Research in particle therapy

Haukeland University Hospital is dedicated to research and development in particle
therapy through support from Bergen Research Foundation, with funding of two
projects: «Establishing a framework for interdisciplinary research at Haukeland
University Hospital» and «Molecular mechanisms of photon and particle radiation
responses in malignant tumours and clinical dosing of carbon ions».

The group focuses on research of biological response, developement of patient models, treatment strategies
as well as implementation of technlogogy such that we in the future will be able to offer an optimal treament with modern photon-and particle therapy to the patients. Below you will find a short summary of the different projects and studies, presentation of the research group and links to our collaborators.

Establishing a framework for interdisciplinary research at Haukeland University Hospital

The research group in the interdisciplinary project
Figure 1. The research group in the interdisciplinary project. From left senior oncologist Marianne Brydøy, post doc/medical physicist Camilla H. Stokkevåg, researcher/medical physicist Sara Thörnqvist, department director/professor Olav Mella, radiation therapist Grete May Engeseth, researcher/medical physicist Liv B. Hysing, senior oncologist/professor Olav Dahl, medical physicist Marcin Sikora, leader of sect. of medical physics Anfinn Mehus.


Department director/professor Olav Mella and medical physicist/Associate Professor II Liv Bolstad Hysing are the leaders of the research group in particle therapy at the department of Oncology and Medical Physics. The research group consists of researchers, oncologists, radiation therapists and medical physicists. The group focuses on developement and implementation models and strategies as well as technlogogy such that we in the future will be able to offer an optimal treament with modern photon-and particle therapy to the patients.

Vacant positions

We have currently the following vacant positions within the project.

Researcher/Technical research support – Department of Oncology and Medical Physics, Haukeland University Hospital, application deadline 11/11-18

PhD Research Fellowship – Department of Oncology and Medical Physics, Haukeland University Hospital, application deadline 25/11-18


Studies initiated by 2018:

A model-based approach for predicting and reducing morbidity in pediatric cancer

A large proportion of head and neck cancer (HNC) patients receiving radiation therapy (RT) will experience late effects like xerostomia and hyposalivation, issues which will impact the patient's well-being and oral/dental health for the rest of his or her lifetime. It has been shown in several simulation studies that new advanced treatment techniques and strategies, like proton therapy and adaptive RT (ART), can reduce normal tissue doses. However it is still unclear for which patients this translates into a clinical benefit. The overall aim of the current project is to improve treatment quality by reducing radiation induced xerostomia in HNC patients. This will be achieved by developing and validating models which can accurately predict xerostomia and hyposalivation, as well as clinically relevant dosimetric changes in individual patients. Patients will be enrolled in a prospective cohort study. They will be asked to fill out a validated quality of life questionnaire assessing subjective symptoms of xerostomia. Further, to include an objective assessment of hyposalivation, saliva flow will also be measured. Detailed analysis of photon and proton dose distributions will be performed, and the correlation between dose-volume parameters and clinical and dosimetric outcome will be established and tested. The models will be used to identify and select those patients who are most likely to benefit from ART and proton therapy.

The main goal of the project is to develop and validate predictive models for use in selection of HNC patients to advanced photon- and proton RT. The project consists of four studies with the following aims:

  1. To validate an established multivariate Normal Tissue Complication Probability (NTCP) model for self-reported xerostomia and to develop a similar model for predicting radiation induced saliva flow reduction, both intended to be used in the selection of patients to proton therapy.
  2. To validate the developed NTCP models on an external proton therapy cohort
  3. To validate and develop models for pre-treatment selection of patients to adaptive photon RT
  4. To develop a model for pre-treatment selection of patients to adaptive proton RT

It is expected that the results from this project will be beneficial for HNC patients for both short and long term. The use of predictive models as a decision tool in the selection of treatment strategy or treatment modality, will lead to a more individualised and tailored treatment for HNC patients. Reduced radiation-related morbidity for HNC patients may be achieved by implementing ART, or by introducing new treatment modalities (i.e. protons), both strategies expected to reduce incidence of adverse effects. ART is resource intensive and leads to increased workload; the models from this study will help better steering the use of the resources, and also ensure that the patients who are at highest risk of developing xerostomia, are enrolled in an ART treatment protocol. Lowering normal tissue doses and potentially reducing treatment related morbidity is the main advantage in proton therapy. Today HNC are considered as a future indication for proton therapy, mainly due to the expected improvement in late morbidity, it is however also recognised that the clinical benefit for some patient would be marginal. Using multivariate NTCP models for individual selection of patients to proton therapy is already adopted in several European countries. Multivariate NTCP models, assuming they have good predictive performance, will therefore be an important tool for future selection of Norwegian patients to head and neck proton therapy.

Dose distribution
The figure shows the dose distributions in a patient derived with proton therapy (top row) and with conventional radiotherapy (bottom row)

Image guidance and treatment adaptation in pelvic patients

Project aim and summary

Particle therapy as compared to radiotherapy using photons has some distinct benefits due to different interaction with matter when depositing their dose to the tissue. When a high energy particle beam is entering the patient it spills only a small amount of dose along its track. The dose deposition increases slowly with depth until it rises sharply to a localized high-dose peak near the end of the track (the Bragg peak). Anatomical changes occurring during the course of treatment resulting in variations in the amount of traversing tissue for the particles can lead to deviations between the planned location of the high-dose and that actually delivered to the patient. With the aim to improve accuracy in delivery, adaptive radiotherapy use images acquired during treatment to monitor and adjust the planned treatment. In this project we will develop methods of adaption suitable for use in particle therapy. Our initial study focus on patient with locally advanced prostate cancer requiring irradiation of the independently moving targets: the prostate and the pelvic lymph nodes. Here we will investigate if we can limit variations in traversing tissue by securing that of bony anatomy in every fraction and adapting the position of the prostate. The different positions of the prostate could be found from previously treated patients and a library of different treatment plans with varying prostate in relation to the bony anatomy/pelvic lymph nodes could be constructed before start of treatment (Fig. Adaption). At each day of treatment, the plan most similar to the ‘anatomy of the day’ can then be selected and delivered.

Adaptation
Fig. Adaptation: To the left motion of the prostate in relation to the bony anatomy/pelvic lymph nodes in previously treated patients resulted in three probable positions of the prostate. To the right these positions of the prostate have been overlaid on the image used for constructing the treatment plan. Three plans will thus be created for the current patient.

Organ motion and dose response modelling in pelvic radiotherapy

Project aim and summary

Dose-response models quantify the relationship between delivered dose and biological effects in terms of tumour control or normal tissue damage. Data from such models are subsequently used when deriving the dose distribution for a patient to assure a safe treatment. The vast majority of dose-response models are based on the planned dose distribution together with the recorded rate of tumour control and/or complications. However, we and others have shown that organ motion causes the planned dose distribution to differ from that delivered. Organ motion is complex, including deformation, stretching and/or displacements caused by e.g. breathing, emptying and filling of organs and digestion. When the organ changes its shape, the same anatomical points on the organ will be located at different positions within the dose distribution from one daily treatment fraction to the other. Knowing the displacement of corresponding anatomical points enables accumulation of the dose to each point and thus account for the variable spatial positions within the dose distribution in the different fractions (Fig. Dose accumulation). In this project we will investigate complication predictions developed from dose-response models using accumulated dose derived from motion models for previously treated prostate cancer patients.

Dose accumulation
Fig. Dose accumulation: Deviations in planned and expected accumulated dose. The arrow is indicating the area of greatest difference


Information about radio and particle therapy

Useful information about radiotherapy including particle therapy can be found at the Norwegian Cancer Society (Norwegian only):

https://kreftforeningen.no/om-kreft/kreftbehandling/stralebehandling/


Information about particle therapy abroad (Norwegian only):

http://kreftlex.no/Om-Kreft/Stralebehandling/Protonterapi?Faq=False


Regional collaboration

Regional collaboration

Haukeland University Hospital is collaborating with Bergen University college, IRIS and MedViz for research within developement of particle therapy.

International collaboration

Links to collaborating projects (mainly in Norwegian)

Kristian Ytre-Hauge, Institutt for fysikk og teknologi, Universitetet i Bergen

http://cmedia.sunrise.dk/uib/2014/11/17/partikkelfysikk-som-vapen-mot-kreft/

https://wiki.uib.no/particletherapy/index.php/Main_Page

 

Ilker Meric, Høgskulen i Bergen

http://www.hib.no/om-hogskolen/avdeling-for-ingenior--og-okonomifag/nytt-fra-avdelingen/protonterapi/

 

Dieter Rörich, Institutt for fysikk og teknologi, Universitetet i Bergen

http://www.uib.no/aktuelt/100846/kreftbehandling-med-mindre-str%C3%A5leskadar

 

Tverrfaglig forsking i medisinsk fysikk, Universitetet i Bergen

http://www.uib.no/ift/84625/medisinsk-fysikk-og-teknologi#avbilding-og-diagnostikk

 

Medviz

http://www.medviz.uib.no/

 

Information about the newly opened Mohn Medical imaging and visualization centre located at Haukeland University Hospital:

https://mmiv.no/

Links to a selection of papers published by the research group

Radiation-induced cancer risk predictions in proton and heavy ion radiotherapy.

Stokkevåg CH, Schneider U, Muren LP, Newhauser W.

Phys Med. 2017 May 13. pii: S1120-1797(17)30109-6. doi: 10.1016/j.ejmp.2017.04.022. [Epub ahead of print] Review. No abstract available.

 

Monte Carlo simulations of a low energy proton beamline for radiobiological experiments.

Dahle TJ, Rykkelid AM, Stokkevåg CH, Mairani A, Görgen A, Edin NJ, Rørvik E, Fjæra LF, Malinen E, Ytre-Hauge KS.

Acta Oncol. 2017 Jun;56(6):779-786. doi: 10.1080/0284186X.2017.1289239. Epub 2017 Feb 22.

 

Linear energy transfer distributions in the brainstem depending on tumour location in intensity-modulated proton therapy of paediatric cancer.

Fjæra LF, Li Z, Ytre-Hauge KS, Muren LP, Indelicato DJ, Lassen-Ramshad Y, Engeseth GM, Brydøy M, Mairani A, Flampouri S, Dahl O, Stokkevåg CH.

Acta Oncol. 2017 Jun;56(6):763-768. doi: 10.1080/0284186X.2017.1314007. Epub 2017 Apr 19.

 

A phenomenological biological dose model for proton therapy based on linear energy transfer spectra.

Rørvik E, Thörnqvist S, Stokkevåg CH, Dahle TJ, Fjaera LF, Ytre-Hauge KS.

Med Phys. 2017 Jun;44(6):2586-2594. doi: 10.1002/mp.12216. Epub 2017 May 22.

 

Beam angle evaluation to improve inter-fraction motion robustness in pelvic lymph node irradiation with proton therapy.

Gravgaard Andersen A, Casares-Magaz O, Petersen J, Toftegaard J, Bentzen L, Thörnqvist S, Muren LP.

Acta Oncol. 2017 Jun;56(6):846-852. doi: 10.1080/0284186X.2017.1317108.

 

Evaluating the influence of organ motion during photon vs. proton therapy for locally advanced prostate cancer using biological models.

Busch K, G Andersen A, Casares-Magaz O, Petersen JBB, Bentzen L, Thörnqvist S, Muren LP.

Acta Oncol. 2017 Jun;56(6):839-845. doi: 10.1080/0284186X.2017.1317107.

 

Modelling of organ-specific radiation-induced secondary cancer risks following particle therapy.

Stokkevåg CH, Fukahori M, Nomiya T, Matsufuji N, Engeseth GM, Hysing LB, Ytre-Hauge KS, Rørvik E, Szostak A, Muren LP.

Radiother Oncol. 2016 Aug;120(2):300-6. doi: 10.1016/j.radonc.2016.07.001. Epub 2016 Jul 13.

 

Adaptive radiotherapy strategies for pelvic tumors - a systematic review of clinical implementations.

Thörnqvist S, Hysing LB, Tuomikoski L, Vestergaard A, Tanderup K, Muren LP, Heijmen BJ.

Acta Oncol. 2016 Aug;55(8):943-58. doi: 10.3109/0284186X.2016.1156738. Epub 2016 Apr 8. Review.

 

Risk of radiation-induced secondary rectal and bladder cancer following radiotherapy of prostate cancer.

Stokkevåg CH, Engeseth GM, Hysing LB, Ytre-Hauge KS, Ekanger C, Muren LP.

Acta Oncol. 2015;54(9):1317-25. doi: 10.3109/0284186X.2015.1061691. Epub 2015 Jul 31.

 

Estimated risk of radiation-induced cancer following paediatric cranio-spinal irradiation with electron, photon and proton therapy.

Stokkevåg CH, Engeseth GM, Ytre-Hauge KS, Röhrich D, Odland OH, Muren LP, Brydøy M, Hysing LB, Szostak A, Palmer MB, Petersen JB.

Acta Oncol. 2014 Aug;53(8):1048-57. doi: 10.3109/0284186X.2014.928420. Epub 2014 Jul 14.

 

Degradation of target coverage due to inter-fraction motion during intensity-modulated proton therapy of prostate and elective targets.

Thörnqvist S, Muren LP, Bentzen L, Hysing LB, Høyer M, Grau C, Petersen JB.

Acta Oncol. 2013 Apr;52(3):521-7. doi: 10.3109/0284186X.2012.752860. Epub 2013 Feb 14.

Funding

The projects are funded by the Bergen Research Foundation and the Norwegian Cancer Society.

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