A template for writing radiotherapy protocols.

Abstract Background. Well-specified and unambiguous treatment protocols are essential both for current practice and for the future development of radiation therapy. In order to provide assistance for writing good protocols, irrespective of treatment intention and complexity, up-to-date guidelines are highly desirable. Methods. We have analysed the radiotherapy work-flow, including clinical and physical aspects, such as preparatory imaging, treatment planning, delivery and evaluation, with the aim to outline a consistent framework covering the entire radiotherapy process. Results. Based on the analysis, a recipe-style template for specifying the description of the radiotherapy process has been designed. The template is written in a general format, which allows for modified phrasing, and should be customised for the specific clinical situation and diagnosis, as well as facility resources. Conclusions. The template can be used as a tool to ensure a consistent and comprehensive description of the radiotherapy section of clinical guidelines, care programmes and clinical trial protocols.

In radiotherapy, adherence to study protocols is important for the evaluation of the treatment outcome, both regarding tumour response and normal tissue complications, and patient-reported outcome, such as quality of life. Furthermore, it has been shown that protocol compliance is associated to better outcome in several malignancies [1,2]. Well-specifi ed and unambiguous protocols are therefore essential both for current practice and its future development. However, it is common that the radiotherapy process is not always suffi ciently dealt with, e.g. in combined treatment regimen protocols with chemotherapy. This opens for local variations, and radiotherapy process-oriented guidelines for writing study protocols are therefore highly desirable in order to reduce such uncertainties and to improve adherence.
The European Organisation for Research and Treatment of Cancer Radiation Oncology Group (EORTC ROG) has recently published new recommendations for writing protocols for multicentre clinical trials, including an extensive description of the quality assurance (QA) programme for EORTC trials [3]. In particular, the radiotherapy part of this document is an update of the corresponding part of the previous EORTC recommendations from 1995 [4], focusing on the requirements of advanced external beam delivery techniques in multicentre clinical trials.
In the recent work within the Swedish Radiation Safety Agency ' s (SSM) Scientifi c Council on Ionizing Acta Oncologica, 2015;54: 275-279 Radiation within Oncology, we analysed the contemporary radiotherapy process and made suggestions for new protocol guidelines applicable both for study protocols and care programmes, irrespective of treatment intention and complexity [5]. Based on this report, we proposed a template-styled master protocol [6]. A preliminary version of this template has been used in Sweden, and found to be very practical.
Based on this experience, we believe that a template-styled master protocol can be very useful, and the aim of this work was to present an improved template also considering the structure of the recent EORTC recommendations.

The template
The proposed template is presented in Table I. The template was produced based on an analysis of the contemporary radiotherapy process, with the focus set on procedural aspects [3,5]. It is written in a general format and should be completed and customised for the specifi c clinical situation and diagnosis, as well as facility resources. It should be incorporated into another document where all other relevant information should be detailed (e.g. inclusion and exclusion criteria in case of a trial, timing and relation to non-concomitant treatments, follow-up of late effects, etc.). In order to facilitate the protocol writing, it has been our intention to format the template in full sentences, rather than as a bullet list. The texts within curly brackets are examples and shall be replaced appropriately. Square brackets shall be replaced with numerical values. Some items may need to be copied in case there are more than one relevant alternative. If needed, the protocol author may decide to add an option to leave a certain item to the protocol user ' s discretion. For instance, the CTV to PTV margin might be individually determined by the centre, depending on the department ' s equipment and routines, but should then be reported. Items that are not applicable to the particular protocol should be deleted, and the fi nal phrasing of the body text is of course at the protocol author ' s preference.

Discussion
The scope of the template presented in this work is similar to chapter 2 of the recent EORTC recommendations [3]. Thus, the template is focused on the radiotherapy process itself, and factors that must be established before the patient is referred to the radiotherapy department are not included. Nevertheless, the entire radiotherapy process is based on these pre-therapeutic decisions, and it is essential that consistency is preserved through all following steps. As an example, procedures for preparatory imaging, treatment planning, delivery and evaluation must all be designed in alignment with the treatment intentions.
Within this scope, we have made an attempt to include some of the recent developments in personalised radiotherapy. While personalised medicine is generally associated with predictive biomarkers, the individualisation of radiotherapy treatments also builds on the development of imaging modalities and the evolution of highly conformal treatment techniques. Therefore, we have in this template included items regarding the use of MRI for dose calculations, biological treatment objectives, inverse treatment planning, and treatment adaption.
In particular we have highlighted the prioritisation of the treatment planning optimisation objectives. In our experience this issue is seldom dealt with properly. As this is of fundamental importance for an effective implementation and fulfi lment of the prescription in the treatment planning optimisation, we recommend that criteria describing what to prioritise when producing, evaluating and comparing plans in the clinical situation are clearly defi ned a priori. An example of such a list of prescription priorities, taken from a clinical protocol for radiotherapy of head-and-neck cancer, is presented in Supplementary Table I (to be found online at http://informahealthcare.com/doi/ abs/ 10.3109/0284186X.2014.981285). This is a useful tool for all kinds of diagnoses (see e.g. [7]), and if it is well-enough specifi ed, it may provide suffi cient basis for protocol-driven, multi-modality treatment planning optimisation [8]. We strongly recommend that a table like this is included in the radiotherapy protocol under planning aims and dose-volume constraints.
Furthermore, we have expanded the section on the treatment verifi cation to also include treatment adaption. This template section contains items regarding geometrical adaption to changes in the patient ' s external or internal anatomy, as well as adaption to tumour and acute normal tissue response. Only the procedural consequences of acute toxicity during the course of the treatment, leading to modifi cations of the treatment, are included. It is recognised that issues regarding clinical evaluation during and post-treatment (e.g. acute and late toxicity, quality of life assessment, unexpected adverse events, and treatment effi cacy) are essential to evaluate the treatment in order to improve outcome for future patients.
To defi ne criteria for radiotherapy follow-up, alone or in combination with other therapy, is important in routine care as well as in clinical trials. However, these aspects are not dealt with in the template, but should be specifi ed in other parts of the study protocol/care programme.

Volume selection and defi nition
• The recommendations made by ICRU shall be followed.

(Continued)
Finally, we have added one section in this template corresponding to chapter 3 in the EORTC recommendation regarding quality assurance. We encourage the use of the EORTC quality assurance levels, although they are not explicitly specifi ed in the template as some of the levels are primarily designed for EORTC ROG multi-centre trials. This section also includes items regarding independent monitor-unit calculations.
In addition, we have included items regarding in vivo dosimetry, the estimation of dose calculation uncertainties, and suggestions for standardised naming convention of target and organs-at-risk volumes, as recently proposed, e.g. by international radiotherapy societies [9,10].
• The make and version of the particular treatment planning system and dose calculation algorithm shall be reported. If possible, dose calculation uncertainties shall be reported. In conclusion, the present report provides a detailed framework and a recipe-style template, based on an analysis of the contemporary radiotherapy process, including clinical as well as physical aspects. A preliminary version was distributed in 2013 to radiotherapy practitioners in Swedish radiotherapy centres and tested in actual protocol writing situations, and their experience was incorporated in the fi nal version. While the EORTC recommendations are specifi cally designed for writing EORTC ROG study protocols, we believe that the template presented here should be applicable also for clinical guidelines, care programmes, irrespective of treatment intention and complexity.