The benefit of co-targeting PARP-1 and c-Met on the efficacy of radiotherapy in wild type BRAF melanoma.

Melanoma is known to be a radioresistant cancer. Melanoma radioresistance can be due to several factors such as pigmentation, antioxidant defenses and high Deoxyribonucleic acid (DNA) repair efficacy. However, irradiation induces intracellular translocation of RTKs, including cMet, which regulates response to DNA damage activating proteins and promotes DNA repair. Accordingly, we hypothesized that co-targeting DNA repair (PARP-1) and relevant activated RTKs, c-Met in particular, may radiosensitize wild-type B-Raf Proto-Oncogene, Serine/Threonine Kinase (WTBRAF) melanomas where RTKs are often upregulated. Firstly, we found that PARP-1 is highly expressed in melanoma cell lines. PARP-1 inhibition by Olaparib or its KO mediates melanoma cell sensitivity to radiotherapy (RT). Similarly, specific inhibition of c-Met by Crizotinib or its KO radiosensitizes the melanoma cell lines. Mechanistically, we show that RT causes c-Met nuclear translocation to interact with PARP-1 promoting its activity. This can be reversed by c-Met inhibition. Accordingly, RT associated with the inhibition of both c-Met and PARP-1 resulted in a synergistic effect not only on tumor growth inhibition but also on tumor regrowth control in all animals following the stop of the treatment. We thus show that combining PARP and c-Met inhibition with RT appears a promising therapeutic approach in WTBRAF melanoma.

Inter-fraction heart displacement during voluntary deep inspiration breath hold radiation therapy without visual feedback measured by daily CBCT.

Purpose/Objective: Deep Inspiration Breath Hold (DIBH) is now considered as the standard of care for many breast cancer patients. However, there are still uncertainties about the dose given to the heart, and it is unknown if patients may improve voluntary DIBH depth by gaining experience during treatment. In this study, we will examine the interfractional three-dimensional (3D) heart displacement throughout voluntary DIBH (vDIBH) radiotherapy by means of daily cone-beam computed tomography (CBCT). Material and methods: Two hundred twenty-five unique CBCTs from 15 patients treated in 15 fractions were analyzed. During CBCT, a vDIBH was conducted without any visual feedback. Patients performed their DIBH freely after receiving explanations and training. After daily CBCT matching to the chest wall (CW), surface-guided radiation therapy (SGRT) tracked DIBH depth to ensure that the CW position was the same as the daily acquired CBCT. The CBCTs were retrospectively registered to the DIBH planning-CT to calculate daily changes in heart displacement relative to the CW. Results: The mean displacement of the heart during DIBH treatment relative to the DIBH planning-CT was as follows: 1.1 mm to the right, interquartile range (IQR) 8.0; 0.5 mm superiorly, IQR 4.8; and 0 mm posteriorly, IQR 6.4. The Spearman correlation coefficients (rs) were -0.15 (p=0.025), 0.04 (p=0.549), and 0.03 (p=0.612) for the X, Y, and Z directions, respectively. The differences in median heart displacement were significant: Friedmann rank sum test p=0.031 and pairwise comparison using the Wilcoxon rank-sum test were p=0.008 for X and Y; p=0.33 for X and Z; and p=0.07 for Y and Z. The total median heart motion was δtot median= 7.26 mm, IQR= 6.86 mm. Conclusion: During DIBH, clinicians must be aware of the wide range of intra- and inter-individual heart position variations. The inter-individual heterogeneity shown in our study should be investigated further in order to avoid unexpected cardiac overexposure and to develop a more accurate heart dose-volume model.

Lymphocyte-sparing pelvic radiotherapy for prostate cancer: An in-silico study.

Background and Purpose: Evidence regarding radiation-induced lymphopenia and its negative impact on oncological outcome is incrementing. Therefore, the aim of this study is to evaluate the feasibility of lymphocyte-rich organs at risk (LOAR) sparing in pelvic irradiation for localized prostate cancer and to estimate its impact on the effective dose to circulating immune cells (EDIC). Materials and Methods: Twenty patients with pelvic nodal and prostate or prostate bed irradiation were included. The following bone marrow (BM) structures were delineated as LOARs using semi-automatic segmentation: lumbosacral spine (Ls-BM), ilium (Il-BM), lower pelvis (Lp-BM), and the combined whole-pelvis (Wp-BM). Twenty new lymphocyte sparing treatment plans (LS plans) were calculated, optimizing doses to LOARs while maintaining strict coverage of the targets and respecting standard OARs dose constraints. Finally, we elaborated an EDIC calculation model for pelvic irradiation. Results: LS plans showed a statistically significant dose decrease for LOAR compared to standard of care plans without compromising target coverage nor classic OAR dose constraints: in prostate plans, the V40Gy for Ls-BM, Il-BM, and Lp-BM was decreased by 23 %, 36 %, 52 % respectively. For prostate bed plans, the V40Gy for Ls-BM, Il-BM, and Lp-BM was decreased by 25 %, 59 %, 56 %, respectively. For Wp-BM, the V10Gy, V20Gy, and Dmean have been decreased by 3 %, 14 %, 15 %, and by 5 %, 15 %, 17 %, respectively for prostate and prostate bed plans. A statistically significant decrease in EDIC was seen for LS plans in both groups. Conclusions: We successfully demonstrated the feasability of lympocyte-sparing treatment planning in pelvic irradiation, also proposing a model for EDIC calculation.

Qualitative evaluation of the role of RTTs IGRT specialists and their influence on treatment delivery.

Purpose: The study aims to investigate qualitatively how Radiation Therapist IGRT specialists (RTT spIGRTs) experience their role and whether they have an impact on the treatment delivery. Methods: Eleven RTTs, i.e. six RTT spIGRTs and five RTTs not specialised in IGRT (RTTs noIGRT) were interviewed during October and November 2020. RTTs noIGRT having knowledge of the daily practice before and after the creation of this RTT spIGRT role, served as control group capable of weighing its impact on the work environment. A qualitative method using face-to-face semi-structured questionnaires was used. Interviews lasted approximately 10-20 min, and were after coded and analysed for thematic content. Results: Five themes and twelve sub-themes were drawn from the analysis. RTT spIGRTs experience their role positively, despite the limited role perception and different work experiences. The implemented role increased autonomy and facilitated decision-making and Radiotherapy (RT) treatment delivery.Interviewees considered the new role useful to very useful. The raised concerns are related to a bigger role involvement and improvement, with focus on visibility, regular meetings and training. Interviewees considered the RTT spIGRT role to have an influence on the treatment delivery when properly carried out. Conclusion: RTT spIGRTs experience their role positively. Their knowledge confidence seems to rely on the training received. The RTT spIGRT role is perceived to have a positive influence on the treatment delivery. Continuous follow up and training were amongst the suggested solutions to improve the RTT spIGRT's role. This study stresses the urgent need for a legal framework to provide formal RTT training and continuous education in order to increase RT treatment quality.

Evaluation of the XVI dual registration tool for image-guided radiotherapy in prostate cancer.

PURPOSE: To compare the reliability and the required time for two cone-beam CT (CBCT) registration methods for prostate irradiation (PI) and prostate bed irradiation (PBI). MATERIAL AND METHODS: Two-hundred treatment fractions (in 10 PI and 10 PBI patients) were reanalyzed, using two CBCT registration methods: (1) a combination of an automated chamfer matching (CM) with manual matching (MM), and (2) the automated XVI dual registration tool (DRT). Bland-Altman 95% Limits of Agreement (LoA) were used to assess agreement with manual registration by Radiation Oncologists. RESULTS: All 95% LoA for CM + MM were ≤ 0.33 cm. For DRT, several 95% LoA were notably larger than the predefined clinical threshold of 0.3 cm: -0.47 to +0.25 cm (PI) and -0.36 to +0.23 cm (PBI) for the superior-inferior direction and -0.52 to +0.24 cm (PI) and -0.38 to +0.31 cm (PBI) for the anterior-posterior direction.For PI, the average time required was 33 s with CM + MM versus only 18 s with DRT (p = 0.002). For PBI, this was 13 versus 19 s, respectively (p = 0.16). CONCLUSION: For PI, DRT was significantly faster than CM + MM, but the accuracy is insufficient to use without manual verification. Therefore, manual verification is still warranted, but could offset the time benefit. For PBI, the CM + MM method was faster and more accurate.

Split-VMAT technique to control the deep inspiration breath hold time for breast cancer radiotherapy.

BACKGROUND: To improve split-VMAT technique by optimizing treatment delivery time for deep-inspiration breath hold (DIBH) radiotherapy in left-sided breast cancer patients, when automatic beam-interruption devices are not available. METHODS: Ten consecutive patients were treated with an eight partial arcs (8paVMAT) plan, standard of care in our center. A four partial arcs (4paVMAT) plan was also created and actual LINAC outputs were measured, to evaluate whether there was a dosimetric difference between both techniques and potential impact on the delivered dose. Subsequently, ten other patients were consecutively treated with a 4paVMAT plan to compare the actual treatment delivery time between both techniques. The prescribed dose was 40.05 Gy/15 fractions on the PTV breast (breast or thoracic wall), lymph nodes (LN) and intramammary lymph node chain (IMN). Treatment delivery time, PTVs coverage, conformity index (CI), organs at risk (OAR) dose, monitor units (MU), and gamma index were compared. RESULTS: Both split-VMAT techniques resulted in similar dose coverage for the PTV Breast and LN, and similar CI. For PTV IMN we observed a 5% increased coverage for the volume receiving ≥ 36 Gy with 4paVMAT, with an identical volume receiving ≥ 32 Gy. There was no difference for the OAR sparing, with the exception of the contralateral organs: there was a 0.6 Gy decrease for contralateral breast mean (p ≤ 0.01) and 1% decrease for the volume of right lung receiving ≥ 5 Gy (p = 0.024). Overall, these results indicate a modest clinical benefit of using 4paVMAT in comparison to 8paVMAT. An increase in the number of MU per arc was observed for the 4paVMAT technique, as expected, while the total number of MU remained comparable for both techniques. All the plans were measured with the Delta4 phantom and passed the gamma index criteria with no significant differences. Finally, the main difference was seen for the treatment delivery time: there was a significant decrease from 8.9 to 5.4 min for the 4paVMAT plans (p < .05). CONCLUSIONS: This study is mainly of interest for centers who are implementing the DIBH technique without automatic beam-holding devices and who therefore may require to manually switch the beam on and off during breast DIBH treatment. Split-VMAT technique with 4 partial arcs significantly reduces the treatment delivery time compared to 8 partial arcs, without compromising the target coverage and the OAR sparing. The technique decreases the number of breath holds per fraction, resulting in a shorter treatment session.

3D Monte Carlo dosimetry of intraoperative electron radiation therapy (IOERT).

PURPOSE: This paper studies the feasibility of using Monte Carlo (MC) for treatment planning of intraoperative electron radiation therapy (IOERT) procedure to get 3D dose by using patient's CT images. METHODS: The IOERT treatment planning was performed using the following successive steps: I) The Mobetron 1000® machine was modelled with the EGSnrc MC codes. II) The MC model was validated with measurements of percentage depth doses and profiles for three energies (12, 9, 6) MeV. III) CT images were imported as DICOM files. IV) Contouring of the planning target volume (PTV) and the organs at risk was done by the radiation oncologist. V) The medical physicist with the radiation oncologist, had chosen the same parameters of IOERT procedures like energy, applicator (type, size) and using or not bolus. VI) Finally, dose calculation and analysis of 3D maps was carried out. RESULTS: The tuning process of the MC model provides good results, as the maximum value of the root mean square deviation (RMSD) was less than 3% between the MC simulated PDDs and the measured PDDs. The contouring and dose analysis review were easy to conduct for the classical treatment planning system. The radiation oncologist had many tools for dose analysis such as DVH and color wash for all the slides. Summation of the 3D dose of IOERT with other radiotherapy plans is possible and helpful for total dose estimation. Archiving and documentation is as good as treatment planning system (TPS). CONCLUSIONS: The method displayed in this paper provides a step forward for IOERT Dosimetry and allows to obtain accurate dosimetry of treated volumes.

Shielding disk position in intra-operative electron radiotherapy (IOERT): A Monte Carlo study.

PURPOSE: In IOERT breast treatments, a shielding disk is frequently used to protect the underlying healthy structures. The disk is usually composed of two materials, a low-Z material intended to be oriented towards the beam and a high-Z material. As tissues are repositioned around the shield before treatment, the disk is no longer visible and its correct alignment with respect to the beam is guaranteed. This paper studies the dosimetric characteristics of four possible clinical positioning scenarios of the shielding disk. A new alignment method for the shielding disk in the beam is introduced. Finally, it suggests a new design for the shielding disk. METHODS: As the first step, the IOERT machine "Mobetron 1000" was modeled by using Monte Carlo simulation, tuning the MC model until an excellent match with the measured PDDs and profiles was achieved. Four possible shielding disk positioning scenarios were considered, determining the dosimetric impact. Furthermore, in our center, to prevent beam misalignment, we have developed a shielding disk equipped with guiding rods. Having ascertained a correct alignment between the disk and the beam, we can propose a new internal design of the shielding disk that can improve the dose distribution with a better coverage of the treated area. RESULTS: All MC simulations were performed with a 12 MeV beam, the maximum energy of Mobetron 1000 and a 5.5 cm diameter flat tip applicator, this applicator being the most clinically used. The simulations were compared with measurements performed in a water phantom and showed good results within 2.2% of root mean square difference (RMSD). The misplacement positions of the shielding disk have dosimetric impacts in the treatment volume and a small translation could have a significant influence on healthy tissues. The D-scenario is the worst which could happens when the shielding disk is flipped upside down, giving up to 144% dose instead of 90% at the surface of the Pb/Al shielding disk. A new shielding design used, together with our alignment tool, is able to give a more homogeneous dose in the target area. CONCLUSIONS: The accuracy of shielding disk position can still be problematic in IOERT dosimetry. Any method that can ascertain the good alignment between the shielding disk and the beam is beneficial for the dose distribution and is a prerequisite for an optimized shield internal design that could improve the coverage of the treated area and the protection of healthy tissues.

Abstract ID: 222 Clinical implementation of a Monte Carlo based QA platform for validation of Tomotherapy and Cyberknife treatment plans.

INTRODUCTION: This work describes the clinical implementation of a Monte Carlo based platform for treatment plan validation for Tomotherapy and Cyberknife, including a semi-automatic plan evaluation module based on dose constraints for organs-at-risk (OAR). METHODS: The Monte Carlo-based platform Moderato [1] is based on BEAMnrc/DOSXYZnrc and allows for automated re-calculation of doses planned with Tomotherapy and Cyberknife techniques. The Prescription/Validation module generates a set of dose constraints based on the anatomical region and fractionation scheme considered. Upon achievement of the planning, dose results are displayed with visual warnings in case of constraint violation. The system was tested on 83 patient cases in order to evaluate the influence of difference in calculation algorithms on OAR constraints. RESULTS: The first results with the Tomotherapy plans allowed for detecting and correcting a problem with the CT Hounsfield units when using a large reconstruction diameter (a CT artifact that lead to air voxels with an overestimated density). The Cyberknife results also showed some dose differences associated with different energy thresholds between Moderato and the Monte Carlo algorithm used in the Treatment Planning Station. Regarding OAR constraints, re-calculation generated few violations in thoracic, pelvic and abdominal cases. However, in spinal and head cases, significant differences can appear (-11% to +6%) on optic pathways and spinal cord, leading to doses above the limits. CONCLUSIONS: The Moderato platform constitutes a promising tool for the validation of plan quality, offering both dose re-calculation and OAR constraints evaluation. First results show the importance of this verification for some specific regions. Further work is ongoing to optimize the quantity and relevance of the information displayed, before fully introducing the system in clinical routine.