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Abstract
Introduction In 2020, the Australian Medical Services Advisory Committee (MSAC) recommended new proton beam therapy (PBT) item numbers be added to the Medicare Benefits Schedule. During the MSAC 1638 application process, MSAC recognised the uncertainties inherent in the cost-utility modelling of PBT. To address these uncertainties, MSAC proposed the establishment of a national registry with the intention to gather evidence to validate the claim of PBT’s superior toxicity outcomes and cost-effectiveness compared with conventional photon radiation therapy.
Methods and analysis The Australian Particle Therapy Clinical Quality Registry is a prospective, observational, longitudinal registry collecting national data on paediatric, adolescent young adult and adult patients with rare tumours receiving any form of radiation therapy for a defined group of diseases, specified by the MSAC 1638 Public Summary Document. Eligible patients undergoing radiation therapy at participating institutions will be provided with information about the registry, including the opt-out procedure. The registry has no enrolment cap and will persist either indefinitely or until the conclusion of the study.
The study design was informed by the Australian Metadata Online Repository and contains a core set of minimum data elements. Representing baseline participant demographics, assessment, diagnosis and treatment; incorporating radiation and systemic therapies, with a specific focus on long-term follow-up, treatment toxicities and specific organ-at-risk testing.
Ethics and dissemination There will be no identifying data used in any reports or presentations of data. Additionally, all identifiable data will be safeguarded according to standard practices and available only to the host institution submitting the data to the registry. Aggregated data for the purposes of research will be stripped of identifiers. The registry has been approved under the National Mutual Agreement by the Central Adelaide Local Health Network Human Research Ethics Committee—HREC: 2021/HRE00394.
Trial registration number Australian and New Zealand Clinical Trials Registry (ANZCTR): ACTRN12622000026729p.
- RADIOTHERAPY
- Radiation oncology
- Paediatric oncology
- Paediatric radiotherapy
- REGISTRIES
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STRENGTHS AND LIMITATIONS OF THIS STUDY
Comprehensive data collection on radiation therapy toxicities and outcomes will offer valuable real-world data for hypothesis generation, theory validation and innovative studies.
Yearly statistics and comprehensive annual reports will enable State and Federal Health Departments to make data-driven policy decisions for better proton beam therapy resource allocation.
Long-term data collection presents a challenge, as some departments may need to adjust their workflows to accommodate follow-up processes.
The ambitious research and data collection effort will require collaboration across departments to ensure smooth adaptation and implementation.
Introduction
Particle therapy is a form of external beam radiation therapy using particles that have a mass greater than that of electrons. Particle therapy offers an alternative to traditional X-ray (photon)-based radiation therapy (XRT). The most common types of particle therapy are proton beam therapy (PBT) and carbon-ion therapy (CIT). Both PBT and CIT have the capacity to confine the precise radiation dose to the vicinity of the target tumour, potentially mitigating toxicities for patients.1 Unlike conventional XRT, which deposits energy along its path through the body, protons have a distinct physical characteristic known as the Bragg peak. This peak allows protons to release the majority of their energy directly at the tumour site with minimal dose to the surrounding healthy tissue.2 This precise dose distribution can result in reduced side effects and improved treatment outcomes, particularly for tumours located near critical structures or in paediatric patients.3 CIT can produce sharper dose gradients than PBT and has an increased biological effect for a given physical dose, however, generates more secondary radiation in the form of neutrons and nuclear interaction by-products than PBT. PBT is viewed as particularly advantageous for paediatric and adolescent young adult (AYA) patients, given their developing organs’ heightened sensitivity to radiation-induced damage.4
In preparation for the opening of Australia’s first particle therapy centre, an application was made to the Medical Services Advisory Committee (MSAC) to have PBT listed on the Medicare Benefits Schedule (MBS). MSAC is an Australian national medical service approving body which provides advice to the Australian Government on whether new medical services should be publicly funded using the best available evidence to determine if the new medical service is comparatively safe, cost effective and clinically effective.5 The MSAC application included a committee review and appraisal process on the population, intervention, comparator and outcomes of PBT.6 During the application process, MSAC recognised the uncertainties in cost-utility modelling of PBT, as outlined in the Public Summary Document, Application No. 1638—PBT for paediatric and rare cancers.7 Considering this, MSAC recommended the establishment of a national registry for particle therapy to provide further evidence regarding the claim of PBT’s superior toxicity outcomes compared with conventional XRT.
Following thorough consultation and a comprehensive review of international registries dedicated to gathering data on cohorts receiving photon and particle therapy, the Australian Particle Therapy Clinical Quality Registry (ASPIRE) was established. This international collaboration assisted not only in registry design but also enabled invaluable insights to be gained from tried experience and allowed leveraging of data-linkage opportunities in the future.
The focus of ASPIRE is on rare tumours, with a nationwide scope, making it a crucial contributor to global evidence on XRT versus PBT treatment outcomes. It represents Australia’s first clinical quality registry dedicated to collecting radiation oncology-specific data, adding significant value to the understanding and advancement of particle therapy within the Australian cohort.
Methods and analysis
Registry design
ASPIRE is a prospective, observational, longitudinal study of paediatric, AYA and adult patients with rare tumours from MBS-eligible disease indications treated with radiation therapy. The study is designed to describe and compare the patterns of care for patients receiving either XRT or PBT. The primary objective is to describe long-term effects and disease control outcomes with a specific focus on toxicity event types as described in tables 1 and 2.
Toxicity event types (adult)
Toxicity event types (paediatric/adolescent young adult (AYA))*
There is no limit to enrolment in the registry and enrolment will continue indefinitely or until the study is terminated.
The ASPIRE protocol design has been reported in accordance with the Standard Protocol Items: Recommendations for Interventional Trials checklist in order to provide an evidence-based framework and address the minimum set of items that should be described when producing a research study protocol.8
Accessibility to PBT across Australia will include collaboration with multiple treatment centres across various states and territories, including the use of telehealth and referral networks to ensure patients from remote or underserved areas can access PBT.
All enrolled participants will receive treatment and follow-up care according to the standard of care at their respective treating institution, as determined by their primary clinician. Participants will remain enrolled in the registry and be followed until their withdrawal of consent, termination of the registry or their demise. It is anticipated that there will be no potential selection bias, as all eligible participants will be recruited into the registry unless they choose to opt out.
The estimated annual participant accrual onto the registry is based on the analysis conducted for the MSAC 1638 application, as well as the model developed to predict the associated public hospital care requirements for patients during PBT9:
25 years—adult: 180 patients per annum.
≤25 years—paediatric/AYA: 265 patients per annum.
Adults are considered 26 years or older, AYA 15–25 years and paediatric 1 month to 14 years at time of diagnosis.10
Eligibility criteria
All adult, AYA and paediatric patients diagnosed with an MBS-approved tumour type, as outlined in the Public Summary Document, Application No. 1638—proton beam therapy for paediatric and rare cancers7 treated with curative intent radiation therapy will be eligible for recruitment.
Participant recruitment
The preferred method for identification of eligible patients is either the International Statistical Classification of Diseases and Related Health Problems (ICD) codes relevant to the MBS-approved tumour types or by cancer diagnosis.11 All radiation oncology departments operate using an oncology information system; these systems allow reports to be generated to determine eligible patients using either an ICD code or by diagnosis. Eligible patients will be identified as per each site and their preferred system reports. Registry education is provided in scheduled appointments with either medical, nursing or allied health staff. An information pamphlet is provided to eligible participants with registry information and relevant opt-out consent information by trained staff on their first day of treatment. The use of an ‘opt out’ consent model is consistent with comparable registries in Australia, as data collected will not exceed data routinely available to clinicians in order to manage patients treated with radiation therapy. Data stored at the coordinating centre will be handled by highly trained staff in an established health and medical research institute.
The National Health and Medical Research Council’s National Statement on Ethical Conduct in Human Research states that a waiver of consent (opt out consent model) can be applied to prospective collection in certain circumstances with population registries an example of this, especially in cases where the research or data collected are considered low risk and of significant benefit, but it is impractical to obtain consent from the large numbers of people whose data will be included.12
Receipt of patient education and participant information will be recorded by site staff completing the ‘ASPIRE Registration Form’ on the registry.
Should there be no opt-out notification from participants within 14 days of enrolment, the project/research team or treating institution will incorporate all patient dataset items into the registry. For participants electing to opt out, the registry will document their decision, precluding the recording of any further information.
Minimum data elements
A modified Delphi study was undertaken to inform the registry’s minimum data elements (MDEs). This approach is widely recognised as a gold-standard structured communication technique for achieving consensus, which relies on an expert panel to answer a research question.13 14 The MDEs obtained from the modified Delphi study were combined with a review of the national minimum data sets as set out in the Australian Metadata Online Repository, which details standards for the collection of Australian metadata for a number of different sectors, including health15 along with the 27 MDEs quantified in the Delphi study.
The Delphi study was completed in three stages, starting with a review of current operational international proton therapy registries. Core data items from each of the registries were recorded. Further consensus agreement on MDE were determined via an online survey poll from members of the Royal Australian and New Zealand College of Radiologists (RANZCR) Particle Therapy Working Group and a live poll conducted at the 2022 RANZCR annual scientific meeting.16
This design supports a disciplined approach to the development, storage and management of the data ASPIRE will collect, while also ensuring that the registry has compliance with international information modelling standards, allowing for future data linkage.
Data collection
ASPIRE will use the web-based electronic data collection system—Research Electronic Data Capture (REDCap).17 18 Each recruiting site will designate data managers who will be tasked with overseeing participant recruitment, appointments and maintain accurate records within the registry. These data managers will be granted secure, password-protected individual access to the centralised REDCap database located at the coordinating centre. Each site will be granted access to their respective data; for access to deidentified data from other regions, they will need to submit requests through the ASPIRE National Steering Committee, with oversight from the Trans-Tasman Radiation Oncology Group (TROG Cancer Research).
The registry will collect all treatment information from the participants’ medical records. This includes any surgery, immunotherapy and chemotherapy (systemic therapy) for the initial treatment and any follow-up therapies the participant may receive as part of their cancer treatment. The outcomes of treatment including side effects, disease response, disease progression, further treatment and survival will also be recorded. These data sets will provide a thorough overview of the participants’ treatment and outcomes.
Participant data will be collected at baseline, at the completion of their radiation therapy and annually thereafter and recorded directly onto REDCap by data managers at each participating site.
Data managers are provided with training in the necessary MDEs and given a data management guide that can be used as a future resource on any of the MDEs. Site principal investigators (PIs), data managers and registry staff at any recruiting sites have regular contact, via meetings with the ASPIRE Working Group. A PI from each participating site is expected to attend quarterly ASPIRE National Steering Committee meetings and site-specific data managers attend monthly data management meetings with the ASPIRE Project Manager. Attendance at these meetings ensures collaboration, consistency with data capture and provides reporting and feedback opportunities on the data collected.
The ASPIRE registry has been meticulously designed to ensure a uniform approach to data management by incorporating standardised data entry elements such as drop-down responses, minimising the use of free text, and employing branching logic to ensure data are consistently formatted. Reporting within the registry is managed through REDCap, which supports regular data cleansing processes to maintain high data quality and reliability.
The ASPIRE registry maintains follow-up data through yearly updates from medical records and late effects or survivorship clinics, ensuring comprehensive long-term monitoring. Future developments for the registry include the introduction of patient-reported outcomes, further enriching the dataset and enhancing the understanding of treatment impacts from the patient’s perspective.
Registry auspices and data custodians
South Australian Health and Medical Research Institute (SAHMRI), as the data custodians of ASPIRE, ensures both effective data management and long-term sustainability through its integration with the SAHMRI Registry Centre of Excellence. This national data asset is well supported within SAHMRI, a leading medical research institute, where custodianship is established both nationally and within a robust health and medical research framework. By being part of SAHMRI’s network, which includes some of Australia’s most significant national registries, ASPIRE not only ensures efficient management but also maximises its impact on improving the quality of care and health outcomes for Australians.
ASPIRE also benefits from its collaboration with TROG Cancer Research, Australia’s leading clinical trial group focused on radiation medicine and improving cancer outcomes. This partnership enhances ASPIRE’s ability to drive advancements in cancer treatment through evidence-based research and ensure national oversite of the registry.
Data management and quality assurance
The computing facilities at SAHMRI are part of a password-secured and firewall-protected system. Raw and collected research data will be stored in secure firewall, password-protected electronic files. Every participant will be assigned a unique identifier number. Deidentified Digital Imaging and Communications in Medicine treatment plan data for ASPIRE will be stored on the ProKnow cloud-based software (Elekta Solutions AB, Stockholm, Sweden).19
Ethics and dissemination
The ASPIRE protocol, approved under the National Mutual Agreement by the Central Adelaide Local Health Network Human Research Ethics Committee—HREC: 2021/HRE00394, is guided by the ASPIRE National Steering Committee to ensure rigorous, ethically sound data collection and continuous quality monitoring.
ASPIRE will enrol participants nationwide to build a real-world dataset, enhancing insights into cancer treatment burden, and outcomes for tumours treated with radiation therapy.
Dissemination will include publications in peer-reviewed journals, conference presentations and public deidentified aggregate data sharing, advancing PBT and supporting evidence-based practices in radiation oncology across Australia.
National steering committee
The registry’s continuous evolution and direction are overseen by the ASPIRE National Steering Committee whose membership originates from various Australian states and territories. This collective contains a broad range of expertise, including consumer advocates, representatives from entities such as TROG, The Hospital Research Foundation Group and clinicians and researchers who specialise in both radiation and paediatric oncology.
The committee convenes regularly, marking its timelines with discernible progress in numerous pivotal arenas. This committee has achieved significant milestones in its work, such as developing clear terms of reference, implementing measures to ensure privacy and data accuracy while also enabling researcher access. Additionally, a comprehensive national recruitment framework has been thoughtfully constructed.20
The committee’s focal objectives underscore a steadfast commitment to the vigilant tracking of scientific progress via the registry. This responsibility encompasses the assurance of data integrity, the promotion of efficient data collection methodologies, and the provision of precise interpretation of the amassed data, thus facilitating evidence-based decision-making in the domain of radiation oncology.
Patient and public involvement
The ASPIRE participant information sheet was provided to patients with lived radiotherapy experience for review at the drafting stage.
The feedback provided by these consumer advocates demonstrated their experiences, priorities and preferences to inclusions in the participant information sheets including language, level of understanding and comprehension.
A consumer advocate is an entrusted member of our ASPIRE National Steering Committee having lived proton therapy experience. They have actively participated in drafting the terms of reference for the committee. Through regular attendance at meetings, they collaborate with other members to ensure the registry is aligned with organisational and national strategies, assess registry progress and report on registry outcomes to relevant stakeholders and participate in determining registry goals and provide much needed feedback on the patient experience.
Discussion
The initiative to secure public funding through Australia’s MBS marked a significant step forward in enhancing access to PBT for particular cancer types. This move was not without its challenges, notably the uncertainties voiced by MSAC about the cost-utility modelling of PBT. The ensuing discussion explores the broader landscape of radiation therapy services in Australia and the vital role of the proposed national registry in addressing these uncertainties.
In Australia, radiation therapy services are provided by both public and private providers. As per established protocols, every centre is mandated to submit fundamental radiation therapy details to the respective cancer registries of each state or territory. When national data are sought, the Australian Institute of Health and Welfare partners with the cancer registries across jurisdictions to assemble a comprehensive national dataset.
While the state/territory cancer registries receive rudimentary treatment data, individual radiation therapy centres maintain more comprehensive records of patient treatment and follow-up data. However, there is notable variation among centres in terms of quality of treatment data recorded and the type of follow-up for specific indications. This variation in the levels and length of follow-up presents numerous challenges in collecting useful data to inform evidence-based participant outcomes, especially in the survivorship space.
The establishment of a national registry would enable a standardised approach to data collection. This would involve capturing MDEs with a particular focus on documenting both short-term and long-term toxicities and outcomes of radiation therapy. By implementing such a registry, uniformity in data collection can be achieved, facilitating better understanding of treatment outcomes and toxicities across the country. As of now, the treatment data recording and follow-up practices vary greatly among individual radiation therapy centres. This discrepancy can result in an uneven distribution of treatment quality and healthcare resources. A national registry would encourage a level playing field, where each patient’s treatment and follow-up are tracked and managed with equal diligence, irrespective of their treatment centre.
The registry will provide yearly statistics relating to case accrual and outcomes to State and Federal Department of Health Services and authorities. A more detailed written report will be provided on an annual basis to clinicians, participating hospitals and their ethics committees. Six monthly quality assurance reports will be prepared for meetings of the ASPIRE Steering Committee and TROG Cancer Research. Organisations, including commercial ventures, providing funding to the registry will also receive a formal written report on an annual basis including aggregate data reports and analysis of participants included in the registry.
In addition to the online hospital data reports, communication will be maintained with stakeholders, consumers via regular newsletters, emails and an annual PI’s meeting.
Moreover, the proposed national registry should not be considered merely a tool for uniform data collection and reporting. It is intended to enable a more collaborative environment in the radiation therapy field. Regular newsletters, emails and an annual PI’s meeting are expected to maintain communication with stakeholders and consumers. This constant interaction will create a two-way flow of information and foster a sense of community and shared purpose among those involved. Stakeholders can gain insights into the broader picture, patients can feel more engaged and the research community can benefit from shared knowledge.
Lastly, the national registry holds promise in unlocking new avenues of clinical research and innovation.
Governance
This project will be carried out according to the National Statement on Ethical Conduct in Human Research (2007) incorporating all updates. This statement has been developed to protect the interests of people who agree to participate in human research studies. The registry has been approved under the National Mutual Agreement by the Central Adelaide Local Health Network Human Research Ethics Committee—HREC: 2021/HRE00394.
Registry status
The ASPIRE registry is currently recruiting participants. The registry is endorsed and registered with the Trans-Tasman Radiation Oncology Group—TROG Cancer Research—TROG 21.12—ASPIRE.
Ethics statements
Patient consent for publication
Acknowledgments
We would like to acknowledge and thank the TROG Scientific Committee for reviewing and providing feedback on the registry protocol. We would also like to acknowledge and thank the ASPIRE National Steering Committee for their ongoing commitment to the registry. Study data collected on ASPIRE will be managed using Research Electronic Data Capture (REDCap) electronic data capture tools hosted at SAHMRI. REDCap is a secure, web-based application designed to support data capture for research studies, providing (1) an intuitive interface for validated data entry; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for importing data from external sources.
Footnotes
Contributors All authors made substantial contributions to the development and writing of the manuscript. KS, as the guarantor, was responsible for the conception and design of the study, coordinating contributions from the author team and ensuring the integrity of the work. PG, SP, AM, DH, AY, SJ, EH, JD and HL participated in drafting and revising the manuscript and provided final approval of the version to be submitted for publication. All authors agree to be accountable for all aspects of the work and ensure that any questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding This work is supported by the Hospital Research Foundation Group under Grant number: 2021/44-QA25310. The funding source had no influence of the design of the registry or the minimum data elements included.
Competing interests None declared.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review Not commissioned; externally peer reviewed.