Abdulhamid Chaikh

The choice of statistical methods for comparisons of dosimetric data in radiotherapy

PurposeNovel irradiation techniques are continuously introduced in radiotherapy to optimize the accuracy, the security and the clinical outcome of treatments. These changes could raise the question of discontinuity in dosimetric presentation and the subsequent need for practice adjustments in case of significant modifications. This study proposes a comprehensive approach to compare different techniques and tests whether their respective dose calculation algorithms give rise to statistically significant differences in the treatment doses for the patient.MethodsStatistical investigation principles are presented in the framework of a clinical example based on 62 fields of radiotherapy for lung cancer. The delivered doses in monitor units were calculated using three different dose calculation methods: the reference method accounts the dose without tissues density corrections using Pencil Beam Convolution (PBC) algorithm, whereas new methods calculate the dose with tissues density correction for 1D and 3D using Modified Batho (MB) method and Equivalent Tissue air ratio (ETAR) method, respectively. The normality of the data and the homogeneity of variance between groups were tested using Shapiro-Wilks and Levene test, respectively, then non-parametric statistical tests were performed. Specifically, the dose means estimated by the different calculation methods were compared using Friedman’s test and Wilcoxon signed-rank test. In addition, the correlation between the doses calculated by the three methods was assessed using Spearman’s rank and Kendall’s rank tests.ResultsThe Friedman’s test showed a significant effect on the calculation method for the delivered dose of lung cancer patients (p <0.001). The density correction methods yielded to lower doses as compared to PBC by on average (−5 ± 4.4 SD) for MB and (−4.7 ± 5 SD) for ETAR. Post-hoc Wilcoxon signed-rank test of paired comparisons indicated that the delivered dose was significantly reduced using density-corrected methods as compared to the reference method. Spearman’s and Kendall’s rank tests indicated a positive correlation between the doses calculated with the different methods.ConclusionThis paper illustrates and justifies the use of statistical tests and graphical representations for dosimetric comparisons in radiotherapy. The statistical analysis shows the significance of dose differences resulting from two or more techniques in radiotherapy.

Impact of dose calculation models on radiotherapy outcomes and quality adjusted life years for lung cancer treatment: do we need to measure radiotherapy outcomes to tune the radiobiological parameters of a normal tissue complication probability model?

BACKGROUND The equivalent uniform dose (EUD) radiobiological model can be applied for lung cancer treatment plans to estimate the tumor control probability (TCP) and the normal tissue complication probability (NTCP) using different dose calculation models. Then, based on the different calculated doses, the quality adjusted life years (QALY) score can be assessed versus the uncomplicated tumor control probability (UTCP) concept in order to predict the overall outcome of the different treatment plans. METHODS Nine lung cancer cases were included in this study. For the each patient, two treatments plans were generated. The doses were calculated respectively from pencil beam model, as pencil beam convolution (PBC) turning on 1D density correction with Modified Bathos (MB) method, and point kernel model as anisotropic analytical algorithm (AAA) using exactly the same prescribed dose, normalized to 100% at isocentre point inside the target and beam arrangements. The radiotherapy outcomes and QALY were compared. The bootstrap method was used to improve the 95% confidence intervals (95% CI) estimation. Wilcoxon paired test was used to calculate P value. RESULTS Compared to AAA considered as more realistic, the PBCMB overestimated the TCP while underestimating NTCP, P<0.05. Thus the UTCP and the QALY score were also overestimated. CONCLUSIONS To correlate measured QALYs obtained from the follow-up of the patients with calculated QALY from DVH metrics, the more accurate dose calculation models should be first integrated in clinical use. Second, clinically measured outcomes are necessary to tune the parameters of the NTCP model used to link the treatment outcome with the QALY. Only after these two steps, the comparison and the ranking of different radiotherapy plans would be possible, avoiding over/under estimation of QALY and any other clinic-biological estimates.

The use of TCP based EUD to rank and compare lung radiotherapy plans: in-silico study to evaluate the correlation between TCP with physical quality indices

BACKGROUND To apply the equivalent uniform dose (EUD) radiobiological model to estimate the tumor control probability (TCP) scores for treatment plans using different radiobiological parameter settings, and to evaluate the correlation between TCP and physical quality indices of the treatment plans. METHODS Ten radiotherapy treatment plans for lung cancer were generated. The dose distributions were calculated using anisotropic analytical algorithm (AAA). Dose parameters and quality indices derived from dose volume histograms (DVH) for target volumes were evaluated. The predicted TCP was computed using EUD model with tissue-specific parameter (a=-10). The assumed radiobiological parameter setting for adjuvant therapy [tumor dose to control 50% of the tumor (TCD50) =36.5 Gy and γ50=0.72] and curative intent (TCD50=51.24 Gy and γ50=0.83) were used. The bootstrap method was used to estimate the 95% confidence interval (95% CI). The coefficients (ρ) from Spearmans rank test were calculated to assess the correlation between quality indices with TCP. Wilcoxon paired test was used to calculate P value. RESULTS The 95% CI of TCP were 70.6-81.5 and 46.6-64.7, respectively, for adjuvant radiotherapy and curative intent. The TCP outcome showed a positive and good correlation with calculated dose to 95% of the target volume (D95%) and minimum dose (Dmin). Consistently, TCP correlate negatively with heterogeneity indices. CONCLUSIONS This study confirms that more relevant and robust radiobiological parameters setting should be integrated according to cancer type. The positive correlation with quality indices gives chance to improve the clinical out-come by optimizing the treatment plans to maximize the Dmin and D95%. This attempt to increase the TCP should be carried out with the respect of dose constraints for organs at risks. However, the negative correlation with heterogeneity indices shows that the optimization of beam arrangements could be also useful. Attention should be paid to obtain an appropriate optimization of initial plans, when comparing and ranking radiotherapy plans using TCP models, to avoid over or underestimated for TCP outcome.

Statistic and dosimetric criteria to assess the shift of the prescribed dose for lung radiotherapy plans when integrating point kernel models in medical physics: are we ready?

BACKGROUND To apply the statistical bootstrap analysis and dosimetric criterias to assess the change of prescribed dose (PD) for lung cancer to maintain the same clinical results when using new generations of dose calculation algorithms. METHODS Nine lung cancer cases were studied. For each patient, three treatment plans were generated using exactly the same beams arrangements. In plan 1, the dose was calculated using pencil beam convolution (PBC) algorithm turning on heterogeneity correction with modified batho (PBC-MB). In plan 2, the dose was calculated using anisotropic analytical algorithm (AAA) and the same PD, as plan 1. In plan 3, the dose was calculated using AAA with monitor units (MUs) obtained from PBC-MB, as input. The dosimetric criterias include MUs, delivered dose at isocentre (Diso) and calculated dose to 95% of the target volume (D95). The bootstrap method was used to assess the significance of the dose differences and to accurately estimate the 95% confidence interval (95% CI). Wilcoxon and Spearmans rank tests were used to calculate P values and the correlation coefficient (ρ). RESULTS Statistically significant for dose difference was found using point kernel model. A good correlation was observed between both algorithms types, with ρ>0.9. Using AAA instead of PBC-MB, an adjustment of the PD in the isocentre is suggested. CONCLUSIONS For a given set of patients, we assessed the need to readjust the PD for lung cancer using dosimetric indices and bootstrap statistical method. Thus, if the goal is to keep on with the same clinical results, the PD for lung tumors has to be adjusted with AAA. According to our simulation we suggest to readjust the PD by 5% and an optimization for beam arrangements to better protect the organs at risks (OARs).

14. Dosimetric and radiobiological evaluation for the clinical validation of Acuros XB algorithm in thoracic radiation therapy

Introduction Acuros-XB (AXB) algorithm has been introduced several years ago in order to improve the accuracy of dose calculation in radiotherapy, especially in the presence of tissue heterogeneities. This type (c) algorithm is based on the deterministic resolution of the linear Boltzmann transport equation and offers results close to Monte Carlo simulations. This study aims to evaluate the clinical impact of a new algorithm by comparing the dosimetric and radiobiological results of the AXB algorithm for its two reporting modes (dose to water AXB-Dw and dose to medium AXB-Dm), compared to a reference algorithm: the Anisotropic Analytical Algorithm (AAA). Methods Ten cases of patients treated for lung cancer with conformational radiotherapy were studied. For each patient, five treatment plans were generated. The dose in plans 1, 2 and 3 was respectively calculated with AAA, AXB(Dm) and AXB(Dw), using the same prescribed dose (PD). In plans 4 and 5, the dose was calculated using the two AXB calculation modes with the same number of monitor units (MU) derived from the AAA calculation (plan 1). The dosimetric evaluation was based on the comparison of dose volume histograms (HDV) and quality metrics (i.e. Conformity, Coverage and Homogeneity indices). Radiobiological assessment was based on the comparison of tumor control probabilities (TCP) and toxicity probabilities (NTCP) for organs at risk (OARs), including lungs, esophagus and heart. Wilcoxon and Spearman’s rank tests were used to calculate p-values and the correlation coefficient (ρ). Results Using the same PD, we observed a significant increase in the number of MU (1–4%), depending on the choice of AXB-Dm or AXB-Dw. In dosimetric terms, dose calculated with AXB is more heterogeneous. This introduces a significant decrease in the minimum dose to the PTV and in the quality indices. These elements can influence the therapeutic results. In addition, the dose to OARs was increased from +2% to +10%. The increase in dose to target volumes and OARs with AXB, using the same PD, explains the increase in TCP (+1% to 2%) and in NTCP (+2%) (p  Conclusions AXB algorithm is known to provide improved calculation accuracy. However, a special attention is required in order to safely implement its clinical use. Depending on the medium density, the technique and the treatment field size, MU can increase as well as the dosimetric values and the NTCPs. Radiation oncologists and medical physicists should define together the attitude to be adopted regarding these dosimetric shifts. A reasonable approach would be to keep the same PD while increasing the sparing of the OARs.

Statistical control process to compare and rank treatment plans in radiation oncology: impact of heterogeneity correction on treatment planning in lung cancer

BACKGROUND This study proposes a statistical process to compare different treatment plans issued from different irradiation techniques or different treatment phases. This approach aims to provide arguments for discussion about the impact on clinical results of any condition able to significantly alter dosimetric or ballistic related data. METHODS The principles of the statistical investigation are presented in the framework of a clinical example based on 40 fields of radiotherapy for lung cancers. Two treatment plans were generated for each patient making a change of dose distribution due to variation of lung density correction. The data from 2D gamma index (γ) including the pixels having γ≤1 were used to determine the capability index (Cp) and the acceptability index (Cpk) of the process. To measure the strength of the relationship between the γ passing rates and the Cp and Cpk indices, the Spearmans rank non-parametric test was used to calculate P values. RESULTS The comparison between reference and tested plans showed that 95% of pixels have γ≤1 with criteria (6%, 6 mm). The values of the Cp and Cpk indices were lower than one showing a significant dose difference. The data showed a strong correlation between γ passing rates and the indices with P>0.8. CONCLUSIONS The statistical analysis using Cp and Cpk, show the significance of dose differences resulting from two plans in radiotherapy. These indices can be used for adaptive radiotherapy to measure the difference between initial plan and daily delivered plan. The significant changes of dose distribution could raise the question about the continuity to treat the patient with the initial plan or the need for adjustments.

Assessing the shift of radiobiological metrics in lung radiotherapy plans using 2D gamma index.

BACKGROUND The purpose of this work is to investigate the 2D gamma (γ) maps to illustrate the change of radiobiological outcomes for lung radiotherapy plans and evaluate the correlation between tumor control probability (TCP), normal tissue complication probability (NTCP) with γ passing rates (γ-rates). METHODS Nine patients with lung cancer were used. The doses were calculated using Modified Batho method integrated with pencil beam convolution (MB-PBC) and anisotropic analytical algorithm (AAA) using the same beam arrangements and prescription dose. The TCP and NTCP were estimated, respectively, using equivalent uniform dose (EUD) model and Lyman-Kutcher-Burman (LKB) model. The correlation between ΔTCP or ΔNTCP with γ-rates, from 2%/2 and 3%/3 mm, were tested to explore the best correlation predicting the relevant γ criteria using Spearmans rank test (ρ). Wilcoxon paired test was used to calculate P value. RESULTS TCP value was significantly lower in the recalculated AAA plans as compared to MB plans. However, AAA predicted more NTCP on lung pneumonitis according to the LKB model and using relevant radiobiological parameters (n, m and TD50) for MB-PBC and AAA, with P=0.03. The data showed a weak correlation between radiobiological metrics with γ-rates or γ-mean, ρ<0.3. CONCLUSIONS AAA and MB yield different TCP values as well as NTCP for lung pneumonitis based on the LKB model parameters. Therefore, 2D γ-maps, generated with 2%/2 or 3%/3 mm, could illustrate visual information about the radiobiological changes. The information is useful to evaluate the clinical outcome of a radiotherapy treatment and to approve the treatment plan of the patient if the dose constraints are respected. On the other hand, the γ-maps tool can be used as quality assurance (QA) process to check the predicted TCP and NTCP from radiobiological models.

Quantitative comparison of dose distribution in radiotherapy plans using 2D gamma maps and X-ray computed tomography.

BACKGROUND The advanced dose calculation algorithms implemented in treatment planning system (TPS) have remarkably improved the accuracy of dose calculation especially the modeling of electrons transport in the low density medium. The purpose of this study is to evaluate the use of 2D gamma (γ) index to quantify and evaluate the impact of the calculation of electrons transport on dose distribution for lung radiotherapy. METHODS X-ray computed tomography images were used to calculate the dose for twelve radiotherapy treatment plans. The doses were originally calculated with Modified Batho (MB) 1D density correction method, and recalculated with anisotropic analytical algorithm (AAA), using the same prescribed dose. Dose parameters derived from dose volume histograms (DVH) and target coverage indices were compared. To compare dose distribution, 2D γ-index was applied, ranging from 1%/1 mm to 6%/6 mm. The results were displayed using γ-maps in 2D. Correlation between DVH metrics and γ passing rates was tested using Spearmans rank test and Wilcoxon paired test to calculate P values. RESULTS the plans generated with AAA predicted more heterogeneous dose distribution inside the target, with P<0.05. However, MB overestimated the dose predicting more coverage of the target by the prescribed dose. The γ analysis showed that the difference between MB and AAA could reach up to ±10%. The 2D γ-maps illustrated that AAA predicted more dose to organs at risks, as well as lower dose to the target compared to MB. CONCLUSIONS Taking into account of the electrons transport on radiotherapy plans showed a significant impact on delivered dose and dose distribution. When considering the AAA represent the true cumulative dose, a readjusting of the prescribed dose and an optimization to protect the organs at risks should be taken in consideration in order to obtain the better clinical outcome.

NTCP shift in radiotherapy of lung cancer when changing either the radiobiologic models or the photon dose calculation algorithms

Introduction and purpose In radiotherapy the tumor control and the Normal Tissues Complication Probability (NTCP) are directly correlated to the delivered dose. The purpose of this work is to evaluate and quantify the variations of NTCP for lung when changing radiobiological models or dose calculation algorithms. Materials and methods Twelve radiotherapy treatment plans were generated. The doses were calculated using the former Pencil Beam Modified Batho (PB-MB) with 1D density correction and the Anisotropic Analytical Algorithm (AAA). Data derived from dose volume histograms (DVH) for healthy lung were compared. NTCP for lung pneumonitis was computed using two radiobiological models: Lyman et al. (LKB) and Equivalent Uniform dose (EUD). Seven sets of radiobiological parameters were tested to explore the best correlation predicting the NTCP, based on dosimetric data, using Spearman’s rank test. The bootstrap method was used to estimate the 95% confidence intervals, and the Wilcoxon paired test to calculate p -values. Results The DVHs showed that AAA predicted higher dose for lung than PB-MB. Consistently, AAA predicted significantly higher NTCP values than PB-MB with p Conclusion This study confirms that relevant radiobiological parameters should be re-established for the most recent, and now recommended, algorithms such as AAA or AcurosXB to obtain trustable predictions of pneumonitis toxicity and avoid over/under estimated NTCP. This is critical if medical decisions have to be based on NTCP estimations. Disclosure None.

Characterization of nanodosimeter for real time measurements in radiotherapy and medical physics

It is common and fundamental technique for developments of hydrogen storage materials to investigate atomic arrangements of hydrogen during the absorption and desorption process. Since neutron is sensitive probe against hydrogen, the structural environment of hydrogen in atomic scale is clarified by neutron scattering method. High intensity total diffractometer, NOVA, was constructed in the pulsed neutron facility of Japan Proton Accelerator Research Complex (J開PARC).The most characteristic feature of NOVA is that it covers a wide scale of atomic distance from nearest neighbor to several ten nano meters by wide-Q (momentum transfer) measurement in short-time. By Fourie,r transformation of the obtained wide-Q diffraction data, Pair Distribution Function (PDF) useful for the analysis of disordered structures can be derived with high real-space resolution. On NOVA, both the wide-d space crystal structure analysis (Rietveld analysis) and the high -resolution PDF analysis can be performed. This means that various structures of crystals, amorphous and liquids for hydrogen storage materials are elucidated with NOVA. Aluminum hydride, Lanthanum hydride under GPa pressure and so on have been analyzed. Furthermore, time-transient measurement during hydrogen absorption and desorption process under hydrogen gas atmosphere (max 10 MPa) have been equipped on NOVA. It is expecting that structural analysis with NOVA will accelerate developments of hydrogen storage materials by industries.T is currently an unmet need for an optimal biomaterial that can substitute for autograft bone or serve as a temporary matrix that can induce regeneration of native bone at implant sites. Developing scaffolds that mimic the architecture of bone tissue at the nanoscale level and that parallel the physical properties of bone tissue in the categories of mechanical strength, pore size, porosity, hardness, and overall three-dimensional (3D) architecture is one of the major focuses in the field of tissue engineering. Our specific objective is to design 3D synthetic biodegradable scaffolds comprising electrospun nanofibers that will not only be osteoconductive but also contain porosity for bone cell ingrowth enhanced with Mesenchymal Stem Cells (MSCs) and a sufficient amount of bioactive ingredients such as Demineralized Bone Matrix (DBM) that would serve as a more conducive framework for cell adhesion, proliferation, and differentiation. Our central hypothesis is that the MSCs can migrate inside the functionalized 3D nanoscaffold to produce abundant extracellular matrix and differentiate into bone cell lineages, and that incorporation of DBM into the network of nanofibers will enhance osteogenesis and bone formation. The rationale for the proposed research is that if such complex constructs can mimic the native in vivo microenvironment, they could provide a promising nanotechnology based surgical tool for bone tissue engineering directed at orthopedic and bone tissue clinical applications.N the scientists are faced with the challenging development of highly sensitive multiple protein detection methods. The outstanding physicochemical properties of noble metal nanoparticles enable to envisage them as robust and versatile support to developing nanotags encapsulated in an antibody-functionalized nanostructure that is active in surface enhanced Raman scattering (SERS). This optical sensing technology allows single molecule detection with high potential to simultaneous recognition of closely related targets based on the narrow bandwidths of the vibrational Raman spectra of the reporter molecules. In this presentation, we will demonstrate how one-spot detection of multiple proteins in parallel can be efficiently achieved by using SERS encoded probes consisting of noble metal NPs each reporting unique Raman code and antibody-tagging entities. Further, this study may contribute to the development of targeting, tracking, and imaging systems for labelling cells..Purpose: The available implantable dosimeters in radiotherapy,i.e. semiconductor, MOSFET, radio luminescence of gallium nitride, etc, are imperfect and need a correction factors. In this study,we probos by simulation the size limit for a new generation of dosimeters at micro/nano scale for real time measurements in routine radiotherapy. Materials & Methods: Monte-Carlo simulations were carried out to study the influence of nanodosimeter size on the accuracy in dose measurements using a water volume irradiated with 60Co photons. The mean specific energy ( ), characterizing the actual deposited dose, was calculated for variousdose values and various radii of cylindrical targets placed within the irradiated volume. Then, the probability that a measurement yields a value outside the intervals [ -γ ; +γ ] with γ equal to 3%, 5% and 10% was calculated. Results & Discussion: The distributions for the smallest target show a very high dispersion of specific energy values, while those for the largest target tend to become gaussian and narrower, with increasing dose. An excessively small radius renders the measurements chaotic and not statistically-reproducible, even for a dose as high as 10 Gy. On the other hand, a target radius of 10 μm may allow for a better reproducibility of the measurements in a wider range of doses. Conclusion: The ability of the nano dosimeter to yield measurements dependent on its size and on the deposited dose.Nano dosimeter should be large enough to produce a statistically-reproducible measurement in the intended range around the irradiation dose value. Biography Abdulhamid Chaikh, has completed his PhD at Grenoble-Alpes University, France. He was qualified for Assistant Professor position in French University. He is working as scientist for Medical Physics & Radiation Oncology and teaching in master degree at the medical school of Grenoble-Alpes University. He has published more than 15 papers in international journals and participated to over 15 national and international conferences. He is carrying out peer reviewed articles and serving as an Editorial Board Member of the Journal of Case Reports in Oncology and Therapy. He is a member of American Association of Physicists in Medicine.T importance of nanostructures made by plasmonic metals, e.g., silver or gold, has been recognized by many researchers because plasmon resonance of such nanostructures, which is a resonant oscillation of conduction electrons stimulated by incident light, causes unique plasmonic properties including surface enhanced spectroscopy, acceleration of photo-catalysis and photo-thermotherapy. Controlling the synthesis and assembly of those metallic nanostructures has been of particular interest and several methods, e.g., random/self-assembly, bond formation and nanolithography, are well established. However, these methods have limitations for fabrication cost and time, thus, more efficient techniques are required to satisfy the basic industrial needs. In recent years, Galvanic Displacement Reaction (GDR) is rediscovered as a rapid and cost-effective technique for preparing various plasmonic nanostructures. Various kinds of nanostructures have been synthesized by GDR. However, most previous works have some limitations in creating efficient plasmonic nanostructures because during GDR processes, nanostructures tend to elongate and overlap with each other, preventing efficient production of plasmonic hot spots. To solve this problem, we introduced a novel GDR for the synthesis of silver Nano-Hexagonal Thin Columns (NHCs). NHCs synthesized generate strong surface-enhanced Raman scattering signals of adsorbates. Thus, they have a potential to be used widely across industry. Multi-elements depth profile analysis of NHCs by X-ray photoelectron spectroscopy shows that NHCs have a less conductive layer on their outermost surface, resulting that NHCs are kept from fusion and high-density plasmonic hot spots remain.