Ultra-hypofractionated prostate cancer radiotherapy: Dosimetric impact of real-time intrafraction prostate motion and daily anatomical changes.

PURPOSE: To retrospectively assess the differences between planned and delivered dose during ultra-hypofractionated (UHF) prostate cancer treatments, by evaluating the dosimetric impact of daily anatomical variations alone, and in combination with prostate intrafraction motion. METHODS: Prostate intrafraction motion was recorded with a transperineal ultrasound probe in 15 patients treated by UHF radiotherapy (36.25 Gy/5 fractions). The dosimetric objective was to cover 99 % of the clinical target volume with the 100 % prescription isodose line. After treatment, planning CT (pCT) images were deformably registered onto daily Cone Beam CT to generate pseudo-CT for dose accumulation (accumulated CT, aCT). The interplay effect was accounted by synchronizing prostatic shifts and beam geometry. Finally, the shifted dose maps were accumulated (moved-accumulated CT, maCT). RESULTS: No significant change in daily CTV volumes was observed. Conversely, CTV V100% was 98.2 ± 0.8 % and 94.7 ± 2.6 % on aCT and maCT, respectively, compared with 99.5 ± 0.2 % on pCT (p < 0.0001). Bladder volume was smaller than planned in 76 % of fractions and D5cc was 33.8 ± 3.2 Gy and 34.4 ± 3.4 Gy on aCT (p = 0.02) and maCT (p = 0.01) compared with the pCT (36.0 ± 1.1 Gy). The rectum was smaller than planned in 50.3 % of fractions, but the dosimetric differences were not statistically significant, except for D1cc, found smaller on the maCT (33.2 ± 3.2 Gy, p = 0.02) compared with the pCT (35.3 ± 0.7 Gy). CONCLUSIONS: Anatomical variations and prostate movements had more important dosimetric impact than anatomical variations alone, although, in some cases, the two phenomena compensated. Therefore, an efficient IGRT protocol is required for treatment implementation to reduce setup errors and control intrafraction motion.

Evaluation of a dedicated software for semi-automated VMAT planning of spine Stereotactic Body Radiotherapy (SBRT).

PURPOSE: To determine whether SBRT of spinal metastasis using a dedicated treatment planning system (TPS) and delivered with a gantry-based LINAC could provide plans of similar quality to the Cyberknife technology. Additional comparison was also done with other commercial TPS used for volumetric modulated arc therapy (VMAT) planning. MATERIALS AND METHODS: Thirty Spine SBRT patients, previously treated in our institution with CyberKnife (Accuray, Sunnyvale) using Multiplan TPS, were replanned in VMAT with an dedicated TPS (Elements Spine SRS, Brainlab, Munich) and our clinical TPS (Monaco, Elekta LTD, Stockholm), using exactly the same arc geometry. The comparison was done by assessing differences in dose delivered to PTV, CTV and spinal cord, calculating modulation complexity scores (MCS) and performing quality control (QA) of the plans. RESULTS: Regardless of the vertebra level, in general, no statistical difference was found in PTV coverage between all TPS. Conversely, PTV and CTV D50% were found significantly higher for the dedicated TPS compared to others. In addition, the dedicated TPS also resulted in better gradient index (GI) than clinical VMAT TPS, whatever the vertebral level, and better GI than Cyberknife TPS for the thoracic level only. The D2% to the spinal cord was generally significantly lower with the dedicated TPS compared with others. No significant difference was found in the MCS between both VMAT TPS. All QA were clinically acceptable. CONCLUSION: The Elements Spine SRS TPS offers very effective and user-friendly semi-automated planning tools and is secure and promising for gantry-based LINAC spinal SBRT.

Evaluation of different algorithms for automatic segmentation of head-and-neck lymph nodes on CT images.

PURPOSE: To investigate the performance of 4 atlas-based (multi-ABAS) and 2 deep learning (DL) solutions for head-and-neck (HN) elective nodes (CTVn) automatic segmentation (AS) on CT images. MATERIAL AND METHODS: Bilateral CTVn levels of 69 HN cancer patients were delineated on contrast-enhanced planning CT. Ten and 49 patients were used for atlas library and for training a mono-centric DL model, respectively. The remaining 20 patients were used for testing. Additionally, three commercial multi-ABAS methods and one commercial multi-centric DL solution were investigated. Quantitative evaluation was assessed using volumetric Dice Similarity Coefficient (DSC) and 95-percentile Hausdorff distance (HD95%). Blind evaluation was performed for 3 solutions by 4 physicians. One recorded the time needed for manual corrections. A dosimetric study was finally conducted using automated planning. RESULTS: Overall DL solutions had better DSC and HD95% results than multi-ABAS methods. No statistically significant difference was found between the 2 DL solutions. However, the contours provided by multi-centric DL solution were preferred by all physicians and were also faster to correct (1.1 min vs 4.17 min, on average). Manual corrections for multi-ABAS contours took on average 6.52 min Overall, decreased contour accuracy was observed from CTVn2 to CTVn3 and to CTVn4. Using the AS contours in treatment planning resulted in underdosage of the elective target volume. CONCLUSION: Among all methods, the multi-centric DL method showed the highest delineation accuracy and was better rated by experts. Manual corrections remain necessary to avoid elective target underdosage. Finally, AS contours help reducing the workload of manual delineation task.

Practical and technical key challenges in head and neck adaptive radiotherapy: The GORTEC point of view.

Anatomical variations occur during head and neck (H&N) radiotherapy (RT) treatment. These variations may result in underdosage to the target volume or overdosage to the organ at risk. Replanning during the treatment course can be triggered to overcome this issue. Due to technological, methodological and clinical evolutions, tools for adaptive RT (ART) are becoming increasingly sophisticated. The aim of this paper is to give an overview of the key steps of an H&N ART workflow and tools from the point of view of a group of French-speaking medical physicists and physicians (from GORTEC). Focuses are made on image registration, segmentation, estimation of the delivered dose of the day, workflow and quality assurance for an implementation of H&N offline and online ART. Practical recommendations are given to assist physicians and medical physicists in a clinical workflow.

Comparison of atlas-based and deep learning methods for organs at risk delineation on head-and-neck CT images using an automated treatment planning system.

BACKGROUND AND PURPOSE: To investigate the performance of head-and-neck (HN) organs-at-risk (OAR) automatic segmentation (AS) using four atlas-based (ABAS) and two deep learning (DL) solutions. MATERIAL AND METHODS: All patients underwent iodine contrast-enhanced planning CT. Fourteen OAR were manually delineated. DL.1 and DL.2 solutions were trained with 63 mono-centric patients and > 1000 multi-centric patients, respectively. Ten and 15 patients with varied anatomies were selected for the atlas library and for testing, respectively. The evaluation was based on geometric indices (DICE coefficient and 95th percentile-Hausdorff Distance (HD95%)), time needed for manual corrections and clinical dosimetric endpoints obtained using automated treatment planning. RESULTS: Both DICE and HD95% results indicated that DL algorithms generally performed better compared with ABAS algorithms for automatic segmentation of HN OAR. However, the hybrid-ABAS (ABAS.3) algorithm sometimes provided the highest agreement to the reference contours compared with the 2 DL. Compared with DL.2 and ABAS.3, DL.1 contours were the fastest to correct. For the 3 solutions, the differences in dose distributions obtained using AS contours and AS + manually corrected contours were not statistically significant. High dose differences could be observed when OAR contours were at short distances to the targets. However, this was not always interrelated. CONCLUSION: DL methods generally showed higher delineation accuracy compared with ABAS methods for AS segmentation of HN OAR. Most ABAS contours had high conformity to the reference but were more time consuming than DL algorithms, especially when considering the computing time and the time spent on manual corrections.

Minimum non-isotropic and asymmetric margins for taking into account intrafraction prostate motion during moderately hypofractionated radiotherapy.

PURPOSE: To investigate the impact on dose distribution of intrafraction motion during moderate hypofractionated prostate cancer treatments and to estimate minimum non-isotropic and asymmetric (NI-AS) treatment margins taking motion into account. METHODS: Prostate intrafraction 3D displacements were recorded with a transperineal ultrasound probe and were evaluated in 46 prostate cancer patients (876 fractions) treated by moderate hypofractionated radiation therapy (60 Gy in 20 fractions). For 18 patients (346 fractions), treatment plans were recomputed increasing CTV-to-PTV margins from 0 to 6 mm with an auto-planning optimization algorithm. Dose distribution was estimated using the voxel shifting method by displacing CTV structure according to the retrieved movements. Time-dependent margins were finally calculated using both van Herk's formula and the voxel shifting method. RESULTS: Mean intrafraction prostate displacements observed were -0.02 ± 0.52 mm, 0.27 ± 0.78 mm and -0.43 ± 1.06 mm in left-right, supero-inferior and antero-posterior directions, respectively. The CTV dosimetric coverage increased with increased CTV-to-PTV margins but it decreased with time. Hence using van Herk's formula, after 7 min of treatment, a margin of 0.4 and 0.5 mm was needed in left and right, 1.5 and 0.7 mm in inferior and superior and 1.1 and 3.2 mm in anterior and posterior directions, respectively. Conversely, using the voxel shifting method, a margin of 0 mm was needed in left-right, 2 mm in superior, 3 mm in inferior and anterior and 5 mm in posterior directions, respectively. With this latter NI-AS margin strategy, the dosimetric target coverage was equivalent to the one obtained with a 5 mm homogeneous margin. CONCLUSIONS: NI-AS margins would be required to optimally take into account intrafraction motion.

Highly hypofractionated schedules for localized prostate cancer: Recommendations of the GETUG radiation oncology group.

Stereotactic body radiotherapy (SBRT) has become treatment option for localized prostate cancer but the evidence base remains incomplete. Several clinical studies, both prospective and retrospective, have been published. However, treatment techniques, target volumes and dose constraints lack consistency between studies. Based on the current available literature, the French Genito-Urinary Group (GETUG) suggests that.

Evaluation of fully automated a priori MCO treatment planning in VMAT for head-and-neck cancer.

PURPOSE: Automated planning techniques aim to reduce manual planning time and inter-operator variability without compromising the plan quality which is particularly challenging for head-and-neck (HN) cancer radiotherapy. The objective of this study was to evaluate the performance of an a priori-multicriteria plan optimization algorithm on a cohort of HN patients. METHODS: A total of 14 nasopharyngeal carcinoma (upper-HN) and 14 "middle-lower indications" (lower-HN) previously treated in our institution were enrolled in this study. Automatically generated plans (autoVMAT) were compared to manual VMAT or Helical Tomotherapy planning (manVMAT-HT) by assessing differences in dose delivered to targets and organs at risk (OARs), calculating plan quality indexes (PQIs) and performing blinded comparisons by clinicians. Quality control of the plans and measurements of the delivery times were also performed. RESULTS: For the 14 lower-HN patients, with equivalent planning target volume (PTV) dosimetric criteria and dose homogeneity, significant decrease in the mean doses to the oral cavity, esophagus, trachea and larynx were observed for autoVMAT compared to manVMAT-HT. Regarding the 14 upper-HN cases, the PTV coverage was generally significantly superior for autoVMAT which was also confirmed with higher calculated PQIs on PTVs for 13 out of 14 patients, whereas PQIs calculated on OARs were generally equivalent. Number of MUs and total delivery time were significantly higher for autoVMAT compared to manVMAT. All plans were considered clinically acceptable by clinicians. CONCLUSIONS: Overall superiority of autoVMAT compared to manVMAT-HT plans was demonstrated for HN cancer. The obtained plans were operator-independent and required no post-optimization or manual intervention.

Head and neck sarcoma: report of a case treated by intensity-modulated radiation therapy.

We report on a 71-year-old woman with parapharyngeal sarcoma. Surgery could not be performed because of the size and location of the tumor. After failure of four cycles of chemotherapy, intensity-modulated radiation therapy (IMRT) achieved complete clinical response and partial magnetic resonance imaging response (80%) at 24 months of follow-up. The results of radiotherapy, especially IMRT, for nonresectable head and neck soft tissue sarcoma are discussed.

Comparison among four immobilization devices for whole breast irradiation with Helical Tomotherapy.

PURPOSE: To evaluate the repositioning accuracy of 4 immobilization devices (ID) used for whole breast Helical Tomotherapy treatments: arm float with VacFix® (Par Scientific, Denmark), all-in-one® (AIO®) system (Orfit, Belgium), MacroCast thermoplastic mask (Macromedics, The Netherlands) and BlueBag® system with Arm-Shuttle (Elekta, Sweden). MATERIALS AND METHODS: Twenty four women with breast cancer with PTV including the breast/chest wall and lymph nodes were involved in this study (6 women per group). Pretreatment registration results were first collected using automatic bone registration + manual adjustment on the vertebra followed by independent registrations on different ROIs representing each treated area (axillary, mammary chain, clavicular, breast/chest wall). The differences in translations and rotations between reference registration and the above mentionned ROIs were calculated. A total of 120 MVCT images were analyzed. RESULTS: Significant differences were found between IDs (p < 0.0001), ROIs (p = 0.0002) and the session number (p < 0.0001) on the observed shifts, when examining 3D translation vectors. 3D-vectors were significantly lower for the BlueBag® than for the VacFix® or for the AIO® (p < 0.0001), but differences were not significant compared to the mask (p = 0.674). Finally, setup margins were overall smaller for the BlueBag® than for other IDs, with values ranging from 1.53 to 1.91 mm on the mammary chain area, 4.52-6.07 mm on the clavicular area, 2.71-4.62 mm on the axillary area, and 3.39-5.10 mm on the breast. CONCLUSION: We demonstrated in this study that the BlueBag® combined with arm shuttle is a robust solution for breast and nodes immobilization during HT treatments.

In vitro and in vivo optimization of an anti-glioma modality based on synchrotron X-ray photoactivation of platinated drugs.

For the past 5 years, a radio-chemotherapy approach based on the photoactivation of platinum atoms (PAT-Plat) consisting of treating tumors with platinated compounds and irradiating them above the platinum K edge (78.4 keV) has been developed at the European Synchrotron Radiation Facility (Grenoble, France). Compared to other preclinical modalities, PAT-Plat provides the highest survivals of rats bearing the rodent F98 glioma. However, further investigations are required to optimize its efficiency and to allow its clinical application. Here we examined in vitro and in vivo whether monochromatic X rays are more efficient than high-energy photons in producing the PAT-Plat effect by measuring DNA double-strand breaks (DSBs) and survival of glioma-bearing rats and whether an increase in the platinum concentration in the tumor results in increased rat survival. DSBs were assessed by pulsed-field gel electrophoresis with different DNA fragment migration programs and with gamma-H2AX immunofluorescence. In vivo, F98 glioma cells were injected intracerebrally, treated with a single intracranial injection of cisplatin or carboplatin 13 days after tumor implantation, and irradiated the day after with 78.8 keV X rays or 6 MV photons. Our results indicate that 78.8 keV X rays are more efficient than high-energy photons at producing the PAT-Plat effect. At low concentrations, cisplatin is more efficient than carboplatin; this is likely due to more efficient DNA binding and DSB repair inhibition. High concentrations of carboplatin inside tumors do not necessarily lead to protracted survival of rats. The therapeutic benefit of anti-glioma synchrotron strategies appears to be correlated with the percentage of unrepaired DSBs but not with the number of DSBs induced.

Comparison of electromagnetic transmitter and ultrasound imaging for intrafraction monitoring of prostate radiotherapy.

BACKGROUND AND PURPOSE: To compare two in-beam monitoring devices for prostate radiotherapy: intra-prostatic electromagnetic transmitters (EM-T) (RayPilot®, Micropos Medical) and ultrasound imaging using transperineal probe (TP-US) (Clarity®, Elekta) used concomitantly on phantom and on patients. MATERIALS AND METHODS: The phantom study evaluated accuracy in presence of known translations and rotations. Then intra-fraction motions were analyzed for 10 prostate cancer patients implanted with the EM-T 8 days before the simulation CT (171 sessions). The percent time in which the differences between the systems were 1-5 mm were scored for each direction. RESULTS: Experiments on phantom confirmed no interference between the systems and showed deviations of less than 0.5 mm when translations were applied progressively. In presence of rotations (5-15°), both systems displayed systematic shifts up to 6.9 and 3.8 mm for the TP-US and the EM-T, respectively. Absolute mean differences between displacements observed on patients with EM-T and TP-US were ≤0.55 mm in all directions except for one patient (≤1.77 mm). With an exception for this patient, a strong correlation was found in left-right direction: differences >2 mm were monitored less than 0.22% of the time (mean acquisition time:164 minutes) and never exceeded 5 s. Maximum differences were observed in supero-inferior direction with differences >2 mm monitored more than 6.5% of the time for 3 patients. Large prostate rotations, the presence of gas and EM-T location in the prostate may explain important differences. CONCLUSION: Apart from the systematic shifts induced by the rotations, the two systems were correlated and represent feasible solutions for monitoring prostate cancer treatment.

Influence of Linear Energy Transfer on the Nucleo-shuttling of the ATM Protein: A Novel Biological Interpretation Relevant for Particles and Radiation.

PURPOSE: Linear energy transfer (LET) plays an important role in radiation response. Recently, the radiation-induced nucleo-shuttling of ATM from cytoplasm to the nucleus was shown to be a major event of the radiation response that permits a normal DNA double-strand break (DSB) recognition and repair. Here, we aimed to verify the relevance of the ATM nucleo-shuttling model for high-LET particles and various radiation types. METHODS AND MATERIALS: ATM- and H2AX-immunofluorescence was used to assess the number of recognized and unrepaired DSB in quiescent fibroblast cell lines exposed to x-rays, γ-rays, 9- and 12-MeV electrons, 3- and 65-MeV protons and 75-MeV/u carbon ions. RESULTS: The rate of radiation-induced ATM nucleo-shuttling was found to be specific to each radiation type tested. By increasing the permeability of the nuclear membrane with statin and bisphosphonates, 2 fibroblast cell lines exposed to high-LET particles were shown to be protected by an accelerated ATM nucleo-shuttling. CONCLUSIONS: Our findings are in agreement with the conclusion that LET and the radiation/particle type influence the formation of ATM monomers in cytoplasm that are required for DSB recognition. A striking analogy was established between the DSB repair kinetics of radioresistant cells exposed to high-LET particles and that of several radiosensitive cells exposed to low-LET radiation. Our data show that the nucleo-shuttling of ATM provides crucial elements to predict radiation response in human quiescent cells, whatever the LET value and their radiosensitivity.

DNA breaks induced by iodine-containing contrast medium in radiodiagnostics: a problem of tungsten?

Iodine-containing contrast media (ICM) are extensively used to improve image quality and information content in x-ray-based examinations, particularly in computed tomography (CT). In parallel, there is increasing evidence that the use of ICM during CT sessions is associated with deoxyribonucleic acid (DNA) breaks that may influence the estimation of the risks linked to x-ray exposure. Why has iodine been preferred to any other heavy elements to enhance contrast in radiodiagnostics? How to understand such DNA breaks effect? We searched for the answers in the early times of x-ray medical use. It appeared that the maximal ratio between the relative iodine and water mass energy absorption coefficients is reached in the range of 40-60 keV, which defines the energy range in which the dose is preferentially absorbed by ICM. This range does not correspond to the K-edge of iodine but to that of tungsten, the major component of the x-ray tube anode of CT scanners. At such energy, radiolysis of the ICM produces sodium or potassium iodide that prevents a normal DNA breaks repair and influences the individual response to x-ray low-dose. Both contrast enhancement and DNA breaks effect may therefore be caused by tungsten of the anodes of x-ray tubes.

Prolonged survival of Fischer rats bearing F98 glioma after iodine-enhanced synchrotron stereotactic radiotherapy.

PURPOSE: Heavy-atom-enhanced synchrotron stereotactic radiotherapy (SSR) is a treatment that involves selective accumulation of high-Z elements in tumors followed by stereotactic irradiation with X-rays from a synchrotron source. The purpose of this study was to determine whether the efficacy of iodine-enhanced SSR could be further improved in the F98 rodent glioma model, by using a concomitant injection of an iodinated contrast agent and a transient blood-brain barrier opener (mannitol) during irradiation. METHODS AND MATERIALS: Fourteen days after intracerebral inoculations of F98 cells, the rats were irradiated with 50-keV X-rays while receiving an infusion of hyperosmotic mannitol with iodine, either intravenously or via the carotid (9 to 15 rats per group, 117 rats total). RESULTS: For doses

Cure of Fisher rats bearing radioresistant F98 glioma treated with cis-platinum and irradiated with monochromatic synchrotron X-rays.

High-grade gliomas are usually of poor prognosis, and conventional radiotherapy, even combined with chemotherapy, still fails to improve the survival of patients. Here, we propose an innovative therapeutic approach combining synchrotron radiation with cis-diamminedichloroplatinum (II) (CDDP). As suggested previously, monochromatic synchrotron irradiation of CDDP at 78.8 keV, just above the 78.4 keV platinum absorption K-edge, leads to an enhanced photoelectric effect and an increased local toxicity. To select a particular radiation energy that could provide supra-additive effect, we used pulsed-field gel electrophoresis to assess yields of DNA double-strand breaks induced in rat F98 glioma cells after CDDP treatment combined with synchrotron X-rays. Thereafter, intracerebral CDDP injection combined with synchrotron X-rays was applied to Fisher rats bearing F98 glioma. CDDP concentrations were mapped by synchrotron X-ray microfluorescence. An extra number of more slowly repaired double strand breaks were observed when irradiating CDDP-treated F98 cells at 78.8 keV. In vivo treatments were then performed with different radiation doses and CDDP concentrations. All cell inoculations in rat brain resulted in tumor development, and tumor presence was controlled by computed tomography. Among all of the conditions tested, the combination of 3 micro g of CDDP with 15 Gy resulted in the largest median survival time (206 days). After 1 year, about 34% of treated rats were still alive. This preclinical finding, validated by molecular analysis, represents the most protracted survival reported with this radioresistant glioma model and demonstrates the interest in powerful monochromatic X-ray sources as new tools for cancer treatments.

Synchrotron photoactivation of cisplatin elicits an extra number of DNA breaks that stimulate RAD51-mediated repair pathways.

Combination of cis-platinum with ionizing radiation is one of the most promising anticancer treatments that appears to be more efficient than radiotherapy alone. Unlike conventional X-ray emitters, accelerators of high energy particles like synchrotrons display powerful and monochromatizable radiation that makes the induction of an Auger electron cascade in cis-platinum molecules [also called photoactivation of cis-platinum (PAT-Plat)] theoretically possible. Here, we examined the molecular consequences of one of the first attempts of synchrotron PAT-Plat, performed at the European Synchrotron Research Facility (Grenoble-France). PAT-Plat was found to result in an extra number of slowly repairable DNA double-strand breaks, inhibition of DNA-protein kinase activity, dramatic nuclear relocalization of RAD51, hyperphosphorylation of the BRCA1 protein, and activation of proto-oncogenic c-Abl tyrosine kinase.

Evaluation of a new transperineal ultrasound probe for inter-fraction image-guidance for definitive and post-operative prostate cancer radiotherapy.

PURPOSE: The aim of this study was to evaluate a new system based on transperineal ultrasound (TP-US) acquisitions for prostate and post-prostatectomy pre-treatment positioning by comparing this device to cone-beam computed tomography (CBCT). METHODS: The differences between CBCT/CT and TP-US/TP-US registrations were analyzed on 427 and 453 sessions for 13 prostate and 14 post-prostatectomy patients, respectively. The inter-operator variability (IOV) of the registration process, and the impact and variability of the probe pressure were also evaluated. RESULTS: CBCT and TP-US shift agreements at ± 5 mm were 76.6%, 95.1%, 96.3% and 90.3%, 85.0%, 97.6% in anterior-posterior, superior-inferior and left-right directions, for prostate and post-prostatectomy patients, respectively. IOV values were similar between the 2 modalities. Displacements above 5 mm due to strong pressures were observed on both localizations, but such pressures were rarely reproduced during treatment courses. CONCLUSIONS: High concordance between CBCT/CT and TP-US/TP-US localization of prostates or prostatic beds was found in this study. TP-US based prepositioning is a feasible method to ensure accurate treatment delivery, and represents an attractive alternative to invasive and/or irradiating imaging modalities.