Periodic Reporting for period 1 - PROTECT-trial (Proton versus Photon Therapy for Esophageal Cancer - a Trimodality Strategy)
Berichtszeitraum: 2021-07-01 bis 2022-12-31
Proton Therapy (PT) has the potential to reduce the adverse effects of radiation therapy and provide better outcomes for cancer patients. However, the clinical evidence supporting its value is still low. Despite a large increase in the number of PT facilities worldwide in the last two decades, there are no reliable data from long-term randomized controlled trials on survival, quality of life, or functional capacity of patients who underwent PT compared with any other treatment modality for any adult cancers. Since PT is currently presumed to be more expensive than conventional photon therapy with x-rays (XT), it is of utmost importance that robust data are generated to justify its use and make it more accessible cancer patients. The first objective for the PROTECT-trial consortium is to provide evidence for the benefits of using PT versus XT in patients with esophageal cancer and hereby expand the use of PT. This requires execution of a phase III randomized clinical trial in a curative trimodality regime with a sufficient patient population to provide robust data. This curative regime includes substantial side-effects from the different treatment modalities, hence a strong quality assurance program for surgery and radiation therapy is crucial to set apart the side effects originating from radiotherapy. To insure a strong recruitment base, the trial was setup as an international multisite study with expected participation of many sites across eight Europe countries. The consortium will address four objectives: 1) Conduct a phase III randomized clinical trial, 2) Provide a measure of cost effectiveness of PT, 3) Compare the randomized trial methodology to other methodologies e.g. model-based clinical evaluation, 4) Generate outreach to stakeholders to promote knowledge of patient selection criteria for PT.
The PROTECT clinical trial protocol was completed and added to online trial registries for visibility. The study protocol also included complete Quality Assurance for RadioTherapy (RTQA) and Surgery, which represents two ambitious instruments for obtaining robust and aligned treatment across all participating sites. Together with the ethical approval, these deliverables were the backbone of the first clinical package sent to all principal investigators in the eight countries. A reviewer group with consortium members was established to implement the RTQA guidelines and review patient treatment. The RTQA group has already completed the QA process at five sites and has published the results in peer-reviewed journals. Likewise, a Surgical QA reviewer group with two external surgeons was established. These will monitor all surgical procedures with the aim of ensuring the highest possible surgical standards throughout the study.
The Clinical Trial Office (CTO) has been setup and has implemented the e-CRF, which collects all clinical patient data entered by the participating sites. The e-CRF was developed on the REDCap platform. To establish compliance between protocol and eCRF and to ensure robust data collection, several partners conducted tests and provided feedback. Through online sessions, the CTO has initiated sites in three countries, and the first patient was enrolled into the PROTECT study in August 2022. Nine patients are active in the study per end 2022.
To assess the cost effectiveness of PT relative to XT for the treatment of esophageal cancer and the access and inequalities of PT, a questionnaire of patient reported outcome measures from standardized questionnaires was produced. Additionally, a resource use questionnaire was designed to understand the cost of delivering PT and XT from a broad perspective. An English version was circulated to partners, and translations along with health care provider specific adaptions are now available for Belgium, Netherlands, Germany, Italy, France and Switzerland. The resource use questionnaire was converted into a dynamic questionnaire, from which questionnaires are sent out automatically to the patients.
To test if our randomised trial provides similar outcome results as the model-based clinical evaluation, the consortium includes three Dutch PT sites conducting a prospective data registration study using model-based selection. The Dutch sites have already included more than 300 patients, surpassing their initial goal.
Outreach activities have been segmented into three parts: 1) Develop a collaborative network of patient and public contributors from different participating countries to embed Patient and Public Involvement in the conduct of the PROTECT-trial activities and support broad dissemination of study results, 2) Liaise with the multidisciplinary professional community, professional societies, industry and other professional stakeholders, to ensure that the goal of the industry of profitability expansion of PT matches the ethic of preserving patient’s best interests. The impact of the proposed collaborative model will be assessed in the various healthcare heterogeneous ecosystems for potential modification of the cancer management strategy on a European level, 3) Maintain an active communication channel with the European commission, and to maximize disseminations activities at conferences and to the public in general.
The patient involvement has established groups in five countries of the consortium. Based on patient feedback, an English information sheet associated with the trial was created and included in the clinical package to the local sites for them to translate into relevant languages. Additionally, a patient infographic that is easily translatable to explain and promote the trial was created with the help of industrial partner IBA. This infographic will be used on our website and as patient handouts. Two patient representatives have also been attending the monthly PROTECT-trial executive meetings to provide input into governance, management, and delivery of the study. PROTECT-trial has created a stakeholder forum with the industry and COCIR and has showcased the PROTECT study and consortium at the Annual Meetings of EPTN, PTCOG and ESTRO. PROTECT was present at ESTRO21 and ESTRO22 conferences with poster and oral presentation, and a physical roll-up in the community networking area. The first PROTECT physical meeting was held at ESTRO22, with 40 people attending a three-hour session on progress in the consortium and with an invited speaker on relevant translational research using circulation tumor DNA. PROTECT-trial has actively used Twitter to promote the consortium.
The Clinical Trial Office (CTO) has been setup and has implemented the e-CRF, which collects all clinical patient data entered by the participating sites. The e-CRF was developed on the REDCap platform. To establish compliance between protocol and eCRF and to ensure robust data collection, several partners conducted tests and provided feedback. Through online sessions, the CTO has initiated sites in three countries, and the first patient was enrolled into the PROTECT study in August 2022. Nine patients are active in the study per end 2022.
To assess the cost effectiveness of PT relative to XT for the treatment of esophageal cancer and the access and inequalities of PT, a questionnaire of patient reported outcome measures from standardized questionnaires was produced. Additionally, a resource use questionnaire was designed to understand the cost of delivering PT and XT from a broad perspective. An English version was circulated to partners, and translations along with health care provider specific adaptions are now available for Belgium, Netherlands, Germany, Italy, France and Switzerland. The resource use questionnaire was converted into a dynamic questionnaire, from which questionnaires are sent out automatically to the patients.
To test if our randomised trial provides similar outcome results as the model-based clinical evaluation, the consortium includes three Dutch PT sites conducting a prospective data registration study using model-based selection. The Dutch sites have already included more than 300 patients, surpassing their initial goal.
Outreach activities have been segmented into three parts: 1) Develop a collaborative network of patient and public contributors from different participating countries to embed Patient and Public Involvement in the conduct of the PROTECT-trial activities and support broad dissemination of study results, 2) Liaise with the multidisciplinary professional community, professional societies, industry and other professional stakeholders, to ensure that the goal of the industry of profitability expansion of PT matches the ethic of preserving patient’s best interests. The impact of the proposed collaborative model will be assessed in the various healthcare heterogeneous ecosystems for potential modification of the cancer management strategy on a European level, 3) Maintain an active communication channel with the European commission, and to maximize disseminations activities at conferences and to the public in general.
The patient involvement has established groups in five countries of the consortium. Based on patient feedback, an English information sheet associated with the trial was created and included in the clinical package to the local sites for them to translate into relevant languages. Additionally, a patient infographic that is easily translatable to explain and promote the trial was created with the help of industrial partner IBA. This infographic will be used on our website and as patient handouts. Two patient representatives have also been attending the monthly PROTECT-trial executive meetings to provide input into governance, management, and delivery of the study. PROTECT-trial has created a stakeholder forum with the industry and COCIR and has showcased the PROTECT study and consortium at the Annual Meetings of EPTN, PTCOG and ESTRO. PROTECT was present at ESTRO21 and ESTRO22 conferences with poster and oral presentation, and a physical roll-up in the community networking area. The first PROTECT physical meeting was held at ESTRO22, with 40 people attending a three-hour session on progress in the consortium and with an invited speaker on relevant translational research using circulation tumor DNA. PROTECT-trial has actively used Twitter to promote the consortium.
It is too early report on progress beyond state of the art and socio-economic impact, since the clinical study and most other activities around the study are only in their initial phases. The RTQA publication on comparison of radiotherapy dose plans in esophageal cancer has highlighted an urgent need for better and more aligned dose-planning guidelines among the European radiotherapy sites. This also emphasise the importance of this ambitious RTQA program in conjunction with the PROTECT study. The expectation of the PROTECT-trial consortium is that its activities will provide statistically robust results at a high level of clinical evidence and thereby providing the best possible background for an international change in clinical practice for esophageal cancer patients and beyond, and ensure that radiotherapy treatment being offered to patients is more consistent across European, being XT or PT.