Kristina Vermeersch

Prevention and management of adverse events related to regorafenib

Regorafenib is an oral multikinase inhibitor that has shown antitumor activity in a range of solid tumors. Based on data from phase III clinical trials, regorafenib is indicated for the treatment of adult patients with metastatic colorectal cancer who have previously been treated with, or are not considered candidates for, other available therapies, and in patients with advanced gastrointestinal stromal tumors that cannot be surgically removed and no longer respond to other appropriate treatments. A panel of oncology nurses, research coordinators, and other medical oncology experts, experienced in the care of patients treated with regorafenib, met to discuss the best practice for the management of regorafenib-associated adverse events (AEs). The panel agreed that, in clinical trials and daily practice with regorafenib, AEs are common but mostly manageable. The most common and/or important AEs associated with regorafenib were considered to be hand–foot skin reaction, rash or desquamation, stomatitis, diarrhea, hypertension, liver abnormalities, and fatigue. This manuscript describes the experience and recommendations of the panel for managing these AEs in everyday clinical practice. Appropriate education, monitoring, and management are considered essential for reducing the incidence, duration, and severity of regorafenib-associated AEs.

Aspergillus fumigatus Detection and Risk Factors in Patients with COPD–Bronchiectasis Overlap

The role of Aspergillus fumigatus in the airways of chronic obstructive pulmonary disease (COPD) patients with bronchiectasis is currently unclear. We searched for a sensitive and noninvasive method for A. fumigatus detection in the sputum of COPD patients and addressed potential risk factors for its presence. Induced sputum samples of 18 COPD patients and 17 COPD patients with bronchiectasis were analyzed for the presence of A. fumigatus by culture, galactomannan detection, and PCR. Of the patients with COPD–bronchiectasis overlap, 23.5% had a positive culture for A. fumigatus versus 10.5% of COPD patients without bronchiectasis (p = 0.39). The median sputum galactomannan optical density index was significantly higher in patients with COPD and bronchiectasis compared with patients with COPD alone (p = 0.026) and ranged between the levels of healthy controls and A. fumigatus-colonized cystic fibrosis patients. Both the presence of bronchiectasis and the administration of systemic corticosteroids were associated with sputum galactomannan (p = 0.0028 and p = 0.0044, respectively) and showed significant interaction (p interaction = 0.022). PCR for Aspergillus was found to be a less sensitive method, but was critically dependent on the extraction technique. The higher sputum galactomannan levels suggest a more abundant presence of A. fumigatus in the airways of patients with COPD–bronchiectasis overlap compared with patients with COPD without bronchiectasis, particularly when systemic corticosteroids are administered.

Sensitization to Aspergillus fumigatus as a risk factor for bronchiectasis in COPD

Background Bronchiectasis–chronic obstructive pulmonary disease (COPD) overlap presents a possible clinical phenotype of COPD, but it is unclear why it develops in a subset of patients. We hypothesized that sensitization to Aspergillus fumigatus (A fum) is associated with bronchiectasis in COPD and occurs more frequently in vitamin D-deficient patients. Methods This observational study investigated sensitization to A fum in an outpatient clinical cohort of 300 COPD patients and 50 (ex-) smoking controls. Total IgE, A fum-specific IgE against the crude extract and against the recombinant antigens and A fum IgG were measured using ImmunoCAP fluoroenzyme immunoassay. Vitamin D was measured by radioimmunoassay, and computed tomography images of the lungs were scored using the modified Reiff score. Results Sensitization to A fum occurred in 18% of COPD patients compared to 4% of controls (P=0.0110). In all, 31 COPD patients (10%) were sensitized to the crude extract and 24 patients (8%) had only IgE against recombinant antigens. A fum IgG levels were significantly higher in the COPD group (P=0.0473). Within COPD, A fum-sensitized patients were more often male (P=0.0293) and more often had bronchiectasis (P=0.0297). Pseudomonas aeruginosa and Serratia marcescens were more prevalent in historical sputum samples of A fum-sensitized COPD patients compared to A fum-non-sensitized COPD patients (P=0.0436). Vitamin D levels were comparable (P=0.2057). Multivariate analysis demonstrated that sensitization to recombinant f1 or f3 had a 2.8-fold increased risk for bronchiectasis (P=0.0030). Conclusion These results highlight a potential role for sensitization to A fum in COPD-related bronchiectasis.

The Belgian trial with azithromycin for acute COPD exacerbations requiring hospitalization: an investigator-initiated study protocol for a multicenter, randomized, double-blind, placebo-controlled trial

Background Long-term use of macrolide antibiotics is effective to prevent exacerbations in chronic obstructive pulmonary disease (COPD). As risks and side effects of long-term intervention outweigh the benefits in the general COPD population, the optimal dose, duration of treatment, and target population are yet to be defined. Hospitalization for an acute exacerbation (AE) of COPD may offer a targeted risk group and an obvious risk period for studying macrolide interventions. Methods/design Patients with COPD, hospitalized for an AE, who have a smoking history of ≥10 pack-years and had ≥1 exacerbation in the previous year will be enrolled in a multicenter, randomized, double-blind, placebo-controlled trial (NCT02135354). On top of a standardized treatment of systemic corticosteroids and antibiotics, subjects will be randomized to receive either azithromycin or placebo during 3 months, at an uploading dose of 500 mg once a day for 3 days, followed by a maintenance dose of 250 mg once every 2 days. The primary endpoint is the time-to-treatment failure during the treatment phase (ie, from the moment of randomization until the end of intervention). Treatment failure is a novel composite endpoint defined as either death, the admission to intensive care or the requirement of additional systemic steroids or new antibiotics for respiratory reasons, or the diagnosis of a new AE after discharge. Discussion We investigate whether azithromycin initiated at the onset of a severe exacerbation, with a limited duration and at a low dose, might be effective and safe in the highest risk period during and immediately after the acute event. If proven effective and safe, this targeted approach may improve the treatment of severe AEs and redirect the preventive use of azithromycin in COPD to a temporary intervention in the subgroup with the highest unmet needs.

Do-not-resuscitate orders as part of advance care planning in patients with COPD

There is growing awareness of the need for advance care planning in patients with chronic obstructive pulmonary disease (COPD). However, do-not-resuscitate (DNR) order implementation remains a challenge in clinical practice. We retrospectively analysed an observational cohort of 569 COPD patients with 2.5–8 years of follow-up in secondary care, to evaluate potential determinants and the prognostic significance of DNR order implementation and specification. 345 patients (61%) had no DNR order, of whom 27% died during a median (interquartile range (IQR)) follow-up of 1935 (1290–2448) days. 194 (39%) patients had a DNR order, of whom 17 had the order at baseline and 82% died (median (IQR) follow-up 528 (137–901) days), while 177 received an order during follow-up and 76% died (median (IQR) follow-up 1322 (721–2018) days). 88% of DNR orders were implemented during hospitalisation. 58% of the patients with a DNR order died within the first year after admission; of them, 66% died in the hospital. Age, forced expiratory volume in 1 s, chronic oxygen dependency and previous mechanical ventilation were significantly and independently associated with DNR order implementation. DNR order specification was significantly associated with increased mortality, even after adjustment for age and disease severity. These findings identify DNR orders as independent determinants of mortality, mainly implemented just before death. DNR orders in COPD patients are preferentially given to older patients with severe disease and are usually implemented during hospitalisation, close to the moment of death. Early end-of-life care planning in COPD remains difficult and challenging http://ow.ly/BGJk30hJCZ5

Significance of prolonged QTc in acute exacerbations of COPD requiring hospitalization

Background A prolonged QT interval is associated with increased risk of Torsade de Pointes and cardiovascular death. The prevalence and clinical relevance of QT prolongation in acute exacerbations of COPD (AECOPD), with high risk for cardiac morbidity and mortality, is currently unclear. Methods A dual cross-sectional study strategy was therefore designed. A retrospective study evaluated 140 patients with an AECOPD requiring hospitalization, half of which had prolonged QTc on the admission ECG. Univariate and multivariate analyses were conducted to determine associated factors; Kaplan–Meier and Cox regression analyses to assess prognostic significance. A prospective study evaluated 180 pulmonary patients with acute respiratory problems requiring hospitalization, to determine whether a prolonged QTc at admission represents an AECOPD-specific finding and to investigate the change in QTc-duration during hospitalization. Results Retrospectively, hypokalemia, cardiac troponin T and conductance abnormalities on ECG were significantly and independently associated with QTc prolongation. A prolonged QTc was associated with increased all-cause mortality (HR 2.698 (95% CI 1.032–7.055), p=0.043), however, this association was no longer significant when corrected for age, FEV1 and cardiac troponin T. Prospectively, QTc prolongation was observed in 1/3 of the patients diagnosed with either an AECOPD, lung cancer, pulmonary infection or miscellaneous acute pulmonary disease, and was not more prevalent in AECOPD. The QTc-duration decreased significantly during hospitalization in patients with and without COPD. Conclusion A prolonged QTc is a marker of underlying cardiovascular disease during an AECOPD. It is not COPD-specific, but a common finding during the acute phase of a pulmonary disease requiring urgent hospital admission.