Inhomogeneous Dose Distribution Research Articles

Multifraction stereotactic radiotherapy utilizing inhomogeneous dose distribution for brainstem metastases: a single-center retrospective analysis.

Brainstem metastases are challenging to manage owing to the critical neurological structures involved. Although stereotactic radiotherapy (SRT) offers targeted high doses while minimizing damage to adjacent normal tissues, the optimal dose fractionation remains undefined. This study evaluated the efficacy and safety of multifraction SRT with an inhomogeneous dose distribution. This retrospective study included 31 patients who underwent 33 treatments for 35 brainstem lesions using linear accelerator-based multifraction SRT (30Gy in five fractions, 35Gy in five fractions or 42Gy in 10 fractions) with an inhomogeneous dose distribution (median isodose, 51.9%). The outcomes of interest were local failure, toxicity and symptomatic failure. The median follow-up time after brainstem SRT for a lesion was 18.6months (interquartile range, 10.0-24.3months; range, 1.8-39.0months). Grade 2 toxicities were observed in two lesions, and local failure occurred in three lesions. No grade 3 or higher toxicities were observed. The 1-year local and symptomatic failure rates were 8.8 and 16.7%, respectively. Toxicity was observed in two of seven treatments with a gross tumor volume (GTV) greater than 1cc, whereas no toxicity was observed in treatments with a GTV less than 1cc. No clear association was observed between the biologically effective dose of the maximum brainstem dose and the occurrence of toxicity. Our findings indicate that multifraction SRT with an inhomogeneous dose distribution offers a favorable balance between local control and toxicity in brainstem metastases. Larger multicenter studies are needed to validate these results and determine the optimal dose fractionation.

Association of increasing gross tumor volume dose with tumor volume reduction and local control in fractionated stereotactic radiosurgery for unresected brain metastases

BackgroundFractionated stereotactic radiosurgery (fSRS) is an important treatment strategy for unresected brain metastases. We previously reported that a good volumetric response 6 months after fSRS can be the first step for local control. Few studies have reported the association between gross tumor volume (GTV) dose, volumetric response, and local control in patients treated with the same number of fractions. Therefore, in this study, we aimed to investigate the GTV dose and volumetric response 6 months after fSRS in five daily fractions and identify the predictive GTV dose for local failure (LF) for unresected brain metastasis.MethodsThis retrospective study included 115 patients with 241 unresected brain metastases treated using fSRS in five daily fractions at our hospital between January 2013 and April 2022. The median prescription dose was 35 Gy (range, 30–35 Gy) in five fractions. The median follow-up time after fSRS was 16 months (range, 7–66 months).ResultsGTV D80 > 42 Gy and GTV D98 > 39 Gy were prognostic factors for over 65% volume reduction (odds ratio, 3.68, p < 0.01; odds ratio, 4.68, p < 0.01, respectively). GTV D80 > 42 Gy was also a prognostic factor for LF (hazard ratio, 0.37; p = 0.01).ConclusionsGTV D80 > 42 Gy in five fractions led to better volume reduction and local control. The goal of planning an inhomogeneous dose distribution for fSRS in brain metastases may be to increase the GTV D80 and GTV D98. Further studies on inhomogeneous dose distributions are required.

Overall survival following heterogeneous FDG-guided dose-escalation for locally advanced NSCLC in the international phase III NARLAL2 trial.

LBA8069 Background: The survival and loco-regional control for patients (pts) with locally advanced non-small cell lung cancer (LA_NSCLC) treated with radiotherapy (RT) are dismal despite adjuvant Durvalumab. However, there have been concerns about dose escalation for these pts since the unexpected result of the dose-escalation trial RTOG0617. A novel approach is therefore warranted to escalate the dose to the tumor. A possible approach is to use the principle from stereotactic body radiotherapy (SBRT) with inhomogeneous dose distribution. SBRT has demonstrated excellent local control in early-stage lung cancer. The international multicenter NARLAL2 (novel approach to RT for LA_NSCLC) phase III trial on dose escalation, randomized pts with LA_NSCLC between standard 66 Gy/ 33 fractions (F) versus heterogeneous FDG-PET driven dose escalation, aiming at mean dose to GTV-tumorPET 95 Gy/ 33 F and mean dose to GTV-nodePET 74 Gy/ 33 F while strictly respecting dose to organs at risk. We here present the data on overall survival (OS) 1 year after the end of recruitment. Methods: Pts aged ≥18 years with LA_NSCLC were recruited from seven institutions in Denmark and Norway. Eligibility criteria included ECOG PS 0-1, histological or cytological confirmed NSCLC stage IIB-IIIB, signed informed consent, and a clinically acceptable plan for RT with conventional 66 Gy/ 33 F. PET-CT and brain MR were part of staging. Pts were randomly assigned to either treatment group (1:1, stratified for center and histology). The trial aimed to have iso-lung toxicity within the treatment arms by creating two RT plans (before randomization) for each patient (one for each treatment arm) with matching mean lung dose and lung V20Gy. The follow-up (FU) were scheduled weekly during RT, every 3rd month for 2 years, and every 6th month for another 3 years after randomization. At FU visit a CT-scan and toxicity scoring were performed. All interim analyses were passed without interventions (toxicity and OS). The trial's primary endpoint was time to loco-regional failure from randomization. Secondary endpoints included OS, acute, and late toxicity. The sample size calculations requested 350 pts to be enrolled in the study. Recruitment of the pre-planned number of pts finalized in March 2023. The trial was registered with ClinicalTrials.gov (NCT02354274). Results: From January 2015 to March 2023, 350 pts were randomized: 177 and 173 pts in standard and escalated arms respectively. The two groups were well-balanced regarding age, gender, stage, and PS. The dose to GTV-tumor was 66.5 Gy [66.2, 67.1] (median [IQR]) in the standard arm and 88.1 Gy [84.9, 90.4] in the escalated arm. Median OS were 35.8 months (m) and 51.6 m for pts treated in the standard and escalated arm, respectively ( p = 0.36). Median FU time 50.8 m (reverse Kaplan-Meier). Conclusions: Dose escalation is safe in the NARLAL2 setting with respect to OS. Clinical trial information: NCT02354274 .

1038: The impact of inhomogeneous dose distribution in fractionated stereotactic radiosurgery

1038: The impact of inhomogeneous dose distribution in fractionated stereotactic radiosurgery

Toward Global Consensus for MR-Guided Treatment Planning for Pancreatic Tumors on a 1.5 T MR-Linac

MR-guided SBRT with a 1.5 T MR-Linac is a relatively new therapy for pancreatic tumors with varying expertise levels. Moreover, treatment planning in the upper abdomen can be challenging as target coverage is often compromised by dosimetric constraints of abutting bowel structures. This may lead to large differences between centers in protocols, practices. To increase harmonization a worldwide consortium was founded among 1.5 T MR-Linac users. In this work we report on the outcome of the first phase within this collaboration, which is the assessment of the baseline variation between the treatment planning protocols and subsequent dose distributions. Twelve centers across three continents (North America, Europe, and Australia) participated in this consortium. Each center was sent the same two anonymized data sets reflecting two cases of locally advanced pancreatic cancer of different complexity levels. The data sets included a CT scan, a predefined structure set containing the gross target volume (GTV) and the OARs, a brief medical history, tumor motion characteristics, and auxiliary CT and MR imaging. Centers were asked to create an MRgRT treatment plan according to their clinical five-fraction SBRT protocol, using their institutional margin structures, beam setup, target prescriptions, and OAR constraints. Key DVH parameters that were evaluated are D99%, D90%, D50%, D1% for the GTV and D0.5cc for the duodenum, small bowel, and stomach. In general, large variations were observed in planning objectives and machine settings yielding widely varying inhomogeneous dose distributions to both the tumor and organs at risk (Table 1). This was especially manifest for case 2 where the tumor abutted with both the duodenum and small bowel over a trajectory of multiple centimeters. Not only were different trade-offs between target coverage and OAR sparing observed, but also different strategies for optimizing the integral dose to the tumor. These results indicate a large variety in the treatment planning strategies that could well translate to differences in outcome. Based on this first evaluation, the consortium will work towards a collective consensus protocol with a second evaluation round after internal discussions.

Conventionally fully fractionated Gamma Knife Icon re-irradiation of primary recurrent intracranial tumors: the first report indicating feasibility and safety.

With the incorporation of real-time image guidance on the Gamma Knife system allowing for mask-based immobilization (Gamma Knife Icon [GKI]), conventionally fully fractionated (1.8-3.0 Gy/day) GKI radiation can now be delivered to take advantage of an inherently minimal margin for delivery uncertainty, sharp dose falloff, and inhomogeneous dose distribution. This case series details the authors' preliminary experience in re-irradiating 7 complex primary intracranial tumors, which were considered to have been previously maximally radiated and situated adjacent to critical organs at risk. The authors retrospectively reviewed all patients who received fractionated re-irradiation using GKI at the Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada, between 2016 and 2021. Patients with brain metastases, and those who received radiotherapy courses in 5 or fewer fractions, were excluded. All radiotherapy doses were converted to the equivalent total dose in 2-Gy fractions (EQD2), with the assumption of an α/β ratio of 2 for late normal tissue toxicity and 10 for the tumor. A total of 7 patients were included in this case series. Three patients had recurrent meningiomas, as well as 1 patient each with ependymoma, intracranial sarcoma, pituitary macroadenoma, and papillary pineal tumor. Six patients had undergone prior linear accelerator-based conventional fractionated radiotherapy and 1 patient had undergone prior proton therapy. Patients were re-irradiated with a median (range) total dose of 50.4 (30-63.4) Gy delivered in a median (range) of 28 (10-38) fractions with GKI. The median (range) target volume was 6.58 (0.2-46.3) cm3. The median (range) cumulative mean EQD2 administered to the tumor was 121.1 (107.9-181.3) Gy, and the median (range) maximum point EQD2 administered to the brainstem, optic nerves, and optic chiasm were 91.6 (74.0-111.5) Gy, 58.9 (6.3-102.9) Gy, and 59.9 (36.7-127.3) Gy, respectively. At a median (range) follow-up of 15 (6-42) months, 6 of 7 patients were alive with 4 having locally controlled disease. Only 3 patients experienced treatment-related toxicities, which were self-limited. Fractionated radiotherapy using GKI may be a safe and effective method for the re-irradiation of complex progressive primary intracranial tumors, where the aim is to minimize the potential for serious late effects.

Feasibility Study on the Radiation Dose by Radioactive Magnetic Core-Shell Nanoparticles for Open-Source Brachytherapy.

Treatment of early-stage breast cancer currently includes surgical removal of the tumor and (partial) breast irradiation of the tumor site performed at fractionated dose. Although highly effective, this treatment is exhaustive for both patient and clinic. In this study, the theoretical potential of an alternative treatment combining thermal ablation with low dose rate (LDR) brachytherapy using radioactive magnetic nanoparticles (RMNPs) containing 103-palladium was researched. The radiation dose characteristics and emission spectra of a single RMNP were calculated, and dose distributions of a commercial brachytherapy seed and an RMNP brachytherapy seed were simulated using Geant4 Monte Carlo toolkit. It was found that the RMNP seeds deliver a therapeutic dose similar to currently used commercial seed, while the dose distribution shows a spherical fall off compared to the more inhomogeneous dose distribution of the commercial seed. Changes in shell thickness only changed the dose profile between 2 × 10-4 mm and 3 × 10-4 mm radial distance to the RMNP, not effecting long-range dose. The dose distribution of the RMNP seed is comparable with current commercial brachytherapy seeds, while anisotropy of the dose distribution is reduced. Because this reduces the dependency of the dose distribution on the orientation of the seed, their surgical placement is easier. This supports the feasibility of the clinical application of the proposed novel treatment modality.

Sunday, June 19, 202210:00 AM - 10:15 AMPO47 Presentation Time: 10:00 AM: Dose Distribution of Permanent Interstitial Brachytherapy (Iodine-125) in Comparison to Temporary Interstitial Brachytherapy (Iridium-192) with a Hydrogel Spacer for Prostate Cancer

<h3>Purpose</h3> Brachytherapy (BT) for prostate cancer can be applied as permanent interstitial brachytherapy BT (LDR, low dose rate) and temporary interstitial brachytherapy BT (HDR, high dose rate), applied also alternatively in many centers. The aim of the study was to analyze the dose distribution in- and outside the prostate. <h3>Methods</h3> The intraoperative dose distribution of 102 LDR-BT patients was compared with the dose distribution of 109 HDR-BT patients (232 HDR-BT fractions). A hydrogel spacer (HS) (10ml) was only applied before HDR-BT. For the analysis of the dose coverage outside the prostate, a 5mm margin was added to prostate volume (PV+). Prostate V100 and V150 denote the PV covered by 100% and 150% of the prescription dose, while prostate D90 and urethra D30 denote the minimum dose in 90% of the PV and 30% of the urethral volume. <h3>Results</h3> The comparison of volume and dose values is shown in the table. HDR-BT patients had on average a slightly larger PV, but considerably larger PV+. The only not significantly different value comparing both methods was prostate V100. LDR-BT was characterized by a considerably more inhomogeneous dose distribution and higher doses to the urethra. However, the minimum dose in 90% of PV+ was lower. As a consequence of the HA in HDR-BT patients, the dose to the rectum was considerably lower. <h3>Conclusion</h3> In comparison to HDR-BT, LDR-BT is characterized by a more inhomogeneous dose inside the prostate, a higher dose to the urethra and a slightly less steep dose drop-off around the prostate. The dose to the rectal wall can be considerably reduced applying the HS.

High-Dose Spatially Fractionated Radiotherapy, Lattice Radiotherapy in Bulky Tumors: Results after One Year Follow-Up

<h3>Purpose/Objective(s)</h3> Spatially Fractionated Radiotherapy (SFRT) or Lattice Radiotherapy (LRT) is a radiotherapy technique that allows to deliver a very high radiation doses spheres inside the tumor in a single fraction, maintaining low dose in OAR, generating an inhomogeneous dose distribution inside the GTV and maintains the PTV marginal dose within planned dose within a multifraction treatment. This can be an option for bulky unresectable tumors with poor local control with standard radiotherapy. The main objective of this study is to assess LTR toxicity in patients with tumors greater than 45 cc and poor candidates for other treatment modalities. <h3>Materials/Methods</h3> From 1 January 2020 to 31 December 2020, 21 patients were treated in our institution. We prescribe 1 cm spheres with a maximum dose over 15 Gy in a single fraction and at least 4 vertices distributed inside of GTV. PTV dose continues as standard dose fractionation of 2.5-3Gy in the LRT session as prescribed in conventional or hypofractionated treatment. Simulation and treatment delivery is as SBRT. LTV (Lattice Tumor Volume) is the structure inside GTV where the VTV spheres (Vertex Tumor Volume), overdose volumes, are located, separated by 2.5-3.0 cm. VV (Valley Volume) is the subtraction of GTV-VTV that must be under 5 Gy. <h3>Results</h3> 21 patients (66,6% of tumors were in the thorax, 28,6% abdomen/pelvis and 4,8% head and neck) were treated. The median follow-up was 12 months (3-25). The median age of the patients was 64 years old (42-84). The median GTV volume was 236cc (80-896cc) and 73 mm (47– 123mm) in greatest axial diameter. The analysis of the results showed 4 patients with complete response (20%), 12 with partial response (57%) and 5 with stable disease (23%). Tumor reduction bigger than 50% has been observed in 75% of cases 2 weeks after LTR session. Local control was 75% at 6 months. Cumulative probability of survival was 76% (95% CI 51-89%) and 59% (95% CI 33-77%) at 6 and 12 months respectively. No additional toxicity has been related. No major grade 3 toxicities were reported according to CTCAE v5.0 grading. <h3>Conclusion</h3> Our experience with LTR protocol is feasible as a technique to be included in radiotherapy treatments for poor prognosis bulky tumors, with reproducibility and adaptability. Our early results confirm good local response and no added toxicity. Further large prospective studies are required to validate these results.

Adaptive margins for online adaptive radiotherapy

Objective. In online adaptive radiotherapy a new plan is generated every fraction based on the organ and clinical target volume (CTV) delineations of that fraction. This allows for a planning target volume margin that does not need to be constant over the whole course of treatment, as is the case in conventional radiotherapy. This work aims to introduce an approach to update the margins each fraction based on the per-patient treatment history and explore the potential benefits of such adaptive margins. Approach. We introduce a novel methodology to implement adaptive margins, isotropic and anisotropic, during a treatment course based on the accumulated dose to the CTV. We then simulate treatment histories for treatments delivered in up to 20 fractions using various choices for the standard deviations of the systematic and random errors and homogeneous and inhomogeneous dose distributions. The treatment-averaged adaptive margin was compared to standard constant margins. The change in the minimum dose delivered to the CTV was compared on a patient and a population level. All simulations were performed within the van Herk approach and its known limitations. Main results. The population mean treatment-averaged margins are down to 70% and 55% of the corresponding necessary constant margins for the isotropic and anisotropic approach. The reduction increases with longer fractionation schemes and an inhomogeneous target dose distribution. Most of the benefit can be attributed to the elimination of the effective systematic error over the course of treatment. Interpatient differences in treatment-averaged margins were largest for the isotropic margins. For the 10% of patients that would receive a lower than prescribed dose to the CTV this minimum dose to the CTV is increased using the adaptive margin approaches. Significance. Adaptive margins can allow to reduce margins in most patients without compromising patients with greater than average target motion.

Safety of Inhomogeneous Dose Distribution IMRT for High-Grade Glioma Reirradiation: A Prospective Phase I/II Trial (GLIORAD TRIAL).

Simple SummaryGlioblastoma multiforme (GBM) is the most frequent primary malignant brain tumor, and despite advances in imaging techniques and treatment options, the outcome remains poor and recurrence is inevitable. Salvage therapy presents a challenge, and re-irradiation can be a therapeutic option in recurrent GBM. The decision-making process for re-irradiation is a challenge for radiation oncologists due to the expected toxicity of a second course of radiotherapy and the limited radiation tolerance of normal tissue; nevertheless, it is being increasingly used, as several studies have demonstrated its feasibility. The current study aimed to investigate the safety of moderate–high-voxel-based dose escalation radiotherapy in recurrent GBM patients after conventional concurrent chemoradiation. Twelve patients were enrolled in this prospective single-center study. Retreatment consisted of re-irradiation with a total dose range of 30–50 Gy over 5 days using the IMRT (arc VMAT) technique using dose painting planning. The treatment was well tolerated. No toxicities greater than 3 were recorded; only one patient had severe G3 acute toxicity, characterized by muscle weakness and fatigue. Median overall survival (OS2) and progression-free survival (PFS2) from the time of re-irradiation were 10.4 months and 5.7 months, respectively. Our phase I study demonstrated an acceptable tolerance profile of this approach, and the future prospective phase II study will analyze the efficacy in terms of PFS and OS.Glioblastoma multiforme (GBM) is the most aggressive astrocytic primary brain tumor, and concurrent temozolomide (TMZ) and radiotherapy (RT) followed by maintenance of adjuvant TMZ is the current standard of care. Despite advances in imaging techniques and multi-modal treatment options, the median overall survival (OS) remains poor. As an alternative to surgery, re-irradiation (re-RT) can be a therapeutic option in recurrent GBM. Re-irradiation for brain tumors is increasingly used today, and several studies have demonstrated its feasibility. Besides differing techniques, the published data include a wide range of doses, emphasizing that no standard approach exists. The current study aimed to investigate the safety of moderate–high-voxel-based dose escalation in recurrent GBM. From 2016 to 2019, 12 patients met the inclusion criteria and were enrolled in this prospective single-center study. Retreatment consisted of re-irradiation with a total dose of 30 Gy (up to 50 Gy) over 5 days using the IMRT (arc VMAT) technique. A dose painting by numbers (DPBN)/dose escalation plan were performed, and a continuous relation between the voxel intensity of the functional image set and the risk of recurrence in that voxel were used to define target and dose distribution. Re-irradiation was well tolerated in all treated patients. No toxicities greater than G3 were recorded; only one patient had severe G3 acute toxicity, characterized by muscle weakness and fatigue. Median overall survival (OS2) and progression-free survival (PFS2) from the time of re-irradiation were 10.4 months and 5.7 months, respectively; 3-, 6-, and 12-month OS2 were 92%, 75%, and 42%, respectively; and 3-, 6-, and 12-month PFS2 were 83%, 42%, and 8%, respectively. Our work demonstrated a tolerable tolerance profile of this approach, and the future prospective phase II study will analyze the efficacy in terms of PFS and OS.

Joint Optimization of Photon-Carbon Ion Treatments for Glioblastoma.

Carbon ions are radiobiologically more effective than photons and are beneficial for treating radioresistant gross tumor volumes (GTV). However, owing to a reduced fractionation effect, they may be disadvantageous for treating infiltrative tumors, in which healthy tissue inside the clinical target volume (CTV) must be protected through fractionation. This work addresses the question: What is the ideal combined photon-carbon ion fluence distribution for treating infiltrative tumors given a specific fraction allocation between photons and carbon ions? We present a method to simultaneously optimize sequentially delivered intensity modulated photon (IMRT) and carbon ion (CIRT) treatments based on cumulative biological effect, incorporating both the variable relative biological effect of carbon ions and the fractionation effect within the linear quadratic model. The method is demonstrated for 6 glioblastoma patients in comparison with the current clinical standard of independently optimized CIRT-IMRT plans. Compared with the reference plan, joint optimization strategies yield inhomogeneous photon and carbon ion dose distributions that cumulatively deliver a homogeneous biological effect distribution. In the optimal distributions, the dose to CTV is mostly delivered by photons and carbon ions are restricted to the GTV with variations depending on tumor size and location. Improvements in conformity of high-dose regions are reflected by a mean EQD2 reduction of 3.29 ± 1.22 Gy in a dose fall-off margin around the CTV. Carbon ions may deliver higher doses to the center of the GTV, and photon contributions are increased at interfaces with CTV and critical structures. This results in a mean EQD2 reduction of 8.3 ± 2.28 Gy, in which the brain stem abuts the target volumes. We have developed a biophysical model to optimize combined photon-carbon ion treatments. For 6 glioblastoma patient cases, we show that our approach results in a more targeted application of carbon ions that (1) reduces dose in normal tissues within the target volume, which can only be protected through fractionation; and (2) boosts central target volume regions to reduce integral dose. Joint optimization of IMRT-CIRT treatments enable the exploration of a new spectrum of plans that can better address physical and radiobiological treatment planning challenges.

Requirements for Designing an Effective Metallic Nanoparticle (NP)-Boosted Radiation Therapy (RT).

Simple SummaryRecent advances in nanotechnology gave rise to trials with various types of metallic nanoparticles (NPs) to enhance the radiosensitization of cancer cells while reducing or maintaining the normal tissue complication probability during radiation therapy. This work reviews the physical and chemical mechanisms leading to the enhancement of ionizing radiation’s detrimental effects on cells and tissues, as well as the plethora of experimental procedures to study these effects of the so-called “NPs’ radiosensitization”. The paper presents the need to a better understanding of all the phases of actions before applying metallic-based NPs in clinical practice to improve the effect of IR therapy. More physical and biological experiments especially in vivo must be performed and simulation Monte Carlo or mathematical codes based on more accurate models for all phases must be developed.Many different tumor-targeted strategies are under development worldwide to limit the side effects and improve the effectiveness of cancer therapies. One promising method is to enhance the radiosensitization of the cancer cells while reducing or maintaining the normal tissue complication probability during radiation therapy using metallic nanoparticles (NPs). Radiotherapy with MV photons is more commonly available and applied in cancer clinics than high LET particle radiotherapy, so the addition of high-Z NPs has the potential to further increase the efficacy of photon radiotherapy in terms of NP radiosensitization. Generally, when using X-rays, mainly the inner electron shells are ionized, which creates cascades of both low and high energy Auger electrons. When using high LET particles, mainly the outer shells are ionized, which give electrons with lower energies than when using X-rays. The amount of the produced low energy electrons is higher when exposing NPs to heavy charged particles than when exposing them to X-rays. Since ions traverse the material along tracks, and therefore give rise to a much more inhomogeneous dose distributions than X-rays, there might be a need to introduce a higher number of NPs when using ions compared to when using X-rays to create enough primary and secondary electrons to get the desired dose escalations. This raises the questions of toxicity. This paper provides a review of the fundamental processes controlling the outcome of metallic NP-boosted photon beam and ion beam radiation therapy and presents some experimental procedures to study the biological effects of NPs’ radiosensitization. The overview shows the need for more systematic studies of the behavior of NPs when exposed to different kinds of ionizing radiation before applying metallic-based NPs in clinical practice to improve the effect of IR therapy.

Enhanced response of radioresistant carcinoma cell line to heterogeneous dose distribution of grid; the role of high-dose bystander effect

Purpose The classical dogma that restricted the radiation effect to the directly irradiated cells has been challenged by the bystander effect. This off-target phenomenon which was manifested in adjacent cells via signaling of fully exposed cells might be involved in high-dose Grid therapy as well. Here, an in-vitro study was performed to examine the possible extent of carcinoma cells response to the inhomogeneous dose distribution of Grid irradiation in the context of the bystander effect. Materials and methods Bystander effect was investigated in human carcinoma cell lines of HeLa and HN5 adjacent to those received high-dose Grid irradiation using ‘medium transfer’ and ‘cell-to-cell contact’ strategies. Based on the Grid peak-to-valley dose profile, medium transfer was exerted from 10 Gy uniformly exposed donors to 1.5 Gy uniformly irradiated recipients. Cell-contact bystander was evaluated after nonuniform dose distribution of 10 Gy Grid irradiation using cloning cylinders. GammaH2AX foci, micronucleus and clonogenic assays besides gene expression analysis were performed. Results Various parameters (ɑ/β, D37, D50) extracted from survival curve which fitted to the Linear Quadratic model, verified more radioresistance of HN5. Survival fraction at 2 Gy (SF2) indicated as 0.42 ± 0.06 in HeLa and 0.5 ± 0.03 in HN5. The level of survival decrease, DNA damages and micronucleus of cells located in the Grid shielded areas (1.5 Gy cell-to-cell contact bystander cells) were significantly more than the values obtained from cells which were irradiated by merely uniform dose of 1.5 Gy. The gH2AX foci and micronuclei frequencies were enhanced in cell-contact bystander approximately more than 1.8 times. Relative expression of DNA damage repair pathway genes (Xrcc6 and H2afx) in bystander cells increased significantly. The most cell survival reduction (11.6 times) was revealed in the Grid bystander cells of radioresistant cell line (HN5). No statistically significant difference between 10 Gy uniform beam and Grid non-uniform beam was observed. Conclusions Various endpoints confirmed an augmented response of cells in the valley dose region of the Grid block significantly (compared with the cells irradiated by identical dose of uniform beam), suggesting the role of high-dose bystander effect which was more pronounced in resistant carcinoma cell lines. These findings could provide a partial explanation for the Grid beneficial response seen in a number of pre-clinical and clinical studies.

Overall and GTV subvolumes tumour control probability (TCP) for head and neck cancer treated by 3D-IMRT with inhomogeneous dose distribution

Introduction. In this study, an original model has been developed to estimate the real TCP that is a product of the TCPs calculated for GTV subvolumes of head and neck cancer based on 3D-IMRT dose planning. Material and methods. Retrospective pilot group consist of 16 cases of oropharyngeal cancer in stage T1–2N0 previously treated with 3D-IMRT with at least 3-year follow-up. The total dose (TD) was 60–70 Gy in 2.0 Gy fractions delivered over 42–49 days. Within GTV two subvolumes were marked out: SVA with the planned 100% TD, and underdosed (90–95%) SVB. The TCP for both was calculated using the original formula developed by Withers and Maciejewski. Results. During 3-year follow-up, 8 local recurrences (LR) occurred. In about 70% of SVB “dose cold spots” encompassed more than 50% GTV volume. This resulted in the TCPSVB decrease to 60%. Thus, the real overall TCP was much lower than a priori predicted, and in these cases local recurrences occurred. Discussion. Both cold spot SVB volumes and their dose deficit strongly correlated with a high risk of LR. Conclusions. In conclusion the magnitude of dose deficit and the size of cold subvolume within GTV have an indepen­dent negative impact on real TCP and demand dose re-planning.

Design and characterization of flattening filter for high dose rate 192Ir and 60Co Leipzig applicators used in skin cancer brachytherapy: A Monte Carlo study

PurposeThis study aimed to design optimal flattening filters for high dose rate (HDR) 192Ir and 60Co Leipzig applicators which are used to treat skin cancer. Materials and methodsMCNPX Monte Carlo code was used to design flattening filters for Leipzig applicators with inner diameters of 1, 2 and 3 cm. Then, their dosimetric characterizations such as dose distribution, dose profile, percentage depth dose, flatness, symmetry and homogeneity were evaluated in a 20 × 20 × 20 cm3 water phantom and compared with those without the flattening filter. ResultsThe flattening filter thickness varied from 0 mm (at the edge) to the maximum values of 0.30, 1.18, and 2.41 mm for the 192Ir Leipzig applicators of H1, H2, and H3 type, respectively. This quantity has maximum values of 0.96, 6.27, and 12.31 mm for the 60Co double wall applicators of D1, D2, and D3 type, respectively. The dose profile flatness values for the H1, H2, and H3 192Ir Leipzig applicators with the optimal flattening filters were 0.76, 1.26, and 1.85%, respectively. Furthermore, the dose profile flatness values for the D1, D2, and D3 60Co double wall applicators with the optimal flattening filters were 1.11, 2.10 and 3.12%, respectively. The dose profile symmetry values obtained from various source-applicator combinations were less than 1.02. Compared to the applicators without flattening filter, the homogeneity values for the H1, H2, and H3 192Ir Leipzig applicators with the optimal flattening filters were improved 1.68, 6.51, and 13.17 times, respectively, and for the D1, D2, and D3 60Co double wall applicators were improved 1.23, 6.21 and 9.54 times, respectively. ConclusionThe findings revealed that the inhomogeneous dose distribution resulted from the Leipzig applicators without the optimal flattening filter at the treatment surface could be improved by insertion of optimal lead flattening filters between the sources and treatment surface.

The risk for developing a secondary cancer after breast radiation therapy: Comparison of photon and proton techniques

Background and purposeTo compare secondary malignancy risks of modern proton and photon therapy techniques for locally advanced breast cancer. Methods and materialsWe utilized dosimetric data from 34 [10 photon-VMAT, 10 photon-3DCRT, 14 pencil beam scanning proton (PBS)] breast cancer patients who received comprehensive nodal irradiation. Employing a model based on organ equivalent dose to account for both inhomogeneous organ dose distributions and non-linear functional dose relationships, we estimated excess absolute risk, excess relative risk, and lifetime attributable risk (LAR) for secondary malignancies. The model uses dose distribution, number of fractions, age at exposure, attained age, the linear-quadratic dose response relationship for cell survival, repopulation factor, as well as gender specific age dependencies, and initial slopes of dose response curves. ResultsThe LAR for carcinoma at age 70 was estimated to be up to 3.64% for esophagus with an advantage of 3DCRT over PBS and VMAT. For the ipsilateral lung, risks were lowest for PBS (up to 5.56%), followed by 3DCRT (up to 6.54%) and VMAT (up to 7.7%). For the contralateral lung, there is a clear advantage of 3DCRT and PBS techniques (risk <0.86%) over VMAT (up to 4.4%). The risk for the contralateral breast is negligible for 3DCRT and PBS but was estimated as up to 1.2% for VMAT. Risks for the thyroid are overall negligible. Independently performed comparative treatment plans on 10 patients revealed that the risk for the contralateral lung and breast using VMAT can be more than an order of magnitude higher compared to PBS. Sarcoma risks were estimated as well showing similar trends but were overall lower compared to carcinoma. ConclusionConventional (3DCRT) techniques led to the lowest estimated risks of, thyroid and esophageal secondary cancers while PBS demonstrated a benefit for secondary lung and contralateral breast cancer risks, with the highest risks overall associated with VMAT techniques.

Radiobiological Difference Between Flattening Filter Free (FFF) Vs. Flattening Filter (FF) X-Ray Beams in Lung Cancer Cells

Stereotactic Body Radiotherapy (SBRT) is a well-established therapeutic option for early lung cancer, and many clinical trials indicate that SBRT can provide excellent local control and survival with limited toxicity. Compared with conventional flattening filter (FF) beams, flattening filter free (FFF) beams are characterized by higher average dose rate with higher dose per pulse and inhomogeneous dose distribution with reduced peripheral dose. These benefits make FFF beams an attractive alternative for SBRT. Therefore, it is crucially to determine whether there are any differences in biological effects of FFF beams compared with FF beams. However, there are still conflicts on them between two beams. Therefore, we investigated the radiobiological effect between FF and FFF beam in human lung cancer cell lines. Three human lung cancer cell lines with different genetic characteristics (A549, NCI-H1299, NCI-H1650) were used. Irradiation was performed with a 10 MV linear accelerator (Versa HD, Elekta AB). The dose rate and dose per pulse for FF and FFF beams were 5 and 22 Gy/min, and 0.042 cGy and 0.171 cGy, respectively. To investigate the effect by different dose rate, but with same dose per pulse, FFF beam of 22 Gy/ min was modified to 5 Gy/min by increasing pulse interval. The radiobiologic effect was studied with three different conditions: FF (5 Gy/min, 0.042 cGy/pulse), FFF (5 Gy/min, and 0.171 cGy/pulse) and FFF (22 Gy/min, 0.171 cGy/pulse). Cell survival was measured using clonogenic assay and protein expression was measured using Western blot analysis. No significant differences in cell survival were observed upon three kinds of irradiation for all the three cell lines. No significant differences were observed in the expression of γ-H2AX and repair proteins (DNA-PKcs, Rad 51) after irradiation in all the three cell lines. There is no radiobiological difference (cell survival, DNA damage and repair) between FF and FFF beams in lung cancer cells.

Research of Biological Dose Conversion Platform Based on a Modified Linear Quadratic Model.

The study aimed to develop a novel dose conversion platform by improving linear-quadratic (LQ) model to more accurately describe radiation response for high fraction/acute doses. This article modified the LQ model via piecewise fitting the biological dose curve using different fractionated dose and optimizing the consistency between mathematical model and experimental data to gain a more reasonable transform. That mathematical development of the LQ model further amended certain deviations of various cell curves with high doses and implied the rationality of the present model at low dose range. The modified biologically effective dose model that solved the dilemma of inaccurate LQ model had been used in comparing between hypofractionated and conventional fractioned dose. It has been verified that the calculated values are similar in the treatment of same efficacy, no matter what α/β is, and provided a more rational explanation for significant differences among various hypofractionations. The equivalent uniform dose based on the subsection function could represent arbitrary inhomogeneous dose distributions including high-dose fractions, providing a foundation for the implementation of detailed evaluation of different cell dose effects.

OA052] Proton minibeam radiation therapy: A promising alternative for high-grade gliomas

Introduction The morbidity of normal tissues continues being the main limitation in radiotherapy. To overcome it, we proposed a novel concept: proton minibeam radiation therapy (pMBRT) [1] . It allies the physical advantages of protons with the normal tissue preservation observed when irradiated with submillimetric spatially fractionated beams (minibeam radiation therapy). We have recently implemented this technique [2] at a clinical center and demonstrated that pMBRT leads to a significant increase of normal tissue tolerances [3] with respect to standard proton therapy. This work aimed at showing that this gain allows using potentially curative doses in the cases of radioresistant tumors, like gliomas. Material and methods Two groups of rats were implanted with RG2 rat glioma cells intracranially. Half of the animals received a whole brain irradiation (pMBRT). The dose distributions were completely inhomogeneous, with areas of very high doses in the minibeam paths (70 Gy in one fraction) and areas of low doses in the spaces between minibeams (around 10 Gy). A third group (n = 8) of normal rats were irradiated (whole brain) in the same configuration and followed for 6 months. Results The controls presented a mean survival time of 20.8 ± 0.4. The group receiving pMBRT showed a substantial increase of mean survival time (as today, a factor 2 gain with respect to the controls). The existence of several long term survivals indicates tumor sterilization. The irradiated normal rats exhibited no clinical symptoms for 6 months after irradiation in contrast to rats irradiated in previous studies with lower doses [4]. No substantial damage was observed in the MRI evaluation. Conclusions These results indicate that pMBRT widens the therapeutic window for gliomas. The fact that a significant tumor control is reached even with inhomogeneous dose distributions contradicts the classical paradigm of standard radiotherapy and points at the participation of distinct radiobiological mechanisms.