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Purpose: Tumor vessels influence the growth and response of tumors to therapy. Imaging vascular changes in vivo using dynamic contrast-enhanced MRI (DCE-MRI) has shown potential to guide clinical decision making for treatment. However, quantitative MR imaging biomarkers of vascular function have not been widely adopted, partly because their relationship to structural changes in vessels remains unclear. We aimed to elucidate the relationships between vessel function and morphology in vivo.Experimental Design: Untreated preclinical tumors with different levels of vascularization were imaged sequentially using DCE-MRI and CT. Relationships between functional parameters from MR (iAUC, Ktrans, and BATfrac) and structural parameters from CT (vessel volume, radius, and tortuosity) were assessed using linear models. Tumors treated with anti-VEGFR2 antibody were then imaged to determine whether antiangiogenic therapy altered these relationships. Finally, functional–structural relationships were measured in 10 patients with liver metastases from colorectal cancer.Results: Functional parameters iAUC and Ktrans primarily reflected vessel volume in untreated preclinical tumors. The relationships varied spatially and with tumor vascularity, and were altered by antiangiogenic treatment. In human liver metastases, all three structural parameters were linearly correlated with iAUC and Ktrans. For iAUC, structural parameters also modified each other's effect.Conclusions: Our findings suggest that MR imaging biomarkers of vascular function are linked to structural changes in tumor vessels and that antiangiogenic therapy can affect this link. Our work also demonstrates the feasibility of three-dimensional functional–structural validation of MR biomarkers in vivo to improve their biological interpretation and clinical utility. Clin Cancer Res; 24(19); 4694–704. ©2018 AACR.

Supplementary methods and data. Supplementary Table 1. Equations of chosen models fit using ordinary least squares regression with the best Bayesian Information Criterion for iAUC90, Ktrans, and BATfrac in untreated preclinical tumors (cohort 1). Goodness of fit for each model was assessed by two measures, residuals vs fitted and Q-Q plots, which are shown in Supplementary Figure 4. Supplementary Table 2. Evaluation of model fits for iAUC90, Ktrans, and BATfrac generated from cohort 1 applied to preclinical data from cohort 2 treated with control IgG or with anti-VEGFR2 antibody DC101. Goodness of fit for each model was assessed by two measures, residuals vs fitted and Q-Q plots, which are shown in Supplementary Figures 6-7. Supplementary Table 3. Equations of chosen linear models with best Bayesian Information Criterion for iAUC90 and Ktrans in clinical tumors. Supplementary Figure 1. Signal-to-noise ratio on DCE-MRI is affected > 5 mm away from surface coil. Supplementary Figure 2. Longitudinal, repeated imaging with CT curbs tumor growth. Supplementary Figure 3. Vascular parameters (vessel length (a), tortuosity (b), and radius (c)) correlate poorly with volume of MC38 and FaDu tumors. Supplementary Figure 4. For each MR parameter of untreated preclinical tumors of cohort 1, the chosen linear model has normal residuals, as assessed by residual vs fitted plots and Q-Q plots, demonstrating goodness of fit. Supplementary Figure 5. For each MR parameter of untreated preclinical tumors of cohort 2, the tested linear model has normal residuals, as assessed by residual vs fitted plots and Q-Q plots, demonstrating goodness of fit. Supplementary Figure 6. Goodness-of-fit, as assessed by residual vs fitted plots and by Q-Q plots, for linear models applied to DC101-treated preclinical tumors of cohort 2. The chosen linear models for iAUC and BAT have residuals that exhibit departures from normality, indicating that the treatment altered these parameters. Supplementary Figure 7. For each MR parameter of clinical tumors, the chosen linear models demonstrate normal residuals, indicating goodness-of-fit.

The limited radiation tolerance of the small-bowel causes toxicity for patients receiving conventionally-fractionated radiotherapy for rectal cancer. Safe radiotherapy dose-escalation will require a better understanding of such toxicity. We conducted a systematic review and meta-analysis using published datasets of small bowel dose-volume and outcomes to analyse the relationship with acute toxicity. SCOPUS, EMBASE & MEDLINE were searched to identify twelve publications reporting small-bowel dose-volumes and toxicity data or analysis. Where suitable data were available (mean absolute volume with parametric error measures), fixed-effects inverse-variance meta-analysis was used to compare cohorts of patients according to Grade ≥3 toxicity. For other data, non-parametric examinations of irradiated small-bowel dose-volume and incidence of toxicity were conducted, and a univariate logistic regression model was fitted. On fixed-effects meta-analysis of three studies (203 patients), each of the dose-volume measures V5Gy-V40Gy were significantly greater (p

Intratumoural heterogeneity (ITH) contributes to local recurrence following radiotherapy in prostate cancer. Recent studies also show that ecological interactions between heterogeneous tumour cell populations can lead to resistance in chemotherapy. Here, we evaluated whether interactions between heterogenous populations could impact growth and response to radiotherapy in prostate cancer. Using mixed 3D cultures of parental and radioresistant populations from two prostate cancer cell lines and a predator-prey mathematical model to investigate various types of ecological interactions, we show that reciprocal interactions between heterogeneous populations enhance overall growth and reduce radiation sensitivity. The type of interaction influences the time of regrowth after radiation, and, at the population level, alters the survival and cell cycle of each population without eliminating either one. These interactions can arise from oxygen constraints and from cellular cross-talk that alter the tumour microenvironment. These findings suggest that ecological-type interactions are important in radiation response and could be targeted to reduce local recurrence., Using co-culture experiments and mathematical modelling, Paczkowski et al discover that prostate cancer spheroids comprising mixed tumour cell populations display enhanced growth and reduced radiation sensitivity due to competitive and antagonistic interactions between cell populations. This interdisciplinary approach reveals a role for ecological-type interactions in the radiation response and may be used to study other cancer types.

Background: In LAPC, additional benefit of CRT over chemotherapy is uncertain. Optimising local therapy for a subset that never develops distant disease may prolong survival. Nelfinavir is thought to enhance radiosensitivity through hypoxia reduction by increasing tumour blood flow. Methods: A non-randomised, single centre phase II study, in FDG-PET-selectedpatients withhistologically proven LAPC. CRT consisted of: nelfinavir 1250 mg bd (days -3 to 45); gemcitabine 300 mg/m2 & cisplatin 30 mg/m2 (days 2, 9, 23 & 30); concurrent radiotherapy: 59.4 Gy/33# to primary tumour, 50.4 Gy/28# to regional nodes. Adjuvant gemcitabine was given for 6 months. Primary endpoint: 1 year overall survival (OS); secondary endpoints included: toxicity, response rate, resectability, median progression free survival (PFS), OS and local PFS. 6 patients had sequential dynamic 18fluoromisonidazole PET (FMISO-PET) and perfusion CT (pCT) before and after 6-7 days of nelfinavir (given from day -8). Results: 23 patients entered between Feb 2010-July2014. The trial was stopped because of unavailability of nelfinavir in Europe. 3 patients did not complete treatment (1 each of PE, biliary sepsis, stroke). Common G3/4 toxicities: thrombocytopenia/leukopenia (both 35%), diarrhoea (17%), nausea/vomiting (17%), fatigue (13%). 1 yr and median OS: 76.7% (95% CI 52.8-89.6) and 17.4 months (95% CI 12.7-22.8) respectively. 1 yr PFS and Local PFS: 36.8% (16.5-57.5) and 52.9% (95% CI 25.2-74.4) respectively. Mean FDG SUVmax reduction was 39% (p < 0.001) and was ≥60% in 29% of patients. 2 patients became resectable. 4/6 patients had reduced FMISO retention and increased pCT derived blood flow (BF) post-nelfinavir. Mean change in FMISO-k3 (2 tissue compartmental model) -50.3% vs 6% and BF 20.1 vs -7.1% in responders vs non-responders. 8/13 demonstrated a reduction in pAKT in peripheral blood mononuclear cells. Conclusions: Nelfinavir with CRT is well tolerated with promising outcomes, as these patients were not pre-selected through induction chemotherapy. Modulation of hypoxia & BF by nelfinavir was demonstrated. A randomised phase II study, SCALOP2, opens in 2015. Clinical trial information: 2008-006302-42.

Background and purpose A recent update of the RTOG 9811, reported differing relapse rates for early and late anal squamous cell carcinoma following chemoradiotherapy (CRT). There may be a role for dose-individualization, however the dose–response relationship for anal cancer is not currently known. Intensity-modulated radiotherapy (IMRT) has been widely adopted with multiple series published. The aim is to fit a tumor control probability (TCP) model to the published IMRT data. Materials and methods We performed a systematic review of PubMed and Embase databases to identify thirteen appropriate papers, including 625 patients. Predefined data fields were collected. A standard linear quadratic TCP model, which included repopulation, was fit by least squares minimization. Results The fitted TCP curve demonstrated a dose–response relationship with α = 0.196 Gy–1. The curve suggests: in early stage tumours, a dose reduction from 50 Gy to 45 Gy reduces 2 year local control from 98% to 95%; in late stage tumours, a dose escalation from 50 Gy to 55 Gy improves the 2 year local control rate from approximately 50% to 80%. Conclusions The published data are broadly consistent with a linear quadratic dose–response model. Dose-individualization in anal cancer should be further investigated in the context of clinical trials.

Purpose: To investigate the effects of an endorectal device during prostate radiotherapy on the spatial distribution of dose to the ano‐rectal region and quantify implications for normal‐tissue‐complication probabilities. Methods: Twenty‐three patients with localised prostate cancer, referred for external beam radiotherapy had 2 CT scans acquired, without and with the rectal obturator (ProSpare) in‐situ. For each patient two dose distributions were generated, based on both CT scans.Dose‐surface maps for the rectal surface and the anal surface were generated and mean dose as well as a spatial measure (circumference of the dose distribution) were determined for all patients, with and without ProSpare. Using previously published NTCP models, the effect of ProSpare on NTCP was investigated for rectal bleeding and subjective sphincter control.Results: In a previous study subjective sphincter control correlated strongest with mean dose and lateral extent at 53 Gy. The use of ProSpare resulted in a highly significant reduction of the lateral extent at 53 Gy (p=0.006), mean dose (p=0.0009) and NTCP according to the LKB model (p=0.002 for grade 2 and p=0.001 for grade >=1). In a previous study we reported that rectal bleeding correlated most strongly with the lateral extent at 55 Gy and presented the constraint that it should not exceed 42% of the circumference. Using ProSpare resulted in a significant reduction of the lateral extent at 55 Gy (p=0.001) and significantly more patients met that proposed constraint (p=0.047). ProSpare resulted in a significant reduction of NTCP for grade‐2 rectal bleeding (p=0.007) and a reduction for rectal bleeding grade >=1 (p=0.053). Conclusions: ProSpare resulted in a significant reduction of mean dose to the anal sphincter and a significant reduction of the lateral extent at 55 Gy. This corresponded to a significant reduction in the predicted risk of reporting subjective sphincter control and grade‐2 rectal bleeding.

Background and purpose Gastro-intestinal toxicity is dose-limiting in abdominal radiotherapy and correlated with duodenum dose-volume parameters. We aimed to derive updated NTCP model parameters using published data and prospective radiotherapy quality-assured cohort data. Material and methods A systematic search identified publications providing duodenum dose-volume histogram (DVH) statistics for clinical studies of conventionally-fractionated radiotherapy. Values for the Lyman-Kutcher-Burman (LKB) NTCP model were derived through sum-squared-error minimisation and using leave-one-out cross-validation. Data were corrected for fraction size and weighted according to patient numbers, and the model refined using individual patient DVH data for two further cohorts from prospective clinical trials. Results Six studies with published DVH data were utilised, and with individual patient data included outcomes for 531 patients in total (median follow-up 16 months). Observed gastro-intestinal toxicity rates ranged from 0% to 14% (median 8%). LKB parameter values for unconstrained fit to published data were: n = 0.070, m = 0.46, TD50(1) [Gy] = 183.8, while the values for the model incorporating the individual patient data were n = 0.193, m = 0.51, TD50(1) [Gy] = 299.1. Conclusions LKB parameters derived using published data are shown to be consistent to those previously obtained using individual patient data, supporting a small volume-effect and dependence on exposure to high threshold dose.

Functional imaging gives information about physiological heterogeneity in tumours. The utility of functional imaging tests in providing predictive and prognostic information after chemoradiotherapy for both oesophageal cancer and pancreatic cancer will be reviewed. The benefit of incorporating functional imaging into radiotherapy planning is also evaluated. In cancers of the upper gastrointestinal tract, the vast majority of functional imaging studies have used 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). Few studies in locally advanced pancreatic cancer have investigated the utility of functional imaging in risk-stratifying patients or aiding target volume definition. Certain themes from the oesophageal data emerge, including the need for a multiparametric assessment of functional images and the added value of response assessment rather than relying on single time point measures. The sensitivity and specificity of FDG-PET to predict treatment response and survival are not currently high enough to inform treatment decisions. This suggests that a multimodal, multiparametric approach may be required. FDG-PET improves target volume definition in oesophageal cancer by improving the accuracy of tumour length definition and by improving the nodal staging of patients. The ideal functional imaging test would accurately identify patients who are unlikely to achieve a pathological complete response after chemoradiotherapy and would aid the delineation of a biological target volume that could be used for treatment intensification. The current limitations of published studies prevent integrating imaging-derived parameters into decision making on an individual patient basis. These limitations should inform future trial design in oesophageal and pancreatic cancers.

Purpose\ud Using radiobiological modelling to estimate normal tissue toxicity, this study investigates the effects of dose escalation for concurrent chemoradiation therapy (CRT) in lower third oesophageal tumours on the stomach.\ud \ud Methods and materials\ud 10 patients with lower third oesophageal cancer were selected from the SCOPE 1 database (ISCRT47718479) with a mean planning target volume (PTV) of 348 cm3. The original 3D conformal plans (50Gy3D) were compared to newly created RapidArc plans of 50GyRA and 60GyRA, the latter using a simultaneous integrated boost (SIB) technique using a boost volume, PTV2. Dose-volume metrics and estimates of normal tissue complication probability (NTCP) were compared.\ud \ud Results\ud There was a significant increase in NTCP of the stomach wall when moving from the 50GyRA to the 60GyRA plans (11–17 %, Wilcoxon signed rank test, p = 0.01). There was a strong correlation between the NTCP values of the stomach wall and the volume of the stomach wall/PTV 1 and stomach wall/PTV2 overlap structures (R = 0.80 and R = 0.82 respectively) for the 60GyRA plans.\ud \ud Conclusion\ud Radiobiological modelling suggests that increasing the prescribed dose to 60Gy may be associated with a significantly increased risk of toxicity to the stomach. It is recommended that stomach toxicity be closely monitored when treating patients with lower third oesophageal tumours with 60Gy.

The oxygen status of a tumor has significant clinical implications for treatment prognosis, with well-oxygenated subvolumes responding markedly better to radiotherapy than poorly supplied regions. Oxygen is essential for tumor growth, yet estimation of local oxygen distribution can be difficult to ascertainin situ, due to chaotic patterns of vasculature. It is possible to avoid this confounding influence by using avascular tumor models, such as tumor spheroids, a much better approximation of realistic tumor dynamics than monolayers, where oxygen supply can be described by diffusion alone. Similar to insitutumours, spheroids exhibit an approximately sigmoidal growth curve, often approximated and fitted by logistic and Gompertzian sigmoid functions. These describe the basic rate of growth well, but do not offer an explicitly mechanistic explanation. This work examines the oxygen dynamics of spheroids and demonstrates that this growth can be derived mechanistically with cellular doubling time and oxygen consumption rate (OCR) being key parameters. The model is fitted to growth curves for a range of cell lines and derived values of OCR are validated using clinical measurement. Finally, we illustrate how changes in OCR due to gemcitabine treatment can be directly inferred using this model.

The presence of oxygen in tumours has substantial impact on treatment outcome; relative to anoxic regions, well-oxygenated cells respond better to radiotherapy by a factor 2.5–3. This increased radio-response is known as the oxygen enhancement ratio. The oxygen effect is most commonly explained by the oxygen fixation hypothesis, which postulates that radical-induced DNA damage can be permanently ‘fixed’ by molecular oxygen, rendering DNA damage irreparable. While this oxygen effect is important in both existing therapy and for future modalities such a radiation dose-painting, the majority of existing mathematical models for oxygen enhancement are empirical rather than based on the underlying physics and radiochemistry. Here we propose a model of oxygen-enhanced damage from physical first principles, investigating factors that might influence the cell kill. This is fitted to a range of experimental oxygen curves from literature and shown to describe them well, yielding a single robust term for oxygen interaction obtained. The model also reveals a small thermal dependency exists but that this is unlikely to be exploitable.

PurposeThe optimum dose and fractionation in radiation therapy of curative intent for non-small cell lung cancer remains uncertain. We undertook a published data meta-analysis of randomized trials to examine whether radiation therapy regimens with higher time-corrected biologically equivalent doses resulted in longer survival, either when given alone or when given with chemotherapy.Methods and MaterialsEligible studies were randomized comparisons of 2 or more radiation therapy regimens, with other treatments identical. Median survival ratios were calculated for each comparison and pooled.Results3795 patients in 25 randomized comparisons of radiation therapy dose were studied. The median survival ratio, higher versus lower corrected dose, was 1.13 (95% confidence interval [CI] 1.04-1.22) when radiation therapy was given alone and 0.83 (95% CI 0.71-0.97) when it was given with concurrent chemotherapy (P for difference=.001). In comparisons of radiation therapy given alone, the survival benefit increased with increasing dose difference between randomized treatment arms (P for trend=.004). The benefit increased with increasing dose in the lower-dose arm (P for trend=.01) without reaching a level beyond which no further survival benefit was achieved. The survival benefit did not differ significantly between randomized comparisons where the higher-dose arm was hyperfractionated and those where it was not. There was heterogeneity in the median survival ratio by geographic region (P

Aims The potential advantages of stereotactic body radiotherapy (SBRT) for early stage non-small cell lung cancer (NSCLC) over conventional fractionated radiotherapy include a higher biological effective dose, a reduction in accelerated repopulation, greater patient convenience and reduced demand on radiotherapy resources. Before introducing SBRT in our department, a review of planning and delivery was undertaken, starting with an assessment of optimum beam number and arrangement. Materials and methods Radiotherapy planning computed tomography scans for five patients previously treated for T1 peripheral NSCLC were selected. In each the contoured tumour had planning target volume (PTV) margins of 1cm in all directions. Forward-planned three-field coplanar and non-coplanar plans and a seven-field coplanar plan were produced and optimised. In-house inverse-planning software (AutoBeam) was used to generate three-, five-, seven- and nine-field coplanar and non-coplanar plans and two volumetric intensity-modulated arc therapy (VMAT) plans. The resulting V 20 , V 11 , PTV 90 , PTV 95 and mean lung dose were compared. Results Analysis of variance showed non-coplanar plans to have lower V 11 and higher PTV 90 and PTV 95 than coplanar plans. VMAT showed equivalent V 20 and target coverage when compared with the best non-coplanar plans, but with a faster delivery time (2min 8s versus 12min 40s). Conclusions Inverse-planned five-field non-coplanar plans and VMAT improve target coverage while minimising the higher dose to normal lung tissue for SBRT of NSCLC compared with coplanar beam arrangements. VMAT is preferable because of significantly shorter treatment delivery times.

Purpose To review the published clinical data on non-small cell lung cancer treated with radical radiotherapy to confirm a dose–response relationship as a basis for further dose-escalation trials. Methods Twenty-four published clinical trials were identified, 16 of which – with 29 different standard, hyper- and hypofractionated treatment schedules – were analysed. Prescription doses were converted to biologically-equivalent dose (BED), with a correction for repopulation. Disease-free survival data were corrected for the stage profile of each cohort to allow better comparison of results. We also analysed moderate (grade II and III) lung and oesophageal acute toxicity related to the corrected BED delivered to the tumour. Results The clinical data analysed showed good agreement between the observed and modelled disease-free survival at 2years when compared to the published models of Fenwick (correlation coefficient 0.525, p =0.003) and Martel (correlation coefficient 0.492, p =0.007), indicating a clear tumour dose–response. In the normally fractionated treatments (∼2Gy per fraction), improved disease-free survival was generally observed in the shorter schedules (maximum around 6weeks). However, the best outcomes were obtained for the hypofractionated schedules. No systematic relationship was seen between prescribed dose and lung or oesophageal acute toxicity, possibly due to dose selection depending on V 20 or MLD in some studies and the diversity of the patients analysed. Conclusions We have demonstrated a dose–response relationship for NSCLC based on clinical data. The clinical data provide a rational basis for selection of dose escalation schedules to be tested in future randomised trials.

There is growing clinical evidence that functional imaging is useful for target volume definition and early assessment of tumour response to external beam radiotherapy. A subject that has perhaps received less attention, but is no less promising, is the application of functional imaging to the prediction or measurement of radiation adverse effects in normal tissues. In this manuscript, we review the current published literature describing the use of positron emission tomography (PET), four-dimensional computed tomography (4D-CT), single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) to study normal tissue function in the context of radiotherapy to the lung, liver and head & neck. Published results to date demonstrate that functional imaging can be used to preferentially avoid normal tissues not easily identifiable on solely anatomical images. It is also a potentially very powerful tool for the early detection of radiotherapy-induced normal tissue adverse effects and could provide valuable data for building predictive models of outcome. However, one of the major challenges to building useful predictive models is that, to date, there are very little data available with combined images of normal function, 3D delivered radiation dose and clinical outcomes. Prospective data collection through well-constructed studies which use established morbidity scores is clearly a priority if significant progress is to be made in this area.

Purpose: Modern radiotherapy treatments can be optimized using dose-volume constraints which specify the volume of tumor and organs-at-risk receiving a given threshold dose. Careful derivation and evaluation of rectal constraints is essential to allow safe dose escalation in radiotherapy of prostate cancer. The authors present a new type of hybrid dosimetric constraint which comprises both volumetric and spatial factors of the dose-distribution. The authors also propose a framework to evaluate these constraints. Methods: The authors used data from the RT01 prostate radiotherapy trial (ISRCTN 47772397) to derive this set of hybrid constraints for the rectum based on measures extracted from dose-surface maps. For comparison, the authors also derive a set of dose-volume constraints. In order to evaluate these dosimetric constraints, the authors propose a new framework for predicting radiation-induced toxicities using Bayesian logistic regression with high-order interactions. The predictive power of the new RT01-based constraints, as well as of two sets of rectal dose-volume constraints proposed in the recent literature—The constraints proposed by other researchers [C. Fiorino, G. Fellin, T. Rancati, V. Vavassori, C. Bianchi, V. C. Borca, G. Girelli, M. Mapelli, L. Menegotti, S. Nava, and R. Valdagni, “Clinical and dosimetric predictors of late rectal syndrome after 3D-CRT for localized prostate cancer: Preliminary results of a multicenter prospective study,” Int. J. Radiat. Oncol., Biol., Phys.70, 1130–1137 (2008)] and the constraints used in the conventional or hypofractionated high dose intensity modulated radiotherapy for prostate cancer (CHHiP) trial [C. P. South, V. S. Khoo, O. Naismith, A. Norman, and D. P. Dearnaley, “A comparison of treatment planning techniques used in two randomised UK external beam radiotherapy trials for localised prostate cancer,” Clin. Oncol. (R Coll. Radiol)20, 15–21 (2008)]—were evaluated using a tenfold cross-validation with follow-up data from the RT01 trial. The predictive power was quantified using receiver-operator characteristic (ROC) curves. Toxicities considered were rectal bleeding, loose stools, and a global toxicity score. Results: Dose-volume constraints had less predictive power than the new type of hybrid constraints. A probabilistic model for predicting rectal bleeding based on the dose-volume constraints proposed by other researchers [C. Fiorino, G. Fellin, T. Rancati, V. Vavassori, C. Bianchi, V. C. Borca, G. Girelli, M. Mapelli, L. Menegotti, S. Nava, and R. Valdagni, “Clinical and dosimetric predictors of late rectal syndrome after 3D-CRT for localized prostate cancer: Preliminary results of a multicenter prospective study,” Int. J. Radiat. Oncol., Biol., Phys.70, 1130–1137 (2008)], the CHHiP dose-volume constraints, the RT01-based dose-volume constraints, and the hybrid constraints resulted in average areas under the ROC curves of 0.56, 0.58, 0.62, and 0.67, respectively. For predicting loose stools, the corresponding values were 0.57, 0.53, 0.66, and 0.71, respectively. The areas under the respective ROC curves for predicting the global toxicity score were 0.58, 0.55, 0.61, and 0.63. Conclusions: Thus, imposing the new type of hybrid constraints when generating a treatment plan should result in a reduction in the incidence of radiation-induced late rectal toxicity.

Quantification of nuclear medicine image data is a prerequisite for personalized absorbed dose calculations and quantitative biodistribution studies. The spatial response of a detector is a governing factor affecting the accuracy of image quantification, and the aim of this work was to model this impact. To simulate spatial response, a value for the intrinsic spatial resolution (R(intrinsic)) of the gamma camera is needed. R(intrinsic) for (99m)Tc was measured over the field of view (FOV) and an experimental setup was designed to measure R(intrinsic) for radioisotopes with higher photon energies. Monte Carlo (MC) simulations, using the codes SIMIND and GATE, were used to investigate the extrinsic effect of R(intrinsic) as a function of energy and its variation across the FOV. A method was developed to calculate energy-dependent blurring values for input to MC simulations, by separate consideration of the Compton scatter and photoelectric effect in the crystal and statistical variation in the signal. Inclusion of energy-specific blurring values in simulations showed excellent agreement with experimental measurements. The maximum pixel count rate can change by up to 18% when imaged at two different points in the FOV, and errors in the maximum pixel count rate of up to 11% were shown if a blurring value for (99m)Tc was used for simulations of (131)I. We demonstrate that the accuracy of MC simulations of gamma cameras can be significantly improved by accounting for the effect of energy on intrinsic spatial resolution.

Methods: Data were acquired using a human torso phantom comprised of a hot F-18-filled spheroidal "tumor" (40 mm in diameter) suspended in an air-filled "lung" cylinder and surrounded by a warm F-18-filled background. Two different sphere-to-background (S/B) ratios were used. The tumor was connected to a 3-axis computer-controlled motion stage and could be moved during PET data acquisition. Images were acquired with a range of count statistics, motion blurring, and CT attenuation correction (CTAC) misalignment. Four simple models were proposed for the assignment of clonogenic cell density according to the voxel value. The impact of image artifacts was then assessed by calculating the TCP, which is the probability that no clonogenic tumor cell remains after a given dose of radiation. TCP was calculated for a uniform dose distribution in the tumor. Results: Reduced count statistics and misaligned CTAC images had the most detrimental impact on the image fidelity. It was found that in both cases the images became less intense, demonstrated by smaller number of voxels at the maximum values. The maximum TCP difference between images with the least and most noise was 3.4% (S/B=3), and with weakest and strongest CT misalignment artifacts, it was 3.2% (S/B=10). Motion blurring only contributed weakly to the TCP imprecision at 1.7% (S/B=10) between best- and worst-case images. However, the model-calculated TCP showed increasing differences from the ground truth as the complexity of the model increased [maximum difference of similar to 8% (model 3)], which could be attributed to the partial volume effect. Conclusions: Based on the results of this study, it is believed that simple techniques of biologically guided radiotherapy planning for lung cancer should be feasible at intermediate contrast levels (tumor-to-background ratio of similar to 10) with the clinically achievable image quality.

Many studies have been performed to assess correlations between measures derived from dose-volume histograms and late rectal toxicities for radiotherapy of prostate cancer. The purpose of this study was to quantify correlations between measures describing the shape and location of the dose distribution and different outcomes. The dose to the rectal wall was projected on a two-dimensional map. In order to characterize the dose distribution, its centre of mass, longitudinal and lateral extent, and eccentricity were calculated at different dose levels. Furthermore, the dose-surface histogram (DSH) was determined. Correlations between these measures and seven clinically relevant rectal-toxicity endpoints were quantified by maximally selected standardized Wilcoxon rank statistics. The analysis was performed using data from the RT01 prostate radiotherapy trial. For some endpoints, the shape of the dose distribution is more strongly correlated with the outcome than simple DSHs. Rectal bleeding was most strongly correlated with the lateral extent of the dose distribution. For loose stools, the strongest correlations were found for longitudinal extent; proctitis was most strongly correlated with DSH. For the other endpoints no statistically significant correlations could be found. The strengths of the correlations between the shape of the dose distribution and outcome differed considerably between the different endpoints. Due to these significant correlations, it is desirable to use shape-based tools in order to assess the quality of a dose distribution.

The technical feasibility and potential benefits of voxel-based nonuniform dose prescriptions for biologically heterogeneous tumors have been widely demonstrated. In some cases, an “ideal” dose prescription has been generated by individualizing the dose to every voxel within the target, but often this voxel-based prescription has been discretized into a small number of compartments. The number of dose levels utilized and the methods used for prescribing doses and assigning tumor voxels to different dose compartments have varied significantly. The authors present an investigation into the relationship between the complexity of the dose prescription and the tumor control probability TCP for a number of these methods. The linear quadratic model of cell killing was used in conjunction with a number of modeled tumors heterogeneous in clonogen density, oxygenation, or proliferation. Models based on simple mathematical functions, published biological data, and biological image data were investigated. Target voxels were assigned to dose compartments using i simple rules based on the initial biological distribution, ii iterative methods designed to maximize the achievable TCP, or iii methods based on an ideal dose prescription. The relative performance of the simple rules was found to depend on the form of heterogeneity of the tumor, while the iterative and ideal dose methods performed comparably for all models investigated. In all cases the maximum achievable TCP was approached within the first few typically two to five compartments. Results suggest that irrespective of the pattern of heterogeneity, the optimal dose prescription can be well approximated using only a few dose levels but only if both the compartment boundaries and prescribed dose levels are well chosen. © 2009 American Association of Physicists in Medicine. DOI: 10.1118/1.3213519

The incidence of late-toxicities after radiotherapy can be modelled based on the dose delivered to the organ under consideration. Most predictive models reduce the dose distribution to a set of dose-volume parameters and do not take the spatial distribution of the dose into account. The aim of this study was to develop a classifier predicting radiation-induced rectal bleeding using all available information on the dose to the rectal wall. The dose was projected on a two-dimensional dose-surface map (DSM) by virtual rectum-unfolding. These DSMs were used as inputs for a classification method based on locally connected neural networks. In contrast to fully connected conventional neural nets, locally connected nets take the topology of the input into account. In order to train the nets, data from 329 patients from the RT01 trial (ISRCTN 47772397) were split into ten roughly equal parts. By using nine of these parts as a training set and the remaining part as an independent test set, a ten-fold cross-validation was performed. Ensemble learning was used and 250 nets were built from randomly selected patients from the training set. Out of these 250 nets, an ensemble of expert nets was chosen. The performances of the full ensemble and of the expert ensemble were quantified by using receiver-operator-characteristic (ROC) curves. In order to quantify the predictive power of the shape, ensembles of fully connected conventional neural nets based on dose-surface histograms (DSHs) were generated and their performances were quantified. The expert ensembles performed better than or equally as well as the full ensembles. The area under the ROC curve for the DSM-based expert ensemble was 0.64. The area under the ROC curve for the DSH-based expert ensemble equalled 0.59. This difference in performance indicates that not only volumetric, but also morphological aspects of the dose distribution are correlated to rectal bleeding after radiotherapy. Thus, the shape of the dose distribution should be taken into account when a predictive model for radiation-induced rectal bleeding is developed.

We present a formalism for using functional imaging both to derive patient-specific radiobiological properties and consequently to prescribe optimal nonuniform radiotherapydose distributions. The ability to quantitatively assess the response to an initial course of radiotherapy would allow the derivation of radiobiological parameters for individual patients. Both an iterative optimization and an analytical approach to this problem were investigated and illustrated by application to the linear-quadratic model of cell killing using simulated parametric data for a modeled tumor. Potential gains in local control were assessed by comparing uniform dose distributions with optimized dose distributions of equal integral dose. The effect on local prescribed dose of variations in effective radiosensitivity, tumor burden, and proliferation rate was investigated, with results suggesting that dose variations would be significant but clinically achievable. The sensitivity of derived parameters to image noise and the effect of varying the initial fractionation and imaging schedule were assessed. The analytical approach proved remarkably robust, with 10% image noise resulting in dose errors of approximately 1% for a clinically relevant set of parameters. Potential benefits were demonstrated by using this formalism to prescribe nonuniform dose distributions for modeltumors using a range of literature-derived parameters. The redistribution of dose improved tumor control probability by factors between 1.03 and 4.27 for a range of modeltumors.

A cellular Monte Carlo model describing radiation damage and repair in normal epithelial tissues is presented. The deliberately simplified model includes cell cycling, cell motility and radiation damage response (cell cycle arrest and cell death) only. Results demonstrate that the model produces a stable equilibrium system for mean cell cycle times in the range 24-96 h. Simulated irradiation of these stable equilibrium systems produced a range of responses that are shown to be consistent with experimental and clinical observation, including (i) re-epithelialization of radiation-induced lesions by a mixture of cell migration into the wound and repopulation at the periphery; (ii) observed radiosensitivity that is quantitatively consistent with both rate of induction of irreparable DNA lesions and, independently, with the observed acute oral and pharyngeal mucosal reactions to radiotherapy; (iii) an observed time between irradiation and maximum toxicity that is consistent with experimental data for skin; (iv) quantitatively accurate predictions of low-dose hyper-radiosensitivity; (v) Gomperzian repopulation for very small lesions ( approximately 2000 cells) and (vi) a linear rate of re-epithelialization of 5-10 microm h(-1) for large lesions (>15 000 cells).

Research on polymer-gel dosimetry has been driven by the need for three-dimensional dosimetry, and because alternative dosimeters are unsatisfactory or too slow for that task. Magnetic resonance tomography is currently the most well-developed technique for determining radiation-induced changes in polymer structure, but quick low-cost alternatives remain of significant interest. In previous work, ultrasound attenuation and speed of sound were found to change as a function of absorbed radiation dose in polymer-gel dosimeters, although the investigations were restricted to one ultrasound frequency. Here, the ultrasound attenuation coefficient mu in one polymer gel (MAGIC) was investigated as a function of radiation dose D and as a function of ultrasonic frequency f in a frequency range relevant for imaging dose distributions. The nonlinearity of the frequency dependence was characterized, fitting a power-law model mu = af(b); the fitting parameters were examined for potential use as additional dose readout parameters. In the observed relationship between the attenuation coefficient and dose, the slopes in a quasi-linear dose range from 0 to 30 Gy were found to vary with the gel batch but lie between 0.0222 and 0.0348 dB cm(-1) Gy(-1) at 2.3 MHz, between 0.0447 and 0.0608 dB cm(-1) Gy(-1) at 4.1 MHz and between 0.0663 and 0.0880 dB cm(-1) Gy(-1) at 6.0 MHz. The mean standard deviation of the slope for all samples and frequencies was 15.8%. The slope was greater at higher frequencies, but so were the intra-batch fluctuations and intra-sample standard deviations. Further investigations are required to overcome the observed variability, which was largely associated with the sample preparation technique, before it can be determined whether any frequency is superior to others in terms of accuracy and precision in dose determination. Nevertheless, lower frequencies will allow measurements through larger samples. The fit parameter a of the frequency dependence, describing the attenuation coefficient at 1 MHz, was found to be dose dependent, which is consistent with our expectations, as polymerization is known to be associated with increased absorption of ultrasound. No significant dose dependence was found for the fit parameter b, which describes the nonlinearity with frequency. This is consistent with the increased absorption being due to the introduction of new relaxation processes with characteristic frequencies similar to those of existing processes. The data presented here will help with optimizing the design of future 3D dose-imaging systems using ultrasound methods.

Background and purpose The study aimed to examine specific avoidance of functional lung (FL) defined by a single photon emission computerized tomography (SPECT) lung perfusion scan, using intensity modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3-DCRT) in patients with non-small cell lung cancer (NSCLC). Materials and methods Patients with NSCLC underwent planning computerized tomography (CT) and lung perfusion SPECT scan in the treatment position using fiducial markers to allow co-registration in the treatment planning system. Radiotherapy (RT) volumes were delineated on the CT scan. FL was defined using co-registered SPECT images. Two inverse coplanar RT plans were generated for each patient: 4-field 3-DCRT and 5-field step-and-shoot IMRT. 3-DCRT plans were created using automated AutoPlan optimisation software, and IMRT plans were generated employing Pinnacle 3 treatment planning system (Philips Radiation Oncology Systems). All plans were prescribed to 64Gy in 32 fractions using data for the 6MV beam from an Elekta linear accelerator. The objectives for both plans were to minimize the volume of FL irradiated to 20Gy (fV 20 ) and dose variation within the planning target volume (PTV). A spinal cord dose was constrained to 46Gy. Volume of PTV receiving 90% of the prescribed dose (PTV 90 ), fV 20 , and functional mean lung dose (fMLD) were recorded. The PTV 90 /fV 20 ratio was used to account for variations in both measures, where a higher value represented a better plan. Results Thirty-four RT plans of 17 patients with stage I–IIIB NSCLC suitable for radical RT were analysed. In 6 patients with stage I–II disease there was no improvement in PTV 90 , fV 20 , PTV/fV 20 ratio and fMLD using IMRT compared to 3-DCRT. In 11 patients with stage IIIA–B disease, the PTV was equally well covered with IMRT and 3-DCRT plans, with IMRT producing better PTV 90 /fV 20 ratio (mean ratio – 7.2 vs. 5.3, respectively, p =0.001) and reduced fMLD figures compared to 3-DCRT (mean value – 11.5 vs. 14.3Gy, p =0.001). This was due to reduction in fV 20 while maintaining PTV coverage. Conclusion The use of IMRT compared to 3-DCRT improves the avoidance of FL defined by perfusion SPECT scan in selected patients with locally advanced NSCLC. If the dose to FL is shown to be the primary determinant of lung toxicity, IMRT would allow for effective dose escalation by specific avoidance of FL.

Activity quantification in nuclear medicine imaging is highly desirable, particularly for dosimetry and biodistribution studies of radiopharmaceuticals. Quantitative (111)In imaging is increasingly important with the current interest in therapy using (90)Y radiolabeled antibodies. One of the major problems in quantification is scatter in the images, which leads to degradation of image quality. The aim of this study was to optimize the energy-window settings for quantitative (111)In imaging with a camera that enabled acquisition in three energy windows. Experimental measurements and Monte Carlo simulations, using the SI-MIND code, were conducted to investigate parameters such as sensitivity, image contrast, and image resolution. Estimated scatter-to-total ratios and distributions, as obtained by the different window settings, were compared with corresponding simulations. Results showed positive agreement between experimental measurements and results from simulations, both quantitatively and qualitatively. We conclude that of the investigated methods, the optimal energy-window setting was two windows centered at 171 and 245 keV, together with a broad scatter window located between the photopeaks.

Dose distributions for proton therapy treatments are almost exclusively calculated using pencil beam algorithms. An essential input to these algorithms is the patient model, derived from x-ray computed tomography (CT), which is used to estimate proton stopping power along the pencil beam paths. This study highlights a potential inaccuracy in the mapping between mass density and proton stopping power used by a clinical pencil beam algorithm in materials less dense than water. It proposes an alternative physically-motivated function (the mass average, or MA, formula) for use in this region. Comparisons are made between dose-depth curves calculated by the pencil beam method and those calculated by the Monte Carlo particle transport code MCNPX in a one-dimensional lung model. Proton range differences of up to 3% are observed between the methods, reduced to

The effective spatial resolution of a positron emission tomography (PET) scanner is determined in part by the initial energy of the positron, which is a function of the radionuclide. For F-18 (Emax=0.633 MeV) the mean positron range in water is small (0.6 mm). However, many other useful positron-emitting nuclides have higher energies, for example Ga-68 (Emax=1.899 MeV, mean range 2.9 mm) has one of the highest. The performance of a non-rotating, 16 module high density avalanche chamber (quad-HIDAC) small animal PET scanner was measured using both F-18 and Ga-68 to represent the extremes of high and low positron energy. The count rate performance—scatter fraction and noise-equivalent count rate (NEC)—were measured for both isotopes. Data were also collected for a spatial resolution phantom with rectangular arrays of holes of diameter 2.0, 1.5, 1.0 and 0.5 mm with the centres separated by 4.0, 3.0, 2.0 and 1.0 mm respectively. The NEC, measured for both 70 and 200 cm3 cylindrical phantoms, was approximately linear up to 30 MBq, but shows a rapid drop-off above this value. The spatial resolution phantom showed that 1 mm objects are just resolved with F-18, but none of the targets are resolved for Ga-68. In conclusion, spatial resolution is dominated by the choice of isotope down to 1 mm, with sensitivity and count-rate data being largely independent of positron range.

Many studies have reported dosimetric characteristics of amorphous silicon electronic portal imaging devices (EPIDs). Some studies ascribed a non-linear signal to gain ghosting and image lag. Other reports, however, state the effect is negligible. This study compares the signal-to-monitor unit (MU) ratio for three different brands of EPID systems. The signal was measured for a wide range of monitor units (5-1000), dose-rates, and beam energies. All EPIDs exhibited a relative under-response for beams of few MUs; giving 4 to 10% lower signal-to-MU ratios relative to that of 1000 MUs. This under-response is consistent with ghosting effects due to charge trapping.

Background and purpose Patients with non-small cell lung cancer (NSCLC) often have inhomogeneous lung perfusion. Radiotherapy planning computed tomography (CT) scans have been accurately co-registered with lung perfusion single photon emission computed tomography (SPECT) scans to design radiotherapy treatments which limit dose to healthy ‘perfused' lung. Patients and methods Patients with localised NSCLC had CT and SPECT scans accurately co-registered in the planning system. The SPECT images were used to define a volume of perfused ‘functioning' lung (FL). Inverse planning software was used to create 3D-conformal plans, the planning objective being either to minimise the dose to whole lungs (WL) or to minimise the dose to FL. Results Four plans were created for each of six patients. The mean difference in volume between WL and FL was 1011.7cm 3 (range 596.2–1581.1cm 3 ). One patient with bilateral upper lobe perfusion deficits had a 16% reduction in FLV 20 (the percentage volume of functioning lung receiving ≥20Gy). The remaining patients had inhomogeneous perfusion deficits such that inverse planning was not able to sufficiently optimise beam angles to avoid functioning lung. Conclusion SPECT perfusion images can be accurately co-registered with radiotherapy planning CT scans and may be helpful in creating treatment plans for patients with large perfusion deficits.

Background and purpose To investigate the feasibility and the advantages of a portal-imaging mode on a medical accelerator, consisting of a thin low-Z bremsstrahlung target and a thin Gd 2 O 2 S/film detector, for patient imaging. Patients and methods The international code of practice for high-energy photon dosimetry was used to calibrate dosimetry instruments for the imaging beam produced by 4.75MeV electrons hitting a 6mm thick aluminium target. Images of the head and neck of a humanoid phantom were taken with a mammography film system and the dose in the phantom was measured with TLDs calibrated for this beam. The first head and neck patient images are compared with conventional images (taken with the treatment beam on a film radiotherapy verification detector). Visibility of structures for six patients was evaluated. Results Images of the head and neck of a humanoid phantom, taken with both imaging systems showed that the contrast increased dramatically for the new system while the dose required to form an image was less than 10 −2 Gy. The patient images taken with the new and the conventional systems showed that air–tissue interfaces were better defined in the new system image. Anatomical structures, visible on both films, are clearer with the new system. Additionally, bony structures, such as vertebrae, were clearly visible only with the new system. The system under evaluation was significantly better for all features in lateral images and most features in anterior images. Conclusions This pilot study of the new portal imaging system showed the image quality is significantly improved.

The aim of this study has been to explicitly include the functional heterogeneity of an organ as a factor that contributes to the probability of complication of normal tissues following radiotherapy. Situations for which the inclusion of this information can be advantageous to the design of treatment plans are then investigated. A Java program has been implemented for this purpose. This makes use of a voxelated model of a patient, which is based on registered anatomical and functional data in order to enable functional voxel weighting. Using this model, the functional dose-volume histogram (fDVH) and the functional normal tissue complication probability (fNTCP) are then introduced as extensions to the conventional dose-volume histogram (DVH) and normal tissue complication probability (NTCP). In the presence of functional heterogeneity, these tools are physically more meaningful for plan evaluation than the traditional indices, as they incorporate additional information and are anticipated to show a better correlation with outcome. New parameters m(f), n(f) and TD(50f) are required to replace the m, n and TD(50) parameters. A range of plausible values was investigated, awaiting fitting of these new parameters to patient outcomes where functional data have been measured. As an example, the model is applied to two lung datasets utilizing accurately registered computed tomography (CT) and single photon emission computed tomography (SPECT) perfusion scans. Assuming a linear perfusion-function relationship, the biological index mean perfusion weighted lung dose (MPWLD) has been extracted from integration over outlined regions of interest. In agreement with the MPWLD ranking, the fNTCP predictions reveal that incorporation of functional imaging in radiotherapy treatment planning is most beneficial for organs with a large volume effect and large focal areas of dysfunction. There is, however, no additional advantage in cases presenting with homogeneous function. Although presented for lung radiotherapy, this model is general. It can also be applied to positron emission tomography (PET)-CT or functional magnetic resonance imaging (fMRI)-CT registered data and extended to the functional description of tumour control probability.

In recent years there has been a large amount of research into the potential use of radiation sensitive gels for three-dimensional verification of clinical radiotherapy doses. In this paper we report the use of a MAGIC gel dosimeter (Fong et al 2001 Phys. Med. Biol. 46 3105) for the verification of a specific patient's radiation therapy dose distribution. A 69-year-old male patient presented with a squamous cell carcinoma extending approximately 180 degrees across the top of the scalp (anterior to posterior) and from just over midline to 90 degrees left of the skull. The patient's treatment was commenced using two electron fields. For gel dosimetry, phantoms were produced in which the outer surface spatially corresponded to the outer contours of the patient's anatomy in the region of irradiation. The phantoms were treated with either electrons or intensity modulated radiation therapy (IMRT) with photons. The results identified a hot spot between the matched electron fields and confirmed the more homogeneous dose distribution produced by the IMRT planning system. The IMRT plan was then clinically implemented. The application of a clinical dose to a phantom shaped to a specific patient as well as the ability to select a slice at will during phantom imaging means that gel dosimetry can no longer be considered to simply have potential alone, but is now in fact a useful dosimetric tool.

Complex dose-delivery techniques, as currently applied in intensity-modulated radiation therapy (IMRT), require a highly efficient treatment-verification process. The present paper deals with the problem of the scatter correction for therapy verification by use of portal images obtained by an electronic portal imaging device (EPID) based on amorphous silicon. It also presents an iterative method for the scatter correction of portal images based on Monte Carlo-generated scatter kernels. First applications of this iterative scatter-correction method for the verification of intensity-modulated treatments are discussed on the basis of MVCT- and dose reconstruction. Several experiments with homogeneous and anthropomorphic phantoms were performed in order to validate the scatter correction method and to investigate the precision and relevance in view of its clinical applicability. It is shown that the devised concept of scatter correction significantly improves the results of MVCT- and dose reconstruction models, which is in turn essential for an exact online IMRT verification.

Spatially fractionated radiotherapy through a grid is a concept which has a long history and was routinely used in orthovoltage radiation therapy in the middle of last century to minimize damage to the skin and subcutaneous tissue. With the advent of megavoltage radiotherapy and its skin sparing effects the use of grids in radiotherapy declined in the 1970s. However there has recently been a revival of the technique for use in palliative treatments with a single fraction of 10 to 20 Gy. In this work the absolute 3D dose distribution in a grid irradiation is measured for photons using a combination of film and gel dosimetry.

Megavoltage portal images suffer from poor quality compared to those produced with kilovoltage x-rays. Several authors have shown that the image quality can be improved by modifying the linear accelerator to generate more low-energy photons. This work addresses the problem of using Monte Carlo simulation and experiment to optimize the beam and detector combination to maximize image quality for a given patient thickness. A simple model of the whole imaging chain was developed for investigation of the effect of the target parameters on the quality of the image. The optimum targets (6 mm thick aluminium and 1.6 mm copper) were installed in an Elekta SL25 accelerator. The first beam will be referred to as A16 and the second as Cu1.6. A tissue-equivalent contrast phantom was imaged with the 6 MV standard photon beam and the experimental beams with standard radiotherapy and mammography film/screen systems. The arrangement with a thin Al target/mammography system improved the contrast from 1.4 cm bone in 5 cm water to 19% compared with 2% for the standard arrangement of a thick, high-Z target/radiotherapy verification system. The linac/phantom/detector system was simulated with the BEAM/EGS4 Monte Carlo code. Contrast calculated from the predicted images was in good agreement with the experiment (to within 2.5%). The use of MC techniques to predict images accurately, taking into account the whole imaging system, is a powerful new method for portal imaging system design optimization.

"A performance comparison of direct and indirect-detection flat-panel imagers. A comparison of the performance of a direct and an indirect detection amorphous silicon flat-panel x-ray imager is presented for a 6 MV beam. Experimental measurements of the noise characteristics image lag spectral response spatial resolution and quantum efficiency are described compared and discussed. The two systems are comprised of 512x512 pixel 400 µm pitch arrays of a-Si:H p-i-n photodiodes and thin-film transistors. In the direct-detection system x-rays interact to produce electron/hole pairs directly in the silicon photodiodes. For the indirect detection system a phosphor screen converts energy from the incident x-rays into visible light which is then detected by the photodiodes. Both systems are shown to be quantum noise limited with the total electronic noise in the detector 10 to 15 times smaller than the Poisson noise level in detected signal. The measured lag for both systems is (1.0 ± 0.1)% or less in the first frame with subsequent signals decaying exponentially with frame read-out with a half-life of between 3.3 and 3.8 frames. Both systems are demonstrated to have a pronounced sensitivity to low-energy multiply-scattered photons although this is shown to be effectively filtered out using a 2 mm copper build-up plate. The direct detection system with the 2 mm Cu build-up shows greater sensitivity to scattered radiation than the indirect system. The spatial resolutions of both systems were effectively equal with an f50 of 0.25 mm-1 when pixel are binned 2x2 although a slight contribution from optical scattering in the phosphor screen is seen for the indirect detection system. The quantum efficiency of the direct detection system is a factor of 0.45 lower than that of the indirect detection system. The application of these detectors to megavoltage CT is discussed with the conclusion that the indirect detection system is to be preferred. "

Gastrointestinal (GI) toxicity impedes dose escalation and likelihood of cure in chemoradiotherapy (CRT) for hepatobiliary malignancies. The risk of toxicity can depend on clinical and radiotherapy (RT) dose-volume metrics. We aimed to identify predictive factors using data from two prospective phase-II clinical trials of locally-advanced pancreatic cancer (LAPC).

AIM: To investigate systematic changes in dose arising when treatment plans optimised using the Anisotropic Analytical Algorithm (AAA) are recalculated using Acuros XB (AXB) in patients treated with definitive chemoradiotherapy (dCRT) for locally advanced oesophageal cancers. BACKGROUND: We have compared treatment plans created using AAA with those recalculated using AXB. Although the Anisotropic Analytical Algorithm (AAA) is currently more widely used in clinical routine, Acuros XB (AXB) has been shown to more accurately calculate the dose distribution, particularly in heterogeneous regions. Studies to predict clinical outcome should be based on modelling the dose delivered to the patient as accurately as possible. METHODS: CT datasets from ten patients were selected for this retrospective study. VMAT (Volumetric modulated arc therapy) plans with 2 arcs, collimator rotation ± 5-10° and dose prescription 50 Gy / 25 fractions were created using Varian Eclipse (v10.0). The initial dose calculation was performed with AAA, and AXB plans were created by re-calculating the dose distribution using the same number of monitor units (MU) and multileaf collimator (MLC) files as the original plan. The difference in calculated dose to organs at risk (OAR) was compared using dose-volume histogram (DVH) statistics and p values were calculated using the Wilcoxon signed rank test. The potential clinical effect of dosimetric differences in the gross tumour volume (GTV) was evaluated using three different TCP models from the literature. RESULTS: PTV Median dose was apparently 0.9 Gy lower (range: 0.5 Gy - 1.3 Gy; p

The enormous advances in the understanding of human anatomy, physiology and pathology in recent decades have led to ever-improving methods of disease prevention, diagnosis and treatment. Many of these achievements have been enabled, at least in part, by advances in ionizing radiation detectors. Radiology has been transformed by the implementation of multi-slice CT and digital x-ray imaging systems, with silver halide films now largely obsolete for many applications. Nuclear medicine has benefited from more sensitive, faster and higher-resolution detectors delivering ever-higher SPECT and PET image quality. PET/MR systems have been enabled by the development of gamma ray detectors that can operate in high magnetic fields. These huge advances in imaging have enabled equally impressive steps forward in radiotherapy delivery accuracy, with 4DCT, PET and MRI routinely used in treatment planning and online image guidance provided by cone-beam CT. The challenge of ensuring safe, accurate and precise delivery of highly complex radiation fields has also both driven and benefited from advances in radiation detectors. Detector systems have been developed for the measurement of electron, intensity-modulated and modulated arc x-ray, proton and ion beams, and around brachytherapy sources based on a very wide range of technologies. The types of measurement performed are equally wide, encompassing commissioning and quality assurance, reference dosimetry, in vivo dosimetry and personal and environmental monitoring. In this article, we briefly introduce the general physical characteristics and properties that are commonly used to describe the behaviour and performance of both discrete and imaging detectors. The physical principles of operation of calorimeters; ionization and charge detectors; semiconductor, luminescent, scintillating and chemical detectors; and radiochromic and radiographic films are then reviewed and their principle applications discussed. Finally, a general discussion of the application of detectors for x-ray nuclear medicine and ion beam imaging and dosimetry is presented.

Purpose/objective: To analyse outcome and toxicity of stereotactic body radiotherapy (SBRT) in pancreatic cancer (PDAC). Material/methods: We systematically reviewed full reports on outcome and toxicity transforming prescription doses to equivalent doses of 2Gy (EQD2) and biological equivalent doses (BED). Pearson product-moment correlation coefficient, regression analysis and Lyman–Kutcher–Burman modelling were used. Results: Sixteen trials (572 patients) were identified. Local control correlated with dose. Additionally 4 upper gastrointestinal-SBRT trials (149 patients) were included for toxicity analysis. Acute toxicity was mild but late toxicity ⩾G2 was substantial and predominantly gastrointestinal. Late toxicity ⩾G2 and ⩾G3 correlated highly with EQD2/BED after linear ( R 2 =0.85 and 0.77, respectively) and Lyman–Kutcher–Burman modelling. Linear regression lines indicated ⩾G2 and ⩾G3 toxicity frequencies of 5% at 65Gy and 80Gy EQD2-α/β=3, respectively. A comparison of toxicity with dose constraints for duodenum revealed partly inadequate dose constraints. Conclusion: Results from multiple fraction regimens could be successfully interpreted to estimate toxicity according to EQD2/BED prescription doses, and dose constraints for the duodenum were derived, whereas local control appeared to be less dose-dependent. This analysis may be useful to plan clinical trials for SBRT and hypofractionated radiotherapy in pancreatic cancer.

The objectives are determine the optimal combination of MR parameters for discriminating tumour within the prostate using linear discriminant analysis (LDA) and to compare model accuracy with that of an experienced radiologist.Multiparameter MRIs in 24 patients before prostatectomy were acquired. Tumour outlines from whole-mount histology, T2-defined peripheral zone (PZ), and central gland (CG) were superimposed onto slice-matched parametric maps. T2, Apparent Diffusion Coefficient, initial area under the gadolinium curve, vascular parameters (K(trans),Kep,Ve), and (choline+polyamines+creatine)/citrate were compared between tumour and non-tumour tissues. Receiver operating characteristic (ROC) curves determined sensitivity and specificity at spectroscopic voxel resolution and per lesion, and LDA determined the optimal multiparametric model for identifying tumours. Accuracy was compared with an expert observer.Tumours were significantly different from PZ and CG for all parameters (all p 0.001). Area under the ROC curve for discriminating tumour from non-tumour was significantly greater (p 0.001) for the multiparametric model than for individual parameters; at 90 % specificity, sensitivity was 41 % (MRSI voxel resolution) and 59 % per lesion. At this specificity, an expert observer achieved 28 % and 49 % sensitivity, respectively.The model was more accurate when parameters from all techniques were included and performed better than an expert observer evaluating these data.• The combined model increases diagnostic accuracy in prostate cancer compared with individual parameters • The optimal combined model includes parameters from diffusion, spectroscopy, perfusion, and anatominal MRI • The computed model improves tumour detection compared to an expert viewing parametric maps.

To demonstrate the feasibility of an 8-Gy focal radiation boost to a dominant intraprostatic lesion (DIL), identified using multiparametric MRI (mpMRI), and to assess the potential outcome compared with a uniform 74-Gy prostate dose.The DIL location was predicted in 23 patients using a histopathologically verified model combining diffusion-weighted imaging, dynamic contrast-enhanced imaging, T2 maps and three-dimensional MR spectroscopic imaging. The DIL defined prior to neoadjuvant hormone downregulation was firstly registered to MRI-acquired post-hormone therapy and subsequently to CT radiotherapy scans. Intensity-modulated radiotherapy (IMRT) treatment was planned for an 8-Gy focal boost with 74-Gy dose to the remaining prostate. Areas under the dose-volume histograms (DVHs) for prostate, bladder and rectum, the tumour control probability (TCP) and normal tissue complication probabilities (NTCPs) were compared with those of the uniform 74-Gy IMRT plan.Deliverable IMRT plans were feasible for all patients with identifiable DILs (20/23). Areas under the DVHs were increased for the prostate (75.1 ± 0.6 vs 72.7 ± 0.3 Gy; p 0.001) and decreased for the rectum (38.2 ± 2.5 vs 43.5 ± 2.5 Gy; p 0.001) and the bladder (29.1 ± 9.0 vs 36.9 ± 9.3 Gy; p 0.001) for the boosted plan. The prostate TCP was increased (80.1 ± 1.3 vs 75.3 ± 0.9 Gy; p 0.001) and rectal NTCP lowered (3.84 ± 3.65 vs 9.70 ± 5.68 Gy; p = 0.04) in the boosted plan. The bladder NTCP was negligible for both plans.Delivery of a focal boost to an mpMRI-defined DIL is feasible, and significant increases in TCP and therapeutic ratio were found.The delivery of a focal boost to an mpMRI-defined DIL demonstrates statistically significant increases in TCP and therapeutic ratio.

Background The best method of identifying regions within pancreatic tumours that might benefit from an increased radiotherapy dose is not known. We investigated the utility of pre-treatment FDG-PET in predicting the spatial distribution of residual metabolic activity following chemoradiotherapy (CRT) in locally advanced pancreatic cancer (LAPC). Methods 17 patients had FDG-PET/CT scans at baseline and six weeks post-CRT. Tumour segmentation was performed at 40% and 50% of SUVmax at baseline and 60%, 70%, 80% and 90% post-CRT. FDG-PET scans were non-rigidly registered to the radiotherapy planning CT using the CT component of the FDG-PET/CT. Percentage overlap of the post-CRT volumes with the pre-CRT volumes with one another and the gross tumour volume (GTV) was calculated. Results SUVmax decreased during CRT (median pre- 8.0 and post- 3.6, p

Hypoxia occurs when oxygen levels within a tissue drop below normal physiological levels. In tumours, hypoxia is associated with poor prognosis, increased likelihood of metastasis and resistance to therapy. Imaging techniques, for example, positron emission tomography, are increasingly used in the monitoring of tumour hypoxia and have the potential to help in the planning of radiotherapy. For this application, improved understanding of the link between image contrast and quantitative underlying oxygen distribution would be very useful. Mathematical models of tissue hypoxia and image formation can help understand this. Hypoxia is caused by an imbalance between vascular supply and tissue demand. While much work has been dedicated to the quantitative description of tumour vascular networks, consideration of tumour oxygen consumption is largely neglected. Oxidative respiration in standard two-dimensional cell culture has been widely studied. However, two-dimensional culture fails to capture the complexities of growing three-dimensional tissue which could impact on the oxygen usage. In this study, we build on previous descriptions of oxygen consumption and diffusion in three-dimensional tumour spheroids and present a method for estimating rates of oxygen consumption from spheroids, validated using stained spheroid sections. Methods for estimating the local partial pressure of oxygen, the diffusion limit and the extents of the necrotic core, hypoxic region and proliferating rim are also derived. These are validated using experimental data from DLD1 spheroids at different stages of growth. A relatively constant experimentally derived diffusion limit of 232 ± 22 μm and an O 2 consumption rate of 7.29 ± 1.4 × 10 −7 m 3 kg −1 s −1 for the spheroids studied was measured, in agreement with laboratory measurements.

Intensity-modulated radiotherapy beams can be delivered using a multileaf collimator by one of two methods: either by superposition of a series of multiple-static fields, or by moving the collimators while the beam is on to produce 'dynamically' modulated beams. The leaf trajectories in this dynamic mode are given by a series of linear steps between control points defining each collimator position at known intervals throughout an exposure. The complexity of the resulting modulation is limited in the first case by the number of fields superposed and in the second case by the number of control points defined. Results are presented for an experimental study that investigates the effect of changing both the number of fields for the multiple-static technique, and the number of control points for a dynamic 'close-in' technique. All deliveries studied are clinical intensity-modulated breast fields. The effect of using a universal wedge in conjunction with the multileaf collimator is also studied, together with a comparison of the relative efficiency, time taken and the absolute dosimetric accuracy of the various delivery options. It is shown that all delivery techniques produce equivalent dose distributions when using 15 control points, with 10 control points being sufficient to produce an adequate breast compensator distribution. Except for the case of a four-control-point dynamic delivery, the universal wedge makes no significant difference to the dose distribution. However, it makes the delivery less efficient. The close-in interpreter consistently produces deliveries that are more efficient than the more conventional sliding-window technique and faster than the multiple-static-field technique. Finally the close-in technique is compared to the more 'standard' leaf-sweep technique and shown to be equivalent.