SCOPE1: a randomised phase II/III multicentre clinical trial of definitive chemoradiation, with or without cetuximab, in carcinoma of the oesophagus

<p>Abstract</p> <p>Background</p> <p>Chemoradiotherapy is the standard of care for patients with oesophageal cancer unsuitable for surgery due to the presence of co-morbidity or extent of disease, and is a standard treatment option for patients with squamous cell carcinoma of the oesophagus. Modern regimens of chemoradiotherapy can lead to significant long-term survival. However the majority of patients will die of their disease, most commonly with local progression/recurrence of their tumours. Cetuximab may overcome one of the principal mechanisms of tumour radio-resistance, namely tumour repopulation, in patients treated with chemoradiotherapy.</p> <p>The purpose of this research is first to determine whether the addition of cetuximab to definitive chemoradiotherapy for treatment of patients with non-metastatic carcinoma of the oesophagus is active (in terms of failure-free rate), safe, and feasible within the context of a multi-centre randomised controlled trial in the UK. If the first stage is successful then the trial will continue to accrue sufficient patients to establish whether the addition of cetuximab to the standard treatment improves overall survival.</p> <p>Methods/Design</p> <p>SCOPE1 is a two arm, open, randomised multicentre Phase II/III trial. Eligible patients will have histologically confirmed carcinoma of the oesophagus and have been chosen to receive definitive chemoradiotherapy by an accredited multidisciplinary team including a specialist Upper GI surgeon. 420 patients will be randomised to receive definitive chemoradiotherapy with or without cetuximab using a 1:1 allocation ratio.</p> <p>During Phase II of the study, the trial will assess safety (toxicity), activity (failure-free rate) and feasibility (recruitment rate and protocol dose modifications/delays) in 90 patients in the experimental arm. If the experimental arm is found to be active, safe, and feasible by the Independent Data Monitoring Committee then recruitment will continue into Phase III. This second stage will recruit a further 120 patients into each arm and compare the overall survival of both groups.</p> <p>All patients randomised into Phase II will contribute to the Phase III comparison of overall survival. In addition to overall survival, Phase III of the study will also assess toxicity, health related quality of life and cost effectiveness. A detailed radiotherapy protocol and quality assurance procedure has been incorporated into this trial.</p> <p>Trial registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN47718479">ISRCTN47718479</a></p

Efficacy of early PET-CT directed switch to carboplatin and paclitaxel based definitive chemoradiotherapy in patients with oesophageal cancer who have a poor early response to induction cisplatin and capecitabine in the UK: a multi-centre randomised controlled phase II trial induction cisplatin and capecitabine in the UK: a multi-centre randomised controlled phase II trial

Background: The utility of early metabolic response assessment to guide selection of the systemic component of definitive chemoradiotherapy (dCRT) for oesophageal cancer is uncertain.// Methods: In this multi-centre, randomised, open-label, phase II substudy of the radiotherapy dose-escalation SCOPE2 trial we evaluated the role of 18F-Fluorodeoxyglucose positron emission tomography (PET) at day 14 of cycle 1 of three-weekly induction cis/cap (cisplatin (60 mg/m2)/capecitabine (625 mg/m2 days 1–21)) in patients with oesophageal squamous cell carcinoma (OSCC) or adenocarcinoma (OAC). Non-responders, who had a less than 35% reduction in maximum standardised uptake value (SUVmax) from pre-treatment baseline, were randomly assigned to continue cis/cap or switch to car/pac (carboplatin AUC 5/paclitaxel 175 mg/m2) for a further induction cycle, then concurrently with radiotherapy over 25 fractions. Responders continued cis/cap for the duration of treatment. All patients (including responders) were randomised to standard (50Gy) or high (60Gy) dose radiation as part of the main study. Primary endpoint for the substudy was treatment failure-free survival (TFFS) at week 24. The trial was registered with International Standard Randomized Controlled Trial Number 97125464 and ClinicalTrials.gov NCT02741856.// Findings: This substudy was closed on 1st August 2021 by the Independent Data Monitoring Committee on the grounds of futility and possible harm. To this point from 22nd November 2016, 103 patients from 16 UK centres had participated in the PET-CT substudy; 63 (61.2%; 52/83 OSCC, 11/20 OAC) of whom were non-responders. Of these, 31 were randomised to car/pac and 32 to remain on cis/cap. All patients were followed up until at least 24 weeks, at which point in OSCC both TFFS (25/27 (92.6%) vs 17/25 (68%); p = 0.028) and overall survival (42.5 vs. 20.4 months, adjusted HR 0.36; p = 0.018) favoured cis/cap over car/pac. There was a trend towards worse survival in OSCC + OAC cis/cap responders (33.6 months; 95%CI 23.1-nr) vs. non-responders (42.5 (95%CI 27.0-nr) months; HR = 1.43; 95%CI 0.67–3.08; p = 0.35).// Interpretation: In OSCC, early metabolic response assessment is not prognostic for TFFS or overall survival and should not be used to personalise systemic therapy in patients receiving dCRT

Searching for Programme theories for a realist evaluation: a case study comparing an academic database search and a simple Google search

Background: Realist methodologies are increasingly being used to evaluate complex interventions in health and social care. Programme theory (ideas and assumptions of how a particular intervention works) development is the first step in a realist evaluation or a realist synthesis, with literature reviews providing important evidence to support this. Deciding how to search for programme theories is challenging and there is limited guidance available. Using an example of identifying programme theories for a realist evaluation of Pressure Ulcer Risk Assessment Instruments in clinical practice, the authors explore and compare several different approaches to literature searching and highlight important methodological considerations for those embarking on a programme theory review. Methods: We compared the performance of an academic database search with a simple Google search and developed an optimised search strategy for the identification primary references (i.e. documents providing the clearest examples of programme theories) associated with the use of Pressure Ulcer Risk Assessment Instruments (PU-RAIs). We identified the number of primary references and the total number of references retrieved per source. We then calculated the number needed to read (NNR) expressed as the total number of titles and abstracts screened to identify one relevant reference from each source. Results: The academic database search (comprising CINAHL, The Cochrane Library, EMBASE, HMIC, Medline) identified 2 /10 primary references with a NNR of 1395.The Google search identified 7/10 primary references with a NNR of 10.1. The combined NNR was 286.3. The optimised search combining Google and CINAHL identified 10/10 primary references with a NNR of 40.2. Conclusion: The striking difference between the efficiency of the review’s academic database and Google searches in finding relevant references prompted an in-depth comparison of the two types of search. The findings indicate the importance of including grey literature sources such as Google in this particular programme theory search, while acknowledging the need for transparency of methods. Further research is needed to facilitate improved guidance for programme theory searches to enhance practice in the realist field and to save researcher time and therefore resource

Hidden depletion of fat-free mass and bone mineral density in adults with cystic fibrosis

Background Weight loss is associated with reduced survival in patients with cystic fibrosis (CF). Objective We hypothesized that some adult patients with a normal body mass index (BMI) have evidence of hidden fat-free mass (FFM) and bone mineral density (BMD) depletion that is linked to more severe disease. Design Fat mass (FM), FFM, and BMD were determined by dual-energy x-ray absorptiometry (DXA) and by bioelectric impedance in 56 adults in clinically stable condition and 20 age-matched healthy subjects. FM index and FFM index (FFMI) [kilograms per meter squared] of the right arm, leg, and trunk (ratio to height squared) were calculated. Lung function, including the maximum inspiratory pressure (MIP) and sustained MIP (SMIP), physical activity, serum C-reactive protein (CRP) and the number of exacerbations in the previous year were recorded. Results Patients had a lower total FFM than healthy subjects (p < 0.01), while FM was similar. Of the 56 patients, 30 patients had a normal BMI, of which 12 patients had a low FFM (hidden loss) by DXA. The right arm, leg, and trunk FFMI and BMD at hip sites were less in these patients than in those with a normal BMI and normal FFM (all p < 0.01). This group had a lower FEV1, SMIP, more frequent exacerbations, and greater circulating CRP (all p < 0.05). Conclusions In adults with CF, apparent or hidden loss of FFM, rather than weight loss, was related to overall disease severity. Hidden depletion of FFM was associated with increased loss of BMD and systemic inflammatory activity

Bone density, body composition, and inflammatory status in Cystic Fibrosis

Low body weight and loss of bone mass are major problems in adults with cystic fibrosis (CF) and chronic pulmonary infection. Although these complications probably have a multifactorial origin, we hypothesized that the continuous acute-phase inflammatory and catabolic state may contribute. We determined body composition, bone turnover, physical activity, and circulating interleukin-6 (IL-6), tumor necrosis factor- α (TNF- α ), and their soluble receptors in 22 adults with CF and 22 age- and sex-matched healthy subjects. Comparisons were also made within patients before and after treatment of an exacerbation of respiratory symptoms. The patients had a lower mean (95% confidence interval [CI]) fat-free mass (FFM) 39.9 (36.3, 43.6) kg than healthy subjects, 49.4 (45.1, 53.7) kg, p < 0.05. The patients were in negative nitrogen balance and 20 had bone mineral density (BMD) Z scores ⩽ 2.5 SD (n = 13) or ⩽ 1 SD (n = 7) at least at one site. They had increased bone collagen breakdown, greatest in those with a reduced FFM. BMD was related to FEV1 (r = 0.44), IL-6 (r = − 0.60), and TNF- α -soluble receptors (r = − 0.42, r = − 0.50). Patients with a low FFM had greater concentrations of IL-6, which suppressed less after antibiotic treatment than in those with a normal FFM. Those with a low FFM were more catabolic and less active than those with a normal FFM. The association between altered body composition, catabolic status, and circulating inflammatory mediators suggests that chronic pulmonary infection in adults with CF may be a contributory factor in the long-term complications of low weight and bone disease. Attainment of adulthood is now common in cystic fibrosis (CF) and survival continues to increase. Such patients experience chronic pulmonary infection from very early in life, which is a major determinant of survival because of its association with lung destruction (1). Additionally, failure to maintain body weight is an indicator of a poor prognosis. The major complications emerging with longer survival are failure to maintain body mass, osteoporosis, and diabetes mellitus (1-10). These metabolic complications have an impact on morbidity as well as mortality. Loss of fat-free mass (FFM) impairs skeletal muscle function including the inspiratory muscles and adds to the severity of pulmonary compromise (11, 12). Reduction in both bone mineral density (BMD) and FFM may be linked by physical inactivity, possible malabsorption, corticosteroid therapy, reduced sex hormone levels, increased resting energy expenditure (REE), and hypoinsulinemia associated with diabetes mellitus. An additional metabolic possibility is a generalized loss of body protein secondary to an association between chronic lung disease and a catabolic intermediary metabolism. Chronic pulmonary infection with associated continuous inflammatory and catabolic responses present in patients even when clinically stable may affect body composition (13). This catabolic state as part of the stress response to infection and inflammation could be mediated by the combined effects of catecholamines, proinflammatory cytokines such as interleukins 1β and 6 (IL-1β, IL-6) and tumor necrosis factor-α (TNF-α), and stress-response hormones such as cortisol, and induce protein breakdown in muscle and bone (13, 14). Supporting a link between the lung disease in CF and body composition is the effect of antibiotic treatment of an exacerbation of respiratory symptoms, which partially reduces the inflammatory response with a modest weight gain (15, 16). We hypothesized that the normally host-protective, acute-phase inflammatory and catabolic responses are sustained in patients with CF and chronic pulmonary infection, and add to other mechanisms of weight loss and bone demineralization. Such links have been suggested to occur in human immunodeficiency virus (HIV) infection, cancer, and cardiac failure where cachexia is associated with excess procatabolic hormones and increased circulating inflammatory mediators (17– 20). To test these ideas, we studied adult patients with CF and chronic pulmonary infection during an exacerbation of respiratory symptoms and its treatment to determine relationships between the host inflammatory response, body composition, bone protein turnover, and catabolic status

Bone Density, Body Composition, and Inflammatory Status in Cystic Fibrosis

Low body weight and loss of bone mass are major problems in adults with cystic fibrosis (CF) and chronic pulmonary infection. Although these complications probably have a multifactorial origin, we hypothesized that the continuous acute-phase inflammatory and catabolic state may contribute. We determined body composition, bone turnover, physical activity, and circulating interleukin-6 (IL-6), tumor necrosis factor- α (TNF- α ), and their soluble receptors in 22 adults with CF and 22 age- and sex-matched healthy subjects. Comparisons were also made within patients before and after treatment of an exacerbation of respiratory symptoms. The patients had a lower mean (95% confidence interval [CI]) fat-free mass (FFM) 39.9 (36.3, 43.6) kg than healthy subjects, 49.4 (45.1, 53.7) kg, p < 0.05. The patients were in negative nitrogen balance and 20 had bone mineral density (BMD) Z scores ⩽ 2.5 SD (n = 13) or ⩽ 1 SD (n = 7) at least at one site. They had increased bone collagen breakdown, greatest in those with a reduced FFM. BMD was related to FEV1 (r = 0.44), IL-6 (r = − 0.60), and TNF- α -soluble receptors (r = − 0.42, r = − 0.50). Patients with a low FFM had greater concentrations of IL-6, which suppressed less after antibiotic treatment than in those with a normal FFM. Those with a low FFM were more catabolic and less active than those with a normal FFM. The association between altered body composition, catabolic status, and circulating inflammatory mediators suggests that chronic pulmonary infection in adults with CF may be a contributory factor in the long-term complications of low weight and bone disease. Attainment of adulthood is now common in cystic fibrosis (CF) and survival continues to increase. Such patients experience chronic pulmonary infection from very early in life, which is a major determinant of survival because of its association with lung destruction (1). Additionally, failure to maintain body weight is an indicator of a poor prognosis. The major complications emerging with longer survival are failure to maintain body mass, osteoporosis, and diabetes mellitus (1-10). These metabolic complications have an impact on morbidity as well as mortality. Loss of fat-free mass (FFM) impairs skeletal muscle function including the inspiratory muscles and adds to the severity of pulmonary compromise (11, 12). Reduction in both bone mineral density (BMD) and FFM may be linked by physical inactivity, possible malabsorption, corticosteroid therapy, reduced sex hormone levels, increased resting energy expenditure (REE), and hypoinsulinemia associated with diabetes mellitus. An additional metabolic possibility is a generalized loss of body protein secondary to an association between chronic lung disease and a catabolic intermediary metabolism. Chronic pulmonary infection with associated continuous inflammatory and catabolic responses present in patients even when clinically stable may affect body composition (13). This catabolic state as part of the stress response to infection and inflammation could be mediated by the combined effects of catecholamines, proinflammatory cytokines such as interleukins 1β and 6 (IL-1β, IL-6) and tumor necrosis factor-α (TNF-α), and stress-response hormones such as cortisol, and induce protein breakdown in muscle and bone (13, 14). Supporting a link between the lung disease in CF and body composition is the effect of antibiotic treatment of an exacerbation of respiratory symptoms, which partially reduces the inflammatory response with a modest weight gain (15, 16). We hypothesized that the normally host-protective, acute-phase inflammatory and catabolic responses are sustained in patients with CF and chronic pulmonary infection, and add to other mechanisms of weight loss and bone demineralization. Such links have been suggested to occur in human immunodeficiency virus (HIV) infection, cancer, and cardiac failure where cachexia is associated with excess procatabolic hormones and increased circulating inflammatory mediators (17– 20). To test these ideas, we studied adult patients with CF and chronic pulmonary infection during an exacerbation of respiratory symptoms and its treatment to determine relationships between the host inflammatory response, body composition, bone protein turnover, and catabolic status