Executive summary of AAPM Report Task Group 113: Guidance for the physics aspects of clinical trials

Abstract The charge of AAPM Task Group 113 is to provide guidance for the physics aspects of clinical trials to minimize variability in planning and dose delivery for external beam trials involving photons and electrons. Several studies have demonstrated the importance of protocol compliance on patient outcome. Minimizing variability for treatments at different centers improves the quality and efficiency of clinical trials. Attention is focused on areas where variability can be minimized through standardization of protocols and processes through all aspects of clinical trials. Recommendations are presented for clinical trial designers, physicists supporting clinical trials at their individual clinics, quality assurance centers, and manufacturers.


| ABOUT TH IS E XECUTIVE SUMMARY
The full report of AAPM Task Group 113 on Guidance for the Physics Aspects of Clinical Trials is available at the AAPM Reports website. This executive summary provides an overview of the major headings of the full report. In addition, details were retained in this report to highlight a few areas where there has been an evolution in clinical trials. Appendices A-D include all of the TG113 recommendations with the reference information contained in the full report.

| INTRODUCTION AND CHARGE OF THE REPORT
There is growing evidence 1-5 on the need for standardization of treatment planning and delivery methods to ensure quality in clinical trials to help support the investigation of new safe and effective treatments and/or assessment methods in multi-institutional settings.
Such standardization will improve the consistency of the radiotherapy received by patients and the radiotherapy data submitted for a given clinical trial. These data are required to validate that all patients in each arm of a given study received the therapy as intended. Violating this assumption can jeopardize the validity of the outcomes reported by the trial group.
A related consideration that affects overall quality is the ability of those participating in clinical trials to create plans as part of their standard clinical flow that are both compliant with protocol specifications and optimal. The importance of compliance in trials and the impact on detecting changes in outcome have been demonstrated in a number of trials, [1][2][3][4]6 such as TROG 02.02 on advanced head and neck cancer (Fig. 1), and in meta-analyses of other trials. When designing a trial, the planning guidelines are set to be able to answer the clinical trial questions. However, there may be variation in planning methods, and a planner may not know when a better (such as improved target coverage with reduced dose to normal tissues) plan is reasonably achievable without real-time feedback during the planning process. Knowledge-based planning, where the achievable dosevolume metrics from previous patients can used to predict each new patient's DVH, was shown to retrospectively identify plans which were clinically acceptable but suboptimal in the context of the clinical trial. 7 For example, plan quality was analyzed for patients treated on RTOG 0126 exploring the relationship between plan quality and rectal toxicity. Suboptimal plans were identified by comparing predictions for target and organ-at-risk doses to those that were submitted as part of a trial for 219 IMRT patients. The library was created from plans which were defined as the best from the protocol based on a risk evaluation. This work highlights the challenge of using a series of DVH points alone as the primary guidance to create a treatment plan.
There is a richness of information available when comparing a new plan against a library of plans that have been previously determined to be optimal and protocol compliant. Improved planning tools such as those with knowledge-based planning have been needed for some time to provide detailed feedback to institutions on whether or not their treatment plans not only meet the dose-volume histogram requirements but are also optimal for use in clinical trials. With respect to quality assurance requirements, there are important ongoing efforts toward global harmonization of quality assurance 6 (such as structure nomenclature addressed by AAPM Task Group (TG) 263 8 ) for radiation therapy clinical trials.
The charge of AAPM TG 113 is to: (1) recommend physics practices for clinical trials involving external photon and electron beam radiation therapy that ensure minimum standards for data quality in clinical trials.
(2) identify opportunities to improve consistency in each part of the planning and delivery process.
(3) provide guidance to QA organizations on how best to support the spectrum of radiotherapy clinical trials, from those with basic to advanced technology.
(4) provide suggestions regarding the credentialing requirements to reduce potential inconsistencies in the radiotherapy process.
The use of protons or brachytherapy in clinical trials is outside of the scope of this document. Throughout the report, recommendations are presented in each section for major areas of the process from simulation through treatment delivery in the context of clinical trials. The recommendations are organized by the categories of clinical trial designers, physicists (at the local institution), quality assurance (QA) centers, manufacturers, and advanced technology trials and are also presented by category in Appendices A-D. The full report includes information on restructuring of the clinical trials network and associated QA centers funded by the NCI.

CLINICAL TRIALS
Physicists play different roles with respect to clinical trials. At institutional, national, and international levels, physicists may be lead or co-investigators representing clinical and technical components. In the context of clinical trial groups, physicists may lead or co-design a clinical trial. For national trials supported at individual institutions, physicists play a key role with physicians in ensuring protocol compliance. Other perspectives include physicist roles in QA centers and as employees of a manufacturer whose products are being used to support clinical trials.
TG 113 considers the entire process designing a trial and its QA through the activities of the local team from simulation to planning and treatment delivery to improve the consistency for clinical trials,  AAPM task group reports are relevant to the work of TG 113. Figure 2 shows an overview of the major areas involved once a patient is Credentialing may evaluate characteristics, such as image quality, spatial integrity, and contrast; the requested characteristics depending on the role of imaging within a given trial. For example, considerations with respect to understanding uncertainties in molecular imaging have been described. 12 More details regarding quantitative imaging in clinical trials are presented in the full report. should be standardized as much as possible with the expectation of evolution of care over time. In addition, the protocol should specify any additional limits to doses to organs outside the treatment field. 15 A final critical concern is that some systems ignore the volume of an organ outside the dose calculation grid when reporting dose-volume parameters. For such systems, the dose-grid should cover the entire organ of interest so that derived dose-volume parameters used for treatment planning represent the entire organ.

| SEGMENTATION
Additional details and recommendations regarding segmentation are found in the full report.

| IMAGE REGISTRATION
Clinical studies that require multiple image datasets need to use image registration software. When multiple image modalities are used for treatment planning, the protocol designers should consider providing specific recommendations for internal or external landmarks that can validate the adequacy of the registration for treatment planning.
If the accuracy of the image registration for each patient affects the quality of the trial (such as in defining the target volume), the protocol designers and QA centers should require credentialing of the image registration software by using phantoms of known geometry and should follow the guidance of AAPM TG 132. 16 The physician directive should specify the goals of the image registration, the method and what anatomical region should be emphasized in the registration. 16 With respect to how image registration is used at the treatment unit, the trials designers should determine if it is necessary to distinguish between applications for target and normal tissue definition compared with daily online treatment guidance. Image registration considerations, which are described in the full report, may also differ if there is a midcourse plan adaptation and dose accumulation methods are utilized. 17

| PATIENT AND TARGET POSITIONING
Patient and target positioning is affected by immobilization and the frequency and type of image guidance used at the treatment unit.
The margins for treatment planning are affected, as well as the achievable accuracy of image registration using multimodality imaging scans which are used to design and assess patient treatments, especially dose-response studies for clinical trials.
In the context of clinical trials, the type of recommended immobilization described and/or required in a particular trial depends on and for treatment planning. 19 Efforts are under way to update that report with guidance needed today for clinic care and clinical trials. "low-quality" initial plans randomly-sampled initial plans "high-quality" initial plans "low-quality" replans randomly-sampled replans "high-quality" replans

| SUMMARY
It has been shown that the quality and consistency of the trial impacts patient outcomes. [1][2][3][4][5] This report identifies physics and other team member practices that specifically improve the treatment plan-   c. For protocols involving monitoring of intra-fraction motion, provide information regarding the acceptable technologies for monitoring and the thresholds for evaluation. Information should be provided as to whether intra-fraction monitoring is required and the acceptable methods.
Treatment planning considerations a. Specify standard structure names that must be used for the clinical trial (follow consensus guidance when available) such as provided by AAPM TG 263 or other appropriate ontologies.
b. Use published information on normal tissue limits such as through consensus efforts as appropriate when specifying the limits to normal tissues.
c. For organs which will be evaluated with DVHs, the protocol should specify how much of the organ must be contoured for structures such as the spinal cord. Motion assessment and management a. Confirm that the motion assessment and management guidance specified in the protocol is followed whenever the range of motion meets published guidance limits.
b. Ensure that the contoured IGTV is reasonable considering the measured motion for a given protocol patient. b. In image registration software, provide the ability to export necessary data for QA centers to be able to assess the quality of a registration (quantitative and qualitative) and export the needed c. Enable use of protocol-specific scripts including standard target and structure names (AAPM TG 263).
d. Create interfaces that import the necessary standard names, beam arrangement (if appropriate), and other information for treatment planning.
e. Create the appropriate software to allow automatic anonymization with coded ID labels of patients and plans.
f. Develop and make available a straightforward export of information to QA centers g. Make treatment planning systems IHE-RO compliant h. Enable tools or scripts that can be shared and then used at the local institution to assess protocol compliance are invaluable.
Conflict of interest: Andrea Molineu is affiliated with the Imaging and Radiation Oncology Core in Houston and James Galvin is affiliated with the Imaging and Radiation Oncology Core in Philadelphia