The national cooperative group clinical trials system is more than 50 years old. In the beginning the newly established cooperative groups placed emphasis on clinical trials involving leukemia and lymphoma. As these trials matured and acquired the confidence and enthusiasm of the clinical oncology community, clinical trials in epithelial oncology began to mature. Accordingly, radiation therapy became incorporated as an important discipline in the clinical cooperative group community. In 1968, the Committee for Radiation Studies recognized the need for consistency in the delivered radiation dose to the patient. The committee was made aware of significant variations in computation algorithms used to calculate radiation dose as well as significant variability in the delivery of daily radiation treatment. In 1969, the Radiologic Physics Center (RPC) was funded by the National Cancer Institute (NCI) with the mission to assure both the NCI and clinical cooperative system that institutions participating in the clinical trials process deliver comparable and consistent radiation therapy compliant to study objectives. Herring and Compton (1970)
published an analysis on patients treated for laryngeal carcinoma in 1970 indicating that radiation therapy had to be delivered to a specific radiation dose and volume within 5% of the intent of treatment in order to achieve optimal clinical outcome, a paradigm that remains as important today as it was in 1970. In early clinical trials there was considerable variability identified in both radiation dose and volume of treatment with many major deviations identified on multiple studies (Table
) making interpretation of the study difficult to assess. To further complicate matters, there was no clear mechanism in place to acquire and review protocol data in a central location, making analysis limited and incomplete. It was challenging to use these studies as a vehicle to identify a standard of care. The Quality Assurance Review Center (QARC) was established in 1976 as a subset of the radiation therapy committee of the Cancer and Leukemia Group B (CALGB) with a responsibility to acquire radiation therapy protocol information, review data with responsible clinical trial investigators, and provide institutional feedback on protocol performance. The office offered similar service for the National Wilms Tumor Study Group (NWTSG) and the Intergroup Rhabdomyosarcoma Study Group (IRSG). QARC became independently funded through Cancer Therapy Evaluation Program (CTEP) in 1980 when the pediatric divisions of both CALGB and Southwest Oncology Group (SWOG) separated from the adult Cooperative Groups and formed the Pediatric Oncology Group (POG). QARC and RPC have been continuously funded to date with quality assurance service portfolio evolving as clinical protocols have matured (FitzGerald et al., 2008
; Ibbott et al., 2008
). The Radiation Therapy Oncology Group (RTOG) developed an internal mechanism for quality assurance as part of the primary program. The image-guided therapy center (ITC) was developed to work in collaboration with the RTOG initially as the resource for three-dimensional planning and has worked in close collaboration with the RTOG since that time point (Eisbruch et al., 2010
). All four organizations are housed under the general umbrella of the Advanced Technology Consortium (ATC) designed to establish transparent guidelines and standards in radiation oncology throughout all of the cooperative groups. By 2014, all radiation therapy and diagnostic imaging quality assurance centers will be integrated as a single entity called the Imaging and Radiation Oncology Core (IROC) as part of the re-organization of the clinical trial effort managed by the NCI.
Comparison of deviation rates for clinical trial studies with and without radiotherapy credentialing.
Review of data from studies for protocol quality assurance management initially was solely performed in a retrospective manner well past completion of the study. As a result, deviation rates on study were (and often remain) unacceptably high and only captured in retrospect. The approach and concept development for quality assurance had to be re-engineered to address the issues surrounding both computational and volumetric deviations on study (FitzGerald, 2012
). In 1985, the Collaborative Ocular Melanoma Study (COMS) recognized the need for a more rigorous quality assurance process to reduce the deviation rate for this disease. Ophthalmologists, radiation oncologists, medical physicists, and statisticians developed a process to vet both individuals and institutions and credential them prior to entering a patient on study. The purpose of this process was to insure to clinical trial investigators and sponsors that the medical team and the institution had the necessary equipment, resources, radiation dose computational tools and algorithms, treatment expertise, and understanding of both the requirements and expectations of the protocol. This required completion of a facility questionnaire, completion of a knowledge assessment test case, submission of previous cases treated in a protocol format, and the viewing of a treatment training video. Due in large part to the credentialing process coupled with continuous feedback to investigators, the deviation rate on these studies was less than 5%. This was a very important contribution as the process created a uniform study population serving to strengthen the validation of the results of the clinical studies (Pettersen et al., 2008
). Data on a series of protocols in Hodgkins lymphoma reviewed at QARC demonstrate the importance of real-time intervention of both imaging and radiation therapy treatment objects for compliance to study radiation dose/volume trial objectives (FitzGerald et al., 2008
; FitzGerald, 2012
In the past decade, cooperative group protocols involving the treatment of cervical cancer permitted institutions to treat patients with both low dose rate brachytherapy (LDR) and high dose rate brachytherapy (HDR). Because LDR was considered standard therapy and well established, decision was made not to perform quality assurance (QA) on patients treated with LDR. It was presumed that LDR therapy had been performed for many years and an assumption was made that treatment standards in the community were uniform. HDR therapy was new and less familiar to the therapy population and decision was made to establish a strong credentialing program including HDR source calibration and submission of two patient cases treated in a similar manner to the protocol submitted for dosimetry and clinical review including validation of the planning system calculation parameters for the intended radiation dose delivery. There was no review of LDR brachytherapy treatments prior to or during the time that patients were entered on study. At closure of the trial, there were no major deviations in the HDR cohort that had undergone the rigorous credentialing process. However, as part of retrospective review of treatment objects, there were 57 (21%) patients with major deviations treated with LDR brachytherapy. This influenced trial analysis. Table lists several NCI clinical trials that had a credentialing requirement or not listed with percent major and minor deviation. As can be seen in studies with credentialing portfolio the deviation rate was considerably decreased in many diverse disease-based studies with a strong credentialing program in place.
The benefit of credentialing is also illustrated by the deviation rates in two head and neck studies that were conducted under industry sponsorship and for which QARC coordinated the quality assurance reviews. Both studies were conducted under the same sponsor, and both included significant international participation. Institutions were credentialed for the first study by completing a “generic” benchmark, which tested some basic treatment planning skills but was not specific to the study in question and did not test the investigator’s expertise in drawing treatment objects for head and neck tumors. The major deviation rate for that study was 24%. Because of this high deviation rate, it was decided to use a protocol-specific benchmark to credential institutions for a follow-up study. For the follow-up study participants were provided with an anonymized CT scan of a select patient that was typical of the patients expected to be seen on the study. They were asked to develop a treatment plan following protocol guidelines, draw all target volumes of interest, and submit all of the data that would be required for an actual protocol patient. The benchmarks were then reviewed exactly as a plan for a protocol patient would be reviewed, including review of target volume delineation as well as the treatment plan itself. The major deviation rate for the follow-up study was only 8%, significantly less than for the initial study.
The concept of what constitutes credentialing has evolved since first introduced and as new radiotherapy delivery technologies, including intensity modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), volume modulated arc therapy (VMAT), and proton therapy, have been included in clinical trials (Summers et al., 2011
). Credentialing should not be confused with ongoing periodic QA activities administered by the various QA centers. Examples of these ongoing QA activities include protocol development, monitoring of the participating institution’s therapy beam outputs (optically-stimulated luminescent/thermoluminescent dosimeter, OSLD/TLD program), completion of generic benchmark cases, on site audits at participating institutions and retrospective clinical and dosimetric review of protocol patient treatments. Credentialing is the examination and review of the institution and/or its staff as to whether they meet certain criteria for participation in a specific clinical trial (FitzGerald et al., 2010
). Failure to meet the criteria may limit the participation of an institution in a specific protocol. However, the mission of the QA centers is not to restrict participation but to assist institutions in any required remedial actions so that they meet the criteria and can treat radiotherapy patients in a consistent manner consistent with other participating institutions. Credentialing requirements may include the following but, are not limited to since they evolve with each new protocol.
- Completion or update of a facility questionnaire
- Demonstration of the ability to transfer radiotherapy data electronically from the institution to a central quality assurance office
- Completion of a protocol knowledge assessment
- Submission and review of previously treated patients treated in a manner required by the protocol
- Completion of a treatment planning protocol-specific benchmark case(s)
- Completion of a modality and/or site-specific benchmark case
- Completion of an end-to-end phantom irradiation study
- Completion of an Image Guidance study
- Pretreatment clinical and/or dosimetric review of an individual protocol patient (rapid review)
The goal of credentialing is fourfold: (1) educate the institution and its staff as to the requirements for treating the specific protocol patient, (2) verify that the institution can indeed perform the required radiotherapy treatment accurately, (3) provide feedback to the institution on how to correct errors or improve their radiotherapy treatment technique, and (4) minimize the number of patients scored as deviations. As part of the process of clinical trial development, decisions are made concerning the appropriateness of both credentialing and data review. There are clinical trials where data capture is the only aspect of chart review and certain protocols (CNS leukemia, etc) do not have an assigned credentialing or radiation therapy (RT) object review objective. This provides the appropriate distribution of resources for the clinical trial effort.
In 1997, the ATC was funded by the NCI to create a forum through which the QA centers, QARC, RPC, ITC, and RTOG QA, can work together to improve the quality of the clinical trial radiotherapy data for all study groups. The ATC has played a key role in unifying the credentialing activities and creating reciprocity of credentialing among all study groups. Through ATC efforts credentialing guidelines have been introduced for new technologies such as recently for proton therapy (http://rpc.mdanderson.org/RPC/home.htm
). The reasoning for each of the possible current credentialing requirements is as follows.