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

https://doi.org/10.1016/j.ejca.2012.02.008Get rights and content

Abstract

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.

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)

There are more references available in the full text version of this article.

Cited by (0)

View full text