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.

Multiple pathways are involved in maintaining the genetic integrity of a cell after its exposure to ionizing radiation. Although repair mechanisms such as homologous recombination and nonhomologous end-joining are important mammalian responses to double-strand DNA damage, cell cycle regulation is perhaps the most important determinant of ionizing radiation sensitivity. A common cellular response to DNA-damaging agents is the activation of cell cycle checkpoints. The DNA damage induced by ionizing radiation initiates signals that can ultimately activate either temporary checkpoints that permit time for genetic repair or irreversible growth arrest that results in cell death (necrosis or apoptosis). Such checkpoint activation constitutes an integrated response that involves sensor (RAD, BRCA, NBS1), transducer (ATM, CHK), and effector (p53, p21, CDK) genes. One of the key proteins in the checkpoint pathways is the tumor suppressor gene p53, which coordinates DNA repair with cell cycle progression and apoptosis. Specifically, in addition to other mediators of the checkpoint response (CHK kinases, p21), p53 mediates the two major DNA damage-dependent cellular checkpoints, one at the G(1)-S transition and the other at the G(2)-M transition, although the influence on the former process is more direct and significant. The cell cycle phase also determines a cell's relative radiosensitivity, with cells being most radiosensitive in the G(2)-M phase, less sensitive in the G(1) phase, and least sensitive during the latter part of the S phase. This understanding has, therefore, led to the realization that one way in which chemotherapy and fractionated radiotherapy may work better is by partial synchronization of cells in the most radiosensitive phase of the cell cycle. We describe how cell cycle and DNA damage checkpoint control relates to exposure to ionizing radiation.

Role of cell cycle in mediating sensitivity to radiotherapy.

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.

https://iopscience.iop.org/article/10.1088/0031-9155/59/22/R419/pdf

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

Prior to the human exploration of Mars or long duration stays on the Earth s moon, the risk of cancer and other diseases from space radiation must be accurately estimated and mitigated Space radiation, comprised of energetic protons and heavy nuclei, has been show to produce distinct biological damage compared to radiation on Earth, leading to large uncertainties in the projection of cancer and other health risks, while obscuring evaluation of the effectiveness of possible countermeasures Here, we describe how research in cancer radiobiology can support human missions to Mars and other planets

/pdf/heavy-ion-carcinogenesis-and-human-space-exploration-3mj0h422kx.pdf

Heavy ion carcinogenesis and human space exploration

Ever since the discovery of X-rays was made by Rontgen more than a hundred years ago, it has always been accepted that the deleterious effects of ionizing radiation such as mutation and carcinogenesis are attributable mainly to direct damage to DNA. Although evidence based on microdosimetric estimation in support of a bystander effect appears to be consistent, direct proof of such extranuclear/extracellular effects are limited. Using a precision charged particle microbeam, we show here that irradiation of 20% of randomly selected AL cells with 20 alpha particles each results in a mutant fraction that is 3-fold higher than expected, assuming no bystander modulation effect. Furthermore, analysis by multiplex PCR shows that the types of mutants induced are significantly different from those of spontaneous origin. Pretreatment of cells with the radical scavenger DMSO had no effect on the mutagenic incidence. In contrast, cells pretreated with a 40 μM dose of lindane, which inhibits cell–cell communication, significantly decreased the mutant yield. The doses of DMSO and lindane used in these experiments are nontoxic and nonmutagenic. We further examined the mutagenic yield when 5–10% of randomly selected cells were irradiated with 20 alpha particles each. Results showed, likewise, a higher mutant yield than expected assuming no bystander effects. Our studies provide clear evidence that irradiated cells can induce a bystander mutagenic response in neighboring cells not directly traversed by alpha particles and that cell–cell communication process play a critical role in mediating the bystander phenomenon.

/pdf/induction-of-a-bystander-mutagenic-effect-of-alpha-particles-qdursurfl4.pdf

Induction of a bystander mutagenic effect of alpha particles in mammalian cells

Purpose: To investigate the mechanisms underlying the induction of chromosome aberrations by ionizing radiation, focusing attention on DNA damage severity, interphase chromosome geometry and the distribution of DNA strand breaks. Methods: An ab initio biophysical model of aberration induction in human lymphocytes specific for light ions was developed, based on the assumption that 'complex lesions' (clustered DNA breaks) produce aberrations, whereas less severe breaks are repaired. It was assumed that interphase chromosomes are spatially localized and that chromosome break free-ends rejoin pairwise randomly; the unrejoining of a certain fraction of freeends was assumed to be possible, and small fragments were neglected in order to reproduce experimental conditions. The yield of di erent aberrations was calculated and compared with some data obtained using Giemsa or FISH techniques. Results: Dose-response curves for dicentrics and centric rings (Giemsa) and for reciprocal, complex and incomplete exchanges (...

Chromosome aberrations induced by light ions: Monte Carlo simulations based on a mechanistic model

Purpose : To measure clonogenic death of Chinese hamster V79 cells following exposure to a defined number of 4.3 MeV alpha particles (track-averaged LET 105 keV/ mu m). Materials and methods : Cells were irradiated at the radiobiological facility installed at the TTT-3 Tandem accelerator in Naples by using a 'Biostack' approach, which allows the positions of incident tracks relative to cells to be carefully determined. Subcellular structure was identified by fluorescence microscopy, while tracks were visualized by LR-115 solid state nuclear track detectors. Results : Particle hits in the cytoplasm did not significantly affect cell survival, yet survival probability decreased exponentially as a function of the number of nuclear traversals. Measured probability of surviving to exactly one 4.3 MeV alpha -particle traversal in the cell nucleus was 0.67 0.10. Inactivation cross-section was substantially higher than expected from conventional survival curves. However, folding of the data with Poisson statistics...

Inactivation of individual mammalian cells by single alpha-particles.

Radiation-induced chromosomal instability in human mammary epithelial cells.

Biological dosimetry in Russian and Italian astronauts.

Inactivation of mouse C3H 10t½ cells in plateau-phase (7·8 × 104 cells/cm2) was studied by using α-particles from the irradiation facility installed for radiobiological experiments at the 3 MV Tandem accelerator, University of Naples. Silicon detectors and CR39 plastic track detectors were employed for dosimetric purposes. The cells were exposed to high LET monoenergetic α-particles (energy of 1·8 MeV at the centre of the cell nucleus, track-averaged LET of 177 keV/µm and dose-rate of 1·1 Gy/min) and low-LET 80 kVp X-rays. The X-ray survival curve showed a significant shoulder (α/β = 9 Gy) while the survival curve for α-particles was close to exponential. The mean lethal dose of α-particles was 0·77 ± 0·02 Gy and the RBE was 5·2 at 80% survival and 3·0 at 5% survival. Survival of exponentially growing cells (2 × 104 cells/cm2) following irradiation with the α-particle beam is also reported. The nuclear areas of 10T½ cells were measured as 299 ± 9 µm2 and 250 ± 8 µm2 for cells in log phase and plateau phas...

G. F. Grossi

Papers

Chromosome aberrations induced by light ions: Monte Carlo simulations based on a mechanistic model

Inactivation of individual mammalian cells by single alpha-particles.

Radiation-induced chromosomal instability in human mammary epithelial cells.

Biological dosimetry in Russian and Italian astronauts.

Inactivation of C3H 10T½ Cells by Monoenergetic High LET Alpha-particles