Position PaperDevelopment of clinical trial protocols involving advanced radiation therapy techniques: The European Organisation for Research and Treatment of Cancer Radiation Oncology Group approach
Introduction
Properly conducted trials in radiation oncology are required to establish new treatment approaches in terms of improved tumour control and/or lower complication rates. Interest in the quality of radiation therapy (RT) delivered within a clinical trial setting has increased in parallel with the growing complexity of diagnostic and therapeutic procedures, cost of studies and numbers of patients accrued.1 The amount of new knowledge generated from each trial must be maximised to optimise shrinking resources.2 Uncertainties in terms of volume delineation, target and normal tissue doses and machine output may not only decrease the effectiveness of therapeutic management, but increase complication rates and reduce patient quality of life.3 The worst case scenario is that non-compliant RT in a comparative phase III trial may contribute to a negative statistical conclusion regarding the primary end-point, reflecting the value of treatment of low quality, and thus failing to assess the benefit of the planned RT.4, 5 Such instances also call into question the feasibility of the study treatment.
RT protocols should define all critical procedures in order to minimise variation between investigators.1 Modern trials are often multidisciplinary, multi-centric and international, further focusing attention on the critically important issue of a clear, well-written protocol, especially if participants’ first language is not English. Although a protocol is usually written by experts in a certain disease site, institution investigators may not be familiar with the subject to the same extent. RT protocols must serve the informational needs of many disciplines, such as radiation oncologists, medical physicists, radiotherapy technologists, study nurses and clinical research associates. Therefore, protocol writing should be supported by an infrastructure of experts in areas including data management, bioinformatics, pharmacovigilance and regulatory affairs. Although it can be difficult to write a simple, straightforward but thorough RT protocol on a complex treatment technique, the aim should be to create this document in a manner that addresses potential areas of ambiguity in all steps of treatment preparation, delivery and reporting.
The European Organisation for the Research and Treatment of Cancer (EORTC) is a pan-European structure charged with improving cancer treatment through the testing of new therapeutic strategies in phase III randomised trials. The EORTC also conducts early phase combined modality trials investigating optimal integration of new molecular agents with radiotherapy, and protocols exploring new RT delivery methods. The concept of a Master Protocol for phase III studies was originally considered by the EORTC Radiation Oncology Group (ROG) in the 1990’s in order to help facilitate writing and increase consistency of study protocols.6 The Master Protocol was also instituted to help address disappointing quality assurance (QA) in RT results of past EORTC ROG studies, which has been explained by misinterpretation of protocol instructions.7, 8, 9, 10, 11 In some cases, this inter-centre variation was significant enough to have triggered protocol amendments.9, 10, 11
The aim of this consensus document is to describe the current EORTC ROG approach to protocol writing of RT trials, focusing on the requirements of advanced external beam delivery techniques in multicentre clinical trials. In addition to the CONSORT guidelines for interpretation and reporting of clinical data,12 ROG protocols should be clearly aligned with the recommendations of the International Committee on Radiation Units & Measurements (ICRU) Report 83 on prescribing and reporting of intensity-modulated radiation therapy (IMRT).13 The following parameters must be included in all EORTC ROG clinical protocols unless their omission is clearly justified (Table 1).
Section snippets
Radiation therapy
A key component of an effective process improvement and workflow management infrastructure is consistent RT structure and terminology. As such, the use of international recommendations on terminology and prescription practices is mandatory, together with inclusion of uniform naming conventions in a common language.13
General overview
In this section of the protocol, provide an overview of the trial QART program, clearly stating which EORTC levels (i.e. levels 1–5) will be included.3 Prospectively define procedures aimed at detecting relevant deviations from protocol criteria, when they will occur, and corrective actions which will be taken. The protocol will detail what constitutes acceptable RT and list minor and major deviations. Procedures required before sites can be authorised to enter the study, those which take place
Conclusions
A clear description of the design and conduct of any clinical trial can avoid variations in practice that make it impossible to provide a definitive answer about the effectiveness of a new approach. The implementation of this updated RT protocol outline as a result of collaboration between the EORTC Headquarters and the ROG has significantly increased data reliability. For trials involving advanced radiation therapy techniques, the minimum acceptable degree of protocol compliance must be
Conflict of interest statement
None declared.
Acknowledgements
The Vlaamse Liga Tegen Kanker supported the development of this project through the ‘Emmanuel van der Schueren Fellowship for Quality Assurance in Radiotherapy’ granted in 2010–2011. We would like to acknowledge the contributions of Akos Gulyban, Paul Fenton, Guido Garavaglia, and Edwin Aird.
References (20)
- et al.
Quality assurance in clinical trials
Crit Rev Onc Hem
(2003) Towards evidence-based radiation oncology: improving the design, analysis and reporting of clinical outcome studies in radiotherapy
Radiother Oncol
(1998)- et al.
Quality assurance for prospective EORTC radiation oncology trials: the challenges of advanced technology in a multicentre setting
Radiother Oncol
(2011) - et al.
The potential impact of treatment variations on the results of radiotherapy of the internal mammary lymph node chain: a quality assurance report on the dummy run of EORTC phase III randomized trial 22922-10925 in stage I–III breast cancer
Int J Radiat Oncol Biol Phys
(2001) - et al.
EORTC guidelines for writing protocols for clinical trials of radiotherapy
Radiother Oncol
(1995) - et al.
Quality assurance in the 22991 EORTC ROG trial in localized prostate cancer: dummy run and individual case review
Radiother Oncol
(2009) - et al.
Quality assurance in breast cancer: EORTC experiences in the phase III trial on irradiation of the internal mammary nodes
Eur J Cancer
(2007) - et al.
Quality assurance of the 22961 EORTC trial. A phase III study of the optimal combination of hormonal adjuvant treatment by LHRH analogue and radiation therapy for the management of locally advanced prostate cancer: the dummy run
Radiother Oncol
(2004) - et al.
Quality assurance of the EORTC radiotherapy trial 22931 for head and neck carcinomas: the dummy run
Radiother Oncol
(1998) Quality assurance issues in conducting multi-institutional advanced technology clinical trials
Int J Radiat Oncol Biol Phys
(2008)