Kenneth Ulin

Clinically evident fat necrosis in women treated with high-dose-rate brachytherapy alone for early-stage breast cancer

PURPOSE To investigate the incidence of and variables associated with clinically evident fat necrosis in women treated on a protocol of high-dose-rate (HDR) brachytherapy alone without external-beam whole-breast irradiation for early-stage breast carcinoma. METHODS AND MATERIALS From 6/1997 until 8/1999, 30 women diagnosed with Stage I or II breast carcinoma underwent surgical excision and postoperative irradiation via HDR brachytherapy implant as part of a multi-institutional clinical Phase I/II protocol. Patients eligible included those with T1, T2, N0, N1 (< or = 3 nodes positive), M0 tumors of nonlobular histology with negative surgical margins, no extracapsular lymph-node extension, and a negative postexcision mammogram. Brachytherapy catheters were placed at the initial excision, re-excision, or at the time of axillary sampling. Direct visualization, surgical clips, ultrasound, or CT scans assisted in delineating the target volume defined as the excision cavity plus 2-cm margin. High activity (192)Ir (3-10 Ci) was used to deliver 340 cGy per fraction, 2 fractions per day, for 5 consecutive days to a total dose of 34 Gy to the target volume. Source position and dwell times were calculated using standard volume optimization techniques. Dosimetric analyses were performed with three-dimensional postimplant dose and volume reconstructions. The median follow-up of all patients was 24 months (range, 12-36 months). RESULTS Eight patients (crude incidence of 27%) developed clinically evident fat necrosis postimplant in the treated breast. Fat necrosis was determined by clinical presentation including pain and swelling in the treated volume, computed tomography, and/or biopsy. All symptomatic patients (7 of 8 cases) were successfully treated with 3 to 12 months of conservative management. Continuous variables that were found to be associated significantly with fat necrosis included the number of source dwell positions (p = 0.04), and the volume of tissue which received fractional doses of 340 cGy, 510 cGy, and 680 cGy (p = 0.03, p = 0.01, and p = 0.01, respectively). Other continuous variables including patient age, total excised tissue volume, tumor size, number of catheters, number of days the catheters were in place, planar separation, dose homogeneity index (DHI), and uniformity index (UI) were not significant. Discrete variables including the presence/absence of DCIS, sentinel versus full axillary nodal assessment, receptor status, presence/absence of diabetes, and the use of chemotherapy or hormone therapy were not found to have a significant association with the risk of fat necrosis. CONCLUSIONS In this study of HDR brachytherapy of the breast tumor excision cavity plus margin, treatment was planned and delivered in accordance with the dosimetric parameters of the protocol resulting in a high degree of target volume dose homogeneity. Nonetheless, at a median follow-up of 24 months, a high rate of clinically definable fat necrosis occurred. The overall implant volume as reflected in the number of source dwell positions and the volume of breast tissue receiving fractional doses of 340, 510, and 680 cGy were significantly associated with fat necrosis. Future dosimetric optimization algorithms for HDR breast brachytherapy will need to include these factors to minimize the risk of fat necrosis.

Results of a multi-institutional benchmark test for cranial CT/MR image registration.

PURPOSE Variability in computed tomography/magnetic resonance imaging (CT/MR) cranial image registration was assessed using a benchmark case developed by the Quality Assurance Review Center to credential institutions for participation in Childrens Oncology Group Protocol ACNS0221 for treatment of pediatric low-grade glioma. METHODS AND MATERIALS Two DICOM image sets, an MR and a CT of the same patient, were provided to each institution. A small target in the posterior occipital lobe was readily visible on two slices of the MR scan and not visible on the CT scan. Each institution registered the two scans using whatever software system and method it ordinarily uses for such a case. The target volume was then contoured on the two MR slices, and the coordinates of the center of the corresponding target in the CT coordinate system were reported. The average of all submissions was used to determine the true center of the target. RESULTS Results are reported from 51 submissions representing 45 institutions and 11 software systems. The average error in the position of the center of the target was 1.8 mm (1 standard deviation = 2.2 mm). The least variation in position was in the lateral direction. Manual registration gave significantly better results than did automatic registration (p = 0.02). CONCLUSION When MR and CT scans of the head are registered with currently available software, there is inherent uncertainty of approximately 2 mm (1 standard deviation), which should be considered when defining planning target volumes and PRVs for organs at risk on registered image sets.

PROCESSES FOR QUALITY IMPROVEMENTS IN RADIATION ONCOLOGY CLINICAL TRIALS

Quality assurance in radiotherapy (RT) has been an integral aspect of cooperative group clinical trials since 1970. In early clinical trials, data acquisition was nonuniform and inconsistent and computational models for radiation dose calculation varied significantly. Process improvements developed for data acquisition, credentialing, and data management have provided the necessary infrastructure for uniform data. With continued improvement in the technology and delivery of RT, evaluation processes for target definition, RT planning, and execution undergo constant review. As we move to multimodality image-based definitions of target volumes for protocols, future clinical trials will require near real-time image analysis and feedback to field investigators. The ability of quality assurance centers to meet these real-time challenges with robust electronic interaction platforms for imaging acquisition, review, archiving, and quantitative review of volumetric RT plans will be the primary challenge for future successful clinical trials.

Radiation therapy quality assurance in clinical trials – Global harmonisation group

Participation in large multi-centre clinical trials aids establishment of the safety and efficacy of new cancer treatments and methods. Oncology clinical trials have contributed to improved local control, overall survival and quality of life for patients with varying disease types [1]. Radiation Therapy is indicated in the course of treatment for more than 50% of all cancer patients [2,3] and consequently a high percentage of oncology clinical trials include radiotherapy within their treatment schema. Collaboration between global clinical trial groups and organisations has increased the number of patient records available for analysis permitting faster recruitment [4], broader acceptance and wider impact of trial results. Global cooperation is also essential in the environment of rare cancers [5], in order to be able to create sufficiently large patient data sets within a reasonable recruitment period. A successful example is the EORTC 26981/National Cancer Institute of Canada (NCIC) CE3 intergroup trial, where 573 Glioblastoma patients were randomised within 20 months [6], despite the low prevalence of the disease among the general population. Globally, clinical trial groups and organisations have independently implemented their own Radiation Therapy (RT) Quality Assurance (QA) programs within their corresponding large multicentre clinical trials. Various trial groups have reported that the implementation of RTQA procedures enhanced protocol compliance [7–13]. In four Radiation Therapy Oncology Group (RTOG) studies compliance with the study protocol was enhanced by incorporating pre-treatment review of RT planning [8]. A Trans-Tasman Radiation Oncology Group (TROG) QA audit identified a reduction in unacceptable protocol violations due to three main factors, among which was the QA procedure itself [7]. More recently, strict RTQA procedures have been shown by TROG to have impacted on both trial protocol compliance as well as general clinical practice in prostate RT [9]. For several EORTC studies it has been shown that centres which previously participated in a Dummy Run (DR) were significantly more likely to be successful at subsequent DR attempts and delivery of protocol-compliant RT [10]. Additionally, the impact of RTQA on actual clinical trial outcome has been recently demonstrated in the setting of various cancer sites [11], stressing its importance and correlation with survival [12,13]. However, the various approaches as to how RTQA in clinical trials is performed, evaluated and described are diverse, making analysis and inter-trial comparisons of RTQA results challenging. This hampers cooperation between trial groups and impedes the exchange and interpretation of RTQA data. The costs of running an RTQA program have also increased with the introduction of new advanced technologies. This increases the need to make RTQA more efficient and streamline the QA workload demanded of clinical centres recruiting into international trials [14,15]. As shown by Pettersen et al [4] these RTQA efforts can potentially reduce the number of patients required for trials which could lead to further substantial savings and faster availability of results. The need for a global forum on harmonisation of RTQA within clinical trials thus became apparent. After initial discussions in Goteborg during ESTRO 27 in 2008 the Global Clinical Trials RTQA Harmonisation Group (GHG) was formally established in 2010. The goals of the GHG are: Collate, homogenise and distribute information regarding the RTQA standards of the clinical trial groups, Provide a platform for prospective discussions on new RTQA procedures, software tools, guidelines and policies of trial groups and Provide a framework to endorse existing and future RTQA procedures and guidelines across various trial groups. Each organisation will have the opportunity to endorse RTQA procedures from other organisations and thus accept them much faster in future collaborative trials. In Table 1 the human resources and number of intergroup trials of the steering committee members of the GHG are given. Further information about terms of reference and current and future projects can be found on its website: www.RTQAHarmonisation.org. Table 1 RTQA within each of the current GHG steering committee members as of August 2013. All RTQA groups and organisations participate in international collaborative work to some degree, although there are differences between the USA and all other groups. These differences can be explained by the differences in the funding levels and that most USA RTQA groups only work with NCI funded clinical trials mainly operated in North America [16]. Recently, the North American RTQA organisations have joined forces in the new Imaging and Radiation Oncology Core (IROC) group. The dedicated human resources also vary significantly, most likely due to differences in the QA philosophy of the funding agencies and their commitment to RTQA, although most of the GHG members have at least one Radiation Oncologist, one Medical Physicist and one Radiation Technologist dedicated full time to RTQA. Until now the GHG has contributed to the harmonisation of naming conventions [17], strategies to develop an efficient evidence-based clinical trials RTQA system [14] and the development of a global model for the international recognition of the activities of national and regional Dosimetry Audit Networks [18]. Currently, each trial group has defined its own RTQA procedures [10,19–24] that differ significantly in number, naming conventions and implementation methods [22,25–31]. The GHG is addressing this by collating all RTQA procedures of each member, comparing them and proposing common, harmonised names and procedures. Although RTQA has been proven to be effective, international differences hamper intergroup collaboration. The Global Clinical Trials RTQA Harmonisation Group has been established to reduce those differences, capitalise on the range of expertise available internationally, increase the power of RT clinical trials, deliver consistency in the reporting of trial quality factors and facilitate the undertaking of effective multi-national trials and data analysis. Although important progress has already been made, many challenges remain to be addressed.

Future vision for the quality assurance of oncology clinical trials

The National Cancer Institute clinical cooperative groups have been instrumental over the past 50 years in developing clinical trials and evidence-based process improvements for clinical oncology patient care. The cooperative groups are undergoing a transformation process as we further integrate molecular biology into personalized patient care and move to incorporate international partners in clinical trials. To support this vision, data acquisition and data management informatics tools must become both nimble and robust to support transformational research at an enterprise level. Information, including imaging, pathology, molecular biology, radiation oncology, surgery, systemic therapy, and patient outcome data needs to be integrated into the clinical trial charter using adaptive clinical trial mechanisms for design of the trial. This information needs to be made available to investigators using digital processes for real-time data analysis. Future clinical trials will need to be designed and completed in a timely manner facilitated by nimble informatics processes for data management. This paper discusses both past experience and future vision for clinical trials as we move to develop data management and quality assurance processes to meet the needs of the modern trial.

Credentialing for participation in clinical trials.

The National Cancer Institute (NCI) clinical cooperative groups have been instrumental over the past 50 years in developing clinical trials and evidence-based clinical trial processes for improvements in patient care. The cooperative groups are undergoing a transformation process to launch, conduct, and publish clinical trials more rapidly. Institutional participation in clinical trials can be made more efficient and include the expansion of relationships with international partners. This paper reviews the current processes that are in use in radiation therapy trials and the importance of maintaining effective credentialing strategies to assure the quality of the outcomes of clinical trials. The paper offers strategies to streamline and harmonize credentialing tools and processes moving forward as the NCI undergoes transformative change in the conduct of clinical trials.

Quality of radiotherapy reporting in randomized controlled trials of Hodgkin's lymphoma and non-Hodgkin's lymphoma: in regard to Bekelman and Yahalom (Int J Radiat Oncol Biol Phys 2009;73:492-498)

Drs. Bekelman and Yahalom’s (1) paper describing radiation therapy (RT) quality assurance (QA) in lymphoma clinical trials places emphasis for RT standards. Insuring study defined dose/volume constraint compliance, RTQA requires central pre-treatment diagnostic imaging and RT plan review. This letter describes Children’s Oncology Group (COG) historical and current RTQA process for Hodgkin’s lymphoma (HL) trials. For 33 years the Quality Assurance Review Center (QARC) has performed RTQA on cooperative group trials. Process improvements demonstrate maturing of clinical trials QA in response to protocol needs. The increasingly crucial role of imaging in clinical trials QA is validated. Pediatric Oncology Group (POG) protocol 8725 (intermediate/advanced staged HL) required 8 chemotherapy cycles +/− Involved Field RT. Initial publication(2) demonstrated no advantage for RT. Retrospective data review revealed 10% survival advantage for patients receiving compliant RT.(3) 30% of patients had treatment deviations including omission of RT to involved sites. To improve compliance, POG required pre-treatment RT review for next generation advanced/early stage HL studies, P9425/P9426(4,5). Strategy improved RT compliance. P9426 required post chemotherapy imaging response treatment adaptation. Retrospective response-imaging central review established that ~50% of patients had discordance between local and central review.(6) COG AHOD0031 (intermediate risk HL) included patient response-adapted therapy. QARC initiated real time response review with integrated imaging (anatomic and metabolic) and RT review prior to RT start. Discordant local and central interpretations were resolved in real time. (7,8) 1733 patients from 251 centers worldwide were enrolled. Near uniform data submission compliance has been obtained with >95% RT compliance in ~600 cases reviewed. Process feasibility allows extension of adaptive treatments based on centrally-confirmed response for the next high risk HL study. QARC-developed an informatics platform and processes that contribute to success of these clinical trials improvements. QARC acquires and manages imaging and RT data in several digital formats(9). The QARC database houses images and RT objects in side-by-side format, enabling remote investigator access. In collaborating with Dr. Purdy and the Advanced Technology Consortium, full digital RT files are received at QARC for review and DVH analysis. Currently strategies to incorporate Dicom compatible pathology objects into the database and use of open-source format for data sharing are being evaluated. The objectives identified in this paper for developing consensus standards and peer-review are in place for cooperative groups. Applying these established programs at enterprise level insures the objectives of this publication are met.

Radiation Therapy Digital Data Submission Process for National Clinical Trials Network

As part of the consolidation of the cooperative group clinical trial program of the National Clinical Trials Network (NCTN) of the National Cancer Institute (NCI), an Imaging and Radiation Oncology Core services organization (IROC) has been formed from current leading quality assurance (QA) centers to provide QA, along with clinical and scientific expertise, for the entire NCTN (1). An integrated information technology (IT) infrastructure, the IROC cloud, has been implemented to foster collaborative and effective interactions among participating institutions, QA centers, NCTN cooperative groups and statistics data management centers, and the IT infrastructure of the NCI (Fig. 1). An integral component of the IROC cloud is the Transfer of Images and Data (TRIAD) system designed for imaging and radiation therapy digital data transmission. The TRIAD system is now being used for digital radiation therapy and imaging data transmission for NCTN (and other) clinical trials. Fig. 1 IROC cloud: An IROC Information Technology (IT) infrastructure vision. Consistency of submitted data contributes to better consistency in the treatment and review of trial data, and it facilitates scientific collaborations and also promotes safe clinical practice. The details of this data submission process are presented here.

SU‐FF‐T‐267: Implementation of ATC Method 1 for Clinical Trials Data Review at the Quality Assurance Review Center

Purpose: To develop the capability at the Quality Assurance Review Center (QARC) to receive and review digital radiation therapytreatment planning data (TPD) for clinical trial case review. Method and Materials: A system of software (“ATC Method 1”) developed at the Image‐guided Therapy QA Center (ITC) as part of the Advanced Technology QA Consortium (ATC) to receive, process, and review volumetric TPD for clinical trials was ported to a Linux workstation at QARC. The system includes an FTP server for receiving TPD (in DICOM or RTOG data exchange format) from protocol participants, utilities for importing TPD into a local file format, and the web‐based Remote Review Tool (RRT) for QA of ROIs, isodoses, DVHs, and dose statistics. (Proprietary software components were used by special arrangement with CMS, Inc.) Results:Software installation and maintenance were performed remotely at QARC by ITC personnel, with weekly teleconferences to coordinate the development effort. ITC software was adapted to better support the QARC QA process. RRT enhancements include selectable DVHs, distance measurement tool, and image grayscale presets. QARC software was adapted to support RRT invocation directly from the QARC databaseuser interface. The system is in use for six COG, CALGB, ACOSOG, and ECOG protocols; 28 cases from 15 institutions have been received and reviewed (3/1/06). Conclusion: Widespread use of new treatment modalities such as IMRT, makes use of 3D datasets essential for complete evaluation of ROI delineation and assessment of agreement of dosimetric parameters with protocol requirements. This project demonstrates that ATC Method 1, successfully used in support of RTOG trials for many years at ITC, can be implemented at other QA centers. The effort required, however, was significant and tools must be tailored to each individual QA centers computer infrastructure/QA process. Supported by NIH U24 Grant CA81647 and NCI‐H Grant 5U10CA02951.

American Association of Physicists in Medicine Task Group 263: Standardizing Nomenclatures in Radiation Oncology

A substantial barrier to the single- and multi-institutional aggregation of data to supporting clinical trials, practice quality improvement efforts, and development of big data analytics resource systems is the lack of standardized nomenclatures for expressing dosimetric data. To address this issue, the American Association of Physicists in Medicine (AAPM) Task Group 263 was charged with providing nomenclature guidelines and values in radiation oncology for use in clinical trials, data-pooling initiatives, population-based studies, and routine clinical care by standardizing: (1) structure names across image processing and treatment planning system platforms; (2) nomenclature for dosimetric data (eg, dose–volume histogram [DVH]-based metrics); (3) templates for clinical trial groups and users of an initial subset of software platforms to facilitate adoption of the standards; (4) formalism for nomenclature schema, which can accommodate the addition of other structures defined in the future. A multisociety, multidisciplinary, multinational group of 57 members representing stake holders ranging from large academic centers to community clinics and vendors was assembled, including physicists, physicians, dosimetrists, and vendors. The stakeholder groups represented in the membership included the AAPM, American Society for Radiation Oncology (ASTRO), NRG Oncology, European Society for Radiation Oncology (ESTRO), Radiation Therapy Oncology Group (RTOG), Children’s Oncology Group (COG), Integrating Healthcare Enterprise in Radiation Oncology (IHE-RO), and Digital Imaging and Communications in Medicine working group (DICOM WG); A nomenclature system for target and organ at risk volumes and DVH nomenclature was developed and piloted to demonstrate viability across a range of clinics and within the framework of clinical trials. The final report was approved by AAPM in October 2017. The approval process included review by 8 AAPM committees, with additional review by ASTRO, European Society for Radiation Oncology (ESTRO), and American Association of Medical Dosimetrists (AAMD). This Executive Summary of the report highlights the key recommendations for clinical practice, research, and trials.