A phase I/II study of acute and late physician assessed and patient-reported morbidity following whole pelvic radiation in high-risk prostate cancer patients.

BACKGROUND: The aim of this study was to assess acute and late morbidity measured by the physician and patient-reported outcomes (PROs) in high-risk prostate cancer (PC) patients receiving whole pelvic intensity-modulated radiotherapy (IMRT) in the setting of a national clinical trial. MATERIAL AND METHODS: A total of 88 patients with adenocarcinoma of the prostate and high-risk parameters were enrolled from 2011 to 2013. All patients received 78 Gy in 39 fractions of IMRT delivering simultaneous 78 Gy to the prostate and 56 Gy to the seminal vesicles and lymph nodes. Physician-reported morbidity was assessed by CTCAE v.4.0. PROs were registered for gastro-intestinal (GI) by the RT-ARD score, genito-urinary (GU) by DAN-PSS, sexual and hormonal by EPIC-26, and quality of life (QoL) by EORTC QLQ-C30. RESULTS: Median follow-up (FU) time was 4.6 years. No persistent late CTCAE grade 3+ morbidity was observed. Prevalence of CTCAE grade 2+ GI morbidities varied from 0 to 6% at baseline throughout FU time, except for diarrhea, which was reported in 19% of the patients post-RT. PROs revealed increased GI morbidity (≥1 monthly episode) for "rectal urgency", "use of pads", "incomplete evacuation", "mucus in stool" and "bowel function impact on QoL" all remained significantly different (p < .05) at 60 months compared to baseline. CTCAE grade 2+ GU and sexual morbidity were unchanged. GU PROs on obstructive and irritative GU items (≥daily episode) increased during RT and normalized at 24 months. No clinically significant differences were found in sexual, hormonal, and QoL scores compared to baseline. CONCLUSIONS: Whole pelvic RT resulted in a mild to the moderate burden of late GI morbidities demonstrated by a relatively high prevalence of PROs. Whereas, physician-assessed morbidity revealed a low prevalence of late GI morbidity scores. This emphasizes the importance of using both PROs and physician-reported scoring scales when reporting late morbidity in clinical trials.

Towards proton arc therapy: physical and biologically equivalent doses with increasing number of beams in pediatric brain irradiation.

Background: Proton arc therapy may improve physical dose conformity and reduce concerns of elevated linear energy transfer (LET) and relative biological effectiveness (RBE) at the end of the proton range, while offering more degrees of freedom for normal tissue sparing. To explore the potential of proton arc therapy, we studied the effect of increasing the number of beams on physical and biologically equivalent dose conformity in the setting of pediatric brain tumors. Material and methods: A cylindrical phantom (Ø = 150 mm) with central cylindrical targets (Ø = 25 and 30 mm) was planned with increasing number of equiangular coplanar proton beams (from 3 to 36). For four anonymized pediatric brain tumor patients, two 'surrogate' proton arc plans (18 equiangular coplanar or sagittal beams) and a reference plan with 3 non-coplanar beams were constructed. Biologically equivalent doses were calculated using two RBE scenarios: RBE1.1; and RBELET, the physical dose weighted by the LET. For both RBE scenarios, dose gradients were assessed, and doses to cognitive brain structures were reported. Results: Increasing the number of beams resulted in an improved dose gradient and reduced volume exposed to intermediate LET levels, at the expense of increased low-dose and low-LET volumes. Most of the differences between the two RBE scenarios were seen around the prescription dose level, where the isodose volumes increased with the RBELET plans, e.g. up to 63% in the 3-beam plan for the smallest phantom target. Overall, the temporal lobes were better spared with the sagittal proton arc surrogate plans, e.g. a mean dose of 3.9 Gy compared to 6 Gy in the reference 3-beam plan (median value, RBE1.1). Conclusion: Proton arc therapy has the potential to improve dose gradients to better spare cognitive brain structures. However, this is at the expense of increased low-dose/low-LET volumes, with possible implications for secondary cancer risks.

Radiation doses to brain substructures associated with cognition in radiotherapy of pediatric brain tumors.

Background: Several brain substructures associated with cognition (BSCs) are located close to typical pediatric brain tumors. Pediatric patients therefore have considerable risks of neurocognitive impairment after brain radiotherapy. In this study, we investigated the radiation doses received by BSCs for three common locations of pediatric brain tumor entities. Material and methods: For ten patients in each group [posterior fossa ependymoma (PFE), craniopharyngioma (CP), and hemispheric ependymoma (HE)], the cumulative fraction of BSCs volumes receiving various dose levels were analyzed. We subsequently explored the differences in dose pattern between the three groups and used available dose response models from the literature to estimate treatment-induced intelligence quotient (IQ) decline. Results: Doses to BSCs were found to differ considerably between the groups, depending on their position relative to the tumor. Large inter-patient variations were observed in the ipsilateral structures of the HE groups, and at low doses for all three groups. IQ decline estimates differed depending on the model applied, presenting larger variations in the HE group. Conclusion: While there were notable differences in the dose patterns between the groups, the extent of estimated IQ decline depended more on the model applied. This inter-model variability should be considered in dose-effect assessments on cognitive outcomes of pediatric patients.

Evaluating the influence of organ motion during photon vs. proton therapy for locally advanced prostate cancer using biological models.

BACKGROUND: Proton therapy (PT) may have a normal tissue sparing potential when co-irradiating pelvic lymph nodes in patients with locally advanced prostate cancer, but may also be more sensitive towards organ motion in the pelvis. Building upon a previous study identifying motion-robust proton beam angles for pelvic irradiation, we aimed to evaluate the influence of organ motion for PT using biological models, and to compare this with contemporary photon-based RT. MATERIAL AND METHODS: Eight locally advanced prostate cancer patients with a planning CT (pCT) and 8-9 repeated CT scans (rCTs) were included. Two PT plans were created, one using two lateral opposed beams at gantry angles of 90°/270° and the other using two lateral oblique beams at 35°/325°; these were compared with volumetric modulated arc therapy (VMAT) plans. All plans were optimised on the pCT and subsequently re-calculated on each rCT (following rigid alignment on the prostate). Dose distributions in organs at risk (OARs) were evaluated using mean dose, generalized equivalent uniform doses (gEUDs) and normal tissue complication probabilities (NTCPs), while mean dose and the volume receiving 98% of the dose (V98%) were used for the targets. RESULTS: PT significantly reduced the mean dose to the OARs and a correlation was seen in the pCTs between the prostate PTV overlapping the relevant OAR and OAR NTCPs, as was also the case for the VMAT plans. The best prostate target coverage across the rCTs for the IMPT plans were seen with two lateral opposed beams, although a poor coverage of the lymph node target was apparent based on V98% compared to the VMAT plans. CONCLUSIONS: PT reduced the mean dose to normal tissues in the irradiation of pelvic lymph nodes and a strong association between the volume overlap and NTCPs in the pCTs were found.

Biological dose and complication probabilities for the rectum and bladder based on linear energy transfer distributions in spot scanning proton therapy of prostate cancer.

BACKGROUND: The increased linear energy transfer (LET) at the end of the Bragg peak causes concern for an elevated and spatially varying relative biological effectiveness (RBE) of proton therapy (PT), often in or close to dose-limiting normal tissues. In this study, we investigated dose-averaged LET (LETd) distributions for spot scanning PT of prostate cancer patients using different beam angle configurations. In addition, we derived RBE-weighted (RBEw) dose distributions and related normal tissue complication probabilities (NTCPs) for the rectum and bladder. MATERIAL AND METHODS: A total of 21 spot scanning proton plans were created for each of six patients using a prescription dose of 78 Gy(RBE1.1), with each plan using two 'mirrored' beams with gantry angles from 110°/250° to 70°/290°, in steps of 2°. Physical dose and LETd distributions were calculated as well as RBEw dose distributions using either RBE = 1.1 or three different variable RBE models. The resulting biological dose distributions were used as input to NTCP models for the rectum and bladder. RESULTS: For anterior oblique (AO) configurations, the rectum LETd volume and RBEw dose increased with increasing angles off the lateral opposing axis, with the RBEw rectum dose being higher than for all posterior oblique (PO) configurations. For PO configurations, the corresponding trend was seen for the bladder. Using variable RBE models, the rectum NTCPs were highest for the AO configurations with up to 3% for the 80°/280° configuration while the bladder NTCPs were highest for the PO configurations with up to 32% for the 100°/260°. The rectum D1cm3 constraint was fulfilled for most patients/configurations when using uniform RBE but not for any patient/configuration with variable RBE models. CONCLUSIONS: Compared to using constant RBE, the variable RBE models predicted increased biological doses to the rectum, bladder and prostate, which in turn lead to substantially higher estimated rectum and bladder NTCPs.

Intra-fractional bladder motion and margins in adaptive radiotherapy for urinary bladder cancer.

BACKGROUND: The bladder is a tumour site well suited for adaptive radiotherapy (ART) due to large inter-fractional changes, but it also displays considerable intra-fractional motion. The aim of this study was to assess target coverage with a clinically applied method for plan selection ART and to estimate population-based and patient-specific intra-fractional margins, also relevant for a future re-optimisation strategy. MATERIAL AND METHODS: Nine patients treated in a clinical phase II ART trial of daily plan selection for bladder cancer were included. In the library plans, 5 mm isotropic margins were added to account for intra-fractional changes. Pre-treatment and weekly repeat magnetic resonance imaging (MRI) series were acquired in which a full three-dimensional (3D) volume was scanned every second min for 10 min (a total of 366 scans in 61 series). Initially, the bladder clinical target volume (CTV) was delineated in all scans. The t = 0 min scan was then rigidly registered to the planning computed tomography (CT) and plan selections were simulated using the CTV_0 (at t = 0 min). To assess intra-fractional motion, coverage of the CTV_10 (at t = 10 min) was quantified using the applied PTV. Population-based margins were calculated using the van Herk margin recipe while patient-specific margins were calculated using a linear model. RESULTS: For 49% of the cases, the CTV_10 extended more than 5 mm outside the CTV_0. However, in 58 of the 61 cases (97%) CTV_10 was covered by the selected PTV. Population-based margins of 14 mm Sup/Ant, 9 mm Post and 5 mm Inf/Lat were sufficient to cover the bladder. Using patient-specific margins, the overlap between PTV and bowel-cavity was reduced from 137 cm(3) with the plan selection strategy to 24 cm(3). CONCLUSION: In this phase II ART trial, 5 mm isotropic margin for intra-fractional motion was sufficient even though considerable intra-fractional motion was observed. In online re-optimised ART, population-based margin can be applied although patient-specific margins are preferable.

A method for evaluation of proton plan robustness towards inter-fractional motion applied to pelvic lymph node irradiation.

BACKGROUND: The benefit of proton therapy may be jeopardized by dose deterioration caused by water equivalent path length (WEPL) variations. In this study we introduced a method to evaluate robustness of proton therapy with respect to inter-fractional motion and applied it to irradiation of the pelvic lymph nodes (LNs) from different beam angles. Patient- versus population-specific patterns in dose deterioration were explored. MATERIAL AND METHODS: Patient data sets consisting of a planning computed tomography (pCT) as well as multiple repeat CT (rCT) scans for three patients were used, with target volumes and organs at risk (ORs) outlined in all scans. Single beam spot scanning proton plans were optimized for the left and right LN targets separately, across all possible beam angle configurations (5° angle intervals). Isotropic margins of 0, 3, 5 and 7 mm from the clinical target volume (CTV) to the planning target volume (PTV) were investigated. The optimized fluence maps for the pCT for each beam were applied onto all rCTs and the dose distributions were re-calculated. WEPL variation for each beam angle was computed by averaging over beams eye view WEPL distributions. RESULTS: Similarity in deterioration patterns were found for the investigated patients, with beam angles delivering less dose to rectum, bladder and overall normal tissue identified around 40° and around 150°-160° for the left LNs, and corresponding angles for the right LNs. These angles were also associated with low values of WEPL variation. CONCLUSION: We have established and explored a method to quantify the robustness towards inter-fractional motion of single beam proton plans treating the pelvic LNs from different beam configurations and with different CTV to PTV margins. For the patients investigated we were able to identify beam orientations that were robust to dose deterioration in the target and ORs.

External validation of a normal tissue complication probability model for radiation-induced hypothyroidism in an independent cohort.

BACKGROUND: A normal tissue complication probability (NTCP) model for radiation-induced hypothyroidism (RIHT) was previously derived in patients with squamous cell carcinoma of the head and neck (HNSCC) discerning thyroid volume (Vthyroid), mean thyroid dose (Dmean), and latency as predictive factors. The purpose of this study was to test the performance of this model in an independent cohort of patients receiving primary radiotherapy (RT) for HNSCC. MATERIAL AND METHODS: A validation cohort of 198 patients with HNSCC was included after plasma thyrotropin (TSH) assessment. RIHT was defined as TSH > 4.0 mU/l from blood samples obtained during follow-up. A new mixture NTCP model was developed from the validation cohort after multivariable analysis. Due to only one follow-up TSH assessment in the validation cohort, the time factor derived from the original cohort was fixed in a mixture model and applied for the NTCP validation. Association between model predictions of the initial model and observed clinical outcome in the validation cohort was investigated by applying the previous model (Vthyroid, Dmean and time) on the new cohort and comparing it to the clinical outcome. RESULTS: Both Dmean and Vthyroid were confirmed as significant risk factors for RIHT in the validation cohort, odds ratio (OR) 1.19 (1.1-1.37) and OR 0.75 (0.57-0.9), respectively. A small difference in overall probability of RIHT was observed between the cohorts, further analysis indicated this to be related to less frequent blood tests in the validation cohort relative to the original cohort. However, Pearson's correlation coefficients between model and clinical outcome were high: r = 0.97 estimated by the original model versus the original cohort, and r = 0.97 estimated by the original model versus the new cohort. CONCLUSION: Dmean and Vthyroid were significant predictors of RIHT in both cohorts. The original NTCP model demonstrated external validity owing to high Pearson's correlation coefficients between estimated and observed incidence rates of RIHT in the original as well as in the validation cohort. This model may facilitate clinically relevant estimations of RIHT after RT to the neck.

Monte Carlo simulations of new 2D ripple filters for particle therapy facilities.

UNLABELLED: At particle therapy facilities with pencil beam scanning, the implementation of a ripple filter (RiFi) broadens the Bragg peak (BP), which leads to fewer energy steps from the accelerator required to obtain an homogeneous dose coverage of the planned target volume (PTV). At the Universitätsklinikum Gießen und Marburg, Germany, a new second generation RiFi has been developed with two-dimensional groove structures. In this work we evaluate this new RiFi design. METHODS: The Monte Carlo (MC) code SHIELD-HIT12A is used to determine the RiFi-induced inhomogeneities in the dose distribution for various ion types, initial particle energies and distances from the RiFi to the phantom surface as well as in the depth of the phantom. The beam delivery and monitor system (BAMS) used at Marburg, the Heidelberg Ionentherapiezentrum (HIT), Universitätsklinikum Heidelberg, Germany and the GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt, Germany is modeled and simulated. To evaluate the PTV dose coverage performance of the new RiFi design, the heavy ion treatment planning system TRiP98 is used for dose optimization. SHIELD-HIT12A is used to prepare the facility-specific physical dose kernels needed by TRiP, and for recalculating the physical dose distribution after TRiP optimization. RESULTS: At short distances from the RiFi to the phantom surface fine structures in the dose distribution are observed. For various RiFis, ion types and initial particle energies the distance dmax at which maximum dose inhomogeneity occurs is found and an expression for dmax is deduced. The distance d0.01 at which the dose inhomogeneity is less than 1% is estimated and used as a threshold distance at which dose distributions are considered homogeneous. The MC data are found to agree with analytical expressions for dmax and d0.01; both are inversely related to the angular distribution. Increasing scatter from the beam delivery and monitoring system results in reduced dmax and d0.01. Furthermore, dmax and d0.01 are found to be proportional to the RiFi period λ. CONCLUSION: Our findings clearly indicate that the dose inhomogeneity induced by RiFis does not add uncertainties to the dose distribution in the clinical setting. The new RiFi design can be used in treatments to obtain homogeneous PTV dose coverage with fewer energy steps while improving lateral penumbra, thereby reducing the required treatment time.

The impact of CBCT reconstruction and calibration for radiotherapy planning in the head and neck region - a phantom study.

BACKGROUND: The applicability of cone-beam computed tomography (CBCT) image sets for dose calculation purposes relies on high image quality and CT number accuracy. In this study we have investigated the use of stoichiometric calibration for transforming CT numbers into physical parameters, in combination with a new CBCT scatter correction algorithm, focusing on head and neck geometries. METHODS: CBCT projections were acquired using an On-Board-Imager (OBI v1.4; Varian Medical Systems) using both low- and high-dose clinical image acquisition protocols. The CBCT projections were reconstructed twice, using both the standard method (OBI) as well as an experimental pre-clinical reconstruction algorithm (Full Fan Experimental - FFE). Stoichiometric calibration was performed using both a phantom from CIRS with nine tissue equivalent inserts (ranging from lung to dense bone) as well as with a custom made cylindrical PMMA head and neck phantom with variable 'head' diameter and with cavities designed to fit the inserts from a Gammex RMI phantom. To benchmark the CBCT performance, the same calibration procedures were performed using two conventional CT scanners. For assessment of influence on dose-volume parameters, the head part of the anthropomorphic Alderson phantom was scanned, reconstructed with both CT and CBCT using the stoichiometric calibration curves, and finally used to compare IMRT dose calculations. RESULTS: The stoichiometric CBCT calibrations with the CIRS phantom resulted in an excellent fit between calculated and measured CT numbers (R = 1.000 for all combinations tested), equivalent to the results for the conventional scanners. Using the PMMA phantom, the stoichiometric calibration curves again showed excellent agreement, although the OBI reconstruction showed marginally increasing deviation from the unity line as the phantom size decreased. For the dose-volume parameters, deviations well within 1% were seen between the different reconstruction methods and acquisition modes. CONCLUSION: This study showed that the combination of an improved reconstruction method and stoichiometric calibration improved the CT number accuracy of CBCT scans acquired for head and neck phantoms. In particular, a radial size dependence of the scanned object similar to that in conventional CT could be achieved. Although high density inhomogeneities still are challenging for the reconstruction process, clinically acceptable agreement in key dose-volume parameters between CT-based and CBCT-based IMRT planning calculations on a humanoid phantom was found.

LET-painting increases tumour control probability in hypoxic tumours.

LET-painting was suggested as a method to overcome tumour hypoxia. In vitro experiments have demonstrated a well-established relationship between the oxygen enhancement ratio (OER) and linear energy transfer (LET), where OER approaches unity for high-LET values. However, high-LET radiation also increases the risk for side effects in normal tissue. LET-painting attempts to restrict high-LET radiation to compartments that are found to be hypoxic, while applying lower LET radiation to normoxic tissues. Methods. Carbon-12 and oxygen-16 ion treatment plans with four fields and with homogeneous dose in the target volume, are applied on an oropharyngeal cancer case with an identified hypoxic entity within the tumour. The target dose is optimised to achieve a tumour control probability (TCP) of 95% when assuming a fully normoxic tissue. Using the same primary particle energy fluence needed for this plan, TCP is recalculated for three cases assuming hypoxia: first, redistributing LET to match the hypoxic structure (LET-painting). Second, plans are recalculated for varying hypoxic tumour volume in order to investigate the threshold volume where TCP can be established. Finally, a slight dose boost (5-20%) is additionally allowed in the hypoxic subvolume to assess its impact on TCP. Results. LET-painting with carbon-12 ions can only achieve tumour control for hypoxic subvolumes smaller than 0.5 cm(3). Using oxygen-16 ions, tumour control can be achieved for tumours with hypoxic subvolumes of up to 1 or 2 cm(3). Tumour control can be achieved for tumours with even larger hypoxic subvolumes, if a slight dose boost is allowed in combination with LET-painting. Conclusion. Our findings clearly indicate that a substantial increase in tumour control can be achieved when applying the LET-painting concept using oxygen-16 ions on hypoxic tumours, ideally with a slight dose boost.

A method for selection of beam angles robust to intra-fractional motion in proton therapy of lung cancer.

BACKGROUND: Proton therapy offers the potential for sparing the normal tissue surrounding the target. However, due to well-defined proton ranges around the Bragg peak, dose deposition is more sensitive to changes in the water equivalent path length (WEPL) than with photons. In this study, we assess WEPL variations caused by breathing-induced motion for all possible beam angles in a series of lung cancer patients. By studying the association between measures for WEPL variation and breathing-induced target dose degradation we aimed to develop and explore a tool to identify beam angles that are robust to patient-specific patterns of intra-fractional motion. MATERIAL AND METHODS: Using four-dimensional computed tomography (4DCT) images of three lung cancer patients we evaluated the impact of the WEPL changes on target dose coverage for a series of coplanar single-beam plans. The plans were optimised for the internal target volume (ITV) at the maximum intensity projection (MIP) CT for every 3° gantry interval. The plans were transferred to the ten 4DCT phases and the average reduction in ITV V95 over the ten phases, relative to the original MIP CT calculation, was quantified. The target dose reduction was associated with the mean difference between the WEPL and the phase-averaged WEPL computed for all beam rays across all possible gantry-couch angle combinations. RESULTS: The gantry-couch angle maps showed areas of both high and low WEPL variation, with overall quite similar patterns yet with individual differences reflecting differences in tumour position and breathing-induced motion. The coplanar plans showed a strong association between WEPL changes and ITV V95 reduction, with a correlation coefficient ranging between 0.92 and 0.98 for the three patients (p < 0.01). CONCLUSION: We have presented a 4DCT-based method to quantify WEPL changes during the breathing cycle. The method identified proton field gantry-couch angle combinations that were either sensitive or robust to WEPL changes. WEPL variations along the beam path were associated with target under-dosage.

Normal tissue sparing in a phase II trial on daily adaptive plan selection in radiotherapy for urinary bladder cancer.

UNLABELLED: Background: Patients with urinary bladder cancer often display large changes in the shape and size of their bladder target during a course of radiotherapy (RT), making adaptive RT (ART) appealing for this tumour site. We are conducting a clinical phase II trial of daily plan selection-based ART for bladder cancer and here report dose-volume data from the first 20 patients treated in the trial. MATERIAL AND METHODS: All patients received 60 Gy in 30 fractions to the bladder; in 13 of the patients the pelvic lymph nodes were simultaneously treated to 48 Gy. Daily patient set-up was by use of cone beam computed tomography (CBCT) guidance. The first 5 fractions were delivered with large, population-based (non-adaptive) margins. The bladder contours from the CBCTs acquired in the first 4 fractions were used to create a patient-specific library of three plans, corresponding to a small, medium and large size bladder. From fraction 6, daily online plan selection was performed, where the smallest plan covering the bladder was selected prior to each treatment delivery. A total of 600 treatment fractions in the 20 patients were evaluated. RESULTS: Small, medium and large size plans were used almost equally often, with an average of 10, 9 and 11 fractions, respectively. The median volume ratio of the course-averaged PTV (PTV-ART) relative to the non-adaptive PTV was 0.70 (range: 0.46-0.89). A linear regression analysis showed a 183 cm(3) (CI 143-223 cm(3)) reduction in PTV-ART compared to the non-adaptive PTV (R(2) = 0.94). CONCLUSION: Daily adaptive plan selection in RT of bladder cancer results in a considerable normal tissue sparing, of a magnitude that we expect will translate into a clinically significant reduction of the treatment-related morbidity.

Estimated risk of radiation-induced cancer following paediatric cranio-spinal irradiation with electron, photon and proton therapy.

BACKGROUND: Improvement in radiotherapy during the past decades has made the risk of developing a radiation-induced secondary cancer as a result of dose to normal tissue a highly relevant survivorship issue. Important factors expected to influence secondary cancer risk include dose level and dose heterogeneity, as well as gender and type of tissue irradiated. The elevated radio-sensitivity in children calls for models particularly tailored to paediatric cancer patients. MATERIAL AND METHODS: Treatment plans of six paediatric medulloblastoma patients were analysed with respect to secondary cancer risk following cranio-spinal irradiation (CSI), using either: 1) electrons and photons combined; 2) conformal photons; 3) double-scattering (DS) protons; or 4) intensity-modulated proton therapy (IMPT). The relative organ equivalent dose (OED) concept was applied in three dose-risk scenarios: a linear response model, a plateau response and an organ specific linear-exponential response. Life attributable risk (LAR) was calculated based on the BEIR VII committee's preferred models for estimating age- and site-specific solid cancer incidence. Uncertainties in the model input parameters were evaluated by error propagation using a Monte Carlo sampling procedure. RESULTS: Both DS protons and IMPT achieved a significantly better dose conformity compared to the photon and electron irradiation techniques resulting in a six times lower overall risk of radiation-induced cancer. Secondary cancer risk in the thyroid and lungs contributed most to the overall risk in all compared modalities, while no significant difference was observed for the bones. Variations between DS protons and IMPT were small, as were differences between electrons and photons. CONCLUSION: Regardless of technique, using protons decreases the estimated risk of secondary cancer following paediatric CSI compared to conventional photon and electron techniques. Substantial uncertainties in the LAR estimates support relative risk comparisons by OED.

Evaluation of an application for intensity-based deformable image registration and dose accumulation in radiotherapy.

BACKGROUND: Methods to accurately accumulate doses in radiotherapy (RT) are important for tumour and normal tissues being influenced by geometric uncertainties. The purpose of this study was to investigate a pre-release deformable image registration (DIR)-based dose accumulation application, in the setting of prostate RT. MATERIAL AND METHODS: Initially accumulated bladder and prostate doses were assessed (based on 8-9 repeat CT scans/patient) for nine prostate cancer patients using an intensity-based DIR and dose accumulation algorithm as provided by the Dynamic Adaptive Radiation Therapy (DART) software. The accumulated bladder and prostate dose-volume histograms (DVHs) were compared on a range of parameters (paired Wilcoxon signed-rank test, 5% significance level) to DVHs derived using an in-house developed dose accumulation method based on biomechanical, contour-driven DIR (SurfaceRegistration). Finally, both these accumulated dose distributions were compared to the 'static' DVH, assessed from the planning CT. RESULTS: Over the population, doses accumulated with DART were overall lower than those from SurfaceRegistration (p < 0.05: D2%, gEUD and NTCP (bladder); Dmin (prostate)). The magnitude of these differences peaked for the bladder gEUD with a population median of 47 Gy for DART versus 57 Gy for SurfaceRegistration. Across the ten bladder dose/volume parameters investigated, the most pronounced individual differences were observed between the 'accumulated' DVHs and the 'static' DVHs, with deviations in mean dose up to 22 Gy. CONCLUSION: Substantial and significant differences were observed in the dose distributions between the two investigated DIR-based dose accumulation applications. The most pronounced individual differences were seen for the bladder and relative to the planned dose distribution, encouraging the use of repeat imaging data in RT planning and evaluation for this organ.

Dose/volume-based evaluation of the accuracy of deformable image registration for the rectum and bladder.

BACKGROUND AND PURPOSE: Deformable image registration (DIR) is a key component of image-guided and adaptive strategies in radiotherapy. DIR based on image intensities alone is promising for online applications, but is challenged in regions with low intensity gradients. In this study we have investigated the performance of intensity- based DIR applied to contour propagation of the rectum and bladder, focusing on the consequences in terms of dose/volume parameters. MATERIAL AND METHODS: The rectum and bladder volumes were delineated in the planning computed tomography (pCT) scan and in 8-9 repeat CTs (Vmanual) for nine prostate cancer patients. The volumes from the pCT were propagated onto the repeat CTs using intensity-based DIR (Vprop). Dose/volume parameters for Vmanual and Vprop were derived by dose re-calculations following rigid registration on prostate fiducials. Linear regression was used to identify qualitative and quantitative volumetric measures of the DIR performance being associated with the differences in dose/volume parameters. RESULTS: The median differences in dose/volume parameters assessed for Vprop and Vmanual were modest, but individual differences ~7 Gy were seen. The observed differences in dose/volume parameters showed strong correlations to the measures of the DIR performance as well as with the volume variations, most pronounced for the rectum (R(2) = 0.63-0.85; p ≤ 0.05). CONCLUSION: Limitations in the intensity-based DIR algorithm resulted in large individual differences in dose/volume parameters between propagated and manually segmented volumes, which were correlated with volumetric measures of the DIR performance.

Degradation of target coverage due to inter-fraction motion during intensity-modulated proton therapy of prostate and elective targets.

UNLABELLED: Internal target and organ motion during treatment is a challenge in radiotherapy (RT) of the prostate and the involved elective targets, with residual motion being present also following image-guidance strategies. The aim of this study was to investigate organ motion-induced dose degradations for the prostate, seminal vesicle and the pelvic lymph node when treating these targets with proton therapy, using different image-guidance and delivery strategies. MATERIAL AND METHODS: Four patients were selected from a larger series as they displayed large inter-fractional variation in bladder and rectum volume. Intensity-modulated proton therapy plans were generated using both simultaneous integrated and sequential boost delivery. For each technique, three isotropic margin expansions (in the range of 4-10 mm) were evaluated for the clinical target volume of prostate (CTV-p), seminal vesicles (CTV-sv) and lymph nodes (CTV-ln). Simulation of the dose degradations for all treatment plans were based on dose re-calculations for the 8-9 repeat CTs available for each patient, after applying rigid registrations to reproduce set-up based on either intra-prostatic fiducials or bony anatomy. RESULTS: The simulated dose received by 99% of the target volume (D(99)) and generalized equivalent dose (gEUD) showed substantial inter-patient variations. For 40% of the investigated scenarios, the patient average simulated D(99) for all targets were within 2 GyE from the planned dose. The largest difference between simulated and planned dose was seen for the CTV-sv when using SIB delivery, with an average relative reduction in D(99) of 13% and 15% for the largest margin expansion, when positioned using fiducials and bony anatomy, respectively. CONCLUSIONS: The most severe dose degradations were found for CTV-sv, but they were also evident for CTV-ln. The degradations could not be completely resolved, neither by using the largest margin expansion nor with the choice of set-up. With fiducial set-up CTV-p was robust against the inter-fraction changes.

Dosimetric verification of complex radiotherapy with a 3D optically based dosimetry system: dose painting and target tracking.

BACKGROUND: The increasing complexity of radiotherapy (RT) has motivated research into three-dimensional (3D) dosimetry. In this study we investigate the use of 3D dosimetry with polymerizing gels and optical computed tomography (optical CT) as a verification tool for complex RT: dose painting and target tracking. MATERIALS AND METHODS: For the dose painting studies, two dosimeters were irradiated with a seven-field intensity modulated radiotherapy (IMRT) plan with and without dose prescription based on a hypoxia image dataset of a head and neck patient. In the tracking experiments, two dosimeters were irradiated with a volumetric modulated arc therapy (VMAT) plan with and without clinically measured prostate motion and a third with both motion and target tracking. To assess the performance, 3D gamma analyses were performed between measured and calculated stationary dose distributions. RESULTS: Gamma pass-rates of 95.3% and 97.3% were achieved for the standard and dose-painted IMRT plans. Gamma pass-rates of 91.4% and 54.4% were obtained for the stationary and moving dosimeter, respectively, while tracking increased the pass-rate for the moving dosimeter to 90.4%. CONCLUSIONS: This study has shown that the 3D dosimetry system can reproduce and thus verify complex dose distributions, also when influenced by motion.

Corrigendum to "Two compound techniques for total body irradiation" [Tech. Innov. Patient Support Radiat. Oncol. 21 (2022) 1-7].

[This corrects the article DOI: 10.1016/j.tipsro.2021.11.006.].