Radiotherapy Quality Assurance for the CHHiP Trial: Conventional Versus Hypofractionated High-Dose Intensity-Modulated Radiotherapy in Prostate Cancer.

AIMS: The CHHiP trial investigated the use of moderate hypofractionation for the treatment of localised prostate cancer using intensity-modulated radiotherapy (IMRT). A radiotherapy quality assurance programme was developed to assess compliance with treatment protocol and to audit treatment planning and dosimetry of IMRT. This paper considers the outcome and effectiveness of the programme. MATERIALS AND METHODS: Quality assurance exercises included a pre-trial process document and planning benchmark cases, prospective case reviews and a dosimetry site visit on-trial and a post-trial feedback questionnaire. RESULTS: In total, 41 centres completed the quality assurance programme (37 UK, four international) between 2005 and 2010. Centres used either forward-planned (field-in-field single phase) or inverse-planned IMRT (25 versus 17). For pre-trial quality assurance exercises, 7/41 (17%) centres had minor deviations in their radiotherapy processes; 45/82 (55%) benchmark plans had minor variations and 17/82 (21%) had major variations. One hundred prospective case reviews were completed for 38 centres. Seventy-one per cent required changes to clinical outlining pre-treatment (primarily prostate apex and base, seminal vesicles and penile bulb). Errors in treatment planning were reduced relative to pre-trial quality assurance results (49% minor and 6% major variations). Dosimetry audits were conducted for 32 centres. Ion chamber dose point measurements were within ±2.5% in the planning target volume and ±8% in the rectum. 28/36 films for combined fields passed gamma criterion 3%/3 mm and 11/15 of IMRT fluence film sets passed gamma criterion 4%/4 mm using a 98% tolerance. Post-trial feedback showed that trial participation was beneficial in evolving clinical practice and that the quality assurance programme helped some centres to implement and audit prostate IMRT. CONCLUSION: Overall, quality assurance results were satisfactory and the CHHiP quality assurance programme contributed to the success of the trial by auditing radiotherapy treatment planning and protocol compliance. Quality assurance supported the introduction of IMRT in UK centres, giving additional confidence and external review of IMRT where it was a newly adopted technique.

Forward- and Inverse-Planned Intensity-Modulated Radiotherapy in the CHHiP Trial: A Comparison of Dosimetry and Normal Tissue Toxicity.

AIMS: The CHHiP (Conventional or Hypofractionated High-dose Intensity Modulated Radiotherapy In Prostate Cancer; CRUK/06/016) trial investigated hypofractionated radiotherapy for localised prostate cancer. Forward- (FP) or inverse-planned (IP) intensity-modulated techniques were permitted. Dose-volume histogram and toxicity data were compared to explore the effects of planning method. MATERIALS AND METHODS: In total, 337 participants with intermediate-risk disease and prospectively collected toxicity data were included. Patients were matched on prostate and rectum/bladder volumes and on radiotherapy dose for toxicity comparisons. The primary outcome was grade 2 or higher Radiation Therapy Oncology Group (RTOG) bowel or bladder toxicity at 2 years. RESULTS: IP patients had smaller volumes of rectum irradiated to 50-70 Gy (P < 0.001); FP patients had smaller volumes of bladder irradiated to 74 Gy (P = 0.001). Acute grade 2 + bowel toxicity was worse with FP (27/53 [52%]; 11/53 [21%] IP; P = 0.0002); with no significant differences in acute urinary toxicity. At 2 years, RTOG grade 2 + bowel toxicity rates were FP 0/53 and IP 2/53 and RTOG grade 2 + bladder rates were FP 0/54 and IP 1/57. CONCLUSIONS: Significant differences were found between dose-volume histograms from FP and IP methods. IP may result in small reductions in acute bowel toxicity but both techniques were associated with low rates of late radiotherapy side-effects.

The stability of imaging biomarkers in radiomics: a framework for evaluation.

This paper studies the sensitivity of a range of image texture parameters used in radiomics to: (i) the number of intensity levels, (ii) the method of quantisation to select the intensity levels and (iii) the use of an intensity threshold. 43 commonly used texture features were studied for the gross target volume outlined on the CT component of PET/CT scans of 50 patients with non-small cell lung carcinoma (NSCLC). All cases were quantised for all values between 4 and 128 intensity levels using four commonly used quantisation methods. All results were analysed with and without a threshold range of -200 HU to 300 HU. Cases were ranked for each texture feature and for all quantisation methods with the Spearman's rank correlation coefficient determined to evaluate stability. Results showed large fluctuations in ranking, particularly for low numbers of levels, differences between quantisation methods and with the use of a threshold, with values Spearman's Rank Correlation for many parameters below 0.2. Our results demonstrated the sensitivity of radiomics features to the parameters used during analysis and highlight the risk of low reproducibility comparing studies with slightly different parameters. In terms of the lung cancer CT datasets, this study supports the use of 128 intensity levels, the same uniform quantiser applied to all scans and thresholding of the data. It also supports several of the features recommended in the literature for such studies such as skewness and kurtosis. A recommended framework is presented for curation of the data analysis process to ensure stability of results.

Does providing written dietary advice improve the ingestion of non-allergic nuts in children with existing nut allergies? - A randomized controlled trial.

BACKGROUND: Allergy to one or more nuts is common in children and often complete nut avoidance is advised. More recently, introduction of non-allergic nuts into the diet is advised by some allergists. OBJECTIVE: This study aims to determine whether the provision of additional written dietary advice increases the ingestion of non-allergic nuts by children with nut allergy. Secondary aims include determining which factors facilitate or prevent successful inclusion of non-allergic nuts in the diet, and how inclusion influences quality of life, sensitization and the rate of nut reactions. METHODS: This is a randomized, double-blinded, controlled trial of children with nut allergy who were asked to ingest one or more non-allergic nuts. Participants were 75 children aged 2-16 years (Intervention=36, Control=39), recruited in Adelaide, Australia. Randomized participants were supplied with the intervention (recipe booklet and monthly reminder text messages) or provided standard verbal dietary advice. After 6 months participants were assessed by a blinded investigator with regard to nut ingestion, quality of life, sensitization and nut reactions. RESULTS: The intervention did not increase the ingestion of non-allergic nuts. A negative hospital challenge was a predictor of successful introduction. Parental report of child concern about a reaction was the greatest barrier. Ingestion of non-allergic nuts did not improve quality of life or change nut sensitization. Few nut reactions occurred during the study. CONCLUSIONS AND CLINICAL RELEVANCE: Ingestion of non-allergic nuts by children with nut allergy was not improved by additional dietary intervention. Selective introduction of non-allergic nuts is difficult to achieve when the child is anxious about introduction and challenges cannot be done in a medically supervised setting. CAPSULE SUMMARY: This dietary intervention did not improve non-allergic nut ingestion by nut allergic children. Hospital challenge increased introduction rates, whilst parentally reported child concern about a reaction reduced success. Non-allergic nut ingestion did not change quality of life or sensitization.

Suspension of milking in dairy cows produces a transient increase in milk lactoferrin concentration and yield after resumption of milking.

Lactoferrin is a multifunctional glycoprotein with a range of antimicrobial and immune-related properties that is found at >10-fold higher concentration in human milk (~1.7 g/L) relative to bovine milk (~0.15 g/L). Consumer demand is increasing for bovine lactoferrin through a wide range of nutritional and cosmetic consumer products. Increasing lactoferrin yield and concentration in bovine milk could assist in satisfying this increasing demand and may also help in increasing resistance to bovine mammary infection. Two experiments with cows in mid and late lactation were carried out to examine milking strategies to increase milk lactoferrin concentration and yield. Milking was suspended in cows normally milked twice daily, for periods of 2, 4, or 7d (mid lactation) or 2 or 4d (late lactation) after which cows were milked out and twice-daily milking resumed for 4d. In all groups, lactoferrin concentration was significantly increased during the remilking period, approaching concentrations similar to those found in human milk (~1 g/L). Lactoferrin yields were significantly higher in all treatment groups, although increasing the nonmilking period beyond 2d offered no advantage. Milk yield was lower initially after resumption of milking but recovered to preexperimental values by the fourth day of remilking in all groups, except the 4-d nonmilking group in late lactation. Milk somatic cell count was significantly elevated in all groups at the start of remilking but had substantially reduced by d 4 and reached a preexperimental level in the 2-d nonmilking group of mid-lactation cows. In summary, extended milking intervals can be used as a tool to produce a short-term increase in the concentration and yield of lactoferrin from bovine milk during established lactation, without any apparent long-term effects on milk yield and quality.

The role of texture analysis in imaging as an outcome predictor and potential tool in radiotherapy treatment planning.

Predicting a tumour's response to radiotherapy prior to the start of treatment could enhance clinical care management by enabling the personalization of treatment plans based on predicted outcome. In recent years, there has been accumulating evidence relating tumour texture to patient survival and response to treatment. Tumour texture could be measured from medical images that provide a non-invasive method of capturing intratumoural heterogeneity and hence could potentially enable a prior assessment of a patient's predicted response to treatment. In this article, work presented in the literature regarding texture analysis in radiotherapy in relation to survival and outcome is discussed. Challenges facing integrating texture analysis in radiotherapy planning are highlighted and recommendations for future directions in research are suggested.

Dose prescription complexity versus tumor control probability in biologically conformal radiotherapy.

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.

A theoretical framework for prescribing radiotherapy dose distributions using patient-specific biological information.

We present a formalism for using functional imaging both to derive patient-specific radiobiological properties and consequently to prescribe optimal nonuniform radiotherapy dose 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 model tumors 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 model tumors.

A comparison of treatment planning techniques used in two randomised UK external beam radiotherapy trials for localised prostate cancer.

AIMS: To compare the radiotherapy planning techniques from two multicentre randomised external beam radiotherapy trials in the UK of conformal radiotherapy vs intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: Sixteen sequential patients with histologically confirmed localised prostate cancer treated in the conventional or hypofractionated IMRT trial (CHHiP) were planned using both the CHHiP and Medical Research Council RT-01 planning protocols to 74 Gy in 37 daily fractions. The CHHiP plan used a single phase simple forward planned three-field IMRT plan for easy multicentre adoption. The RT-01 plan used two phases: three-field conformal radiotherapy plan to 64 Gy followed by a six-field boost of 10 Gy. After coverage of the planning target volumes according to the respective trial protocols, the dose to the rectum and bladder was assessed for the two planning techniques. RESULTS: There was acceptable planning target volume coverage by both the CHHiP and RT-01 plans. All CHHiP plans produced lower mean irradiated rectal volumes at all measured dose levels compared with the RT-01 plans, particularly for irradiated rectal volumes at 50 and 70 Gy (P<0.05). In the cases when a CHHiP plan failed to meet its own trial dose constraints, the volumes of irradiated rectum were less than if an RT-01 planning technique had been used. The CHHiP plans gave lower mean irradiated bladder volumes at both 50 and 60 Gy, but higher volumes at 74 Gy. These differences in irradiated bladder volumes were significant at the 60 and 74 Gy dose levels (P<0.05) in favour of the CHHiP and RT-01 plans, respectively. CONCLUSION: The forward planned CHHiP IMRT planning solution gives more favourable rectal sparing than the RT-01 plan. This is important to limit any potential increase in late rectal toxicity for prostate cancer patients treated with high-dose conventional or hypofractionated schedules.

Distortion-corrected T2 weighted MRI: a novel approach to prostate radiotherapy planning.

The purpose of this study was to evaluate distortion-corrected MRI as a radiotherapy planning tool for prostate cancer and the resultant implications for dose sparing of organs at risk. 11 men who were to be treated with radical conformal radiotherapy for localized prostate cancer had an MRI scan under radiotherapy planning conditions, which was corrected for geometric distortion. Radiotherapy plans were created for planning target volumes derived from the MRI- and CT-defined prostate. Dose volume histograms were produced for the rectum, bladder and penile bulb. The mean volume of the prostate as defined on CT and MRI was 41 cm3 and 36 cm3, respectively (p = 0.009). The predicted percentage of the rectum treated to dose levels of 45-65 Gy was significantly lower for plans delineating the prostate with MRI than for those with CT. The rectal-sparing effect was confined to the lowermost 4 cm of the rectum (anal canal). There were no differences between the predicted doses to bladder or penile bulb (as defined using MRI) between plans. In conclusion, prostate radiotherapy planning based on distortion-corrected MRI is feasible and results in a smaller target volume than does CT. This leads to a lower predicted proportion of the rectum, in particular the lower rectum (anal canal), treated to a given dose than with CT.