Cooking fuels and prevalence of asthma: a global analysis of phase three of the International Study of Asthma and Allergies in Childhood (ISAAC).


Background

Indoor air pollution from a range of household cooking fuels has been implicated in the development and exacerbation of respiratory diseases. In both rich and poor countries, the effects of cooking fuels on asthma and allergies in childhood are unclear. We investigated the association between asthma and the use of a range of cooking fuels around the world.

Methods

For phase three of the International Study of Asthma and Allergies in Childhood (ISAAC), written questionnaires were self-completed at school by secondary school students aged 13—14 years, 244 734 (78%) of whom were then shown a video questionnaire on wheezing symptoms. Parents of children aged 6—7 years completed the written questionnaire at home. We investigated the association between types of cooking fuels and symptoms of asthma using logistic regression. Adjustments were made for sex, region of the world, language, gross national income, maternal education, parental smoking, and six other subject-specific covariates. The ISAAC study is now closed, but researchers can continue to use the instruments for further research.

Findings

Data were collected between 1999 and 2004. 512 707 primary and secondary school children from 108 centres in 47 countries were included in the analysis. The use of an open fire for cooking was associated with an increased risk of symptoms of asthma and reported asthma in both children aged 6—7 years (odds ratio [OR] for wheeze in the past year, 1·78, 95% CI 1·51—2·10) and those aged 13—14 years (OR 1·20, 95% CI 1·06—1·37). In the final multivariate analyses, ORs for wheeze in the past year and the use of solely an open fire for cooking were 2·17 (95% CI 1·64—2·87) for children aged 6—7 years and 1·35 (1·11—1·64) for children aged 13—14 years. Odds ratios for wheeze in the past year and the use of open fire in combination with other fuels for cooking were 1·51 (1·25—1·81 for children aged 6—7 years and 1·35 (1·15—1·58) for those aged 13—14 years. In both age groups, we detected no evidence of an association between the use of gas as a cooking fuel and either asthma symptoms or asthma diagnosis.

Interpretation

The use of open fires for cooking is associated with an increased risk of symptoms of asthma and of asthma diagnosis in children. Because a large percentage of the world population uses open fires for cooking, this method of cooking might be an important modifiable risk factor if the association is proven to be causal.

Source: Lancet

Treatment of low bone density in young people with cystic fibrosis: a multicentre, prospective, open-label observational study of calcium and calcifediol followed by a randomised placebo-controlled trial of alendronate.


Background
Long-term complications of cystic fibrosis include osteoporosis and fragility fractures, but few data are available about effective treatment strategies, especially in young patients. We investigated treatment of low bone mineral density in children, adolescents, and young adults with cystic fibrosis.
Methods
We did a multicentre trial in two phases. We enrolled patients aged 5—30 years with cystic fibrosis and low bone mineral density, from ten cystic fibrosis regional centres in Italy. The first phase was an open-label, 12-month observational study of the effect of adequate calcium intake plus calcifediol. The second phase was a 12-month, double-blind, randomised, placebo-controlled, parallel group study of the efficacy and safety of oral alendronate in patients whose bone mineral apparent density had not increased by 5% or more by the end of the observational phase. Patients were randomly assigned to either alendronate or placebo. Both patients and investigators were masked to treatment assignment. We used dual x-ray absorptiometry at baseline and every 6 months thereafter, corrected for body size, to assess lumbar spine bone mineral apparent density. We assessed bone turnover markers and other laboratory parameters every 3—6 months. The primary endpoint was mean increase of lumbar spine bone mineral apparent density, assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01812551.
Findings
We screened 540 patients and enrolled 171 (mean age 13•8 years, SD 5•9, range 5—30). In the observational phase, treatment with calcium and calcifediol increased bone mineral apparent density by 5% or more in 43 patients (25%). 128 patients entered the randomised phase. Bone mineral apparent density increased by 16•3% in the alendronate group (n=65) versus 3•1% in the placebo group (n=63; p=0•0010). 19 of 57 young people (33•3%) receiving alendronate attained a normal-for-age bone mineral apparent density Z score. In the observational phase, five patients had moderate episodes of hypercalciuria, which resolved after short interruption of calcifediol treatment. During the randomised phase, one patient taking alendronate had mild fever versus none in the placebo group; treatment groups did not differ significantly for other adverse events.
Interpretation
Correct calcium intake plus calcifediol can improve bone mineral density in some young patients with cystic fibrosis. In those who do not respond to calcium and calcifediol alone, alendronate can safely and effectively increase bone mineral density.
Source: Lancet

Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials.


Background

Abnormal acid gastro-oesophageal reflux is common in patients with idiopathic pulmonary fibrosis (IPF) and is considered a risk factor for development of IPF. Retrospective studies have shown improved outcomes in patients given anti-acid treatment. The aim of this study was to investigate the association between anti-acid treatment and disease progression in IPF.

Methods

In an analysis of data from three randomised controlled trials, we identified patients with IPF assigned to receive placebo. Case report forms had been designed to prospectively obtain data about diagnosis and treatment of abnormal acid gastro-oesophageal reflux in each trial. The primary outcome was estimated change in forced vital capacity (FVC) at 30 weeks (mean follow-up) in patients who were and were not using a proton-pump inhibitor or histamine-receptor-2 (H2) blocker.

Findings

Of the 242 patients randomly assigned to the placebo groups of the three trials, 124 (51%) were taking a proton-pump inhibitor or H2 blocker at enrolment. After adjustment for sex, baseline FVC as a percentage of predicted, and baseline diffusing capacity of the lung for carbon monoxide as a percentage of predicted, patients taking anti-acid treatment at baseline had a smaller decrease in FVC at 30 weeks (—0·06 L, 95% CI −0·11 to −0·01) than did those not taking anti-acid treatment (—0·12 L, −0·17 to −0·08; difference 0·07 L, 95% CI 0—0·14; p=0·05).

Interpretation

Anti-acid treatment could be beneficial in patients with IPF, and abnormal acid gastro-oesophageal reflux seems to contribute to disease progression. Controlled clinical trials of anti-acid treatments are now needed.

Source: Lancet

Pulmonary drug delivery: from generating aerosols to overcoming biological barriers—therapeutic possibilities and technological challenges.


Research in pulmonary drug delivery has focused mainly on new particle or device technologies to improve the aerosol generation and pulmonary deposition of inhaled drugs. Although substantial progress has been made in this respect, no significant advances have been made that would lead pulmonary drug delivery beyond the treatment of some respiratory diseases. One main reason for this stagnation is the still very scarce knowledge about the fate of inhaled drug or carrier particles after deposition in the lungs. Improvement of the aerosol component alone is no longer sufficient for therapeutic success of inhalation drugs; a paradigm shift is needed, with an increased focus on the pulmonary barriers to drug delivery. In this Review, we discuss some pathophysiological disorders that could benefit from better control of the processes after aerosol deposition, and pharmaceutical approaches to achieve improved absorption across the alveolar epithelium, prolonged pulmonary clearance, and targeted delivery to specific cells or tissues.
Source: Lancet

Fluticasone furoate and vilanterol for COPD.


The Article by Mark Dransfield and colleagues1 reports replicate studies of the efficacy of fluticasone furoate and vilanterol on exacerbations in chronic obstructive pulmonary disease (COPD). The primary objective was to test the effect of a once-daily combination inhaler, so it is surprising that there was no comparator group of conventional twice-daily dosing. The distinctly modest improvement in comparison to the once-daily long-acting β agonist is certainly not greater, and perhaps even less than, that seen in several other studies using the twice-daily regimen. One cannot conclude that superior efficacy has been demonstrated for the once-daily dosing. Compliance may be improved with once-daily therapy but remains unproven for this class of drug.

Furthermore, as in many other studies of inhaled corticosteroid and long-acting β agonists, the significance of pre-study therapy is ignored. Over two thirds of patients in the studies of Dransfield and colleagues were taking an inhaled corticosteroid at study entry. Thus, those randomised to vilanterol alone underwent steroid withdrawal. Figure 4 in the Article shows that any difference in exacerbation rate occurs within 90 days of treatment initiation. The hypothesis that withdrawal of steroids increases exacerbations in COPD is well established.2 Re-analysis of the OPTIMAL study by Suissa and colleagues3 demonstrated no advantage for inhaled corticosteroids in addition to long-acting β agonists in steroid-naive patients, whereas those previously taking inhaled corticosteroids who were assigned to long-acting β agonist alone had a worse prognosis. We ask the authors to present the effects of fluticasone furoate and vilanterol on exacerbation rates stratified by inhaled corticosteroid pre-trial therapy. Until such evidence is forthcoming, we cannot rule out that any positive effects reported may be due to a simple artefact of trial design.

Even if anticipated, the confirmation of a significant excess of pneumonia with fluticasone furoate in a 1 year study is disappointing. This excess of pneumonia has been difficult to demonstrate with other inhaled corticosteroids4 and may be due to the greater lipophilicity and slower clearance of fluticasone, which with repeated dosing results in accumulation in the lung. Given this confirmation of fluticasone toxicity, should the position of high-dose fluticasone drugs be re-examined? In England, the market leader is fluticasone propionate (250 μg), salmeterol (25 μg) metred-dose inhaler, with sales of £170 million in 2011.5 Although unlicensed for COPD, its market position indicates confusion among doctors as to the diagnostic subtleties between severe asthma and COPD. We believe that the withdrawal of high-dose fluticasone preparations on safety grounds is now justified, and would also save patients and health-care providers a great deal of money.

JBM has received speaker fees and sponsorship to attend the ERS, ATS, BPS, and BTS conferences, and educational grants from pharmaceutical companies including Novartis, Boehringer Ingelheim, GlaxoSmithKline, Chiesi, Merck Sharp & Dohme, Pfizer, Amgen, Napp, Almirall, and Teva. AHM has received speaker fees and sponsorship to attend the ERS, ATS, and BPS conferences from pharmaceutical companies including Novartis, Boehringer Ingelheim, GlaxoSmithKline, Chiesi, Proctor & Gamble, Almirall, AstraZeneca, Glenmark, and Philips Home Healthcare Solutions.

References

1 Dransfield MT, Bourbeau J, Jones PW, et al. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir Med 2013; 1: 210-223. PubMed

2 Suissa S, Barnes PJ. Inhaled corticosteroids in COPD: the case against. Eur Respir J 2009; 34: 13-16. CrossRef | PubMed

3 Suissa S, Ernst P, Vandemheen KL, Aaron SD. Methodological issues in therapeutic trials of COPD. Eur Respir J 2008; 31:927-933. CrossRef | PubMed

4 Sin DD, Tashkin D, Zhang X, et al. Budesonide and the risk of pneumonia: a meta-analysis of individual patient data. Lancet2009; 374: 712-719. Summary | Full Text | PDF(174KB) | CrossRef | PubMed

5 Health and Social Care Information Centre, Prescribing and Primary Care. Prescription cost analysis—England.http://www.ic.nhs.uk/article/2021/WebsiteSearch?productid=5461&q=+prescriptions+cost+analysis+2011&sort=Relevance&size=10&page=1&area=both#top. (accessed May 10, 2013).

Source: Lancet

Subsequent neoplasms of the CNS among survivors of childhood cancer: a systematic review.


Childhood cancer survivors are at risk for development of subsequent neoplasms of the CNS. Better understanding of the rates, risk factors, and outcomes of subsequent neoplasms of the CNS among survivors of childhood cancer could lead to more informed screening guidelines. Two investigators independently did a systematic search of Medline and Embase (from January, 1966, through March, 2012) for studies examining subsequent neoplasms of the CNS among survivors of childhood cancer. Articles were selected to answer three questions: what is the risk of CNS tumours after radiation to the cranium for a paediatric cancer, compared with the risk in the general population; what are the outcomes in children with subsequent neoplasms of the CNS who received CNS-directed radiation for a paediatric cancer; and, are outcomes of subsequent neoplasms different from primary neoplasms of the same histology? Our search identified 72 reports, of which 18 were included in this Review. These studies reported that childhood cancer survivors have an 8·1—52·3-times higher incidence of subsequent CNS neoplasms compared with the general population. Nearly all cancer survivors who developed a CNS neoplasm had been exposed to cranial radiation, and some studies showed a correlation between radiation dose and risk of subsequent CNS tumours. 5-year survival ranged from 0—19·5% for subsequent high-grade gliomas and 57·3—100% for meningiomas, which are similar rates to those observed in patients with primary gliomas or meningiomas. The quality of evidence was limited by variation in study design, heterogeneity of details regarding treatment and outcomes, limited follow-up, and small sample sizes. We conclude that survivors of childhood cancer who received cranial radiation therapy have an increased risk for subsequent CNS neoplasms. The current literature is insufficient to comment about the potential harms and benefits of routine screening for subsequent CNS neoplasms.

Source: Lancet

 

Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study.


Background

No standard treatment exists for patients with platinum-refractory urothelial cancer. Taxanes and vinflunine are commonly used, but response is less than 20% with no survival benefit. In this phase 2 study, we assessed efficacy and tolerability of nanoparticle albumin-bound (nab) paclitaxel in platinum-refractory urothelial cancer.

Methods

We did an open-label, single-group, two-stage study at five centres in Canada. We enrolled patients aged at least 18 years with histologically confirmed, locally advanced, or metastatic measurable urothelial cancer, with documented progression on or within 12 months of treatment with one previous platinum-containing regimen. Patients received nab-paclitaxel at 260 mg/m2 intravenously every 3 weeks. Treatment continued until disease progression or occurrence of unacceptable toxic effects. The primary endpoint was objective tumour response, defined by a complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (version 1.0) criteria. Tumour response and safety were assessed in all patients who received at least one cycle of nab-paclitaxel. This study is registered with ClinicalTrials.gov, numberNCT00683059.

Findings

We enrolled 48 patients between Oct 16, 2008, and June 23, 2010. Patients received a median of six cycles (range one to 15). 47 patients were evaluable; one (2·1%) had a CR and 12 (25·5%) had PRs, resulting in an overall response of 27·7% (95% CI 17·3—44·4). The most frequently recorded adverse events of any grade were fatigue (38 of 48; 79%), pain (37 of 48; 77%), alopecia (34 of 48; 71%), and neuropathy (30 of 48; 77%). The most frequently recorded adverse events of grade 3 or higher were pain (11 of 48; 23%), fatigue (five of 48; 23%), hypertension (three of 48; 6%), neuropathy (three of 48, 6%), and joint stiffness or pain (two of 48; 4%).

Interpretation

Nab-paclitaxel was well tolerated in this population of patients with pretreated advanced urothelial cancer with an encouraging tumour response. These results warrant further study of nab-paclitaxel in second-line treatment of urothelial cancer.

Source: Lancet

6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial.


Background

Since 2005, 12 months of adjuvant trastuzumab has been the standard treatment for patients with HER2-positive early-stage breast cancer. However, the optimum duration of treatment has been debated. We did a non-inferiority trial of a shorter exposure of 6 months versus the standard 12 months of trastuzumab for patients with early breast cancer.

Methods

We did an open-label, randomised, phase 3 trial in 156 centres in France. Patients with HER2-positive early breast cancer who had received at least four cycles of chemotherapy, had breast-axillary surgery, and had received up to 6 months of trastuzumab (administered by intravenous infusions over 30—90 min every 3 weeks; initial loading dose 8 mg/kg; 6 mg/kg thereafter) before randomisation were eligible. Patients were randomly assigned via central randomisation procedure with web-based software to continue trastuzumab for another 6 months (12 months total duration; control group) or to discontinue trastuzumab at 6 months (6 months total duration; experimental group). Randomisation was stratified by concomitant or sequential administration of trastuzumab with chemotherapy, oestrogen-receptor status, and centre using a minimisation algorithm. The primary endpoint was disease-free survival, with a prespecified non-inferiority margin of 1·15. Analyses were done in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00381901.

Findings

1691 patients were randomly assigned to receive 12 months of trastuzumab and 1693 to receive 6 months of trastuzumab; 1690 patients in each group were included in the intention-to-treat analyses. After a median follow-up of 42·5 months (IQR 30·1—51·6), 175 disease-free survival events were noted in the 12-month group and 219 in the 6-month group. 2-year disease-free survival was 93·8% (95% CI 92·6—94·9) in the 12-month group and 91·1% (89·7—92·4) in the 6-month group (hazard ratio 1·28, 95% CI 1·05—1·56; p=0·29). 119 (93%) of the 128 cardiac events (clinical or based on assessment of left ventricular ejection fraction) occurred while patients were receiving trastuzumab. Significantly more patients in the 12-month group experienced a cardiac event than did those in the 6-month group (96 [5·7%] of 1690 patients vs 32 [1·9%] of 1690 patients, p<0·0001).

Interpretation

After 3·5 years follow-up, we failed to show that 6 months of treatment with trastuzumab was non-inferior to 12 months of trastuzumab. Despite the higher rates of cardiac events, 12 months of adjuvant trastuzmab should remain the standard of care.

Source: Lancet

Depression and anxiety in long-term cancer survivors compared with spouses and healthy controls: a systematic review and meta-analysis..


Background

Cancer survival has improved in the past 20 years, affecting the long-term risk of mood disorders. We assessed whether depression and anxiety are more common in long-term survivors of cancer compared with their spouses and with healthy controls.

Methods

We systematically searched Medline, PsycINFO, Embase, Science Direct, Ingenta Select, Ovid, and Wiley Interscience for reports about the prevalence of mood disorders in patients diagnosed with cancer at least 2 years previously. We also searched the records of the International Psycho-oncology Society and for reports that cited relevant references. Three investigators independently extracted primary data. We did a random-effects meta-analysis of the prevalences of depression and anxiety in cancer patients compared with spouses and healthy controls.

Findings

Our search returned 144 results, 43 were included in the main analysis: for comparisons with healthy controls, 16 assessed depression and ten assessed anxiety; of the comparisons with spouses, 12 assessed depression and five assessed anxiety. The prevalence of depression was 11·6% (95% CI 7·7—16·2) in the pooled sample of 51 381 cancer survivors and 10·2% (8·0—12·6) in 217 630 healthy controls (pooled relative risk [RR] 1·11, 95% CI 0·96—1·27; p=0·17). The prevalence of anxiety was 17·9% (95% CI 12·8—23·6) in 48 964 cancer survivors and 13·9% (9·8—18·5) in 226 467 healthy controls (RR 1·27, 95% CI 1·08—1·50; p=0·0039). Neither the prevalence of depression (26·7% vs 26·3%; RR 1·01, 95% CI 0·86—1·20; p=0·88) nor the prevalence of anxiety (28·0% vs 40·1%; RR 0·71, 95% CI 0·44—1·14; p=0·16) differed significantly between cancer patients and their spouses.

Interpretation

Our findings suggest that anxiety, rather than depression, is most likely to be a problem in long-term cancer survivors and spouses compared with healthy controls. Efforts should be made to improve recognition and treatment of anxiety in long-term cancer survivors and their spouses.

Source: Lancet

Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial.


Background

Previous trials have shown that anti-EGFR monoclonal antibodies can improve clinical outcomes of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN). We assessed the efficacy and safety of panitumumab combined with cisplatin and fluorouracil as first-line treatment for these patients.

Methods

This open-label phase 3 randomised trial was done at 126 sites in 26 countries. Eligible patients were aged at least 18 years; had histologically or cytologically confirmed SCCHN; had distant metastatic or locoregionally recurrent disease, or both, that was deemed to be incurable by surgery or radiotherapy; had an Eastern Cooperative Oncology Group performance status of 1 or less; and had adequate haematological, renal, hepatic, and cardiac function. Patients were randomly assigned according to a computer-generated randomisation sequence (1:1; stratified by previous treatment, primary tumour site, and performance status) to one of two groups. Patients in both groups received up to six 3-week cycles of intravenous cisplatin (100 mg/m2 on day 1 of each cycle) and fluorouracil (1000 mg/m2 on days 1—4 of each cycle); those in the experimental group also received intravenous panitumumab (9 mg/kg on day 1 of each cycle). Patients in the experimental group could choose to continue maintenance panitumumab every 3 weeks. The primary endpoint was overall survival and was analysed by intention to treat. In a prospectively defined retrospective analysis, we assessed tumour human papillomavirus (HPV) status as a potential predictive biomarker of outcomes with a validated p16-INK4A (henceforth, p16) immunohistochemical assay. Patients and investigators were aware of group assignment; study statisticians were masked until primary analysis; and the central laboratory assessing p16 status was masked to identification of patients and treatment. This trial is registered with ClinicalTrials.gov, number NCT00460265.

Findings

Between May 15, 2007, and March 10, 2009, we randomly assigned 657 patients: 327 to the panitumumab group and 330 to the control group. Median overall survival was 11·1 months (95% CI 9·8—12·2) in the panitumumab group and 9·0 months (8·1—11·2) in the control group (hazard ratio [HR] 0·873, 95% CI 0·729—1·046; p=0·1403). Median progression-free survival was 5·8 months (95% CI 5·6—6·6) in the panitumumab group and 4·6 months (4·1—5·4) in the control group (HR 0·780, 95% CI 0·659—0·922; p=0·0036). Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group: skin or eye toxicity (62 [19%] of 325 included in safety analyses vs six [2%] of 325), diarrhoea (15 [5%] vs four [1%]), hypomagnesaemia (40 [12%] vs 12 [4%]), hypokalaemia (33 [10%] vs 23 [7%]), and dehydration (16 [5%] vs seven [2%]). Treatment-related deaths occurred in 14 patients (4%) in the panitumumab group and eight (2%) in the control group. Five (2%) of the fatal adverse events in the panitumumab group were attributed to the experimental agent. We had appropriate samples to assess p16 status for 443 (67%) patients, of whom 99 (22%) were p16 positive. Median overall survival in patients with p16-negative tumours was longer in the panitumumab group than in the control group (11·7 months [95% CI 9·7—13·7] vs8·6 months [6·9—11·1]; HR 0·73 [95% CI 0·58—0·93]; p=0·0115), but this difference was not shown for p16-positive patients (11·0 months [7·3—12·9] vs 12·6 months [7·7—17·4]; 1·00 [0·62—1·61]; p=0·998). In the control group, p16-positive patients had numerically, but not statistically, longer overall survival than did p16-negative patients (HR 0·70 [95% CI 0·47—1·04]).

Interpretation

Although the addition of panitumumab to chemotherapy did not improve overall survival in an unselected population of patients with recurrent or metastatic SCCHN, it improved progression-free survival and had an acceptable toxicity profile. p16 status could be a prognostic and predictive marker in patients treated with panitumumab and chemotherapy. Prospective assessment will be necessary to validate our biomarker findings.

Source: Lancet