A Hackshaw

Safety of long-acting β-agonists: urgent need to clear the air remains

The introduction of long-acting β-agonist (LABA) drugs in the 1990s was considered a major advance in bronchodilator therapy with evidence that their use led to improved lung function and quality of life 1, 2. There were also potential safety advantages due to the twice daily, fixed dose usage, which reduced the risk of overuse of β-agonist therapy in the situation of severe exacerbations. The subsequent introduction of the combination of LABA/inhaled corticosteroid (ICS) products had the added potential value of ensuring that the patient received concomitant ICS therapy while improving compliance with ICS therapy 3, 4.nnHowever, concerns about the possible risks associated with LABA therapy were raised soon after their introduction into clinical practice, with the evidence that regular LABA use had the potential to reduce bronchodilator sensitivity to β-agonists 5, 6 and induce tolerance to their bronchoprotective effects 7, which may not be restored by concurrent use of ICS 8. It also became apparent that patients using LABAs may be at risk of severe exacerbations if the symptom control achieved with LABA use led to a discontinuation of ICS therapy 9. There were also concerns about a potential risk of mortality from the Salmeterol Nationwide Surveillance Study 10. In this UK-based study of >25,000 subjects, there was a nonsignificant three-fold increased risk of asthma death in subjects treated with salmeterol compared with regular salbutamol; however, there was no increase in hospital admissions or life-threatening events. This led to the USA-based Salmeterol Multicenter Asthma Research Trial (SMART), a placebo-controlled study of the safety of salmeterol in adults with unstable asthma 11. The trial was stopped after an interim analysis of 26,000 subjects because it showed a statistically significant, four-fold increase in asthma mortality with salmeterol. Unfortunately, due to low …

The influence of sex and histology on outcomes in non-small-cell lung cancer: a pooled analysis of five randomized trials.

BACKGROUNDnSome non-small-cell lung cancer (NSCLC) surgical series have indicated that the positive prognostic effect of female sex is limited to patients with adenocarcinoma. We carried out a retrospective analysis to investigate the role of sex and histology on efficacy, toxicity, and dose delivery after chemotherapy.nnnPATIENT AND METHODSnIndividual patient data were pooled from five randomized, phase III, advanced NSCLC chemotherapy trials. Primary outcomes were response rate, overall survival (OS), toxicity, and dose delivery. A secondary analysis examined survival by sex in histological subgroups.nnnRESULTSnOf 2349 patients, 34% were women. Women had a higher response rate to chemotherapy (42% versus 40%, P = 0.01) and longer survival than men (median OS 9.6 versus 8.6 months, P = 0.002). The difference in OS remained after adjusting for age, stage, performance status, and histology (hazard ratio 0.83, 95% confidence interval 0.74-0.92, P = 0.0005). Upon further examination, longer survival in women was only seen in patients with adenocarcinoma (test for interaction P = 0.006). There were no differences in hematological toxicity or transfusions. Women experienced more grade 3-4 emesis than men (P < 0.0001) and more dose delays (P = 0.02) or dose reductions (P < 0.0001).nnnCONCLUSIONnThe positive prognostic effect among women is confirmed in patients receiving platinum-based chemotherapy but appears confined to those with adenocarcinoma histology.

Investigating the heterogeneity of alkylating agents' efficacy and toxicity between sexes: A systematic review and meta-analysis of randomized trials comparing cyclophosphamide and ifosfamide (MAIAGE study)

A marginal interaction between sex and the type of alkylating agent was observed for event‐free survival in the Euro‐EWING99‐R1 randomized controlled trial (RCT) comparing cyclophosphamide and ifosfamide in Ewing sarcoma. To further evaluate this interaction, we performed an individual patient data meta‐analysis of RCTs assessing cyclophosphamide versus ifosfamide in any type of cancer.