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.

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.

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.