Peripheral blood lymphocytes differ in DNA damage response after exposure to X-rays with different physical properties.

Introduction: In radiology, low X-ray energies (<140 keV) are used to obtain an optimal image while in radiotherapy, higher X-ray energies (MeV) are used to eradicate tumor tissue. In radiation research, both these X-ray energies being used to extrapolate in vitro research to clinical practice. However, the energy deposition of X-rays depends on their energy spectrum, which might lead to changes in biological response. Therefore, this study compared the DNA damage response (DDR) in peripheral blood lymphocytes (PBLs) exposed to X-rays with varying beam quality, mean photon energy (MPE) and dose rate.Methods: The DDR was evaluated in peripheral blood lymphocytes (PBLs) by the É£-H2AX foci assay, the cytokinesis-block micronucleus assay and an SYTOX-based cell death assay, combined with specific cell death inhibitors. Cell cultures were irradiated with a 220 kV X-ray research cabinet (SARRP, X-Strahl) or a 6 MV X-ray linear accelerator (Elekta Synergy). Three main physical parameters were investigated: beam quality (V), MPE (eV) and dose rate (Gy/min). Additional copper (Cu) filtration caused variation in the MPE (78 keV, 94 keV, 118 keV) at SARRP; dose rates were varied by adjusting tube current for 220 kV X-rays (0.33-3 Gy/min) or water-phantom depth in the 6 MV set-up (3-6 Gy/min).Results: The induction of chromosomal damage and initial (30 min) DNA double-stranded breaks (DSBs) were significantly higher for 220 kV X-rays compared to 6 MV X-rays, while cell death induction was similar. Specific cell death inhibitors for apoptosis, necroptosis and ferroptosis were not capable of blocking cell death after irradiation using low or high-energy X-rays. Additional Cu filtration increased the MPE, which significantly decreased the amount of chromosomal damage and DSBs. Within the tested ranges no specific effects of dose rate variation were observed.Conclusion: The DDR in PBLs is influenced by the beam quality and MPE. This study reinforces the need for consideration and inclusion of all physical parameters in radiation-related studies.

Microbiome and metabolome dynamics during radiotherapy for prostate cancer.

BACKGROUND: Prostate cancer patients treated with radiotherapy are susceptible to acute gastrointestinal (GI) toxicity due to substantial overlap of the intestines with the radiation volume. Due to their intimate relationship with GI toxicity, faecal microbiome and metabolome dynamics during radiotherapy were investigated. MATERIAL & METHODS: This prospective study included 50 prostate cancer patients treated with prostate (bed) only radiotherapy (PBRT) (n = 28) or whole pelvis radiotherapy (WPRT) (n = 22) (NCT04638049). Longitudinal sampling was performed prior to radiotherapy, after 10 fractions, near the end of radiotherapy and at follow-up. Patient symptoms were dichotomized into a single toxicity score. Microbiome and metabolome fingerprints were analyzed by 16S rRNA gene sequencing and ultra-high-performance liquid chromatography hybrid high-resolution mass spectrometry, respectively. RESULTS: The individual α-diversity did not significantly change over time. Microbiota composition (ß-diversity) changed significantly over treatment (PERMANOVA p-value = 0.03), but there was no significant difference in stability when comparing PBRT versus WPRT. Levels of various metabolites were significantly altered during radiotherapy. Baseline α-diversity was not associated with any toxicity outcome. Based on the metabolic fingerprint, no natural clustering according to toxicity profile could be achieved. CONCLUSIONS: Radiation dose and treatment volume demonstrated limited effects on microbiome and metabolome fingerprints. In addition, no distinctive signature for toxicity status could be established. There is an ongoing need for toxicity risk stratification tools for diagnostic and therapeutic purposes, but the current evidence implies that the translation of metabolic and microbial biomarkers into routine clinical practice remains challenging.

Impact of proton therapy on the DNA damage induction and repair in hematopoietic stem and progenitor cells.

Proton therapy is of great interest to pediatric cancer patients because of its optimal depth dose distribution. In view of healthy tissue damage and the increased risk of secondary cancers, we investigated DNA damage induction and repair of radiosensitive hematopoietic stem and progenitor cells (HSPCs) exposed to therapeutic proton and photon irradiation due to their role in radiation-induced leukemia. Human CD34+ HSPCs were exposed to 6 MV X-rays, mid- and distal spread-out Bragg peak (SOBP) protons at doses ranging from 0.5 to 2 Gy. Persistent chromosomal damage was assessed with the micronucleus assay, while DNA damage induction and repair were analyzed with the γ-H2AX foci assay. No differences were found in induction and disappearance of γ-H2AX foci between 6 MV X-rays, mid- and distal SOBP protons at 1 Gy. A significantly higher number of micronuclei was found for distal SOBP protons compared to 6 MV X-rays and mid- SOBP protons at 0.5 and 1 Gy, while no significant differences in micronuclei were found at 2 Gy. In HSPCs, mid-SOBP protons are as damaging as conventional X-rays. Distal SOBP protons showed a higher number of micronuclei in HSPCs depending on the radiation dose, indicating possible changes of the in vivo biological response.

Accuracy and reliability of a commercial treatment planning system in nontarget regions in modern prostate radiotherapy.

BACKGROUND: The currently available treatment planning systems (TPSs) are neither designed nor intended for accurate dose calculations in nontarget regions. The aim of this work is to quantify the accuracy and reliability of nontarget doses calculated by a commercially available TPS. METHODS: Nontarget doses calculated by the collapsed cone (CC) (v5.2) algorithm implemented in the RayStation (v6) TPS were compared to measured values. Different scenarios were investigated, from simple static fields to intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) treatment plans. Deviations and confidence limits (CLs) were calculated between results of calculations and measurements-applying both local (δ) and global (Δ) normalization-for various points of interest (POIs). Results were based on a single-institution experience for one clinical test case (prostate) and evaluated against internationally accepted criteria. RESULTS: Overall, the TPS underestimated the nontarget dose by an average of -17.7% ± 25.3% for IMRT. Quantitatively similar results were obtained for VMAT (-17.6% ± 21.2%). POIs receiving < 5% of the prescription dose were significantly underestimated by the TPS (p-value < 0.05 for both IMRT and VMAT). Dose calculation accuracy was also determined by the contribution of secondary radiation, with measured doses for out-of-field POIs being significantly different from calculated values (p-value < 0.01 for both IMRT and VMAT). Although the CLδ in nontarget regions failed the proposed tolerance criteria (40%) for both IMRT (68.8%) and VMAT (52.6%), the CLΔ was within the tolerance limit (4%) for both treatment techniques (1.9% for IMRT and 1.3% for VMAT). No action levels (7%) were exceeded. CONCLUSIONS: Based on the currently available benchmarks our TPS is considered acceptable for clinical use, although the dose in some POIs was poorly predicted by the CC algorithm. Some areas were pointed out where TPSs and linear accelerator control systems can be improved.

Measurement-based validation of a commercial Monte Carlo dose calculation algorithm for electron beams.

PURPOSE: This work presents the clinical validation of RayStation's electron Monte Carlo code by the use of diodes and plane parallel radiation detectors in homogenous and heterogeneous tissues. Results are evaluated against internationally accepted criteria. METHODS: The Monte Carlo-based electron beam dose calculation code was validated using diodes, air- and liquid-filled parallel radiation detectors on an Elekta linac with beam energies of 4, 6, 8, 10, and 12 MeV. Treatment setups with varying source-to-skin distances, different applicators, various cutouts, and oblique beam incidences were addressed, together with dose prediction behind lung-, air-, and bone-equivalent inserts. According to NCS (Netherlands Commission for Radiation Dosimetry) report 15 for nonstandard treatment setups, a dose agreement of 3% in the δ1 region (high-dose region around Zref ), a distance-to-agreement (DTA) of 3 mm or a dose agreement of 10% in the δ2 region (regions with high-dose gradients), and 4% in the δ4 region (photon tail/low-dose region) were applied. During validation, clinical routine settings of 2 × 2 × 2-mm3 dose voxels and a statistically dose uncertainty of 0.6% (250 000 histories/cm2 ) were used. RESULTS: RayStation's electron Monte Carlo code dose prediction was able to achieve the tolerances of NCS report 15. Output predictions as a function of the SSD improve with energy and applicator size. Cutout data revealed no field size or energy dependence on the accuracy of the dose prediction. Excellent agreement for the oblique incidence data was achieved and a maximum of one voxel difference was obtained for the DTA behind heterogeneous inserts. CONCLUSIONS: The accuracy of RayStation's Monte Carlo-based electron beam dose prediction for Elekta accelerators is confirmed for clinical treatment planning that is not only performed within an acceptable timeframe in terms of the number of histories but also addresses for homogenous and heterogeneous media.

Impact of radiotherapy parameters on the risk of lymphopenia in urological tumors: A systematic review of the literature.

BACKGROUND: We investigated how radiotherapy (RT) parameters may contribute to the risk of lymphopenia in urological tumors and we discussed how this may impact clinical outcomes. MATERIAL & METHODS: A systematic review was performed according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. The PubMed, Embase and ISI Web Of Knowledge databases were searched. Study quality was assessed according to the Newcastle-Ottawa Scale. RESULTS: Overall, 8 articles reporting on a total of 549 urological cancer patients met the inclusion criteria. The pooled mean incidence of acute severe lymphopenia (absolute lymphocyte count < 500 cells/µL) was 17.1%. Extended radiation volumes may lead to an increased risk of developing lymphopenia. Medium-high doses (≥ 40 Gy) to the whole pelvic (odds ratio (OR) = 1.01; 95% confidence interval (CI) 1.00-1.01; p = 0.025) and iliac (OR = 1.04; 95% CI 1.01-1.08; p = 0.009) bone marrow (BM) were associated with acute grade 3 and late grade 2 lymphopenia, respectively. CONCLUSION: Multiple studies reported high and severe incidences of lymphopenia. Minimizing radiation volumes and unintentional irradiation of pelvic BM may reduce the incidence of lymphopenia, potentially improving clinical outcomes. More research is needed to further elucidate these findings and effectively implement recently developed new risk assessment tools.

A comparative analysis of Acuros XB and the analytical anisotropic algorithm for volumetric modulation arc therapy.

BACKGROUND: This study aimed to verify the dosimetric impact of Acuros XB (AXB) (AXB, Varian Medical Systems Palo Alto CA, USA), a two model-based algorithm, in comparison with Anisotropic Analytical Algorithm (AAA ) calculations for prostate, head and neck and lung cancer treatment by volumetric modulated arc therapy (VMAT ), without primary modification to AA. At present, the well-known and validated AA algorithm is clinically used in our department for VMAT treatments of different pathologies. AXB could replace it without extra measurements. The treatment result and accuracy of the dose delivered depend on the dose calculation algorithm. MATERIALS AND METHOD: Ninety-five complex VMAT plans for different pathologies were generated using the Eclipse version 15.0.4 treatment planning system (TPS). The dose distributions were calculated using AA and AXB (dose-to-water, AXBw and dose-to-medium, AXBm), with the same plan parameters for all VMAT plans. The dosimetric parameters were calculated for each planning target volume (PTV) and involved organs at risk (OA R). The patient specific quality assurance of all VMAT plans has been verified by Octavius®-4D phantom for different algorithms. RESULTS: The relative differences among AA, AXBw and AXBm, with respect to prostate, head and neck were less than 1% for PTV D95%. However, PTV D95% calculated by AA tended to be overestimated, with a relative dose difference of 3.23% in the case of lung treatment. The absolute mean values of the relative differences were 1.1 ± 1.2% and 2.0 ± 1.2%, when comparing between AXBw and AA, AXBm and AA, respectively. The gamma pass rate was observed to exceed 97.4% and 99.4% for the measured and calculated doses in most cases of the volumetric 3D analysis for AA and AXBm, respectively. CONCLUSION: This study suggests that the dose calculated to medium using AXBm algorithm is better than AAA and it could be used clinically. Switching the dose calculation algorithm from AA to AXB does not require extra measurements.

Longitudinal radiomics of cone-beam CT images from non-small cell lung cancer patients: Evaluation of the added prognostic value for overall survival and locoregional recurrence.

BACKGROUND AND PURPOSE: The prognostic value of radiomics for non-small cell lung cancer (NSCLC) patients has been investigated for images acquired prior to treatment, but no prognostic model has been developed that includes the change of radiomic features during treatment. Therefore, the aim of this study was to investigate the potential added prognostic value of a longitudinal radiomics approach using cone-beam computed tomography (CBCT) for NSCLC patients. MATERIALS AND METHODS: This retrospective study includes a training dataset of 141 stage I-IV NSCLC patients and three external validation datasets of 94, 61 and 41 patients, all treated with curative intended (chemo)radiotherapy. The change of radiomic features extracted from CBCT images was summarized as the slope of a linear regression. The CBCT slope-features and CT-extracted features were used as input for a Cox proportional hazards model. Moreover, prognostic performance of clinical parameters was investigated for overall survival and locoregional recurrence. Model performances were assessed using the Kaplan-Meier curves and c-index. RESULTS: The radiomics model contained only CT-derived features and reached a c-index of 0.63 for overall survival and could be validated on the first validation dataset. No model for locoregional recurrence could be developed that validated on the validation datasets. The clinical parameters model could not be validated for either overall survival or locoregional recurrence. CONCLUSION: In this study we could not confirm our hypothesis that longitudinal CBCT-extracted radiomic features contribute to improved prognostic information. Moreover, performance of baseline radiomic features or clinical parameters was poor, probably affected by heterogeneity within and between datasets.

Automated Instead of Manual Treatment Planning? A Plan Comparison Based on Dose-Volume Statistics and Clinical Preference.

PURPOSE: Automated planning aims to speed up treatment planning and improve plan quality. We compared manual planning with automated planning for lung stereotactic body radiation therapy based on dose-volume histogram statistics and clinical preference. METHODS AND MATERIALS: Manual and automated intensity modulated radiation therapy plans were generated for 56 patients by use of software developed in-house and Pinnacle 9.10 Auto-Planning, respectively. Optimization times were measured in 10 patients, and the impact of the automated plan (AP) on the total treatment cost was estimated. For the remaining 46 patients, each plan was checked against our clinical objectives, and a pair-wise dose-volume histogram comparison was performed. Three experienced radiation oncologists evaluated each plan and indicated their preference. RESULTS: APs reduced the average optimization time by 77.3% but only affected the total treatment cost by 3.6%. Three APs and 0 manual plans failed our clinical objectives, and 13 APs and 9 manual plans showed a minor deviation. APs significantly reduced D2% (2% of the volume receives a dose of at least D2%) for the spinal cord, esophagus, heart, aorta, and main stem bronchus (P < .05) while preserving target coverage. The radiation oncologists found >75% of the APs clinically acceptable without any further fine-tuning. CONCLUSIONS: APs may help to create satisfactory treatment plans quickly and effectively. Because critical appraisal by qualified professionals remains necessary, there is no such thing as "fully automated" planning yet.

Absorbed dose measurements in the build-up region of flattened versus unflattened megavoltage photon beams.

This study evaluated absorbed dose measurements in the build-up region of conventional (FF) versus flattening filter-free (FFF) photon beams. The absorbed dose in the build-up region of static 6 and 10MV FF and FFF beams was measured using radiochromic film and extrapolation chamber dosimetry for single beams with a variety of field sizes, shapes and positions relative to the central axis. Removing the flattening filter generally resulted in slightly higher relative build-up doses. No considerable impact on the depth of maximum dose was found.

Radiation-induced lung damage promotes breast cancer lung-metastasis through CXCR4 signaling.

Radiotherapy is a mainstay in the postoperative treatment of breast cancer as it reduces the risks of local recurrence and mortality after both conservative surgery and mastectomy. Despite recent efforts to decrease irradiation volumes through accelerated partial irradiation techniques, late cardiac and pulmonary toxicity still occurs after breast irradiation. The importance of this pulmonary injury towards lung metastasis is unclear. Preirradiation of lung epithelial cells induces DNA damage, p53 activation and a secretome enriched in the chemokines SDF-1/CXCL12 and MIF. Irradiated lung epithelial cells stimulate adhesion, spreading, growth, and (transendothelial) migration of human MDA-MB-231 and murine 4T1 breast cancer cells. These metastasis-associated cellular activities were largely mimicked by recombinant CXCL12 and MIF. Moreover, an allosteric inhibitor of the CXCR4 receptor prevented the metastasis-associated cellular activities stimulated by the secretome of irradiated lung epithelial cells. Furthermore, partial (10%) irradiation of the right lung significantly stimulated breast cancer lung-specific metastasis in the syngeneic, orthotopic 4T1 breast cancer model.Our results warrant further investigation of the potential pro-metastatic effects of radiation and indicate the need to develop efficient drugs that will be successful in combination with radiotherapy to prevent therapy-induced spread of cancer cells.

Hair-sparing whole brain radiotherapy with volumetric arc therapy in patients treated for brain metastases: dosimetric and clinical results of a phase II trial.

PURPOSE: To report the dosimetric results and impact of volumetric arc therapy (VMAT) on temporary alopecia and hair-loss related quality of life (QOL) in whole brain radiotherapy (WBRT). METHODS: The potential of VMAT-WBRT to reduce the dose to the hair follicles was assessed. A human cadaver was treated with both VMAT-WBRT and conventional opposed field (OF) WBRT, while the subcutaneously absorbed dose was measured by radiochromic films and calculated by the planning system. The impact of these dose reductions on temporary alopecia was examined in a prospective phase II trial, with the mean score of hair loss at 1 month after VMAT-WBRT (EORTC-QOL BN20) as a primary endpoint and delivering a dose of 20 Gy in 5 fractions. An interim analysis was planned after including 10 patients to rule out futility, defined as a mean score of hair loss exceeding 56.7. A secondary endpoint was the global alopecia areata severity score measured with the "Severity of Alopecia Tool" (SALT) with a scale of 0 (no hair loss) to 100 (complete alopecia). RESULTS: For VMAT-WBRT, the cadaver measurements demonstrated a dose reduction to the hair follicle volume of 20.5% on average and of 41.8% on the frontal-vertex-occipital medial axis as compared to OF-WBRT. In the phase II trial, a total of 10 patients were included before the trial was halted due to futility. The EORTC BN20 hair loss score following WBRT was 95 (SD 12.6). The average median dose to the hair follicle volume was 12.6 Gy (SD 0.9), corresponding to a 37% dose reduction compared to the prescribed dose. This resulted in a mean SALT-score of 75. CONCLUSIONS: Compared to OF-WBRT, VMAT-WBRT substantially reduces hair follicle dose. These dose reductions could not be related to an improved QOL or SALT score.

Radiation-induced myosin IIA expression stimulates collagen type I matrix reorganization.

BACKGROUND AND PURPOSE: Extracellular matrix (ECM) reorganization critically contributes to breast cancer (BC) progression and radiotherapy response. We investigated the molecular background and functional consequences of collagen type I (col-I) reorganization by irradiated breast cancer cells (BCC). MATERIALS AND METHODS: Radiation-induced (RI) col-I reorganization was evaluated for MCF-7/6, MCF-7/AZ, T47D and SK-BR-3 BCC. Phase-contrast microscopy and a stressed matrix contraction assay were used for visualization and quantification of col-I reorganization. Cell-matrix interactions were assessed by the inhibition of ß1 integrin (neutralizing antibody 'P5D2') or focal adhesion kinase (FAK; GSK22560098 small molecule kinase inhibitor). The role of the actomyosin cytoskeleton was explored by western blotting analysis of myosin II expression and activity; and by gene silencing of myosin IIA and pharmacological inhibition of the actomyosin system (blebbistatin, cytochalasin D). BCC death was evaluated by propidium iodide staining. RESULTS: We observed a radiation dose-dependent increase of col-I reorganization by BCC. ß1 Integrin/FAK-mediated cell-matrix interactions are essential for RI col-I reorganization. Irradiated BCC are characterized by increased myosin IIA expression and myosin IIA-dependent col-I reorganization. Moreover, RI col-I reorganization by BCC is associated with decreased BCC death, as suggested by pharmacological targeting of the ß1 integrin/FAK/myosin IIA pathway. CONCLUSIONS: Our data indicate the role of myosin IIA in col-I reorganization by irradiated BCC and reciprocal BCC death.

Unraveling the mechanisms behind the enhanced MTT conversion by irradiated breast cancer cells.

Previously, we described the radiation-induced (RI) 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) effect as the increased MTT metabolization at the intermediate dose region after the irradiation of an MCF-7/6 cell monolayer with an X-ray dose gradient. We wondered if the cell monolayer at the intermediate dose region was characterized by an increased metabolic activity. In this study, we unraveled the mechanisms behind the RI MTT effect. Comparison of the MTT, sulforhodamine B (SRB), 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H tetrazolium (WST-8), and nitroblue tetrazolium (NBT) assays indicated that the RI MTT effect is not due to an increased cell density, but to an exclusively intracellular MTT conversion. Our results for the MTT and NBT assays after digitonin pretreatment of the irradiated cell monolayer indicated a role of the plasma membrane permeability in the RI MTT effect. Assessment of the radiation impact on the oxidative phosphorylation system by Western blot analysis, spectrophotometric measurement and Blue Native gel electrophoresis showed a dose-dependent downregulation of the oxidative phosphorylation system complexes, whereby the radiosensitivity of each complex was proportional to the number of mitochondrial DNA-encoded subunits. Further, only treatment of the irradiated cell monolayer with a cocktail and not with the individual inhibitors of complexes I, II and IV during the MTT assay prevented the RI MTT effect. In general, our results demonstrate that the RI MTT effect is not due to an increased metabolic activity, but rather to an enhanced cellular MTT entry and mitochondrial MTT conversion.

Improving positioning in high-dose radiotherapy for prostate cancer: safety and visibility of frequently used gold fiducial markers.

PURPOSE: The use of gold fiducial markers (GFMs) for prostate positioning in high-dose radiotherapy is gaining interest. The purpose of this study was to compare five GFMs regarding feasibility of ultrasound-based implantation in the prostate and intraprostatic lesion (IPL); toxicity; visibility on transabdominal ultrasound (TU) and cone-beam CT (CBCT); reliability of automatic, soft tissue, and GFM-based CBCT patient positioning by comparing manual and automatic fusion CBCT. METHODS AND MATERIALS: Twenty-five patients were included. Pain and toxicity were scored after implantation and high-dose radiotherapy. Fisher exact test was used to evaluate the correlation of patients' characteristics and prostatitis. Positioning was evaluated on TU and kilovoltage CBCT images. CBCT fusion was performed automatically (Elekta XVI technology, release 3.5.1 b27, based on grey values) and manually on soft tissue and GFMs. Pearson correlation statistics and Bland-Altman evaluation were used. Five GFMs were compared. RESULTS: Twenty percent of the patients developed prostatitis despite antibiotic prophylaxis. Cigarette smoking was significantly correlated with prostatitis. The visualization of all GFMs on TU was disappointing. Consequently we cannot recommend the use of these GFMs for TU-based prostate positioning. For all GFMs, there was only fair to poor linear correlation between automatic and manual CBCT images, indicating that even when GFMs are used, an operator evaluation is imperative. However, when GFMs were analyzed individually, a moderate to very strong correlation between automatic and manual positioning was found for larger GFMs in all directions. CONCLUSION: The incidence of prostatitis in our series was high. Further research is imperative to define the ideal preparation protocol preimplantation and to select patients. Automatic fusion is more reliable with larger GFMs at the cost of more scatter. The stability of all GFMs was proven.

Optimizing image acquisition settings for cone-beam computed tomography in supine and prone breast radiotherapy.

Volumetric discrepancies between cone-beam computed tomography (CBCT) and planning CT image sets were investigated for both prone and supine breast radiotherapy. A phantom study was performed in order to examine the artefacts' dependency on CBCT acquisition parameters and to minimize their effect on patient set-up accuracy.

Preliminary results on setup precision of prone-lateral patient positioning for whole breast irradiation.

PURPOSE: The aim of this study was to develop a rapid and reproducible technique for prone positioning and to compare dose-volume indices in prone and supine positions. METHODS AND MATERIALS: Eighteen patients underwent computed tomography imaging for radiotherapy planning in prone and supine position. Experience was gained in the first eight patients, which lead to modifications of the Horizon prone breast board (Civco Medical Solutions, Orange City, Iowa, USA) and the patient setup technique. A unilateral breast holder (U-BH) was developed (Van de Velde, Schellebelle, Belgium) to retract the contralateral breast away from the treated breast. The technique was then applied to an additional 10 patients. The setup precision was evaluated using daily cone-beam CT. RESULTS: Modifications to the breast board were made to secure a prone-lateral rather then a pure prone position. We evolved from a classical setup using laser marks on the patients' body to a direct breast setup using marks on the breast only. The setup precision of the direct positioning procedure with the modified breast board and the U-BH is comparable to supine setup data in the literature. Dose-volume indices for heart and lung show significantly better results for prone than for supine position, and dose homogeneity within the treated breast did not differ according to the treatment position. CONCLUSIONS: The setup precision of our prone-lateral positioning technique is comparable to supine data in literature. Our data show the advantage of prone radiotherapy to spare the lung and heart. Further research is necessary to reduce the duration of prone setup.

From clinical observations of intensity-modulated radiotherapy to dedicated in vitro designs.

In this review, an overview of intensity-modulated radiotherapy (IMRT) and related high precision radiation techniques is presented. In addition, the related radiobiological issues are discussed. Hereby, we try to point to the potential differences in radiobiological effect between popular intensity-modulated radiotherapy and related techniques (IMRT+) and conventional or three-dimensional radiotherapy (3D-RT). Further, an overview of the existing in vitro and in vivo radiobiological models to investigate the effect of spatially and/or temporally fractionated dose distributions, as applied in IMRT+, on the biological outcome is given. More in detail, our radiobiological models will be presented. Additionally, we will discuss the (dis)advantages of the presented models, and give some consideration to improve the existing radiobiological models in terms of set-up and clinical relevance.

Intensity-modulated arc therapy with simultaneous integrated boost in the treatment of primary irresectable cervical cancer. Treatment planning, quality control, and clinical implementation.

PURPOSE: To report on the planning procedure, quality control, and clinical implementation of intensity-modulated arc therapy (IMAT) delivering a simultaneous integrated boost (SIB) in patients with primary irresectable cervix carcinoma. PATIENTS AND METHODS: Six patients underwent PET-CT (positron emission tomography-computed tomography) and MRI (magnetic resonance imaging) before treatment planning. Prescription (25 fractions) was (1) a median dose (D(50)) of 62, 58 and 56 Gy to the primary tumor (GTV_cervix), primary clinical target volume (CTV_cervix) and its planning target volume (PTV_cervix), respectively; (2) a D(50) of 60 Gy to the PET-positive lymph nodes (GTV_nodes); (3) a minimal dose (D(98)) of 45 Gy to the planning target volume of the elective lymph nodes (PTV_nodes). IMAT plans were generated using an anatomy-based exclusion tool with the aid of weight and leaf position optimization. The dosimetric delivery of IMAT was validated preclinically using radiochromic film dosimetry. RESULTS: Five to nine arcs were needed to create valid IMAT plans. Dose constraints on D(50) were not met in two patients (both GTV_cervix: 1 Gy and 3 Gy less). D(98) for PTV_nodes was not met in three patients (1 Gy each). Film dosimetry showed excellent gamma evaluation. There were no treatment interruptions. CONCLUSION: IMAT allows delivering an SIB to the macroscopic tumor without compromising the dose to the elective lymph nodes or the organs at risk. The clinical implementation is feasible.