NCTN clinical trial standardization for radiotherapy through IROC and CIRO

Abstract

Evidence‐based practice is the cornerstone of modern medicine. Randomized clinical trials across multiple institutions are the gold standard for modern evidence collection. National Cancer Trials Network (NCTN) instruments the clinical trials through the new infrastructure for improvements in cancer treatment. Radiation therapy is an integral component of cancer treatment and is involved in many of the NCTN clinical trials. Radiotherapy is experiencing exciting developments in new treatment modalities and multi‐modality image guidance. One of NCTN network groups NRG Oncology brings together the research areas of the National Surgical Adjuvant Breast and Bowel Project (NSABP), the Radiation Therapy Oncology Group (RTOG), and the Gynecologic Oncology Group (GOG). The Imaging and Radiation Oncology Core (IROC) and Center for Innovation in Radiation Oncology(CIRO) of NRG Oncology complement each other's functions in development and implementation of the new radiotherapy and imaging technologies in clinical trials with standardization and other strategies for quality. The standardization process is the essential step to make the data collected for clinical trials of high quality, interoperable, and reusable.

1. The NCTN infrastructure overview

The National Cancer Institute's (NCI) Clinical Trials Cooperative Group Program has played a key role in developing new and improved cancer therapies for more than 50 yr. It was recently transformed to the new National Clinical Trials Network (NCTN) which continues to play essential roles in improving cancer detection, treatment, and prevention.¹ This dynamic system aims to efficiently respond to emerging scientific knowledge and technologies, such as SBRT in immunotherapy, systemic radiotherapy, adaptive therapy with in‐room imaging, proton radiotherapy, big data and machine learning; involving the broad cooperation of stakeholders; and leveraging evolving technologies to provide high‐quality, practice‐changing research. The NCTN structure includes five U.S. Network groups and the Canadian Collaborating Clinical Trials Network. The five US Network Groups are Alliance for Clinical Trials in Oncology that unites a broad community of scientists and clinicians to reduce the impact of cancer, ECOG‐ACRIN Cancer Research Group that includes two founding organizations — the Eastern Cooperative Oncology Group (ECOG) and the American College of Radiology Imaging Network (ACRIN) — and designs and conducts biomarker‐driven cancer research, NRG Oncology that brings together the unique and complementary research areas of the National Surgical Adjuvant Breast and Bowel Project (NSABP), the Radiation Therapy Oncology Group (RTOG), and the Gynecologic Oncology Group (GOG), SWOG (Southwest Oncology Group) which is a part of the nation's oldest and largest publicly funded cancer research network, and Children's Oncology Group (COG). A number of centralized core support groups were established to support functions that are common to all the network groups. One of the core support groups is the Imaging and Radiation Oncology Core (IROC) which was established for quality assurance of imaging and radiotherapy (RT) as part of clinical trials.¹

2. IROC and CIRO

IROC's core functions include site qualification, protocol development support, credentialing for specific clinical trials, pre‐review data management, case review and post review data management and analysis. Special expertise is established within selected network groups to meet challenges from advanced radiation oncology technologies, as well as from innovative imaging. IROC assists all of the NCTN groups that use imaging and/or radiotherapy and has close interactions with all NCTN groups and their associated operation centers and statistics center. IROC leaders and key personnel attend all meetings of the cooperative groups where the status of clinical trials is reported, and new concepts are proposed and discussed. IROC leaders present reports to the radiation oncology committees and imaging committees during these meetings. IROC key personnel and staff interact regularly and are directly involved in the daily operations of the NCTN groups. Additional important collaborations are with the advanced radiation oncology technology and imaging development and research. NRG Center for Innovation in Radiation Oncology (CIRO) was established as an essential component of NCTN focusing on innovation in radiotherapy. The aims of CIRO include: (a) Promote innovative RT research within the entire NCTN: to accelerate the testing of new radiation oncology innovations in NCTN clinical trials in all groups; to facilitate the application of innovations across all appropriate protocols; (b) Foster intergroup collaboration and protocol harmonization in terms of inclusion and description of RT techniques and delivery devices to reduce timelines for development of new protocols and to improve the clarity of NCTN protocols.² IROC and CIRO develop processes and research topics together. Functions of IROC and CIRO are complimentary in the quality implementation of radiotherapy and associated imaging since CIRO provides guidance in the protocols developed for clinical trials, with quality guidelines strictly enforced through IROC's core functions. IROC similarly maintains a close relationship with ECOG‐ACRIN's experimental imaging committee (EIC) and imaging scientific advisory committee (ISAC) that emphasize novel imaging techniques. IROC QA Center directors and staff directly participate in the efforts of these RT and imaging groups to assist and facilitate harmonization of the activities. The relationship of IROC, CIRO, and NCTN/NCI groups is illustrated in Fig. 1. Table 1 lists the specifics of IROC and CIRO.

Figure 1.

The relationship of IROC, CIRO and NCTN/NCI groups.

Table 1.

The specifics of IROC and CIRO

	IROC	CIRO
Relationship with NCTN	One of NCTN centralized function groups	Essential component of NRG Oncology subgroup
Functions	Site qualification, protocol development support, credentialing for specific clinical trials, pre‐review data management, case review and post review data management and analysis	Implement advanced radiotherapy technologies for NCTN, e.g., atlases, RT guidelines, and applications to facilitate RT quality assurance
Mutual relationship	IROC and CIRO develop processes and research topics together. Functions of the IROC and the CIRO are complimentary in the quality implementation of radiotherapy and associated imaging since CIRO provides guidance in the protocols developed for clinical trials, with quality guidelines strictly enforced through IROC's core functions

3. Establishment of the radiotherapy clinical trial standards from NRG/CIRO

CIRO provides multiple resources for NCTN clinical trial standardization including atlases, protocol templates for RT sections, and applications to facilitate RT data preparation and submission.²

Radiation therapy section templates are being developed for various disease sites including but not limited to brain, breast, gastrointestinal, genitourinary, gynecologic, lung, and head and neck. The templates are published after rigorous reviews by NRG medical physics subcommittee, NRG radiation oncology committee and by NCI representatives. These templates offer example narratives for guidelines that cover the entire radiotherapy process. They include the following subsections: treatment technology; immobilization and simulation; imaging for structure definition, image registration/fusion; definition of target volumes and margins; definition of critical structures and margins; dose prescription; compliance criteria; treatment planning priorities and instructions; patient specific QA; treatment localization/IGRT. The contouring atlases for multiple disease sites are included to assist target and normal structures delineation for accuracy and consistency.

For each disease site, a structure name library that contains all the structures used in NRG and active legacy Radiation Therapy Oncology Group (RTOG) protocols is provided on the CIRO website. This library is a joint production of NRG and AAPM Task Group 263. It is fully compliant with the rules and regulations specified in the task group report that is to be published.

Software tools and templates can be downloaded to aid institutions to be compliant with these standards. Structure name templates for newly activated NRG trials are created, reviewed and published, along with dose volume histogram evaluation tools, for different treatment planning system vendors. To improve the quality consistency of IMRT plans, the RapidPlan tool^{3, 4, 5} and other plan optimization models will be published in the very near future.

4. IROC Implementation of the standards

The standards and guidelines developed in CIRO are enforced through IROC's various core functions. For instance, the standardization of structure names used in radiotherapy is being validated through the radiotherapy data submission process. As an integral component of IROC, the Transfer of Images and Data (TRIAD) is a standard‐based system built by the American College of Radiology (ACR) to provide a seamless exchange of images and data for accreditation of clinical trials and registries.^{6, 7} TRIAD currently supports different layers of filters and rules and allows the definition of one layer or multiple layers depending on the complexity of the clinical trials. Filters are criteria which allow for the inclusion or exclusion of submissions with the application of rules, whereas the rules themselves evaluate the submission for protocol adherence. Upon submission of digital data in TRIAD, the users are prompted to select the layers that apply to the data. Users are able to see which structure(s) is (are) missing within the TRIAD submission window prior to sending the data for validation. TRIAD allows the administrator to apply “hard” or “soft stop” to the validation. If a hard stop is applied, the user cannot proceed with submission if any of the list structures or validation parameters are missing, misspelled, or do not meet the defined protocol criteria. Therefore, the user must adjust the structures (number of structures and their correct names) list according to the clinical trial. However, when a soft stop is applied, even a failed validation allows users to proceed with submission. The implementation of these validation profiles and the ability to view the results at the time of submission provide valuable initial feedback to the submitting site and improve the efficiency of clinical trials data submissions.

The dosimetric compliance criteria are also defined in a standardized manner fully compliant with AAPM Task Group 263 recommendations. Templates for dose volume evaluation in various formats for individual trials are publicly available. For evaluation of submitted cases to IROC, scripts are developed for each trial to extract DVH data points and to streamline upload in a standard format to MediDataRave,⁸ the clinical trial data management system adopted by NCTN. For crucial data points not included in the initial design of the protocol, a software system is developed for real time extraction of any DVH data points from exported full DVH files of a large number of cases saved into archive.⁹

The quality of radiotherapy treatment plans varies across institutions and depends on the experience of the planner. For intra‐ and inter‐institutional standardization of treatment plan quality, the knowledge‐based planning approach is used to build models that learn the organs‐at‐risk (OARs) sparing patterns from submitted quality plans. Thereafter, based on the anatomy similarities, the models predict the dose that similar organs receive in radiotherapy plans for newly submitted cases. These models can also be used to predict the feasibility of planning objectives, in addition to objective assessment of the quality of radiotherapy plans.^{10, 11, 12} The predictive models cover different treatment modalities including both photon and proton and multiple disease sites, including head and neck, brain, lung, spine, and prostate. These models are validated with cases other than the ones used for the model building and evaluated against other predictive approaches.^{13, 14, 15}

Standardization of targets and critical structures delineation are of utmost importance in the radiotherapy process. Variations in structure delineation are found to be the most significant among all the radiotherapy processes.¹⁶ To facilitate contour review with automation, IROC has built atlases for multiple disease sites from the submitted cases. IROC has evaluated and established the feasibility of automated QA of cardiac structures using the atlases created from RTOG 0617.¹⁷

5. Impact in the big data era

Implementation and enforcement of the standardization for radiotherapy with protocol guidelines, libraries and software systems assure the clinical trial data quality. These efforts enable meaningful and efficient big data analysis and explorations to improve the outcomes of cancer treatments.

Conflict of Interests

This project was supported by NCI grants U24CA180803 (IROC), U10CA180868 (NRG), and PA CURE grants.