The effects of cancer therapies on physical fitness before oesophagogastric cancer surgery: a prospective, blinded, multi-centre, observational, cohort study [version 1; peer review: 2 approved]

Background: Neoadjuvant cancer treatment is associated with improved survival following major oesophagogastric cancer surgery. The impact of neoadjuvant chemo/chemoradiotherapy on physical fitness and operative outcomes is however unclear. This study aims to investigate the impact of neoadjuvant chemo/chemoradiotherapy on fitness and post-operative mortality. / Methods: Patients with oesophagogastric cancer scheduled for chemo/chemoradiotherapy and surgery were recruited to a prospective, blinded, multi-centre, observational cohort study. Primary outcomes were changes in fitness with chemo/chemoradiotherapy, measured using cardiopulmonary exercise testing and its association with mortality one-year after surgery. Patients were followed up for re-admission at 30-days, in-hospital morbidity and quality of life (exploratory outcomes). / Results: In total, 384 patients were screened, 217 met the inclusion criteria, 160 consented and 159 were included (72% male, mean age 65 years). A total of 132 patients (83%) underwent chemo/chemoradiotherapy, 109 (71%) underwent chemo/chemoradiotherapy and two exercise tests, 100 (63%) completed surgery and follow-up. A significant decline in oxygen uptake at anaerobic threshold and oxygen uptake peak was observed following chemo/chemoradiotherapy: -1.25ml.kg-1.min-1 (-1.80 to -0.69) and -3.02ml.kg-1.min-1 (-3.85 to -2.20); p<0.0001). Baseline chemo/chemoradiotherapy anaerobic threshold and peak were associated with one-year mortality (HR=0.72, 95%CI 0.59 to 0.88; p=0.001 and HR=0.85, 0.76 to 0.95; p=0.005). The change in physical fitness was not associated with one-year mortality. / Conclusion: Chemo/chemoradiotherapy prior to oesophagogastric cancer surgery reduced physical fitness. Lower baseline fitness was associated with reduced overall survival at one-year. Careful consideration of fitness prior to chemo/chemoradiotherapy and surgery is urgently needed

The effect of neoadjuvant chemotherapy and chemoradiotherapy on exercise capacity and outcome following upper gastrointestinal cancer surgery: an observational cohort study

Background: In 2014 approximately 21,200 patients were diagnosed with oesophageal and gastric cancer in England and Wales, of whom 37 % underwent planned curative treatments. Potentially curative surgical resection is associated with significant morbidity and mortality. For operable locally advanced disease, neoadjuvant chemotherapy (NAC) improves survival over surgery alone. However, NAC carries the risk of toxicity and is associated with a decrease in physical fitness, which may in turn influence subsequent clinical outcome. Lower levels of physical fitness are associated with worse outcome following major surgery in general and Upper Gastrointestinal Surgery (UGI) surgery in particular. Cardiopulmonary exercise testing (CPET) provides an objective assessment of physical fitness. The aim of this study is to test the hypothesis that NAC prior to upper gastrointestinal cancer surgery is associated with a decrease in physical fitness and that the magnitude of the change in physical fitness will predict mortality 1 year following surgery.Methods: This study is a multi-centre, prospective, blinded, observational cohort study of participants with oesophageal and gastric cancer scheduled for neoadjuvant cancer treatment (chemo- and chemoradiotherapy) and surgery. The primary endpoints are physical fitness (oxygen uptake at lactate threshold measured using CPET) and 1-year mortality following surgery; secondary endpoints include post-operative morbidity (Post-Operative Morbidity Survey (POMS)) 5 days after surgery and patient related quality of life (EQ-5D-5 L).Discussion: The principal benefits of this study, if the underlying hypothesis is correct, will be to facilitate better selection of treatments (e.g. NAC, Surgery) in patients with oesophageal or gastric cancer. It may also be possible to develop new treatments to reduce the effects of neoadjuvant cancer treatment on physical fitness. These results will contribute to the design of a large, multi-centre trial to determine whether an in-hospital exercise-training programme that increases physical fitness leads to improved overall survival.<br/

A perspective on SIDS pathogenesis. The hypotheses: plausibility and evidence

Several theories of the underlying mechanisms of Sudden Infant Death Syndrome (SIDS) have been proposed. These theories have born relatively narrow beach-head research programs attracting generous research funding sustained for many years at expense to the public purse. This perspective endeavors to critically examine the evidence and bases of these theories and determine their plausibility; and questions whether or not a safe and reasoned hypothesis lies at their foundation. The Opinion sets specific criteria by asking the following questions: 1. Does the hypothesis take into account the key pathological findings in SIDS? 2. Is the hypothesis congruent with the key epidemiological risk factors? 3. Does it link 1 and 2? Falling short of any one of these answers, by inference, would imply insufficient grounds for a sustainable hypothesis. Some of the hypotheses overlap, for instance, notional respiratory failure may encompass apnea, prone sleep position, and asphyxia which may be seen to be linked to co-sleeping. For the purposes of this paper, each element will be assessed on the above criteria

Continuous positive airway pressure versus standard care for the treatment of people with mild obstructive sleep apnoea (MERGE): a multicentre, randomised controlled trial

BACKGROUND: The evidence base for the treatment of mild obstructive sleep apnoea is limited and definitions of disease severity vary. The MERGE trial investigated the clinical effectiveness of continuous positive airway pressure in patients with mild obstructive sleep apnoea. METHODS: MERGE, a multicentre, parallel, randomised controlled trial enrolled patients (≥18 years to ≤80 years) with mild obstructive sleep apnoea (apnoea-hypopnoea index [AHI] ≥5 to ≤15 events per h using either AASM 2007 or AASM 2012 scoring criteria) from 11 UK sleep centres. Participants were assigned (1:1) to either 3 months of continuous positive airway pressure plus standard care (sleep counselling), or standard care alone, by computer-generated randomisation; neither participants nor researchers were blinded. The primary outcome was a change in the score on the Short Form-36 questionnaire vitality scale in the intention-to-treat population of patients with mild obstructive sleep apnoea diagnosed using the American Academy of Sleep Medicine 2012 scoring criteria. The study is registered with ClinicalTrials.gov, NCT02699463. FINDINGS: Between Nov 28, 2016 and Feb 12, 2019, 301 patients were recruited and randomised. 233 had mild obstructive sleep apnoea using AASM 2012 criteria and were included in the intention-to-treat analysis: 115 were allocated to receive continuous positive airway pressure and 118 to receive standard care. 209 (90%) of these participants completed the trial. The vitality score significantly increased with a treatment effect of a mean of 10·0 points (95% CI 7·2-12·8; p<0·0001) after 3 months of continuous positive airway pressure, compared with standard care alone (9·2 points [6·8 to 11·6] vs -0·8 points [-3·2 to 1·5]). Using the ANCOVA last-observation-carried-forward analysis, a more conservative estimate, the vitality score also significantly increased with a treatment effect of a mean of 7·5 points (95% CI 5·3 to 9·6; p<0·0001) after 3 months of continuous positive airway pressure, compared with standard care alone (7·5 points [6·0 to 9·0] vs 0·0 points [-1·5 to 1·5]). Three serious adverse events occurred (one allocated to the continuous positive airway pressure group) and all were unrelated to the intervention. INTERPRETATION: 3 months of treatment with continuous positive airway pressure improved the quality of life in patients with mild obstructive sleep apnoea. These results highlight the need for health-care professionals and providers to consider treatment for patients with mild obstructive sleep apnoea. FUNDING: ResMed Ltd