C.W. Hurkmans

Recommendations for implementing stereotactic radiotherapy in peripheral stage IA non-small cell lung cancer: report from the Quality Assurance Working Party of the randomised phase III ROSEL study

BackgroundA phase III multi-centre randomised trial (ROSEL) has been initiated to establish the role of stereotactic radiotherapy in patients with operable stage IA lung cancer. Due to rapid changes in radiotherapy technology and evolving techniques for image-guided delivery, guidelines had to be developed in order to ensure uniformity in implementation of stereotactic radiotherapy in this multi-centre study.Methods/DesignA Quality Assurance Working Party was formed by radiation oncologists and clinical physicists from both academic as well as non-academic hospitals that had already implemented stereotactic radiotherapy for lung cancer. A literature survey was conducted and consensus meetings were held in which both the knowledge from the literature and clinical experience were pooled. In addition, a planning study was performed in 26 stage I patients, of which 22 were stage 1A, in order to develop and evaluate the planning guidelines. Plans were optimised according to parameters adopted from RTOG trials using both an algorithm with a simple homogeneity correction (Type A) and a more advanced algorithm (Type B). Dose conformity requirements were then formulated based on these results.ConclusionBased on current literature and expert experience, guidelines were formulated for this phase III study of stereotactic radiotherapy versus surgery. These guidelines can serve to facilitate the design of future multi-centre clinical trials of stereotactic radiotherapy in other patient groups and aid a more uniform implementation of this technique outside clinical trials.

European Organisation for Research and Treatment of Cancer Recommendations for Planning and Delivery of High-Dose, High-Precision Radiotherapy for Lung Cancer

PURPOSEnTo derive recommendations for routine practice and clinical trials for techniques used in high-dose, high-precision thoracic radiotherapy for lung cancer.nnnMETHODSnA literature search was performed to identify published articles considered both clinically relevant and practical to use. Recommendations were categorized under the following headings: patient selection, patient positioning and immobilization, tumor motion, computed tomography and [18F]fluorodeoxyglucose-positron emission technology scanning, generating target volumes, radiotherapy treatment planning, treatment delivery, and scoring of response and toxicity. The American College of Chest Physicians grading of recommendations was used.nnnRESULTSnRecommendations were identified for each of the recommendation categories. Although most of the recommended techniques have not been evaluated in multicenter clinical trials, their use in high-precision thoracic radiotherapy and stereotactic body radiotherapy (SBRT) appears to be justified on the basis of available evidence.nnnCONCLUSIONnRecommendations to facilitate the clinical implementation of high-precision conformal radiotherapy and SBRT for lung tumors were identified from the literature. Some techniques that are considered investigational at present were also highlighted.

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.

LungTech, an EORTC Phase II trial of stereotactic body radiotherapy for centrally located lung tumours: a clinical perspective

Evidence supports stereotactic body radiotherapy (SBRT) as a curative treatment option for inoperable early stage non-small-cell lung cancer (NSCLC) resulting in high rates of tumour control and low risk of toxicity. However, promising results are mainly derived from SBRT of peripheral pulmonary lesions, whereas SBRT for the central tumours can lead to severe radiation sequelae owing to the spatial proximity to the serial organs at risk. Robust data on the tolerance of mediastinal structures to high-dose hypofractionated radiation are limited; furthermore, there are many open questions regarding the efficiency, safety and response assessment of SBRT in inoperable, centrally located early stage NSCLC, which are addressed in a prospective multicentre study [sponsored by the European Organization for Research and Treatment of Cancer (EORTC 22113-08113-LungTech)]. In this review, we summarize the current status regarding SBRT for centrally located early stage NSCLC that leads to the rationale of the LungTech trial. Outline and some essential features of the study with focus on a summary of current experiences in dose/fraction-toxicity coherences after SBRT to the mediastinal structures that lead to LungTech normal tissue constraints are provided.

Redesigning radiotherapy quality assurance: Opportunities to develop an efficient, evidence-based system to support clinical trials - Report of the National Cancer Institute work group on radiotherapy quality assurance

PURPOSEnIn the context of national calls for reorganizing cancer clinical trials, the National Cancer Institute sponsored a 2-day workshop to examine challenges and opportunities for optimizing radiotherapy quality assurance (QA) in clinical trial design.nnnMETHODS AND MATERIALSnParticipants reviewed the current processes of clinical trial QA and noted the QA challenges presented by advanced technologies. The lessons learned from the radiotherapy QA programs of recent trials were discussed in detail. Four potential opportunities for optimizing radiotherapy QA were explored, including the use of normal tissue toxicity and tumor control metrics, biomarkers of radiation toxicity, new radiotherapy modalities such as proton beam therapy, and the international harmonization of clinical trial QA.nnnRESULTSnFour recommendations were made: (1) to develop a tiered (and more efficient) system for radiotherapy QA and tailor the intensity of QA to the clinical trial objectives (tiers include general credentialing, trial-specific credentialing, and individual case review); (2) to establish a case QA repository; (3) to develop an evidence base for clinical trial QA and introduce innovative prospective trial designs to evaluate radiotherapy QA in clinical trials; and (4) to explore the feasibility of consolidating clinical trial QA in the United States.nnnCONCLUSIONnRadiotherapy QA can affect clinical trial accrual, cost, outcomes, and generalizability. To achieve maximum benefit, QA programs must become more efficient and evidence-based.

Global Harmonization of Quality Assurance Naming Conventions in Radiation Therapy Clinical Trials

PURPOSEnTo 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.nnnMETHODS AND MATERIALSnA 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.nnnRESULTSnThe 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.nnnCONCLUSIONSnHarmonized 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.

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. n nCollaboration 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. n nGlobally, 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]. n nHowever, 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. n nThe 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. n n nThe goals of the GHG are: n n nCollate, homogenise and distribute information regarding the RTQA standards of the clinical trial groups, n n nProvide a platform for prospective discussions on new RTQA procedures, software tools, guidelines and policies of trial groups and n n nProvide a framework to endorse existing and future RTQA procedures and guidelines across various trial groups. n n n n nEach organisation will have the opportunity to endorse RTQA procedures from other organisations and thus accept them much faster in future collaborative trials. n nIn 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. n n n nTable 1 n nRTQA within each of the current GHG steering committee members as of August 2013. n n n nAll 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. n nUntil 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. n nAlthough 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.

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 purposeIntensity-modulated radiotherapy (IMRT) credentialing for a EORTC study was performed using an anthropomorphic head phantom from the Radiological Physics Center (RPC; RPCPH). Institutions were retrospectively requested to irradiate their institutional phantom (INSTPH) using the same treatment plan in the framework of a Virtual Phantom Project (VPP) for IMRT credentialing.Materials and methodsCT 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 RPCPH and INSTPH were thereafter centrally analyzed and inter-compared by the QA team using commercially available software (RIT; ver.5.2; Colorado Springs, USA).ResultsEighteen 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%/4xa0mm credentialing criteria. At the 5%/5xa0mm gamma criteria (90% of pixels passing), 11(92%) as compared to 12 (100%) centers pass the credentialing process with RPCPH and INSTPH (pu2009=u20090.29), respectively. The corresponding pass rate for the 3%/3xa0mm gamma criteria (90% of pixels passing) was 2 (17%) and 9 (75%; pu2009=u20090.01), respectively.ConclusionsIMRT dosimetry gamma evaluations in a single plane for a H&N prospective trial using the INSTPH measurements showed agreement at the gamma index criteria of ±5%/5xa0mm (90% of pixels passing) for a small number of VPP measurements. Using more stringent, criteria, the RPCPH and INSTPH comparison showed disagreement. More data is warranted and urgently required within the framework of prospective studies.

Development of clinical trial protocols involving advanced radiation therapy techniques: The European Organisation for Research and Treatment of Cancer Radiation Oncology Group approach

The European Organisation for Research and Treatment of Cancer (EORTC) Master Protocol for phase III radiation therapy (RT) studies was published in 1995 to define in a consistent sequence the parameters which must be addressed when designing a phase III trial from the rationale to the references. This was originally implemented to assist study investigators and writing committees, and to increase homogeneity within Radiation Oncology Group (ROG) study protocols. However, RT planning, delivery, treatment verification and quality assurance (QA) have evolved significantly over the last 15 years and clinical trial protocols must reflect these developments. The goal of this update is to describe the incorporation of these developments into the EORTC-ROG protocol template. Implementation of QA procedures for advanced RT trials is also briefly described as these essential elements must also be clearly articulated. This guide may assist both investigators participating in current ROG trials and others involved in writing an advanced RT trial protocol.