Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

Multidisciplinary care in oncology: Medicolegal implications of group decisions

Consensus is growing that multidisciplinary meetings (MDMs) provide the best means of formulating comprehensive treatment plans for patients with cancer. Although many doctors attend MDMs and contribute to the decision-making process, only a few will become involved in a patient's care after the team meeting. Despite this, if a patient was grieved by a decision made in a MDM and wished to recover damages, all doctors present at the meeting would be personally accountable for decisions related to their area of expertise. Doctors should be made aware of the legal implications of their participation in such meetings. A greater awareness of these responsibilities and improved team dynamics should optimise outcomes for patients while limiting exposure of the participants to legal liability. Special attention should be given to providing patients with adequate information in this combined speciality setting

Why Do Some Lung Cancer Patients Receive No Anticancer Treatment?

IntroductionA significant proportion of lung cancer patients receive no anticancer treatment. This varies from 19% in USA, 33% in Australia, 37% in Scotland, and 50% in Ireland. The aim of this study was to identify the reasons behind this.MethodsThe Lung Cancer Multidisciplinary Meeting (MDM) in South-West Sydney prospectively collects data on all patients presented. All new lung cancer patients presented between December 1, 2005, and December 31, 2007, were reviewed. Patients were assigned optimal treatment based on evidence-based guidelines. Those patients in whom guidelines recommended no treatment (GNT) were compared with those whom the MDM recommended no treatment (MNT) and with those who actually received no treatment (ANT).ResultsThere were 335 patients with a median age of 69 years. A total of 82% had non-small cell lung cancer, 14% had small cell lung cancer, and 4% had no pathologic diagnosis. Eighty-five percent had locally advanced or metastatic disease. GNT was recommended in 4% (n = 13), MNT in 10% (n = 32) but ANT comprised 20% (n = 66). The differences between GNT and MNT were mainly due to patient comorbidities and clinician decision, but the differences between MNT and ANT were due to patient preference and declining performance status. In multivariate analysis, older age, poorer Eastern Cooperative Oncology Group status, non-small cell lung cancer, and non-English language predicted for ANT.ConclusionsThe proportion of patients with lung cancer receiving no treatment is greater than that predicted by guidelines or recommended by the MDM but lower than that described in population-based studies suggesting that MDMs can improve treatment utilization in lung cancer

FROGG patterns of practice survey and consensus recommendations on radiation therapy for MIBC

Muscle invasive bladder cancer (MIBC) is a life-threatening malignancy with a five-year overall survival of approximately 50 to 60%. Bladder cancer was the 14th leading cause of cancer death in the world in 2018, with approximately 200,000 deaths related to bladder cancer that year. Traditionally, the cornerstone of curative treatment of MIBC is a radical cystectomy (RC), which involves the removal of the bladder, a pelvic lymph node dissection and reconstruction of the urinary tract. However, RC is associated with a significant perioperative mortality risk with high readmission rates, substantial morbidity and changes in patient’s quality of life (QOL)

Endorectal balloons in the post prostatectomy setting: Do gains in stability lead to more predictable dosimetry?

To perform a comparative study assessing potential benefits of endorectal-balloons (ERB) in post-prostatectomy patients. Ten retrospective post-prostatectomy patients treated without ERB and ten prospective patients treated with the ERB in situ were recruited. All patients received IMRT and IGRT using kilovoltage cone-beam computed tomography (kVCBCT). kVCBCT datasets were registered to the planning dataset, recontoured and the original plan recalculated on the kVCBCTs to recreate anatomical conditions during treatment. The imaging, structure and dose data were imported into in-house software for the assessment of geometric variation and cumulative equivalent uniform dose (EUD) in the two groups. The difference in location (DCOV) for the bladder between planning and each CBCT was similar for each group. The use of ERBs in the post-prostatectomy setting did improve geometric reproducibility of the target and surrounding normal tissues, however no improvement in dosimetric stability was observed for the margins employed

A multi-center prospective study for implementation of an MRI-only prostate treatment planning workflow

Purpose: This project investigates the feasibility of implementation of MRI-only prostate planning in a prospective multi-center study. Method and Materials: A two-phase implementation model was utilized where centers performed retrospective analysis of MRI-only plans for five patients followed by prospective MRI-only planning for subsequent patients. Feasibility was assessed if at least 23/25 patients recruited to phase 2 received MRI-only treatment workflow. Whole-pelvic MRI scans (T2 weighted, isotropic 1.6 mm voxel 3D sequence) were converted to pseudo-CT using an established atlas-based method. Dose plans were generated using MRI contoured anatomy with pseudo-CT for dose calculation. A conventional CT scan was acquired subsequent to MRI-only plan approval for quality assurance purposes (QA-CT). 3D Gamma evaluation was performed between pseudo-CT calculated plan dose and recalculation on QA-CT. Criteria was 2%, 2 mm criteria with 20% low dose threshold. Gold fiducial marker positions for image guidance were compared between pseudo-CT and QA-CT scan prior to treatment. Results: All 25 patients recruited to phase 2 were treated using the MRI-only workflow. Isocenter dose differences between pseudo-CT and QA-CT were −0.04 ± 0.93% (mean ± SD). 3D Gamma dose comparison pass-rates were 99.7% ± 0.5% with mean gamma 0.22 ± 0.07. Results were similar for the two centers using two different scanners. All gamma comparisons exceeded the 90% pass-rate tolerance with a minimum gamma pass-rate of 98.0%. In all cases the gold fiducial markers were correctly identified on MRI and the distances of all seeds to centroid were within the tolerance of 1.0 mm of the distances on QA-CT (0.07 ± 0.41 mm), with a root-mean-square difference of 0.42 mm. Conclusion: The results support the hypothesis that an MRI-only prostate workflow can be implemented safely and accurately with appropriate quality assurance methods

Automatic radiotherapy delineation quality assurance on prostate MRI with deep learning in a multicentre clinical trial

Volume delineation quality assurance (QA) is particularly important in clinical trial settings where consistent protocol implementation is required, as outcomes will affect future as well current patients. Currently, where feasible, this is conducted manually, which is time consuming and resource intensive. Although previous studies mostly focused on automating delineation QA on CT, magnetic resonance imaging (MRI) is being increasingly used in radiotherapy treatment. In this work, we propose to perform automatic delineation QA on prostate MRI for both the clinical target volume (CTV) and organs-at-risk (OARs) by using delineations generated by 3D Unet variants as benchmarks for QA. These networks were trained on a small gold standard atlas set and applied on a multicentre radiotherapy clinical trial dataset to generate benchmark delineations. Then, a QA stage was designed to recommend \u27pass\u27, \u27minor correction\u27 and \u27major correction\u27 for each manual delineation in the trial set by thresholding its Dice similarity coefficient to the network generated delineation. Among all 3D Unet variants explored, the Unet with anatomical gates in an AtlasNet architecture performed the best in delineation QA, achieving an area under the receiver operating characteristics curve of 0.97, 0.92, 0.89 and 0.97 for identifying unacceptable (major correction) delineations with a sensitivity of 0.93, 0.73, 0.74 and 0.90 at a specificity of 0.93, 0.86, 0.86 and 0.95 for bladder, prostate CTV, rectum and gel spacer respectively. To the best of our knowledge, this is the first study to propose automated delineation QA for a multicentre radiotherapy clinical trial with treatment planning MRI. The methods proposed in this work can potentially improve the accuracy and consistency of CTV and OAR delineation in radiotherapy treatment planning