Summary Background Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) progressing after first-line platinum regimens have a poor prognosis and few treatment ...options. Afatinib, an irreversible ERBB family blocker, has shown efficacy in a phase 2 study in this setting. We aimed to assess the efficacy and safety of afatinib compared with methotrexate as second-line treatment in patients with recurrent or metastatic HNSCC progressing on or after platinum-based therapy. Methods In this open-label, phase 3, randomised controlled trial conducted in 101 centres in 19 countries, we enrolled patients aged 18 years or older with histologically or cytologically confirmed HNSCC that was recurrent, metastatic, or both who had progressed on or after first-line platinum-based therapy, were not amenable for salvage surgery or radiotherapy, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Previous treatment with more than one systemic regimen in this setting was not allowed; previous treatment with EGFR-targeted antibody therapy (but not EGFR-targeted tyrosine-kinase inhibitors) was allowed. We randomly assigned eligible patients in a 2:1 ratio to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m2 per week), stratified by ECOG performance status and previous EGFR-targeted antibody therapy for recurrent or metastatic disease. Randomisation was done centrally with an interactive voice or web-based response system. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. The primary endpoint was progression-free survival as assessed by an independent, central imaging review committee. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov , number NCT01345682. Findings Between Jan 10, 2012, and Dec 12, 2013, we enrolled 483 patients and randomly assigned 322 to afatinib and 161 to methotrexate. After a median follow-up of 6·7 months (IQR 3·1–9·0), progression-free survival was longer in the afatinib group than in the methotrexate group (median 2·6 months 95% CI 2·0–2·7 for the afatinib group vs 1·7 months 1·5–2·4 for the methotrexate group; hazard ratio HR 0·80 95% CI 0·65–0·98, p=0·030). The most frequent grade 3 or 4 drug-related adverse events were rash or acne (31 10% of 320 patients in the afatinib group vs none of 160 patients in the methotrexate group), diarrhoea (30 9% vs three 2%), stomatitis (20 6% vs 13 8%), fatigue (18 6% vs five 3%), and neutropenia (1 <1% vs 11 7%); serious adverse events occurred in 44 (14%) of afatinib-treated patients and 18 (11%) of methotrexate-treated patients. Interpretation Afatinib was associated with significant improvements in progression-free survival and had a manageable safety profile. These findings provide important new insights into the treatment of this patient population and support further investigations with irreversible ERBB family blockers in HNSCC. Funding Boehringer Ingelheim.
Summary Background Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and ...fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer. Methods In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB–IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m2 ) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2–21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT01015118. Findings Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (17·2 months 95% CI 16·6–19·9 vs 16·6 months 13·9–19·1; hazard ratio 0·84 95% CI 0·72–0·98; p=0·024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 21% of 902 grade 3 and three <1% grade 4 vs placebo group nine 2% of 450 grade 3 only) and haematological (neutropenia: nintedanib group 180 20% grade 3 and 200 (22%) grade 4 vs placebo group 90 20% grade 3 and 72 16% grade 4; thrombocytopenia: 105 12% and 55 6% vs 21 5% and eight 2%; anaemia: 108 12% and 13 1% vs 26 6% and five 1%). Serious adverse events were reported in 376 (42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in the placebo group. 29 (3%) of 902 patients in the nintedanib group experienced serious adverse events associated with death compared with 16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib group and six (1%) in the placebo group with a malignant neoplasm progression classified as an adverse event by the investigator. Drug-related adverse events leading to death occurred in three patients in the nintedanib group (one without diagnosis of cause; one due to non-drug-related sepsis associated with drug-related diarrhoea and renal failure; and one due to peritonitis) and in one patient in the placebo group (cause unknown). Interpretation Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability. Funding Boehringer Ingelheim.
Rationale Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is an entity well differentiated from NSAID-induced urticaria/angioedema (NIUA).
Gut microbiota provides beneficial effects under physiological conditions, but is able to contribute to inflammatory diseases in susceptible individuals. Thus, we designed this study to test whether ...additional intake of symbiotic gel affects specific modifications of gut microbiota in patients with end-stage renal disease (ESRD).
Eighteen patients with ESRD diagnosis with renal replacement therapy (hemodialysis) were included in this study. They were randomly assigned to 2 treatment groups: (1) test group (nutritional counseling + symbiotic) and (2) control group (nutritional counseling + placebo). Clinical history and the evaluation of Gastrointestinal Symptom Rating Scale were performed. Gut microbiota composition was analyzed by real-time polymerase chain reaction from fecal samples. All subjects were followed for 2 months.
Bifidobacterial counts were higher in the second samples (mean: 5.5 ± 1.72 log10 cells/g) than in first samples (4.2 ± 0.88 log 10 cells/g) in the patients of the test group (P = .0344). Also, lactobacilli counts had a little decrease in the test group (2.3 ± 0.75 to 2.0 ± 0.88 log 10 cells/g) and the control group (2.2 ± 0.90 to 1.8 ± 1.33 log 10 cells/g), between the first and the second samples. Gastrointestinal symptoms scores (scale 8-40) were reduced in the test group (start 12 10-14 and end 9 8-10) compared with control group (start 11 8-21 and end 11 9-15).
Short-term symbiotic treatment in patients with ESRD can lead to the increase of Bifidobacterium counts, maintaining the intestinal microbial balance.
We retrospectively analyzed the predictive factors of successfully electrical cardioversion in patients with chronic atrial fibrillation.
We included 118 patients, 68 men and 50 women, with a mean ...age of 65.1 years and a length of arrhythmia evolution of 83.3 days. These patients consecutively underwent electrical cardioversion in our Cardiology Department with a follow-up of one year to determine relapses. Structural cardiopathy was observed in 63.6% of the patients and 43.7% presented a left atrium between 4 and 5 cms. We analyzed the clinical and echocardiographic factors which predict the acute and first year success of electrical cardioversion.
The cardioversion was effective in 73.7% (CI 95%, 64.6%-81.1%) of the patients and 35.6% (CI 95%, 25.8%-46.6%) had a relapse within the first year. The inexistence of cardiomyopathy and therapy with amiodarone were predictive of acute success (p < 0.04 and p < 0.03, respectively). The length of arrhythmia evolution did not predict acute success but did so when relapses were analyzed. The size of the left atrium is predictive of both acute and long term success (p < 0.02 and p < 0.001, respectively). Logistic regression showed that the size of the left atrium and the patient's age were the only predictive factors of acute and first year success.
Electrical cardioversion is very efficient in the short-term, despite numerous relapses. Patient age and the size of left atrium are associated with acute and long-term success of cardioversion.
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