Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.

Chemoradiotherapy is the standard of care for unresected locally advanced squamous cell carcinoma of the head and neck. We aimed to assess if addition of avelumab (anti-PD-L1) to chemoradiotherapy could improve treatment outcomes for this patient population. In this randomised, double-blind, placebo-controlled, phase 3 study, patients were recruited from 196 hospitals and cancer treatment centres in 22 countries. Patients aged 18 years or older, with histologically confirmed, previously untreated, locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx, or oral cavity (unselected for PD-L1 status), an Eastern Cooperative Oncology Group performance status score of 0 or 1, and who could receive chemoradiotherapy were eligible. Patients were randomly assigned (1:1) centrally by means of stratified block randomisation with block size four (stratified by human papillomavirus status, tumour stage, and nodal stage, and done by an interactive response technology system) to receive 10 mg/kg avelumab intravenously every 2 weeks plus chemoradiotherapy (100 mg/m <sup>2</sup> cisplatin every 3 weeks plus intensity-modulated radiotherapy with standard fractionation of 70 Gy [35 fractions during 7 weeks]; avelumab group) or placebo plus chemoradiotherapy (placebo group). This was preceded by a single 10 mg/kg avelumab or placebo lead-in dose given 7 days previously and followed by 10 mg/kg avelumab or placebo every 2 weeks maintenance therapy for up to 12 months. The primary endpoint was progression-free survival by investigator assessment per modified Response Evaluation Criteria in Solid Tumors, version 1.1, in all randomly assigned patients. Adverse events were assessed in patients who received at least one dose of avelumab or placebo. This trial is registered with ClinicalTrials.gov, NCT02952586. Enrolment is no longer ongoing, and the trial has been discontinued. Between Dec 12, 2016, and Jan 29, 2019, from 907 patients screened, 697 patients were randomly assigned to the avelumab group (n=350) or the placebo group (n=347). Median follow-up for progression-free survival was 14·6 months (IQR 8·5-19·6) in the avelumab group and 14·8 months (11·6-18·8) in the placebo group. Median progression-free survival was not reached (95% CI 16·9 months-not estimable) in the avelumab group and not reached (23·0 months-not estimable) in the placebo group (stratified hazard ratio 1·21 [95% CI 0·93-1·57] favouring the placebo group; one-sided p=0·92). The most common grade 3 or worse treatment-related adverse events were neutropenia (57 [16%] of 348 patients in the avelumab group vs 52 [15%] of 344 patients in the placebo group), mucosal inflammation (50 [14%] vs 45 [13%]), dysphagia (49 [14%] vs 47 [14%]), and anaemia (41 [12%] vs 44 [13%]). Serious treatment-related adverse events occurred in 124 (36%) patients in the avelumab group and in 109 (32%) patients in the placebo group. Treatment-related deaths occurred in two (1%) patients in the avelumab group (due to general disorders and site conditions, and vascular rupture) and one (<1%) in the placebo group (due to acute respiratory failure). The primary objective of prolonging progression-free survival with avelumab plus chemoradiotherapy followed by avelumab maintenance in patients with locally advanced squamous cell carcinoma of the head and neck was not met. These findings may help inform the design of future trials investigating the combination of immune checkpoint inhibitors plus CRT. Pfizer and Merck KGaA, Darmstadt, Germany

Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial

Background: Chemoradiotherapy is the standard of care for unresected locally advanced squamous cell carcinoma of the head and neck. We aimed to assess if addition of avelumab (anti-PD-L1) to chemoradiotherapy could improve treatment outcomes for this patient population. Methods: In this randomised, double-blind, placebo-controlled, phase 3 study, patients were recruited from 196 hospitals and cancer treatment centres in 22 countries. Patients aged 18 years or older, with histologically confirmed, previously untreated, locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx, or oral cavity (unselected for PD-L1 status), an Eastern Cooperative Oncology Group performance status score of 0 or 1, and who could receive chemoradiotherapy were eligible. Patients were randomly assigned (1:1) centrally by means of stratified block randomisation with block size four (stratified by human papillomavirus status, tumour stage, and nodal stage, and done by an interactive response technology system) to receive 10 mg/kg avelumab intravenously every 2 weeks plus chemoradiotherapy (100 mg/m2 cisplatin every 3 weeks plus intensity-modulated radiotherapy with standard fractionation of 70 Gy [35 fractions during 7 weeks]; avelumab group) or placebo plus chemoradiotherapy (placebo group). This was preceded by a single 10 mg/kg avelumab or placebo lead-in dose given 7 days previously and followed by 10 mg/kg avelumab or placebo every 2 weeks maintenance therapy for up to 12 months. The primary endpoint was progression-free survival by investigator assessment per modified Response Evaluation Criteria in Solid Tumors, version 1.1, in all randomly assigned patients. Adverse events were assessed in patients who received at least one dose of avelumab or placebo. This trial is registered with ClinicalTrials.gov, NCT02952586. Enrolment is no longer ongoing, and the trial has been discontinued. Findings: Between Dec 12, 2016, and Jan 29, 2019, from 907 patients screened, 697 patients were randomly assigned to the avelumab group (n=350) or the placebo group (n=347). Median follow-up for progression-free survival was 14·6 months (IQR 8·5–19·6) in the avelumab group and 14·8 months (11·6–18·8) in the placebo group. Median progression-free survival was not reached (95% CI 16·9 months–not estimable) in the avelumab group and not reached (23·0 months–not estimable) in the placebo group (stratified hazard ratio 1·21 [95% CI 0·93–1·57] favouring the placebo group; one-sided p=0·92). The most common grade 3 or worse treatment-related adverse events were neutropenia (57 [16%] of 348 patients in the avelumab group vs 52 [15%] of 344 patients in the placebo group), mucosal inflammation (50 [14%] vs 45 [13%]), dysphagia (49 [14%] vs 47 [14%]), and anaemia (41 [12%] vs 44 [13%]). Serious treatment-related adverse events occurred in 124 (36%) patients in the avelumab group and in 109 (32%) patients in the placebo group. Treatment-related deaths occurred in two (1%) patients in the avelumab group (due to general disorders and site conditions, and vascular rupture) and one (<1%) in the placebo group (due to acute respiratory failure). Interpretation: The primary objective of prolonging progression-free survival with avelumab plus chemoradiotherapy followed by avelumab maintenance in patients with locally advanced squamous cell carcinoma of the head and neck was not met. These findings may help inform the design of future trials investigating the combination of immune checkpoint inhibitors plus CRT. Funding: Pfizer and Merck KGaA, Darmstadt, Germany. © 2021 Elsevier Lt

Modeling time-to-cure from severe acute malnutrition: application of various parametric frailty models

BACKGROUND: In developing countries about 3.5% of children aged 0–5 years are victims of severe acute malnutrition (SAM). Once the morbidity has developed the cure process takes variable period depending on various factors. Knowledge of time-to-cure from SAM will enable health care providers to plan resources and monitor the progress of cases with SAM. The current analysis presents modeling time-to-cure from SAM starting from the day of diagnosis in Wolisso St. Luke Catholic hospital, southwest Ethiopia. METHODS: With the aim of coming up with appropriate survival (time-to-event) model that describes the SAM dataset, various parametric clustered time-to-event (frailty) models were compared. Frailty model, which is an extension of the proportional hazards Cox survival model, was used to analyze time-to-cure from SAM. Kebeles (villages) of the children were considered as the clustering variable in all the models. We used exponential, weibull and log-logistic as baseline hazard functions and the gamma as well as inverse Gaussian for the frailty distributions and then based on AIC criteria, all models were compared for their performance. RESULTS: The median time-to-cure from SAM cases was 14 days with the maximum of 63 days of which about 83% were cured. The log-logistic model with inverse Gaussian frailty has the minimum AIC value among the models compared. The clustering effect was significant in modeling time-to-cure from SAM. The results showed that age of a child and co-infection were the determinant prognostic factors for SAM, but sex of the child and the type of malnutrition were not significant. CONCLUSIONS: The log-logistic with inverse Gaussian frailty model described the SAM dataset better than other distributions used in this study. There is heterogeneity between the kebeles in the time-to-cure from SAM, indicating that one needs to account for this clustering variable using appropriate clustered time-to-event frailty models

EIN FESTTAG IM GEBIRGE = IN THE ALPS

Comprend : BARTMANN-SCOTTISCH / SEIDL ; le Blaskappelle und Bayrischzeller Schuhplattergruppe - ALMGRUSSE / BAUER ; Alfons BAUER, die Lohmayer Dirndl, die Funkschrammein - SUSI POLKA musique de danse / folk. - 'S GAMSEL-SCHLESSEN / CHAMOIS - SHOOTING - YODEL ; jodler duo par Anderl OSTLER - GRUSSE AUS DEN BERGEN / BAUER ; Die Funkschrammein - OH DU SCHONE SUSSE NACHTIGALL / folk. ; Die Lohmayer Dirndl - STELERISCHE LANDLER / LOFFELMEYER ; Alfons BAUER, cithare - KRANZL-POLKA musique de danse / FREI - SO KLINGTS' BEI UNS marche-polka / Hans et Hansi SABER harpe - SCHWEIZER GRUSSE / WILD ; le Handörgele Duett Heinrich Frei - GRUSS DU GOTT, DIRNDL / ELLERSDORFER ; le Garmisch-Partenkirchener Heimatsanger - RUND UM MUNCHEN : marche / BAUER ; le Blaskapelle Franz SCHMIDT - KIRCHWEIH POLKA musique de danse / BAUER - JE HOHER DER KIRCHTURM / folkl. ; Die Lohmayer Dirndl - VOGLEIN IN DEN ZWEIGEN / OBERMEIER ; Alfons BAUER, cithare - HEUT GEHN MA AUF DIE HOHE ALM / MEIKE-KUSTER ; le Garmisch-Partenkirchener Heimatsanger - GEBURTSTAGSMARSCH / SEIDL ; le Blaskappelle Franz SCHMIDT - LUZERNER JODLER / folk. ; le Jodlerin Peppi Reichi - WILLISAUER RINGLI, landler / HARTMANN ; Handorgele Duett Heinrich Frei - LIEBELEI / STELZL ; Alfons BAUER, cithare - WO DIE TANNEN STEHN / BAUER-HERTHA ; le Garmisch - Partenkirchener Heimatsanger - LUSTIGE JAGERBUB'N / GONETZ ; Die Funkschrammeln - DIE MADL VON BERN / FISHMANN ; le Jodler Franz LANGER - AM LUCKENKOPF / SEIDL ; le Blaskapell Frans SCHMIDT und die Bayerischzeller SchuhlplattlergruppeBnF-Partenariats, Collection sonore - BelieveContient une table des matière