Objectives The WP will be responsible for the following aspects of scientific trial:

• Trial governance
• Protocol writing
• Supervise QA procedures
• Supervise and support institutions in recruitment of patients
• Lead committee activities 
• Follow-up of patient recruitment
• Supervise reporting of data

Description of work

• Task 1.1: Trial governance (M1-72) Lead partner AUH. Participants: KULeuven
  •  Scientific governance of the RCT including TMC, TSC
• Task 1.2: Clinical study protocol (M1-2) Lead partner: AUH. Participants: KULeuven, UMCG, UCL, HPTC, TUD, PSI, MAASTRO, CNAO, APSS, CAL, IC, CLB.
  • Final version of the clinical study protocol
  • Registration number of the study in an approved registry (ClinicalTrials.gov)
• Task 1.3: Ethical approval of the protocol (M3-4) Lead partner: AUH. Participants: KULeuven, UMCG, UCL, HPTC, TUD, PSI, MAASTRO, CNAO, APSS, CAL, IC, CLB.
  • Obtain ethical approval of the trial protocol at all participating centers
  • Distribute the protocol to all participating centers, support local ethical and legal approval, with WP2
• Task 1.4: Initiation of study (M4-8) Lead partner: AUH. Participants: KULeuven, UMCG, UCL, HPTC, TUD, PSI, MAASTRO, CNAO, APSS, CAL, IC, CLB
  • Initiation of study at participating departments, in collaboration with WP2, WP3, WP4, WP6.
• Task 1.5: Recruitment, treatment and data reporting (M5-72) Lead partner: AUH. Participants: KULeuven, UMCG, UCL, HPTC, TUD, PSI, MAASTRO, CNAO, APSS, CAL, IC, CLB
  • Continuous patient inclusion in trial.
  • Patient treatment according to protocol. 
• Task 1.6. Analysis and reporting of outcome (M50-66) Lead AUH. Participants KULeuven, UNIVLEEDS, UMCG, AU.
  • Interpreting and reporting based on WP 5 statistical analysis of outcome when the last patient has reached the time of primary endpoint (further follow-up and analyses will be conducted up to five years after the last patient has been included)
  • Analysis of dose response for the two dose levels and relation between observed toxicity, initial NTCP and dose to organs at risk (with WP3).

Deliverables

• D1.1*: A study protocol for a non-blinded multi-center RCT (M2)
• D1.2*: Registration of study in an approved registry (M2)
• D1.3: Manuscript with results of the study submitted to peer reviewed journal (M66)  

Objectives

To establish a system for data collection (e.g. case report form, CRF), continuous data monitoring and data export. Daily clinical trial and data management, conduct QA procedures at the clinical trial unit, point of contact for trialists, independent data monitoring committee (IDMC), assign independent experts and patient representatives. All according to Good Clinical Practice. 

Description of work

• Task 2.1: Collect and communicate regulatory approval documents (M3-4) Lead partner: AU.
  • Approach PIs and National coordinators for approval documents obtained from Health Authorities, Ethics Committees and Data Protection Agencies prior trial initiation (with WP1 and WP11)
  • First study subject approvals package to EU (prior to enrolment of first study subject), containing:
  • Final version of study protocol as approved by first regulator / ethics committee(s)
  • Registration number of the clinical study in ClinicalTrials.gov
  • Approvals required for invitation / enrolment of first subject in at least one clinical center: ethics committees, national competent authorities and copies of opinion or confirmation by the competent Institutional Data Protection Officer and/or authorization or notification by the National Data Protection Authority with its opinion/confirmation that all data collection and processing will be carried out according to EU and national legislation
  • Communication with regulatory authorities related to amendments (with WP1 and WP11)
  • Communication of valid approvals to participating sites.
  • Authorization of approvals from participating countries, in cooperation with the Research Support Office, AU (WP11)
  • Initiation of centers.
• Task 2.2: Trial management (M1-72) Lead partner: AU. Participants: AUH 
  • Coordination of trial set-up, contracts with sites, keep log of trial staff at participating centers (delegation log)
  • Maintenance protocol updates and manage trial documents (site files)
  • Daily advice to recruiting sites, continuous communication of project activities
• Task 2.3: Data management (M1-72) Lead partner: AU. Participants: AUH
  • Establish system for randomization • Configuration, development, update and maintenance of database for electronic data collection (eCRF). • Continuous data monitoring, data set validation and data export
  • Recruitment reports, data collection reports, query and missing data reports to CI and TMC
  • Prepare final dataset collected and reported in compliance with FAIR principles
• Task 2.4 Midterm Recruitment Report to EU (M30-32) Lead partner: AU. Participants: AUH
  • Mandatory report to be scheduled for the time point when 50% of the study population is expected to have been recruited. The report will include an overview of recruited subjects by study site, potential recruiting problems and, if applicable, a detailed description of implemented and planned measures to compensate delays in the study subject recruitment
• Task 2.5: Support patient inclusion (M5-M40) Lead partner: AU. Participants: AUH
  • Online registration and randomization
  • Supervision of sites
  • Offline backup procedure
• Task 2.6: Safety (M5-M72) Lead partner: AU. Participants: AUH
  • Handling Serious Adverse Events Reporting as reported from the participating centers 
  • Offline backup procedures
  • Annual Safety Reports, data monitoring and audits, risk assessment

Deliverables

• D2.1*: First study subject approvals package (M4)
• D2.2*: Midterm recruitment report to EU (M32)
• D2.3*: A final dataset collected and reported in compliance with the FAIR principles, with WP1, WP3, WP4, WP5, WP7 (M72) 

Objectives 

To develop and supervise the radiation therapy QA program, i.e.

• Ensure consistently high quality of treatment preparation and delivery.
• Secure adherence of treatment procedures with main protocol and XT and PT QA guidelines.
• Develop sub-studies related to radiotherapy data, e.g. dose response.
• Report results to all participating centers during inclusion period and publish outcome.

Description of work

• Task 3.1: Radiation therapy QA protocol (M1-4) Lead partner: AUH. Participants: AU, UMCG, MAASTRO, Varian.
  • Distribute atlas for target and organs at risk delineations based on literature review and pre-trial comparative delineations in a subset of centers.
  • Configuration, regulatory approval, and maintenance of electronic platform for radiation therapy QA, including dose plan bank.
  • Analyze retrospective data for the effect of respiratory motion and inter-fractional changes on delivered dose. The retrospective analysis has been initiated and is based on a large imaging database at AUH. The data set will further be used to investigate strategies for patient set-up
  • Compare dose plans from a subset of centers and use output to optimize the QA guidelines to ensure robustness of plans towards respiration and anatomical changes before trial initiation. This work has been initiated in six centers.
  • Develop state-of-the-art PT and XT guidelines covering all aspects of the treatment procedure, including the following requirements:
  • Time-resolve 4D-CT scan for treatment planning. For all patients treated at a PT center, the CT calibration curve should adhere to the center’s best possible standard. Site specific calibration curves based on thorax sized phantom measurements and beam hardening corrections should be used if it results in more correct dose calculation.
  • Advanced dose calculation algorithms accounting for inhomogeneities (Monte Carlo, Acuros, AAA, Collapsed Cone or equivalent).
  • Advanced planning techniques such as IMRT (XT), VMAT (XT) or IMPT (PT).
  • Adherence to strict constraints on target coverage and organs at risk for treatment plan. Identical constraints for PT and XT.
  • Requirement of evaluation of the effect of respiratory motion, and setup and range uncertainties for both XT and PT for nominal treatment plan. Adherence to the constraint for target coverage is mandatory.
  • For all patients, both XT and PT plans including evaluation of robustness must be made.
  • Validation of the daily treatment position. The validation must be based on evaluation of the tumor position on daily CT or cone-beam CT scans or implanted fiducial markers in or nearby the tumor visualized on daily kV imaging.
  • A strategy for treatment adaptation if deviations are observed.
  • Acquisition of a 4D-CT scan at fraction 5,10,15. The treatment plan must be recalculated on these scans and dose to target and selected organs at risk must comply with strict constraints. If the constraints are not fulfilled, the treatment plan should be adapted to the anatomical changes which have occurred.
  • Robust optimization for PT. PTV margin or robust optimization for XT.
• Task 3.2: Initiation of radiation therapy QA program (M1-4) Lead partner: AUH. Participants: AU, UMCG.
  • Secure that all centers complete a facility questionnaire, a dosimetry audit, five delineation benchmark cases and four treatment planning benchmark cases before entering the trial. Only after successful compliance can a center start patient inclusion in the trial.
• Task 3.3: Supervise on-trial radiation therapy QA program (M5-66) Lead partner: AUH. Participants: AU, UMCG.
  • Appoint a QA group consisting of QA chairs and a QA manager from AUH and 3-4 radiation oncologists (RO) and 3-4 medical physicists (MP) from different European centers. This group will perform QA site visits, continuous QA and arrange yearly workshops.
  • Arrange on-site QA visit when a center has included the first two patients and go through all steps related to treatment planning and delivery. One RO, one MP and the QA manager will perform the site visits in order to minimize the workload and speed up the QA process.
  • Conduct individual case review (ICR) for first two and every fifth patient enrolled in the trial based on patient scans, delineations and treatment plans uploaded to the trial database. Give feedback and request changes in case of deviation from protocol.
  • Arrange yearly workshops where participants from all centers will discuss treatment of selected retrospective patients • Secure that all centers, irrespective of PT or XT center, will receive on-site visit and ICR.
  • Secure that the QA procedure is identical for all centers and that the compliance is independent of the center being a PT or XT center.
  • Secure that all scans, delineations and treatment plans are uploaded to the dose plan bank and make the data available for studies related to the trial, e.g. dose response analysis, dose accumulation strategies, retrospective bulk segmentation of additional organs at risk, etc.
  • Monitor individual patient comparative XT and PT dose planning; summarize results as part or standard on-trial reporting of radiotherapy QA to TSC and IDMC and highlight any variations likely to impact the trial outcome.
• Task 3.4: Radiation therapy QA reports and manuscript (M5-60) Lead partner: AUH. Participants: AU, UMCG.
  • Report delineation guidelines and pre-trial comparative delineations and planning studies.
  • Investigate optimal set-up strategy and report the results.
  • Determine the impact of respiration, set-up uncertainties, and anatomical changes on treatment delivered by the two modalities.
  • Report findings on the full set of uploaded dose plans and delineations from all participating centers after trial closure.
  • Manuscript with main results of QA experience submitted to peer review journal.

Deliverables

• D3.1: Protocol for radiation therapy QA (M3)
• D3.2: Electronic platform for radiation therapy QA (M3)
• D3.3: Annual QA workshops for all centers (M15, M27, M39)
• D3.4: Manuscript with main results of QA experience submitted to peer review journal (M66). 

Objectives

To develop a QA program to secure accurate and complete recording of surgical aspects in the trial. Quality of the surgical act as such and the recording of complications is of the utmost importance, as surgery is the most invasive and potentially most critical cause of severe and potentially lethal morbidity/mortality. Quality of the surgical act will be evaluated based on surgical criteria (operating notes, in-operation pictures to define extent of surgery) and pathologic criteria (completeness of resection, number of lymph nodes resected/lymph node stations explored [40, 41].

Description of work

• Task 4.1: Surgery QA preparation (M1-4) Lead partner: KULeuven. Participants: AUH, UCL
  • Describe recording system for operation technique, extent of lymph node dissection and location of anastomosis. Include in-operation pictures as documentation of extent of surgery/quality of surgery (especially lymph node dissection)
  • Describe recording system for the postoperative complications according to ECCG/Esodata definitions and CCI scoring system [35, 42]
  • Describe recording system for final pathologic examination
  • Review cases operated in participating centers before start of trial as quality control check
  • QA approval of recruiting centers (surgery) with review of volume (based on database report) and quality of surgery (review of in-operation pictures of patients operated before start of trial. (M3).
• Task 4.2: Supervise on-trial surgery QA (M5-46) Lead partner: KULeuven. Participants: AUH, UCL
  • Close monitoring of complications occurrence in comparison with ECCG rates (with WP1 and WP2) • Review of in-operation pictures as quality control (KULeuven-UCL-AUH)
  • Annual reports on surgery QA.
• Task 4.3: Analyze dataset and create final QA report (M50-60) Lead partner: KULeuven. Participants: AUH, UCL
  • Analyze and report findings of the surgery QA recordings in final report, including recurrence in/out of surgical field, and location of anastomosis relative to the irradiated volume and anastomotic leakage.

Deliverables

• D4.1: Protocol with definition of dataset for surgery and pathology, data entry module for surgical technique, postoperative complications, and pathology, with WP2 (M3)
• D4.2: Annual surgery QA reports (M12,24,36,48)
• D4.3: Manuscript with main results of surgery experience submitted to peer review journal (M66). 

Objectives

Ensure high quality clinical trial methodology including study design, contributions to developing and writing the appropriate sections in the protocol, monitoring study conduct, developing the statistical analysis plan (SAP), writing the final statistical report and interpreting the study results. Provide ongoing statistical monitoring of the study including reviewing treatment balance within the strata, monitoring compliance, adherence to treatment, rate of events and completeness of data. Provide summary reports to the trial leadership and providing appropriate reports and statistical commentary to the Independent Data Monitoring Committee. Deliver final statistical analysis/report to address the study questions required in publications of the primary and secondary endpoints. Provide statistical advice/leadership on all aspects of the methodological science of the trial.

Description of work

• Task 5.1: Pre-trial initiation and trial set-up related tasks (M1-4) Lead partner: UNIVLEEDS
  • Deliver statistical input to the statistical methods within the trial protocol, including description & definition of trial endpoints, methods of randomization, and methodological aspects of data analysis & interpretation (intention-to-treat, handling of missing data, extent of follow-up, treatment of protocol deviations/withdrawals etc.). Identification of important subgroups and outline of proposed analysis methods.
  • Review and approve trial protocol prior to first clinical research ethics committee submission.
  • Review and approve CRFs to ensure that data collection will allow evaluation of trial endpoints and safety.
  • Review and approve randomization module, including stratification methodology.
• Task 5.2: Statistical on-trial overview (M5-40) Lead partner: UNIVLEEDS
  • Provide regular reports to the Trial Steering Committee and the Independent Data Monitoring Committee, including overview of recruitment rates, safety data (SAEs), lack of protocol adherence (particularly rates of patients not progressing to surgery), comparative dose plan data, and completeness of trial data In collaboration with trial leadership, review and if necessary update trial design in case of major changes to standard-of-care.
  • In collaboration with CIs review and if necessary, update trial design in case of major changes to standard-of-care.
• Task 5.3: Final analysis (M50-72) Lead partner: UNIVLEEDS
  • Prior to unblinding of the study results, develop a statistical analysis plan as the cornerstone of the final statistical report and for approval by the Trial Steering Committee.
  • Following final patient inclusion and end of data collection for primary endpoint, oversee data cleaning and produce final statistical analysis and commentary to support primary trial publication.

Deliverables

• D5.1:Full statistical analysis plan for all primary and secondary endpoints (but excluding planned translational research, and any QoL and health economics analyses) (M42).
• D5.2: Final statistical analysis report with a statistical commentary on the interpretation of the results (M66). 

Objectives

• Develop a collaborative network of Patient and Public contributors from different participating countries.
• Embed Patient and Public Involvement (PPI) in the conduct of the PROTECT activities supporting the study.
• Support widespread dissemination of trial results and outcomes including on Patient Reported Outcome Measures (PROMs).

Description of work

We have identified the potential representatives from participating centers and aspects of involvement that would be attractive for PPI. Patients and contributors from partner countries, with comparable backgrounds to patients eligible for the PROTECT study, will be identified and invited to participate.

• Task 6.1: Pre-study activation of patients (M1-4) Lead partner: UCL. Participants: AUH.
  •  Name Patient Involvement Lead & groups in different participating countries
  •  Create a new virtual network of patient, public and clinician collaborators with representation from major European PT centers utilizing links from existing patient networks such as national esophageal cancer patients groups, UK NCRI (National Cancer Research Institute) consumer groups and European Cancer Patient Coalition (ECPC).
  • Undertake focus group meetings (via videoconference) with patients in different countries. Topics covered will include patient perception of PT (to ensure patient equipoise), potential barriers to trial entry, feedback on logistics (e.g. travel and accommodation at proton beam centers) and discussions on potential translational research. Focus group participants will form the core PPI contributors throughout the duration of the study. Feedback and input into any patient-fronted materials (including written information sheets and multi-media content).
  • PROMs: Review of validated Health-related Quality of Life questionnaires to increase acceptability and patient compliance.
• Task 6.2: During study activation of patients (M5-49) Lead partner: UCL. Participants: AUH, Varian, IBA
  • Invite patient representatives to provide input into governance, management, and delivery of the study
  • PPI groups in different countries to review yearly ongoing progress (incl. patient experience), discussing possible protocol/pathway amendments including recommendations to improve recruitment
  • PPI groups promote engagement by disseminating study information through patient networks and organizations (e.g. support groups), social media to facilitate recruitment
  • Annual newsletter to update patients and other stakeholders of trial progress and milestones
  • Patient information materials, including easily translatable multi-media content to explain and promote the trial, and patient handouts.
• Task 6.3: Post-Study Reporting (M50-72) Lead partner: UCL. Participants: AUH, Varian, IBA.
  • Contribute to analysis and interpretation of data on PROMs and PPI activities
  • Post-trial patient information materials including easily translatable multi-media content to help disseminate trial outcomes through patient networks and associations.

Deliverables

• D6.1: Patient information materials, including easily translatable multi-media content to explain and promote the trial, and patient handouts (M6)
• D6.2: During trial patient information materials including easily translatable multi-media content to explain and promote the trial and patient handouts for focus groups every 18 months (M18)
• D6.3: Post-trial patient information materials including easily translatable multi-media content to help disseminate trial outcomes (M66) 

Objectives

To assess the cost effectiveness of PT relative to XT for the treatment of esophageal cancer and the access and inequalities of PT, and to develop an HTA model, which is adaptable to different country settings.

Description of work

Short- and long-term economic, clinical, patient-related, and organizational aspects will be studied. Parameters relating to resource use, cost and health related quality of life will be collected and used to estimate cost effectiveness within the trial. Evidence from the literature will supplement the trial findings, and cost effectiveness beyond the trial will be estimated. We will additionally assess patient access to PT and any potential effects on health inequalities.

• Task 7.1: Estimate the cost-effectiveness based on trial data (M50-72) Lead partner: UCL. Participants: HollandPTC, AU, IBA.
  • Develop Health Economics Analysis Plan
  • Collect data for cost estimation: healthcare resource use, patient and family costs, caregiver or companion costs, and productivity losses will be collected as part of the eCRF. Value health care resource use by applying national reference costs or where these are not available undertake primary costing studies. Aggregate costs at a patient level to estimate the average costs of PT and XT from a health care and societal perspective
  • Outcomes analysis: Collect patient reported and clinical outcomes: health related quality of life (EQ-5D-5L, EQ-VAS, EORTC QLQ-C30), other PROMs/PREMs (as determined in WP6), and toxicity, tumor control, response, disease-free survival and overall survival will be collected as part of the eCRF. Collected at baseline and various follow-up points, the EQ-5D-5L will be used to estimate quality adjusted life years (QALYs) over time.
  • Estimate incremental cost effectiveness ratios (ICER), cost per QALY gained, cost per complication avoided, and cost per total toxicity burden avoided.
  • Perform health technology assessment (HTA) to support evidence-based decision making and aid the efficient allocation of scarce resources.
• Task 7.2: Lifetime cost-effectiveness and HTA model (M12-60) Lead partner: HollandPTC. Participants: UCL, AU.
  • Develop conceptual health economic model.
  • Estimate lifetime cost effectiveness using the health economic model to extrapolate outcomes from the trial (Task 7.1) to a lifetime horizon as required by reimbursement agencies. The model will estimate ICERs for the cost per life-year gained and the cost per QALY gained.
  • The model can be used for cost-effectiveness analysis as required by HTA agencies for reimbursement of PT.
• Task 7.3: Patient access and health inequalities (M12-48) Lead partner: UCL. Participants: HollandPTC, AU.
  • Analyse data on patient access to PT consider patient characteristics such as sociodemographic variables (age, gender, employment status), geographic region and insurance status as collected in eCRF.
  • After local approval, data from cancer registries (e.g. in the United Kingdom and Netherlands) will be used to compare patient characteristics and outcomes of the trial patients to the patient population in clinical practice.  

Deliverables

• D7.1: Report on resource use and cost aspects of PROTECT from a health care and societal perspective and health related quality of life (M72)
• D7.2: Decision analytic model (demonstrator) to assess the cost-effectiveness of PT relative to XT for esoph-ageal cancer as per requirements of HTA agencies (including training and upskilling industry partners) (M42)
• D7.3: Report describing assessment of long-term cost-effectiveness of PT (M72)
• D7.4: Report on patient sociodemographic characteristics, accessibility, and any potential health inequali-ties/inequities (M48)  

Objectives

To describe, coordinate and facilitate collaboration within translational research among PROTECT participants and beyond. In addition to mandatory banking of blood samples at the participating partner sites, projects could include optional development of: predictive imaging biomarkers (e.g. correlation of FDG-PET/CT image features with locoregional control and functional tests of pulmonary or cardiac toxicity), models of Relative Biological Effectiveness (RBE), comparison of (adapted) treatment plans for all patients for both modalities, comparison of treatment plan quality with protons or photons and correlation with treatment outcome, and assessment of target motion using e.g. implanted fiducial markers.

Description of work

• Task 8.1: Instructions for blood and tissue sample banking (M1-3) Lead partner: TUD. Participants: AUH, KULeuven, AU
  • Create instructions for blood (incl. serum, plasma) banking at the participating partner sites as mandatory part of the clinical protocol to be followed
  • Create instructions for optional tumor tissue and liquid biopsy banking (e.g. saliva).
• Task 8.2: Create and maintain inventory of optional translational research (M1-39) Lead partner: TUD. Participants: AUH, KULeuven, AU
  • Create inventory of optional translational research portfolio including the leading partner site, the participating partner sites and the project status (planned, conducted, finished, published) to be shared among PROTECT participants.
• Task 8.3: Facilitate collaboration and funding (M1-M60) Lead partner: TUD. Participants: AUH, KULeuven, AU, UMCG, UNIVLEEDS, UCL, HollandPTC, PSI, MAASTRO, Varian, IBA
  • Facilitate collaboration and funding through seminars, focus groups and other means, preferably to be held during annual conferences, e.g., ESTRO or PTCOG.

Deliverables

• D8.1: Instructions for blood and tissue sample banking (M2)
• D8.2: Inventory of translational research projects (M6)
• D8.3: Annual translational research updates, seminars and workshops (M12, 24, 36, 48) 

Objectives

To liaise with the multidisciplinary professional community, professional societies, industry and other professional stakeholders. To assure that the primary goal of the industry of profitability expansion of PT matches the primary ethic of health professionals in preserving patient’s best interests and mitigate any strategic divergence among the industrial partners. To maximize the output of the proposed collaborative model to exploit fully the impact of the study for the role of PT in oncology. In the latter objective, to assess the potential impact of the outcome of the PROTECT study in the various healthcare heterogeneous ecosystems and the implementations of the potential modification of the cancer management strategy on a European level. To list the industries’ deliverables within the framework of the PROTECT project

Description of work

• Task 9.1: Foster European PT clinical research eco-system (M1-60) Lead partner: PSI. Participants: AU, UMCG, CLB.
  • Using the European Particle Therapy Network, further networks and activities will be catalyzed that will foster clinical PT research (M1-60).
• Task 9.2: Establish industry relations to support evidence generation (M1-39) Lead partner: PSI. Participants: AU, UMCG, CLB, IBA, Varian.
  • Build adherence to secure relations with industry, software developers and vendors, to motivate their active participation in generation of high-quality data in the field of PT (M1-M39).
• Task 9.3: Create multi-stakeholder collaborations (M1-60) Lead partner: PSI. Participants: AU, UMCG, CLB, Varian, IBA.
  • Use the study to create joint innovative approaches to address the key challenges of PT through multi-stakeholder collaborations, including vendors, scientific and professional community, patients, payers, HTA bodies, EU (M1-39).
• Task 9.4: Strategic alignment of COCIR industry (M40-72) Lead partner: IBA. Participants: Varian.
  • Assess the impact of the PROTECT study for the non-participating industry and detail the mitigation strategy of strategic non-alignment of PROTECT’s industrial partners (M40-60).
• Task 9.5: Plan how the results can be implemented in European PT (M40-72) Lead partner: PSI. Participants: AU, UMCG, CLB, Varian, IBA.
  • Use the outcome of PROTECT to create plans for how the results can impact and be implemented in European PT and the national European lists of indications for PT (M40-60)

Deliverables

• D9.1: Annual meeting with EPTN and other networks, societies, and industry. (M5, 17, 29, 41, 53) D9.2: COCIR organized meeting to drive active dissemination of results to relevant authorities, e.g. healthcare providers, societies, HTA bodies, payers (M54) 

Objectives

To test the hypothesis that an RCT and model-based clinical evaluation (innovative trial methodology) provide similar outcome regarding the ability of protons to reduce acute and late radiation-induced toxicity. The ultimate objective is:

1) To reach international consensus on which methodology is most suitable to select patients for proton therapy.

2) To evaluate if the added value of PT can be tested with model-based clinical evaluation as well.

Description of work

• In the Netherlands, an alternative methodology has been developed to select patients for PT and to validate the benefit of protons over photons: the so-called model-based approach (MBA). The MBA is an alternative evidence-based methodology designed to yield evidence for a more rational selection of patients who would most likely derive clinically relevant benefits from PT in terms of prevention of radiation-induced toxicity. The rationale behind the MBA is that PT will only result in broadening the therapeutic window by decreasing toxicity, when three essential requirements are met: (1) the dose to the target is equivalent to photons and considered current standard (similar local control); (2) normal tissue sparing can be obtained with protons compared to photons (ΔDose), and (3) ΔDose results in a clinically significant lower complication risk (or else lower normal tissue complication probability (ΔNTCP)).
• Task 10.1: Prepare MBA/MBCE data set (M42-49) Lead partner: UMCG. Participants: HollandPTC, MAASTRO. Patients treated with PT in the Netherlands are subjected to a national Model-Based Clinical Evaluation (MBCE) program. Of these patients, a subset who meets the same eligibility criteria as defined for PROTECT will be identified retrospectively, after obtaining the necessary national regulatory approval. • The data set will be selected using an MBA NTCP-model for the primary endpoint of the PROTECT RCT, i.e. pulmonary complications after neo-adjuvant chemoradiation. All other pre-treatment characteristics, fractionation, chemotherapy regimens and prospective assessments are similar to the PROTECT RCT. Based on our current prospective data registration program, we expect that around 215 MBA cases will meet the eligibility criteria of the trial in a 3-year recruitment period in the centers that use model-based selection, while the power calculation indicates a required number of patients of 200 (alfa = 0.05 and power = 0.80). to show a difference of 11% for of the incidence of pulmonary complications during and following chemoradiotherapy and surgery (up to 90 days post-surgery) between the observed rate with protons versus the expected rate based on the background photon plan. Patient cases included in this analysis will have been subjected to similar QA programs for XT, PT and surgery as applied in the PROTECT RCT.
• Task 10.2: (M52-M58): Compare MBCE and PROTECT RCT (M50-66) Lead partner: UMCG. Participants: AU, AUH, KULeuven, UNIVLEEDS, UCL, HollandPTC, TUD, PSI, MAASTRO • For all patients included in this Model-Based Clinical Evaluation (MBCE) study, a comparison between the photon plan and the proton plan is made, resulting in a corresponding NTCP-profile for protons and photons and a ΔNTCP-profile (NTCPprotons- NTCPphotons). • When the ΔNTCP-profile meets the criteria of the national indication protocol, patients are treated according to the proton arm of the RCT (41.4 Gy). In an MBCE-trial, the observed rates of toxicity among patients treated with PT will be compared with the expected average NTCP-values based on the photon plans. In this design, each patient is its own control. As in the RCT, both photon plans and proton plans are made, the same selection procedure can be retrospectively done in the patients treated in the RCT, which will result in a model-based enriched RCT-population that forms the basis for the MBCE (lower panel Figure 6). • Ultimately, the outcome and conclusions of the MBCE will be compared with the outcome of the enriched subpopulations of the RCT. This procedure will be done for the primary endpoint of the RCT as well as for other toxicity endpoints.
• Task 10.3.: Innovative PT trial methodologies consensus (M54-M72) Lead partner: UMCG. Participants: AU, AUH, KULeuven, UNIVLEEDS, UCL, HollandPTC, TUD, PSI, MAASTRO, CLB, IBA, Varian • Based on the experience and findings of the joint analysis (Task 10.2) and other emerging experience and methods, a consensus report on innovative PT trial methodologies and their future use will be produced and presented.

• Figure 6: Outline of the study design of the model-based clinical evaluation (MBCE) study (lower panel)

Deliverables

• D10.1. Report on MBCE and PROTECT joint analysis (M59)
• D10.2* Manuscript describing a proposal for a European methodology for multi-center clinical trials in PT submitted (M72) 

Objectives

• Ensure timely and structured execution of the project according to the work plan
• Report project progress to the European Commission. 

Description of work

• Task 11.1: Project management (M1-72) Lead partner: AU. Participants: AUH, KULeuven, UMCG, UCL, HPTC, TUD, PSI, MAASTRO, CNAO, APSS, CAL, IC, CLB, Varian, IBA.
  • Establish management structure as described in section 3.2.
  • Prepare Consortium Agreement to be signed during kick-off meeting.
  • Organize all project meetings, incl. kick-off and meetings of organizational bodies.
  • Internal and external communication efforts to ensure constant dialogue and communication across the consortium. Communication with the European Commission will solely be handled by the Coordinator. This includes preparation and submission of cost statements and progress reports to the EC
  • Monitor project planning, achievement of milestones and deliverables, as well as specific project activities, method transfer and assistance to other partners in activities.
  • Monitor overall project progress, quality of data and inter-work package alignment.
  • Coordinate work packages together with WP leaders based on progress and output.
  • Guide the process of addressing ethical issues • Resolve conflicts within the consortium
• Task 11.2: Financial management (M1-72) Lead partner: AU. Participants: AUH, KULeuven, UMCG, UCL, HPTC, TUD, PSI, MAASTRO, CNAO, APSS, CAL, IC, CLB, Varian, IBA.
  • Monitor the budget status in line with the overall budget and with the Grant Agreement.
  • Propose budget amendments in case of significant changes to the work plan and timing.
  • Transfer of payments from the EC to consortium members. This will be done by the Coordinator in accordance with the Grant and the Consortium Agreement.
  • Report the status of the budget and effected payments to the Project Coordinator, Management Board and Consortium Council.
  • Provide certified financial statements for submission to the EC.
  • Final financial report to European Commission.
• Task 11.3: Risk Management (M1-72) Lead partner: AU. Participants: AUH, KULeuven, UMCG, UCL, HPTC, TUD, PSI, MAASTRO, CNAO, APSS, CAL, IC, CLB, Varian, IBA.
  • Activities will be carried out to monitor, prevent, and mitigate project risks. The Coordinator and The Project Management Team will manage a) regulatory risks, b) project management risks (deliverables, milestones, conflict mediation between partners), and C) safety management risks.
• Task 11.4: Data and IPR management (M1-72) Lead partner: AU. Participants: AUH, KULeuven, UMCG, UCL, HPTC, TUD, PSI, MAASTRO, CNAO, APSS, CAL, IC, CLB, Varian, IBA.
  • Draft a data management plan for the project, including a long-time storage and archiving strategy that will be actualized in the Data Management Plan (with WP2 and WP5)
  • Identify and handle IPR related issues.
  • Identify and earmark outputs for valorization and exploitation.
• Task 11.5: Communication & dissemination strategy (M1-5) Lead partner: AU. Participants: AUH, KULeuven, UMCG, UCL, HPTC, TUD, PSI, MAASTRO, CNAO, APSS, CAL, IC, CLB, Varian, IBA.
  • Create guidelines for Communication and dissemination activities.
  • Develop a dissemination toolkit (D11.5) incl. the project’s corporate identity and templates for presentations, reports, posters, external & internal documents.
  • Establish a project website (D11.6) to present developments and achievements.
  • Develop a sound social media strategy considering the most appropriate platforms (e.g. Twitter, LinkedIn) and decide how best to exploit existing channels of partners, related initiatives, and projects.
  • Distribute a Plan for the Dissemination and Exploitation of project results (D11.4), summarizing communication and dissemination activities.
• Task 11.6: Dissemination of outcome (M50-72) Lead partner: AU. Participants: AUH, KULeuven, UMCG, UCL, HPTC, TUD, PSI, MAASTRO, CNAO, APSS, CAL, IC, CLB, Varian, IBA.
  • Organize, support and supervise dissemination of project results.
  • Active dissemination to relevant authorities, e.g. healthcare providers, societies, HTA bodies, payers.
• Task 11.7: Report on status of posting results to EU (M66-72) Lead partner: AU. Participants: AUH, KULeuven, UMCG, UCL, HPTC, TUD, PSI, MAASTRO, CNAO, APSS, CAL, IC, CLB, Varian, IBA.
  • Mandatory report on the status of posting results in the study registry (including timelines when final posting of results is scheduled after end of funding period). The report is scheduled for the last months of the project.

Deliverables

• D11.1: Project handbook, including timeline for meetings, reporting and related activities (M2).
• D11.2*: Data and IPR Management Plan (M5).
• D11.3: Risk management plan (M1).
• D11.4: Dissemination and Exploitation Plan (M5)
• D11.5: External project webpage (M5).
• D11.6: Dissemination toolkit (M6).
• D11.7: General Assembly (M18,36,54,72).
• D11.8: Progress report to the European Commission (M30).
• D11.9: Dissemination, publications & conference presentations on the results of the study (M72).
• D11.10*: Final (financial) report to the European Commission (M72).
• D11.11*: Report on status of posting results to EU (M72) 

Objectives

The objective is to ensure compliance with the 'ethics requirements' set out in this work package.

Description of work

This work package sets out the 'ethics requirements' that the project must comply with.

Deliverables

• D12.1: H - Requirement No. 1
• D12.2: HCT - Requirement No. 2
• D12.3: POPD - Requirement No. 3
• D12.4:  EPQ - Requirement No. 4
• D12.5: GEN - Requirement No. 5