Pediatric Outcome after Maternal Cancer Diagnosed during Pregnancy.

BACKGROUND: Data on the long-term outcome of children who are exposed to maternal cancer with or without treatment during pregnancy are lacking. METHODS: In this multicenter case-control study, we compared children whose mothers received a diagnosis of cancer during the pregnancy with matched children of women without a cancer diagnosis. We used a health questionnaire and medical files to collect data regarding neonatal and general health. All children were prospectively assessed (by means of a neurologic examination and the Bayley Scales of Infant Development) at 18 months, 36 months, or both. A cardiac assessment was performed at 36 months. RESULTS: A total of 129 children (median age, 22 months; range, 12 to 42) were included in the group whose mother had cancer (prenatal-exposure group) with a matching number in the control group. During pregnancy, 96 children (74.4%) were exposed to chemotherapy (alone or in combination with other treatments), 11 (8.5%) to radiotherapy (alone or in combination), 13 (10.1%) to surgery alone, 2 (1.6%) to other drug treatments, and 14 (10.9%) to no treatment. Birth weight was below the 10th percentile in 28 of 127 children (22.0%) in the prenatal-exposure group and in 19 of 125 children (15.2%) in the control group (P=0.16). There was no significant between-group difference in cognitive development on the basis of the Bayley score (P=0.08) or in subgroup analyses. The gestational age at birth was correlated with the cognitive outcome in the two study groups. Cardiologic evaluation among 47 children at 36 months of age showed normal cardiac findings. CONCLUSIONS: Prenatal exposure to maternal cancer with or without treatment did not impair the cognitive, cardiac, or general development of children in early childhood. Prematurity was correlated with a worse cognitive outcome, but this effect was independent of cancer treatment. (Funded by Research Foundation-Flanders and others; ClinicalTrials.gov number, NCT00330447.).

Efficacy and workload analysis of a fixed vertical couch position technique and a fixed-action-level protocol in whole-breast radiotherapy.

Quantification of the setup errors is vital to define appropriate setup margins preventing geographical misses. The no-action-level (NAL) correction protocol reduces the systematic setup errors and, hence, the setup margins. The manual entry of the setup corrections in the record-and-verify software, however, increases the susceptibility of the NAL protocol to human errors. Moreover, the impact of the skin mobility on the anteroposterior patient setup reproducibility in whole-breast radiotherapy (WBRT) is unknown. In this study, we therefore investigated the potential of fixed vertical couch position-based patient setup in WBRT. The possibility to introduce a threshold for correction of the systematic setup errors was also explored. We measured the anteroposterior, mediolateral, and superior-inferior setup errors during fractions 1-12 and weekly thereafter with tangential angled single modality paired imaging. These setup data were used to simulate the residual setup errors of the NAL protocol, the fixed vertical couch position protocol, and the fixed-action-level protocol with different correction thresholds. Population statistics of the setup errors of 20 breast cancer patients and 20 breast cancer patients with additional regional lymph node (LN) irradiation were calculated to determine the setup margins of each off-line correction protocol. Our data showed the potential of the fixed vertical couch position protocol to restrict the systematic and random anteroposterior residual setup errors to 1.8 mm and 2.2 mm, respectively. Compared to the NAL protocol, a correction threshold of 2.5mm reduced the frequency of mediolateral and superior-inferior setup corrections with 40% and 63%, respectively. The implementation of the correction threshold did not deteriorate the accuracy of the off-line setup correction compared to the NAL protocol. The combination of the fixed vertical couch position protocol, for correction of the anteroposterior setup error, and the fixed-action-level protocol with 2.5 mm correction threshold, for correction of the mediolateral and the superior-inferior setup errors, was proved to provide adequate and comparable patient setup accuracy in WBRT and WBRT with additional LN irradiation.

Accuracy of a new paired imaging technique for position correction in whole breast radiotherapy.

Image-guided position verification in breast radiotherapy is accurately performed with kilovoltage cone beam CT (kV-CBCT). The technique is, however, time-consuming and there is a risk for patient collision. Online position verification performed with orthogonal-angled mixed modality paired imaging is less time-consuming at the expense of inferior accuracy compared to kV-CBCT. We therefore investigated whether a new tangential-angled single modality paired imaging technique can reduce the residual error (RE) of orthogonal-angled mixed modality paired imaging. The latter was applied to 20 breast cancer patients. Tangential-angled single modality paired imaging was investigated in 20 breast and 20 breast cancer patients with locoregional lymph node irradiation. The central lung distance (CLD) residual error and the longitudinal residual error were determined during the first 5 treatment fractions. Off-line matching of the tangential breast field images, acquired after online position correction, was used. The mean, systematic, and random REs of each patient group were calculated. The systematic REs were checked for significant differences using the F-test. Tangential-angled single modality paired imaging significantly reduced the systematic CLD residual error of orthogonal-angled mixed modality paired imaging for the breast cancer patients, from 2.3 mm to 1.0 mm, and also significantly decreased the systematic longitudinal RE from 2.4 mm to 1.3 mm. PTV margins, which account for the residual error (PTVRE), were also calculated. The PTVRE margin needed to account for the RE of orthogonal-angled mixed modality paired imaging (i.e., 8 mm) was halved by tangential-angled single modality paired imaging. The differences between the systematic REs of tangential-angled single modality paired imaging of the breast cancer patients and the breast cancer patients with locoregional lymph node irradiation were not significant, yielding comparable PTVRE margins. In this study, we showed that tangential-angled single modality paired imaging is superior to orthogonal-angled mixed modality paired imaging to correct the position errors in whole breast radiotherapy.

Gynecologic cancers in pregnancy: guidelines of a second international consensus meeting.

OBJECTIVES: This study aimed to provide timely and effective guidance for pregnant women and health care providers to optimize maternal treatment and fetal protection and to promote effective management of the mother, fetus, and neonate when administering potentially teratogenic medications. New insights and more experience were gained since the first consensus meeting 5 years ago. METHODS: Members of the European Society of Gynecological Oncology task force "Cancer in Pregnancy" in concert with other international experts reviewed the existing literature on their respective areas of expertise. The summaries were subsequently merged into a complete article that served as a basis for discussion during the consensus meeting. All participants approved the final article. RESULTS: In the experts' view, cancer can be successfully treated during pregnancy in collaboration with a multidisciplinary team, optimizing maternal treatment while considering fetal safety. To maximize the maternal outcome, cancer treatment should follow a standard treatment protocol as for nonpregnant patients. Iatrogenic prematurity should be avoided. Individualization of treatment and effective psychologic support is imperative to provide throughout the pregnancy period. Diagnostic procedures, including staging examinations and imaging, such as magnetic resonance imaging and sonography, are preferable. Pelvic surgery, either open or laparoscopic, as part of a treatment protocol, may reveal beneficial outcomes and is preferably performed by experts. Most standard regimens of chemotherapy can be administered from 14 weeks gestational age onward. Apart from cervical and vulvar cancer, as well as important vulvar scarring, the mode of delivery is determined by the obstetrician. Term delivery is aimed for. Breast-feeding should be considered based on individual drug safety and neonatologist-breast-feeding expert's consult. CONCLUSIONS: Despite limited evidence-based information, cancer treatment during pregnancy can succeed. State-of-the-art treatment should be provided for this vulnerable population to preserve maternal and fetal prognosis. SUPPLEMENTARY INFORMATION: Supplementary data on teratogenic effects, ionizing examinations, sentinel lymph node biopsy, tumor markers during pregnancy, as well as additional references and tables are available at the extended online version of this consensus article, go to http://links.lww.com/IGC/A197.

The photon dose calculation algorithm used in breast radiotherapy has significant impact on the parameters of radiobiological models.

The comparison of the pencil beam dose calculation algorithm with modified Batho heterogeneity correction (PBC-MB) and the analytical anisotropic algorithm (AAA) and the mutual comparison of advanced dose calculation algorithms used in breast radiotherapy have focused on the differences between the physical dose distributions. Studies on the radiobiological impact of the algorithm (both on the tumor control and the moderate breast fibrosis prediction) are lacking. We, therefore, investigated the radiobiological impact of the dose calculation algorithm in whole breast radiotherapy. The clinical dose distributions of 30 breast cancer patients, calculated with PBC-MB, were recalculated with fixed monitor units using more advanced algorithms: AAA and Acuros XB. For the latter, both dose reporting modes were used (i.e., dose-to-medium and dose-to-water). Next, the tumor control probability (TCP) and the normal tissue complication probability (NTCP) of each dose distribution were calculated with the Poisson model and with the relative seriality model, respectively. The endpoint for the NTCP calculation was moderate breast fibrosis five years post treatment. The differences were checked for significance with the paired t-test. The more advanced algorithms predicted a significantly lower TCP and NTCP of moderate breast fibrosis then found during the corresponding clinical follow-up study based on PBC calculations. The differences varied between 1% and 2.1% for the TCP and between 2.9% and 5.5% for the NTCP of moderate breast fibrosis. The significant differences were eliminated by determination of algorithm-specific model parameters using least square fitting. Application of the new parameters on a second group of 30 breast cancer patients proved their appropriateness. In this study, we assessed the impact of the dose calculation algorithms used in whole breast radiotherapy on the parameters of the radiobiological models. The radiobiological impact was eliminated by determination of algorithm specific model parameters.

Quantification of radiation-induced lung damage with CT scans: the possible benefit for radiogenomics.

BACKGROUND: Radiation-induced lung damage (RILD) is an important problem. Although physical parameters such as the mean lung dose are used in clinical practice, they are not suited for individualised radiotherapy. Objective, quantitative measurements of RILD on a continuous instead of on an ordinal, semi-quantitative, semi-subjective scale, are needed. METHODS: Hounsfield unit (HU) changes before versus three months post-radiotherapy were correlated per voxel with the radiotherapy dose in 95 lung cancer patients. Deformable registration was used to register pre- and post-CT scans and the density increase was quantified for various dose bins. The dose-response curve for increased HU was quantified using the slope of a linear regression (HU/Gy). The end-point for the toxicity analysis was dyspnoea ≥ grade 2. RESULTS: Radiation dose was linearly correlated with the change in HU (mean R(2) = 0.74 ± 0.28). No differences in HU/Gy between groups treated with stereotactic radiotherapy, conventional radiotherapy alone, sequential or concurrent chemo- radiotherapy were observed. In the whole patient group, 33/95 (34.7%) had dyspnoea ≥ G2. Of the 48 patients with a HU/Gy below the median, 16 (33.3%) developed dyspnoea ≥ G2, while in the 47 patients with a HU/Gy above the median, 17 (36.1%) had dyspnoea ≥ G2 (not significant). Individual patients showed a nearly 21-fold difference in radiosensitivity, with HU/Gy ranging from 0 to 10 HU/Gy. CONCLUSIONS: HU changes identify objectively the whole range of individual radiosensitivity on a continuous, quantitative scale. CT density changes may allow more robust and accurate radiogenomics studies.

Machine learning for normal tissue complication probability prediction: Predictive power with versatility and easy implementation.

Background and purpose: A popular Normal tissue Complication (NTCP) model deployed to predict radiotherapy (RT) toxicity is the Lyman-Burman Kutcher (LKB) model of tissue complication. Despite the LKB model's popularity, it can suffer from numerical instability and considers only the generalized mean dose (GMD) to an organ. Machine learning (ML) algorithms can potentially offer superior predictive power of the LKB model, and with fewer drawbacks. Here we examine the numerical characteristics and predictive power of the LKB model and compare these with those of ML. Materials and methods: Both an LKB model and ML models were used to predict G2 Xerostomia on patients following RT for head and neck cancer, using the dose volume histogram of parotid glands as the input feature. Model speed, convergence characteristics and predictive power was evaluated on an independent training set. Results: We found that only global optimization algorithms could guarantee a convergent and predictive LKB model. At the same time our results showed that ML models remained unconditionally convergent and predictive, while staying robust to gradient descent optimization. ML models outperform LKB in Brier score and accuracy but compare to LKB in ROC-AUC. Conclusion: We have demonstrated that ML models can quantify NTCP better than or as well as LKB models, even for a toxicity that the LKB model is particularly well suited to predict. ML models can offer this performance while offering fundamental advantages in model convergence, speed, and flexibility, and so could offer an alternative to the LKB model that could potentially be used in clinical RT planning decisions.

Using oxygen dose histograms to quantify voxelised ultra-high dose rate (FLASH) effects in multiple radiation modalities.

Purpose.To introduce a methodology to predict tissue sparing effects in pulsed ultra-high dose rate radiation exposures which could be included in a dose-effect prediction system or treatment planning system and to illustrate it by using three published experiments.Methods and materials.The proposed system formalises the variability of oxygen levels as an oxygen dose histogram (ODH), which provides an instantaneous oxygen level at a delivered dose. The histogram concept alleviates the need for a mechanistic approach. At each given oxygen level the oxygen fixation concept is used to calculate the change in DNA-damage induction compared to the fully hypoxic case. Using the ODH concept it is possible to estimate the effect even in the case of multiple pulses, partial oxygen depletion, and spatial oxygen depletion. The system is illustrated by applying it to the seminal results by Town (Nat. 1967) on cell cultures and the pre-clinical experiment on cognitive effects by Montay-Gruelet al(2017Radiother. Oncol.124365-9).Results.The proposed system predicts that a possible FLASH-effect depends on the initial oxygenation level in tissue, the total dose delivered, pulse length and pulse repetition rate. The magnitude of the FLASH-effect is the result of a redundant system, in that it will have the same specific value for a different combination of these dependencies. The cell culture data are well represented, while a correlation between the pre-clinical experiments and the calculated values is highly significant (p < 0.01).Conclusions. A system based only on oxygen related effects is able to quantify most of the effects currently observed in FLASH-radiation.

Companding technique for high dynamic range measurements using Gafchromic films.

PURPOSE: To introduce a methodology to perform dose measurements using Gafchromic films which can span several decades of dose levels. METHODS: The technique is based on a rescaling approach using different films irradiated at different dose levels. This is combined with a registration protocol correcting positioning and scaling factors for each film. The methodology is validated using TLD's for out-of-field doses. Furthermore, two examples are provided using the technique to characterize small sized radiosurgery cones and compared with measurements made with a pinpoint chamber. RESULTS: Excellent agreement with TLD, planning systems and measurement was found. The superior resolution of the film technique was apparent. CONCLUSIONS: The authors have introduced a new technique allowing users to quantify very low doses in conjunction with commissioning measurements. The use of film also provides 2D information on beam characteristics in high resolution measurements.

Incorporating oxygenation levels in analytical DNA-damage models-quantifying the oxygen fixation mechanism.

Purpose.To develop a framework to include oxygenation effects in radiation therapy treatment planning which is valid for all modalities, energy spectra and oxygen levels. The framework is based on predicting the difference in DNA-damage resulting from ionising radiation at variable oxygenation levels.Methods.Oxygen fixation is treated as a statistical process in a simplified model of complex and simple damage. We show that a linear transformation of the microscopic oxygen fixation process allows to extend this to all energies and modalities, resulting in a relatively simple rational polynomial expression. The model is expanded such that it can be applied for polyenergetic beams. The methodology is validated using Microdosimetric Monte Carlo Damage Simulation code (MCDS). This serves as a bootstrap to determine relevant parameters in the analytical expression, as MCDS is shown to be extensively verified with published empirical data. Double-strand break induction as calculated by this methodology is compared to published proton experiments. Finally, an example is worked out where the oxygen enhancement ratio (OER) is calculated at different positions in a clinically relevant spread out Bragg peak (SOBP) dose deposition in water. This dose deposition is obtained using a general Monte Carlo code (FLUKA) to determine dose deposition and locate fluence spectra.Results.For all modalities (electrons, protons), the damage categorised as complex could be parameterised to within 0.3% of the value calculated using microdosimetric Monte Carlo. The proton beam implementation showed some variation in OERs which differed slightly depending on where the assessment was made; before the SOBP, mid-SOBP or at the distal edge. Environment oxygenation was seen to be the more important variable.Conclusions.An analytic expression calculating complex damage depending on modality, energy spectrum, and oxygenation levels was shown to be effective and can be readily incorporated in treatment planning software, to take into account the impact of variable oxygenation, forming a first step to an optimised treatment based on biological factors.

Fast, accurate, and robust automatic marker detection for motion correction based on oblique kV or MV projection image pairs.

PURPOSE: A robust and accurate method that allows the automatic detection of fiducial markers in MV and kV projection image pairs is proposed. The method allows to automatically correct for inter or intrafraction motion. METHODS: Intratreatment MV projection images are acquired during each of five treatment beams of prostate cancer patients with four implanted fiducial markers. The projection images are first preprocessed using a series of marker enhancing filters. 2D candidate marker locations are generated for each of the filtered projection images and 3D candidate marker locations are reconstructed by pairing candidates in subsequent projection images. The correct marker positions are retrieved in 3D by the minimization of a cost function that combines 2D image intensity and 3D geometric or shape information for the entire marker configuration simultaneously. This optimization problem is solved using dynamic programming such that the globally optimal configuration for all markers is always found. Translational interfraction and intrafraction prostate motion and the required patient repositioning is assessed from the position of the centroid of the detected markers in different MV image pairs. The method was validated on a phantom using CT as ground-truth and on clinical data sets of 16 patients using manual marker annotations as ground-truth. RESULTS: The entire setup was confirmed to be accurate to around 1 mm by the phantom measurements. The reproducibility of the manual marker selection was less than 3.5 pixels in the MV images. In patient images, markers were correctly identified in at least 99% of the cases for anterior projection images and 96% of the cases for oblique projection images. The average marker detection accuracy was 1.4 +/- 1.8 pixels in the projection images. The centroid of all four reconstructed marker positions in 3D was positioned within 2 mm of the ground-truth position in 99.73% of all cases. Detecting four markers in a pair of MV images takes a little less than a second where most time is spent on the image preprocessing. CONCLUSIONS: The authors have developed a method to automatically detect multiple markers in a pair of projection images that is robust, accurate, and sufficiently fast for clinical use. It can be used for kV, MV, or mixed image pairs and can cope with limited motion between the projection images.

High Quality Clinical Stereotactic Radiosurgery Planning and Delivery With Standard Resolution (5 mm) Multileaf Collimation and Multiple Isocenters.

PURPOSE: Our purpose was to demonstrate the use of novel planning techniques in producing high-quality stereotactic radiosurgery (SRS) plans using a standard 5 mm multileaf collimator (MLC) and multiple isocenters delivered clinically at a local institution. METHODS AND MATERIALS: Novel planning techniques consisted of offset isocenter, variable asymmetrical jaws, and Digital Imagine and Communications in Medicine (DICOM) edits to reduce leaf tip transmission, all with the aim of maximizing dose conformity. A local institution clinical cohort was planned (1-4 targets), and plan conformity metrics common to SRS were compared against conformity metrics from selected previous publications comparing Gamma Knife to linear accelerator SRS using high-definition MLC (2.5 mm). Additionally, local institution plan conformity metrics for 2 benchmark SRS planning cases (3 and 7 targets) were compared with metrics from other centers treating SRS clinically in England. Pretreatment quality assurance results, both point dose measurement and film analysis, are presented to demonstrate plan deliverability. RESULTS: Clinical conformity metrics are shown to be comparable to previously published results using either Gamma Knife or linear accelerator with high-definition MLC. Metrics from benchmark planning cases are shown to be comparable and to have better prescription dose conformity than average nationally in England. Pretreatment quality assurance results demonstrate suitable plan deliverability. CONCLUSIONS: SRS planning using standard 5 mm MLC and multiple isocenters produces high-quality treatment plans for a limited number of targets with a high degree of dose conformity and dose fall off when employing novel planning techniques to compensate for MLC leaf size and multiple isocenters.

Assessment of robustness against setup uncertainties using probabilistic scenarios in lung cancer: a comparison of proton with photon therapy.

OBJECTIVE: We compared the sensitivity of intensity modulated proton therapy (IMPT) and photon volumetric modulated arc therapy (VMAT) plans to setup uncertainties in locally advanced non-small cell lung cancer (NSCLC) using probabilistic scenarios. METHODS: Minimax robust (MM) and planning target volume (PTV) optimised IMPT and VMAT nominal plans were created with physical dose of 70 Gy in 35 fractions in 10 representative patients. Using population data of setup errors, a fractionated treatment course was simulated, summed (Dsum) and compared to the nominal plan. Three treatment-course simulations were done for each plan. Target robustness criteria were: dose deviation of ≤5% to clinical target volume (CTV) D98% and CTV V95% ≥ 99.9%. Voxelwise simulation repeatability was analysed using Bland-Altman plots. Acceptable limits of agreement were 2% of the prescription dose. RESULTS: All Dsum met target robustness criteria. While fraction VMAT and MM-IMPT doses were excellent, simulated fraction doses in PTV-IMPT were suboptimal. Almost all (>99%) of VMAT and MM-IMPT fraction doses met both target robustness criteria. For PTV-IMPT, only 96.9 and 80.3% of fractions met CTVD98% and V95% criteria respectively. Simulation repeatability was excellent (limits of agreement range: 0.41-1.1 Gy) with strong positive correlations. CONCLUSION: When considering the whole treatment course, setup errors do not influence robustness irrespective of planning techniques used. However, on a fraction level, VMAT and MM-IMPT plans are superior compared to PTV-IMPT plans. ADVANCES IN KNOWLEDGE: Probabilistic analysis provides a fast and practical method for evaluating VMAT and IMPT plan sensitivity against setup uncertainty. VMAT and robust-optimised IMPT plans have comparable sensitivity to setup uncertainties in conventionally fractionated treatment for NSCLC.

Is an analytical dose engine sufficient for intensity modulated proton therapy in lung cancer?

OBJECTIVE: To identify a subgroup of lung cancer plans where the analytical dose calculation (ADC) algorithm may be clinically acceptable compared to Monte Carlo (MC) dose calculation in intensity modulated proton therapy (IMPT). METHODS: Robust-optimised IMPT plans were generated for 20 patients to a dose of 70 Gy (relative biological effectiveness) in 35 fractions in Raystation. For each case, four plans were generated: three with ADC optimisation using the pencil beam (PB) algorithm followed by a final dose calculation with the following algorithms: PB (PB-PB), MC (PB-MC) and MC normalised to prescription dose (PB-MC scaled). A fourth plan was generated where MC optimisation and final dose calculation was performed (MC-MC). Dose comparison and γ analysis (PB-PB vs PB-MC) at two dose thresholds were performed: 20% (D20) and 99% (D99) with PB-PB plans as reference. RESULTS: Overestimation of the dose to 99% and mean dose of the clinical target volume was observed in all PB-MC compared to PB-PB plans (median: 3.7 Gy(RBE) (5%) (range: 2.3 to 6.9 Gy(RBE)) and 1.8 Gy(RBE) (3%) (0.5 to 4.6 Gy(RBE))). PB-MC scaled plans resulted in significantly higher CTVD2 compared to PB-PB (median difference: -4 Gy(RBE) (-6%) (-5.3 to -2.4 Gy(RBE)), p ≤ .001). The overall median γ pass rates (3%-3 mm) at D20 and D99 were 93.2% (range:62.2-97.5%) and 71.3 (15.4-92.0%). On multivariate analysis, presence of mediastinal disease and absence of range shifters were significantly associated with high γ pass rates. Median D20 and D99 pass rates with these predictors were 96.0% (95.3-97.5%) and 85.4% (75.1-92.0%). MC-MC achieved similar target coverage and doses to OAR compared to PB-PB plans. CONCLUSION: In the presence of mediastinal involvement and absence of range shifters Raystation ADC may be clinically acceptable in lung IMPT. Otherwise, MC algorithm would be recommended to ensure accuracy of treatment plans. ADVANCES IN KNOWLEDGE: Although MC algorithm is more accurate compared to ADC in lung IMPT, ADC may be clinically acceptable where there is mediastinal involvement and absence of range shifters.

Stereotactic body radiotherapy for moderately central and ultra-central oligometastatic disease: Initial outcomes.

BACKGROUND: Delivery of SBRT to central thoracic tumours within 2 cm of the proximal bronchial tree (PBT), and especially ultra-central tumours which directly abut the PBT, has been controversial due to concerns about high risk of toxicity and treatment-related death when delivering high doses close to critical mediastinal structures. We present dosimetric and clinical outcomes from a group of oligometastatic patients treated with a risk-adapted SBRT approach. METHODS: Between September 2015 and October 2018, 27 patients with 28 central thoracic oligometastases (6 moderately central, 22 ultra-central) were treated with 60 Gy in 8 fractions under online CBCT guidance. PTV dose was compromised where necessary to meet mandatory OAR constraints. Patients were followed up for toxicity and disease status. RESULTS: Mandatory OAR constraints were met in all cases; this required PTV coverage compromise in 23 cases, with V100% reduced to <70% in 11 cases. No acute or late toxicities of Grade ≥ 3 were reported. One and 2 year in-field control rates were 95.2% and 85.7% respectively, progression-free survival rates were 42.8% and 23.4% respectively, and overall survival rates were 82.7% and 69.5% respectively. No significant differences were seen in control or survival rates by extent of PTV underdosage or between moderately and ultra-central cases. CONCLUSION: It appears that compromising PTV coverage to meet OAR constraints allows safe and effective delivery of SBRT to moderately and ultra-central tumours, with low toxicity rates and high in-field control rates. This treatment can be delivered on standard linear accelerators with widely available imaging technology.

Response of FDG avid pelvic bone marrow to concurrent chemoradiation for anal cancer.

BACKGROUND AND PURPOSE: To determine if suppression of active bone marrow, as defined on FDG PETCT, is seen in on-treatment imaging of anal cancer patients receiving concurrent chemoradiation. METHODS AND MATERIALS: Scans from 26 patients participating in the ART trial (full title: Anal squamous cell carcinoma: Investigation of functional imaging during chemoRadioTherapy), a single center observational study with FDG PETCT prior to radiotherapy and at fraction 8-10 of concurrent chemoradiation were analysed. Active bone marrow was contoured in both the pelvis and un-irradiated thoracic spine. SUV and volume of active bone marrow after 8-10 fractions of treatment were compared to baseline. Dose metrics to pelvic active bone marrow were extracted and compared to reduction in SUV/active bone marrow volume and to blood count nadir using linear regression. RESULTS: Suppression of active bone marrow is seen in the pelvis by a reduction in mean SUV and volume of active bone marrow after 8-10 fractions of treatment. Suppression is not seen in un-irradiated thoracic spine. Dose metrics were associated with reduced SUV and reduced volume of active bone marrow. Volume of active bone marrow receiving <20 Gy was associated with WCC/ANC nadir. 20 Gy was identified as the most likely clinically meaningful dose threshold for toxicity. Volume of active bone marrow receiving <20 Gy correlated to WCC and ANC with an increase of 100 cc being associated with an increase of 0.4 and 0.3 respectively. CONCLUSION: The effect of concurrent chemoradiation in suppression of active bone marrow is seen in on-treatment FDG PETCT scans. Chemotherapy appears well tolerated after 2 weeks of treatment.

A systematic review of health economic evaluations of proton beam therapy for adult cancer: Appraising methodology and quality.

BACKGROUND AND PURPOSE: With high treatment costs and limited capacity, decisions on which adult patients to treat with proton beam therapy (PBT) must be based on the relative value compared to the current standard of care. Cost-utility analyses (CUAs) are the gold-standard method for doing this. We aimed to appraise the methodology and quality of CUAs in this area. MATERIALS AND METHODS: We performed a systematic review of the literature to identify CUA studies of PBT in adult disease using MEDLINE, EMBASE, EconLIT, NHS Economic Evaluation Database (NHS EED), Web of Science, and the Tufts Medical Center Cost-Effectiveness Analysis Registry from 1st January 2010 up to 6th June 2018. General characteristics, information relating to modelling approaches, and methodological quality were extracted and synthesized narratively. RESULTS: Seven PBT CUA studies in adult disease were identified. Without randomised controlled trials to inform the comparative effectiveness of PBT, studies used either results from one-armed studies, or dose-response models derived from radiobiological and epidemiological studies of PBT. Costing methods varied widely. The assessment of model quality highlighted a lack of transparency in the identification of model parameters, and absence of external validation of model outcomes. Furthermore, appropriate assessment of uncertainty was often deficient. CONCLUSION: In order to foster credibility, future CUA studies must be more systematic in their approach to evidence synthesis and expansive in their consideration of uncertainties in light of the lack of clinical evidence.

Impact of abdominal compression on setup error and image matching during radical abdominal radiotherapy.

PURPOSE: To determine the impact of abdominal compression (AC) on setup error and image matching time. MATERIALS AND METHODS: This study included 72 liver, pancreas and abdominal node patients treated radically from 2016 to 2019 in a single centre. Patients received either SBRT or conventional radical fractionation (CRF). Compressed patients were supine, arms up with kneefix and AC equipment. Uncompressed patients were supine, arms up with kneefix. All patients received daily online-matched CBCTs before treatment. Initial setup error was determined for all patients. Registration error was assessed for 10 liver and 10 pancreas patients. Image matching times were determined using beam on times. Statistical tests conducted were an F-test to compare variances in setup error, Student's t-tests for setup error and average image analysis, and a Wilcoxon Mann Whitney test for imaging matching time analysis. RESULTS: Initial setup displacement was similar between compressed and uncompressed patients. Displacements > 1 cm occurred more frequently in the longitudinal direction for most patients. SBRT patients required more additional manual positioning following imaging. Mean absolute registration error in the SI direction was 5.4 mm and 3.3 mm for uncompressed and compressed pancreas patients respectively and 1.7 mm and 0.8 mm for uncompressed and compressed liver patients respectively. Compressed patients required less time for image matching and fewer images per fraction on average. Repeat imaging occurred more frequently in SBRT and uncompressed patients. CONCLUSIONS: Although abdominal compression has no significant impact on setup error, it can reduce imaging matching times resulting in improved treatment accuracy.

Technical Note: Defining cyclotron-based clinical scanning proton machines in a FLUKA Monte Carlo system.

PURPOSE: Cyclotron-based pencil beam scanning (PBS) proton machines represent nowadays the majority and most affordable choice for proton therapy facilities, however, their representation in Monte Carlo (MC) codes is more complex than passively scattered proton system- or synchrotron-based PBS machines. This is because degraders are used to decrease the energy from the cyclotron maximum energy to the desired energy, resulting in a unique spot size, divergence, and energy spread depending on the amount of degradation. This manuscript outlines a generalized methodology to characterize a cyclotron-based PBS machine in a general-purpose MC code. The code can then be used to generate clinically relevant plans starting from commercial TPS plans. METHODS: The described beam is produced at the Provision Proton Therapy Center (Knoxville, TN, USA) using a cyclotron-based IBA Proteus Plus equipment. We characterized the Provision beam in the MC FLUKA using the experimental commissioning data. The code was then validated using experimental data in water phantoms for single pencil beams and larger irregular fields. Comparisons with RayStation TPS plans are also presented. RESULTS: Comparisons of experimental, simulated, and planned dose depositions in water plans show that same doses are calculated by both programs inside the target areas, while penumbrae differences are found at the field edges. These differences are lower for the MC, with a γ(3%-3 mm) index never below 95%. CONCLUSIONS: Extensive explanations on how MC codes can be adapted to simulate cyclotron-based scanning proton machines are given with the aim of using the MC as a TPS verification tool to check and improve clinical plans. For all the tested cases, we showed that dose differences with experimental data are lower for the MC than TPS, implying that the created FLUKA beam model is better able to describe the experimental beam.