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Purpose:Radiotherapy is important in managing pelvic cancers. However, radiation enteropathy may occur and can be dose limiting. The gut microbiota may contribute to the pathogenesis of radiation enteropathy. We hypothesized that the microbiome differs between patients with and without radiation enteropathy.Experimental Design: Three cohorts of patients (n = 134) were recruited. The early cohort (n = 32) was followed sequentially up to 12 months post-radiotherapy to assess early radiation enteropathy. Linear mixed models were used to assess microbiota dynamics. The late cohort (n = 87) was assessed cross-sectionally to assess late radiation enteropathy. The colonoscopy cohort compared the intestinal mucosa microenvironment in patients with radiation enteropathy (cases, n = 9) with healthy controls (controls, n = 6). Fecal samples were obtained from all cohorts. In the colonoscopy cohort, intestinal mucosa samples were taken. Metataxonomics (16S rRNA gene) and imputed metataxonomics (Piphillin) were used to characterize the microbiome. Clinician- and patient-reported outcomes were used for clinical characterization.Results:In the acute cohort, we observed a trend for higher preradiotherapy diversity in patients with no self-reported symptoms (P = 0.09). Dynamically, diversity decreased less over time in patients with rising radiation enteropathy (P = 0.05). A consistent association between low bacterial diversity and late radiation enteropathy was also observed, albeit nonsignificantly. Higher counts of Clostridium IV, Roseburia, and Phascolarctobacterium significantly associated with radiation enteropathy. Homeostatic intestinal mucosa cytokines related to microbiota regulation and intestinal wall maintenance were significantly reduced in radiation enteropathy [IL7 (P = 0.05), IL12/IL23p40 (P = 0.03), IL15 (P = 0.05), and IL16 (P = 0.009)]. IL15 inversely correlated with counts of Roseburia and Propionibacterium.Conclusions:The microbiota presents opportunities to predict, prevent, or treat radiation enteropathy. We report the largest clinical study to date into associations of the microbiota with acute and late radiation enteropathy. An altered microbiota associates with early and late radiation enteropathy, with clinical implications for risk assessment, prevention, and treatment of radiation-induced side-effects.See related commentary by Lam et al., p. 6280

Aims With interest in normal tissue sparing and dose-escalated radiotherapy in the treatment of inoperable locally advanced non-small cell lung cancer, this study investigated the impact of motion-managed moderate deep inspiration breath hold (mDIBH) on normal tissue sparing and dose-escalation potential and compared this to planning with a four-dimensional motion-encompassing internal target volume or motion-compensating mid-ventilation approach. Materials and methods Twenty-one patients underwent four-dimensional and mDIBH planning computed tomography scans. Internal and mid-ventilation target volumes were generated on the four-dimensional scan, with mDIBH target volumes generated on the mDIBH scan. Isotoxic target dose-escalation guidelines were used to generate six plans per patient: three with a target dose cap and three without. Target dose-escalation potential, normal tissue complication probability and differences in pre-specified dose-volume metrics were evaluated for the three motion-management techniques. Results The mean total lung volume was significantly greater with mDIBH compared with four-dimensional scans. Lung dose (mean and V21 Gy) and mean heart dose were significantly reduced with mDIBH in comparison with four-dimensional-based approaches, and this translated to a significant reduction in heart and lung normal tissue complication probability with mDIBH. In 20/21 patients, the trial target prescription dose cap of 79.2 Gy was achievable with all motion-management techniques. Conclusion mDIBH aids lung and heart dose sparing in isotoxic dose-escalated radiotherapy compared with four-dimensional planning techniques. Given concerns about lung and cardiac toxicity, particularly in an era of consolidation immunotherapy, reduced normal tissue doses may be advantageous for treatment tolerance and outcome.

Purpose Radiation therapy to the prostate and pelvic lymph nodes (PLNRT) is part of the curative treatment of high-risk prostate cancer. Yet, the broader influence of radiation therapy on patient physiology is poorly understood. We conducted comprehensive global metabolomic profiling of urine, plasma, and stools sampled from patients undergoing PLNRT for high-risk prostate cancer. Methods and Materials Samples were taken from 32 patients at 6 timepoints: baseline, 2 to 3 and 4 to 5 weeks of PLNRT; and 3, 6, and 12 months after PLNRT. We characterized the global metabolome of urine and plasma using 1H nuclear magnetic resonance spectroscopy and ultraperformance liquid chromatography-mass spectrometry, and of stools with nuclear magnetic resonance. Linear mixed-effects modeling was used to investigate metabolic changes between timepoints for each biofluid and assay and determine metabolites of interest. Results Metabolites in urine, plasma and stools changed significantly after PLNRT initiation. Metabolic profiles did not return to baseline up to 1 year post-PLNRT in any biofluid. Molecules associated with cardiovascular risk were increased in plasma. Pre-PLNRT fecal butyrate levels directly associated with increasing gastrointestinal side effects, as did a sharper fall in those levels during and up to 1 year postradiation therapy, mirroring our previous results with metataxonomics. Conclusions We showed for the first time that an overall metabolic effect is observed in patients undergoing PLNRT up to 1 year posttreatment. These metabolic changes may effect on long-term morbidity after treatment, which warrants further investigation.

Aims Twenty per cent of patients with non-small cell lung cancer present with stage III locally advanced disease. Precision radiotherapy with pencil beam scanning (PBS) protons may improve outcomes. However, stage III is a heterogeneous group and accounting for complex tumour motion is challenging. As yet, it remains unclear as to whom will benefit. In our retrospective planning study, we explored if patients with superior sulcus tumours (SSTs) are a select cohort who might benefit from this treatment. Materials and methods Patients with SSTs treated with radical radiotherapy using four-dimensional planning computed tomography between 2010 and 2015 were identified. Tumour motion was assessed and excluded if greater than 5 mm. Photon volumetric-modulated arc therapy (VMAT) and PBS proton single-field optimisation plans, with and without inhomogeneity corrections, were generated retrospectively. Robustness analysis was assessed for VMAT and PBS plans involving: (i) 5 mm geometric uncertainty, with an additional 3.5% range uncertainty for proton plans; (ii) verification plans at maximal inhalation and exhalation. Comparative dosimetric and robustness analyses were carried out. Results Ten patients were suitable. The mean clinical target volume D95 was 98.1% ± 0.4 (97.5–98.8) and 98.4% ± 0.2 (98.1–98.9) for PBS and VMAT plans, respectively. All normal tissue tolerances were achieved. The same four PBS and VMAT plans failed robustness assessment. Inhomogeneity corrections minimally impacted proton plan robustness and made it worse in one case. The most important factor affecting target coverage and robustness was the clinical target volume entering the spinal canal. Proton plans significantly reduced the mean lung dose (by 21.9%), lung V5, V10, V20 (by 47.9%, 36.4%, 12.1%, respectively), mean heart dose (by 21.4%) and thoracic vertebra dose (by 29.2%) (P, Highlights • Robust scanning proton plans are feasible in patients with superior sulcus tumours. • Target coverage is comparable to volumetric-modulated arc therapy plans. • Considerable dose reduction to the thoracic vertebra, lungs and heart is possible. • Using an inhomogeneity correction did not improve robustness. • The same proton and photon plans failed robustness assessment.

Purpose Reducing margins during treatment planning to decrease dose to healthy organs surrounding the prostate can risk inadequate treatment of subclinical disease. This study aimed to investigate whether lack of dose to subclinical disease is associated with increased disease progression by using high-quality prostate radiation therapy clinical trial data to identify anatomically localized regions where dose variation is associated with prostate-specific antigen progression (PSAP). Methods and Materials Planned dose distributions for 683 patients of the Trans-Tasman Radiation Oncology Group 03.04 Randomized Androgen Deprivation and Radiotherapy (RADAR) trial were deformably registered onto a single exemplar computed tomography data set. These were divided into high-risk and intermediate-risk subgroups for analysis. Three independent voxel-based statistical tests, using permutation testing, Cox regression modeling, and least absolute shrinkage selection operator feature selection, were applied to identify regions where dose variation was associated with PSAP. Results from the intermediate-risk RADAR subgroup were externally validated by registering dose distributions from the RT01 (n = 388) and Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer Trial (CHHiP) (n = 253) trials onto the same exemplar and repeating the tests on each of these data sets. Results Voxel-based Cox regression revealed regions where reduced dose was correlated with increased prostate-specific androgen progression. Reduced dose in regions associated with coverage at the posterior prostate, in the immediate periphery of the posterior prostate, and in regions corresponding to the posterior oblique beams or posterior lateral beam boundary, was associated with increased PSAP for RADAR and RT01 patients, but not for CHHiP patients. Reduced dose to the seminal vesicle region was also associated with increased PSAP for RADAR intermediate-risk patients. Conclusions Ensuring adequate dose coverage at the posterior prostate and immediately surrounding posterior region (including the seminal vesicles), where aggressive cancer spread may be occurring, may improve tumor control. It is recommended that particular care be taken when defining margins at the prostate posterior, acknowledging the trade-off between quality of life due to rectal dose and the preferences of clinicians and patients.

Proton beam therapy is a rapidly developing tool in cancer treatment. This educational piece will outline the key physical, biological and clinical parameters that give a basic understanding of the radiobiology of proton therapy (Figure 1). In particular, it will focus on the important parameters of linear energy transfer (LET) and relative biological effectiveness (RBE).

Highlights • Dosimetric benefits to the penile bulb was seen in patients treated with IGRT and reduced CTV-PTV margins. • Patients who had a lower planned dose to the penile bulb reported less erectile dysfunction. • A threshold mean penile bulb dose for erectile dysfunction was determined to around 20 Gy., Background and purpose The penile bulb (PB) dose may be critical in development of post prostate radiotherapy erectile dysfunction (ED). This study aimed to generate PB dose constraints based on dose-volume histograms (DVHs) in patients treated with prostate radiotherapy, and to identify clinical and dosimetric parameters that predict the risk of ED post prostate radiotherapy. Materials and methods Penile bulb DVHs were generated for 276 patients treated within the randomised IGRT substudy of the multicentre randomised trial, CHHiP. Incidence of ED in relation to dose and randomised IGRT groups were evaluated using Wilcoxon rank sum, Chi-squared test and atlases of complication incidence. Youden index was used to find dose-volume constraints that discriminated for ED. Multivariate analysis (MVA) of effect of dosimetry, clinical and patient-related variables was performed. Results Reduced treatment margins using IGRT (IGRT-R) produced significantly reduced mean PB dose compared with standard margins (IGRT-S) (median: 25 Gy (IGRT-S) versus 11 Gy (IGRT-R); p

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.

In the UK, the recent introduction of high-energy proton beam therapy into national clinical practice provides an opportunity for new clinical trials, particularly those comparing proton and photon treatments. However, comparing these different modalities can present many challenges. Although protons may confer an advantage in terms of reduced normal tissue dose, they can also be more sensitive to uncertainty. Uncertainty analysis is fundamental in ensuring that proton plans are both safe and effective in the event of unavoidable discrepancies, such as variations in patient setup and proton beam range. Methods of evaluating and mitigating the effect of these uncertainties can differ from those approaches established for photon therapy treatments, such as the use of expansion margins to assure safety. These differences should be considered when comparing protons and photons. An overview of the effect of uncertainties on proton plans is presented together with an introduction to some of the concepts and terms that should become familiar to those involved in proton therapy trials. This report aims to provide guidance for those engaged in UK clinical trials comparing protons and photons. This guidance is intended to take a pragmatic approach considering the tools that are available to practising centres and represents a consensus across multidisciplinary groups involved in proton therapy in the UK.

Background and purpose This study aimed to identify anatomically-localised regions where planned radiotherapy dose is associated with gastrointestinal toxicities in healthy tissues throughout the pelvic anatomy. Materials and methods Planned dose distributions for up to 657 patients of the Trans Tasman Radiation Oncology Group 03.04 RADAR trial were deformably registered onto a single exemplar computed tomography dataset. Voxel-based multiple comparison permutation dose difference testing, Cox regression modelling and LASSO feature selection were used to identify regions where dose-increase was associated with grade ≥2 rectal bleeding (RB) or tenesmus, according to the LENT/SOMA scale. This was externally validated by registering dose distributions from the RT01 (n = 388) and CHHiP (n = 241) trials onto the same exemplar and repeating the tests on each of these data sets, and on all three datasets combined. Results Voxel-based Cox regression and permutation dose difference testing revealed regions where increased dose was correlated with gastrointestinal toxicity. Grade ≥2 RB was associated with posteriorly extended lateral beams that manifested high doses (>55 Gy) in a small rectal volume adjacent to the clinical target volume. A correlation was found between grade ≥2 tenesmus and increased low-intermediate dose (∼25 Gy) at the posterior beam region, including the posterior rectum and perirectal fat space (PRFS). Conclusions The serial response of the rectum with respect to RB has been demonstrated in patients with posteriorly extended lateral beams. Similarly, the parallel response of the PRFS with respect to tenesmus has been demonstrated in patients treated with the posterior beam.

Highlights • Introduction of daily online prostate IGRT was feasible in a national randomised trial. • Dosimetric benefits seen in patients treated with IGRT and reduced CTV-PTV margins. • Overall side effect profiles were acceptable in all groups but lowest with IGRT and reduced margins., Background and purpose Image-guided radiotherapy (IGRT) improves treatment set-up accuracy and provides the opportunity to reduce target volume margins. We introduced IGRT methods using standard (IGRT-S) or reduced (IGRT-R) margins in a randomised phase 2 substudy within CHHiP trial. We present a pre-planned analysis of the impact of IGRT on dosimetry and acute/late pelvic side effects using gastrointestinal and genitourinary clinician and patient-reported outcomes (PRO) and evaluate efficacy. Materials and methods CHHiP is a randomised phase 3, non-inferiority trial for men with localised prostate cancer. 3216 patients were randomly assigned to conventional (74 Gy in 2 Gy/fraction (f) daily) or moderate hypofractionation (60 or 57 Gy in 3 Gy/f daily) between October 2002 and June 2011. The IGRT substudy included a second randomisation assigning to no-IGRT, IGRT-S (standard CTV-PTV margins), or IGRT-R (reduced CTV-PTV margins). Primary substudy endpoint was late RTOG bowel and urinary toxicity at 2 years post-radiotherapy. Results Between June 2010 to July 2011, 293 men were recruited from 16 centres. Median follow-up is 56.9(IQR 54.3–60.9) months. Rectal and bladder dose-volume and surface percentages were significantly lower in IGRT-R compared to IGRT-S group; (p

Traditionally rectal symptoms following pelvic/prostate radiotherapy are correlated to the dosimetry of the anorectum or a substructure of this. It has been suggested that the perirectal fat space (PRS) surrounding the rectum may also be relevant. This study considers the delineation and dosimetry of the PRS related to both rectal bleeding and control-related toxicity. Initially, a caseâcontrol cohort of 100 patients from the RADAR study were chosen based on presence/absence of rectal control-related toxicity. Automated contouring was developed to delineate the PRS. 79 of the 100 auto-segmentations were considered successful. Balanced caseâcontrol cohorts were defined from these cases. Atlas of Complication Incidence (ACI) were generated to relate the DVH of the PRS with specific rectal symptoms; rectal bleeding and control-related symptoms (LENT/SOM). ACI demonstrated that control-related symptoms were related to the dose distribution to the PRS which was confirmed with Wilcoxon rank sum test (pâ¯

International audience; For decades, dose-volume information for segmented anatomy has provided the essential data for correlating radiotherapy dosimetry with treatment-induced complications. Dose-volume information has formed the basis for modelling those associations via normal tissue complication (NTCP) models and for driving treatment planning. Limitations to this approach have been identified. Many studies have emerged demonstrating that the incorporation of information describing the spatial nature of the dose distribution, and potentially its correlation with anatomy, can provide more robust associations with toxicity and seed more general NTCP models. Such approaches are culminating in the application of computationally intensive processes such as machine learning and the application of neural networks. The opportunities these approaches have for individualising treatment, predicting toxicity and expanding the solution space for radiation therapy are substantial and have clearly widespread and disruptive potential. Impediments to reaching that potential include issues associated with data collection, model generalisation and validation. This review examines the role of spatial models of complication and summarises relevant published studies. Sources of data for these studies, appropriate statistical methodology, frameworks for processing spatial dose information and extracting relevant features are described. Spatial complication modelling is consolidated as a pathway to guiding future developments towards effective, complication-free radiotherapy treatment.

The CHHiP trial randomized 3216 men with localized prostate cancer (1:1:1) to 3 radiation therapy fractionation schedules: 74 Gy in 37 fractions over 7.4 weeks; 60 Gy in 20 fractions over 4 weeks; and 57 Gy in 19 fractions over 3.8 weeks. Literature-based dose constraints were applied with arithmetic adjustment for the hypofractionated arms. This study aimed to derive anorectal dose constraints using prospectively collected clinician-reported outcomes (CROs) and patient-reported outcomes (PROs) and to assess the added predictive value of spatial dose metrics.A case-control study design was used; 7 CRO and 5 PRO bowel symptoms were evaluated. Cases experienced a moderate or worse symptom 1 to 5 years after-radiation therapy and did not have the symptom before radiation therapy. Controls did not experience the symptom at baseline or between 1 to 5 years after radiation therapy. The anorectum was recontoured from the anal verge to the rectosigmoid junction; dose/volume parameters were extracted. Univariate logistic regression, atlases of complication indices, and bootstrapped receiver-operating-characteristic analysis (1000 replicates, balanced outcomes) were used to derive dose constraints for the whole cohort (hypofractionated schedules were converted to 2-Gy equivalent schedules using α/β = 3 Gy) and separate hypofractionated/conventional fractionation cohorts. Only areas under the curve with 95% confidence interval lower limits0.5 were considered statistically significant. Any constraint derived in95% to 99% of bootstraps was excluded.Statistically significant dose constraints were derived for CROs but not PROs. Intermediate to high doses were important for rectal bleeding, whereas intermediate doses were important for increased bowel frequency, fecal incontinence, and rectal pain. Spatial dose metrics did not improve prediction of CROs or PROs. A new panel of dose constraints for hypofractionated schedules to 60 Gy or 57 Gy are V20Gy85%, V30Gy57%, V40Gy38%, V50Gy22%, and V60Gy0.01%.Dose constraints differed among symptoms, indicating potentially different pathogenesis of radiation-induced side effects. Derived dose constraints were stricter than those used in CHHiP and may reduce bowel symptoms after radiation therapy.

Radiotherapy is important in managing pelvic cancers. However, radiation enteropathy may occur and can be dose limiting. The gut microbiota may contribute to the pathogenesis of radiation enteropathy. We hypothesized that the microbiome differs between patients with and without radiation enteropathy.In the acute cohort, we observed a trend for higher preradiotherapy diversity in patients with no self-reported symptoms (The microbiota presents opportunities to predict, prevent, or treat radiation enteropathy. We report the largest clinical study to date into associations of the microbiota with acute and late radiation enteropathy. An altered microbiota associates with early and late radiation enteropathy, with clinical implications for risk assessment, prevention, and treatment of radiation-induced side-effects.

Purpose Current normal tissue complication probability modeling using logistic regression suffers from bias and high uncertainty in the presence of highly correlated radiation therapy (RT) dose data. This hinders robust estimates of dose-response associations and, hence, optimal normal tissue–sparing strategies from being elucidated. Using functional data analysis (FDA) to reduce the dimensionality of the dose data could overcome this limitation. Methods and Materials FDA was applied to modeling of severe acute mucositis and dysphagia resulting from head and neck RT. Functional partial least squares regression (FPLS) and functional principal component analysis were used for dimensionality reduction of the dose-volume histogram data. The reduced dose data were input into functional logistic regression models (functional partial least squares–logistic regression [FPLS-LR] and functional principal component–logistic regression [FPC-LR]) along with clinical data. This approach was compared with penalized logistic regression (PLR) in terms of predictive performance and the significance of treatment covariate–response associations, assessed using bootstrapping. Results The area under the receiver operating characteristic curve for the PLR, FPC-LR, and FPLS-LR models was 0.65, 0.69, and 0.67, respectively, for mucositis (internal validation) and 0.81, 0.83, and 0.83, respectively, for dysphagia (external validation). The calibration slopes/intercepts for the PLR, FPC-LR, and FPLS-LR models were 1.6/−0.67, 0.45/0.47, and 0.40/0.49, respectively, for mucositis (internal validation) and 2.5/−0.96, 0.79/−0.04, and 0.79/0.00, respectively, for dysphagia (external validation). The bootstrapped odds ratios indicated significant associations between RT dose and severe toxicity in the mucositis and dysphagia FDA models. Cisplatin was significantly associated with severe dysphagia in the FDA models. None of the covariates was significantly associated with severe toxicity in the PLR models. Dose levels greater than approximately 1.0 Gy/fraction were most strongly associated with severe acute mucositis and dysphagia in the FDA models. Conclusions FPLS and functional principal component analysis marginally improved predictive performance compared with PLR and provided robust dose-response associations. FDA is recommended for use in normal tissue complication probability modeling.

Aims To establish whether there is a difference in recovery of salivary function with bilateral superficial lobe parotid-sparing intensity-modulated radiotherapy (BSLPS-IMRT) versus contralateral parotid-sparing IMRT (CLPS-IMRT) in patients with locally advanced head and neck squamous cell cancers. Materials and methods A dosimetric analysis was carried out on data from two studies in which patients received BSLPS-IMRT (PARSPORT II) or CLPS-IMRT (PARSPORT). Acute (National Cancer Institute, Common Terminology Criteria for adverse events – NCI CTCAEv3.0) and late (Late Effects of Normal Tissue- subjective, objective, management analytical – LENTSOMA and Radiation Therapy Oncology Group) xerostomia scores were dichotomised: recovery (grade 0–1) versus no recovery (≥grade 2). Incidence of recovery of salivary function was compared between the two techniques and dose-response relationships were determined by fitting dose-response curves to the data using non-linear logistic regression analysis. Results Seventy-one patients received BSLPS-IMRT and 35 received CLPS-IMRT. Patients received 65 Gy in 30 fractions to the primary site and involved nodal levels and 54 Gy in 30 fractions to elective nodal levels. There were significant differences in mean doses to contralateral parotid gland (29.4 Gy versus 24.9 Gy, P, Highlights • Two different parotid gland sparing IMRT techniques are described. • Bilateral superficial lobe parotid sparing IMRT may reduce high grade xerostomia compared to contralateral parotid sparing IMRT.

Aims There are limited data on dosimetric correlates of toxicity in stereotactic body radiotherapy (SBRT) for prostate cancer. We aimed to identify potential relationships between dose and toxicity using conventional dose–volume histograms (DVHs) and dose–surface maps (DSMs). Materials and methods Urinary bladder trigone and rectum DSMs were produced for a single-institution service evaluation cohort of 50 patients receiving SBRT for localised prostate cancer, together with conventional DVHs for bladder and rectum. Patients had been prospectively recruited to this cohort and treated according to a pre-defined protocol to a dose of 36.25 Gy in five fractions. Radiation Therapy Oncology Group (RTOG) and International Prostate Symptom Score (IPSS) toxicity data were recorded prospectively. Logistic regression was used to identify dosimetric predictors of acute IPSS+10 (rise of 10 points or more above baseline) and grade 2+ RTOG toxicity. Results On univariate analysis, trigone area receiving 40 Gy and trigone D max were associated with IPSS+10 (odds ratio 1.06 [1.02–1.11], P = 0.007 and odds ratio 1.54 [1.06–2.25], P = 0.024, respectively). These two variables were highly correlated. In a multivariate model, including all baseline variables, trigone D max remained associated with IPSS+10 (odds ratio 1.91 [1.13–3.22], P = 0.016). These findings were not significant with Holm–Bonferroni correction for multiple testing (corrected P value threshold 0.006). No associations were seen between rectal toxicity and DVH or DSM parameters. Conclusions Our study suggests a potential relationship between high doses to the urinary bladder trigone and patient-reported urinary toxicity in prostate SBRT, and is consistent with previous studies in conventionally fractionated radiotherapy, justifying further evaluation in larger cohorts.

Purpose To use a high-quality multicenter trial dataset to determine dose-volume effects for gastrointestinal (GI) toxicity following radiation therapy for prostate carcinoma. Influential dose-volume histogram regions were to be determined as functions of dose, anatomical location, toxicity, and clinical endpoint. Methods and Materials Planning datasets for 754 participants in the TROG 03.04 RADAR trial were available, with Late Effects of Normal Tissues (LENT) Subjective, Objective, Management, and Analytic (SOMA) toxicity assessment to a median of 72 months. A rank sum method was used to define dose-volume cut-points as near-continuous functions of dose to 3 GI anatomical regions, together with a comprehensive assessment of significance. Univariate and multivariate ordinal regression was used to assess the importance of cut-points at each dose. Results Dose ranges providing significant cut-points tended to be consistent with those showing significant univariate regression odds-ratios (representing the probability of a unitary increase in toxicity grade per percent relative volume). Ranges of significant cut-points for rectal bleeding validated previously published results. Separation of the lower GI anatomy into complete anorectum, rectum, and anal canal showed the impact of mid-low doses to the anal canal on urgency and tenesmus, completeness of evacuation and stool frequency, and mid-high doses to the anorectum on bleeding and stool frequency. Derived multivariate models emphasized the importance of the high-dose region of the anorectum and rectum for rectal bleeding and mid- to low-dose regions for diarrhea and urgency and tenesmus, and low-to-mid doses to the anal canal for stool frequency, diarrhea, evacuation, and bleeding. Conclusions Results confirm anatomical dependence of specific GI toxicities. They provide an atlas summarizing dose-histogram effects and derived constraints as functions of anatomical region, dose, toxicity, and endpoint for informing future radiation therapy planning.

Aims Increases to radiotherapy dose are constrained by normal tissue effects. The relationship between bowel dose volume data and late bowel toxicity in patients with muscle-invasive bladder cancer treated with radical radiotherapy was assessed. Materials and methods The bowel was contoured retrospectively on radiotherapy plans of 47 patients recruited to the BC2001 trial (CRUK/01/004). The relationship between bowel volume at various dose levels and prospectively collected late bowel toxicity was explored. Results Fifteen per cent and 6% of patients experienced grade 1 and grade 2 or more late bowel toxicity, respectively. The mean bowel volume was significantly less at doses ≥50 Gy in those treated with reduced high dose volume radiotherapy compared with standard radiotherapy. The probability of late bowel toxicity increased as bowel volume increased ( P ≤ 0.05 for dose levels 30–50 Gy). No grade 2 or more late bowel toxicity was observed in patients with bowel volumes under the thresholds given in the model that predict for 25% probability of late bowel toxicity. Conclusions There is a dose volume effect for late bowel toxicity in radical bladder radiotherapy. We have modelled the probability of late bowel toxicity from absolute bowel volumes to guide clinicians in assessing radical bladder radiotherapy plans. Thresholds predicting for a 25% probability of late bowel toxicity are proposed as dose volume constraints.

Radical radiotherapy has a pivotal role in the treatment of head and neck cancer (HNC) and cures a significant proportion of patients while simultaneously sparing critical normal organs. Some patients treated with radical radiotherapy for HNC receive significant radiation doses to large volumes of brain tissue. In fact, intensity-modulated radiotherapy techniques for HNC have been associated with a net increase in irradiated brain volumes. The increasing use of chemoradiotherapy for HNC has additionally exposed this patient population to potential neurotoxicity due to cytotoxic drugs. Patients with HNC may be particularly at risk for adverse late brain effects after (chemo)-radiotherapy, such as impaired neurocognitive function (NCF), as risk factors for the development of HNC, such as smoking, excess alcohol consumption and poor diet, are also associated with impaired NCF. The relatively good survival rates with modern treatment for HNC, and exposure to multiple potentially neurotoxic factors, means that it is important to understand the impact of (chemo)-radiotherapy for HNC on NCF, and to consider what measures can be taken to minimise treatment-related neurotoxicity. Here, we review evidence relating to the late neurotoxicity of radical (chemo)-radiotherapy for HNC, with a focus on studies of NCF in this patient population.

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.

Aims A normal tissue complication probability (NTCP) model of severe acute mucositis would be highly useful to guide clinical decision making and inform radiotherapy planning. We aimed to improve upon our previous model by using a novel oral mucosal surface organ at risk (OAR) in place of an oral cavity OAR. Materials and methods Predictive models of severe acute mucositis were generated using radiotherapy dose to the oral cavity OAR or mucosal surface OAR and clinical data. Penalised logistic regression and random forest classification (RFC) models were generated for both OARs and compared. Internal validation was carried out with 100-iteration stratified shuffle split cross-validation, using multiple metrics to assess different aspects of model performance. Associations between treatment covariates and severe mucositis were explored using RFC feature importance. Results Penalised logistic regression and RFC models using the oral cavity OAR performed at least as well as the models using mucosal surface OAR. Associations between dose metrics and severe mucositis were similar between the mucosal surface and oral cavity models. The volumes of oral cavity or mucosal surface receiving intermediate and high doses were most strongly associated with severe mucositis. Conclusions The simpler oral cavity OAR should be preferred over the mucosal surface OAR for NTCP modelling of severe mucositis. We recommend minimising the volume of mucosa receiving intermediate and high doses, where possible.

Background and purpose This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity 2years after radiotherapy. Materials and methods A genome wide association study was performed in 1850 patients from the RAPPER study: 1217 received adjuvant breast radiotherapy and 633 had radical prostate radiotherapy. Genotype associations with both overall and individual endpoints of toxicity were tested via univariable and multivariable regression. Replication of potentially associated SNPs was carried out in three independent patient cohorts who had radiotherapy for prostate (516 RADIOGEN and 862 Gene-PARE) or breast (355 LeND) cancer. Results Quantile–quantile plots show more associations at the P −7 level than expected by chance (164 vs. 9 for the prostate cases and 29 vs. 4 for breast cases), providing evidence that common genetic variants are associated with risk of toxicity. Strongest associations were for individual endpoints rather than an overall measure of toxicity in all patients . However, in general, significant associations were not validated at a nominal 0.05 level in the replication cohorts. Conclusions This largest GWAS to date provides evidence of true association between common genetic variants and toxicity. Associations with toxicity appeared to be tumour site-specific. Future GWAS require higher statistical power, in particular in the validation stage, to test clinically relevant effect sizes of SNP associations with individual endpoints, but the required sample sizes are achievable.

Background An unexpected finding from the phase III parotid sparing radiotherapy trial, PARSPORT (ISRCTN48243537, CRUK/03/005), was a statistically significant increase in acute fatigue for those patients who were treated with intensity-modulated radiotherapy (IMRT) compared to standard conventional radiotherapy (CRT). One possible explanation was the difference in dose to central nervous system (CNS) structures due to differing beam portals. Using data from the trial, a dosimetric analysis of individual CNS structures was performed. Method Dosimetric and toxicity data were available for 67 patients (27 CRT, 40 IMRT). Retrospective delineation of the posterior fossa, brainstem, cerebellum, pituitary gland, pineal gland, hypothalamus, hippocampus and basal ganglia was performed. Dosimetry was reviewed using summary statistics and dose–volume atlases. Results A statistically significant increase in maximum and mean doses to each structure was observed for patients who received IMRT compared to those who received CRT. Both maximum and mean doses were significantly higher for the posterior fossa, brainstem and cerebellum for the 42 patients who reported acute fatigue of Grade 2 or higher ( p ⩽0.01) compared to the 25 who did not. Dose–volume atlases of the same structures indicated that regions representing larger volumes and higher doses to each structure were consistent with a higher incidence of acute fatigue. There was no association between the dose distribution and acute fatigue for the other structures tested. Conclusions The excess fatigue reported in the IMRT arm of the trial may, at least in part, be attributed to the dose distribution to the posterior fossa, cerebellum and brainstem. Future studies that modify dose delivery to these structures may allow us to test the hypothesis that radiation-induced fatigue is avoidable.

Dose-response curves (DRCs) and the quantitative parameters describing these curves were generated for grade 3 oral mucositis and dysphagia in 144 patients using individual patient DVHs. Curve fits to the oral mucositis clinical data yielded parameter values of mean dose in 2 Gy equivalent, MD(50) = 51 Gy (95% CI 40-61), slope of the curve, k = 1(95% CI 0.6-1.5). R(2) value for the goodness of fit was 0.80. Fits to the grade 3 dysphagia clinical data yielded parameter values of MD(50) = 44.5 Gy (95% CI 36-53), k = 2.6 (95% CI 0.8-4.5). R(2) value for the goodness of fit was 0.65. This is the first study to derive DRCs in patients receiving induction chemotherapy followed by chemo-radiation (IC-C-IMRT) for head and neck cancer. The dose-response model described in this study could be useful for comparing acute mucositis rates for different dose-fractionation schedules when using IMRT for head and neck cancer.

Purpose: This study describes the acute response of oral and pharyngeal mucosa to chemo-IMRT schedules using different doses per fraction. Materials and methods: Patients, treated in prospective trials of concomitant chemo-IMRT with 2.17 Gy, 2.25 Gy and 2.4 Gy per fraction and identical dose of cisplatin, were included in this study. Acute toxicity was recorded prospectively using the CTCAE v2.0. We describe the incidence and prevalence of grade 3 oral mucositis and dysphagia over time and report the influence of overall treatment time (OTT). The association between the lengths of pharyngeal mucosa receiving 50 Gy (L50) and 60 Gy (L60) and grade 3 dysphagia was tested. Results: The incidence and the peak prevalence of grade 3 dysphagia were significantly higher in patients receiving 2.4 Gy per fraction. The peak prevalence of grade 3 dysphagia was higher and the recovery was slower in patients with lower OTT (median 38 days vs. 42 days) treatment. There was a significant correlation between L50, L60 and grade 3 dysphagia. A L50 and L60 greater than 8 cm resulted in greater than 60% and 70% incidence of grade 3 dysphagia, respectively. Conclusion: The length of pharyngeal mucosa receiving doses close to the prescription dose correlates with grade 3 dysphagia. It was observed that incidence of grade 3 dysphagia was lower and recovery from it was quicker in patients with greater OTT.

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.

135 Background: ED remains a common toxicity of prostate RT despite technological advances. Penile bulb (PB) dose has been proposed as a predictor of ED post RT. The main objective of this study was to develop NTCP models for ED. Methods: 162 men treated within the CHHiP IGRT substudy (CRUK/06/16) had baseline clinical data, PB dosimetric data & evaluation of ED using EPIC-26 at least 3 years post RT. Planning CT and reference dose distributions were imported into analysis software (VODCA, MSS GmbH) and PB retrospectively contoured by one clinician. The defined endpoint (severe ED) was a standardised average value of 0-33 for EPIC-26 sexual domain. Predictive models of ED were generated using PB dose in EQD2 (α/β ratio = 3Gy) & clinical data (age, diabetes, hypertension, NCCN risk group, baseline PSA, hormone therapy, IGRT, margin size, PB volume). Multivariate logistic regression method using resampling methods was applied to select model order and parameters. Models were fitted using logistic regression of the form Probability = eA(x)/1+eA(x), where A(x) = constant + sum of (variables * associated regression coefficients). Model performance was evaluated through area under the receiver operating characteristic curve (AUC) and Hosmer-Lemeshow (HL) goodness-of-fit test. Results: 101/162 (62%) men had severe ED with statistically significant difference in PB max and mean dose between those patients with or without severe ED (max: 61.8Gy vs 43Gy & mean: 27.4Gy vs 14Gy respectively; p = 0.001). In the univariate analyses, age, diabetes, risk group, PB mean and max doses were significantly associated with EPIC calculated severe ED. The optimal NTCP model (AUC 0.78; CI 0.71-0.86: p for HL = 0.75) for EPIC calculated severe ED included age, PB mean dose and diabetes where A(x) = -10.13+(0.14*age)+(0.03*PB mean dose)+(2.88 if diabetic). A comparable model using clinician completed outcomes will be reported. Conclusions: This study provides the first known clinical prediction model for ED including PB dose, with good model performance. The determined predictors for the NTCP model of severe ED in this cohort were PB mean dose, age & diabetes. External validation of this model is desirable. Clinical trial information: 97182923.

87 Background: CHHiP (ISRCTN97182923, CRUK/06/016) randomised 3216 men with localised prostate cancer (1:1:1) to 3 RT fractionation schedules: 74Gy/37 fractions (f) over 7.4 weeks, 60Gy/20f/4 weeks and 57Gy/19f/3.8 weeks. Literature-based dose constraints were applied with adjustment for the hypofractionated arms. For standard fractionation the constraints (absolute dose) included V30Gy≤80%, V40Gy≤70%, V50Gy≤60%, V60Gy≤50%, V70Gy≤15%. This study aimed to derive anorectal dose constraints based on prospectively collected CRO. Methods: A case-control study design was used, 4 bowel symptoms were independently evaluated. Cases were patients experiencing a moderate or worse grade symptom 1 to 5 years post RT, who had not had the symptom pre-RT. Controls did not experience the symptom between 1 and 5 years post RT. The anorectum was re-contoured from the anal verge to the recto-sigmoid junction using VODCA software. Dose/volume parameters were extracted and hypofractionated dose schedules were converted to 2Gy equivalent schedules using an α/β ratio of 3Gy. Bootstrapped ROC analysis (1000 replicates, balanced outcomes) was used to derive dose constraints using both the Youden index and “Closest top Left” (CtL). Only AUC with a lower limit of the 95% confidence interval >0.5 were considered statistically significant. Any constraint derived in

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 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.

Purpose The study aimed to apply the atlas of complication incidence (ACI) method to patients receiving radical treatment for head and neck squamous cell carcinomas (HNSCC), to generate constraints based on dose-volume histograms (DVHs), and to identify clinical and dosimetric parameters that predict the risk of grade 3 oral mucositis (g3OM) and pharyngeal dysphagia (g3PD). Methods and Materials Oral and pharyngeal mucosal DVHs were generated for 253 patients who received radiation (RT) or chemoradiation (CRT). They were used to produce ACI for g3OM and g3PD. Multivariate analysis (MVA) of the effect of dosimetry, clinical, and patient-related variables was performed using logistic regression and bootstrapping. Receiver operating curve (ROC) analysis was also performed, and the Youden index was used to find volume constraints that discriminated between volumes that predicted for toxicity. Results We derived statistically significant dose-volume constraints for g3OM over the range v28 to v70. Only 3 statistically significant constraints were derived for g3PD v67, v68, and v69. On MVA, mean dose to the oral mucosa predicted for g3OM and concomitant chemotherapy and mean dose to the inferior constrictor (IC) predicted for g3PD. Conclusions We have used the ACI method to evaluate incidences of g3OM and g3PD and ROC analysis to generate constraints to predict g3OM and g3PD derived from entire individual patient DVHs. On MVA, the strongest predictors were radiation dose (for g3OM) and concomitant chemotherapy (for g3PD).