Radiobiology of protons: the clinical perspective - PDF Version

Protons display a different radiobiology from that displayed by photons. This topic has received increasing interest in the last few years due to the increasing number of proton treatment facilities. In last year’s May-June newsletter from the European SocieTy for Radiotherapy and Oncology (ESTRO), Heidi Lyng (Department of Radiation Biology, Institute for Cancer Research Norwegian Radium Hospital, Oslo University Hospital, Norway) gave an informative overview of the radiobiology of protons, and reviewed relevant papers on the subject. This issue of the Radiobiology Corner provides an update on important recent publications on proton radiobiology, models and setups for relative biological effectiveness (RBE) in vivo studies, and clinical evidence for a variable RBE, reviewed by researchers from Aarhus University, Denmark. 

Treatment in the clinic with protons or heavier particles relies on the relative biological effectiveness (RBE); this factor converts a physical dose to a biological equivalent dose. At present, in proton therapy a constant RBE of 1.1 is generically used, as recommended by the International Commission on Radiation Units [1].  This figure means that a given proton dose is expected to be equivalent to a 10% higher x-ray dose for all tumours, tissues and doses. However, researchers debate whether this single figure is adequate [2–5], as an RBE of 1.1 is a simplification of the actual biological response to proton irradiation. The RBE is a complex factor, which is influenced by a number of aspects. The RBE is known to be affected by tissue type, dose and fractionation, as well as the linear energy transfer (LET) [6,7]. In a proton treatment field, the LET increases moderately through the spread-out Bragg peak (SOBP) but increases considerably in the very distal edge of the SOBP. This finding has been demonstrated in vitro to translate into an increased distal-edge RBE [8–11]. This is a critical issue, as the distal edge of an SOBP in a patient treatment plan may be located in the tumour that surrounds normal tissue. This increase in RBE has been a subject of discussion, as the clinical impact has been unclear. 

To shed light on this issue, the European Particle Therapy Network (EPTN) held a workshop in Manchester in February 2020. The workshop was supported by INSPIRE (Infrastructure in Proton International Research)  (https://protonsinspire.eu/). Participants came from many of the European proton therapy centres. The main topic of this workshop, which was organised by the EPTN work package 6 on RBE and Radiobiology, was the clinical perspective and use of a variable proton RBE. This subject was addressed in four sessions: 

1. Clinical problem – significance of elevated RBE in proton therapy 
2. Current clinical practice 
3. Backtranslation from clinics to radiobiology research 
4. How can we implement RBE in clinical treatment planning? 

During these sessions, the current experimental and clinical data were presented and discussed. Representatives from clinical centres that were involved in patient treatment laid out the current clinical practice regarding the risk  of a variable RBE in their centres. This overview revealed that to counteract the risk, the centres employed different strategies, which ranged from delivery of more than one field, through a focus on placing the distal edge outside an organ at risk, to the evaluation of the LET distribution in treatment plans for individual patients. 

Published research that contains clinical data showing evidence of a variable RBE is emerging. Armin Lühr and co-workers from Dresden, Germany, have developed a Monte Carlo-based simulation model, which enables them to perform dose and LET simulations for individual passive scattering patient treatment plans [12]. They have applied this tool to analyse late morphological image changes in follow-up magnetic resonance images of glioma (grade II and III) in patients treated with proton therapy [13]. The analysis shows a correlation of dose and LET with late brain-tissue damage. This finding suggests that RBE variability should be considered during prediction of chronic radiation-induced brain toxicities.  

Emanuel Bahn and co-workers from Heidelberg, Germany, have very recently also published data regarding patients who were treated with proton therapy for brain tumours [14].They analysed 110 patients who had low-grade glioma and who were treated with pencil-beam scanning. The study aimed to use magnetic resonance imaging (MRI) to determine whether the risk of late radiation-induced contrast-enhancing brain lesions was increased in proximity to the ventricular system, and if there was a relationship between RBE and LET. The data show that the risk of lesions in ventricular proximity was increased and that the proton RBE increased significantly with increasing LET.  

High-precision image-guided proton irradiation of mouse brain sub-volumes 

Proton irradiation increases the necessity for homologous recombination repair along with the indispensability of non-homologous end joining      

     

Brita Singers Sørensen, professor
Danish Centre for Particle Therapy (DCPT) &
Experimental Clinical Oncology 
Department of Oncology
Aarhus University Hospital
Aarhus, Denmark 

References: 

1. ICRU Report 78. Prescribing, recording and reporting proton-beam therapy. J ICRU 2007. 
2. Ödén J, DeLuca PM, Orton CG. The use of a constant RBE=1.1 for proton radiotherapy is no longer appropriate: Med Phys 2018;45:502–5. 
3. Jones B. Why RBE must be a variable and not a constant in proton therapy. Br J Radiol 2016;89:20160116. 
4. Mohan R, Peeler CR, Guan F, Bronk L, Cao W, Grosshans DR. Radiobiological issues in proton therapy. Acta Oncol (Madr) 2017;56:1367–73. 
5. Lühr A, von Neubeck C, Pawelke J, Seidlitz A, Peitzsch C, Bentzen SM, et al. “Radiobiology of Proton Therapy”: Results of an international expert workshop. Radiother Oncol 2018;128:56–67. 
6. Paganetti H, van Luijk P. Biological Considerations When Comparing Proton Therapy With Photon Therapy. Semin Radiat Oncol 2013;23:77–87. 
7. Tommasino F, Durante M. Proton radiobiology. Cancers (Basel) 2015;7:353–81. 
8. Bettega D, Calzolari P, Chauvel P, Courdi A, Herault J, Iborra N, et al. Radiobiological studies on the 65 MeV therapeutic proton beam at Nice using human tumour cells. Int J Radiat Biol 2000;76:1297–303. 
9. Sørensen BS, Overgaard J, Bassler N. In vitro RBE-LET dependence for multiple particle types. Acta Oncol 2011;50:757–62. 
10. Britten RA, Nazaryan V, Davis LK, Klein SB, Nichiporov D, Mendonca MS, et al. Variations in the RBE for cell killing along the depth-dose profile of a modulated proton therapy beam. Radiat Res 2013;179:21–8. 
11. Wouters BG, Skarsgard LD, Gerweck LE, Carabe-Fernandez A, Wong M, Durand RE, et al. Radiobiological Intercomparison of the 160 MeV and 230 MeV Proton Therapy Beams at the Harvard Cyclotron Laboratory and at Massachusetts General Hospital. Radiat Res 2015;183:174–87. 
12. Eulitz J, Lutz B, Wohlfahrt P, Dutz A, Enghardt W, Karpowitz C, et al. A Monte Carlo based radiation response modelling framework to assess variability of clinical RBE in proton therapy. Phys Med Biol 2019;64. 
13. Eulitz J, Troost EGC, Raschke F, Schulz E, Lutz B, Dutz A, et al. Predicting late magnetic resonance image changes in glioma patients after proton therapy. Acta Oncol (Madr) 2019:1–4. 
14. Bahn E, Bauer J, Harrabi S, Herfarth K, Debus J, Alber M. Late contrast enhancing brain lesions in proton treated low-grade glioma patients: clinical evidence for increased periventricular sensitivity and variable RBE. Int J Radiat Oncol 2020.