Biological optimization of simultaneous boost on intra-prostatic lesions (DILs): Sensitivity to TCP parameters

The aim of this investigation was to explore the potential of biological optimization in the case of simultaneous integrated boost on intra-prostatic dominant lesions (DIL) and evaluating the impact of TCP parameters uncertainty.Different combination of TCP parameters (TD50 and γ50 in the Poisson-like model), were considered for DILs and the prostate outside DILs (CTV) for 7 intermediate/high-risk prostate patients. The aim was to maximize TCP while constraining NTCPs below 5% for all organs at risk. TCP values were highly depending on the parameters used and ranged between 38.4% and 99.9%; the optimized median physical doses were in the range 94–116 Gy and 69–77 Gy for DIL and CTV respectively. TCP values were correlated with the overlap PTV-rectum and the minimum distance between rectum and DIL. In conclusion, biological optimization for selective dose escalation is feasible and suggests prescribed dose around 90–120 Gy to the DILs. The obtained result is critically depending on the assumptions concerning the higher radioresistence in the DILs. In case of very resistant clonogens into the DIL, it may be difficult to maximize TCP to acceptable levels without violating NTCP constraints.     

Dosimetric and radiobiological comparison in head-and-neck radiotherapy using JO-IMRT and 3D-CRT

IntroductionDosimetric and radiobiological evaluations for the Jaws-only Intensity-modulated radiotherapy (JO-IMRT) technique for head and neck jaws-only intensity-modulated radiation therapy (JO-IMRT) and 3D conformal radiation therapy (3D-CRT). To compare the head-and-neck therapeutic approaches utilizing JO-IMRT and 3D-CRT techniques, different radiation dose indices were calculated, including: conformity index (CI), homogeneity index (HI), and radiobiological variables like Niemierko's equivalent uniform dose based tumor control probability (TCP) of planning target volume (PTV), normal tissue complication probability (NTCP) of organs at risk (OAR) (brainstem, spinal cord, and parotid grand).Materials and methodsTwenty-five nasopharynx patients were studied using the Prowess Panther Treatment Planning System (Prowess Inc). The results were compared with the dose distribution obtained using 3D-CRT.ResultsRegarding tumor coverage and CI, JO-IMRT showed better results than 3D-CRT. The average doses received by the PTVs were quite similar: 72.1 ± 0.8 Gy by 3D-CRT and 72.5 ± 0.6 Gy by JO-IMRT plans (p > 0.05). The mean doses received by the parotid gland were 56.7 ± 0.7 Gy by 3D-CRT and 26.8 ± 0.3 Gy by JO-IMRT (p > 0.05). The HI and CI were 0.13 ± 0.01 and 0.14 ± 0.05 and (p > 0.05) by 3D-CRT and 0.83 ± 0.05 and 0.73 ± 0.10 by JO-IMRT (p < 0.05). The average TCP of PTV was 0.82 ± 0.08 by 3D-CRT and 0.92 ± 0.02 by JO-IMRT. Moreover, the NTCP of the parotid glands, brain stem, and spinal cord were lower using the JO-IMRT than 3D-CRT plans. In comparison to the 3D-CRT approach, the JO-IMRT technique was able to boost dose coverage to the PTV, improve the target's CI and HI, and spare the parotid glands. This suggests the power of the JO-IMRT over 3D-CRT in head-and-neck radiotherapy.     

RADBIOMOD: A simple program for utilising biological modelling in radiotherapy plan evaluation

PurposeRadiotherapy plan evaluation is currently performed by assessing physical parameters, which has many limitations. Biological modelling can potentially allow plan evaluation that is more reflective of clinical outcomes, however further research is required into this field before it can be used clinically.MethodsA simple program, RADBIOMOD, has been developed using Visual Basic for Applications (VBA) for Microsoft Excel that incorporates multiple different biological models for radiotherapy plan evaluation, including modified Poisson tumour control probability (TCP), modified Zaider–Minerbo TCP, Lyman–Kutcher–Burman normal tissue complication probability (NTCP), equivalent uniform dose (EUD), EUD-based TCP, EUD-based NTCP, and uncomplicated tumour control probability (UTCP). RADBIOMOD was compared to existing biological modelling calculators for 15 sample cases.ResultsComparing RADBIOMOD to the existing biological modelling calculators, all models tested had mean absolute errors and root mean square errors less than 1%.ConclusionsRADBIOMOD produces results that are non-significantly different from existing biological modelling calculators for the models tested. It is hoped that this freely available, user-friendly program will aid future research into biological modelling.     

The Use of Biologically Related Model (Eclipse) for the Intensity-Modulated Radiation Therapy Planning of Nasopharyngeal Carcinomas

Purpose

Intensity-modulated radiation therapy (IMRT) is the most common treatment technique for nasopharyngeal carcinoma (NPC). Physical quantities such as dose/dose-volume parameters are used conventionally for IMRT optimization. The use of biological related models has been proposed and can be a new trend. This work was to assess the performance of the biologically based IMRT optimization model installed in a popular commercial treatment planning system (Eclipse) as compared to its dose/dose volume optimization model when employed in the clinical environment for NPC cases.

Methods

Ten patients of early stage NPC and ten of advanced stage NPC were selected for this study. IMRT plans optimized using biological related approach (BBTP) were compared to their corresponding plans optimized using the dose/dose volume based approach (DVTP). Plan evaluation was performed using both biological indices and physical dose indices such as tumor control probability (TCP), normal tissue complication probability (NTCP), target coverage, conformity, dose homogeneity and doses to organs at risk. The comparison results of the more complex advanced stage cases were reported separately from those of the simpler early stage cases.

Results

The target coverage and conformity were comparable between the two approaches, with BBTP plans producing more hot spots. For the primary targets, BBTP plans produced comparable TCP for the early stage cases and higher TCP for the advanced stage cases. BBTP plans reduced the volume of parotid glands receiving doses of above 40 Gy compared to DVTP plans. The NTCP of parotid glands produced by BBTP were 8.0±5.8 and 7.9±8.7 for early and advanced stage cases, respectively, while those of DVTP were 21.3±8.3 and 24.4±12.8, respectively. There were no significant differences in the NTCP values between the two approaches for the serial organs.

Conclusions

Our results showed that the BBTP approach could be a potential alternative approach to the DVTP approach for NPC.     

Complication probability model for subcutaneous fibrosis based on published data of partial and whole breast irradiation

PurposeTo extend the application of current radiation therapy (RT) based normal tissue complication probability (NTCP) models of radiation-induced fibrosis (RIF) of the breast to include the effects of fractionation, inhomogeneous dose, incomplete recovery, and time after the end of radiotherapy in partial breast irradiation (PBI).Materials and methodsAn NTCP Lyman model with biologically effective uniform dose (BEUD) with and without a correction for the effect of incomplete repair was used. The time to occurrence of RIF was also taken into account. The radiobiological parameters were determined by fitting incidences of moderate/severe RIF in published randomized studies on RT of the breast. The NTCP model was used to calculate the risk of toxicity in 35 patients treated with intensity modulated, non-accelerated PBI and the result was compared with observed incidence of RIF.ResultsWith α/β fixed at 3Gy the parameters of the model without correction for incomplete repair extracted from fitting were: 50% complication probability biologically effective dose BEUD₅₀ = 107.2 Gy (95%CI = 95.9–118.6 Gy), volume parameter n = 0.06 (95%CI = 0–0.23), and slope of dose response m = 0.22, (95%CI = 0.20–0.23). After including the correction for incomplete repair with repair halftime for subcutaneous tissue of τ = 4.4 h we obtained BEUD₅₀ = 105.8 Gy (95%CI = 96.9–114.6Gy), n = 0.15 (95%CI = 0–0.33), m = 0.22 (95%CI = 0.20–0.23). Average NTCP predicted by these models, 4.3% and 2.0% respectively, offered a good agreement with RIF incidence in our patients, 5.7%, after an average follow-up of 12 months.ConclusionThe NTCP models of RIF, incorporating the effects of fractionation, volume effect, and latency of toxicity look promising to model PBI. Clinical validation from a prospective PBI treatment study is under development and will help test this preliminary result.     

Two-dimensional imaging of tumour control probabilities and normal tissue complication probabilities

Aim

To create a presentation method of TCP and NTCP distributions calculated based on dose distribution for a selected CT slice.

Materials and methods

Three 24-bit colour maps – of dose distribution, delineated structures and CT information – were converted into m-by-n-by-3 data arrays, containing intensities of red, green, and blue colour components for each pixel. All calculations were performed with Matlab v.6.5. The transformation function, which consists of five linear functions, was prepared to translate the colour map into a one-dimensional data array of dose values. A menu-driven application based on the transformation function and mathematical models of complication risk (NTCP) and treatment control probability (TCP) was designed to allow pixel-by-pixel translation of colour maps into one-dimensional arrays of TCP and NTCP values.

Results

The result of this work is an application created to visualize the TCP and NTCP distribution for a single CT scan based on the spatial dose distribution calculated in the treatment planning system. The application allows 10 targets (PTV) and 10 organs at risks (OaR) to be defined. The interface allows alpha/beta values to be inserted for each delineated structure. The application computes TCP and NTCP matrices, which are presented as colour maps superimposed on the corresponding CT slice. There is a set of parameters used for TCP/NTCP calculations which can be defined by the user.

Conclusion

Our application is a prototype of an evaluation tool. Although limited to a single plane of the treatment plan, it is believed to be a starting point for further development.     

The potential value of the neutral comet assay and the expression of genes associated with DNA damage in assessing the radiosensitivity of tumor cells

The assessment of tumor radiosensitivity would be particularly useful in optimizing the radiation dose during radiotherapy. Therefore, the degree of correlation between radiation-induced DNA damage, as measured by the alkaline and the neutral comet assays, and the clonogenic survival of different human tumor cells was studied. Further, tumor radiosensitivity was compared with the expression of genes associated with the cellular response to radiation damage. Five different human tumor cell lines were chosen and the radiosensitivity of these cells was established by clonogenic assay. Alkaline and neutral comet assays were performed in γ-irradiated cells (2-8Gy; either acute or fractionated). Quantitative PCR was performed to evaluate the expression of DNA damage response genes in control and irradiated cells. The relative radiosensitivity of the cell lines assessed by the extent of DNA damage (neutral comet assay) immediately after irradiation (4Gy or 6Gy) was in agreement with radiosensitivity pattern obtained by the clonogenic assay. The survival fraction of irradiated cells showed a better correlation with the magnitude of DNA damage measured by the neutral comet assay (r=-0.9; P<0.05; 6Gy) than evaluated by alkaline comet assay (r=-0.73; P<0.05; 6Gy). Further, a significant correlation between the clonogenic survival and DNA damage was observed in cells exposed to fractionated doses of radiation. Of 15 genes investigated in the gene expression study, HSP70, KU80 and RAD51 all showed significant positive correlations (r=0.9; P<0.05) with tumor radiosensitivity. Our study clearly demonstrated that the neutral comet assay was better than alkaline comet assay for assessment of radiosensitivities of tumor cells after acute or fractionated doses of irradiation.     

Image-guided volumetric arc radiotherapy of pancreatic cancer with simultaneous integrated boost: Optimization strategies and dosimetric results

PurposeTo introduce volumetric modulated arc therapy treatments (VMAT) with simultaneous integrated boost (SIB) for pancreatic cancer and describe dosimetric results on a large patient series.Methods and materials45 patients with pancreatic malignancies were treated with 18 MV single-arc VMAT. Image guidance was performed with daily online kilo-volt cone-beam computed tomography (CBCT). The conformity index (CI) and homogeneity index (HI) to the target volumes, PTV_45Gy and PTV_54Gy, and dose–volume indices to OARs from the QUANTEC task group were reported. The risk of clinical nephritis was evaluated using normal tissue complication probability (NTCP). Treatments were verified in-phantom with the Delta4 system.ResultsAverage CI was 1.06 with 95% confidence intervals (95% CI) of 0.97–1.22 for PTV_45Gy and 1.17 (0.66–1.61) for PTV_54Gy. HI of PTV_54Gy was 1.06 (1.04–1.10). OAR constraints were achieved in all patients, except for kidneys V_12Gy of 48 (35.4–72.3)%. NTCP of the kidneys was 0.98 (0.6–1.7)%. Kidneys V_12Gy and V_20Gy were inversely related to PTV_54Gy CI and maximum dose. All in-phantom tests had gamma pass rates exceeding 95% with global 3% dose difference and 3 mm distance to agreement. Patient shifts measured with CBCT had 95% CI of −0.8, +0.8 in the RL, −0.7, +0.8 in the SI, and −0.8, +0.7 cm in the AP directions.ConclusionsDosimetric results of VMAT were excellent on PTVs and organs at risk. The kidneys represent the dose-limiting organ at risk for this technique. NTCP indicates that this technique is safe from radiation-induced side effects to the kidneys.     

Initial slope of radiation survival curves is characteristic of the origin of primary and established cultures of human tumor cells and fibroblasts

The published survival curves of 110 human tumor cell lines and 147 nontransformed human fibroblast strains have been reanalyzed using three different statistical methods: the single hit multitarget model, the linear-quadratic model, and the mean inactivation dose. The 110 tumor cell lines were classified in two ways: (a) into three categories defined by clinical radiocurability criteria, and (b) into seven categories based on histopathology. The 147 fibroblast strains were divided into eight genetic groups. Differences in the radiosensitivities of both the tumor cell and fibroblast groups could be demonstrated only by parameters that describe the slopes of the initial part of the survival curves. The capacity of the survival level to identify significant differences between groups was dose dependent over the range 1 to 6 Gy. This relationship showed a bell-shaped curve with a maximum at 1.5 Gy for the tumor cell lines and 3 Gy for the fibroblasts. Values for intrinsic radiosensitivity for a number of groups of tumors have also been obtained by primary culture of tumor cells. These values are strictly comparable to those obtained by clonogenic methods. This confirms that intrinsic radiosensitivity is a determinant of the response of tumor cells to radiotherapy and suggests that tissue culture methods may be used as a predictive assay.     

Occupational exposure to low doses of ionizing radiation and cataract development: a systematic literature review and perspectives on future studies

Ionizing radiation is a well-known but little understood risk factor for lens opacities. Until recently, cataract development was considered to be a deterministic effect occurring at lens doses exceeding a threshold of 5–8 Gy. Substantial uncertainty about the level and the existence of a threshold subsists. The International Commission on Radiation Protection recently revised it to 0.5 Gy. Based on a systematic literature review of epidemiological studies on exposure to low levels of ionizing radiation and the occurrence of lens opacities, a list of criteria for new epidemiological studies was compiled, and a list of potential study populations was reviewed. Among 24 publications finally identified, six report analyses of acute exposures in atomic bomb survivors and Chernobyl liquidators, and the others report analyses of protracted exposures in occupationally, medically or accidentally exposed populations. Three studies investigated a dose threshold: in atomic bomb survivors, the best estimates were 1 Sv (95 % CI <0–0.8 Sv) regarding lensectomies; in survivors exposed as children, 0.6 Sv (90 % CI <0.0–1.2 Sv) for cortical cataract prevalence and 0.7 Sv (90 % CI 0.0–2.8 Sv) for posterior subcapsular cataract; and in Chernobyl liquidators, 0.34 Sv (95 % CI 0.19–0.68 Sv) for stage 1 cataract. Current studies are heterogeneous and inconclusive regarding the dose–response relationship. Protracted exposures and high lens doses occur in several occupational groups, for instance, in physicians performing fluoroscopy-guided interventional procedures, and in accidentally exposed populations. New studies with a good retrospective exposure assessment are feasible and should be initiated.     

Assessment of the Relative Biological Efficiency of Pencil Beam Scanning of Protons in Mice in Vivo

Doklady Biochemistry and Biophysics - The effect of proton pencil beam scanning in the dose range of 4.5–15 Gy on the radiosensitivity of mice under irradiation in two regions of the Bragg...     

A radiobiological comparison of hypo-fractionation versus conventional fractionation for breast cancer 3D-conformal radiation therapy

BackgroundThe present research was aimed to compare the toxicity and effectiveness of conventional fractionated radiotherapy versus hypo-fractionated radiotherapy in breast cancer utilizing a radiobiological model.Materials and methodsThirty-five left-sided breast cancer patients without involvement of the supraclavicular and axillary lymph nodes (with the nodal stage of N0) that had been treated with conventional or hypo-fractionated were incorporated in this study. A radiobiological model was performed to foretell normal tissue complication probability (NTCP) and tumor control probability (TCP).ResultsThe data represented that TCP values for conventional and hypo-fractionated regimens were 99.16 ± 0.09 and 95.96 ± 0.48, respectively (p = 0.00). Moreover, the NTCP values of the lung for conventional and hypo-fractionated treatment were 0.024 versus 0.13 (p = 0.035), respectively. Also, NTCP values of the heart were equal to zero for both regimens.ConclusionIn summary, hypo-fractionated regimens had comparable efficacy to conventional fraction radiation therapy in the case of dosimetry parameters for patients who had left breast cancer. But, utilizing the radiobiological model, conventional fractionated regimens presented better results compared to hypo-fractionated regimens.     

The degree of pigmentation modulates the radiosensitivity of human melanoma cells

The relationship between cell pigmentation and radiosensitivity was investigated in two selected human melanoma cell lines with different melanin content (mixed type: eumelanin and pheomelanin, and pheomelanotic phenotypes). The same study was also done after stimulation of melanogenesis (1) by addition of the melanin precursor l-tyrosine to each of the cell lines separately and (2) by irradiation alone with doses ranging from 0 to 10 Gy. We found that a decrease in cell radiosensitivity was correlated with the type of melanin, with a clear involvement of eumelanin rather than pheomelanin. Increasing the intracellular content of both melanins promoted the growth of irradiated cells. Moreover, at a dose of 10 Gy, both tyrosinase activity and melanin cell content were significantly increased in the absence of any other melanogenesis promoter. Our data suggest that the amount of intracellular melanin is inversely related to the radiosensitivity of melanoma cells and may explain at least in part the controversial responses to ionizing radiations reported for melanoma.     

Normal tissue complication probability models for severe acute radiological lung injury after radiotherapy for lung cancer

PurposeTo derive Normal Tissue Complication Probability (NTCP) models for severe patterns of early radiological radiation-induced lung injury (RRLI) in patients treated with radiotherapy (RT) for lung tumors. Second, derive threshold doses and optimal doses for prediction of RRLI to be used in differential diagnosis of tumor recurrence from RRLI during follow-up.Methods and materialsLyman-EUD (LEUD), Logit-EUD (LogEUD), relative seriality (RS) and critical volume (CV) NTCP models, with DVH corrected for fraction size, were used to model the presence of severe early RRLI in follow-up CTs. The models parameters, including α/β, were determined by fitting data from forty-five patients treated with IMRT for lung cancer. Models were assessed using Akaike information criterion (AIC) and area under receiver operating characteristic curve (AUC). Threshold doses for risk of RRLI and doses corresponding to the optimal point of the receiver operating characteristic (ROC) curve were determined.ResultsThe α/βs obtained with different models were 2.7–3.2 Gy. The thresholds and optimal doses curves were EUDs of 3.2–7.8 Gy and 15.2–18.1 Gy with LEUD, LogEUD and RS models, and μ_d of 0.013 and 0.071 with the CV model. NTCP models had AUCs significantly higher than 0.5. Occurrence and severity of RRLI were correlated with patients’ values of EUD and μ_d.ConclusionsThe models and dose levels derived can be used in differential diagnosis of tumor recurrence from RRLI in patients treated with RT. Cross validation is needed to prove prediction performance of the model outside the dataset from which it was derived.     

The influence of chronic and of acute irradiation on the polymorphism of RAPD-markers in offspring for irradiated mice

On mice lines BALB/c and CBA/lac was performed the study of molecular-genetics effects in mice progeny after the chronic (dose rate -0.0017 Gy/day, total dose -0.36 Gy) and acute (dose range 1-3 Gy) exposure of y-radiation on the parents. For variability analysis was used technique of amplification DNA with series of random primers (RAPD-assay). Random primers were used as single primer and in mixture of ones. In this work were held the comparative analysis of the genetic radiosensitivity for stem spermatogonia and spermatides. After the acute exposure the dose dependence for levels of polymorphism of RAPD-markers were obtained. After the chronic irradiation, significant differences from control group were obtained only by use primers mixture M1. Comparative analysis of the genetic radiosensitivity of different stages of mice spermatogenesis are display is similar sensitivity of stem spermatogonia and spermatides after doses of irradiation 1 Gy and 3 Gy. Indicated that after irradiation by dose 2 Gy, spermatogonia are more sensitivity than spermatides.     

Image fusion analysis of volumetric changes after interstitial low-dose-rate iodine-125 irradiation of supratentorial low-grade gliomas

The aim of this study was to compare the volumes of tumor necrosis, reactive zone and edema with the three-dimensional dose distributions after brachytherapy treatments of gliomas. The investigation was performed an average of 14.2 months after low-dose-rate (125)I interstitial irradiation of 25 inoperable low-grade gliomas. The prescribed dose was 50-60 Gy to the tumor surface. Dose planning and image fusion were performed with the BrainLab-Target 1.19 software. In the CT/ MRI images, the "triple ring" (tumor necrosis, reactive ring and edema) developing after the interstitial irradiation of the brain tumors was examined. The images with the triple ring were fused with the planning images, and the isodose curves were superimposed on them. The volumes of the three regions were measured. The average dose at the necrosis border was determined from the isodose distribution. For quantitative assessment of the dose distributions, the dose nonuniformity ratio (DNR), homogeneity index (HI), coverage index (CI) and conformal index (COIN) were calculated. The relative volumes of the different parts of the triple ring after the interstitial irradiation compared to the reference dose volume were the following: necrosis, 40.9%, reactive zone, 47.1%, and edema, 367%. The tumor necrosis developed at 79.1 Gy on average. The average DNR, HI, CI and COIN were 0.45, 0.24, 0.94 and 0.57, respectively. The image fusion analysis of the volume of tumor necrosis, reactive ring and edema caused by interstitial irradiation and their correlation with the dose distribution provide valuable information for patient follow-up, treatment options, and effects and side effects of radio therapy.