Applying physical science techniques and CERN technology to an unsolved problem in radiation treatment for cancer: the multidisciplinary ‘VoxTox’ research programme

The VoxTox research programme has applied expertise from the physical sciences to the problem of radiotherapy toxicity, bringing together expertise from engineering, mathematics, high energy physics (including the Large Hadron Collider), medical physics and radiation oncology. In our initial cohort of 109 men treated with curative radiotherapy for prostate cancer, daily image guidance computed tomography (CT) scans have been used to calculate delivered dose to the rectum, as distinct from planned dose, using an automated approach. Clinical toxicity data have been collected, allowing us to address the hypothesis that delivered dose provides a better predictor of toxicity than planned dose.JES was supported by Cancer Research UK through the Cambridge Cancer Centre. NGB, ASP and MG are supported by the National Institute of Health Research Cambridge Biomedical Research Centre. KH, MR AMB, EW and SJB were supported by the VoxTox Research Programme, funded by Cancer Research UK. DJN is supported by Addenbrooke’s Charitable Trust and Cancer Research UK through the Cambridge Cancer Centre. FMB was supported by the Science and Technology Facilities Council. MPDS was part supported by the VoxTox Research Programme, funded by Cancer Research UK. RJ was part supported by the VoxTox Research Programme, funded by Cancer Research UK. LS is supported by the Armstrong Trust. XC was supported by the Isaac Newton Trust. CBS acknowledges support from the EPSRC Centre for Mathematical and Statistical Analysis of Multimodal Clinical Imaging, the Leverhulme Trust, the EU-RISE project CHiPS and the Cantab Capital Institute for the Mathematics of Information. NT was supported by a Gates-Cambridge Scholarship, funded by the Bill and Melinda Gates Foundation, PLY and SYKS by the Singapore Government

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment

Applying physical science techniques and CERN technology to an unsolved problem in radiation treatment for cancer: the multidisciplinary ‘VoxTox’ research programme

The VoxTox research programme has applied expertise from the physical sciences to the problem of radiotherapy toxicity, bringing together expertise from engineering, mathematics, high energy physics (including the Large Hadron Collider), medical physics and radiation oncology. In our initial cohort of 109 men treated with curative radiotherapy for prostate cancer, daily image guidance computed tomography (CT) scans have been used to calculate delivered dose to the rectum, as distinct from planned dose, using an automated approach. Clinical toxicity data have been collected, allowing us to address the hypothesis that delivered dose provides a better predictor of toxicity than planned dose

Baseline Characteristics and Risk Profiles of Participants in the ISCHEMIA Randomized Clinical Trial

Importance: It is unknown whether coronary revascularization, when added to optimal medical therapy, improves prognosis in patients with stable ischemic heart disease (SIHD) at increased risk of cardiovascular events owing to moderate or severe ischemia. Objective: To describe baseline characteristics of participants enrolled and randomized in the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial and to evaluate whether qualification by stress imaging or nonimaging exercise tolerance test (ETT) influenced risk profiles. Design, Setting, and Participants: The ISCHEMIA trial recruited patients with SIHD with moderate or severe ischemia on stress testing. Blinded coronary computed tomography angiography was performed in most participants and reviewed by a core laboratory to exclude left main stenosis of at least 50% or no obstructive coronary artery disease (CAD) (<50% for imaging stress test and <70% for ETT). The study included 341 enrolling sites (320 randomizing) in 38 countries and patients with SIHD and moderate or severe ischemia on stress testing. Data presented were extracted on December 17, 2018. Main Outcomes and Measures: Enrolled, excluded, and randomized participants' baseline characteristics. No clinical outcomes are reported. Results: A total of 8518 patients were enrolled, and 5179 were randomized. Common reasons for exclusion were core laboratory determination of insufficient ischemia, unprotected left main stenosis of at least 50%, or no stenosis that met study obstructive CAD criteria on study coronary computed tomography angiography. Randomized participants had a median age of 64 years, with 1168 women (22.6%), 1726 nonwhite participants (33.7%), 748 Hispanic participants (15.5%), 2122 with diabetes (41.0%), and 4643 with a history of angina (89.7%). Among the 3909 participants randomized after stress imaging, core laboratory assessment of ischemia severity (in 3901 participants) was severe in 1748 (44.8%), moderate in 1600 (41.0%), mild in 317 (8.1%) and none or uninterpretable in 236 (6.0%), Among the 1270 participants who were randomized after nonimaging ETT, core laboratory determination of ischemia severity (in 1266 participants) was severe (an eligibility criterion) in 1051 (83.0%), moderate in 101 (8.0%), mild in 34 (2.7%) and none or uninterpretable in 80 (6.3%). Among the 3912 of 5179 randomized participants who underwent coronary computed tomography angiography, 79.0% had multivessel CAD (n = 2679 of 3390) and 86.8% had left anterior descending (LAD) stenosis (n = 3190 of 3677) (proximal in 46.8% [n = 1749 of 3739]). Participants undergoing ETT had greater frequency of 3-vessel CAD, LAD, and proximal LAD stenosis than participants undergoing stress imaging. Conclusions and Relevance: The ISCHEMIA trial randomized an SIHD population with moderate or severe ischemia on stress testing, of whom most had multivessel CAD

Baseline characteristics and risk profiles of participants in the ISCHEMIA randomized clinical trial

Importance It is unknown whether coronary revascularization, when added to optimal medical therapy, improves prognosis in patients with stable ischemic heart disease (SIHD) at increased risk of cardiovascular events owing to moderate or severe ischemia. Objective To describe baseline characteristics of participants enrolled and randomized in the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial and to evaluate whether qualification by stress imaging or nonimaging exercise tolerance test (ETT) influenced risk profiles. Design, Setting, and Participants The ISCHEMIA trial recruited patients with SIHD with moderate or severe ischemia on stress testing. Blinded coronary computed tomography angiography was performed in most participants and reviewed by a core laboratory to exclude left main stenosis of at least 50% or no obstructive coronary artery disease (CAD) (<50% for imaging stress test and <70% for ETT). The study included 341 enrolling sites (320 randomizing) in 38 countries and patients with SIHD and moderate or severe ischemia on stress testing. Data presented were extracted on December 17, 2018. Main Outcomes and Measures Enrolled, excluded, and randomized participants’ baseline characteristics. No clinical outcomes are reported. Results A total of 8518 patients were enrolled, and 5179 were randomized. Common reasons for exclusion were core laboratory determination of insufficient ischemia, unprotected left main stenosis of at least 50%, or no stenosis that met study obstructive CAD criteria on study coronary computed tomography angiography. Randomized participants had a median age of 64 years, with 1168 women (22.6%), 1726 nonwhite participants (33.7%), 748 Hispanic participants (15.5%), 2122 with diabetes (41.0%), and 4643 with a history of angina (89.7%). Among the 3909 participants randomized after stress imaging, core laboratory assessment of ischemia severity (in 3901 participants) was severe in 1748 (44.8%), moderate in 1600 (41.0%), mild in 317 (8.1%) and none or uninterpretable in 236 (6.0%), Among the 1270 participants who were randomized after nonimaging ETT, core laboratory determination of ischemia severity (in 1266 participants) was severe (an eligibility criterion) in 1051 (83.0%), moderate in 101 (8.0%), mild in 34 (2.7%) and none or uninterpretable in 80 (6.3%). Among the 3912 of 5179 randomized participants who underwent coronary computed tomography angiography, 79.0% had multivessel CAD (n = 2679 of 3390) and 86.8% had left anterior descending (LAD) stenosis (n = 3190 of 3677) (proximal in 46.8% [n = 1749 of 3739]). Participants undergoing ETT had greater frequency of 3-vessel CAD, LAD, and proximal LAD stenosis than participants undergoing stress imaging. Conclusions and Relevance The ISCHEMIA trial randomized an SIHD population with moderate or severe ischemia on stress testing, of whom most had multivessel CAD. Trial Registration ClinicalTrials.gov Identifier: NCT0147152