Preklinisch onderzoek

De drie protonencentra werken, zowel zelfstandig als binnen nationale en internationale samenwerkingsverbanden, aan diverse preklinische onderzoeksprojecten op het gebied van protontherapie. Deze projecten richten zich op fysica, radiobiologie en een combinatie hiervan. Het fysisch onderzoek draagt bij aan de verdere ontwikkeling en optimalisatie van protontherapie, terwijl het radiobiologisch onderzoek meer inzicht geeft in de effecten van protonen op tumoren en gezond weefsel. Hieronder worden de verschillende onderzoeksprojecten binnen beide onderzoeksgebieden toegelicht.

Fysica

Protonentherapie maakt het mogelijk om de stralingsdosis zeer gericht aan de tumor toe te dienen en tegelijkertijd de dosis in omliggend gezond weefsel zoveel mogelijk te beperken. Dit komt door de specifieke fysische eigenschappen van protonen: zij geven het grootste deel van hun energie af op een bepaalde diepte in het lichaam, rond de zogenoemde Bragg-piek. Deze eigenschap biedt belangrijke voordelen, maar stelt ook hoge eisen aan de nauwkeurigheid waarmee de behandeling wordt gepland en uitgevoerd.

Fysisch onderzoek richt zich daarom op het verder verbeteren van de precisie, betrouwbaarheid en effectiviteit van protonentherapie. Daarbij wordt onderzocht hoe de toegediende dosis zo nauwkeurig mogelijk kan worden berekend, gemeten en gecontroleerd, hoe veranderingen in anatomie en beweging tijdens de behandeling kunnen worden opgevangen en hoe beeldvorming kan worden ingezet om de behandeling beter af te stemmen op de individuele patiënt. Ook nieuwe technologieën, behandeltechnieken en methoden voor behandelplanning spelen hierin een belangrijke rol.

Door ontwikkelingen op het gebied van beeldvorming, dosimetrie, adaptieve radiotherapie, behandeling van bewegende tumoren, modellering en kunstmatige intelligentie te combineren, kan protonentherapie steeds nauwkeuriger en robuuster worden toegepast. Het uiteindelijke doel is de stralingsdosis in gezond weefsel verder te verminderen, onzekerheden tijdens de behandeling te beperken en waar mogelijk de effectiviteit van de behandeling te vergroten.

Binnen DUPROTON wordt fysische en technologische expertise van de drie Nederlandse protonencentra samengebracht. Door gezamenlijk nieuwe methoden en technologieën te ontwikkelen, testen en evalueren, draagt het fysisch onderzoek bij aan de verdere ontwikkeling en optimalisatie van protonentherapie en aan de vertaling van technologische innovaties naar de klinische praktijk.

Onderzoeksgebieden

Enhancing the value of proton therapy through the development and implementation of new technologies and methodologies, including advanced pre- and intra-treatment imaging, online treatment plan adaptation, motion management, artificial intelligence (AI), and automated and probabilistic treatment planning.
 

Researchers: Prof. M.S. Hoogeman (HPTC), Prof. Dr. S. Both (UMCG), Prof. dr. C.R.A. Rasch (LUMC), Prof. dr. B. Heijmen (Erasmus MC), dr. ir. M. Staring (LUMC), dr. A. Vilanova (TU Delft), dr. R. van Egmond (TU Delft), dr. Z. Perkó (TU Delft), dr. ir. D. Schaart (TU Delft) 
 

Consortia and studies to highlight

  • Fully-automated multi-criterial planning for intensity-modulated proton therapy for clinical practice

    Principal Investigators: Prof. dr. C.R.A. Rasch (LUMC), Prof. dr. B. Heijmen (Erasmus MC)

    Funding: HollandPTC-Varian 2019

    Summary: This project aims to develop and validate fully automated, multi-criterial, and robust treatment planning for intensity-modulated proton therapy (IMPT). Current IMPT planning relies on a time-consuming trial-and-error process that can lead to suboptimal plans, high workload, and variability due to planner experience. The project builds on the proven iCycle autoplanning optimizer, which has been extensively validated for photon therapy. New functionality will be added to enable automated beam angle selection for proton therapy while accounting for treatment robustness. The goal is to improve plan quality, consistency, and efficiency for clinical IMPT planning.

     

  • Human-centric AI for contouring in head-and-neck cancer therapy 

    Principal Investigators: Dr. ir. M. Staring (LUMC), dr. A. Vilanova (TU Delft), dr. R. van Egmond (TU Delft)

    Funding: HollandPTC-Varian 2019

    Summary: This project aims to develop human-centric deep learning methods for rapid and accurate segmentation of tumors and organs-at-risk in head-and-neck cancer. An initial AI model automatically generates contours, after which clinicians provide limited feedback in areas requiring attention. A second AI model incorporates this feedback to refine the segmentation, with the process repeated until clinically acceptable results are achieved. By combining AI and targeted human input, the workflow avoids time-consuming manual contouring. The approach is expected to substantially improve delineation efficiency and quality assurance in image-guided online adaptive proton therapy (IGOAPT).

     

  • Improved healthy-tissue sparing by automated daily online plan adaptation in proton therapy for head and neck cancer 

    Principal Investigators: Prof. dr. M. Hoogeman (Erasmus MC), dr. Z. Perkó (TU Delft) 

    Funding: HollandPTC – Varian 2018

    Summary: The project’s goal is to reduce the probability of side effects in Proton Therapy for head and neck cancer by investigating and clinically implementing automated daily online plan adaptation. A successful implementation will provide the means to very precisely target the tumour to potentially escalated doses and to maximally avoid organs-at-risk.

     

  • Cone-beam spectral CT: enabling in-situ adaptation in proton therapy

    Principal Investigator: Dr. ir. D. Schaart (TU Delft) 

    Funding: HollandPTC – Varian 2018

    Summary: The main objective is to initiate a research program targeted at the development, implementation, and clinical validation of cone-beam spectral CT (CBSCT) as an ideal image guidance modality for image-guided online-adaptive proton therapy.

     

  • PEARL: Precision of proton therapy increased by advanced robustness analysis

    Principal Investigator: Prof. dr. M. Hoogeman (Erasmus MC), dr. Z. Perkó (TU Delft) 

    Funding: KWF 2017

    Summary: PEARL aims to increase the precision of IMPT by providing end users (e.g. radiation oncologists) the practical tools to optimally balance tumor control probability and dose conformity in the presence of residual treatment uncertainties. This goal will be achieved by engaging specialists from TU Delft who are working at the forefront of state-of- the- art robustness analysis in radiotherapy, (medical) experts in IMPT treatment plan optimization, and end users of IMPT.

FLASH radiotherapy (FLASH-RT) is an emerging irradiation technique that delivers radiation at ultra-high dose rates. Compared with conventional radiotherapy, FLASH-RT has demonstrated the potential to lessen radiation-related damage to normal tissues while maintaining comparable anti-tumor efficacy.

Within DUPROTON and the individual centers we focus on understanding, developing and clinically testing ultra-high dose rate proton therapy, with a specific focus on the FLASH effect.
 

Consortia and studies to highlight

  • Flash beyond doubt, and beyond

    Developing and clinically preparing advanced FLASH proton therapy strategies to extend its potential to deep-seated tumours while reducing normal tissue effects

    Principal Investigator: Dr. S. Habraken (Erasmus MC), Dr. ir. D. Schaart (TU Delft), Prof dr. C.R.N. Rasch (LUMC), Prof. dr. M. Hoogeman (HollandPTC)

    Funding: HollandPTC-Varian 2020

    Summary: Despite the precision of proton therapy, treatment-related side effects remain a challenge. FLASH radiotherapy, which delivers high doses at ultrahigh dose rates, has shown the potential to reduce normal tissue toxicity by up to 30–40% without compromising tumor control, thereby widening the therapeutic window. However, current FLASH techniques are largely limited to superficial tumors. Because proton beams can achieve FLASH dose rates while reaching deep-seated targets, FLASH proton therapy (FLASH-PT) offers a promising route for clinical translation. This project aims to advance FLASH-PT by developing gated delivery, clinically realistic treatment planning and robustness evaluation, independent dose-rate monitoring, and biological optimization strategies for both transmission and Bragg-peak proton beams.

     

  • Towards FLASH proton therapy for breast cancer

    Principal Investigators: Prof. dr. ir. R.P. Coppes (UMCG) and Prof. S. Both (UMCG)

    Co-investigator: Dr. L. Barazzuol (UMCG)

    Funding: IBA

    Summary: Ultra-High Dose Rate proton therapy (UHDR-PT) is the irradiation of subjects using dose rates ≥40 Gy/s. UHDR-PT is observed to elicit the FLASH effect, a reduction of normal tissue complications while maintaining tumour control. Mammary cancer is one of the most prevalent cancer types in the world. The FLASH effect has the potential to significantly reduce healthy tissue complications, and paired with a single fraction of proton therapy may be able to fully control early stage mammary tumours. Additionally, the reduction of irradiation time combined with possibility to hypo-fractionate warrants a significant improvement in patient quality of life and proton center patient throughput. Thus, we aim to investigate if (single fraction) UHDR-PT is a suitable treatment methodology for early-stage mammary cancers.

Proton Arc Therapy (PAT) is a new modality undergoing rapid development in which proton radiation is delivered from a large number of gantry angles. Therefore providing greater flexibility in treatment planning than conventional IMPT, and potentially allow for the generation of more favorable dose distributions.

Research focuses on optimizing beam configurations and delivery techniques and evaluating whether PAT can further improve dose distributions while reducing exposure to healthy tissues. Consequently, it is evaluated whether the fraction of patients that qualify for proton therapy according to the MBA increases with PAT compared to IMPT.
 

Researchers: Prof. dr. S. Both (UMCG), dr. ir. E. Korevaar (UMCG), dr. J. Free (UMCG), dr. B.A. de Jong (UMCG)
 

More information to follow.


Researchers: Prof. Dr. S. Both, Dr. ir. E. Korevaar, Dr. L.V. van Dijk

Relevante links

 Radiobiologie

Protonentherapie wordt steeds vaker toegepast bij de behandeling van uiteenlopende vormen van kanker. De techniek maakt het mogelijk om de stralingsdosis nauwkeurig aan de tumor toe te dienen, terwijl de blootstelling van omliggend gezond weefsel zoveel mogelijk wordt beperkt. De biologische mechanismen die ten grondslag liggen aan de respons van tumoren, schade aan gezond weefsel en verschillen tussen patiënten zijn echter nog niet volledig bekend.

In tegenstelling tot conventionele bestraling met röntgenstraling heeft protonenbestraling een karakteristiek diepte-dosisprofiel, waarbij de maximale energieafgifte plaatsvindt nabij het einde van het bereik van de protonen, de zogenoemde Bragg-piek. Hierdoor kunnen ook de biologische effecten langs de protonenbundel variëren, bijvoorbeeld in de aard en omvang van DNA-schade en in de activatie van immuunresponsen. Eerder onderzoek heeft deze verschillen in relatieve biologische effectiviteit (RBE) op verschillende posities langs de protonenbundel onderzocht.

Ons onderzoek richt zich op het ontrafelen van de radiobiologische effecten van protonenbestraling, het optimaliseren van combinaties met andere behandelingen, in het bijzonder immunotherapie, en het identificeren van strategieën om de antitumor immuunrespons te behouden of te versterken. Daarnaast onderzoeken we innovatieve vormen van radiotherapie, waaronder ultra-high dose rate radiotherapy (FLASH) en spatially fractionated radiotherapy (SFRT). Het doel is om de tumorcontrole te verbeteren en tegelijkertijd bijwerkingen in gezond weefsel te verminderen.

Binnen DUPROTON brengen we preklinische en translationele expertise samen om biologisch onderbouwde protontherapie verder te ontwikkelen. Door geavanceerde bestralingsfaciliteiten te combineren met patiënt-afgeleide modellen en uitgebreide moleculaire en immunologische analyses, biedt DUPROTON een uniek platform voor onderzoek naar de respons van tumoren en gezond weefsel, het optimaliseren van combinaties met immunotherapie en het versnellen van de vertaling van radiobiologische inzichten naar betere behandelresultaten voor patiënten met kanker.

Onderzoeksgebieden

We investigate the biological mechanisms underlying responses to proton irradiation and how these may differ from conventional photon irradiation. By studying factors such as DNA damage responses, biological variability and normal tissue effects, we aim to better understand and predict individual responses to proton therapy and identify opportunities to improve treatment outcomes.
 

Researchers: dr. D. van Gent (Erasmus MC), dr. ir. D. Lathouwers (TU Delft), dr. J. Brown (TU Delft), dr. J. Essers (ErasmusMC), Prof. dr. R. Kanaar (ErasmusMC), Prof. dr. M. Reinders (TU Delft), Prof. M. Tijsterman (LUMC), dr. L. Barazzuol (UMCG) and dr. J.H. Maduro (UMCG), dr. P. van Luijk (UMCG) and Prof. dr. R.P. Coppes (UMCG).

Consortia and studies to highlight

  • Influence of intrinsic biological variability on the outcomes of proton radiotherapy in head and neck cancer

    Principal Investigators: dr. D van Gent (Erasmus MC), dr. ir. D. Lathouwers (TU Delft) and dr. J. Brown (TU Delft)

    Funding: HollandPTC – Varian 2019

    Summary: The main goal of this project is to identify biological factors that influence the outcomes of proton radiotherapy in squamous cell carcinomas in the head and neck region (HNSCC). These factors are subsequently used to develop a predictive framework to estimate the response of cells or tissues in relation to linear energy transfer (LET) and the dose (or dose-dose rate).

     

  • Proton-DDR: elucidating mechanisms of proton-induced DNA damage response and molecular signatures to enhance tumor control

    Principal Investigators: Prof. Dr. M. Tijsterman, dr. J. Essers (Erasmus MC), prof. dr. R. Kanaar (Erasmus MC), prof. dr. M. Reinders (TU Delft)

    Funding: HollandPTC – Varian 2019

    Summary: Proton and photon irradiation can induce various biological effects, offering new clinical possibilities. The aim is to increase biological knowledge to optimize proton therapy, particularly for head and neck cancer. This involves investigating the mechanisms by which cells repair DNA damage caused by protons. Molecular characteristics, cell sensitivity, and stochastic effects, such as genomic changes, are also being studied. These effects are evaluated at various values of linear energy transfer (LET). Additionally, modulators are being investigated that can improve tumor control in combination with proton therapy, without causing additional damage to healthy tissue.

     

  • BRAINAtomy: Investigating brain region sensitivity and neurocognitive effects of proton therapy in paediatric patients

    Principal Investigator: dr. M. McCabe (University of Manchester), dr. T. Merchant (St. Jude Children’s Research Hospital), dr. L. Barazzuol (UMCG) and dr. J.H. Maduro (UMCG)

    Institutes: University of Manchester, Christe Hospital, St. Jude Children’s Research Hospital, UMCG and Princess Maxima Center (PMC)

    Funding: Cancer Research UK and Stand Up To Cancer

    Summary: Within this international consortium, funded by Cancer Research UK and Stand Up To Cancer, the project seeks to improve long-term cognitive outcomes for paediatric brain and CNS tumour patients receiving proton therapy. The radiobiology work package will investigate the radiation sensitivity of specific brain regions and assess how endocrine dysfunction following treatment influences neurocognitive development and function, with the goal of identifying strategies to mitigate late effects.

     

  • AVERTMore: Developing pharmacological strategies to reduce cardiopulmonary side effects of thoracic radiotherapy

    Principal Investigator: dr. P. van Luijk (UMCG)
    Co-investigator: Prof. dr. R.P. Coppes (UMCG)

    Funding: KWF

    Summary: We develop pharmacological interventions to prevent cardiopulmonary side effects of thoracic radiotherapy.
     

Although proton therapy and immunotherapy are increasingly used in cancer treatment, little is known about how they interact or how they can best be combined. We investigate how proton irradiation influences immune responses and aim to use this knowledge to optimize combined treatment strategies, improve tumour control and limit adverse effects.
 

Consortia and studies to highlight

  • IMMUNO-PROT: Optimizing the combination of proton therapy and immunotherapy in head and neck cancer:

    Principal Investigator: Dr. L. Barazzuol (UMCG)

    Co-investigators:  Prof. dr. M. van Vugt (UMCG), Prof. M. Vooijs (Maastricht University/Maastro), Prof. K. Rouschop (Maastricht University/Maastro), Prof. G. Adema (Radboudumc), dr. J. Essers (Erasmus MC), dr. D. van Gent (Erasmus MC) and Prof. dr. ir. R.P. Coppes (UMCG)

    Funding: KWF

    Summary: The research focuses on three interconnected areas. First, the team will identify key molecular and immunological targets that play a role in proton therapy-induced inflammation. Second, the project investigates how proton therapy influences the interaction between the immune system, the tumor, and surrounding healthy tissue. Third, researchers will develop and test improved irradiation strategies in preclinical models, with the aim of increasing tumor control while simultaneously reducing normal tissue adverse effects.

Novel radiotherapy approaches may provide opportunities to improve tumour control while reducing adverse effects in healthy tissues. We investigate ultra-high dose rate (FLASH) proton therapy to better understand its biological effects and explore its potential for future treatment strategies.


Researchers:  Prof. dr. ir. R.P. Coppes (UMCG), dr. L. Barazzuol (UMCG), dr. P. van Luijk (UMCG), Prof. S. Both (UMCG), dr. N Krah (HPTC), dr. A. Puspitasari Kokko (HPTC) , dr. Y. Klaver (HPTC), dr. M. Slingerland (LUMC), dr. A. Valles Marti (LUMC), dr. C.J. van Doorn-Wink (LUMC) and dr. L Hawinkels (LUMC)

Consortia and studies to highlight

  • Towards FLASH proton therapy for breast cancer

    Principal Investigators: Prof. dr. ir. R.P. Coppes (UMCG) and Prof. S. Both (UMCG)

    Co-investigator: Dr. L. Barazzuol (UMCG)

    Funding: IBA

    Summary: Ultra-High Dose Rate proton therapy (UHDR-PT) is the irradiation of subjects using dose rates ≥40 Gy/s. UHDR-PT is observed to elicit the FLASH effect, a reduction of normal tissue complications while maintaining tumour control. Mammary cancer is one of the most prevalent cancer types in the world. The FLASH effect has the potential to significantly reduce healthy tissue complications, and paired with a single fraction of proton therapy may be able to fully control early stage mammary tumours. Additionally, the reduction of irradiation time combined with possibility to hypo-fractionate warrants a significant improvement in patient quality of life and proton center patient throughput. Thus, we aim to investigate if (single fraction) UHDR-PT is a suitable treatment methodology for early-stage mammary cancers.

     

  • FLASH proton therapy: elucidating late normal tissue responses

    Principal Investigator: Dr. L. Barazzuol (UMCG)

    Co-investigator: Dr. P. van Luijk (UMCG)

    Funding: KWF

    Summary: We aim to define the biological basis of late normal tissue responses following FLASH proton therapy. Using the spinal cord as a model tissue, we investigate the cellular and molecular mechanisms that govern radiation-induced damage and functional impairment after conventional and ultra-high dose rate proton irradiation.

     

  • FLASH radiobiology: optimising healthy tissue sparing while maintaining tumour control

    Principal Investigators: Dr. N. Krah (HPTC) and dr. A. Puspitasari-Kokko (HPTC)

    Co-investigators: Dr. A. Valles Marti (LUMC), Dr. L. Hawinkels (LUMC), Dr. J. Esser (ErasmusMC), dr. Y. Klaver (HollandPTC), dr. M. Slingerland (LUMC), dr. C.J. van Doorn-Wink (LUMC) and dr. A. Accardo (TU Delft)

    Funding: KWF

    Summary: Ultra-high dose rate (FLASH) irradiation can reduce damage to healthy tissue while maintaining tumour control, offering new clinical opportunities. At HollandPTC, we lead the development and optimisation of FLASH proton delivery on our preclinical beamline, enabling both in vitro and in vivo studies. In collaboration with LUMC and Erasmus MC, who contribute the biological models, we aim to expand biological knowledge to optimise FLASH proton therapy, particularly for tumours near radiosensitive organs. We investigate the mechanisms underlying the FLASH effect across different doses and linear energy transfer (LET). In addition, we explore modulators that can enhance normal tissue sparing in combination with FLASH without compromising tumour control.

Advanced preclinical models enable us to study the biological effects of proton irradiation in more representative tumour environments. We develop innovative 3D models to investigate tumour responses to proton therapy and support the development of improved treatment strategies.


Researchers: Dr. A. Accardo (TU Delft)

Consortia and studies to highlight

  • 3D-engineered brain cancer microenvironments

    Principal Investigator: Dr. A. Accardo

    Co-investigators: Q. Akolawala, A. Puspitasari-Kokko, A. Rondon, H. Versteeg and N. Pertiwi

    Summary: Glioblastoma is an aggressive brain tumor with a median survival of only 15 to 17 months despite standard treatment. Proton therapy enables more precise tumor targeting than conventional photon radiotherapy, but its effects on both tumour and healthy brain cells remain insufficiently understood. This project uses light-based 3D bioprinting to create biomimetic glioblastoma microenvironments, known as Onco-Neuro-Scaffolds (ONSs). These engineered 3D cell models mimic brain tissue and support the growth of both healthy neural cells and glioblastoma cells. ONSs will serve as a physiologically relevant platform for investigating proton radiobiology and evaluating treatment responses.

Relevante links