The irradiation of V79 mammalian cells by protons with energies below 2 MeV. Part I: Experimental arrangement and measurements of cell survival.
01 Jan 1989-International Journal of Radiation Biology (Taylor & Francis)-Vol. 56, Iss: 3, pp 221-237
TL;DR: Measurements of the survival of V79 Chinese hamster cells suggest that protons are most effective at about 40-50 keV microns-1, and it is shown that the proton RBEs can be reconciled with those of other light ions if plotted against z*2/beta 2 rather than against LET.
Abstract: The relative biological effectiveness (RBE) has been determined for protons with mean energies of 1.9, 1.15 and 0.76 MeV, from measurements of the survival of V79 Chinese hamster cells. The cells are supported as a monolayer and are swept through a beam of scattered protons produced using a 4 MeV Van de Graaff accelerator. An estimation of the dose and unrestricted linear energy transfer (LET) variation within the sensitive volume of the cells is given for the three proton energies. The RBEs for cell survival (relative to 250 kVp X-rays) at the 10 per cent survival level are 1.6, 1.9 and 3.36 for protons with track-average LETs of 17, 24 and 32 keV microns-1 respectively, and the data suggest that protons are most effective at about 40-50 keV microns-1. It is shown that the proton RBEs can be reconciled with those of other light ions if plotted against z*2/beta 2 (where z* is the effective charge and beta is the relative velocity) rather than against LET.
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TL;DR: There is too much uncertainty in the RBE value for any human tissue to propose RBE values specific for tissue, dose/fraction, proton energy, etc, and experimental in vivo and clinical data indicate that continued employment of a generic RBEvalue is reasonable.
Abstract: Purpose: Clinical proton beam therapy has been based on the use of a generic relative biological effectiveness (RBE) of 1.0 or 1.1, since the available evidence has been interpreted as indicating that the magnitude of RBE variation with treatment parameters is small relative to our abilities to determine RBEs. As substantial clinical experience and additional experimental determinations of RBE have accumulated and the number of proton radiation therapy centers is projected to increase, it is appropriate to reassess the rationale for the continued use of a generic RBE and for that RBE to be 1.0–1.1. Methods and Materials: Results of experimental determinations of RBE of in vitro and in vivo systems are examined, and then several of the considerations critical to a decision to move from a generic to tissue-, dose/fraction-, and LET-specific RBE values are assessed. The impact of an error in the value assigned to RBE on normal tissue complication probability (NTCP) is discussed. The incidence of major morbidity in proton-treated patients at Massachusetts General Hospital (MGH) for malignant tumors of the skull base and of the prostate is reviewed. This is followed by an analysis of the magnitude of the experimental effort to exclude an error in RBE of ≥10% using in vivo systems. Results: The published RBE values, using colony formation as the measure of cell survival, from in vitro studies indicate a substantial spread between the diverse cell lines. The average value at mid SOBP (Spread Out Bragg Peak) over all dose levels is ≈1.2, ranging from 0.9 to 2.1. The average RBE value at mid SOBP in vivo is ≈1.1, ranging from 0.7 to 1.6. Overall, both in vitro and in vivo data indicate a statistically significant increase in RBE for lower doses per fraction, which is much smaller for in vivo systems. There is agreement that there is a measurable increase in RBE over the terminal few millimeters of the SOBP, which results in an extension of the bioeffective range of the beam in the range of 1–2 mm. There is no published report to indicate that the RBE of 1.1 is low. However, a substantial proportion of patients treated at ≈2 cobalt Gray equivalent (CGE)/fraction 5 or more years ago were treated by a combination of both proton and photon beams. Were the RBE to be erroneously underestimated by ≈10%, the increase in complication frequency would be quite serious were the complication incidence for the reference treatment ≥3% and the slope of the dose response curves steep, e.g., a γ50 ≈ 4. To exclude ≥1.2 as the correct RBE for a specific condition or tissue at the 95% confidence limit would require relatively large and multiple assays. Conclusions: At present, there is too much uncertainty in the RBE value for any human tissue to propose RBE values specific for tissue, dose/fraction, proton energy, etc. The experimental in vivo and clinical data indicate that continued employment of a generic RBE value and for that value to be 1.1 is reasonable. However, there is a local “hot region” over the terminal few millimeters of the SOBP and an extension of the biologically effective range. This needs to be considered in treatment planning, particularly for single field plans or for an end of range in or close to a critical structure. There is a clear need for prospective assessments of normal tissue reactions in proton irradiated patients and determinations of RBE values for several late responding tissues in laboratory animal systems, especially as a function of dose/fraction in the range of 1–4 Gy.
1,182 citations
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.
664 citations
Additional excerpts
...…A 250 kVp 0.202 0.050 4.056 0.399 0.272 9.23 (Bird et al 1980) G1/S phase C 250 kVp 0.110 0.027 4.074 1.030 0.000 32.00 (Folkard et al 1989) C 250 kVp 0.110 0.027 4.074 0.330 0.066 24.00 (Folkard et al 1989) C 250 kVp 0.110 0.027 4.074 0.110 0.027 17.00 (Folkard et al 1989) (Continued) Table A1....
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...…et al 2014) Plateau phase A 250 kVp 0.202 0.050 4.056 0.399 0.272 9.23 (Bird et al 1980) G1/S phase C 250 kVp 0.110 0.027 4.074 1.030 0.000 32.00 (Folkard et al 1989) C 250 kVp 0.110 0.027 4.074 0.330 0.066 24.00 (Folkard et al 1989) C 250 kVp 0.110 0.027 4.074 0.110 0.027 17.00 (Folkard et al…...
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...…in fact list all of these parameters (Bird et al 1980, Perris et al 1986, Hei et al 1988b, Belli et al 1989, 1990, 1991, 1992a, 1993, 1998, 2000a, Folkard et al 1989, 1996, Bettega et al 1990, 1998, Prise et al 1990, Goodhead et al 1992, Courdi et al 1994, Sgura et al 2000, Green et al 2001,…...
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...…energy ( 6 MeV) (Bettega et al 1979, 1998, Bird et al 1980, Perris et al 1986, Hei et al 1988a, 1988b, Belli et al 1989, 1992a, 1993, 1998, 2000a, Folkard et al 1989, 1996, Prise et al 1990, Goodhead et al 1992, Ogheri et al 1997, Sgura et al 2000, Schettino et al 2001, Baggio et al 2002,…...
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TL;DR: A simplified method for the calculation of mammalian cell survival after charged particle irradiation is presented that is based on the track structure model of Scholz and Kraft, and yields linear-quadratic relations also for heavy ion irradiation.
Abstract: A simplified method for the calculation of mammalian cell survival after charged particle irradiation is presented that is based on the track structure model of Scholz and Kraft [1, 2]. Utilizing a modified linear-quadratic relation for the x-ray survival curve, one finds that the model yields linear-quadratic relations also for heavy ion irradiation. If survival is calculated as a function of specific energy, z, in the cell nucleus--thus reducing the stochastic fluctuations of energy deposition--the increase in slope of the survival curve and therefore the coefficient beta z can be estimated with sufficient accuracy from the initial slope, alpha z. This permits the tabulation of the coefficients alpha z for the particle types and energies of interest, and subsequent fast calculations of survival levels at any point in a mixed particle beam. The complexity of the calculations can thereby be reduced in a wide range of applications, which permits the rapid calculations that are required for treatment planning in heavy ion therapy. The validity of the modified computations is assessed by the comparison with explicit calculations in terms of the original model and with experimental results for track-segment conditions. The model is then used to analyze the influence of beam fragmentation on the biological effect of charged particle beams penetrating to different depths in tissue. In addition, cell-survival rates after neuron irradiation are computed from the slowing-down spectra of secondary charged particles and are compared to experimental observations.
413 citations
TL;DR: A new approach for the calculation of biological effects of heavy charged particles is discussed, in contrast to other models, the biological effect is determined locally as a function of the local dose deposited by the charged particle tracks.
254 citations
TL;DR: A model to predict proton RBE based on dose, dose average LET (LETd) and the ratio of the linear-quadratic model parameters for the reference radiation (α/β)x, as the tissue specific parameter is developed, based on the linear quadratic model and was derived from a nonlinear regression fit to 287 experimental data points.
Abstract: Proton therapy treatments are currently planned and delivered using the assumption that the proton relative biological effectiveness (RBE) relative to photons is 1.1. This assumption ignores strong experimental evidence that suggests the RBE varies along the treatment field, i.e. with linear energy transfer (LET) and with tissue type. A recent review study collected over 70 experimental reports on proton RBE, providing a comprehensive dataset for predicting RBE for cell survival. Using this dataset we developed a model to predict proton RBE based on dose, dose average LET (LETd) and the ratio of the linear-quadratic model parameters for the reference radiation (α/β)x, as the tissue specific parameter. The proposed RBE model is based on the linear quadratic model and was derived from a nonlinear regression fit to 287 experimental data points. The proposed model predicts that the RBE increases with increasing LETd and decreases with increasing (α/β)x. This agrees with previous theoretical predictions on the relationship between RBE, LETd and (α/β)x. The model additionally predicts a decrease in RBE with increasing dose and shows a relationship between both α and β with LETd. Our proposed phenomenological RBE model is derived using the most comprehensive collection of proton RBE experimental data to date. Previously published phenomenological models, based on a limited data set, may have to be revised.
249 citations
Cites result from "The irradiation of V79 mammalian ce..."
...…another two studies (Goodhead et al 1992, Wéra et al 2011) as well as selected data points from other studies (Belli et al 1989, 1992, 1993, 1998, 2000, Folkard et al 1989, Prise et al 1990, Ogheri et al 1997, Bettega et al 1998, Sgura et al 2000, Schettino et al 2001, Schuff et al 2002, Fiorini…...
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References
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01 Jan 1980
TL;DR: This book contains the proceedings of a symposium held in February and March 1979 and represents a timely appearance of the 40 scientific presentations and conference summary from a rather large meeting.
Abstract: This book contains the proceedings of a symposium held in February and March 1979. The publication of the book in early 1980 represents a timely appearance of the 40 scientific presentations and conference summary from a rather large meeting. The papers are organized into six categories ranging from basic biophysics of radiation damage to new methods and combinations in radiation therapy of human malignancies. This organization, going from the basic mechanisms of radiation damage to new therapy applications, is a logical one, and the relatively large emphasis on papers in the first category is a refreshing change for a symposium of this sort. The quality of editing, production, and illustrations is high.
315 citations
TL;DR: It is suggested that a proportion of the radiation-induced mutants suffer extensive genetic damage, and that some forms of this damage may be induced with high efficiency by radiations of high linear energy transfer.
Abstract: SummaryInactivation and mutation to thioguanine-resistance of V79 hamster cells were studied after irradiation with accelerated helium, boron or nitrogen ions covering a range of linear energy transfer from 28 to 470 keV µm−1. For all radiation qualities a dose-dependent increase in mutant frequency was found for doses giving surviving fractions greater than about 0·20. The effectiveness per unit dose for both inactivation and mutation induction increased with the linear energy transfer of the radiation to a maximum in the range 90–200 keV µm−1. However, the maximum mutagenic effectiveness relative to γ-rays was about two or more times that for inactivation. It is suggested that a proportion of the radiation-induced mutants suffer extensive genetic damage, and that some forms of this damage may be induced with high efficiency by radiations of high linear energy transfer.
258 citations
TL;DR: Results obtained from cyclotron-accelerated a-particles and deuterons show that in this region the RBE varies rapidly with LET, especially at low levels of damage.
Abstract: If investigations of the relative biological effectiveness of ionizing radiations with different linear energy transfer are to provide a better insight into certain aspects of radiation-induced damage to biological systems, it is desirable to use as wide a range of radiations as possible. In previous papers results were given of experiments in which the inhibition of clone formation by human cells in tissue culture was studied after various doses of a-, /-, 200-kv X-, and 20-kv X-radiation (1, 2). The present report is concerned with results obtained from cyclotron-accelerated a-particles and deuterons. These particles have LET's between 5 kev/, and 100 kev/u of unit density tissue, and the results to be presented show that in this region the RBE varies rapidly with LET, especially at low levels of damage.
229 citations
TL;DR: The data seem to indicate that the RBE-LET curve depends on the type of radiation and this could imply that LET is not a good reference for the dose-effectiveness relationship.
Abstract: SummaryThe survival of V79 Chinese hamster cells irradiated with proton beams with energies of 0·73, 0·84, 1·16, 1·70 and 3·36 MeV, corresponding to LET values, evaluated at the cell midplane, of 34·5, 30·4, 23·9, 17·8 and 10·6 keV/μm respectively, have been studied in the dose range 0·5–6·0 Gy. As a reference, the survival curve obtained with 200 kV X-rays was used.The initial shoulder, typical of survival curves obtained with sparsely ionizing radiation, decreases as the LET increases and completely disappears at 23·9 keV/μm. This value corresponds to the maximum of the RBE, expressed as the initial slope ratio. In the energy range we have considered, the RBEs for protons are higher than those reported for other ions of comparable LET and the RBE-LET relationship results shifted to lower LET values. Our data seem to indicate that the RBE-LET curve depends on the type of radiation and this could imply that LET is not a good reference for the dose-effectiveness relationship.
156 citations
31 Oct 1968
151 citations