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Functional imaging allows the evaluation of numerous biological properties that could be considered at all steps of the therapeutic management of patients treated with brachytherapy. Indeed, it enables better initial staging of the disease, and some parameters may also be used as predictive biomarkers for treatment response, allowing better selection of patients eligible for brachytherapy. It may also improve the definition of target volumes with the aim of dose escalations by dose-painting. Finally, it could be useful during the follow-up to assess response to treatment. In this review, we report how functional imaging is integrated at the present time during the brachytherapy procedure, and what are its potential future contributions in the main tumour locations where brachytherapy is recommended. Functional imaging has great potential in the contact of brachytherapy, but still, several issues remain to be resolved before integrating it into clinical practice, especially as a biomarker or in dose painting strategies.

PURPOSE: Although 24 Gy single-dose radiation therapy (SDRT) renders >90% 5-year local relapse-free survival in human solid tumor lesions, SDRT delivery is not feasible in ~50% of oligometastatic lesions owing to interference by dose/volume constraints of a serial organ at risk (OAR). Conformal OAR avoidance is based on a hypothetical model positing that the recently described SDRT biology specifically permits volumetric subdivision of the SDRT dose, such that high-intensity vascular drivers of SDRT lethality, generated within a major tumor subvolume exposed to a high 24 Gy dose (high-dose planning target volume [PTV(HD])), would equilibrate SDRT signaling intensity throughout the tumor interstitial space, rendering bystander radiosensitization of a minor subvolume (perfusion-modulated dose sculpting PTV [PTV(PMDS)]), dose-sculpted to meet a serial OAR dose/volume constraint. An engineered PTV(PMDS) may thus yield tumor ablation despite PMDS dose reduction and conformally avoiding OAR exposure to a toxic dose. METHODS AND MATERIALS: Dose fall-off within the PTV(PMDS) penumbra of oligometastatic lesions was planned and delivered by intensity modulated inverse dose painting. SDRT- and SDRT-PMDS–treated lesions were followed with periodic positron emission tomography/computed tomography imaging to assess local tumor control. RESULTS: Cumulative baseline 5-year local relapse rates of oligometastases treated with 24 Gy SDRT alone (8% relapses, n = 292) were similar in moderate PTV(PMDS) dose-sculpted (23-18 Gy, n = 76, 11% relapses, P = .36) and extreme dose-sculpted (

The purpose of this work is to present useful recommendations for the use of [F]FDG-PET/CT imaging in radiotherapy planning and monitoring under different versions of EARL accreditation for harmonization of PET devices. A proof-of-concept experiment designed on an an-thropomorphic phantom was carried out to establish the most suitable interpolation methods of the PET images in the different steps of the planning procedure. Based on PET/CT images obtained by using these optimal interpolations for the old EARL accreditation (EARL1) and for the new one (EARL2), the treatment plannings of representative actual clinical cases were calculated, and the clinical implications of the resulting differences were analyzed. As expected, EARL2 provided smaller volumes with higher resolution than EARL1. The increase in the size of the reconstructed volumes with EARL1 accreditation caused high doses in the organs at risk and in the regions adjacent to the target volumes. EARL2 accreditation allowed an improvement in the accuracy of the PET imaging precision, allowing more personalized radiotherapy. This work provides recommendations for those centers that intend to benefit from the new accreditation, EARL2, and can help build confidence of those that must continue working under the EARL1 accreditation., Project P20_01053 funded by the European Union and the Junta de Andalucía through the European Regional Development Fund (FEDER).

Purpose Intratumoral dose response can be detected using serial fluoro-2-deoxyglucose-(FDG) positron emission tomography (PET)/computed tomography (CT) imaging feedback during treatment and used to guide adaptive dose painting by number (DPbN). However, to reliably implement this technique, the effect of uncertainties in quantitative PET/CT imaging feedback on tumor voxel dose-response assessment and DPbN needs to be determined and reduced. Methods Three major uncertainties, induced by (a) PET imaging partial volume effect (PVE) and (b) tumor deformable image registration (DIR), and (c) variation of the time interval between FDG injection and PET image acquisition (TI), were determined using serial FDG-PET/CT images acquired during chemoradiotherapy of 18 head and neck cancer patients. PET imaging PVE was simulated using the discrepancy between with and without iterative deconvolution-based PVE corrections. Effect of tumor DIR uncertainty was simulated using the discrepancy between two DIR algorithms, including one with and one without soft-tissue mechanical correction for the voxel displacement. The effect of TI variation was simulated using linear interpolation on the dual-point PET/CT images. Tumor voxel pretreatment metabolic activity (SUV0 ) and dose-response matrix (DRM) discrepancies induced by each of the three uncertainties were quantified, respectively. Adverse effects of tumor voxel SUV0 and DRM discrepancies on tumor control probability (TCP) in DPbN were assessed. Results Partial volume effect and TI variations of 10 mins induced a mean ± standard deviation (SD) of tumor voxel SUV0 discrepancies to be -0.7% ± 9.2% and 0% ± 4.8%, respectively. Tumor voxel DRM discrepancies induced by PVE, tumor DIR discrepancy, and TI variations were 0.6% ± 8.9%, 1.7% ± 9.1%, and 0% ± 7%, respectively. Partial volume effect induced SUV0 and DRM discrepancies correlated significantly with the tumor shape and FDG uptake heterogeneity. Tumor DIR uncertainty-induced DRM discrepancy correlated significantly with the tumor volume and shrinkage during treatment. Among the three uncertainties, PVE dominated the adverse effects on the TCP, with a mean ± SD of TCP reduction to be 12.7% ± 9.8% for all tumors if no compensation was applied for. Conclusions Effect of uncertainties in quantitative FDG-PET/CT imaging feedback on intratumoral dose-response quantification was not negligible. These uncertainties primarily caused by PVE and tumor DIR were highly dependent on individual tumor shape, volume, shrinkage during treatment, and pretreatment SUV heterogeneity, which can be managed individually. The adverse effects of these uncertainties could be minimized by using proper PVE corrections and DIR methods and compensated for in the clinical implementation of DPbN.

Background and purpose Radiotherapy dose painting is a promising technique which enables dose escalation to areas of higher tumour cell density within the prostate which are associated with radioresistance, known as dominant intraprostatic lesions (DILs). The aim of this study was to determine factors affecting the feasibility of radiotherapy dose painting in patients with high and intermediate risk prostate cancer. Materials & Methods Twenty patients were recruited into the study for imaging using a 3 T magnetic resonance imaging (MRI) scanner. Identified DILs were outlined and the scan registered with the planning computed tomography (CT) dataset. Intensity-modulated plans were produced and evaluated to determine the effect of the organ-at-risk constraints on the dose that could be delivered to the DILs. Measurements were made to verify that the distribution could be safely delivered. Results MRI scans were obtained for nineteen patients. Fourteen patients had one to two DILs with ten overlapping the urethra and/or rectum. The target boost of 86 Gy was achieved in seven plans but was limited to 80 Gy for five patients whose boost volume overlapped or abutted the urethra. Dosimetric measurements gave a satisfactory gamma pass rate at 3%/3 mm. Conclusions It was feasible to produce dose-painted plans for a boost of 86 Gy for approximately half the patients with DILs. The main limiting factor was the proximity of the urethra to the boost volumes. For a small proportion of patients, rigid registration between CT and MRI images was not adequate for planning purposes.

The origin of radiotherapy dates back to 1895-immediately after the discovery of X-rays. Since the beginning, efforts were focused on developing ways to improve the accuracy of radiation delivery. Molecular imaging allows the visualization of surrogates of several pathophysiological characteristics of tumor tissue (e.g., proliferation, metabolism, hypoxia, perfusion), allowing tailoring of dose distribution based on the tissue's features and biological patterns within the tumor. A significant improvement in the ability of modern radiotherapy to precisely target tumor while avoiding irradiating normal tissues can be achieved by integrating molecular imaging into an individualized radiation treatment planning. PET data are the most common molecular images used for tumor volume delineation and assessment of pathophysiological characteristics of tissue. The type of radiopharmaceutical used allows visualization and understanding of different pathophysiologic information. The most commonly used among all PET tracers is the 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG). [18F]FDG is currently the mainstay of PET use in radiotherapy. With the aim of identifying specific biological tumor processes and offering valuable information that can assist radiation oncologist to modulate radiotherapy's doses and volumes, several other molecular imaging tracers emerged in the last few years. Non-[18F]FDG tracers commonly used in radiation oncology include [11C]Methionine ([11C]MET) for brain tumors; [18F]FDOPA for brain and neuroendocrine tumors; radiolabeled somatostatin analogs for somatostatin-receptor positive tumors; 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) and 18F-fluoromisonidazole (18F-FMISO) to identify regions of radiation resistance within the tumor; and [11C]/[18F]Choline, [18F]/68Ga-PSMA, and 18F-Fluciclovine for prostate cancer.

Background: The purpose of this study was to investigate the feasibility and dosimetric characteristics of dose painting for non-enhancing low-grade gliomas (NE-LGGs) guided by three-dimensional arterial spin labeling (3D-ASL) perfusion magnetic resonance imaging.Methods: Eighteen patients with NE-LGGs were enrolled. 3D-ASL, T2 fluid attenuated inversion recovery (T2 FLAIR) and contrast-enhanced T1-weight magnetic resonance images were obtained. The gross tumor volume (GTV) was delineated on the T2 FLAIR. The hyper-perfusion region of the GTV (GTV-ASL) was determined by 3D-ASL, and the GTV-SUB was obtained by subtracting the GTV-ASL from the GTV. The planning target volume (PTV), PTV-ASL and PTV-SUB were developed by expanding the external margins of the GTV, GTV-ASL and GTV-SUB, respectively. Three plans were established for each patient: in plan 1, the traditional homogeneous prescription dose to the PTV was 45-60 Gy; in plan 2 and plan 3, the dose to the PTV-ASL increased by 10-20% based on plan 1, without the maximum dose constraint to the PTV-ASL in plan 3. The dosimetric differences among the three plans were compared.Results: Compared with plan 1, the dose to 2% (D2%), 98% (D98%) and 50% (Dmean) of PTV-ASL volumes increased by 14.67%, 16.17% and 14.31% in plan 2 and 19.84%, 15.52% and 14.27% in plan 3, respectively (P < 0.05); the D2% of the PTV, PTV-SUB increased by 11.89% and 8.34% in plan 2, 15.89% and 8.49% in plan 3, respectively (P< 0.05). The PTV coverages were comparable among the three plans (P > 0.05). In Plan 2 and plan 3, the conformity indexs decreased by 18.60% and 12.79%; while the homogeneity indexs increased by 1.43 and 2 times (PP > 0.05).Conclusions: The sub-volume with hyper-perfusion for NE-LGG radiotherapy can be segmented based on the perfusion difference guided by 3D-ASL. And the radiation dose to the hyper-perfusion area increased safely by 10-20% through dose painting.

Hypoxia dose painting is a radiotherapy technique to increase the dose to hypoxic regions of the tumour. Still, the clinical effect relies on the reproducibility of the hypoxic region shown in the medical image.Eight HNC patients undergoing twoThe mean (SD) correlation coefficient between DPBN prescription and plan was 0.92 (0.02) and 0.93 (0.02) for sessions A and B, respectively, with corresponding quality factors of 0.02 (0.002) and 0.02 (0.003), respectively. The mean correlation between dose prescriptions at day A and B was 0.72 (0.13), and 0.77 (0.12) for the corresponding plans. A mean correlation of 0.80 (0.08) was found between plan A, recalculated on image basis B, and plan B.Hypoxia DPBN planning based on

Objective The aim of this pilot study was to explore the integrated positron emission tomography and magnetic resonance imaging scanner (PET/MR) for biological characterization of nasopharyngeal carcinoma (NPC) and potential therapeutic applications of dose painting (DP). Patients and methods Twenty-one NPC patients with PET/MR were included in this study. Overlap of tumor volumes was analyzed on T2-weighted images (volume of interest, VOIT2), diffusion-weighted magnetic resonance imaging (VOIDWI) and 18F-fluorodeoxyglucose positron emission tomography (VOIPET). The overlap percentages of low-metabolic sub-region (cluster 1) and high-metabolic sub-region (cluster 2) in VOIPET and VOIDWI were analyzed by cluster analysis. Results Both the VOIDWI and VOIPET were encompassed in the VOIT2, respectively 99.6% and 97.5%. The median tumor overlap was 94.4% (VOIDWI within VOIPET). The median overlap of cluster 2 in VOIPET and VOIDWI was 43.61% (27.67–52.66%) and 21.86%(10.47–40.89%), respectively. The median overlap of cluster 1 in VOIPET and VOIDWI was 48.03% (23.91–63.15%) and 24.40% (7.44–51.44%), respectively. Separation between clusters appeared to be defined by a SUV value. Conclusion For NPC, the VOIs of DWI and FDG PET were not overlapped completely and the volume defined by cluster-analysis might be meaningful for DP.

Purpose To construct a tumor voxel dose response matrix ( DRM ) and dose prescription function (DPF) for adaptive dose painting by number (DPbN) based on treatment feedback of fluoro-2-deoxyglucose (FGD) positron emission tomography (PET)/computed tomography (CT) imaging. Methods and Materials FDG-PET/CT images obtained before and after chemoradiation therapy and at weekly chemoradiation therapy sessions for each of 18 patients with head and neck cancer, as well as the treatment outcomes, were used in the modeling. All weekly and posttreatment PET/CT images were registered voxel-to-voxel to the corresponding pretreatment baseline PET/CT image. Tumor voxel DRM was created using serial FDG-PET imaging of each patient with respect to the baseline standardized uptake value ( SUV 0 ). A tumor voxel control probability (TVCP) lookup table was created using the maximum likelihood estimation on the tumor voxel ( SUV 0 , DRM ) domain of all tumors. Tumor voxel DPF was created from the TVCP lookup table and used as the objective function for DPbN-based inverse planning optimization. Results Large intertumoral and intratumoral variations on both tumor voxels ( SUV 0 , DRM ) were identified. Tumor voxel dose resistance did not show correlation with its baseline SUV 0 value and was the major cause of the tumor local failures. Tumor voxel DPF as the function of tumor voxel ( SUV 0 , DRM ) values also showed a very large intertumoral and intratumoral heterogeneity. Most human papillomavirus–negative tumors require a treatment dose >100 Gy to certain local tumor regions. These treatment doses, which are most unlikely to be implementable in conventional radiation therapy, can be achieved using adaptive DPbN treatment. Clinical feasibility was evaluated by comparing the adaptive DPbN treatment plan with the conventional intensity modulated radiation therapy plan. Conclusions Tumor voxel ( SUV 0 , DRM ) provides an intratumoral prognostic map to target tumor locoregional-resistant regions. The corresponding TVCP or DPF provides a quantitative objective to optimize the intratumoral dose distribution for the individuals. The adaptive DPbN with FDG-PET/CT imaging feedback is feasible to implement in clinics.

Purpose Endoscopic endonasal surgery (EES) is becoming a standard for most malignant sinonasal tumours. Margin analysis after piecemeal resection is complex and optimally relies on accurate histosurgical mapping. Postoperative radiotherapy may be adapted based on margin assessment mapping to reduce the dose to some sinonasal subvolumes. We assessed the use of histosurgical mapping by radiation oncologists (RO). Material and methods A French practice survey was performed across 29 ENT expert RO (2 did not answer) regarding integration of information on EES, as well as quality of operative and pathology reportsto refine radiotherapy planning after EES. This was assessed through an electronic questionnaire. Results EES was ubiquitously performed in France. Operative and pathology reports yielded accurate description of EES samples according to 66.7% of interviewed RO. Accuracy of margin assessment was however insufficient according to more than 40.0% of RO. Additional margins/biopsies of the operative bed were available in 55.2% (16/29) of the centres. In the absence of additional margins, quality of resection after EES was considered as microscopically incomplete in 48.3% or dubious in 48.3% of RO. As performed, histosurgical mapping allowed radiotherapy dose and volumes adaptation according to 26.3% of RO only. Conclusions Standardized histosurgical mapping with margin and additional margin analysis could be more systematic. Advantages of accurate EES reporting could be dose painting radiotherapy to further decrease morbidity in sinonasal tumours.

Radiation therapy remains important in the modern management of both Hodgkin and non-Hodgkin lymphoma. Radiation is applied as both consolidation therapy post chemotherapy and primary therapy for selected limited volume clinically favorable histology. Application of modern therapy techniques permits more sparing of normal tissue in all anatomical locations. Modern image guidance permits both security in daily patient treatment set up and permits strategic titration of the planning target volume to further spare normal tissue. Four-dimensional planning makes certain targets are fully treated in all phases of the breathing cycle. Dose painting with altered fractionation permits identification of low, intermediate, and high-risk areas of concern and treat each in a single plan with multiple fractionation schemes saving both time of treatment and cost of therapy. In this paper we present multiple examples of the application of modern therapy techniques in lymphoma management and demonstrate advantages of modern radiation in several anatomical regions.

In radiotherapy, hypoxia is a known negative factor, occurring especially in solid malignant tumours. Nitroimidazole-based positron emission tomography (PET) tracers, due to their selective binding to hypoxic cells, could be used as surrogates to image and quantify the underlying oxygen distributions in tissues. The spatial resolution of a clinical PET image, however, is much larger than the cellular spatial scale where hypoxia occurs. A question therefore arises regarding the possibility of quantifying different hypoxia levels based on PET images, and the aim of the present study is the prescription of corresponding therapeutic doses and its exploration.A tumour oxygenation model was created consisting of two concentric spheres with different oxygen partial pressure (pO2) distributions. In order to mimic a PET image of the simulated tumour, given the relation between uptake and pO2, fundamental effects that limit spatial resolution in a PET imaging system were considered: the uptake distribution was processed with a Gaussian 3D filter, and a re-binning to reach a typical PET image voxel size was performed. Prescription doses to overcome tumour hypoxia and predicted tumour control probability (TCP) were calculated based on the processed images for several fractionation schemes. Knowing the underlying oxygenation at microscopic scale, the actual TCP expected after the delivery of the calculated prescription doses was evaluated. Results are presented for three different dose painting strategies: by numbers, by contours and by using a voxel grouping-based approach.The differences between predicted TCP and evaluated TCP indicate that careful consideration must be taken on the dose prescription strategy and the selection of the number of fractions, depending on the severity of hypoxia.

Purpose: To investigate dose escalation for brain metastases (BM) subvolumes with low cerebral blood flow (CBF) using dose-painting technology based on MR 3D arterial spin labeling (3D-ASL) images.Methods: A total of 50 patients with single BM were selected for this study. CT and MR simulation images, including contrast-enhanced T1-weighted (T1W) images and CBF images, were obtained. The gross tumor volume (GTV) was determined by fusion of contrast-enhanced CT and T1W images, and this volume was divided into high- and low-perfusion areas according to the difference in CBF. Sub-volume with less than 25% of the maximum CBF was defined as hypoxic region GTVH which was settled for dose escalation. The planning target volume (PTV) and PTVH were calculated from the GTV and the GTVH, respectively. The PTVN was calculated by subtracting the PTVH from the PTV. Plan 1 was defined as the conventional plan with a prescription dose of 60 Gy for the PTV. Plan 2 and Plan 3, respectively, escalated the prescription dose for the PTVH to 72 Gy with and without the maximum dose constrained based on Plan 1. Dosimetric indices were compared among the three plans.Results: On average, the GTV volume was 34.53 cm3, and the GTVH volume was 16.95 cm3, accounting for 49.09% of the GTV. Compared to Plan 1, the D2%, D98% and Dmean values of the PTVH escalated by 20.50%, 19.32%, and 19.60%, respectively, in Plan 2 and by 24.05%, 6.77%, and 17.00%, respectively, in Plan 3 (all P<0.05). The doses administered in Plans 2 and 3 were 73.67±0.34 Gy and 72.37±0.61 Gy, respectively (both P<0.05). In Plans 2 and 3, respectively, the conformity index of PTVH was increased by 45.45% and 63.64%; meanwhile, the homogeneity index was sacrificed, increasing from 0.04 to 0.05 and 0.11 (all P<0.05). Plan 2 achieved better values of D98% and Dmean, as well as a smaller increase in the homogeneity index, than Plan 3. The doses received by organs at risk (OARs) did not significantly differ between the conventional plans and the boost plans (all P >0.05).Conclusions: Targeted dose escalation guided by the 3D-ASL-based CBF differences in BM effectively escalated the dose delivered to low-CBF subvolumes without increasing the dose to OARs.

Background: For patients with recurrent or second primary disease, re-irradiation can be challenging due to overlap with previously irradiated volumes. Dose painting may be attractive for these patients, as the focus is on delivering maximal dose to areas of high tumor activity. Here, we compare dose painting by contours (DPBC) treatment plans based on 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) with conventional plans. Material and methods: We included 10 patients with recurrent or second primary head and neck cancer (HNC) eligible for re-irradiation. Our conventional re-irradiation regimen is hyperfractionated radiotherapy 1.5 Gy twice daily over 4 weeks, giving a total dose of 60 Gy. For DPBC, we defined two prescription volumes, PV33 and PV66, corresponding to 33 and 66% of the highest FDG uptake in the tumor. The clinical target volume (CTV) prescription dose was 60 Gy, PV33; 65–67 Gy and PV66; 70–73 Gy. The DPBC plan is to be given the first 20 fractions and the conventional plan the last 20 fractions. Dose to organs at risk (OARs) were compared for DPBC and conventional treatment. By summation of the initial curative plan and the re-irradiation plan, we also evaluated differences in dose to the 2 ccm hot spot (D2cc). Results: We achieved DPBC plans with adequate target coverage for all 10 patients. There were no significant differences in OAR doses between the standard plans and the DPBC plans (p=.7). Summation of the initial curative plan and the re-irradiation plan showed that the median D2cc increased from 130 Gy (range 113–132 Gy; conventional) to 140 Gy (range 115–145 Gy; DPBC). Conclusions: Our proposed DPBC could be straightforwardly implemented and all plans met the objectives. Re-irradiation of HNC with DPBC may increase tumor control without more side effects compared to conventional radiotherapy.

PURPOSE Dose painting techniques based on dose escalation to hypoxic regions are usually governed by the spatial distribution of Oxygen Enhancement Ratio (OER) derived from PET or MRI images. The goal of this article is to show that the volume of the hypoxic region is also a parameter which may affect the radiobiological effectiveness of hypoxia-targeted dose escalation. METHODS Our analysis is performed using the equation for Tumor Control Probability (TCP) derived from Poisson statistics. A tumor response model based on two levels of oxygenated and hypoxic cells with the survival curves described by the Linear Quadratic (LQ) model was used in the calculations. The model allows for analytical solutions which can be used for additional validation of our numerical simulations. The model was used to compute the average tumor cell survival that defines TCP. Dependence of average tumor cell survival on the relative hypoxic volume and dose escalation was computed for the conventional 30 × 2 Gy and hypofractionated 4 × 12 Gy dose regimens in a model problem with radiobiological parameters for nonsmall cell lung cancer. RESULTS We show that equal average tumor cell survival and TCP can be achieved with smaller hypoxia-targeted dose escalation for smaller relative hypoxic volumes if the dose escalation does not exceed 50% of dose in the oxygenated region. This effect is explained by the dependence of average tumor cell survival and TCP mostly on the hypoxic tumor volume in this dose escalation range. Assuming a linear relationship between the number of clonogens and the hypoxic volume, smaller hypoxic volumes have smaller number of clonogens, therefore, smaller doses are needed to eradicate them. CONCLUSIONS The theoretical analysis performed in this article predicts that tumors with smaller relative hypoxic volumes may require smaller hypoxia-targeted dose escalation to maintain equal TCP. The results of this research can be used for dose de-escalation strategies in dose painting techniques which may reduce dose to normal tissue and normal tissue complications without deterioration of TCP.

Purpose: FDG-PET scans have shown spatial consistency in NSCLC patients before and following chemoradiotherapy, implying radioresistance. We hypothesized that patients, who received FDG-PET redistributed dose painting, would demonstrate reduced spatial consistency when compared to registered patients or to escalated dose treatment. Methods: Stage II-IIIB, inoperable NSCLC patients were randomized in a phase II trial (NCT01024829) to (chemo) radiotherapy of either homogeneous boosting to the primary tumor, or redistributed inhomogeneous boosting to the GTV subvolume (FDG-SUV > 50% SUVmax). Patients who could not be boosted (>= 72 Gy) received 66 Gy in 24 fractions. Spatial consistency of pre-treatment and post-treatment (3 months) FDG-PET scans was measured by various overlap fraction thresholds. Results: 66/82 patients analyzed received randomized treatment in the trial. Thresholds of 50% SUVmax pre-treatment and 70% SUVmax post-treatment yielded a median overlap fraction of 0.63 [interquartile range: 0.15-0.93], with similar results for other thresholds. No significant differences were found among overlap fractions of the treatment groups. A high incidence of FDG-uptake in normal lung (grade-1 pneumonitis: 73%) was found post-treatment. Conclusion: FDG redistributed boosting did not reduce FDG spatial consistency from pre-treatment to post-treatment, which was highly variable among patients. The study found high numbers of patients with lung inflammation after treatment. (C) 2018 Elsevier B.V. All rights reserved.

Gleason scores for prostate cancer correlates with an increased recurrence risk after radiotherapy (RT). Furthermore, higher Gleason scores correlates with decreasing apparent diffusion coefficient (ADC) data from diffusion weighted MRI (DWI-MRI). Based on these observations, we present a formalism for dose painting prescriptions of prostate volumes based on ADC images mapped to Gleason score driven dose-responses.The Gleason score driven dose-responses were derived from a learning data set consisting of pre-RT biopsy data and post-RT outcomes for 122 patients treated with a homogeneous dose to the prostate. For a test data set of 18 prostate cancer patients with pre-RT ADC images, we mapped the ADC data to the Gleason driven dose-responses by using probability distributions constructed from published Gleason score correlations with ADC data. We used the Gleason driven dose-responses to optimize dose painting prescriptions that maximize the tumor control probability (TCP) with equal average dose as for the learning sets homogeneous treatment dose.The dose painting prescriptions increased the estimated TCP compared to the homogeneous dose by 0-51% for the learning set and by 4-30% for the test set. The potential for individual TCP gains with dose painting correlated with increasing Gleason score spread and larger prostate volumes. The TCP gains were also found to be larger for patients with a low expected TCP for the homogeneous dose prescription.We have from retrospective treatment data demonstrated a formalism that yield ADC driven dose painting prescriptions for prostate volumes that potentially can yield significant TCP increases without increasing dose burdens as compared to a homogeneous treatment dose. This motivates further development of the approach to consider more accurate ADC to Gleason mappings, issues with delivery robustness of heterogeneous dose distributions, and patient selection criteria for design of clinical trials.

BACKGROUND Previously, a rat glioblastoma model to mimic chemo-radiation treatment of human glioblastoma in the clinic was established. Similarly to the clinic, CT and MRI were combined during the treatment planning process. PET imaging was subsequently added which allowed us to implement sub-volume boosting using a micro-irradiation system. However, combining three imaging modalities (CT, MRI and PET) using a micro-irradiation system, proved to be labour intensive because multimodal imaging, treatment planning and dose delivery have to be completed sequentially in the preclinical setting. MATERIAL AND METHODS Two different methodologies were compared in silico for performing preclinical [18F]FET PET based radiation therapy (20 Gy based on MRI, 8 Gy boost based on PET) based on three different cases. Method 1 is based on the previously published methods1,2. However, the process is automated using an in-house developed MATLAB code. Method 2 consists of a more sophisticated method where a series of isocenters and jaw dimensions for the motorised variable collimator were determined based on the [18F]FET PET uptake. Both methods were evaluated by means of the dose volume histograms (DVH) and Q-volume histograms. RESULTS The setup parameters for both methods were calculated. The DVHs for method 2 are systematically closer to the ideal dose distribution compared to method 1. These findings are confirmed by the D90 and D50 values which are considerably lower for method 1. When observing the Q-factor, method 2 always results in dose distributions that are closer to the dose objectives (method 1: 0.141±0.046; method 2: 0.064±0.011). CONCLUSION The described novel method to optimize the preclinical treatment planning process has many advantages in terms of dose delivery, time efficiency and variability, when compared to the previously used methods1,2. These improvements are important to narrow the gap between clinical and preclinical radiation research and for the development of new therapeutics and/or radiation therapy procedures for glioblastoma. 1. Bolcaen, J., Descamps, B., Boterberg, T., Vanhove, C. & Goethals, I. PET and MRI Guided Irradiation of a Glioblastoma Rat Model Using a Micro-irradiator. J. Vis. Exp. 1–10 (2017) doi:10.3791/56601. 2. Verhoeven, J. et al. Technical feasibility of [18F]FET and [18F]FAZA PET guided radiotherapy in a F98 glioblastoma rat model. Radiat. Oncol. 14, (2019).

To identify predictive factors for the development of late grade 4 mucosal ulcers in adaptive dose-escalated treatments for head-and-neck cancer.Patient data of four dose-escalated three-phase adaptive dose-painting by numbers (DPBN) clinical trials were analyzed in this study. Correlations between the development of late grade 4 ulcers and factors related with the treatment, disease characteristics and the patient were investigated. Dosimetrical thresholds were searched among the highest doses received by 1.75 cmFrom 39 studied patients, nine developed late grade 4 mucosal ulcers. The continuation to either smoke or drink alcohol after therapy was the factor that showed a strong (eight out of nine patients) association with the occurrence of grade 4 ulcers. Six of the patients who continued to smoke or/and drink had DThe search for patterns provided strong reasons to apply a dosimetrical threshold for the peak-dose volume of 1.75 cm

In recent years, a huge progress in the field of radiotherapy could be observed. From treating patients with kilo-voltage X-rays units to cutting edge technology that can deliver a certain dose with an extreme precision. Modern radiotherapy is characterized, among others, by an individualized approach to the patient. This can be provided by functional imaging which is another step toward a better tumor control. In this paper, we discuss the potential application of functional imaging modalities in personalized radiotherapy planning with emphasis on dose painting. Some limitations of this approach will also be evaluated.

Purpose To demonstrate the feasibility and to evaluate the tumour control probability (TCP) and normal tissue complication probability (NTCP) of IMRT dose painting using 68 Ga-HBED-CC PSMA PET/CT for target delineation in prostate cancer (PCa). Methods and materials 10 patients had PSMA PET/CT scans prior to prostatectomy. GTV-PET was generated on the basis of an intraprostatic SUVmax of 30%. Two IMRT plans were generated for each patient: Plan 77 which consisted of whole-prostate IMRT to 77Gy, and Plan 95 which consisted of whole-prostate IMRT to 77Gy and a simultaneous integrated boost to the GTV-PET up to 95Gy (35 fractions). The feasibility of these plans was judged by their ability to adhere to the FLAME trial protocol. TCP-histo/-PET were calculated on co-registered histology (GTV-histo) and GTV-PET, respectively. NTCPs for rectum and bladder were calculated. Results All plans reached prescription doses whilst adhering to dose constraints. In Plan 77 and Plan 95 mean doses in GTV-histo were 75.8±0.3Gy and 96.9±1Gy, respectively. Average TCP-histo values for Plan 77 and Plan 95 were 70% (range: 15–97%), and 96% (range: 78–100%, p 77 and Plan 95 were 55% (range: 27–82%), and 100% (range: 99–100%, p 95 ( p =0.25). There were no significant differences in rectal ( p =0.563) and bladder ( p =0.3) NTCPs. Conclusions IMRT dose painting using PSMA PET/CT was technically feasible and resulted in significantly higher TCPs without higher NTCPs.

Introduction: For patients with high risk prostate cancer, conventionally fractionated treatment of the pelvic lymphatics and hypofractionated treatment to the prostate can be delivered simultaneously with dose painting. The purpose of this technical note is to highlight unexpected hot spots within the low dose lymphatic target volume as a clinical problem that we have observed with dose painting, and to describe a simple approach to account for this during treatment planning. Summary: We describe the creation of a control structure that can be incorporated into the optimization objective function. An upper constraint objective can be placed on the control structure such that heterogeneity within the plan is limited to the area near the high dose target volume and better emulates the dosimetry of a conventionally fractionated sequential boost plan.

Imaging provides the basis for radiotherapy. Multi-modality images are used for target delineation (primary tumor and nodes, boost volume) and organs at risk, treatment guidance, outcome prediction, and treatment assessment. Next to anatomical information, more and more functional imaging is being used. The current paper provides a brief overview of the different applications of imaging techniques used in the radiotherapy process, focusing on uncertainties and QA. The paper mainly focuses on PET and MRI, but also provides a short discussion on DCE-CT. A close collaboration between radiology, nuclear medicine and radiotherapy departments provides the key to improve the quality of radiotherapy. Jointly developed imaging protocols (RT position setup, immobilization tools, lasers, flat table…), and QA programs are mandatory. For PET, suitable windowing in consultation with a Nuclear Medicine Physician is crucial (differentiation benign/malignant lesions, artifacts…). A basic knowledge of MRI sequences is required, in such a way that geometrical distortions are easily recognized by all members the RT and RT physics team. If this is not the case, then the radiologist should be introduced systematically in the delineation process and multidisciplinary meetings need to be organized regularly. For each image modality and each image registration process, the associated uncertainties need to be determined and integrated in the PTV margin. When using functional information for dose painting, response assessment or outcome prediction, collaboration between the different departments is even more important. Limitations of imaging based biomarkers (specificity, sensitivity) should be known.

INTRODUCTION Owing to their heterogeneity and radioresistance, the prognosis of primitive brain tumors, which are mainly glial tumors, remains poor. Dose escalation in radioresistant areas is a potential issue for improving local control and overall survival. This review focuses on advances in biological and metabolic imaging of brain tumors that are proving to be essential for defining tumor target volumes in radiation therapy (RT) and for increasing the use of DPRT (dose painting RT) and ART (adaptative RT), to optimize dose in radio-resistant areas. EVIDENCE ACQUISITION Various biological imaging modalities such as PET (hypoxia, glucidic metabolism, protidic metabolism, cellular proliferation, inflammation, cellular membrane synthesis) and MRI (spectroscopy) may be used to identify these areas of radioresistance. The integration of these biological imaging modalities improves the diagnosis, prognosis and treatment of brain tumors. EVIDENCE SYNTHESIS Technological improvements (PET and MRI), the development of research, and intensive cooperation between different departments are necessary before using daily metabolic imaging (PET and MRI) to treat patients with brain tumors. CONCLUSIONS The adaptation of treatment volumes during RT (ART) seems promising, but its development requires improvements in several areas and an interdisciplinary approach involving radiology, nuclear medicine and radiotherapy. We review the literature on biological imaging to outline the perspectives for using DPRT and ART in brain tumors.

e20529 Background: Dose-painting radiotherapy is a promising technique which enables different dose distribution to different areas within the lung cancer. However, the efficacy and safety of this irradiation technique are still uncertain. In this study, we observed and analyzed the outcomes of dose-painting radiotherapy with chemotherapy for the locally advanced non-small cell lung cancer. Methods: Patients with stage III non-small cell lung cancer undergoing chemoradiotherapy were enrolled in this study. The dose-painting target was defined according to the distance between the tumor and the mediastinum (GTVwithin 2cm and GTVout-of 2cm). Doses of 60-80 Gy( 3-4Gy/fraction, bid) and 40-60 Gy (2-3Gy/fraction, bid) were prescribed to the GTVwithin 2cm and GTVout-of 2cm, respectively, in 20 fractions, using simultaneous integrated boost. All the patients received 2-4 cycles of chemotherapy using cisplatin plus paclitaxel or pemetrexed. Results: In total, 65 patients were included in this study. Median follow-up was 66.1 months (range 8.0-117.3months). The incidence of ≥Grade 2 radiation pneumonitis and esophagitis were was 30.8% and 38.5%, respectively. The 1, 3, 5-year OS and PFS were 78.4% and 58.5%, 32.3% and 26.1%, 18.5% and 13.8%, respectively. Late radiation esophagitis were seen in 3 patients and 2 patients were observed severe pulmonary fibrosis. None of the patients experienced fatal bronchopulmonary hemorrhage or tracheal fistula. Conclusions: Radiation dose painting with concurrent chemotherapy is feasible and well tolerated for locally advanced non-small cell lung cancer. It needs to be further confirmed by large randomized controlled clinical studies.

The emergence and success of stereotactic body radiation therapy (SBRT) for the treatment of lung cancer have led to its rapid adoption for liver cancers. SBRT can achieve excellent results for small liver tumors. However, the vast majority of physicians interpret SBRT as meaning doses of radiation (range, 4-20 Gray [Gy]) that may not be ablative but are delivered within about 1 week (ie, in 3-6 fractions). Adherence to this approach has limited the effectiveness of SBRT for large liver tumors (>7 cm) because of the need to reduce doses to meet organ constraints. The prognosis for patients who present with large liver tumors is poor, with a median survival ≤12 months, and most of these patients die from tumor-related liver failure. Herein, the authors present a comprehensive solution to achieve ablative SBRT doses for patients with large liver tumors by using a combination of classic, modern, and novel concepts of radiotherapy: fractionation, dose painting, motion management, image guidance, and simultaneous integrated protection. The authors discuss these concepts in the context of large, inoperable liver tumors and review how this approach can substantially prolong survival for patients, most of whom otherwise have a very poor prognosis and few effective treatment options. Cancer 2016;122:1974-86. © 2016 American Cancer Society.

Background We sought to assess patterns of failure in pediatric patients with intracranial germ cell tumors (GCT) treated with intensity-modulated radiation therapy with dose painting (DP-IMRT). Procedure Between July 2007 and October 2013, 11 patients with localized GCT—five germinomas and six nongerminoma GCT (NGGCT)—received definitive treatment with DP-IMRT. Three representative patients were selected for replanning with (i) whole ventricular irradiation (WVI) with opposed lateral beams plus IMRT to the primary tumor and (ii) sequential IMRT. These plans were compared to the patients’ original DP-IMRT plans for dosimetric analyses. Results Four patients with germinoma received radiation therapy alone: 45 Gy in 1.8 Gy fractions to the primary tumor and 25 Gy in 1.0 Gy fractions to whole ventricles using a dose-painting plan. One patient with germinoma received a reduced dose of 30.6 Gy to the primary tumor after neoadjuvant chemotherapy. Patients with NGGCT (n = 6) underwent multimodality treatment including chemotherapy (n = 6) and surgery (n = 3). These patients received 54 Gy to the primary tumor and 32.4–36 Gy to the whole ventricles. Dosimetric analyses showed DP-IMRT delivered decreased mean dose to whole brain, temporal lobes, hippocampi, cochleae, and optic nerves. With median follow-up of 4 years, 3-year failure-free survival was 100% for patients with germinoma and 67% for patients with NGGCT. One patient with a pineal NGGCT experienced a local recurrence within the high dose–volume while another experienced an isolated biochemical failure. Conclusions DP-IMRT is dosimetrically superior to standard IMRT techniques for sparing of normal tissues. Disease control in this small series appears at least comparable to published results.

Introduction: It has been known for over a century that all living systems develop radiation resistance under hypoxic conditions - low pO2. But giving extra radiation - dose painting - or boosting hypoxic tumors regions has not shown enhanced control in mammalian tumors. Pulse EPR quantitative pO2 values can be tomographically imaged as a magnetic resonance measurement with fixed stepped gradients. If there are distinct hypoxic regions, their images can then be extra radiation dose boosts. An isocentric animal irradiation system allowed conformal boosts to tiny resistant tumor subvolumes with 3D printed tungsten loaded plastic blocks. A randomized trial compared radiation boosts to hypoxic tumor vs well oxygenated tumor to determine hypoxic boost control advantage. Methods: Carcinomas (MCa4) and fibrosarcomas (FSa) in mouse legs with mean volume of 350 μl were treated with an XRAD225Cx animal irradiator to a dose that controlled 15% of tumors (TCD15), determined in separate experiments. Pulse electron paramagnetic resonance (EPR) using Spin Lattice Relaxation (SLR) and a soluble trityl spin probe has been shown to quantitatively image solution and tumor pO2. This and boost treatments were given after EPR pO2 imaging, reconstruction, registration with tumor defining T2 MRI, determination of all tumor hypoxic regions (pO2 ≤10 torr) and 3D printed tungsten loaded plastic aperture fabrication to radiate either well oxygenated or hypoxic tumor regions. Mice were followed for either 180 days (MCa4) or 90 days (FSa) sufficient for 99% of local failures to occur. Treatment of 3D hypoxic volumes was also analyzed for control dependence on surface to volume ratio (SVR). Results: Tumor control was doubled by radiating hypoxic tumor relative to well oxygenated tumor in 48 MCa4 tumors (p=0.013) and 54 FSa tumors (p=0.04). This was the first demonstration in mammalian tumors of an advantage to targeting hypoxic regions in tumors. It provides the first evidence of image based dose painting within the volume of the tumor. For MCa4 tumors, SVR values below median had significant increased survival (p=0.003) while for FSa tumors below median SVR tumors trended to increased survival (p=0.3). Clinical Relevance: Modern radiation delivery used intensity modulated radiation therapy (IMRT) for dose gradients outside the tumor volume to reduce doses to critical structures. Dose within the tumor have strict inhomogeneity limits. Allowance of higher dose variation within the tumor volume allows “hot spots” to resistant tumor volumes, sharper gradients outside the volume to protect critical structures. This will enhance the therapeutic ratio. Citation Format: Howard Halpern, Matthew Maggio, Eugene Barth, Darwin Bodero, Richard C. Miller, Charles A. Pelizzari, Martyna Krzykawska-Serda, Subramanian V. Sundramoorthy, Bulent Aydogan, Ralph R. Weichselbaum, Victor M. Tormyshev, Inna Gertsenshteyn, Boris Epel. Increased tumor control boosting hypoxic regions identified with EPR pO2 imaging in 2 tumor types [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2773.

558 Background: High rates of local control are achievable with hypofractionated proton therapy with passive techniques for hepatocellular carcinoma (HCC), but may have limitations when tumors are adjacent to organs-at-risk (OARs), which may result in tumor underdosage and lead to inferior local control. We present the first reported series of HCC patients treated with pencil beam scanning (PBS) intensity-modulated proton therapy (IMPT) using a simultaneous-integrated boost and protection (SIB/SIP) technique to escalate tumor dose while protecting adjacent OARs. Methods: Twenty-five HCC patients were treated between 2015-2019 with a 15-fraction regimen using IMPT SIB/SIP. SIB/SIP dose levels generally ranged from 36.0-67.5 GyRBE to minimize dose to OARs at their respective dose-limiting thresholds (e.g. luminal gastrointestinal organs, chest wall). Radiation-induced liver disease (RILD) was defined by a Child-Pugh (CP) score increase of 2 or greater and/or any RTOG grade 3 enzyme elevation. Other toxicities were graded by CTCAEv5.0. Overall survival (OS), progression-free survival (PFS), and local control were calculated using the Kaplan-Meier method. Results: Patients most commonly had BCLC stage B or C disease (84%) and CP-A (80%) and ALBI grade 2 (60%) liver function. Median gross tumor volume (GTV) size and volume were 12.3 cm (range 2.17-20.57) and 461 cc (range 4.68-2439), and 32% had gross vascular invasion. Median mean and minimum dose delivered to the gross tumor volume (GTV) was 64.0 GyRBE (EQD2 76.1, BED 91.3, range 54.3-69.6) and 45.1 GyRBE (EQD2 48.9, BED 58.7, range 33.4-67.7), respectively. Median mean dose to liver minus GTV was 15.0 GyRBE (range, 8.2-19.6). 1-year OS, PFS, and local control were 66%, 32%, and 84%, respectively. No isolated local failures occurred. Two patients experienced RILD with no RILD-related deaths. Two grade 3 non-GI toxicities occurred: 1 rib fracture and 1 pneumonitis. No acute or late GI grade ≥2 occurred. Conclusions: In our series of HCC patients with large tumors near OARs, IMPT SIB/SIP allows for tumor dose escalation while sparing of OARs and results in favorable local control and acceptable toxicities.

Focused ultrasound combined with microbubble for blood-brain barrier disruption (FUS-BBBD) is a promising technique for noninvasive and localized brain drug delivery. This study demonstrates that passive cavitation imaging (PCI) is capable of predicting the location and concentration of nanoclusters delivered by FUS-BBBD. During FUS-BBBD treatment of mice, the acoustic emissions from FUS-activated microbubbles were passively detected by an ultrasound imaging system and processed offline using a frequency-domain PCI algorithm. After the FUS treatment, radiolabeled gold nanoclusters, 64Cu-AuNCs, were intravenously injected into the mice and imaged by positron emission tomography/computed tomography (PET/CT). The centers of the stable cavitation dose (SCD) maps obtained by PCI and the corresponding centers of the 64Cu-AuNCs concentration maps obtained by PET coincided within 0.3 ± 0.4 mm and 1.6 ± 1.1 mm in the transverse and axial directions of the FUS beam, respectively. The SCD maps were found to be linearly correlated with the 64Cu-AuNCs concentration maps on a pixel-by-pixel level. These findings suggest that SCD maps can spatially “paint” the delivered nanocluster concentration, a technique that we named as cavitation dose painting. This PCI-based cavitation dose painting technique in combination with FUS-BBBD opens new horizons in spatially targeted and modulated brain drug delivery.

Purpose Tumor hypoxia, often found in nonsmall cell lung cancer (NSCLC), implies an increased resistance to radiotherapy. Pretreatment assessment of tumor oxygenation is, therefore, warranted in these patients, as functional imaging of hypoxia could be used as a basis for dose painting. This study aimed at investigating the feasibility of using a method for calculating the dose required in hypoxic subvolumes segmented on F-18-HX4 positron emission tomography (PET) imaging of NSCLC. Methods Positron emission tomography imaging data based on the hypoxia tracer F-18-HX4 of 19 NSCLC patients were included in the study. Normalized tracer uptake was converted to oxygen partial pressure (pO(2)) and hypoxic target volumes (HTVs) were segmented using a threshold of 10 mmHg. Uniform doses required to overcome the hypoxic resistance in the target volumes were calculated based on a previously proposed method taking into account the effect of interfraction reoxygenation, for fractionation schedules ranging from extremely hypofractionated stereotactic body radiotherapy (SBRT) to conventionally fractionated radiotherapy. Results Gross target volumes ranged between 6.2 and 859.6 cm(3), and the hypoxic fraction

Quantitative measurement and analysis of tumor metabolic activities could provide a more optimal solution to personalized accurate dose painting. We collected PET images of 58 lung cancer patients, in which the tumor exhibits heterogeneous FDG uptake. We design an automated delineation and quantitative heterogeneity measurement of the lung tumor for dose-escalation. For tumor delineation, our algorithm firstly separates the tumor from its adjacent high-uptake tissues using 3D projection masks; then the tumor boundary is delineated with our stopping criterion of joint gradient and intensity affinities. For dose-escalation, tumor sub-volumes with low, moderate and high metabolic activities are extracted and measured. Based on our quantitative heterogeneity measurement, a sub-volume oriented dose-escalation plan is implemented in intensity modulated radiation therapy (IMRT) planning system. With respect to manual tumor delineations by two radiation oncologists, the paired t-test demonstrated our model outperformed the other computational methods in comparison (p 0.05).

Background In intensity modulated radiation therapy (IMRT) quality assurance (QA), evaluation of QA result using a pass/non-pass strategy under an acceptance criterion often suffers from lack of information on how good the plan is in absolute manner. In this study, we suggested adding an index system, previously developed for dose painting technique, to current IMRT QA process for better understanding of QA result. Methods The index system consists of three indices, index of achievement (IOA), index of hotness (IOH) and index of coldness (IOC). As indicated by its name, IOA does measure the level of agreement. IOH and IOC, on the other hand, measure the magnitude of overdose and underdose, respectively. A systematic analysis was performed with three 1-dimensional hypothetical dose distributions to investigate the characteristics of the index system. The feasibility of the system was also assessed with clinical volumetric modulated arc therapy (VMAT) QA cases from 8 head & neck and 5 prostate patients. In both simulation studies, certain amount of errors was intentionally induced to each dose distribution. Furthermore, we applied the proposed system to compare calculated with actual measured data for a total of 60 patients (30 head & neck and 30 prostate cases). QA analysis was made using both the index system and gamma method, and results were compared. Results While the gamma evaluation showed limited sensitivity in evaluating QA result depending on the level of tolerance criteria used, the proposed indices tended to better distinguish plans in terms of the amount of errors. Hotness and coldness of prescribed dose in the plan could be evaluated quantitatively by the indices. Conclusions The proposed index system provides information with which IMRT QA result would be better evaluated, especially when gamma pass rates are identical or similar among multiple plans. In addition, the independency of the index system on acceptance criteria would help making clear communications among readers of published articles and researchers in multi-institutional studies.

Recent developments in radiation therapy aimed at more precise dose delivery along with higher dose gradients (dose painting) and more efficient dose delivery with higher dose rates e.g. flattening filter free (FFF) irradiation. Magnetic-resonance-imaging based polymer gel dosimetry offers 3D information for precise dose delivery techniques. Many of the proposed polymer gels have been reported to exhibit a dose response, measured as relaxation rate ΔR2(D), which is dose rate dependent. A lack of or a reduced dose-rate sensitivity is very important for dosimetric accuracy, especially with regard to the increasing clinical use of FFF irradiation protocols with LINACs at high dose rates. Some commonly used polymer gels are based on Methacrylic-Acid-Gel-Initiated-by-Copper (MAGIC). Here, we report on the dose sensitivity (ΔR2/ΔD) of MAGIC-type gels with different oxygen scavenger concentration for their specific dependence on the applied dose rate in order to improve the dosimetric performance, especially for high dose rates. A preclinical x-ray machine ('Yxlon', E = 200 kV) was used for irradiation to cover a range of dose rates from low [Formula: see text] min = 0.6 Gy min-1 to high [Formula: see text] max = 18 Gy min-1. The dose response was evaluated using R2-imaging of the gel on a human high-field (7T) MR-scanner. The results indicate that all of the investigated dose rates had an impact on the dose response in polymer gel dosimeters, being strongest in the high dose region and less effective for low dose levels. The absolute dose rate dependence [Formula: see text] of the dose response in MAGIC-type gel is significantly reduced using higher concentrations of oxygen scavenger at the expense of reduced dose sensitivity. For quantitative dose evaluations the relative dose rate dependence of a polymer gel, normalized to its sensitivity is important. Based on this normalized sensitivity the dose rate sensitivity was reduced distinctly using an increased oxygen scavenger concentration with reference to standard MAGIC-type gel formulation at high dose rate levels. The proposed gel composition with high oxygen scavenger concentration exhibits a larger linear active dose response and might be used especially in FFF-radiation applications and preclinical dosimetry at high dose rates. We propose in general to use high dose rates for calibration and evaluation as the change in relative dose sensitivity is reduced at higher dose rates in all of the investigated gel types.

Tra le opzioni di trattamento per i gliomi di alto grado recidivi, la re-irradiazione è sempre stata la più controversa, per i timori legati alla possibile tossicità. Gli avanzamenti nel campo della radioterapia, in particolare l’introduzione della radioterapia ad intensità modulata (IMRT) con la possibilità di erogare le dosi in modo disomogeneo (dose painting), consentono tuttavia di aumentarne l’efficacia, riducendone gli effetti tossici. Inoltre le tecniche avanzate di risonanza magnetica (RM) permettono di caratterizzare la struttura, il comportamento biologico e l’eterogeneità spaziale e temporale del tessuto tumorale fornendo informazioni molto utili per la programmazione terapeutica. In questo studio di fase I è stata valutata la tollerabilità di un trattamento IMRT con approccio dose painting basato sulle immagini RM di Diffusione in pazienti con glioma di alto grado recidivo. Dal momento che esistono pochi dati sulla tolleranza del tessuto cerebrale alla re-irradiazione, è stato scelto un endpoint primario di sicurezza. Lo studio, di natura prospettica, prevede un trattamento di IMRT ipofrazionata (30-50 Gy/5 Frazioni) con distribuzione disomogenea di dose, sulla base dei valori di ADC, in paziente adulti con recidiva di glioma di alto grado. L’obiettivo primario è la sicurezza del trattamento proposto. Sono previsti due step di valutazione intermedia della sicurezza dopo il trattamento del terzo e del sesto paziente (campione totale di 12 pazienti). Da febbraio 2016 ad oggi sono stati arruolati cinque pazienti (un maschio e quattro femmine), con un intervallo di tempo mediano tra il primo ed il secondo ciclo di radioterapia di 12 mesi. Il trattamento è risultato ben tollerato e non si sono registrati eventi avversi significativi dopo il trattamento dei primi 3 pazienti. I risultati preliminari dello studio mostrano che il trattamento proposto risulta essere associato a modesta tossicità acuta e subacuta e potrebbe quindi rappresentare in futuro una valida alternativa terapeutica in un ambito, quello dei gliomi maligni recidivi, in cui non esiste ancora uno standard di cura.

Volumetric Modulated Arc Therapy (VMAT) is a recently developed technology which, similar to Intensity Modulated Radiotherapy (IMRT), utilizes optimization algorithms to find an acceptable solution. VMAT optimization algorithms are more complex and resource intensive than IMRT algorithms, as the former have to account for many more variables including machine-specific limitations. VMAT is distinguished from traditional fixed-beam IMRT in that radiation is delivered while the gantry rotates around the patient. It is a significant advancement over fixed gantry angle IMRT in terms of the efficiency of delivery of desired complex dose distributions (dose painting) in modern-day radiotherapy. The purpose of this review is to discuss the technological development, clinical applications and quality assurance of VMAT.