Estimation of the radiation risks in diagnostic procedures to populations and patients

Since 1895, when X-rays were discovered, ionizing radiation became part of our life. Its use in medicine has brought significant health benefits to the population globally. The benefit of any diagnostic procedure is to reduce the uncertainty about the patient's health. However, there are potential detrimental effects of radiation exposure. Therefore, radiation protection authorities have become strict regarding the control of radiation risks.¦There are various situations where the radiation risk needs to be evaluated. International authority bodies point to the increasing number of radiologic procedures and recommend population surveys. These surveys provide valuable data to public health authorities which helps them to prioritize and focus on patient groups in the population that are most highly exposed. On the other hand, physicians need to be aware of radiation risks from diagnostic procedures in order to justify and optimize the procedure and inform the patient.¦The aim of this work was to examine the different aspects of radiation protection and investigate a new method to estimate patient radiation risks.¦The first part of this work concerned radiation risk assessment from the regulatory authority point of view. To do so, a population dose survey was performed to evaluate the annual population exposure. This survey determined the contribution of different imaging modalities to the total collective dose as well as the annual effective dose per caput. It was revealed that although interventional procedures are not so frequent, they significantly contribute to the collective dose. Among the main results of this work, it was shown that interventional cardiological procedures are dose-intensive and therefore more attention should be paid to optimize the exposure.¦The second part of the project was related to the patient and physician oriented risk assessment. In this part, interventional cardiology procedures were studied by means of Monte Carlo simulations. The organ radiation doses as well as effective doses were estimated. Cancer incidence risks for different organs were calculated for different sex and age-at-exposure using the lifetime attributable risks provided by the Biological Effects of Ionizing Radiations Report VII. Advantages and disadvantages of the latter results were examined as an alternative method to estimate radiation risks. The results show that this method is the most accurate, currently available, to estimate radiation risks. The conclusions of this work may guide future studies in the field of radiation protection in medicine.¦-¦Depuis la découverte des rayons X en 1895, ce type de rayonnement a joué un rôle important dans de nombreux domaines. Son utilisation en médecine a bénéficié à la population mondiale puisque l'avantage d'un examen diagnostique est de réduire les incertitudes sur l'état de santé du patient. Cependant, leur utilisation peut conduire à l'apparition de cancers radio-induits. Par conséquent, les autorités sanitaires sont strictes quant au contrôle du risque radiologique.¦Le risque lié aux radiations doit être estimé dans différentes situations pratiques, dont l'utilisation médicale des rayons X. Les autorités internationales de radioprotection indiquent que le nombre d'examens et de procédures radiologiques augmente et elles recommandent des enquêtes visant à déterminer les doses de radiation délivrées à la population. Ces enquêtes assurent que les groupes de patients les plus à risque soient prioritaires. D'un autre côté, les médecins ont également besoin de connaître le risque lié aux radiations afin de justifier et optimiser les procédures et informer les patients.¦Le présent travail a pour objectif d'examiner les différents aspects de la radioprotection et de proposer une manière efficace pour estimer le risque radiologique au patient.¦Premièrement, le risque a été évalué du point de vue des autorités sanitaires. Une enquête nationale a été réalisée pour déterminer la contribution des différentes modalités radiologiques et des divers types d'examens à la dose efficace collective due à l'application médicale des rayons X. Bien que les procédures interventionnelles soient rares, elles contribuent de façon significative à la dose délivrée à la population. Parmi les principaux résultats de ce travail, il a été montré que les procédures de cardiologie interventionnelle délivrent des doses élevées et devraient donc être optimisées en priorité.¦La seconde approche concerne l'évaluation du risque du point de vue du patient et du médecin. Dans cette partie, des procédures interventionnelles cardiaques ont été étudiées au moyen de simulations Monte Carlo. La dose délivrée aux organes ainsi que la dose efficace ont été estimées. Les risques de développer des cancers dans plusieurs organes ont été calculés en fonction du sexe et de l'âge en utilisant la méthode établie dans Biological Effects of Ionizing Radiations Report VII. Les avantages et inconvénients de cette nouvelle technique ont été examinés et comparés à ceux de la dose efficace. Les résultats ont montré que cette méthode est la plus précise actuellement disponible pour estimer le risque lié aux radiations. Les conclusions de ce travail pourront guider de futures études dans le domaine de la radioprotection en médicine.

Evaluation of organ-specific peripheral doses after 2-dimensional, 3-dimensional and hybrid intensity modulated radiation therapy for breast cancer based on Monte Carlo and convolution/superposition algorithms: implications for secondary cancer risk assessment.

To make a comprehensive evaluation of organ-specific out-of-field doses using Monte Carlo (MC) simulations for different breast cancer irradiation techniques and to compare results with a commercial treatment planning system (TPS). Three breast radiotherapy techniques using 6MV tangential photon beams were compared: (a) 2DRT (open rectangular fields), (b) 3DCRT (conformal wedged fields), and (c) hybrid IMRT (open conformal+modulated fields). Over 35 organs were contoured in a whole-body CT scan and organ-specific dose distributions were determined with MC and the TPS. Large differences in out-of-field doses were observed between MC and TPS calculations, even for organs close to the target volume such as the heart, the lungs and the contralateral breast (up to 70% difference). MC simulations showed that a large fraction of the out-of-field dose comes from the out-of-field head scatter fluence (>40%) which is not adequately modeled by the TPS. Based on MC simulations, the 3DCRT technique using external wedges yielded significantly higher doses (up to a factor 4-5 in the pelvis) than the 2DRT and the hybrid IMRT techniques which yielded similar out-of-field doses. In sharp contrast to popular belief, the IMRT technique investigated here does not increase the out-of-field dose compared to conventional techniques and may offer the most optimal plan. The 3DCRT technique with external wedges yields the largest out-of-field doses. For accurate out-of-field dose assessment, a commercial TPS should not be used, even for organs near the target volume (contralateral breast, lungs, heart).

A New Twist on Radiation Oncology: Low-Dose Irradiation Elicits Immunostimulatory Macrophages that Unlock Barriers to Tumor Immunotherapy.

Tumor-infiltrating macrophages typically promote angiogenesis while suppressing antitumoral T cell responses. In this issue of Cancer Cell, Klug and colleagues report that clinically-feasible, low-dose irradiation redirects macrophage differentiation from a tumor-promoting/immunosuppressive state to one that enables cytotoxic T cells to infiltrate tumors and kill cancer cells, rendering immunotherapy successful in mice.

Techniques for CT and MR, post-processing, radiation

Brain perfusion can be assessed by CT and MR. For CT, two major techniques are used. First, Xenon CT is an equilibrium technique based on a freely diffusible tracer. First pass of iodinated contrast injected intravenously is a second method, more widely available. Both methods are proven to be robust and quantitative, thanks to the linear relationship between contrast concentration and x-ray attenuation. For the CT methods, concern regarding x-ray doses delivered to the patients need to be addressed. MR is also able to assess brain perfusion using the first pass of gadolinium based contrast agent injected intravenously. This method has to be considered as a semi-quantitative because of the non linear relationship between contrast concentration and MR signal changes. Arterial spin labeling is another MR method assessing brain perfusion without injection of contrast. In such case, the blood flow in the carotids is magnetically labelled by an external radiofrequency pulse and observed during its first pass through the brain. Each of this various CT and MR techniques have advantages and limits that will be illustrated and summarized.Learning Objectives:1. To understand and compare the different techniques for brain perfusion imaging.2. To learn about the methods of acquisition and post-processing of brain perfusion by first pass of contrast agent for CT and MR.3. To learn about non contrast MR methods (arterial spin labelling).

Early and late skin reactions to radiotherapy for breast cancer and their correlation with radiation-induced DNA damage in lymphocytes

INTRODUCTION Radiotherapy outcomes might be further improved by a greater understanding of the individual variations in normal tissue reactions that determine tolerance. Most published studies on radiation toxicity have been performed retrospectively. Our prospective study was launched in 1996 to measure the in vitro radiosensitivity of peripheral blood lymphocytes before treatment with radical radiotherapy in patients with breast cancer, and to assess the early and the late radiation skin side effects in the same group of patients. We prospectively recruited consecutive breast cancer patients receiving radiation therapy after breast surgery. To evaluate whether early and late side effects of radiotherapy can be predicted by the assay, a study was conducted of the association between the results of in vitro radiosensitivity tests and acute and late adverse radiation effects. METHODS Intrinsic molecular radiosensitivity was measured by using an initial radiation-induced DNA damage assay on lymphocytes obtained from breast cancer patients before radiotherapy. Acute reactions were assessed in 108 of these patients on the last treatment day. Late morbidity was assessed after 7 years of follow-up in some of these patients. The Radiation Therapy Oncology Group (RTOG) morbidity score system was used for both assessments. RESULTS Radiosensitivity values obtained using the in vitro test showed no relation with the acute or late adverse skin reactions observed. There was no evidence of a relation between acute and late normal tissue reactions assessed in the same patients. A positive relation was found between the treatment volume and both early and late side effects. CONCLUSION After radiation treatment, a number of cells containing major changes can have a long survival and disappear very slowly, becoming a chronic focus of immunological system stimulation. This stimulation can produce, in a stochastic manner, late radiation-related adverse effects of varying severity. Further research is warranted to identify the major determinants of normal tissue radiation response to make it possible to individualize treatments and improve the outcome of radiotherapy in cancer patients.

The prognostic value of health-related quality-of-life data in predicting survival in glioblastoma cancer patients: results from an international randomised phase III EORTC Brain Tumour and Radiation Oncology Groups, and NCIC Clinical Trials Group study.

This is one of the few studies that have explored the value of baseline symptoms and health-related quality of life (HRQOL) in predicting survival in brain cancer patients. Baseline HRQOL scores (from the EORTC QLQ-C30 and the Brain Cancer Module (BN 20)) were examined in 490 newly diagnosed glioblastoma cancer patients for the relationship with overall survival by using Cox proportional hazards regression models. Refined techniques as the bootstrap re-sampling procedure and the computation of C-indexes and R(2)-coefficients were used to try and validate the model. Classical analysis controlled for major clinical prognostic factors selected cognitive functioning (P=0.0001), global health status (P=0.0055) and social functioning (P<0.0001) as statistically significant prognostic factors of survival. However, several issues question the validity of these findings. C-indexes and R(2)-coefficients, which are measures of the predictive ability of the models, did not exhibit major improvements when adding selected or all HRQOL scores to clinical factors. While classical techniques lead to positive results, more refined analyses suggest that baseline HRQOL scores add relatively little to clinical factors to predict survival. These results may have implications for future use of HRQOL as a prognostic factor in cancer patients.

Dummy run and conformity indices in the ongoing EORTC low-grade glioma trial 22033-26033: First evaluation of quality of radiotherapy planning.

PURPOSE: Early assessment of radiotherapy (RT) quality in the ongoing EORTC trial comparing primary temozolomide versus RT in low-grade gliomas. MATERIALS AND METHODS: RT plans provided for dummy cases were evaluated and compared against expert plans. We analysed: (1) tumour and organs-at-risk delineation, (2) geometric and dosimetric characteristics, (3) planning parameters, compliance with dose prescription and Dmax for OAR (4) indices: RTOG conformity index (CI), coverage factor (CF), tissue protection factor (PF); conformity number (CN = PF x CF); dose homogeneity in PTV (U). RESULTS: Forty-one RT plans were evaluated. Only two (5%) centres were requested to repeat CTV-PTV delineations. Three (7%) plans had a significant under-dosage and dose homogeneity in one deviated > 10%. Dose distribution was good with mean values of 1.5, 1, 0.68, and 0.68 (ideal values = 1) for CI, CF, PF, and CN, respectively. CI and CN strongly correlated with PF and they correlated with PTV. Planning with more beams seems to increase PTV(Dmin), improving CF. U correlated with PTV(Dmax). CONCLUSION: Preliminary results of the dummy run procedure indicate that most centres conformed to protocol requirements. To quantify plan quality we recommend systematic calculation of U and either CI or CN, both of which measure the amount of irradiated normal brain tissue.

Canakinumab relieves symptoms of acute flares and improves health-related quality of life in patients with difficult-to-treat Gouty Arthritis by suppressing inflammation: results of a randomized, dose-ranging study.

INTRODUCTION: We report the impact of canakinumab, a fully human anti-interleukin-1β monoclonal antibody, on inflammation and health-related quality of life (HRQoL) in patients with difficult-to-treat Gouty Arthritis. METHODS: In this eight-week, single-blind, double-dummy, dose-ranging study, patients with acute Gouty Arthritis flares who were unresponsive or intolerant to--or had contraindications for--non-steroidal anti-inflammatory drugs and/or colchicine were randomized to receive a single subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg) (N = 143) or an intramuscular dose of triamcinolone acetonide 40 mg (N = 57). Patients assessed pain using a Likert scale, physicians assessed clinical signs of joint inflammation, and HRQoL was measured using the 36-item Short-Form Health Survey (SF-36) (acute version). RESULTS: At baseline, 98% of patients were suffering from moderate-to-extreme pain. The percentage of patients with no or mild pain was numerically greater in most canakinumab groups compared with triamcinolone acetonide from 24 to 72 hours post-dose; the difference was statistically significant for canakinumab 150 mg at these time points (P < 0.05). Treatment with canakinumab 150 mg was associated with statistically significant lower Likert scores for tenderness (odds ratio (OR), 3.2; 95% confidence interval (CI), 1.27 to 7.89; P = 0.014) and swelling (OR, 2.7; 95% CI, 1.09 to 6.50, P = 0.032) at 72 hours compared with triamcinolone acetonide. Median C-reactive protein and serum amyloid A levels were normalized by seven days post-dose in most canakinumab groups, but remained elevated in the triamcinolone acetonide group. Improvements in physical health were observed at seven days post-dose in all treatment groups; increases in scores were highest for canakinumab 150 mg. In this group, the mean SF-36 physical component summary score increased by 12.0 points from baseline to 48.3 at seven days post-dose. SF-36 scores for physical functioning and bodily pain for the canakinumab 150 mg group approached those for the US general population by seven days post-dose and reached norm values by eight weeks post-dose. CONCLUSIONS: Canakinumab 150 mg provided significantly greater and more rapid reduction in pain and signs and symptoms of inflammation compared with triamcinolone acetonide 40 mg. Improvements in HRQoL were seen in both treatment groups with a faster onset with canakinumab 150 mg compared with triamcinolone acetonide 40 mg. TRIAL REGISTRATION: clinicaltrials.gov: NCT00798369.

RTOG 0525: A randomized phase iii trial comparing standard adjuvant temozolomide (tmz) with a dose-dense (dd) schedule in newly diagnosed glioblastoma (gbm)

Radiotherapy with concomitant and adjuvant TMZ is the standard of care for newly diagnosed GBM. MGMT methylation status may be an important determinant of treatment response. This trial, conducted by the RTOG, EORTC, and NCCTG, determined if intensified TMZ improves survival (OS) or progression free survival (PFS) in all patients or specific to MGMT status. Eligibility criteria included age . 18 yrs, KPS ≥ 60, and existence of a tissue block with . 1cm2 tumor for prospective MGMT and retrospective molecular analysis. Patients were randomized to Arm 1: standard TMZ (150-200 mg/m2 x 5 d) or Arm 2: dd TMZ (75-100 mg/m2 x 21 d) q 4 wks for 6-12 cycles. Symptom burden, quality of life (QOL), and neurocognition were prospectively and longitudinally assessed in a patient subset. 833 patients were randomized (1173 registered). Inadequate tissue (n ¼ 144) was the most frequent reason for nonrandomization.No statistical difference was observed between Arms 1 and 2 for median OS (16.6, 14.9 mo, p ¼ 0.63), median PFS (5.5, 6.7 mo, p ¼ 0.06), or methylation status. MGMT methylation was associated with improved OS (21.2, 14 mo, p , 0.0001), PFS (8.7, 5.7 mo, p , 0.0001), and treatment response (p ¼ 0.012). Cox modeling identifiedMGMT status and RPA class as significant predictors of OS; treatment arm and radiation technique (EORTC vs. RTOG) were not. There was increased grade ≥ 3 toxicity in Arm 2 (19%, 27%, p ¼ 0.008), which was mostly lymphopenia and fatigue. This study did not demonstrate improved efficacy for dd TMZ for newly diagnosed GBM regardless of methylation status. However, it confirmed the prognostic significance of MGMT methylation in GBM, demonstrated the feasibility of tumor tissue collection, molecular stratification, and collection of patient outcomes in a large transatlantic intergroup trial, thereby establishing a viable clinical trial paradigm. Support: NCI U10 CA 21661 and U10 CA37422.

Carotid Dose Spring in Definitive Irradiation of T1N0 Squamous Cell Laryngeal Carcinoma Using Helical Tomotherapy

Purpose/Objective(s): To implement a carotid dose sparing protocol using helical Tomotherapy in T1N0 squamous cell laryngeal carcinoma.Materials/Methods: Between July and August 2010, 7 men with stage T1N0 laryngeal carcinoma were included in this study. Age ranged from 47 - 74 years. Staging included endoscopic examination, CT-scan and MRI when indicated. Planned irradiation dose was 70 Gy in 35 fractions over 7 weeks. A simple treatment planning algorithm for carotid sparing was used: maximum point dose to the carotids 35 Gy, to the spinal cord 30 Gy, and 100% PTV volume to be covered with 95% of the prescribed dose. Carotid volume of interest extended to 1 cm above and below of the PTV. Doses to the carotid arteries, to the critical organs, and to the planned target volume (PTV) with our standard laryngeal irradiation protocol was compared. Daily megavoltage scans were obtained before each fraction. When necessary, the Planned Adaptive software (TomoTherapy Inc., Madison, WI) was used to evaluatethe need for a re-planning, which has never been indicated. Dose data were extracted using the VelocityAI software (Atlanta, GA), and data normalization and dose-volume histogram (DVH) interpolation were realized using the Igor Pro software (Portland, OR).Results:A significant (p\0.05) carotid dose sparing compared to our standard protocol with an average maximum point dose of 38.3 Gy (standard deviation [SD] 4.05 Gy), average mean dose of 18.59 Gy (SD 0.83 Gy) was achieved. In all patients, 95% of the carotid volume received less than 28.4 Gy (SD 0.98 Gy). The average maximum point dose to the spinal cord was 25.8 Gy (SD 3.24 Gy). PTV was fully covered with more than 95% of the prescribed dose for all patients with an average maximum point dose of 74.1 Gy and the absolute maximum dose in a single patient of 75.2 Gy. To date, the clinical outcomes have been excellent. Three patients (42%) developed stage 1 mucositis that was conservatively managed, and all the patients presented a mild to moderate dysphonia. All adverse effects resolved spontaneously in the month following the end of treatment. Early local control rate is 100% considering a 4 - 5 months post treatment follow-up.Conclusions: Helical Tomotherapy allows a clinically significant decrease of carotid irradiation dose compared to standard irradiation protocols with an acceptable spinal cord dose tradeoff. Moreover, this technique allows the PTV to be homogenously covered with a curative irradiation dose. Daily control imaging brings added security margins especially when working with high dose gradients. Further investigations and follow-up are underway to better evaluate the late clinical outcomes especially the local control rate, late laryngeal and vascular toxicity, and expected potential impact on cerebrovascular events.

Optimisation des doses en tomographie computérisée pédiatrique [Patient dose optimization in pediatric computerized tomography]

The development of CT applications might become a public health problem if no effort is made on the justification and the optimisation of the examinations. This paper presents some hints to assure that the risk-benefit compromise remains in favour of the patient, especially when one deals with the examinations of young patients. In this context a particular attention has to be made on the justification of the examination. When performing the acquisition one needs to optimise the extension of the volume investigated together with the number of acquisition sequences used. Finally, the use of automatic exposure systems, now available on all the units, and the use of the Diagnostic Reference Levels (DRL) should allow help radiologists to control the exposure of their patients.

Quality of assessement of CMR images in the setting of the European cardiovascular magnetic resonance registry : description and validation of standardized criteria

l'imagerie par résonance magnétique (IRMC) est une technologie utilisée depuis les aimées quatre¬-vingts dans le monde de la cardiologie. Cette technique d'imagerie non-invasive permet d'acquérir Ses images du coeur en trois dimensions, dans n'importe quel, plan, sans application de radiation, et en haute résolution. Actuellement, cette technique est devenue un référence dans l'évaluation et 'l'investigation de différentes pathologies cardiaques. La morphologie cardiaque, la fonction des ventricules ainsi que leur contraction, la perfusion tissulaire ainsi que la viabilité tissulaire peuvent être caractérisés en utilisant différentes séquences d'imagerie. Cependant, cette technologie repose sur des principes physiques complexes et la mise en pratique de cette technique se heurte à la difficulté d'évaluer un organe en mouvement permanent. L'IRM cardiaque est donc sujette à différents artefacts qui perturbent l'interprétation des examens et peuvent diminuer la précision diagnostique de cette technique. A notre connaissance, la plupart des images d'IRMC sont analysées et interprétées sans évaluation rigoureuse de la qualité intrinsèque de l'examen. Jusqu'à présent, et à notre connaissance, aucun critère d'évaluation de la qualité des examens d'IRMC n'a été clairement déterminé. L'équipe d'IRMC du CHUV, dirigée par le Prof J. Schwitter, a recensé une liste de 35 critères qualitatifs et 12 critères quantitatifs évaluant la qualité d'un examen d'IRMC et les a introduit dans une grille d'évaluation. L'objet de cette étude est de décrire et de valider la reproductibilité des critères figurant dans cette grille d'évaluation, par l'interprétation simultanée d'examens IRMC par différents observateurs (cardiologues spécialisés en IRM, étudiant en médecine, infirmière spécialisée). Notre étude a permis de démontrer que les critères définis pour l'évaluation des examens d'IRMC sont robustes, et permettent une bonne reproductibilité intra- et inter-observateurs. Cette étude valide ainsi l'utilisation de ces critères de qualité dans le cadre de l'imagerie par résonance magnétique cardiaque. D'autres études sont encore nécessaires afin de déterminer l'impact de la qualité de l'image sur la précision diagnostique de cette technique. Les critères standardisés que nous avons validés seront utilisés pour évaluer la qualité des images dans le cadre d'une étude à échelle européenne relative à l'IRMC : "l'EuroCMR registry". Parmi les autres utilités visées par ces critères de qualité, citons notamment la possibilité d'avoir une référence d'évaluation de la qualité d'examen pour toutes les futures études cliniques utilisant la technologie d'IRMC, de permettre aux centres d'IRMC de quantifier leur niveau de qualité, voire de créer un certificat de standard de qualité pour ces centres, d'évaluer la reproductibilité de l'évaluation des images par différents observateurs d'un même centre, ou encore d'évaluer précisément la qualité des séquences développées à l'avenir dans le monde de l'IRMC.