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BACKGROUND: Targeted radiotherapies with low-energy ions show interesting possibilities for the selective irradiation of tumor cells, a strategy particularly appropriate for the treatment of disseminated cancer. Two promising examples are boron neutron capture therapy (BNCT) and targeted radionuclide therapy with α $\alpha$ -particle emitters (TAT). The successful clinical translation of these radiotherapies requires the implementation of accurate radiation dosimetry approaches able to take into account the impact on treatments of the biological effectiveness of ions and the heterogeneity in the therapeutic agent distribution inside the tumor cells. To this end, biophysical models can be applied to translate the interactions of radiations with matter into biological endpoints, such as cell survival. PURPOSE: The NanOx model was initially developed for predicting the cell survival fractions resulting from irradiations with the high-energy ion beams encountered in hadrontherapy. We present in this work a new implementation of the model that extends its application to irradiations with low-energy ions, as the ones found in TAT and BNCT. METHODS: The NanOx model was adapted to consider the energy loss of primary ions within the sensitive volume (i.e., the cell nucleus). Additional assumptions were introduced to simplify the practical implementation of the model and reduce computation time. In particular, for low-energy ions the narrow-track approximation allowed to neglect the energy deposited by secondary electrons outside the sensitive volume, increasing significantly the performance of simulations. Calculations were performed to compare the original hadrontherapy implementation of the NanOx model with the present one in terms of the inactivation cross sections of human salivary gland cells as a function of the kinetic energy of incident α $\alpha$ -particles. RESULTS: The predictions of the previous and current versions of NanOx agreed for incident energies higher than 1 MeV/n. For lower energies, the new NanOx implementation predicted a decrease in the inactivation cross sections that depended on the length of the sensitive volume. CONCLUSIONS: We reported in this work an extension of the NanOx biophysical model to consider irradiations with low-energy ions, such as the ones found in TAT and BNCT. The excellent agreement observed at intermediate and high energies between the original hadrontherapy implementation and the present one showed that NanOx offers a consistent, self-integrated framework for describing the biological effects induced by ion irradiations. Future work will focus on the application of the latest version of NanOx to cases closer to the clinical setting.

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For the evaluation of the biological effects, Monte Carlo toolkits were used to provide an RBE-weighted dose using databases of survival fraction coefficients predicted through biophysical models. Biophysics models, such as the mMKM and NanOx models, have previously been developed to estimate a biological dose. Using the mMKM model, we calculated the saturation corrected dose mean specific energy z1D* (Gy) and the dose at 10% D10 for human salivary gland (HSG) cells using Monte Carlo Track Structure codes LPCHEM and Geant4-DNA, and compared these with data from the literature for monoenergetic ions. These two models were used to create databases of survival fraction coefficients for several ion types (hydrogen, carbon, helium and oxygen) and for energies ranging from 0.1 to 400 MeV/n. We calculated α values as a function of LET with the mMKM and the NanOx models, and compared these with the literature. In order to estimate the biological dose for SOBPs, these databases were used with a Monte Carlo toolkit. We considered GATE, an open-source software based on the GEANT4 Monte Carlo toolkit. We implemented a tool, the BioDoseActor, in GATE, using the mMKM and NanOx databases of cell survival predictions as input, to estimate, at a voxel scale, biological outcomes when treating a patient. We modeled the HIBMC 320 MeV/u carbon-ion beam line. We then tested the BioDoseActor for the estimation of biological dose, the relative biological effectiveness (RBE) and the cell survival fraction for the irradiation of the HSG cell line. We then tested the implementation for the prediction of cell survival fraction, RBE and biological dose for the HIBMC 320 MeV/u carbon-ion beamline. For the cell survival fraction, we obtained satisfying results. Concerning the prediction of the biological dose, a 10% relative difference between mMKM and NanOx was reported.

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PURPOSE: In hadrontherapy, biophysical models can be used to predict the biological effect received by cancerous tissues and organs at risk. The input data of these models generally consist of information on nano/micro dosimetric quantities and, concerning some models, reactive species produced in water radiolysis. In order to fully account for the radiation stochastic effects, these input data have to be provided by Monte Carlo track structure (MCTS) codes allowing to estimate physical, physico-chemical, and chemical effects of radiation at the molecular scale. The objective of this study is to benchmark two MCTS codes, Geant4-DNA and LPCHEM, that are useful codes for estimating the biological effects of ions during radiation therapy treatments. MATERIAL AND METHODS: In this study we considered the simulation of specific energy spectra for monoenergetic proton beams (10 MeV) as well as radiolysis species production for both electron (1 MeV) and proton (10 MeV) beams with Geant4-DNA and LPCHEM codes. Options 2, 4, and 6 of the Geant4-DNA physics lists have been benchmarked against LPCHEM. We compared probability distributions of energy transfer points in cylindrical nanometric targets (10 nm) positioned in a liquid water box. Then, radiochemical species (· OH, e aq - ${\rm{e}}_{{\rm{aq}}}^ - $ , H 3 O + , H 2 O 2 ${{\rm{H}}_3}{{\rm{O}}^ + },{\rm{\;}}{{\rm{H}}_2}{{\rm{O}}_2}$ , H2 , and O H - ) ${\rm{O}}{{\rm{H}}^ - }){\rm{\;}}$ yields simulated between 10-12 and 10-6 s after irradiation are compared. RESULTS: Overall, the specific energy spectra and the chemical yields obtained by the two codes are in good agreement considering the uncertainties on experimental data used to calibrate the parameters of the MCTS codes. For 10 MeV proton beams, ionization and excitation processes are the major contributors to the specific energy deposition (larger than 90%) while attachment, solvation, and vibration processes are minor contributors. LPCHEM simulates tracks with slightly more concentrated energy depositions than Geant4-DNA which translates into slightly faster recombination than Geant4-DNA. Relative deviations (CEV ) with respect to the average of evolution rates of the radical yields between 10-12 and 10-6 s remain below 10%. When comparing execution times between the codes, we showed that LPCHEM is faster than Geant4-DNA by a factor of about four for 1000 primary particles in all simulation stages (physical, physico-chemical, and chemical). In multi-thread mode (four threads), Geant4-DNA computing times are reduced but remain slower than LPCHEM by ∼20% up to ∼50%. CONCLUSIONS: For the first time, the entire physical, physico-chemical, and chemical models of two track structure Monte Carlo codes have been benchmarked along with an extensive analysis on the effects on the water radiolysis simulation. This study opens up new perspectives in using specific energy distributions and radiolytic species yields from monoenergetic ions in biophysical models integrated to Monte Carlo software.

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Hypoxia-Inducible Factor 1α (HIF-1α), which promotes cancer cell survival, is the main regulator of oxygen homeostasis. Hypoxia combined with photon and carbon ion irradiation (C-ions) stabilizes HIF-1α. Silencing HIF-1α under hypoxia leads to substantial radiosensitization of Head-and-Neck Squamous Cell Carcinoma (HNSCC) cells after both photons and C-ions. Thus, this study aimed to clarify a potential involvement of HIF-1α in the detection, signaling, and repair of DNA Double-Strand-Breaks (DSBs) in response to both irradiations, in two HNSCC cell lines and their subpopulations of Cancer-Stem Cells (CSCs). After confirming the nucleoshuttling of HIF-1α in response to both exposure under hypoxia, we showed that silencing HIF-1α in non-CSCs and CSCs decreased the initiation of the DSB detection (P-ATM), and increased the residual phosphorylated H2AX (γH2AX) foci. While HIF-1α silencing did not modulate 53BP1 expression, P-DNA-PKcs (NHEJ-c) and RAD51 (HR) signals decreased. Altogether, our experiments demonstrate the involvement of HIF-1α in the detection and signaling of DSBs, but also in the main repair pathways (NHEJ-c and HR), without favoring one of them. Combining HIF-1α silencing with both types of radiation could therefore present a potential therapeutic benefit of targeting CSCs mostly present in tumor hypoxic niches.

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PURPOSE: To develop a particle transport code to compute w-values and stopping power of swift ions in liquid water and gases of interest for reference dosimetry in hadrontherapy. To analyze the relevance of inelastic and post-collisional processes considered. METHODS: The Monte Carlo code MDM was extended to the case of swift ion impact on liquid water (MDM-Ion). Relativistic corrections in the inelastic cross sections and the post-collisional Auger emission were considered. The effects of introducing different electronic excitation cross sections were also studied. RESULTS: The stopping power of swift ions on liquid water, calculated with MDM-Ion, are in excellent agreement with recommended data. The w-values show a strong dependence on the electronic excitation cross sections and on the Auger electron emission. Comparisons with other Monte Carlo codes show the relevance of both the processes considered and of the cross sections employed. W and w-values for swift electron, proton, and carbon ions calculated with the MDM and MDM-Ion codes are in very close agreement with each other and with the 20.8 eV experimental value. CONCLUSION: We found that w-values in liquid water are independent of ion charge and energy, as assumed in reference dosimetry for hadrontherapy from sparse experimental results for electron and ion impact on gases. Excitation cross sections and Auger emission included in Monte Carlo codes are critical in w-values calculations. The computation of this physical parameter should be used as a benchmark for micro-dosimetry investigations, to assess the reliability of the cross sections employed.

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The goal of this paper is to calculate a complex internal respiratory and tumoral movements by measuring respiratory air flows and thorax movements. In this context, we present a new lung tumor tracking approach based on a patient-specific biomechanical model of the respiratory system, which takes into account the physiology of respiratory motion to simulate the real non-reproducible motion. The behavior of the lungs, is directly driven by the simulated actions of the breathing muscles, i.e. the diaphragm and the intercostal muscles (the rib cage). In this paper, the lung model is monitored and controlled by a personalized lung pressure/volume relationship during a whole respiratory cycle. The lung pressure and rib kinematics are patient specific and obtained by surrogate measurement. The rib displacement corresponding to the transformation which was computed by finite helical axis method from the end of exhalation (EE) to the end of inhalation (EI). The lung pressure is calculated by an optimization framework based on inverse finite element analysis, by minimizing the lung volume errors, between the respiratory volume (respiratory airflow exchange) and the simulated volume (calculated by biomechanical simulation). We have evaluated the model accuracy on five public datasets. We have also evaluated the lung tumor motion identified in 4D CT scan images and compared it with the trajectory that was obtained by finite element simulation. The effects of rib kinematics on lung tumor trajectory were investigated. Over all phases of respiration, our developed model is able to predict the lung tumor motion with an average landmark error of [Formula: see text]. The results demonstrate the effectiveness of our physics-based model. We believe that this model can be potentially used in 4D dose computation, removal of breathing motion artifacts in positron emission tomography (PET) or gamma prompt image reconstruction.

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PURPOSE: For the past two decades, high-Z nanoparticles have been of high interest to improve the therapeutic outcomes of radiation therapy, especially for low-energy x-rays. Monte Carlo (MC) simulations have been used to evaluate the boost of dose deposition induced by Auger electrons near the nanoparticle surface, by calculating average energy deposition at the nanoscale. In this study, we propose to go beyond average quantities and quantify the stochastic nature of energy deposition at such a scale. We present results of probability density of the specific energy (restricted to ionization, excitation and electron attachment events) in cylindrical nanotargets of height and radius set at 10 nm. This quantity was evaluated for nanotargets located within 200 nm around 5-50 nm gold nanoparticles (GNPs), for 20-90 keV photon irradiation. METHODS: This nanodosimetry study was based on the MC simulation MDM that allows tracking of electrons down to thermalization energy. We introduced a new quantity, namely the probability enhancement ratio (PER), by estimating the probability of imparting to nanotargets a restricted specific energy larger than a threshold z 0 (1, 10, and 20 kGy), normalized to the probability for pure water. The PER was calculated as a function of the distance between the nanotarget and the GNP surface. The threshold values were chosen in light of the biophysical model NanOx that predicts cell survival by calculating local lethal events based on the restricted specific energy and an effective local lethal function. z 0 then represents a threshold above which the nanotarget damages induce efficiently cell death. RESULTS: Our calculations showed that the PER varied a lot with the GNP radius, the photon energy, z 0 and the distance of the GNP to the nanotarget. The highest PER was 95 when the nanotarget was located at 5 nm from the GNP surface, for a photon energy of 20 keV, a threshold of 20 kGy, and a GNP radius of 50 nm. This enhancement dramatically decreased with increasing GNP-nanotarget distances as it went below 1.5 for distances larger than 200 nm. CONCLUSIONS: The PER seems better adapted than the mean dose deposition to describe the formation of biological damages. The significant increase of the PER within 200 nm around the GNP suggests that severe damages could occur for biological nanotargets located near the GNP. These calculations will be used as an input of the biophysical model NanOx to convert PER into estimation of radiation-induced cell death enhanced by GNPs.

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DNA double-strand breaks (DSBs) induced by photon irradiation are the most deleterious damage for cancer cells and their efficient repair may contribute to radioresistance, particularly in hypoxic conditions. Carbon ions (C-ions) act independently of the oxygen concentration and trigger complex- and clustered-DSBs difficult to repair. Understanding the interrelation between hypoxia, radiation-type, and DNA-repair is therefore essential for overcoming radioresistance. The DSBs signaling and the contribution of the canonical non-homologous end-joining (NHEJ-c) and homologous-recombination (HR) repair pathways were assessed by immunostaining in two cancer-stem-cell (CSCs) and non-CSCs HNSCC cell lines. Detection and signaling of DSBs were lower in response to C-ions than photons. Hypoxia increased the decay-rate of the detected DSBs (γH2AX) in CSCs after photons and the initiation of DSB repair signaling (P-ATM) in CSCs and non-CSCs after both radiations, but not the choice of DSB repair pathway (53BP1). Additionally, hypoxia increased the NHEJ-c (DNA-PK) and the HR pathway (RAD51) activation only after photons. Furthermore, the involvement of the HR seemed to be higher in CSCs after photons and in non-CSCs after C-ions. Taken together, our results show that C-ions may overcome the radioresistance of HNSCC associated with DNA repair, particularly in CSCs, and independently of a hypoxic microenvironment.

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Functionalized gold nanoparticles are investigated by density functional theory calculations in the context of cancer radiotherapy. Several typical experimental shapes, including nanostars, nanospheres, and nanorods, are modeled by optimizing Au clusters covered by organic monolayers composed of hydrated short-chain polyethylene glycol (PEG) ligands. The PEGylation stabilizes significantly the stellation of decahedral Au54 by deforming significantly its geometry at the spikes. The higher stability of the PEG molecules adsorbed on this stellated nanocluster with respect to the more spherical icosahedral Au55 and truncated octahedral Au79 leads to a larger energy cost to desorb them and thus a weaker propensity for the starred nanoparticle to exchange ligands with the cell membrane, in agreement with experiments. These results open interesting possibilities for advancing our understanding of the cellular uptake of gold nanoparticles.

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NanOx is a biophysical model recently developed in the context of hadrontherapy to predict the cell survival probability from ionizing radiation. It postulates that this may be factorized into two independent terms describing the cell response to two classes of biological events that occur in the sequence of an irradiation: the local lethal events that occur at nanometric scale and can by themselves induce cell death, and the non-local lethal events that lead to cell death by an effect of accumulation and/or interaction at a larger scale. Here we address how local lethal events are modeled in terms of the inactivation of undifferentiated nanometric targets via an "effective local lethal function F", which characterizes the response of each cell line to the spectra of "restricted specific energy". F is initially determined as a linear combination of basis functions. Then, a parametric expression is used to reproduce the function's main features, a threshold and a saturation, while at the same time reducing the number of free parameters. This strategy was applied to three cell lines in response to ions of different type and energy, which allows for benchmarking of the α(LET) curves predicted with both effective local lethal functions against the experimental data.

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Although conventional radiotherapy promotes the migration/invasion of cancer stem cells (CSCs) under normoxia, carbon ion (C-ion) irradiation actually decreases these processes. Unraveling the mechanisms of this discrepancy, particularly under the hypoxic conditions that pertain in niches where CSCs are preferentially localized, would provide a better understanding of the origins of metastases. Invasion/migration, proteins involved in epithelial-to-mesenchymal transition (EMT), and expression of MMP-2 and HIF-1α were quantified in the CSC subpopulations of two head-and-neck squamous cell carcinoma (HNSCC) cell lines irradiated with X-rays or C-ions. X-rays triggered HNSCC-CSC migration/invasion under normoxia, however this effect was significantly attenuated under hypoxia. C-ions induced fewer of these processes in both oxygenation conditions. The differential response to C-ions was associated with a lack of HIF-1α stabilization, MMP-2 expression, or activation of kinases of the main EMT signaling pathways. Furthermore,we demonstrated a major role of reactive oxygen species (ROS) in the triggering of invasion/migration in response to X-rays. Monte-Carlo simulations demonstrated that HO● radicals are quantitatively higher after C-ions than after X-rays, however they are very differently distributed within cells. We postulate that the uniform distribution of ROS after X-rays induces the mechanisms leading to invasion/migration, which ROS concentrated in C-ion tracks are unable to trigger.

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Solvated gold nanoparticles have been modeled in the fluxional regime by density functional theory including dispersion forces for an extensive set of conventional morphologies. The study of isolated adsorption of one water molecule shows that the most stable adsorption forms are similar (corners and edges) regardless of the nanoparticle shape and size, although the adsorption strength differs significantly (0.15 eV). When a complete and explicit water solvation shell interacts with gold nanoclusters, metastable in vacuum and presenting a predominance of (100) square facets (ino-decahedra Au55 and Au147), these nanoparticles are found unstable and transform into the closest morphologies exhibiting mainly (111) triangular facets and symmetries. The corresponding adsorption strength per water molecule becomes independent of shape and size and is enhanced by the formation of two hydrogen bonds on average. For applications in radiotherapy, this study suggests that the shapes of small gold nanoparticles should be homogenized by interacting with the biological environment.

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The relative biological effectiveness (RBE) in particle therapy is currently estimated using biophysical models. We compared experimental measurements to the α curves as function of linear energy transfer computed by the Local Effect Model (LEM I-IV), the Microdosimetric Kinetic Model (MKM) and the NanOx model for HSG, V79 and CHO-K1 cells in response to monoenergetic irradiations. Although the LEM IV and the MKM predictions accurately reproduced the trend observed in the data, NanOx yielded a better agreement than the other models for more irradiation configurations. Its χ 2 estimator was indeed the lowest for three over seven considered cases.

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The use of tetrahedral-based phantoms in conjunction with Monte Carlo dose calculation techniques has shown high capabilities in radiation therapy. However, the generation of a precise dose distribution can be very time-consuming since a fine tetrahedral mesh is required. In this work, we propose a new method that defines the density distribution of patient-specific tetrahedral phantoms, based upon the CT-scans and the direction of the particle beam. The final purpose is to coarsen the tetrahedral mesh to improve computational performance in Monte Carlo simulations while guaranteeing a precise dose distribution in the target volume. Contrarily to the state of the art methods that calculate the density value of a tetrahedron, locally based only on the CT-scans, our approach also takes into account the direction of the beam to minimize the error of the water equivalent thickness of the tetrahedrons before the tumor volume. In this study, the experiments carried out on a multi-layer computational phantom, and a thorax geometry, show that by applying our method on a coarse mesh, we offer a better dose distribution inside the tumor compared to other density mapping methods, in the same level of detail. This is due to the reduction of the water equivalent path length error from 9.65 mm to 0.62 mm in the case of the multi-layer phantom, and from 2.42 mm to 0.48 mm for the thorax geometry. Moreover, a similar dose coverage is obtained with refined tetrahedral meshes. As a consequence of the reduction of the number of tetrahedrons, computational time is found to be 25% shorter than both the refined tetrahedral mesh and the voxel-based structure in most cases. Using a coarse tetrahedral mesh to have accurate dose distributions on a given target is feasible as long as the water equivalent path length in the direction of the beam is respected.

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PURPOSE: Our study aimed at evaluating: 1) whether well-established variability in radioadaptive response (AR) in various donor blood lymphocytes might be attributed to inter-individual differences in radiosensitivity to different low dose levels; 2) whether AR is reproducibly present over time in the lymphocytes of AR-positive individuals. Experimental procedure: Whole blood samples of three donors were exposed to low doses (2-30 cGy) of γ-radiation alone (G0 phase) or followed by a 1 Gy challenge dose (late S/early G2 phase), and chromosome aberration were scored to assess the dose-response relationship and adaptive response, correspondingly. Three experiments were performed on blood samples of the same donors at six month intervals. RESULTS: Significant differences in dose response relationship for blood lymphocytes were found among individuals. In most cases, the donors exhibited initial low-dose hypersensitivity (HRS) followed by an increase in radioresistance (IRR). AR could be successfully induced by some particular priming doses in the lymphocytes of each donor; however, the doses resulting in a protective response were quite different for all three donors. These protective doses could equally belong to either HRS or IRR region on the individual dose-response curves. In most cases, no clear AR outcome dependence on the priming dose was found at all. Moreover, pre-exposure to the same low dose could result in opposite effects in the lymphocytes of the same donor in different experiments. CONCLUSIONS: AR variability in human lymphocytes is not attributed to variation in radiosensitivity among individuals and is more drastic than was believed. It seems doubtful that AR is a universal phenomenon which has a consistent impact on the effects of radiation exposure on humans.

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Hadrontherapy presents the major advantage of improving tumor sterilization while sparing surrounding healthy tissues because of the particular ballistic (Bragg peak) of carbon ions. However, its efficacy is still limited in the most resistant cancers, such as grade III-IV head and neck squamous cell carcinoma (HNSCC), in which the association of carbon ions with gadolinium-based nanoparticles (AGuIX®) could be used as a Trojan horse. We report for the first time the radioenhancing effect of AGuIX® when combined with carbon ion irradiation in human tumor cells. An increase in relative biological effectiveness (1.7) in three HNSCC cell lines (SQ20B, FaDu, and Cal33) was associated with a significant reduction in the radiation dose needed for killing cells. Radiosensitization goes through a higher number of unrepaired DNA double-strand breaks. These results underline the strong potential of AGuIX® in sensitizing aggressive tumors to hadrontherapy and, therefore, improving local control while lowering acute/late toxicity.

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BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) are resistant to standard treatments, partly due to cancer stem cells (CSCs) localised in hypoxic niches. Compared to X-rays, carbon ion irradiation relies on better ballistic properties, higher relative biological effectiveness and the absence of oxygen effect. Hypoxia-inducible factor-1α (HIF-1α) is involved in the resistance to photons, whereas its role in response to carbon ions remains unclear. METHODS: Two HNSCC cell lines and their CSC sub-population were studied in response to photons or carbon ion irradiation, in normoxia or hypoxia, after inhibition or not of HIF-1α. RESULTS: Under hypoxia, compared to non-CSCs, HIF-1α is expressed earlier in CSCs. A combined effect photons/hypoxia, less observed with carbon ions, results in a synergic and earlier HIF-1α expression in both subpopulations. The diffuse ROS production by photons is concomitant with HIF-1α expression and essential to its activation. There is no oxygen effect in response to carbon ions and the ROS localised in the track might be insufficient to stabilise HIF-1α. Finally, in hypoxia, cells were sensitised to both types of radiations after HIF-1α inhibition. CONCLUSIONS: Hypoxia-inducible factor-1α plays a main role in the response of CSCs and non-CSCs to carbon ion and photon irradiations, which makes the HIF-1α targeting an attractive therapeutic challenge.

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Head and neck cancer remains a significant public health concern. About 60% of patients die within 5years due to local recurrence. Head and neck squamous cell carcinoma (HNSCC) cell lines are important preclinical models in the search for new therapies against this disease. Furthermore, there is a need to test novel drugs before introduction into clinical practice. A preclinical model that closely resembles the in vivo situation would be highly valuable. In the last few decades, a multicellular spheroid model has gained attention as its behavior was comparable to in vivo tumors. Basic research is necessary to achieve an understanding of the normal and pathological state but cannot, in itself, provide sufficient information for clinical applications. Indeed, animal models are an inevitable prelude to assess the efficacy of new therapeutic approaches in HNSCC. The present review proposes an overview of HNSCC pre-clinical models in order to further understand the oncogenic properties for HNSCC and translate these findings into clinic for patients.

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Cancer Stem Cells (CSCs) in Head and Neck Squamous Cell Carcinoma (HNSCC) have extremely aggressive profile (high migratory and invasive potential). These characteristics can explain their resistance to conventional treatment. Efficacy of photon and carbon ion irradiation with addition of cetuximab (5 nM) is studied on clonogenic death, migration and invasion of two HNSCC populations: SQ20B and SQ20B/CSCs. SQ20B express E-cadherin and overexpress EGFR while SQ20B/CSCs express N-cadherin and low EGFR. Cetuximab strongly inhibits SQ20B proliferation but has no effect on SQ20B/CSCs. 2 Gy photon irradiation enhances migration and invasiveness in both populations (p < 0.05), while cetuximab only stops SQ20B migration (p < 0.005). Carbon irradiation significantly inhibits invasion in both populations (p < 0.05), and the association with cetuximab significantly inhibits invasion in both populations (p < 0.005). These results highlight CSCs characteristics: EGFRLow, cetuximab-resistant, and highly migratory. Carbon ion irradiation appears to be a very promising therapeutic modality counteracting migration/invasion process in both parental cells and CSCs in contrast to photon irradiation.

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Nowadays, head and neck squamous cell carcinoma (HNSCC) treatment failure is mostly explained by locoregional progression or intrinsic radioresistance. Radiotherapy (RT) has recently evolved with the emergence of heavy ion radiations or new fractionation schemes of photon therapy, which modify the dose rate of treatment delivery. The aim of the present study was then to evaluate the in vitro influence of a dose rate variation during conventional RT or carbon ion hadrontherapy treatment in order to improve the therapeutic care of patient. In this regard, two HNSCC cell lines were irradiated with photons or 72 MeV/n carbon ions at a dose rate of 0.5, 2, or 10 Gy/min. For both radiosensitive and radioresistant cells, the change in dose rate significantly affected cell survival in response to photon exposure. This variation of radiosensitivity was associated with the number of initial and residual DNA double-strand breaks (DSBs). By contrast, the dose rate change did not affect neither cell survival nor the residual DNA DSBs after carbon ion irradiation. As a result, the relative biological efficiency at 10% survival increased when the dose rate decreased. In conclusion, in the RT treatment of HNSCC, it is advised to remain very careful when modifying the classical schemes toward altered fractionation. At the opposite, as the dose rate does not seem to have any effects after carbon ion exposure, there is less need to adapt hadrontherapy treatment planning during active system irradiation.