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Journal ArticleDOI

Low-LET Proton Irradiation of A549 Non-small Cell Lung Adenocarcinoma Cells: Dose Response and RBE Determination

31 Jan 2013-Radiation Research (The Radiation Research Society)-Vol. 179, Iss: 3, pp 273-281

TL;DR: Comparisons with X ray results indicate that proton irradiation at 10 keV/μm enhanced the tumor radiosensitivity with a significant dose-dependent decrease in the survival fraction.

AbstractSince 1957, broad proton beam radiotherapy with a spread out Bragg peak has been used for cancer treatment. More recently, studies on the use of proton therapy in the treatment of non-small cell lung cancer (NSCLC) were performed and although the benefit of using protons for the treatment of NSCLC is recognized, more work is needed to gather additional data for the understanding of cell response. Human A549 cell survival was evaluated by colony forming assay 11 days after 10 keV/μm proton beam irradiation at 0.1 and 1 Gy/min. The residual energy of the proton beam at the location of the irradiated cells was 3.9 MeV. In parallel, early effects on the cell viability and DNA damage were assessed and DNA synthesis was measured. The survival curve obtained was fitted with both the linear and the induced-repair models, as a hyper-radiosensitivity was evidenced at very low doses. Above 0.5 Gy, a linear shape was observed with the α parameter equal to 0.824 ± 0.029 Gy−1. In addition, early cell death and cell pro...

Topics: Proton therapy (54%), Radiation therapy (51%)

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Citations
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Journal ArticleDOI
TL;DR: This review can serve as a source for defining input parameters for applying or refining biophysical models and to identify endpoints where additional radiobiological data are needed in order to reduce the uncertainties in proton RBE values to clinically acceptable levels.
Abstract: Proton therapy treatments are based on a proton RBE (relative biological effectiveness) relative to high-energy photons of 1.1. The use of this generic, spatially invariant RBE within tumors and normal tissues disregards the evidence that proton RBE varies with linear energy transfer (LET), physiological and biological factors, and clinical endpoint.Based on the available experimental data from published literature, this review analyzes relationships of RBE with dose, biological endpoint and physical properties of proton beams. The review distinguishes between endpoints relevant for tumor control probability and those potentially relevant for normal tissue complication. Numerous endpoints and experiments on sub-cellular damage and repair effects are discussed.Despite the large amount of data, considerable uncertainties in proton RBE values remain. As an average RBE for cell survival in the center of a typical spread-out Bragg peak (SOBP), the data support a value of ~1.15 at 2 Gy/fraction. The proton RBE increases with increasing LETd and thus with depth in an SOBP from ~1.1 in the entrance region, to ~1.15 in the center, ~1.35 at the distal edge and ~1.7 in the distal fall-off (when averaged over all cell lines, which may not be clinically representative). For small modulation widths the values could be increased. Furthermore, there is a trend of an increase in RBE as (α/β)x decreases. In most cases the RBE also increases with decreasing dose, specifically for systems with low (α/β)x. Data on RBE for endpoints other than clonogenic cell survival are too diverse to allow general statements other than that the RBE is, on average, in line with a value of ~1.1.This review can serve as a source for defining input parameters for applying or refining biophysical models and to identify endpoints where additional radiobiological data are needed in order to reduce the uncertainties to clinically acceptable levels.

541 citations


Journal ArticleDOI
TL;DR: Particle radiobiology is now entering into a new phase, where beyond RBE, the tissue response is considered, and these results may open new applications for both cancer therapy and protection in deep space.
Abstract: Densely ionizing radiation has always been a main topic in radiobiology. In fact, α-particles and neutrons are sources of radiation exposure for the general population and workers in nuclear power plants. More recently, high-energy protons and heavy ions attracted a large interest for two applications: hadrontherapy in oncology and space radiation protection in manned space missions. For many years, studies concentrated on measurements of the relative biological effectiveness (RBE) of the energetic particles for different end points, especially cell killing (for radiotherapy) and carcinogenesis (for late effects). Although more recently, it has been shown that densely ionizing radiation elicits signalling pathways quite distinct from those involved in the cell and tissue response to photons. The response of the microenvironment to charged particles is therefore under scrutiny, and both the damage in the target and non-target tissues are relevant. The role of individual susceptibility in therapy and risk is obviously a major topic in radiation research in general, and for ion radiobiology as well. Particle radiobiology is therefore now entering into a new phase, where beyond RBE, the tissue response is considered. These results may open new applications for both cancer therapy and protection in deep space.

102 citations


Cites methods from "Low-LET Proton Irradiation of A549 ..."

  • ...The single-fraction C-ion data point with the highest BED is described in Tsujii and Kamada,46 while the highest TCP has been achieved at Tsukuba University, Ibaraki, Japan, in a trial on 58 (T1/T2, 30/28) patients treated with 66Gy(RBE)/10 fractions for peripherally located and 72.6Gy(RBE)/22 fractions for centrally located tumours.42 BED for CPT was calculated using the formula above with d in Gy(RBE) as reported in the publications and the same a/b ratio as for X-rays....

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  • ...Slow protons aremore effective than X-rays in the inactivation of human tumour cell lines.47 A recent experiment in a human NSCLC cell line reported an RBE5 1.9 for 3.9MeV protons compared with X-rays.48 The Tsukuba proton beam line used for the NSCLC treatment42 has been used for in vitro experiments in different human cell lines.49 Apoptosis induction was greater than two-fold the level induced by 10MeV X-ray.49 Other experiments have shown that the signalling cascade following exposure to protons can substantially differ from the damage response to photons.50 A potential advantage of CPT in hypofractionation is the reduced oxygen enhancement ratio (OER) using high-LET radiation....

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  • ...There could be a dose threshold, and it seems to be charge- and energy-dependent, and defining an RBE is even more difficult, considering that most of these end points are not observed at all with X-rays.131 These observations have therefore triggered a number of cellular and molecular studies on neural cells and tissue, to gain understanding of the mechanisms of heavy ion-induced damage in the brain....

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  • ...9MeV protons compared with X-rays.(48) The Tsukuba proton beam line used for the NSCLC treatment(42) has been used for in vitro experiments in different human cell lines....

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Journal ArticleDOI
TL;DR: It is demonstrated that the phenomenon-based MultiScale Approach to the assessment of radiation damage with ions gives a positive answer to the question whether it is possible to quantitatively predict macroscopic biological effects caused by ion radiation on the basis of physical and chemical effects related to the ion-medium interactions on a nanometre scale.
Abstract: Ion-beam therapy provides advances in cancer treatment, offering the possibility of excellent dose localization and thus maximising cell-killing within the tumour. The full potential of such therapy can only be realised if the fundamental mechanisms leading to lethal cell damage under ion irradiation are well understood. The key question is whether it is possible to quantitatively predict macroscopic biological effects caused by ion radiation on the basis of physical and chemical effects related to the ion-medium interactions on a nanometre scale. We demonstrate that the phenomenon-based MultiScale Approach to the assessment of radiation damage with ions gives a positive answer to this question. We apply this approach to numerous experiments where survival curves were obtained for different cell lines and conditions. Contrary to other, in essence empirical methods for evaluation of macroscopic effects of ionising radiation, the MultiScale Approach predicts the biodamage based on the physical effects related to ionisation of the medium, transport of secondary particles, chemical interactions, thermo-mechanical pathways of biodamage, and heuristic biological criteria for cell survival. We anticipate this method to give great impetus to the practical improvement of ion-beam cancer therapy and the development of more efficient treatment protocols.

60 citations


Journal ArticleDOI
TL;DR: Analysis indicated that non‐linear models could give a better representation of the RBE‐LET relationship, as differences between the models were observed for the SOBP scenario, and both non‐ linear LET spectrum‐ and linear LETd based models should be further evaluated in clinically realistic scenarios.
Abstract: Purpose The relative biological effectiveness (RBE) of protons varies with the radiation quality, quantified by the linear energy transfer (LET). Most phenomenological models employ a linear dependency of the dose-averaged LET (LETd) to calculate the biological dose. However, several experiments have indicated a possible non-linear trend. Our aim was to investigate if biological dose models including non-linear LET dependencies should be considered, by introducing a LET spectrum based dose model. Method The RBE-LET relationship was investigated by fitting of polynomials from 1st to 5th degree to a database of 85 data points from aerobic in vitro experiments. We included both unweighted and weighted regression, the latter taking into account experimental uncertainties. Statistical testing was performed to decide whether higher degree polynomials provided better fits to the data as compared to lower degrees. The newly developed models were compared to three published LETd based models for a simulated spread out Bragg peak (SOBP) scenario. Results The statistical analysis of the weighted regression analysis favoured a non-linear RBE-LET relationship, with the quartic polynomial found to best represent the experimental data (p=0.010). The results of the unweighted regression analysis were on the borderline of statistical significance for non-linear functions (p=0.053), and with the current database a linear dependency could not be rejected. For the SOBP scenario, the weighted non-linear model estimated a similar mean RBE value (1.14) compared to the three established models (1.13-1.17). The unweighted model calculated a considerably higher RBE value (1.22). Conclusion The analysis indicated that non-linear models could give a better representation of the RBE-LET relationship. However, this is not decisive, as inclusion of the experimental uncertainties in the regression analysis had a significant impact on the determination and ranking of the models. As differences between the models were observed for the SOBP scenario, both non-linear LET spectrum- and linear LETd based models should be further evaluated in clinically realistic scenarios. This article is protected by copyright. All rights reserved.

30 citations


Journal ArticleDOI
TL;DR: The effect of proton- and gamma- irradiation on cell cycle, death, epithelial-mesenchymal transition (EMT) and "stemness" in human non-small cell lung carcinoma cells (A549) is investigated.
Abstract: Proton beam therapy is a cutting edge modality over conventional gamma radiotherapy because of its physical dose deposition advantage. However, not much is known about its biological effects vis-a-vis gamma irradiation. Here we investigated the effect of proton- and gamma- irradiation on cell cycle, death, epithelial-mesenchymal transition (EMT) and "stemness" in human non-small cell lung carcinoma cells (A549). Proton beam (3MeV) was two times more cytotoxic than gamma radiation and induced higher and longer cell cycle arrest. At equivalent doses, numbers of genes responsive to proton irradiation were ten times higher than those responsive to gamma irradiation. At equitoxic doses, the proton-irradiated cells had reduced cell adhesion and migration ability as compared to the gamma-irradiated cells. It was also more effective in reducing population of Cancer Stem Cell (CSC) like cells as revealed by aldehyde dehydrogenase activity and surface phenotyping by CD44(+), a CSC marker. These results can have significant implications for proton therapy in the context of suppression of molecular and cellular processes that are fundamental to tumor expansion.

23 citations


References
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Book
J.P. Biersack, James F. Ziegler1
01 Aug 1985
Abstract: The stopping and range of ions in matter is physically very complex, and there are few simple approximations which are accurate. However, if modern calculations are performed, the ion distributions can be calculated with good accuracy, typically better than 10%. This review will be in several sections: a) A brief exposition of what can be determined by modern calculations. b) A review of existing widely-cited tables of ion stopping and ranges. c) A review of the calculation of accurate ion stopping powers.

9,987 citations


Journal ArticleDOI
TL;DR: The total number of new cases of cancer in Europe appears to have increased by 300,000 since 2004 and the ageing of the European population will cause these numbers to continue to increase even if age-specific rates remain constant.
Abstract: Background: Monitoring the evolution of the cancer burden in Europe is of great value. Estimates of the cancer burden in Europe have been published for 2004 and estimates are now being presented for cancer incidence and mortality in Europe for 2006. Methods: The most recent sources of cancer incidence and mortality data have been collected and projections have been carried out using short-term prediction methods to produce estimated rates for 2006. Additional estimation was required where national incidence data were not available, and the method involved the projection of the aggregations of cancer incidence and mortality data from representative cancer registries. The estimated 2006 rates were applied to the corresponding estimated country population to obtain the best estimates of the cancer incidence and mortality in Europe in 2006. Results: In 2006 in Europe, there were an estimated 3 191 600 cancer cases diagnosed (excluding nonmelanoma skin cancers) and 1 703 000 deaths from cancer. The most common form of cancers was breast cancer (429 900 cases, 13.5% of all cancer cases), followed by colorectal cancers (412 900, 12.9%) and lung cancer (386 300, 12.1%). Lung cancer, with an estimated 334 800 deaths (19.7% of total), was the most common cause of death from cancer, followed by colorectal (207 400 deaths), breast (131 900) and stomach (118 200) cancers. Conclusions: The total number of new cases of cancer in Europe appears to have increased by 300 000 since 2004. With an estimated 3.2 million new cases (53% occurring in men, 47% in women) and 1.7 million deaths (56% in men, 44% in women) each year, cancer remains an important public health problem in Europe and the ageing of the European population will cause these numbers to continue to increase even if age-specific rates remain constant. Evidence-based public health measures exist to reduce the mortality of breast and colorectal cancer while the incidence of lung cancer, and several other forms of cancer, could be diminished by improved tobacco control.

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TL;DR: The statistical models used used to estimate incidence and mortality data for 25 cancers in 40 European countries in 2008 used to obtain an estimate of the numbers of cancer cases and deaths in Europe in 2008.
Abstract: Up-to-date statistics on cancer occurrence and outcome are essential for the planning and evaluation of programmes for cancer control. Since the relevant information for 2008 is not generally available as yet, we used statistical models to estimate incidence and mortality data for 25 cancers in 40 European countries (grouped and individually) in 2008. The calculations are based on published data. If not collected, national rates were estimated from national mortality data and incidence and mortality data provided by local cancer registries of the same or neighbouring country. The estimated 2008 rates were applied to the corresponding country population estimates for 2008 to obtain an estimate of the numbers of cancer cases and deaths in Europe in 2008. There were an estimated 3.2 million new cases of cancer and 1.7 million deaths from cancer in 2008. The most common cancers were colorectal cancers (436,000 cases, 13.6% of the total), breast cancer (421,000, 13.1%), lung cancer (391,000, 12.2%) and prostate cancer (382,000, 11.9%). The most common causes of death from cancer were lung cancer (342,000 deaths, 19.9% of the total), colorectal cancer (212,000 deaths, 12.3%), breast cancer (129,000, 7.5%) and stomach cancer (117,000, 6.8%).

2,294 citations


"Low-LET Proton Irradiation of A549 ..." refers background in this paper

  • ...(1), LET and flux must be controlled over the entire irradiation field and throughout the irradiation of the cells....

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Journal ArticleDOI
TL;DR: Cancer incidence and mortality estimates for 1995 are presented for the 38 countries in the four United Nations-defined areas of Europe, using World Health Organization mortality data and published estimates of incidence from national cancer registries to demonstrate the very substantial burden of cancer in Europe, and the scope for prevention.
Abstract: Cancer incidence and mortality estimates for 1995 are presented for the 38 countries in the four United Nations-defined areas of Europe, using World Health Organization mortality data and published estimates of incidence from national cancer registries. Additional estimation was required where national incidence data was not available, and the method involved incorporating the high quality incidence and mortality data available from the expanding number of population-based cancer registries in Europe. There were an estimated 2.6 million new cases of cancer in Europe in 1995, representing over one-quarter of the world burden of cancer. The corresponding number of deaths from cancer was approximately 1.6 million. After adjusting for differing population age structures, overall incidence rates in men were highest in the Western European countries (420.9 per 100,000), with only Austria having a rate under 400. Eastern European men had the second highest rates of cancer (414.2), with extremely high rates being observed in Hungary (566.6) and in the Czech Republic (480.5). The lowest male all-cancer rate by area was observed in the Northern European countries, with fairly low rates seen in Sweden (356.6) and the UK (377.8). In contrast to men, the highest rates in women were observed in Northern Europe (315.9) and were particularly high in Denmark (396.2) and the other Nordic countries excepting Finland. The rates of cancer in Eastern European women were lower than in the other three areas, although as with men, female rates were very high in Hungary (357.2) and in the Czech Republic (333.6). There was greater disparity in the mortality rates within Europe--generally, rates were highest in Eastern European countries, notably in Hungary, reflecting a combination of poorer cancer survival rates and a higher incidence of the more lethal neoplasms, notably cancer of the lung. Lung cancer, with an estimated 377,000 cases, was the most common cancer in Europe in 1995. Rates were particularly high in much of Eastern Europe reflecting current and past tobacco smoking habits of many of its inhabitants. Together with cancers of colon and rectum (334,000), and female breast (321,000), the three cancers represented approximately 40% of new cases in Europe. In men, the most common primary sites were lung (22% of all cancer cases), colon and rectum (12%) and prostate (11%), and in females, breast (26%), colon and rectum (14%) and stomach (7%). The number of deaths is determined by survival, as well as incidence; by far the most common cause of death was lung cancer (330,000)--about one-fifth of the total number of cancer deaths in Europe in 1995. Deaths from cancers of the colon and rectum (189,000) ranked second, followed by deaths from stomach cancer (152,000), which due to poorer survival ranked higher than breast cancer (124,000). Lung cancer was the most common cause of death from cancer in men (29%). Breast cancer was the leading cause of death in females (17%). Cancer registries are a unique source of information on cancer incidence and survival, and are used here with national mortality to demonstrate the very substantial burden of cancer in Europe, and the scope for prevention. Despite some provisos about data quality, the general patterns which emerge in Europe verify the role of past exposures and interventions, and more importantly, firmly establish the need for cancer control measures which target specific populations. In particular, there is a clear urgency to combat the ongoing tobacco epidemic, now prevalent in much of Europe, particularly in the Eastern countries.

1,210 citations


Journal ArticleDOI
TL;DR: The object of this paper is to acquaint medical and biological workers with some of the physical properties and possibilities of high-energy protons, and to be as simple as possible, let us consider only high- energy protons.
Abstract: Except for electrons, the particles which have been accelerated to high energies by machines such as cyclotrons or Van de Graaff generators have not been directly used therapeutically Rather, the neutrons, gamma rays, or artificial radioactivities produced in various reactions of the primary particles have been applied to medical problems This has, in large part, been due to the very short penetration in tissue of protons, deuterons, and alpha particles from present accelerators Higher-energy machines are now under construction, however, and the ions from them will in general be energetic enough to have a range in tissue comparable to body dimensions It must have occurred to many people that the particles themselves now become of considerable therapeutic interest The object of this paper is to acquaint medical and biological workers with some of the physical properties and possibilities of such rays To be as simple as possible, let us consider only high-energy protons: later we can generalize to oth

1,140 citations


"Low-LET Proton Irradiation of A549 ..." refers background in this paper

  • ...Wilson in 1946, recognizing that the unique physical properties of protons might have distinct advantages over photon radiation (4)....

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