1: hazard ratio (HR) 1.63, 95% confidence interval (CI) 1.21 to 2.19, P = 0.001; biomarker #2: HR 1.42, 95% CI 1.03 to 1.96, P = 0.030). Further, despite being underpowered for stage-specific analyses, both biomarkers successfully stratified stage II patients and biomarker #1 also stratified stage IB patients. We then systematically evaluated reasons for reported validation failures and find they can be directly attributed to technical challenges in data analysis. By examining 24 separate pre-processing techniques we show that minor alterations in pre-processing can change a successful prognostic biomarker (HR 1.85, 95% CI 1.37 to 2.50, P < 0.001) into one indistinguishable from random chance (HR 1.15, 95% CI 0.86 to 1.54, P = 0.348). Finally, we develop a new method, based on ensembles of analysis methodologies, to exploit this technical variability to improve biomarker robustness and to provide an independent confidence metric.ConclusionsBiomarkers comprise a fundamental component of personalized medicine. We first validated two NSCLC prognostic biomarkers in an independent patient cohort. Power analyses demonstrate that even this large, 442-patient cohort is under-powered for stage-specific analyses. We then use these results to discover an unexpected sensitivity of validation to subtle data analysis decisions. Finally, we develop a novel algorithmic approach to exploit this sensitivity to improve biomarker robustness

'They're battle scars, I wear them well': A phenomenological exploration of young women's experiences of building resilience following adversity in adolescence

This is an Author's Accepted Manuscript of an article published in Journal of Youth Studies, 13(3), 273 - 290, 2010 [copyright Taylor & Francis], available online at: http://www.tandfonline.com/10.1080/13676260903520886.This phenomenological study explored young women's accounts of building resilience following chains of adverse life experiences in adolescence. Six participants were interviewed, aged 20–25 years. Most had, or were receiving, a university education. They described their recovery from adversity as starting with certain pivotal moments, followed by both short-term and longer-term strategies. Short-term strategies tended to offer respite from distress and emotional comfort, increased clarity about their experiences and social affirmation. Recovery involved gaining new perspectives on their adverse situation and recovering a positive self-image through three longer-term strategies. These involved making visible progress in their education, rebuilding relationships with family and friends, and participating in the ‘normalizing’ activities and developmental projects of adolescence. Participants believed that they were stronger and more compassionate although positive achievements co-existed with some regrets. Most perceived the adversity as catalyzing personal growth. These accounts of resilience revealed the complex psychosocial processes and resources available to some adolescents

Cancer Incidence Among Canadian Kidney Transplant Recipients

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73838/1/j.1600-6143.2007.01736.x.pd

The Differential Efficacy of Pemetrexed According to NSCLC Histology: A Review of Two Phase III Studies

Abstract Background. Recent studies of pemetrexed have identified a predictive role for non-small cell lung cancer (NSCLC) histology. We further reviewed the differential efficacy of pemetrexed according to histology in two large, phase III NSCLC trials. Methods. One study tested pemetrexed versus docetaxel in previously treated patients (n = 571) and the other tested cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemotherapy-naive patients (n = 1,725) with advanced NSCLC. Cox proportional hazard models were used to test for covariate-adjusted treatment-by-histology interactions (THIs) for overall survival (OS) and progression-free survival (PFS). For each histologic subgroup, the Kaplan–Meier method was used to estimate unadjusted within-arm medians, and Cox models were used to estimate covariate-adjusted between-arm hazard ratios (HRs). Results. In both studies, treatment arms were well balanced for histology. THIs were statistically significant (p < .005) for both OS and PFS. Nonsquamous patients treated with pemetrexed-based therapy experienced longer survival than the comparators (HR, 0.78 and 0.84, respectively), whereas squamous patients had shorter survival (HR, 1.56 and 1.23, respectively). Whereas the efficacy of pemetrexed regimens differed according to histology, it did not differ for docetaxel or for cisplatin plus gemcitabine. Pemetrexed was well tolerated across histologic groups. Conclusions. The consistency of these results across studies confirms the predictive effect of histology for pemetrexed and the survival advantage for pemetrexed in patients with nonsquamous histology. These analyses suggest pemetrexed should not be recommended for the treatment of squamous cell carcinoma, but, because of efficacy and safety advantages, pemetrexed may be preferable to other agents for treatment of patients with nonsquamous NSCLC

Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis.

In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis.Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum-pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points.A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum-pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum-pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67-1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5-31.5) versus 22.5 months (95% CI 20.2-28.8) for osimertinib and platinum-pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18-1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16-0.28; P0.001). At DCO, 99/136 (73%) patients in the platinum-pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3,1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum-pemetrexed arm.In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum-pemetrexed, which possibly reflects the high crossover rate of patients from platinum-pemetrexed to osimertinib.ClinicalTrials.gov NCT02151981; https://clinicaltrials.gov/ct2/show/NCT02151981