Periodic Reporting for period 2 - PROTECT-trial (Proton versus Photon Therapy for Esophageal Cancer - a Trimodality Strategy)
Reporting period: 2023-01-01 to 2024-06-30
Proton Therapy (PT) holds promise for reducing the adverse effects of radiation therapy and improving outcomes for cancer patients. However, the clinical evidence supporting its efficacy remains limited. Despite a significant increase in PT facilities globally over the past two decades, there is a lack of reliable data from long-term randomized controlled trials (RCTs) on survival, quality of life, or functional capacity of patients treated with PT compared to other treatment modalities for adult cancers. Given that PT is currently considered more expensive than conventional photon therapy with X-rays (XT), it is crucial to generate robust data to justify its use and enhance its accessibility for cancer patients.
The primary goal of the PROTECT-trial consortium is to provide evidence for the benefits of PT versus XT in patients with esophageal cancer, thereby expanding the use of PT. This necessitates the execution of a phase III randomized clinical trial within a curative trimodality regime, involving a sufficient patient population to yield robust data. This curative regime includes substantial side effects from the different treatment modalities, making a strong quality assurance program for surgery and radiation therapy essential to distinguish the side effects originating from radiotherapy.
To ensure a strong recruitment base, the trial is designed as an international multisite study, with expected participation from numerous sites across seven European 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, such as model-based clinical evaluation, and 4) Generate outreach to stakeholders to promote knowledge of patient selection criteria for PT.
The primary goal of the PROTECT-trial consortium is to provide evidence for the benefits of PT versus XT in patients with esophageal cancer, thereby expanding the use of PT. This necessitates the execution of a phase III randomized clinical trial within a curative trimodality regime, involving a sufficient patient population to yield robust data. This curative regime includes substantial side effects from the different treatment modalities, making a strong quality assurance program for surgery and radiation therapy essential to distinguish the side effects originating from radiotherapy.
To ensure a strong recruitment base, the trial is designed as an international multisite study, with expected participation from numerous sites across seven European 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, such as model-based clinical evaluation, and 4) Generate outreach to stakeholders to promote knowledge of patient selection criteria for PT.
The PROTECT clinical protocol has been published and submitted to an online trial registry. The study has also been presented at several conferences and meetings to maximize visibility. Currently, the PROTECT study is active and has enrolled 45 patients at clinical sites in Denmark, Belgium, and Switzerland. Four additional countries—Germany, Italy, France, and Norway—are in the process of initiation and are expected to start between late 2024 and spring 2025.
A RadioTherapy Quality Assurance (RTQA) reviewer group, consisting of consortium members, was established to implement RTQA guidelines and review patient treatments. This ambitious initiative aims to ensure robust and consistent treatment across all participating sites. The RTQA group has completed the QA process at six proton sites and their corresponding photon sites, with results published in peer-reviewed journals, providing new insights into standardized treatment across sites and countries. Additionally, a Surgical QA reviewer group, including two external surgeons, was established to continuously monitor surgical quality and collaborate with participating surgeons. Three annual reports on surgical quality have been produced. The main coordination of the study is managed by the Clinical Trial Office (CTO), which has initiated five sites and performed centralized monitoring of all active patients to ensure complete and accurate data. The CTO has also compiled safety reports for the ethical board and the independent data and safety monitoring board.
The Health Economics workgroup is focused on evaluating the cost-effectiveness of PT compared to XT for esophageal cancer treatment, addressing access and inequalities of PT, and developing a versatile Health Technology Assessment (HTA) model. They have translated the PROTECT study Resource Utilization Questionnaire (RUQ) and adapted it for several European countries, with Norway set to join in early 2025. The Health Economics workgroup has established a network with universities in London, Rotterdam, and Auckland, and assigned a PhD student to aid in HTA model development. Their progress and models were presented at the second Trial Investigator Group meeting.
To determine if our randomized trial yields similar outcomes to the model-based clinical evaluation, the consortium includes three Dutch PT sites conducting a prospective data registration study using model-based selection. These Dutch sites have already enrolled over 450 patients, exceeding their initial target. Preliminary data from one PT site was presented at ESTRO2024, and a publication is currently being drafted.
Outreach activities have been divided into three main objectives:
1. Develop a Collaborative Network: Establish a network of patient and public contributors from various participating countries to integrate Patient and Public Involvement in the PROTECT trial activities and support the broad dissemination of study results. The patient involvement group held regular meetings with their patient representatives. Two of these representatives are members of the PROTECT-trial Executive Committee, providing input on the study's governance, management, and delivery. The PROTECT patient infographic, developed with patient input and designed with help from IBA, was added to the trial's homepage. It was also redesigned into a poster format for translation into other languages, enhancing visibility at local sites and conferences.
2. Engage with Professional Stakeholders: Collaborate with the multidisciplinary professional community, societies, industry, and other stakeholders to ensure that the industry's goal of expanding PT profitability aligns with the ethic of preserving patients' best interests. The impact of this collaborative model will be assessed across different healthcare systems in Europe to potentially modify cancer management strategies. The PROTECT project, including stakeholder involvement from industry and the EU, was showcased at major PT and XT meetings in Europe, such as the Annual Meetings of EPTN, PTCOG, and ESTRO. Dissemination and outreach activities were recorded by WP11 and presented to the Executive Committee, where industry representatives were present. The PROTECT study has been highlighted through 18 dissemination activities, including posters, publications, oral presentations, meetings, and workshops.
3. Maintain Active Communication Channels: Keep an active communication channel with the European Commission and maximize dissemination activities at conferences and to the public. PROTECT-trial has been present at ESTRO since 2021 with posters and presentations. A twiiter (X) channel with +90 followers supoorts this effort to ensure visibility for the consortium and the clinical study.
A RadioTherapy Quality Assurance (RTQA) reviewer group, consisting of consortium members, was established to implement RTQA guidelines and review patient treatments. This ambitious initiative aims to ensure robust and consistent treatment across all participating sites. The RTQA group has completed the QA process at six proton sites and their corresponding photon sites, with results published in peer-reviewed journals, providing new insights into standardized treatment across sites and countries. Additionally, a Surgical QA reviewer group, including two external surgeons, was established to continuously monitor surgical quality and collaborate with participating surgeons. Three annual reports on surgical quality have been produced. The main coordination of the study is managed by the Clinical Trial Office (CTO), which has initiated five sites and performed centralized monitoring of all active patients to ensure complete and accurate data. The CTO has also compiled safety reports for the ethical board and the independent data and safety monitoring board.
The Health Economics workgroup is focused on evaluating the cost-effectiveness of PT compared to XT for esophageal cancer treatment, addressing access and inequalities of PT, and developing a versatile Health Technology Assessment (HTA) model. They have translated the PROTECT study Resource Utilization Questionnaire (RUQ) and adapted it for several European countries, with Norway set to join in early 2025. The Health Economics workgroup has established a network with universities in London, Rotterdam, and Auckland, and assigned a PhD student to aid in HTA model development. Their progress and models were presented at the second Trial Investigator Group meeting.
To determine if our randomized trial yields similar outcomes to the model-based clinical evaluation, the consortium includes three Dutch PT sites conducting a prospective data registration study using model-based selection. These Dutch sites have already enrolled over 450 patients, exceeding their initial target. Preliminary data from one PT site was presented at ESTRO2024, and a publication is currently being drafted.
Outreach activities have been divided into three main objectives:
1. Develop a Collaborative Network: Establish a network of patient and public contributors from various participating countries to integrate Patient and Public Involvement in the PROTECT trial activities and support the broad dissemination of study results. The patient involvement group held regular meetings with their patient representatives. Two of these representatives are members of the PROTECT-trial Executive Committee, providing input on the study's governance, management, and delivery. The PROTECT patient infographic, developed with patient input and designed with help from IBA, was added to the trial's homepage. It was also redesigned into a poster format for translation into other languages, enhancing visibility at local sites and conferences.
2. Engage with Professional Stakeholders: Collaborate with the multidisciplinary professional community, societies, industry, and other stakeholders to ensure that the industry's goal of expanding PT profitability aligns with the ethic of preserving patients' best interests. The impact of this collaborative model will be assessed across different healthcare systems in Europe to potentially modify cancer management strategies. The PROTECT project, including stakeholder involvement from industry and the EU, was showcased at major PT and XT meetings in Europe, such as the Annual Meetings of EPTN, PTCOG, and ESTRO. Dissemination and outreach activities were recorded by WP11 and presented to the Executive Committee, where industry representatives were present. The PROTECT study has been highlighted through 18 dissemination activities, including posters, publications, oral presentations, meetings, and workshops.
3. Maintain Active Communication Channels: Keep an active communication channel with the European Commission and maximize dissemination activities at conferences and to the public. PROTECT-trial has been present at ESTRO since 2021 with posters and presentations. A twiiter (X) channel with +90 followers supoorts this effort to ensure visibility for the consortium and the clinical study.
It is still too early to report on progress beyond the current state-of-the-art and socio-economic impact, as the clinical study and most related activities are only in their initial phases. However, the RTQA publication comparing radiotherapy dose plans for esophageal cancer has highlighted an urgent need for improved and more consistent dose-planning guidelines across European radiotherapy sites. This underscores the importance of the ambitious RTQA program in conjunction with the PROTECT study.
The PROTECT-trial consortium expects that its activities will yield statistically robust results with a high level of clinical evidence. This will provide a strong foundation for international changes in clinical practice for esophageal cancer patients and beyond, ensuring that radiotherapy treatments, whether XT or PT, are more consistent across Europe.
The PROTECT-trial consortium expects that its activities will yield statistically robust results with a high level of clinical evidence. This will provide a strong foundation for international changes in clinical practice for esophageal cancer patients and beyond, ensuring that radiotherapy treatments, whether XT or PT, are more consistent across Europe.