Real-world applicability of differentiated thyroid cancer guidelines.

OBJECTIVE: Thyroid cancer (TC) is the most common endocrine malignancy with constantly growing incidence. Radioiodine ablation is a safe and effective method for managing TC. Recently various Guidelines (GL) have been published on whom should be ablated, when and under which circumstances. Our study compares 6 GL with a given patient cohort. Additionally, we evaluated each GL's quality via an independent tool. MATERIAL AND METHODS: We compared six Guidelines (GL) for TC ablation on a cohort of 336 patients, implementing GL retrospectively: 2009 and 2016 American Thyroid Association (ATA), European Thyroid Association's (ETA) Consensus Statement, UK's National Institute for Health and Care Excellence (NICE), German position paper from Surgery and Nuclear Medicine (German) and European Association of Nuclear Medicine and Society of Nuclear Medicine and Molecular Image (EANM/SNMMI). Quality assessment was conducted using the Appraisal of Guidelines, Research and Evaluation instrument II (AGREE II). RESULTS: Results showed significant variability among GL. American Thyroid Association 2016, a clear improvement of the ATA 2009, presents a large grey area of "probable ablation candidates". European Thyroid Association and NICE agree that only a small portion of our ablated patients would benefit from it and the AGREE II tool shows a lack of applicability, but very good scores elsewhere. German and EANM/SNMMI GL agree that most of our clinical decisions to ablate were correct and their AGREE II scores are the highest in all six domains. CONCLUSION: Considering that dynamic risk classification plays a major role in determining the most appropriate treatment, it appears that the guidelines should be updated in order to support individualized patient management. However, it is the experience of the individual physician that will determine the final decision.

Intuitive control of mobile robots: an architecture for autonomous adaptive dynamic behaviour integration.

In this paper, we present a novel approach to human-robot control. Taking inspiration from behaviour-based robotics and self-organisation principles, we present an interfacing mechanism, with the ability to adapt both towards the user and the robotic morphology. The aim is for a transparent mechanism connecting user and robot, allowing for a seamless integration of control signals and robot behaviours. Instead of the user adapting to the interface and control paradigm, the proposed architecture allows the user to shape the control motifs in their way of preference, moving away from the case where the user has to read and understand an operation manual, or it has to learn to operate a specific device. Starting from a tabula rasa basis, the architecture is able to identify control patterns (behaviours) for the given robotic morphology and successfully merge them with control signals from the user, regardless of the input device used. The structural components of the interface are presented and assessed both individually and as a whole. Inherent properties of the architecture are presented and explained. At the same time, emergent properties are presented and investigated. As a whole, this paradigm of control is found to highlight the potential for a change in the paradigm of robotic control, and a new level in the taxonomy of human in the loop systems.

The role of medical physics experts in clinical trials: A guideline from the European Federation of Organisations for Medical Physics.

The EFOMP working group on the Role of Medical Physics Experts (MPEs) in Clinical Trials was established in 2010, with experts from across Europe and different areas of medical physics. Their main aims were: (1) To develop a consensus guidance document for the work MPEs do in clinical trials across Europe. (2) Complement the work by American colleagues in AAPM TG 113 and guidance from National Member Organisations. (3) To cover external beam radiotherapy, brachytherapy, nuclear medicine, molecular radiotherapy, and imaging. This document outlines the main output from this working group. Giving guidance to MPEs, and indeed all Medical Physicists (MP) and MP trainees wishing to work in clinical trials. It also gives guidance to the wider multidisciplinary team, advising where MPEs must legally be involved, as well as highlighting areas where MPEs skills and expertise can really add value to clinical trials.

A 4.000 € way to improve perceived quality and meet expectations of thyroid cancer patients receiving therapeutic dose of Iodine-131.

BACKGROUND: Thyroid cancer is the most common malignant disease of the endocrine system and radioiodine therapy (RAIT) is still very often used, resulting in patients staying hospitalized for a few days alone and without visitors, augmenting their stress and discomfort. Our objective was to find simple ways of improving RAIT patients' feelings and perceived quality of the nuclear medicine (NM) department services. MATERIAL AND METHODS: We designed a two-year study in order to enhance RAIT patients' perceived quality of the nuclear medicine (NM) department services and expectations' fulfillment. A questionnaire was used in order to capture patients' perceived quality and expectations from their RAIT. RESULTS: 549 replies were collected. Many intrinsic and extrinsic determinants were found to be positively or negatively related to the perceived quality and fulfillment of patients' expectations of receiving RAIT. A 1% increase could be achieved by spending 110 € per RAIT room. CONCLUSIONS: In this article, we present some easily implemented changes in both personnel behavior and room amenities that could, at least in theory and based on our results, offer a 37.9% improvement in RAIT patients' perceived quality and expectations' fulfillment at a cost of 4169 €.

The role of medical physicists in clinical trials across Europe.

INTRODUCTION: The roles and responsibilities of medical physicists (MPs) are growing together with the evolving science and technology. The complexity of today's clinical trials requires the skills and knowledge of MPs for their safe and efficient implementation. However, it is unclear to what extent the skillsets offered by MPs are being exploited in clinical trials across Europe. METHODS: The EFOMP Working Group on the role of Medical Physics Experts in Clinical Trials has designed a survey that targeted all 36 current National Member Organisations, receiving a response from 31 countries. The survey included both quantitative and qualitative queries regarding the involvement of MPs in trial design, setup, and coordination, either as trial team members or principal investigators. RESULTS: The extent of MPs involvement in clinical trials greatly varies across European countries. The results showed disparities between the roles played by MPs in trial design, conduct or data processing. Similarly, differences among the 31 European countries that responded to the survey were found regarding the existence of national bodies responsible for trials or the available training offered to MPs. The role of principal investigator or co-investigator was reported by 12 countries (39%), a sign of efficient collaboration with medical doctors in designing and implementing clinical studies. CONCLUSION: Organisation of specific training courses and guideline development for clinical trial design and conduct would encourage the involvement of a larger number of MPs in all stages of trials across Europe, leading to a better standardisation of clinical practice.

[Comment] Ethical and practical considerations on cancer recommendations during COVID-19 pandemic.

National and international authorities and societies have recently published important cancer treatment recommendations in order to propose extra measures that should be taken during the COVID-19 pandemic, such as prioritisation of intend-to-cure treatments and younger patients, omission of non-urgent cases, and reduction of personnel present. These measures raise important ethical considerations, since they prioritise protection of Health Systems and Professionals without seemingly taking cancer patient feelings of stress into consideration. This could lead to an erosion of the physician-patient relationship, which is considered the core element of medical ethics. Moreover, they raise practical concerns about the continuous education of Health Professionals, the status of reference centres and the evaluation of the hitherto cancer treatments.

Ecological Study on Thyroid Cancer Incidence and Mortality in Association with European Union Member States' Air Pollution.

Over the last few decades, thyroid cancer incidence has had a significant increase. Despite well-known genetic and epigenetic factors (radiation, overdiagnosis, already existing benign thyroid tumors), the effect of air pollution on its incidence and mortality has not yet been fully elucidated. In this study, air pollution data from 27 EU member states is used in order to analyze its association with thyroid cancer incidence, and mortality and socioeconomic factors are examined as confounders. This ecological study used age standardized thyroid cancer incidence and mortality rates per 100,000 people for the year 2012 from 27 EU member states, collected from the International Agency for Research on Cancer, World Health Organization and European Cancer. Data regarding mean air pollutant mass concentrations for 1992, 2002 and 2012 was collected from the European Environment Agency. Data analysis was carried out using Prism 5.0 and SPSS v.20. Multiple regression analysis showed a statistically significant positive association between thyroid cancer incidence in men and the environmental 2012 masse of Benzo (k) Fluoranthene (r2 = 0.2142, p = 0.042) and HexaChlorocycloHexane (r2 = 0.9993, p = 0.0166). Additionally, a statistically significant positive association was observed between the thyroid cancer mortality rate in men and the 1992 environmental concentrations of Hg (r2 = 0.1704, p = 0.043). Data indicates that some air pollutants may have an effect on increased thyroid cancer incidence and mortality, at least in men. However, causal relationships cannot be fully supported via ecological studies, and this article only focuses on the EU and uses only three distinct time periods.

Dynamic Risk Stratification for Predicting Treatment Response in Differentiated Thyroid Cancer.

Prognosis in Differentiated Thyroid Cancer (DTC) patients is excellent, but a significant degree of overtreatment still exists because of the inability to accurately identify small patient cohorts who experience a more aggressive form of the disease, often associated with certain poor prognostic factors. Identifying these cohorts at an early stage would allow patients at high risk to receive more aggressive treatment while avoiding unnecessary and invasive treatments in those at low risk. Most risk stratification systems include age, tumor size, grade, presence of local invasion, and regional or distant metastases. Here we discuss these common factors as well as their association with treatment response, but also other upcoming markers including histology and multifocality of primary tumor, dose administered and preparation method for Radioiodine Therapy (RAI), Thyroglobulin (Tg), Anti-thyroglobulin Antibodies (Tg-Ab) levels both at initial management and during follow-up, and the presence of previously existing benign thyroid disease. In addition, we examine the role of remnant size and avidity as well as surgeons' experience in performing thyroidectomies with recurrence rate, discussing its impact on disease prognosis. Our results reveal that treatment response has a statistically significant association with histology, T and M stages, surgeons' experience, Tg levels and remnant score both during RAI and follow up and Tg-Ab levels during follow-up whole body scan (WBS).

A test of the adaptive network explanation of functional disorders using a machine learning analysis of symptoms.

The classification and etiology of functional disorders is controversial. Evidence supports both psychological and biological (disease) models that show, respectively, that functional disorders should be classified as one (bodily distress syndrome) and many (e.g., irritable bowel syndrome (IBS), fibromyalgia syndrome (FMS), and chronic fatigue syndrome (CFS)). Two network models (symptom network and adaptive network) can explain the specificity and covariation of symptomatology, but only the adaptive network model can explain the covariation of the somatic symptoms of functional disorders. The adaptive network model is based on the premise that a network of biological mechanisms has emergent properties and can exhibit adaptation. The purpose of this study was to test the predictions that symptom similarity increases with pathology and that network connection strengths vary with pathology, as this would be consistent with the notion that functional disorder pathology arises from network adaptation. We conducted a symptom internet survey followed by machine learning analysis. Participants were 1751 people reporting IBS, FMS or CFS diagnosis who completed a 61-item symptom questionnaire. Eleven symptom clusters were identified. Differences in symptom clusters between IBS, FMS and CFS groups decreased as overall symptom frequency increased. The strength of outgoing connections between clusters varied as a function of symptom frequency and single versus multiple diagnoses. The findings suggest that the pathology of functional disorders involves an increase in the activity and causal connections between several symptom causing mechanisms. The data provide support for the proposal that the body is capable of complex adaptation and that functional disorders result when rules that normally improve adaptation create maladaptive change.

Lungtech, a phase II EORTC trial of SBRT for centrally located lung tumours - a clinical physics perspective.

BACKGROUND: The EORTC has launched a phase II trial to assess safety and efficacy of SBRT for centrally located NSCLC: The EORTC 22113-08113-Lungtech trial. Due to neighbouring critical structures, these tumours remain challenging to treat. To guarantee accordance to protocol and treatment safety, an RTQA procedure has been implemented within the frame of the EORTC RTQA levels. These levels are here expanded to include innovative tools beyond protocol compliance verification: the actual dose delivered to each patient will be estimated and linked to trial outcomes to enable better understanding of dose related response and toxicity. METHOD: For trial participation, institutions must provide a completed facility questionnaire and beam output audit results. To insure ability to comply with protocol specifications a benchmark case is sent to all centres. After approval, institutions are allowed to recruit patients. Nonetheless, each treatment plan will be prospectively reviewed insuring trial compliance consistency over time. As new features, patient's CBCT images and applied positioning corrections will be saved for dose recalculation on patient's daily geometry. To assess RTQA along the treatment chain, institutions will be visited once during the time of the trial. Over the course of this visit, end-to-end tests will be performed using the 008ACIRS-breathing platform with two separate bodies. The first body carries EBT3 films and an ionization chamber. The other body newly developed for PET- CT evaluation is fillable with a solution of high activity. 3D or 4D PET-CT and 4D-CT scanning techniques will be evaluated to assess the impact of motion artefacts on target volume accuracy. Finally, a dosimetric evaluation in static and dynamic conditions will be performed. DISCUSSION: Previous data on mediastinal toxicity are scarce and source of cautiousness for setting-up SBRT treatments for centrally located NSCLC. Thanks to the combination of documented patient related outcomes and CBCT based dose recalculation we expect to provide improved models for dose response and dose related toxicity. CONCLUSION: We have developed a comprehensive RTQA model for trials involving modern radiotherapy. These procedures could also serve as examples of extended RTQA for future radiotherapy trials involving quantitative use of PET and tumour motion.

IMRT credentialing for prospective trials using institutional virtual phantoms: results of a joint European Organization for the Research and Treatment of Cancer and Radiological Physics Center project.

BACKGROUND AND PURPOSE: Intensity-modulated radiotherapy (IMRT) credentialing for a EORTC study was performed using an anthropomorphic head phantom from the Radiological Physics Center (RPC; RPC(PH)). Institutions were retrospectively requested to irradiate their institutional phantom (INST(PH)) using the same treatment plan in the framework of a Virtual Phantom Project (VPP) for IMRT credentialing. MATERIALS AND METHODS: CT data set of the institutional phantom and measured 2D dose matrices were requested from centers and sent to a dedicated secure EORTC uploader. Data from the RPC(PH) and INST(PH) were thereafter centrally analyzed and inter-compared by the QA team using commercially available software (RIT; ver.5.2; Colorado Springs, USA). RESULTS: Eighteen institutions participated to the VPP. The measurements of 6 (33%) institutions could not be analyzed centrally. All other centers passed both the VPP and the RPC ±7%/4 mm credentialing criteria. At the 5%/5 mm gamma criteria (90% of pixels passing), 11(92%) as compared to 12 (100%) centers pass the credentialing process with RPC(PH) and INST(PH) (p = 0.29), respectively. The corresponding pass rate for the 3%/3 mm gamma criteria (90% of pixels passing) was 2 (17%) and 9 (75%; p = 0.01), respectively. CONCLUSIONS: IMRT dosimetry gamma evaluations in a single plane for a H&N prospective trial using the INST(PH) measurements showed agreement at the gamma index criteria of ±5%/5 mm (90% of pixels passing) for a small number of VPP measurements. Using more stringent, criteria, the RPC(PH) and INST(PH) comparison showed disagreement. More data is warranted and urgently required within the framework of prospective studies.

Outcome impact and cost-effectiveness of quality assurance for radiotherapy planned for the EORTC 22071-24071 prospective study for head and neck cancer.

INTRODUCTION: One of the goals of Quality Assurance in Radiotherapy (QART) is to reduce the variability and uncertainties related to treatment planning and beam delivery. The purpose of this study was to assess the outcome impact and cost-effectiveness (CE) of various QART levels for a head and neck (H&N) cancer study. MATERIALS AND METHODS: QART levels were defined as: basic QART with a dummy run (level 2), level 2 plus prospective Individual Case Reviews (ICRs) for 15% of patients (level 3) and level 2 plus prospective ICRs for all patients (level 4). The follow-up of patients was modeled using a multi-state model with parameters derived from EORTC, TROG and RTOG prospective studies. Individual patient data, linking QART results with outcome, were retrieved from the TROG database. Results for each QART level were expressed as percentage of mortality and local failure at 5 years. RESULTS: Quality-of-life-adjusted and recurrence-free survival increased with increasing QART levels. The increase of all these metrics was more sizeable with an increased QART level from 2 or 3 to 4. The estimated quality-adjusted-life-years (QALYs) for an increase of QART levels of 3-4 and 2-4 were 0.09 and 0.15, respectively. The incremental CE ratio was €5525 and €3659 Euros per QALY for these QART levels. Compared to QART level 2 or 3, level 4 was cost-effective. CONCLUSIONS: Increasing QART levels resulted in better patient outcome in this simulated study. The increased complexity of the QART program was also cost-effective.

Global harmonization of quality assurance naming conventions in radiation therapy clinical trials.

PURPOSE: To review the various radiation therapy quality assurance (RTQA) procedures used by the Global Clinical Trials RTQA Harmonization Group (GHG) steering committee members and present the harmonized RTQA naming conventions by amalgamating procedures with similar objectives. METHODS AND MATERIALS: A survey of the GHG steering committee members' RTQA procedures, their goals, and naming conventions was conducted. The RTQA procedures were classified as baseline, preaccrual, and prospective/retrospective data capture and analysis. After all the procedures were accumulated and described, extensive discussions took place to come to harmonized RTQA procedures and names. RESULTS: The RTQA procedures implemented within a trial by the GHG steering committee members vary in quantity, timing, name, and compliance criteria. The procedures of each member are based on perceived chances of noncompliance, so that the quality of radiation therapy planning and treatment does not negatively influence the trial measured outcomes. A comparison of these procedures demonstrated similarities among the goals of the various methods, but the naming given to each differed. After thorough discussions, the GHG steering committee members amalgamated the 27 RTQA procedures to 10 harmonized ones with corresponding names: facility questionnaire, beam output audit, benchmark case, dummy run, complex treatment dosimetry check, virtual phantom, individual case review, review of patients' treatment records, and protocol compliance and dosimetry site visit. CONCLUSIONS: Harmonized RTQA harmonized naming conventions, which can be used in all future clinical trials involving radiation therapy, have been established. Harmonized procedures will facilitate future intergroup trial collaboration and help to ensure comparable RTQA between international trials, which enables meta-analyses and reduces RTQA workload for intergroup studies.

Quality assurance of radiotherapy in the ongoing EORTC 22042-26042 trial for atypical and malignant meningioma: results from the dummy runs and prospective individual case Reviews.

BACKGROUND: The ongoing EORTC 22042-26042 trial evaluates the efficacy of high-dose radiotherapy (RT) in atypical/malignant meningioma. The results of the Dummy Run (DR) and prospective Individual Case Review (ICR) were analyzed in this Quality Assurance (QA) study. MATERIAL/METHODS: Institutions were requested to submit a protocol compliant treatment plan for the DR and ICR, respectively. DR-plans (n=12) and ICR-plans (n=50) were uploaded to the Image-Guided Therapy QA Center of Advanced Technology Consortium server (http://atc.wustl.edu/) and were assessed prospectively. RESULTS: Major deviations were observed in 25% (n=3) of DR-plans while no minor deviations were observed. Major and minor deviations were observed in 22% (n=11) and 10% (n=5) of the ICR-plans, respectively. Eighteen% of ICRs could not be analyzed prospectively, as a result of corrupted or late data submission. CTV to PTV margins were respected in all cases. Deviations were negatively associated with the number of submitted cases per institution (p=0.0013), with a cutoff of 5 patients per institutions. No association (p=0.12) was observed between DR and ICR results, suggesting that DR's results did not predict for an improved QA process in accrued brain tumor patients. CONCLUSIONS: A substantial number of protocol deviations were observed in this prospective QA study. The number of cases accrued per institution was a significant determinant for protocol deviation. These data suggest that successful DR is not a guarantee for protocol compliance for accrued patients. Prospective ICRs should be performed to prevent protocol deviations.

QA makes a clinical trial stronger: evidence-based medicine in radiation therapy.

Quality assurance (QA) for radiation therapy (RT) in clinical trials is necessary to ensure treatment is safely and effectively administered. QA assurance requires however substantial human and financial resources, as it has become more comprehensive and labor intensive in recent RT trials. It is presumed that RT deviations decrease therapeutic effectiveness of the studied regimen. This study assesses the impact of RT protocol-deviations on patient's outcome in prospective phase II-III RT trials. PubMed, Medline and Embase identified nine prospective RT trials detailing QA RT violation and patient's outcome. Planned QA analysis was preformed retrospectively and prospectively in eight and one studies, respectively. Non-adherence to protocol-specified RT requirements in prospective trials is frequent: the observed major deviation rates range from 11.8% to 48.0% (mean, 28.1 ± 17.9%). QA RT deviations had a significant impact on the primary study end-point in a majority (62.5%) of studies. The number of patients accrued per center was a significant predictive factor for RT deviations in the largest series. These QA data stemming from prospective clinical trials show undisputedly that non adherence to protocol-specified RT requirements is associated with reduced survival, local control and potentially increased toxicity.