Proton Therapy (PT) treatment delivered by pencil beam scanning (PBS) is a promising treatment modality as protons exhibit a high physical selectivity. The depth-dose distribution of protons is characterized by a slow rise from the entrance point followed by a steep increase of the dose and a sharp dose fall-off called the “Bragg peak”. Protons exhibit a non-uniform RadioBiological Effectiveness (RBE) with a considerable RBE increase at the vicinity of the Bragg peak because of the corresponding increase in Linear Energy Transfer (LET) of the protons [A.R. Smith, Phys Med Biol, 2006 and Paganetti H, Phys Med Biol, 2014]. By optimizing the position of the Bragg peak in the tumour according to the LET, a higher biological effect can be obtained for an identical physical dose, a method called LET-painting [E. Malinen, Acta Oncol, 2015] which makes PT an attractive technique in the treatment of cancer.
On top of that, and particularly important for children, PT allows reduction of the dose burden during PT, because the dose is strongly reduced upstream the tumour and negligible downstream. Nevertheless some researchers are cautious that the existing knowledge and understanding of the out-of-field doses and associated risk of inducing Secondary Malignant Neoplasms (SMNs) is not sufficiently mature to justify the use of modern techniques, such as PT, for treating children. Much of the concern is related to the carcinogenic risk from secondary neutrons, which are unavoidably produced by the beam modifying devices and tissues traversed [Newhauser, et al., Nat Rev Cancer, 2011]. Furthermore, non-elastic nuclear reactions will also produce secondary protons, heavier ions and photons. Especially the secondary protons and heavier nuclei might have a significant detrimental effect on the surrounding healthy tissue and should be studied carefully. Therefore a full characterization of the secondary irradiation, particularly at the PT field edge requires special attention for radiation protection and prevention of SMNs.
The above mentioned issues demand a renewed dosimetry approach at the cellular/subcellular level, i.e. microdosimetry, and an important attention to unravel biological effects and mechanism behind relative biological effectiveness (RBE) in the treatment field and at the lateral and distal edges of the PT field as well as out-of-the field.
Today in vivo microdosimetry is still mostly limited to Monte Carlo (MC) simulations, however new techniques are emerging to perform microdosimetry in small volumes inside phantoms simulating the human body. In SCK•CEN we have experience with active devices such as a silicon microdosimetric sensor (microplus) and a mini-Tissue Equivalent Proportional Counter (mini-TEPC) that allow to evaluate microdosimetric LET spectra at the edge of the proton field and out-of-the proton field. Currently we also have passive devices like Fluorescent Nuclear track detectors (FNTDs), homemade superheated droplet detectors (specific for neutrons) and a combination of thermoluminescence detectors (TLD) that allow to measure the dose in mixed irradiation fields with an important advantage to be small in size and to be easily positioned inside (paediatric) anthropomorphic phantoms. A wide experience with different MC simulation packages will allow to calculate (micro)dosimetric spectra and complement the measured data (MCNPx, PHITS, GEANT4-DNA). The modelling of RBE from the physical measurements will be possible through cell experiments exploring healthy and tumour cells in the radiobiology (RDB) unit, with a focus on healthy cells. These experiments will be based on well-established cell survival studies.
Ultimatelly this PhD will address important concerns in view of radiation protection in PT. By developing a methodology to determine microdosimetric dose quantities, LET and the correlation with RBE, the impact can be investigated of an extensive array of clinical parameters that affect the dose burden such as patient orientation, modulation width, proton range, collimator aperture, compensator thickness and air gap size. Also the effect of LET painting on the secondary dose distribution will be investigated. The secondary dose variation will be modelled as a function of relevant parameters to allow monitoring each individual patient treated in PT in all its individual complexities. This evolution will render our current understanding of radiation side effects absolute and allow algorithmically minimizing the risk of radiation side effects.