Radiobiological Processes Research Articles

Radiobiology of Proton Therapy in Human Papillomavirus-Negative and Human Papillomavirus-Positive Head and Neck Cancer Cells.

Photon-based radiotherapy (XRT) is one of the most frequently used treatment modalities for HPV-negative and HPV-positive locally advanced head and neck squamous cell carcinoma (HNSCC). However, locoregional recurrences and normal RT-associated toxicity remain major problems for these patients. Proton therapy (PT), with its dosimetric advantages, can present a solution to the normal toxicity problem. However, issues concerning physical delivery and the lack of insights into the underlying biology of PT hamper the full exploitation of PT. Here, we assessed the radiobiological processes involved in PT in HPV-negative and HPV-positive HNSCC cells. We show that PT and XRT activate the DNA damage-repair and stress response in both HPV-negative and HPV-positive cells to a similar extent. The activation of these major radiobiological mechanisms resulted in equal levels of clonogenic survival and mitotic cell death. Altogether, PT resulted in similar biological effectiveness when compared to XRT. These results emphasize the importance of dosimetric parameters when exploiting the potential of increased clinical effectiveness and reduced normal tissue toxicity in PT treatment.

Comparative analysis of mathematical models describing radiobiological processes in radiotherapy

Comparative analysis of mathematical models describing radiobiological processes in radiotherapy

Electron ionization of clusters containing the formamide molecule

Studies on electron interactions with formamide (FA) clusters promote scientific interest as a model system to understand phenomena relevant to astrophysical, prebiotic, and radiobiological processes. In this work, mass spectrometric detection of cationic species for both small bare and microhydrated formamide clusters was performed at an electron ionization of 70 eV. Furthermore, a comparative analysis of the cluster spectra with the literature-reported gas-phase spectra is presented and discussed, revealing different reaction channels affected by the cluster environment. This study is essential in developing our understanding of both low-energy electron phenomena in clusters that can bridge the complexity gap between gas and realistic systems and the effect of hydration on electron-induced processes.

Cytoproliferative effect of low dose alpha radiation in human lung cancer cells is associated with connexin 43, caveolin-1, and survivin pathway

Purpose High LET including alpha radiation-based approaches have been proved as a promising mode for cancer therapy owing to their biophysical and radiobiological advantages compared to photon beams. Studies pertaining to effect of α-radiation on cancer cells are limited to cytotoxic high doses. Materials and methods In this study, human lung adenocarcinoma (A549) cells were α-irradiated using 241Am α-irradiator and effects of low dose of alpha radiation on these cells was studied under in vitro and in vivo conditions. Results Clonogenic and other assays showed increased cellular proliferation at lower doses (1.36 and 6.8 cGy) but killing at higher doses (13.6–54.4 cGy). Further studies at low dose of alpha (1.36 cGy) showed increased TGF-β1 in the conditioned medium (CM) at early time point (24 h) but CM replacement did not affect the clonogenic survival. In these cells, increased phosphorylation of connexin 43 was correlated with decrease in gap-junction communication observed by dye transfer co-culture experiment. A decrease in caveolin-1 but increase in survivin expression was observed in low dose α-irradiated cells. An increase in cyclinD1 and decrease in Bcl-2, the target proteins of survivin, was observed in these cells. Low dose α-irradiated cancer cells transplanted in SCID mice showed significantly higher tumor volume, which was accompanied with an increased fraction of mitotic and PCNA/Ki67 positive cells in these tumor tissues. Conclusions Taken together, our results suggest an increase in proliferation and tumor volume at in vitro and in vivo levels, respectively, when A549 cells were irradiated with low dose of α-radiation. These findings may be relevant for a better understanding of radiobiological processes during high LET-based cancer radiotherapy.

Challenges in Monte Carlo Simulations as Clinical and Research Tool in Particle Therapy: A Review

The use and interest in Monte Carlo (MC) techniques in the field of medical physics have been rapidly increasing in the past years. This is the case especially in particle therapy, where accurate simulations of different physics processes in complex patient geometries are crucial for a successful patient treatment and for many related research and development activities. Thanks to the detailed implementation of physics processes in any type of material, to the capability of tracking particles in 3D, and to the possibility of including the most important radiobiological effects, MC simulations have become an essential calculation tool not only for dose calculations but also for many other purposes, like the design and commissioning of novel clinical facilities, shielding and radiation protection, the commissioning of treatment planning systems, and prediction and interpretation of data for range monitoring strategies. MC simulations are starting to be more frequently used in clinical practice, especially in the form of specialized codes oriented to dose calculations that can be performed in short time. The use of general purpose MC codes is instead more devoted to research. Despite the increased use of MC simulations for patient treatments, the existing literature suggests that there are still a number of challenges to be faced in order to increase the accuracy of MC calculations for patient treatments. The goal of this review is to discuss some of these remaining challenges. Undoubtedly, it is a work for which a multidisciplinary approach is required. Here, we try to identify some of the aspects where the community involved in applied nuclear physics, radiation biophysics, and computing development can contribute to find solutions. We have selected four specific challenges: i) the development of models in MC to describe nuclear physics interactions, ii) modeling of radiobiological processes in MC simulations, iii) developments of MC-based treatment planning tools, and iv) developments of fast MC codes. For each of them, we describe the underlying problems, present selected examples of proposed solutions, and try to give recommendations for future research.

Imaging Biomarkers of Tumour Proliferation and Invasion for Personalised Lung Cancer Therapy.

Personalised treatment in oncology has seen great developments over the last decade, due to both technological advances and more in-depth knowledge of radiobiological processes occurring in tumours. Lung cancer therapy is no exception, as new molecular targets have been identified to further increase treatment specificity and sensitivity. Yet, tumour resistance to treatment is still one of the main reasons for treatment failure. This is due to a number of factors, among which tumour proliferation, the presence of cancer stem cells and the metastatic potential of the primary tumour are key features that require better controlling to further improve cancer management in general, and lung cancer treatment in particular. Imaging biomarkers play a key role in the identification of biological particularities within tumours and therefore are an important component of treatment personalisation in radiotherapy. Imaging techniques such as PET, SPECT, MRI that employ tumour-specific biomarkers already play a critical role in patient stratification towards individualized treatment. The aim of the current paper is to describe the radiobiological challenges of lung cancer treatment in relation to the latest imaging biomarkers that can aid in the identification of hostile cellular features for further treatment adaptation and tailoring to the individual patient’s needs.

Water acting as a catalyst for electron-driven molecular break-up of tetrahydrofuran

Low-energy electron-induced reactions in hydrated molecular complexes are important in various fields ranging from the Earth’s environment to radiobiological processes including radiation therapy. Nevertheless, our understanding of the reaction mechanisms in particular in the condensed phase and the role of water in aqueous environments is incomplete. Here we use small hydrogen-bonded pure and mixed dimers of the heterocyclic molecule tetrahydrofuran (THF) and water as models for biochemically relevant systems. For electron-impact-induced ionization of these dimers, a molecular ring-break mechanism is observed, which is absent for the THF monomer. Employing coincident fragment ion mass and electron momentum spectroscopy, and theoretical calculations, we find that ionization of the outermost THF orbital initiates significant rearrangement of the dimer structure increasing the internal energy and leading to THF ring-break. These results demonstrate that the local environment in form of hydrogen-bonded molecules can considerably affect the stability of molecular covalent bonds.

More Ions for Radiotherapy: About Treatment Planning and Track Simulations

In the recent years, irradiation with swift light ions - from protons up to oxygen -has become an established method in tumour radiotherapy.A prerequisite for successful treatment is the sufficient knowledge of physical and radiobiological processes down to the microscopic or even nanoscopic scale. This report summarizes recent developments. In particular the application of ions other than protons and carbon will be addressed, as well as modelling approaches on the nanoscale.

Mechanism of carcinogenesis after exposure of actinide radionuclides: Emerging concepts and missing links

Radiation carcinogenesis may be associated with external and/or internal sources of radiation exposure during accidental, occupational, or diagnostic/therapeutic conditions. Most of the radiation carcinogenic events are established after acute doses of low linear energy transfer external radiation. Moreover, the carcinogenic effects of internalized radioisotopes are also reported at their acute/chronic doses. In this regard, actinide radionuclides (like 238U, 239Pu, 232Th, and 241Am) are of great importance as fuel material or waste generated during nuclear power production. These radionuclides may result in incidence of cancer when internalized at high doses while accidental or occupation exposure. Even though the basic carcinogenic mechanism after external or internal radiation exposure remains the same, the magnitude of systemic or target specific radiation effects may vary in these radiation exposure conditions. The majority of the studies investigating biological, carcinogenic, and other health effects of actinide radionuclides are limited only up to quantification of these effects without much mechanistic insights. Moreover, the radiobiological processes, such as bystander effect, genomic instability, and adaptive response, governing the cellular radiosensitivity of targeted/nontargeted cells also need to be studied in the context of carcinogenesis after actinide radionuclides internalization. The review aims to highlight the emerging radiobiological concepts and missing links about actinide radionuclides-induced carcinogenesis. In addition, an overview has been presented about biological and health effects of major actinide radionuclides.

A laser-driven nanosecond proton source for radiobiological studies

Ion beams are relevant for radiobiological studies and for tumor therapy. In contrast to conventional accelerators, laser-driven ion acceleration offers a potentially more compact and cost-effective means of delivering ions for radiotherapy. Here, we show that by combining advanced acceleration using nanometer thin targets and beam transport, truly nanosecond quasi-monoenergetic proton bunches can be generated with a table-top laser system, delivering single shot doses up to 7 Gy to living cells. Although in their infancy, laser-ion accelerators allow studying fast radiobiological processes as demonstrated here by measurements of the relative biological effectiveness of nanosecond proton bunches in human tumor cells.

Ion beams in radiotherapy - from tracks to treatment planning

Several dozen clinical sites around the world apply beams of fast light ions for radiotherapeutical purposes. Thus there is a vested interest in the various physical and radiobiological processes governing the interaction of ion beams with matter, specifically living systems. We discuss the various modelling steps which lead from basic interactions to the application in actual patient treatment planning. The nano- and microscopic scale is covered by sample calculations with our TRAX code. On the macroscopic scale we feature the TRiP98 treatment planning system, which was clinically used in GSI's radiotherapy pilot project.

SU-E-T-245: Survival Fractions for Head-And-Neck Cancer Derived from Tumor-Volume Variation Curves Using a 2-Level Cell Population Model.

Volumetric tumor response to radiotherapy is an integrated process which includes several radiobiological mechanisms, such as cell killing, cell proliferation, dead-cell removal and tumor reoxygenation. Our goal is to reconstruct the information about these underlying radiobiological processes and specifically the cell survival fractions by fitting a 2-level cell-population tumor-volume model to imaging-derived tumor-volume variation curves obtained during radiotherapy for head-and-neck cancer. Modeling tumor-volume during radiotherapy is a challenging problem because it is described by a sum of exponentials; therefore, the problem of accurately fitting a model to measured data is ill-posed. As an initial point of this research, we utilize a simplest 2-level cell-population tumor-volume model which separates the entire tumor-cell population into oxygenated viable cells and oxygenated lethally damaged cells. The 2-level cell population tumor model has the advantage of being conditionally well-posed. We integrated this parameterized radiobiological model with a least squares objective function and a simulated annealing optimization algorithm to characterize individual patients' time-dependent tumor-volume regression rates. The measured tumor-volume variation curves were taken from a clinical study on tumor-volume variation during radiotherapy for 14 head-and-neck cancer patients in which an integrated CT/linac system was used for tumor-volume measurements. The 2-level tumor volume modeling is able to predict tumor behavior throughout an entire treatment for 8 of 14 patients. The average survival fraction 0.44 agrees very well with the published survival fraction of 0.45 for the head-and-neck squamous cell carcinoma. However, the 2-level model cannot describe the variation of the cell disintegration rate which is observed at the end of treatment for some of the head-and-neck cancer patients. The 2-level cell population model is an acceptable approximation for the tumor-volume for some clinical cases, but it cannot describe all tumor-volume regression cases. This may be explained by omitting hypoxia in the 2-level model.

Using radiation risk for assessment of space radiation hazard

Radiation hazard caused by exposure during a spaceflight is characterized by radiobiological consequences at all levels of organism. These consequences have a stochastic nature. Even deterministic effects are basically random quantity having all attributes of such mathematical values. The radiation risk is defined in this case as an additional probability of health damage or as a death probability in extreme case. For the manned spaceflight additional peculiarity of a human’s exposure is added. A natural space radiation environment has a stochastic character because solar particle events and crew of a spacecraft can be exposed to dose from background level up to lethal one. The report presents a procedure of radiation risk assessment for quantitative expression of radiation hazard level during a flight and using this value for developing protection recommendations. It is emphasized that the risk value is connected specifically with the time interval of possible hazard’s existent. The form of risk representation must be chosen depending on a time scale of radiobiological processes induced by the exposure (expressing in fact the radiation hazard model). Surviving function specified for the crewmember mortality rate changed by the professional exposure must be used for risk calculation. Solar particle events determine a stochastic character of radiation environment in space that must be taken into account for a risk assessment. The reliability of radiation risk assessment can be used for this goal.

Datamining approaches for modeling tumor control probability

Background. Tumor control probability (TCP) to radiotherapy is determined by complex interactions between tumor biology, tumor microenvironment, radiation dosimetry, and patient-related variables. The complexity of these heterogeneous variable interactions constitutes a challenge for building predictive models for routine clinical practice. We describe a datamining framework that can unravel the higher order relationships among dosimetric dose-volume prognostic variables, interrogate various radiobiological processes, and generalize to unseen data before when applied prospectively. Material and methods. Several datamining approaches are discussed that include dose-volume metrics, equivalent uniform dose, mechanistic Poisson model, and model building methods using statistical regression and machine learning techniques. Institutional datasets of non-small cell lung cancer (NSCLC) patients are used to demonstrate these methods. The performance of the different methods was evaluated using bivariate Spearman rank correlations (rs). Over-fitting was controlled via resampling methods. Results. Using a dataset of 56 patients with primary NCSLC tumors and 23 candidate variables, we estimated GTV volume and V75 to be the best model parameters for predicting TCP using statistical resampling and a logistic model. Using these variables, the support vector machine (SVM) kernel method provided superior performance for TCP prediction with an rs=0.68 on leave-one-out testing compared to logistic regression (rs=0.4), Poisson-based TCP (rs=0.33), and cell kill equivalent uniform dose model (rs=0.17). Conclusions. The prediction of treatment response can be improved by utilizing datamining approaches, which are able to unravel important non-linear complex interactions among model variables and have the capacity to predict on unseen data for prospective clinical applications.

EXTRAPOLATING RADIATION-INDUCED CANCER RISKS FROM LOW DOSES TO VERY LOW DOSES

There is strong evidence that ionizing radiation increases cancer risks at high doses (e.g., >or=1 Gy), and persuasive, if controversial, epidemiological evidence that cancer risks are increased at low doses ( approximately 10 mGy). Discussed here are the issues related to extrapolating radiation risks from low radiation doses to very low doses (<or=1 mGy) - for which purpose we are forced to rely on radiobiological evidence and biophysical arguments. At high doses, cells are typically hit by many tracks of radiation, while at low doses most cells are typically hit by a single track of radiation; at very low doses proportionately fewer cells are hit, again only by a single track of radiation. Thus, in comparing low doses to very low doses, the damage to hit cells remains essentially the same (a single radiation track passing through a cell), but what changes is the number of cells that are subjected to this same damage, which decreases linearly as the dose decreases. This is the argument for a linear no-threshold (LNT) model. It is important to emphasize that this LNT argument only applies to the extrapolation from low doses to very low doses, not from high to low doses. Of course there are caveats to this argument, such as the potential effects of phenomena such as inter-cellular communication and immunosurveillance, and the possibility of different radiobiological processes at very low doses, compared to low doses. However, there is little conclusive experimental evidence about the significance of these phenomena at very low doses, and comparative mechanistic studies at high doses vs. low doses will not be informative in this context. At present, we do not know whether such radiobiological phenomena would produce small or large perturbations, or even whether they would increase or decrease cancer risks at very low doses, compared with the prediction of a linear extrapolation from low doses.

WE-C-AUD B-02: Tumor Volume Simulation in Radiotherapy Using Four-Level Cell Population Model

Purpose: To develop a fast computational radiobiological model for qualitative and quantitative analysis of tumor volume variation during fractionated radiotherapy. This model can be used in 4D treatment planning for evaluation of dose variations due to time-dependent density variations in highly conformal radiotherapeutic modalities as IMRT and proton therapy. Method and Materials: The analysis is performed using two approximations: 1) tumor volume is a linear function of total cell number in tumor and 2) tumor cell population is separated into four subpopulations: oxygenated live and dead cells and hypoxic live and dead cells. The “dead” cells are lethally damaged by radiation and not able to proliferate; however, they stay in the tumor and contribute to the tumor volume until they disintegrate and their debris is removed. The number of living oxygenated and hypoxic cells is governed by the radiobiological mechanisms as LQ survival model, exponential repopulation and reoxygenation. The oxygenated dead cells are removed from the tumor using an exponential decay model. Results: We have computed tumor volume variation during fractionated radiotherapy for the head-and-neck cancer. The computational results have been compared to the clinical data previously obtained for the head-and-neck cancer using an integrated CT/linear accelerator system. We show that the model predicts the tumor volume variation for the majority of head-and-neck cases. Largest discrepancies between the model and clinical data are obtained during the first days of treatment. Conclusion: The tumor volume during radiotherapy can be qualitatively described using a relatively simple radiobiological model. The potential impact on the tumor volume of other radiobiological processes which have not been included into the current model as cell cycle analysis, accelerated repopulation and chemotherapy should be studied in the future. Research sponsored by Elekta corporation.

重イオンマイクロビームを用いた細胞１個の狙い撃ち照射

Heavy charged particles transfer their energy to biological organisms through high-density ionization along the particle trajectories. The population of cells exposed to a very low dose of heavy-ion beams contains a few cells hit by a particle, while the majority of the cells receive no radiation damage. At somewhat higher doses, some of the cells receive two or more events according to the Poisson distribution of ion injections. This fluctuation of particle trajectories through individual cells makes interpretation of radiological effects of heavy ions difficult. Furthermore, there has recently been an increasing interest in ionizing radiation-induced “bystander effects”, that is, radiation effects transmitted from hit cells to neighboring un-hit cells. Therefore, we have established a single-cell/single-particle irradiation system using a heavy-ion microbeam apparatus at JAEA-Takasaki to study radiobiological processes in hit cells and bystander cells exposed to low dose and low dose-rate high-LET radiations, in ways that cannot be achieved using conventional broad-field exposures.

A theoretical radiobiological assessment of the influence of radionuclide half-life on tumor response in targeted radiotherapy when a constant kidney toxicity is maintained.

The potential of targeted radionuclide therapy may be limited if the antibody affinity to the tumor is relatively low and if significant normal tissue damage occurs while the tumor is sterilized. One way to increase the efficiency of the antibody-radionuclide complex might be to use knowledge of the radiobiological processes to select a near-optimal radionuclide half-life. In this paper, the role of physical half-life in targeted radiotherapy optimization is investigated using the linear quadratic (LQ) radiobiological model in conjunction with a range of radiobiological parameters relevant to the tumor. Five radionuclides ((211)At, (90)Y, (131)I, (86)Rb, and (114m)In) were selected, providing a half-life range from 0.3-49.5 days. The dose-limiting organ was assumed to be the kidney, with a simple fractional link between the initial (extrapolated) dose-rate to the tumor and the initial dose-rate to the kidney. The results suggest that short-lived radionuclides (half-life in the range of 1-10 days) have an advantage over medium- and long-lived radionuclides. Furthermore, for very rapid tumor uptake (uptake half-time of a few hours), very short-lived radionuclides (half-life of less than 1 day) could be efficiently employed. Ultimately, however, treatment outcome (in terms of tumor cell kill) is limited by the antibody affinity to the tumor.

Microbeams of Heavy Charged Particles

We have established a single cell irradiation system, which allows selected cells to be individually hit with defined number of heavy charged particles, using a collimated heavy-ion microbeam apparatus at JAERI-Takasaki. This system has been developed to study radiobiological processes in hit cells and bystander cells exposed to low dose and low dose-rate high-LET radiations, in ways that cannot be achieved using conventional broad-field exposures. Individual cultured cells grown in special dishes were irradiated in the atmosphere with a single or defined numbers of 18.3 MeV/amu 12C, 13.0 MeV/amu 20Ne, and 11.5 MeV/amu 40Ar ions. Targeting and irradiation of the cells were performed automatically at the on-line microscope of the microbeam apparatus according to the positional data of the target cells obtained at the off-line microscope before irradiation. The actual number of particle tracks that pass through cell nuclei was detected with prompt etching of the bottom of the cell dish made of ion track detector TNF-1 (modified CR-39), with alkaline-ethanol solution at 37 degrees C for 15-30 minutes. Using this system, separately inoculated Chinese hamster ovary cells, confluent normal human fibroblasts, and single plant cells (tobacco protoplasts) have been irradiated. These are the first studies in which single-ion direct hit effect and the bystander effect have been investigated using a high-LET heavy particle microbeam.

Impact of microgravity on radiobiological processes and efficiency of DNA repair

To study the influence of microgravity on radiobiological processes in space, space experiments have been performed, using an on-board 1× g reference centrifuge as in-flight control. The trajectory of individual heavy ions was localized in relation to the biological systems by use of the Biostack concept, or an additional high dose of radiation was applied either before the mission or during the mission from an on-board radiation source. In embryonic systems, such as early developmental stages of Drosophila melanogaster and Carausius morosus, the occurrence of chromosomal translocations and larval malformations was dramatically increased in response to microgravity and radiation. It has been hypothesized that these synergistic effects might be caused by an interference of microgravity with DNA repair processes. However, recent studies on bacteria, yeast cells and human fibroblasts suggest that a disturbance of cellular repair processes in the microgravity environment might not be a complete explanation for the reported synergism of radiation and microgravity. As an alternative explanation, an impact of microgravity on signal transduction, on the metabolic/physiological state or on the chromatin structure at the cellular level, or modification of self-assembly, intercellular communication, cell migration, pattern formation or differentiation at the tissue and organ level should be considered.