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Mechanisms and Review of Clinical Evidence of Variations in Relative Biological Effectiveness in Proton Therapy.

ABSTRACT: Proton therapy is increasingly being used as a radiation therapy modality. There is uncertainty about the biological effectiveness of protons relative to photon therapies as it depends on several physical and biological parameters. Radiation oncology currently applies a constant and generic value for the relative biological effectiveness (RBE) of 1.1, which was chosen conservatively to ensure tumor coverage. The use of a constant value has been challenged particularly when considering normal tissue constraints. Potential variations in RBE have been assessed in several published reviews but have mostly focused on data from clonogenic cell survival experiments with unclear relevance for clinical proton therapy. The goal of this review is to put in vitro findings in relation to clinical observations. Relevant in vivo pathways determining RBE for tumors and normal tissues are outlined, including not only damage to tumor cells and parenchyma but also vascular damage and immune response. Furthermore, the current clinical evidence of varying RBE is reviewed. The assessment can serve as guidance for treatment planning, personalized dose prescriptions, and outcome analysis.

SUBMITTER: Paganetti H

PROVIDER: S-EPMC8688199 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Mechanisms and Review of Clinical Evidence of Variations in Relative Biological Effectiveness in Proton Therapy.

Paganetti Harald H

International journal of radiation oncology, biology, physics 20210815 1

Proton therapy is increasingly being used as a radiation therapy modality. There is uncertainty about the biological effectiveness of protons relative to photon therapies as it depends on several physical and biological parameters. Radiation oncology currently applies a constant and generic value for the relative biological effectiveness (RBE) of 1.1, which was chosen conservatively to ensure tumor coverage. The use of a constant value has been challenged particularly when considering normal tis ...[more]

PMID: 34407443

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Project description:PurposeClinical proton beam therapy has been based on the use of a generic relative biological effectiveness (RBE) of ∼1.1. However, emerging data have suggested that Fanconi anemia (FA) and homologous recombination pathway defects can lead to a variable RBE, at least in vitro. We investigated the role of SLX4 (FANCP), which acts as a docking platform for the assembly of multiple structure-specific endonucleases, in the response to proton irradiation.Methods and materialsIsogenic cell pairs for the study of SLX4, XPF/ERCC1, MUS81, and SLX1 were irradiated at the mid-spread-out Bragg peak of a clinical proton beam (linear energy transfer 2.5 keV/μm) or with 250 kVp x-rays, and the clonogenic survival fractions were determined. To estimate the RBE of the protons relative to cobalt-60 photons (Co60Eq), we assigned a RBE(Co60Eq) of 1.1 to x-rays to correct the physical dose measured. Standard DNA repair foci assays were used to monitor the damage responses, and the cell cycle distributions were assessed by flow cytometry. The poly(ADP-ribose) polymerase inhibitor olaparib was used for comparison.ResultsLoss of SLX4 function resulted in an enhanced proton RBE(Co60Eq) of 1.42 compared with 1.11 for wild-type cells (at a survival fraction of 0.1; P<.05), which correlated with increased persistent DNA double-strand breaks in cells in the S/G2 phase. Genetic analysis identified the SLX4-binding partner MUS81 as a mediator of resistance to proton radiation. Both proton irradiation and olaparib treatment resulted in a similar prolonged accumulation of RAD51 foci in SLX4/MUS81-deficient cells, suggesting a common defect in the repair of DNA replication fork-associated damage.ConclusionsA defect in the FA pathway at the level of SLX4 results in hypersensitivity to proton radiation, which is, at least in part, due to impaired MUS81-mediated processing of replication forks that stall at clustered DNA damage. In vivo and clinical studies are needed to confirm these findings in human cancers.

Dataset Information

Mechanisms and Review of Clinical Evidence of Variations in Relative Biological Effectiveness in Proton Therapy.

Publications

Mechanisms and Review of Clinical Evidence of Variations in Relative Biological Effectiveness in Proton Therapy.

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