Biological Effectiveness Of Ion Beams for Cancer Therapy

Lead Research Organisation: Queen's University of Belfast
Department Name: Medicine Dentistry and Biomedical Sci

Abstract

Cancer radiotherapy employing charged particles (i.e. protons and carbon ions) is currently the fastest growing cancer treatment approach with over 30 centres worldwide and an extra 30 (including 3 in the UK) planned to be operational in the next 3-5 years. Compared to conventional photon based approaches, the energy deposition profiles of ion beams are such that their destructive power can be better confined to the tumour volume with minimal damage to surrounding healthy tissues. However, despite the impressive tumour control probabilities reported, there are still uncertainties on the biological effects caused by ion beams especially related to late effects in healthy tissues which prevent further optimization of cancer particle therapy. Ultimately, it is normal tissue effects, including risks of secondary cancers, which will determine the treatment outcome. The main issue is related to the change of biological effectiveness as the ions penetrate into the tissue and a higher probability of inducing late effects when compared to X-rays. Current lack of experimental data is forcing treatment plans to adopt broadly averaged parameters for estimating tumour cell killing and neglect late effects. This project aims to investigate in parallel DNA damage, acute and late cellular effect in a variety of normal and cancerous cell lines induced by therapeutically relevant ion beams across and around their trajectory. Our central hypothesis is that damage and cellular response will vary greatly along and around the ion path as a function of depth, energy deposited, cell line and ion characteristics. Data collected will help improving current knowledge of the biological effectiveness along the ion path and how it varies with physical and biological parameters. Attention will be focused on late effects and how biological depth curves for radiation risks need to be further investigated and included in existing models in order to design optimal cancer treatment strategies. Additionally, we anticipate DNA damage caused by secondary electrons and cell signalling to have non-negligible effects whose contribution to the cancer treatment plans has still to be fully investigated.

Technical Summary

Cancer radiotherapy employing charged particles (i.e. protons and carbon ions) is currently the fastest growing cancer treatment approach with over 30 centres worldwide and an extra 30 (including 3 in the UK) planned to be operational in the next 3-5 years. Despite the impressive results so far reported, there are still uncertainties on the biological effects caused by ion beams especially related to non-lethal and late effects in healthy tissues which prevent further optimization of cancer particle therapy. The main issue is related to the change of biological effectiveness as the ions penetrate into the tissue and a higher probability of inducing late effects when compared to X-rays. Ultimately, it is normal tissue effects, including risks of secondary cancers, which will determine the treatment outcome. Current lack of experimental data is forcing treatment plans to adopt broadly averaged parameters for estimating tumour cell killing and neglect late effects. More accurate investigations are therefore essential to develop a rigorous theory of ion radiation action at cellular and molecular level to further improve tumour hadrontherapy. Experimental studies investigating the biological response of charged particles have focused mainly on the cell killing effect of tumour cells or tissues at the Bragg peak. Damage caused at the beam entrance channel, beyond the Bragg peak and indeed in the immediate proximity of the ion path is unavoidable and needs to be addressed. Our central hypothesis is that damage and cellular response will vary greatly along and around the ion path as a function of both physics and biological parameters (i.e. depth, physical dose, cell line, ion characteristics). Using a variety of approaches, the present proposal aims to investigate in parallel DNA damage, acute and sub-lethal cellular response caused by therapeutically relevant ion beams (mainly protons but also carbon ions) on a range of normal and cancerous cell lines along the ion path and in its proximity. Data collected will help evaluating more accurate RBE values to be included in new and existing models to design optimal cancer treatment strategies. Determination of biological Bragg curves for radiation risks including late effects will provide critical information for the development and improvement of biological models aimed to improve the therapeutic use of ion beams. Additionally, we anticipate DNA damage caused by secondary electrons and cell signalling between exposed and un-exposed samples to play a non-negligible role whose contribution to cancer treatment plans has still to be fully investigated.

Publications

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Chaudhary P (2016) Variations in the Processing of DNA Double-Strand Breaks Along 60-MeV Therapeutic Proton Beams. in International journal of radiation oncology, biology, physics

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Jones B (2018) The Radiobiology of Proton Therapy: Challenges and Opportunities Around Relative Biological Effectiveness. in Clinical oncology (Royal College of Radiologists (Great Britain))

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Kavanagh JN (2013) DNA double strand break repair: a radiation perspective. in Antioxidants & redox signaling

 
Description COST ACTION MP1002
Amount € 1,500 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 12/2011 
End 01/2012
 
Description ENSAR 262010
Amount € 3,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 09/2012 
End 06/2013
 
Description EPSRC Programmatic Funding
Amount £4,636,962 (GBP)
Funding ID Ep/K022415/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 05/2013 
End 04/2019
 
Description Collaboration with The Prague Proton Therapy Facility 
Organisation Academy of Sciences of the Czech Republic
Department Nuclear Physics Institute
Country Czech Republic 
Sector Public 
PI Contribution Access clincal beams to perform experiments for publication and collaborate with local researchers.
Collaborator Contribution Access to clinical beamlines at the Prague Protontherapy Centre and Research infrastructure within the University of Dept of Radiation Dosimetry, Nuclear Physics Institute ASCR, as part of a longer term collaboration.
Impact Joint poster presented at the US Radiation Research Society Meeting in Las Vegas in September 2014. Physics/Biology/Medicine collaboration
Start Year 2014
 
Description Collaboration with The Prague Proton Therapy Facility 
Organisation Prague Protontherapy Centre
Country Czech Republic 
Sector Hospitals 
PI Contribution Access clincal beams to perform experiments for publication and collaborate with local researchers.
Collaborator Contribution Access to clinical beamlines at the Prague Protontherapy Centre and Research infrastructure within the University of Dept of Radiation Dosimetry, Nuclear Physics Institute ASCR, as part of a longer term collaboration.
Impact Joint poster presented at the US Radiation Research Society Meeting in Las Vegas in September 2014. Physics/Biology/Medicine collaboration
Start Year 2014
 
Description Collaboration with the Clatterbridge Oncology Centre Proton Therapy Facility 
Organisation The Clatterbridge Cancer Centre NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution We have accessed the protontherapy beamline as part of joint experiments with Dr Andrzej Kacperek.
Collaborator Contribution Access in kind to the protontherapy beamline at the Clatterbridge Cancer Centre
Impact Draft manuscript in preparation. Physics/Biology/Medicine collaboration
Start Year 2014
 
Description EPSRC CDT 
Organisation Queen's University Belfast
Department School of Mathematics and Physics
Country United Kingdom 
Sector Academic/University 
PI Contribution Proving radio-biological expertise for laser driven ion beam experiments Teaching and supervising PhD students
Collaborator Contribution Funds and consumables for PhD studentships. Access to laser driven ion beams Networking opportunites with the 5 other partners in the CDT
Impact 1 PhD secured for 2013 intake 6 weeks beam time at the GEMINI laser facility at the Central Laser Facility, Didcot (UK) 1 pubblication
Start Year 2011
 
Description INFN-LNS Dosimetry 
Organisation National Institute for Nuclear Physics
Department National Laboratories of the South
Country Italy 
Sector Academic/University 
PI Contribution Providing radio-biological measurement to validate and support dosimetric measurement Supervising PhD studentship aimed to model INFN-LNS proton and carbon beam line for radiotherapy and radiobiological applications
Collaborator Contribution Proving MonteCarlo support (Geant4) for PhD student, dosimetric instrumentation/support for exeriments at the INFN-LNS (62 MeV/u proton and carbon ions) Catania Facility
Impact Securing PhD studentship funds from Queen's University Belfast
Start Year 2012
 
Description MGH - Held 
Organisation Massachusetts General Hospital
Department Francis H. Burr Proton Therapy Centre
Country United States 
Sector Hospitals 
PI Contribution Collaboration with Drs Harald Paganetti and Dr Kathy Held. Design of radiobiological experiments for passive and scanning proton beam at the MGH
Collaborator Contribution Providing clinical proton beam and dosimetry for radiobiological experiments
Impact 1 publication Access to clinical proton beam facility
Start Year 2011