INDIVIDUAL RADIOSENSITIVITY MEASURED WITH LYMPHOCYTES: LATE EFFECTS ARE THE KEY POINT: IN REGARD TO BORGMANN ET AL. (INT J RADlAT ONCOL BIOL PHYS 2008;71:256-264) (original) (raw)
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International Journal of Radiation Oncology*Biology*Physics, 2003
Purpose: New insights into the kinetics of late complications occurring after radiation therapy indicated that all patients have a constant risk of developing late tissue complications. These observations might have a great impact on studies relating normal tissue complications to individual radiosensitivity. Methods and Materials: Data previously published by Peacock et al. were used for analysis. In this study, 39 breast cancer patients with severe reactions (responders) were compared with 65 matched patients showing no reactions (nonresponders). Cellular radiosensitivity as measured in vitro in terms of D 0.01 did not show significant differences between the two groups, both for high-dose-rate (5.84 ؎ 0.06 vs. 5.85 ؎ 0.07 Gy) and low-dose-rate (7.44 ؎ 0.10 vs. 7.56 ؎ 0.09 Gy) irradiation. Results: A theoretical distribution was calculated for the individual radiosensitivity of patients with Grade < 1, Grade 2, or Grade 3 reactions under the following assumptions: (1) The variation of the individual radiosensitivity is described by a normal distribution. (2) All patients and not only a subgroup have a risk of developing late complications. Based on the normal distribution of low-dose-rate data (mean value [MV] ؍ 7.56 Gy, standard deviation [SD] ؍ 0.5 Gy), a total of 200 hypothetical patients were divided into three groups: a resistant group with a sensitivity >(MV ؉ , a normal group with a sensitivity between MV ؊ SD and MV ؉ SD, and a sensitive group <(MV ؊ SD), the relative fractions being 16%, 68%, and 16%, respectively. It was assumed that these groups differed in the risk of developing late complication; for Grade 3 the annual incidence rate was set at 1%, 2%, and 4% and for Grade 2 at 5%, 10%, and 20% per year, respectively. It was shown that the mean cellular sensitivity calculated for Grade 3 (7.39 ؎ 0.10 Gy) or Grade 2 patients (7.46 ؎ 0.06 Gy) was slightly but not significantly lower than that of Grade < 1 patients (7.65 ؎ 0.04 Gy). This result demonstrated that even if the risk was assumed to depend clearly on the individual radiosensitivity, significant differences in the mean cellular sensitivity between responders and nonresponders were not expected, just as found by Peacock et al. It was shown that a significant correlation between these two parameters could be detected only when the risk was analyzed separately for each group of patients. Conclusion: Most data published so far aiming at establishing a relationship between cellular radiosensitivity and the risk of late complications might need to be reevaluated, because the questions asked up to now were inadequate to arrive at a meaningful answer.
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 1994
There is a wide variation in normal tissue reactions to radiotherapy and in many situations the severity of these reactions limits radiotherapy dose. Clinical fractionation studies carried out in Gothenburg have demonstrated that a large part of the spectrum of normal tissue reactions is due to differences in individual normal tissue sensitivity. If this variation in normal tissue reactions is due to differences in intrinsic cellular radiosensitivity, it should be possible to predict tissue response based on measurement of cellular sensitivity. Here we report the initial results of a study aimed at establishing whether a direct relationship exists between cellular radiosensitivity and tissue response. Ten fibroblasts strains, including four duplicates, were established from a group of patients in the Gothenburg fractionation trials who had received radiotherapy following mastectomy. Skin doses were measured and both acute and late skin changes were observed following radiotherapy. R...
Frontiers in Oncology
Introduction: Adverse effects of radiotherapy (RT) significantly affect patient's quality of life (QOL). The possibility to identify patient-related factors that are associated with individual radiosensitivity would optimize adjuvant RT treatment, limiting the severity of normal tissue reactions, and improving patient's QOL. In this study, we analyzed the relationships between genetic features and toxicity grading manifested by RT patients looking for possible biomarkers of individual radiosensitivity. Methods: Early radiation toxicity was evaluated on 143 oncological patients according to the Common Terminology Criteria for Adverse Events (CTCAE). An individual radiosensitivity (IRS) index defining four classes of radiosensitivity (highly radiosensitive, radiosensitive, normal, and radioresistant) was determined by a G 2-chromosomal assay on ex vivo irradiated, patient-derived blood samples. The expression level of 15 radioresponsive genes has been measured by quantitative real-time PCR at 24 h after the first RT fraction, in blood samples of a subset of 57 patients, representing the four IRS classes. Results: By applying univariate and multivariate statistical analyses, we found that fatigue was significantly associated with IRS index. Interestingly, associations were detected between clinical radiation toxicity and gene expression (ATM, CDKN1A, FDXR, SESN1, XPC, ZMAT3, and BCL2/BAX ratio) and between IRS index and gene expression (BBC3, FDXR, GADD45A, and BCL2/BAX). Conclusions: In this prospective cohort study we found that associations exist between normal tissue reactions and genetic features in RT-treated patients. Overall, our findings can contribute to the identification of biological markers to predict RT toxicity in normal tissues.
Normal tissue radiosensitivity — How important is it?
Clinical Oncology, 1996
The success of radiotherapy in eradicating tumours depends on the total radiation dose, but what limits this dose is the tolerance of the normal tissues within the treatment volume. Selection of the appropriate dose for all patients is based on a balance between minimising the incidence of severe normal tissue complications and maximizing the probability of local control. In patients treated to the same radical dose, a wide range of reactions is seen; in many clinical situations, radical doses are limited by the minority of patients whose normal tissues are particularly sensitive. Clinical studies of radiotherapy reactions have demonstrated that a large part of the spectrum of normal tissue reactions, perhaps as much as 80%, is due to differences in individual normal tissue sensitivity. This suggests that it might be possible to measure this sensitivity and to change treatment accordingly. The main objective of normal tissue sensitivity testing is to permit dose escalation without increased normal tissue complication rates in patients with more resistant normal tissues. Calculations suggest that the most 'resistant' 40% of patients could be dose escalated by 17%-18%, which is likely to be associated with significant gains in local control, perhaps by as much as 34%-36%; this should translate into an increase in overall survival. It should also be possible to identify those relatively few patients who suffer serious normal tissue morbidity with conventional doses. Thus, if successful, predictive testing of normal tissue response should improve the therapeutic ratio of radiotherapy.
Cancer research, 1992
The existence of heritable radiosensitivity syndromes and clinical observations in radiotherapy patients suggests that human cellular radiosensitivity differs among individuals. We report here an in vitro study of radiosensitivity in 30 fibroblast and 29 lymphocyte cultures obtained from cancer patients and controls. In 25 cases, both fibroblasts and lymphocytes were obtained from the same donors. Fibroblasts were cultured from skin biopsy samples, and peripheral T-cell lymphocytes were cultured from blood. Clonogenic survival assays were performed by using high- and low-dose-rate irradiation; lymphocytes were in G0 phase and fibroblasts in confluent plateau phase. Various end points were calculated and compared (i.e., surviving fraction at 2 Gy, initial slope of the survival curve, and doses resulting in 10 and 1% survival, respectively). Depending on the end point, the coefficient of variation of the survival parameters ranged from 31 to 68% for lymphocytes and 21 to 41% for fibro...
Inherent radiosensitivity and its impact on breast cancer chemo-radiotherapy
2017
About 10% of apparently normal individuals are sensi ve to clastogenic effects of physico-chemical agents. More than 45% of breast cancer pa ents’ exhibit elevated radiosensi vity. Although the nature of inherent radiosensi vity is not fully understood, but insufficiency and impaired DNA repair mechanism might be prime cause of radiosensi vity. This is evident from gene cally affected individuals such as ataxia telangiectasia, severe combined immunodeficiency, Xeroderma pigmentasum, Fanconi anemia who show sensi vity to ionizing radia on, ultraviolet light and alkyla ng agents. All these gene c diseases are caused due to impaired DNA damage repair mechanism. Radia on therapy (RT) is a common and effec ve way of treatment in several types of malignant tumors. Some cancer pa ents suffer from side effects of RT such as radia on induced early or late adverse responses in normal ssues within weeks, months, or even years post irradia on, due to intrinsic radiosensi vity. The RT efficiency...
Biomedicines
About 5% of patients undergoing radiotherapy (RT) develop RT-related side effects. To assess individual radiosensitivity, we collected peripheral blood from breast cancer patients before, during and after the RT, and γH2AX/53BP1 foci, apoptosis, chromosomal aberrations (CAs) and micronuclei (MN) were analyzed and correlated with the healthy tissue side effects assessed by the RTOG/EORTC criteria. The results showed a significantly higher level of γH2AX/53BP1 foci before the RT in radiosensitive (RS) patients in comparison to normal responding patients (NOR). Analysis of apoptosis did not reveal any correlation with side effects. CA and MN assays displayed an increase in genomic instability during and after RT and a higher frequency of MN in the lymphocytes of RS patients. We also studied time kinetics of γH2AX/53BP1 foci and apoptosis after in vitro irradiation of lymphocytes. Higher levels of primary 53BP1 and co-localizing γH2AX/53BP1 foci were detected in cells from RS patients a...