C. Melidis

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 patients outcome in prospective phase II-III RT trials. PubMed, Medline and Embase identified nine prospective RT trials detailing QA RT violation and patients 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.

Radiation therapy quality assurance in clinical trials – Global harmonisation group

Participation in large multi-centre clinical trials aids establishment of the safety and efficacy of new cancer treatments and methods. Oncology clinical trials have contributed to improved local control, overall survival and quality of life for patients with varying disease types [1]. Radiation Therapy is indicated in the course of treatment for more than 50% of all cancer patients [2,3] and consequently a high percentage of oncology clinical trials include radiotherapy within their treatment schema. Collaboration between global clinical trial groups and organisations has increased the number of patient records available for analysis permitting faster recruitment [4], broader acceptance and wider impact of trial results. Global cooperation is also essential in the environment of rare cancers [5], in order to be able to create sufficiently large patient data sets within a reasonable recruitment period. A successful example is the EORTC 26981/National Cancer Institute of Canada (NCIC) CE3 intergroup trial, where 573 Glioblastoma patients were randomised within 20 months [6], despite the low prevalence of the disease among the general population. Globally, clinical trial groups and organisations have independently implemented their own Radiation Therapy (RT) Quality Assurance (QA) programs within their corresponding large multicentre clinical trials. Various trial groups have reported that the implementation of RTQA procedures enhanced protocol compliance [7–13]. In four Radiation Therapy Oncology Group (RTOG) studies compliance with the study protocol was enhanced by incorporating pre-treatment review of RT planning [8]. A Trans-Tasman Radiation Oncology Group (TROG) QA audit identified a reduction in unacceptable protocol violations due to three main factors, among which was the QA procedure itself [7]. More recently, strict RTQA procedures have been shown by TROG to have impacted on both trial protocol compliance as well as general clinical practice in prostate RT [9]. For several EORTC studies it has been shown that centres which previously participated in a Dummy Run (DR) were significantly more likely to be successful at subsequent DR attempts and delivery of protocol-compliant RT [10]. Additionally, the impact of RTQA on actual clinical trial outcome has been recently demonstrated in the setting of various cancer sites [11], stressing its importance and correlation with survival [12,13]. However, the various approaches as to how RTQA in clinical trials is performed, evaluated and described are diverse, making analysis and inter-trial comparisons of RTQA results challenging. This hampers cooperation between trial groups and impedes the exchange and interpretation of RTQA data. The costs of running an RTQA program have also increased with the introduction of new advanced technologies. This increases the need to make RTQA more efficient and streamline the QA workload demanded of clinical centres recruiting into international trials [14,15]. As shown by Pettersen et al [4] these RTQA efforts can potentially reduce the number of patients required for trials which could lead to further substantial savings and faster availability of results. The need for a global forum on harmonisation of RTQA within clinical trials thus became apparent. After initial discussions in Goteborg during ESTRO 27 in 2008 the Global Clinical Trials RTQA Harmonisation Group (GHG) was formally established in 2010. The goals of the GHG are: Collate, homogenise and distribute information regarding the RTQA standards of the clinical trial groups, Provide a platform for prospective discussions on new RTQA procedures, software tools, guidelines and policies of trial groups and Provide a framework to endorse existing and future RTQA procedures and guidelines across various trial groups. Each organisation will have the opportunity to endorse RTQA procedures from other organisations and thus accept them much faster in future collaborative trials. In Table 1 the human resources and number of intergroup trials of the steering committee members of the GHG are given. Further information about terms of reference and current and future projects can be found on its website: www.RTQAHarmonisation.org. Table 1 RTQA within each of the current GHG steering committee members as of August 2013. All RTQA groups and organisations participate in international collaborative work to some degree, although there are differences between the USA and all other groups. These differences can be explained by the differences in the funding levels and that most USA RTQA groups only work with NCI funded clinical trials mainly operated in North America [16]. Recently, the North American RTQA organisations have joined forces in the new Imaging and Radiation Oncology Core (IROC) group. The dedicated human resources also vary significantly, most likely due to differences in the QA philosophy of the funding agencies and their commitment to RTQA, although most of the GHG members have at least one Radiation Oncologist, one Medical Physicist and one Radiation Technologist dedicated full time to RTQA. Until now the GHG has contributed to the harmonisation of naming conventions [17], strategies to develop an efficient evidence-based clinical trials RTQA system [14] and the development of a global model for the international recognition of the activities of national and regional Dosimetry Audit Networks [18]. Currently, each trial group has defined its own RTQA procedures [10,19–24] that differ significantly in number, naming conventions and implementation methods [22,25–31]. The GHG is addressing this by collating all RTQA procedures of each member, comparing them and proposing common, harmonised names and procedures. Although RTQA has been proven to be effective, international differences hamper intergroup collaboration. The Global Clinical Trials RTQA Harmonisation Group has been established to reduce those differences, capitalise on the range of expertise available internationally, increase the power of RT clinical trials, deliver consistency in the reporting of trial quality factors and facilitate the undertaking of effective multi-national trials and data analysis. Although important progress has already been made, many challenges remain to be addressed.

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

BackgroundThe 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/methodsInstitutions 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.ResultsMajor 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.ConclusionsA 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.

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.

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

BackgroundThe 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.MethodFor 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.DiscussionPrevious 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.ConclusionWe 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.

OC-0066 MULTINATIONAL IMRT CREDENTIALING BY PHANTOM IRRADIATION: A JOINT RPC AND EORTC ROG EXPERIENCE

Authors: Hurkmans CW (EORTC-ROG, Brussels, Belgium and Department of Radiation Therapy, Catharina hospital Eindhoven, The Netherlands, presenting author), Molineu A (Radiological Physics Center, Houston, Texas, USA), Followill D (Radiological Physics Center, Houston, Texas, USA), Moeckli R (Institute of radiation physics, Lausanne university hospital, Lausanne, Switzerland), Vallet V. (Institute of radiation physics, Lausanne university hospital, Lausanne, Switzerland) Melidis C (EORTC-ROG, Brussels, Belgium), Weber D (EORTC-ROG, Brussels, Belgium)

EP-1549: 8-year per continent and country beam output audit results of centers participating in prospective clinical trials

Results: Figure 1a shows the cube propagation in the coronal direction and DVF of the inserts. Mean S-I distance are 0.16±0.14cm for cube and 0.27±0.12cm for sphere. DVF have a mean magnitude scale of 0.00-1.11cm for the 4DCT. The mean transition has same dimension, according to the space covered by the objects during phases bin. The motion direction is obtained by reverse mode, otherwise uncorrected track is provided by the DVF module. Graph (Figure1b) shows the displacement of 2 ROIs in S-I directions per phases. A strong correlation (R=0.95) with position, time and direction of the inserts (cube and sphere) is obtained (Figure 1c).