A Comparison of Isotoxic Dose-escalated Radiotherapy in Lung Cancer with Moderate Deep Inspiration Breath Hold, Mid-ventilation and Internal Target Volume Techniques.

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.

What Can Proton Beam Therapy Achieve for Patients with Pectus Excavatum Requiring Left Breast, Axilla and Internal Mammary Nodal Radiotherapy?

AIMS: Exposure of the heart to radiation increases the risk of ischaemic heart disease, proportionate to the mean heart dose (MHD). Radiotherapy techniques including proton beam therapy (PBT) can reduce MHD. The aims of this study were to quantify the MHD reduction achievable by PBT compared with volumetric modulated arc therapy in breath hold (VMAT-BH) in patients with pectus excavatum (PEx), to identify an anatomical metric from a computed tomography scan that might indicate which patients will achieve the greatest MHD reductions from PBT. MATERIALS AND METHODS: Sixteen patients with PEx (Haller Index ≥2.7) were identified from radiotherapy planning computed tomography images. Left breast/chest wall, axilla (I-IV) and internal mammary node (IMN) volumes were delineated. VMAT and PBT plans were prepared, all satisfying target coverage constraints. Signed-rank comparisons of techniques were undertaken for the mean dose to the heart, ipsilateral lung and contralateral breast. Spearman's rho correlations were calculated for anatomical metrics against MHD reduction achieved by PBT. RESULTS: The mean MHD for VMAT-BH plans was 4.1 Gy compared with 0.7 Gy for PBT plans. PBT reduced MHD by an average of 3.4 Gy (range 2.8-4.4 Gy) compared with VMAT-BH (P < 0.001). PBT significantly reduced the mean dose to the ipsilateral lung (4.7 Gy, P < 0.001) and contralateral breast (2.7 Gy, P < 0.001). The distance (mm) at the most inferomedial extent of IMN volume (IMN to heart distance) negatively correlated with MHD reduction achieved by PBT (Spearman's rho -0.88 (95% confidence interval -0.96 to -0.67, P < 0.001)). CONCLUSION: For patients with PEx requiring left-sided breast and IMN radiotherapy, a clinically significant MHD reduction is achievable using PBT, compared with the optimal photon technique (VMAT-BH). This is a patient group in whom PBT could have the greatest benefit.

Retrospective Planning Study of Patients with Superior Sulcus Tumours Comparing Pencil Beam Scanning Protons to Volumetric-Modulated Arc Therapy.

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 < 0.05). CONCLUSIONS: In this planning study, robust PBS plans were achievable in carefully selected patients. Considerable dose reductions to the lung, heart and thoracic vertebra were possible without compromising target coverage. Sparing these lymphopenia-related organs may be particularly important in this era of immunotherapy.

Comparing Proton to Photon Radiotherapy Plans: UK Consensus Guidance for Reporting Under Uncertainty for Clinical Trials.

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.

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.

Dosimetry and Gastrointestinal Toxicity Relationships in a Phase II Trial of Pelvic Lymph Node Radiotherapy in Advanced Localised Prostate Cancer.

AIMS: Pelvic lymph node (PLN) radiotherapy for high-risk prostate cancer is limited by late gastrointestinal toxicity. Application of rectal and bowel constraints may reduce risks of side-effects. We evaluated associations between intensity-modulated radiotherapy (IMRT) dose-volume data and long-term gastrointestinal toxicity. MATERIALS AND METHODS: Data from a single-centre dose-escalation trial of PLN-IMRT were analysed, including conventionally fractionated (CFRT) and hypofractionated (HFRT) radiotherapy schedules. Associations between volumes of rectum and bowel receiving specified doses and clinician- and patient-reported toxicity outcomes were investigated independently. A metric, δ median (δM), was defined as the difference in the medians of a volume between groups with and without toxicity at a specified dose and was used to test for statistically significant differences. RESULTS: Constraints were respected in most patients and, when exceeded, led to higher rates of gastrointestinal toxicity. Biologically relevant associations between rectum dose-points and toxicity were more numerous with both mild and moderate toxicity thresholds, but statistical significance was limited after correction for false discovery rate. Rectal V50Gy (CFRT) associated with grade 2+ bleeding; bowel V43Gy and V47 (HFRT/4 days/week schedule) associated with patient-reported loose stools and diarrhoea, respectively. Further investigation showed that CFRT patients with rectal bleeding had a mean rectal V50Gy above the treatment planning constraint. CONCLUSIONS: When dose-volume parameters are kept below tight constraints, toxicity is low. Residual dosimetry loses much of its predictive power for gastrointestinal toxicity in the setting of PLN-IMRT for prostate cancer. We have benchmarked dose-volume constraints for safely delivering PLN-IMRT using CFRT or HFRT.

An Investigation of Dosimetric Correlates of Acute Toxicity in Prostate Stereotactic Body Radiotherapy: Dose to Urinary Trigone is Associated with Acute Urinary Toxicity.

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 Dmax 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 Dmax 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.

Normal Tissue Complication Probability (NTCP) Modelling of Severe Acute Mucositis using a Novel Oral Mucosal Surface Organ at Risk.

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.

Radiotherapy dose-distribution to the perirectal fat space (PRS) is related to gastrointestinal control-related complications.

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 case-control 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 case-control 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 (p < 0.05). To the authors knowledge this is the first study implicating the dose distribution to the PRS to the incidence of control-related symptoms of rectal toxicity.

Recovery of Salivary Function: Contralateral Parotid-sparing Intensity-modulated Radiotherapy versus Bilateral Superficial Lobe Parotid-sparing Intensity-modulated Radiotherapy.

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 < 0.005) and superficial lobes (26.8 Gy versus 30.5 Gy, P = 0.02) for BSLPS and CLPS-IMRT, respectively. Lower risk of long-term ≥grade 2 subjective xerostomia (LENTSOMA) was reported with BSLPS-IMRT (odds ratio 0.50; 95% confidence interval 0.29-0.86; P = 0.012). The percentage of patients who reported recovery of parotid saliva flow at 1 year was higher with BSLPS-IMRT compared with CLPS-IMRT techniques (67.1% versus 52.8%), but the difference was not statistically significant (P = 0.12). For the whole parotid gland, the tolerance doses, D50, were 25.6 Gy (95% confidence interval 20.6-30.5), k = 2.7 (0.9-4.5) (CLPS-IMRT) and 28.9 Gy (26.1-31.9), k = 2.4 (1.4-3.4) (BSLPS-IMRT). For the superficial lobe, D50 were similar: BSLPS-IMRT 23.5 Gy (19.3-27.6), k = 1.9 (0.5-3.8); CLPS-IMRT 24.0 Gy (17.7-30.1), k = 2.1 (0.1-4.1). CONCLUSION: BSLPS-IMRT reduces the risk of developing high-grade subjective xerostomia compared with CLPS-IMRT. The D50 of the superficial lobe may be a more reliable predictor of recovery of parotid function than the whole gland mean dose.

Defining bowel dose volume constraints for bladder radiotherapy treatment 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.

Neurocognitive function after (chemo)-radiotherapy for head and neck cancer.

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.

Two non-parametric methods for derivation of constraints from radiotherapy dose-histogram data.

Dose constraints based on histograms provide a convenient and widely-used method for informing and guiding radiotherapy treatment planning. Methods of derivation of such constraints are often poorly described. Two non-parametric methods for derivation of constraints are described and investigated in the context of determination of dose-specific cut-points-values of the free parameter (e.g., percentage volume of the irradiated organ) which best reflect resulting changes in complication incidence. A method based on receiver operating characteristic (ROC) analysis and one based on a maximally-selected standardized rank sum are described and compared using rectal toxicity data from a prostate radiotherapy trial. Multiple test corrections are applied using a free step-down resampling algorithm, which accounts for the large number of tests undertaken to search for optimal cut-points and the inherent correlation between dose-histogram points. Both methods provide consistent significant cut-point values, with the rank sum method displaying some sensitivity to the underlying data. The ROC method is simple to implement and can utilize a complication atlas, though an advantage of the rank sum method is the ability to incorporate all complication grades without the need for grade dichotomization.

SU-E-T-255: A Novel Rectal Obturator for Prostate Radiotherapy Improves the Spatial Distribution of Dose and Reduces the Predicted Risk for Rectal Bleeding and Subjective Sphincter Control.

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.

The impact of clinical factors on the development of late radiation toxicity: results from the Medical Research Council RT01 trial (ISRCTN47772397).

AIMS: A variety of dosimetric parameters have been shown to influence the incidence of late radiation toxicity. The effect of other treatment- and patient-related factors is less well established. The aim of this study was to elucidate the influence of such factors in the development of late symptoms after radical radiotherapy to the prostate. MATERIALS AND METHODS: Patient- and treatment-related factors that are thought to influence the development of late toxicity were analysed in 788 patients who had received radical radiotherapy to the prostate in the Medical Research Council RT01 trial. Late toxicity data were recorded using the Radiation Therapy Oncology Group, Late Effects of Normal Tissues/Subjective, Objective, Management, Analytic, Royal Marsden Hospital and the University of California, Los Angeles, Prostate Cancer Index. Acute toxicity was measured using the Radiation Therapy Oncology Group grading system. RESULTS: On multivariate analysis, acute bowel toxicity was statistically significantly associated with increased proctitis (hazard ratio=1.63, 95% confidence interval 1.18, 2.24; P=0.003) and increased stool frequency (hazard ratio=1.77, 95% confidence interval 1.27, 2.46; P=0.001). Hypertension was strongly associated with a decreased risk of poor urinary stream (hazard ratio=0.25, 95% confidence interval 0.09, 0.71; P=0.009). There was an increased risk of rectal bleeding with increased age (hazard ratio=1.04 per year of age, 95% confidence interval 1.01, 1.08; P=0.009). As expected, a higher prescribed dose increased the risk of several late toxicity end points. Although acute bladder toxicity was associated with the presence of bladder symptoms at 5 years, the effect disappeared for all symptoms except increased urinary frequency and haematuria when a change in bladder function from baseline was calculated. Patients with any pretreatment bladder symptoms were more likely to report increased urinary frequency (hazard ratio=2.09, 95% confidence interval 1.48, 2.95; P<0.0005), increased urinary incontinence (hazard ratio=4.22, 95% confidence interval 2.13, 8.35; P<0.0005) and decreased stream (hazard ratio=2.64, 95% confidence interval 1.62, 4.31; P<0.0005), after treatment and before the most recent follow-up assessment. CONCLUSIONS: In this study, increased acute gastrointestinal and bladder symptoms and prescribed dose were associated with increased late radiation toxicity. The presence of hypertension seemed to be protective for the development of late effects. Baseline symptoms should be taken into account when radiation toxicity is analysed.

Using Bayesian logistic regression to evaluate a new type of dosimetric constraint for prostate radiotherapy treatment planning.

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.