Quality Assurance in Radiation Oncology

Abstract

The Children’s Oncology Group (COG) has a strong quality assurance (QA) program managed by the Imaging and Radiation Oncology Core (IROC). This program consists of credentialing centers and providing real time management of each case for protocol compliant target definition and radiation delivery. In the International Society of Pediatric Oncology (SIOP), the lack of an available, reliable online data platform has been a challenge and the European Society for Paediatric Oncology (SIOPE) Quality and Excellence in Radiotherapy and Imaging for Children and Adolescents with Cancer across Europe in Clinical Trials (QUARTET) program currently provides QA review for prospective clinical trials. The COG and SIOP are fully committed to a QA program that ensures uniform execution of protocol treatments and provides validity of the clinical data used for analysis.

Introduction

To ensure successful clinical trial management in radiation oncology, the Children’s Oncology Group (COG) has developed a strong radiation oncology quality assurance (QA) program. This program is managed by the Imaging and Radiation Oncology Core (IROC) offices in Houston, Texas (TX) and Lincoln, Rhode Island (Rl). The program consists of qualifying and credentialing radiotherapy (RT) sites for participation in clinical trials and providing real time management of each case for protocol compliant target definition and RT treatment delivery. Pediatric oncology patients are treated at diverse centers around the world. Clinical trials are an important part of pediatric oncology practices. Each site participating in the trial may see a limited number of patients for that trial. Successful completion of the trial requires uniform execution of the RT.

The IROC program ensures that QA guidelines are written into each study and RT sites and site investigators are credentialed for trial participation. Real time review of objects ensures that the quality of RT meets study objectives, the data collected are valid and the analysis of trial outcome can be believed.

History

Challenges in Early QA Programs

In the early development of pediatric oncology protocols involving RT, the primary focus of QA programs was directed towards computational algorithms of RT dose computation. Institutions had varied methods of calculating dose and dose delivery.

Many institutions and physics colleagues calculated dose to the surface of the target and others calculated to depth and/or isocenter, therefore a significant discrepancy could be seen in dose to target even if the treatment intent was identical. Each investigator could specify the same dose but the dose delivered could be significantly different and biologically meaningful. Calculations were often institution-specific and subject to dose delivery asymmetry across centers, therefore doses to intended targets could be varied. Imaging was not imbedded in data acquisition processes of early clinical trials, only RT planning objects, simulation two-dimensional imaging, and accelerator portal images. These data were acquired for QA review and only evaluated by study investigators after the trial was completed as objects had to be submitted in hard copy. This did not permit interventional review as the QA processes were part of a retrospective analysis of data. Review of computational algorithms and assessment of radiation fields post therapy was considered standard management of protocol objects. This limited the perception of the value of RT pediatric oncology and left the impression these issues could not be reconciled for successful trial management.

Imaging as Part of Radiation Therapy Planning

Imaging became an adjudicator as the RT targets had a foundation that could be reviewed and conformed by multiple investigators and calculations could be generated for a volume using volumetric-based planning computational algorithms. This approach was initially applied in more modern protocols involving Hodgkin lymphoma. Imaging objects, including pre and post-chemotherapy computer tomography studies, were used to define target volumes for RT. Pediatric Oncology Group (POG) Hodgkin lymphoma protocol 8725 altered the paradigm of QA. The study evaluated what today would be referred to as intermediate and high-risk patients treated with eight cycles of hybrid chemotherapy. RT was the point of randomization with all sites of original disease treated in half of the patient population with the other half receiving chemotherapy as the sole modality of care. The initial publication reported no advantage to the addition of RT.¹ Because imaging and RT objects were acquired for review of the RT fields after therapy completion, the fields could be reviewed for study compliance from a therapy volume perspective by study investigators. If treatment was delivered in a study compliant manner with all original sites of disease included in the RT treatment fields, there was a 10% survival advantage for patients treated with study compliant RT.² The RT deviation rate on study was 30%, indicating that a visible segment of the study population did not have study compliant therapy. Essentially all study deviations were due to omitting areas of original disease from the therapy treatment fields at the discretion of the site investigator. For patients with RT delivered in a manner not study compliant, survival was equal to chemotherapy alone.

To address this point, the clinical trial radiation committee decided to begin pre-treatment review of RT treatment objects for the next generation of early stage and intermediate risk patients with Hodgkin lymphoma coupled with therapeutic titration based on response to chemotherapy. This proved to be extremely successful in improving radiation oncology study compliance, however, submitted pre- and post-chemotherapy imaging revealed a new problem as there was a 50% discrepancy between site assessment and central review of response to chemotherapy.^3,4

Integration of Imaging and Radiation Oncology Objects into a Uniform Review Platform The issue with real time response assessment and the application of protocol compliant RT pre-treatment was addressed in adaptive therapy COG study AHOD0031. In this study, which accrued more than 1700 patients with intermediate risk Hodgkin lymphoma, had imaging and RT objects centrally reviewed in real time at multiple time points to ensure study compliance for response assessment and application of RT (Fig. 1).⁵

Figure 1.

Imaging and radiation therapy real time central reviews in COG AHOD0031

Copyright© FitzGerald TJ, Bishop-Jodoin M, Bosch WR, Curran WJ, Followill DS, Galvin JM, Hanusik R, King SR, Knopp MV, Laurie F, O’Meara E, Michalski JM, Saltz JH, Schnall MD, Schwartz L, Ulin K, Xiao Y, Urie M. Front Oncol. 2013;3:31. Doi: 10.3389/fonc.2013.00031.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

Imaging and RT objects were displayed in the digital database for onsite or web-based review in a side by side format and could be reviewed in real time by site and study investigators to ensure stage, appropriateness of study entry, and study compliant application of objects. Web-based media were used to resolve issues before study entry or adaptive randomization.⁵ These ground-breaking changes brought protocol QA to a different level of execution as the quality of the study could be reviewed and adjusted during the clinical management decision process. Clinical management of each study became aligned with the QA process. World experts could be together in a virtual format with study and site investigators and could participate in real time clinical trial execution by reviewing objects in digital format with web-based tools. This process resulted in harmonization and uniformity of the study population and in turn, enhanced confidence in the analysis of clinical trial outcome.

Site qualification and credentialing processes and real time imaging and RT interventional reviews now function at an enterprise level and are imbedded in daily protocol activity. Clinical trials in every disease site in pediatric oncology including neuro-oncology, bone/soft tissue sarcoma, Wilms tumor, neuroblastoma, leukemia/lymphoma, and other rare diseases include real time review of objects for study compliance. As imaging and image sequences have become more complex, multiple imaging data sets are now integrated into RT planning imaging for target definition in most disease areas. The processes are well established in the COG community and are an important aspect of the pediatric oncology clinical trial portfolio.

Status of I ROC/COG

Credentialing for Participation in Clinical Trials for RT

The portfolio of site qualification and credentialing core services within IROC managed by the Houston QA Center is large and functions in an enterprise manner. Over the past five years, 1840 radiation oncology (4800 radiation oncology machines) sites were identified as the National Cancer Institute’s (NCI) National Clinical Trials Network (NCTN) participants (556 have identified as being affiliated with COG). Site demographic data is collected at qualification, credentialing and annually after.

Radiation Beam Output Validation

A key component of the radiation oncology site qualification is the annual dose output verification using IROC Houston’s mailed dosimeter program. Institutions irradiate a dosimeter and this would be reviewed by a single review station housed in IROC Houston. A total of 74,000 RT machine beam outputs were audited in the first five years of IROC’s existence. Unlike radiation oncology sites that deliver treatments only with photon beams, the proton centers must comply with the (National Cancer Institute) NCI’s guidelines for participating in NCI multi-institutional clinical trials.

Proton Therapy

As a part of those guidelines, each new proton center must go through a multi-step approval process, including remote monitoring of proton beam outputs, irradiation of baseline anthropomorphic QA phantoms and a site visit. To date, 26 of the 31 clinically active proton therapy centers have been approved for participation in the NCTN clinical trials. IROC radiation oncology core services also rely heavily on credentialing of sites to participate in NCTN clinical trials utilizing advanced technologies. As NCTN trials become more complex and utilize new treatment machines and imaging devices, IROC has developed credentialing mechanisms that provide confidence to the NCTN groups that sites are qualified to treat or image clinical trial patients in compliance with protocol specifications. During the past five years, over 2500 imaging systems were evaluated. A total of 2985 RT credentialing anthropomorphic QA phantoms was sent to institutions (Fig. 2) and evaluated. Approximately 1600 RT benchmark cases were reviewed and 897 image-guided radiation oncology processes were assessed. Overall, 12,943 credentials were issued to RT and imaging sites for participation in the NCTN’s clinical trials. These processes, developed and maintained at IROC Houston, ensure that sites and investigators participating in NCTN and COG clinical trials have the infrastructure and expertise onsite to successfully execute clinical care per protocol guidelines.^6–8

Figure 2.

IROC Houston anthropomorphic QA phantoms shipped for credentialing Image courtesy of David S. Followill, PhD; IROC Principal Investigator

Review of Objects

Once sites are qualified and credentialed, real time review of imaging and RT treatment objects is managed by the IROC RI QA Center. Since the early success in the pre-treatment review program and real time review of imaging objects in response-adaptive trials in Hodgkin lymphoma, data acquisition and management of the COG portfolio has advanced to a dynamic enterprise level. All disease sites are represented by this process and interventional review has been of significant value for successful clinical trial conduct for COG. While a large percentage of all pediatric cancer patients are treated on clinical trials, the number of pediatric cases at any one site is small. Completion of clinical trials requires a large number of sites participating and, therefore, demands uniform execution of RT within each trial. Although major cancer centers make significant contributions to study accrual, pediatric malignancies are geographically distributed and oncology centers both large and small are needed to meet study accrual objectives. In standard risk medulloblastoma COG protocol A9961, 189 institutions were needed to enroll 421 patients.⁹ Pediatric oncology requires a strong centralized QA program to ensure that each patient is 1) entered onto the correct study 2) staged correctly 3) imaging is interpreted in a study compliant manner and 4) RT treatment objects are applied consistent with study objectives. For example, in current COG medulloblastoma study, images are reviewed in a screening step to be sure patients are eligible, the review includes 1) no spinal metastasis per criteria established by the study imaging coordinator 2) no residual post resection disease in the posterior fossa measuring more than 1.5 cc 3) the quality of the spinal imaging was study compliant without motion artifact and 4) all appropriate image sequences were acquired. These issues are important in all disease areas to ensure that everyone can have confidence in the study outcome and these principles are applied across all disease sites.

Relevance of QA in Clinical Trials

The QA program has a strong and symbiotic relationship with the COG data center. Central assessment of disease response and or disease progression can be entered in real time to trigger secondary and tertiary randomization points embedded in the study. Real time review is of increasing importance in clinical trials managed by COG. With the advent of digital media and near immediate transfer of objects for real time review, the radiation oncology deviation rate in pediatric rhabdomyosarcoma has decreased from 30% to 5%.¹⁰

Answering radiation therapy study questions in pediatric oncology is important as it is challenging to power a study and determine statistical significance through a traditional randomization process. This is especially true as the small numbers of patients are further limited by studies designed for molecular sub-types of a disease. The current COG medulloblastoma protocol, ACNS1422, is an example of a study testing reducing therapy for good risk patients with a particular molecular expression. To keep radiation oncology as a viable treatment option in many disease areas, we need to be cognizant of the quality of our work. Therefore, every patient matters for successful clinical trial management. Similarly, these real time QA processes are critical in diagnostic imaging reviews. In A9961, more than 10% of patients were deemed ineligible in retrospective review of imaging objects as both image quality and motion artifact influenced interpretation. High risk medulloblastoma patients unintentionally entered on the incorrect low risk study had a significantly worse outcome, therefore important to identify metastasis and residual disease to reclassify patients and ensure the correct patient is entered onto the correct protocol.¹¹ Current RT QA processes for COG studies require real-time review to confirm eligibility and/or relapse.

The importance of the quality of the information under review cannot be overstated. In a recent submission of a secondary research project evaluating the patterns of failure in Hodgkin lymphoma, reviewers commented that the QA processes were important for data analysis as the rigor of the review and the quality of the information made the results believable and could be applied to daily practice.^12,13

International Society of Pediatric Oncology (SIOP)

The SIOP experience also highlights the importance of radiation therapy QA on treatment outcomes. Several reports have shown that there is both a significant incidence of errors and that deviations may be associated with worse outcomes and/or increased toxicity.^14–17 Taylor et al. have shown a significant increase in relapse associated with errors in target coverage in supratentorial primitive neuroectodermal tumors.¹⁴ In SIOPEN (European SIOP Neuroblastoma Group) High Risk Neuroblastoma 1 Study, Gaze et al. identified deviations from the protocol in 52% of cases.¹⁸ In 34 patients (65% of cases with deviations) this was completely justified by the need to respect normal tissue tolerance, but in 17 other patients (33% of all cases with deviations) no reason was apparent. There is concern that there will be an adverse impact on tumor control rates especially with the increasing complexity of radiation therapy treatment delivery for neuroblastoma.¹⁹ Prospective radiotherapy QA is currently utilized for the SIOPEN low and intermediate risk (LINES) study and will be fully implemented and investigated in the SIOPEN high risk HR-NBL-2 study expected to start in 2019. For rhabdomyosarcomas, prospective RT QA will be included in the current European pediatric Soft Tissue Sarcoma Study Group (EpSSG) study, FaR-RMS (Frontline and Relapsed Rhabdomyosarcoma Study). For medulloblastoma, reports have shown that the radiotherapy QA has an important influence on treatment results and long term side effects, and inadequate radiotherapy has already been demonstrated to significantly and negatively affect survival, especially in medulloblastoma.²⁰ The current SIOP study for medulloblastoma (SIOP PNET 5) includes prospective radiotherapy quality review as a prerequisite of the treatment and wants to explore the impact of prospective quality review on disease control and (long term) side effects.

Future Efforts and Conclusions

A strong and viable QA program requires interactions across the broad range of participants within the Group Operations/Data Management/Statistical teams, the IROC QA Centers and the variety of participating sites and investigators around the world. Data acquisition processes and data management need to ensure that the correct information is collected and collated at the appropriate time points. Site and study investigators need to participate in real time to ensure correct application of protocol guidelines. Study investigators need to participate on a near daily basis, especially as their participation is important to real time trial management. In protocols with adaptive trial design and secondary/tertiary objectives based on response, study investigators including imaging colleagues log into the QA Center database to review their assigned work and provide assessment of response. For example, in modern clinical trials of patients with Stage 4 Wilms tumor, complete response to chemotherapy at six weeks of treatment requires no radiation therapy. Therefore real time review of response influences next steps in protocol management. Fig. 3 represents investigator logins to review protocol cases archived at IROC Rhode Island. Establishing and maintaining these tools for protocol use has permitted protocols to be managed with worldwide investigators in real time. The database at IROC Rhode Island securely stores protocol patient objects including DICOM imaging, DICOM radiation therapy treatment plans and other digital files of treatment records, reports and forms relevant to protocol management in a single database with facile query function to ask questions not always anticipated by study design. It also permits study investigators to have objects available to confirm the information that is provided by COG statistical data center. All this information including novel and modern tissue pathology and biomarkers are essential to resolving modern study questions as treatment evolves and becomes biomarker and patient specific. For future efforts, this de-identified information will reside in a public archive for use by investigators. The Cancer Imaging Archive (TCIA)’s open-access design accommodates such an approach with experts in data archiving, data management, pathology, and imaging science collaborating to enable the information to be available for review. The information will likewise be used to support secondary studies.²¹ The COG data collected in the RT QA process and archived at IROC Rhode Island can provide the research collections for to support young investigators in their academic pursuits.

Figure 3.

Investigator use of the IROC RI database to review clinical trial data and imaging. Image courtesy of IROC RI.

Although there is an increasing number of clinical trials trying to incorporate prospective review of treatment planning, in Europe, one of the hurdles is the availability of a reliable, fast and safe online data platform that allows reviewers to assess radiotherapy plans and give feedback to the treating radiation oncologist in a timely manner. The SIOPE QUARTET project will investigate and establish the effectiveness of radiotherapy and imaging in pediatric cancers through an online prospective quality assurance program. QUARTET officially began in 2016 and will ensure centralized review of all RT plans for every child and adolescent before radiotherapy. Over a period of five years and with an estimated number of 500 patients included per year, the project will cover children and adolescents treated for neuroblastoma, rhabdomyosarcoma and brain tumors as part of nine European prospective clinical trials.

QA is an integral component to successful clinical trials in COG and SIOP. The QA program provides important elements to assure the uniform execution of protocol treatments and the validity of the data used in the trial outcome analyses.

Abbreviations

COG

Children’s Oncology Group

DICOM

Digital Imaging and Communications in Medicine

EpSSG

European paediatric Soft Tissue Sarcoma Study Group

FaR-RMS EpSSG

Frontline and Relapsed Rhabdomyosarcoma Study

IROC

Imaging and Radiation Oncology Core

NCI

National Cancer Institute

NCTN

National Clinical Trials Network

PNET 5

SIOP Medulloblastoma Clinical Trial

POG

Pediatric Oncology Group

QA

Quality Assurance

QUARTET

Quality and Excellence in Radiotherapy and Imaging for Children and Adolescents with Cancer across Europe in Clinical Trials

RI

Rhode Island

SIOP

International Society of Pediatric Oncology

SIOPE

European Society for Paediatric Oncology

SIOPEN

European SIOP Neuroblastoma Group

TCIA

The Cancer Imaging Archive

TX

Texas