Summary Background Serum CA125 concentration often rises several months before clinical or symptomatic relapse in women with ovarian cancer. In the MRC OV05/EORTC 55955 collaborative trial, we aimed ...to establish the benefits of early treatment on the basis of increased CA125 concentrations compared with delayed treatment on the basis of clinical recurrence. Methods Women with ovarian cancer in complete remission after first-line platinum-based chemotherapy and a normal CA125 concentration were registered for this randomised controlled trial. Clinical examination and CA125 measurement were done every 3 months. Patients and investigators were masked to CA125 results, which were monitored by coordinating centres. If CA125 concentration exceeded twice the upper limit of normal, patients were randomly assigned (1:1) by minimisation to early or delayed chemotherapy. Patients and clinical sites were informed of allocation to early treatment, and treatment was started as soon as possible within 28 days of the increased CA125 measurement. Patients assigned to delayed treatment continued masked CA125 measurements, with treatment commencing at clinical or symptomatic relapse. All patients were treated according to standard local practice. The primary outcome was overall survival. Analysis was by intention to treat. This study is registered, ISRCTN87786644. Findings 1442 patients were registered for the trial, of whom 529 were randomly assigned to treatment groups and were included in our analysis (265 early, 264 delayed). With a median follow-up of 56·9 months (IQR 37·4–81·8) from randomisation and 370 deaths (186 early, 184 delayed), there was no evidence of a difference in overall survival between early and delayed treatment (HR 0·98, 95% CI 0·80–1·20, p=0·85). Median survival from randomisation was 25·7 months (95% CI 23·0–27·9) for patients on early treatment and 27·1 months (22·8–30·9) for those on delayed treatment. Interpretation Our findings showed no evidence of a survival benefit with early treatment of relapse on the basis of a raised CA125 concentration alone, and therefore the value of routine measurement of CA125 in the follow-up of patients with ovarian cancer who attain a complete response after first-line treatment is not proven. Funding UK Medical Research Council and the European Organisation for Research and Treatment of Cancer.
Summary Background Angiogenesis is a validated clinical target in advanced epithelial ovarian cancer. Cediranib is an oral antiangiogenic vascular endothelial growth factor receptor 1–3 inhibitor ...that has shown antitumour activity in recurrent ovarian cancer. We assessed efficacy and safety of cediranib in combination with platinum-based chemotherapy and as continued maintenance treatment in patients with first relapse of platinum-sensitive ovarian cancer. Methods In this randomised, three-arm, double-blind, placebo-controlled phase 3 trial, we randomly assigned patients aged 18 years or older with relapsed platinum-sensitive ovarian cancer at 63 centres in Australia, Canada, New Zealand, Spain, and the UK. Participants received up to six cycles of platinum-based chemotherapy (once every 3 weeks) then entered a maintenance phase. Participants were randomly allocated (2:3:3), with five stratification factors and in alternating blocks, to receive placebo alongside chemotherapy and then placebo only maintenance (arm A; reference), cediranib 20 mg once-daily alongside chemotherapy then placebo only maintenance (arm B; concurrent), or cediranib 20 mg once-daily alongside chemotherapy then cediranib 20 mg once-daily maintenance (arm C; maintenance). Patients continued treatment to progression or excessive toxic effects. The primary efficacy endpoint was progression-free survival between arms A and C. Efficacy analysis was by intention to treat. Safety was assessed in all patients who received the allocated study drug. This trial is registered with ClinicalTrials.gov , number NCT00532194 ; the ISRCTN registry, number ISRCTN68510403; and ANZ Clinical Trials Registry, number ACTRN1261000016003. Findings We randomly assigned 486 women between Nov 13, 2007, and Dec 23, 2011; results presented are for 456 patients randomly assigned subsequent to the 30mg safety phase. During a median of 19·5 months (IQR 14–26) follow-up, 113 (96%) of 118 women assigned to arm A and 141 (86%) of 164 assigned to arm C had disease progression. Median progression-free survival was 11·0 months (95% CI 10·4–11·7) in arm C and 8·7 months (7·7–9·4) in arm A (hazard ratio 0·56, 0·44–0·72, p<0·0001). 156 (90%) of 174 patients in arm B had disease progression, and median progression-free survival was 9·9 months (95% CI 9·4–10·5). Diarrhoea, neutropenia, hypertension, and voice changes were significantly more common, during chemotherapy with cediranib, and diarrhoea, hypothyroidism and voice changes were more common during maintenance. Poor compliance with cediranib was noted during maintenance treatment with toxic effects being the most common cause for discontinuation. Interpretation Cediranib, when given orally with chemotherapy and continued as maintenance, yielded a meaningful improvement in progression-free survival in women with recurrent platinum-sensitive ovarian cancer, albeit with added toxic effects. The positive results in ICON6 could provide women with a new therapeutic option for recurrent ovarian cancer. Assessment of the secondary endpoint of overall survival will need longer follow-up. Funding Medical Research Council, Cancer Research UK, Canadian Cancer Society Research Institute, Cancer Australia, National Gynecological Cancer Centre, and AstraZeneca.
Summary Background The ICON7 trial previously reported improved progression-free survival in women with ovarian cancer with the addition of bevacizumab to standard chemotherapy, with the greatest ...effect in patients at high risk of disease progression. We report the final overall survival results of the trial. Methods ICON7 was an international, phase 3, open-label, randomised trial undertaken at 263 centres in 11 countries across Europe, Canada, Australia and New Zealand. Eligible adult women with newly diagnosed ovarian cancer that was either high-risk early-stage disease (International Federation of Gynecology and Obstetrics FIGO stage I–IIa, grade 3 or clear cell histology) or more advanced disease (FIGO stage IIb–IV), with an Eastern Cooperative Oncology Group performance status of 0–2, were enrolled and randomly assigned in a 1:1 ratio to standard chemotherapy (six 3-weekly cycles of intravenous carboplatin AUC 5 or 6 and paclitaxel 175 mg/m2 of body surface area) or the same chemotherapy regimen plus bevacizumab 7·5 mg per kg bodyweight intravenously every 3 weeks, given concurrently and continued with up to 12 further 3-weekly cycles of maintenance therapy. Randomisation was done by a minimisation algorithm stratified by FIGO stage, residual disease, interval between surgery and chemotherapy, and Gynecologic Cancer InterGroup group. The primary endpoint was progression-free survival; the study was also powered to detect a difference in overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN91273375. Findings Between Dec 18, 2006, and Feb 16, 2009, 1528 women were enrolled and randomly assigned to receive chemotherapy (n=764) or chemotherapy plus bevacizumab (n=764). Median follow-up at the end of the trial on March 31, 2013, was 48·9 months (IQR 26·6–56·2), at which point 714 patients had died (352 in the chemotherapy group and 362 in the bevacizumab group). Our results showed evidence of non-proportional hazards, so we used the difference in restricted mean survival time as the primary estimate of effect. No overall survival benefit of bevacizumab was recorded (restricted mean survival time 44·6 months 95% CI 43·2–45·9 in the standard chemotherapy group vs 45·5 months 44·2–46·7 in the bevacizumab group; log-rank p=0·85). In an exploratory analysis of a predefined subgroup of 502 patients with poor prognosis disease, 332 (66%) died (174 in the standard chemotherapy group and 158 in the bevacizumab group), and a significant difference in overall survival was noted between women who received bevacizumab plus chemotherapy and those who received chemotherapy alone (restricted mean survival time 34·5 months 95% CI 32·0–37·0 with standard chemotherapy vs 39·3 months 37·0–41·7 with bevacizumab; log-rank p=0·03). However, in non-high-risk patients, the restricted mean survival time did not differ significantly between the two treatment groups (49·7 months 95% CI 48·3–51·1) in the standard chemotherapy group vs 48·4 months 47·0–49·9 in the bevacizumab group; p=0·20). An updated analysis of progression-free survival showed no difference between treatment groups. During extended follow-up, one further treatment-related grade 3 event (gastrointestinal fistula in a bevacizumab-treated patient), three grade 2 treatment-related events (cardiac failure, sarcoidosis, and foot fracture, all in bevacizumab-treated patients), and one grade 1 treatment-related event (vaginal haemorrhage, in a patient treated with standard chemotherapy) were reported. Interpretation Bevacizumab, added to platinum-based chemotherapy, did not increase overall survival in the study population as a whole. However, an overall survival benefit was recorded in poor-prognosis patients, which is concordant with the progression-free survival results from ICON7 and GOG-218, and provides further evidence towards the optimum use of bevacizumab in the treatment of ovarian cancer. Funding The National Institute for Health Research through the UK National Cancer Research Network, the Medical Research Council, and Roche.
Summary
Background
Risankizumab has demonstrated efficacy and safety in patients with moderate‐to‐severe plaque psoriasis in randomized clinical trials.
Objectives
To evaluate safety data from ...risankizumab psoriasis phase I–III clinical trials.
Methods
Short‐term safety (through week 16) was analysed using integrated data from five phase II and III clinical trials. Long‐term safety was evaluated using integrated data from 17 phase I–III completed and ongoing trials.
Results
Short‐term safety analyses included 1306 patients receiving risankizumab 150 mg and 300 patients receiving placebo 402·2 and 92·0 patient‐years (PY) of exposure, respectively. Long‐term analyses included 3072 risankizumab‐treated patients (exposure: 7927 PY). The median (excluding four outliers) treatment duration was 2·9 years (range 2 days to 5·9 years). Exposure‐adjusted adverse event rates did not increase with long‐term treatment (318 vs. 171 events per 100 PY for short‐ and long‐term analyses). With long‐term risankizumab treatment, rates of serious adverse events were 7·8 per 100 PY, serious infections 1·2 per 100 PY, nonmelanoma skin cancer (NMSC) 0·7 per 100 PY, malignant tumours excluding NMSC 0·5 per 100 PY, and adjudicated major adverse cardiovascular events 0·3 per 100 PY, with no important identified risks. Limitations include that the study inclusion and exclusion criteria varied and that three studies enrolled ≤ 50 patients.
Conclusions
Risankizumab demonstrated a favourable safety profile over short‐ and long‐term treatment in patients with moderate‐to‐severe psoriasis.
What is already known about this topic?
In clinical trials of patients with moderate‐to‐severe plaque psoriasis, risankizumab, a selective interleukin‐23 inhibitor, was well tolerated and efficacious.
What does this study add?
In this comprehensive evaluation of risankizumab safety in patients with moderate‐to‐severe psoriasis, adverse event rates were comparable between risankizumab (n = 1306, 402 patient‐years) and placebo (n = 300, 92 patient‐years) in the short‐term (16‐week) analysis set, and were consistent with those in the long‐term analysis (n = 3072, 7927 patient‐years of risankizumab exposure).
These findings are consistent with the known safety profile of risankizumab and support its long‐term use in moderate‐to‐severe psoriasis.
Linked Comment: S. Mirali et al. Br J Dermatol 2022; 186:394–395.
Plain language summary available online
Cystic fibrosis (CF) lung disease is defined by large numbers of neutrophils and associated damaging products in the airway. Delayed neutrophil apoptosis is described in CF although it is unclear ...whether this is a primary neutrophil defect or a response to chronic inflammation. Increased levels of neutrophil extracellular traps (NETs) have been measured in CF and we aimed to investigate the causal relationship between these phenomena and their potential to serve as a driver of inflammation. We hypothesised that the delay in apoptosis in CF is a primary defect and preferentially allows CF neutrophils to form NETs, contributing to inflammation.
Blood neutrophils were isolated from patients with CF, CF pigs and appropriate controls. Neutrophils were also obtained from patients with CF before and after commencing ivacaftor. Apoptosis was assessed by morphology and flow cytometry. NET formation was determined by fluorescent microscopy and DNA release assays. NET interaction with macrophages was examined by measuring cytokine generation with ELISA and qRT-PCR.
CF neutrophils live longer due to decreased apoptosis. This was observed in both cystic fibrosis transmembrane conductance regulator (CFTR) null piglets and patients with CF, and furthermore was reversed by ivacaftor (CFTR potentiator) in patients with gating (G551D) mutations. CF neutrophils formed more NETs and this was reversed by cyclin-dependent kinase inhibitor exposure. NETs provided a proinflammatory stimulus to macrophages, which was enhanced in CF.
CF neutrophils have a prosurvival phenotype that is associated with an absence of CFTR function and allows increased NET production, which can in turn induce inflammation. Augmenting neutrophil apoptosis in CF may allow more appropriate neutrophil disposal, decreasing NET formation and thus inflammation.
Summary
Background An unmet need remains for safe and effective long‐term treatments of psoriasis.
Objectives To evaluate ustekinumab efficacy and safety for up to 3 years in the PHOENIX 1 trial.
...Methods Patients (n = 766) with moderate‐to‐severe psoriasis were randomized to ustekinumab 45 mg or 90 mg at weeks 0 and 4, and then every 12 weeks, or placebo at weeks 0 and 4, with crossover to ustekinumab at week 12. Ustekinumab responders ≥ 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) at weeks 28 and 40 were re‐randomized at week 40 to continue or withdraw from treatment until psoriasis recurrence. Partial responders (week 28: PASI 50–74; week 40: < PASI 75) switched to dosing every 8 weeks. Clinical efficacy was assessed by PASI, the Physician’s Global Assessment (PGA), and the Dermatology Life Quality Index (DLQI) measures.
Results Overall, 79·8% of the ustekinumab‐treated patients remained in the study for 3 years. PASI 75 response rates (45 mg: 61·2%; 90 mg: 72·4%) at week 76 were maintained through year 3 (45 mg: 62·7%; 90 mg: 72·2%); PGA response was similarly durable. At year 3, 80·9% (45 mg) and 82·7% (90 mg) of week 40 responders continuing treatment every 12 weeks achieved a PASI 75 response, while 42·6% (45 mg) and 58·0% (90 mg) achieved a PASI 90 response. Among partial responders adjusted to dosing every 8 weeks, 50·9% (45 mg) and 52·0% (90 mg) had a PASI 75 response at year 3. DLQI responses paralleled the PASI responses. Through year 3, no dose response was observed in rates of adverse events (AEs), overall infections, serious AEs, or AEs leading to discontinuation; nor was there evidence of cumulative organ toxicity.
Conclusions Continuous, stable, maintenance dosing with ustekinumab was generally well tolerated and sustained durable efficacy for up to 3 years of treatment.
Both CoII(qpy)(H2O)22+ and FeII(qpy)(H2O)22+ (with qpy = 2,2′:6′,2″:6′′,2‴-quaterpyridine) are efficient homogeneous electrocatalysts and photoelectrocatalysts for the reduction of CO2 to CO. The ...Co catalyst is more efficient in the electrochemical reduction, while the Fe catalyst is an excellent photoelectrocatalyst ( ACS Catal. 2018, 8, 3411−3417 ). This work uses density functional theory to shed light on the contrasting catalytic pathways. While both catalysts experience primarily ligand-based reductions, the second reduction in the Co catalyst is delocalized onto the metal via a metal–ligand bonding interaction, causing a spin transition and a distorted ligand framework. This orbital interaction explains the experimentally observed mild reduction potential and slow kinetics of the second reduction. The decreased hardness and doubly occupied d z 2 -orbital facilitate a σ-bond with the CO2-π* in an η1-κC binding mode. CO2 binding is only possible after two reductions resulting in an EEC mechanism (E = electron transfer, C = chemical reaction), and the second protonation is rate-limiting. In contrast, the Fe catalyst maintains a Lewis acidic metal center throughout the reduction process because the metal orbitals do not strongly mix with the qpy-π* orbitals. This allows binding of the activated CO2 in an η2-binding mode. This interaction stabilizes the activated CO2 via a π-type interaction of a Fe-t2g orbital and the CO2-π* and a dative bond of the oxygen lone pair. This facilitates CO2 binding to a singly reduced catalyst resulting in an ECE mechanism. The barrier for CO2 addition and the second protonation are higher than those for the Co catalyst and rate-limiting.
Summary
Background
Psoriasis is a chronic disease requiring long‐term therapy.
Objectives
Physician‐ and patient‐reported outcomes were evaluated through week 252 in VOYAGE 1 and VOYAGE 2.
Methods
In ...total, 1829 patients were randomized at baseline to receive guselkumab 100 mg every 8 weeks, placebo or adalimumab. Patients receiving placebo crossed over to guselkumab at week 16. Patients receiving adalimumab crossed over to guselkumab at week 52 in VOYAGE 1, and randomized withdrawal and retreatment occurred at weeks 28–76 in VOYAGE 2; all patients then received open‐label guselkumab through week 252. Efficacy and health‐related quality of life (HRQoL) endpoints were analysed through week 252. Safety was monitored through week 264.
Results
The proportions of patients in the guselkumab group who achieved clinical responses at week 252 in VOYAGE 1 and VOYAGE 2, respectively, were 84·1% and 82·0% ≥ 90% improvement in Psoriasis Area and Severity Index (PASI); 82·4% and 85·0% Investigator’s Global Assessment (IGA) 0 or 1; 52·7% and 53·0% (100% improvement in PASI) and 54·7% and 55·5% (IGA 0). HRQoL endpoints were achieved as follows: 72·7% and 71·1% of patients (Dermatology Life Quality Index 0 or 1: no effect on patient’s life); 42·4% and 42·0% Psoriasis Symptoms and Signs Diary (PSSD) symptom score = 0 and 33·0% and 31·0% (PSSD sign score = 0). As measured in VOYAGE 2 only, approximately 45% of patients achieved ≥ 5‐point reduction in Short Form‐36 physical and mental component scores, and 80% reported no anxiety or depression (Hospital Anxiety and Depression Scale scores < 8). Similar findings were reported for adalimumab crossovers. These effects were maintained from week 52 in VOYAGE 1 and week 100 in VOYAGE 2. No new safety signals were identified.
Conclusions
Guselkumab maintains high levels of clinical response and improvement in patient‐reported outcomes through 5 years in patients with moderate‐to‐severe psoriasis.
What is already known about this topic?
Psoriasis is a chronic disease requiring long‐term treatment.
Guselkumab has been shown to be effective in improving clinical response and health‐related quality of life (HRQoL) in more than 1800 patients through 4 years in the VOYAGE 1 and VOYAGE 2 trials.
What does this study add?
Guselkumab maintained improvements in clinical response as well as positive effects on HRQoL and general health through 5 years in patients with moderate‐to‐severe psoriasis.
Linked Comment: I. Kotb. Br J Dermatol 2021; 185:1087–1088.
Plain language summary available online
Translating Evidence to Optimize Patient Care Using GRADE Chu, Derek K; Golden, David B K; Guyatt, Gordon H
The journal of allergy and clinical immunology in practice (Cambridge, MA),
12/2021, Volume:
9, Issue:
12
Journal Article
Peer reviewed
Optimal evidence-based clinical practice requires systematic summaries of the best available evidence, including ratings of the quality of that evidence, and is facilitated by the availability of ...trustworthy guidelines. In this review, we describe the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to rating quality of evidence and moving from evidence to recommendations using examples from allergy-immunology. GRADE focuses on systematic summaries of the best evidence, systematic reviews and trustworthy guidelines, and emphasizes a structured approach to determining quality (certainty) of bodies of evidence, absolute magnitude of effects of desirable and undesirable consequences (benefits and harms), and use of evidence to develop clinical recommendations. Adopted by over 110 organizations worldwide, including the American Academy of Allergy, Asthma, and Immunology/American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters, GRADE is foundational to the optimal interpretation of research evidence and its application in clinical practice. This review supports the clinician's ability to find and use the information in GRADE guidelines to help care for patients in the clinic.
Summary
Background
Biologics are being used increasingly to treat moderate‐to‐severe psoriasis. Efficacy may differ in patients with previous exposure to biologics.
Objectives
To investigate the ...impact of previous biologic exposure on the efficacy and safety of brodalumab and ustekinumab in patients with moderate‐to‐severe plaque psoriasis.
Methods
Two placebo‐ and ustekinumab‐controlled phase III clinical trials. There was an initial 12‐week induction phase where patients were treated with brodalumab 210 mg or 140 mg every 2 weeks (Q2W), ustekinumab or placebo. Efficacy end points included ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and static Physician's Global Assessment (score of 0 or 1) vs. placebo, PASI 100 vs. ustekinumab, Dermatology Life Quality Index and Psoriasis Symptom Inventory. Adverse events were monitored throughout.
Results
In total, 493 patients 334 (27%) brodalumab 210 mg Q2W and 159 (26%) ustekinumab had received prior biologics; 150 (12%) and 62 (10%), respectively, reported previously failed treatment with a biologic. Brodalumab efficacy in patients with or without previous exposure to biologics was statistically equivalent: 40·9% and 39·5% of biologic‐naive and ‐experienced patients achieved PASI 100 at week 12, compared with 21·1% and 17·0% with ustekinumab (both P < 0·001). In patients where prior biologics had been successful or failed, 41·7% and 32·0% achieved PASI 100, compared with 21·1% and 11·3% with ustekinumab. Tolerability was similar, and did not appear to be influenced by previous treatment with biologics.
Conclusions
The efficacy of brodalumab 210 mg Q2W was similar regardless of prior biological therapy (P = 0·31, 0·32 and 0·64 for PASI 75, 90 and 100, respectively). Almost twice as many patients achieved PASI 100 or complete clearance with brodalumab at week 12 compared with ustekinumab; the differences were most noticeable where previous biologics had failed. Both treatments were well tolerated.
What's already known about this topic?
Biologics are highly effective in treating moderate‐to‐severe psoriasis.
Efficacy rates may differ in patients with previous exposure to biologics, and in patients where previous biologics have failed.
Published data are not conclusive regarding the effect of prior biologic use, and the efficacy of subsequent biologics in patients who had failed prior biological therapy has not been published.
What does this study add?
The efficacy of brodalumab was similar regardless of prior biological therapy.
Approximately twice as many patients on brodalumab achieved 100% improvement in Psoriasis Area and Severity Index (PASI 100) compared with ustekinumab, irrespectively of whether they had prior biologic experience.
The efficacy results in those patients who had failed previous biologics are most noteworthy, where the benefits are three times those seen with ustekinumab for PASI 100 (32·0% vs. 11·3%).
Safety results were similar in patients who had previous exposure to biologics vs. those who were biologic naive.
Linked Comment: Albrecht and Gerdes. Br J Dermatol 2018; 179:241–242.
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