Randomised, multicentre, phase III, open-label study of alectinib vs crizotinib in treatment-naïve anaplastic lymphoma kinase (ALK)-positive advanced NSCLC (ALEX study).

Background: In ∼5% of advanced NSCLC tumours, ALK tyrosine kinase is constitutively activated after translocation of ALK. ALK+ NSCLC was shown to be highly sensitive to the first approved ALK inhibitor, crizotinib. However, all pts eventually relapse on crizotinib mainly due to secondary ALK mutations/amplification or CNS metastases. Alectinib is a highly selective, potent, oral next-generation ALK inhibitor. Clinical phase II alectinib data in 46 crizotinib-naïve pts with ALK+ NSCLC reported an objective response rate (ORR) of 93.5% and a 1-year progression-free rate of 83% (95% CI: 68-92) (Inoue et al. J Thorac Oncol 2013). CNS activity was seen: of 14 pts with baseline brain metastasis, 11 had prior CNS radiation, 9 of these experienced CNS and systemic PFS of >12 months; of the 3 pts without prior CNS radiation, 2 were >15 months progression free. Trial design: Randomised, multicentre, phase III, open-label study in pts with treatment-naïve ALK+ advanced, recurrent, or metastatic NSCLC. All pts must provide pretreatment tumour tissue to confirm ALK rearrangement (by IHC). Pts (∼286 from ∼180 centres, ∼30 countries worldwide) will be randomised to alectinib (600mg oral bid, with food) or crizotinib (250mg oral bid, with/without food) until disease progression (PD), unacceptable toxicity, withdrawal of consent, or death. Stratification factors are: ECOG PS (0/1 vs 2), race (Asian vs non-Asian), baseline CNS metastases (yes vs no). Primary endpoint: PFS by investigators (RECIST v1.1). Secondary endpoints: PFS by Independent Review Committee (IRC); ORR; duration of response; OS; safety; pharmacokinetics; quality of life. Additionally, time to CNS progression will be evaluated (MRI) for the first time in a prospective randomised NSCLC trial as a secondary endpoint. Pts with isolated asymptomatic CNS progression will be allowed to continue treatment beyond documented progression until systemic PD and/or symptomatic CNS progression, according to investigator opinion. Time to CNS progression will be retrospectively assessed by the IRC using two separate criteria, RECIST and RANO. Further details: ClinicalTrials.gov (NCT02075840). Disclosure: T.S.K. Mok: Advisory boards: AZ, Roche, Eli Lilly, Merck Serono, Eisai, BMS, AVEO, Pfizer, Taiho, Boehringer Ingelheim, Novartis, GSK Biologicals, Clovis Oncology, Amgen, Janssen, BioMarin; board of directors: IASLC; corporate sponsored research: AZ; M. Perol: Advisory boards: Roche; S.I. Ou: Consulting: Pfizer, Chugai, Genentech Speaker Bureau: Pfizer, Genentech, Boehringer Ingelheim; I. Bara: Employee: F. Hoffmann-La Roche Ltd; V. Henschel: Employee and stock: F. Hoffmann-La Roche Ltd.; D.R. Camidge: Honoraria: Roche/Genentech. All other authors have declared no conflicts of interest.

Iterative reconstruction in CT : using mathematical model observers to determine low dose images' trustworthiness

La tomodensitométrie (TDM) est une technique d'imagerie pour laquelle l'intérêt n'a cessé de croitre depuis son apparition au début des années 70. De nos jours, l'utilisation de cette technique est devenue incontournable, grâce entre autres à sa capacité à produire des images diagnostiques de haute qualité. Toutefois, et en dépit d'un bénéfice indiscutable sur la prise en charge des patients, l'augmentation importante du nombre d'examens TDM pratiqués soulève des questions sur l'effet potentiellement dangereux des rayonnements ionisants sur la population. Parmi ces effets néfastes, l'induction de cancers liés à l'exposition aux rayonnements ionisants reste l'un des risques majeurs. Afin que le rapport bénéfice-risques reste favorable au patient il est donc nécessaire de s'assurer que la dose délivrée permette de formuler le bon diagnostic tout en évitant d'avoir recours à des images dont la qualité est inutilement élevée. Ce processus d'optimisation, qui est une préoccupation importante pour les patients adultes, doit même devenir une priorité lorsque l'on examine des enfants ou des adolescents, en particulier lors d'études de suivi requérant plusieurs examens tout au long de leur vie. Enfants et jeunes adultes sont en effet beaucoup plus sensibles aux radiations du fait de leur métabolisme plus rapide que celui des adultes. De plus, les probabilités des évènements auxquels ils s'exposent sont également plus grandes du fait de leur plus longue espérance de vie. L'introduction des algorithmes de reconstruction itératifs, conçus pour réduire l'exposition des patients, est certainement l'une des plus grandes avancées en TDM, mais elle s'accompagne de certaines difficultés en ce qui concerne l'évaluation de la qualité des images produites. Le but de ce travail est de mettre en place une stratégie pour investiguer le potentiel des algorithmes itératifs vis-à-vis de la réduction de dose sans pour autant compromettre la qualité du diagnostic. La difficulté de cette tâche réside principalement dans le fait de disposer d'une méthode visant à évaluer la qualité d'image de façon pertinente d'un point de vue clinique. La première étape a consisté à caractériser la qualité d'image lors d'examen musculo-squelettique. Ce travail a été réalisé en étroite collaboration avec des radiologues pour s'assurer un choix pertinent de critères de qualité d'image. Une attention particulière a été portée au bruit et à la résolution des images reconstruites à l'aide d'algorithmes itératifs. L'analyse de ces paramètres a permis aux radiologues d'adapter leurs protocoles grâce à une possible estimation de la perte de qualité d'image liée à la réduction de dose. Notre travail nous a également permis d'investiguer la diminution de la détectabilité à bas contraste associée à une diminution de la dose ; difficulté majeure lorsque l'on pratique un examen dans la région abdominale. Sachant que des alternatives à la façon standard de caractériser la qualité d'image (métriques de l'espace Fourier) devaient être utilisées, nous nous sommes appuyés sur l'utilisation de modèles d'observateurs mathématiques. Nos paramètres expérimentaux ont ensuite permis de déterminer le type de modèle à utiliser. Les modèles idéaux ont été utilisés pour caractériser la qualité d'image lorsque des paramètres purement physiques concernant la détectabilité du signal devaient être estimés alors que les modèles anthropomorphes ont été utilisés dans des contextes cliniques où les résultats devaient être comparés à ceux d'observateurs humain, tirant profit des propriétés de ce type de modèles. Cette étude a confirmé que l'utilisation de modèles d'observateurs permettait d'évaluer la qualité d'image en utilisant une approche basée sur la tâche à effectuer, permettant ainsi d'établir un lien entre les physiciens médicaux et les radiologues. Nous avons également montré que les reconstructions itératives ont le potentiel de réduire la dose sans altérer la qualité du diagnostic. Parmi les différentes reconstructions itératives, celles de type « model-based » sont celles qui offrent le plus grand potentiel d'optimisation, puisque les images produites grâce à cette modalité conduisent à un diagnostic exact même lors d'acquisitions à très basse dose. Ce travail a également permis de clarifier le rôle du physicien médical en TDM: Les métriques standards restent utiles pour évaluer la conformité d'un appareil aux requis légaux, mais l'utilisation de modèles d'observateurs est inévitable pour optimiser les protocoles d'imagerie. -- Computed tomography (CT) is an imaging technique in which interest has been quickly growing since it began to be used in the 1970s. Today, it has become an extensively used modality because of its ability to produce accurate diagnostic images. However, even if a direct benefit to patient healthcare is attributed to CT, the dramatic increase in the number of CT examinations performed has raised concerns about the potential negative effects of ionising radiation on the population. Among those negative effects, one of the major risks remaining is the development of cancers associated with exposure to diagnostic X-ray procedures. In order to ensure that the benefits-risk ratio still remains in favour of the patient, it is necessary to make sure that the delivered dose leads to the proper diagnosis without producing unnecessarily high-quality images. This optimisation scheme is already an important concern for adult patients, but it must become an even greater priority when examinations are performed on children or young adults, in particular with follow-up studies which require several CT procedures over the patient's life. Indeed, children and young adults are more sensitive to radiation due to their faster metabolism. In addition, harmful consequences have a higher probability to occur because of a younger patient's longer life expectancy. The recent introduction of iterative reconstruction algorithms, which were designed to substantially reduce dose, is certainly a major achievement in CT evolution, but it has also created difficulties in the quality assessment of the images produced using those algorithms. The goal of the present work was to propose a strategy to investigate the potential of iterative reconstructions to reduce dose without compromising the ability to answer the diagnostic questions. The major difficulty entails disposing a clinically relevant way to estimate image quality. To ensure the choice of pertinent image quality criteria this work was continuously performed in close collaboration with radiologists. The work began by tackling the way to characterise image quality when dealing with musculo-skeletal examinations. We focused, in particular, on image noise and spatial resolution behaviours when iterative image reconstruction was used. The analyses of the physical parameters allowed radiologists to adapt their image acquisition and reconstruction protocols while knowing what loss of image quality to expect. This work also dealt with the loss of low-contrast detectability associated with dose reduction, something which is a major concern when dealing with patient dose reduction in abdominal investigations. Knowing that alternative ways had to be used to assess image quality rather than classical Fourier-space metrics, we focused on the use of mathematical model observers. Our experimental parameters determined the type of model to use. Ideal model observers were applied to characterise image quality when purely objective results about the signal detectability were researched, whereas anthropomorphic model observers were used in a more clinical context, when the results had to be compared with the eye of a radiologist thus taking advantage of their incorporation of human visual system elements. This work confirmed that the use of model observers makes it possible to assess image quality using a task-based approach, which, in turn, establishes a bridge between medical physicists and radiologists. It also demonstrated that statistical iterative reconstructions have the potential to reduce the delivered dose without impairing the quality of the diagnosis. Among the different types of iterative reconstructions, model-based ones offer the greatest potential, since images produced using this modality can still lead to an accurate diagnosis even when acquired at very low dose. This work has clarified the role of medical physicists when dealing with CT imaging. The use of the standard metrics used in the field of CT imaging remains quite important when dealing with the assessment of unit compliance to legal requirements, but the use of a model observer is the way to go when dealing with the optimisation of the imaging protocols.

Under what conditions? Therapist and client characteristics moderate the role of change talk in brief motivational intervention.

OBJECTIVE: Client change talk has been proposed as a mechanism of change in motivational interviewing (MI) by mediating the link between therapist MI-consistent behaviors (MICO) and client behavioral outcomes. We tested under what circumstances this mechanism was supported in the context of a clinical trial of brief MI for heavy drinking among nontreatment seeking young men. METHOD: We conducted psycholinguistic coding of 174 sessions using the MI Skill Code 2.1 and derived the frequency of MICO and the strength of change talk (CTS) averaged over the session. CTS was examined as a mediator of the relationship between MICO and a drinking composite score measured at 3-month follow-up, controlling for the composite measure at baseline. Finally, we tested therapist gender and MI experience as well as client readiness to change and alcohol problem severity as moderators of this mediation model. RESULTS: CTS significantly predicted outcome (higher strength related to less drinking), but MICO did not predict CTS. However, CTS mediated the relationship between MICO and drinking outcomes when therapists had more experience in MI and when clients had more severe alcohol problems (i.e., significant conditional indirect effects). CONCLUSIONS: The mechanism hypothesized by MI theory was operative in our brief MI with heavy drinking young men, but only under particular conditions. Our results suggest that attention should be paid to therapist selection, training, and/or supervision until they reach a certain level of competence, and that MI might not be appropriate for nontreatment seeking clients drinking at a lower level of risk. (PsycINFO Database Record