S. Favaretto

Bio: S. Favaretto is an academic researcher. The author has contributed to research in topics: Radiosensitivity & Linear energy transfer. The author has an hindex of 6, co-authored 10 publications receiving 199 citations.

Inactivation of human normal and tumour cells irradiated with low energy protons.

Abstract: Purpose : To analyse the cell inactivation frequencies induced by low energy protons in human cells with different sensitivity to photon radiation. Materials and methods : Four human cell lines with various sensitivities to photon irradiation were used: the SCC25 and SQ20B derived from human epithelium tumours of the tongue and larynx, respectively, and the normal lines M/10, derived from human mammary epithelium, and HF19 derived from a lung fibroblast. The cells were irradiated with γ-rays and proton beams with linear energy transfer (LET) from 7 to 33keV/ μ m. Clonogenic survival was assessed. Results : Survival curves are reported for each cell line following irradiation with γ-rays and with various proton LETs. The surviving fraction after 2 Gy of γ-rays was 0.72 for SQ20B cells, and 0.28–0.35 for the other cell lines. The maximum LET proton effectiveness was generally greater than that of γ-rays. In particular there was a marked increase in beam effectiveness with increasing LET for the most resista...

Inactivation of C3H10T1/2 cells by low energy protons and deuterons.

Abstract: Purpose To determine the RBE-LET relationship for C3H10T1/2 cell inactivation by protons in the LET range 11-33 keV/microm and to compare inactivation frequencies induced in C3H10T1/2 cells by protons and deuterons at two matching LET values in the range 11-20 keV/microm. Materials and methods C3H10T1/2 cells were irradiated with protons and deuterons at the radiobiological facility set up at the 7MV Van de Graaff accelerator at the LNL, Legnaro, Padova. Gamma rays from 60Co were used as reference radiation. Results Proton RBE values (alpha/alphagamma) for inactivation of C3H10T1/2 cells are constant around a value of 2 between 11 and 20 keV/microm and then rise sharply to reach a value of 4.2+/-1.0 at 33 keV/microm. Deuteron RBE values are 1.7+/-0.4 and 2.2+/-0.6 at LET values of 13 and 18 keV/microm respectively. Conclusions Proton RBE values with C3H10T1/2 cells are significantly larger than unity at LET values as low as 11 keV/microm. No difference in effectiveness for inactivation of C3H10T1/2 has been found between protons and deuterons at two LET values in the range 10-20 keV/microm.

Inactivation of Human Cells Exposed to Fractionated Doses of Low Energy Protons: Relationship between Cell Sensitivity and Recovery Efficiency

Abstract: Within the framework of radiation biophysics research in the hadrontherapy field, split-dose studies have been performed on four human cell lines with different radiation sensitivity (SCC25, HF19, H184B5 F5-1 M10, and SQ20B). Low energy protons of about 8 and 20 keV/μm LET and gamma-rays were used to study the relationship between the recovery ratio and the radiation quality. Each cell line was irradiated with two dose values corresponding to survival levels of about 5% and 1%. The same total dose was also delivered in two equal fractions separated by 1.5, 3, and 4.5 hours. A higher maximum recovery ratio was observed for radiosensitive cell lines as compared to radioresistant cells. The recovery potential after split doses was small for slow protons, compared to low-LET radiation. These data show that radiosensitivity may not be related to a deficient recovery, and suggest a possible involvement of inducible repair mechanisms.

Minisatellite and Hprt mutations in V79 cells irradiated with helium ions and gamma rays.

Abstract: Purpose : To evaluate and compare cytotoxic and mutational effects of graded doses of γ-rays and 4 He ++ ions at different LET values (nominally 80 and 123 keV/ μ m) in V79 cells. Materials and methods : 4 He ++ ion beams at 80 and 123 keV/ μ m were supplied by the 7 MV Van de Graaff CN accelerator of the INFN-LNL in the dose range 0.3-2.4 Gy at a dose rate of 1 Gy/min. Gamma-irradiation was performed by the 60 Co ' γbeam' of CNR-FRAE (at the INFN-LNL) in the dose range 0.5-6.0 Gy at a dose rate of 1 Gy/min. After irradiation, the cells were seeded to measure surviving fraction (SF) and mutant frequency (MF) at the Hprt locus on the basis of 6-thioguanine resistance. Alterations at minisatellite sequences (MS) of clones derived from irradiated and unirradiated cells were detected by Southern blot analysis using a multi-locus probe (DNA fingerprinting). Results : Survival data from 4 He ++ irradiation at two LET values (80 and 123 keV/ μ m) yielded similar results: α =(1.08 ±0.04)/Gy and (0.90 ±0.03)/Gy, r...

Relative biological effectiveness (RBE) values for proton beam therapy.

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.

Relative biological effectiveness (RBE) values for proton beam therapy. Variations as a function of biological endpoint, dose, and linear energy transfer

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.

A phenomenological relative biological effectiveness (RBE) model for proton therapy based on all published in vitro cell survival data.

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.

Systematic analysis of RBE and related quantities using a database of cell survival experiments with ion beam irradiation

Abstract: For tumor therapy with light ions and for experimental aspects in particle radiobiology the relative biological effectiveness (RBE) is an important quantity to describe the increased effectiveness of particle radiation. By establishing and analysing a database of ion and photon cell survival data, some remarkable properties of RBE-related quantities were observed. The database consists of 855 in vitro cell survival experiments after ion and photon irradiation. The experiments comprise curves obtained in different labs, using different ion species, different irradiation modalities, the whole range of accessible energies and linear energy transfers (LETs) and various cell types. Each survival curve has been parameterized using the linear-quadratic (LQ) model. The photon parameters, α and β, appear to be slightly anti-correlated, which might point toward an underlying biological mechanism. The RBE values derived from the survival curves support the known dependence of RBE on LET, on particle species and dose. A positive correlation of RBE with the ratio α/β of the photon LQ parameters is found at low doses, which unexpectedly changes to a negative correlation at high doses. Furthermore, we investigated the course of the β coefficient of the LQ model with increasing LET, finding typically a slight initial increase and a final falloff to zero. The observed fluctuations in RBE values of comparable experiments resemble overall RBE uncertainties, which is of relevance for treatment planning. The database can also be used for extensive testing of RBE models. We thus compare simulations with the local effect model to achieve this goal.

A model for the relative biological effectiveness of protons: the tissue specific parameter α/β of photons is a predictor for the sensitivity to LET changes.

Abstract: Background. The biological effects of particles are often expressed in relation to that of photons through the concept of relative biological effectiveness, RBE. In proton radiotherapy, a constant RBE of 1.1 is usually assumed. However, there is experimental evidence that RBE depends on various factors. The aim of this study is to develop a model to predict the RBE based on linear energy transfer (LET), dose, and the tissue specific parameter α/β of the linear-quadratic model for the reference radiation. Moreover, the model should capture the basic features of the RBE using a minimum of assumptions, each supported by experimental data. Material and methods. The α and β parameters for protons were studied with respect to their dependence on LET. An RBE model was proposed where the dependence of LET is affected by the (α/β)phot ratio of photons. Published cell survival data with a range of well-defined LETs and cell types were selected for model evaluation rendering a total of 10 cell lines and 24 R...