Variation In Radiation Sensitivity Research Articles

Radiation-sensitive genetic prognostic model identifies individuals at risk for radiation resistance in head and neck squamous cell carcinoma.

The advantages of radiotherapy for head and neck squamous cell carcinoma (HNSCC) depend on the radiation sensitivity of the patient. Here, we established and verified radiological factor-related gene signature and built a prognostic risk model to predict whether radiotherapy would be beneficial. Data from The Cancer Genome Atlas, Gene Expression Omnibus, and RadAtlas databases were subjected to LASSO regression, univariate COX regression, and multivariate COX regression analyses to integrate genomic and clinical information from patients with HNSCC. HNSCC radiation-related prognostic genes were identified, and patients classified into high- and low-risk groups, based on risk scores. Variations in radiation sensitivity according to immunological microenvironment, functional pathways, and immunotherapy response were investigated. Finally, the expression of HNSCC radiation-related genes was verified by qRT-PCR. We built a clinical risk prediction model comprising a 15-gene signature and used it to divide patients into two groups based on their susceptibility to radiation: radiation-sensitive and radiation-resistant. Overall survival was significantly greater in the radiation-sensitive than the radiation-resistant group. Further, our model was an independent predictor of radiotherapy response, outperforming other clinical parameters, and could be combined with tumor mutational burden, to identify the target population with good predictive value for prognosis at 1, 2, and 3 years. Additionally, the radiation-resistant group was more vulnerable to low levels of immune infiltration, which are significantly associated with DNA damage repair, hypoxia, and cell cycle regulation. Tumor Immune Dysfunction and Exclusion scores also suggested that the resistant group would respond less favorably to immunotherapy. Our prognostic model based on a radiation-related gene signature has potential for application as a tool for risk stratification of radiation therapy for patients with HNSCC, helping to identify candidates for radiation therapy and overcome radiation resistance.

Radiation-sensitive genetic prognostic model to identify individuals at risk for radiation resistance in head and neck squamous cell carcinoma.

e18042 Background: The advantages of radiotherapy for head and neck squamous cell carcinoma (HNSCC) depend on the radiation sensitivity of the patient. Here, we established and verified radiological factor-related gene signature and built a prognostic risk model to predict whether radiotherapy would be beneficial. Methods: Data from The Cancer Genome Atlas, Gene Expression Omnibus, and RadAtlas databases were subjected to LASSO regression, univariate COX regression, and multivariate COX regression analyses to integrate genomic and clinical information from patients with HNSCC. HNSCC radiation-related prognostic genes were identified, and patients classified into high- and low-risk groups, based on risk scores. Variations in radiation sensitivity according to immunological microenvironment, functional pathways, and immunotherapy response were investigated. Results: We built a clinical risk prediction model comprising a 15-genes signature and used it to divide patients into two groups based on their susceptibility to radiation: radiation-sensitive and radiation-resistant. Overall survival was significantly greater in the radiation-sensitive than the radiation-resistant group. Further, our model was an independent predictor of radiotherapy response, outperforming other clinical parameters, and could be combined with tumor mutational burden, to identify the target population with good predictive value for prognosis at 1, 2, and 3 years. Additionally, the radiation-resistant group was more vulnerable to low levels of immune infiltration, which are significantly associated with DNA damage repair, hypoxia, and cell cycle regulation. Tumor Immune Dysfunction and Exclusion scores also suggested that the resistant group would respond less favorably to immunotherapy. Conclusions: Our prognostic model based on a radiation-related gene signature has potential for application as a tool for risk stratification of radiation therapy for patients with HNSCC, helping to identify candidates for radiation therapy and overcome radiation resistance.

FDG PET/CT parameters and correlations with tumor-absorbed doses in a phase 1 trial of 177Lu-lilotomab satetraxetan for treatment of relapsed non-Hodgkin lymphoma

Purpose177Lu-lilotomab satetraxetan targets the CD37 antigen and has been investigated in a first-in-human phase 1/2a study for relapsed non-Hodgkin lymphoma (NHL). Tumor dosimetry and response evaluation can be challenging after radioimmunotherapy (RIT). Changes in FDG PET/CT parameters after RIT and correlations with tumor-absorbed doses has not been examined previously in patients with lymphoma. Treatment-induced changes were measured at FDG PET/CT and ceCT to evaluate response at the lesion level after treatment, and correlations with tumor-absorbed doses were investigated.MethodsForty-five tumors in 16 patients, with different pre-treatment and pre-dosing regimens, were included. Dosimetry was performed based on multiple SPECT/CT images. FDG PET/CT was performed at baseline and at 3 and 6 months. SUVmax, MTV, TLG, and changes in these parameters were calculated for each tumor. Lesion response was evaluated at 3 and 6 months (PET3months and PET6months) based on Deauville criteria. Anatomical changes based on ceCT at baseline and at 6 and 12 months were investigated by the sum of perpendiculars (SPD).ResultsTumor-absorbed doses ranged from 35 to 859 cGy. Intra- and interpatient variations were observed. Mean decreases in PET parameters from baseline to 3 months were ΔSUVmax-3months 61%, ΔMTV3months 80%, and ΔTLG3months 77%. There was no overall correlation between tumor-absorbed dose and change in FDG PET or ceCT parameters at the lesion level or significant difference in tumor-absorbed doses between metabolic responders and non-responders after treatment.ConclusionOur analysis does not show any correlation between tumor-absorbed doses and changes in FDG PET or ceCT parameters for the included lesions. The combination regimen, including cold antibodies, may be one of the factors precluding such a correlation. Increased intra-patient response with increased tumor-absorbed doses was observed for most patients, implying individual variations in radiation sensitivity or biology.Trial registrationClinicalTrials.gov Identifier (NCT01796171). Registered December 2012

A Potential Biomarker for Predicting the Risk of Radiation-Induced Fibrosis in the Lung

Biomarkers could play an essential role during triage in the aftermath of a radiological event, where exposure to radiation will be heterogeneous and complicated by concurrent trauma. Used alongside biodosimetry, biomarkers can identify victims in need of treatment for acute radiation effects, and might also provide valuable information on later developing consequences that need to be addressed as part of a treatment strategy. Indeed, because the lung is particularly sensitive to radiation and resultant late effects not only affect quality of life, but can also lead to morbidity, the risk of developing downstream pulmonary complications in exposed individuals requires assessment. In this study, analyses of changes in pulmonary and circulating content of club cell secretory protein (CCSP) and surfactant protein D (SP-D), expressed by epithelial club cells and type II pneumocytes in the lung, respectively, were used to evaluate pulmonary epithelial damage in several lung injury models. Using a combined radiation exposure model, fibrosis-susceptible C57BL/6J (C57) and alveolitis-prone C3H/HeJ (C3H) mice received 5 Gy total-body irradiation plus 2.5-10 Gy whole-lung irradiation, and lung and plasma samples were collected throughout the course of the radiation response, at time points ranging from 24 h to 26 weeks postirradiation. Radiation significantly reduced bronchiole CCSP coverage in C57 mice at 26 weeks, a response that varied in extent among animals, but correlated with the severity of fibrosis in each animal. Interestingly, plasma CCSP content was elevated in C57 mice at multiple time points preceding and during the fibrotic period; this response that was not observed in C3H mice. Circulating CCSP/SP-D ratios, calculated as an index of lung integrity, were similarly increased throughout the time course in C57, but not C3H, mice. Furthermore, when the thoracic doses were reduced to subthreshold levels for fibrosis induction (2.5 or 7.5 Gy), although the CCSP/SP-D ratio in lung homogenates demonstrated dose-responsive changes, this was not reflected in the plasma ratios at acute and late time points. Importantly, plasma CCSP/SP-D ratios also were not significantly altered in C57 mice exposed to LPS, and only transiently decreased in influenza-exposed mice, demonstrating a level of specificity for radiation-induced lung injury. These results indicate that the CCSP/SP-D ratio, measured in plasma, is sensitive to individual variation in radiation sensitivity, correlates with fibrosis development, can be detected early after exposure and is specific to radiation-induced injury. This suggests that the CCSP/SP-D ratio may be useful as a biomarker of radiation-induced pulmonary fibrosis.

Abstract 847: Optimization of radiation regimen in a carcinogen-induced mouse model for lung cancer

Abstract Purpose: Lung cancer remains the most common cause of cancer-related mortality in United States and worldwide. The major cause of lung cancer is attributed to carcinogens present in tobacco smoke, air pollution, diet and food supplements, occupational and other environmental exposures. Lung Cancer Mutation Consortium has identified many recognized “driver mutations” in nearly two-thirds of the patients who developed advanced form of lung cancer. Our primary goal is to understand the mechanism underlying the variations in radiation sensitivity with driver mutations and optimize radiation dose and treatment regimen. A better understanding of the most frequent driving mutations is required for progression towards personalized therapy. Methods: Urethane, a carcinogen injected via intraperitoneal route into A/J mice induced multiple lung tumors by week 25 that resembled non-small cell lung carcinoma. These lung tumors were assessed via MRI and each tumor was longitudinally tracked via surface rendered 3D imaging following X-ray exposure using small animal radiation research platform (SARRP). We employed acute high single dose (12 Gy) and clinically relevant fractionated dose (3 X 5 Gy). Individual lung tumor was also dissected from non-irradiated and irradiated mice followed by collagenase digestion and then cultured in a specific media for in-vitro mutational analysis. Results: Urethane induced multiple lung tumors (20-25 tumors with 1mg/kg urethane) of varying size (0.5 - 2mm) were detectable by MRI at 25 week following injection. Longitudinal MRI performed on irradiated tumor bearing mice showed significant regression after radiation with commitment survival benefit. Mice performed better when exposed to fractionated regimen than high single dose with relatively low level radiation toxicity. Primary lung cancer cells were prepared from the explanted tumors for prospectively examining relevant driver mutations and studying the genetic determinants of resistance and to identify novel targets. We also have collected body fluids for investigating changes in molecular profile of exosomes at time points after irradiation. Conclusions: Our study thus far set up a platform for longitudinal 3D tracking of individual lung tumors following treatment and recurrence. Tumor regression was evident after a week of radiation exposure. Primary lung tumor cell cultures were successfully established for molecular analysis and mechanistic studies Citation Format: Sagar Bhayana, Joseph Liu, Arnab Chakravarti, Naduparambil K. Jacob. Optimization of radiation regimen in a carcinogen-induced mouse model for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 847.

Genetic and epigenetic changes in clonal descendants of irradiated human fibroblasts

To study delayed genetic and epigenetic radiation effects, which may trigger radiation-induced carcinogenesis, we have established single-cell clones from irradiated and non-irradiated primary human fibroblasts. Stable clones were endowed with the same karyotype in all analyzed metaphases after 20 population doublings (PDs), whereas unstable clones displayed mosaics of normal and abnormal karyotypes. To account for variation in radiation sensitivity, all experiments were performed with two different fibroblast strains. After a single X-ray dose of 2 Gy more than half of the irradiated clones exhibited radiation-induced genome instability (RIGI). Irradiated clones displayed an increased rate of loss of chromosome Y (LOY) and copy number variations (CNVs), compared to controls. CNV breakpoints clustered in specific chromosome regions, in particular 3p14.2 and 7q11.21, coinciding with common fragile sites. CNVs affecting the FHIT gene in FRA3B were observed in independent unstable clones and may drive RIGI. Bisulfite pyrosequencing of control clones and the respective primary culture revealed global hypomethylation of ALU, LINE-1, and alpha-satellite repeats as well as rDNA hypermethylation during in vitro ageing. Irradiated clones showed further reduced ALU and alpha-satellite methylation and increased rDNA methylation, compared to controls. Methylation arrays identified several hundred differentially methylated genes and several enriched pathways associated with in vitro ageing. Methylation changes in 259 genes and the MAP kinase signaling pathway were associated with delayed radiation effects (after 20 PDs). Collectively, our results suggest that both genetic (LOY and CNVs) and epigenetic changes occur in the progeny of exposed cells that were not damaged directly by irradiation, likely contributing to radiation-induced carcinogenesis. We did not observe epigenetic differences between stable and unstable irradiated clones. The fact that the DNA methylation (DNAm) age of clones derived from the same primary culture varied greatly suggests that DNAm age of a single cell (represented by a clone) can be quite different from the DNAm age of a tissue. We propose that DNAm age reflects the emergent property of a large number of individual cells whose respective DNAm ages can be highly variable.

Radiobiological Implications of Fukushima Nuclear Accident for Personalized Medical Approach.

On March 11, 2011, a devastating earthquake and subsequent tsunami caused serious damage to areas of the Pacific coast in Fukushima prefecture and prompted fears among the residents about a possible meltdown of the Fukushima Daiichi Nuclear Power Plant reactors. As of 2017, over six years have passed since the Fukushima nuclear crisis and yet the full ramifications of the biological exposures to this accidental release of radioactive substances remain unclear. Furthermore, although several genetic studies have determined that the variation in radiation sensitivity among different individuals is wider than expected, personalized medical approaches for Fukushima victims have seemed to be insufficient. In this commentary, we discuss radiobiological issues arising from low-dose radiation exposure, from the cell-based to the population level. We also introduce the scientific utility of the Integrative Japanese Genome Variation Database (iJGVD), an online database released by the Tohoku Medical Megabank Organization, Tohoku University that covered the whole genome sequences of 2,049 healthy individuals in the northeastern part of Japan in 2016. Here we propose a personalized radiation risk assessment and medical approach, which considers the genetic variation of radiation sensitivity among individuals, for next-step developments in radiological protection.

SU-E-T-146: Effects of Uncertainties of Radiation Sensitivity of Biological Modelling for Treatment Planning

Purpose: The aim of this study was to evaluate the distribution of uncertainty of cell survival by radiation, and assesses the usefulness of stochastic biological model applying for gaussian distribution. Methods: For single cell experiments, exponentially growing cells were harvested from the standard cell culture dishes by trypsinization, and suspended in test tubes containing 1 ml of MEM(2x106 cells/ml). The hypoxic cultures were treated with 95% N2−5% CO2 gas for 30 minutes. In vitro radiosensitization was also measured in EMT6/KU single cells to add radiosensitizer under hypoxic conditions. X-ray irradiation was carried out by using an Xray unit (Hitachi X-ray unit, model MBR-1505R3) with 0.5 mm Al/1.0 mm Cu filter, 150 kV, 4 Gy/min). In vitro assay, cells on the dish were irradiated with 1 Gy to 24 Gy, respectively. After irradiation, colony formation assays were performed. Variations of biological parameters were investigated at standard cell culture(n=16), hypoxic cell culture(n=45) and hypoxic cell culture(n=21) with radiosensitizers, respectively. The data were obtained by separate schedule to take account for the variation of radiation sensitivity of cell cycle. Results: At standard cell culture, hypoxic cell culture and hypoxic cell culture with radiosensitizers, median and standard deviation of alpha/beta ratio were 37.1±73.4 Gy, 9.8±23.7 Gy, 20.7±21.9 Gy, respectively. Average and standard deviation of D5 0 were 2.5±2.5 Gy, 6.1±2.2 Gy, 3.6±1.3 Gy, respectively. Conclusion: In this study, we have challenged to apply these uncertainties of parameters for the biological model. The variation of alpha values, beta values, D5 0 as well as cell culture might have highly affected by probability of cell death. Further research is in progress for precise prediction of the cell death as well as tumor control probability for treatment planning.

Genetic association on radiation induced mucosal and skin toxicity in patients with nasopharyngeal carcinoma

Radiation therapy (RT) is the primary treatment for many head and neck cancers including nasopharyngeal carcinoma (NPC). While prognosis has been greatly improved with the advancement of RT technique, radiation-induced complications especially normal tissue surrounding tumour volume is unavoidable. Genetic factors are thought to be the most important factors contributing to individual variation in radiation sensitivity. Over 120 studies have been published since year 2000 to investigate the association of genetic variants to radiation-induced toxicities in various types of cancer. Candidate gene approach is the most commonly used approach in published studies, including studies in patients with NPC. Skin and mucosal toxicities are two of the most common radiation induced complications in the radiotherapy of NPC patients. However, studies focused on radiation toxicity in NPC patients are limited. Published literatures focused on genetic variations and radiation sensitivity in NPC patients are summarized in this review, and recommendations for future studies are also suggested.

SU‐E‐T‐31: The Evaluation of Dosimetric Characteristics of OSLDs Based On Output Correction Factor in Low Energy

Purpose: The output of General X‐ray unit (low energy) has variation against 60Co unit. So it is necessary to minimize output variation when evaluating dosimetric characteristics of optical stimulated luminance dosimeters (OSLDs). Considering output variation of X‐ray unit, we evaluated dosimetric characteristics of OSLDs in low energyMethods: The OSLDs that used were nanoDotTM Dosimeter (Landauer Inc, Glenwood, USA) and this dosimeter had never been irradiated. Through single irradiate them (test dose was 7mGy), we certified batch homogeneity and sampled dosimeters with variation of radiation sensitivity within ± 1.5% among them. Using to these dosimeters certified reproducibility considering output variation every time when irradiated OSLDs. Through this process, we certified element correction factor (ECF) and coefficient of variation (COV) about each OSLD. Based on these OSLDs, we studied linearity, energy dependence and angular dependenceResults: The batch homogeneity was 1.21% of the coefficient of variation (after sampling). The average value of COV about reproducibility of OSLDs was reduced from 1.3% to 0.96% after applying to output correction factor. The linearity was that the correlation of between dose and count was fitted by linear function (R2 =0.997). The energy dependence study showed a range of ion chamber‐to OSLD rations from 0.23 (24.7 keV) to 0.27 (34.5 keV). According to energy, the range of angular dependence was from 0.1% to 8.4% variation when each degree was normalized by zero degreeConclusion: Considering output correction factor, reduced uncertainty occurred in general x‐ray unit. We acquired information that was ECF, COV of OSLDs in low energy. Using to these OLDs, It is feasible to measure patient dose of diagnostic radiography and Cone beam computed tomography for radiotherapy

SU‐E‐T‐38: The Evaluation of High Dose and Dosimetric Characteristics of Optical Stimulated Luminance Dosimeters in the 60CO Unit

Purpose: We aimed to evaluate optical stimulated luminance dosimeters (OSLD) to estimate high dose in 60Co unit and to compare to advanced study about OSLDMethods: OSLDs were grouped into three groups by radiation sensitivity (serial No.) and each groups consisted of dosimeters with variation of radiation sensitivity within ± 1.5% among them by sampling. When we evaluated dosimetric characteristics of OSLD, indicated used OSLD groups in list of evaluation of the dosimetric characteristics of them. OSLD had supra‐linear response from more than 3 Gy. So the correlation of between dose delivered from 60Co and count was fitted by quadratic function. We compared to calculation dose and delivery dose in more than 3 GyResults: The reproducibility was 0.76% of the coefficient of variation, the batch homogeneity was within 1.5 % of the coefficient of variation and the depletion by repeat reading was 0.04% per reading. The half time of count decay curve after irradiation according to reading time was 0.68 min. (1 Gy), 1.04 min. (5 Gy), and 1.10 min. (10 Gy), respectively and the count decay was stable after 11 min, After stability, coefficient of variation was within 0.4%.The removal rate of count by optical annealing time (30min.) after OSLD reading was 88% (1 Gy), 90% (5 Gy), and 92% (10 Gy), respectively and was 99% when they were annealed for 4hour. The diff. % of between delivery dose form 60Co unit and calculated dose from fitting model was within ± 4.0%. But the OSLDs irradiated dose above 20 Gy changed their radiation sensitivity. So it is necessary to use carefully them and to calibrate radiation sensitivity of themConclusion: Considering to uncertainty of count for procedure, if delivery dose was calculated, it is feasible to use OSLD for evaluation of high dose in 60Co unit. Acknowledgement:This research was supported by the Ministry of education, Science and Technology(MEST)

Functional MRI for radiotherapy dose painting

Modern radiation therapy techniques are exceptionally flexible in the deposition of radiation dose in a target volume. Complex distributions of dose can be delivered reliably, so that the tumor is exposed to a high dose, whereas nearby healthy structures can be avoided. As a result, an increase in curative dose is no longer invariably associated with an increased level of toxicity. This modern technology can be exploited further by modulating the required dose in space so as to match the variation in radiation sensitivity in the tumor. This approach is called dose painting.For dose painting to be effective, functional imaging techniques are essential to identify regions in a tumor that require a higher dose. Several techniques are available in nuclear medicine and radiology. In recent years, there has been a considerable research effort concerning the integration of magnetic resonance imaging (MRI) into the external radiotherapy workflow motivated by the superior soft tissue contrast as compared to computed tomography. In MRI, diffusion-weighted MRI reflects the cell density of tissue and thus may indicate regions with a higher tumor load. Dynamic contrast-enhanced MRI reflects permeability of the microvasculature and blood flow, correlated to the oxygenation of the tumor. These properties have impact on its radiation sensitivity.New questions must be addressed when these techniques are applied in radiation therapy: scanning in treatment position requires alternative solutions to the standard patient setup in the choice of receive coils compared to a diagnostic department. This standard positioning also facilitates repeated imaging. The geometrical accuracy of MR images is critical for high-precision radiotherapy. In particular, when multiparametric functional data are used for dose painting, quantification of functional parameters at a high spatial resolution becomes important.In this review, we will address these issues and describe clinical developments in MRI-guided dose painting.

Abstract A8: Cytogenetic evaluation of human individual radiation sensitivity with the purpose of primary prevention of radiogenic cancer

Abstract Background: Rising of cancer incidences in population of Ukraine is connected with the increasing of cancerogenic loading where ionizing radiation has been recognized as a strong cancer causing agent. Today variations in radiation sensitivity between individuals are shown to be genetically determined and connected with the effectiveness of cell signaling system function after exposure to damaging agents. Recent reports have suggested that elevated chromosome aberration yields observed following radiation exposure of peripheral lymphocytes in G2 phase of cell cycle caused by the impaired DNA repair and hereditary predisposition to cancer. The goal of the presented study was to evaluate chromosomal sensitivity of lymphocytes of healthy individuals on the basis of the modified G2-test. Materials and Methods: Test-system of human peripheral blood lymphocytes (PBL) of 110 healthy donors with the next metaphase analysis of chromosomal aberrations (chromatid breaks) was used. Test -irradiation of cell cultures was carried out at 1,5 Gy in the late G2-stage. Cells were analyzed in the first mitosis. Results: The obtained cytogenetic data has revealed high interindividual variability in the levels of radiation induced chromatid breaks (CV = 24%). It was shown that distribution of the examined cytogenetic parameter in the group did not correspond to normal distribution and had bimodal character. Application of variation statistics' methods has revealed existence of two subgroups of donors - with “normal” and “increased” (11,6 % of the group) radiation sensitivity of lymphocytes on chromosomal level. Taking into account correlations of high radiation-induced genome instability of human somatic cells with cancer predisposition it is competent to relate these individuals with the group of increased radiogenic cancer risk. Application of cytogenetic examinations on the basis of G2-assay is recommended for the formation of groups with the increased radiogenic cancer risk and promotes the efficiency of primary cancer prevention in the cohorts of occupationally exposed individuals. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A8.

Novel dosimetric phantom for quality assurance of volumetric modulated arc therapy

The objective of this work is to assess the suitability and performance of a new dosimeter system with a novel geometry for the quality assurance (QA) of volumetric modulated arc therapy (VMAT). The new dosimeter system consists of a hollow cylinder (15 and 25 cm inner and outer diameters) with 124 diodes embedded in the phantom's cylindrical wall forming four rings of detectors. For coplanar beams, the cylindrical geometry and the ring diode pattern offer the advantage of invariant perpendicular incidence on the beam central axis for any gantry angle and also have the benefit of increasing the detector density as both walls of the cylinder sample the beam. Other advantages include real-time readout and reduced weight with the hollow phantom shape. A calibration method taking into account the variation in radiation sensitivity of the diodes as a function of gantry angle was developed and implemented. In this work, the new dosimeter system was used in integrating mode to perform composite dose measurements along the cylindrical surface supporting the diodes. The reproducibility of the dosimeter response and the angular dependence of the diodes were assessed using simple 6 MV photon static beams. The performance of the new dosimeter system for VMAT QA was then evaluated using VMAT plans designed for a head and neck, an abdominal sarcoma, and a prostate patient. These plans were optimized with 90 control points (CPs) and additional versions of each plan were generated by increasing the number of CPs to 180 and 360 using linear interpolation. The relative dose measured with the dosimeter system for the VMAT plans was compared to the corresponding TPS dose map in terms of relative dose difference (% deltaD) and distance to agreement (DTA). The dosimeter system's sensitivity to gantry rotation offset and scaling errors as well as setup errors was also evaluated. For static beams, the dosimeter system offered good reproducibility and demonstrated small residual diode angular dependence after calibration. For VMAT deliveries, the agreement between measured and calculated doses was good with > or = 86.4% of the diodes satisfying 3% of % deltaD or 2 mm DTA for the 180 CP plans. The phantom offered sufficient sensitivity for the detection of small gantry rotation offset (3 degrees) and scaling errors (1 degree) as well as phantom setup errors of 1 mm, although the results were plan dependent. With its novel geometry, the dosimeter system was also able to experimentally demonstrate the discretization effect of the number of CPs used in the TPS to simulate a continuous arc. These results demonstrate the suitability of the new dosimeter system for the patient-specific QA of VMAT plans and suggest that the dosimeter system can be an effective tool in the routine QA and commissioning of treatment machines capable of VMAT delivery and cone-beam CT image guidance.

Variation in radiation sensitivity and repair kinetics in different parts of the spinal cord

Background. The spinal cord, known for its strongly serial character and high sensitivity to radiation even when a small segment is irradiated, is one of the most critical organs at risk to be spared during radiation therapy. To compare the sensitivity of different parts of the spinal cord, data for radiation myelopathy have been used. Material and methods. In the present study, the relative seriality model was fitted to two different datasets of clinical radiation myelitis concerning cervical spinal cord after treating 248 patients for head and neck cancer and thoracic spinal cord after treating 43 patients with lung carcinoma. The maximum likelihood method was applied to fit the clinical data. The model parameters and their 68% confidence intervals were calculated for each dataset. The α/β ratio for the thoracic cord was also was also found to be 0.9 (0–3.0) Gy. Results. The dose-response curve for the more sensitive cervical myelopathy is well described by the parameters D50=55.9 (54.8–57.1) Gy, γ=6.9 (5.0–9.2), s=0.13 (0.07–0.24), whereas the thoracic myelopathy is described by the parameters D50=75.5 (70.5–80.8) Gy, γ=1.1 (0.6–1.6), s=36 (3.3−∞). Discussion and conclusions. Large differences in radiation response between the cervical and thoracic region of spinal cord are thus observed: cervical myelopathy seems to be characterized by medium seriality, while thoracic spinal cord is characterized by a highly serial dose-response. The much steeper dose-response curve for cervical spinal cord myelopathy can be interpreted as a higher number of functional subunits consistent with a higher amount of white matter close to the brain.

Haplotype-Based Analysis of Genes Associated With Risk of Adverse Skin Reactions After Radiotherapy in Breast Cancer Patients

To identify haplotypes of single nucleotide polymorphism markers associated with the risk of early adverse skin reactions (EASRs) after radiotherapy in breast cancer patients. DNA was sampled from 399 Japanese breast cancer patients who qualified for breast-conserving radiotherapy. Using the National Cancer Institute-Common Toxicity Criteria scoring system, version 2, the patients were grouped according to EASRs, defined as those occurring within 3 months of starting radiotherapy (Grade 1 or less, n = 290; Grade 2 or greater, n = 109). A total of 999 single nucleotide polymorphisms from 137 candidate genes for radiation susceptibility were genotyped, and the haplotype associations between groups were assessed. The global haplotype association analysis (p < 0.05 and false discovery rate < 0.05) indicated that estimated haplotypes in six loci were associated with EASR risk. A comparison of the risk haplotype with the most frequent haplotype in each locus showed haplotype GGTT in CD44 (odds ratio [OR] = 2.17; 95% confidence interval [CI], 1.07-4.43) resulted in a significantly greater EASR risk. Five haplotypes, CG in MAD2L2 (OR = 0.55; 95% CI, 0.35-0.87), GTTG in PTTG1 (OR = 0.48; 95% CI, 0.24-0.96), TCC (OR = 0.48; 95% CI, 0.26-0.89) and CCG (OR = 0.50; 95% CI, 0.27-0.92) in RAD9A, and GCT in LIG3 (OR = 0.46; 95% CI, 0.22-0.93) were associated with a reduced EASR risk. No significant risk haplotype was observed in REV3L. Individual radiosensitivity can be partly determined by these haplotypes in multiple loci. Our findings may lead to a better understanding of the mechanisms underlying the genetic variation in radiation sensitivity and resistance among breast cancer patients.

Physical Models and Simpler Dosimetric Descriptors of Radiation Late Toxicity

Predicting radiation damage to specific organs is becoming ever more challenging with the use of intensity-modulated beams, nonuniform dose distributions, partial organ irradiation, and interpatient and even intraorgan variations in radiation sensitivity. Data-based physical models can be of use in summarizing complicated dose-volume data to help describe clinical outcomes and ultimately aid in the prediction of clinical toxicity. This article attempts to provide a brief overview of the use of normal tissue complication probability (NTCP) models and other simple dose/volume metrics to describe a few clinically significant complications (either frequent or serious) associated with radiation therapy of the head and neck, thorax, and abdominal-pelvic regions. Specifically, it reviews the application of these methods for late toxicities of the parotid, lung, heart, spinal cord, liver, and rectum. It focuses on organ-specific NTCP parameters as well as simple dosimetric descriptors that might be used to help treatment plan evaluation in clinical practice.

Characterization of responses and comparison of calibration factor for commercial MOSFET detectors

A commercial metal oxide silicon field effect transistor (MOSFET) dosimeter of model TN502-RD has been characterized for its linearity, reproducibility, field size dependency, dose rate dependency, and angular dependency for Cobalt-60 ( 60Co), 6-MV, and 15-MV beam energies. The performance of the MOSFET clearly shows that it is highly reproducible, independent of field size and dose rate. Furthermore, MOSFET has a very high degree of linearity, with r-value > 0.9 for all 3 energies. The calibration factor for 2 similar MOSFET detectors of model TN502-RD were also estimated and compared for all 3 energies. The calibration factor between the 2 similar MOSFET detectors shows a variation of about 1.8% for 60Co and 15 MV, and for 6 MV it shows variation of about 2.5%, indicating that calibration should be done whenever a new MOSFET is used. However, the detector shows considerable angular dependency of about 8.8% variation. This may be due to the variation in radiation sensitivity between flat and bubble sides of the MOSFET, and indicates that positional care must be taken while using MOSFET for stereotactic radiosurgery and stereotactic radiotherapy dosimetric applications.

The Irreversibility of Radiation-Induced Fibrosis: Fact or Folklore?

As the number of long-term cancer survivors increases, late complications of therapy will become an increasingly important concern to both patients and physicians. In administering radiation therapy, the physician typically has attempted to prevent complications primarily by limiting the irradiated dose and volume. Unfortunately, the relationship between radiation dose, volume of tissue irradiated, development of complications, and tumor control is complex and not precisely defined for most normal tissues and malignancies. Unlike medical oncology, there are few formal prospective studies in radiation oncology designed to establish the maximum-tolerated dose for a particular tumor or normal tissue. Commonly accepted normal tissue tolerance doses of radiation, for the most part, have been derived empirically, often with little supporting data. Although these estimates may be reasonably generalized, there remains considerable individual variation in radiation sensitivity. Recently, however, much progress has been made toward better elucidating the molecular mechanisms underlying radiation injury. Late radiation damage in most tissues is characterized by loss of parenchymal cells and excessive formation of fibrous tissue. For years, it was taught that radiation fibrosis is a permanent irreversible condition, but its underlying mechanism remained uncertain. It has been known for decades that the biologic effects of ionizing radiation begin almost instantaneously with the generation of reactive oxygen species. More recently, however, we are beginning to learn that these immediate biochemical events lead to clinically and histologically recognizable injury through a series of genetic and molecular responses. This process is dynamic and involves a number of proinflammatory cytokines, profibrotic cytokines, and chemokines produced by a variety of cell types, including macrophages, epithelial cells, and fibroblasts. Furthermore, these events seem to be sustained for months or even years after therapy is completed. For example, the presence of progressive hypoxia has been noted after radiation of the lung and spinal cord. Because hypoxia itself is known to generate reactive oxygen species, promote inflammation and vascular damage, activate profibrotic cytokines, and promote collagen formation, it has been suggested that postradiation hypoxia may be an important contributor to maintenance of the injured phenotype. These findings have also suggested that, because the process is dynamic, it may not be irreversible. In this issue, Delanian et al contribute significantly to the growing body of knowledge that indicates that, indeed, radiation-induced fibrosis is at least partially reversible. They also demonstrate for the first time that long-term antifibrotic therapy will be needed to sustain benefit. The authors report on a retrospective series of 44 patients with 55 distinct superficial progressive fibrotic lesions induced by radiation therapy for breast cancer. The patients were administered the combination of pentoxifylline and vitamin E twice daily for either 6 to 12 months or 24 to 48 months. Both drugs have antioxidant properties, and pentoxifylline may also have antifibrotic effects, although neither agent is clearly effective as a single agent in reversing radiation-induced fibrosis. The main end points were reduction in the size of the fibrotic region and reduction in the global score of late injury. Delanian et al demonstrated the following: both treatment regimens produced significant improvements in both outcome measures; the maximum regression to be expected is approximately 69%; improvement occurred sooner in younger lesions ( 6 years since radiotherapy); and stopping the drugs resulted in a rebound effect that was more severe in the patients treated for a short duration. Tolerance of the regimen was good, and no patient discontinued therapy as a result of toxicity. Although oncologists should be encouraged by the mounting evidence that radiation-induced fibrosis may be reversible, many questions remain unanswered. First, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 34 DECEMBER 1 2005

TH-B-I-611-01: Science Behind Proposed ICRP Recommendations: Dosimetric Quantities and Units Used in Radiation Protection

The International Commission on Radiological Protection (ICRP) and the International Commission on Radiation Units and Measurements (ICRU) have developed two types of special dosimetric quantities for radiation protection: those that are related to risk and demonstrate compliance with exposure limits, and operational quantities that are used in monitoring and measuring external exposure and intakes of radionuclides. All are based on mean absorbed dose with its distributions in time and in linear energy transfer (linear collision stopping power). In Publication 26 (1977), ICRP introduced the concepts of dose equivalent and effective dose equivalent to take into account the varying effectiveness of different radiations (the Q factors) and the variations in radiation sensitivity of different tissues (6 were specifically considered) for the induction of stochastic effects (the weighting factors, wT). In Publication 60 (1991), the ICRP introduced equivalent dose, effective dose and the subsidiary quantities committed dose and collective dose. Q factors were superseded by wR values and the number of tissues was increased to 12, with new values for wT. In 2005, the ICRP proposes the terms radiation‐weighted dose, effective dose, committed dose and collective effective dose. Based on new scientific evidence, wR values are unchanged for photons and alphas, but have changed for neutrons and protons. wT are different for the gonads, the breast an the “remainder” (the treatment of which has also changed); the number of tissues has increased to 14. The operational quantities for external exposure, defined by ICRU (1993, 2001), include ambient dose equivalent and directional dose equivalent for area monitoring, and personal dose equivalent for individual monitoring. For internal exposure, the ICRP proposes to use activity quantities in combination with dose coefficients based on physiological models and 4‐D computations. The unit for all the quantities listed above is the Sievert (although the ICRP would like a different unit for the radiation‐weighted dose). The weighting factors and the dosimetric quantities based on wR and wT relate only to stochastic health effects, cancer induction and hereditary disease. The risk factors, from which wR and wT values are derived, have been obtained from epidemiological and experimental radiobiological data in the medium and higher dose ranges and have been extrapolated to the lower dose ranges using the linear no threshold model, which bears a high degree of uncertainty. The assumed linearity and additivity are, however, necessary conditions for all the dosimetric considerations. Effective dose is to be used by regulators for occupationally exposed workers and members of the public, where doses are assumed to be low. At doses above about 0.5–1 Sv, tissue reactions (deterministic effects) may occur. At these levels, the dosimetric quantity to use is the absorbed dose in the irradiated tissue modified by the radiobiological effectiveness of the radiation for the biological endpoint of concern. The unit is the Gray. Effective dose should not be used for retrospective evaluation of exposed populations or to assess individual risks, as is the case in medical exposures, which are not subject to dose limitations. Educational Objectives: 1. To understand the dosimetric concepts involved in radiation protection. 2. To understand the uses of and the limitations and uncertainties associated with the dosimetric quantities.