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Intensity Modulated Radiation Fields Induce Protective Effects and Reduce Importance of Dose-Rate Effects.

ABSTRACT: In advanced radiotherapy, intensity modulated radiation fields and complex dose-delivery are utilized to prescribe higher doses to tumours. Here, we investigated the impact of modulated radiation fields on radio-sensitivity and cell recovery during dose delivery. We generated experimental survival data after single-dose, split-dose and fractionated irradiation in normal human skin fibroblast cells (AGO1522) and human prostate cancer cells (DU145). The dose was delivered to either 50% of the area of a T25 flask containing the cells (half-field) or 100% of the flask (uniform-field). We also modelled the impact of dose-rate effects and intercellular signalling on cell-killing. Applying the model to the survival data, it is found that (i) in-field cell survival under half-field exposure is higher than uniform-field exposure for the same delivered dose; (ii) the importance of sub-lethal damage repair (SLDR) in AGO1522 cells is reduced under half-field exposure; (iii) the yield of initial DNA lesions measured with half-field exposure is smaller than that with uniform-field exposure. These results suggest that increased cell survival under half-field exposure is predominantly attributed not to rescue effects (increased SLDR) but protective effects (reduced induction of initial DNA lesions). In support of these protective effects, the reduced DNA damage leads to modulation of cell-cycle dynamics, i.e., less G1 arrest 6?h after irradiation. These findings provide a new understanding of the impact of dose-rate effects and protective effects measured after modulated field irradiation.

SUBMITTER: Matsuya Y

PROVIDER: S-EPMC6603191 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Intensity Modulated Radiation Fields Induce Protective Effects and Reduce Importance of Dose-Rate Effects.

Matsuya Yusuke Y McMahon Stephen J SJ Ghita Mihaela M Yoshii Yuji Y Sato Tatsuhiko T Date Hiroyuki H Prise Kevin M KM

Scientific reports 20190701 1

In advanced radiotherapy, intensity modulated radiation fields and complex dose-delivery are utilized to prescribe higher doses to tumours. Here, we investigated the impact of modulated radiation fields on radio-sensitivity and cell recovery during dose delivery. We generated experimental survival data after single-dose, split-dose and fractionated irradiation in normal human skin fibroblast cells (AGO1522) and human prostate cancer cells (DU145). The dose was delivered to either 50% of the area ...[more]

PMID: 31263149

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Project description:PurposeIntensity-modulated radiation therapy (IMRT) has allowed optimization of three-dimensional spatial radiation dose distributions permitting target coverage while reducing normal tissue toxicity. However, radiation-induced normal tissue toxicity is a major contributor to patients' quality of life and often a dose-limiting factor in the definitive treatment of cancer with radiation therapy. We propose the next logical step in the evolution of IMRT using canonical radiobiological principles, optimizing the temporal dimension through which radiation therapy is delivered to further reduce radiation-induced toxicity by increased time for normal tissue recovery. We term this novel treatment planning strategy "temporally feathered radiation therapy" (TFRT).MethodsTemporally feathered radiotherapy plans were generated as a composite of five simulated treatment plans each with altered constraints on particular hypothetical organs at risk (OARs) to be delivered sequentially. For each of these TFRT plans, OARs chosen for feathering receive higher doses while the remaining OARs receive lower doses than the standard fractional dose delivered in a conventional fractionated IMRT plan. Each TFRT plan is delivered a specific weekday, which in effect leads to a higher dose once weekly followed by four lower fractional doses to each temporally feathered OAR. We compared normal tissue toxicity between TFRT and conventional fractionated IMRT plans by using a dynamical mathematical model to describe radiation-induced tissue damage and repair over time.ResultsModel-based simulations of TFRT demonstrated potential for reduced normal tissue toxicity compared to conventionally planned IMRT. The sequencing of high and low fractional doses delivered to OARs by TFRT plans suggested increased normal tissue recovery, and hence less overall radiation-induced toxicity, despite higher total doses delivered to OARs compared to conventional fractionated IMRT plans. The magnitude of toxicity reduction by TFRT planning was found to depend on the corresponding standard fractional dose of IMRT and organ-specific recovery rate of sublethal radiation-induced damage.ConclusionsTFRT is a novel technique for treatment planning and optimization of therapeutic radiotherapy that considers the nonlinear aspects of normal tissue repair to optimize toxicity profiles. Model-based simulations of TFRT to carefully conceptualized clinical cases have demonstrated potential for radiation-induced toxicity reduction in a previously described dynamical model of normal tissue complication probability (NTCP).

Project description:Purpose:To evaluate 2 published normal tissue complication probability models for radiation-induced hypothyroidism (RHT) on a large cohort of oropharyngeal carcinoma (OPC) patients who were treated with intensity-modulated radiation therapy (IMRT). Methods and Materials:OPC patients treated with retrievable IMRT Digital Imaging and Communications in Medicine (DICOMs) data and available baseline and follow-up thyroid function tests were included. Mean dose (Dmean) to the thyroid gland (TG) and its volume were calculated. The study outcome was clinical HT at least 6 months after radiation therapy, which was defined as grade ?2 HT per Common Terminology Criteria for Adverse Events grading system (symptomatic hypothyroidism that required thyroid replacement therapy). Regression analyses and Wilcoxon rank-sum test were used. Receiver operating characteristic curves and area under the curve for the fitted model were calculated. Results:In the study, 360 OPC patients were included. The median age was 58 years. Most tumors (51%) originated from the base of tongue. IMRT-split field was used in 95%, and median radiation therapy dose was 69.96 Gy. In the study, 233 patients (65%) developed clinical RHT that required thyroid replacement therapy. On multivariate analysis higher Dmean and smaller TG volume maintained the statistically significant association with the risk of clinical RHT (P < .0001). Dmean was significantly higher in patients with clinical RHT versus those without (50 vs 42 Gy, P < .0001). Patients with RHT had smaller TG volume compared with those without (11.8 compared with 12.8 mL, P < .0001). AUC of 0.72 and 0.66 were identified for fitted model versus for the applied Boomsma et al and Cella et al models, respectively. Conclusions:Volume and Dmean of the TG are important predictors of clinical RHT and shall be integrated into normal tissue complication probability models for RHT. Dmean and thyroid volume should be considered during the IMRT plan optimization in OPC patients.

Project description:Purpose:Intensity modulated proton beam radiation therapy (IMPT) has a clinically significant dosimetric advantage over intensity modulated photon radiation therapy (IMRT) for the treatment of patients with esophageal cancer, particularly for sparing the heart and lungs. We compared acute radiation therapy-related toxicities and short-term clinical outcomes of patients with esophageal cancer who received treatment with IMPT or IMRT. Methods and Materials:We retrospectively reviewed the electronic health records of consecutive adult patients with esophageal cancer who underwent concurrent chemoradiotherapy with IMPT or IMRT in the definitive or neoadjuvant setting from January 1, 2014, through June 30, 2018, with additional follow-up data collected through January 31, 2019. Treatment-related toxicities were evaluated per the Common Terminology Criteria for Adverse Events, version 4. Survival outcomes were estimated with the Kaplan-Meier method. Results:A total of 64 patients (32 per group) were included (median follow-up time: 10 months for IMPT patients vs 14 months for IMRT patients). The most common radiation therapy regimen was 45 Gy in 25 fractions, and 80% of patients received a simultaneous integrated boost to a median cumulative dose of 50 Gy. Similar numbers of IMPT patients (n = 15; 47%) and IMRT patients (n = 18; 56%) underwent surgery (P = .07), with no difference in pathologic complete response rates (IMPT: n = 5; 33% vs IMRT: n = 7; 39%; P = .14). At 1 year, the clinical outcomes also were similar for IMPT and IMRT patients, respectively. Local control was 92% versus 84% (P = .87), locoregional control 92% versus 80% (P = .76), distant metastasis-free survival 87% versus 65% (P = .08), progression-free survival 71% versus 45% (P = .15), and overall survival 74% versus 71% (P = .62). The rate of acute treatment-related grade 3 toxicity was similar between the groups (P = .71). Conclusions:In our early experience, IMPT is a safe and effective treatment when administered as part of definitive or trimodality therapy. Longer follow-up is required to evaluate the effectiveness of IMPT.

Project description:BACKGROUND:To evaluate the modulation indices (MIs) for predicting the plan delivery accuracies of intensity-modulated radiation therapy (IMRT) plans. METHODS:A total of 100 dynamic IMRT plans that used TrueBeam STx and 102 dynamic IMRT plans that used Trilogy were selected. For each plan, various MIs were calculated, which included the modulation complexity score (MCS), plan-averaged beam area (PA), plan-averaged beam irregularity (PI), plan-averaged beam modulation (PM), MI quantifying multi-leaf collimator (MLC) speeds (MIs), MI quantifying MLC acceleration (MIa), and MI quantifying MLC acceleration and segment aperture irregularity (MIc,IMRT). To determine plan delivery accuracy, global gamma passing rates, MLC errors of log files, and dose-volumetric parameter differences between original and log file-reconstructed IMRT plans were obtained. To assess the ability of each MI for predicting plan delivery accuracy, Spearman's rank correlation coefficients (rs) between MIs and plan delivery accuracy measures were calculated. RESULTS:PI showed moderately strong correlations with gamma passing rates in MapCHECK2 measurements of both TrueBeam STx and Trilogy (rs?=?-?0.591 with p?<? 0.001 and?-?0.427 with p?<? 0.001 to with gamma criterion of 2%/2?mm, respectively). For ArcCHECK measurements, PI also showed moderately strong correlations with the gamma passing rates in the ArcCHECK measurements of TrueBeam STx and Trilogy (rs?=?-?0.545 with p?<? 0.001 and rs?=?-?0.581 with p?<? 0.001 with gamma criterion of 2%/2?mm, respectively). The PI showed the second strongest correlation with MLC errors in both TrueBeam STx and Trilogy (rs?=?0.861 with p?<? 0.001 and rs?=?0.767 with p?<? 0.001, respectively). In general, the PI showed moderately strong correlations with every plan delivery accuracy measure. CONCLUSIONS:The PI showed moderately strong correlations with every plan delivery accuracy measure and therefore is a useful predictor of IMRT delivery accuracy.

Dataset Information

Intensity Modulated Radiation Fields Induce Protective Effects and Reduce Importance of Dose-Rate Effects.

Publications

Intensity Modulated Radiation Fields Induce Protective Effects and Reduce Importance of Dose-Rate Effects.

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