Relative biological effectiveness of the 60-MeV therapeutic proton beam at the Institute of Nuclear Physics (IFJ PAN) in Kraków, Poland

Dorota Sonina 0 1 2 Beata Biesaga 0 1 2 Jan Swakon 0 1 2 Damian Kabat 0 1 2 Leszek Grzanka 0 1 2 Marta Ptaszkiewicz 0 1 2 Urszula Sowa 0 1 2 0 D. Kabat Department of Medical Physics, Centre of Oncology, Maria Skodowska-Curie Memorial Institute , Krakow, Poland 1 J. Swakon L. Grzanka M. Ptaszkiewicz U. Sowa Institute of Nuclear Physics, Polish Academy of Sciences , Krakow, Poland 2 D. Sonina (&) B. Biesaga Department of Applied Radiobiology, Centre of Oncology, Maria Skodowska-Curie Memorial Institute , Garncarska 11, 31-115 Krakow, Poland The aim of the study was to determine the relative biological effectiveness (RBE) of a 60-MeV proton radiotherapy beam at the Institute of Nuclear Physics, Polish Academy of Sciences (IFJ PAN) in Krakow, the first one to operate in Poland. RBE was assessed at the surviving fractions (SFs) of 0.01, 0.1, and 0.37, for normal human fibroblasts from three cancer patients. The cells were irradiated near the Bragg peak of the pristine beam and at three depths within a 28.4-mm spread-out Bragg peak (SOBP). Reference radiation was provided by 6-MV X-rays. The mean RBE value at SF = 0.01 for fibroblasts irradiated near the Bragg peak of pristine beam ranged between 1.06 and 1.15. The mean RBE values at SF = 0.01 for these cells exposed at depths of 2, 15, and 27 mm of the SOBP ranged between 0.95-1.00, 0.97-1.02, and 1.05-1.11, respectively. A trend was observed for RBE values to increase with survival level and with depth in the SOBP: at SF = 0.37 and at the depth of 27 mm, RBE values attained their maximum (1.19-1.24). The RBE values estimated at SF = 0.01 using normal human fibroblasts for the 60-MeV proton radiotherapy beam at the IFJ PAN in Krakow are close to values of 1.0 and 1.1, used in clinical practice. - To date, some 94,000 patients have received proton therapy in 36 proton therapy centres worldwide (Particle Therapy Co-Operative Group 2012). In 2011, a 60-MeV proton radiotherapy facility, the first one to operate in Poland, began to treat patients with eye tumours (mainly uveal melanoma) at the Institute of Nuclear Physics of the Polish Academy of Sciences (IFJ PAN) in Krakow, Poland. The proton beam is accelerated using the AIC-144 isochronous cyclotron, which was designed and constructed around 1980 at the IFJ PAN for physics research (Bakewicz et al. 2003) and adapted around 2008 to supply a 60-MeV proton beam to the proton ocular treatment facility (Swakon et al. 2010). The first patient was irradiated at IFJ PAN in February 2011 and by June 2014, 62 patients were treated. The physical advantage of protons is the spatial distribution of dose delivered to the tumour volume. Protons and heavier ions show an increasing energy loss with depth in tissue that they penetrate, leading to maximum dose deposition, known as the Bragg peak, at the distal range of the proton beam. For protons, no significant dose is deposited at depths exceeding that of the Bragg peak. Such physical properties of ions are desirable in radiotherapy because they allow targeting the therapeutic dose within the tumour volume with high accuracy, sparing normal tissues and critical organs located beyond the beams range. Therefore, patients with tumours located close to critical organs are preferentially referred to proton centres. For the purposes of radiotherapy, the Bragg peak in a pristine beam is too narrow to homogeneously cover the tumour volume; therefore, beam energy modulation is required to produce a spread-out Bragg peak (SOBP; Paganetti and Bortfeld 2006). The radiobiological properties of a therapeutic proton beam are comparable to those of a photon beam. A generic value of relative biological effectiveness (RBE) of 1.1 is accepted and usually applied in routine proton radiotherapy, independently of the initial beam energy, position within the SOBP, dose fractionation scheme, or type of irradiated tissue (ICRU 78 2007). Although it has been recognised that these physical and biological factors affect the RBE value (Gerweck and Kozin 1999; Paganetti and Goitein 2000; Paganetti et al. 2002), they are usually disregarded in clinical proton therapy practice. Most authors show that RBE increases with depth along the SOBP, due to the increase in the linear energy transfer (LET). For human tumour cells in vitro, RBE values reach 1.21.3 at the distal part of the SOBP (Courdi et al. 1994; Bettega et al. 2000; Ando et al. 2001; Calugaru et al. 2011), although recently Britten et al. (2013) found a much higher value of 2.1. Due to this increase, the biological effective range of the proton beam may extend by about 13 mm over its physical range (Bettega et al. 2000; Paganetti and Goitein 2000; Carabe et al. 2012). Thus, critical organs located just behind the target volume may be affected. It was suggested that this extension of the effective beam range depends on dose and tissue type (i.e. on its a/b value), and that it should be considered for low doses and tissues characterised by low a/b ratios (Gerweck and Kozin 1999). The clinical relevance of the RBE variation and range uncertainty of the proton beam is still a matter of debate (Carabe et al. 2012; Dasu and Toma-Dasu 2013; Frese et al. 2011; Paganetti 2012). It was shown that beam-modulating devices for proton therapy may affect the dose distribution and the proton energy spectrum of the beam, and consequently its RBE (Paganetti and Goitein 2000). Because different therapy centres apply different beam modulation systems, prior to their clinical use, independent radiobiological assessment of the RBE of each proton beam at each centre is required. To date, normal human cells in vitro have not been extensively used for determining the RBE values for proton radiotherapy beams. Here, we report the results of radiobiological studies performed in vitro using primary normal fibroblasts derived from three patients with cervix cancer. Our aim was to evaluate the RBE value for the IFJ PAN 60-MeV proton beam and its dependence on the level of survival (dose level) and position in the SOBP or within the Bragg peak of the pristine beam. Skin fibroblasts were chosen firstly because they represent target cells of lateresponding tissue (fibrosis) and thus exhibit a low a/b ratio (Bentzen and Joiner 2009), and secondly, because of their known high individual variation in radiosensitivity (Peacock et al. 2000; Sonina et al. 2007). Materials and methods Proton beam and dosimetry Cell irradiation was performed at the IFJ PAN proton beam facility used for the therapy of uveal melanoma. The 60-MeV proton beam is accelerated in the AIC-144 isochronous cyclotron (Bakewicz et al. 2003). Protons are transported by a 25-m-long beam line system to the radiotherapy room. The beam line system consists of evacuated pipes of 10-cm internal diameter, bending magnets, and a system of quadrupole and correction magnets. The horizontal proton beam is spread out laterally using a single scattering system with a 25-lm tantalum foil l (...truncated)